Clinical Review

This year’s Menopause Update focuses on 2 menopause-related issues relevant to ObGyns and our menopausal patients:

• choosing the safest regimens, particularly with respect to risk of breast cancer, when prescribing hormone therapy (HT) to menopausal women
• reviewing the risks and benefits of premenopausal bilateral salpingo-oophorectomy and the pros and cons of replacement HT in surgically menopausal patients.

We hope that you find this updated information useful as you care for menopausal women.

Revisiting menopausal HT  and the risk of breast cancer:  What we know now

Abenhaim HA, Suissa S,  Azoulay L, et al. Menopausal hormone therapy formulation and breast cancer risk. Obstet Gynecol. 2022;139:1103-1110. doi: 10.1097/AOG.0000000000004723.

Reevaluation of the Women’s Health Initiative randomized controlled trials (WHI RCTs), long-term (median follow-up more than 20 years) cumulative  follow-up data, and results from additional studies have suggested that estrogen therapy (ET) alone in menopausal women with prior hysterectomy does not increase the risk of breast cancer. By contrast, estrogen with progestin (synthetic progestogens that include medroxyprogesterone acetate [MPA] and norethindrone acetate) slightly increases the risk of breast cancer. In the past 10 years, several publications have shed light on whether the type of progestogen affects the risk of breast cancer and can help provide evidence-based information to guide clinicians.

Breast cancer risk with combined HT and synthetic progestin

In the first part of the WHI RCT, women were randomly assigned to receive either conjugated equine estrogen (CEE) plus synthetic progestin (MPA) or a placebo. Combined estrogen-progestin therapy (EPT) was associated with a modestly elevated risk of breast cancer.¹ In the second part of the WHI trial, CEE only (estrogen alone, ET) was compared with placebo among women with prior  hysterectomy, with no effect found on breast cancer incidence.²

Most older observational studies published in 2003 to 2005 found that neither CEE nor estradiol appeared to increase the risk of breast cancer when used alone.^3-5 However, estrogen use in combination with synthetic progestins (MPA, norethindrone, levonorgestrel, and norgestrel) has been associated with an increased risk of breast cancer,^4,6 while the elevated risk of breast cancer with micronized progesterone has been less substantial.^7,8

Continue to: Newer data suggest the type of progestogen used affects risk...

 

 

Newer data suggest the type of progestogen used affects risk

In a report published in the June 2022 issue of Obstetrics and Gynecology, Abenhaim and colleagues used a nested population-based case-control study of administrative data available in the UK Clinical Practice Research Datalink and provider prescriptions to evaluate the additive effect on the risk of breast cancer of the type of progestogen (micronized progesterone or synthetic progestins) when combined with estradiol for the treatment of menopausal symptoms.⁹ A cohort of 561,379 women was included in the case-control study (10:1 ratio), 43,183 in the case group (patients diagnosed with invasive breast cancer), and 431,830 in the matched control group.

Overall, in the stratified analysis, a small but significant increase in the risk of breast cancer was found in ever users of menopausal HT (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.09–1.15). Neither estradiol (OR, 1.04; 95% CI, 1.00–1.09) nor CEE (OR, 1.01; 95% CI, 0.96–1.06) was associated with an elevated risk of being diagnosed with invasive breast cancer. Of note, no elevated risk of breast cancer was associated with combination estrogen-progesterone therapy. However, the risk of breast cancer for women who had used synthetic progestins, mostly MPA, was significantly elevated (OR, 1.28; 95% CI, 1.22-1.35). Notably, this modestly elevated odds ratio with the use of estrogen-progestin HT is almost identical to that observed with CEE/ MPA in the WHI.¹ Similar findings were found in women aged 50 to 60 years.

The adjusted analyses from the large WHI RCTs provide additional support: the synthetic progestin MPA combined with CEE showed a higher risk of breast cancer than CEE alone in women with prior hysterectomy.¹⁰

In the long-term follow-up of the WHI RCTs, after a median of 20.3 years postrandomization, prior randomization to CEE alone for postmenopausal women with prior hysterectomy was associated with a significantly lowered risk of breast cancer incidence and mortality.¹¹ By contrast, prior randomization to CEE plus MPA (EPT) for women with an intact uterus was associated with a small but significantly increased incidence of breast cancer but no significant difference in breast cancer mortality.

In the French E3N EPIC population-based prospective cohort study, Fournier and colleagues^4,5 found that women who received estrogen combined with synthetic progestins (mostly MPA) had a higher risk of breast cancer, with an age-adjusted relative risk of 1.4 (95% CI, 1.2–1.7), a finding not seen in women who received estrogen combined with micronized progesterone, similar to findings by Cordina-Duverger and colleagues and Simin and colleagues.^12,13 In the E3N study, only 948 women were identified with breast cancer; 268 of these had used synthetic progestins.^4,5

Both the Abenhaim cohort⁹ and the longterm outcomes of WHI RCT trial data¹¹ found a significant contributing effect of MPA (synthetic progestin) in the risk of breast cancer. Progestogens are not thought to exert a class effect. Although it is clear that progestogens (progesterone or progestins) prevent estrogeninduced endometrial neoplasia when dosed adequately, different types of progestogens have a differential risk of breast epithelium proliferation and carcinogenic potential.¹⁴ A systematic review by Stute and colleagues found that micronized progesterone did not appear to alter mammographic breast density assessments or breast biopsy results.¹⁵

Race considerations

The study by Abenhaim and colleagues was unable to address the issues of race or ethnicity.⁹ However, in the racially diverse WHI trial of women with prior hysterectomy, estrogen-alone use significantly reduced breast cancer incidence in all participants.^10,16 Post hoc analysis of the 1,616 Black women with prior hysterectomy in the WHI RCT showed a significantly decreased breast cancer incidence with use of estrogen alone (hazard ratio [HR], 0.47; 95% CI, 0.26–0.82).¹ When race was evaluated in the long-term cumulative follow-up of the WHI trial, estrogen-alone use significantly reduced breast cancer incidence in Black women, with no adverse effect on coronary heart disease, global index, or all-cause mortality, and with fewer cases of venous thromboembolism.¹⁷ The global index findings were favorable for Black women in their 50s and those with vasomotor symptoms.

Continue to: Impact of HT in women with an elevated risk of breast cancer...

Impact of HT in women with an elevated risk of breast cancer

Abenhaim and colleagues could not evaluate the effect of HT in women with a baseline elevated risk of breast cancer.⁹ For these women, HT may be recommended after premature surgical menopause due to increased risks for coronary heart disease, osteoporosis, genitourinary syndrome of menopause, and cognitive changes when estrogen is not taken postsurgery through to at least the average age of menopause, considered age 51.^18,19

Marchetti and colleagues reviewed 3 clinical trials that assessed breast cancer events in 1,100 BRCA gene mutation carriers with intact breasts who underwent risk-reducing salpingo-oophorectomy (RRSO) who used or did not use HT.²⁰ For BRCA1 and BRCA2 mutation carriers who received HT after RRSO, no elevated risk of breast cancer risk was seen (HR, 0.98; 95% CI, 0.63–1.52). There was a nonsignificant reduction in breast cancer risk for the estrogen-alone users compared with EPT HT (OR, 0.53; 95% CI, 0.25–1.15). Thus, short-term use of HT, estrogen alone or EPT, does not appear to elevate the risk of breast cancer after RRSO in these high-risk women.

Individualizing HT  for menopausal symptoms

The data presented provide reassuring evidence that longer-term use of ET does not appear to increase breast cancer risk, regardless of the type of estrogen (CEE or estradiol).^4,5,9,11 For women with a uterus, micronized progesterone has less (if any) effect on breast cancer risk. By contrast, the use of synthetic progestins (such as MPA), when combined with estrogen, has been associated with a small but real increased breast cancer risk.

The most evident benefit of HT is in treating vasomotor symptoms and preventing bone loss for those at elevated risk in healthy women without contraindications who initiate systemic HT when younger than age 60 or within 10 years of menopause onset. Benefit and risk ratio depends on age and time from menopause onset when HT is initiated. Hormone therapy safety varies depending on type, dose, duration, route of administration, timing of initiation, and whether, and type, of progestogen is used. Transdermal estradiol, particularly when dosed at 0.05 mg or less, has been shown to have less thrombotic and stroke risk than oral estrogen.²¹

Individualizing treatment includes using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of benefits and risks of continuing or discontinuing HT or changing to lower doses. ObGyns who follow best practices in prescribing systemic HT can now help menopausal patients with bothersome symptoms take advantage of systemic HT’s benefits while providing reassurance regarding menopausal HT’s safety.¹⁸ Transdermal therapy is a safer option for women at elevated baseline risk of venous thrombosis (for example, obese women) and older patients. Likewise, given its safety with respect to risk of breast cancer, the use of micronized progesterone over synthetic progestins should be considered when prescribing EPT to women with an intact uterus.

Continue to: Benefits of avoiding BSO in women at average risk of ovarian cancer...

Benefits of avoiding BSO in women at average risk of ovarian cancer

Erickson Z, Rocca WA, Smith CY, et al. Time trends in unilateral and bilateral oophorectomy in a geographically defined American population. Obstet Gynecol. 2022;139:724-734. doi: 10.1097/ AOG.0000000000004728.

In 2005, gynecologist William Parker, MD, and colleagues used modeling methodology to assess the long-term risks and benefits of performing bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign disease in women at average risk for ovarian cancer.²³ They concluded that practicing ovarian conservation until age 65 increased women’s long-term survival. Among their findings were that women with BSO before age 55 had an 8.6% excess overall mortality by age 80, while those with oophorectomy before age 59 had 3.9% excess mortality. They noted a sustained, but decreasing, mortality benefit until the age of 75 and stated that at no age did their model suggest higher mortality in women who chose ovarian conservation. Parker and colleagues concluded that ovarian conservation until at least age 65 benefited long-term survival for women at average risk for ovarian cancer when undergoing hysterectomy for benign disease.²³

Certain risks decreased, others increased

A second report in 2009 by Parker and colleagues from the large prospective Nurses’ Health Study found that, while BSO at the time of hysterectomy for benign disease was associated with a decreased risk of breast and ovarian cancer, BSO was associated with an increased risk of all-cause mortality, fatal and nonfatal coronary heart disease, and lung cancer.²⁴ Similar to the findings of the 2005 report, the authors noted that in no analysis or age group was BSO associated with increased survival. They also noted that compared with those who underwent BSO before age 50 and used ET, women with no history of ET use had an approximately 2-fold elevated risk of new onset coronary heart disease (HR, 1.98; 95% CI, 1.18–3.32).²⁴

In 2007, Walter Rocca, MD, a Mayo Clinic neurologist with a particular interest in the epidemiology of dementia, and colleagues at the Mayo Clinic published results of a study that assessed a cohort of women who had undergone unilateral oophorectomy or BSO prior to the onset of menopause.²⁵ The risk of cognitive impairment or dementia was higher in these women compared with women who had intact ovaries (HR, 1.46; 95% CI, 1.13-1.90). Of note, this elevated risk was confined to those who underwent oophorectomy before 49 years of age and were not prescribed estrogen until age 50 or older.²⁵

In a subsequent publication, Rocca and colleagues pointed out that BSO prior to menopause not only is associated with higher rates of all-cause mortality and cognitive impairment but also with coronary heart disease, parkinsonism, osteoporosis, and other chronic conditions associated with aging, including metabolic, mental health, and arthritic disorders.²⁶

Oophorectomy trends tracked

Given these and other reports²⁷ that highlighted the health risks of premenopausal BSO in women at average risk for ovarian cancer, Rocca and colleagues recently assessed trends in the occurrence of unilateral oophorectomy or BSO versus ovarian conservation among all women residing in the Minnesota county (Olmsted) in which Mayo Clinic is located, and who underwent gynecologic surgery between 1950 and 2018.²⁸

The investigators limited their analysis to women who had undergone unilateral oophorectomy or BSO between ages 18 and 49 years (these women are assumed to have been premenopausal). The authors considered as indications for oophorectomy primary or metastatic ovarian cancer, risk-reducing BSO for women at elevated risk for ovarian cancer (for example, strong family history or known BRCA gene mutation), adnexal mass, endometriosis, torsion, and other benign gynecologic conditions that included pelvic pain, abscess, oophoritis, or ectopic pregnancy. When more than 1 indication for ovarian surgery was present, the authors used the most clinically important indication. Unilateral oophorectomy or BSO was considered not indicated if the surgery was performed during another primary procedure (usually hysterectomy) without indication, or if the surgeon referred to the ovarian surgery as elective.

Results. Among 5,154 women who had oophorectomies between 1950 and 2018, the proportion of these women who underwent unilateral oophorectomy and BSO was 40.6% and 59.4%, respectively.

For most years between 1950 and 1979, the incidence of unilateral oophorectomy was higher than BSO. However, from 1980 to 2004, the incidence of BSO increased more than 2-fold while the incidence of unilateral surgery declined. After 2005, however, both types of ovarian surgery declined. During the years 2005–2018, a marked decline in BSO occurred, with the reduced incidence in premenopausal BSO most notable among women undergoing hysterectomy or those without an indication for oophorectomy.

Historically, ObGyns were taught that the benefits of removing normal ovaries (to prevent ovarian cancer) in average-risk women at the time of hysterectomy outweighed the risks. We agree with the authors’ speculation that beginning with Parker’s 2005 publication,²³ ObGyns have become more conservative in performing unindicated BSO in women at average risk for ovarian cancer, now recognizing that the harms of this procedure often outweigh any benefits.²⁸

Women with BRCA1 and BRCA2 gene mutations are at elevated risk for ovarian, tubal, and breast malignancies. In this population, risk-reducing BSO dramatically lowers future risk of ovarian and tubal cancer.

Data addressing the effect of RRSO in BRCA1 and BRCA2 gene mutation carriers continue to be evaluated, with differences between the 2 mutations, but they suggest that the surgery reduces not only ovarian cancer and tubal cancer but also possibly breast cancer.²⁹

Continue to: Trends show decline in ET use in surgically menopausal women... 

Trends show decline in ET use in surgically menopausal women 

Suzuki Y, Huang Y, Melamed A, et al. Use of estrogen therapy after surgical menopause in women who are premenopausal. Obstet Gynecol. 2022;139:756-763. doi: 10.1097/AOG.0000000000004762.

In addition to highlighting the risks associated with premenopausal BSO in women at average risk for ovarian cancer, the reports referred to above also underscore that the use of replacement menopausal HT in premenopausal women who undergo BSO prevents morbidity and mortality that otherwise accompanies surgical menopause. In addition, the North American Menopause Society (NAMS) recommends replacement menopausal HT in the setting of induced early menopause when no contraindications are present.¹⁸

To assess the prevalence of HT use in surgically menopausal women, investigators at Columbia University College of Physicians and Surgeons used a national database that captures health insurance claims for some 280 million US patients, focusing on women aged 18 to 50 years who underwent BSO from 2008 to 2019.³⁰ The great majority of women in this database have private insurance. Although the authors used the term estrogen therapy in their article, this term refers to systemic estrogen alone or with progestogen, as well as vaginal ET (personal communication with Jason Wright, MD, a coauthor of the study, May 19, 2022). In this Update section, we use the term HT to include use of any systemic HT or vaginal estrogen.

Prevalence of HT use changed over time period and patient age range

Among almost 61,980 evaluable women who had undergone BSO (median age, 45 years; 75.1% with concomitant hysterectomy; median follow-up time, 27 months), with no history of gynecologic or breast cancer, HT was used within 3 years of BSO by 64.5%. The highest percentage of women in this cohort who used HT peaked in 2008 (69.5%), declining to 58.2% by 2016. The median duration of HT use was 5.3 months. The prevalence of HT use 3 years after BSO declined with age, from 79.1% in women aged 18–29 to 60.0% in women aged 45–50.³⁰

This report, published in the June 2022 issue of Obstetrics and Gynecology, makes several sobering observations: Many surgically menopausal women aged 50 years and younger are not prescribed HT, the proportion of such women receiving a prescription for HT is declining over time, and the duration of HT use following BSO is short. ●

This year’s Menopause Update focuses on 2 menopause-related issues relevant to ObGyns and our menopausal patients:

• choosing the safest regimens, particularly with respect to risk of breast cancer, when prescribing hormone therapy (HT) to menopausal women
• reviewing the risks and benefits of premenopausal bilateral salpingo-oophorectomy and the pros and cons of replacement HT in surgically menopausal patients.

We hope that you find this updated information useful as you care for menopausal women.

Revisiting menopausal HT  and the risk of breast cancer:  What we know now

Abenhaim HA, Suissa S,  Azoulay L, et al. Menopausal hormone therapy formulation and breast cancer risk. Obstet Gynecol. 2022;139:1103-1110. doi: 10.1097/AOG.0000000000004723.

Reevaluation of the Women’s Health Initiative randomized controlled trials (WHI RCTs), long-term (median follow-up more than 20 years) cumulative  follow-up data, and results from additional studies have suggested that estrogen therapy (ET) alone in menopausal women with prior hysterectomy does not increase the risk of breast cancer. By contrast, estrogen with progestin (synthetic progestogens that include medroxyprogesterone acetate [MPA] and norethindrone acetate) slightly increases the risk of breast cancer. In the past 10 years, several publications have shed light on whether the type of progestogen affects the risk of breast cancer and can help provide evidence-based information to guide clinicians.

Breast cancer risk with combined HT and synthetic progestin

In the first part of the WHI RCT, women were randomly assigned to receive either conjugated equine estrogen (CEE) plus synthetic progestin (MPA) or a placebo. Combined estrogen-progestin therapy (EPT) was associated with a modestly elevated risk of breast cancer.¹ In the second part of the WHI trial, CEE only (estrogen alone, ET) was compared with placebo among women with prior  hysterectomy, with no effect found on breast cancer incidence.²

Most older observational studies published in 2003 to 2005 found that neither CEE nor estradiol appeared to increase the risk of breast cancer when used alone.^3-5 However, estrogen use in combination with synthetic progestins (MPA, norethindrone, levonorgestrel, and norgestrel) has been associated with an increased risk of breast cancer,^4,6 while the elevated risk of breast cancer with micronized progesterone has been less substantial.^7,8

Continue to: Newer data suggest the type of progestogen used affects risk...

 

 

Newer data suggest the type of progestogen used affects risk

In a report published in the June 2022 issue of Obstetrics and Gynecology, Abenhaim and colleagues used a nested population-based case-control study of administrative data available in the UK Clinical Practice Research Datalink and provider prescriptions to evaluate the additive effect on the risk of breast cancer of the type of progestogen (micronized progesterone or synthetic progestins) when combined with estradiol for the treatment of menopausal symptoms.⁹ A cohort of 561,379 women was included in the case-control study (10:1 ratio), 43,183 in the case group (patients diagnosed with invasive breast cancer), and 431,830 in the matched control group.

Overall, in the stratified analysis, a small but significant increase in the risk of breast cancer was found in ever users of menopausal HT (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.09–1.15). Neither estradiol (OR, 1.04; 95% CI, 1.00–1.09) nor CEE (OR, 1.01; 95% CI, 0.96–1.06) was associated with an elevated risk of being diagnosed with invasive breast cancer. Of note, no elevated risk of breast cancer was associated with combination estrogen-progesterone therapy. However, the risk of breast cancer for women who had used synthetic progestins, mostly MPA, was significantly elevated (OR, 1.28; 95% CI, 1.22-1.35). Notably, this modestly elevated odds ratio with the use of estrogen-progestin HT is almost identical to that observed with CEE/ MPA in the WHI.¹ Similar findings were found in women aged 50 to 60 years.

The adjusted analyses from the large WHI RCTs provide additional support: the synthetic progestin MPA combined with CEE showed a higher risk of breast cancer than CEE alone in women with prior hysterectomy.¹⁰

In the long-term follow-up of the WHI RCTs, after a median of 20.3 years postrandomization, prior randomization to CEE alone for postmenopausal women with prior hysterectomy was associated with a significantly lowered risk of breast cancer incidence and mortality.¹¹ By contrast, prior randomization to CEE plus MPA (EPT) for women with an intact uterus was associated with a small but significantly increased incidence of breast cancer but no significant difference in breast cancer mortality.

In the French E3N EPIC population-based prospective cohort study, Fournier and colleagues^4,5 found that women who received estrogen combined with synthetic progestins (mostly MPA) had a higher risk of breast cancer, with an age-adjusted relative risk of 1.4 (95% CI, 1.2–1.7), a finding not seen in women who received estrogen combined with micronized progesterone, similar to findings by Cordina-Duverger and colleagues and Simin and colleagues.^12,13 In the E3N study, only 948 women were identified with breast cancer; 268 of these had used synthetic progestins.^4,5

Both the Abenhaim cohort⁹ and the longterm outcomes of WHI RCT trial data¹¹ found a significant contributing effect of MPA (synthetic progestin) in the risk of breast cancer. Progestogens are not thought to exert a class effect. Although it is clear that progestogens (progesterone or progestins) prevent estrogeninduced endometrial neoplasia when dosed adequately, different types of progestogens have a differential risk of breast epithelium proliferation and carcinogenic potential.¹⁴ A systematic review by Stute and colleagues found that micronized progesterone did not appear to alter mammographic breast density assessments or breast biopsy results.¹⁵

Race considerations

The study by Abenhaim and colleagues was unable to address the issues of race or ethnicity.⁹ However, in the racially diverse WHI trial of women with prior hysterectomy, estrogen-alone use significantly reduced breast cancer incidence in all participants.^10,16 Post hoc analysis of the 1,616 Black women with prior hysterectomy in the WHI RCT showed a significantly decreased breast cancer incidence with use of estrogen alone (hazard ratio [HR], 0.47; 95% CI, 0.26–0.82).¹ When race was evaluated in the long-term cumulative follow-up of the WHI trial, estrogen-alone use significantly reduced breast cancer incidence in Black women, with no adverse effect on coronary heart disease, global index, or all-cause mortality, and with fewer cases of venous thromboembolism.¹⁷ The global index findings were favorable for Black women in their 50s and those with vasomotor symptoms.

Continue to: Impact of HT in women with an elevated risk of breast cancer...

Impact of HT in women with an elevated risk of breast cancer

Abenhaim and colleagues could not evaluate the effect of HT in women with a baseline elevated risk of breast cancer.⁹ For these women, HT may be recommended after premature surgical menopause due to increased risks for coronary heart disease, osteoporosis, genitourinary syndrome of menopause, and cognitive changes when estrogen is not taken postsurgery through to at least the average age of menopause, considered age 51.^18,19

Marchetti and colleagues reviewed 3 clinical trials that assessed breast cancer events in 1,100 BRCA gene mutation carriers with intact breasts who underwent risk-reducing salpingo-oophorectomy (RRSO) who used or did not use HT.²⁰ For BRCA1 and BRCA2 mutation carriers who received HT after RRSO, no elevated risk of breast cancer risk was seen (HR, 0.98; 95% CI, 0.63–1.52). There was a nonsignificant reduction in breast cancer risk for the estrogen-alone users compared with EPT HT (OR, 0.53; 95% CI, 0.25–1.15). Thus, short-term use of HT, estrogen alone or EPT, does not appear to elevate the risk of breast cancer after RRSO in these high-risk women.

Individualizing HT  for menopausal symptoms

The data presented provide reassuring evidence that longer-term use of ET does not appear to increase breast cancer risk, regardless of the type of estrogen (CEE or estradiol).^4,5,9,11 For women with a uterus, micronized progesterone has less (if any) effect on breast cancer risk. By contrast, the use of synthetic progestins (such as MPA), when combined with estrogen, has been associated with a small but real increased breast cancer risk.

The most evident benefit of HT is in treating vasomotor symptoms and preventing bone loss for those at elevated risk in healthy women without contraindications who initiate systemic HT when younger than age 60 or within 10 years of menopause onset. Benefit and risk ratio depends on age and time from menopause onset when HT is initiated. Hormone therapy safety varies depending on type, dose, duration, route of administration, timing of initiation, and whether, and type, of progestogen is used. Transdermal estradiol, particularly when dosed at 0.05 mg or less, has been shown to have less thrombotic and stroke risk than oral estrogen.²¹

Individualizing treatment includes using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of benefits and risks of continuing or discontinuing HT or changing to lower doses. ObGyns who follow best practices in prescribing systemic HT can now help menopausal patients with bothersome symptoms take advantage of systemic HT’s benefits while providing reassurance regarding menopausal HT’s safety.¹⁸ Transdermal therapy is a safer option for women at elevated baseline risk of venous thrombosis (for example, obese women) and older patients. Likewise, given its safety with respect to risk of breast cancer, the use of micronized progesterone over synthetic progestins should be considered when prescribing EPT to women with an intact uterus.

Continue to: Benefits of avoiding BSO in women at average risk of ovarian cancer...

Benefits of avoiding BSO in women at average risk of ovarian cancer

Erickson Z, Rocca WA, Smith CY, et al. Time trends in unilateral and bilateral oophorectomy in a geographically defined American population. Obstet Gynecol. 2022;139:724-734. doi: 10.1097/ AOG.0000000000004728.

