Clinical Review

Long COVID (postacute sequelae of SARS-CoV-2 infection, or PASC) is an emerging syndrome that affects 50% to 70% of people who survive COVID-19 for up to 3 months or longer after acute disease.¹ It is a multisystem condition that causes dysfunction of respiratory, cardiac, and nervous tissue, at least in part likely due to alterations in cellular energy metabolism and reduced oxygen supply to tissue.³ Patients who have had SARS-CoV-2 infection report persistent symptoms and signs that affect their quality of life. These may include neurocognitive, cardiorespiratory, gastrointestinal, and musculoskeletal symptoms; loss of taste and smell; and constitutional symptoms.² There is no one test to determine if symptoms are due to COVID-19.³

Acute COVID-19 mortality risk factors include increasing age, chronic comorbidities, and male sex. However, long COVID risk factors are quite different. A meta-analysis and review of 20 articles that met inclusion criteria (n = 13,340 study participants), limited by pooling of crude estimates, found that risk factors were female sex and severity of acute disease.⁴ A second meta-analysis of 37 studies with 1 preprint found that female sex and comorbidities such as pulmonary disease, diabetes, and obesity were risk factors for long COVID.⁵ Qualitative analysis of single studies (n = 18 study participants) suggested that older adults can develop more long COVID symptoms than younger adults, but this association between advancing age and long COVID was not supported when data were pooled into a meta-analysis.³ However, both single studies (n = 16 study participants) and the meta-analysis (n = 7 study participants) did support female sex as a risk factor for long COVID, along with single studies suggesting increased risk with medical comorbidities for pulmonary disease, diabetes, and organ transplantation.⁵ In this discussion, we focus on long COVID and its relationship with perimenopause and chronic fatigue syndrome.

Perimenopause

Perimenopause: A temporary disruption to physiologic ovarian steroid hormone production following COVID could acutely exacerbate symptoms of perimenopause and menopause.

JoAnn V. Pinkerton, MD, MSCP

The higher prevalence of long COVID in women younger than 50 years⁶ supports the overlap that studies have shown between symptoms of long COVID and perimenopause,⁷ as the median age of natural menopause is 51 years. Thus, health care providers need to differentiate between long COVID and other conditions, such as perimenopause, which share similar symptoms (FIGURE). Perimenopause might be diagnosed as long COVID, or the 2 might affect each other.

Symptoms of long COVID include fatigue, brain fog, and increased heart rate after recovering from COVID-19 and may continue or increase after an initial infection.⁸ Common symptoms of perimenopause and menopause, which also could be seen with long COVID, include typical menopausal symptoms such as hot flashes, night sweats, or disrupted sleep; changes in mood including dysthymia, depression, anxiety, or emotional lability; cognitive concerns such as brain fog or decreased concentration; and decreased stamina, fatigue, joint and muscle pains, or more frequent headaches. Therefore, women in their 40s or 50s with persistent symptoms after having COVID-19 without an alternative diagnosis, and who present with menstrual irregularity,⁹hot flashes, or night sweats, could be having an exacerbation of perimenopausal symptoms, or they could be experiencing a combination of long COVID and perimenopausal symptoms.

Continue to: Potential pathophysiology...

Potential pathophysiology

Inflammation is likely to be critical in the pathogenesis of postacute sequelae of SARS-CoV-2 infection, or PASC. Individuals with long COVID have elevated inflammatory markers for several months.¹⁰ The chronic inflammation associated with long COVID could cause disturbances in the ovary and ovarian hormone production.^2,10,11

During perimenopause, the ovary is more sensitive to illnesses such as COVID-19and to stress. The current theory is that COVID-19 affects the ovary with declines in ovarian reserve and ovarian function⁷ and with potential disruptions to the menstrual cycle, gonadal function, and ovarian sufficiency that lead to issues with menopause or fertility, as well as symptom exacerbation around menstruation.¹² Another theory is that SARS-CoV-2 infection affects ovary hormone production, as there is an abundance of angiotensin-converting enzyme-2 receptors on ovarian and endometrial tissue.¹¹ Thus, it makes sense that long COVID could bring on symptoms of perimenopause or menopause more acutely or more severely or lengthen the duration of perimenopausal symptoms.

Sex differentiation has been seen with regard to symptomatic COVID-19, with women generally faring better.^13,14Estradiol has been shown to have beneficial effects during acute COVID-19.¹⁵ With acute COVID-19 infection, women had lower mortality, lower levels of inflammation, higher lymphocyte counts, and faster antibody responses than men.^13,14 In addition, estradiol has been shown to help perimenopausal and menopausal hot flashes, night sweats, and sleep and to improve mood during perimenopause.¹⁶ So it is likely that perimenopausal or menopausal symptomatic women with long COVID treated with estrogen would see improvements in their symptoms both due to the action of estradiol on the ovary as seen during COVID-19 and in perimenopause.

Perimenopause is the transitional period prior to menopause, when the ovaries gradually produce fewer hormones and is associated with erratic hormonal fluctuations. The length of this transitional period varies from 4 to 10 years. Ethnic variations in the duration of hot flashes have been found, noting that Black and Hispanic women have them for an average of 8 to 10 years (longer), White women for an average of 7 years, and Asian, Japanese, and Chinese women for an average of 5 to 6 years (shorter).¹⁷

What should health care providers ask?

Distinguishing perimenopause from long COVID. It is important to try to differentiate between perimenopause and long COVID, and it is possible to have both, with long COVID exacerbating the menopausal symptoms.^7,8 Health care providers should be alert to consider perimenopause if women present with shorter or longer cycles (21-40 days), missed periods (particularly 60 days or 2 months), or worsening perimenopausal mood, migraines, insomnia, or hot flashes. Clinicians should actively enquire about all of these symptoms.

Moreover, if a perimenopausal woman reports acutely worsening symptoms after COVID-19, health care providers should address the perimenopausal symptoms and determine whether hormone therapy is appropriate and could improve their symptoms. Women do not need to wait until they go 1 year without a period to be treated with hormone therapy to improve perimenopausal and menopausal symptoms. If women with long COVID have perimenopause or menopause symptoms, they should have access to evidence-based information and discuss menopausal hormone therapy if appropriate. Hormone therapy could improve both perimenopausal symptoms and the long COVID symptoms if some of the symptoms are due to changes in ovary function. Health care providers could consider progesterone or antidepressants during the second half of the cycle (luteal phase) or estrogen combined with progesterone for the entire cycle.¹⁸

For health care providers working in long COVID clinics, in addition to asking when symptoms started, what makes symptoms worse, the frequency of symptoms, and which activities are affected, ask about perimenopausal and menopausal symptoms. If a woman has irregular periods, sleep disturbances, fatigue, or mood changes, consider that these could be related to long COVID, perimenopause, or both.^8,18 Be able to offer treatment or refer patients to a women’s health specialist who can assess and offer treatment.

A role for vitamin D? A recent retrospective case-matched study found that 6 months after hospital discharge, patients with long COVID had lower levels of 25(OH) vitamin D with the most notable symptom being brain fog.¹⁹ Thus, there may be a role for vitamin D supplementation as a preventive strategy in those being discharged after hospitalization. Vitamin D levels and supplementation have not been otherwise evaluated to date.

Lifestyle strategies for women with perimenopause and long COVID

Lifestyle strategies should be encouraged for women during perimenopause and long COVID. This includes good nutrition (avoiding carbs and sweets, particularly before menses), getting at least 7 hours of sleep and using sleep hygiene (regular bedtimes, sleep regimen, no late screens), getting regular exercise 5 days per week, reducing stress, avoiding excess alcohol, and not smoking. All of these factors can help women and their ovarian function during this period of ovarian fluctuations.

The timing of menopause and COVID may coincide with midlife stressors, including relationship issues (separations or divorce), health issues for the individual or their partner, widowhood, parenting challenges (care of young children, struggles with adolescents, grown children returning home), being childless, concerns about aging parents and caregiving responsibilities, as well as midlife career, community, or education issues—all of which make both long COVID and perimenopause more challenging to navigate.

Need for research

There is a need for future research to understand the epidemiologic basis and underlying biological mechanisms of sex differences seen in women with long COVID. Studying the effects of COVID-19 on ovarian function could lead to a better understanding of perimenopause, what causes ovarian failure to speed up, and possibly ways to slow it down⁸ since there are health risks of early menopause.¹⁶

References

1. Fernández-de-Las-Peñas C, Palacios-Ceña D, GómezMayordomo V, et al. Defining post-COVID symptoms (postacute COVID, long COVID, persistent post-COVID): an integrative classification. Int J Environ Res Public Health. 2021;18:2621. doi: 10.3390/ijerph18052621
2. Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27:601-615. doi: 10.1038/s41591 -021-01283-z
3. Davis HE, McCorkell L, Vogel JM, et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21:133-146. doi: 10.1038/s41579-022-00846-2
4. Maglietta G, Diodati F, Puntoni M, et al. Prognostic factors for post-COVID-19 syndrome: a systematic review and meta-analysis. J Clin Med. 2022;11:1541. doi: 10.3390 /jcm11061541
5. Notarte KI, de Oliveira MHS, Peligro PJ, et al. Age, sex and previous comorbidities as risk factors not associated with SARS-CoV-2 infection for long COVID-19: a systematic review and meta-analysis. J Clin Med. 2022;11:7314. doi: 10.3390 /jcm11247314
6. Sigfrid L, Drake TM, Pauley E, et al. Long COVID in adults discharged from UK hospitals after COVID-19: a prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol. Lancet Reg Health Eur. 2021;8:100186. doi: 10.1016/j.lanepe.2021.100186
7. Pollack B, von Saltza E, McCorkell L, et al. Female reproductive health impacts of long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: a literature review. Front Rehabil Sci. 2023;4:1122673.  doi: 10.3389/fresc.2023.1122673
8. Stewart S, Newson L, Briggs TA, et al. Long COVID risk - a signal to address sex hormones and women’s health. Lancet Reg Health Eur. 2021;11:100242. doi: 10.1016 /j.lanepe.2021.100242
9. Li K, Chen G, Hou H, et al. Analysis of sex hormones and menstruation in COVID-19 women of child-bearing age. Reprod Biomed Online. 2021;42:260-267. doi: 10.1016 /j.rbmo.2020.09.020
10. Phetsouphanh C, Darley DR, Wilson DB, et al. Immunological dysfunction persists for 8 months following initial mild-tomoderate SARS-CoV-2 infection. Nat Immunol. 2022;23:210216. doi: 10.1038/s41590-021-01113-x
11. Sharp GC, Fraser A, Sawyer G, et al. The COVID-19 pandemic and the menstrual cycle: research gaps and opportunities. Int J Epidemiol. 2022;51:691-700. doi: 10.1093/ije/dyab239
12. Ding T, Wang T, Zhang J, et al. Analysis of ovarian injury associated with COVID-19 disease in reproductive-aged women in Wuhan, China: an observational study. Front Med (Lausanne). 2021;8:635255. doi: 10.3389/fmed.2021.635255
13. Huang B, Cai Y, Li N, et al. Sex-based clinical and immunological differences in COVID-19. BMC Infect Dis. 2021;21:647. doi: 10.1186/s12879-021-06313-2
14. Connor J, Madhavan S, Mokashi M, et al. Health risks and outcomes that disproportionately affect women during the Covid-19 pandemic: a review. Soc Sci Med. 2020;266:113364. doi: 10.1016/j.socscimed.2020.113364
15. Mauvais-Jarvis F, Klein SL, Levin ER. Estradiol, progesterone, immunomodulation, and COVID-19 outcomes. Endocrinology. 2020;161:bqaa127. doi:10.1210/endocr/bqaa127
16. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29:767-794. doi: 10.1097/GME.0000000000002028
17. Avis NE, Crawford SL, Greendale G, et al. Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med. 2015;175:531-539. doi:10.1001 /jamainternmed.2014.8063
18. Newson L, Lewis R, O’Hara M. Long COVID and menopause - the important role of hormones in long COVID must be considered. Maturitas. 2021;152:74. doi: 10.1016 /j.maturitas.2021.08.026
19. di Filippo L, Frara S, Nannipieri F, et al. Low Vitamin D levels are associated with long COVID syndrome in COVID-19 survivors. J Clin Endocrinol Metab. 2023;108:e1106-e1116. doi: 10.1210/clinem/dgad207

Continue to: Chronic fatigue syndrome...

Chronic fatigue syndrome

Chronic fatigue syndrome: A large number of patients have “post-COVID conditions” affecting everyday function, including depression/anxiety, insomnia, and chronic fatigue (with a 3:1 female predominance)

Alexandra Kadl, MD

After 3 years battling acute COVID-19 infections, we encounter now a large number of patients with PASC— also known as “long COVID,” “COVID long-hauler syndrome,” and “post-COVID conditions”—a persistent multisystem syndrome that impacts everyday function.¹ As of October 2023, there are more than 100 million COVID-19 survivors reported in the United States; 10% to 85% of COVID survivors2-4 may show lingering, life-altering symptoms after recovery. Common reported symptoms include fatigue, depression/ anxiety, insomnia, and brain fog/difficulty concentrating, which are particularly high in women who often had experienced only mild acute COVID-19 disease and were not even hospitalized. More recently, chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has been recognized as major component of PASC5 with a 3:1 female predominance.6 Up to 75% of patients with this diagnosis are not able to maintain their jobs and normal life, and up to 25% are so disabled that they are bedbound.⁶

Diagnosis

Although illnesses resembling CFS have been reported for more than 200 years,⁷ the diagnosis of CFS/ME remains difficult to make. There is a likely underreporting due to fear of being labeled as malingering when reaching out to health care providers, and there is a reporting bias toward higher socioeconomic groups due to better access to health care. The current criteria for the diagnosis of CFS/ME include the following 3 components⁸:

1. substantial impairment in the ability to function for more than 6 months, accompanied by profound fatigue, not alleviated by rest
2. post-exertional malaise (PEM; prolonged, disabling exacerbation of the patient’s baseline symptoms after exercise)
3. non-refreshing sleep, PLUS either cognitive impairment or orthostatic intolerance.

Pathophysiology

Originally found to evolve in a small patient population with Epstein-Barr virus infection and Lyme disease, CFS/ME has moved to centerstage after the COVID-19 pandemic. While the diagnosis of COVID-19–related CFS/ME has advanced in the field, a clear mechanistic explanation of why it occurs is still missing. Certain risk factors have been identified for the development of CFS/ME, including female sex, reactivation of herpesviruses, and presence of connective tissue disorders; however, about one-third of patients with CFS/ME do not have identifiable risk factors.^9,10 Persistence of viral particles¹¹ and prolonged inflammatory states are speculated to affect the nervous system and mitochondrial function and metabolism. Interestingly, there is no correlation between severity of initial COVID-19 illness and the development of CFS/ME, similar to observations in non–COVID-19–related CFS/ME.

Proposed therapy

There is currently no proven therapy for CFS/ME. At this time, several immunomodulatory, antiviral, and neuromodulator drugs are being tested in clinical trial networks around the world.¹² Usual physical therapy with near maximum intensity has been shown to exacerbate symptoms and often results in PEM, which is described as a “crash” or “full collapse” by patients. The time for recovery after such episodes can be several days.¹³

Instead, the focus should be on addressing “treatable” concomitant symptoms, such as sleep disorders, anxiety and depression, and chronic pain. Lifestyle changes, avoidance of triggers, and exercise without over exertion are currently recommended to avoid incapacitating PEM.

Gaps in knowledge

There is a large knowledge gap regarding the pathophysiology, prevention, and therapy for CFS/ME. Many health care practitioners are not familiar with the disease and have focused on measurable parameters of exercise limitations and fatigue, such as anemias and lung and cardiac impairments, thus treating CFS/ME as a form of deconditioning. Given the large number of patients who recovered from acute COVID-19 that are now disabled due to CFS/ME, a patient-centered research opportunity has arisen. Biomedical/mechanistic research is ongoing, and well-designed clinical trials evaluating pharmacologic intervention as well as tailored exercise programs are needed.

Conclusion

General practitioners and women’s health specialists need to be aware of CFS/ME, especially when managing patients with long COVID. They also need to know that typical physical therapy may worsen symptoms. Furthermore, clinicians should shy away from trial drugs with a theoretical benefit outside of a clinical trial. ●

References

1. Soriano JB, Murthy S, Marshall JC, et al. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022;22:e102-e107. doi: 10.1016 /S1473-3099(21)00703-9
2. Chen C, Haupert SR, Zimmermann L, et al. Global prevalence of post-coronavirus disease 2019 (COVID-19) condition or long COVID: a meta-analysis and systematic review. J Infect Dis. 2022;226:1593-1607. doi: 10.1093/infdis/jiac136
3. Davis HE, McCorkell L, Vogel JM, et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21:133-146. doi: 10.1038/s41579-022 -00846-2
4. Pavli A, Theodoridou M, Maltezou HC. Post-COVID syndrome: incidence, clinical spectrum, and challenges for primary healthcare professionals. Arch Med Res. 2021;52:575-581.  doi: 10.1016/j.arcmed.2021.03.010
5. Kedor C, Freitag H, Meyer-Arndt L, et al. A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nat Commun. 2022;13:5104. doi: 10.1038/s41467-022-32507-6
6. Bateman L, Bested AC, Bonilla HF, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: essentials of diagnosis and management. Mayo Clin Proc. 2021;96:28612878. doi: 10.1016/j.mayocp.2021.07.004
7. Wessely S. History of postviral fatigue syndrome. Br Med Bull. 1991;47:919-941. doi: 10.1093/oxfordjournals.bmb.a072521
8. Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. National Academies Press; 2015. doi: 10.17226/19012
9. Ceban F, Ling S, Lui LMW, et al. Fatigue and cognitive impairment in post-COVID-19 syndrome: a systematic review and meta-analysis. Brain Behav Immun. 2022;101:93135. doi: 10.1016/j.bbi.2021.12.020
10. Davis HE, Assaf GS, McCorkell L, et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021;38:101019.  doi: 10.1016/j.eclinm.2021.101019
11. Hanson MR. The viral origin of myalgic encephalomyelitis/ chronic fatigue syndrome. PLoS Pathog. 2023;19:e1011523. doi: 10.1371/journal.ppat.1011523
12. Scheibenbogen C, Bellmann-Strobl JT, Heindrich C, et al. Fighting post-COVID and ME/CFS—development of curative therapies. Front Med (Lausanne). 2023;10:1194754.  doi: 10.3389/fmed.2023.1194754
13. Stussman B, Williams A, Snow J, et al. Characterization of post-exertional malaise in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Front Neurol. 2020;11:1025. doi: 10.3389/fneur.2020.01025

Long COVID (postacute sequelae of SARS-CoV-2 infection, or PASC) is an emerging syndrome that affects 50% to 70% of people who survive COVID-19 for up to 3 months or longer after acute disease.¹ It is a multisystem condition that causes dysfunction of respiratory, cardiac, and nervous tissue, at least in part likely due to alterations in cellular energy metabolism and reduced oxygen supply to tissue.³ Patients who have had SARS-CoV-2 infection report persistent symptoms and signs that affect their quality of life. These may include neurocognitive, cardiorespiratory, gastrointestinal, and musculoskeletal symptoms; loss of taste and smell; and constitutional symptoms.² There is no one test to determine if symptoms are due to COVID-19.³

Acute COVID-19 mortality risk factors include increasing age, chronic comorbidities, and male sex. However, long COVID risk factors are quite different. A meta-analysis and review of 20 articles that met inclusion criteria (n = 13,340 study participants), limited by pooling of crude estimates, found that risk factors were female sex and severity of acute disease.⁴ A second meta-analysis of 37 studies with 1 preprint found that female sex and comorbidities such as pulmonary disease, diabetes, and obesity were risk factors for long COVID.⁵ Qualitative analysis of single studies (n = 18 study participants) suggested that older adults can develop more long COVID symptoms than younger adults, but this association between advancing age and long COVID was not supported when data were pooled into a meta-analysis.³ However, both single studies (n = 16 study participants) and the meta-analysis (n = 7 study participants) did support female sex as a risk factor for long COVID, along with single studies suggesting increased risk with medical comorbidities for pulmonary disease, diabetes, and organ transplantation.⁵ In this discussion, we focus on long COVID and its relationship with perimenopause and chronic fatigue syndrome.

Perimenopause

Perimenopause: A temporary disruption to physiologic ovarian steroid hormone production following COVID could acutely exacerbate symptoms of perimenopause and menopause.

JoAnn V. Pinkerton, MD, MSCP

The higher prevalence of long COVID in women younger than 50 years⁶ supports the overlap that studies have shown between symptoms of long COVID and perimenopause,⁷ as the median age of natural menopause is 51 years. Thus, health care providers need to differentiate between long COVID and other conditions, such as perimenopause, which share similar symptoms (FIGURE). Perimenopause might be diagnosed as long COVID, or the 2 might affect each other.

Symptoms of long COVID include fatigue, brain fog, and increased heart rate after recovering from COVID-19 and may continue or increase after an initial infection.⁸ Common symptoms of perimenopause and menopause, which also could be seen with long COVID, include typical menopausal symptoms such as hot flashes, night sweats, or disrupted sleep; changes in mood including dysthymia, depression, anxiety, or emotional lability; cognitive concerns such as brain fog or decreased concentration; and decreased stamina, fatigue, joint and muscle pains, or more frequent headaches. Therefore, women in their 40s or 50s with persistent symptoms after having COVID-19 without an alternative diagnosis, and who present with menstrual irregularity,⁹hot flashes, or night sweats, could be having an exacerbation of perimenopausal symptoms, or they could be experiencing a combination of long COVID and perimenopausal symptoms.

Continue to: Potential pathophysiology...

Potential pathophysiology

Inflammation is likely to be critical in the pathogenesis of postacute sequelae of SARS-CoV-2 infection, or PASC. Individuals with long COVID have elevated inflammatory markers for several months.¹⁰ The chronic inflammation associated with long COVID could cause disturbances in the ovary and ovarian hormone production.^2,10,11

During perimenopause, the ovary is more sensitive to illnesses such as COVID-19and to stress. The current theory is that COVID-19 affects the ovary with declines in ovarian reserve and ovarian function⁷ and with potential disruptions to the menstrual cycle, gonadal function, and ovarian sufficiency that lead to issues with menopause or fertility, as well as symptom exacerbation around menstruation.¹² Another theory is that SARS-CoV-2 infection affects ovary hormone production, as there is an abundance of angiotensin-converting enzyme-2 receptors on ovarian and endometrial tissue.¹¹ Thus, it makes sense that long COVID could bring on symptoms of perimenopause or menopause more acutely or more severely or lengthen the duration of perimenopausal symptoms.

Sex differentiation has been seen with regard to symptomatic COVID-19, with women generally faring better.^13,14Estradiol has been shown to have beneficial effects during acute COVID-19.¹⁵ With acute COVID-19 infection, women had lower mortality, lower levels of inflammation, higher lymphocyte counts, and faster antibody responses than men.^13,14 In addition, estradiol has been shown to help perimenopausal and menopausal hot flashes, night sweats, and sleep and to improve mood during perimenopause.¹⁶ So it is likely that perimenopausal or menopausal symptomatic women with long COVID treated with estrogen would see improvements in their symptoms both due to the action of estradiol on the ovary as seen during COVID-19 and in perimenopause.

Perimenopause is the transitional period prior to menopause, when the ovaries gradually produce fewer hormones and is associated with erratic hormonal fluctuations. The length of this transitional period varies from 4 to 10 years. Ethnic variations in the duration of hot flashes have been found, noting that Black and Hispanic women have them for an average of 8 to 10 years (longer), White women for an average of 7 years, and Asian, Japanese, and Chinese women for an average of 5 to 6 years (shorter).¹⁷

What should health care providers ask?

Distinguishing perimenopause from long COVID. It is important to try to differentiate between perimenopause and long COVID, and it is possible to have both, with long COVID exacerbating the menopausal symptoms.^7,8 Health care providers should be alert to consider perimenopause if women present with shorter or longer cycles (21-40 days), missed periods (particularly 60 days or 2 months), or worsening perimenopausal mood, migraines, insomnia, or hot flashes. Clinicians should actively enquire about all of these symptoms.

Moreover, if a perimenopausal woman reports acutely worsening symptoms after COVID-19, health care providers should address the perimenopausal symptoms and determine whether hormone therapy is appropriate and could improve their symptoms. Women do not need to wait until they go 1 year without a period to be treated with hormone therapy to improve perimenopausal and menopausal symptoms. If women with long COVID have perimenopause or menopause symptoms, they should have access to evidence-based information and discuss menopausal hormone therapy if appropriate. Hormone therapy could improve both perimenopausal symptoms and the long COVID symptoms if some of the symptoms are due to changes in ovary function. Health care providers could consider progesterone or antidepressants during the second half of the cycle (luteal phase) or estrogen combined with progesterone for the entire cycle.¹⁸

For health care providers working in long COVID clinics, in addition to asking when symptoms started, what makes symptoms worse, the frequency of symptoms, and which activities are affected, ask about perimenopausal and menopausal symptoms. If a woman has irregular periods, sleep disturbances, fatigue, or mood changes, consider that these could be related to long COVID, perimenopause, or both.^8,18 Be able to offer treatment or refer patients to a women’s health specialist who can assess and offer treatment.

A role for vitamin D? A recent retrospective case-matched study found that 6 months after hospital discharge, patients with long COVID had lower levels of 25(OH) vitamin D with the most notable symptom being brain fog.¹⁹ Thus, there may be a role for vitamin D supplementation as a preventive strategy in those being discharged after hospitalization. Vitamin D levels and supplementation have not been otherwise evaluated to date.

Lifestyle strategies for women with perimenopause and long COVID

Lifestyle strategies should be encouraged for women during perimenopause and long COVID. This includes good nutrition (avoiding carbs and sweets, particularly before menses), getting at least 7 hours of sleep and using sleep hygiene (regular bedtimes, sleep regimen, no late screens), getting regular exercise 5 days per week, reducing stress, avoiding excess alcohol, and not smoking. All of these factors can help women and their ovarian function during this period of ovarian fluctuations.

The timing of menopause and COVID may coincide with midlife stressors, including relationship issues (separations or divorce), health issues for the individual or their partner, widowhood, parenting challenges (care of young children, struggles with adolescents, grown children returning home), being childless, concerns about aging parents and caregiving responsibilities, as well as midlife career, community, or education issues—all of which make both long COVID and perimenopause more challenging to navigate.

Need for research

There is a need for future research to understand the epidemiologic basis and underlying biological mechanisms of sex differences seen in women with long COVID. Studying the effects of COVID-19 on ovarian function could lead to a better understanding of perimenopause, what causes ovarian failure to speed up, and possibly ways to slow it down⁸ since there are health risks of early menopause.¹⁶

References

1. Fernández-de-Las-Peñas C, Palacios-Ceña D, GómezMayordomo V, et al. Defining post-COVID symptoms (postacute COVID, long COVID, persistent post-COVID): an integrative classification. Int J Environ Res Public Health. 2021;18:2621. doi: 10.3390/ijerph18052621
2. Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27:601-615. doi: 10.1038/s41591 -021-01283-z
3. Davis HE, McCorkell L, Vogel JM, et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21:133-146. doi: 10.1038/s41579-022-00846-2
4. Maglietta G, Diodati F, Puntoni M, et al. Prognostic factors for post-COVID-19 syndrome: a systematic review and meta-analysis. J Clin Med. 2022;11:1541. doi: 10.3390 /jcm11061541
5. Notarte KI, de Oliveira MHS, Peligro PJ, et al. Age, sex and previous comorbidities as risk factors not associated with SARS-CoV-2 infection for long COVID-19: a systematic review and meta-analysis. J Clin Med. 2022;11:7314. doi: 10.3390 /jcm11247314
6. Sigfrid L, Drake TM, Pauley E, et al. Long COVID in adults discharged from UK hospitals after COVID-19: a prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol. Lancet Reg Health Eur. 2021;8:100186. doi: 10.1016/j.lanepe.2021.100186
7. Pollack B, von Saltza E, McCorkell L, et al. Female reproductive health impacts of long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: a literature review. Front Rehabil Sci. 2023;4:1122673.  doi: 10.3389/fresc.2023.1122673
8. Stewart S, Newson L, Briggs TA, et al. Long COVID risk - a signal to address sex hormones and women’s health. Lancet Reg Health Eur. 2021;11:100242. doi: 10.1016 /j.lanepe.2021.100242
9. Li K, Chen G, Hou H, et al. Analysis of sex hormones and menstruation in COVID-19 women of child-bearing age. Reprod Biomed Online. 2021;42:260-267. doi: 10.1016 /j.rbmo.2020.09.020
10. Phetsouphanh C, Darley DR, Wilson DB, et al. Immunological dysfunction persists for 8 months following initial mild-tomoderate SARS-CoV-2 infection. Nat Immunol. 2022;23:210216. doi: 10.1038/s41590-021-01113-x
11. Sharp GC, Fraser A, Sawyer G, et al. The COVID-19 pandemic and the menstrual cycle: research gaps and opportunities. Int J Epidemiol. 2022;51:691-700. doi: 10.1093/ije/dyab239
12. Ding T, Wang T, Zhang J, et al. Analysis of ovarian injury associated with COVID-19 disease in reproductive-aged women in Wuhan, China: an observational study. Front Med (Lausanne). 2021;8:635255. doi: 10.3389/fmed.2021.635255
13. Huang B, Cai Y, Li N, et al. Sex-based clinical and immunological differences in COVID-19. BMC Infect Dis. 2021;21:647. doi: 10.1186/s12879-021-06313-2
14. Connor J, Madhavan S, Mokashi M, et al. Health risks and outcomes that disproportionately affect women during the Covid-19 pandemic: a review. Soc Sci Med. 2020;266:113364. doi: 10.1016/j.socscimed.2020.113364
15. Mauvais-Jarvis F, Klein SL, Levin ER. Estradiol, progesterone, immunomodulation, and COVID-19 outcomes. Endocrinology. 2020;161:bqaa127. doi:10.1210/endocr/bqaa127
16. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29:767-794. doi: 10.1097/GME.0000000000002028
17. Avis NE, Crawford SL, Greendale G, et al. Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med. 2015;175:531-539. doi:10.1001 /jamainternmed.2014.8063
18. Newson L, Lewis R, O’Hara M. Long COVID and menopause - the important role of hormones in long COVID must be considered. Maturitas. 2021;152:74. doi: 10.1016 /j.maturitas.2021.08.026
19. di Filippo L, Frara S, Nannipieri F, et al. Low Vitamin D levels are associated with long COVID syndrome in COVID-19 survivors. J Clin Endocrinol Metab. 2023;108:e1106-e1116. doi: 10.1210/clinem/dgad207

Continue to: Chronic fatigue syndrome...

Chronic fatigue syndrome

Chronic fatigue syndrome: A large number of patients have “post-COVID conditions” affecting everyday function, including depression/anxiety, insomnia, and chronic fatigue (with a 3:1 female predominance)

Alexandra Kadl, MD

After 3 years battling acute COVID-19 infections, we encounter now a large number of patients with PASC— also known as “long COVID,” “COVID long-hauler syndrome,” and “post-COVID conditions”—a persistent multisystem syndrome that impacts everyday function.¹ As of October 2023, there are more than 100 million COVID-19 survivors reported in the United States; 10% to 85% of COVID survivors2-4 may show lingering, life-altering symptoms after recovery. Common reported symptoms include fatigue, depression/ anxiety, insomnia, and brain fog/difficulty concentrating, which are particularly high in women who often had experienced only mild acute COVID-19 disease and were not even hospitalized. More recently, chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has been recognized as major component of PASC5 with a 3:1 female predominance.6 Up to 75% of patients with this diagnosis are not able to maintain their jobs and normal life, and up to 25% are so disabled that they are bedbound.⁶

Diagnosis

Although illnesses resembling CFS have been reported for more than 200 years,⁷ the diagnosis of CFS/ME remains difficult to make. There is a likely underreporting due to fear of being labeled as malingering when reaching out to health care providers, and there is a reporting bias toward higher socioeconomic groups due to better access to health care. The current criteria for the diagnosis of CFS/ME include the following 3 components⁸:

1. substantial impairment in the ability to function for more than 6 months, accompanied by profound fatigue, not alleviated by rest
2. post-exertional malaise (PEM; prolonged, disabling exacerbation of the patient’s baseline symptoms after exercise)
3. non-refreshing sleep, PLUS either cognitive impairment or orthostatic intolerance.

Pathophysiology

Originally found to evolve in a small patient population with Epstein-Barr virus infection and Lyme disease, CFS/ME has moved to centerstage after the COVID-19 pandemic. While the diagnosis of COVID-19–related CFS/ME has advanced in the field, a clear mechanistic explanation of why it occurs is still missing. Certain risk factors have been identified for the development of CFS/ME, including female sex, reactivation of herpesviruses, and presence of connective tissue disorders; however, about one-third of patients with CFS/ME do not have identifiable risk factors.^9,10 Persistence of viral particles¹¹ and prolonged inflammatory states are speculated to affect the nervous system and mitochondrial function and metabolism. Interestingly, there is no correlation between severity of initial COVID-19 illness and the development of CFS/ME, similar to observations in non–COVID-19–related CFS/ME.

Proposed therapy

There is currently no proven therapy for CFS/ME. At this time, several immunomodulatory, antiviral, and neuromodulator drugs are being tested in clinical trial networks around the world.¹² Usual physical therapy with near maximum intensity has been shown to exacerbate symptoms and often results in PEM, which is described as a “crash” or “full collapse” by patients. The time for recovery after such episodes can be several days.¹³

Instead, the focus should be on addressing “treatable” concomitant symptoms, such as sleep disorders, anxiety and depression, and chronic pain. Lifestyle changes, avoidance of triggers, and exercise without over exertion are currently recommended to avoid incapacitating PEM.

Gaps in knowledge

There is a large knowledge gap regarding the pathophysiology, prevention, and therapy for CFS/ME. Many health care practitioners are not familiar with the disease and have focused on measurable parameters of exercise limitations and fatigue, such as anemias and lung and cardiac impairments, thus treating CFS/ME as a form of deconditioning. Given the large number of patients who recovered from acute COVID-19 that are now disabled due to CFS/ME, a patient-centered research opportunity has arisen. Biomedical/mechanistic research is ongoing, and well-designed clinical trials evaluating pharmacologic intervention as well as tailored exercise programs are needed.

Conclusion

General practitioners and women’s health specialists need to be aware of CFS/ME, especially when managing patients with long COVID. They also need to know that typical physical therapy may worsen symptoms. Furthermore, clinicians should shy away from trial drugs with a theoretical benefit outside of a clinical trial. ●

References

1. Soriano JB, Murthy S, Marshall JC, et al. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022;22:e102-e107. doi: 10.1016 /S1473-3099(21)00703-9
2. Chen C, Haupert SR, Zimmermann L, et al. Global prevalence of post-coronavirus disease 2019 (COVID-19) condition or long COVID: a meta-analysis and systematic review. J Infect Dis. 2022;226:1593-1607. doi: 10.1093/infdis/jiac136
3. Davis HE, McCorkell L, Vogel JM, et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21:133-146. doi: 10.1038/s41579-022 -00846-2
4. Pavli A, Theodoridou M, Maltezou HC. Post-COVID syndrome: incidence, clinical spectrum, and challenges for primary healthcare professionals. Arch Med Res. 2021;52:575-581.  doi: 10.1016/j.arcmed.2021.03.010
5. Kedor C, Freitag H, Meyer-Arndt L, et al. A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nat Commun. 2022;13:5104. doi: 10.1038/s41467-022-32507-6
6. Bateman L, Bested AC, Bonilla HF, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: essentials of diagnosis and management. Mayo Clin Proc. 2021;96:28612878. doi: 10.1016/j.mayocp.2021.07.004
7. Wessely S. History of postviral fatigue syndrome. Br Med Bull. 1991;47:919-941. doi: 10.1093/oxfordjournals.bmb.a072521
8. Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. National Academies Press; 2015. doi: 10.17226/19012
9. Ceban F, Ling S, Lui LMW, et al. Fatigue and cognitive impairment in post-COVID-19 syndrome: a systematic review and meta-analysis. Brain Behav Immun. 2022;101:93135. doi: 10.1016/j.bbi.2021.12.020
10. Davis HE, Assaf GS, McCorkell L, et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021;38:101019.  doi: 10.1016/j.eclinm.2021.101019
11. Hanson MR. The viral origin of myalgic encephalomyelitis/ chronic fatigue syndrome. PLoS Pathog. 2023;19:e1011523. doi: 10.1371/journal.ppat.1011523
12. Scheibenbogen C, Bellmann-Strobl JT, Heindrich C, et al. Fighting post-COVID and ME/CFS—development of curative therapies. Front Med (Lausanne). 2023;10:1194754.  doi: 10.3389/fmed.2023.1194754
13. Stussman B, Williams A, Snow J, et al. Characterization of post-exertional malaise in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Front Neurol. 2020;11:1025. doi: 10.3389/fneur.2020.01025

Long COVID (postacute sequelae of SARS-CoV-2 infection, or PASC) is an emerging syndrome that affects 50% to 70% of people who survive COVID-19 for up to 3 months or longer after acute disease.¹ It is a multisystem condition that causes dysfunction of respiratory, cardiac, and nervous tissue, at least in part likely due to alterations in cellular energy metabolism and reduced oxygen supply to tissue.³ Patients who have had SARS-CoV-2 infection report persistent symptoms and signs that affect their quality of life. These may include neurocognitive, cardiorespiratory, gastrointestinal, and musculoskeletal symptoms; loss of taste and smell; and constitutional symptoms.² There is no one test to determine if symptoms are due to COVID-19.³

Acute COVID-19 mortality risk factors include increasing age, chronic comorbidities, and male sex. However, long COVID risk factors are quite different. A meta-analysis and review of 20 articles that met inclusion criteria (n = 13,340 study participants), limited by pooling of crude estimates, found that risk factors were female sex and severity of acute disease.⁴ A second meta-analysis of 37 studies with 1 preprint found that female sex and comorbidities such as pulmonary disease, diabetes, and obesity were risk factors for long COVID.⁵ Qualitative analysis of single studies (n = 18 study participants) suggested that older adults can develop more long COVID symptoms than younger adults, but this association between advancing age and long COVID was not supported when data were pooled into a meta-analysis.³ However, both single studies (n = 16 study participants) and the meta-analysis (n = 7 study participants) did support female sex as a risk factor for long COVID, along with single studies suggesting increased risk with medical comorbidities for pulmonary disease, diabetes, and organ transplantation.⁵ In this discussion, we focus on long COVID and its relationship with perimenopause and chronic fatigue syndrome.

Perimenopause

Perimenopause: A temporary disruption to physiologic ovarian steroid hormone production following COVID could acutely exacerbate symptoms of perimenopause and menopause.

JoAnn V. Pinkerton, MD, MSCP

The higher prevalence of long COVID in women younger than 50 years⁶ supports the overlap that studies have shown between symptoms of long COVID and perimenopause,⁷ as the median age of natural menopause is 51 years. Thus, health care providers need to differentiate between long COVID and other conditions, such as perimenopause, which share similar symptoms (FIGURE). Perimenopause might be diagnosed as long COVID, or the 2 might affect each other.

Symptoms of long COVID include fatigue, brain fog, and increased heart rate after recovering from COVID-19 and may continue or increase after an initial infection.⁸ Common symptoms of perimenopause and menopause, which also could be seen with long COVID, include typical menopausal symptoms such as hot flashes, night sweats, or disrupted sleep; changes in mood including dysthymia, depression, anxiety, or emotional lability; cognitive concerns such as brain fog or decreased concentration; and decreased stamina, fatigue, joint and muscle pains, or more frequent headaches. Therefore, women in their 40s or 50s with persistent symptoms after having COVID-19 without an alternative diagnosis, and who present with menstrual irregularity,⁹hot flashes, or night sweats, could be having an exacerbation of perimenopausal symptoms, or they could be experiencing a combination of long COVID and perimenopausal symptoms.

Continue to: Potential pathophysiology...

Potential pathophysiology

Inflammation is likely to be critical in the pathogenesis of postacute sequelae of SARS-CoV-2 infection, or PASC. Individuals with long COVID have elevated inflammatory markers for several months.¹⁰ The chronic inflammation associated with long COVID could cause disturbances in the ovary and ovarian hormone production.^2,10,11

During perimenopause, the ovary is more sensitive to illnesses such as COVID-19and to stress. The current theory is that COVID-19 affects the ovary with declines in ovarian reserve and ovarian function⁷ and with potential disruptions to the menstrual cycle, gonadal function, and ovarian sufficiency that lead to issues with menopause or fertility, as well as symptom exacerbation around menstruation.¹² Another theory is that SARS-CoV-2 infection affects ovary hormone production, as there is an abundance of angiotensin-converting enzyme-2 receptors on ovarian and endometrial tissue.¹¹ Thus, it makes sense that long COVID could bring on symptoms of perimenopause or menopause more acutely or more severely or lengthen the duration of perimenopausal symptoms.

Sex differentiation has been seen with regard to symptomatic COVID-19, with women generally faring better.^13,14Estradiol has been shown to have beneficial effects during acute COVID-19.¹⁵ With acute COVID-19 infection, women had lower mortality, lower levels of inflammation, higher lymphocyte counts, and faster antibody responses than men.^13,14 In addition, estradiol has been shown to help perimenopausal and menopausal hot flashes, night sweats, and sleep and to improve mood during perimenopause.¹⁶ So it is likely that perimenopausal or menopausal symptomatic women with long COVID treated with estrogen would see improvements in their symptoms both due to the action of estradiol on the ovary as seen during COVID-19 and in perimenopause.

Perimenopause is the transitional period prior to menopause, when the ovaries gradually produce fewer hormones and is associated with erratic hormonal fluctuations. The length of this transitional period varies from 4 to 10 years. Ethnic variations in the duration of hot flashes have been found, noting that Black and Hispanic women have them for an average of 8 to 10 years (longer), White women for an average of 7 years, and Asian, Japanese, and Chinese women for an average of 5 to 6 years (shorter).¹⁷

What should health care providers ask?