In 2005, gynecologist William Parker, MD, and colleagues used modeling methodology to assess the long-term risks and benefits of performing bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign disease in women at average risk for ovarian cancer.²³ They concluded that practicing ovarian conservation until age 65 increased women’s long-term survival. Among their findings were that women with BSO before age 55 had an 8.6% excess overall mortality by age 80, while those with oophorectomy before age 59 had 3.9% excess mortality. They noted a sustained, but decreasing, mortality benefit until the age of 75 and stated that at no age did their model suggest higher mortality in women who chose ovarian conservation. Parker and colleagues concluded that ovarian conservation until at least age 65 benefited long-term survival for women at average risk for ovarian cancer when undergoing hysterectomy for benign disease.²³

Certain risks decreased, others increased

A second report in 2009 by Parker and colleagues from the large prospective Nurses’ Health Study found that, while BSO at the time of hysterectomy for benign disease was associated with a decreased risk of breast and ovarian cancer, BSO was associated with an increased risk of all-cause mortality, fatal and nonfatal coronary heart disease, and lung cancer.²⁴ Similar to the findings of the 2005 report, the authors noted that in no analysis or age group was BSO associated with increased survival. They also noted that compared with those who underwent BSO before age 50 and used ET, women with no history of ET use had an approximately 2-fold elevated risk of new onset coronary heart disease (HR, 1.98; 95% CI, 1.18–3.32).²⁴

In 2007, Walter Rocca, MD, a Mayo Clinic neurologist with a particular interest in the epidemiology of dementia, and colleagues at the Mayo Clinic published results of a study that assessed a cohort of women who had undergone unilateral oophorectomy or BSO prior to the onset of menopause.²⁵ The risk of cognitive impairment or dementia was higher in these women compared with women who had intact ovaries (HR, 1.46; 95% CI, 1.13-1.90). Of note, this elevated risk was confined to those who underwent oophorectomy before 49 years of age and were not prescribed estrogen until age 50 or older.²⁵

In a subsequent publication, Rocca and colleagues pointed out that BSO prior to menopause not only is associated with higher rates of all-cause mortality and cognitive impairment but also with coronary heart disease, parkinsonism, osteoporosis, and other chronic conditions associated with aging, including metabolic, mental health, and arthritic disorders.²⁶

Oophorectomy trends tracked

Given these and other reports²⁷ that highlighted the health risks of premenopausal BSO in women at average risk for ovarian cancer, Rocca and colleagues recently assessed trends in the occurrence of unilateral oophorectomy or BSO versus ovarian conservation among all women residing in the Minnesota county (Olmsted) in which Mayo Clinic is located, and who underwent gynecologic surgery between 1950 and 2018.²⁸

The investigators limited their analysis to women who had undergone unilateral oophorectomy or BSO between ages 18 and 49 years (these women are assumed to have been premenopausal). The authors considered as indications for oophorectomy primary or metastatic ovarian cancer, risk-reducing BSO for women at elevated risk for ovarian cancer (for example, strong family history or known BRCA gene mutation), adnexal mass, endometriosis, torsion, and other benign gynecologic conditions that included pelvic pain, abscess, oophoritis, or ectopic pregnancy. When more than 1 indication for ovarian surgery was present, the authors used the most clinically important indication. Unilateral oophorectomy or BSO was considered not indicated if the surgery was performed during another primary procedure (usually hysterectomy) without indication, or if the surgeon referred to the ovarian surgery as elective.

Results. Among 5,154 women who had oophorectomies between 1950 and 2018, the proportion of these women who underwent unilateral oophorectomy and BSO was 40.6% and 59.4%, respectively.

For most years between 1950 and 1979, the incidence of unilateral oophorectomy was higher than BSO. However, from 1980 to 2004, the incidence of BSO increased more than 2-fold while the incidence of unilateral surgery declined. After 2005, however, both types of ovarian surgery declined. During the years 2005–2018, a marked decline in BSO occurred, with the reduced incidence in premenopausal BSO most notable among women undergoing hysterectomy or those without an indication for oophorectomy.

Historically, ObGyns were taught that the benefits of removing normal ovaries (to prevent ovarian cancer) in average-risk women at the time of hysterectomy outweighed the risks. We agree with the authors’ speculation that beginning with Parker’s 2005 publication,²³ ObGyns have become more conservative in performing unindicated BSO in women at average risk for ovarian cancer, now recognizing that the harms of this procedure often outweigh any benefits.²⁸

Women with BRCA1 and BRCA2 gene mutations are at elevated risk for ovarian, tubal, and breast malignancies. In this population, risk-reducing BSO dramatically lowers future risk of ovarian and tubal cancer.

Data addressing the effect of RRSO in BRCA1 and BRCA2 gene mutation carriers continue to be evaluated, with differences between the 2 mutations, but they suggest that the surgery reduces not only ovarian cancer and tubal cancer but also possibly breast cancer.²⁹

Continue to: Trends show decline in ET use in surgically menopausal women... 

Trends show decline in ET use in surgically menopausal women 

Suzuki Y, Huang Y, Melamed A, et al. Use of estrogen therapy after surgical menopause in women who are premenopausal. Obstet Gynecol. 2022;139:756-763. doi: 10.1097/AOG.0000000000004762.

In addition to highlighting the risks associated with premenopausal BSO in women at average risk for ovarian cancer, the reports referred to above also underscore that the use of replacement menopausal HT in premenopausal women who undergo BSO prevents morbidity and mortality that otherwise accompanies surgical menopause. In addition, the North American Menopause Society (NAMS) recommends replacement menopausal HT in the setting of induced early menopause when no contraindications are present.¹⁸

To assess the prevalence of HT use in surgically menopausal women, investigators at Columbia University College of Physicians and Surgeons used a national database that captures health insurance claims for some 280 million US patients, focusing on women aged 18 to 50 years who underwent BSO from 2008 to 2019.³⁰ The great majority of women in this database have private insurance. Although the authors used the term estrogen therapy in their article, this term refers to systemic estrogen alone or with progestogen, as well as vaginal ET (personal communication with Jason Wright, MD, a coauthor of the study, May 19, 2022). In this Update section, we use the term HT to include use of any systemic HT or vaginal estrogen.

Prevalence of HT use changed over time period and patient age range

Among almost 61,980 evaluable women who had undergone BSO (median age, 45 years; 75.1% with concomitant hysterectomy; median follow-up time, 27 months), with no history of gynecologic or breast cancer, HT was used within 3 years of BSO by 64.5%. The highest percentage of women in this cohort who used HT peaked in 2008 (69.5%), declining to 58.2% by 2016. The median duration of HT use was 5.3 months. The prevalence of HT use 3 years after BSO declined with age, from 79.1% in women aged 18–29 to 60.0% in women aged 45–50.³⁰

This report, published in the June 2022 issue of Obstetrics and Gynecology, makes several sobering observations: Many surgically menopausal women aged 50 years and younger are not prescribed HT, the proportion of such women receiving a prescription for HT is declining over time, and the duration of HT use following BSO is short. ●

This year’s Menopause Update focuses on 2 menopause-related issues relevant to ObGyns and our menopausal patients:

• choosing the safest regimens, particularly with respect to risk of breast cancer, when prescribing hormone therapy (HT) to menopausal women
• reviewing the risks and benefits of premenopausal bilateral salpingo-oophorectomy and the pros and cons of replacement HT in surgically menopausal patients.

We hope that you find this updated information useful as you care for menopausal women.

Revisiting menopausal HT  and the risk of breast cancer:  What we know now

Abenhaim HA, Suissa S,  Azoulay L, et al. Menopausal hormone therapy formulation and breast cancer risk. Obstet Gynecol. 2022;139:1103-1110. doi: 10.1097/AOG.0000000000004723.

Reevaluation of the Women’s Health Initiative randomized controlled trials (WHI RCTs), long-term (median follow-up more than 20 years) cumulative  follow-up data, and results from additional studies have suggested that estrogen therapy (ET) alone in menopausal women with prior hysterectomy does not increase the risk of breast cancer. By contrast, estrogen with progestin (synthetic progestogens that include medroxyprogesterone acetate [MPA] and norethindrone acetate) slightly increases the risk of breast cancer. In the past 10 years, several publications have shed light on whether the type of progestogen affects the risk of breast cancer and can help provide evidence-based information to guide clinicians.

Breast cancer risk with combined HT and synthetic progestin

In the first part of the WHI RCT, women were randomly assigned to receive either conjugated equine estrogen (CEE) plus synthetic progestin (MPA) or a placebo. Combined estrogen-progestin therapy (EPT) was associated with a modestly elevated risk of breast cancer.¹ In the second part of the WHI trial, CEE only (estrogen alone, ET) was compared with placebo among women with prior  hysterectomy, with no effect found on breast cancer incidence.²

Most older observational studies published in 2003 to 2005 found that neither CEE nor estradiol appeared to increase the risk of breast cancer when used alone.^3-5 However, estrogen use in combination with synthetic progestins (MPA, norethindrone, levonorgestrel, and norgestrel) has been associated with an increased risk of breast cancer,^4,6 while the elevated risk of breast cancer with micronized progesterone has been less substantial.^7,8

Continue to: Newer data suggest the type of progestogen used affects risk...

 

 

Newer data suggest the type of progestogen used affects risk

In a report published in the June 2022 issue of Obstetrics and Gynecology, Abenhaim and colleagues used a nested population-based case-control study of administrative data available in the UK Clinical Practice Research Datalink and provider prescriptions to evaluate the additive effect on the risk of breast cancer of the type of progestogen (micronized progesterone or synthetic progestins) when combined with estradiol for the treatment of menopausal symptoms.⁹ A cohort of 561,379 women was included in the case-control study (10:1 ratio), 43,183 in the case group (patients diagnosed with invasive breast cancer), and 431,830 in the matched control group.

Overall, in the stratified analysis, a small but significant increase in the risk of breast cancer was found in ever users of menopausal HT (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.09–1.15). Neither estradiol (OR, 1.04; 95% CI, 1.00–1.09) nor CEE (OR, 1.01; 95% CI, 0.96–1.06) was associated with an elevated risk of being diagnosed with invasive breast cancer. Of note, no elevated risk of breast cancer was associated with combination estrogen-progesterone therapy. However, the risk of breast cancer for women who had used synthetic progestins, mostly MPA, was significantly elevated (OR, 1.28; 95% CI, 1.22-1.35). Notably, this modestly elevated odds ratio with the use of estrogen-progestin HT is almost identical to that observed with CEE/ MPA in the WHI.¹ Similar findings were found in women aged 50 to 60 years.

The adjusted analyses from the large WHI RCTs provide additional support: the synthetic progestin MPA combined with CEE showed a higher risk of breast cancer than CEE alone in women with prior hysterectomy.¹⁰

In the long-term follow-up of the WHI RCTs, after a median of 20.3 years postrandomization, prior randomization to CEE alone for postmenopausal women with prior hysterectomy was associated with a significantly lowered risk of breast cancer incidence and mortality.¹¹ By contrast, prior randomization to CEE plus MPA (EPT) for women with an intact uterus was associated with a small but significantly increased incidence of breast cancer but no significant difference in breast cancer mortality.

In the French E3N EPIC population-based prospective cohort study, Fournier and colleagues^4,5 found that women who received estrogen combined with synthetic progestins (mostly MPA) had a higher risk of breast cancer, with an age-adjusted relative risk of 1.4 (95% CI, 1.2–1.7), a finding not seen in women who received estrogen combined with micronized progesterone, similar to findings by Cordina-Duverger and colleagues and Simin and colleagues.^12,13 In the E3N study, only 948 women were identified with breast cancer; 268 of these had used synthetic progestins.^4,5

Both the Abenhaim cohort⁹ and the longterm outcomes of WHI RCT trial data¹¹ found a significant contributing effect of MPA (synthetic progestin) in the risk of breast cancer. Progestogens are not thought to exert a class effect. Although it is clear that progestogens (progesterone or progestins) prevent estrogeninduced endometrial neoplasia when dosed adequately, different types of progestogens have a differential risk of breast epithelium proliferation and carcinogenic potential.¹⁴ A systematic review by Stute and colleagues found that micronized progesterone did not appear to alter mammographic breast density assessments or breast biopsy results.¹⁵

Race considerations

The study by Abenhaim and colleagues was unable to address the issues of race or ethnicity.⁹ However, in the racially diverse WHI trial of women with prior hysterectomy, estrogen-alone use significantly reduced breast cancer incidence in all participants.^10,16 Post hoc analysis of the 1,616 Black women with prior hysterectomy in the WHI RCT showed a significantly decreased breast cancer incidence with use of estrogen alone (hazard ratio [HR], 0.47; 95% CI, 0.26–0.82).¹ When race was evaluated in the long-term cumulative follow-up of the WHI trial, estrogen-alone use significantly reduced breast cancer incidence in Black women, with no adverse effect on coronary heart disease, global index, or all-cause mortality, and with fewer cases of venous thromboembolism.¹⁷ The global index findings were favorable for Black women in their 50s and those with vasomotor symptoms.

Continue to: Impact of HT in women with an elevated risk of breast cancer...

Impact of HT in women with an elevated risk of breast cancer

Abenhaim and colleagues could not evaluate the effect of HT in women with a baseline elevated risk of breast cancer.⁹ For these women, HT may be recommended after premature surgical menopause due to increased risks for coronary heart disease, osteoporosis, genitourinary syndrome of menopause, and cognitive changes when estrogen is not taken postsurgery through to at least the average age of menopause, considered age 51.^18,19

Marchetti and colleagues reviewed 3 clinical trials that assessed breast cancer events in 1,100 BRCA gene mutation carriers with intact breasts who underwent risk-reducing salpingo-oophorectomy (RRSO) who used or did not use HT.²⁰ For BRCA1 and BRCA2 mutation carriers who received HT after RRSO, no elevated risk of breast cancer risk was seen (HR, 0.98; 95% CI, 0.63–1.52). There was a nonsignificant reduction in breast cancer risk for the estrogen-alone users compared with EPT HT (OR, 0.53; 95% CI, 0.25–1.15). Thus, short-term use of HT, estrogen alone or EPT, does not appear to elevate the risk of breast cancer after RRSO in these high-risk women.

Individualizing HT  for menopausal symptoms

The data presented provide reassuring evidence that longer-term use of ET does not appear to increase breast cancer risk, regardless of the type of estrogen (CEE or estradiol).^4,5,9,11 For women with a uterus, micronized progesterone has less (if any) effect on breast cancer risk. By contrast, the use of synthetic progestins (such as MPA), when combined with estrogen, has been associated with a small but real increased breast cancer risk.

The most evident benefit of HT is in treating vasomotor symptoms and preventing bone loss for those at elevated risk in healthy women without contraindications who initiate systemic HT when younger than age 60 or within 10 years of menopause onset. Benefit and risk ratio depends on age and time from menopause onset when HT is initiated. Hormone therapy safety varies depending on type, dose, duration, route of administration, timing of initiation, and whether, and type, of progestogen is used. Transdermal estradiol, particularly when dosed at 0.05 mg or less, has been shown to have less thrombotic and stroke risk than oral estrogen.²¹

Individualizing treatment includes using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of benefits and risks of continuing or discontinuing HT or changing to lower doses. ObGyns who follow best practices in prescribing systemic HT can now help menopausal patients with bothersome symptoms take advantage of systemic HT’s benefits while providing reassurance regarding menopausal HT’s safety.¹⁸ Transdermal therapy is a safer option for women at elevated baseline risk of venous thrombosis (for example, obese women) and older patients. Likewise, given its safety with respect to risk of breast cancer, the use of micronized progesterone over synthetic progestins should be considered when prescribing EPT to women with an intact uterus.

Continue to: Benefits of avoiding BSO in women at average risk of ovarian cancer...

Benefits of avoiding BSO in women at average risk of ovarian cancer

Erickson Z, Rocca WA, Smith CY, et al. Time trends in unilateral and bilateral oophorectomy in a geographically defined American population. Obstet Gynecol. 2022;139:724-734. doi: 10.1097/ AOG.0000000000004728.

In 2005, gynecologist William Parker, MD, and colleagues used modeling methodology to assess the long-term risks and benefits of performing bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign disease in women at average risk for ovarian cancer.²³ They concluded that practicing ovarian conservation until age 65 increased women’s long-term survival. Among their findings were that women with BSO before age 55 had an 8.6% excess overall mortality by age 80, while those with oophorectomy before age 59 had 3.9% excess mortality. They noted a sustained, but decreasing, mortality benefit until the age of 75 and stated that at no age did their model suggest higher mortality in women who chose ovarian conservation. Parker and colleagues concluded that ovarian conservation until at least age 65 benefited long-term survival for women at average risk for ovarian cancer when undergoing hysterectomy for benign disease.²³

Certain risks decreased, others increased

A second report in 2009 by Parker and colleagues from the large prospective Nurses’ Health Study found that, while BSO at the time of hysterectomy for benign disease was associated with a decreased risk of breast and ovarian cancer, BSO was associated with an increased risk of all-cause mortality, fatal and nonfatal coronary heart disease, and lung cancer.²⁴ Similar to the findings of the 2005 report, the authors noted that in no analysis or age group was BSO associated with increased survival. They also noted that compared with those who underwent BSO before age 50 and used ET, women with no history of ET use had an approximately 2-fold elevated risk of new onset coronary heart disease (HR, 1.98; 95% CI, 1.18–3.32).²⁴

In 2007, Walter Rocca, MD, a Mayo Clinic neurologist with a particular interest in the epidemiology of dementia, and colleagues at the Mayo Clinic published results of a study that assessed a cohort of women who had undergone unilateral oophorectomy or BSO prior to the onset of menopause.²⁵ The risk of cognitive impairment or dementia was higher in these women compared with women who had intact ovaries (HR, 1.46; 95% CI, 1.13-1.90). Of note, this elevated risk was confined to those who underwent oophorectomy before 49 years of age and were not prescribed estrogen until age 50 or older.²⁵

In a subsequent publication, Rocca and colleagues pointed out that BSO prior to menopause not only is associated with higher rates of all-cause mortality and cognitive impairment but also with coronary heart disease, parkinsonism, osteoporosis, and other chronic conditions associated with aging, including metabolic, mental health, and arthritic disorders.²⁶

Oophorectomy trends tracked

Given these and other reports²⁷ that highlighted the health risks of premenopausal BSO in women at average risk for ovarian cancer, Rocca and colleagues recently assessed trends in the occurrence of unilateral oophorectomy or BSO versus ovarian conservation among all women residing in the Minnesota county (Olmsted) in which Mayo Clinic is located, and who underwent gynecologic surgery between 1950 and 2018.²⁸

The investigators limited their analysis to women who had undergone unilateral oophorectomy or BSO between ages 18 and 49 years (these women are assumed to have been premenopausal). The authors considered as indications for oophorectomy primary or metastatic ovarian cancer, risk-reducing BSO for women at elevated risk for ovarian cancer (for example, strong family history or known BRCA gene mutation), adnexal mass, endometriosis, torsion, and other benign gynecologic conditions that included pelvic pain, abscess, oophoritis, or ectopic pregnancy. When more than 1 indication for ovarian surgery was present, the authors used the most clinically important indication. Unilateral oophorectomy or BSO was considered not indicated if the surgery was performed during another primary procedure (usually hysterectomy) without indication, or if the surgeon referred to the ovarian surgery as elective.

Results. Among 5,154 women who had oophorectomies between 1950 and 2018, the proportion of these women who underwent unilateral oophorectomy and BSO was 40.6% and 59.4%, respectively.

For most years between 1950 and 1979, the incidence of unilateral oophorectomy was higher than BSO. However, from 1980 to 2004, the incidence of BSO increased more than 2-fold while the incidence of unilateral surgery declined. After 2005, however, both types of ovarian surgery declined. During the years 2005–2018, a marked decline in BSO occurred, with the reduced incidence in premenopausal BSO most notable among women undergoing hysterectomy or those without an indication for oophorectomy.

Historically, ObGyns were taught that the benefits of removing normal ovaries (to prevent ovarian cancer) in average-risk women at the time of hysterectomy outweighed the risks. We agree with the authors’ speculation that beginning with Parker’s 2005 publication,²³ ObGyns have become more conservative in performing unindicated BSO in women at average risk for ovarian cancer, now recognizing that the harms of this procedure often outweigh any benefits.²⁸

Women with BRCA1 and BRCA2 gene mutations are at elevated risk for ovarian, tubal, and breast malignancies. In this population, risk-reducing BSO dramatically lowers future risk of ovarian and tubal cancer.

Data addressing the effect of RRSO in BRCA1 and BRCA2 gene mutation carriers continue to be evaluated, with differences between the 2 mutations, but they suggest that the surgery reduces not only ovarian cancer and tubal cancer but also possibly breast cancer.²⁹

Continue to: Trends show decline in ET use in surgically menopausal women... 

Trends show decline in ET use in surgically menopausal women 

Suzuki Y, Huang Y, Melamed A, et al. Use of estrogen therapy after surgical menopause in women who are premenopausal. Obstet Gynecol. 2022;139:756-763. doi: 10.1097/AOG.0000000000004762.

In addition to highlighting the risks associated with premenopausal BSO in women at average risk for ovarian cancer, the reports referred to above also underscore that the use of replacement menopausal HT in premenopausal women who undergo BSO prevents morbidity and mortality that otherwise accompanies surgical menopause. In addition, the North American Menopause Society (NAMS) recommends replacement menopausal HT in the setting of induced early menopause when no contraindications are present.¹⁸

To assess the prevalence of HT use in surgically menopausal women, investigators at Columbia University College of Physicians and Surgeons used a national database that captures health insurance claims for some 280 million US patients, focusing on women aged 18 to 50 years who underwent BSO from 2008 to 2019.³⁰ The great majority of women in this database have private insurance. Although the authors used the term estrogen therapy in their article, this term refers to systemic estrogen alone or with progestogen, as well as vaginal ET (personal communication with Jason Wright, MD, a coauthor of the study, May 19, 2022). In this Update section, we use the term HT to include use of any systemic HT or vaginal estrogen.

Prevalence of HT use changed over time period and patient age range

Among almost 61,980 evaluable women who had undergone BSO (median age, 45 years; 75.1% with concomitant hysterectomy; median follow-up time, 27 months), with no history of gynecologic or breast cancer, HT was used within 3 years of BSO by 64.5%. The highest percentage of women in this cohort who used HT peaked in 2008 (69.5%), declining to 58.2% by 2016. The median duration of HT use was 5.3 months. The prevalence of HT use 3 years after BSO declined with age, from 79.1% in women aged 18–29 to 60.0% in women aged 45–50.³⁰

This report, published in the June 2022 issue of Obstetrics and Gynecology, makes several sobering observations: Many surgically menopausal women aged 50 years and younger are not prescribed HT, the proportion of such women receiving a prescription for HT is declining over time, and the duration of HT use following BSO is short. ●

The evaluation and management of chronic pelvic pain in patients with a history of Essure device (Bayer HealthCare Pharmaceuticals Inc, Whippany, New Jersey) insertion have posed many challenges for both clinicians and patients. The availability of high-quality, evidence-based clinical guidance has been limited. We have reviewed the currently available published data, and here provide an overview of takeaways, as well as share our perspective and approach on evaluating and managing chronic pelvic pain in this unique patient population.

The device

The Essure microinsert is a hysteroscopically placed device that facilitates permanent sterilization by occluding the bilateral proximal fallopian tubes. The microinsert has an inner and outer nitinol coil that attaches the device to the proximal fallopian tube to ensure retention. The inner coil releases polyethylene terephthalate fibers that cause tubal fiber proliferation to occlude the lumen of the fallopian tube and achieve sterilization.

The device was first approved by the US Food and Drug Administration (FDA) in 2002. In subsequent years, the device was well received and widely used, with approximately 750,000 women worldwide undergoing Essure placement.^1,2 Shortly after approval, many adverse events (AEs), including pelvic pain and abnormal uterine bleeding, were reported, resulting in a public meeting of the FDA Obstetrics and Gynecology Devices Panel in September 2015. A postmarket surveillance study on the device ensued to assess complication rates including unplanned pregnancy, pelvic pain, and surgery for removal. In February 2016, the FDA issued a black box warning and a patient decision checklist.^3,4 In December 2018, Bayer stopped selling and distributing Essure in the United States.⁵ A 4-year follow-up surveillance study on Essure was submitted to the FDA in March 2020.

Adverse outcomes

Common AEs related to the Essure device include heavy uterine bleeding, pelvic pain, and other quality-of-life symptoms such as fatigue and weight gain.^6-8 The main safety endpoints for the mandated FDA postmarket 522 surveillance studies were chronic lower abdominal and pelvic pain; abnormal uterine bleeding; hypersensitivity; allergic reaction, as well as autoimmune disorders incorporating inflammatory markers and human leukocyte antigen; and gynecologic surgery for device removal.⁹ Postmarket surveillence has shown that most AEs are related to placement complications or pelvic pain after Essure insertion. However, there have been several reports of autoimmune diseases categorized as serious AEs, such as new-onset systemic lupus erythematosus, rheumatoid arthritis, and worsening ulcerative colitis, after Essure insertion.⁵

Evaluation of symptoms

Prevalence of pelvic pain following device placement

We conducted a PubMed and MEDLINE search from January 2000 to May 2020, which identified 43 studies citing AEs related to device placement, including pelvic or abdominal pain, abnormal uterine bleeding, hypersensitivity, and autoimmune disorders. A particularly debilitating and frequently cited AE was new-onset pelvic pain or worsening of preexisting pelvic pain. Perforation of the uterus or fallopian tube, resulting in displacement of the device into the peritoneal cavity, or fragmentation of the microinsert was reported as a serious AE that occurred after device placement. However, due to the complexity of chronic pelvic pain pathogenesis, the effect of the insert on patients with existing chronic pelvic pain remains unknown.

Authors of a large retrospective study found that approximately 2.7% of 1,430 patients developed new-onset or worsening pelvic pain after device placement. New-onset pelvic pain in 1% of patients was thought to be secondary to device placement, without a coexisting pathology or diagnosis.¹⁰

In a retrospective study by Clark and colleagues, 22 of 50 women (44%) with pelvic pain after microinsert placement were found to have at least one other cause of pelvic pain. The most common alternative diagnoses were endometriosis, adenomyosis, salpingitis, and adhesive disease. Nine of the 50 patients (18%) were found to have endometriosis upon surgical removal of the microinsert.⁷

Another case series examined outcomes in 29 patients undergoing laparoscopic device removal due to new-onset pelvic pain. Intraoperative findings included endometriosis in 5 patients (17.2%) and pelvic adhesions in 3 (10.3%).² Chronic pelvic pain secondary to endometriosis may be exacerbated with Essure insertion due to discontinuation of hormonal birth control after device placement,⁷ and this diagnosis along with adenomyosis should be strongly considered in patients whose pelvic pain began when hormonal contraception was discontinued after placement of the device.

Continue to: Risk factors...

 

 

Risk factors

Authors of a retrospective cohort study found that patients with prior diagnosis of a chronic pain syndrome, low back pain, headaches, or fibromyalgia were 5 to 6 times more likely to report acute and chronic pain after hysteroscopic sterilization with Essure.¹¹ Since chronic pain is often thought to be driven by a hyperalgesic state of the central nervous system, as previously shown in patients with conditions such as vulvodynia, interstitial cystitis, and fibromyalgia,¹² a hyperalgesic state can potentially explain why some patients are more susceptible to developing worsening pain.

Van Limburg and colleagues conducted a retrospective cohort study with prospective follow-up on 284 women who underwent Essure sterilization. Among these patients, 48% reported negative AEs; risk factors included young age at placement, increasing gravidity, and no prior abdominal surgery.¹³

Onset of pain

The timing and onset of pelvic pain vary widely, suggesting there is no particular time frame for this AE after device placement.^2,6,14-18 A case series by Arjona and colleagues analyzed the incidence of chronic pelvic pain in 4,274 patients after Essure sterilization. Seven patients (0.16%) reported chronic pelvic pain that necessitated device removal. In 6 of the women, the pelvic pain began within 1 week of device placement. In 3 of the 6 cases, the surgeon reported the removal procedures as “difficult.” In all 6 cases, the level of pelvic pain increased with time and was not alleviated with standard analgesic medications.⁶

In another case series of 26 patients, the authors evaluated patients undergoing laparoscopic removal of Essure secondary to pelvic pain and reported that the time range for symptom presentation was immediate to 85 months. Thirteen of 26 patients (50%) reported pain onset within less than 1 month of device placement, 5 of 26 patients (19.2%) reported pain between 1 and 12 months after device placement, and 8 of 26 patients (30.8%) reported pain onset more than 12 months after microinsert placement.² In this study, 17.2% of operative reports indicated difficulty with device placement. It is unclear whether difficulty with placement was associated with development of subsequent abdominal or pelvic pain; however, the relevance of initial insertion difficulty diminished with longer follow-up.

Workup and evaluation

We found 5 studies that provided some framework for evaluating a patient with new-onset or worsening pelvic pain after microinsert placement. Overall, correct placement and functionality of the device should be confirmed by either hysterosalpingogram (HSG) or transvaginal ultrasonography (TVUS). The gold standard to determine tubal occlusion is the HSG. However, TVUS may be a dependable alternative, and either test can accurately demonstrate Essure location.¹⁹ Patients often prefer TVUS over HSG due to the low cost, minimal discomfort, and short examination time.¹ TVUS is a noninvasive and reasonable test to start the initial assessment. The Essure devices are highly echogenic on pelvic ultrasound and easily identifiable by the proximity of the device to the uterotubal junction and its relationship with the surrounding soft tissue. If the device perforates the peritoneal cavity, then the echogenic bowel can impede adequate visualization of the Essure microinsert. If the Essure insert is not visualized on TVUS, an HSG will not only confirm placement but also test insert functionality. After confirming correct placement of the device, the provider can proceed with standard workup for chronic pelvic pain.

If one or more of the devices are malpositioned, the devices are generally presumed to be the etiology of the new pain. Multiple case reports demonstrate pain due to Essure misconfiguration or perforation with subsequent resolution of symptoms after device removal.^18,20,21 A case study by Alcantara and colleagues described a patient with chronic pelvic pain and an Essure coil that was curved in an elliptical shape, not adhering to the anatomic course of the fallopian tube. The patient reported pain resolution after laparoscopic removal of the device.²⁰ Another case report by Mahmoud et al described a subserosal malpositioned device that caused acute pelvic pain 4 months after sterilization. The patient reported resolution of pain after the microinsert was removed via laparoscopy.²¹ These reports highlight the importance of considering malpositioned devices as the etiology of new pelvic pain after Essure placement.

Continue to: Device removal and patient outcomes...

 

 

Device removal and patient outcomes

Removal

Several studies that we evaluated included a discussion on the methods for Essure removal. which are divided into 2 general categories: hysteroscopy and laparoscopy.

Hysteroscopic removal is generally used when the device was placed less than 12 weeks prior to removal.^7,19 After 12 weeks, removal is more difficult due to fibrosis within the fallopian tubes. A risk with hysteroscopic removal is failure to remove all fibers, which allows inflammation and fibrosis to continue.⁷ This risk is mitigated via laparoscopic hysterectomy or mini-cornuectomy with bilateral salpingectomy, where the devices can be removed en bloc and without excessive traction.

Laparoscopic Essure removal procedures described in the literature include salpingostomy and traction on the device, salpingectomy, and salpingectomy with mini-cornuectomy. The incision and traction method is typically performed via a 2- to 3-cm incision on the antimesial edge of the fallopian tube along with a circumferential incision to surround the interstitial tubal area. The implant is carefully extracted from the fallopian tube and cornua, and a salpingectomy is then performed.²² The implant is removed prior to the salpingectomy to ensure that the Essure device is removed in its entirety prior to performing a salpingectomy.

A prospective observational study evaluated laparoscopic removal of Essure devices in 80 women with or without cornual excision. Results suggest that the incision and traction method poses more technical difficulties than the cornuectomy approach.²³ Surgeons reported significant difficulty controlling the tensile pressure with traction, whereas use of the cornuectomy approach eliminated this risk and decreased the risk of fragmentation and incomplete removal.^23,24

Charavil and colleagues demonstrated in a prospective observational study that a vaginal hysterectomy with bilateral salpingectomy is a feasible approach to Essure removal. Twenty-six vaginal hysterectomies with bilateral salpingectomy and Essure removal were performed without conversion to laparoscopy or laparotomy. The surgeons performed an en bloc removal of each hemiuterus along with the ipsilateral tube, which ensured complete removal of the Essure device. Each case was confirmed with an x-ray of the surgical specimen.²⁵

If device fragmentation occurs, there are different methods recommended for locating fragments. A case report of bilateral uterine perforation after uncomplicated Essure placement used a preoperative computed tomography (CT) scan to locate the Essure fragments, but no intraoperative imaging was performed to confirm complete fragment removal.²⁶ The patient continued reporting chronic pelvic pain and ultimately underwent exploratory laparotomy with intraoperative fluoroscopy. Using fluoroscopy, investigators identified omental fragments that were missed on preoperative CT imaging. Fluoroscopy is not commonly used intraoperatively, but it may have added benefit for localizing retained fragments.

A retrospective cohort study reviewed the use of intraoperative x-ray of the removed specimen to confirm complete Essure removal.²⁷ If an x-ray of the removed specimen showed incomplete removal, an intraoperative pelvic x-ray was performed to locate missing fragments. X-ray of the removed devices confirmed complete removal in 63 of 72 patients (87.5%). Six of 9 women with an unsatisfactory specimen x-ray had no residual fragments identified during pelvic x-ray, and the device removal was deemed adequate. The remaining 3 women had radiologic evidence of incomplete device removal and required additional dissection for complete removal. Overall, use of x-ray or fluoroscopy is a relatively safe and accessible way to ensure complete removal of the Essure device and is worth consideration, especially when retained device fragments are suspected.

Symptom resolution

We reviewed 5 studies that examined pain outcomes after removal of the Essure devices. Casey et al found that 23 of 26 patients (88.5%) reported significant pain relief at the postoperative visit, while 3 of 26 (11.5%) reported persistent pelvic pain.² Two of 3 case series examined other outcomes in addition to postoperative pelvic pain, including sexual function and activities of daily living.^7,14 In the first case series by Brito and colleagues, 8 of 11 patients (72.7%) reported an improvement in pelvic pain, ability to perform daily activities, sexual life, and overall quality of life after Essure removal. For the remaining 3 patients with persistent pelvic pain after surgical removal of the device, 2 patients reported worsening pain symptoms and dyspareunia.¹⁴ In this study, 5 of 11 patients reported a history of chronic pelvic pain at baseline. In a retrospective case series by Clark et al, 28 of 32 women (87.5%) reported some improvement in all domains, with 24 of 32 patients (75%) reporting almost total or complete improvement in quality of life, sexual life, pelvic pain, and scores related to activities of daily living. Pain and quality-of-life scores were similar for women who underwent uterine-preserving surgery and for those who underwent hysterectomy. Ten of 32 women (31.3%) reported persistent or worsening symptoms after the Essure removal surgery. In these patients, the authors recommended consideration of other autoimmune and hypersensitivity etiologies.⁷

In a retrospective cohort study by Kamencic et al from 2002 to 2013 of 1,430 patients who underwent Essure placement with postplacement imaging, 62 patients (4.3%) required a second surgery after Essure placement due to pelvic pain.¹⁰ This study also found that 4 of 62 patients (0.3%) had no other obvious cause for the pelvic pain. All 4 of these women had complete resolution of their pain with removal of the Essure microinsert device. A prospective observational study by Chene et al examined health-related quality-of-life outcomes in 80 women who underwent laparoscopic Essure removal for pelvic pain. This survey study demonstrated significant improvement in the quality of life in both psychological and physical aspects, and these results were maintained at 3- and 6-month follow-up examinations.²³

Summary

Although Essure products were withdrawn from the market in the United States in 2018, many patients still experience significant AEs associated with the device. The goal of the perspectives and data presented here is to assist clinicians in addressing and managing the pain experienced by patients after device insertion. ●

​​​​​​​

The evaluation and management of chronic pelvic pain in patients with a history of Essure device (Bayer HealthCare Pharmaceuticals Inc, Whippany, New Jersey) insertion have posed many challenges for both clinicians and patients. The availability of high-quality, evidence-based clinical guidance has been limited. We have reviewed the currently available published data, and here provide an overview of takeaways, as well as share our perspective and approach on evaluating and managing chronic pelvic pain in this unique patient population.

The device

The Essure microinsert is a hysteroscopically placed device that facilitates permanent sterilization by occluding the bilateral proximal fallopian tubes. The microinsert has an inner and outer nitinol coil that attaches the device to the proximal fallopian tube to ensure retention. The inner coil releases polyethylene terephthalate fibers that cause tubal fiber proliferation to occlude the lumen of the fallopian tube and achieve sterilization.

The device was first approved by the US Food and Drug Administration (FDA) in 2002. In subsequent years, the device was well received and widely used, with approximately 750,000 women worldwide undergoing Essure placement.^1,2 Shortly after approval, many adverse events (AEs), including pelvic pain and abnormal uterine bleeding, were reported, resulting in a public meeting of the FDA Obstetrics and Gynecology Devices Panel in September 2015. A postmarket surveillance study on the device ensued to assess complication rates including unplanned pregnancy, pelvic pain, and surgery for removal. In February 2016, the FDA issued a black box warning and a patient decision checklist.^3,4 In December 2018, Bayer stopped selling and distributing Essure in the United States.⁵ A 4-year follow-up surveillance study on Essure was submitted to the FDA in March 2020.

Adverse outcomes

Common AEs related to the Essure device include heavy uterine bleeding, pelvic pain, and other quality-of-life symptoms such as fatigue and weight gain.^6-8 The main safety endpoints for the mandated FDA postmarket 522 surveillance studies were chronic lower abdominal and pelvic pain; abnormal uterine bleeding; hypersensitivity; allergic reaction, as well as autoimmune disorders incorporating inflammatory markers and human leukocyte antigen; and gynecologic surgery for device removal.⁹ Postmarket surveillence has shown that most AEs are related to placement complications or pelvic pain after Essure insertion. However, there have been several reports of autoimmune diseases categorized as serious AEs, such as new-onset systemic lupus erythematosus, rheumatoid arthritis, and worsening ulcerative colitis, after Essure insertion.⁵

Evaluation of symptoms

Prevalence of pelvic pain following device placement

We conducted a PubMed and MEDLINE search from January 2000 to May 2020, which identified 43 studies citing AEs related to device placement, including pelvic or abdominal pain, abnormal uterine bleeding, hypersensitivity, and autoimmune disorders. A particularly debilitating and frequently cited AE was new-onset pelvic pain or worsening of preexisting pelvic pain. Perforation of the uterus or fallopian tube, resulting in displacement of the device into the peritoneal cavity, or fragmentation of the microinsert was reported as a serious AE that occurred after device placement. However, due to the complexity of chronic pelvic pain pathogenesis, the effect of the insert on patients with existing chronic pelvic pain remains unknown.

Authors of a large retrospective study found that approximately 2.7% of 1,430 patients developed new-onset or worsening pelvic pain after device placement. New-onset pelvic pain in 1% of patients was thought to be secondary to device placement, without a coexisting pathology or diagnosis.¹⁰

In a retrospective study by Clark and colleagues, 22 of 50 women (44%) with pelvic pain after microinsert placement were found to have at least one other cause of pelvic pain. The most common alternative diagnoses were endometriosis, adenomyosis, salpingitis, and adhesive disease. Nine of the 50 patients (18%) were found to have endometriosis upon surgical removal of the microinsert.⁷

Another case series examined outcomes in 29 patients undergoing laparoscopic device removal due to new-onset pelvic pain. Intraoperative findings included endometriosis in 5 patients (17.2%) and pelvic adhesions in 3 (10.3%).² Chronic pelvic pain secondary to endometriosis may be exacerbated with Essure insertion due to discontinuation of hormonal birth control after device placement,⁷ and this diagnosis along with adenomyosis should be strongly considered in patients whose pelvic pain began when hormonal contraception was discontinued after placement of the device.

Continue to: Risk factors...

 

 

Risk factors

Authors of a retrospective cohort study found that patients with prior diagnosis of a chronic pain syndrome, low back pain, headaches, or fibromyalgia were 5 to 6 times more likely to report acute and chronic pain after hysteroscopic sterilization with Essure.¹¹ Since chronic pain is often thought to be driven by a hyperalgesic state of the central nervous system, as previously shown in patients with conditions such as vulvodynia, interstitial cystitis, and fibromyalgia,¹² a hyperalgesic state can potentially explain why some patients are more susceptible to developing worsening pain.

Van Limburg and colleagues conducted a retrospective cohort study with prospective follow-up on 284 women who underwent Essure sterilization. Among these patients, 48% reported negative AEs; risk factors included young age at placement, increasing gravidity, and no prior abdominal surgery.¹³

Onset of pain

The timing and onset of pelvic pain vary widely, suggesting there is no particular time frame for this AE after device placement.^2,6,14-18 A case series by Arjona and colleagues analyzed the incidence of chronic pelvic pain in 4,274 patients after Essure sterilization. Seven patients (0.16%) reported chronic pelvic pain that necessitated device removal. In 6 of the women, the pelvic pain began within 1 week of device placement. In 3 of the 6 cases, the surgeon reported the removal procedures as “difficult.” In all 6 cases, the level of pelvic pain increased with time and was not alleviated with standard analgesic medications.⁶

In another case series of 26 patients, the authors evaluated patients undergoing laparoscopic removal of Essure secondary to pelvic pain and reported that the time range for symptom presentation was immediate to 85 months. Thirteen of 26 patients (50%) reported pain onset within less than 1 month of device placement, 5 of 26 patients (19.2%) reported pain between 1 and 12 months after device placement, and 8 of 26 patients (30.8%) reported pain onset more than 12 months after microinsert placement.² In this study, 17.2% of operative reports indicated difficulty with device placement. It is unclear whether difficulty with placement was associated with development of subsequent abdominal or pelvic pain; however, the relevance of initial insertion difficulty diminished with longer follow-up.

Workup and evaluation

We found 5 studies that provided some framework for evaluating a patient with new-onset or worsening pelvic pain after microinsert placement. Overall, correct placement and functionality of the device should be confirmed by either hysterosalpingogram (HSG) or transvaginal ultrasonography (TVUS). The gold standard to determine tubal occlusion is the HSG. However, TVUS may be a dependable alternative, and either test can accurately demonstrate Essure location.¹⁹ Patients often prefer TVUS over HSG due to the low cost, minimal discomfort, and short examination time.¹ TVUS is a noninvasive and reasonable test to start the initial assessment. The Essure devices are highly echogenic on pelvic ultrasound and easily identifiable by the proximity of the device to the uterotubal junction and its relationship with the surrounding soft tissue. If the device perforates the peritoneal cavity, then the echogenic bowel can impede adequate visualization of the Essure microinsert. If the Essure insert is not visualized on TVUS, an HSG will not only confirm placement but also test insert functionality. After confirming correct placement of the device, the provider can proceed with standard workup for chronic pelvic pain.

If one or more of the devices are malpositioned, the devices are generally presumed to be the etiology of the new pain. Multiple case reports demonstrate pain due to Essure misconfiguration or perforation with subsequent resolution of symptoms after device removal.^18,20,21 A case study by Alcantara and colleagues described a patient with chronic pelvic pain and an Essure coil that was curved in an elliptical shape, not adhering to the anatomic course of the fallopian tube. The patient reported pain resolution after laparoscopic removal of the device.²⁰ Another case report by Mahmoud et al described a subserosal malpositioned device that caused acute pelvic pain 4 months after sterilization. The patient reported resolution of pain after the microinsert was removed via laparoscopy.²¹ These reports highlight the importance of considering malpositioned devices as the etiology of new pelvic pain after Essure placement.

Continue to: Device removal and patient outcomes...

 

 

Device removal and patient outcomes

Removal

Several studies that we evaluated included a discussion on the methods for Essure removal. which are divided into 2 general categories: hysteroscopy and laparoscopy.

Hysteroscopic removal is generally used when the device was placed less than 12 weeks prior to removal.^7,19 After 12 weeks, removal is more difficult due to fibrosis within the fallopian tubes. A risk with hysteroscopic removal is failure to remove all fibers, which allows inflammation and fibrosis to continue.⁷ This risk is mitigated via laparoscopic hysterectomy or mini-cornuectomy with bilateral salpingectomy, where the devices can be removed en bloc and without excessive traction.

Laparoscopic Essure removal procedures described in the literature include salpingostomy and traction on the device, salpingectomy, and salpingectomy with mini-cornuectomy. The incision and traction method is typically performed via a 2- to 3-cm incision on the antimesial edge of the fallopian tube along with a circumferential incision to surround the interstitial tubal area. The implant is carefully extracted from the fallopian tube and cornua, and a salpingectomy is then performed.²² The implant is removed prior to the salpingectomy to ensure that the Essure device is removed in its entirety prior to performing a salpingectomy.

A prospective observational study evaluated laparoscopic removal of Essure devices in 80 women with or without cornual excision. Results suggest that the incision and traction method poses more technical difficulties than the cornuectomy approach.²³ Surgeons reported significant difficulty controlling the tensile pressure with traction, whereas use of the cornuectomy approach eliminated this risk and decreased the risk of fragmentation and incomplete removal.^23,24

Charavil and colleagues demonstrated in a prospective observational study that a vaginal hysterectomy with bilateral salpingectomy is a feasible approach to Essure removal. Twenty-six vaginal hysterectomies with bilateral salpingectomy and Essure removal were performed without conversion to laparoscopy or laparotomy. The surgeons performed an en bloc removal of each hemiuterus along with the ipsilateral tube, which ensured complete removal of the Essure device. Each case was confirmed with an x-ray of the surgical specimen.²⁵

If device fragmentation occurs, there are different methods recommended for locating fragments. A case report of bilateral uterine perforation after uncomplicated Essure placement used a preoperative computed tomography (CT) scan to locate the Essure fragments, but no intraoperative imaging was performed to confirm complete fragment removal.²⁶ The patient continued reporting chronic pelvic pain and ultimately underwent exploratory laparotomy with intraoperative fluoroscopy. Using fluoroscopy, investigators identified omental fragments that were missed on preoperative CT imaging. Fluoroscopy is not commonly used intraoperatively, but it may have added benefit for localizing retained fragments.

A retrospective cohort study reviewed the use of intraoperative x-ray of the removed specimen to confirm complete Essure removal.²⁷ If an x-ray of the removed specimen showed incomplete removal, an intraoperative pelvic x-ray was performed to locate missing fragments. X-ray of the removed devices confirmed complete removal in 63 of 72 patients (87.5%). Six of 9 women with an unsatisfactory specimen x-ray had no residual fragments identified during pelvic x-ray, and the device removal was deemed adequate. The remaining 3 women had radiologic evidence of incomplete device removal and required additional dissection for complete removal. Overall, use of x-ray or fluoroscopy is a relatively safe and accessible way to ensure complete removal of the Essure device and is worth consideration, especially when retained device fragments are suspected.

Symptom resolution

We reviewed 5 studies that examined pain outcomes after removal of the Essure devices. Casey et al found that 23 of 26 patients (88.5%) reported significant pain relief at the postoperative visit, while 3 of 26 (11.5%) reported persistent pelvic pain.² Two of 3 case series examined other outcomes in addition to postoperative pelvic pain, including sexual function and activities of daily living.^7,14 In the first case series by Brito and colleagues, 8 of 11 patients (72.7%) reported an improvement in pelvic pain, ability to perform daily activities, sexual life, and overall quality of life after Essure removal. For the remaining 3 patients with persistent pelvic pain after surgical removal of the device, 2 patients reported worsening pain symptoms and dyspareunia.¹⁴ In this study, 5 of 11 patients reported a history of chronic pelvic pain at baseline. In a retrospective case series by Clark et al, 28 of 32 women (87.5%) reported some improvement in all domains, with 24 of 32 patients (75%) reporting almost total or complete improvement in quality of life, sexual life, pelvic pain, and scores related to activities of daily living. Pain and quality-of-life scores were similar for women who underwent uterine-preserving surgery and for those who underwent hysterectomy. Ten of 32 women (31.3%) reported persistent or worsening symptoms after the Essure removal surgery. In these patients, the authors recommended consideration of other autoimmune and hypersensitivity etiologies.⁷

In a retrospective cohort study by Kamencic et al from 2002 to 2013 of 1,430 patients who underwent Essure placement with postplacement imaging, 62 patients (4.3%) required a second surgery after Essure placement due to pelvic pain.¹⁰ This study also found that 4 of 62 patients (0.3%) had no other obvious cause for the pelvic pain. All 4 of these women had complete resolution of their pain with removal of the Essure microinsert device. A prospective observational study by Chene et al examined health-related quality-of-life outcomes in 80 women who underwent laparoscopic Essure removal for pelvic pain. This survey study demonstrated significant improvement in the quality of life in both psychological and physical aspects, and these results were maintained at 3- and 6-month follow-up examinations.²³

Summary

Although Essure products were withdrawn from the market in the United States in 2018, many patients still experience significant AEs associated with the device. The goal of the perspectives and data presented here is to assist clinicians in addressing and managing the pain experienced by patients after device insertion. ●

​​​​​​​

The evaluation and management of chronic pelvic pain in patients with a history of Essure device (Bayer HealthCare Pharmaceuticals Inc, Whippany, New Jersey) insertion have posed many challenges for both clinicians and patients. The availability of high-quality, evidence-based clinical guidance has been limited. We have reviewed the currently available published data, and here provide an overview of takeaways, as well as share our perspective and approach on evaluating and managing chronic pelvic pain in this unique patient population.

The device

The Essure microinsert is a hysteroscopically placed device that facilitates permanent sterilization by occluding the bilateral proximal fallopian tubes. The microinsert has an inner and outer nitinol coil that attaches the device to the proximal fallopian tube to ensure retention. The inner coil releases polyethylene terephthalate fibers that cause tubal fiber proliferation to occlude the lumen of the fallopian tube and achieve sterilization.

The device was first approved by the US Food and Drug Administration (FDA) in 2002. In subsequent years, the device was well received and widely used, with approximately 750,000 women worldwide undergoing Essure placement.^1,2 Shortly after approval, many adverse events (AEs), including pelvic pain and abnormal uterine bleeding, were reported, resulting in a public meeting of the FDA Obstetrics and Gynecology Devices Panel in September 2015. A postmarket surveillance study on the device ensued to assess complication rates including unplanned pregnancy, pelvic pain, and surgery for removal. In February 2016, the FDA issued a black box warning and a patient decision checklist.^3,4 In December 2018, Bayer stopped selling and distributing Essure in the United States.⁵ A 4-year follow-up surveillance study on Essure was submitted to the FDA in March 2020.

Adverse outcomes

Common AEs related to the Essure device include heavy uterine bleeding, pelvic pain, and other quality-of-life symptoms such as fatigue and weight gain.^6-8 The main safety endpoints for the mandated FDA postmarket 522 surveillance studies were chronic lower abdominal and pelvic pain; abnormal uterine bleeding; hypersensitivity; allergic reaction, as well as autoimmune disorders incorporating inflammatory markers and human leukocyte antigen; and gynecologic surgery for device removal.⁹ Postmarket surveillence has shown that most AEs are related to placement complications or pelvic pain after Essure insertion. However, there have been several reports of autoimmune diseases categorized as serious AEs, such as new-onset systemic lupus erythematosus, rheumatoid arthritis, and worsening ulcerative colitis, after Essure insertion.⁵

Evaluation of symptoms

Prevalence of pelvic pain following device placement

We conducted a PubMed and MEDLINE search from January 2000 to May 2020, which identified 43 studies citing AEs related to device placement, including pelvic or abdominal pain, abnormal uterine bleeding, hypersensitivity, and autoimmune disorders. A particularly debilitating and frequently cited AE was new-onset pelvic pain or worsening of preexisting pelvic pain. Perforation of the uterus or fallopian tube, resulting in displacement of the device into the peritoneal cavity, or fragmentation of the microinsert was reported as a serious AE that occurred after device placement. However, due to the complexity of chronic pelvic pain pathogenesis, the effect of the insert on patients with existing chronic pelvic pain remains unknown.

Authors of a large retrospective study found that approximately 2.7% of 1,430 patients developed new-onset or worsening pelvic pain after device placement. New-onset pelvic pain in 1% of patients was thought to be secondary to device placement, without a coexisting pathology or diagnosis.¹⁰

In a retrospective study by Clark and colleagues, 22 of 50 women (44%) with pelvic pain after microinsert placement were found to have at least one other cause of pelvic pain. The most common alternative diagnoses were endometriosis, adenomyosis, salpingitis, and adhesive disease. Nine of the 50 patients (18%) were found to have endometriosis upon surgical removal of the microinsert.⁷

Another case series examined outcomes in 29 patients undergoing laparoscopic device removal due to new-onset pelvic pain. Intraoperative findings included endometriosis in 5 patients (17.2%) and pelvic adhesions in 3 (10.3%).² Chronic pelvic pain secondary to endometriosis may be exacerbated with Essure insertion due to discontinuation of hormonal birth control after device placement,⁷ and this diagnosis along with adenomyosis should be strongly considered in patients whose pelvic pain began when hormonal contraception was discontinued after placement of the device.

Continue to: Risk factors...

 

 

Risk factors

Authors of a retrospective cohort study found that patients with prior diagnosis of a chronic pain syndrome, low back pain, headaches, or fibromyalgia were 5 to 6 times more likely to report acute and chronic pain after hysteroscopic sterilization with Essure.¹¹ Since chronic pain is often thought to be driven by a hyperalgesic state of the central nervous system, as previously shown in patients with conditions such as vulvodynia, interstitial cystitis, and fibromyalgia,¹² a hyperalgesic state can potentially explain why some patients are more susceptible to developing worsening pain.

Van Limburg and colleagues conducted a retrospective cohort study with prospective follow-up on 284 women who underwent Essure sterilization. Among these patients, 48% reported negative AEs; risk factors included young age at placement, increasing gravidity, and no prior abdominal surgery.¹³

Onset of pain

The timing and onset of pelvic pain vary widely, suggesting there is no particular time frame for this AE after device placement.^2,6,14-18 A case series by Arjona and colleagues analyzed the incidence of chronic pelvic pain in 4,274 patients after Essure sterilization. Seven patients (0.16%) reported chronic pelvic pain that necessitated device removal. In 6 of the women, the pelvic pain began within 1 week of device placement. In 3 of the 6 cases, the surgeon reported the removal procedures as “difficult.” In all 6 cases, the level of pelvic pain increased with time and was not alleviated with standard analgesic medications.⁶

In another case series of 26 patients, the authors evaluated patients undergoing laparoscopic removal of Essure secondary to pelvic pain and reported that the time range for symptom presentation was immediate to 85 months. Thirteen of 26 patients (50%) reported pain onset within less than 1 month of device placement, 5 of 26 patients (19.2%) reported pain between 1 and 12 months after device placement, and 8 of 26 patients (30.8%) reported pain onset more than 12 months after microinsert placement.² In this study, 17.2% of operative reports indicated difficulty with device placement. It is unclear whether difficulty with placement was associated with development of subsequent abdominal or pelvic pain; however, the relevance of initial insertion difficulty diminished with longer follow-up.