Distinguishing perimenopause from long COVID. It is important to try to differentiate between perimenopause and long COVID, and it is possible to have both, with long COVID exacerbating the menopausal symptoms.^7,8 Health care providers should be alert to consider perimenopause if women present with shorter or longer cycles (21-40 days), missed periods (particularly 60 days or 2 months), or worsening perimenopausal mood, migraines, insomnia, or hot flashes. Clinicians should actively enquire about all of these symptoms.

Moreover, if a perimenopausal woman reports acutely worsening symptoms after COVID-19, health care providers should address the perimenopausal symptoms and determine whether hormone therapy is appropriate and could improve their symptoms. Women do not need to wait until they go 1 year without a period to be treated with hormone therapy to improve perimenopausal and menopausal symptoms. If women with long COVID have perimenopause or menopause symptoms, they should have access to evidence-based information and discuss menopausal hormone therapy if appropriate. Hormone therapy could improve both perimenopausal symptoms and the long COVID symptoms if some of the symptoms are due to changes in ovary function. Health care providers could consider progesterone or antidepressants during the second half of the cycle (luteal phase) or estrogen combined with progesterone for the entire cycle.¹⁸

For health care providers working in long COVID clinics, in addition to asking when symptoms started, what makes symptoms worse, the frequency of symptoms, and which activities are affected, ask about perimenopausal and menopausal symptoms. If a woman has irregular periods, sleep disturbances, fatigue, or mood changes, consider that these could be related to long COVID, perimenopause, or both.^8,18 Be able to offer treatment or refer patients to a women’s health specialist who can assess and offer treatment.

A role for vitamin D? A recent retrospective case-matched study found that 6 months after hospital discharge, patients with long COVID had lower levels of 25(OH) vitamin D with the most notable symptom being brain fog.¹⁹ Thus, there may be a role for vitamin D supplementation as a preventive strategy in those being discharged after hospitalization. Vitamin D levels and supplementation have not been otherwise evaluated to date.

Lifestyle strategies for women with perimenopause and long COVID

Lifestyle strategies should be encouraged for women during perimenopause and long COVID. This includes good nutrition (avoiding carbs and sweets, particularly before menses), getting at least 7 hours of sleep and using sleep hygiene (regular bedtimes, sleep regimen, no late screens), getting regular exercise 5 days per week, reducing stress, avoiding excess alcohol, and not smoking. All of these factors can help women and their ovarian function during this period of ovarian fluctuations.

The timing of menopause and COVID may coincide with midlife stressors, including relationship issues (separations or divorce), health issues for the individual or their partner, widowhood, parenting challenges (care of young children, struggles with adolescents, grown children returning home), being childless, concerns about aging parents and caregiving responsibilities, as well as midlife career, community, or education issues—all of which make both long COVID and perimenopause more challenging to navigate.

Need for research

There is a need for future research to understand the epidemiologic basis and underlying biological mechanisms of sex differences seen in women with long COVID. Studying the effects of COVID-19 on ovarian function could lead to a better understanding of perimenopause, what causes ovarian failure to speed up, and possibly ways to slow it down⁸ since there are health risks of early menopause.¹⁶

References

1. Fernández-de-Las-Peñas C, Palacios-Ceña D, GómezMayordomo V, et al. Defining post-COVID symptoms (postacute COVID, long COVID, persistent post-COVID): an integrative classification. Int J Environ Res Public Health. 2021;18:2621. doi: 10.3390/ijerph18052621
2. Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27:601-615. doi: 10.1038/s41591 -021-01283-z
3. Davis HE, McCorkell L, Vogel JM, et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21:133-146. doi: 10.1038/s41579-022-00846-2
4. Maglietta G, Diodati F, Puntoni M, et al. Prognostic factors for post-COVID-19 syndrome: a systematic review and meta-analysis. J Clin Med. 2022;11:1541. doi: 10.3390 /jcm11061541
5. Notarte KI, de Oliveira MHS, Peligro PJ, et al. Age, sex and previous comorbidities as risk factors not associated with SARS-CoV-2 infection for long COVID-19: a systematic review and meta-analysis. J Clin Med. 2022;11:7314. doi: 10.3390 /jcm11247314
6. Sigfrid L, Drake TM, Pauley E, et al. Long COVID in adults discharged from UK hospitals after COVID-19: a prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol. Lancet Reg Health Eur. 2021;8:100186. doi: 10.1016/j.lanepe.2021.100186
7. Pollack B, von Saltza E, McCorkell L, et al. Female reproductive health impacts of long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: a literature review. Front Rehabil Sci. 2023;4:1122673.  doi: 10.3389/fresc.2023.1122673
8. Stewart S, Newson L, Briggs TA, et al. Long COVID risk - a signal to address sex hormones and women’s health. Lancet Reg Health Eur. 2021;11:100242. doi: 10.1016 /j.lanepe.2021.100242
9. Li K, Chen G, Hou H, et al. Analysis of sex hormones and menstruation in COVID-19 women of child-bearing age. Reprod Biomed Online. 2021;42:260-267. doi: 10.1016 /j.rbmo.2020.09.020
10. Phetsouphanh C, Darley DR, Wilson DB, et al. Immunological dysfunction persists for 8 months following initial mild-tomoderate SARS-CoV-2 infection. Nat Immunol. 2022;23:210216. doi: 10.1038/s41590-021-01113-x
11. Sharp GC, Fraser A, Sawyer G, et al. The COVID-19 pandemic and the menstrual cycle: research gaps and opportunities. Int J Epidemiol. 2022;51:691-700. doi: 10.1093/ije/dyab239
12. Ding T, Wang T, Zhang J, et al. Analysis of ovarian injury associated with COVID-19 disease in reproductive-aged women in Wuhan, China: an observational study. Front Med (Lausanne). 2021;8:635255. doi: 10.3389/fmed.2021.635255
13. Huang B, Cai Y, Li N, et al. Sex-based clinical and immunological differences in COVID-19. BMC Infect Dis. 2021;21:647. doi: 10.1186/s12879-021-06313-2
14. Connor J, Madhavan S, Mokashi M, et al. Health risks and outcomes that disproportionately affect women during the Covid-19 pandemic: a review. Soc Sci Med. 2020;266:113364. doi: 10.1016/j.socscimed.2020.113364
15. Mauvais-Jarvis F, Klein SL, Levin ER. Estradiol, progesterone, immunomodulation, and COVID-19 outcomes. Endocrinology. 2020;161:bqaa127. doi:10.1210/endocr/bqaa127
16. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29:767-794. doi: 10.1097/GME.0000000000002028
17. Avis NE, Crawford SL, Greendale G, et al. Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med. 2015;175:531-539. doi:10.1001 /jamainternmed.2014.8063
18. Newson L, Lewis R, O’Hara M. Long COVID and menopause - the important role of hormones in long COVID must be considered. Maturitas. 2021;152:74. doi: 10.1016 /j.maturitas.2021.08.026
19. di Filippo L, Frara S, Nannipieri F, et al. Low Vitamin D levels are associated with long COVID syndrome in COVID-19 survivors. J Clin Endocrinol Metab. 2023;108:e1106-e1116. doi: 10.1210/clinem/dgad207

Continue to: Chronic fatigue syndrome...

Chronic fatigue syndrome

Chronic fatigue syndrome: A large number of patients have “post-COVID conditions” affecting everyday function, including depression/anxiety, insomnia, and chronic fatigue (with a 3:1 female predominance)

Alexandra Kadl, MD

After 3 years battling acute COVID-19 infections, we encounter now a large number of patients with PASC— also known as “long COVID,” “COVID long-hauler syndrome,” and “post-COVID conditions”—a persistent multisystem syndrome that impacts everyday function.¹ As of October 2023, there are more than 100 million COVID-19 survivors reported in the United States; 10% to 85% of COVID survivors2-4 may show lingering, life-altering symptoms after recovery. Common reported symptoms include fatigue, depression/ anxiety, insomnia, and brain fog/difficulty concentrating, which are particularly high in women who often had experienced only mild acute COVID-19 disease and were not even hospitalized. More recently, chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has been recognized as major component of PASC5 with a 3:1 female predominance.6 Up to 75% of patients with this diagnosis are not able to maintain their jobs and normal life, and up to 25% are so disabled that they are bedbound.⁶

Diagnosis

Although illnesses resembling CFS have been reported for more than 200 years,⁷ the diagnosis of CFS/ME remains difficult to make. There is a likely underreporting due to fear of being labeled as malingering when reaching out to health care providers, and there is a reporting bias toward higher socioeconomic groups due to better access to health care. The current criteria for the diagnosis of CFS/ME include the following 3 components⁸:

1. substantial impairment in the ability to function for more than 6 months, accompanied by profound fatigue, not alleviated by rest
2. post-exertional malaise (PEM; prolonged, disabling exacerbation of the patient’s baseline symptoms after exercise)
3. non-refreshing sleep, PLUS either cognitive impairment or orthostatic intolerance.

Pathophysiology

Originally found to evolve in a small patient population with Epstein-Barr virus infection and Lyme disease, CFS/ME has moved to centerstage after the COVID-19 pandemic. While the diagnosis of COVID-19–related CFS/ME has advanced in the field, a clear mechanistic explanation of why it occurs is still missing. Certain risk factors have been identified for the development of CFS/ME, including female sex, reactivation of herpesviruses, and presence of connective tissue disorders; however, about one-third of patients with CFS/ME do not have identifiable risk factors.^9,10 Persistence of viral particles¹¹ and prolonged inflammatory states are speculated to affect the nervous system and mitochondrial function and metabolism. Interestingly, there is no correlation between severity of initial COVID-19 illness and the development of CFS/ME, similar to observations in non–COVID-19–related CFS/ME.

Proposed therapy

There is currently no proven therapy for CFS/ME. At this time, several immunomodulatory, antiviral, and neuromodulator drugs are being tested in clinical trial networks around the world.¹² Usual physical therapy with near maximum intensity has been shown to exacerbate symptoms and often results in PEM, which is described as a “crash” or “full collapse” by patients. The time for recovery after such episodes can be several days.¹³

Instead, the focus should be on addressing “treatable” concomitant symptoms, such as sleep disorders, anxiety and depression, and chronic pain. Lifestyle changes, avoidance of triggers, and exercise without over exertion are currently recommended to avoid incapacitating PEM.

Gaps in knowledge

There is a large knowledge gap regarding the pathophysiology, prevention, and therapy for CFS/ME. Many health care practitioners are not familiar with the disease and have focused on measurable parameters of exercise limitations and fatigue, such as anemias and lung and cardiac impairments, thus treating CFS/ME as a form of deconditioning. Given the large number of patients who recovered from acute COVID-19 that are now disabled due to CFS/ME, a patient-centered research opportunity has arisen. Biomedical/mechanistic research is ongoing, and well-designed clinical trials evaluating pharmacologic intervention as well as tailored exercise programs are needed.

Conclusion

General practitioners and women’s health specialists need to be aware of CFS/ME, especially when managing patients with long COVID. They also need to know that typical physical therapy may worsen symptoms. Furthermore, clinicians should shy away from trial drugs with a theoretical benefit outside of a clinical trial. ●

References

1. Soriano JB, Murthy S, Marshall JC, et al. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022;22:e102-e107. doi: 10.1016 /S1473-3099(21)00703-9
2. Chen C, Haupert SR, Zimmermann L, et al. Global prevalence of post-coronavirus disease 2019 (COVID-19) condition or long COVID: a meta-analysis and systematic review. J Infect Dis. 2022;226:1593-1607. doi: 10.1093/infdis/jiac136
3. Davis HE, McCorkell L, Vogel JM, et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21:133-146. doi: 10.1038/s41579-022 -00846-2
4. Pavli A, Theodoridou M, Maltezou HC. Post-COVID syndrome: incidence, clinical spectrum, and challenges for primary healthcare professionals. Arch Med Res. 2021;52:575-581.  doi: 10.1016/j.arcmed.2021.03.010
5. Kedor C, Freitag H, Meyer-Arndt L, et al. A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nat Commun. 2022;13:5104. doi: 10.1038/s41467-022-32507-6
6. Bateman L, Bested AC, Bonilla HF, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: essentials of diagnosis and management. Mayo Clin Proc. 2021;96:28612878. doi: 10.1016/j.mayocp.2021.07.004
7. Wessely S. History of postviral fatigue syndrome. Br Med Bull. 1991;47:919-941. doi: 10.1093/oxfordjournals.bmb.a072521
8. Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. National Academies Press; 2015. doi: 10.17226/19012
9. Ceban F, Ling S, Lui LMW, et al. Fatigue and cognitive impairment in post-COVID-19 syndrome: a systematic review and meta-analysis. Brain Behav Immun. 2022;101:93135. doi: 10.1016/j.bbi.2021.12.020
10. Davis HE, Assaf GS, McCorkell L, et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021;38:101019.  doi: 10.1016/j.eclinm.2021.101019
11. Hanson MR. The viral origin of myalgic encephalomyelitis/ chronic fatigue syndrome. PLoS Pathog. 2023;19:e1011523. doi: 10.1371/journal.ppat.1011523
12. Scheibenbogen C, Bellmann-Strobl JT, Heindrich C, et al. Fighting post-COVID and ME/CFS—development of curative therapies. Front Med (Lausanne). 2023;10:1194754.  doi: 10.3389/fmed.2023.1194754
13. Stussman B, Williams A, Snow J, et al. Characterization of post-exertional malaise in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Front Neurol. 2020;11:1025. doi: 10.3389/fneur.2020.01025

CASE New patient presents with a history of endometrial hyperplasia

A 51-year-old patient (G2P2002) presents to a new gynecologist’s office after moving from a different state. In her medical history, the gynecologist notes that 5 years ago she underwent dilation and curettage and endometrial ablation procedures for heavy menstrual bleeding (HMB). Ultrasonography performed prior to those procedures showed a slightly enlarged uterus, a simple left ovarian cyst, and a non ̶ visualized right ovary. The patient had declined a 2-step procedure due to concerns with anesthesia, and surgical pathology at the time of ablation revealed hyperplasia without atypia. The patient’s medical history was otherwise notable for prediabetes (recent hemoglobin A_1c [HbA_1c] measurement, 6.0%) and obesity (body mass index, 43 kg/m²). Pertinent family history included her mother’s diagnosis of endometrial cancer at age 36. Given the patient’s diagnosis of endometrial hyperplasia, she was referred to gynecologic oncology, but she ultimately declined hysterectomy, stating that she was happy with the resolution of her abnormal bleeding. At the time of her initial gynecologic oncology consultation, the consultant suggested lifestyle changes to combat prediabetes and obesity to reduce the risk of endometrial cancer, as future signs of cancer, namely bleeding, may be masked by the endometrial ablation. The patient was prescribed metformin given these medical comorbidities.

At today’s appointment, the patient notes continued resolution of bleeding since the procedure. She does, however, note a 6-month history of vasomotor symptoms and one episode of spotting 3 months ago. Three years ago she was diagnosed with type 2 diabetes mellitus, and her current HbA_1c is 6.9%. She has gained 10 lb since being diagnosed with endometrial cancer 5 years ago, and she has continued to take metformin.

An in-office endometrial biopsy is unsuccessful due to cervical stenosis. The treating gynecologist orders a transvaginal ultrasound, which reveals a small left ovarian cyst and a thickened endometrium (measuring 10 mm). Concerned that these findings could represent endometrial cancer, the gynecologist refers the patient to gynecologic oncology for further evaluation.
 

Sequelae and complications following endometrial ablation are often managed by a gynecologic oncologist. Indeed, a 2018 poll of Society of Gynecologic Oncology (SGO) members revealed that 93.8% of respondents had received such a referral, and almost 20% of respondents were managing more than 20 patients with post-ablation complications in their practices.¹ These complications, including hematometra, post-ablation tubal sterilization syndrome, other pain syndromes associated with retrograde menstruation, and thickened endometrium with scarring leading to an inability to sample the endometrium to investigate post-ablation bleeding are symptoms and findings that often lead to further surgery, including hysterectomy.² General gynecologists faced with these complications may refer patients to gynecologic oncology given an inability to sample the post-ablation endometrium or anticipated difficulties with hysterectomy. A recent meta-analysis revealed a 12.4% hysterectomy rate 5 years after endometrial ablation. Among these patients, the incidence of endometrial cancer ranged from 0% to 1.6%.³

In 2023, endometrial cancer incidence continues to increase, as does the incidence of obesity in women of all ages. Endometrial cancer mortality rates are also increasing, and these trends disproportionately affects non-Hispanic Black women.⁴ As providers and advocates work to narrow these disparities, gynecologic oncologists are simultaneously noting increased referrals for very likely benign conditions.⁵ Patients referred for post-ablation bleeding are a subset of these, as most patients who undergo endometrial ablation will not develop cancer. Considering the potential bottlenecks created en route to a gynecologic oncology evaluation, it seems prudent to minimize practices, like endometrial ablation, that may directly or indirectly prevent timely referral of patients with cancer to a gynecologic oncologist.

In this review we focus on the current use of endometrial ablation, associated complications, the incidence of treatment failure, and patient selection. Considering these issues in the context of the current endometrial cancer landscape, we posit best practices aimed at optimizing patient outcomes, and empowering general gynecologists to practice cancer prevention and to triage their surgical patients.

Continue to: Current use of endometrial ablation in the US...

In 2015, more than 500,000 endometrial ablations were performed in the United States.Given the ability to perform in-office ablation, this number is growing and potentially underestimated each year.⁶ In 2022, the global endometrial ablation market was valued at $3.4 billion, a figure projected to double in 10 years.⁷ The procedure has evolved as different devices and approaches have developed, offering patients different means to manage bleeding without hysterectomy. The minimally invasive procedure, performed in premenopausal patients with heavy menstrual bleeding (HMB) due to benign causes who have completed childbearing, has been associated with faster recovery times and fewer short-term complications compared with more invasive surgery.⁸ There are several non-resectoscope ablative devices approved by the US Food and Drug Administration (FDA), and each work to destroy the endometrial lining via thermal or cryoablation. Endometrial ablation can be performed in premenopausal patients with HMB due to benign causes who have completed childbearing.

Recently, promotional literature has begun to report on so-called overuse of hysterectomy, despite decreasing overall hysterectomy rates. This reporting proposes and applies “appropriateness criteria,” accounting for the rate of preoperative counseling regarding alternatives to hysterectomy, as well as the rate of “unsupportive” final pathology.⁹ The adoption of endometrial ablation and increasing market value of such vendors suggest that this campaign is having its desired effect. From the oncology perspective, we are concerned the pendulum could swing too far away from hysterectomy, a procedure that definitively cures abnormal uterine bleeding, toward endometrial ablation without explicit acknowledgement of the trade-offs involved.

Endometrial ablation complications: Late-onset procedure failure

A number of post-ablation syndromes may present at least 1 month following the procedure. Collectively known as late-onset endometrial ablation failure (LOEAF), these syndromes are characterized by recurrent vaginal bleeding, and/or new cyclic pelvic pain.¹⁰ It is difficult to measure the true incidence of LOEAF. Thomassee and colleagues examined a Canadian retrospective cohort of 437 patients who underwent endometrial ablation; 20.8% reported post-ablation pelvic pain after a median 301 days.¹¹ The subsequent need for surgical intervention, often hysterectomy, is a surrogate for LOEAF.

It should be noted that LOEAF is distinct from post-ablation tubal sterilization syndrome (PATSS), which describes cornual menstrual bleeding impeded by the ligated proximal fallopian tube.¹² Increased awareness of PATSS, along with the discontinuation of Essure (a permanent hysteroscopic sterilization device) in 2018, has led some surgeons to advocate for concomitant salpingectomy at the time of endometrial ablation.¹³ The role of opportunistic salpingectomy in primary prevention of epithelial ovarian cancer is well described, and while we strongly support this practice at the time of endometrial ablation, we do not feel that it effectively prevents LOEAF.¹⁴

The post-ablation inability to adequately sample the endometrium is also considered a LOEAF. A prospective study of 57 women who underwent endometrial ablation assessed post-ablation sampling feasibility via transvaginal ultrasonography, saline infusion sonohysterography (SIS), and in-office endometrial biopsies. In 23% of the cohort, endometrial sampling failed, and the authors noted decreased reliability of pathologic assessment.¹⁵ One systematic review, in which authors examined the incidence of endometrial cancer following endometrial ablation, characterized 38 cases of endometrial cancer and reported a post-ablation endometrial sampling success rate of 89%. This figure was based on a self-selected sample of 18 patients; cases in which endometrial sampling was thought to be impossible were excluded. The study also had a 30% missing data rate and several other biases.¹⁶

In the previously mentioned poll of SGO members,¹ 84% of the surveyed gynecologic oncologists managing post-ablation patients reported that endometrial sampling following endometrial ablation was “moderately” or “extremely” difficult. More than half of the survey respondents believed that hysterectomy was required for accurate diagnosis.¹ While we acknowledge the likely sampling bias affecting the survey results, we are not comforted by any data that minimizes this diagnostic challenge.

Appropriate patient selection and contraindications

The ideal candidate for endometrial ablation is a premenopausal patient with HMB who does not desire future fertility. According to the FDA, absolute contraindications include pregnancy or desired fertility, prior ablation, current IUD in place, inadequate preoperative endometrial assessment, known or suspected malignancy, active infection, or unfavorable anatomy.¹⁷

What about patients who may be at increased risk for endometrial cancer?

There is a paucity of data regarding the safety of endometrial ablation in patients at increased risk for developing endometrial cancer in the future. The American College of Obstetricians and Gynecologists (ACOG) 2007 practice bulletin on endometrial ablation (no longer accessible online) alludes to this concern and other contraindications,¹⁸ but there are no established guidelines. Currently, no ACOG practice bulletin or committee opinion lists relative contraindications to endometrial ablation, long-term complications (except risks associated with future pregnancy), or risk of subsequent hysterectomy. The risk that “it may be harder to detect endometrial cancer after ablation” is noted on ACOG’s web page dedicated to frequently asked questions (FAQs) regarding abnormal uterine bleeding.¹⁹ It is not mentioned on their web page dedicated to the FAQs regarding endometrial ablation.²⁰

In the absence of high-quality published data on established contraindications for endometrial ablation, we advocate for the increased awareness of possible relative contraindications—namely well-established risk factors for endometrial cancer (TABLE 1).For example, in a pooled analysis of 24 epidemiologic studies, authors found that the odds of developing endometrial cancer was 7 times higher among patients with a body mass index (BMI) ≥ 40 kg/m², compared with controls (odds ratio [OR], 7.14; 95% confidence interval [CI], 6.33–8.06).²¹ Additionally, patients with Lynch syndrome, a history of extended tamoxifen use, or those with a history of chronic anovulation or polycystic ovary syndrome are at increased risk for endometrial cancer.^22-24 If the presence of one or more of these factors does not dissuade general gynecologists from performing an endometrial ablation (even armed with a negative preoperative endometrial biopsy), we feel they should at least prompt thoughtful guideline-driven pause.

Continue to: Hysterectomy—A disincentivized option...

Hysterectomy—A disincentivized option

The annual number of hysterectomies performed by general gynecologists has declined over time. One study by Cadish and colleagues revealed that recent residency graduates performed only 3 to 4 annually.²⁵ These numbers partly reflect the decreasing number of hysterectomies performed during residency training. Furthermore, other factors—including the increasing rate of placenta accreta spectrum, the focus on risk stratification of adnexal masses via the ovarian-adnexal reporting and data classification system (O-RADs), and the emphasis on minimally invasive approaches often acquired in subspecialty training—have likely contributed to referral patterns to such specialists as minimally invasive gynecologic surgeons and gynecologic oncologists.²⁶ This trend is self-actualizing, as quality metrics funnel patients to high-volume surgeons, and general gynecologists risk losing hysterectomy privileges.

These factors lend themselves to a growing emphasis on endometrial ablation. Endometrial ablations can be performed in several settings, including in the hospital, in outpatient clinics, and more and more commonly, in ambulatory surgery centers. This increased access to endometrial ablation in the ambulatory surgery setting has corresponded with an annual endometrial ablation market value growth rate of 5% to 7%.²⁷ These rates are likely compounded by payer reimbursement policies that promote endometrial ablation and other alternatives to hysterectomy that are cost savings in the short term.²⁸ While the actual payer models are unavailable to review, they may not consider the costs of LOEAFs, including subsequent hysterectomy up to 5 years after initial ablation procedures. Provocatively, they almost certainly do not consider the costs of delayed care of patients with endometrial cancer vying for gynecologic oncology appointment slots occupied by post-ablation patients.

We urge providers, patients, and advocates to question who benefits from the uptake of ablation procedures: Patients? Payors? Providers? And how will the field of gynecology fare if hysterectomy skills and privileges are supplanted by ablation?

Post-ablation bleeding: Management by the gyn oncologist

Patients with post-ablation bleeding, either immediately or years later, are sometimes referred to a gynecologic oncologist given the possible risk for cancer and need for surgical staging if cancer is found on the hysterectomy specimen. In practice, assuming normal preoperative ultrasonography and no other clinical or radiologic findings suggestive of malignancy (eg, computed tomography findings concerning for metastases, abnormal cervical cytology, etc.), the presence of cancer is extremely unlikely to be determined at the time of surgery. Frozen section is not generally performed on the endometrium; intraoperative evaluation of even the unablated endometrium is notoriously unreliable; and histologic assessment of the ablated endometrium is limited by artifact (FIGURE 1). The abnormalities caused by ablation further impede selection of a representative focus, obfuscating any actionable result.

Some surgeons routinely bivalve the excised uterus prior to fixation to assess presence of tumor, tumor size, and the degree of myometrial invasion.²⁹ A combination of factors may compel surgeons to perform lymphadenectomy if not already performed, or if sentinel lymph node mapping was unsuccessful. But this practice has not been studied in patients with post-ablation bleeding, and applying these principles relies on a preoperative diagnosis establishing the presence and grade of a cancer. Furthermore, the utility of frozen section and myometrial assessment to decide whether or not to proceed with lymphadenectomy is less relevant in the era of molecular classification guiding adjuvant therapy. In summary, assuming no pathologic or radiologic findings suggestive of cancer, gynecologic oncologists are unlikely to perform lymphadenectomy at the time of hysterectomy in these post-ablation cases, which therefore can safely be performed by general gynecologists.

Our recommendations

Consider the LNG-IUD as an alternative to ablation. A recent randomized controlled trial by Beelen and colleagues compared the effectiveness of LNG-releasing IUDs with endometrial ablation in patients with HMB. While the LNG-IUD was inferior to endometrial ablation, quality-of-life measures were similar up to 2 years.³¹ Realizing that the hysterectomy rate following endometrial ablation increases significantly beyond that time point (2 years), this narrative may be incomplete. A 5- to 10-year follow-up time-frame may be a more helpful gauge of long-term outcomes. This prolonged time-frame also may allow study of the LNG-IUD’s protective effects on the endometrium in the prevention of endometrial hyperplasia and cancer.

Consider hysterectomy. A 2021 Cochrane review revealed that, compared with endometrial ablation, minimally invasive hysterectomy is associated with higher quality-of-life metrics, higher self-reported patient satisfaction, and similar rates of adverse events.³² While patient autonomy is paramount, the developing step-wise approach from endometrial ablation to hysterectomy, and its potential effects on the health care system at a time when endometrial cancer incidence and mortality rates are rising, is troubling.

Postablation, consider hysterectomy by the general gynecologist. Current trends appear to disincentivize general gynecologists from performing hysterectomy either for HMB or LOEAF. We would offer reassurance that they can safely perform this procedure. Referral to oncology may not be necessary since, in the absence of an established diagnosis of cancer, a lymphadenectomy is not typically required. A shift away from referral for these patients can preserve access to oncology for those women, especially minority women, with an explicit need for oncologic care.

In FIGURE 2, we propose a management algorithm for the patient who presents with post–ablation bleeding. We acknowledge that the evidence base for our management recommendations is limited. Still, we hope providers, ACOG, and other guidelines-issuing organizations consider them as they adapt their own practices and recommendations. We believe this is one of many steps needed to improve outcomes for patients with gynecologic cancer, particularly those in marginalized communities disproportionately impacted by current trends.

CASE Resolution

After reviewing the relevant documentation and examining the patient, the gynecologic oncology consultant contacts the referring gynecologist. They review the low utility of frozen section and the overall low risk of cancer on the final hysterectomy specimen if the patient were to undergo hysterectomy. The consultant clarifies that there is no other concern for surgical complexity beyond the skill of the referring provider, and they discuss the possibility of referral to a minimally invasive specialist for the surgery.

Ultimately, the patient undergoes uncomplicated laparoscopic hysterectomy performed by the original referring gynecologist. Final pathology reveals inactive endometrium with ablative changes and cornual focus of endometrial hyperplasia without atypia. ●

Acknowledgement

The authors acknowledge Ian Hagemann, MD, PhD, for his review of the manuscript.

CASE New patient presents with a history of endometrial hyperplasia

A 51-year-old patient (G2P2002) presents to a new gynecologist’s office after moving from a different state. In her medical history, the gynecologist notes that 5 years ago she underwent dilation and curettage and endometrial ablation procedures for heavy menstrual bleeding (HMB). Ultrasonography performed prior to those procedures showed a slightly enlarged uterus, a simple left ovarian cyst, and a non ̶ visualized right ovary. The patient had declined a 2-step procedure due to concerns with anesthesia, and surgical pathology at the time of ablation revealed hyperplasia without atypia. The patient’s medical history was otherwise notable for prediabetes (recent hemoglobin A_1c [HbA_1c] measurement, 6.0%) and obesity (body mass index, 43 kg/m²). Pertinent family history included her mother’s diagnosis of endometrial cancer at age 36. Given the patient’s diagnosis of endometrial hyperplasia, she was referred to gynecologic oncology, but she ultimately declined hysterectomy, stating that she was happy with the resolution of her abnormal bleeding. At the time of her initial gynecologic oncology consultation, the consultant suggested lifestyle changes to combat prediabetes and obesity to reduce the risk of endometrial cancer, as future signs of cancer, namely bleeding, may be masked by the endometrial ablation. The patient was prescribed metformin given these medical comorbidities.

At today’s appointment, the patient notes continued resolution of bleeding since the procedure. She does, however, note a 6-month history of vasomotor symptoms and one episode of spotting 3 months ago. Three years ago she was diagnosed with type 2 diabetes mellitus, and her current HbA_1c is 6.9%. She has gained 10 lb since being diagnosed with endometrial cancer 5 years ago, and she has continued to take metformin.

An in-office endometrial biopsy is unsuccessful due to cervical stenosis. The treating gynecologist orders a transvaginal ultrasound, which reveals a small left ovarian cyst and a thickened endometrium (measuring 10 mm). Concerned that these findings could represent endometrial cancer, the gynecologist refers the patient to gynecologic oncology for further evaluation.
 

Sequelae and complications following endometrial ablation are often managed by a gynecologic oncologist. Indeed, a 2018 poll of Society of Gynecologic Oncology (SGO) members revealed that 93.8% of respondents had received such a referral, and almost 20% of respondents were managing more than 20 patients with post-ablation complications in their practices.¹ These complications, including hematometra, post-ablation tubal sterilization syndrome, other pain syndromes associated with retrograde menstruation, and thickened endometrium with scarring leading to an inability to sample the endometrium to investigate post-ablation bleeding are symptoms and findings that often lead to further surgery, including hysterectomy.² General gynecologists faced with these complications may refer patients to gynecologic oncology given an inability to sample the post-ablation endometrium or anticipated difficulties with hysterectomy. A recent meta-analysis revealed a 12.4% hysterectomy rate 5 years after endometrial ablation. Among these patients, the incidence of endometrial cancer ranged from 0% to 1.6%.³

In 2023, endometrial cancer incidence continues to increase, as does the incidence of obesity in women of all ages. Endometrial cancer mortality rates are also increasing, and these trends disproportionately affects non-Hispanic Black women.⁴ As providers and advocates work to narrow these disparities, gynecologic oncologists are simultaneously noting increased referrals for very likely benign conditions.⁵ Patients referred for post-ablation bleeding are a subset of these, as most patients who undergo endometrial ablation will not develop cancer. Considering the potential bottlenecks created en route to a gynecologic oncology evaluation, it seems prudent to minimize practices, like endometrial ablation, that may directly or indirectly prevent timely referral of patients with cancer to a gynecologic oncologist.

In this review we focus on the current use of endometrial ablation, associated complications, the incidence of treatment failure, and patient selection. Considering these issues in the context of the current endometrial cancer landscape, we posit best practices aimed at optimizing patient outcomes, and empowering general gynecologists to practice cancer prevention and to triage their surgical patients.

Continue to: Current use of endometrial ablation in the US...

In 2015, more than 500,000 endometrial ablations were performed in the United States.Given the ability to perform in-office ablation, this number is growing and potentially underestimated each year.⁶ In 2022, the global endometrial ablation market was valued at $3.4 billion, a figure projected to double in 10 years.⁷ The procedure has evolved as different devices and approaches have developed, offering patients different means to manage bleeding without hysterectomy. The minimally invasive procedure, performed in premenopausal patients with heavy menstrual bleeding (HMB) due to benign causes who have completed childbearing, has been associated with faster recovery times and fewer short-term complications compared with more invasive surgery.⁸ There are several non-resectoscope ablative devices approved by the US Food and Drug Administration (FDA), and each work to destroy the endometrial lining via thermal or cryoablation. Endometrial ablation can be performed in premenopausal patients with HMB due to benign causes who have completed childbearing.

Recently, promotional literature has begun to report on so-called overuse of hysterectomy, despite decreasing overall hysterectomy rates. This reporting proposes and applies “appropriateness criteria,” accounting for the rate of preoperative counseling regarding alternatives to hysterectomy, as well as the rate of “unsupportive” final pathology.⁹ The adoption of endometrial ablation and increasing market value of such vendors suggest that this campaign is having its desired effect. From the oncology perspective, we are concerned the pendulum could swing too far away from hysterectomy, a procedure that definitively cures abnormal uterine bleeding, toward endometrial ablation without explicit acknowledgement of the trade-offs involved.

Endometrial ablation complications: Late-onset procedure failure

A number of post-ablation syndromes may present at least 1 month following the procedure. Collectively known as late-onset endometrial ablation failure (LOEAF), these syndromes are characterized by recurrent vaginal bleeding, and/or new cyclic pelvic pain.¹⁰ It is difficult to measure the true incidence of LOEAF. Thomassee and colleagues examined a Canadian retrospective cohort of 437 patients who underwent endometrial ablation; 20.8% reported post-ablation pelvic pain after a median 301 days.¹¹ The subsequent need for surgical intervention, often hysterectomy, is a surrogate for LOEAF.

It should be noted that LOEAF is distinct from post-ablation tubal sterilization syndrome (PATSS), which describes cornual menstrual bleeding impeded by the ligated proximal fallopian tube.¹² Increased awareness of PATSS, along with the discontinuation of Essure (a permanent hysteroscopic sterilization device) in 2018, has led some surgeons to advocate for concomitant salpingectomy at the time of endometrial ablation.¹³ The role of opportunistic salpingectomy in primary prevention of epithelial ovarian cancer is well described, and while we strongly support this practice at the time of endometrial ablation, we do not feel that it effectively prevents LOEAF.¹⁴

The post-ablation inability to adequately sample the endometrium is also considered a LOEAF. A prospective study of 57 women who underwent endometrial ablation assessed post-ablation sampling feasibility via transvaginal ultrasonography, saline infusion sonohysterography (SIS), and in-office endometrial biopsies. In 23% of the cohort, endometrial sampling failed, and the authors noted decreased reliability of pathologic assessment.¹⁵ One systematic review, in which authors examined the incidence of endometrial cancer following endometrial ablation, characterized 38 cases of endometrial cancer and reported a post-ablation endometrial sampling success rate of 89%. This figure was based on a self-selected sample of 18 patients; cases in which endometrial sampling was thought to be impossible were excluded. The study also had a 30% missing data rate and several other biases.¹⁶

In the previously mentioned poll of SGO members,¹ 84% of the surveyed gynecologic oncologists managing post-ablation patients reported that endometrial sampling following endometrial ablation was “moderately” or “extremely” difficult. More than half of the survey respondents believed that hysterectomy was required for accurate diagnosis.¹ While we acknowledge the likely sampling bias affecting the survey results, we are not comforted by any data that minimizes this diagnostic challenge.

Appropriate patient selection and contraindications

The ideal candidate for endometrial ablation is a premenopausal patient with HMB who does not desire future fertility. According to the FDA, absolute contraindications include pregnancy or desired fertility, prior ablation, current IUD in place, inadequate preoperative endometrial assessment, known or suspected malignancy, active infection, or unfavorable anatomy.¹⁷

What about patients who may be at increased risk for endometrial cancer?

There is a paucity of data regarding the safety of endometrial ablation in patients at increased risk for developing endometrial cancer in the future. The American College of Obstetricians and Gynecologists (ACOG) 2007 practice bulletin on endometrial ablation (no longer accessible online) alludes to this concern and other contraindications,¹⁸ but there are no established guidelines. Currently, no ACOG practice bulletin or committee opinion lists relative contraindications to endometrial ablation, long-term complications (except risks associated with future pregnancy), or risk of subsequent hysterectomy. The risk that “it may be harder to detect endometrial cancer after ablation” is noted on ACOG’s web page dedicated to frequently asked questions (FAQs) regarding abnormal uterine bleeding.¹⁹ It is not mentioned on their web page dedicated to the FAQs regarding endometrial ablation.²⁰

In the absence of high-quality published data on established contraindications for endometrial ablation, we advocate for the increased awareness of possible relative contraindications—namely well-established risk factors for endometrial cancer (TABLE 1).For example, in a pooled analysis of 24 epidemiologic studies, authors found that the odds of developing endometrial cancer was 7 times higher among patients with a body mass index (BMI) ≥ 40 kg/m², compared with controls (odds ratio [OR], 7.14; 95% confidence interval [CI], 6.33–8.06).²¹ Additionally, patients with Lynch syndrome, a history of extended tamoxifen use, or those with a history of chronic anovulation or polycystic ovary syndrome are at increased risk for endometrial cancer.^22-24 If the presence of one or more of these factors does not dissuade general gynecologists from performing an endometrial ablation (even armed with a negative preoperative endometrial biopsy), we feel they should at least prompt thoughtful guideline-driven pause.

Continue to: Hysterectomy—A disincentivized option...

Hysterectomy—A disincentivized option

The annual number of hysterectomies performed by general gynecologists has declined over time. One study by Cadish and colleagues revealed that recent residency graduates performed only 3 to 4 annually.²⁵ These numbers partly reflect the decreasing number of hysterectomies performed during residency training. Furthermore, other factors—including the increasing rate of placenta accreta spectrum, the focus on risk stratification of adnexal masses via the ovarian-adnexal reporting and data classification system (O-RADs), and the emphasis on minimally invasive approaches often acquired in subspecialty training—have likely contributed to referral patterns to such specialists as minimally invasive gynecologic surgeons and gynecologic oncologists.²⁶ This trend is self-actualizing, as quality metrics funnel patients to high-volume surgeons, and general gynecologists risk losing hysterectomy privileges.

These factors lend themselves to a growing emphasis on endometrial ablation. Endometrial ablations can be performed in several settings, including in the hospital, in outpatient clinics, and more and more commonly, in ambulatory surgery centers. This increased access to endometrial ablation in the ambulatory surgery setting has corresponded with an annual endometrial ablation market value growth rate of 5% to 7%.²⁷ These rates are likely compounded by payer reimbursement policies that promote endometrial ablation and other alternatives to hysterectomy that are cost savings in the short term.²⁸ While the actual payer models are unavailable to review, they may not consider the costs of LOEAFs, including subsequent hysterectomy up to 5 years after initial ablation procedures. Provocatively, they almost certainly do not consider the costs of delayed care of patients with endometrial cancer vying for gynecologic oncology appointment slots occupied by post-ablation patients.

We urge providers, patients, and advocates to question who benefits from the uptake of ablation procedures: Patients? Payors? Providers? And how will the field of gynecology fare if hysterectomy skills and privileges are supplanted by ablation?

Post-ablation bleeding: Management by the gyn oncologist

Patients with post-ablation bleeding, either immediately or years later, are sometimes referred to a gynecologic oncologist given the possible risk for cancer and need for surgical staging if cancer is found on the hysterectomy specimen. In practice, assuming normal preoperative ultrasonography and no other clinical or radiologic findings suggestive of malignancy (eg, computed tomography findings concerning for metastases, abnormal cervical cytology, etc.), the presence of cancer is extremely unlikely to be determined at the time of surgery. Frozen section is not generally performed on the endometrium; intraoperative evaluation of even the unablated endometrium is notoriously unreliable; and histologic assessment of the ablated endometrium is limited by artifact (FIGURE 1). The abnormalities caused by ablation further impede selection of a representative focus, obfuscating any actionable result.

Some surgeons routinely bivalve the excised uterus prior to fixation to assess presence of tumor, tumor size, and the degree of myometrial invasion.²⁹ A combination of factors may compel surgeons to perform lymphadenectomy if not already performed, or if sentinel lymph node mapping was unsuccessful. But this practice has not been studied in patients with post-ablation bleeding, and applying these principles relies on a preoperative diagnosis establishing the presence and grade of a cancer. Furthermore, the utility of frozen section and myometrial assessment to decide whether or not to proceed with lymphadenectomy is less relevant in the era of molecular classification guiding adjuvant therapy. In summary, assuming no pathologic or radiologic findings suggestive of cancer, gynecologic oncologists are unlikely to perform lymphadenectomy at the time of hysterectomy in these post-ablation cases, which therefore can safely be performed by general gynecologists.

Our recommendations

Consider the LNG-IUD as an alternative to ablation. A recent randomized controlled trial by Beelen and colleagues compared the effectiveness of LNG-releasing IUDs with endometrial ablation in patients with HMB. While the LNG-IUD was inferior to endometrial ablation, quality-of-life measures were similar up to 2 years.³¹ Realizing that the hysterectomy rate following endometrial ablation increases significantly beyond that time point (2 years), this narrative may be incomplete. A 5- to 10-year follow-up time-frame may be a more helpful gauge of long-term outcomes. This prolonged time-frame also may allow study of the LNG-IUD’s protective effects on the endometrium in the prevention of endometrial hyperplasia and cancer.

Consider hysterectomy. A 2021 Cochrane review revealed that, compared with endometrial ablation, minimally invasive hysterectomy is associated with higher quality-of-life metrics, higher self-reported patient satisfaction, and similar rates of adverse events.³² While patient autonomy is paramount, the developing step-wise approach from endometrial ablation to hysterectomy, and its potential effects on the health care system at a time when endometrial cancer incidence and mortality rates are rising, is troubling.

Postablation, consider hysterectomy by the general gynecologist. Current trends appear to disincentivize general gynecologists from performing hysterectomy either for HMB or LOEAF. We would offer reassurance that they can safely perform this procedure. Referral to oncology may not be necessary since, in the absence of an established diagnosis of cancer, a lymphadenectomy is not typically required. A shift away from referral for these patients can preserve access to oncology for those women, especially minority women, with an explicit need for oncologic care.

In FIGURE 2, we propose a management algorithm for the patient who presents with post–ablation bleeding. We acknowledge that the evidence base for our management recommendations is limited. Still, we hope providers, ACOG, and other guidelines-issuing organizations consider them as they adapt their own practices and recommendations. We believe this is one of many steps needed to improve outcomes for patients with gynecologic cancer, particularly those in marginalized communities disproportionately impacted by current trends.

CASE Resolution

After reviewing the relevant documentation and examining the patient, the gynecologic oncology consultant contacts the referring gynecologist. They review the low utility of frozen section and the overall low risk of cancer on the final hysterectomy specimen if the patient were to undergo hysterectomy. The consultant clarifies that there is no other concern for surgical complexity beyond the skill of the referring provider, and they discuss the possibility of referral to a minimally invasive specialist for the surgery.

Ultimately, the patient undergoes uncomplicated laparoscopic hysterectomy performed by the original referring gynecologist. Final pathology reveals inactive endometrium with ablative changes and cornual focus of endometrial hyperplasia without atypia. ●

Acknowledgement

The authors acknowledge Ian Hagemann, MD, PhD, for his review of the manuscript.

CASE New patient presents with a history of endometrial hyperplasia

A 51-year-old patient (G2P2002) presents to a new gynecologist’s office after moving from a different state. In her medical history, the gynecologist notes that 5 years ago she underwent dilation and curettage and endometrial ablation procedures for heavy menstrual bleeding (HMB). Ultrasonography performed prior to those procedures showed a slightly enlarged uterus, a simple left ovarian cyst, and a non ̶ visualized right ovary. The patient had declined a 2-step procedure due to concerns with anesthesia, and surgical pathology at the time of ablation revealed hyperplasia without atypia. The patient’s medical history was otherwise notable for prediabetes (recent hemoglobin A_1c [HbA_1c] measurement, 6.0%) and obesity (body mass index, 43 kg/m²). Pertinent family history included her mother’s diagnosis of endometrial cancer at age 36. Given the patient’s diagnosis of endometrial hyperplasia, she was referred to gynecologic oncology, but she ultimately declined hysterectomy, stating that she was happy with the resolution of her abnormal bleeding. At the time of her initial gynecologic oncology consultation, the consultant suggested lifestyle changes to combat prediabetes and obesity to reduce the risk of endometrial cancer, as future signs of cancer, namely bleeding, may be masked by the endometrial ablation. The patient was prescribed metformin given these medical comorbidities.

At today’s appointment, the patient notes continued resolution of bleeding since the procedure. She does, however, note a 6-month history of vasomotor symptoms and one episode of spotting 3 months ago. Three years ago she was diagnosed with type 2 diabetes mellitus, and her current HbA_1c is 6.9%. She has gained 10 lb since being diagnosed with endometrial cancer 5 years ago, and she has continued to take metformin.

An in-office endometrial biopsy is unsuccessful due to cervical stenosis. The treating gynecologist orders a transvaginal ultrasound, which reveals a small left ovarian cyst and a thickened endometrium (measuring 10 mm). Concerned that these findings could represent endometrial cancer, the gynecologist refers the patient to gynecologic oncology for further evaluation.
 

Sequelae and complications following endometrial ablation are often managed by a gynecologic oncologist. Indeed, a 2018 poll of Society of Gynecologic Oncology (SGO) members revealed that 93.8% of respondents had received such a referral, and almost 20% of respondents were managing more than 20 patients with post-ablation complications in their practices.¹ These complications, including hematometra, post-ablation tubal sterilization syndrome, other pain syndromes associated with retrograde menstruation, and thickened endometrium with scarring leading to an inability to sample the endometrium to investigate post-ablation bleeding are symptoms and findings that often lead to further surgery, including hysterectomy.² General gynecologists faced with these complications may refer patients to gynecologic oncology given an inability to sample the post-ablation endometrium or anticipated difficulties with hysterectomy. A recent meta-analysis revealed a 12.4% hysterectomy rate 5 years after endometrial ablation. Among these patients, the incidence of endometrial cancer ranged from 0% to 1.6%.³

In 2023, endometrial cancer incidence continues to increase, as does the incidence of obesity in women of all ages. Endometrial cancer mortality rates are also increasing, and these trends disproportionately affects non-Hispanic Black women.⁴ As providers and advocates work to narrow these disparities, gynecologic oncologists are simultaneously noting increased referrals for very likely benign conditions.⁵ Patients referred for post-ablation bleeding are a subset of these, as most patients who undergo endometrial ablation will not develop cancer. Considering the potential bottlenecks created en route to a gynecologic oncology evaluation, it seems prudent to minimize practices, like endometrial ablation, that may directly or indirectly prevent timely referral of patients with cancer to a gynecologic oncologist.

In this review we focus on the current use of endometrial ablation, associated complications, the incidence of treatment failure, and patient selection. Considering these issues in the context of the current endometrial cancer landscape, we posit best practices aimed at optimizing patient outcomes, and empowering general gynecologists to practice cancer prevention and to triage their surgical patients.

Continue to: Current use of endometrial ablation in the US...

In 2015, more than 500,000 endometrial ablations were performed in the United States.Given the ability to perform in-office ablation, this number is growing and potentially underestimated each year.⁶ In 2022, the global endometrial ablation market was valued at $3.4 billion, a figure projected to double in 10 years.⁷ The procedure has evolved as different devices and approaches have developed, offering patients different means to manage bleeding without hysterectomy. The minimally invasive procedure, performed in premenopausal patients with heavy menstrual bleeding (HMB) due to benign causes who have completed childbearing, has been associated with faster recovery times and fewer short-term complications compared with more invasive surgery.⁸ There are several non-resectoscope ablative devices approved by the US Food and Drug Administration (FDA), and each work to destroy the endometrial lining via thermal or cryoablation. Endometrial ablation can be performed in premenopausal patients with HMB due to benign causes who have completed childbearing.

Recently, promotional literature has begun to report on so-called overuse of hysterectomy, despite decreasing overall hysterectomy rates. This reporting proposes and applies “appropriateness criteria,” accounting for the rate of preoperative counseling regarding alternatives to hysterectomy, as well as the rate of “unsupportive” final pathology.⁹ The adoption of endometrial ablation and increasing market value of such vendors suggest that this campaign is having its desired effect. From the oncology perspective, we are concerned the pendulum could swing too far away from hysterectomy, a procedure that definitively cures abnormal uterine bleeding, toward endometrial ablation without explicit acknowledgement of the trade-offs involved.

Endometrial ablation complications: Late-onset procedure failure

A number of post-ablation syndromes may present at least 1 month following the procedure. Collectively known as late-onset endometrial ablation failure (LOEAF), these syndromes are characterized by recurrent vaginal bleeding, and/or new cyclic pelvic pain.¹⁰ It is difficult to measure the true incidence of LOEAF. Thomassee and colleagues examined a Canadian retrospective cohort of 437 patients who underwent endometrial ablation; 20.8% reported post-ablation pelvic pain after a median 301 days.¹¹ The subsequent need for surgical intervention, often hysterectomy, is a surrogate for LOEAF.

It should be noted that LOEAF is distinct from post-ablation tubal sterilization syndrome (PATSS), which describes cornual menstrual bleeding impeded by the ligated proximal fallopian tube.¹² Increased awareness of PATSS, along with the discontinuation of Essure (a permanent hysteroscopic sterilization device) in 2018, has led some surgeons to advocate for concomitant salpingectomy at the time of endometrial ablation.¹³ The role of opportunistic salpingectomy in primary prevention of epithelial ovarian cancer is well described, and while we strongly support this practice at the time of endometrial ablation, we do not feel that it effectively prevents LOEAF.¹⁴

The post-ablation inability to adequately sample the endometrium is also considered a LOEAF. A prospective study of 57 women who underwent endometrial ablation assessed post-ablation sampling feasibility via transvaginal ultrasonography, saline infusion sonohysterography (SIS), and in-office endometrial biopsies. In 23% of the cohort, endometrial sampling failed, and the authors noted decreased reliability of pathologic assessment.¹⁵ One systematic review, in which authors examined the incidence of endometrial cancer following endometrial ablation, characterized 38 cases of endometrial cancer and reported a post-ablation endometrial sampling success rate of 89%. This figure was based on a self-selected sample of 18 patients; cases in which endometrial sampling was thought to be impossible were excluded. The study also had a 30% missing data rate and several other biases.¹⁶

In the previously mentioned poll of SGO members,¹ 84% of the surveyed gynecologic oncologists managing post-ablation patients reported that endometrial sampling following endometrial ablation was “moderately” or “extremely” difficult. More than half of the survey respondents believed that hysterectomy was required for accurate diagnosis.¹ While we acknowledge the likely sampling bias affecting the survey results, we are not comforted by any data that minimizes this diagnostic challenge.

Appropriate patient selection and contraindications

The ideal candidate for endometrial ablation is a premenopausal patient with HMB who does not desire future fertility. According to the FDA, absolute contraindications include pregnancy or desired fertility, prior ablation, current IUD in place, inadequate preoperative endometrial assessment, known or suspected malignancy, active infection, or unfavorable anatomy.¹⁷

What about patients who may be at increased risk for endometrial cancer?

There is a paucity of data regarding the safety of endometrial ablation in patients at increased risk for developing endometrial cancer in the future. The American College of Obstetricians and Gynecologists (ACOG) 2007 practice bulletin on endometrial ablation (no longer accessible online) alludes to this concern and other contraindications,¹⁸ but there are no established guidelines. Currently, no ACOG practice bulletin or committee opinion lists relative contraindications to endometrial ablation, long-term complications (except risks associated with future pregnancy), or risk of subsequent hysterectomy. The risk that “it may be harder to detect endometrial cancer after ablation” is noted on ACOG’s web page dedicated to frequently asked questions (FAQs) regarding abnormal uterine bleeding.¹⁹ It is not mentioned on their web page dedicated to the FAQs regarding endometrial ablation.²⁰

In the absence of high-quality published data on established contraindications for endometrial ablation, we advocate for the increased awareness of possible relative contraindications—namely well-established risk factors for endometrial cancer (TABLE 1).For example, in a pooled analysis of 24 epidemiologic studies, authors found that the odds of developing endometrial cancer was 7 times higher among patients with a body mass index (BMI) ≥ 40 kg/m², compared with controls (odds ratio [OR], 7.14; 95% confidence interval [CI], 6.33–8.06).²¹ Additionally, patients with Lynch syndrome, a history of extended tamoxifen use, or those with a history of chronic anovulation or polycystic ovary syndrome are at increased risk for endometrial cancer.^22-24 If the presence of one or more of these factors does not dissuade general gynecologists from performing an endometrial ablation (even armed with a negative preoperative endometrial biopsy), we feel they should at least prompt thoughtful guideline-driven pause.

Continue to: Hysterectomy—A disincentivized option...

Hysterectomy—A disincentivized option

The annual number of hysterectomies performed by general gynecologists has declined over time. One study by Cadish and colleagues revealed that recent residency graduates performed only 3 to 4 annually.²⁵ These numbers partly reflect the decreasing number of hysterectomies performed during residency training. Furthermore, other factors—including the increasing rate of placenta accreta spectrum, the focus on risk stratification of adnexal masses via the ovarian-adnexal reporting and data classification system (O-RADs), and the emphasis on minimally invasive approaches often acquired in subspecialty training—have likely contributed to referral patterns to such specialists as minimally invasive gynecologic surgeons and gynecologic oncologists.²⁶ This trend is self-actualizing, as quality metrics funnel patients to high-volume surgeons, and general gynecologists risk losing hysterectomy privileges.

These factors lend themselves to a growing emphasis on endometrial ablation. Endometrial ablations can be performed in several settings, including in the hospital, in outpatient clinics, and more and more commonly, in ambulatory surgery centers. This increased access to endometrial ablation in the ambulatory surgery setting has corresponded with an annual endometrial ablation market value growth rate of 5% to 7%.²⁷ These rates are likely compounded by payer reimbursement policies that promote endometrial ablation and other alternatives to hysterectomy that are cost savings in the short term.²⁸ While the actual payer models are unavailable to review, they may not consider the costs of LOEAFs, including subsequent hysterectomy up to 5 years after initial ablation procedures. Provocatively, they almost certainly do not consider the costs of delayed care of patients with endometrial cancer vying for gynecologic oncology appointment slots occupied by post-ablation patients.

We urge providers, patients, and advocates to question who benefits from the uptake of ablation procedures: Patients? Payors? Providers? And how will the field of gynecology fare if hysterectomy skills and privileges are supplanted by ablation?

Post-ablation bleeding: Management by the gyn oncologist

Patients with post-ablation bleeding, either immediately or years later, are sometimes referred to a gynecologic oncologist given the possible risk for cancer and need for surgical staging if cancer is found on the hysterectomy specimen. In practice, assuming normal preoperative ultrasonography and no other clinical or radiologic findings suggestive of malignancy (eg, computed tomography findings concerning for metastases, abnormal cervical cytology, etc.), the presence of cancer is extremely unlikely to be determined at the time of surgery. Frozen section is not generally performed on the endometrium; intraoperative evaluation of even the unablated endometrium is notoriously unreliable; and histologic assessment of the ablated endometrium is limited by artifact (FIGURE 1). The abnormalities caused by ablation further impede selection of a representative focus, obfuscating any actionable result.

Some surgeons routinely bivalve the excised uterus prior to fixation to assess presence of tumor, tumor size, and the degree of myometrial invasion.²⁹ A combination of factors may compel surgeons to perform lymphadenectomy if not already performed, or if sentinel lymph node mapping was unsuccessful. But this practice has not been studied in patients with post-ablation bleeding, and applying these principles relies on a preoperative diagnosis establishing the presence and grade of a cancer. Furthermore, the utility of frozen section and myometrial assessment to decide whether or not to proceed with lymphadenectomy is less relevant in the era of molecular classification guiding adjuvant therapy. In summary, assuming no pathologic or radiologic findings suggestive of cancer, gynecologic oncologists are unlikely to perform lymphadenectomy at the time of hysterectomy in these post-ablation cases, which therefore can safely be performed by general gynecologists.

Our recommendations

Consider the LNG-IUD as an alternative to ablation. A recent randomized controlled trial by Beelen and colleagues compared the effectiveness of LNG-releasing IUDs with endometrial ablation in patients with HMB. While the LNG-IUD was inferior to endometrial ablation, quality-of-life measures were similar up to 2 years.³¹ Realizing that the hysterectomy rate following endometrial ablation increases significantly beyond that time point (2 years), this narrative may be incomplete. A 5- to 10-year follow-up time-frame may be a more helpful gauge of long-term outcomes. This prolonged time-frame also may allow study of the LNG-IUD’s protective effects on the endometrium in the prevention of endometrial hyperplasia and cancer.

Consider hysterectomy. A 2021 Cochrane review revealed that, compared with endometrial ablation, minimally invasive hysterectomy is associated with higher quality-of-life metrics, higher self-reported patient satisfaction, and similar rates of adverse events.³² While patient autonomy is paramount, the developing step-wise approach from endometrial ablation to hysterectomy, and its potential effects on the health care system at a time when endometrial cancer incidence and mortality rates are rising, is troubling.

Postablation, consider hysterectomy by the general gynecologist. Current trends appear to disincentivize general gynecologists from performing hysterectomy either for HMB or LOEAF. We would offer reassurance that they can safely perform this procedure. Referral to oncology may not be necessary since, in the absence of an established diagnosis of cancer, a lymphadenectomy is not typically required. A shift away from referral for these patients can preserve access to oncology for those women, especially minority women, with an explicit need for oncologic care.

In FIGURE 2, we propose a management algorithm for the patient who presents with post–ablation bleeding. We acknowledge that the evidence base for our management recommendations is limited. Still, we hope providers, ACOG, and other guidelines-issuing organizations consider them as they adapt their own practices and recommendations. We believe this is one of many steps needed to improve outcomes for patients with gynecologic cancer, particularly those in marginalized communities disproportionately impacted by current trends.

CASE Resolution

After reviewing the relevant documentation and examining the patient, the gynecologic oncology consultant contacts the referring gynecologist. They review the low utility of frozen section and the overall low risk of cancer on the final hysterectomy specimen if the patient were to undergo hysterectomy. The consultant clarifies that there is no other concern for surgical complexity beyond the skill of the referring provider, and they discuss the possibility of referral to a minimally invasive specialist for the surgery.

Ultimately, the patient undergoes uncomplicated laparoscopic hysterectomy performed by the original referring gynecologist. Final pathology reveals inactive endometrium with ablative changes and cornual focus of endometrial hyperplasia without atypia. ●

Acknowledgement

The authors acknowledge Ian Hagemann, MD, PhD, for his review of the manuscript.

CASE A new patient office visit

A new patient is waiting for you in the exam room. You review the chart and see the sex demographic field is blank, and the patient’s name is Alex. As an ObGyn, most of your patients are female, but you have treated your patients’ partners for sexually transmitted infections. As you enter the room, you see 2 androgynously dressed individuals; you introduce yourself and ask,

“What brings you in today, and who is your friend?”

“This is my partner Charlie, and we are worried I have an STD.”
 

Estimates suggest that between 7% to 12% of the US population identifies as lesbian, gay, bisexual, transgender/non-binary, queer/questioning, intersex, or asexual (LGBTQI+).¹ If you practice in an urban area, the odds are quite high that you have encountered an LGBTQI+ person who openly identified as such; if you are in a rural area, you also likely have had an LGBTQI+ patient, but they may not have disclosed this about themselves.² Maybe you have had training in cultural relevance or are a member of this community and you feel confident in providing quality care to LGBTQI+ patients. Or maybe you think that, as a responsibly practicing health care clinician, you treat all patients the same, so whether or not you know their sexual orientation or gender identity does not impact the care you provide. As the proportion of US adults who identify as LGBTQI+ increases,¹ it becomes more important for health care clinicians to understand the challenges these patients face when trying to access health care. To start, let’s review the meaning of LGBTQI+, the history of the community, what it means to be culturally relevant or humble, and how to create a welcoming and safe practice environment.

LGBTQI+ terms and definitions

The first step in providing quality care to LGBTQI+ patients is to understand the terminology associated with sexual orientation, gender identity, and gender expression.^3–5

Sexual orientation refers to whom a person is sexually attracted. The term straight/heterosexual suggests a person is sexually attracted to a person of the opposite gender. Lesbian or gay refers to those who are attracted to their same gender. Some people use bisexual (attracted to both the same and opposite gender) and pansexual (attracted to all humans regardless of gender). Still others refer to themselves as queer—people who identify as someone who is not heterosexual or cisgender. A variety of other terms exist to describe one’s sexual attraction. There are also some people who identify as asexual, which suggests they are not sexually attracted to anyone.

Gender identity relates to how one views their own gender. If you were assigned female at birth and identify as a woman, you are cisgender. If you were assigned male at birth and identify as a woman, you may identify as transgender whether or not you have had gender transitioning surgery or have taken hormones. Some people do not identify with the terms male or female and may view themselves as nonbinary. The terms gender queer, gender fluid, gender diverse, and gender non-conforming also may be used to describe various ways that an individual may not identify as male or female. We also can refer to people as “assigned female at birth” or “assigned male at birth”. People with intersex conditions may require taking a unique medical history that includes asking about genetic testing (eg, 46,XX congenital adrenal hyperplasia or 46,XY complete gonadal dysgenesis).

Gender expression refers to how one pre-sents themselves to others through appearance, dress, and behavior. A person may be assigned female at birth, dress in a conventional male fashion, and still identify as a woman. Still others may choose to express their gender in a variety of ways that may not have anything to do with their sexual orientation or gender identity, such as dressing in ways that represent their culture.

People may be fluid in their sexual orientation or gender identity; it may change from day to day, month to month, or even year to year.^6,7

*The term LGBTQI+ is not used consistently in the literature. Throughout this article, the terminology used matches that used in the cited reference(s).

Continue to: Health care and the LGBTQI+ community...

Health care and the LGBTQI+ community

The LGBTQI+ community has a history of experiencing societal discrimination and stigma, which stems from medical mistrust often due to a lack of understanding of their medical and psychosocial needs.^8,9 A 2019 survey of US LGBTQ adults, found that about 50% of people who identified as transgender reported having negative or discriminatory experiences with a health care clinician.¹⁰ About 18% of transgender people anticipated being refused medical care due to their gender identity.¹⁰ About 18% of LGBTQ individuals avoid any type of medical care, fearing discrimination.¹⁰ Lesbian women are 3 times more likely to have not seen an ObGyn than women who identify as straight.¹¹ Sixty-two percent of lesbian women have biological children and received prenatal care; however, of those, 47% do not receive routine cancer screenings.^10,11 Only 45% of age-eligible lesbian women have received at least 1 dose of the HPV vaccine, compared with 60% of straight women.^10,11

Due to societal stigma, more than 40% of transgender people have attempted suicide.¹² Felt or perceived stigma is also associated with risky health behaviors that contribute to health disparities. LGBTQI+ people are more likely to use substances,¹³ lesbian women are more likely to be obese,¹⁴ and 19% of transgender men are living with HIV/AIDS.¹⁵ Rates of unintended pregnancy among lesbian women and transgender men are 28%, compared with 6% in straight women, and 12% in heterosexual teens.^15,16

In addition to real or perceived discrimination, there are medical misperceptions among the LGBTQI+ community. For instance, sexual minority women (SMW) are less likely to receive regular screening for cervical cancer. In one survey of more than 400 SMW, about 25% reported not receiving regular screening. SMW may mistakenly believe they do not need Pap testing and pelvic exams because they do not have penile-vaginal intercourse.^17,18 Transgender men may not identify with having a cervix, or may perceive ObGyns to be “gendered” toward people who identify as women.¹⁸

Embracing cultural humility

Cultural humility expands upon the term cultural competence, with the idea that one can never be fully competent in the culture of another person.^19,20 The National Institutes of Health defines cultural humility as “a lifelong process of self-reflection and self-critique whereby the individual not only learns about another’s culture, but one starts with an examination of his/her own beliefs and cultural identities.”²¹

Having cultural humility is the recognition that, in order to treat your ObGyn patient as a whole person and engage in shared medical decision making in the office setting, you need to know their sexual orientation and gender identity. Treating each patient the same is not providing equitable care (equality does not equal equity) because each patient has different medical and psychosocial needs. Embracing cultural humility is the first step in creating safe and welcoming spaces in the ObGyn office.²⁰

CASE Ways to better introduce yourself

To revisit the case, what options does the clinician have to start off on a best foot to create a safe space for Alex?

• Open with your own preferred pronouns. For instance, for an introduction, consider: “I’m Dr. X, my pronouns are she/her.”
• Don’t assume. Do not make assumptions about the relationship between Alex and the person accompanying them.

4 ways for creating welcoming and affirming spaces in ObGyn

1. Make sure your intake form is inclusive. Include a space for pronouns and the patient’s preferred name (which may differ from their legal name). Also allow patients to choose more than 1 sexual orientation and gender identity.²⁰ (An example form is available from the LGBT National Health Education Center: https://www.lgbtqiahealtheducation.org/publication/focus-forms-policy-creating-inclusive-environment-lgbt-patients/.)
2. Create a safe environment in the waiting area. Try to ensure that at least 1 bathroom is labeled “All Gender” or “Family.” Gendered bathrooms (eg, Ladies’ or Men’s rooms) are not welcoming. Make sure your non-discrimination policy is displayed and includes sexual orientation and gender identity. Review the patient education and reading materials in your waiting room to ensure they are inclusive. Do they show people with varied gender expression? Do they show same-sex couples or interracial couples?
3. Use a trauma-informed approach when taking a sexual history and while conducting a physical exam. Determine if a pelvic exam is necessary at this visit or can it be postponed for another visit, when trust has been established with the patient. Explain each part of the pelvic/vaginal exam prior to conducting and again while performing the exam. Before taking a sexual history, explain why you are asking the questions and be sure to remain neutral with your questioning. For instance, you can say, “It’s important for me to understand your medical history in detail to provide you with the best health care possible.” Instead of asking, “Do you have sex with men, women, or both?” ask, “Do you have sex with people with a penis, vagina, or both? Do you have anal sex?” Recognize that some patients may be in a polyamorous relationship and may have more than 1 committed partner. For sexually active patients consider asking if they have ever exchanged sex for money or other goods, making sure to avoid judgmental body language or wording. Patients who do engage in “survival sex” may benefit from a discussion on pre-exposure prophylaxis to reduce HIV transmission.²²
4. Provide appropriate counsel based on their feedback.

• Explain their risk for HPV infection and vaccination options.
• Respectfully ask if there is a need for contraception and review options appropriate for their situation.
• Ask about the use of “toys” and provide guidance on sanitation and risk of infection with shared toys.
• Determine current or past hormone use for patients who identify as transgender and nonbinary (although many do not take hormones and have not had gender-affirming procedures, some may be considering these procedures). Be sure to ask these patients if they have had any surgeries or other procedures.

The receipt of gynecologic care can be traumatic for some LGBTQI+ people. Explain to the patient why you are doing everything during your examination and how it might feel. If a pelvic exam is not absolutely necessary that day, perhaps the patient can return another time. For transgender men who have been taking testosterone,vaginal atrophy may be a concern, and you could consider a pediatric speculum.

Personal introspection may be necessary

In summary, the number of people who identify as lesbian, gay, bisexual, transgender/nonbinary, queer/questioning, intersex, or asexual is not insignificant. Many of these patients or their partners may present for ObGyn care at your office. Clinicians need to understand that there is a new language relative to sexual orientation and gender identity. Incorporating cultural humility into one’s practice requires personal introspection and is a first step to creating safe and welcoming spaces in the ObGyn office. ●

CASE A new patient office visit

A new patient is waiting for you in the exam room. You review the chart and see the sex demographic field is blank, and the patient’s name is Alex. As an ObGyn, most of your patients are female, but you have treated your patients’ partners for sexually transmitted infections. As you enter the room, you see 2 androgynously dressed individuals; you introduce yourself and ask,

“What brings you in today, and who is your friend?”

“This is my partner Charlie, and we are worried I have an STD.”
 

Estimates suggest that between 7% to 12% of the US population identifies as lesbian, gay, bisexual, transgender/non-binary, queer/questioning, intersex, or asexual (LGBTQI+).¹ If you practice in an urban area, the odds are quite high that you have encountered an LGBTQI+ person who openly identified as such; if you are in a rural area, you also likely have had an LGBTQI+ patient, but they may not have disclosed this about themselves.² Maybe you have had training in cultural relevance or are a member of this community and you feel confident in providing quality care to LGBTQI+ patients. Or maybe you think that, as a responsibly practicing health care clinician, you treat all patients the same, so whether or not you know their sexual orientation or gender identity does not impact the care you provide. As the proportion of US adults who identify as LGBTQI+ increases,¹ it becomes more important for health care clinicians to understand the challenges these patients face when trying to access health care. To start, let’s review the meaning of LGBTQI+, the history of the community, what it means to be culturally relevant or humble, and how to create a welcoming and safe practice environment.

LGBTQI+ terms and definitions

The first step in providing quality care to LGBTQI+ patients is to understand the terminology associated with sexual orientation, gender identity, and gender expression.^3–5

Sexual orientation refers to whom a person is sexually attracted. The term straight/heterosexual suggests a person is sexually attracted to a person of the opposite gender. Lesbian or gay refers to those who are attracted to their same gender. Some people use bisexual (attracted to both the same and opposite gender) and pansexual (attracted to all humans regardless of gender). Still others refer to themselves as queer—people who identify as someone who is not heterosexual or cisgender. A variety of other terms exist to describe one’s sexual attraction. There are also some people who identify as asexual, which suggests they are not sexually attracted to anyone.

Gender identity relates to how one views their own gender. If you were assigned female at birth and identify as a woman, you are cisgender. If you were assigned male at birth and identify as a woman, you may identify as transgender whether or not you have had gender transitioning surgery or have taken hormones. Some people do not identify with the terms male or female and may view themselves as nonbinary. The terms gender queer, gender fluid, gender diverse, and gender non-conforming also may be used to describe various ways that an individual may not identify as male or female. We also can refer to people as “assigned female at birth” or “assigned male at birth”. People with intersex conditions may require taking a unique medical history that includes asking about genetic testing (eg, 46,XX congenital adrenal hyperplasia or 46,XY complete gonadal dysgenesis).

Gender expression refers to how one pre-sents themselves to others through appearance, dress, and behavior. A person may be assigned female at birth, dress in a conventional male fashion, and still identify as a woman. Still others may choose to express their gender in a variety of ways that may not have anything to do with their sexual orientation or gender identity, such as dressing in ways that represent their culture.

People may be fluid in their sexual orientation or gender identity; it may change from day to day, month to month, or even year to year.^6,7

*The term LGBTQI+ is not used consistently in the literature. Throughout this article, the terminology used matches that used in the cited reference(s).

Continue to: Health care and the LGBTQI+ community...

Health care and the LGBTQI+ community

The LGBTQI+ community has a history of experiencing societal discrimination and stigma, which stems from medical mistrust often due to a lack of understanding of their medical and psychosocial needs.^8,9 A 2019 survey of US LGBTQ adults, found that about 50% of people who identified as transgender reported having negative or discriminatory experiences with a health care clinician.¹⁰ About 18% of transgender people anticipated being refused medical care due to their gender identity.¹⁰ About 18% of LGBTQ individuals avoid any type of medical care, fearing discrimination.¹⁰ Lesbian women are 3 times more likely to have not seen an ObGyn than women who identify as straight.¹¹ Sixty-two percent of lesbian women have biological children and received prenatal care; however, of those, 47% do not receive routine cancer screenings.^10,11 Only 45% of age-eligible lesbian women have received at least 1 dose of the HPV vaccine, compared with 60% of straight women.^10,11

Due to societal stigma, more than 40% of transgender people have attempted suicide.¹² Felt or perceived stigma is also associated with risky health behaviors that contribute to health disparities. LGBTQI+ people are more likely to use substances,¹³ lesbian women are more likely to be obese,¹⁴ and 19% of transgender men are living with HIV/AIDS.¹⁵ Rates of unintended pregnancy among lesbian women and transgender men are 28%, compared with 6% in straight women, and 12% in heterosexual teens.^15,16

In addition to real or perceived discrimination, there are medical misperceptions among the LGBTQI+ community. For instance, sexual minority women (SMW) are less likely to receive regular screening for cervical cancer. In one survey of more than 400 SMW, about 25% reported not receiving regular screening. SMW may mistakenly believe they do not need Pap testing and pelvic exams because they do not have penile-vaginal intercourse.^17,18 Transgender men may not identify with having a cervix, or may perceive ObGyns to be “gendered” toward people who identify as women.¹⁸

Embracing cultural humility

Cultural humility expands upon the term cultural competence, with the idea that one can never be fully competent in the culture of another person.^19,20 The National Institutes of Health defines cultural humility as “a lifelong process of self-reflection and self-critique whereby the individual not only learns about another’s culture, but one starts with an examination of his/her own beliefs and cultural identities.”²¹

Having cultural humility is the recognition that, in order to treat your ObGyn patient as a whole person and engage in shared medical decision making in the office setting, you need to know their sexual orientation and gender identity. Treating each patient the same is not providing equitable care (equality does not equal equity) because each patient has different medical and psychosocial needs. Embracing cultural humility is the first step in creating safe and welcoming spaces in the ObGyn office.²⁰

CASE Ways to better introduce yourself

To revisit the case, what options does the clinician have to start off on a best foot to create a safe space for Alex?

• Open with your own preferred pronouns. For instance, for an introduction, consider: “I’m Dr. X, my pronouns are she/her.”
• Don’t assume. Do not make assumptions about the relationship between Alex and the person accompanying them.

4 ways for creating welcoming and affirming spaces in ObGyn

1. Make sure your intake form is inclusive. Include a space for pronouns and the patient’s preferred name (which may differ from their legal name). Also allow patients to choose more than 1 sexual orientation and gender identity.²⁰ (An example form is available from the LGBT National Health Education Center: https://www.lgbtqiahealtheducation.org/publication/focus-forms-policy-creating-inclusive-environment-lgbt-patients/.)
2. Create a safe environment in the waiting area. Try to ensure that at least 1 bathroom is labeled “All Gender” or “Family.” Gendered bathrooms (eg, Ladies’ or Men’s rooms) are not welcoming. Make sure your non-discrimination policy is displayed and includes sexual orientation and gender identity. Review the patient education and reading materials in your waiting room to ensure they are inclusive. Do they show people with varied gender expression? Do they show same-sex couples or interracial couples?
3. Use a trauma-informed approach when taking a sexual history and while conducting a physical exam. Determine if a pelvic exam is necessary at this visit or can it be postponed for another visit, when trust has been established with the patient. Explain each part of the pelvic/vaginal exam prior to conducting and again while performing the exam. Before taking a sexual history, explain why you are asking the questions and be sure to remain neutral with your questioning. For instance, you can say, “It’s important for me to understand your medical history in detail to provide you with the best health care possible.” Instead of asking, “Do you have sex with men, women, or both?” ask, “Do you have sex with people with a penis, vagina, or both? Do you have anal sex?” Recognize that some patients may be in a polyamorous relationship and may have more than 1 committed partner. For sexually active patients consider asking if they have ever exchanged sex for money or other goods, making sure to avoid judgmental body language or wording. Patients who do engage in “survival sex” may benefit from a discussion on pre-exposure prophylaxis to reduce HIV transmission.²²
4. Provide appropriate counsel based on their feedback.

• Explain their risk for HPV infection and vaccination options.
• Respectfully ask if there is a need for contraception and review options appropriate for their situation.
• Ask about the use of “toys” and provide guidance on sanitation and risk of infection with shared toys.
• Determine current or past hormone use for patients who identify as transgender and nonbinary (although many do not take hormones and have not had gender-affirming procedures, some may be considering these procedures). Be sure to ask these patients if they have had any surgeries or other procedures.

The receipt of gynecologic care can be traumatic for some LGBTQI+ people. Explain to the patient why you are doing everything during your examination and how it might feel. If a pelvic exam is not absolutely necessary that day, perhaps the patient can return another time. For transgender men who have been taking testosterone,vaginal atrophy may be a concern, and you could consider a pediatric speculum.

Personal introspection may be necessary

In summary, the number of people who identify as lesbian, gay, bisexual, transgender/nonbinary, queer/questioning, intersex, or asexual is not insignificant. Many of these patients or their partners may present for ObGyn care at your office. Clinicians need to understand that there is a new language relative to sexual orientation and gender identity. Incorporating cultural humility into one’s practice requires personal introspection and is a first step to creating safe and welcoming spaces in the ObGyn office. ●

CASE A new patient office visit

A new patient is waiting for you in the exam room. You review the chart and see the sex demographic field is blank, and the patient’s name is Alex. As an ObGyn, most of your patients are female, but you have treated your patients’ partners for sexually transmitted infections. As you enter the room, you see 2 androgynously dressed individuals; you introduce yourself and ask,

“What brings you in today, and who is your friend?”

“This is my partner Charlie, and we are worried I have an STD.”
 

Estimates suggest that between 7% to 12% of the US population identifies as lesbian, gay, bisexual, transgender/non-binary, queer/questioning, intersex, or asexual (LGBTQI+).¹ If you practice in an urban area, the odds are quite high that you have encountered an LGBTQI+ person who openly identified as such; if you are in a rural area, you also likely have had an LGBTQI+ patient, but they may not have disclosed this about themselves.² Maybe you have had training in cultural relevance or are a member of this community and you feel confident in providing quality care to LGBTQI+ patients. Or maybe you think that, as a responsibly practicing health care clinician, you treat all patients the same, so whether or not you know their sexual orientation or gender identity does not impact the care you provide. As the proportion of US adults who identify as LGBTQI+ increases,¹ it becomes more important for health care clinicians to understand the challenges these patients face when trying to access health care. To start, let’s review the meaning of LGBTQI+, the history of the community, what it means to be culturally relevant or humble, and how to create a welcoming and safe practice environment.

LGBTQI+ terms and definitions

The first step in providing quality care to LGBTQI+ patients is to understand the terminology associated with sexual orientation, gender identity, and gender expression.^3–5

Sexual orientation refers to whom a person is sexually attracted. The term straight/heterosexual suggests a person is sexually attracted to a person of the opposite gender. Lesbian or gay refers to those who are attracted to their same gender. Some people use bisexual (attracted to both the same and opposite gender) and pansexual (attracted to all humans regardless of gender). Still others refer to themselves as queer—people who identify as someone who is not heterosexual or cisgender. A variety of other terms exist to describe one’s sexual attraction. There are also some people who identify as asexual, which suggests they are not sexually attracted to anyone.

Gender identity relates to how one views their own gender. If you were assigned female at birth and identify as a woman, you are cisgender. If you were assigned male at birth and identify as a woman, you may identify as transgender whether or not you have had gender transitioning surgery or have taken hormones. Some people do not identify with the terms male or female and may view themselves as nonbinary. The terms gender queer, gender fluid, gender diverse, and gender non-conforming also may be used to describe various ways that an individual may not identify as male or female. We also can refer to people as “assigned female at birth” or “assigned male at birth”. People with intersex conditions may require taking a unique medical history that includes asking about genetic testing (eg, 46,XX congenital adrenal hyperplasia or 46,XY complete gonadal dysgenesis).

Gender expression refers to how one pre-sents themselves to others through appearance, dress, and behavior. A person may be assigned female at birth, dress in a conventional male fashion, and still identify as a woman. Still others may choose to express their gender in a variety of ways that may not have anything to do with their sexual orientation or gender identity, such as dressing in ways that represent their culture.

People may be fluid in their sexual orientation or gender identity; it may change from day to day, month to month, or even year to year.^6,7

*The term LGBTQI+ is not used consistently in the literature. Throughout this article, the terminology used matches that used in the cited reference(s).

Continue to: Health care and the LGBTQI+ community...

Health care and the LGBTQI+ community

The LGBTQI+ community has a history of experiencing societal discrimination and stigma, which stems from medical mistrust often due to a lack of understanding of their medical and psychosocial needs.^8,9 A 2019 survey of US LGBTQ adults, found that about 50% of people who identified as transgender reported having negative or discriminatory experiences with a health care clinician.¹⁰ About 18% of transgender people anticipated being refused medical care due to their gender identity.¹⁰ About 18% of LGBTQ individuals avoid any type of medical care, fearing discrimination.¹⁰ Lesbian women are 3 times more likely to have not seen an ObGyn than women who identify as straight.¹¹ Sixty-two percent of lesbian women have biological children and received prenatal care; however, of those, 47% do not receive routine cancer screenings.^10,11 Only 45% of age-eligible lesbian women have received at least 1 dose of the HPV vaccine, compared with 60% of straight women.^10,11

Due to societal stigma, more than 40% of transgender people have attempted suicide.¹² Felt or perceived stigma is also associated with risky health behaviors that contribute to health disparities. LGBTQI+ people are more likely to use substances,¹³ lesbian women are more likely to be obese,¹⁴ and 19% of transgender men are living with HIV/AIDS.¹⁵ Rates of unintended pregnancy among lesbian women and transgender men are 28%, compared with 6% in straight women, and 12% in heterosexual teens.^15,16

In addition to real or perceived discrimination, there are medical misperceptions among the LGBTQI+ community. For instance, sexual minority women (SMW) are less likely to receive regular screening for cervical cancer. In one survey of more than 400 SMW, about 25% reported not receiving regular screening. SMW may mistakenly believe they do not need Pap testing and pelvic exams because they do not have penile-vaginal intercourse.^17,18 Transgender men may not identify with having a cervix, or may perceive ObGyns to be “gendered” toward people who identify as women.¹⁸

Embracing cultural humility

Cultural humility expands upon the term cultural competence, with the idea that one can never be fully competent in the culture of another person.^19,20 The National Institutes of Health defines cultural humility as “a lifelong process of self-reflection and self-critique whereby the individual not only learns about another’s culture, but one starts with an examination of his/her own beliefs and cultural identities.”²¹

Having cultural humility is the recognition that, in order to treat your ObGyn patient as a whole person and engage in shared medical decision making in the office setting, you need to know their sexual orientation and gender identity. Treating each patient the same is not providing equitable care (equality does not equal equity) because each patient has different medical and psychosocial needs. Embracing cultural humility is the first step in creating safe and welcoming spaces in the ObGyn office.²⁰

CASE Ways to better introduce yourself

To revisit the case, what options does the clinician have to start off on a best foot to create a safe space for Alex?

• Open with your own preferred pronouns. For instance, for an introduction, consider: “I’m Dr. X, my pronouns are she/her.”
• Don’t assume. Do not make assumptions about the relationship between Alex and the person accompanying them.

4 ways for creating welcoming and affirming spaces in ObGyn

1. Make sure your intake form is inclusive. Include a space for pronouns and the patient’s preferred name (which may differ from their legal name). Also allow patients to choose more than 1 sexual orientation and gender identity.²⁰ (An example form is available from the LGBT National Health Education Center: https://www.lgbtqiahealtheducation.org/publication/focus-forms-policy-creating-inclusive-environment-lgbt-patients/.)
2. Create a safe environment in the waiting area. Try to ensure that at least 1 bathroom is labeled “All Gender” or “Family.” Gendered bathrooms (eg, Ladies’ or Men’s rooms) are not welcoming. Make sure your non-discrimination policy is displayed and includes sexual orientation and gender identity. Review the patient education and reading materials in your waiting room to ensure they are inclusive. Do they show people with varied gender expression? Do they show same-sex couples or interracial couples?
3. Use a trauma-informed approach when taking a sexual history and while conducting a physical exam. Determine if a pelvic exam is necessary at this visit or can it be postponed for another visit, when trust has been established with the patient. Explain each part of the pelvic/vaginal exam prior to conducting and again while performing the exam. Before taking a sexual history, explain why you are asking the questions and be sure to remain neutral with your questioning. For instance, you can say, “It’s important for me to understand your medical history in detail to provide you with the best health care possible.” Instead of asking, “Do you have sex with men, women, or both?” ask, “Do you have sex with people with a penis, vagina, or both? Do you have anal sex?” Recognize that some patients may be in a polyamorous relationship and may have more than 1 committed partner. For sexually active patients consider asking if they have ever exchanged sex for money or other goods, making sure to avoid judgmental body language or wording. Patients who do engage in “survival sex” may benefit from a discussion on pre-exposure prophylaxis to reduce HIV transmission.²²
4. Provide appropriate counsel based on their feedback.