Workup and evaluation

We found 5 studies that provided some framework for evaluating a patient with new-onset or worsening pelvic pain after microinsert placement. Overall, correct placement and functionality of the device should be confirmed by either hysterosalpingogram (HSG) or transvaginal ultrasonography (TVUS). The gold standard to determine tubal occlusion is the HSG. However, TVUS may be a dependable alternative, and either test can accurately demonstrate Essure location.¹⁹ Patients often prefer TVUS over HSG due to the low cost, minimal discomfort, and short examination time.¹ TVUS is a noninvasive and reasonable test to start the initial assessment. The Essure devices are highly echogenic on pelvic ultrasound and easily identifiable by the proximity of the device to the uterotubal junction and its relationship with the surrounding soft tissue. If the device perforates the peritoneal cavity, then the echogenic bowel can impede adequate visualization of the Essure microinsert. If the Essure insert is not visualized on TVUS, an HSG will not only confirm placement but also test insert functionality. After confirming correct placement of the device, the provider can proceed with standard workup for chronic pelvic pain.

If one or more of the devices are malpositioned, the devices are generally presumed to be the etiology of the new pain. Multiple case reports demonstrate pain due to Essure misconfiguration or perforation with subsequent resolution of symptoms after device removal.^18,20,21 A case study by Alcantara and colleagues described a patient with chronic pelvic pain and an Essure coil that was curved in an elliptical shape, not adhering to the anatomic course of the fallopian tube. The patient reported pain resolution after laparoscopic removal of the device.²⁰ Another case report by Mahmoud et al described a subserosal malpositioned device that caused acute pelvic pain 4 months after sterilization. The patient reported resolution of pain after the microinsert was removed via laparoscopy.²¹ These reports highlight the importance of considering malpositioned devices as the etiology of new pelvic pain after Essure placement.

Continue to: Device removal and patient outcomes...

 

 

Device removal and patient outcomes

Removal

Several studies that we evaluated included a discussion on the methods for Essure removal. which are divided into 2 general categories: hysteroscopy and laparoscopy.

Hysteroscopic removal is generally used when the device was placed less than 12 weeks prior to removal.^7,19 After 12 weeks, removal is more difficult due to fibrosis within the fallopian tubes. A risk with hysteroscopic removal is failure to remove all fibers, which allows inflammation and fibrosis to continue.⁷ This risk is mitigated via laparoscopic hysterectomy or mini-cornuectomy with bilateral salpingectomy, where the devices can be removed en bloc and without excessive traction.

Laparoscopic Essure removal procedures described in the literature include salpingostomy and traction on the device, salpingectomy, and salpingectomy with mini-cornuectomy. The incision and traction method is typically performed via a 2- to 3-cm incision on the antimesial edge of the fallopian tube along with a circumferential incision to surround the interstitial tubal area. The implant is carefully extracted from the fallopian tube and cornua, and a salpingectomy is then performed.²² The implant is removed prior to the salpingectomy to ensure that the Essure device is removed in its entirety prior to performing a salpingectomy.

A prospective observational study evaluated laparoscopic removal of Essure devices in 80 women with or without cornual excision. Results suggest that the incision and traction method poses more technical difficulties than the cornuectomy approach.²³ Surgeons reported significant difficulty controlling the tensile pressure with traction, whereas use of the cornuectomy approach eliminated this risk and decreased the risk of fragmentation and incomplete removal.^23,24

Charavil and colleagues demonstrated in a prospective observational study that a vaginal hysterectomy with bilateral salpingectomy is a feasible approach to Essure removal. Twenty-six vaginal hysterectomies with bilateral salpingectomy and Essure removal were performed without conversion to laparoscopy or laparotomy. The surgeons performed an en bloc removal of each hemiuterus along with the ipsilateral tube, which ensured complete removal of the Essure device. Each case was confirmed with an x-ray of the surgical specimen.²⁵

If device fragmentation occurs, there are different methods recommended for locating fragments. A case report of bilateral uterine perforation after uncomplicated Essure placement used a preoperative computed tomography (CT) scan to locate the Essure fragments, but no intraoperative imaging was performed to confirm complete fragment removal.²⁶ The patient continued reporting chronic pelvic pain and ultimately underwent exploratory laparotomy with intraoperative fluoroscopy. Using fluoroscopy, investigators identified omental fragments that were missed on preoperative CT imaging. Fluoroscopy is not commonly used intraoperatively, but it may have added benefit for localizing retained fragments.

A retrospective cohort study reviewed the use of intraoperative x-ray of the removed specimen to confirm complete Essure removal.²⁷ If an x-ray of the removed specimen showed incomplete removal, an intraoperative pelvic x-ray was performed to locate missing fragments. X-ray of the removed devices confirmed complete removal in 63 of 72 patients (87.5%). Six of 9 women with an unsatisfactory specimen x-ray had no residual fragments identified during pelvic x-ray, and the device removal was deemed adequate. The remaining 3 women had radiologic evidence of incomplete device removal and required additional dissection for complete removal. Overall, use of x-ray or fluoroscopy is a relatively safe and accessible way to ensure complete removal of the Essure device and is worth consideration, especially when retained device fragments are suspected.

Symptom resolution

We reviewed 5 studies that examined pain outcomes after removal of the Essure devices. Casey et al found that 23 of 26 patients (88.5%) reported significant pain relief at the postoperative visit, while 3 of 26 (11.5%) reported persistent pelvic pain.² Two of 3 case series examined other outcomes in addition to postoperative pelvic pain, including sexual function and activities of daily living.^7,14 In the first case series by Brito and colleagues, 8 of 11 patients (72.7%) reported an improvement in pelvic pain, ability to perform daily activities, sexual life, and overall quality of life after Essure removal. For the remaining 3 patients with persistent pelvic pain after surgical removal of the device, 2 patients reported worsening pain symptoms and dyspareunia.¹⁴ In this study, 5 of 11 patients reported a history of chronic pelvic pain at baseline. In a retrospective case series by Clark et al, 28 of 32 women (87.5%) reported some improvement in all domains, with 24 of 32 patients (75%) reporting almost total or complete improvement in quality of life, sexual life, pelvic pain, and scores related to activities of daily living. Pain and quality-of-life scores were similar for women who underwent uterine-preserving surgery and for those who underwent hysterectomy. Ten of 32 women (31.3%) reported persistent or worsening symptoms after the Essure removal surgery. In these patients, the authors recommended consideration of other autoimmune and hypersensitivity etiologies.⁷

In a retrospective cohort study by Kamencic et al from 2002 to 2013 of 1,430 patients who underwent Essure placement with postplacement imaging, 62 patients (4.3%) required a second surgery after Essure placement due to pelvic pain.¹⁰ This study also found that 4 of 62 patients (0.3%) had no other obvious cause for the pelvic pain. All 4 of these women had complete resolution of their pain with removal of the Essure microinsert device. A prospective observational study by Chene et al examined health-related quality-of-life outcomes in 80 women who underwent laparoscopic Essure removal for pelvic pain. This survey study demonstrated significant improvement in the quality of life in both psychological and physical aspects, and these results were maintained at 3- and 6-month follow-up examinations.²³

Summary

Although Essure products were withdrawn from the market in the United States in 2018, many patients still experience significant AEs associated with the device. The goal of the perspectives and data presented here is to assist clinicians in addressing and managing the pain experienced by patients after device insertion. ●

​​​​​​​

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

CASE Part 1: CPR initiated during induction of labor

A 32-year-old gravida 4 para 3-0-0-3 is undergoing induction of labor with intravenous (IV) oxytocin at 39 weeks of gestation. She has no significant medical or obstetric history. Fifteen minutes after reaching complete cervical dilation, she says “I don’t feel right,” then suddenly loses consciousness. The nurse finds no detectable pulse, calls a “code blue,” and initiates cardiopulmonary resuscitation (CPR). The obstetrician is notified, appears promptly, assesses the situation, and delivers a 3.6-kg baby via vacuum extraction. Apgar score is 2/10 at 1 minute and 6/10 at 5 minutes. After delivery of the placenta, there is uterine atony and brisk hemorrhage with 2 L of blood loss.

Management of AFE: A rare complication

This case demonstrates a classic presentation of amniotic fluid embolism (AFE) syndrome—a patient in labor or within 30 minutes after delivery has sudden onset of cardiorespiratory collapse followed by disseminated intravascular coagulation (DIC). AFE is rare, affecting only about 2 to 6 per 100,000 births, but classic cases have a reported maternal mortality rate that exceeds 50%.¹ It is thought to reflect a complex, systemic proinflammatory response to maternal intravasation of pregnancy material, such as trophoblast, thromboplastins, fetal cells, or amniotic fluid. Because the syndrome is not necessarily directly caused by emboli or by amniotic fluid per se,² it has been proposed that AFE be called “anaphylactoid syndrome of pregnancy,” but this terminology has not yet been widely adopted.³

Guidelines from the Society for Maternal-Fetal Medicine (SMFM) recommend several time-critical steps for the initial stabilization and management of patients with AFE.⁴ However, because AFE is rare, most obstetric providers may not encounter a case for many years or even decades after they have received training, so it is unrealistic to expect that they will remember these guidelines when they are needed. For this reason, when AFE occurs, it is important to have a readily accessible cognitive aid, such as a checklist that summarizes the key management steps. The SMFM provides a checklist for initial management of AFE that can be used at your institution; it is presented in the FIGURE and provides the outline for this discussion.⁵

Provide CPR immediately

Most AFE cases are accompanied by cardiorespiratory arrest. If the patient has no pulse, call a “code” to mobilize additional help and immediately start CPR. Use a backboard to make cardiac compressions most effective and manually displace the uterus or tilt the patient to avoid supine hypotension. Designate a timekeeper to call out 1-minute intervals and record critical data, such as medication administration and laboratory orders/results.

Expedite delivery

Immediate delivery is needed if maternal cardiac activity is not restored within 4 minutes of starting CPR, with a target to have delivery completed within 5 minutes. Operative vaginal delivery may be an option if delivery is imminent, as in the case presented, but cesarean delivery (CD) will be needed in most cases. This was previously called “perimortem cesarean” delivery, but the term “resuscitative hysterotomy” has been proposed because the primary goal is to improve the effectiveness of CPR⁶ and prevent both maternal and perinatal death. CPR is less effective in pregnant women because the pregnant uterus takes a substantial fraction of the maternal cardiac output, as well as compresses the vena cava. Some experts suggest that, rather than waiting 4 minutes, CD should be started as soon as an obstetrician or other surgeon is present, unless there is an immediate response to electrical cardioversion.^6,7

In most cases, immediate CD should be performed wherever the patient is located rather than using precious minutes to move the patient to an operating room. Antiseptic preparation is expedited by simply pouring povidone-iodine or chlorhexidine over the lower abdomen if readily available; if not available, skip this step. Enter the abdomen and uterus as rapidly as possible using only a scalpel to make generous midline incisions.

If CPR is not required, proceed with cesarean or operative vaginal delivery as soon as the mother has been stabilized. These procedures should be performed using standard safety precautions outlined in the SMFM patient safety checklists for cesarean or operative vaginal delivery.^8,9

Continue to: Anticipate hemorrhage...

 

 

Anticipate hemorrhage

Be prepared for uterine atony, coagulopathy, and catastrophic hemorrhage. Initiate IV oxytocin prophylaxis as soon as the infant is delivered. Have a low threshold for giving other uterotonic agents such as methylergonovine, carboprost, or misoprostol. If hemorrhage or DIC occurs, give tranexamic acid. Have the anesthesiologist or trauma team (if available) insert an intraosseous line for fluid resuscitation if peripheral IV access is inadequate.

Massive transfusion is often needed to treat DIC, which occurs in most AFE cases. Anticipate—do not wait—for DIC to occur. We propose activating your hospital’s massive transfusion protocol (MTP) as soon as you diagnose AFE so that blood products will be available as soon as possible. A typical MTP provides several units of red blood cells, a pheresis pack of platelets, and fresh/frozen plasma (FFP). If clinically indicated, administer cryoprecipitate instead of FFP to minimize volume overload, which may occur with FFP.

CASE Part 2: MTP initiated to treat DIC

The MTP is initiated. Laboratory results immediately pre-transfusion include hemoglobin 11.3 g/dL, platelet count 46,000 per mm³, fibrinogen 87 mg/dL, and an elevated prothrombin time international normalized ratio.

Expect heart failure

The initial hemodynamic picture in AFE is right heart failure, which should optimally be managed by a specialist from anesthesiology, cardiology, or critical care as soon as they are available. An emergency department physician may manage the hemodynamics until a specialist arrives. Avoidance of fluid overload is one important principle. If fluid challenges are needed for hypovolemic shock, boluses should be restricted to 500 mL rather than the traditional 1000 mL.

Pharmacologic treatment may include vasopressors, inotropic agents, and pulmonary vasodilators. Example medications and dosages recommended by SMFM are summarized in the checklist (FIGURE).⁵

After the initial phase of recovery, the hemodynamic picture often changes from right heart failure to left heart failure. Management of left heart failure is not covered in the SMFM checklist because, by the time it appears, the patient will usually be in the intensive care unit, managed by the critical care team. Management of left heart failure generally includes diuresis as needed for cardiogenic pulmonary edema, optimization of cardiac preload, and inotropic agents or vasopressors if needed to maintain cardiac output or perfusion pressure.⁴

Debrief, learning opportunities

Complex emergencies such as AFE are rarely handled 100% perfectly, even those with a good outcome, so they present opportunities for team learning and improvement. The team should conduct a 10- to 15-minute debrief soon after the patient is stabilized. Make an explicit statement that the main goal of the debrief is to gather suggestions as to how systems and processes could be improved for next time, not to find fault or lay blame on individuals. Encourage all personnel involved in the initial management to attend and discuss what went well and what did not. Another goal is to provide support for individuals who may feel traumatized by the dramatic, frightening events surrounding an AFE and by the poor patient outcome or guarded prognosis that frequently follows. Another goal is to discuss the plan for providing support and disclosure to the patient and family.

The vast majority of AFE cases meet criteria to be designated as “sentinel events,” because of patient transfer to the intensive care unit, multi-unit blood transfusion, other severe maternal morbidities, or maternal death. Therefore, most AFE cases will trigger a root cause analysis (RCA) or other formal sentinel event analysis conducted by the hospital’s Safety or Quality Department. As with the immediate post-event debrief, the first goal of the RCA is to identify systems issues that may have resulted in suboptimal care and that can be modified to improve future care. Specific issues regarding the checklist should also be addressed:

• Was the checklist used?
• Was the checklist available?
• Are there items on the checklist that need to be modified, added, or deleted?

The RCA concludes with the development of a performance improvement plan.

Ultimately, we encourage all AFE cases be reported to the registry maintained by the Amniotic Fluid Embolism Foundation at https://www.afesupport.org/, regardless of whether the outcome was favorable for the mother and newborn. The registry includes over 130 AFE cases since 2013 from around the world. Researchers periodically report on the registry findings.¹⁰ If providers report cases with both good and bad outcomes, the registry may provide future insights regarding which adjunctive or empiric treatments may or may not be promising.

Continue to: Empiric treatments...

 

 

Empiric treatments

From time-to-time, new regimens for empiric treatment of AFE are reported. It is important to recognize that these reports are generally uncontrolled case reports of favorable outcomes and that, without a control group, it is impossible to determine to what extent the treatment contributed to the outcome or was merely incidental. Given the rarity of AFE, it seems unlikely that there will ever be a randomized clinical trial or even a controlled prospective study comparing treatment regimens.

The “A-OK” regimen is an empiric treatment that has garnered some interest after an initial case report.¹¹ It consists of an anticholinergic agent (atropine 0.2 mg IV), a selective 5-HT3 receptor antagonist (ondansetron 8 mg IV), and a nonsteroidal anti-inflammatory drug (ketorolac 15 mg IV). We have some reservations about this regimen, however, because atropine is relatively contraindicated if the patient has tachycardia (which is common in patients with hemorrhage) and ketorolac may suppress platelet function, which might be harmful for patients with DIC or thrombocytopenia.

Another empiric treatment is the “50-50-500” regimen, which includes an H1 antihistamine (diphenhydramine 50 mg IV), an H2 antihistamine (famotidine 50 mg IV), and a corticosteroid (hydrocortisone 500 mg IV). This regimen aims to suppress histamine-mediated and cell-mediated inflammatory responses, based on the notion that proinflammatory responses likely mediate much of the underlying pathophysiology of the AFE syndrome.

We would emphasize that these empiric regimens are not clinically validated, US Food and Drug Administration approved for treatment of AFE, or considered standard of care. Future reports of these and other regimens will be needed to evaluate their efficacy, limitations, and risks. Again, we encourage providers to report all AFE cases to the AFE Foundation registry, regardless of whether the treatments are successful.

CASE Conclusion

The hemorrhage stops after administration of oxytocin, carboprost, 6 units of cryoprecipitate, and a 6-unit platelet pheresis pack. The patient is transferred to the intensive care unit where she eventually requires a total of 10 units of red cells, 8 more units of cryoprecipitate, and another platelet pheresis pack. She is discharged to home in stable condition on postpartum day 4.

Be prepared, have the checklist ready

Because AFE is rare, most members of the health care team will have no prior experience managing a real case. It may have been years or decades since they had any education on AFE or they last read a review article such as this one. It is even possible the anesthesiologist, cardiologist, or critical care specialist has never heard of AFE. Thus if they rely on memory alone, there is substantial risk of forgetting items, getting dosages wrong, or other errors. With this in mind, what is the best way to prepare the team to expeditiously employ the management steps outlined here?

Use of a checklist that summarizes these key steps for early management, such as the SMFM checklist in the FIGURE, will help ensure that all relevant steps are performed in every AFE case. It is designed to be printed on a single sheet of letter-sized paper, and we propose that every labor and delivery (L&D) unit keep laminated copies of this checklist in several places where they will be immediately available should an AFE occur. Copies can be kept on the anesthesia carts in the L&D operating rooms, in an emergency procedures binder on the unit, and on the “crash carts” and hemorrhage supply carts in the L&D unit. Effective implementation of an AFE checklist requires all personnel know where to readily find it and have some familiarity with its contents.

An interdisciplinary team comprising representatives from nursing, obstetrics, and anesthesia should meet to discuss whether the checklist needs to be modified to fit the local hospital formulary or other unique local circumstances. The team should develop an implementation plan that includes where to keep checklist copies, a process to periodically ensure that the copies are still present and readable, a roll-out plan to inform all personnel about the checklist process, and most importantly a training plan that includes incorporating AFE cases into the schedule of multidisciplinary simulations and drills for obstetric emergencies. Other implementation strategies are outlined in the SMFM document.⁵

Ultimately an organized, systematic approach is recommended for management of AFE. There is no single best treatment of AFE; it is supportive and directed toward the underlying pathophysiology, which may vary from patient to patient. Therefore, although a checklist, in conjunction with regular education and simulation activities, may help optimize care and improve outcomes, there is still a high risk of maternal morbidity and mortality from AFE. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

CASE Part 1: CPR initiated during induction of labor

A 32-year-old gravida 4 para 3-0-0-3 is undergoing induction of labor with intravenous (IV) oxytocin at 39 weeks of gestation. She has no significant medical or obstetric history. Fifteen minutes after reaching complete cervical dilation, she says “I don’t feel right,” then suddenly loses consciousness. The nurse finds no detectable pulse, calls a “code blue,” and initiates cardiopulmonary resuscitation (CPR). The obstetrician is notified, appears promptly, assesses the situation, and delivers a 3.6-kg baby via vacuum extraction. Apgar score is 2/10 at 1 minute and 6/10 at 5 minutes. After delivery of the placenta, there is uterine atony and brisk hemorrhage with 2 L of blood loss.

Management of AFE: A rare complication

This case demonstrates a classic presentation of amniotic fluid embolism (AFE) syndrome—a patient in labor or within 30 minutes after delivery has sudden onset of cardiorespiratory collapse followed by disseminated intravascular coagulation (DIC). AFE is rare, affecting only about 2 to 6 per 100,000 births, but classic cases have a reported maternal mortality rate that exceeds 50%.¹ It is thought to reflect a complex, systemic proinflammatory response to maternal intravasation of pregnancy material, such as trophoblast, thromboplastins, fetal cells, or amniotic fluid. Because the syndrome is not necessarily directly caused by emboli or by amniotic fluid per se,² it has been proposed that AFE be called “anaphylactoid syndrome of pregnancy,” but this terminology has not yet been widely adopted.³

Guidelines from the Society for Maternal-Fetal Medicine (SMFM) recommend several time-critical steps for the initial stabilization and management of patients with AFE.⁴ However, because AFE is rare, most obstetric providers may not encounter a case for many years or even decades after they have received training, so it is unrealistic to expect that they will remember these guidelines when they are needed. For this reason, when AFE occurs, it is important to have a readily accessible cognitive aid, such as a checklist that summarizes the key management steps. The SMFM provides a checklist for initial management of AFE that can be used at your institution; it is presented in the FIGURE and provides the outline for this discussion.⁵

Provide CPR immediately

Most AFE cases are accompanied by cardiorespiratory arrest. If the patient has no pulse, call a “code” to mobilize additional help and immediately start CPR. Use a backboard to make cardiac compressions most effective and manually displace the uterus or tilt the patient to avoid supine hypotension. Designate a timekeeper to call out 1-minute intervals and record critical data, such as medication administration and laboratory orders/results.

Expedite delivery

Immediate delivery is needed if maternal cardiac activity is not restored within 4 minutes of starting CPR, with a target to have delivery completed within 5 minutes. Operative vaginal delivery may be an option if delivery is imminent, as in the case presented, but cesarean delivery (CD) will be needed in most cases. This was previously called “perimortem cesarean” delivery, but the term “resuscitative hysterotomy” has been proposed because the primary goal is to improve the effectiveness of CPR⁶ and prevent both maternal and perinatal death. CPR is less effective in pregnant women because the pregnant uterus takes a substantial fraction of the maternal cardiac output, as well as compresses the vena cava. Some experts suggest that, rather than waiting 4 minutes, CD should be started as soon as an obstetrician or other surgeon is present, unless there is an immediate response to electrical cardioversion.^6,7

In most cases, immediate CD should be performed wherever the patient is located rather than using precious minutes to move the patient to an operating room. Antiseptic preparation is expedited by simply pouring povidone-iodine or chlorhexidine over the lower abdomen if readily available; if not available, skip this step. Enter the abdomen and uterus as rapidly as possible using only a scalpel to make generous midline incisions.

If CPR is not required, proceed with cesarean or operative vaginal delivery as soon as the mother has been stabilized. These procedures should be performed using standard safety precautions outlined in the SMFM patient safety checklists for cesarean or operative vaginal delivery.^8,9

Continue to: Anticipate hemorrhage...

 

 

Anticipate hemorrhage

Be prepared for uterine atony, coagulopathy, and catastrophic hemorrhage. Initiate IV oxytocin prophylaxis as soon as the infant is delivered. Have a low threshold for giving other uterotonic agents such as methylergonovine, carboprost, or misoprostol. If hemorrhage or DIC occurs, give tranexamic acid. Have the anesthesiologist or trauma team (if available) insert an intraosseous line for fluid resuscitation if peripheral IV access is inadequate.

Massive transfusion is often needed to treat DIC, which occurs in most AFE cases. Anticipate—do not wait—for DIC to occur. We propose activating your hospital’s massive transfusion protocol (MTP) as soon as you diagnose AFE so that blood products will be available as soon as possible. A typical MTP provides several units of red blood cells, a pheresis pack of platelets, and fresh/frozen plasma (FFP). If clinically indicated, administer cryoprecipitate instead of FFP to minimize volume overload, which may occur with FFP.

CASE Part 2: MTP initiated to treat DIC

The MTP is initiated. Laboratory results immediately pre-transfusion include hemoglobin 11.3 g/dL, platelet count 46,000 per mm³, fibrinogen 87 mg/dL, and an elevated prothrombin time international normalized ratio.

Expect heart failure

The initial hemodynamic picture in AFE is right heart failure, which should optimally be managed by a specialist from anesthesiology, cardiology, or critical care as soon as they are available. An emergency department physician may manage the hemodynamics until a specialist arrives. Avoidance of fluid overload is one important principle. If fluid challenges are needed for hypovolemic shock, boluses should be restricted to 500 mL rather than the traditional 1000 mL.

Pharmacologic treatment may include vasopressors, inotropic agents, and pulmonary vasodilators. Example medications and dosages recommended by SMFM are summarized in the checklist (FIGURE).⁵

After the initial phase of recovery, the hemodynamic picture often changes from right heart failure to left heart failure. Management of left heart failure is not covered in the SMFM checklist because, by the time it appears, the patient will usually be in the intensive care unit, managed by the critical care team. Management of left heart failure generally includes diuresis as needed for cardiogenic pulmonary edema, optimization of cardiac preload, and inotropic agents or vasopressors if needed to maintain cardiac output or perfusion pressure.⁴

Debrief, learning opportunities

Complex emergencies such as AFE are rarely handled 100% perfectly, even those with a good outcome, so they present opportunities for team learning and improvement. The team should conduct a 10- to 15-minute debrief soon after the patient is stabilized. Make an explicit statement that the main goal of the debrief is to gather suggestions as to how systems and processes could be improved for next time, not to find fault or lay blame on individuals. Encourage all personnel involved in the initial management to attend and discuss what went well and what did not. Another goal is to provide support for individuals who may feel traumatized by the dramatic, frightening events surrounding an AFE and by the poor patient outcome or guarded prognosis that frequently follows. Another goal is to discuss the plan for providing support and disclosure to the patient and family.