• Explain their risk for HPV infection and vaccination options.
• Respectfully ask if there is a need for contraception and review options appropriate for their situation.
• Ask about the use of “toys” and provide guidance on sanitation and risk of infection with shared toys.
• Determine current or past hormone use for patients who identify as transgender and nonbinary (although many do not take hormones and have not had gender-affirming procedures, some may be considering these procedures). Be sure to ask these patients if they have had any surgeries or other procedures.

The receipt of gynecologic care can be traumatic for some LGBTQI+ people. Explain to the patient why you are doing everything during your examination and how it might feel. If a pelvic exam is not absolutely necessary that day, perhaps the patient can return another time. For transgender men who have been taking testosterone,vaginal atrophy may be a concern, and you could consider a pediatric speculum.

Personal introspection may be necessary

In summary, the number of people who identify as lesbian, gay, bisexual, transgender/nonbinary, queer/questioning, intersex, or asexual is not insignificant. Many of these patients or their partners may present for ObGyn care at your office. Clinicians need to understand that there is a new language relative to sexual orientation and gender identity. Incorporating cultural humility into one’s practice requires personal introspection and is a first step to creating safe and welcoming spaces in the ObGyn office. ●

Dear OBG Management Reader:

Frontline Medical Communications Inc has made the difficult decision to discontinue publication of OBG Management, effective with this issue. We thank OBG Management’s esteemed Editorial Board, loyal readers, and dedicated authors for their support. It has been our privilege to publish OBG Management for 35 years. 

The online archive of clinical content for OBG Management (2002–2023) remains accessible on MDedge ObGyn. Reprint requests can be directed to Wright’s Media via email [email protected] or telephone (877-652-5295). 

For the latest news and information on obstetrics and gynecology, continue to turn to MDedge ObGyn. 

Goodbye to OBG Management

Robert L. Barbieri, MD

OBG Management was founded in 1988 by Carroll Dowden, a giant in the field of medical publishing. During his career he served as the editor or publisher of Medical Economics, Physician’s Desk Reference, and Mayo Clinic Proceedings. In creating OBG Management, Mr. Dowden’s vision was to edit and publish a monthly magazine focused on issues that impact the practice of obstetrics and gynecology, including patient care and practice management. Dr. Jeffrey Phelan was the founding editor-in-chief of OBG Management, serving from 1988 through 2000, when I became the editor-in-chief. It is with the greatest sadness that we announce that publication of OBG Management will cease with the December 2023 issue, 35 years after its inception.

Over 4 decades, the work of the OBG Management editorial team and authors has been guided by our mission to “enhance the quality of women’s health care and the professional development of ObGyns and all women’s health care clinicians.” The teamwork of our editorial board is the primary reason for the success of OBG Management, ensuring that we consistently provided practical clinical guidance on the most important topics in our field with the goal of improving the health care of our patients. We are proud that OBG Management has been recognized as #1 in readership among obstetrics and gynecology publications.

Our editorial board members are nationally recognized experts in our field and innovators in clinical care. Our editorial members include: Arnold P. Advincula, MD; Linda D. Bradley, MD; Amy L. Garcia, MD; Steven R. Goldstein, MD, MSCP, CCD; Andrew M. Kaunitz, MD, MSCP; Barbara Levy, MD; David G. Mutch, MD; Errol R. Norwitz, MD, PhD, MBA; Jaimey Pauli, MD; JoAnn V. Pinkerton, MD, MSCP; Joseph S. Sanfilippo, MD; and James A. Simon, MD, CCD, IF, MSCP. Prior to his retirement, Dr. John Repke was an important member of our editorial board. Over the past decade our editorial team—Lila O’Connor, Editorial Manager, and Kathy Christie, Senior Medical Content Editor—have ensured that the articles written by our authors are expertly prepared for publication and presentation to our readers.

In clinical practice, we sometimes do not achieve the optimal patient outcomes we desire. Over the past 4 decades, the OBG Management team has strived to identify opportunities to improve patient outcomes and offer practical approaches to optimize practice. We will miss the opportunity to work with you, our community of clinical experts in women’s health care. ●

Dear OBG Management Reader:

Frontline Medical Communications Inc has made the difficult decision to discontinue publication of OBG Management, effective with this issue. We thank OBG Management’s esteemed Editorial Board, loyal readers, and dedicated authors for their support. It has been our privilege to publish OBG Management for 35 years. 

The online archive of clinical content for OBG Management (2002–2023) remains accessible on MDedge ObGyn. Reprint requests can be directed to Wright’s Media via email [email protected] or telephone (877-652-5295). 

For the latest news and information on obstetrics and gynecology, continue to turn to MDedge ObGyn. 

Goodbye to OBG Management

Robert L. Barbieri, MD

OBG Management was founded in 1988 by Carroll Dowden, a giant in the field of medical publishing. During his career he served as the editor or publisher of Medical Economics, Physician’s Desk Reference, and Mayo Clinic Proceedings. In creating OBG Management, Mr. Dowden’s vision was to edit and publish a monthly magazine focused on issues that impact the practice of obstetrics and gynecology, including patient care and practice management. Dr. Jeffrey Phelan was the founding editor-in-chief of OBG Management, serving from 1988 through 2000, when I became the editor-in-chief. It is with the greatest sadness that we announce that publication of OBG Management will cease with the December 2023 issue, 35 years after its inception.

Over 4 decades, the work of the OBG Management editorial team and authors has been guided by our mission to “enhance the quality of women’s health care and the professional development of ObGyns and all women’s health care clinicians.” The teamwork of our editorial board is the primary reason for the success of OBG Management, ensuring that we consistently provided practical clinical guidance on the most important topics in our field with the goal of improving the health care of our patients. We are proud that OBG Management has been recognized as #1 in readership among obstetrics and gynecology publications.

Our editorial board members are nationally recognized experts in our field and innovators in clinical care. Our editorial members include: Arnold P. Advincula, MD; Linda D. Bradley, MD; Amy L. Garcia, MD; Steven R. Goldstein, MD, MSCP, CCD; Andrew M. Kaunitz, MD, MSCP; Barbara Levy, MD; David G. Mutch, MD; Errol R. Norwitz, MD, PhD, MBA; Jaimey Pauli, MD; JoAnn V. Pinkerton, MD, MSCP; Joseph S. Sanfilippo, MD; and James A. Simon, MD, CCD, IF, MSCP. Prior to his retirement, Dr. John Repke was an important member of our editorial board. Over the past decade our editorial team—Lila O’Connor, Editorial Manager, and Kathy Christie, Senior Medical Content Editor—have ensured that the articles written by our authors are expertly prepared for publication and presentation to our readers.

In clinical practice, we sometimes do not achieve the optimal patient outcomes we desire. Over the past 4 decades, the OBG Management team has strived to identify opportunities to improve patient outcomes and offer practical approaches to optimize practice. We will miss the opportunity to work with you, our community of clinical experts in women’s health care. ●

Dear OBG Management Reader:

Frontline Medical Communications Inc has made the difficult decision to discontinue publication of OBG Management, effective with this issue. We thank OBG Management’s esteemed Editorial Board, loyal readers, and dedicated authors for their support. It has been our privilege to publish OBG Management for 35 years. 

The online archive of clinical content for OBG Management (2002–2023) remains accessible on MDedge ObGyn. Reprint requests can be directed to Wright’s Media via email [email protected] or telephone (877-652-5295). 

For the latest news and information on obstetrics and gynecology, continue to turn to MDedge ObGyn. 

Goodbye to OBG Management

Robert L. Barbieri, MD

OBG Management was founded in 1988 by Carroll Dowden, a giant in the field of medical publishing. During his career he served as the editor or publisher of Medical Economics, Physician’s Desk Reference, and Mayo Clinic Proceedings. In creating OBG Management, Mr. Dowden’s vision was to edit and publish a monthly magazine focused on issues that impact the practice of obstetrics and gynecology, including patient care and practice management. Dr. Jeffrey Phelan was the founding editor-in-chief of OBG Management, serving from 1988 through 2000, when I became the editor-in-chief. It is with the greatest sadness that we announce that publication of OBG Management will cease with the December 2023 issue, 35 years after its inception.

Over 4 decades, the work of the OBG Management editorial team and authors has been guided by our mission to “enhance the quality of women’s health care and the professional development of ObGyns and all women’s health care clinicians.” The teamwork of our editorial board is the primary reason for the success of OBG Management, ensuring that we consistently provided practical clinical guidance on the most important topics in our field with the goal of improving the health care of our patients. We are proud that OBG Management has been recognized as #1 in readership among obstetrics and gynecology publications.

Our editorial board members are nationally recognized experts in our field and innovators in clinical care. Our editorial members include: Arnold P. Advincula, MD; Linda D. Bradley, MD; Amy L. Garcia, MD; Steven R. Goldstein, MD, MSCP, CCD; Andrew M. Kaunitz, MD, MSCP; Barbara Levy, MD; David G. Mutch, MD; Errol R. Norwitz, MD, PhD, MBA; Jaimey Pauli, MD; JoAnn V. Pinkerton, MD, MSCP; Joseph S. Sanfilippo, MD; and James A. Simon, MD, CCD, IF, MSCP. Prior to his retirement, Dr. John Repke was an important member of our editorial board. Over the past decade our editorial team—Lila O’Connor, Editorial Manager, and Kathy Christie, Senior Medical Content Editor—have ensured that the articles written by our authors are expertly prepared for publication and presentation to our readers.

In clinical practice, we sometimes do not achieve the optimal patient outcomes we desire. Over the past 4 decades, the OBG Management team has strived to identify opportunities to improve patient outcomes and offer practical approaches to optimize practice. We will miss the opportunity to work with you, our community of clinical experts in women’s health care. ●

Individuals spend close to half of their lives preventing, or planning for, pregnancy. As such, contraception plays a major role in patient-provider interactions. Contraception counseling and management is a common scenario encountered in the general gynecologist’s practice. Luckily, we have 2 evidence-based guidelines developed by the US Centers for Disease Control and Prevention (CDC) that support the provision of contraceptive care:

1. US Medical Eligibility for Contraceptive Use (US-MEC),¹ which provides guidance on which patients can safely use a method
2. US Selected Practice Recommendations for Contraceptive Use (US-SPR),² which provides method-specific guidance on how to use a method (including how to: initiate or start a method; manage adherence issues, such as a missed pill, etc; and manage common issues like breakthrough bleeding). 

Both of these guidelines are updated routinely and are publicly available online or for free, through smartphone applications.

While most contraceptive care is straightforward, there are circumstances that require additional consideration. In the concluding part of this series on contraceptive conundrums, we review 2 clinical cases, existing evidence to guide management decisions, and our recommendations.

CASE 1 Patient presents with hard-to-remove implant

A 44-year-old patient (G2P2) with a new diagnosis of estrogen and progesterone-receptor–positive breast cancer is undergoing her evaluation with her oncologist who recommends removal of her contraceptive implant, which has been in place for 2 years. She presents to your office for removal; however, the device is no longer palpable.

What are your next steps?

Conundrum 1. Should you attempt to remove it?

No, never attempt implant removal if you cannot palpate or localize it. Localization of the implant needs to occur prior to any attempt. However, we recommend checking the contra-lateral arm before sending the patient to obtain imaging, especially if you have no formal documentation regarding in which arm the implant was placed. The next step is identifying what type of implant the patient likely has so you can correctly interpret imaging studies.

Conundrum 2. What type of subdermal contraceptive device is it likely to be?

Currently, the only subdermal contraceptive device available for placement in the United States is the 68-mg etonogestrel implant, marketed with the brand name Nexplanon. This device was initially approved by the US Food and Drug Administration in 2001 and measures 4 cm in length by 2 mm in diameter. It is placed in the medial upper arm, about 8 cm proximal to the medial epicondyle and 3 cm posterior to the sulcus between the biceps and triceps muscles. (The implant should no longer be placed over the bicipital groove.) The implant is impregnated with 15 mg of barium sulfate, making it radiopaque and able to be seen on imaging modalities such as ultrasonography (10–18 mHz high frequency transducer) and x-ray (arm anteroposterior and lateral) for localization in cases in which the device becomes nonpalpable.³

Clinicians also may encounter devices which are no longer marketed in the United States, or which are only available in other countries, and thus should be aware of the appearance and imaging characteristics. It is important to let your imaging team know these characteristics as well:

• From 2006–2010, a 68-mg etonogestrel implant marketed under the name Implanon was available in the United States.⁴ It has the same dimensions and general placement recommendations as the Nexplanon etonogestrel device but is not able to be seen via imaging.
• A 2-arm, 75-mg levonorgestrel (LNG) device known as Jadelle (or, Norplant II; FIGURE 1) received FDA approval in 1996 and is currently only available overseas.⁵ It is also placed in the upper, inner arm in a V-shape using a single incision, and has dimensions similar to the etonogestrel implants.
• From 1990– 2002, the 6-rod device known as Norplant was available in the United States. Each rod measured 3.4 cm in length and contained 36 mg of LNG (FIGURE 2).

ILLUSTRATION: MARY ELLEN NIATAS FOR OBG MANAGEMENT

Continue to: How do you approach removal of a deep contraceptive implant?...

How do you approach removal of a deep contraceptive implant?

Clinicians who are not trained in deep or difficult implant removal should refer patients to a trained provider (eg, a complex family planning subspecialist), or if not available, partner with a health care practitioner that has expertise in the anatomy of the upper arm (eg, vascular surgery, orthopedics, or interventional radiology). A resource for finding a nearby trained provider is the Organon Information Center (1-877-467-5266). However, when these services are not readily available, consider the following 3-step approach to complex implant removal.

1. Be familiar with the anatomy of the upper arm (FIGURE 3). Nonpalpable implants may be close to or under the biceps or triceps fascia or be near critically important and fragile structures like the neurovascular bundle of the upper arm. Prior to attempting a difficult implant removal, ensure that you are well acquainted with critical structures in the upper arm. 
2. Locate the device. Prior to attempting removal, localize the device using either x-ray or ultrasonography, depending on local availability. Ultrasound offers the advantage of mapping the location in 3 dimensions, with the ability to map the device with skin markings immediately prior to removal. Typically, a highfrequency transducer (15- or 18-MHz) is used, such as for breast imaging, either in a clinician’s office or in coordination with radiology. If device removal is attempted the same day, the proximal, midportion, and distal aspects of the device should be marked with a skin pen, and it should be noted what position the arm is in when the device is marked (eg, arm flexed at elbow and externally rotated so that the wrist is parallel to the ear). 

ILLUSTRATION: MARY ELLEN NIATAS FOR OBG MANAGEMENT

Rarely, if a device is not seen in the expected extremity, imaging of the contralateral arm or a chest x-ray can be undertaken to rule out mis-documented laterality or a migrated device. Lastly, if no device is seen, and the patient has no memory of device removal, you can obtain the patient’s etonogestrel levels. (Resource: Merck National Service Center, 1-877-888-4231.)

Removal procedure. For nonpalpable implants, strong consideration should be given to performing the procedure with ultrasonography guidance. Rarely, fluoroscopic guidance may be useful for orientation in challenging cases, which may require coordination with other services, such as interventional radiology.

Cleaning and anesthetizing the site is similar to routine removal of a palpable implant. A 2- to 3-mm skin incision is made, either at the distal end of the implant (if one end is amenable to traditional pop-out technique) or over the midportion of the device (if a clinician has experience using the “U” technique).⁶ The incision should be parallel to the long axis of the implant and not perpendicular, to facilitate extension of the incision if needed during the procedure. Straight or curved hemostat clamps can then be used for blunt dissection of the subcutaneous tissues and to grasp the end of the device. Experienced clinicians may have access to a modified vasectomy clamp (with a 2.2-mm aperture) to grasp around the device in the midportion (the “U” technique). Blunt and careful sharp dissection may be needed to free the implant from the surrounding fibrin sheath or if under the muscle fascia. At the conclusion, the device should be measured to ensure that it was completely removed (4 cm).

Indications for referral. Typically, referral to a complex family planning specialist or vascular surgeon is required for cases that involve dissection of the muscular fascia or where dissection would be in close proximity to critical neurologic or vascular structures.

CASE 1 Conclusion

Ultrasonography of the patient’s extremity demonstrated a 4-cm radiopaque implant in the deep subcutaneous tissues of the upper arm, above the fascia and overlying the triceps muscle. The patient was counseled on the risks, benefits, and alternatives to an ultrasound-guided removal, and she desired to move forward with a procedure under sedation. She was able to schedule this concurrently with her chest port placement with interventional radiology. The device was again mapped using high frequency ultrasound. Her arm was then prepped, anesthetized, and a 3-mm linear incision was made over the most superficial portion, the distal 1/3 of the length of the device. The subcutaneous tissues were dissected using a curved Hemostat, and the implant was grasped with the modified vasectomy clamp. Blunt and sharp dissection were then used to free the device from the surrounding capsule of scar tissue, and the device was removed intact.

CASE 2 Patient enquires about immediate IUD insertion

A 28-year-old patient (G1P0) arrives at your clinic for a contraceptive consultation. They report a condom break during intercourse 4 days ago. Prior to that they used condoms consistently with each act of intercourse. They have used combined hormonal contraceptive pills in the past but had difficulty remembering to take them consistently. The patient and their partner have been mutually monogamous for 6 months and have no plans for pregnancy. Last menstrual period was 12 days ago. Their cycles are regular but heavy and painful. They are interested in using a hormonal IUD for contraception and would love to get it today.

Continue to: Is same-day IUD an option?...

Yes. This patient needs EC given the recent condom break, but they are still eligible for having an IUD placed today if their pregnancy test is negative and after counseling of the potential risks and benefits. According to the US-SPR it is reasonable to insert an IUD at any time during the cycle as long as you are reasonably certain the patient is not pregnant.⁷

Options for EC are:

• 1.5-mg oral LNG pill
• 30-mg oral UPA pill
• copper IUD (cu-IUD).

If they are interested in the cu-IUD for long-term contraception, by having a cu-IUD placed they can get both their needs met—EC and an ongoing method of contraception. Any patient receiving EC, whether a pill or an IUD, should be counseled to repeat a home urine pregnancy test in 2 to 4 weeks.

Given the favorable non–contraceptive benefits associated with 52-mg LNG-IUDs, many clinicians and patients have advocated for additional evidence regarding the use of hormonal IUDs alone for EC.

What is the evidence concerning LNG-IUD placement as EC?

The 52-mg LNG-IUD has not been mechanistically proven to work as an EC, but growing evidence exists showing that it is safe for same-day or “quick start” placement even in a population seeking EC—if their pregnancy test result is negative at the time of presentation.

Turok and colleagues performed a noninferiority trial comparing 1-month pregnancy rates after placement of either an LNG-IUD or a cu-IUD for EC.⁸ This study concluded that the LNG-IUD (which resulted in 1 pregnancy in 317 users; pregnancy rate, 0.3%; 95% confidence interval [CI], 0.01–1.70) is noninferior to cu-IUD (0 pregnancies in 321 users; pregnancy rate, 0%; 95% CI, 0.0–1.1) for EC. Although encouraging, only a small percentage of the study population seeking EC who received an IUD were actually at high risk of pregnancy (eg, they were not mid-cycle or were recently using contraception), which is why it is difficult to determine if the LNG-IUD actually works mechanistically as an EC. More likely, the LNG-IUD helps prevent pregnancy due to its ongoing contraceptive effect.⁹ Ongoing acts of intercourse post–oral EC initiation without starting a method of contraception is one of the main reasons for EC failure, which is why starting a method immediately is so effective at preventing pregnancy.¹⁰

A systematic review conducted by Ramanadhan and colleagues concluded that Turok’s 2021 trial is the only relevant study specific to 52-mg LNG-IUD use as EC, but they also mention that its results are limited in the strength of its conclusions due to biases in randomization, including¹¹:

• the study groups were not balanced in that there was a 10% difference in reported use of contraception at last intercourse, which means that the LNG-IUD group had a lower baseline risk of pregnancy
• and a rare primary outcome (ie, pregnancy, which requires a larger sample size to know if the method works as an EC).

The review authors concluded that more studies are needed to further validate the effectiveness of using the 52-mg LNG-IUD as EC. Thus, for those at highest risk of pregnancy from recent unprotected sex and desiring a 52-mg IUD, it is probably best to continue combining oral EC with a 52-mg LNG-IUD and utilizing the LNG-IUD only as EC on a limited, case-by-case basis.

What we recommend

For anyone with a negative pregnancy test on the day of presentation, the studies mentioned further support the practice of same-day placement of a 52-mg LNG-IUD. However, those seeking EC who are at highest risk for an unplanned pregnancy (ie, the unprotected sex was mid-cycle), we recommend co-administering the LNG-IUD with oral LNG for EC.

CASE 2 Conclusion

After a conversation with the patient about all contraceptive options, through shared decision making the patient decided to take 1.5 mg of oral LNG and have a 52-mg LNG-IUD placed in the office today. They do not wish to be pregnant at this time and would choose termination if they became pregnant. They understood their pregnancy risk and opted to plan a urine pregnancy test at home in 2 weeks with a clear understanding that they should return to clinic immediately if the test is positive. ●

Individuals spend close to half of their lives preventing, or planning for, pregnancy. As such, contraception plays a major role in patient-provider interactions. Contraception counseling and management is a common scenario encountered in the general gynecologist’s practice. Luckily, we have 2 evidence-based guidelines developed by the US Centers for Disease Control and Prevention (CDC) that support the provision of contraceptive care:

1. US Medical Eligibility for Contraceptive Use (US-MEC),¹ which provides guidance on which patients can safely use a method
2. US Selected Practice Recommendations for Contraceptive Use (US-SPR),² which provides method-specific guidance on how to use a method (including how to: initiate or start a method; manage adherence issues, such as a missed pill, etc; and manage common issues like breakthrough bleeding). 

Both of these guidelines are updated routinely and are publicly available online or for free, through smartphone applications.

While most contraceptive care is straightforward, there are circumstances that require additional consideration. In the concluding part of this series on contraceptive conundrums, we review 2 clinical cases, existing evidence to guide management decisions, and our recommendations.

CASE 1 Patient presents with hard-to-remove implant

A 44-year-old patient (G2P2) with a new diagnosis of estrogen and progesterone-receptor–positive breast cancer is undergoing her evaluation with her oncologist who recommends removal of her contraceptive implant, which has been in place for 2 years. She presents to your office for removal; however, the device is no longer palpable.

What are your next steps?

Conundrum 1. Should you attempt to remove it?

No, never attempt implant removal if you cannot palpate or localize it. Localization of the implant needs to occur prior to any attempt. However, we recommend checking the contra-lateral arm before sending the patient to obtain imaging, especially if you have no formal documentation regarding in which arm the implant was placed. The next step is identifying what type of implant the patient likely has so you can correctly interpret imaging studies.

Conundrum 2. What type of subdermal contraceptive device is it likely to be?

Currently, the only subdermal contraceptive device available for placement in the United States is the 68-mg etonogestrel implant, marketed with the brand name Nexplanon. This device was initially approved by the US Food and Drug Administration in 2001 and measures 4 cm in length by 2 mm in diameter. It is placed in the medial upper arm, about 8 cm proximal to the medial epicondyle and 3 cm posterior to the sulcus between the biceps and triceps muscles. (The implant should no longer be placed over the bicipital groove.) The implant is impregnated with 15 mg of barium sulfate, making it radiopaque and able to be seen on imaging modalities such as ultrasonography (10–18 mHz high frequency transducer) and x-ray (arm anteroposterior and lateral) for localization in cases in which the device becomes nonpalpable.³

Clinicians also may encounter devices which are no longer marketed in the United States, or which are only available in other countries, and thus should be aware of the appearance and imaging characteristics. It is important to let your imaging team know these characteristics as well:

• From 2006–2010, a 68-mg etonogestrel implant marketed under the name Implanon was available in the United States.⁴ It has the same dimensions and general placement recommendations as the Nexplanon etonogestrel device but is not able to be seen via imaging.
• A 2-arm, 75-mg levonorgestrel (LNG) device known as Jadelle (or, Norplant II; FIGURE 1) received FDA approval in 1996 and is currently only available overseas.⁵ It is also placed in the upper, inner arm in a V-shape using a single incision, and has dimensions similar to the etonogestrel implants.
• From 1990– 2002, the 6-rod device known as Norplant was available in the United States. Each rod measured 3.4 cm in length and contained 36 mg of LNG (FIGURE 2).

ILLUSTRATION: MARY ELLEN NIATAS FOR OBG MANAGEMENT

Continue to: How do you approach removal of a deep contraceptive implant?...

How do you approach removal of a deep contraceptive implant?

Clinicians who are not trained in deep or difficult implant removal should refer patients to a trained provider (eg, a complex family planning subspecialist), or if not available, partner with a health care practitioner that has expertise in the anatomy of the upper arm (eg, vascular surgery, orthopedics, or interventional radiology). A resource for finding a nearby trained provider is the Organon Information Center (1-877-467-5266). However, when these services are not readily available, consider the following 3-step approach to complex implant removal.

1. Be familiar with the anatomy of the upper arm (FIGURE 3). Nonpalpable implants may be close to or under the biceps or triceps fascia or be near critically important and fragile structures like the neurovascular bundle of the upper arm. Prior to attempting a difficult implant removal, ensure that you are well acquainted with critical structures in the upper arm. 
2. Locate the device. Prior to attempting removal, localize the device using either x-ray or ultrasonography, depending on local availability. Ultrasound offers the advantage of mapping the location in 3 dimensions, with the ability to map the device with skin markings immediately prior to removal. Typically, a highfrequency transducer (15- or 18-MHz) is used, such as for breast imaging, either in a clinician’s office or in coordination with radiology. If device removal is attempted the same day, the proximal, midportion, and distal aspects of the device should be marked with a skin pen, and it should be noted what position the arm is in when the device is marked (eg, arm flexed at elbow and externally rotated so that the wrist is parallel to the ear). 

ILLUSTRATION: MARY ELLEN NIATAS FOR OBG MANAGEMENT

Rarely, if a device is not seen in the expected extremity, imaging of the contralateral arm or a chest x-ray can be undertaken to rule out mis-documented laterality or a migrated device. Lastly, if no device is seen, and the patient has no memory of device removal, you can obtain the patient’s etonogestrel levels. (Resource: Merck National Service Center, 1-877-888-4231.)

Removal procedure. For nonpalpable implants, strong consideration should be given to performing the procedure with ultrasonography guidance. Rarely, fluoroscopic guidance may be useful for orientation in challenging cases, which may require coordination with other services, such as interventional radiology.

Cleaning and anesthetizing the site is similar to routine removal of a palpable implant. A 2- to 3-mm skin incision is made, either at the distal end of the implant (if one end is amenable to traditional pop-out technique) or over the midportion of the device (if a clinician has experience using the “U” technique).⁶ The incision should be parallel to the long axis of the implant and not perpendicular, to facilitate extension of the incision if needed during the procedure. Straight or curved hemostat clamps can then be used for blunt dissection of the subcutaneous tissues and to grasp the end of the device. Experienced clinicians may have access to a modified vasectomy clamp (with a 2.2-mm aperture) to grasp around the device in the midportion (the “U” technique). Blunt and careful sharp dissection may be needed to free the implant from the surrounding fibrin sheath or if under the muscle fascia. At the conclusion, the device should be measured to ensure that it was completely removed (4 cm).

Indications for referral. Typically, referral to a complex family planning specialist or vascular surgeon is required for cases that involve dissection of the muscular fascia or where dissection would be in close proximity to critical neurologic or vascular structures.

CASE 1 Conclusion

Ultrasonography of the patient’s extremity demonstrated a 4-cm radiopaque implant in the deep subcutaneous tissues of the upper arm, above the fascia and overlying the triceps muscle. The patient was counseled on the risks, benefits, and alternatives to an ultrasound-guided removal, and she desired to move forward with a procedure under sedation. She was able to schedule this concurrently with her chest port placement with interventional radiology. The device was again mapped using high frequency ultrasound. Her arm was then prepped, anesthetized, and a 3-mm linear incision was made over the most superficial portion, the distal 1/3 of the length of the device. The subcutaneous tissues were dissected using a curved Hemostat, and the implant was grasped with the modified vasectomy clamp. Blunt and sharp dissection were then used to free the device from the surrounding capsule of scar tissue, and the device was removed intact.

CASE 2 Patient enquires about immediate IUD insertion

A 28-year-old patient (G1P0) arrives at your clinic for a contraceptive consultation. They report a condom break during intercourse 4 days ago. Prior to that they used condoms consistently with each act of intercourse. They have used combined hormonal contraceptive pills in the past but had difficulty remembering to take them consistently. The patient and their partner have been mutually monogamous for 6 months and have no plans for pregnancy. Last menstrual period was 12 days ago. Their cycles are regular but heavy and painful. They are interested in using a hormonal IUD for contraception and would love to get it today.

Continue to: Is same-day IUD an option?...

Yes. This patient needs EC given the recent condom break, but they are still eligible for having an IUD placed today if their pregnancy test is negative and after counseling of the potential risks and benefits. According to the US-SPR it is reasonable to insert an IUD at any time during the cycle as long as you are reasonably certain the patient is not pregnant.⁷

Options for EC are:

• 1.5-mg oral LNG pill
• 30-mg oral UPA pill
• copper IUD (cu-IUD).

If they are interested in the cu-IUD for long-term contraception, by having a cu-IUD placed they can get both their needs met—EC and an ongoing method of contraception. Any patient receiving EC, whether a pill or an IUD, should be counseled to repeat a home urine pregnancy test in 2 to 4 weeks.

Given the favorable non–contraceptive benefits associated with 52-mg LNG-IUDs, many clinicians and patients have advocated for additional evidence regarding the use of hormonal IUDs alone for EC.

What is the evidence concerning LNG-IUD placement as EC?

The 52-mg LNG-IUD has not been mechanistically proven to work as an EC, but growing evidence exists showing that it is safe for same-day or “quick start” placement even in a population seeking EC—if their pregnancy test result is negative at the time of presentation.

Turok and colleagues performed a noninferiority trial comparing 1-month pregnancy rates after placement of either an LNG-IUD or a cu-IUD for EC.⁸ This study concluded that the LNG-IUD (which resulted in 1 pregnancy in 317 users; pregnancy rate, 0.3%; 95% confidence interval [CI], 0.01–1.70) is noninferior to cu-IUD (0 pregnancies in 321 users; pregnancy rate, 0%; 95% CI, 0.0–1.1) for EC. Although encouraging, only a small percentage of the study population seeking EC who received an IUD were actually at high risk of pregnancy (eg, they were not mid-cycle or were recently using contraception), which is why it is difficult to determine if the LNG-IUD actually works mechanistically as an EC. More likely, the LNG-IUD helps prevent pregnancy due to its ongoing contraceptive effect.⁹ Ongoing acts of intercourse post–oral EC initiation without starting a method of contraception is one of the main reasons for EC failure, which is why starting a method immediately is so effective at preventing pregnancy.¹⁰

A systematic review conducted by Ramanadhan and colleagues concluded that Turok’s 2021 trial is the only relevant study specific to 52-mg LNG-IUD use as EC, but they also mention that its results are limited in the strength of its conclusions due to biases in randomization, including¹¹:

• the study groups were not balanced in that there was a 10% difference in reported use of contraception at last intercourse, which means that the LNG-IUD group had a lower baseline risk of pregnancy
• and a rare primary outcome (ie, pregnancy, which requires a larger sample size to know if the method works as an EC).

The review authors concluded that more studies are needed to further validate the effectiveness of using the 52-mg LNG-IUD as EC. Thus, for those at highest risk of pregnancy from recent unprotected sex and desiring a 52-mg IUD, it is probably best to continue combining oral EC with a 52-mg LNG-IUD and utilizing the LNG-IUD only as EC on a limited, case-by-case basis.

What we recommend

For anyone with a negative pregnancy test on the day of presentation, the studies mentioned further support the practice of same-day placement of a 52-mg LNG-IUD. However, those seeking EC who are at highest risk for an unplanned pregnancy (ie, the unprotected sex was mid-cycle), we recommend co-administering the LNG-IUD with oral LNG for EC.

CASE 2 Conclusion

After a conversation with the patient about all contraceptive options, through shared decision making the patient decided to take 1.5 mg of oral LNG and have a 52-mg LNG-IUD placed in the office today. They do not wish to be pregnant at this time and would choose termination if they became pregnant. They understood their pregnancy risk and opted to plan a urine pregnancy test at home in 2 weeks with a clear understanding that they should return to clinic immediately if the test is positive. ●

Individuals spend close to half of their lives preventing, or planning for, pregnancy. As such, contraception plays a major role in patient-provider interactions. Contraception counseling and management is a common scenario encountered in the general gynecologist’s practice. Luckily, we have 2 evidence-based guidelines developed by the US Centers for Disease Control and Prevention (CDC) that support the provision of contraceptive care:

1. US Medical Eligibility for Contraceptive Use (US-MEC),¹ which provides guidance on which patients can safely use a method
2. US Selected Practice Recommendations for Contraceptive Use (US-SPR),² which provides method-specific guidance on how to use a method (including how to: initiate or start a method; manage adherence issues, such as a missed pill, etc; and manage common issues like breakthrough bleeding). 

Both of these guidelines are updated routinely and are publicly available online or for free, through smartphone applications.

While most contraceptive care is straightforward, there are circumstances that require additional consideration. In the concluding part of this series on contraceptive conundrums, we review 2 clinical cases, existing evidence to guide management decisions, and our recommendations.

CASE 1 Patient presents with hard-to-remove implant

A 44-year-old patient (G2P2) with a new diagnosis of estrogen and progesterone-receptor–positive breast cancer is undergoing her evaluation with her oncologist who recommends removal of her contraceptive implant, which has been in place for 2 years. She presents to your office for removal; however, the device is no longer palpable.

What are your next steps?

Conundrum 1. Should you attempt to remove it?

No, never attempt implant removal if you cannot palpate or localize it. Localization of the implant needs to occur prior to any attempt. However, we recommend checking the contra-lateral arm before sending the patient to obtain imaging, especially if you have no formal documentation regarding in which arm the implant was placed. The next step is identifying what type of implant the patient likely has so you can correctly interpret imaging studies.

Conundrum 2. What type of subdermal contraceptive device is it likely to be?

Currently, the only subdermal contraceptive device available for placement in the United States is the 68-mg etonogestrel implant, marketed with the brand name Nexplanon. This device was initially approved by the US Food and Drug Administration in 2001 and measures 4 cm in length by 2 mm in diameter. It is placed in the medial upper arm, about 8 cm proximal to the medial epicondyle and 3 cm posterior to the sulcus between the biceps and triceps muscles. (The implant should no longer be placed over the bicipital groove.) The implant is impregnated with 15 mg of barium sulfate, making it radiopaque and able to be seen on imaging modalities such as ultrasonography (10–18 mHz high frequency transducer) and x-ray (arm anteroposterior and lateral) for localization in cases in which the device becomes nonpalpable.³

Clinicians also may encounter devices which are no longer marketed in the United States, or which are only available in other countries, and thus should be aware of the appearance and imaging characteristics. It is important to let your imaging team know these characteristics as well:

• From 2006–2010, a 68-mg etonogestrel implant marketed under the name Implanon was available in the United States.⁴ It has the same dimensions and general placement recommendations as the Nexplanon etonogestrel device but is not able to be seen via imaging.
• A 2-arm, 75-mg levonorgestrel (LNG) device known as Jadelle (or, Norplant II; FIGURE 1) received FDA approval in 1996 and is currently only available overseas.⁵ It is also placed in the upper, inner arm in a V-shape using a single incision, and has dimensions similar to the etonogestrel implants.
• From 1990– 2002, the 6-rod device known as Norplant was available in the United States. Each rod measured 3.4 cm in length and contained 36 mg of LNG (FIGURE 2).

ILLUSTRATION: MARY ELLEN NIATAS FOR OBG MANAGEMENT

Continue to: How do you approach removal of a deep contraceptive implant?...

How do you approach removal of a deep contraceptive implant?

Clinicians who are not trained in deep or difficult implant removal should refer patients to a trained provider (eg, a complex family planning subspecialist), or if not available, partner with a health care practitioner that has expertise in the anatomy of the upper arm (eg, vascular surgery, orthopedics, or interventional radiology). A resource for finding a nearby trained provider is the Organon Information Center (1-877-467-5266). However, when these services are not readily available, consider the following 3-step approach to complex implant removal.

1. Be familiar with the anatomy of the upper arm (FIGURE 3). Nonpalpable implants may be close to or under the biceps or triceps fascia or be near critically important and fragile structures like the neurovascular bundle of the upper arm. Prior to attempting a difficult implant removal, ensure that you are well acquainted with critical structures in the upper arm. 
2. Locate the device. Prior to attempting removal, localize the device using either x-ray or ultrasonography, depending on local availability. Ultrasound offers the advantage of mapping the location in 3 dimensions, with the ability to map the device with skin markings immediately prior to removal. Typically, a highfrequency transducer (15- or 18-MHz) is used, such as for breast imaging, either in a clinician’s office or in coordination with radiology. If device removal is attempted the same day, the proximal, midportion, and distal aspects of the device should be marked with a skin pen, and it should be noted what position the arm is in when the device is marked (eg, arm flexed at elbow and externally rotated so that the wrist is parallel to the ear). 

ILLUSTRATION: MARY ELLEN NIATAS FOR OBG MANAGEMENT

Rarely, if a device is not seen in the expected extremity, imaging of the contralateral arm or a chest x-ray can be undertaken to rule out mis-documented laterality or a migrated device. Lastly, if no device is seen, and the patient has no memory of device removal, you can obtain the patient’s etonogestrel levels. (Resource: Merck National Service Center, 1-877-888-4231.)

Removal procedure. For nonpalpable implants, strong consideration should be given to performing the procedure with ultrasonography guidance. Rarely, fluoroscopic guidance may be useful for orientation in challenging cases, which may require coordination with other services, such as interventional radiology.

Cleaning and anesthetizing the site is similar to routine removal of a palpable implant. A 2- to 3-mm skin incision is made, either at the distal end of the implant (if one end is amenable to traditional pop-out technique) or over the midportion of the device (if a clinician has experience using the “U” technique).⁶ The incision should be parallel to the long axis of the implant and not perpendicular, to facilitate extension of the incision if needed during the procedure. Straight or curved hemostat clamps can then be used for blunt dissection of the subcutaneous tissues and to grasp the end of the device. Experienced clinicians may have access to a modified vasectomy clamp (with a 2.2-mm aperture) to grasp around the device in the midportion (the “U” technique). Blunt and careful sharp dissection may be needed to free the implant from the surrounding fibrin sheath or if under the muscle fascia. At the conclusion, the device should be measured to ensure that it was completely removed (4 cm).

Indications for referral. Typically, referral to a complex family planning specialist or vascular surgeon is required for cases that involve dissection of the muscular fascia or where dissection would be in close proximity to critical neurologic or vascular structures.

CASE 1 Conclusion

Ultrasonography of the patient’s extremity demonstrated a 4-cm radiopaque implant in the deep subcutaneous tissues of the upper arm, above the fascia and overlying the triceps muscle. The patient was counseled on the risks, benefits, and alternatives to an ultrasound-guided removal, and she desired to move forward with a procedure under sedation. She was able to schedule this concurrently with her chest port placement with interventional radiology. The device was again mapped using high frequency ultrasound. Her arm was then prepped, anesthetized, and a 3-mm linear incision was made over the most superficial portion, the distal 1/3 of the length of the device. The subcutaneous tissues were dissected using a curved Hemostat, and the implant was grasped with the modified vasectomy clamp. Blunt and sharp dissection were then used to free the device from the surrounding capsule of scar tissue, and the device was removed intact.

CASE 2 Patient enquires about immediate IUD insertion

A 28-year-old patient (G1P0) arrives at your clinic for a contraceptive consultation. They report a condom break during intercourse 4 days ago. Prior to that they used condoms consistently with each act of intercourse. They have used combined hormonal contraceptive pills in the past but had difficulty remembering to take them consistently. The patient and their partner have been mutually monogamous for 6 months and have no plans for pregnancy. Last menstrual period was 12 days ago. Their cycles are regular but heavy and painful. They are interested in using a hormonal IUD for contraception and would love to get it today.

Continue to: Is same-day IUD an option?...

Yes. This patient needs EC given the recent condom break, but they are still eligible for having an IUD placed today if their pregnancy test is negative and after counseling of the potential risks and benefits. According to the US-SPR it is reasonable to insert an IUD at any time during the cycle as long as you are reasonably certain the patient is not pregnant.⁷

Options for EC are:

• 1.5-mg oral LNG pill
• 30-mg oral UPA pill
• copper IUD (cu-IUD).

If they are interested in the cu-IUD for long-term contraception, by having a cu-IUD placed they can get both their needs met—EC and an ongoing method of contraception. Any patient receiving EC, whether a pill or an IUD, should be counseled to repeat a home urine pregnancy test in 2 to 4 weeks.

Given the favorable non–contraceptive benefits associated with 52-mg LNG-IUDs, many clinicians and patients have advocated for additional evidence regarding the use of hormonal IUDs alone for EC.

What is the evidence concerning LNG-IUD placement as EC?

The 52-mg LNG-IUD has not been mechanistically proven to work as an EC, but growing evidence exists showing that it is safe for same-day or “quick start” placement even in a population seeking EC—if their pregnancy test result is negative at the time of presentation.