The vast majority of AFE cases meet criteria to be designated as “sentinel events,” because of patient transfer to the intensive care unit, multi-unit blood transfusion, other severe maternal morbidities, or maternal death. Therefore, most AFE cases will trigger a root cause analysis (RCA) or other formal sentinel event analysis conducted by the hospital’s Safety or Quality Department. As with the immediate post-event debrief, the first goal of the RCA is to identify systems issues that may have resulted in suboptimal care and that can be modified to improve future care. Specific issues regarding the checklist should also be addressed:

• Was the checklist used?
• Was the checklist available?
• Are there items on the checklist that need to be modified, added, or deleted?

The RCA concludes with the development of a performance improvement plan.

Ultimately, we encourage all AFE cases be reported to the registry maintained by the Amniotic Fluid Embolism Foundation at https://www.afesupport.org/, regardless of whether the outcome was favorable for the mother and newborn. The registry includes over 130 AFE cases since 2013 from around the world. Researchers periodically report on the registry findings.¹⁰ If providers report cases with both good and bad outcomes, the registry may provide future insights regarding which adjunctive or empiric treatments may or may not be promising.

Continue to: Empiric treatments...

 

 

Empiric treatments

From time-to-time, new regimens for empiric treatment of AFE are reported. It is important to recognize that these reports are generally uncontrolled case reports of favorable outcomes and that, without a control group, it is impossible to determine to what extent the treatment contributed to the outcome or was merely incidental. Given the rarity of AFE, it seems unlikely that there will ever be a randomized clinical trial or even a controlled prospective study comparing treatment regimens.

The “A-OK” regimen is an empiric treatment that has garnered some interest after an initial case report.¹¹ It consists of an anticholinergic agent (atropine 0.2 mg IV), a selective 5-HT3 receptor antagonist (ondansetron 8 mg IV), and a nonsteroidal anti-inflammatory drug (ketorolac 15 mg IV). We have some reservations about this regimen, however, because atropine is relatively contraindicated if the patient has tachycardia (which is common in patients with hemorrhage) and ketorolac may suppress platelet function, which might be harmful for patients with DIC or thrombocytopenia.

Another empiric treatment is the “50-50-500” regimen, which includes an H1 antihistamine (diphenhydramine 50 mg IV), an H2 antihistamine (famotidine 50 mg IV), and a corticosteroid (hydrocortisone 500 mg IV). This regimen aims to suppress histamine-mediated and cell-mediated inflammatory responses, based on the notion that proinflammatory responses likely mediate much of the underlying pathophysiology of the AFE syndrome.

We would emphasize that these empiric regimens are not clinically validated, US Food and Drug Administration approved for treatment of AFE, or considered standard of care. Future reports of these and other regimens will be needed to evaluate their efficacy, limitations, and risks. Again, we encourage providers to report all AFE cases to the AFE Foundation registry, regardless of whether the treatments are successful.

CASE Conclusion

The hemorrhage stops after administration of oxytocin, carboprost, 6 units of cryoprecipitate, and a 6-unit platelet pheresis pack. The patient is transferred to the intensive care unit where she eventually requires a total of 10 units of red cells, 8 more units of cryoprecipitate, and another platelet pheresis pack. She is discharged to home in stable condition on postpartum day 4.

Be prepared, have the checklist ready

Because AFE is rare, most members of the health care team will have no prior experience managing a real case. It may have been years or decades since they had any education on AFE or they last read a review article such as this one. It is even possible the anesthesiologist, cardiologist, or critical care specialist has never heard of AFE. Thus if they rely on memory alone, there is substantial risk of forgetting items, getting dosages wrong, or other errors. With this in mind, what is the best way to prepare the team to expeditiously employ the management steps outlined here?

Use of a checklist that summarizes these key steps for early management, such as the SMFM checklist in the FIGURE, will help ensure that all relevant steps are performed in every AFE case. It is designed to be printed on a single sheet of letter-sized paper, and we propose that every labor and delivery (L&D) unit keep laminated copies of this checklist in several places where they will be immediately available should an AFE occur. Copies can be kept on the anesthesia carts in the L&D operating rooms, in an emergency procedures binder on the unit, and on the “crash carts” and hemorrhage supply carts in the L&D unit. Effective implementation of an AFE checklist requires all personnel know where to readily find it and have some familiarity with its contents.

An interdisciplinary team comprising representatives from nursing, obstetrics, and anesthesia should meet to discuss whether the checklist needs to be modified to fit the local hospital formulary or other unique local circumstances. The team should develop an implementation plan that includes where to keep checklist copies, a process to periodically ensure that the copies are still present and readable, a roll-out plan to inform all personnel about the checklist process, and most importantly a training plan that includes incorporating AFE cases into the schedule of multidisciplinary simulations and drills for obstetric emergencies. Other implementation strategies are outlined in the SMFM document.⁵

Ultimately an organized, systematic approach is recommended for management of AFE. There is no single best treatment of AFE; it is supportive and directed toward the underlying pathophysiology, which may vary from patient to patient. Therefore, although a checklist, in conjunction with regular education and simulation activities, may help optimize care and improve outcomes, there is still a high risk of maternal morbidity and mortality from AFE. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

CASE Part 1: CPR initiated during induction of labor

A 32-year-old gravida 4 para 3-0-0-3 is undergoing induction of labor with intravenous (IV) oxytocin at 39 weeks of gestation. She has no significant medical or obstetric history. Fifteen minutes after reaching complete cervical dilation, she says “I don’t feel right,” then suddenly loses consciousness. The nurse finds no detectable pulse, calls a “code blue,” and initiates cardiopulmonary resuscitation (CPR). The obstetrician is notified, appears promptly, assesses the situation, and delivers a 3.6-kg baby via vacuum extraction. Apgar score is 2/10 at 1 minute and 6/10 at 5 minutes. After delivery of the placenta, there is uterine atony and brisk hemorrhage with 2 L of blood loss.

Management of AFE: A rare complication

This case demonstrates a classic presentation of amniotic fluid embolism (AFE) syndrome—a patient in labor or within 30 minutes after delivery has sudden onset of cardiorespiratory collapse followed by disseminated intravascular coagulation (DIC). AFE is rare, affecting only about 2 to 6 per 100,000 births, but classic cases have a reported maternal mortality rate that exceeds 50%.¹ It is thought to reflect a complex, systemic proinflammatory response to maternal intravasation of pregnancy material, such as trophoblast, thromboplastins, fetal cells, or amniotic fluid. Because the syndrome is not necessarily directly caused by emboli or by amniotic fluid per se,² it has been proposed that AFE be called “anaphylactoid syndrome of pregnancy,” but this terminology has not yet been widely adopted.³

Guidelines from the Society for Maternal-Fetal Medicine (SMFM) recommend several time-critical steps for the initial stabilization and management of patients with AFE.⁴ However, because AFE is rare, most obstetric providers may not encounter a case for many years or even decades after they have received training, so it is unrealistic to expect that they will remember these guidelines when they are needed. For this reason, when AFE occurs, it is important to have a readily accessible cognitive aid, such as a checklist that summarizes the key management steps. The SMFM provides a checklist for initial management of AFE that can be used at your institution; it is presented in the FIGURE and provides the outline for this discussion.⁵

Provide CPR immediately

Most AFE cases are accompanied by cardiorespiratory arrest. If the patient has no pulse, call a “code” to mobilize additional help and immediately start CPR. Use a backboard to make cardiac compressions most effective and manually displace the uterus or tilt the patient to avoid supine hypotension. Designate a timekeeper to call out 1-minute intervals and record critical data, such as medication administration and laboratory orders/results.

Expedite delivery

Immediate delivery is needed if maternal cardiac activity is not restored within 4 minutes of starting CPR, with a target to have delivery completed within 5 minutes. Operative vaginal delivery may be an option if delivery is imminent, as in the case presented, but cesarean delivery (CD) will be needed in most cases. This was previously called “perimortem cesarean” delivery, but the term “resuscitative hysterotomy” has been proposed because the primary goal is to improve the effectiveness of CPR⁶ and prevent both maternal and perinatal death. CPR is less effective in pregnant women because the pregnant uterus takes a substantial fraction of the maternal cardiac output, as well as compresses the vena cava. Some experts suggest that, rather than waiting 4 minutes, CD should be started as soon as an obstetrician or other surgeon is present, unless there is an immediate response to electrical cardioversion.^6,7

In most cases, immediate CD should be performed wherever the patient is located rather than using precious minutes to move the patient to an operating room. Antiseptic preparation is expedited by simply pouring povidone-iodine or chlorhexidine over the lower abdomen if readily available; if not available, skip this step. Enter the abdomen and uterus as rapidly as possible using only a scalpel to make generous midline incisions.

If CPR is not required, proceed with cesarean or operative vaginal delivery as soon as the mother has been stabilized. These procedures should be performed using standard safety precautions outlined in the SMFM patient safety checklists for cesarean or operative vaginal delivery.^8,9

Continue to: Anticipate hemorrhage...

 

 

Anticipate hemorrhage

Be prepared for uterine atony, coagulopathy, and catastrophic hemorrhage. Initiate IV oxytocin prophylaxis as soon as the infant is delivered. Have a low threshold for giving other uterotonic agents such as methylergonovine, carboprost, or misoprostol. If hemorrhage or DIC occurs, give tranexamic acid. Have the anesthesiologist or trauma team (if available) insert an intraosseous line for fluid resuscitation if peripheral IV access is inadequate.

Massive transfusion is often needed to treat DIC, which occurs in most AFE cases. Anticipate—do not wait—for DIC to occur. We propose activating your hospital’s massive transfusion protocol (MTP) as soon as you diagnose AFE so that blood products will be available as soon as possible. A typical MTP provides several units of red blood cells, a pheresis pack of platelets, and fresh/frozen plasma (FFP). If clinically indicated, administer cryoprecipitate instead of FFP to minimize volume overload, which may occur with FFP.

CASE Part 2: MTP initiated to treat DIC

The MTP is initiated. Laboratory results immediately pre-transfusion include hemoglobin 11.3 g/dL, platelet count 46,000 per mm³, fibrinogen 87 mg/dL, and an elevated prothrombin time international normalized ratio.

Expect heart failure

The initial hemodynamic picture in AFE is right heart failure, which should optimally be managed by a specialist from anesthesiology, cardiology, or critical care as soon as they are available. An emergency department physician may manage the hemodynamics until a specialist arrives. Avoidance of fluid overload is one important principle. If fluid challenges are needed for hypovolemic shock, boluses should be restricted to 500 mL rather than the traditional 1000 mL.

Pharmacologic treatment may include vasopressors, inotropic agents, and pulmonary vasodilators. Example medications and dosages recommended by SMFM are summarized in the checklist (FIGURE).⁵

After the initial phase of recovery, the hemodynamic picture often changes from right heart failure to left heart failure. Management of left heart failure is not covered in the SMFM checklist because, by the time it appears, the patient will usually be in the intensive care unit, managed by the critical care team. Management of left heart failure generally includes diuresis as needed for cardiogenic pulmonary edema, optimization of cardiac preload, and inotropic agents or vasopressors if needed to maintain cardiac output or perfusion pressure.⁴

Debrief, learning opportunities

Complex emergencies such as AFE are rarely handled 100% perfectly, even those with a good outcome, so they present opportunities for team learning and improvement. The team should conduct a 10- to 15-minute debrief soon after the patient is stabilized. Make an explicit statement that the main goal of the debrief is to gather suggestions as to how systems and processes could be improved for next time, not to find fault or lay blame on individuals. Encourage all personnel involved in the initial management to attend and discuss what went well and what did not. Another goal is to provide support for individuals who may feel traumatized by the dramatic, frightening events surrounding an AFE and by the poor patient outcome or guarded prognosis that frequently follows. Another goal is to discuss the plan for providing support and disclosure to the patient and family.

The vast majority of AFE cases meet criteria to be designated as “sentinel events,” because of patient transfer to the intensive care unit, multi-unit blood transfusion, other severe maternal morbidities, or maternal death. Therefore, most AFE cases will trigger a root cause analysis (RCA) or other formal sentinel event analysis conducted by the hospital’s Safety or Quality Department. As with the immediate post-event debrief, the first goal of the RCA is to identify systems issues that may have resulted in suboptimal care and that can be modified to improve future care. Specific issues regarding the checklist should also be addressed:

• Was the checklist used?
• Was the checklist available?
• Are there items on the checklist that need to be modified, added, or deleted?

The RCA concludes with the development of a performance improvement plan.

Ultimately, we encourage all AFE cases be reported to the registry maintained by the Amniotic Fluid Embolism Foundation at https://www.afesupport.org/, regardless of whether the outcome was favorable for the mother and newborn. The registry includes over 130 AFE cases since 2013 from around the world. Researchers periodically report on the registry findings.¹⁰ If providers report cases with both good and bad outcomes, the registry may provide future insights regarding which adjunctive or empiric treatments may or may not be promising.

Continue to: Empiric treatments...

 

 

Empiric treatments

From time-to-time, new regimens for empiric treatment of AFE are reported. It is important to recognize that these reports are generally uncontrolled case reports of favorable outcomes and that, without a control group, it is impossible to determine to what extent the treatment contributed to the outcome or was merely incidental. Given the rarity of AFE, it seems unlikely that there will ever be a randomized clinical trial or even a controlled prospective study comparing treatment regimens.

The “A-OK” regimen is an empiric treatment that has garnered some interest after an initial case report.¹¹ It consists of an anticholinergic agent (atropine 0.2 mg IV), a selective 5-HT3 receptor antagonist (ondansetron 8 mg IV), and a nonsteroidal anti-inflammatory drug (ketorolac 15 mg IV). We have some reservations about this regimen, however, because atropine is relatively contraindicated if the patient has tachycardia (which is common in patients with hemorrhage) and ketorolac may suppress platelet function, which might be harmful for patients with DIC or thrombocytopenia.

Another empiric treatment is the “50-50-500” regimen, which includes an H1 antihistamine (diphenhydramine 50 mg IV), an H2 antihistamine (famotidine 50 mg IV), and a corticosteroid (hydrocortisone 500 mg IV). This regimen aims to suppress histamine-mediated and cell-mediated inflammatory responses, based on the notion that proinflammatory responses likely mediate much of the underlying pathophysiology of the AFE syndrome.

We would emphasize that these empiric regimens are not clinically validated, US Food and Drug Administration approved for treatment of AFE, or considered standard of care. Future reports of these and other regimens will be needed to evaluate their efficacy, limitations, and risks. Again, we encourage providers to report all AFE cases to the AFE Foundation registry, regardless of whether the treatments are successful.

CASE Conclusion

The hemorrhage stops after administration of oxytocin, carboprost, 6 units of cryoprecipitate, and a 6-unit platelet pheresis pack. The patient is transferred to the intensive care unit where she eventually requires a total of 10 units of red cells, 8 more units of cryoprecipitate, and another platelet pheresis pack. She is discharged to home in stable condition on postpartum day 4.

Be prepared, have the checklist ready

Because AFE is rare, most members of the health care team will have no prior experience managing a real case. It may have been years or decades since they had any education on AFE or they last read a review article such as this one. It is even possible the anesthesiologist, cardiologist, or critical care specialist has never heard of AFE. Thus if they rely on memory alone, there is substantial risk of forgetting items, getting dosages wrong, or other errors. With this in mind, what is the best way to prepare the team to expeditiously employ the management steps outlined here?

Use of a checklist that summarizes these key steps for early management, such as the SMFM checklist in the FIGURE, will help ensure that all relevant steps are performed in every AFE case. It is designed to be printed on a single sheet of letter-sized paper, and we propose that every labor and delivery (L&D) unit keep laminated copies of this checklist in several places where they will be immediately available should an AFE occur. Copies can be kept on the anesthesia carts in the L&D operating rooms, in an emergency procedures binder on the unit, and on the “crash carts” and hemorrhage supply carts in the L&D unit. Effective implementation of an AFE checklist requires all personnel know where to readily find it and have some familiarity with its contents.

An interdisciplinary team comprising representatives from nursing, obstetrics, and anesthesia should meet to discuss whether the checklist needs to be modified to fit the local hospital formulary or other unique local circumstances. The team should develop an implementation plan that includes where to keep checklist copies, a process to periodically ensure that the copies are still present and readable, a roll-out plan to inform all personnel about the checklist process, and most importantly a training plan that includes incorporating AFE cases into the schedule of multidisciplinary simulations and drills for obstetric emergencies. Other implementation strategies are outlined in the SMFM document.⁵

Ultimately an organized, systematic approach is recommended for management of AFE. There is no single best treatment of AFE; it is supportive and directed toward the underlying pathophysiology, which may vary from patient to patient. Therefore, although a checklist, in conjunction with regular education and simulation activities, may help optimize care and improve outcomes, there is still a high risk of maternal morbidity and mortality from AFE. ●

A patient presenting with a hand pustule is a phenomenon encountered worldwide requiring careful history-taking. Some occupations, activities, and various religious practices (eg, Eid al-Adha, Passover, Easter) have been implicated worldwide in orf infection. In the United States, orf virus usually is spread from infected animal hosts to humans. Herein, we review the differential for a single hand pustule, which includes both infectious and noninfectious causes. Recognizing orf virus as the etiology of a cutaneous hand pustule in patients is important, as misdiagnosis can lead to unnecessary invasive testing and/or treatments with suboptimal clinical outcomes.

Case Series

When conducting a search for orf virus cases at our institution (University of Iowa Hospitals and Clinics, Iowa City, Iowa), 5 patient cases were identified.

Patient 1—A 27-year-old otherwise healthy woman presented to clinic with a tender red bump on the right ring finger that had been slowly growing over the course of 2 weeks and had recently started to bleed. A social history revealed that she owned several goats, which she frequently milked; 1 of the goats had a cyst on the mouth, which she popped approximately 1 to 2 weeks prior to the appearance of the lesion on the finger. She also endorsed that she owned several cattle and various other animals with which she had frequent contact. A biopsy was obtained with features consistent with orf virus.

Patient 2—A 33-year-old man presented to clinic with a lesion of concern on the left index finger. Several days prior to presentation, the patient had visited the emergency department for swelling and erythema of the same finger after cutting himself with a knife while preparing sheep meat. Radiographs were normal, and the patient was referred to dermatology. In clinic, there was a 0.5-cm fluctuant mass on the distal interphalangeal joint of the third finger. The patient declined a biopsy, and the lesion healed over 4 to 6 weeks without complication.

Patient 3—A 38-year-old man presented to clinic with 2 painless, large, round nodules on the right proximal index finger, with open friable centers noted on physical examination (Figure 1). The patient reported cutting the finger while preparing sheep meat several days prior. The nodules had been present for a few weeks and continued to grow. A punch biopsy revealed evidence of parapoxvirus infection consistent with a diagnosis of orf.

Patient 4—A 48-year-old man was referred to our dermatology clinic for evaluation of a bleeding lesion on the left middle finger. Physical examination revealed an exophytic, friable, ulcerated nodule on the dorsal aspect of the left middle finger (Figure 2). Upon further questioning, the patient mentioned that he handled raw lamb meat after cutting the finger. A punch biopsy was obtained and was consistent with orf virus infection.

Patient 5—A 43-year-old woman presented to clinic with a chronic wound on the mid lower back that was noted to drain and crust over. She thought the lesion was improving, but it had become painful over the last few weeks. A shave biopsy of the lesion was consistent with orf virus. At follow-up, the patient was unable to identify any recent contact with animals.

 

 

Comment

Transmission From Animals to Humans—Orf virus is a member of the Parapoxvirus genus of the Poxviridae family.¹ This virus is highly contagious among animals and has been described around the globe. The resulting disease also is known as contagious pustular dermatitis,² soremuzzle,³ ecthyma contagiosum of sheep,⁴ and scabby mouth.⁵ This virus most commonly infects young lambs and manifests as raw to crusty papules, pustules, or vesicles around the mouth and nose of the animal.⁴ Additional signs include excessive salivation and weight loss or starvation from the inability to suckle because of the lesions.⁵ Although ecthyma contagiosum infection of sheep and goats has been well known for centuries, human infection was first reported in the literature in 1934.⁶

Transmission of orf to humans can occur when direct contact with an infected animal exhibiting active lesions occurs.⁷ Orf virus also can be transmitted through fomites (eg, from knives, wool, buildings, equipment) that previously were in contact with infected animals, making it relevant to ask all farmers about any animals with pustules around the mouth, nose, udders, or other commonly affected areas. Although sanitation efforts are important for prevention, orf virus is hardy, and fomites can remain on surfaces for many months.⁸ Transmission among animals and from animals to humans frequently occurs; however, human-to-human transmission is less common.⁹ Ecthyma contagiosum is considered an occupational hazard, with the disease being most prevalent in shepherds, veterinarians, and butchers.^1,8 Disease prevalence in these occupations has been reported to be as high as 50%.¹⁰ Infections also are seen in patients who attend petting zoos or who slaughter goats and sheep for cultural practices.⁸

Clinical Characteristics in Humans—The clinical diagnosis of orf is dependent on taking a thorough patient history that includes social, occupational, and religious activities. Development of a nodule or papule on a patient’s hand with recent exposure to fomites or direct contact with a goat or sheep up to 1 week prior is extremely suggestive of an orf virus infection.

Clinically, orf most often begins as an individual papule or nodule on the dorsal surface of the patient’s finger or hand and ranges from completely asymptomatic to pruritic or even painful.^1,8 Depending on how the infection was inoculated, lesions can vary in size and number. Other sites that have been reported less frequently include the genitals, legs, axillae, and head.^11,12 Lesions are roughly 1 cm in diameter but can vary in size. Ecthyma contagiosum is not a static disease but changes in appearance over the course of infection. Typically, lesions will appear 3 to 7 days after inoculation with the orf virus and will self-resolve 6 to 8 weeks later.

Orf lesions have been described to progress through 6 distinct phases before resolving: maculopapular (erythematous macule or papule forms), targetoid (formation of a necrotic center with red outer halo), acute (lesion begins to weep), regenerative (lesion becomes dry), papilloma (dry crust becomes papillomatous), and regression (skin returns to normal appearance).^1,8,9 Each phase of ecthyma contagiosum is unique and will last up to 1 week before progressing. Because of this prolonged clinical course, patients can present at any stage.

Reports of systemic symptoms are uncommon but can include lymphadenopathy, fever, and malaise.¹³ Although the disease course in immunocompetent individuals is quite mild, immunocompromised patients may experience persistent orf lesions that are painful and can be much larger, with reports of several centimeters in diameter.¹⁴

Dermatopathology and Molecular Studies—When a clinical diagnosis is not possible, biopsy or molecular studies can be helpful.⁸ Histopathology can vary depending on the phase of the lesion. Early stages are characterized by spongiform degeneration of the epidermis with variable vesiculation of the superficial epidermis and eosinophilic cytoplasmic inclusion bodies of keratinocytes (Figure 3). Later stages demonstrate full-thickness necrosis with epidermal balloon degeneration and dense inflammation of the dermis with edema and extravasated erythrocytes from dilated blood vessels. Both early- and late-stage disease commonly show characteristic elongated thin rete ridges.⁸

Molecular studies are another reliable method for diagnosis, though these are not always readily available. Polymerase chain reaction can be used for sensitive and rapid diagnosis.¹⁵ Less commonly, electron microscopy, Western blot, or enzyme-linked immunosorbent assays are used.¹⁶ Laboratory studies, such as complete blood cell count with differential, erythrocyte sedimentation rate, and C-reactive protein, often are unnecessary but may be helpful in ruling out other infectious causes. Tissue culture can be considered if bacterial, fungal, or acid-fast bacilli are in the differential; however, no growth will be seen in the case of orf viral infection.

Differential Diagnosis—The differential diagnosis for patients presenting with a large pustule on the hand or fingers can depend on geographic location, as the potential etiology may vary widely around the world. Several zoonotic viral infections other than orf can present with pustular lesions on the hands (Table).^17-24

Clinically, infection with these named viruses can be hard to distinguish; however, appropriate social history or polymerase chain reaction can be obtained to differentiate them. Other infectious entities include herpetic whitlow, giant molluscum, and anthrax (eTable).^24-26 Biopsy of the lesion with bacterial tissue culture may lead to definitive diagnosis.²⁶

Treatment—Because of the self-resolving nature of orf, treatment usually is not needed in immunocompetent patients with a solitary lesion. However, wound care is essential to prevent secondary infections of the lesion. If secondarily infected, topical or oral antibiotics may be prescribed. Immunocompromised individuals are at increased risk for developing large persistent lesions and sometimes require intervention for successful treatment. Several successful treatment methods have been described and include intralesional interferon injections, electrocautery, topical imiquimod, topical cidofovir, and cryotherapy.^8,14,27-30 Infections that continue to be refractory to less-invasive treatment can be considered for wide local excision; however, recurrence is possible.⁸ Vaccinations are available for animals to prevent the spread of infection in the flock, but there are no formulations of vaccines for human use. Prevention of spread to humans can be done through animal vaccination, careful handling of animal products while wearing nonporous gloves, and proper sanitation techniques.

Complications—Orf has an excellent long-term prognosis in immunocompetent patients, as the virus is epitheliotropic, and inoculation does not lead to viremia.² Although lesions typically are asymptomatic in most patients, complications can occur, especially in immunosuppressed individuals. These complications include systemic symptoms, giant persistent lesions prone to infection or scarring, erysipelas, lymphadenitis, and erythema multiforme.^8,31 Common systemic symptoms of ecthyma contagiosum include fever, fatigue, and myalgia. Lymphadenitis can occur along with local swelling and lymphatic streaking. Although erythema multiforme is a rare complication occurring after initial ecthyma contagiosum infection, this hypersensitivity reaction is postulated to be in response to the immunologic clearing of the orf virus.^32,33 Patients receiving systemic immunosuppressive medications are at an increased risk of developing complications from infection and may even be required to pause systemic treatment for complete resolution of orf lesions.³⁴ Other cutaneous diseases that decrease the skin’s barrier protection, such as bullous pemphigoid or eczema, also can place patients at an increased risk for complications.³⁵ Although human-to-human orf virus transmission is exceptionally rare, there is a case report of this phenomenon in immunosuppressed patients residing in a burn unit.³⁶ Transplant recipients on immunosuppressive medications also can experience orf lesions with exaggerated presentations that continue to grow up to several centimeters in diameter.³¹ Long-term prognosis is still good in these patients with appropriate disease recognition and treatment. Reinfection is not uncommon with repeated exposure to the source, but lesions are less severe and resolve faster than with initial infection.^1,8

Conclusion

The contagious hand pustule caused by orf virus is a distinct clinical entity that is prevalent worldwide and requires thorough evaluation of the clinical course of the lesion and the patient’s social history. Several zoonotic viral infections have been implicated in this presentation. Although biopsy and molecular studies can be helpful, the expert diagnostician can make a clinical diagnosis with careful attention to social history, geographic location, and cultural practices.