Turok and colleagues performed a noninferiority trial comparing 1-month pregnancy rates after placement of either an LNG-IUD or a cu-IUD for EC.⁸ This study concluded that the LNG-IUD (which resulted in 1 pregnancy in 317 users; pregnancy rate, 0.3%; 95% confidence interval [CI], 0.01–1.70) is noninferior to cu-IUD (0 pregnancies in 321 users; pregnancy rate, 0%; 95% CI, 0.0–1.1) for EC. Although encouraging, only a small percentage of the study population seeking EC who received an IUD were actually at high risk of pregnancy (eg, they were not mid-cycle or were recently using contraception), which is why it is difficult to determine if the LNG-IUD actually works mechanistically as an EC. More likely, the LNG-IUD helps prevent pregnancy due to its ongoing contraceptive effect.⁹ Ongoing acts of intercourse post–oral EC initiation without starting a method of contraception is one of the main reasons for EC failure, which is why starting a method immediately is so effective at preventing pregnancy.¹⁰

A systematic review conducted by Ramanadhan and colleagues concluded that Turok’s 2021 trial is the only relevant study specific to 52-mg LNG-IUD use as EC, but they also mention that its results are limited in the strength of its conclusions due to biases in randomization, including¹¹:

• the study groups were not balanced in that there was a 10% difference in reported use of contraception at last intercourse, which means that the LNG-IUD group had a lower baseline risk of pregnancy
• and a rare primary outcome (ie, pregnancy, which requires a larger sample size to know if the method works as an EC).

The review authors concluded that more studies are needed to further validate the effectiveness of using the 52-mg LNG-IUD as EC. Thus, for those at highest risk of pregnancy from recent unprotected sex and desiring a 52-mg IUD, it is probably best to continue combining oral EC with a 52-mg LNG-IUD and utilizing the LNG-IUD only as EC on a limited, case-by-case basis.

What we recommend

For anyone with a negative pregnancy test on the day of presentation, the studies mentioned further support the practice of same-day placement of a 52-mg LNG-IUD. However, those seeking EC who are at highest risk for an unplanned pregnancy (ie, the unprotected sex was mid-cycle), we recommend co-administering the LNG-IUD with oral LNG for EC.

CASE 2 Conclusion

After a conversation with the patient about all contraceptive options, through shared decision making the patient decided to take 1.5 mg of oral LNG and have a 52-mg LNG-IUD placed in the office today. They do not wish to be pregnant at this time and would choose termination if they became pregnant. They understood their pregnancy risk and opted to plan a urine pregnancy test at home in 2 weeks with a clear understanding that they should return to clinic immediately if the test is positive. ●

Cutaneous malignant melanoma represents an aggressive form of skin cancer, with 132,000 new cases of melanoma and 50,000 melanoma-related deaths diagnosed worldwide each year.¹ In recent decades, major progress has been made in the treatment of melanoma, especially metastatic and advanced-stage disease. Approval of new treatments, such as immunotherapy with anti–PD-1 (pembrolizumab and nivolumab) and anti–CTLA-4 (ipilimumab) antibodies, has revolutionized therapeutic strategies (Figure 1). Molecularly, melanoma has the highest mutational burden among solid tumors. Approximately 40% of melanomas harbor the BRAF V600 mutation, leading to constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway.² The other described genomic subtypes are mutated RAS (accounting for approximately 28% of cases), mutated NF1 (approximately 14% of cases), and triple wild type, though these other subtypes have not been as successfully targeted with therapy to date.³ Dual inhibition of this pathway using combination therapy with BRAF and MEK inhibitors confers high response rates and survival benefit, though efficacy in metastatic patients often is limited by development of resistance. The US Food and Drug Administration (FDA) has approved 3 combinations of targeted therapy in unresectable tumors: dabrafenib and trametinib, vemurafenib and cobimetinib, and encorafenib and binimetinib. The oncolytic herpesvirus talimogene laherparepvec also has received FDA approval for local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with recurrent melanoma after initial surgery.²

In this review, we explore new therapeutic agents and novel combinations that are being tested in early-phase clinical trials (Table). We discuss newer promising tools such as nanotechnology to develop nanosystems that act as drug carriers and/or light absorbents to potentially improve therapy outcomes. Finally, we highlight challenges such as management after resistance and intervention with novel immunotherapies and the lack of predictive biomarkers to stratify patients to targeted treatments after primary treatment failure.

Targeted Therapies

Vemurafenib was approved by the FDA in 2011 and was the first BRAF-targeted therapy approved for the treatment of melanoma based on a 48% response rate and a 63% reduction in the risk for death vs dacarbazine chemotherapy.⁴ Despite a rapid and clinically significant initial response, progression-free survival (PFS) was only 5.3 months, which is indicative of the rapid development of resistance with monotherapy through MAPK reactivation. As a result, combined BRAF and MEK inhibition was introduced and is now the standard of care for targeted therapy in melanoma. Treatment with dabrafenib and trametinib, vemurafenib and cobimetinib, or encorafenib and binimetinib is associated with prolonged PFS and overall survival (OS) compared to BRAF inhibitor monotherapy, with response rates exceeding 60% and a complete response rate of 10% to 18%.⁵ Recently, combining atezolizumab with vemurafenib and cobimetinib was shown to improve PFS compared to combined targeted therapy.⁶ Targeted therapy usually is given as first-line treatment to symptomatic patients with a high tumor burden because the response may be more rapid than the response to immunotherapy. Ultimately, most patients with advanced BRAF-mutated melanoma receive both targeted therapy and immunotherapy.

Mutations of KIT (encoding proto-oncogene receptor tyrosine kinase) activate intracellular MAPK and phosphatidylinositol 3-kinase (PI3K) pathways (Figure 2).⁷ KIT mutations are found in mucosal and acral melanomas as well as chronically sun-damaged skin, with frequencies of 39%, 36%, and 28%, respectively. Imatinib was associated with a 53% response rate and PFS of 3.9 months among patients with KIT-mutated melanoma but failed to cause regression in melanomas with KIT amplification.⁸

Anti–CTLA-4 Immune Checkpoint Inhibition

CTLA-4 is a protein found on T cells that binds with another protein, B7, preventing T cells from killing cancer cells. Hence, blockade of CTLA-4 antibody avoids the immunosuppressive state of lymphocytes, strengthening their antitumor action.⁹ Ipilimumab, an anti–CTLA-4 antibody, demonstrated improvement in median OS for management of unresectable or metastatic stage IV melanoma, resulting in its FDA approval.⁸ A combination of ipilimumab with dacarbazine in stage IV melanoma showed notable improvement of OS.¹⁰ Similarly, tremelimumab showed evidence of tumor regression in a phase 1 trial but with more severe immune-related side effects compared with ipilimumab.¹¹ A second study on patients with stage IV melanoma treated with tremelimumab as first-line therapy in comparison with dacarbazine demonstrated differences in OS that were not statistically significant, though there was a longer duration of an objective response in patients treated with tremelimumab (35.8 months) compared with patients responding to dacarbazine (13.7 months).¹²

Anti–PD-1 Immune Checkpoint Inhibition

PD-1 is a transmembrane protein with immunoreceptor tyrosine-based inhibitory signaling, identified as an apoptosis-associated molecule.¹³ Upon activation, it is expressed on the cell surface of CD4, CD8, B lymphocytes, natural killer cells, monocytes, and dendritic cells.¹⁴ PD-L1, the ligand of PD-1, is constitutively expressed on different hematopoietic cells, as well as on fibroblasts, endothelial cells, mesenchymal cells, neurons, and keratinocytes.^15,16 Reactivation of effector T lymphocytes by PD-1:PD-L1 pathway inhibition has shown clinically significant therapeutic relevance.¹⁷ The PD-1:PD-L1 interaction is active only in the presence of T- or B-cell antigen receptor cross-link. This interaction prevents PI3K/AKT signaling and MAPK/extracellular signal-regulated kinase pathway activation with the net result of lymphocytic functional exhaustion.^18,19 PD-L1 blockade is shown to have better clinical benefit and minor toxicity compared to anti–CTLA-4 therapy. Treatment with anti-PD1 nivolumab in a phase 1b clinical trial (N=107) demonstrated highly specific action, durable tumor remission, and long-term safety in 32% of patients with advanced melanoma.²⁰ These promising results led to the FDA approval of nivolumab for the treatment of patients with advanced and unresponsive melanoma. A recent clinical trial combining ipilimumab and nivolumab resulted in an impressive increase of PFS compared with ipilimumab monotherapy (11.5 months vs 2.9 months).²¹ Similarly, treatment with pembrolizumab in advanced melanoma demonstrated improvement in PFS and OS compared with anti–CTLA-4 therapy,^22,23 which resulted in FDA approval of pembrolizumab for the treatment of advanced melanoma in patients previously treated with ipilimumab or BRAF inhibitors in BRAF V600 mutation–positive patients.²⁴

Lymphocyte-Activated Gene 3–Targeted Therapies

Lymphocyte-activated gene 3 (LAG-3)(also known as CD223 or FDC protein) is a type of immune checkpoint receptor transmembrane protein that is located on chromosome 12.²⁵ It is present on the surface of effector T cells and regulatory T cells that regulate the adaptive immune response.²⁶ Lymphocyte-activated gene 3 is reported to be highly expressed on the surface of tumor-infiltrating lymphocytes, thus the level of LAG-3 expression was found to corelate with the prognosis of tumors. In some tumors involving the kidneys, lungs, and bladder, a high level of LAG-3 was associated with a worse prognosis; in gastric carcinoma and melanoma, a high level of LAG-3 indicates better prognosis.²⁷ Similar to PD-1, LAG-3 also is found to be an inhibitory checkpoint that contributes to decreased T cells. Therefore, antibodies targeting LAG-3 have been gaining interest as modalities in cancer immunotherapy. The initial clinical trials employing only LAG-3 antibody on solid tumors found an objective response rate and disease control rate of 6% and 17%, respectively.^25,26,28 Given the unsatisfactory results, the idea that combination therapy with an anti–PD-L1 drug and LAG-3 antibody started gaining attention. A randomized, double-blind clinical trial, RELATIVITY-047, studying the effects of a combination of relatlimab (a first-in-class LAG-3 antibody) and nivolumab (an anti–PD-L1 antibody) on melanoma found longer PFS (10.1 months vs 4.6 months) and a 25% lower risk for disease progression or death with the combination of relatlimab and nivolumab vs nivolumab alone.²⁸ The FDA approved the combination of relatlimab and nivolumab for individuals aged 12 years or older with previously untreated melanoma that is surgically unresectable or has metastasized.²⁹ Zhao et al³⁰ demonstrated that LAG-3/PD-1 and CTLA-4/PD-1 inhibition showed similar PFS, and LAG-3/PD-1 inhibition showed earlier survival benefit and fewer treatment-related adverse effects, with grade 3 or 4 treatment-related adverse effects occurring in 18.9% of patients on anti–LAG-3 and anti–PD-1 combination (relatlimab plus nivolumab) compared with 55.0% in patients treated with anti–CTL-4 and anti–PD-1 combination (ipilimumab plus nivolumab)(N=1344). Further studies are warranted to understand the exact mechanism of LAG-3 signaling pathways, effects of its inhibition and efficacy, and adverse events associated with its combined use with anti–PD-1 drugs.

The use of nanotechnology represents one of the newer alternative therapies employed for treatment of melanoma and is especially gaining interest due to reduced adverse effects in comparison with other conventional treatments for melanoma. Nanotechnology-based drug delivery systems precisely target tumor cells and improve the effect of both the conventional and innovative antineoplastic treatment.^27,31 Tumor vasculature differs from normal tissues by being discontinuous and having interspersed small gaps/holes that allow nanoparticles to exit the circulation and enter and accumulate in the tumor tissue, leading to enhanced and targeted release of the antineoplastic drug to tumor cells.³² This mechanism is called the enhanced permeability and retention effect.³³

Another mechanism by which nanoparticles work is ligand-based targeting in which ligands such as monoclonal antibodies, peptides, and nucleic acids located on the surface of nanoparticles can bind to receptors on the plasma membrane of tumor cells and lead to targeted delivery of the drug.³⁴ Nanomaterials used for melanoma treatment include vesicular systems such as liposomes and niosomes, polymeric nanoparticles, noble metal-based nanoparticles, carbon nanotubes, dendrimers, solid lipid nanoparticles and nanostructures, lipid carriers, and microneedles. In melanoma, nanoparticles can be used to enhance targeted delivery of drugs, including immune checkpoint inhibitors (ICIs). Cai et al³⁵ described usage of scaffolds in delivery systems. Tumor-associated antigens, adjuvant drugs, and chemical agents that influence the tumor microenvironment can be loaded onto these scaffolding agents. In a study by Zhu et al,³⁶ photosensitizer chlorin e6 and immunoadjuvant aluminum hydroxide were used as a novel nanosystem that effectively destroyed tumor cells and induced a strong systemic antitumor response. IL-2 is a cytokine produced by B or T lymphocytes. Its use in melanoma has been limited by a severe adverse effect profile and lack of complete response in most patients. Cytokine-containing nanogels have been found to selectively release IL-2 in response to activation of T-cell receptors, and a mouse model in melanoma showed better response compared to free IL-1 and no adverse systemic effects.³⁷

Nanovaccines represent another interesting novel immunotherapy modality. A study by Conniot et al³⁸ showed that nanoparticles can be used in the treatment of melanoma. Nanoparticles made of biodegradable polymer were loaded with Melan-A/MART-1 (26–35 A27L) MHC class I-restricted peptide (MHC class I antigen), and the limited peptide MHC class II Melan-A/MART-1 51–73 (MHC class II antigen) and grafted with mannose that was then combined with an anti–PD-L1 antibody and injected into mouse models. This combination resulted in T-cell infiltration at early stages and increased infiltration of myeloid-derived suppressor cells. Ibrutinib, a myeloid-derived suppressor cell inhibitor, was added and demonstrated marked tumor remission and prolonged survival.³⁸

Overexpression of certain microRNAs (miRNAs), especially miR-204-5p and miR-199b-5p, has been shown to inhibit growth of melanoma cells in vitro, both alone and in combination with MAPK inhibitors, but these miRNAs are easily degradable in body fluids. Lipid nanoparticles can bind these miRNAs and have been shown to inhibit tumor cell proliferation and improve efficacy of BRAF and MEK inhibitors.³⁹

Triple-Combination Therapy

Immune checkpoint inhibitors such as anti–PD-1 or anti–CTLA-4 drugs have become the standard of care in treatment of advanced melanoma. Approximately 40% to 50% of cases of melanoma harbor BRAF mutations, and patients with these mutations could benefit from BRAF and MEK inhibitors. Data from clinical trials on BRAF and MEK inhibitors even showed initial high objective response rates, but the response was short-lived, and there was frequent acquired resistance.⁴⁰ With ICIs, the major limitation was primary resistance, with only 50% of patients initially responding.⁴¹ Studies on murine models demonstrated that BRAF-mutated tumors had decreased expression of IFN-γ, tumor necrosis factor α, and CD40 ligand on CD4⁺ tumor-infiltrating lymphocytes and increased accumulation of regulatory T cells and myeloid-derived suppressor cells, leading to a protumor microenvironment. BRAF and MEK pathway inhibition were found to improve intratumoral CD4⁺ T-cell activity, leading to improved antitumor T-cell responses.⁴² Because of this enhanced immune response by BRAF and MEK inhibitors, it was hypothesized and later supported by clinical research that a combination of these targeted treatments and ICIs can have a synergistic effect, leading to increased antitumor activity.⁴³ A randomized phase 2 clinical trial (KEYNOTE-022) in which the treatment group was given pembrolizumab, dabrafenib, and trametinib and the control group was treated with dabrafenib and trametinib showed increased medial OS in the treatment group vs the control group (46.3 months vs 26.3 months) and more frequent complete response in the treatment group vs the control group (20% vs 15%).⁴⁴ In the IMspire150 phase 3 clinical trial, patients with advanced stage IIIC to IV BRAF-mutant melanoma were treated with either a triple combination of the PDL-1 inhibitor atezolizumab, vemurafenib, and cobimetinib or vemurafenib and cobimetinib. Although the objective response rate was similar in both groups, the median duration of response was longer in the triplet group compared with the doublet group (21 months vs 12.6 months). Given these results, the FDA approved the triple-combination therapy with atezolizumab, vemurafenib, and cobimetinib. Although triple-combination therapy has shown promising results, it is expected that there will be an increase in the frequency of treatment-related adverse effects. In the phase 3 COMBi-I study, patients with advanced stage IIIC to IV BRAF V600E mutant cutaneous melanoma were treated with either a combination of spartalizumab, dabrafenib, and trametinib or just dabrafenib and trametinib. Although the objective response rates were not significantly different (69% vs 64%), there was increased frequency of treatment-related adverse effects in patients receiving triple-combination therapy.⁴³ As more follow-up data come out of these ongoing clinical trials, benefits of triple-combination therapy and its adverse effect profile will be more definitely established.

Challenges and Future Perspectives

One of the major roadblocks in the treatment of melanoma is the failure of response to ICI with CTLA-4 and PD-1/PD-L1 blockade in a large patient population, which has resulted in the need for new biomarkers that can act as potential therapeutic targets. Further, the main underlying factor for both adjuvant and neoadjuvant approaches remains the selection of patients, optimizing therapeutic outcomes while minimizing the number of patients exposed to potentially toxic treatments without gaining clinical benefit. Clinical and pathological factors (eg, Breslow thickness, ulceration, the number of positive lymph nodes) play a role in stratifying patients as per risk of recurrence.⁴⁵ Similarly, peripheral blood biomarkers have been proposed as prognostic tools for high-risk stage II and III melanoma, including markers of systemic inflammation previously explored in the metastatic setting.⁴⁶ However, the use of these parameters has not been validated for clinical practice. Currently, despite promising results of BRAF and MEK inhibitors and therapeutic ICIs, as well as IL-2 or interferon alfa, treatment options in metastatic melanoma are limited because of its high heterogeneity, problematic patient stratification, and high genetic mutational rate. Recently, the role of epigenetic modifications andmiRNAs in melanoma progression and metastatic spread has been described. Silencing of CDKN2A locus and encoding for p16^INK4A and p14^ARF by DNA methylation are noted in 27% and 57% of metastatic melanomas, respectively, which enables melanoma cells to escape from growth arrest and apoptosis generated by Rb protein and p53 pathways.⁴⁷ Demethylation of these and other tumor suppressor genes with proapoptotic function (eg, RASSF1A and tumor necrosis factor–related apoptosis-inducing ligand) can restore cell death pathways, though future clinical studies in melanoma are warranted.⁴⁸

Cutaneous malignant melanoma represents an aggressive form of skin cancer, with 132,000 new cases of melanoma and 50,000 melanoma-related deaths diagnosed worldwide each year.¹ In recent decades, major progress has been made in the treatment of melanoma, especially metastatic and advanced-stage disease. Approval of new treatments, such as immunotherapy with anti–PD-1 (pembrolizumab and nivolumab) and anti–CTLA-4 (ipilimumab) antibodies, has revolutionized therapeutic strategies (Figure 1). Molecularly, melanoma has the highest mutational burden among solid tumors. Approximately 40% of melanomas harbor the BRAF V600 mutation, leading to constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway.² The other described genomic subtypes are mutated RAS (accounting for approximately 28% of cases), mutated NF1 (approximately 14% of cases), and triple wild type, though these other subtypes have not been as successfully targeted with therapy to date.³ Dual inhibition of this pathway using combination therapy with BRAF and MEK inhibitors confers high response rates and survival benefit, though efficacy in metastatic patients often is limited by development of resistance. The US Food and Drug Administration (FDA) has approved 3 combinations of targeted therapy in unresectable tumors: dabrafenib and trametinib, vemurafenib and cobimetinib, and encorafenib and binimetinib. The oncolytic herpesvirus talimogene laherparepvec also has received FDA approval for local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with recurrent melanoma after initial surgery.²

In this review, we explore new therapeutic agents and novel combinations that are being tested in early-phase clinical trials (Table). We discuss newer promising tools such as nanotechnology to develop nanosystems that act as drug carriers and/or light absorbents to potentially improve therapy outcomes. Finally, we highlight challenges such as management after resistance and intervention with novel immunotherapies and the lack of predictive biomarkers to stratify patients to targeted treatments after primary treatment failure.

Targeted Therapies

Vemurafenib was approved by the FDA in 2011 and was the first BRAF-targeted therapy approved for the treatment of melanoma based on a 48% response rate and a 63% reduction in the risk for death vs dacarbazine chemotherapy.⁴ Despite a rapid and clinically significant initial response, progression-free survival (PFS) was only 5.3 months, which is indicative of the rapid development of resistance with monotherapy through MAPK reactivation. As a result, combined BRAF and MEK inhibition was introduced and is now the standard of care for targeted therapy in melanoma. Treatment with dabrafenib and trametinib, vemurafenib and cobimetinib, or encorafenib and binimetinib is associated with prolonged PFS and overall survival (OS) compared to BRAF inhibitor monotherapy, with response rates exceeding 60% and a complete response rate of 10% to 18%.⁵ Recently, combining atezolizumab with vemurafenib and cobimetinib was shown to improve PFS compared to combined targeted therapy.⁶ Targeted therapy usually is given as first-line treatment to symptomatic patients with a high tumor burden because the response may be more rapid than the response to immunotherapy. Ultimately, most patients with advanced BRAF-mutated melanoma receive both targeted therapy and immunotherapy.

Mutations of KIT (encoding proto-oncogene receptor tyrosine kinase) activate intracellular MAPK and phosphatidylinositol 3-kinase (PI3K) pathways (Figure 2).⁷ KIT mutations are found in mucosal and acral melanomas as well as chronically sun-damaged skin, with frequencies of 39%, 36%, and 28%, respectively. Imatinib was associated with a 53% response rate and PFS of 3.9 months among patients with KIT-mutated melanoma but failed to cause regression in melanomas with KIT amplification.⁸

Anti–CTLA-4 Immune Checkpoint Inhibition

CTLA-4 is a protein found on T cells that binds with another protein, B7, preventing T cells from killing cancer cells. Hence, blockade of CTLA-4 antibody avoids the immunosuppressive state of lymphocytes, strengthening their antitumor action.⁹ Ipilimumab, an anti–CTLA-4 antibody, demonstrated improvement in median OS for management of unresectable or metastatic stage IV melanoma, resulting in its FDA approval.⁸ A combination of ipilimumab with dacarbazine in stage IV melanoma showed notable improvement of OS.¹⁰ Similarly, tremelimumab showed evidence of tumor regression in a phase 1 trial but with more severe immune-related side effects compared with ipilimumab.¹¹ A second study on patients with stage IV melanoma treated with tremelimumab as first-line therapy in comparison with dacarbazine demonstrated differences in OS that were not statistically significant, though there was a longer duration of an objective response in patients treated with tremelimumab (35.8 months) compared with patients responding to dacarbazine (13.7 months).¹²

Anti–PD-1 Immune Checkpoint Inhibition

PD-1 is a transmembrane protein with immunoreceptor tyrosine-based inhibitory signaling, identified as an apoptosis-associated molecule.¹³ Upon activation, it is expressed on the cell surface of CD4, CD8, B lymphocytes, natural killer cells, monocytes, and dendritic cells.¹⁴ PD-L1, the ligand of PD-1, is constitutively expressed on different hematopoietic cells, as well as on fibroblasts, endothelial cells, mesenchymal cells, neurons, and keratinocytes.^15,16 Reactivation of effector T lymphocytes by PD-1:PD-L1 pathway inhibition has shown clinically significant therapeutic relevance.¹⁷ The PD-1:PD-L1 interaction is active only in the presence of T- or B-cell antigen receptor cross-link. This interaction prevents PI3K/AKT signaling and MAPK/extracellular signal-regulated kinase pathway activation with the net result of lymphocytic functional exhaustion.^18,19 PD-L1 blockade is shown to have better clinical benefit and minor toxicity compared to anti–CTLA-4 therapy. Treatment with anti-PD1 nivolumab in a phase 1b clinical trial (N=107) demonstrated highly specific action, durable tumor remission, and long-term safety in 32% of patients with advanced melanoma.²⁰ These promising results led to the FDA approval of nivolumab for the treatment of patients with advanced and unresponsive melanoma. A recent clinical trial combining ipilimumab and nivolumab resulted in an impressive increase of PFS compared with ipilimumab monotherapy (11.5 months vs 2.9 months).²¹ Similarly, treatment with pembrolizumab in advanced melanoma demonstrated improvement in PFS and OS compared with anti–CTLA-4 therapy,^22,23 which resulted in FDA approval of pembrolizumab for the treatment of advanced melanoma in patients previously treated with ipilimumab or BRAF inhibitors in BRAF V600 mutation–positive patients.²⁴

Lymphocyte-Activated Gene 3–Targeted Therapies

Lymphocyte-activated gene 3 (LAG-3)(also known as CD223 or FDC protein) is a type of immune checkpoint receptor transmembrane protein that is located on chromosome 12.²⁵ It is present on the surface of effector T cells and regulatory T cells that regulate the adaptive immune response.²⁶ Lymphocyte-activated gene 3 is reported to be highly expressed on the surface of tumor-infiltrating lymphocytes, thus the level of LAG-3 expression was found to corelate with the prognosis of tumors. In some tumors involving the kidneys, lungs, and bladder, a high level of LAG-3 was associated with a worse prognosis; in gastric carcinoma and melanoma, a high level of LAG-3 indicates better prognosis.²⁷ Similar to PD-1, LAG-3 also is found to be an inhibitory checkpoint that contributes to decreased T cells. Therefore, antibodies targeting LAG-3 have been gaining interest as modalities in cancer immunotherapy. The initial clinical trials employing only LAG-3 antibody on solid tumors found an objective response rate and disease control rate of 6% and 17%, respectively.^25,26,28 Given the unsatisfactory results, the idea that combination therapy with an anti–PD-L1 drug and LAG-3 antibody started gaining attention. A randomized, double-blind clinical trial, RELATIVITY-047, studying the effects of a combination of relatlimab (a first-in-class LAG-3 antibody) and nivolumab (an anti–PD-L1 antibody) on melanoma found longer PFS (10.1 months vs 4.6 months) and a 25% lower risk for disease progression or death with the combination of relatlimab and nivolumab vs nivolumab alone.²⁸ The FDA approved the combination of relatlimab and nivolumab for individuals aged 12 years or older with previously untreated melanoma that is surgically unresectable or has metastasized.²⁹ Zhao et al³⁰ demonstrated that LAG-3/PD-1 and CTLA-4/PD-1 inhibition showed similar PFS, and LAG-3/PD-1 inhibition showed earlier survival benefit and fewer treatment-related adverse effects, with grade 3 or 4 treatment-related adverse effects occurring in 18.9% of patients on anti–LAG-3 and anti–PD-1 combination (relatlimab plus nivolumab) compared with 55.0% in patients treated with anti–CTL-4 and anti–PD-1 combination (ipilimumab plus nivolumab)(N=1344). Further studies are warranted to understand the exact mechanism of LAG-3 signaling pathways, effects of its inhibition and efficacy, and adverse events associated with its combined use with anti–PD-1 drugs.

The use of nanotechnology represents one of the newer alternative therapies employed for treatment of melanoma and is especially gaining interest due to reduced adverse effects in comparison with other conventional treatments for melanoma. Nanotechnology-based drug delivery systems precisely target tumor cells and improve the effect of both the conventional and innovative antineoplastic treatment.^27,31 Tumor vasculature differs from normal tissues by being discontinuous and having interspersed small gaps/holes that allow nanoparticles to exit the circulation and enter and accumulate in the tumor tissue, leading to enhanced and targeted release of the antineoplastic drug to tumor cells.³² This mechanism is called the enhanced permeability and retention effect.³³

Another mechanism by which nanoparticles work is ligand-based targeting in which ligands such as monoclonal antibodies, peptides, and nucleic acids located on the surface of nanoparticles can bind to receptors on the plasma membrane of tumor cells and lead to targeted delivery of the drug.³⁴ Nanomaterials used for melanoma treatment include vesicular systems such as liposomes and niosomes, polymeric nanoparticles, noble metal-based nanoparticles, carbon nanotubes, dendrimers, solid lipid nanoparticles and nanostructures, lipid carriers, and microneedles. In melanoma, nanoparticles can be used to enhance targeted delivery of drugs, including immune checkpoint inhibitors (ICIs). Cai et al³⁵ described usage of scaffolds in delivery systems. Tumor-associated antigens, adjuvant drugs, and chemical agents that influence the tumor microenvironment can be loaded onto these scaffolding agents. In a study by Zhu et al,³⁶ photosensitizer chlorin e6 and immunoadjuvant aluminum hydroxide were used as a novel nanosystem that effectively destroyed tumor cells and induced a strong systemic antitumor response. IL-2 is a cytokine produced by B or T lymphocytes. Its use in melanoma has been limited by a severe adverse effect profile and lack of complete response in most patients. Cytokine-containing nanogels have been found to selectively release IL-2 in response to activation of T-cell receptors, and a mouse model in melanoma showed better response compared to free IL-1 and no adverse systemic effects.³⁷

Nanovaccines represent another interesting novel immunotherapy modality. A study by Conniot et al³⁸ showed that nanoparticles can be used in the treatment of melanoma. Nanoparticles made of biodegradable polymer were loaded with Melan-A/MART-1 (26–35 A27L) MHC class I-restricted peptide (MHC class I antigen), and the limited peptide MHC class II Melan-A/MART-1 51–73 (MHC class II antigen) and grafted with mannose that was then combined with an anti–PD-L1 antibody and injected into mouse models. This combination resulted in T-cell infiltration at early stages and increased infiltration of myeloid-derived suppressor cells. Ibrutinib, a myeloid-derived suppressor cell inhibitor, was added and demonstrated marked tumor remission and prolonged survival.³⁸

Overexpression of certain microRNAs (miRNAs), especially miR-204-5p and miR-199b-5p, has been shown to inhibit growth of melanoma cells in vitro, both alone and in combination with MAPK inhibitors, but these miRNAs are easily degradable in body fluids. Lipid nanoparticles can bind these miRNAs and have been shown to inhibit tumor cell proliferation and improve efficacy of BRAF and MEK inhibitors.³⁹

Triple-Combination Therapy

Immune checkpoint inhibitors such as anti–PD-1 or anti–CTLA-4 drugs have become the standard of care in treatment of advanced melanoma. Approximately 40% to 50% of cases of melanoma harbor BRAF mutations, and patients with these mutations could benefit from BRAF and MEK inhibitors. Data from clinical trials on BRAF and MEK inhibitors even showed initial high objective response rates, but the response was short-lived, and there was frequent acquired resistance.⁴⁰ With ICIs, the major limitation was primary resistance, with only 50% of patients initially responding.⁴¹ Studies on murine models demonstrated that BRAF-mutated tumors had decreased expression of IFN-γ, tumor necrosis factor α, and CD40 ligand on CD4⁺ tumor-infiltrating lymphocytes and increased accumulation of regulatory T cells and myeloid-derived suppressor cells, leading to a protumor microenvironment. BRAF and MEK pathway inhibition were found to improve intratumoral CD4⁺ T-cell activity, leading to improved antitumor T-cell responses.⁴² Because of this enhanced immune response by BRAF and MEK inhibitors, it was hypothesized and later supported by clinical research that a combination of these targeted treatments and ICIs can have a synergistic effect, leading to increased antitumor activity.⁴³ A randomized phase 2 clinical trial (KEYNOTE-022) in which the treatment group was given pembrolizumab, dabrafenib, and trametinib and the control group was treated with dabrafenib and trametinib showed increased medial OS in the treatment group vs the control group (46.3 months vs 26.3 months) and more frequent complete response in the treatment group vs the control group (20% vs 15%).⁴⁴ In the IMspire150 phase 3 clinical trial, patients with advanced stage IIIC to IV BRAF-mutant melanoma were treated with either a triple combination of the PDL-1 inhibitor atezolizumab, vemurafenib, and cobimetinib or vemurafenib and cobimetinib. Although the objective response rate was similar in both groups, the median duration of response was longer in the triplet group compared with the doublet group (21 months vs 12.6 months). Given these results, the FDA approved the triple-combination therapy with atezolizumab, vemurafenib, and cobimetinib. Although triple-combination therapy has shown promising results, it is expected that there will be an increase in the frequency of treatment-related adverse effects. In the phase 3 COMBi-I study, patients with advanced stage IIIC to IV BRAF V600E mutant cutaneous melanoma were treated with either a combination of spartalizumab, dabrafenib, and trametinib or just dabrafenib and trametinib. Although the objective response rates were not significantly different (69% vs 64%), there was increased frequency of treatment-related adverse effects in patients receiving triple-combination therapy.⁴³ As more follow-up data come out of these ongoing clinical trials, benefits of triple-combination therapy and its adverse effect profile will be more definitely established.

Challenges and Future Perspectives

One of the major roadblocks in the treatment of melanoma is the failure of response to ICI with CTLA-4 and PD-1/PD-L1 blockade in a large patient population, which has resulted in the need for new biomarkers that can act as potential therapeutic targets. Further, the main underlying factor for both adjuvant and neoadjuvant approaches remains the selection of patients, optimizing therapeutic outcomes while minimizing the number of patients exposed to potentially toxic treatments without gaining clinical benefit. Clinical and pathological factors (eg, Breslow thickness, ulceration, the number of positive lymph nodes) play a role in stratifying patients as per risk of recurrence.⁴⁵ Similarly, peripheral blood biomarkers have been proposed as prognostic tools for high-risk stage II and III melanoma, including markers of systemic inflammation previously explored in the metastatic setting.⁴⁶ However, the use of these parameters has not been validated for clinical practice. Currently, despite promising results of BRAF and MEK inhibitors and therapeutic ICIs, as well as IL-2 or interferon alfa, treatment options in metastatic melanoma are limited because of its high heterogeneity, problematic patient stratification, and high genetic mutational rate. Recently, the role of epigenetic modifications andmiRNAs in melanoma progression and metastatic spread has been described. Silencing of CDKN2A locus and encoding for p16^INK4A and p14^ARF by DNA methylation are noted in 27% and 57% of metastatic melanomas, respectively, which enables melanoma cells to escape from growth arrest and apoptosis generated by Rb protein and p53 pathways.⁴⁷ Demethylation of these and other tumor suppressor genes with proapoptotic function (eg, RASSF1A and tumor necrosis factor–related apoptosis-inducing ligand) can restore cell death pathways, though future clinical studies in melanoma are warranted.⁴⁸

Cutaneous malignant melanoma represents an aggressive form of skin cancer, with 132,000 new cases of melanoma and 50,000 melanoma-related deaths diagnosed worldwide each year.¹ In recent decades, major progress has been made in the treatment of melanoma, especially metastatic and advanced-stage disease. Approval of new treatments, such as immunotherapy with anti–PD-1 (pembrolizumab and nivolumab) and anti–CTLA-4 (ipilimumab) antibodies, has revolutionized therapeutic strategies (Figure 1). Molecularly, melanoma has the highest mutational burden among solid tumors. Approximately 40% of melanomas harbor the BRAF V600 mutation, leading to constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway.² The other described genomic subtypes are mutated RAS (accounting for approximately 28% of cases), mutated NF1 (approximately 14% of cases), and triple wild type, though these other subtypes have not been as successfully targeted with therapy to date.³ Dual inhibition of this pathway using combination therapy with BRAF and MEK inhibitors confers high response rates and survival benefit, though efficacy in metastatic patients often is limited by development of resistance. The US Food and Drug Administration (FDA) has approved 3 combinations of targeted therapy in unresectable tumors: dabrafenib and trametinib, vemurafenib and cobimetinib, and encorafenib and binimetinib. The oncolytic herpesvirus talimogene laherparepvec also has received FDA approval for local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with recurrent melanoma after initial surgery.²

In this review, we explore new therapeutic agents and novel combinations that are being tested in early-phase clinical trials (Table). We discuss newer promising tools such as nanotechnology to develop nanosystems that act as drug carriers and/or light absorbents to potentially improve therapy outcomes. Finally, we highlight challenges such as management after resistance and intervention with novel immunotherapies and the lack of predictive biomarkers to stratify patients to targeted treatments after primary treatment failure.

Targeted Therapies

Vemurafenib was approved by the FDA in 2011 and was the first BRAF-targeted therapy approved for the treatment of melanoma based on a 48% response rate and a 63% reduction in the risk for death vs dacarbazine chemotherapy.⁴ Despite a rapid and clinically significant initial response, progression-free survival (PFS) was only 5.3 months, which is indicative of the rapid development of resistance with monotherapy through MAPK reactivation. As a result, combined BRAF and MEK inhibition was introduced and is now the standard of care for targeted therapy in melanoma. Treatment with dabrafenib and trametinib, vemurafenib and cobimetinib, or encorafenib and binimetinib is associated with prolonged PFS and overall survival (OS) compared to BRAF inhibitor monotherapy, with response rates exceeding 60% and a complete response rate of 10% to 18%.⁵ Recently, combining atezolizumab with vemurafenib and cobimetinib was shown to improve PFS compared to combined targeted therapy.⁶ Targeted therapy usually is given as first-line treatment to symptomatic patients with a high tumor burden because the response may be more rapid than the response to immunotherapy. Ultimately, most patients with advanced BRAF-mutated melanoma receive both targeted therapy and immunotherapy.

Mutations of KIT (encoding proto-oncogene receptor tyrosine kinase) activate intracellular MAPK and phosphatidylinositol 3-kinase (PI3K) pathways (Figure 2).⁷ KIT mutations are found in mucosal and acral melanomas as well as chronically sun-damaged skin, with frequencies of 39%, 36%, and 28%, respectively. Imatinib was associated with a 53% response rate and PFS of 3.9 months among patients with KIT-mutated melanoma but failed to cause regression in melanomas with KIT amplification.⁸

Anti–CTLA-4 Immune Checkpoint Inhibition

CTLA-4 is a protein found on T cells that binds with another protein, B7, preventing T cells from killing cancer cells. Hence, blockade of CTLA-4 antibody avoids the immunosuppressive state of lymphocytes, strengthening their antitumor action.⁹ Ipilimumab, an anti–CTLA-4 antibody, demonstrated improvement in median OS for management of unresectable or metastatic stage IV melanoma, resulting in its FDA approval.⁸ A combination of ipilimumab with dacarbazine in stage IV melanoma showed notable improvement of OS.¹⁰ Similarly, tremelimumab showed evidence of tumor regression in a phase 1 trial but with more severe immune-related side effects compared with ipilimumab.¹¹ A second study on patients with stage IV melanoma treated with tremelimumab as first-line therapy in comparison with dacarbazine demonstrated differences in OS that were not statistically significant, though there was a longer duration of an objective response in patients treated with tremelimumab (35.8 months) compared with patients responding to dacarbazine (13.7 months).¹²

Anti–PD-1 Immune Checkpoint Inhibition

PD-1 is a transmembrane protein with immunoreceptor tyrosine-based inhibitory signaling, identified as an apoptosis-associated molecule.¹³ Upon activation, it is expressed on the cell surface of CD4, CD8, B lymphocytes, natural killer cells, monocytes, and dendritic cells.¹⁴ PD-L1, the ligand of PD-1, is constitutively expressed on different hematopoietic cells, as well as on fibroblasts, endothelial cells, mesenchymal cells, neurons, and keratinocytes.^15,16 Reactivation of effector T lymphocytes by PD-1:PD-L1 pathway inhibition has shown clinically significant therapeutic relevance.¹⁷ The PD-1:PD-L1 interaction is active only in the presence of T- or B-cell antigen receptor cross-link. This interaction prevents PI3K/AKT signaling and MAPK/extracellular signal-regulated kinase pathway activation with the net result of lymphocytic functional exhaustion.^18,19 PD-L1 blockade is shown to have better clinical benefit and minor toxicity compared to anti–CTLA-4 therapy. Treatment with anti-PD1 nivolumab in a phase 1b clinical trial (N=107) demonstrated highly specific action, durable tumor remission, and long-term safety in 32% of patients with advanced melanoma.²⁰ These promising results led to the FDA approval of nivolumab for the treatment of patients with advanced and unresponsive melanoma. A recent clinical trial combining ipilimumab and nivolumab resulted in an impressive increase of PFS compared with ipilimumab monotherapy (11.5 months vs 2.9 months).²¹ Similarly, treatment with pembrolizumab in advanced melanoma demonstrated improvement in PFS and OS compared with anti–CTLA-4 therapy,^22,23 which resulted in FDA approval of pembrolizumab for the treatment of advanced melanoma in patients previously treated with ipilimumab or BRAF inhibitors in BRAF V600 mutation–positive patients.²⁴

Lymphocyte-Activated Gene 3–Targeted Therapies

Lymphocyte-activated gene 3 (LAG-3)(also known as CD223 or FDC protein) is a type of immune checkpoint receptor transmembrane protein that is located on chromosome 12.²⁵ It is present on the surface of effector T cells and regulatory T cells that regulate the adaptive immune response.²⁶ Lymphocyte-activated gene 3 is reported to be highly expressed on the surface of tumor-infiltrating lymphocytes, thus the level of LAG-3 expression was found to corelate with the prognosis of tumors. In some tumors involving the kidneys, lungs, and bladder, a high level of LAG-3 was associated with a worse prognosis; in gastric carcinoma and melanoma, a high level of LAG-3 indicates better prognosis.²⁷ Similar to PD-1, LAG-3 also is found to be an inhibitory checkpoint that contributes to decreased T cells. Therefore, antibodies targeting LAG-3 have been gaining interest as modalities in cancer immunotherapy. The initial clinical trials employing only LAG-3 antibody on solid tumors found an objective response rate and disease control rate of 6% and 17%, respectively.^25,26,28 Given the unsatisfactory results, the idea that combination therapy with an anti–PD-L1 drug and LAG-3 antibody started gaining attention. A randomized, double-blind clinical trial, RELATIVITY-047, studying the effects of a combination of relatlimab (a first-in-class LAG-3 antibody) and nivolumab (an anti–PD-L1 antibody) on melanoma found longer PFS (10.1 months vs 4.6 months) and a 25% lower risk for disease progression or death with the combination of relatlimab and nivolumab vs nivolumab alone.²⁸ The FDA approved the combination of relatlimab and nivolumab for individuals aged 12 years or older with previously untreated melanoma that is surgically unresectable or has metastasized.²⁹ Zhao et al³⁰ demonstrated that LAG-3/PD-1 and CTLA-4/PD-1 inhibition showed similar PFS, and LAG-3/PD-1 inhibition showed earlier survival benefit and fewer treatment-related adverse effects, with grade 3 or 4 treatment-related adverse effects occurring in 18.9% of patients on anti–LAG-3 and anti–PD-1 combination (relatlimab plus nivolumab) compared with 55.0% in patients treated with anti–CTL-4 and anti–PD-1 combination (ipilimumab plus nivolumab)(N=1344). Further studies are warranted to understand the exact mechanism of LAG-3 signaling pathways, effects of its inhibition and efficacy, and adverse events associated with its combined use with anti–PD-1 drugs.