A patient presenting with a hand pustule is a phenomenon encountered worldwide requiring careful history-taking. Some occupations, activities, and various religious practices (eg, Eid al-Adha, Passover, Easter) have been implicated worldwide in orf infection. In the United States, orf virus usually is spread from infected animal hosts to humans. Herein, we review the differential for a single hand pustule, which includes both infectious and noninfectious causes. Recognizing orf virus as the etiology of a cutaneous hand pustule in patients is important, as misdiagnosis can lead to unnecessary invasive testing and/or treatments with suboptimal clinical outcomes.

Case Series

When conducting a search for orf virus cases at our institution (University of Iowa Hospitals and Clinics, Iowa City, Iowa), 5 patient cases were identified.

Patient 1—A 27-year-old otherwise healthy woman presented to clinic with a tender red bump on the right ring finger that had been slowly growing over the course of 2 weeks and had recently started to bleed. A social history revealed that she owned several goats, which she frequently milked; 1 of the goats had a cyst on the mouth, which she popped approximately 1 to 2 weeks prior to the appearance of the lesion on the finger. She also endorsed that she owned several cattle and various other animals with which she had frequent contact. A biopsy was obtained with features consistent with orf virus.

Patient 2—A 33-year-old man presented to clinic with a lesion of concern on the left index finger. Several days prior to presentation, the patient had visited the emergency department for swelling and erythema of the same finger after cutting himself with a knife while preparing sheep meat. Radiographs were normal, and the patient was referred to dermatology. In clinic, there was a 0.5-cm fluctuant mass on the distal interphalangeal joint of the third finger. The patient declined a biopsy, and the lesion healed over 4 to 6 weeks without complication.

Patient 3—A 38-year-old man presented to clinic with 2 painless, large, round nodules on the right proximal index finger, with open friable centers noted on physical examination (Figure 1). The patient reported cutting the finger while preparing sheep meat several days prior. The nodules had been present for a few weeks and continued to grow. A punch biopsy revealed evidence of parapoxvirus infection consistent with a diagnosis of orf.

Patient 4—A 48-year-old man was referred to our dermatology clinic for evaluation of a bleeding lesion on the left middle finger. Physical examination revealed an exophytic, friable, ulcerated nodule on the dorsal aspect of the left middle finger (Figure 2). Upon further questioning, the patient mentioned that he handled raw lamb meat after cutting the finger. A punch biopsy was obtained and was consistent with orf virus infection.

Patient 5—A 43-year-old woman presented to clinic with a chronic wound on the mid lower back that was noted to drain and crust over. She thought the lesion was improving, but it had become painful over the last few weeks. A shave biopsy of the lesion was consistent with orf virus. At follow-up, the patient was unable to identify any recent contact with animals.

 

 

Comment

Transmission From Animals to Humans—Orf virus is a member of the Parapoxvirus genus of the Poxviridae family.¹ This virus is highly contagious among animals and has been described around the globe. The resulting disease also is known as contagious pustular dermatitis,² soremuzzle,³ ecthyma contagiosum of sheep,⁴ and scabby mouth.⁵ This virus most commonly infects young lambs and manifests as raw to crusty papules, pustules, or vesicles around the mouth and nose of the animal.⁴ Additional signs include excessive salivation and weight loss or starvation from the inability to suckle because of the lesions.⁵ Although ecthyma contagiosum infection of sheep and goats has been well known for centuries, human infection was first reported in the literature in 1934.⁶

Transmission of orf to humans can occur when direct contact with an infected animal exhibiting active lesions occurs.⁷ Orf virus also can be transmitted through fomites (eg, from knives, wool, buildings, equipment) that previously were in contact with infected animals, making it relevant to ask all farmers about any animals with pustules around the mouth, nose, udders, or other commonly affected areas. Although sanitation efforts are important for prevention, orf virus is hardy, and fomites can remain on surfaces for many months.⁸ Transmission among animals and from animals to humans frequently occurs; however, human-to-human transmission is less common.⁹ Ecthyma contagiosum is considered an occupational hazard, with the disease being most prevalent in shepherds, veterinarians, and butchers.^1,8 Disease prevalence in these occupations has been reported to be as high as 50%.¹⁰ Infections also are seen in patients who attend petting zoos or who slaughter goats and sheep for cultural practices.⁸

Clinical Characteristics in Humans—The clinical diagnosis of orf is dependent on taking a thorough patient history that includes social, occupational, and religious activities. Development of a nodule or papule on a patient’s hand with recent exposure to fomites or direct contact with a goat or sheep up to 1 week prior is extremely suggestive of an orf virus infection.

Clinically, orf most often begins as an individual papule or nodule on the dorsal surface of the patient’s finger or hand and ranges from completely asymptomatic to pruritic or even painful.^1,8 Depending on how the infection was inoculated, lesions can vary in size and number. Other sites that have been reported less frequently include the genitals, legs, axillae, and head.^11,12 Lesions are roughly 1 cm in diameter but can vary in size. Ecthyma contagiosum is not a static disease but changes in appearance over the course of infection. Typically, lesions will appear 3 to 7 days after inoculation with the orf virus and will self-resolve 6 to 8 weeks later.

Orf lesions have been described to progress through 6 distinct phases before resolving: maculopapular (erythematous macule or papule forms), targetoid (formation of a necrotic center with red outer halo), acute (lesion begins to weep), regenerative (lesion becomes dry), papilloma (dry crust becomes papillomatous), and regression (skin returns to normal appearance).^1,8,9 Each phase of ecthyma contagiosum is unique and will last up to 1 week before progressing. Because of this prolonged clinical course, patients can present at any stage.

Reports of systemic symptoms are uncommon but can include lymphadenopathy, fever, and malaise.¹³ Although the disease course in immunocompetent individuals is quite mild, immunocompromised patients may experience persistent orf lesions that are painful and can be much larger, with reports of several centimeters in diameter.¹⁴

Dermatopathology and Molecular Studies—When a clinical diagnosis is not possible, biopsy or molecular studies can be helpful.⁸ Histopathology can vary depending on the phase of the lesion. Early stages are characterized by spongiform degeneration of the epidermis with variable vesiculation of the superficial epidermis and eosinophilic cytoplasmic inclusion bodies of keratinocytes (Figure 3). Later stages demonstrate full-thickness necrosis with epidermal balloon degeneration and dense inflammation of the dermis with edema and extravasated erythrocytes from dilated blood vessels. Both early- and late-stage disease commonly show characteristic elongated thin rete ridges.⁸

Molecular studies are another reliable method for diagnosis, though these are not always readily available. Polymerase chain reaction can be used for sensitive and rapid diagnosis.¹⁵ Less commonly, electron microscopy, Western blot, or enzyme-linked immunosorbent assays are used.¹⁶ Laboratory studies, such as complete blood cell count with differential, erythrocyte sedimentation rate, and C-reactive protein, often are unnecessary but may be helpful in ruling out other infectious causes. Tissue culture can be considered if bacterial, fungal, or acid-fast bacilli are in the differential; however, no growth will be seen in the case of orf viral infection.

Differential Diagnosis—The differential diagnosis for patients presenting with a large pustule on the hand or fingers can depend on geographic location, as the potential etiology may vary widely around the world. Several zoonotic viral infections other than orf can present with pustular lesions on the hands (Table).^17-24

Clinically, infection with these named viruses can be hard to distinguish; however, appropriate social history or polymerase chain reaction can be obtained to differentiate them. Other infectious entities include herpetic whitlow, giant molluscum, and anthrax (eTable).^24-26 Biopsy of the lesion with bacterial tissue culture may lead to definitive diagnosis.²⁶

Treatment—Because of the self-resolving nature of orf, treatment usually is not needed in immunocompetent patients with a solitary lesion. However, wound care is essential to prevent secondary infections of the lesion. If secondarily infected, topical or oral antibiotics may be prescribed. Immunocompromised individuals are at increased risk for developing large persistent lesions and sometimes require intervention for successful treatment. Several successful treatment methods have been described and include intralesional interferon injections, electrocautery, topical imiquimod, topical cidofovir, and cryotherapy.^8,14,27-30 Infections that continue to be refractory to less-invasive treatment can be considered for wide local excision; however, recurrence is possible.⁸ Vaccinations are available for animals to prevent the spread of infection in the flock, but there are no formulations of vaccines for human use. Prevention of spread to humans can be done through animal vaccination, careful handling of animal products while wearing nonporous gloves, and proper sanitation techniques.

Complications—Orf has an excellent long-term prognosis in immunocompetent patients, as the virus is epitheliotropic, and inoculation does not lead to viremia.² Although lesions typically are asymptomatic in most patients, complications can occur, especially in immunosuppressed individuals. These complications include systemic symptoms, giant persistent lesions prone to infection or scarring, erysipelas, lymphadenitis, and erythema multiforme.^8,31 Common systemic symptoms of ecthyma contagiosum include fever, fatigue, and myalgia. Lymphadenitis can occur along with local swelling and lymphatic streaking. Although erythema multiforme is a rare complication occurring after initial ecthyma contagiosum infection, this hypersensitivity reaction is postulated to be in response to the immunologic clearing of the orf virus.^32,33 Patients receiving systemic immunosuppressive medications are at an increased risk of developing complications from infection and may even be required to pause systemic treatment for complete resolution of orf lesions.³⁴ Other cutaneous diseases that decrease the skin’s barrier protection, such as bullous pemphigoid or eczema, also can place patients at an increased risk for complications.³⁵ Although human-to-human orf virus transmission is exceptionally rare, there is a case report of this phenomenon in immunosuppressed patients residing in a burn unit.³⁶ Transplant recipients on immunosuppressive medications also can experience orf lesions with exaggerated presentations that continue to grow up to several centimeters in diameter.³¹ Long-term prognosis is still good in these patients with appropriate disease recognition and treatment. Reinfection is not uncommon with repeated exposure to the source, but lesions are less severe and resolve faster than with initial infection.^1,8

Conclusion

The contagious hand pustule caused by orf virus is a distinct clinical entity that is prevalent worldwide and requires thorough evaluation of the clinical course of the lesion and the patient’s social history. Several zoonotic viral infections have been implicated in this presentation. Although biopsy and molecular studies can be helpful, the expert diagnostician can make a clinical diagnosis with careful attention to social history, geographic location, and cultural practices.

A patient presenting with a hand pustule is a phenomenon encountered worldwide requiring careful history-taking. Some occupations, activities, and various religious practices (eg, Eid al-Adha, Passover, Easter) have been implicated worldwide in orf infection. In the United States, orf virus usually is spread from infected animal hosts to humans. Herein, we review the differential for a single hand pustule, which includes both infectious and noninfectious causes. Recognizing orf virus as the etiology of a cutaneous hand pustule in patients is important, as misdiagnosis can lead to unnecessary invasive testing and/or treatments with suboptimal clinical outcomes.

Case Series

When conducting a search for orf virus cases at our institution (University of Iowa Hospitals and Clinics, Iowa City, Iowa), 5 patient cases were identified.

Patient 1—A 27-year-old otherwise healthy woman presented to clinic with a tender red bump on the right ring finger that had been slowly growing over the course of 2 weeks and had recently started to bleed. A social history revealed that she owned several goats, which she frequently milked; 1 of the goats had a cyst on the mouth, which she popped approximately 1 to 2 weeks prior to the appearance of the lesion on the finger. She also endorsed that she owned several cattle and various other animals with which she had frequent contact. A biopsy was obtained with features consistent with orf virus.

Patient 2—A 33-year-old man presented to clinic with a lesion of concern on the left index finger. Several days prior to presentation, the patient had visited the emergency department for swelling and erythema of the same finger after cutting himself with a knife while preparing sheep meat. Radiographs were normal, and the patient was referred to dermatology. In clinic, there was a 0.5-cm fluctuant mass on the distal interphalangeal joint of the third finger. The patient declined a biopsy, and the lesion healed over 4 to 6 weeks without complication.

Patient 3—A 38-year-old man presented to clinic with 2 painless, large, round nodules on the right proximal index finger, with open friable centers noted on physical examination (Figure 1). The patient reported cutting the finger while preparing sheep meat several days prior. The nodules had been present for a few weeks and continued to grow. A punch biopsy revealed evidence of parapoxvirus infection consistent with a diagnosis of orf.

Patient 4—A 48-year-old man was referred to our dermatology clinic for evaluation of a bleeding lesion on the left middle finger. Physical examination revealed an exophytic, friable, ulcerated nodule on the dorsal aspect of the left middle finger (Figure 2). Upon further questioning, the patient mentioned that he handled raw lamb meat after cutting the finger. A punch biopsy was obtained and was consistent with orf virus infection.

Patient 5—A 43-year-old woman presented to clinic with a chronic wound on the mid lower back that was noted to drain and crust over. She thought the lesion was improving, but it had become painful over the last few weeks. A shave biopsy of the lesion was consistent with orf virus. At follow-up, the patient was unable to identify any recent contact with animals.

 

 

Comment

Transmission From Animals to Humans—Orf virus is a member of the Parapoxvirus genus of the Poxviridae family.¹ This virus is highly contagious among animals and has been described around the globe. The resulting disease also is known as contagious pustular dermatitis,² soremuzzle,³ ecthyma contagiosum of sheep,⁴ and scabby mouth.⁵ This virus most commonly infects young lambs and manifests as raw to crusty papules, pustules, or vesicles around the mouth and nose of the animal.⁴ Additional signs include excessive salivation and weight loss or starvation from the inability to suckle because of the lesions.⁵ Although ecthyma contagiosum infection of sheep and goats has been well known for centuries, human infection was first reported in the literature in 1934.⁶

Transmission of orf to humans can occur when direct contact with an infected animal exhibiting active lesions occurs.⁷ Orf virus also can be transmitted through fomites (eg, from knives, wool, buildings, equipment) that previously were in contact with infected animals, making it relevant to ask all farmers about any animals with pustules around the mouth, nose, udders, or other commonly affected areas. Although sanitation efforts are important for prevention, orf virus is hardy, and fomites can remain on surfaces for many months.⁸ Transmission among animals and from animals to humans frequently occurs; however, human-to-human transmission is less common.⁹ Ecthyma contagiosum is considered an occupational hazard, with the disease being most prevalent in shepherds, veterinarians, and butchers.^1,8 Disease prevalence in these occupations has been reported to be as high as 50%.¹⁰ Infections also are seen in patients who attend petting zoos or who slaughter goats and sheep for cultural practices.⁸

Clinical Characteristics in Humans—The clinical diagnosis of orf is dependent on taking a thorough patient history that includes social, occupational, and religious activities. Development of a nodule or papule on a patient’s hand with recent exposure to fomites or direct contact with a goat or sheep up to 1 week prior is extremely suggestive of an orf virus infection.

Clinically, orf most often begins as an individual papule or nodule on the dorsal surface of the patient’s finger or hand and ranges from completely asymptomatic to pruritic or even painful.^1,8 Depending on how the infection was inoculated, lesions can vary in size and number. Other sites that have been reported less frequently include the genitals, legs, axillae, and head.^11,12 Lesions are roughly 1 cm in diameter but can vary in size. Ecthyma contagiosum is not a static disease but changes in appearance over the course of infection. Typically, lesions will appear 3 to 7 days after inoculation with the orf virus and will self-resolve 6 to 8 weeks later.

Orf lesions have been described to progress through 6 distinct phases before resolving: maculopapular (erythematous macule or papule forms), targetoid (formation of a necrotic center with red outer halo), acute (lesion begins to weep), regenerative (lesion becomes dry), papilloma (dry crust becomes papillomatous), and regression (skin returns to normal appearance).^1,8,9 Each phase of ecthyma contagiosum is unique and will last up to 1 week before progressing. Because of this prolonged clinical course, patients can present at any stage.

Reports of systemic symptoms are uncommon but can include lymphadenopathy, fever, and malaise.¹³ Although the disease course in immunocompetent individuals is quite mild, immunocompromised patients may experience persistent orf lesions that are painful and can be much larger, with reports of several centimeters in diameter.¹⁴

Dermatopathology and Molecular Studies—When a clinical diagnosis is not possible, biopsy or molecular studies can be helpful.⁸ Histopathology can vary depending on the phase of the lesion. Early stages are characterized by spongiform degeneration of the epidermis with variable vesiculation of the superficial epidermis and eosinophilic cytoplasmic inclusion bodies of keratinocytes (Figure 3). Later stages demonstrate full-thickness necrosis with epidermal balloon degeneration and dense inflammation of the dermis with edema and extravasated erythrocytes from dilated blood vessels. Both early- and late-stage disease commonly show characteristic elongated thin rete ridges.⁸

Molecular studies are another reliable method for diagnosis, though these are not always readily available. Polymerase chain reaction can be used for sensitive and rapid diagnosis.¹⁵ Less commonly, electron microscopy, Western blot, or enzyme-linked immunosorbent assays are used.¹⁶ Laboratory studies, such as complete blood cell count with differential, erythrocyte sedimentation rate, and C-reactive protein, often are unnecessary but may be helpful in ruling out other infectious causes. Tissue culture can be considered if bacterial, fungal, or acid-fast bacilli are in the differential; however, no growth will be seen in the case of orf viral infection.

Differential Diagnosis—The differential diagnosis for patients presenting with a large pustule on the hand or fingers can depend on geographic location, as the potential etiology may vary widely around the world. Several zoonotic viral infections other than orf can present with pustular lesions on the hands (Table).^17-24

Clinically, infection with these named viruses can be hard to distinguish; however, appropriate social history or polymerase chain reaction can be obtained to differentiate them. Other infectious entities include herpetic whitlow, giant molluscum, and anthrax (eTable).^24-26 Biopsy of the lesion with bacterial tissue culture may lead to definitive diagnosis.²⁶

Treatment—Because of the self-resolving nature of orf, treatment usually is not needed in immunocompetent patients with a solitary lesion. However, wound care is essential to prevent secondary infections of the lesion. If secondarily infected, topical or oral antibiotics may be prescribed. Immunocompromised individuals are at increased risk for developing large persistent lesions and sometimes require intervention for successful treatment. Several successful treatment methods have been described and include intralesional interferon injections, electrocautery, topical imiquimod, topical cidofovir, and cryotherapy.^8,14,27-30 Infections that continue to be refractory to less-invasive treatment can be considered for wide local excision; however, recurrence is possible.⁸ Vaccinations are available for animals to prevent the spread of infection in the flock, but there are no formulations of vaccines for human use. Prevention of spread to humans can be done through animal vaccination, careful handling of animal products while wearing nonporous gloves, and proper sanitation techniques.

Complications—Orf has an excellent long-term prognosis in immunocompetent patients, as the virus is epitheliotropic, and inoculation does not lead to viremia.² Although lesions typically are asymptomatic in most patients, complications can occur, especially in immunosuppressed individuals. These complications include systemic symptoms, giant persistent lesions prone to infection or scarring, erysipelas, lymphadenitis, and erythema multiforme.^8,31 Common systemic symptoms of ecthyma contagiosum include fever, fatigue, and myalgia. Lymphadenitis can occur along with local swelling and lymphatic streaking. Although erythema multiforme is a rare complication occurring after initial ecthyma contagiosum infection, this hypersensitivity reaction is postulated to be in response to the immunologic clearing of the orf virus.^32,33 Patients receiving systemic immunosuppressive medications are at an increased risk of developing complications from infection and may even be required to pause systemic treatment for complete resolution of orf lesions.³⁴ Other cutaneous diseases that decrease the skin’s barrier protection, such as bullous pemphigoid or eczema, also can place patients at an increased risk for complications.³⁵ Although human-to-human orf virus transmission is exceptionally rare, there is a case report of this phenomenon in immunosuppressed patients residing in a burn unit.³⁶ Transplant recipients on immunosuppressive medications also can experience orf lesions with exaggerated presentations that continue to grow up to several centimeters in diameter.³¹ Long-term prognosis is still good in these patients with appropriate disease recognition and treatment. Reinfection is not uncommon with repeated exposure to the source, but lesions are less severe and resolve faster than with initial infection.^1,8

Conclusion

The contagious hand pustule caused by orf virus is a distinct clinical entity that is prevalent worldwide and requires thorough evaluation of the clinical course of the lesion and the patient’s social history. Several zoonotic viral infections have been implicated in this presentation. Although biopsy and molecular studies can be helpful, the expert diagnostician can make a clinical diagnosis with careful attention to social history, geographic location, and cultural practices.

Basal cell carcinoma (BCC) is the most common keratinocyte carcinoma and affects more than 3 million individuals per year in the United States.¹ Approximately 40% of patients diagnosed with BCC will develop another BCC within 5 years of the initial diagnosis.² Most cases are successfully treated with surgical excision and occasionally topical therapy or radiotherapy. Despite the high cure rate with conventional treatments, BCC can recur and can cause substantial destruction of the surrounding tissue if left untreated.^3-5 In some instances, BCC can even metastasize and lead to death.⁶ For patients who are poor candidates for surgical or topical treatment modalities because of locally advanced BCC (laBCC) or metastatic BCC (mBCC), systemic treatment may be indicated. Vismodegib, sonidegib, and cemiplimab are the only systemic medications approved by the US Food and Drug Administration (FDA) for the treatment of laBCC and/or mBCC. Vismodegib and sonidegib target the sonic hedgehog (SHH) signaling pathway that is abnormally activated in more than 90% of BCCs.⁷ Cemiplimab is an immune checkpoint inhibitor (ICI) that targets the programmed cell death protein 1 (PD-1) receptor.⁸ Herein, we review the clinical utility of these medications and their evolving roles in the treatment of BCC.

SHH Pathway Inhibitors

The SHH pathway is a key regulator of cell proliferation and differentiation during embryogenesis.⁷ During adulthood, SHH signaling decreases but still plays an important role in stem cell activation and in regulation of the hair follicle growth cycle.^9,10 However, de novo mutations in the genes that comprise the SHH pathway can result in aberrant constitutive activation, leading to unrestricted cell proliferation. Genetic mutations resulting in activation of Smoothened (SMO), a G-protein–coupled receptor involved in the signal transduction and propagation of the SHH pathway, have been implicated in the pathogenesis of BCC. Inactivating mutations also are commonly observed in patched homolog 1, an upstream cell-surface protein that inhibits SMO.⁷ The mechanism by which vismodegib and sonidegib, 2 of the FDA-approved oral medications for the treatment of advanced BCC, block the SHH pathway is through the selective inhibition of SMO.^7,11

Vismodegib first received FDA approval in 2012 for the treatment of laBCC and mBCC after initial results from the pivotal ERIVANCE phase 2 trial demonstrated an objective response rate (ORR) of 43% (27/63) and 30% (10/33) in patients with locally advanced and metastatic disease, respectively. In this single-arm study, all enrolled patients (63 with laBCC and 33 with mBCC) received 150 mg of oral vismodegib daily.¹² Updated results at 39 months demonstrated improved ORRs of 60% (38/63) and 48% (16/33) for the laBCC and mBCC groups, respectively. A complete response (CR) and partial response (PR) were observed in 32% (n=20) and 29% (n=18) of patients with laBCC, respectively.¹³ These results have been confirmed in subsequent studies, including the large international open-label trial known as STEVIE, with ORRs of 68.5% for 1119 cases of laBCC and 37% for 96 cases of mBCC.^14-17 The CR and PR rates were 33% and 35%, respectively, for the laBCC group. The CR and PR rates for the mBCC group were 5% and 32%, respectively.¹⁴

The FDA approval of sonidegib for laBCC—but not mBCC—occurred in 2015 after the pivotal BOLT randomized phase 2 trial demonstrated an initial ORR of 43% (18/42) for laBCC and 15% (2/13) for mBCC after administration of 200 mg of sonidegib daily.¹⁸ A final follow-up analysis at 42 months resulted in ORRs of 56% (37/66) and 8% (1/13) for the laBCC and mBCC groups, respectively.¹⁹ Additionally, improved efficacy was not observed in the 151 patients who were randomized to receive treatment with the higher 800-mg dose; however, they did experience a higher incidence of adverse events.^18,19

Currently, the true clinical differences between vismodegib and sonidegib remain uncertain, as no head-to-head trials have been conducted. Moreover, direct comparison of the data from the ERIVANCE and BOLT trials is challenging owing to fundamental differences in methodologic design, including the criteria used to assess BCC severity. The ERIVANCE trial utilized the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while BOLT used the rigorous modified RECIST. However, an expert consensus study attempted to compare the 2 trials by modifying the outcomes from BOLT with the former RECIST criteria. The expert group found that the 2 SHH inhibitors had comparable efficacy and adverse event profiles.²⁰ Nevertheless, a recent meta-analysis found that although ORRs for laBCC were similar between the 2 drugs, the CR rate for vismodegib was 31% compared with 3% for sonidegib. Additionally, for mBCC, they reported the ORR of vismodegib to be 2.7 times higher than that of sonidegib (39% vs 15%).²¹

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors have successfully been utilized in the treatment of cutaneous squamous cell carcinoma (cSCC); however, their use for treating BCC has been limited until recently.^22-25 In February 2021, cemiplimab became the first and only ICI approved for the treatment of laBCC and mBCC in patients who did not respond to or were intolerant to prior SHH inhibitor therapy.²⁶ Cemiplimab—a human monoclonal antibody against the PD-1 receptor expressed on T cells—blocks its interaction with programmed cell death ligand 1 and programmed cell death ligand 2 present on tumor cells. The blockade of the PD-1 pathway releases the inhibition of the antitumor immune response and enables appropriate cytotoxic T-cell activity to occur.⁸

The FDA approval of cemiplimab for the treatment of advanced BCC was based on an open-label, multicenter, single-arm phase 2 trial (NCT03132636) evaluating 84 patients with laBCC refractory or intolerant to SHH inhibitor therapy.²⁶ Patients received an intravenous infusion of cemiplimab 350 mg every 3 weeks for up to 93 weeks or until disease progression or unacceptable toxicity. An ORR of 31% (26/84) was observed with a CR and PR of 6% (5/84) and 25% (21/84), respectively. The median duration of follow-up was 15 months.²⁶ Given the clinically meaningful results of this trial, investigating the efficacy of other PD-1 inhibitors, such as pembrolizumab and nivolumab, for treatment of advanced BCC may prove worthwhile.