The use of nanotechnology represents one of the newer alternative therapies employed for treatment of melanoma and is especially gaining interest due to reduced adverse effects in comparison with other conventional treatments for melanoma. Nanotechnology-based drug delivery systems precisely target tumor cells and improve the effect of both the conventional and innovative antineoplastic treatment.^27,31 Tumor vasculature differs from normal tissues by being discontinuous and having interspersed small gaps/holes that allow nanoparticles to exit the circulation and enter and accumulate in the tumor tissue, leading to enhanced and targeted release of the antineoplastic drug to tumor cells.³² This mechanism is called the enhanced permeability and retention effect.³³

Another mechanism by which nanoparticles work is ligand-based targeting in which ligands such as monoclonal antibodies, peptides, and nucleic acids located on the surface of nanoparticles can bind to receptors on the plasma membrane of tumor cells and lead to targeted delivery of the drug.³⁴ Nanomaterials used for melanoma treatment include vesicular systems such as liposomes and niosomes, polymeric nanoparticles, noble metal-based nanoparticles, carbon nanotubes, dendrimers, solid lipid nanoparticles and nanostructures, lipid carriers, and microneedles. In melanoma, nanoparticles can be used to enhance targeted delivery of drugs, including immune checkpoint inhibitors (ICIs). Cai et al³⁵ described usage of scaffolds in delivery systems. Tumor-associated antigens, adjuvant drugs, and chemical agents that influence the tumor microenvironment can be loaded onto these scaffolding agents. In a study by Zhu et al,³⁶ photosensitizer chlorin e6 and immunoadjuvant aluminum hydroxide were used as a novel nanosystem that effectively destroyed tumor cells and induced a strong systemic antitumor response. IL-2 is a cytokine produced by B or T lymphocytes. Its use in melanoma has been limited by a severe adverse effect profile and lack of complete response in most patients. Cytokine-containing nanogels have been found to selectively release IL-2 in response to activation of T-cell receptors, and a mouse model in melanoma showed better response compared to free IL-1 and no adverse systemic effects.³⁷

Nanovaccines represent another interesting novel immunotherapy modality. A study by Conniot et al³⁸ showed that nanoparticles can be used in the treatment of melanoma. Nanoparticles made of biodegradable polymer were loaded with Melan-A/MART-1 (26–35 A27L) MHC class I-restricted peptide (MHC class I antigen), and the limited peptide MHC class II Melan-A/MART-1 51–73 (MHC class II antigen) and grafted with mannose that was then combined with an anti–PD-L1 antibody and injected into mouse models. This combination resulted in T-cell infiltration at early stages and increased infiltration of myeloid-derived suppressor cells. Ibrutinib, a myeloid-derived suppressor cell inhibitor, was added and demonstrated marked tumor remission and prolonged survival.³⁸

Overexpression of certain microRNAs (miRNAs), especially miR-204-5p and miR-199b-5p, has been shown to inhibit growth of melanoma cells in vitro, both alone and in combination with MAPK inhibitors, but these miRNAs are easily degradable in body fluids. Lipid nanoparticles can bind these miRNAs and have been shown to inhibit tumor cell proliferation and improve efficacy of BRAF and MEK inhibitors.³⁹

Triple-Combination Therapy

Immune checkpoint inhibitors such as anti–PD-1 or anti–CTLA-4 drugs have become the standard of care in treatment of advanced melanoma. Approximately 40% to 50% of cases of melanoma harbor BRAF mutations, and patients with these mutations could benefit from BRAF and MEK inhibitors. Data from clinical trials on BRAF and MEK inhibitors even showed initial high objective response rates, but the response was short-lived, and there was frequent acquired resistance.⁴⁰ With ICIs, the major limitation was primary resistance, with only 50% of patients initially responding.⁴¹ Studies on murine models demonstrated that BRAF-mutated tumors had decreased expression of IFN-γ, tumor necrosis factor α, and CD40 ligand on CD4⁺ tumor-infiltrating lymphocytes and increased accumulation of regulatory T cells and myeloid-derived suppressor cells, leading to a protumor microenvironment. BRAF and MEK pathway inhibition were found to improve intratumoral CD4⁺ T-cell activity, leading to improved antitumor T-cell responses.⁴² Because of this enhanced immune response by BRAF and MEK inhibitors, it was hypothesized and later supported by clinical research that a combination of these targeted treatments and ICIs can have a synergistic effect, leading to increased antitumor activity.⁴³ A randomized phase 2 clinical trial (KEYNOTE-022) in which the treatment group was given pembrolizumab, dabrafenib, and trametinib and the control group was treated with dabrafenib and trametinib showed increased medial OS in the treatment group vs the control group (46.3 months vs 26.3 months) and more frequent complete response in the treatment group vs the control group (20% vs 15%).⁴⁴ In the IMspire150 phase 3 clinical trial, patients with advanced stage IIIC to IV BRAF-mutant melanoma were treated with either a triple combination of the PDL-1 inhibitor atezolizumab, vemurafenib, and cobimetinib or vemurafenib and cobimetinib. Although the objective response rate was similar in both groups, the median duration of response was longer in the triplet group compared with the doublet group (21 months vs 12.6 months). Given these results, the FDA approved the triple-combination therapy with atezolizumab, vemurafenib, and cobimetinib. Although triple-combination therapy has shown promising results, it is expected that there will be an increase in the frequency of treatment-related adverse effects. In the phase 3 COMBi-I study, patients with advanced stage IIIC to IV BRAF V600E mutant cutaneous melanoma were treated with either a combination of spartalizumab, dabrafenib, and trametinib or just dabrafenib and trametinib. Although the objective response rates were not significantly different (69% vs 64%), there was increased frequency of treatment-related adverse effects in patients receiving triple-combination therapy.⁴³ As more follow-up data come out of these ongoing clinical trials, benefits of triple-combination therapy and its adverse effect profile will be more definitely established.

Challenges and Future Perspectives

One of the major roadblocks in the treatment of melanoma is the failure of response to ICI with CTLA-4 and PD-1/PD-L1 blockade in a large patient population, which has resulted in the need for new biomarkers that can act as potential therapeutic targets. Further, the main underlying factor for both adjuvant and neoadjuvant approaches remains the selection of patients, optimizing therapeutic outcomes while minimizing the number of patients exposed to potentially toxic treatments without gaining clinical benefit. Clinical and pathological factors (eg, Breslow thickness, ulceration, the number of positive lymph nodes) play a role in stratifying patients as per risk of recurrence.⁴⁵ Similarly, peripheral blood biomarkers have been proposed as prognostic tools for high-risk stage II and III melanoma, including markers of systemic inflammation previously explored in the metastatic setting.⁴⁶ However, the use of these parameters has not been validated for clinical practice. Currently, despite promising results of BRAF and MEK inhibitors and therapeutic ICIs, as well as IL-2 or interferon alfa, treatment options in metastatic melanoma are limited because of its high heterogeneity, problematic patient stratification, and high genetic mutational rate. Recently, the role of epigenetic modifications andmiRNAs in melanoma progression and metastatic spread has been described. Silencing of CDKN2A locus and encoding for p16^INK4A and p14^ARF by DNA methylation are noted in 27% and 57% of metastatic melanomas, respectively, which enables melanoma cells to escape from growth arrest and apoptosis generated by Rb protein and p53 pathways.⁴⁷ Demethylation of these and other tumor suppressor genes with proapoptotic function (eg, RASSF1A and tumor necrosis factor–related apoptosis-inducing ligand) can restore cell death pathways, though future clinical studies in melanoma are warranted.⁴⁸

The US Preventive Services Task Force (USPSTF)¹ is comprised of an independent panel of preventive services clinician experts who make evidence-based recommendations, with the letter grade assigned based on the strength of the evidence, from A through D (TABLE 1), on preventive services such as health screenings, shared decision making patient counseling, and preventive medications.  Both A and B recommendations are generally accepted by both government and most private health insurance companies as a covered preventive benefit with no or minimal co-pays.

In 2002, the USPSTF released a Grade B recommendation that screening mammography for average-risk patients (with patients referring to persons assigned female at birth who have not undergone bilateral mastectomy) should take place starting at age 40 and be repeated every 1 to 2 years.² This was consistent with or endorsed by most other national breast cancer screening guidelines,  including the American College of Obstetricians and Gynecologists (ACOG), National Comprehensive Cancer Network (NCCN), the American Cancer Society (ACS), and the American College of Radiology. 

In 2009, the USPSTF changed this Grade B recommendation, instead recommending biennial screening mammography for women aged 50 to 74.³ The most significant change in the revised guideline was for patients aged 40 to 49, where the recommendation was “against routine screening mammography.” They went on to say that the decision to start “biennial screening mammography before the age of 50 years should be an individual one and take patient context into account, including the patient’s values regarding specific benefits and harms.” Other prominent national guideline groups (ACOG, NCCN, ACS) did not agree with this recommendation and maintained that patients aged 40 to 49 should continue to be offered routine screening mammography either annually (NCCN, ACS) or at 1-to-2-year intervals (ACOG).^4-6 The American College of Physicians and the American Academy of Family Practice endorsed the 2016 USPSTF guidelines, creating a disparity in breast cancer mammography counseling for averagerisk patients in their 40s.⁷

In 2016, the USPSTF revisited their breast cancer screening recommendation and renewed their 2009 recommendation against routine screening in patients aged 40 to 49, with the American College of Physicians and the American Academy of Family Practice again endorsing these guidelines.⁸ ACOG, ACS, NCCN, and ACR continued to recommend age 40 as a starting age for routine mammography screening (TABLE 2). As a result, over the past 14 years, patients aged 40 to 49 were placed in an awkward position of potentially hearing different recommendations from their health care providers, those differences often depending on the specialty of the provider they were seeing. 

In 2023. On May 9, the USPSTF released a draft of their latest recommendation statement stating that all patients at average risk for breast cancer should get screened every other year beginning at age 40, bringing most of the national guideline groups into alignment with regard to age to start mammographic screening.⁹ 

Why the change? 

To answer this question, we need to examine the relevant epidemiology of breast cancer. 

Continue to: Incidence...

Incidence

It is estimated that, in the United States in 2023, there will be 300,590 new cases of breast cancer, resulting in 43,700 deaths.¹⁰ From 2015–2019, there were 128.1 new breast cancer cases/100,000 population, which is the highest rate of cancer in the United States, regardless of sex.¹¹ Diagnoses among patients aged 40 to 49 are rising at a faster rate than previously, about 2% per year between 2015 and 2019. 

Racial and ethnic differences

In addition to the racial and ethnic epidemiologic differences in breast cancer, there are also disparities in breast cancer care and outcomes that need to be considered when making national guidelines/policy recommendations. 

Black women have high mortality rates from breast cancer. While non-Hispanic White patients have the highest rates of breast cancer (TABLE 3), non-Hispanic Black patients have the highest rates of death due to breast cancer.¹⁰ There appear to be several reasons for the estimated 40%-higher rate of mortality among Black women, including: 

• systemic racism in primary research, guidelines, and policy
• inequities in diagnostic follow-up and access to evidence-based cancer treatments
• biologic differences in breast cancer (ie, the incidence of triple-negative breast cancer (TNBC) is 2-fold higher in Black women compared with the other racial and ethnic groups in the United States).^12-14 

While prior studies have suggested that screening mammography might be less effective for patients with TNBC, a recent study demonstrated that patients who had mammography–screened-detected TNBC tumors were smaller and more likely to be node- negative compared with non-screened patients with TNBC.(14) Patients with screened-detected TNBCs were also more likely to undergo a lumpectomy instead of a mastectomy compared with non–screened detected TNBC (68.3% vs 46.1%; P = .002) (TABLE 4). These data strongly suggest that screening mammography is indeed effective in detecting TNBC at earlier stages, one of the best proxies for breast cancer mortality. 

Non-White patients have higher incidence rates of breast cancer in their 40s. A second factor to consider in racial differences is the relatively higher incidence of breast cancer in Hispanic, Black, and Asian patients in their 40s compared with non-Hispanic White patients. In a recent analysis of data from 1973 to 2010 from the Surveillance, Epidemiology, and End Results (SEER) Program, the median age of patients with breast cancer in the United States was 58.0 years (interquartile range [IQR], 50.0–67.0 years).¹⁶ Across all US demographic populations by age at diagnosis, more than 20% of patients will have their initial diagnosis of  breast cancer under the age of 50, and 1.55% (1 in 65) patients between ages 40 and 49 years will be diagnosed with breast cancer.4 However, among patients aged 50 and younger diagnosed with breast cancer, a significantly higher proportion are Black (31%), Hispanic (34.9%), or Asian (32.8%) versus White (23.1%) (P < .001 for all).¹⁶ So, for there to be similar racial and ethnic mammography capture rates with White patients, starting mammography screening ages would need to be lower for Black (age 47 years), Hispanic (and 46 years), and Asian (age 47 years) patients. Data from this study of the SEER database16 also demonstrated that more Black and Hispanic patients at age of diagnosis were diagnosed with advanced (regional or distant) breast cancer (46.6% and 42.9%, respectively) versus White or Asian patients (37.1% and 35.6%, respectively; P < .001 for all). 

These findings led the authors of the study to conclude that the “Current [2016] USPSTF breast cancer screening recommendations do not reflect age-specific patterns based on race.” The USPSTF stated that this is one of the reasons why they reconsidered their stance on screening , and now recommend screening for all patients starting at age 40. 

My current counseling approach

I encourage all racial and ethnic patients between the ages of 40 and 49 to undergo screening mammography because of the associated relative risk mortality reduction rates, which range from 15% to 50%. I also share that with my patients that, because of the younger average age of onset of breast cancer in Black, Hispanic, and Asian patients, they may derive additional benefit from screening starting at age 40.⁴ 

Impact of draft guidelines on breast cancer screening and mortality in younger patients

There is clear, unequivocal, and repeatable Level 1 evidence that screening mammography in the general population of patients aged 40 to 49 reduces breast cancer mortality. Breast cancer is the leading cause of cancer in the United States, the second leading cause of cancer mortality in patients, and 1 in 5 new breast cancer diagnoses occur in patients between the ages of 40 and 49. While recent efforts have been made to come to consensus on a screening starting age of 40 for patients at average risk for breast cancer, the USPSTF appeared to be an outlier with their 2016 recommendation to routinely start mammography screening at age 50 instead of 40.¹⁷ 

The USPSTF is a very important national voice in cancer prevention, and their 2023 (draft) revised guidelines to age 40 as the recommended starting screening age now agrees with the leading US guideline groups listed in Table 2. These guideline groups have gone through varying processes, and now have finally arrived at the same conclusion for age to start screening mammography in women of average risk. This agreement should come as a significant comfort to health care providers and patients alike. Changing the starting age to 40 years will result in thousands of lives and hundreds of thousands of life-years saved for patients aged 40 to 49. ● 

The US Preventive Services Task Force (USPSTF)¹ is comprised of an independent panel of preventive services clinician experts who make evidence-based recommendations, with the letter grade assigned based on the strength of the evidence, from A through D (TABLE 1), on preventive services such as health screenings, shared decision making patient counseling, and preventive medications.  Both A and B recommendations are generally accepted by both government and most private health insurance companies as a covered preventive benefit with no or minimal co-pays.

In 2002, the USPSTF released a Grade B recommendation that screening mammography for average-risk patients (with patients referring to persons assigned female at birth who have not undergone bilateral mastectomy) should take place starting at age 40 and be repeated every 1 to 2 years.² This was consistent with or endorsed by most other national breast cancer screening guidelines,  including the American College of Obstetricians and Gynecologists (ACOG), National Comprehensive Cancer Network (NCCN), the American Cancer Society (ACS), and the American College of Radiology. 

In 2009, the USPSTF changed this Grade B recommendation, instead recommending biennial screening mammography for women aged 50 to 74.³ The most significant change in the revised guideline was for patients aged 40 to 49, where the recommendation was “against routine screening mammography.” They went on to say that the decision to start “biennial screening mammography before the age of 50 years should be an individual one and take patient context into account, including the patient’s values regarding specific benefits and harms.” Other prominent national guideline groups (ACOG, NCCN, ACS) did not agree with this recommendation and maintained that patients aged 40 to 49 should continue to be offered routine screening mammography either annually (NCCN, ACS) or at 1-to-2-year intervals (ACOG).^4-6 The American College of Physicians and the American Academy of Family Practice endorsed the 2016 USPSTF guidelines, creating a disparity in breast cancer mammography counseling for averagerisk patients in their 40s.⁷

In 2016, the USPSTF revisited their breast cancer screening recommendation and renewed their 2009 recommendation against routine screening in patients aged 40 to 49, with the American College of Physicians and the American Academy of Family Practice again endorsing these guidelines.⁸ ACOG, ACS, NCCN, and ACR continued to recommend age 40 as a starting age for routine mammography screening (TABLE 2). As a result, over the past 14 years, patients aged 40 to 49 were placed in an awkward position of potentially hearing different recommendations from their health care providers, those differences often depending on the specialty of the provider they were seeing. 

In 2023. On May 9, the USPSTF released a draft of their latest recommendation statement stating that all patients at average risk for breast cancer should get screened every other year beginning at age 40, bringing most of the national guideline groups into alignment with regard to age to start mammographic screening.⁹ 

Why the change? 

To answer this question, we need to examine the relevant epidemiology of breast cancer. 

Continue to: Incidence...

Incidence

It is estimated that, in the United States in 2023, there will be 300,590 new cases of breast cancer, resulting in 43,700 deaths.¹⁰ From 2015–2019, there were 128.1 new breast cancer cases/100,000 population, which is the highest rate of cancer in the United States, regardless of sex.¹¹ Diagnoses among patients aged 40 to 49 are rising at a faster rate than previously, about 2% per year between 2015 and 2019. 

Racial and ethnic differences

In addition to the racial and ethnic epidemiologic differences in breast cancer, there are also disparities in breast cancer care and outcomes that need to be considered when making national guidelines/policy recommendations. 

Black women have high mortality rates from breast cancer. While non-Hispanic White patients have the highest rates of breast cancer (TABLE 3), non-Hispanic Black patients have the highest rates of death due to breast cancer.¹⁰ There appear to be several reasons for the estimated 40%-higher rate of mortality among Black women, including: 

• systemic racism in primary research, guidelines, and policy
• inequities in diagnostic follow-up and access to evidence-based cancer treatments
• biologic differences in breast cancer (ie, the incidence of triple-negative breast cancer (TNBC) is 2-fold higher in Black women compared with the other racial and ethnic groups in the United States).^12-14 

While prior studies have suggested that screening mammography might be less effective for patients with TNBC, a recent study demonstrated that patients who had mammography–screened-detected TNBC tumors were smaller and more likely to be node- negative compared with non-screened patients with TNBC.(14) Patients with screened-detected TNBCs were also more likely to undergo a lumpectomy instead of a mastectomy compared with non–screened detected TNBC (68.3% vs 46.1%; P = .002) (TABLE 4). These data strongly suggest that screening mammography is indeed effective in detecting TNBC at earlier stages, one of the best proxies for breast cancer mortality. 

Non-White patients have higher incidence rates of breast cancer in their 40s. A second factor to consider in racial differences is the relatively higher incidence of breast cancer in Hispanic, Black, and Asian patients in their 40s compared with non-Hispanic White patients. In a recent analysis of data from 1973 to 2010 from the Surveillance, Epidemiology, and End Results (SEER) Program, the median age of patients with breast cancer in the United States was 58.0 years (interquartile range [IQR], 50.0–67.0 years).¹⁶ Across all US demographic populations by age at diagnosis, more than 20% of patients will have their initial diagnosis of  breast cancer under the age of 50, and 1.55% (1 in 65) patients between ages 40 and 49 years will be diagnosed with breast cancer.4 However, among patients aged 50 and younger diagnosed with breast cancer, a significantly higher proportion are Black (31%), Hispanic (34.9%), or Asian (32.8%) versus White (23.1%) (P < .001 for all).¹⁶ So, for there to be similar racial and ethnic mammography capture rates with White patients, starting mammography screening ages would need to be lower for Black (age 47 years), Hispanic (and 46 years), and Asian (age 47 years) patients. Data from this study of the SEER database16 also demonstrated that more Black and Hispanic patients at age of diagnosis were diagnosed with advanced (regional or distant) breast cancer (46.6% and 42.9%, respectively) versus White or Asian patients (37.1% and 35.6%, respectively; P < .001 for all). 

These findings led the authors of the study to conclude that the “Current [2016] USPSTF breast cancer screening recommendations do not reflect age-specific patterns based on race.” The USPSTF stated that this is one of the reasons why they reconsidered their stance on screening , and now recommend screening for all patients starting at age 40. 

My current counseling approach

I encourage all racial and ethnic patients between the ages of 40 and 49 to undergo screening mammography because of the associated relative risk mortality reduction rates, which range from 15% to 50%. I also share that with my patients that, because of the younger average age of onset of breast cancer in Black, Hispanic, and Asian patients, they may derive additional benefit from screening starting at age 40.⁴ 

Impact of draft guidelines on breast cancer screening and mortality in younger patients

There is clear, unequivocal, and repeatable Level 1 evidence that screening mammography in the general population of patients aged 40 to 49 reduces breast cancer mortality. Breast cancer is the leading cause of cancer in the United States, the second leading cause of cancer mortality in patients, and 1 in 5 new breast cancer diagnoses occur in patients between the ages of 40 and 49. While recent efforts have been made to come to consensus on a screening starting age of 40 for patients at average risk for breast cancer, the USPSTF appeared to be an outlier with their 2016 recommendation to routinely start mammography screening at age 50 instead of 40.¹⁷ 

The USPSTF is a very important national voice in cancer prevention, and their 2023 (draft) revised guidelines to age 40 as the recommended starting screening age now agrees with the leading US guideline groups listed in Table 2. These guideline groups have gone through varying processes, and now have finally arrived at the same conclusion for age to start screening mammography in women of average risk. This agreement should come as a significant comfort to health care providers and patients alike. Changing the starting age to 40 years will result in thousands of lives and hundreds of thousands of life-years saved for patients aged 40 to 49. ● 

The US Preventive Services Task Force (USPSTF)¹ is comprised of an independent panel of preventive services clinician experts who make evidence-based recommendations, with the letter grade assigned based on the strength of the evidence, from A through D (TABLE 1), on preventive services such as health screenings, shared decision making patient counseling, and preventive medications.  Both A and B recommendations are generally accepted by both government and most private health insurance companies as a covered preventive benefit with no or minimal co-pays.

In 2002, the USPSTF released a Grade B recommendation that screening mammography for average-risk patients (with patients referring to persons assigned female at birth who have not undergone bilateral mastectomy) should take place starting at age 40 and be repeated every 1 to 2 years.² This was consistent with or endorsed by most other national breast cancer screening guidelines,  including the American College of Obstetricians and Gynecologists (ACOG), National Comprehensive Cancer Network (NCCN), the American Cancer Society (ACS), and the American College of Radiology. 

In 2009, the USPSTF changed this Grade B recommendation, instead recommending biennial screening mammography for women aged 50 to 74.³ The most significant change in the revised guideline was for patients aged 40 to 49, where the recommendation was “against routine screening mammography.” They went on to say that the decision to start “biennial screening mammography before the age of 50 years should be an individual one and take patient context into account, including the patient’s values regarding specific benefits and harms.” Other prominent national guideline groups (ACOG, NCCN, ACS) did not agree with this recommendation and maintained that patients aged 40 to 49 should continue to be offered routine screening mammography either annually (NCCN, ACS) or at 1-to-2-year intervals (ACOG).^4-6 The American College of Physicians and the American Academy of Family Practice endorsed the 2016 USPSTF guidelines, creating a disparity in breast cancer mammography counseling for averagerisk patients in their 40s.⁷

In 2016, the USPSTF revisited their breast cancer screening recommendation and renewed their 2009 recommendation against routine screening in patients aged 40 to 49, with the American College of Physicians and the American Academy of Family Practice again endorsing these guidelines.⁸ ACOG, ACS, NCCN, and ACR continued to recommend age 40 as a starting age for routine mammography screening (TABLE 2). As a result, over the past 14 years, patients aged 40 to 49 were placed in an awkward position of potentially hearing different recommendations from their health care providers, those differences often depending on the specialty of the provider they were seeing. 

In 2023. On May 9, the USPSTF released a draft of their latest recommendation statement stating that all patients at average risk for breast cancer should get screened every other year beginning at age 40, bringing most of the national guideline groups into alignment with regard to age to start mammographic screening.⁹ 

Why the change? 

To answer this question, we need to examine the relevant epidemiology of breast cancer. 

Continue to: Incidence...

Incidence

It is estimated that, in the United States in 2023, there will be 300,590 new cases of breast cancer, resulting in 43,700 deaths.¹⁰ From 2015–2019, there were 128.1 new breast cancer cases/100,000 population, which is the highest rate of cancer in the United States, regardless of sex.¹¹ Diagnoses among patients aged 40 to 49 are rising at a faster rate than previously, about 2% per year between 2015 and 2019. 

Racial and ethnic differences

In addition to the racial and ethnic epidemiologic differences in breast cancer, there are also disparities in breast cancer care and outcomes that need to be considered when making national guidelines/policy recommendations. 

Black women have high mortality rates from breast cancer. While non-Hispanic White patients have the highest rates of breast cancer (TABLE 3), non-Hispanic Black patients have the highest rates of death due to breast cancer.¹⁰ There appear to be several reasons for the estimated 40%-higher rate of mortality among Black women, including: 

• systemic racism in primary research, guidelines, and policy
• inequities in diagnostic follow-up and access to evidence-based cancer treatments
• biologic differences in breast cancer (ie, the incidence of triple-negative breast cancer (TNBC) is 2-fold higher in Black women compared with the other racial and ethnic groups in the United States).^12-14 

While prior studies have suggested that screening mammography might be less effective for patients with TNBC, a recent study demonstrated that patients who had mammography–screened-detected TNBC tumors were smaller and more likely to be node- negative compared with non-screened patients with TNBC.(14) Patients with screened-detected TNBCs were also more likely to undergo a lumpectomy instead of a mastectomy compared with non–screened detected TNBC (68.3% vs 46.1%; P = .002) (TABLE 4). These data strongly suggest that screening mammography is indeed effective in detecting TNBC at earlier stages, one of the best proxies for breast cancer mortality. 

Non-White patients have higher incidence rates of breast cancer in their 40s. A second factor to consider in racial differences is the relatively higher incidence of breast cancer in Hispanic, Black, and Asian patients in their 40s compared with non-Hispanic White patients. In a recent analysis of data from 1973 to 2010 from the Surveillance, Epidemiology, and End Results (SEER) Program, the median age of patients with breast cancer in the United States was 58.0 years (interquartile range [IQR], 50.0–67.0 years).¹⁶ Across all US demographic populations by age at diagnosis, more than 20% of patients will have their initial diagnosis of  breast cancer under the age of 50, and 1.55% (1 in 65) patients between ages 40 and 49 years will be diagnosed with breast cancer.4 However, among patients aged 50 and younger diagnosed with breast cancer, a significantly higher proportion are Black (31%), Hispanic (34.9%), or Asian (32.8%) versus White (23.1%) (P < .001 for all).¹⁶ So, for there to be similar racial and ethnic mammography capture rates with White patients, starting mammography screening ages would need to be lower for Black (age 47 years), Hispanic (and 46 years), and Asian (age 47 years) patients. Data from this study of the SEER database16 also demonstrated that more Black and Hispanic patients at age of diagnosis were diagnosed with advanced (regional or distant) breast cancer (46.6% and 42.9%, respectively) versus White or Asian patients (37.1% and 35.6%, respectively; P < .001 for all). 

These findings led the authors of the study to conclude that the “Current [2016] USPSTF breast cancer screening recommendations do not reflect age-specific patterns based on race.” The USPSTF stated that this is one of the reasons why they reconsidered their stance on screening , and now recommend screening for all patients starting at age 40. 

My current counseling approach

I encourage all racial and ethnic patients between the ages of 40 and 49 to undergo screening mammography because of the associated relative risk mortality reduction rates, which range from 15% to 50%. I also share that with my patients that, because of the younger average age of onset of breast cancer in Black, Hispanic, and Asian patients, they may derive additional benefit from screening starting at age 40.⁴ 

Impact of draft guidelines on breast cancer screening and mortality in younger patients

There is clear, unequivocal, and repeatable Level 1 evidence that screening mammography in the general population of patients aged 40 to 49 reduces breast cancer mortality. Breast cancer is the leading cause of cancer in the United States, the second leading cause of cancer mortality in patients, and 1 in 5 new breast cancer diagnoses occur in patients between the ages of 40 and 49. While recent efforts have been made to come to consensus on a screening starting age of 40 for patients at average risk for breast cancer, the USPSTF appeared to be an outlier with their 2016 recommendation to routinely start mammography screening at age 50 instead of 40.¹⁷ 

The USPSTF is a very important national voice in cancer prevention, and their 2023 (draft) revised guidelines to age 40 as the recommended starting screening age now agrees with the leading US guideline groups listed in Table 2. These guideline groups have gone through varying processes, and now have finally arrived at the same conclusion for age to start screening mammography in women of average risk. This agreement should come as a significant comfort to health care providers and patients alike. Changing the starting age to 40 years will result in thousands of lives and hundreds of thousands of life-years saved for patients aged 40 to 49. ● 

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Cervical cancer was the most common cancer killer of persons with a cervix in the early 1900s in the United States. Widespread adoption of the Pap test in the mid-20th century followed by large-scale outreach through programs such as the National Breast and Cervical Cancer Early Detection Program have dramatically reduced deaths from cervical cancer. The development of a highly effective vaccine that targets human papillomavirus (HPV), the virus implicated in all cervical cancers, has made prevention even more accessible and attainable. Primary prevention with HPV vaccination in conjunction with regular screening as recommended by current guidelines is the most effective way we can prevent cervical cancer.

Despite these advances, the incidence and death rates from cervical cancer have plateaued over the last decade.¹ Additionally, many fear that due to the poor attendance at screening visits since the beginning of the COVID-19 pandemic, the incidence might further rise in the United States.² Among those in the United States diagnosed with cervical cancer, more than 50% have not been screened in over 5 years or had their abnormal results not managed as recommended by current guidelines, suggesting that operational and access issues are contributors to incident cervical cancer. In addition, HPV vaccination rates have increased only slightly from year to year. According to the most recent data from the Centers for Disease Control and Prevention (CDC), coverage with 1 or more doses of HPV vaccine in 2021 increased only by 1.8% and has stagnated, with administration to about 75% of those for whom it is recommended.³ The plateauing will limit our ability to eradicate cervical cancer in the United States, permitting death from a largely preventable disease.

Establishing the framework for the eradication of cervical cancer

The World Health Organization (WHO) adopted a global strategy called the Cervical Cancer Elimination Initiative in August 2020. This initiative is a multipronged effort that focuses on vaccination (90% of girls fully vaccinated by age 15), screening (70% of women screened by age 35 with an effective test and again at age 45), and treatment (90% treatment of precancer and 90% management of women with invasive cancer).⁴

These are the numbers we need to achieve if all countries are to reach a cervical cancer incidence of less than 4 per 100,000 persons with a cervix. The WHO further suggests that each country should meet the “90-70-90” targets by 2030 if we are to achieve the low incidence by the turn of the century.⁴ To date, few regions of the world have achieved these goals, and sadly the United States is not among them.

In response to this call to action, many medical and policymaking organizations are taking inventory and implementing strategies to achieve the WHO 2030 targets for cervical cancer eradication. In the United States, the Society of Gynecologic Oncology (SGO; www.sgo.org), the American Society for Colposcopy and Cervical Pathology (ASCCP; www.ASCCP.org), the American College of Obstetricians and Gynecologists (ACOG; www.acog.org), the American Cancer Society (ACS; www.cancer.org), and many others have initiated programs in a collaborative esprit de corps with the aim of eradicating this deadly disease.

In this Update, we review several studies with evidence of screening and management strategies that show promise of accelerating the eradication of cervical cancer.

Continue to: Transitioning to primary HPV screening in the United States...

Downs LS Jr, Nayar R, Gerndt J, et al; American Cancer Society Primary HPV Screening Initiative Steering Committee. Implementation in action: collaborating on the transition to primary HPV screening for cervical cancer in the United States. CA Cancer J Clin. 2023;73:458-460.

The American Cancer Society released an updated cervical cancer screening guideline in July 2020 that recommended testing for HPV as the preferred strategy. Reasons behind the change, moving away from a Pap test as part of the initial screen, are:

• increased sensitivity of primary HPV testing when compared with conventional cervical cytology (Pap test)
• improved risk stratification to identify who is at risk for cervical cancer now and in the future
• improved efficiency in identifying those who need colposcopy, thus limiting unnecessary procedures without increasing the risk of false-negative tests, thereby missing cervical precancer or invasive cancer.

Some countries with organized screening programs have already made the switch. Self-sampling for HPV is currently being considered for an approved use in the United States, further improving access to screening for cervical cancer when the initial step can be completed by the patient at home or simplified in nontraditional health care settings.²

ACS initiative created to address barriers to primary HPV testing

Challenges to primary HPV testing remain, including laboratory implementation, payment, and operationalizing clinical workflow (for example, HPV testing with reflex cytology instead of cytology with reflex HPV testing).⁵ There are undoubtedly other unforeseen barriers in the current US health care environment.

In a recent commentary, Downs and colleagues described how the ACS has convened the Primary HPV Screening Initiative (PHSI), nested under the ACS National Roundtable on Cervical Cancer, which is charged with identifying critical barriers to, and opportunities for, transitioning to primary HPV screening.⁵ The deliverable will be a roadmap with tools and recommendations to support health systems, laboratories, providers, patients, and payers as they make this evolution.

Work groups will develop resources

Patients, particularly those who have had routine cervical cancer screening over their lifetime, also will be curious about the changes in recommendations. The Provider Needs Workgroup within the PHSI structure will develop tools and patient education materials regarding the data, workflow, benefits, and safety of this new paradigm for cervical cancer screening.

Laboratories that process and interpret tests likely will bear the heaviest load of changes. For example, not all commercially available HPV tests in the United States are approved by the US Food and Drug Administration (FDA) for primary HPV testing. Some sites will need to adapt their equipment to ensure adherence to FDA-approved tests. Laboratory workflows will need to be altered for aliquots to be tested for HPV first, and the remainder for cytology. Quality assurance and accreditation requirements for testing will need modifications, and further efforts will be needed to ensure sufficient numbers of trained cytopathologists, whose workforce is rapidly declining, for processing and reading cervical cytology.

In addition, payment for HPV testing alone, without the need for a Pap test, might not be supported by payers that support safety-net providers and sites, who arguably serve the most vulnerable patients and those most at risk for cervical cancer. Collaboration across medical professionals, societies, payers, and policymakers will provide a critical infrastructure to make the change in the most seamless fashion and limit the harm from missed opportunities for screening.

Continue to: The quest for a “molecular Pap”: Dual-stain testing as a predictor of high-grade CIN...

Magkana M, Mentzelopoulou P, Magkana E, et al. p16/Ki-67 Dual staining is a reliable biomarker for risk stratification for patients with borderline/mild cytology in cervical cancer screening. Anticancer Res. 2022;42:2599-2606.

Stanczuk G, Currie H, Forson W, et al. Clinical performance of triage strategies for Hr-HPV-positive women; a longitudinal evaluation of cytology, p16/K-67 dual stain cytology, and HPV16/18 genotyping. Cancer Epidemiol Biomarkers Prev. 2022;31:1492-1498.
 

One new technology that was recently FDA approved and recommended for management of abnormal cervical cancer screening testing is dual-stain (DS) testing. Dual-stain testing is a cytology-based test that evaluates the concurrent expression of p16, a tumor suppressor protein upregulated in HPV oncogenesis, and Ki-67, a cell proliferation marker.^6,7 Two recent studies have showcased the outstanding clinical performance of DS testing and triage strategies that incorporate DS testing.

Higher specificity, fewer colposcopies needed with DS testing

Magkana and colleagues prospectively evaluated patients with atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), or negative for intraepithelial lesion or malignancy (NILM) cytology referred for colposcopy, and they compared p16/Ki-67 DS testing with high-risk HPV (HR-HPV) testing for the detection of cervical intraepithelial neoplasia grade 2 or worse (CIN 2+); comparable sensitivities for CIN 2+ detection were seen (97.3% and 98.7%, respectively).⁸

Dual-stain testing exhibited higher specificity at 99.3% compared with HR-HPV testing at 52.2%. Incorporating DS testing into triage strategies also led to fewer colposcopies needed to detect CIN 2+ compared with current ASCCP guidelines that use traditional cervical cancer screening algorithms.

DS cytology strategy had the highest sensitivity for CIN 2+ detection

An additional study by Stanczuk and colleagues evaluated triage strategies in a cohort of HR-HPV positive patients who participated in the Scottish Papillomavirus Dumfries and Galloway study with HPV 16/18 genotyping (HPV 16/18), liquid-based cytology (LBC), and p16/Ki-67 DS cytology.⁹ Of these 3 triage strategies, DS cytology had the highest sensitivity for the detection of CIN 2+, at 77.7% (with a specificity of 74.2%), performance that is arguably better than cytology.

When evaluated in sequence as part of a triage strategy after HPV primary screening, HPV 16/18–positive patients reflexed to DS testing showed a similar sensitivity as those who would be triaged with LBC (TABLE).⁹

DS testing’s potential

These studies add to the growing body of literature that supports the use of DS testing in cervical cancer screening management guidelines and that are being incorporated into currently existing workflows. Furthermore, with advancements in digital imaging and machine learning, DS testing holds the potential for a high throughput, reproducible, and accurate risk stratification that can replace the current reliance on cytology, furthering the potential for a fully molecular Pap test.^10,11

Continue to: Cervical cancer screening in women older than age 65: Is there benefit?...

Firtina Tuncer S, Tuncer HA. Cervical cancer screening in women aged older than 65 years. J Low Genit Tract Dis. 2023;27:207-211.

Booth BB, Tranberg M, Gustafson LW, et al. Risk of cervical intraepithelial neoplasia grade 2 or worse in women aged  ≥ 69 referred to colposcopy due to an HPV-positive screening test. BMC Cancer. 2023;23:405.
 

Current guidelines in the United States recommend that cervical cancer screening for all persons with a cervix end at age 65. These age restrictions were a change in guidelines updated in 2012 and endorsed by the US Preventive Services Task Force.^12,13 Evidence suggests that because of high likelihood of regression and slow progression of disease, risks of screening prior to age 21 outweigh its benefits. With primary HPV testing, the age at screening debut is 25 for the same reasons.¹⁴ In people with a history of CIN 2+, active surveillance should continue for at least 25 years with HPV-based screening regardless of age. In the absence of a history of CIN 2+, however, the data to support discontinuation of screening after age 65 are less clear.

HPV positivity found to be most substantial risk for CIN 2+

In a study published this year in the Journal of Lower Genital Tract Disease, Firtina Tuncer and colleagues described their experience extending “routine screening” in patients older than 65 years.¹⁵ Data including cervical cytology, HPV test results, biopsy findings, and endocervical curettage results were collected, and abnormal findings were managed according to the 2012 and 2019 ASCCP guidelines.

When compared with negative HPV testing and normal cytology, the authors found that HPV positivity and abnormal cytology increased the risk of CIN 2+(odds ratio [OR], 136.1 and 13.1, respectively). Patients whose screening prior to age 65 had been insufficient or demonstrated CIN 2+ in the preceding 10 years were similarly more likely to have findings of CIN 2+ (OR, 9.7 when compared with HPV-negative controls).

The authors concluded that, among persons with a cervix older than age 65, previous screening and abnormal cytology were important in risk stratifications for CIN 2+; however, HPV positivity conferred the most substantial risk.

Study finds cervical dysplasia is prevalent in older populations

It has been suggested that screening for cervical cancer should continue beyond age 65 as cytology-based screening may have decreased sensitivity in older patients, which may contribute to the higher rates of advanced-stage diagnoses and cancer-related death in this population.^16,17

Authors of an observational study conducted in Denmark invited persons with a cervix aged 69 and older to have one additional HPV-based screening test, and they referred them for colposcopy if HPV positive or in the presence of ASCUS or greater cytology.¹⁸ Among the 191 patients with HPV-positive results, 20% were found to have a diagnosis of CIN 2+, and 24.4% had CIN 2+ detected at another point in the study period. Notably, most patients diagnosed with CIN 2+ had no abnormalities visualized on colposcopy, and the majority of biopsies taken (65.8%) did not contain the transitional zone.

Biopsies underestimated CIN 2+ in 17.9% of cases compared with loop electrosurgical excision procedure (LEEP). These findings suggest both that high-grade cervical dysplasia is prevalent in an older population and that older populations may be susceptible to false-negative results. They also further support the use of HPV-based screening.

Harnessing the immune system to improve survival rates in recurrent cervical cancer

Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856-1867.

Unfortunately, most clinical trials for recurrent or metastatic cervical cancer are negative trials or have results that show limited impact on disease outcomes. Currently, cervical cancer is treated with multiple agents, including platinum-based chemotherapy and bevacizumab, a medication that targets vascular growth. Despite these usually very effective drugs given in combination to cervical cancer patients, long-term survival remains low. Over the past few decades, many trials have been designed to help patients with this terrible disease, but few have shown significant promise.

Immune checkpoint inhibitors, such as pembrolizumab, have revolutionized care for many cancers. Checkpoint inhibitors block the proteins that cause a tumor to remain undetected by the immune system’s army of T cells. By blocking these proteins, the cancer cells can then be recognized by the immune system as foreign. Several studies have concluded that including immune checkpoint inhibitors in the comprehensive regimen for recurrent cervical cancer improves survival.