 

 

Adverse Effects of Systemic Treatments

The 2 approved SHH inhibitors—vismodegib and sonidegib—appear to have similar side-effect profiles, with the most common adverse effects being muscle spasms, dysgeusia, alopecia, nausea, vomiting, diarrhea, weight loss, and fatigue.^20,21,27 These side effects occur at high frequencies (>40%) for both SHH inhibitors and often lead to discontinuation of the medication.²¹ Rates of treatment discontinuation range from 15% to 50% on average.^12-14,18 Fortunately, the majority of these adverse effects do not appear to increase in severity or frequency with prolonged use of these medications.^14,16,28

Various conservative and pharmacologic measures can be implemented to help manage side effects. For muscle spasms, which are the most commonly reported adverse effect, supplementation with magnesium, transcutaneous electrical nerve stimulation, acupuncture, massages, stretching, and thermal compresses can potentially be beneficial.²⁹ Calcium channel blockers also may be effective, as one small prospective cohort study reported a reduction in the frequency of muscle cramps with amlodipine 10 mg daily.³⁰ For alopecia, which typically is reversible and caused by SHH inhibition of the normal hair cycle, minoxidil theoretically can help, as it reduces telogen arrest and extends the anagen growth phase.^31,32 Although usually mild and self-limiting, management of dysgeusia, weight loss, and gastrointestinal upset often can be managed with dietary changes, such as smaller, more frequent meals.^33,34 Finally, alternative dosing strategies and drug holidays have been employed to mitigate these side effects and increase drug tolerability.^35,36 These are discussed in the Alternative Dosing section.

Given the essential role of the SHH pathway in embryologic development, SHH inhibitors carry a black box warning of embryofetal teratogenicity and are contraindicated in females who are pregnant or breastfeeding. For females of reproductive potential, verification of pregnancy status should be performed prior to initiating treatment with an SHH inhibitor. These patients should be counseled on the use of contraception during treatment and for at least 24 months and 20 months after cessation of vismodegib and sonidegib, respectively.^27,37,38 Male patients, even after a vasectomy, should use barrier contraception during treatment and for at least 3 months and 8 months after the final dose of vismodegib and sonidegib, respectively.^37,38

Laboratory abnormalities commonly associated with SHH inhibitors include elevated hepatic enzymes, particularly with vismodegib, and elevated creatine kinase levels, particularly with sonidegib.^28,39 Other laboratory abnormalities that can occur include hypercholesterolemia, hypercreatininemia, hyperglycemia, and increased serum lipase levels.^19,28 Although these laboratory abnormalities usually are asymptomatic and self-limiting, regular monitoring should be performed.

There also is concern that SHH inhibitors may induce the development of cSCC. A case-control study of 55 cases and 125 control patients found an increased risk for cSCC in those previously treated with vismodegib, with a hazard ratio of 8.12.⁴⁰ However, a subsequent retrospective cohort study of 1675 patients with BCC failed to find any association with cSCC among those treated with vismodegib compared to those who received standard surgical therapy.⁴¹ Clinical data for sonidegib are lacking, but the BOLT trial found that cSCC occurred in 3 patients receiving treatment with the SHH inhibitor.¹⁸ Thus, further studies are needed to more thoroughly assess this concern. Close monitoring for cSCC may be warranted in patients prescribed SHH inhibitors at this time.

Cemiplimab has demonstrated an acceptable safety profile and is generally well tolerated. In the phase 2 trial of cemiplimab for cSCC, approximately 5% of patients discontinued treatment because of adverse effects. The most commonly reported side effects of cemiplimab were diarrhea (27%), fatigue (24%), nausea (17%), constipation (15%), and rash (15%).²³ In the phase 2 trial for laBCC, grade 3 or 4 adverse events occurred in 48% of patients, with hypertension (5%) being the most common.²⁶ Although rare, immune-mediated adverse reactions also can occur, given the mechanism of action of ICIs. These side effects, ranging in severity from mild to fatal, include pneumonitis, colitis, hepatitis, nephritis, myocarditis, and hypophysitis. Therefore, close monitoring for these immune-mediated reactions is critical, but most can be managed with corticosteroids or treatment interruption if they occur.^42,43

No absolute contraindications exist for cemiplimab; however, extreme caution should be taken in immunosuppressed individuals, such as solid organ transplant recipients and those with chronic lymphocytic leukemia (CLL), as safety data are limited in these patients.^44,45 Although small retrospective studies have reported reasonable tolerability in solid organ transplant recipients treated with ICIs, an allograft rejection rate of 41% was found in a meta-analysis of 64 patients.^46-48 In CLL patients with keratinocyte carcinomas, ICIs have been safely used and have even demonstrated efficacy for CLL in some cases.^49-52

Alternative Dosing

The side effects of SHH inhibitors have led to alternative dosing strategies to prevent medication discontinuation and improve adherence. In patients with basal cell nevus syndrome, multimonth drug holidays have been shown to increase drug tolerability without compromising efficacy.^35,36 Weekly intermittent dosing regimens of vismodegib ranging from 1 week on followed by 1 to 3 weeks off demonstrated efficacy in a retrospective study of 7 patients with advanced BCC.⁵³ All 7 patients experienced improvement in their BCCs, with 3 patients experiencing CR. Importantly, treatment-related adverse effects were mild and well tolerated, with no patients terminating the medication.⁵³ Two other retrospective case series of patients with advanced BCC treated with vismodegib reported similar findings for those placed on an intermittent dosing schedule ranging from once every other day to once per week.^54,55

In the large phase 2 randomized trial known as MIKIE, 2 different intermittent dosing regimens of 150 mg vismodegib daily for patients with multiple BCCs were found to have good activity and tolerability.⁵⁶ The first group (n=116) received vismodegib for 12 weeks, then 3 rounds of 8 weeks of placebo, followed by 12 weeks of vismodegib; there was a 63% reduction in clinically evident BCCs after 73 weeks. The second group (n=113) received the medication for 24 weeks, then 3 rounds of 8 weeks of placebo, followed by 8 weeks of vismodegib; there was a 54% reduction at the end of 73 weeks.⁵⁶ Subsequent analyses found improvements in health-related quality-of-life outcomes that were similar for both groups.⁵⁷

Consequently, alternative dosing schedules appear to be a viable option for patients at risk of discontinuing treatment because of adverse effects, and current data support the recently approved recommendations of dose interruptions of up to 8 weeks to manage adverse effects in patients with laBCC or mBCC.⁵⁸ Nevertheless, further clinical studies are required to determine the optimal intermittent dosing regimen for patients treated with SHH inhibitors.

Neoadjuvant Administration

Recently, vismodegib has been studied as a neoadjuvant therapy for BCC with promising results. Several small retrospective studies and case reports have documented successful treatment of both operable and inoperable periocular laBCC, with preservation of the eye in all patients.^59-61 An open-label trial of 15 patients with advanced BCC who received neoadjuvant vismodegib for 3 to 6 months prior to surgical excision reported a mean reduction of 35% in the final surgical defect size, with no recurrence at 22 months.^62,63 The latest and largest study performed was a phase 2 open-label trial known as VISMONEO, where 44 of 55 laBCC patients (80%) receiving neoadjuvant vismodegib for a mean duration of 6 months (range, 4–10 months) achieved the primary end point of tumor surgical downstaging.⁶⁴ Of the 44 patients who had tumor downstaging, 27 (61%) experienced histologically proven CRs. Additionally, a 66% reduction in the average target lesion size was reported in this group compared to29% in the 11 patients who did not have tumor downstaging (P=.0002).⁶⁴ Thus, SHH inhibitors may hold an important neoadjuvant role in the treatment of BCC by decreasing surgical defect size and allowing for surgical management of previously inoperable cases.

Synergism With Radiation

Preliminary data suggest SHH inhibitors may help potentiate the effects of radiation therapy for the treatment of BCC. Currently, the evidence primarily is limited to case studies, with several reports describing complete remission in patients with advanced BCCs who were considered unsuitable candidates for surgery. In these cases, vismodegib was administered either prior to or concurrently with radiation treatment.^65-69 An in vitro study also documented the radiation-sensitizing effects of vismodegib in a BCC cell line.⁷⁰ Recently, a phase 2 trial (ClinicalTrials.gov identifier NCT01835626) evaluating the concurrent use of vismodegib and radiotherapy for patients with advanced BCC was completed, but data has yet to be published.

Synergism With and Benefit of Antifungal Therapy

The antifungal drug itraconazole is a potent inhibitor of the SHH pathway and may have an adjunctive role in the treatment of BCC. Similar to vismodegib and sonidegib, itraconazole acts as a direct antagonist of SMO. However, it is thought to bind to a distinct site on SMO.^71,72 An open-label, exploratory phase 2 trial of 19 patients with BCC found that oral itraconazole 200 to 400 mg daily decreased tumor proliferative index by 45% (P=.04), as measured by Ki-67; SHH activity by 65% (P=.03), as measured by GLI1 messenger RNA; and mean tumor area by 24%.⁷³ In a case series of 5 patients with mBCC refractory to conventional SHH inhibitor therapy, combined treatment with itraconazole and arsenic trioxide resulted in stable disease and a 75% reduction in SHH activity (P<.001).⁷⁴ One case report documented tumor regression leading to stable disease for 15 months in a patient with laBCC treated with itraconazole monotherapy due to being unable to afford vismodegib or sonidegib. However, within 2 months of treatment discontinuation, the lesion progressed considerably.⁷⁵ The efficacy of a topical formulation of itraconazole also has been tested in an open-label, placebo-controlled phase 2 trial, but no benefit was observed.⁷⁶

Posaconazole is a second-generation antifungal agent that may serve as a potential alternative to itraconazole.⁷⁷ Although clinical data are lacking, a basic science study found that posaconazole could inhibit the growth of SHH-dependent BCC in vivo (in mice).⁷⁸ Furthermore, posaconazole has demonstrated a better safety profile with fewer and more mild side effects than itraconazole and does not require dose adjustment for those with hepatic or renal failure.^79,80 Thus, posaconazole may be a safer alternative to itraconazole for the treatment of BCC. Further clinical studies are needed to elucidate the potential synergistic effects of these antifungal agents with the 2 currently approved SHH inhibitors for the treatment of advanced BCC.

 

 

Drug Resistance

Treatment resistance to SHH inhibitors, though uncommon, is a growing concern. Acquired mutations in the SMO binding site or downstream mediators of the SHH pathway have been shown to confer resistance to vismodegib and sonidegib.^72,81-83 In addition, it appears that there may be shared resistance among the drugs in this class. One study assessing the efficacy of sonidegib in 9 patients with laBCC resistant to vismodegib found that these patients also did not respond to sonidegib.⁸⁴ Interestingly, 1 case report documented tumor regression of an intracranial BCC in a patient treated with sonidegib and itraconazole after failure with vismodegib.⁸⁵ An in vitro study also found that itraconazole maintained SHH inhibitory activity for all drug-resistant SMO mutations that have been reported.⁷² Therefore, itraconazole monotherapy or combination therapy with a canonical SHH inhibitor may be considered for patients with recalcitrant BCC and warrants further investigation.

Taladegib is a newly developed SMO inhibitor that may serve as another promising alternative for patients who develop resistance to vismodegib or sonidegib. A phase 1 trial of taladegib for advanced BCC found an ORR of 69% (11/16) in the SHH inhibitor–naïve group and an ORR of 36% (11/32) in the group previously treated with a SHH inhibitor.⁸⁶ Additionally, the safety profile and frequency of adverse effects appear to be similar to those associated with vismodegib and sonidegib.^86,87 Unfortunately, no clinical trials evaluating taladegib for BCC are ongoing or in development at this time.

Recurrence

There appears to be a relatively high rate of recurrence for BCC patients who achieve a CR to SHH inhibitors. In a retrospective study of 116 laBCC patients who experienced a CR after vismodegib therapy, 54 patients (47%) relapsed at 36 months. Among the 54 patients that relapsed, 27 were re-treated with vismodegib, which resulted in an ORR of 85% (23/27), a CR rate of 37% (10/27), and a PR rate of 48% (13/27).⁸⁸ Another retrospective study of 35 laBCC patients who relapsed after vismodegib treatment reported a 31% (11/35) clinical recurrence rate at 6-month follow-up.⁸⁹ An observational retrospective study also assessed the efficacy of SHH inhibitor maintenance therapy for advanced BCC patients who achieved a CR.⁹⁰ In the study, 27 (64%) patients received a maintenance dose of 150 mg vismodegib once per week for 1 year, while 15 (36%) patients decided not to take a maintenance dose following CR of their BCC. All patients who took the maintenance therapy did not experience clinical recurrence at 1-year follow-up, whereas 26% of patients not on the maintenance dose relapsed.⁹⁰ Consequently, these results indicate that BCC recurrence is frequent after SHH inhibitor therapy and highlights the importance of close surveillance after CR is attained. Nevertheless, most patients still respond to treatment with SHH inhibitors after relapsing, and intermittent maintenance doses may be an effective means to reduce risk of recurrence.

Conclusion

Vismodegib and sonidegib are SHH inhibitors approved for the treatment of laBCC and mBCC. Cemiplimab is now also approved for patients who do not respond to SHH inhibitors or for whom SHH inhibitors are not tolerable. Although these systemic targeted therapies can lead to notable tumor shrinkage and even complete regression in some patients, recurrence is common, and adverse effects may limit their use. Drug resistance is an emerging issue that requires additional examination. Further clinical studies are needed to determine which patients are likely to respond to these targeted treatments.

Various intermittent and maintenance drug regimens should be evaluated for their potential to mitigate adverse effects and reduce risk of recurrence, respectively. The synergistic effects of these medications with other therapies as well as their neoadjuvant and adjuvant roles should be further investigated. For example, administration of an SHH inhibitor prior to surgical excision of a BCC may allow for a smaller surgical defect size, thereby improving cosmetic and functional outcomes. Moreover, these systemic targeted medications may allow for previously inoperable tumors to become amenable to surgical treatment.

Although SHH inhibitors and PD-1 inhibitors represent a major advancement in the field of oncodermatology, real-world efficacy and safety data in the upcoming years will be important for elucidating their true benefit for patients with BCC.

Basal cell carcinoma (BCC) is the most common keratinocyte carcinoma and affects more than 3 million individuals per year in the United States.¹ Approximately 40% of patients diagnosed with BCC will develop another BCC within 5 years of the initial diagnosis.² Most cases are successfully treated with surgical excision and occasionally topical therapy or radiotherapy. Despite the high cure rate with conventional treatments, BCC can recur and can cause substantial destruction of the surrounding tissue if left untreated.^3-5 In some instances, BCC can even metastasize and lead to death.⁶ For patients who are poor candidates for surgical or topical treatment modalities because of locally advanced BCC (laBCC) or metastatic BCC (mBCC), systemic treatment may be indicated. Vismodegib, sonidegib, and cemiplimab are the only systemic medications approved by the US Food and Drug Administration (FDA) for the treatment of laBCC and/or mBCC. Vismodegib and sonidegib target the sonic hedgehog (SHH) signaling pathway that is abnormally activated in more than 90% of BCCs.⁷ Cemiplimab is an immune checkpoint inhibitor (ICI) that targets the programmed cell death protein 1 (PD-1) receptor.⁸ Herein, we review the clinical utility of these medications and their evolving roles in the treatment of BCC.

SHH Pathway Inhibitors

The SHH pathway is a key regulator of cell proliferation and differentiation during embryogenesis.⁷ During adulthood, SHH signaling decreases but still plays an important role in stem cell activation and in regulation of the hair follicle growth cycle.^9,10 However, de novo mutations in the genes that comprise the SHH pathway can result in aberrant constitutive activation, leading to unrestricted cell proliferation. Genetic mutations resulting in activation of Smoothened (SMO), a G-protein–coupled receptor involved in the signal transduction and propagation of the SHH pathway, have been implicated in the pathogenesis of BCC. Inactivating mutations also are commonly observed in patched homolog 1, an upstream cell-surface protein that inhibits SMO.⁷ The mechanism by which vismodegib and sonidegib, 2 of the FDA-approved oral medications for the treatment of advanced BCC, block the SHH pathway is through the selective inhibition of SMO.^7,11

Vismodegib first received FDA approval in 2012 for the treatment of laBCC and mBCC after initial results from the pivotal ERIVANCE phase 2 trial demonstrated an objective response rate (ORR) of 43% (27/63) and 30% (10/33) in patients with locally advanced and metastatic disease, respectively. In this single-arm study, all enrolled patients (63 with laBCC and 33 with mBCC) received 150 mg of oral vismodegib daily.¹² Updated results at 39 months demonstrated improved ORRs of 60% (38/63) and 48% (16/33) for the laBCC and mBCC groups, respectively. A complete response (CR) and partial response (PR) were observed in 32% (n=20) and 29% (n=18) of patients with laBCC, respectively.¹³ These results have been confirmed in subsequent studies, including the large international open-label trial known as STEVIE, with ORRs of 68.5% for 1119 cases of laBCC and 37% for 96 cases of mBCC.^14-17 The CR and PR rates were 33% and 35%, respectively, for the laBCC group. The CR and PR rates for the mBCC group were 5% and 32%, respectively.¹⁴

The FDA approval of sonidegib for laBCC—but not mBCC—occurred in 2015 after the pivotal BOLT randomized phase 2 trial demonstrated an initial ORR of 43% (18/42) for laBCC and 15% (2/13) for mBCC after administration of 200 mg of sonidegib daily.¹⁸ A final follow-up analysis at 42 months resulted in ORRs of 56% (37/66) and 8% (1/13) for the laBCC and mBCC groups, respectively.¹⁹ Additionally, improved efficacy was not observed in the 151 patients who were randomized to receive treatment with the higher 800-mg dose; however, they did experience a higher incidence of adverse events.^18,19

Currently, the true clinical differences between vismodegib and sonidegib remain uncertain, as no head-to-head trials have been conducted. Moreover, direct comparison of the data from the ERIVANCE and BOLT trials is challenging owing to fundamental differences in methodologic design, including the criteria used to assess BCC severity. The ERIVANCE trial utilized the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while BOLT used the rigorous modified RECIST. However, an expert consensus study attempted to compare the 2 trials by modifying the outcomes from BOLT with the former RECIST criteria. The expert group found that the 2 SHH inhibitors had comparable efficacy and adverse event profiles.²⁰ Nevertheless, a recent meta-analysis found that although ORRs for laBCC were similar between the 2 drugs, the CR rate for vismodegib was 31% compared with 3% for sonidegib. Additionally, for mBCC, they reported the ORR of vismodegib to be 2.7 times higher than that of sonidegib (39% vs 15%).²¹

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors have successfully been utilized in the treatment of cutaneous squamous cell carcinoma (cSCC); however, their use for treating BCC has been limited until recently.^22-25 In February 2021, cemiplimab became the first and only ICI approved for the treatment of laBCC and mBCC in patients who did not respond to or were intolerant to prior SHH inhibitor therapy.²⁶ Cemiplimab—a human monoclonal antibody against the PD-1 receptor expressed on T cells—blocks its interaction with programmed cell death ligand 1 and programmed cell death ligand 2 present on tumor cells. The blockade of the PD-1 pathway releases the inhibition of the antitumor immune response and enables appropriate cytotoxic T-cell activity to occur.⁸

The FDA approval of cemiplimab for the treatment of advanced BCC was based on an open-label, multicenter, single-arm phase 2 trial (NCT03132636) evaluating 84 patients with laBCC refractory or intolerant to SHH inhibitor therapy.²⁶ Patients received an intravenous infusion of cemiplimab 350 mg every 3 weeks for up to 93 weeks or until disease progression or unacceptable toxicity. An ORR of 31% (26/84) was observed with a CR and PR of 6% (5/84) and 25% (21/84), respectively. The median duration of follow-up was 15 months.²⁶ Given the clinically meaningful results of this trial, investigating the efficacy of other PD-1 inhibitors, such as pembrolizumab and nivolumab, for treatment of advanced BCC may prove worthwhile.

 

 

Adverse Effects of Systemic Treatments

The 2 approved SHH inhibitors—vismodegib and sonidegib—appear to have similar side-effect profiles, with the most common adverse effects being muscle spasms, dysgeusia, alopecia, nausea, vomiting, diarrhea, weight loss, and fatigue.^20,21,27 These side effects occur at high frequencies (>40%) for both SHH inhibitors and often lead to discontinuation of the medication.²¹ Rates of treatment discontinuation range from 15% to 50% on average.^12-14,18 Fortunately, the majority of these adverse effects do not appear to increase in severity or frequency with prolonged use of these medications.^14,16,28

Various conservative and pharmacologic measures can be implemented to help manage side effects. For muscle spasms, which are the most commonly reported adverse effect, supplementation with magnesium, transcutaneous electrical nerve stimulation, acupuncture, massages, stretching, and thermal compresses can potentially be beneficial.²⁹ Calcium channel blockers also may be effective, as one small prospective cohort study reported a reduction in the frequency of muscle cramps with amlodipine 10 mg daily.³⁰ For alopecia, which typically is reversible and caused by SHH inhibition of the normal hair cycle, minoxidil theoretically can help, as it reduces telogen arrest and extends the anagen growth phase.^31,32 Although usually mild and self-limiting, management of dysgeusia, weight loss, and gastrointestinal upset often can be managed with dietary changes, such as smaller, more frequent meals.^33,34 Finally, alternative dosing strategies and drug holidays have been employed to mitigate these side effects and increase drug tolerability.^35,36 These are discussed in the Alternative Dosing section.

Given the essential role of the SHH pathway in embryologic development, SHH inhibitors carry a black box warning of embryofetal teratogenicity and are contraindicated in females who are pregnant or breastfeeding. For females of reproductive potential, verification of pregnancy status should be performed prior to initiating treatment with an SHH inhibitor. These patients should be counseled on the use of contraception during treatment and for at least 24 months and 20 months after cessation of vismodegib and sonidegib, respectively.^27,37,38 Male patients, even after a vasectomy, should use barrier contraception during treatment and for at least 3 months and 8 months after the final dose of vismodegib and sonidegib, respectively.^37,38

Laboratory abnormalities commonly associated with SHH inhibitors include elevated hepatic enzymes, particularly with vismodegib, and elevated creatine kinase levels, particularly with sonidegib.^28,39 Other laboratory abnormalities that can occur include hypercholesterolemia, hypercreatininemia, hyperglycemia, and increased serum lipase levels.^19,28 Although these laboratory abnormalities usually are asymptomatic and self-limiting, regular monitoring should be performed.

There also is concern that SHH inhibitors may induce the development of cSCC. A case-control study of 55 cases and 125 control patients found an increased risk for cSCC in those previously treated with vismodegib, with a hazard ratio of 8.12.⁴⁰ However, a subsequent retrospective cohort study of 1675 patients with BCC failed to find any association with cSCC among those treated with vismodegib compared to those who received standard surgical therapy.⁴¹ Clinical data for sonidegib are lacking, but the BOLT trial found that cSCC occurred in 3 patients receiving treatment with the SHH inhibitor.¹⁸ Thus, further studies are needed to more thoroughly assess this concern. Close monitoring for cSCC may be warranted in patients prescribed SHH inhibitors at this time.

Cemiplimab has demonstrated an acceptable safety profile and is generally well tolerated. In the phase 2 trial of cemiplimab for cSCC, approximately 5% of patients discontinued treatment because of adverse effects. The most commonly reported side effects of cemiplimab were diarrhea (27%), fatigue (24%), nausea (17%), constipation (15%), and rash (15%).²³ In the phase 2 trial for laBCC, grade 3 or 4 adverse events occurred in 48% of patients, with hypertension (5%) being the most common.²⁶ Although rare, immune-mediated adverse reactions also can occur, given the mechanism of action of ICIs. These side effects, ranging in severity from mild to fatal, include pneumonitis, colitis, hepatitis, nephritis, myocarditis, and hypophysitis. Therefore, close monitoring for these immune-mediated reactions is critical, but most can be managed with corticosteroids or treatment interruption if they occur.^42,43

No absolute contraindications exist for cemiplimab; however, extreme caution should be taken in immunosuppressed individuals, such as solid organ transplant recipients and those with chronic lymphocytic leukemia (CLL), as safety data are limited in these patients.^44,45 Although small retrospective studies have reported reasonable tolerability in solid organ transplant recipients treated with ICIs, an allograft rejection rate of 41% was found in a meta-analysis of 64 patients.^46-48 In CLL patients with keratinocyte carcinomas, ICIs have been safely used and have even demonstrated efficacy for CLL in some cases.^49-52

Alternative Dosing

The side effects of SHH inhibitors have led to alternative dosing strategies to prevent medication discontinuation and improve adherence. In patients with basal cell nevus syndrome, multimonth drug holidays have been shown to increase drug tolerability without compromising efficacy.^35,36 Weekly intermittent dosing regimens of vismodegib ranging from 1 week on followed by 1 to 3 weeks off demonstrated efficacy in a retrospective study of 7 patients with advanced BCC.⁵³ All 7 patients experienced improvement in their BCCs, with 3 patients experiencing CR. Importantly, treatment-related adverse effects were mild and well tolerated, with no patients terminating the medication.⁵³ Two other retrospective case series of patients with advanced BCC treated with vismodegib reported similar findings for those placed on an intermittent dosing schedule ranging from once every other day to once per week.^54,55

In the large phase 2 randomized trial known as MIKIE, 2 different intermittent dosing regimens of 150 mg vismodegib daily for patients with multiple BCCs were found to have good activity and tolerability.⁵⁶ The first group (n=116) received vismodegib for 12 weeks, then 3 rounds of 8 weeks of placebo, followed by 12 weeks of vismodegib; there was a 63% reduction in clinically evident BCCs after 73 weeks. The second group (n=113) received the medication for 24 weeks, then 3 rounds of 8 weeks of placebo, followed by 8 weeks of vismodegib; there was a 54% reduction at the end of 73 weeks.⁵⁶ Subsequent analyses found improvements in health-related quality-of-life outcomes that were similar for both groups.⁵⁷

Consequently, alternative dosing schedules appear to be a viable option for patients at risk of discontinuing treatment because of adverse effects, and current data support the recently approved recommendations of dose interruptions of up to 8 weeks to manage adverse effects in patients with laBCC or mBCC.⁵⁸ Nevertheless, further clinical studies are required to determine the optimal intermittent dosing regimen for patients treated with SHH inhibitors.

Neoadjuvant Administration

Recently, vismodegib has been studied as a neoadjuvant therapy for BCC with promising results. Several small retrospective studies and case reports have documented successful treatment of both operable and inoperable periocular laBCC, with preservation of the eye in all patients.^59-61 An open-label trial of 15 patients with advanced BCC who received neoadjuvant vismodegib for 3 to 6 months prior to surgical excision reported a mean reduction of 35% in the final surgical defect size, with no recurrence at 22 months.^62,63 The latest and largest study performed was a phase 2 open-label trial known as VISMONEO, where 44 of 55 laBCC patients (80%) receiving neoadjuvant vismodegib for a mean duration of 6 months (range, 4–10 months) achieved the primary end point of tumor surgical downstaging.⁶⁴ Of the 44 patients who had tumor downstaging, 27 (61%) experienced histologically proven CRs. Additionally, a 66% reduction in the average target lesion size was reported in this group compared to29% in the 11 patients who did not have tumor downstaging (P=.0002).⁶⁴ Thus, SHH inhibitors may hold an important neoadjuvant role in the treatment of BCC by decreasing surgical defect size and allowing for surgical management of previously inoperable cases.