Addition of pembrolizumab increased survival

Investigators in the phase 3 double-blinded KEYNOTE-826 trial evaluated whether or not the addition of pembrolizumab to standard of care improved progression-free and overall survival in advanced, recurrent, or persistent cervical cancer.¹⁹ As part of the evaluation, the investigators measured the protein that turns off the immune system’s ability to recognize tumors, anti-programmed cell death protein-1 (PD-1).

Compared with placebo, the investigators found that, regardless of PD-1 status, the addition of pembrolizumab immunotherapy to the standard regimen increased progression-free survival and overall survival without any significantly increased adverse effects or safety concerns (FIGURE).¹⁹ At 1 year after treatment, more patients who received pembrolizumab were still alive regardless of PD-1 status, and their responses lasted longer. The most profound improvements were seen in patients whose tumors exhibited high expression of PD-L1, the target of pembrolizumab and many other immune checkpoint inhibitors.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Cervical cancer was the most common cancer killer of persons with a cervix in the early 1900s in the United States. Widespread adoption of the Pap test in the mid-20th century followed by large-scale outreach through programs such as the National Breast and Cervical Cancer Early Detection Program have dramatically reduced deaths from cervical cancer. The development of a highly effective vaccine that targets human papillomavirus (HPV), the virus implicated in all cervical cancers, has made prevention even more accessible and attainable. Primary prevention with HPV vaccination in conjunction with regular screening as recommended by current guidelines is the most effective way we can prevent cervical cancer.

Despite these advances, the incidence and death rates from cervical cancer have plateaued over the last decade.¹ Additionally, many fear that due to the poor attendance at screening visits since the beginning of the COVID-19 pandemic, the incidence might further rise in the United States.² Among those in the United States diagnosed with cervical cancer, more than 50% have not been screened in over 5 years or had their abnormal results not managed as recommended by current guidelines, suggesting that operational and access issues are contributors to incident cervical cancer. In addition, HPV vaccination rates have increased only slightly from year to year. According to the most recent data from the Centers for Disease Control and Prevention (CDC), coverage with 1 or more doses of HPV vaccine in 2021 increased only by 1.8% and has stagnated, with administration to about 75% of those for whom it is recommended.³ The plateauing will limit our ability to eradicate cervical cancer in the United States, permitting death from a largely preventable disease.

Establishing the framework for the eradication of cervical cancer

The World Health Organization (WHO) adopted a global strategy called the Cervical Cancer Elimination Initiative in August 2020. This initiative is a multipronged effort that focuses on vaccination (90% of girls fully vaccinated by age 15), screening (70% of women screened by age 35 with an effective test and again at age 45), and treatment (90% treatment of precancer and 90% management of women with invasive cancer).⁴

These are the numbers we need to achieve if all countries are to reach a cervical cancer incidence of less than 4 per 100,000 persons with a cervix. The WHO further suggests that each country should meet the “90-70-90” targets by 2030 if we are to achieve the low incidence by the turn of the century.⁴ To date, few regions of the world have achieved these goals, and sadly the United States is not among them.

In response to this call to action, many medical and policymaking organizations are taking inventory and implementing strategies to achieve the WHO 2030 targets for cervical cancer eradication. In the United States, the Society of Gynecologic Oncology (SGO; www.sgo.org), the American Society for Colposcopy and Cervical Pathology (ASCCP; www.ASCCP.org), the American College of Obstetricians and Gynecologists (ACOG; www.acog.org), the American Cancer Society (ACS; www.cancer.org), and many others have initiated programs in a collaborative esprit de corps with the aim of eradicating this deadly disease.

In this Update, we review several studies with evidence of screening and management strategies that show promise of accelerating the eradication of cervical cancer.

Continue to: Transitioning to primary HPV screening in the United States...

Downs LS Jr, Nayar R, Gerndt J, et al; American Cancer Society Primary HPV Screening Initiative Steering Committee. Implementation in action: collaborating on the transition to primary HPV screening for cervical cancer in the United States. CA Cancer J Clin. 2023;73:458-460.

The American Cancer Society released an updated cervical cancer screening guideline in July 2020 that recommended testing for HPV as the preferred strategy. Reasons behind the change, moving away from a Pap test as part of the initial screen, are:

• increased sensitivity of primary HPV testing when compared with conventional cervical cytology (Pap test)
• improved risk stratification to identify who is at risk for cervical cancer now and in the future
• improved efficiency in identifying those who need colposcopy, thus limiting unnecessary procedures without increasing the risk of false-negative tests, thereby missing cervical precancer or invasive cancer.

Some countries with organized screening programs have already made the switch. Self-sampling for HPV is currently being considered for an approved use in the United States, further improving access to screening for cervical cancer when the initial step can be completed by the patient at home or simplified in nontraditional health care settings.²

ACS initiative created to address barriers to primary HPV testing

Challenges to primary HPV testing remain, including laboratory implementation, payment, and operationalizing clinical workflow (for example, HPV testing with reflex cytology instead of cytology with reflex HPV testing).⁵ There are undoubtedly other unforeseen barriers in the current US health care environment.

In a recent commentary, Downs and colleagues described how the ACS has convened the Primary HPV Screening Initiative (PHSI), nested under the ACS National Roundtable on Cervical Cancer, which is charged with identifying critical barriers to, and opportunities for, transitioning to primary HPV screening.⁵ The deliverable will be a roadmap with tools and recommendations to support health systems, laboratories, providers, patients, and payers as they make this evolution.

Work groups will develop resources

Patients, particularly those who have had routine cervical cancer screening over their lifetime, also will be curious about the changes in recommendations. The Provider Needs Workgroup within the PHSI structure will develop tools and patient education materials regarding the data, workflow, benefits, and safety of this new paradigm for cervical cancer screening.

Laboratories that process and interpret tests likely will bear the heaviest load of changes. For example, not all commercially available HPV tests in the United States are approved by the US Food and Drug Administration (FDA) for primary HPV testing. Some sites will need to adapt their equipment to ensure adherence to FDA-approved tests. Laboratory workflows will need to be altered for aliquots to be tested for HPV first, and the remainder for cytology. Quality assurance and accreditation requirements for testing will need modifications, and further efforts will be needed to ensure sufficient numbers of trained cytopathologists, whose workforce is rapidly declining, for processing and reading cervical cytology.

In addition, payment for HPV testing alone, without the need for a Pap test, might not be supported by payers that support safety-net providers and sites, who arguably serve the most vulnerable patients and those most at risk for cervical cancer. Collaboration across medical professionals, societies, payers, and policymakers will provide a critical infrastructure to make the change in the most seamless fashion and limit the harm from missed opportunities for screening.

Continue to: The quest for a “molecular Pap”: Dual-stain testing as a predictor of high-grade CIN...

Magkana M, Mentzelopoulou P, Magkana E, et al. p16/Ki-67 Dual staining is a reliable biomarker for risk stratification for patients with borderline/mild cytology in cervical cancer screening. Anticancer Res. 2022;42:2599-2606.

Stanczuk G, Currie H, Forson W, et al. Clinical performance of triage strategies for Hr-HPV-positive women; a longitudinal evaluation of cytology, p16/K-67 dual stain cytology, and HPV16/18 genotyping. Cancer Epidemiol Biomarkers Prev. 2022;31:1492-1498.
 

One new technology that was recently FDA approved and recommended for management of abnormal cervical cancer screening testing is dual-stain (DS) testing. Dual-stain testing is a cytology-based test that evaluates the concurrent expression of p16, a tumor suppressor protein upregulated in HPV oncogenesis, and Ki-67, a cell proliferation marker.^6,7 Two recent studies have showcased the outstanding clinical performance of DS testing and triage strategies that incorporate DS testing.

Higher specificity, fewer colposcopies needed with DS testing

Magkana and colleagues prospectively evaluated patients with atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), or negative for intraepithelial lesion or malignancy (NILM) cytology referred for colposcopy, and they compared p16/Ki-67 DS testing with high-risk HPV (HR-HPV) testing for the detection of cervical intraepithelial neoplasia grade 2 or worse (CIN 2+); comparable sensitivities for CIN 2+ detection were seen (97.3% and 98.7%, respectively).⁸

Dual-stain testing exhibited higher specificity at 99.3% compared with HR-HPV testing at 52.2%. Incorporating DS testing into triage strategies also led to fewer colposcopies needed to detect CIN 2+ compared with current ASCCP guidelines that use traditional cervical cancer screening algorithms.

DS cytology strategy had the highest sensitivity for CIN 2+ detection

An additional study by Stanczuk and colleagues evaluated triage strategies in a cohort of HR-HPV positive patients who participated in the Scottish Papillomavirus Dumfries and Galloway study with HPV 16/18 genotyping (HPV 16/18), liquid-based cytology (LBC), and p16/Ki-67 DS cytology.⁹ Of these 3 triage strategies, DS cytology had the highest sensitivity for the detection of CIN 2+, at 77.7% (with a specificity of 74.2%), performance that is arguably better than cytology.

When evaluated in sequence as part of a triage strategy after HPV primary screening, HPV 16/18–positive patients reflexed to DS testing showed a similar sensitivity as those who would be triaged with LBC (TABLE).⁹

DS testing’s potential

These studies add to the growing body of literature that supports the use of DS testing in cervical cancer screening management guidelines and that are being incorporated into currently existing workflows. Furthermore, with advancements in digital imaging and machine learning, DS testing holds the potential for a high throughput, reproducible, and accurate risk stratification that can replace the current reliance on cytology, furthering the potential for a fully molecular Pap test.^10,11

Continue to: Cervical cancer screening in women older than age 65: Is there benefit?...

Firtina Tuncer S, Tuncer HA. Cervical cancer screening in women aged older than 65 years. J Low Genit Tract Dis. 2023;27:207-211.

Booth BB, Tranberg M, Gustafson LW, et al. Risk of cervical intraepithelial neoplasia grade 2 or worse in women aged  ≥ 69 referred to colposcopy due to an HPV-positive screening test. BMC Cancer. 2023;23:405.
 

Current guidelines in the United States recommend that cervical cancer screening for all persons with a cervix end at age 65. These age restrictions were a change in guidelines updated in 2012 and endorsed by the US Preventive Services Task Force.^12,13 Evidence suggests that because of high likelihood of regression and slow progression of disease, risks of screening prior to age 21 outweigh its benefits. With primary HPV testing, the age at screening debut is 25 for the same reasons.¹⁴ In people with a history of CIN 2+, active surveillance should continue for at least 25 years with HPV-based screening regardless of age. In the absence of a history of CIN 2+, however, the data to support discontinuation of screening after age 65 are less clear.

HPV positivity found to be most substantial risk for CIN 2+

In a study published this year in the Journal of Lower Genital Tract Disease, Firtina Tuncer and colleagues described their experience extending “routine screening” in patients older than 65 years.¹⁵ Data including cervical cytology, HPV test results, biopsy findings, and endocervical curettage results were collected, and abnormal findings were managed according to the 2012 and 2019 ASCCP guidelines.

When compared with negative HPV testing and normal cytology, the authors found that HPV positivity and abnormal cytology increased the risk of CIN 2+(odds ratio [OR], 136.1 and 13.1, respectively). Patients whose screening prior to age 65 had been insufficient or demonstrated CIN 2+ in the preceding 10 years were similarly more likely to have findings of CIN 2+ (OR, 9.7 when compared with HPV-negative controls).

The authors concluded that, among persons with a cervix older than age 65, previous screening and abnormal cytology were important in risk stratifications for CIN 2+; however, HPV positivity conferred the most substantial risk.

Study finds cervical dysplasia is prevalent in older populations

It has been suggested that screening for cervical cancer should continue beyond age 65 as cytology-based screening may have decreased sensitivity in older patients, which may contribute to the higher rates of advanced-stage diagnoses and cancer-related death in this population.^16,17

Authors of an observational study conducted in Denmark invited persons with a cervix aged 69 and older to have one additional HPV-based screening test, and they referred them for colposcopy if HPV positive or in the presence of ASCUS or greater cytology.¹⁸ Among the 191 patients with HPV-positive results, 20% were found to have a diagnosis of CIN 2+, and 24.4% had CIN 2+ detected at another point in the study period. Notably, most patients diagnosed with CIN 2+ had no abnormalities visualized on colposcopy, and the majority of biopsies taken (65.8%) did not contain the transitional zone.

Biopsies underestimated CIN 2+ in 17.9% of cases compared with loop electrosurgical excision procedure (LEEP). These findings suggest both that high-grade cervical dysplasia is prevalent in an older population and that older populations may be susceptible to false-negative results. They also further support the use of HPV-based screening.

Harnessing the immune system to improve survival rates in recurrent cervical cancer

Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856-1867.

Unfortunately, most clinical trials for recurrent or metastatic cervical cancer are negative trials or have results that show limited impact on disease outcomes. Currently, cervical cancer is treated with multiple agents, including platinum-based chemotherapy and bevacizumab, a medication that targets vascular growth. Despite these usually very effective drugs given in combination to cervical cancer patients, long-term survival remains low. Over the past few decades, many trials have been designed to help patients with this terrible disease, but few have shown significant promise.

Immune checkpoint inhibitors, such as pembrolizumab, have revolutionized care for many cancers. Checkpoint inhibitors block the proteins that cause a tumor to remain undetected by the immune system’s army of T cells. By blocking these proteins, the cancer cells can then be recognized by the immune system as foreign. Several studies have concluded that including immune checkpoint inhibitors in the comprehensive regimen for recurrent cervical cancer improves survival.

Addition of pembrolizumab increased survival

Investigators in the phase 3 double-blinded KEYNOTE-826 trial evaluated whether or not the addition of pembrolizumab to standard of care improved progression-free and overall survival in advanced, recurrent, or persistent cervical cancer.¹⁹ As part of the evaluation, the investigators measured the protein that turns off the immune system’s ability to recognize tumors, anti-programmed cell death protein-1 (PD-1).

Compared with placebo, the investigators found that, regardless of PD-1 status, the addition of pembrolizumab immunotherapy to the standard regimen increased progression-free survival and overall survival without any significantly increased adverse effects or safety concerns (FIGURE).¹⁹ At 1 year after treatment, more patients who received pembrolizumab were still alive regardless of PD-1 status, and their responses lasted longer. The most profound improvements were seen in patients whose tumors exhibited high expression of PD-L1, the target of pembrolizumab and many other immune checkpoint inhibitors.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Cervical cancer was the most common cancer killer of persons with a cervix in the early 1900s in the United States. Widespread adoption of the Pap test in the mid-20th century followed by large-scale outreach through programs such as the National Breast and Cervical Cancer Early Detection Program have dramatically reduced deaths from cervical cancer. The development of a highly effective vaccine that targets human papillomavirus (HPV), the virus implicated in all cervical cancers, has made prevention even more accessible and attainable. Primary prevention with HPV vaccination in conjunction with regular screening as recommended by current guidelines is the most effective way we can prevent cervical cancer.

Despite these advances, the incidence and death rates from cervical cancer have plateaued over the last decade.¹ Additionally, many fear that due to the poor attendance at screening visits since the beginning of the COVID-19 pandemic, the incidence might further rise in the United States.² Among those in the United States diagnosed with cervical cancer, more than 50% have not been screened in over 5 years or had their abnormal results not managed as recommended by current guidelines, suggesting that operational and access issues are contributors to incident cervical cancer. In addition, HPV vaccination rates have increased only slightly from year to year. According to the most recent data from the Centers for Disease Control and Prevention (CDC), coverage with 1 or more doses of HPV vaccine in 2021 increased only by 1.8% and has stagnated, with administration to about 75% of those for whom it is recommended.³ The plateauing will limit our ability to eradicate cervical cancer in the United States, permitting death from a largely preventable disease.

Establishing the framework for the eradication of cervical cancer

The World Health Organization (WHO) adopted a global strategy called the Cervical Cancer Elimination Initiative in August 2020. This initiative is a multipronged effort that focuses on vaccination (90% of girls fully vaccinated by age 15), screening (70% of women screened by age 35 with an effective test and again at age 45), and treatment (90% treatment of precancer and 90% management of women with invasive cancer).⁴

These are the numbers we need to achieve if all countries are to reach a cervical cancer incidence of less than 4 per 100,000 persons with a cervix. The WHO further suggests that each country should meet the “90-70-90” targets by 2030 if we are to achieve the low incidence by the turn of the century.⁴ To date, few regions of the world have achieved these goals, and sadly the United States is not among them.

In response to this call to action, many medical and policymaking organizations are taking inventory and implementing strategies to achieve the WHO 2030 targets for cervical cancer eradication. In the United States, the Society of Gynecologic Oncology (SGO; www.sgo.org), the American Society for Colposcopy and Cervical Pathology (ASCCP; www.ASCCP.org), the American College of Obstetricians and Gynecologists (ACOG; www.acog.org), the American Cancer Society (ACS; www.cancer.org), and many others have initiated programs in a collaborative esprit de corps with the aim of eradicating this deadly disease.

In this Update, we review several studies with evidence of screening and management strategies that show promise of accelerating the eradication of cervical cancer.

Continue to: Transitioning to primary HPV screening in the United States...

Downs LS Jr, Nayar R, Gerndt J, et al; American Cancer Society Primary HPV Screening Initiative Steering Committee. Implementation in action: collaborating on the transition to primary HPV screening for cervical cancer in the United States. CA Cancer J Clin. 2023;73:458-460.

The American Cancer Society released an updated cervical cancer screening guideline in July 2020 that recommended testing for HPV as the preferred strategy. Reasons behind the change, moving away from a Pap test as part of the initial screen, are:

• increased sensitivity of primary HPV testing when compared with conventional cervical cytology (Pap test)
• improved risk stratification to identify who is at risk for cervical cancer now and in the future
• improved efficiency in identifying those who need colposcopy, thus limiting unnecessary procedures without increasing the risk of false-negative tests, thereby missing cervical precancer or invasive cancer.

Some countries with organized screening programs have already made the switch. Self-sampling for HPV is currently being considered for an approved use in the United States, further improving access to screening for cervical cancer when the initial step can be completed by the patient at home or simplified in nontraditional health care settings.²

ACS initiative created to address barriers to primary HPV testing

Challenges to primary HPV testing remain, including laboratory implementation, payment, and operationalizing clinical workflow (for example, HPV testing with reflex cytology instead of cytology with reflex HPV testing).⁵ There are undoubtedly other unforeseen barriers in the current US health care environment.

In a recent commentary, Downs and colleagues described how the ACS has convened the Primary HPV Screening Initiative (PHSI), nested under the ACS National Roundtable on Cervical Cancer, which is charged with identifying critical barriers to, and opportunities for, transitioning to primary HPV screening.⁵ The deliverable will be a roadmap with tools and recommendations to support health systems, laboratories, providers, patients, and payers as they make this evolution.

Work groups will develop resources

Patients, particularly those who have had routine cervical cancer screening over their lifetime, also will be curious about the changes in recommendations. The Provider Needs Workgroup within the PHSI structure will develop tools and patient education materials regarding the data, workflow, benefits, and safety of this new paradigm for cervical cancer screening.

Laboratories that process and interpret tests likely will bear the heaviest load of changes. For example, not all commercially available HPV tests in the United States are approved by the US Food and Drug Administration (FDA) for primary HPV testing. Some sites will need to adapt their equipment to ensure adherence to FDA-approved tests. Laboratory workflows will need to be altered for aliquots to be tested for HPV first, and the remainder for cytology. Quality assurance and accreditation requirements for testing will need modifications, and further efforts will be needed to ensure sufficient numbers of trained cytopathologists, whose workforce is rapidly declining, for processing and reading cervical cytology.

In addition, payment for HPV testing alone, without the need for a Pap test, might not be supported by payers that support safety-net providers and sites, who arguably serve the most vulnerable patients and those most at risk for cervical cancer. Collaboration across medical professionals, societies, payers, and policymakers will provide a critical infrastructure to make the change in the most seamless fashion and limit the harm from missed opportunities for screening.

Continue to: The quest for a “molecular Pap”: Dual-stain testing as a predictor of high-grade CIN...

Magkana M, Mentzelopoulou P, Magkana E, et al. p16/Ki-67 Dual staining is a reliable biomarker for risk stratification for patients with borderline/mild cytology in cervical cancer screening. Anticancer Res. 2022;42:2599-2606.

Stanczuk G, Currie H, Forson W, et al. Clinical performance of triage strategies for Hr-HPV-positive women; a longitudinal evaluation of cytology, p16/K-67 dual stain cytology, and HPV16/18 genotyping. Cancer Epidemiol Biomarkers Prev. 2022;31:1492-1498.
 

One new technology that was recently FDA approved and recommended for management of abnormal cervical cancer screening testing is dual-stain (DS) testing. Dual-stain testing is a cytology-based test that evaluates the concurrent expression of p16, a tumor suppressor protein upregulated in HPV oncogenesis, and Ki-67, a cell proliferation marker.^6,7 Two recent studies have showcased the outstanding clinical performance of DS testing and triage strategies that incorporate DS testing.

Higher specificity, fewer colposcopies needed with DS testing

Magkana and colleagues prospectively evaluated patients with atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), or negative for intraepithelial lesion or malignancy (NILM) cytology referred for colposcopy, and they compared p16/Ki-67 DS testing with high-risk HPV (HR-HPV) testing for the detection of cervical intraepithelial neoplasia grade 2 or worse (CIN 2+); comparable sensitivities for CIN 2+ detection were seen (97.3% and 98.7%, respectively).⁸

Dual-stain testing exhibited higher specificity at 99.3% compared with HR-HPV testing at 52.2%. Incorporating DS testing into triage strategies also led to fewer colposcopies needed to detect CIN 2+ compared with current ASCCP guidelines that use traditional cervical cancer screening algorithms.

DS cytology strategy had the highest sensitivity for CIN 2+ detection

An additional study by Stanczuk and colleagues evaluated triage strategies in a cohort of HR-HPV positive patients who participated in the Scottish Papillomavirus Dumfries and Galloway study with HPV 16/18 genotyping (HPV 16/18), liquid-based cytology (LBC), and p16/Ki-67 DS cytology.⁹ Of these 3 triage strategies, DS cytology had the highest sensitivity for the detection of CIN 2+, at 77.7% (with a specificity of 74.2%), performance that is arguably better than cytology.

When evaluated in sequence as part of a triage strategy after HPV primary screening, HPV 16/18–positive patients reflexed to DS testing showed a similar sensitivity as those who would be triaged with LBC (TABLE).⁹

DS testing’s potential

These studies add to the growing body of literature that supports the use of DS testing in cervical cancer screening management guidelines and that are being incorporated into currently existing workflows. Furthermore, with advancements in digital imaging and machine learning, DS testing holds the potential for a high throughput, reproducible, and accurate risk stratification that can replace the current reliance on cytology, furthering the potential for a fully molecular Pap test.^10,11

Continue to: Cervical cancer screening in women older than age 65: Is there benefit?...

Firtina Tuncer S, Tuncer HA. Cervical cancer screening in women aged older than 65 years. J Low Genit Tract Dis. 2023;27:207-211.

Booth BB, Tranberg M, Gustafson LW, et al. Risk of cervical intraepithelial neoplasia grade 2 or worse in women aged  ≥ 69 referred to colposcopy due to an HPV-positive screening test. BMC Cancer. 2023;23:405.
 

Current guidelines in the United States recommend that cervical cancer screening for all persons with a cervix end at age 65. These age restrictions were a change in guidelines updated in 2012 and endorsed by the US Preventive Services Task Force.^12,13 Evidence suggests that because of high likelihood of regression and slow progression of disease, risks of screening prior to age 21 outweigh its benefits. With primary HPV testing, the age at screening debut is 25 for the same reasons.¹⁴ In people with a history of CIN 2+, active surveillance should continue for at least 25 years with HPV-based screening regardless of age. In the absence of a history of CIN 2+, however, the data to support discontinuation of screening after age 65 are less clear.

HPV positivity found to be most substantial risk for CIN 2+

In a study published this year in the Journal of Lower Genital Tract Disease, Firtina Tuncer and colleagues described their experience extending “routine screening” in patients older than 65 years.¹⁵ Data including cervical cytology, HPV test results, biopsy findings, and endocervical curettage results were collected, and abnormal findings were managed according to the 2012 and 2019 ASCCP guidelines.

When compared with negative HPV testing and normal cytology, the authors found that HPV positivity and abnormal cytology increased the risk of CIN 2+(odds ratio [OR], 136.1 and 13.1, respectively). Patients whose screening prior to age 65 had been insufficient or demonstrated CIN 2+ in the preceding 10 years were similarly more likely to have findings of CIN 2+ (OR, 9.7 when compared with HPV-negative controls).

The authors concluded that, among persons with a cervix older than age 65, previous screening and abnormal cytology were important in risk stratifications for CIN 2+; however, HPV positivity conferred the most substantial risk.

Study finds cervical dysplasia is prevalent in older populations

It has been suggested that screening for cervical cancer should continue beyond age 65 as cytology-based screening may have decreased sensitivity in older patients, which may contribute to the higher rates of advanced-stage diagnoses and cancer-related death in this population.^16,17

Authors of an observational study conducted in Denmark invited persons with a cervix aged 69 and older to have one additional HPV-based screening test, and they referred them for colposcopy if HPV positive or in the presence of ASCUS or greater cytology.¹⁸ Among the 191 patients with HPV-positive results, 20% were found to have a diagnosis of CIN 2+, and 24.4% had CIN 2+ detected at another point in the study period. Notably, most patients diagnosed with CIN 2+ had no abnormalities visualized on colposcopy, and the majority of biopsies taken (65.8%) did not contain the transitional zone.

Biopsies underestimated CIN 2+ in 17.9% of cases compared with loop electrosurgical excision procedure (LEEP). These findings suggest both that high-grade cervical dysplasia is prevalent in an older population and that older populations may be susceptible to false-negative results. They also further support the use of HPV-based screening.

Harnessing the immune system to improve survival rates in recurrent cervical cancer

Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856-1867.

Unfortunately, most clinical trials for recurrent or metastatic cervical cancer are negative trials or have results that show limited impact on disease outcomes. Currently, cervical cancer is treated with multiple agents, including platinum-based chemotherapy and bevacizumab, a medication that targets vascular growth. Despite these usually very effective drugs given in combination to cervical cancer patients, long-term survival remains low. Over the past few decades, many trials have been designed to help patients with this terrible disease, but few have shown significant promise.

Immune checkpoint inhibitors, such as pembrolizumab, have revolutionized care for many cancers. Checkpoint inhibitors block the proteins that cause a tumor to remain undetected by the immune system’s army of T cells. By blocking these proteins, the cancer cells can then be recognized by the immune system as foreign. Several studies have concluded that including immune checkpoint inhibitors in the comprehensive regimen for recurrent cervical cancer improves survival.

Addition of pembrolizumab increased survival

Investigators in the phase 3 double-blinded KEYNOTE-826 trial evaluated whether or not the addition of pembrolizumab to standard of care improved progression-free and overall survival in advanced, recurrent, or persistent cervical cancer.¹⁹ As part of the evaluation, the investigators measured the protein that turns off the immune system’s ability to recognize tumors, anti-programmed cell death protein-1 (PD-1).

Compared with placebo, the investigators found that, regardless of PD-1 status, the addition of pembrolizumab immunotherapy to the standard regimen increased progression-free survival and overall survival without any significantly increased adverse effects or safety concerns (FIGURE).¹⁹ At 1 year after treatment, more patients who received pembrolizumab were still alive regardless of PD-1 status, and their responses lasted longer. The most profound improvements were seen in patients whose tumors exhibited high expression of PD-L1, the target of pembrolizumab and many other immune checkpoint inhibitors.

Individuals spend close to half of their lives preventing, or planning for, pregnancy. As such, contraception plays a major role in patient-provider interactions. Contraception counseling and management is a common scenario encountered in the general gynecologist’s practice. Luckily, we have two evidence-based guidelines developed by the US Centers for Disease Control and Prevention (CDC) that support the provision of contraceptive care:

1. US Medical Eligibility for Contraceptive Use (US-MEC),¹ which provides guidance on which patients can safely use a method
2. US Selected Practice Recommendations for Contraceptive Use (US-SPR),² which provides method-specific guidance on how to use a method (including how to: initiate or start a method; manage adherence issues, such as a missed pill, etc; and manage common issues like breakthrough bleeding). Both of these guidelines are updated routinely and are publicly available online or for free, through smartphone applications.

While most contraceptive care is straightforward, there are circumstances that require additional consideration. In this 3-part series we review 3 clinical cases, existing evidence to guide management decisions, and our recommendations. In part 1, we focus on restarting hormonal contraception after ulipristal acetate administration. In parts 2 and 3, we will discuss removal of a nonpalpable contraceptive implant and the consideration of a levonorgestrel-releasing intrauterine device (LNG-IUD) for emergency contraception.

CASE Meeting emergency and follow-up contraception needs

A 27-year-old woman (G0) presents to you after having unprotected intercourse 4 days ago. She does not formally track her menstrual cycles and is unsure when her last menstrual period was. She is not using contraception but is interested in starting a method. After counseling, she elects to take a dose of oral ulipristal acetate (UPA; Ella) now for emergency contraception and would like to start a combined oral contraceptive (COC) pill moving forward.

How soon after taking UPA should you tell her to start the combined hormonal pill?

Effectiveness of hormonal contraception following UPA

UPA does not appear to decrease the efficacy of COCs when started around the same time. However, immediately starting a hormonal contraceptive can decrease the effectiveness of UPA, and as such, it is recommended to take UPA and then abstain or use a backup method for 7 days before initiating a hormonal contraceptive method.¹ By obtaining some additional information from your patient and with the use of shared decision making, though, your patient may be able to start their contraceptive method earlier than 5 days after UPA.

What is UPA

UPA is a progesterone receptor modulator used for emergency contraception intenhded to prevent pregnancy after unprotected intercourse or contraceptive failure.³ It works by delaying follicular rupture at least 5 days, if taken before the peak of the luteinizing hormone (LH) surge. If taken after that timeframe, it does not work. Since UPA competes for the progesterone receptor, there is a concern that the effectiveness of UPA may be decreased if a progestin-containing form of contraception is started immediately after taking UPA, or vice versa.⁴ Several studies have now specifically looked at the interaction between UPA and progestin-containing contraceptives, including at how UPA is impacted by the contraceptive method, and conversely, how the contraceptive method is impacted by UPA.^5-8

Data on types of hormonal contraception. Brache and colleagues demonstrated that UPA users who started a desogestrel progestin-only pill (DSG POP) the next day had higher rates of ovulation within 5 days of taking UPA (45%), compared with those who the next day started a placebo pill (3%).⁶ This type of progestin-only pill is not available in the United States.

A study by Edelman and colleagues demonstrated similar findings in those starting a COC pill containing estrogen and progestin. When taking a COC two days after UPA use, more participants had evidence of follicular rupture in less than 5 days.⁵ It should be noted that these studies focused on ovulation, which—while necessary for conception to occur—is a surrogate biomarker for pregnancy risk. Additional studies have looked at the impact of UPA on the COC and have not found that UPA impacts ovulation suppression of the COC with its initiation or use.⁸

Considering unprotected intercourse and UPA timing. Of course, the risk of pregnancy is reliant on cycle timing plus the presence of viable sperm in the reproductive tract. Sperm have been shown to only be viable in the reproductive tract for 5 days, which could result in fertilization and subsequent pregnancy. Longevity of an egg is much shorter, at 12 to 24 hours after ovulation. For this patient, her exposure was 4 days ago, but sperm are only viable for approximately 5 days—she could consider taking the UPA now and then starting a COC earlier than 5 days since she only needs an extra day or two of protection from the UPA from the sperm in her reproductive tract. Your patient’s involvement in this decision making is paramount, as only they can prioritize their desire to avoid pregnancy from their recent act of unprotected intercourse versus their immediate needs for starting their method of contraception. It is important that individuals abstain from sexual activity or use an additional back-up method during the first 7 days of starting their method of contraception.

Continue to: Counseling considerations for the case patient...

For a patient planning to start or resume a hormonal contraceptive method after taking UPA, the waiting period recommended by the CDC (5 days) is most beneficial for patients who are uncertain about their menstrual cycle timing in relation to the act of unprotected intercourse that already occurred and need to prioritize maximum effectiveness of emergency contraception.

Patients with unsure cycle-sex timing planning to self-start or resume a short-term hormonal contraceptive method (eg, pills, patches, or rings), should be counseled to wait 5 days after the most recent act of unprotected sex, before taking their hormonal contraceptive method.⁷ Patients with unsure cycle-sex timing planning to use provider-dependent hormonal contraceptive methods (eg, those requiring a prescription, including a progestin-contraceptive implant or depot medroxyprogesterone acetate) should also be counseled to wait. Timing of levonorgestrel and copper intrauterine devices are addressed in part 3 of this series.

However, if your patient has a good understanding of their menstrual cycle, and the primary concern is exposure from subsequent sexual encounters and not the recent unprotected intercourse, it is advisable to provide UPA and immediately initiate a contraceptive method. One of the primary reasons for emergency contraception failure is that its effectiveness is limited to the most recent act of unprotected sexual intercourse and does not extend to subsequent acts throughout the month.

For these patients with sure cycle-sex timing who are planning to start or resume short-or long-term contraceptive methods, and whose primary concern is to prevent pregnancy risk from subsequent sexual encounters, immediately initiating a contraceptive method is advisable. For provider-dependent methods, we must weigh the risk of unintended pregnancy from the act of intercourse that already occurred (and the potential to increase that risk by initiating a method that could compromise UPA efficacy) versus the future risk of pregnancy if the patient cannot return for a contraception visit.⁷

In short, starting the contraceptive method at the time of UPA use can be considered after shared decision making with the patient and understanding what their primary concerns are.

Important point

Counsel on using backup barrier contraception after UPA

Oral emergency contraception only covers that one act of unprotected intercourse and does not continue to protect a patient from pregnancy for the rest of their cycle. When taken before ovulation, UPA works by delaying follicular development and rupture for at least 5 days. Patients who continue to have unprotected intercourse after taking UPA are at a high risk of an unintended pregnancy from this ‘stalled’ follicle that will eventually ovulate. Follicular maturation resumes after UPA’s effects wane, and the patient is primed for ovulation (and therefore unintended pregnancy) if ongoing unprotected intercourse occurs for the rest of their cycle.

Therefore, it is important to counsel patients on the need, if they do not desire a pregnancy, to abstain or start a method of contraception.

Final question

What about starting or resuming non–hormonal contraceptive methods?

Non-hormonal contraceptive methods can be started immediately with UPA use.¹

CASE Resolved

After shared decision making, the patient decides to start using the COC pill. You prescribe her both UPA for emergency contraception and a combined hormonal contraceptive pill. Given her unsure cycle-sex timing, she expresses to you that her most important priority is preventing unintended pregnancy. You counsel her to set a reminder on her phone to start taking the pill 5 days from her most recent act of unprotected intercourse. You also counsel her to use a back-up barrier method of contraception for 7 days after starting her COC pill. ●

Individuals spend close to half of their lives preventing, or planning for, pregnancy. As such, contraception plays a major role in patient-provider interactions. Contraception counseling and management is a common scenario encountered in the general gynecologist’s practice. Luckily, we have two evidence-based guidelines developed by the US Centers for Disease Control and Prevention (CDC) that support the provision of contraceptive care:

1. US Medical Eligibility for Contraceptive Use (US-MEC),¹ which provides guidance on which patients can safely use a method
2. US Selected Practice Recommendations for Contraceptive Use (US-SPR),² which provides method-specific guidance on how to use a method (including how to: initiate or start a method; manage adherence issues, such as a missed pill, etc; and manage common issues like breakthrough bleeding). Both of these guidelines are updated routinely and are publicly available online or for free, through smartphone applications.

While most contraceptive care is straightforward, there are circumstances that require additional consideration. In this 3-part series we review 3 clinical cases, existing evidence to guide management decisions, and our recommendations. In part 1, we focus on restarting hormonal contraception after ulipristal acetate administration. In parts 2 and 3, we will discuss removal of a nonpalpable contraceptive implant and the consideration of a levonorgestrel-releasing intrauterine device (LNG-IUD) for emergency contraception.

CASE Meeting emergency and follow-up contraception needs

A 27-year-old woman (G0) presents to you after having unprotected intercourse 4 days ago. She does not formally track her menstrual cycles and is unsure when her last menstrual period was. She is not using contraception but is interested in starting a method. After counseling, she elects to take a dose of oral ulipristal acetate (UPA; Ella) now for emergency contraception and would like to start a combined oral contraceptive (COC) pill moving forward.

How soon after taking UPA should you tell her to start the combined hormonal pill?

Effectiveness of hormonal contraception following UPA

UPA does not appear to decrease the efficacy of COCs when started around the same time. However, immediately starting a hormonal contraceptive can decrease the effectiveness of UPA, and as such, it is recommended to take UPA and then abstain or use a backup method for 7 days before initiating a hormonal contraceptive method.¹ By obtaining some additional information from your patient and with the use of shared decision making, though, your patient may be able to start their contraceptive method earlier than 5 days after UPA.

What is UPA

UPA is a progesterone receptor modulator used for emergency contraception intenhded to prevent pregnancy after unprotected intercourse or contraceptive failure.³ It works by delaying follicular rupture at least 5 days, if taken before the peak of the luteinizing hormone (LH) surge. If taken after that timeframe, it does not work. Since UPA competes for the progesterone receptor, there is a concern that the effectiveness of UPA may be decreased if a progestin-containing form of contraception is started immediately after taking UPA, or vice versa.⁴ Several studies have now specifically looked at the interaction between UPA and progestin-containing contraceptives, including at how UPA is impacted by the contraceptive method, and conversely, how the contraceptive method is impacted by UPA.^5-8

Data on types of hormonal contraception. Brache and colleagues demonstrated that UPA users who started a desogestrel progestin-only pill (DSG POP) the next day had higher rates of ovulation within 5 days of taking UPA (45%), compared with those who the next day started a placebo pill (3%).⁶ This type of progestin-only pill is not available in the United States.

A study by Edelman and colleagues demonstrated similar findings in those starting a COC pill containing estrogen and progestin. When taking a COC two days after UPA use, more participants had evidence of follicular rupture in less than 5 days.⁵ It should be noted that these studies focused on ovulation, which—while necessary for conception to occur—is a surrogate biomarker for pregnancy risk. Additional studies have looked at the impact of UPA on the COC and have not found that UPA impacts ovulation suppression of the COC with its initiation or use.⁸

Considering unprotected intercourse and UPA timing. Of course, the risk of pregnancy is reliant on cycle timing plus the presence of viable sperm in the reproductive tract. Sperm have been shown to only be viable in the reproductive tract for 5 days, which could result in fertilization and subsequent pregnancy. Longevity of an egg is much shorter, at 12 to 24 hours after ovulation. For this patient, her exposure was 4 days ago, but sperm are only viable for approximately 5 days—she could consider taking the UPA now and then starting a COC earlier than 5 days since she only needs an extra day or two of protection from the UPA from the sperm in her reproductive tract. Your patient’s involvement in this decision making is paramount, as only they can prioritize their desire to avoid pregnancy from their recent act of unprotected intercourse versus their immediate needs for starting their method of contraception. It is important that individuals abstain from sexual activity or use an additional back-up method during the first 7 days of starting their method of contraception.

Continue to: Counseling considerations for the case patient...

For a patient planning to start or resume a hormonal contraceptive method after taking UPA, the waiting period recommended by the CDC (5 days) is most beneficial for patients who are uncertain about their menstrual cycle timing in relation to the act of unprotected intercourse that already occurred and need to prioritize maximum effectiveness of emergency contraception.

Patients with unsure cycle-sex timing planning to self-start or resume a short-term hormonal contraceptive method (eg, pills, patches, or rings), should be counseled to wait 5 days after the most recent act of unprotected sex, before taking their hormonal contraceptive method.⁷ Patients with unsure cycle-sex timing planning to use provider-dependent hormonal contraceptive methods (eg, those requiring a prescription, including a progestin-contraceptive implant or depot medroxyprogesterone acetate) should also be counseled to wait. Timing of levonorgestrel and copper intrauterine devices are addressed in part 3 of this series.

However, if your patient has a good understanding of their menstrual cycle, and the primary concern is exposure from subsequent sexual encounters and not the recent unprotected intercourse, it is advisable to provide UPA and immediately initiate a contraceptive method. One of the primary reasons for emergency contraception failure is that its effectiveness is limited to the most recent act of unprotected sexual intercourse and does not extend to subsequent acts throughout the month.

For these patients with sure cycle-sex timing who are planning to start or resume short-or long-term contraceptive methods, and whose primary concern is to prevent pregnancy risk from subsequent sexual encounters, immediately initiating a contraceptive method is advisable. For provider-dependent methods, we must weigh the risk of unintended pregnancy from the act of intercourse that already occurred (and the potential to increase that risk by initiating a method that could compromise UPA efficacy) versus the future risk of pregnancy if the patient cannot return for a contraception visit.⁷

In short, starting the contraceptive method at the time of UPA use can be considered after shared decision making with the patient and understanding what their primary concerns are.

Important point

Counsel on using backup barrier contraception after UPA

Oral emergency contraception only covers that one act of unprotected intercourse and does not continue to protect a patient from pregnancy for the rest of their cycle. When taken before ovulation, UPA works by delaying follicular development and rupture for at least 5 days. Patients who continue to have unprotected intercourse after taking UPA are at a high risk of an unintended pregnancy from this ‘stalled’ follicle that will eventually ovulate. Follicular maturation resumes after UPA’s effects wane, and the patient is primed for ovulation (and therefore unintended pregnancy) if ongoing unprotected intercourse occurs for the rest of their cycle.

Therefore, it is important to counsel patients on the need, if they do not desire a pregnancy, to abstain or start a method of contraception.

Final question

What about starting or resuming non–hormonal contraceptive methods?

Non-hormonal contraceptive methods can be started immediately with UPA use.¹

CASE Resolved

After shared decision making, the patient decides to start using the COC pill. You prescribe her both UPA for emergency contraception and a combined hormonal contraceptive pill. Given her unsure cycle-sex timing, she expresses to you that her most important priority is preventing unintended pregnancy. You counsel her to set a reminder on her phone to start taking the pill 5 days from her most recent act of unprotected intercourse. You also counsel her to use a back-up barrier method of contraception for 7 days after starting her COC pill. ●

Individuals spend close to half of their lives preventing, or planning for, pregnancy. As such, contraception plays a major role in patient-provider interactions. Contraception counseling and management is a common scenario encountered in the general gynecologist’s practice. Luckily, we have two evidence-based guidelines developed by the US Centers for Disease Control and Prevention (CDC) that support the provision of contraceptive care:

1. US Medical Eligibility for Contraceptive Use (US-MEC),¹ which provides guidance on which patients can safely use a method
2. US Selected Practice Recommendations for Contraceptive Use (US-SPR),² which provides method-specific guidance on how to use a method (including how to: initiate or start a method; manage adherence issues, such as a missed pill, etc; and manage common issues like breakthrough bleeding). Both of these guidelines are updated routinely and are publicly available online or for free, through smartphone applications.

While most contraceptive care is straightforward, there are circumstances that require additional consideration. In this 3-part series we review 3 clinical cases, existing evidence to guide management decisions, and our recommendations. In part 1, we focus on restarting hormonal contraception after ulipristal acetate administration. In parts 2 and 3, we will discuss removal of a nonpalpable contraceptive implant and the consideration of a levonorgestrel-releasing intrauterine device (LNG-IUD) for emergency contraception.

CASE Meeting emergency and follow-up contraception needs

A 27-year-old woman (G0) presents to you after having unprotected intercourse 4 days ago. She does not formally track her menstrual cycles and is unsure when her last menstrual period was. She is not using contraception but is interested in starting a method. After counseling, she elects to take a dose of oral ulipristal acetate (UPA; Ella) now for emergency contraception and would like to start a combined oral contraceptive (COC) pill moving forward.

How soon after taking UPA should you tell her to start the combined hormonal pill?

Effectiveness of hormonal contraception following UPA

UPA does not appear to decrease the efficacy of COCs when started around the same time. However, immediately starting a hormonal contraceptive can decrease the effectiveness of UPA, and as such, it is recommended to take UPA and then abstain or use a backup method for 7 days before initiating a hormonal contraceptive method.¹ By obtaining some additional information from your patient and with the use of shared decision making, though, your patient may be able to start their contraceptive method earlier than 5 days after UPA.

What is UPA

UPA is a progesterone receptor modulator used for emergency contraception intenhded to prevent pregnancy after unprotected intercourse or contraceptive failure.³ It works by delaying follicular rupture at least 5 days, if taken before the peak of the luteinizing hormone (LH) surge. If taken after that timeframe, it does not work. Since UPA competes for the progesterone receptor, there is a concern that the effectiveness of UPA may be decreased if a progestin-containing form of contraception is started immediately after taking UPA, or vice versa.⁴ Several studies have now specifically looked at the interaction between UPA and progestin-containing contraceptives, including at how UPA is impacted by the contraceptive method, and conversely, how the contraceptive method is impacted by UPA.^5-8

Data on types of hormonal contraception. Brache and colleagues demonstrated that UPA users who started a desogestrel progestin-only pill (DSG POP) the next day had higher rates of ovulation within 5 days of taking UPA (45%), compared with those who the next day started a placebo pill (3%).⁶ This type of progestin-only pill is not available in the United States.

A study by Edelman and colleagues demonstrated similar findings in those starting a COC pill containing estrogen and progestin. When taking a COC two days after UPA use, more participants had evidence of follicular rupture in less than 5 days.⁵ It should be noted that these studies focused on ovulation, which—while necessary for conception to occur—is a surrogate biomarker for pregnancy risk. Additional studies have looked at the impact of UPA on the COC and have not found that UPA impacts ovulation suppression of the COC with its initiation or use.⁸

Considering unprotected intercourse and UPA timing. Of course, the risk of pregnancy is reliant on cycle timing plus the presence of viable sperm in the reproductive tract. Sperm have been shown to only be viable in the reproductive tract for 5 days, which could result in fertilization and subsequent pregnancy. Longevity of an egg is much shorter, at 12 to 24 hours after ovulation. For this patient, her exposure was 4 days ago, but sperm are only viable for approximately 5 days—she could consider taking the UPA now and then starting a COC earlier than 5 days since she only needs an extra day or two of protection from the UPA from the sperm in her reproductive tract. Your patient’s involvement in this decision making is paramount, as only they can prioritize their desire to avoid pregnancy from their recent act of unprotected intercourse versus their immediate needs for starting their method of contraception. It is important that individuals abstain from sexual activity or use an additional back-up method during the first 7 days of starting their method of contraception.

Continue to: Counseling considerations for the case patient...

For a patient planning to start or resume a hormonal contraceptive method after taking UPA, the waiting period recommended by the CDC (5 days) is most beneficial for patients who are uncertain about their menstrual cycle timing in relation to the act of unprotected intercourse that already occurred and need to prioritize maximum effectiveness of emergency contraception.

Patients with unsure cycle-sex timing planning to self-start or resume a short-term hormonal contraceptive method (eg, pills, patches, or rings), should be counseled to wait 5 days after the most recent act of unprotected sex, before taking their hormonal contraceptive method.⁷ Patients with unsure cycle-sex timing planning to use provider-dependent hormonal contraceptive methods (eg, those requiring a prescription, including a progestin-contraceptive implant or depot medroxyprogesterone acetate) should also be counseled to wait. Timing of levonorgestrel and copper intrauterine devices are addressed in part 3 of this series.

However, if your patient has a good understanding of their menstrual cycle, and the primary concern is exposure from subsequent sexual encounters and not the recent unprotected intercourse, it is advisable to provide UPA and immediately initiate a contraceptive method. One of the primary reasons for emergency contraception failure is that its effectiveness is limited to the most recent act of unprotected sexual intercourse and does not extend to subsequent acts throughout the month.

For these patients with sure cycle-sex timing who are planning to start or resume short-or long-term contraceptive methods, and whose primary concern is to prevent pregnancy risk from subsequent sexual encounters, immediately initiating a contraceptive method is advisable. For provider-dependent methods, we must weigh the risk of unintended pregnancy from the act of intercourse that already occurred (and the potential to increase that risk by initiating a method that could compromise UPA efficacy) versus the future risk of pregnancy if the patient cannot return for a contraception visit.⁷

In short, starting the contraceptive method at the time of UPA use can be considered after shared decision making with the patient and understanding what their primary concerns are.

Important point

Counsel on using backup barrier contraception after UPA

Oral emergency contraception only covers that one act of unprotected intercourse and does not continue to protect a patient from pregnancy for the rest of their cycle. When taken before ovulation, UPA works by delaying follicular development and rupture for at least 5 days. Patients who continue to have unprotected intercourse after taking UPA are at a high risk of an unintended pregnancy from this ‘stalled’ follicle that will eventually ovulate. Follicular maturation resumes after UPA’s effects wane, and the patient is primed for ovulation (and therefore unintended pregnancy) if ongoing unprotected intercourse occurs for the rest of their cycle.

Therefore, it is important to counsel patients on the need, if they do not desire a pregnancy, to abstain or start a method of contraception.

Final question

What about starting or resuming non–hormonal contraceptive methods?

Non-hormonal contraceptive methods can be started immediately with UPA use.¹

CASE Resolved

After shared decision making, the patient decides to start using the COC pill. You prescribe her both UPA for emergency contraception and a combined hormonal contraceptive pill. Given her unsure cycle-sex timing, she expresses to you that her most important priority is preventing unintended pregnancy. You counsel her to set a reminder on her phone to start taking the pill 5 days from her most recent act of unprotected intercourse. You also counsel her to use a back-up barrier method of contraception for 7 days after starting her COC pill. ●

Nonthermal atmospheric plasma (NTAP)(or cold atmospheric plasma [CAP]) is a rapidly developing treatment modality for a wide range of dermatologic conditions. Plasma (or ionized gas) refers to a state of matter composed of electrons, protons, and neutral atoms that generate reactive oxygen and nitrogen species.¹ Plasma previously was created using thermal energy, but recent advances have allowed the creation of plasma using atmospheric pressure and room temperature; thus, NTAP can be used without causing damage to living tissue through heat.¹ Plasma technology varies greatly, but it generally can be classified as either direct or indirect therapy; direct therapy uses the human body as an electrode, whereas indirect therapy creates plasma through the interaction between 2 electrode devices.^1,2 When used on the skin, important dose-dependent relationships have been observed, with CAP application longer than 2 minutes being associated with increased keratinocyte and fibroblast apoptosis.² Thus, CAP can cause diverse changes to the skin depending on application time and methodology. At adequate yet low concentrations, plasma can promote fibroblast proliferation and upregulate genes involved in collagen and transforming growth factor synthesis.¹ Additionally, the reactive oxygen and nitrogen species created by NTAP have been shown to inactivate microorganisms through the destruction of biofilms, lead to diminished immune cell infiltration and cytokine release in autoimmune dermatologic conditions, and exert antitumor properties through cellular DNA damage.^1-3 In dermatology, these properties can be harvested to promote wound healing at low doses and the treatment of proliferative skin conditions at high doses.¹

Because of its novelty, the safety profile of NTAP is still under investigation, but preliminary studies are promising and show no damage to the skin barrier when excessive plasma exposure is avoided.⁴ However, dose- and time-dependent damage to cells has been shown. As a result, the exact dose of plasma considered safe is highly variable depending on the vessel, technique, and user, and future clinical research is needed to guide this methodology.⁴ Additionally, CAP has been shown to cause little pain at the skin surface and may lead to decreased levels of pain in healing wound sites.⁵ Given this promising safety profile and minimal discomfort to patients, NTAP technology remains promising for use in pediatric dermatology, but there are limited data to characterize its potential use in this population. In this systematic review, we aimed to elucidate reported applications of NTAP for skin conditions in children and discuss the trajectory of this technology in the future of pediatric dermatology.

Methodology

A comprehensive literature review was conducted to identify studies evaluating NTAP technology in pediatric populations using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. A search of PubMed, Embase, and Web of Science articles was conducted in April 2023 using the terms nonthermal atmospheric plasma or cold atmospheric plasma. All English-language articles that described the use of NTAP as a treatment in pediatric populations or articles that described NTAP use in the treatment of common conditions in this patient group were included based on a review of the article titles and abstracts by 2 independent reviewers, followed by full-text review of relevant articles (M.G., C.L.). Any discrepancies in eligible articles were settled by a third independent researcher (M.V.). One hundred twenty studies were identified, and 95 were screened for inclusion; 9 studies met inclusion criteria and were summarized in this review.

Results

A total of 9 studies were included in this review: 3 describing the success of NTAP in pediatric populations^6-8 and 6 describing the potential success of NTAP for dermatologic conditions commonly seen in children (Table).^9-14

Studies Describing Success of NTAP—Three clinical reports described the efficacy of NTAP in pediatric dermatology. A case series from 2020 showed full clearance of warts in 100% of patients (n=5) with a 0% recurrence rate when NTAP treatment was applied for 2 minutes to each lesion during each treatment session with the electrode held 1 mm from the lesional surface.⁶ Each patient was followed up at 3 to 4 weeks, and treatment was repeated if lesions persisted. Patients reported no pain during the procedure, and no adverse effects were noted over the course of treatment.⁶ Second, a case report described full clearance of diaper dermatitis with no recurrence after 6 months following 6 treatments with NTAP in a 14-month-old girl.⁷ After treatment with econazole nitrate cream, oral antibiotics, and prednisone failed, CAP treatment was initiated. Each treatment lasted 15 minutes with 3-day time intervals between each of the 6 treatments. There were no adverse events or recurrence of rash at 6-month follow-up.⁷ A final case report described full clearance of molluscum contagiosum (MC), with no recurrence after 2 months following 4 treatments with NTAP in a 12-year-old boy.⁸ The patient had untreated MC on the face, neck, shoulder, and thighs. Lesions of the face were treated with CAP, while the other sites were treated with cantharidin using a 0.7% collodion-based solution. Four CAP treatments were performed at 1-month intervals, with CAP applied 1 mm from the lesional surfaces in a circular pattern for 2 minutes. At follow-up 2 months after the final treatment, the patient had no adverse effects and showed no pigmentary changes or scarring.⁸

Studies Describing the Potential Success of NTAP—Beyond these studies, limited research has been done on NTAP in pediatric populations. The Table summarizes 6 additional studies completed with promising treatment results for dermatologic conditions commonly seen in children: striae distensae, keloids, atopic dermatitis, psoriasis, inverse psoriasis, and acne vulgaris. Across all reports and studies, patients showed significant improvement in their dermatologic conditions following the use of NTAP technology with limited adverse effects reported (P<.05). Suwanchinda and Nararatwanchai⁹ studied the use of CAP for the treatment of striae distensae. They recruited 23 patients and treated half the body with CAP biweekly for 5 sessions; the other half was left untreated. At follow-up 30 days after the final treatment, striae distensae had improved for both patient and observer assessment scores.⁹ Another study performed by Suwanchinda and Nararatwanchai¹⁰ looked at the efficacy of CAP in treating keloids. They recruited 18 patients, and keloid scars were treated in halves—one half treated with CAP biweekly for 5 sessions and the other left untreated. At follow-up 30 days after the final treatment, keloids significantly improved in color, melanin, texture, and hemoglobin based on assessment by the Antera 3D imaging system (Miravex Limited)(P<.05).¹⁰

Kim et al¹¹ studied the efficacy of CAP for the treatment of atopic dermatitis in 22 patients. Each patient had mild to moderate atopic dermatitis that had not been treated with topical agents or antibiotics for at least 2 weeks prior to beginning the study. Additionally, only patients with symmetric lesions—meaning only patients with lesions on both sides of the anatomical extremities—were included. Each patient then received CAP on 1 symmetric lesion and placebo on the other. Cold atmospheric plasma treatment was done 5 mm away from the lesion, and each treatment lasted for 5 minutes. Treatments were done at weeks 0, 1, and 2, with follow-up 4 weeks after the final treatment. The clinical severity of disease was assessed at weeks 0, 1, 2, and 4. Results showed that at week 4, the mean (SD) modified Atopic Dermatitis Antecubital Severity score decreased from 33.73 (21.21) at week 0 to 13.12 (15.92). Additionally, the pruritic visual analog scale showed significant improvement with treatment vs baseline (P≤.0001).¹¹

Two studies examined how NTAP can be used in the treatment of psoriasis. First, Gareri et al¹² used CAP to treat a psoriatic plaque in a 20-year-old woman. These plaques on the left hand previously had been unresponsive to topical psoriasis treatments. The patient received 2 treatments with CAP on days 0 and 3; at 14 days, the plaque completely resolved with an itch score of 0.¹² Next, Zheng et al¹³ treated 2 patients with NTAP for inverse psoriasis. The first patient was a 26-year-old woman with plaques in the axilla and buttocks as well as inframammary lesions that failed to respond to treatment with topicals and vitamin D analogues. She received CAP treatments 2 to 3 times weekly for 5 total treatments with application to each region occurring 1 mm from the skin surface. The lesions completely resolved with no recurrence at 6 weeks. The second patient was a 38-year-old woman with inverse psoriasis in the axilla and groin; she received treatment every 3 days for 8 total treatments, which led to complete remission, with no recurrence noted at 1 month.¹³

Arisi et al¹⁴ used NTAP to treat acne vulgaris in 2 patients. The first patient was a 24-year-old man with moderate acne on the face that did not improve with topicals or oral antibiotics. The patient received 5 CAP treatments with no adverse events noted. The patient discontinued treatment on his own, but the number of lesions decreased after the fifth treatment. The second patient was a 21-year-old woman with moderate facial acne that failed to respond to treatment with topicals and oral tetracycline. The patient received 8 CAP treatments and experienced a reduction in the number of lesions during treatment. There were no adverse events, and improvement was maintained at 3-month follow-up.¹⁴

Comment

Although the use of NTAP in pediatric dermatology is scarcely described in the literature, the technology will certainly have applications in the future treatment of a wide variety of pediatric disorders. In addition to the clinical success shown in several studies,^6-14 this technology has been shown to cause minimal damage to skin when application time is minimized. One study conducted on ex vivo skin showed that NTAP technology can safely be used for up to 2 minutes without major DNA damage.¹⁵ Through its diverse mechanisms of action, NTAP can induce modification of proteins and cell membranes in a noninvasive manner.² In conditions with impaired barrier function, such as atopic and diaper dermatitis, studies in mouse models have shown improvement in lesions via upregulation of mesencephalic astrocyte-derived neurotrophic factor that contributes to decreased inflammation and cell apoptosis.¹⁶ Additionally, the generation of reactive oxygen and nitrogen species has been shown to decrease Staphylococcus aureus colonization to improve atopic dermatitis lesions in patients.¹¹

Many other proposed benefits of NTAP in dermatologic disease also have been proposed. Nonthermal atmospheric plasma has been shown to increase messenger RNA expression of proinflammatory cytokines (IL-1, IL-6) and upregulate type III collagen production in early stages of wound healing.¹⁷ Furthermore, NTAP has been shown to stimulate nuclear factor erythroid 2–related pathways involved in antioxidant production in keratinocytes, further promoting wound healing.¹⁸ Additionally, CAP has been shown to increase expression of caspases and induce mitochondrial dysfunction that promotes cell death in different cancer cell lines.¹⁹ It is clear that the exact breadth of NTAP’s biochemical effects are unknown, but the current literature shows promise for its use in cutaneous healing and cancer treatment.

Beyond its diverse applications, treatment with NTAP yields a unique advantage to pharmacologic therapies in that there is no risk for medication interactions or risk for pharmacologic adverse effects. Cantharidin is not approved by the US Food and Drug Administration but commonly is used to treat MC. It is a blister beetle extract that causes a blister to form when applied to the skin. When orally ingested, the drug is toxic to the gastrointestinal tract and kidneys because of its phosphodiesterase inhibition, a feared complication in pediatric patients who may inadvertently ingest it during treatment.²⁰ This utility extends beyond MC, such as the beneficial outcomes described by Suwanchinda and Nararatwanchai¹⁰ in using NTAP for keloid scars. Treatment with NTAP may replace triamcinolone injections, which are commonly associated with skin atrophy and ulceration. In addition, NTAP application to the skin has been reported to be relatively painless.⁵ Thus, NTAP maintains a distinct advantage over other commonly used nonpharmacologic treatment options, including curettage and cryosurgery. Curettage has widely been noted to be traumatic for the patient, may be more likely to leave a mark, and is prone to user error.²⁰ Cryosurgery is a common form of treatment for MC because it is cost-effective and has good cosmetic results; however, it is more painful than cantharidin or anesthetized curettage.²¹ Treatment with NTAP is an emerging therapeutic tool with an expanding role in the treatment of dermatologic patients because it provides advantages over many standard therapies due to its minimal side-effect profile involving pain and nonpharmacologic nature.

Limitations of this report include exclusion of non–English-language articles and lack of control or comparison groups to standard therapies across studies. Additionally, reports of NTAP success occurred in many conditions that are self-limited and may have resolved on their own. Regardless, we aimed to summarize how NTAP currently is being used in pediatric populations and highlight its potential uses moving forward. Given its promising safety profile and painless nature, future clinical trials should prioritize the investigation of NTAP use in common pediatric dermatologic conditions to determine if they are equal or superior to current standards of care.

Nonthermal atmospheric plasma (NTAP)(or cold atmospheric plasma [CAP]) is a rapidly developing treatment modality for a wide range of dermatologic conditions. Plasma (or ionized gas) refers to a state of matter composed of electrons, protons, and neutral atoms that generate reactive oxygen and nitrogen species.¹ Plasma previously was created using thermal energy, but recent advances have allowed the creation of plasma using atmospheric pressure and room temperature; thus, NTAP can be used without causing damage to living tissue through heat.¹ Plasma technology varies greatly, but it generally can be classified as either direct or indirect therapy; direct therapy uses the human body as an electrode, whereas indirect therapy creates plasma through the interaction between 2 electrode devices.^1,2 When used on the skin, important dose-dependent relationships have been observed, with CAP application longer than 2 minutes being associated with increased keratinocyte and fibroblast apoptosis.² Thus, CAP can cause diverse changes to the skin depending on application time and methodology. At adequate yet low concentrations, plasma can promote fibroblast proliferation and upregulate genes involved in collagen and transforming growth factor synthesis.¹ Additionally, the reactive oxygen and nitrogen species created by NTAP have been shown to inactivate microorganisms through the destruction of biofilms, lead to diminished immune cell infiltration and cytokine release in autoimmune dermatologic conditions, and exert antitumor properties through cellular DNA damage.^1-3 In dermatology, these properties can be harvested to promote wound healing at low doses and the treatment of proliferative skin conditions at high doses.¹

Because of its novelty, the safety profile of NTAP is still under investigation, but preliminary studies are promising and show no damage to the skin barrier when excessive plasma exposure is avoided.⁴ However, dose- and time-dependent damage to cells has been shown. As a result, the exact dose of plasma considered safe is highly variable depending on the vessel, technique, and user, and future clinical research is needed to guide this methodology.⁴ Additionally, CAP has been shown to cause little pain at the skin surface and may lead to decreased levels of pain in healing wound sites.⁵ Given this promising safety profile and minimal discomfort to patients, NTAP technology remains promising for use in pediatric dermatology, but there are limited data to characterize its potential use in this population. In this systematic review, we aimed to elucidate reported applications of NTAP for skin conditions in children and discuss the trajectory of this technology in the future of pediatric dermatology.

Methodology

A comprehensive literature review was conducted to identify studies evaluating NTAP technology in pediatric populations using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. A search of PubMed, Embase, and Web of Science articles was conducted in April 2023 using the terms nonthermal atmospheric plasma or cold atmospheric plasma. All English-language articles that described the use of NTAP as a treatment in pediatric populations or articles that described NTAP use in the treatment of common conditions in this patient group were included based on a review of the article titles and abstracts by 2 independent reviewers, followed by full-text review of relevant articles (M.G., C.L.). Any discrepancies in eligible articles were settled by a third independent researcher (M.V.). One hundred twenty studies were identified, and 95 were screened for inclusion; 9 studies met inclusion criteria and were summarized in this review.

Results

A total of 9 studies were included in this review: 3 describing the success of NTAP in pediatric populations^6-8 and 6 describing the potential success of NTAP for dermatologic conditions commonly seen in children (Table).^9-14

Studies Describing Success of NTAP—Three clinical reports described the efficacy of NTAP in pediatric dermatology. A case series from 2020 showed full clearance of warts in 100% of patients (n=5) with a 0% recurrence rate when NTAP treatment was applied for 2 minutes to each lesion during each treatment session with the electrode held 1 mm from the lesional surface.⁶ Each patient was followed up at 3 to 4 weeks, and treatment was repeated if lesions persisted. Patients reported no pain during the procedure, and no adverse effects were noted over the course of treatment.⁶ Second, a case report described full clearance of diaper dermatitis with no recurrence after 6 months following 6 treatments with NTAP in a 14-month-old girl.⁷ After treatment with econazole nitrate cream, oral antibiotics, and prednisone failed, CAP treatment was initiated. Each treatment lasted 15 minutes with 3-day time intervals between each of the 6 treatments. There were no adverse events or recurrence of rash at 6-month follow-up.⁷ A final case report described full clearance of molluscum contagiosum (MC), with no recurrence after 2 months following 4 treatments with NTAP in a 12-year-old boy.⁸ The patient had untreated MC on the face, neck, shoulder, and thighs. Lesions of the face were treated with CAP, while the other sites were treated with cantharidin using a 0.7% collodion-based solution. Four CAP treatments were performed at 1-month intervals, with CAP applied 1 mm from the lesional surfaces in a circular pattern for 2 minutes. At follow-up 2 months after the final treatment, the patient had no adverse effects and showed no pigmentary changes or scarring.⁸

Studies Describing the Potential Success of NTAP—Beyond these studies, limited research has been done on NTAP in pediatric populations. The Table summarizes 6 additional studies completed with promising treatment results for dermatologic conditions commonly seen in children: striae distensae, keloids, atopic dermatitis, psoriasis, inverse psoriasis, and acne vulgaris. Across all reports and studies, patients showed significant improvement in their dermatologic conditions following the use of NTAP technology with limited adverse effects reported (P<.05). Suwanchinda and Nararatwanchai⁹ studied the use of CAP for the treatment of striae distensae. They recruited 23 patients and treated half the body with CAP biweekly for 5 sessions; the other half was left untreated. At follow-up 30 days after the final treatment, striae distensae had improved for both patient and observer assessment scores.⁹ Another study performed by Suwanchinda and Nararatwanchai¹⁰ looked at the efficacy of CAP in treating keloids. They recruited 18 patients, and keloid scars were treated in halves—one half treated with CAP biweekly for 5 sessions and the other left untreated. At follow-up 30 days after the final treatment, keloids significantly improved in color, melanin, texture, and hemoglobin based on assessment by the Antera 3D imaging system (Miravex Limited)(P<.05).¹⁰

Kim et al¹¹ studied the efficacy of CAP for the treatment of atopic dermatitis in 22 patients. Each patient had mild to moderate atopic dermatitis that had not been treated with topical agents or antibiotics for at least 2 weeks prior to beginning the study. Additionally, only patients with symmetric lesions—meaning only patients with lesions on both sides of the anatomical extremities—were included. Each patient then received CAP on 1 symmetric lesion and placebo on the other. Cold atmospheric plasma treatment was done 5 mm away from the lesion, and each treatment lasted for 5 minutes. Treatments were done at weeks 0, 1, and 2, with follow-up 4 weeks after the final treatment. The clinical severity of disease was assessed at weeks 0, 1, 2, and 4. Results showed that at week 4, the mean (SD) modified Atopic Dermatitis Antecubital Severity score decreased from 33.73 (21.21) at week 0 to 13.12 (15.92). Additionally, the pruritic visual analog scale showed significant improvement with treatment vs baseline (P≤.0001).¹¹

Two studies examined how NTAP can be used in the treatment of psoriasis. First, Gareri et al¹² used CAP to treat a psoriatic plaque in a 20-year-old woman. These plaques on the left hand previously had been unresponsive to topical psoriasis treatments. The patient received 2 treatments with CAP on days 0 and 3; at 14 days, the plaque completely resolved with an itch score of 0.¹² Next, Zheng et al¹³ treated 2 patients with NTAP for inverse psoriasis. The first patient was a 26-year-old woman with plaques in the axilla and buttocks as well as inframammary lesions that failed to respond to treatment with topicals and vitamin D analogues. She received CAP treatments 2 to 3 times weekly for 5 total treatments with application to each region occurring 1 mm from the skin surface. The lesions completely resolved with no recurrence at 6 weeks. The second patient was a 38-year-old woman with inverse psoriasis in the axilla and groin; she received treatment every 3 days for 8 total treatments, which led to complete remission, with no recurrence noted at 1 month.¹³

Arisi et al¹⁴ used NTAP to treat acne vulgaris in 2 patients. The first patient was a 24-year-old man with moderate acne on the face that did not improve with topicals or oral antibiotics. The patient received 5 CAP treatments with no adverse events noted. The patient discontinued treatment on his own, but the number of lesions decreased after the fifth treatment. The second patient was a 21-year-old woman with moderate facial acne that failed to respond to treatment with topicals and oral tetracycline. The patient received 8 CAP treatments and experienced a reduction in the number of lesions during treatment. There were no adverse events, and improvement was maintained at 3-month follow-up.¹⁴

Comment

Although the use of NTAP in pediatric dermatology is scarcely described in the literature, the technology will certainly have applications in the future treatment of a wide variety of pediatric disorders. In addition to the clinical success shown in several studies,^6-14 this technology has been shown to cause minimal damage to skin when application time is minimized. One study conducted on ex vivo skin showed that NTAP technology can safely be used for up to 2 minutes without major DNA damage.¹⁵ Through its diverse mechanisms of action, NTAP can induce modification of proteins and cell membranes in a noninvasive manner.² In conditions with impaired barrier function, such as atopic and diaper dermatitis, studies in mouse models have shown improvement in lesions via upregulation of mesencephalic astrocyte-derived neurotrophic factor that contributes to decreased inflammation and cell apoptosis.¹⁶ Additionally, the generation of reactive oxygen and nitrogen species has been shown to decrease Staphylococcus aureus colonization to improve atopic dermatitis lesions in patients.¹¹

Many other proposed benefits of NTAP in dermatologic disease also have been proposed. Nonthermal atmospheric plasma has been shown to increase messenger RNA expression of proinflammatory cytokines (IL-1, IL-6) and upregulate type III collagen production in early stages of wound healing.¹⁷ Furthermore, NTAP has been shown to stimulate nuclear factor erythroid 2–related pathways involved in antioxidant production in keratinocytes, further promoting wound healing.¹⁸ Additionally, CAP has been shown to increase expression of caspases and induce mitochondrial dysfunction that promotes cell death in different cancer cell lines.¹⁹ It is clear that the exact breadth of NTAP’s biochemical effects are unknown, but the current literature shows promise for its use in cutaneous healing and cancer treatment.

Beyond its diverse applications, treatment with NTAP yields a unique advantage to pharmacologic therapies in that there is no risk for medication interactions or risk for pharmacologic adverse effects. Cantharidin is not approved by the US Food and Drug Administration but commonly is used to treat MC. It is a blister beetle extract that causes a blister to form when applied to the skin. When orally ingested, the drug is toxic to the gastrointestinal tract and kidneys because of its phosphodiesterase inhibition, a feared complication in pediatric patients who may inadvertently ingest it during treatment.²⁰ This utility extends beyond MC, such as the beneficial outcomes described by Suwanchinda and Nararatwanchai¹⁰ in using NTAP for keloid scars. Treatment with NTAP may replace triamcinolone injections, which are commonly associated with skin atrophy and ulceration. In addition, NTAP application to the skin has been reported to be relatively painless.⁵ Thus, NTAP maintains a distinct advantage over other commonly used nonpharmacologic treatment options, including curettage and cryosurgery. Curettage has widely been noted to be traumatic for the patient, may be more likely to leave a mark, and is prone to user error.²⁰ Cryosurgery is a common form of treatment for MC because it is cost-effective and has good cosmetic results; however, it is more painful than cantharidin or anesthetized curettage.²¹ Treatment with NTAP is an emerging therapeutic tool with an expanding role in the treatment of dermatologic patients because it provides advantages over many standard therapies due to its minimal side-effect profile involving pain and nonpharmacologic nature.

Limitations of this report include exclusion of non–English-language articles and lack of control or comparison groups to standard therapies across studies. Additionally, reports of NTAP success occurred in many conditions that are self-limited and may have resolved on their own. Regardless, we aimed to summarize how NTAP currently is being used in pediatric populations and highlight its potential uses moving forward. Given its promising safety profile and painless nature, future clinical trials should prioritize the investigation of NTAP use in common pediatric dermatologic conditions to determine if they are equal or superior to current standards of care.

Nonthermal atmospheric plasma (NTAP)(or cold atmospheric plasma [CAP]) is a rapidly developing treatment modality for a wide range of dermatologic conditions. Plasma (or ionized gas) refers to a state of matter composed of electrons, protons, and neutral atoms that generate reactive oxygen and nitrogen species.¹ Plasma previously was created using thermal energy, but recent advances have allowed the creation of plasma using atmospheric pressure and room temperature; thus, NTAP can be used without causing damage to living tissue through heat.¹ Plasma technology varies greatly, but it generally can be classified as either direct or indirect therapy; direct therapy uses the human body as an electrode, whereas indirect therapy creates plasma through the interaction between 2 electrode devices.^1,2 When used on the skin, important dose-dependent relationships have been observed, with CAP application longer than 2 minutes being associated with increased keratinocyte and fibroblast apoptosis.² Thus, CAP can cause diverse changes to the skin depending on application time and methodology. At adequate yet low concentrations, plasma can promote fibroblast proliferation and upregulate genes involved in collagen and transforming growth factor synthesis.¹ Additionally, the reactive oxygen and nitrogen species created by NTAP have been shown to inactivate microorganisms through the destruction of biofilms, lead to diminished immune cell infiltration and cytokine release in autoimmune dermatologic conditions, and exert antitumor properties through cellular DNA damage.^1-3 In dermatology, these properties can be harvested to promote wound healing at low doses and the treatment of proliferative skin conditions at high doses.¹

Because of its novelty, the safety profile of NTAP is still under investigation, but preliminary studies are promising and show no damage to the skin barrier when excessive plasma exposure is avoided.⁴ However, dose- and time-dependent damage to cells has been shown. As a result, the exact dose of plasma considered safe is highly variable depending on the vessel, technique, and user, and future clinical research is needed to guide this methodology.⁴ Additionally, CAP has been shown to cause little pain at the skin surface and may lead to decreased levels of pain in healing wound sites.⁵ Given this promising safety profile and minimal discomfort to patients, NTAP technology remains promising for use in pediatric dermatology, but there are limited data to characterize its potential use in this population. In this systematic review, we aimed to elucidate reported applications of NTAP for skin conditions in children and discuss the trajectory of this technology in the future of pediatric dermatology.

Methodology

A comprehensive literature review was conducted to identify studies evaluating NTAP technology in pediatric populations using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. A search of PubMed, Embase, and Web of Science articles was conducted in April 2023 using the terms nonthermal atmospheric plasma or cold atmospheric plasma. All English-language articles that described the use of NTAP as a treatment in pediatric populations or articles that described NTAP use in the treatment of common conditions in this patient group were included based on a review of the article titles and abstracts by 2 independent reviewers, followed by full-text review of relevant articles (M.G., C.L.). Any discrepancies in eligible articles were settled by a third independent researcher (M.V.). One hundred twenty studies were identified, and 95 were screened for inclusion; 9 studies met inclusion criteria and were summarized in this review.

Results

A total of 9 studies were included in this review: 3 describing the success of NTAP in pediatric populations^6-8 and 6 describing the potential success of NTAP for dermatologic conditions commonly seen in children (Table).^9-14

Studies Describing Success of NTAP—Three clinical reports described the efficacy of NTAP in pediatric dermatology. A case series from 2020 showed full clearance of warts in 100% of patients (n=5) with a 0% recurrence rate when NTAP treatment was applied for 2 minutes to each lesion during each treatment session with the electrode held 1 mm from the lesional surface.⁶ Each patient was followed up at 3 to 4 weeks, and treatment was repeated if lesions persisted. Patients reported no pain during the procedure, and no adverse effects were noted over the course of treatment.⁶ Second, a case report described full clearance of diaper dermatitis with no recurrence after 6 months following 6 treatments with NTAP in a 14-month-old girl.⁷ After treatment with econazole nitrate cream, oral antibiotics, and prednisone failed, CAP treatment was initiated. Each treatment lasted 15 minutes with 3-day time intervals between each of the 6 treatments. There were no adverse events or recurrence of rash at 6-month follow-up.⁷ A final case report described full clearance of molluscum contagiosum (MC), with no recurrence after 2 months following 4 treatments with NTAP in a 12-year-old boy.⁸ The patient had untreated MC on the face, neck, shoulder, and thighs. Lesions of the face were treated with CAP, while the other sites were treated with cantharidin using a 0.7% collodion-based solution. Four CAP treatments were performed at 1-month intervals, with CAP applied 1 mm from the lesional surfaces in a circular pattern for 2 minutes. At follow-up 2 months after the final treatment, the patient had no adverse effects and showed no pigmentary changes or scarring.⁸

Studies Describing the Potential Success of NTAP—Beyond these studies, limited research has been done on NTAP in pediatric populations. The Table summarizes 6 additional studies completed with promising treatment results for dermatologic conditions commonly seen in children: striae distensae, keloids, atopic dermatitis, psoriasis, inverse psoriasis, and acne vulgaris. Across all reports and studies, patients showed significant improvement in their dermatologic conditions following the use of NTAP technology with limited adverse effects reported (P<.05). Suwanchinda and Nararatwanchai⁹ studied the use of CAP for the treatment of striae distensae. They recruited 23 patients and treated half the body with CAP biweekly for 5 sessions; the other half was left untreated. At follow-up 30 days after the final treatment, striae distensae had improved for both patient and observer assessment scores.⁹ Another study performed by Suwanchinda and Nararatwanchai¹⁰ looked at the efficacy of CAP in treating keloids. They recruited 18 patients, and keloid scars were treated in halves—one half treated with CAP biweekly for 5 sessions and the other left untreated. At follow-up 30 days after the final treatment, keloids significantly improved in color, melanin, texture, and hemoglobin based on assessment by the Antera 3D imaging system (Miravex Limited)(P<.05).¹⁰

Kim et al¹¹ studied the efficacy of CAP for the treatment of atopic dermatitis in 22 patients. Each patient had mild to moderate atopic dermatitis that had not been treated with topical agents or antibiotics for at least 2 weeks prior to beginning the study. Additionally, only patients with symmetric lesions—meaning only patients with lesions on both sides of the anatomical extremities—were included. Each patient then received CAP on 1 symmetric lesion and placebo on the other. Cold atmospheric plasma treatment was done 5 mm away from the lesion, and each treatment lasted for 5 minutes. Treatments were done at weeks 0, 1, and 2, with follow-up 4 weeks after the final treatment. The clinical severity of disease was assessed at weeks 0, 1, 2, and 4. Results showed that at week 4, the mean (SD) modified Atopic Dermatitis Antecubital Severity score decreased from 33.73 (21.21) at week 0 to 13.12 (15.92). Additionally, the pruritic visual analog scale showed significant improvement with treatment vs baseline (P≤.0001).¹¹

Two studies examined how NTAP can be used in the treatment of psoriasis. First, Gareri et al¹² used CAP to treat a psoriatic plaque in a 20-year-old woman. These plaques on the left hand previously had been unresponsive to topical psoriasis treatments. The patient received 2 treatments with CAP on days 0 and 3; at 14 days, the plaque completely resolved with an itch score of 0.¹² Next, Zheng et al¹³ treated 2 patients with NTAP for inverse psoriasis. The first patient was a 26-year-old woman with plaques in the axilla and buttocks as well as inframammary lesions that failed to respond to treatment with topicals and vitamin D analogues. She received CAP treatments 2 to 3 times weekly for 5 total treatments with application to each region occurring 1 mm from the skin surface. The lesions completely resolved with no recurrence at 6 weeks. The second patient was a 38-year-old woman with inverse psoriasis in the axilla and groin; she received treatment every 3 days for 8 total treatments, which led to complete remission, with no recurrence noted at 1 month.¹³

Arisi et al¹⁴ used NTAP to treat acne vulgaris in 2 patients. The first patient was a 24-year-old man with moderate acne on the face that did not improve with topicals or oral antibiotics. The patient received 5 CAP treatments with no adverse events noted. The patient discontinued treatment on his own, but the number of lesions decreased after the fifth treatment. The second patient was a 21-year-old woman with moderate facial acne that failed to respond to treatment with topicals and oral tetracycline. The patient received 8 CAP treatments and experienced a reduction in the number of lesions during treatment. There were no adverse events, and improvement was maintained at 3-month follow-up.¹⁴

Comment

Although the use of NTAP in pediatric dermatology is scarcely described in the literature, the technology will certainly have applications in the future treatment of a wide variety of pediatric disorders. In addition to the clinical success shown in several studies,^6-14 this technology has been shown to cause minimal damage to skin when application time is minimized. One study conducted on ex vivo skin showed that NTAP technology can safely be used for up to 2 minutes without major DNA damage.¹⁵ Through its diverse mechanisms of action, NTAP can induce modification of proteins and cell membranes in a noninvasive manner.² In conditions with impaired barrier function, such as atopic and diaper dermatitis, studies in mouse models have shown improvement in lesions via upregulation of mesencephalic astrocyte-derived neurotrophic factor that contributes to decreased inflammation and cell apoptosis.¹⁶ Additionally, the generation of reactive oxygen and nitrogen species has been shown to decrease Staphylococcus aureus colonization to improve atopic dermatitis lesions in patients.¹¹

Many other proposed benefits of NTAP in dermatologic disease also have been proposed. Nonthermal atmospheric plasma has been shown to increase messenger RNA expression of proinflammatory cytokines (IL-1, IL-6) and upregulate type III collagen production in early stages of wound healing.¹⁷ Furthermore, NTAP has been shown to stimulate nuclear factor erythroid 2–related pathways involved in antioxidant production in keratinocytes, further promoting wound healing.¹⁸ Additionally, CAP has been shown to increase expression of caspases and induce mitochondrial dysfunction that promotes cell death in different cancer cell lines.¹⁹ It is clear that the exact breadth of NTAP’s biochemical effects are unknown, but the current literature shows promise for its use in cutaneous healing and cancer treatment.

Beyond its diverse applications, treatment with NTAP yields a unique advantage to pharmacologic therapies in that there is no risk for medication interactions or risk for pharmacologic adverse effects. Cantharidin is not approved by the US Food and Drug Administration but commonly is used to treat MC. It is a blister beetle extract that causes a blister to form when applied to the skin. When orally ingested, the drug is toxic to the gastrointestinal tract and kidneys because of its phosphodiesterase inhibition, a feared complication in pediatric patients who may inadvertently ingest it during treatment.²⁰ This utility extends beyond MC, such as the beneficial outcomes described by Suwanchinda and Nararatwanchai¹⁰ in using NTAP for keloid scars. Treatment with NTAP may replace triamcinolone injections, which are commonly associated with skin atrophy and ulceration. In addition, NTAP application to the skin has been reported to be relatively painless.⁵ Thus, NTAP maintains a distinct advantage over other commonly used nonpharmacologic treatment options, including curettage and cryosurgery. Curettage has widely been noted to be traumatic for the patient, may be more likely to leave a mark, and is prone to user error.²⁰ Cryosurgery is a common form of treatment for MC because it is cost-effective and has good cosmetic results; however, it is more painful than cantharidin or anesthetized curettage.²¹ Treatment with NTAP is an emerging therapeutic tool with an expanding role in the treatment of dermatologic patients because it provides advantages over many standard therapies due to its minimal side-effect profile involving pain and nonpharmacologic nature.

Limitations of this report include exclusion of non–English-language articles and lack of control or comparison groups to standard therapies across studies. Additionally, reports of NTAP success occurred in many conditions that are self-limited and may have resolved on their own. Regardless, we aimed to summarize how NTAP currently is being used in pediatric populations and highlight its potential uses moving forward. Given its promising safety profile and painless nature, future clinical trials should prioritize the investigation of NTAP use in common pediatric dermatologic conditions to determine if they are equal or superior to current standards of care.