Synergism With Radiation

Preliminary data suggest SHH inhibitors may help potentiate the effects of radiation therapy for the treatment of BCC. Currently, the evidence primarily is limited to case studies, with several reports describing complete remission in patients with advanced BCCs who were considered unsuitable candidates for surgery. In these cases, vismodegib was administered either prior to or concurrently with radiation treatment.^65-69 An in vitro study also documented the radiation-sensitizing effects of vismodegib in a BCC cell line.⁷⁰ Recently, a phase 2 trial (ClinicalTrials.gov identifier NCT01835626) evaluating the concurrent use of vismodegib and radiotherapy for patients with advanced BCC was completed, but data has yet to be published.

Synergism With and Benefit of Antifungal Therapy

The antifungal drug itraconazole is a potent inhibitor of the SHH pathway and may have an adjunctive role in the treatment of BCC. Similar to vismodegib and sonidegib, itraconazole acts as a direct antagonist of SMO. However, it is thought to bind to a distinct site on SMO.^71,72 An open-label, exploratory phase 2 trial of 19 patients with BCC found that oral itraconazole 200 to 400 mg daily decreased tumor proliferative index by 45% (P=.04), as measured by Ki-67; SHH activity by 65% (P=.03), as measured by GLI1 messenger RNA; and mean tumor area by 24%.⁷³ In a case series of 5 patients with mBCC refractory to conventional SHH inhibitor therapy, combined treatment with itraconazole and arsenic trioxide resulted in stable disease and a 75% reduction in SHH activity (P<.001).⁷⁴ One case report documented tumor regression leading to stable disease for 15 months in a patient with laBCC treated with itraconazole monotherapy due to being unable to afford vismodegib or sonidegib. However, within 2 months of treatment discontinuation, the lesion progressed considerably.⁷⁵ The efficacy of a topical formulation of itraconazole also has been tested in an open-label, placebo-controlled phase 2 trial, but no benefit was observed.⁷⁶

Posaconazole is a second-generation antifungal agent that may serve as a potential alternative to itraconazole.⁷⁷ Although clinical data are lacking, a basic science study found that posaconazole could inhibit the growth of SHH-dependent BCC in vivo (in mice).⁷⁸ Furthermore, posaconazole has demonstrated a better safety profile with fewer and more mild side effects than itraconazole and does not require dose adjustment for those with hepatic or renal failure.^79,80 Thus, posaconazole may be a safer alternative to itraconazole for the treatment of BCC. Further clinical studies are needed to elucidate the potential synergistic effects of these antifungal agents with the 2 currently approved SHH inhibitors for the treatment of advanced BCC.

 

 

Drug Resistance

Treatment resistance to SHH inhibitors, though uncommon, is a growing concern. Acquired mutations in the SMO binding site or downstream mediators of the SHH pathway have been shown to confer resistance to vismodegib and sonidegib.^72,81-83 In addition, it appears that there may be shared resistance among the drugs in this class. One study assessing the efficacy of sonidegib in 9 patients with laBCC resistant to vismodegib found that these patients also did not respond to sonidegib.⁸⁴ Interestingly, 1 case report documented tumor regression of an intracranial BCC in a patient treated with sonidegib and itraconazole after failure with vismodegib.⁸⁵ An in vitro study also found that itraconazole maintained SHH inhibitory activity for all drug-resistant SMO mutations that have been reported.⁷² Therefore, itraconazole monotherapy or combination therapy with a canonical SHH inhibitor may be considered for patients with recalcitrant BCC and warrants further investigation.

Taladegib is a newly developed SMO inhibitor that may serve as another promising alternative for patients who develop resistance to vismodegib or sonidegib. A phase 1 trial of taladegib for advanced BCC found an ORR of 69% (11/16) in the SHH inhibitor–naïve group and an ORR of 36% (11/32) in the group previously treated with a SHH inhibitor.⁸⁶ Additionally, the safety profile and frequency of adverse effects appear to be similar to those associated with vismodegib and sonidegib.^86,87 Unfortunately, no clinical trials evaluating taladegib for BCC are ongoing or in development at this time.

Recurrence

There appears to be a relatively high rate of recurrence for BCC patients who achieve a CR to SHH inhibitors. In a retrospective study of 116 laBCC patients who experienced a CR after vismodegib therapy, 54 patients (47%) relapsed at 36 months. Among the 54 patients that relapsed, 27 were re-treated with vismodegib, which resulted in an ORR of 85% (23/27), a CR rate of 37% (10/27), and a PR rate of 48% (13/27).⁸⁸ Another retrospective study of 35 laBCC patients who relapsed after vismodegib treatment reported a 31% (11/35) clinical recurrence rate at 6-month follow-up.⁸⁹ An observational retrospective study also assessed the efficacy of SHH inhibitor maintenance therapy for advanced BCC patients who achieved a CR.⁹⁰ In the study, 27 (64%) patients received a maintenance dose of 150 mg vismodegib once per week for 1 year, while 15 (36%) patients decided not to take a maintenance dose following CR of their BCC. All patients who took the maintenance therapy did not experience clinical recurrence at 1-year follow-up, whereas 26% of patients not on the maintenance dose relapsed.⁹⁰ Consequently, these results indicate that BCC recurrence is frequent after SHH inhibitor therapy and highlights the importance of close surveillance after CR is attained. Nevertheless, most patients still respond to treatment with SHH inhibitors after relapsing, and intermittent maintenance doses may be an effective means to reduce risk of recurrence.

Conclusion

Vismodegib and sonidegib are SHH inhibitors approved for the treatment of laBCC and mBCC. Cemiplimab is now also approved for patients who do not respond to SHH inhibitors or for whom SHH inhibitors are not tolerable. Although these systemic targeted therapies can lead to notable tumor shrinkage and even complete regression in some patients, recurrence is common, and adverse effects may limit their use. Drug resistance is an emerging issue that requires additional examination. Further clinical studies are needed to determine which patients are likely to respond to these targeted treatments.

Various intermittent and maintenance drug regimens should be evaluated for their potential to mitigate adverse effects and reduce risk of recurrence, respectively. The synergistic effects of these medications with other therapies as well as their neoadjuvant and adjuvant roles should be further investigated. For example, administration of an SHH inhibitor prior to surgical excision of a BCC may allow for a smaller surgical defect size, thereby improving cosmetic and functional outcomes. Moreover, these systemic targeted medications may allow for previously inoperable tumors to become amenable to surgical treatment.

Although SHH inhibitors and PD-1 inhibitors represent a major advancement in the field of oncodermatology, real-world efficacy and safety data in the upcoming years will be important for elucidating their true benefit for patients with BCC.

Basal cell carcinoma (BCC) is the most common keratinocyte carcinoma and affects more than 3 million individuals per year in the United States.¹ Approximately 40% of patients diagnosed with BCC will develop another BCC within 5 years of the initial diagnosis.² Most cases are successfully treated with surgical excision and occasionally topical therapy or radiotherapy. Despite the high cure rate with conventional treatments, BCC can recur and can cause substantial destruction of the surrounding tissue if left untreated.^3-5 In some instances, BCC can even metastasize and lead to death.⁶ For patients who are poor candidates for surgical or topical treatment modalities because of locally advanced BCC (laBCC) or metastatic BCC (mBCC), systemic treatment may be indicated. Vismodegib, sonidegib, and cemiplimab are the only systemic medications approved by the US Food and Drug Administration (FDA) for the treatment of laBCC and/or mBCC. Vismodegib and sonidegib target the sonic hedgehog (SHH) signaling pathway that is abnormally activated in more than 90% of BCCs.⁷ Cemiplimab is an immune checkpoint inhibitor (ICI) that targets the programmed cell death protein 1 (PD-1) receptor.⁸ Herein, we review the clinical utility of these medications and their evolving roles in the treatment of BCC.

SHH Pathway Inhibitors

The SHH pathway is a key regulator of cell proliferation and differentiation during embryogenesis.⁷ During adulthood, SHH signaling decreases but still plays an important role in stem cell activation and in regulation of the hair follicle growth cycle.^9,10 However, de novo mutations in the genes that comprise the SHH pathway can result in aberrant constitutive activation, leading to unrestricted cell proliferation. Genetic mutations resulting in activation of Smoothened (SMO), a G-protein–coupled receptor involved in the signal transduction and propagation of the SHH pathway, have been implicated in the pathogenesis of BCC. Inactivating mutations also are commonly observed in patched homolog 1, an upstream cell-surface protein that inhibits SMO.⁷ The mechanism by which vismodegib and sonidegib, 2 of the FDA-approved oral medications for the treatment of advanced BCC, block the SHH pathway is through the selective inhibition of SMO.^7,11

Vismodegib first received FDA approval in 2012 for the treatment of laBCC and mBCC after initial results from the pivotal ERIVANCE phase 2 trial demonstrated an objective response rate (ORR) of 43% (27/63) and 30% (10/33) in patients with locally advanced and metastatic disease, respectively. In this single-arm study, all enrolled patients (63 with laBCC and 33 with mBCC) received 150 mg of oral vismodegib daily.¹² Updated results at 39 months demonstrated improved ORRs of 60% (38/63) and 48% (16/33) for the laBCC and mBCC groups, respectively. A complete response (CR) and partial response (PR) were observed in 32% (n=20) and 29% (n=18) of patients with laBCC, respectively.¹³ These results have been confirmed in subsequent studies, including the large international open-label trial known as STEVIE, with ORRs of 68.5% for 1119 cases of laBCC and 37% for 96 cases of mBCC.^14-17 The CR and PR rates were 33% and 35%, respectively, for the laBCC group. The CR and PR rates for the mBCC group were 5% and 32%, respectively.¹⁴

The FDA approval of sonidegib for laBCC—but not mBCC—occurred in 2015 after the pivotal BOLT randomized phase 2 trial demonstrated an initial ORR of 43% (18/42) for laBCC and 15% (2/13) for mBCC after administration of 200 mg of sonidegib daily.¹⁸ A final follow-up analysis at 42 months resulted in ORRs of 56% (37/66) and 8% (1/13) for the laBCC and mBCC groups, respectively.¹⁹ Additionally, improved efficacy was not observed in the 151 patients who were randomized to receive treatment with the higher 800-mg dose; however, they did experience a higher incidence of adverse events.^18,19

Currently, the true clinical differences between vismodegib and sonidegib remain uncertain, as no head-to-head trials have been conducted. Moreover, direct comparison of the data from the ERIVANCE and BOLT trials is challenging owing to fundamental differences in methodologic design, including the criteria used to assess BCC severity. The ERIVANCE trial utilized the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while BOLT used the rigorous modified RECIST. However, an expert consensus study attempted to compare the 2 trials by modifying the outcomes from BOLT with the former RECIST criteria. The expert group found that the 2 SHH inhibitors had comparable efficacy and adverse event profiles.²⁰ Nevertheless, a recent meta-analysis found that although ORRs for laBCC were similar between the 2 drugs, the CR rate for vismodegib was 31% compared with 3% for sonidegib. Additionally, for mBCC, they reported the ORR of vismodegib to be 2.7 times higher than that of sonidegib (39% vs 15%).²¹

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors have successfully been utilized in the treatment of cutaneous squamous cell carcinoma (cSCC); however, their use for treating BCC has been limited until recently.^22-25 In February 2021, cemiplimab became the first and only ICI approved for the treatment of laBCC and mBCC in patients who did not respond to or were intolerant to prior SHH inhibitor therapy.²⁶ Cemiplimab—a human monoclonal antibody against the PD-1 receptor expressed on T cells—blocks its interaction with programmed cell death ligand 1 and programmed cell death ligand 2 present on tumor cells. The blockade of the PD-1 pathway releases the inhibition of the antitumor immune response and enables appropriate cytotoxic T-cell activity to occur.⁸

The FDA approval of cemiplimab for the treatment of advanced BCC was based on an open-label, multicenter, single-arm phase 2 trial (NCT03132636) evaluating 84 patients with laBCC refractory or intolerant to SHH inhibitor therapy.²⁶ Patients received an intravenous infusion of cemiplimab 350 mg every 3 weeks for up to 93 weeks or until disease progression or unacceptable toxicity. An ORR of 31% (26/84) was observed with a CR and PR of 6% (5/84) and 25% (21/84), respectively. The median duration of follow-up was 15 months.²⁶ Given the clinically meaningful results of this trial, investigating the efficacy of other PD-1 inhibitors, such as pembrolizumab and nivolumab, for treatment of advanced BCC may prove worthwhile.

 

 

Adverse Effects of Systemic Treatments

The 2 approved SHH inhibitors—vismodegib and sonidegib—appear to have similar side-effect profiles, with the most common adverse effects being muscle spasms, dysgeusia, alopecia, nausea, vomiting, diarrhea, weight loss, and fatigue.^20,21,27 These side effects occur at high frequencies (>40%) for both SHH inhibitors and often lead to discontinuation of the medication.²¹ Rates of treatment discontinuation range from 15% to 50% on average.^12-14,18 Fortunately, the majority of these adverse effects do not appear to increase in severity or frequency with prolonged use of these medications.^14,16,28

Various conservative and pharmacologic measures can be implemented to help manage side effects. For muscle spasms, which are the most commonly reported adverse effect, supplementation with magnesium, transcutaneous electrical nerve stimulation, acupuncture, massages, stretching, and thermal compresses can potentially be beneficial.²⁹ Calcium channel blockers also may be effective, as one small prospective cohort study reported a reduction in the frequency of muscle cramps with amlodipine 10 mg daily.³⁰ For alopecia, which typically is reversible and caused by SHH inhibition of the normal hair cycle, minoxidil theoretically can help, as it reduces telogen arrest and extends the anagen growth phase.^31,32 Although usually mild and self-limiting, management of dysgeusia, weight loss, and gastrointestinal upset often can be managed with dietary changes, such as smaller, more frequent meals.^33,34 Finally, alternative dosing strategies and drug holidays have been employed to mitigate these side effects and increase drug tolerability.^35,36 These are discussed in the Alternative Dosing section.

Given the essential role of the SHH pathway in embryologic development, SHH inhibitors carry a black box warning of embryofetal teratogenicity and are contraindicated in females who are pregnant or breastfeeding. For females of reproductive potential, verification of pregnancy status should be performed prior to initiating treatment with an SHH inhibitor. These patients should be counseled on the use of contraception during treatment and for at least 24 months and 20 months after cessation of vismodegib and sonidegib, respectively.^27,37,38 Male patients, even after a vasectomy, should use barrier contraception during treatment and for at least 3 months and 8 months after the final dose of vismodegib and sonidegib, respectively.^37,38

Laboratory abnormalities commonly associated with SHH inhibitors include elevated hepatic enzymes, particularly with vismodegib, and elevated creatine kinase levels, particularly with sonidegib.^28,39 Other laboratory abnormalities that can occur include hypercholesterolemia, hypercreatininemia, hyperglycemia, and increased serum lipase levels.^19,28 Although these laboratory abnormalities usually are asymptomatic and self-limiting, regular monitoring should be performed.

There also is concern that SHH inhibitors may induce the development of cSCC. A case-control study of 55 cases and 125 control patients found an increased risk for cSCC in those previously treated with vismodegib, with a hazard ratio of 8.12.⁴⁰ However, a subsequent retrospective cohort study of 1675 patients with BCC failed to find any association with cSCC among those treated with vismodegib compared to those who received standard surgical therapy.⁴¹ Clinical data for sonidegib are lacking, but the BOLT trial found that cSCC occurred in 3 patients receiving treatment with the SHH inhibitor.¹⁸ Thus, further studies are needed to more thoroughly assess this concern. Close monitoring for cSCC may be warranted in patients prescribed SHH inhibitors at this time.

Cemiplimab has demonstrated an acceptable safety profile and is generally well tolerated. In the phase 2 trial of cemiplimab for cSCC, approximately 5% of patients discontinued treatment because of adverse effects. The most commonly reported side effects of cemiplimab were diarrhea (27%), fatigue (24%), nausea (17%), constipation (15%), and rash (15%).²³ In the phase 2 trial for laBCC, grade 3 or 4 adverse events occurred in 48% of patients, with hypertension (5%) being the most common.²⁶ Although rare, immune-mediated adverse reactions also can occur, given the mechanism of action of ICIs. These side effects, ranging in severity from mild to fatal, include pneumonitis, colitis, hepatitis, nephritis, myocarditis, and hypophysitis. Therefore, close monitoring for these immune-mediated reactions is critical, but most can be managed with corticosteroids or treatment interruption if they occur.^42,43

No absolute contraindications exist for cemiplimab; however, extreme caution should be taken in immunosuppressed individuals, such as solid organ transplant recipients and those with chronic lymphocytic leukemia (CLL), as safety data are limited in these patients.^44,45 Although small retrospective studies have reported reasonable tolerability in solid organ transplant recipients treated with ICIs, an allograft rejection rate of 41% was found in a meta-analysis of 64 patients.^46-48 In CLL patients with keratinocyte carcinomas, ICIs have been safely used and have even demonstrated efficacy for CLL in some cases.^49-52

Alternative Dosing

The side effects of SHH inhibitors have led to alternative dosing strategies to prevent medication discontinuation and improve adherence. In patients with basal cell nevus syndrome, multimonth drug holidays have been shown to increase drug tolerability without compromising efficacy.^35,36 Weekly intermittent dosing regimens of vismodegib ranging from 1 week on followed by 1 to 3 weeks off demonstrated efficacy in a retrospective study of 7 patients with advanced BCC.⁵³ All 7 patients experienced improvement in their BCCs, with 3 patients experiencing CR. Importantly, treatment-related adverse effects were mild and well tolerated, with no patients terminating the medication.⁵³ Two other retrospective case series of patients with advanced BCC treated with vismodegib reported similar findings for those placed on an intermittent dosing schedule ranging from once every other day to once per week.^54,55

In the large phase 2 randomized trial known as MIKIE, 2 different intermittent dosing regimens of 150 mg vismodegib daily for patients with multiple BCCs were found to have good activity and tolerability.⁵⁶ The first group (n=116) received vismodegib for 12 weeks, then 3 rounds of 8 weeks of placebo, followed by 12 weeks of vismodegib; there was a 63% reduction in clinically evident BCCs after 73 weeks. The second group (n=113) received the medication for 24 weeks, then 3 rounds of 8 weeks of placebo, followed by 8 weeks of vismodegib; there was a 54% reduction at the end of 73 weeks.⁵⁶ Subsequent analyses found improvements in health-related quality-of-life outcomes that were similar for both groups.⁵⁷

Consequently, alternative dosing schedules appear to be a viable option for patients at risk of discontinuing treatment because of adverse effects, and current data support the recently approved recommendations of dose interruptions of up to 8 weeks to manage adverse effects in patients with laBCC or mBCC.⁵⁸ Nevertheless, further clinical studies are required to determine the optimal intermittent dosing regimen for patients treated with SHH inhibitors.

Neoadjuvant Administration

Recently, vismodegib has been studied as a neoadjuvant therapy for BCC with promising results. Several small retrospective studies and case reports have documented successful treatment of both operable and inoperable periocular laBCC, with preservation of the eye in all patients.^59-61 An open-label trial of 15 patients with advanced BCC who received neoadjuvant vismodegib for 3 to 6 months prior to surgical excision reported a mean reduction of 35% in the final surgical defect size, with no recurrence at 22 months.^62,63 The latest and largest study performed was a phase 2 open-label trial known as VISMONEO, where 44 of 55 laBCC patients (80%) receiving neoadjuvant vismodegib for a mean duration of 6 months (range, 4–10 months) achieved the primary end point of tumor surgical downstaging.⁶⁴ Of the 44 patients who had tumor downstaging, 27 (61%) experienced histologically proven CRs. Additionally, a 66% reduction in the average target lesion size was reported in this group compared to29% in the 11 patients who did not have tumor downstaging (P=.0002).⁶⁴ Thus, SHH inhibitors may hold an important neoadjuvant role in the treatment of BCC by decreasing surgical defect size and allowing for surgical management of previously inoperable cases.

Synergism With Radiation

Preliminary data suggest SHH inhibitors may help potentiate the effects of radiation therapy for the treatment of BCC. Currently, the evidence primarily is limited to case studies, with several reports describing complete remission in patients with advanced BCCs who were considered unsuitable candidates for surgery. In these cases, vismodegib was administered either prior to or concurrently with radiation treatment.^65-69 An in vitro study also documented the radiation-sensitizing effects of vismodegib in a BCC cell line.⁷⁰ Recently, a phase 2 trial (ClinicalTrials.gov identifier NCT01835626) evaluating the concurrent use of vismodegib and radiotherapy for patients with advanced BCC was completed, but data has yet to be published.

Synergism With and Benefit of Antifungal Therapy

The antifungal drug itraconazole is a potent inhibitor of the SHH pathway and may have an adjunctive role in the treatment of BCC. Similar to vismodegib and sonidegib, itraconazole acts as a direct antagonist of SMO. However, it is thought to bind to a distinct site on SMO.^71,72 An open-label, exploratory phase 2 trial of 19 patients with BCC found that oral itraconazole 200 to 400 mg daily decreased tumor proliferative index by 45% (P=.04), as measured by Ki-67; SHH activity by 65% (P=.03), as measured by GLI1 messenger RNA; and mean tumor area by 24%.⁷³ In a case series of 5 patients with mBCC refractory to conventional SHH inhibitor therapy, combined treatment with itraconazole and arsenic trioxide resulted in stable disease and a 75% reduction in SHH activity (P<.001).⁷⁴ One case report documented tumor regression leading to stable disease for 15 months in a patient with laBCC treated with itraconazole monotherapy due to being unable to afford vismodegib or sonidegib. However, within 2 months of treatment discontinuation, the lesion progressed considerably.⁷⁵ The efficacy of a topical formulation of itraconazole also has been tested in an open-label, placebo-controlled phase 2 trial, but no benefit was observed.⁷⁶

Posaconazole is a second-generation antifungal agent that may serve as a potential alternative to itraconazole.⁷⁷ Although clinical data are lacking, a basic science study found that posaconazole could inhibit the growth of SHH-dependent BCC in vivo (in mice).⁷⁸ Furthermore, posaconazole has demonstrated a better safety profile with fewer and more mild side effects than itraconazole and does not require dose adjustment for those with hepatic or renal failure.^79,80 Thus, posaconazole may be a safer alternative to itraconazole for the treatment of BCC. Further clinical studies are needed to elucidate the potential synergistic effects of these antifungal agents with the 2 currently approved SHH inhibitors for the treatment of advanced BCC.

 

 

Drug Resistance

Treatment resistance to SHH inhibitors, though uncommon, is a growing concern. Acquired mutations in the SMO binding site or downstream mediators of the SHH pathway have been shown to confer resistance to vismodegib and sonidegib.^72,81-83 In addition, it appears that there may be shared resistance among the drugs in this class. One study assessing the efficacy of sonidegib in 9 patients with laBCC resistant to vismodegib found that these patients also did not respond to sonidegib.⁸⁴ Interestingly, 1 case report documented tumor regression of an intracranial BCC in a patient treated with sonidegib and itraconazole after failure with vismodegib.⁸⁵ An in vitro study also found that itraconazole maintained SHH inhibitory activity for all drug-resistant SMO mutations that have been reported.⁷² Therefore, itraconazole monotherapy or combination therapy with a canonical SHH inhibitor may be considered for patients with recalcitrant BCC and warrants further investigation.

Taladegib is a newly developed SMO inhibitor that may serve as another promising alternative for patients who develop resistance to vismodegib or sonidegib. A phase 1 trial of taladegib for advanced BCC found an ORR of 69% (11/16) in the SHH inhibitor–naïve group and an ORR of 36% (11/32) in the group previously treated with a SHH inhibitor.⁸⁶ Additionally, the safety profile and frequency of adverse effects appear to be similar to those associated with vismodegib and sonidegib.^86,87 Unfortunately, no clinical trials evaluating taladegib for BCC are ongoing or in development at this time.

Recurrence

There appears to be a relatively high rate of recurrence for BCC patients who achieve a CR to SHH inhibitors. In a retrospective study of 116 laBCC patients who experienced a CR after vismodegib therapy, 54 patients (47%) relapsed at 36 months. Among the 54 patients that relapsed, 27 were re-treated with vismodegib, which resulted in an ORR of 85% (23/27), a CR rate of 37% (10/27), and a PR rate of 48% (13/27).⁸⁸ Another retrospective study of 35 laBCC patients who relapsed after vismodegib treatment reported a 31% (11/35) clinical recurrence rate at 6-month follow-up.⁸⁹ An observational retrospective study also assessed the efficacy of SHH inhibitor maintenance therapy for advanced BCC patients who achieved a CR.⁹⁰ In the study, 27 (64%) patients received a maintenance dose of 150 mg vismodegib once per week for 1 year, while 15 (36%) patients decided not to take a maintenance dose following CR of their BCC. All patients who took the maintenance therapy did not experience clinical recurrence at 1-year follow-up, whereas 26% of patients not on the maintenance dose relapsed.⁹⁰ Consequently, these results indicate that BCC recurrence is frequent after SHH inhibitor therapy and highlights the importance of close surveillance after CR is attained. Nevertheless, most patients still respond to treatment with SHH inhibitors after relapsing, and intermittent maintenance doses may be an effective means to reduce risk of recurrence.

Conclusion

Vismodegib and sonidegib are SHH inhibitors approved for the treatment of laBCC and mBCC. Cemiplimab is now also approved for patients who do not respond to SHH inhibitors or for whom SHH inhibitors are not tolerable. Although these systemic targeted therapies can lead to notable tumor shrinkage and even complete regression in some patients, recurrence is common, and adverse effects may limit their use. Drug resistance is an emerging issue that requires additional examination. Further clinical studies are needed to determine which patients are likely to respond to these targeted treatments.

Various intermittent and maintenance drug regimens should be evaluated for their potential to mitigate adverse effects and reduce risk of recurrence, respectively. The synergistic effects of these medications with other therapies as well as their neoadjuvant and adjuvant roles should be further investigated. For example, administration of an SHH inhibitor prior to surgical excision of a BCC may allow for a smaller surgical defect size, thereby improving cosmetic and functional outcomes. Moreover, these systemic targeted medications may allow for previously inoperable tumors to become amenable to surgical treatment.

Although SHH inhibitors and PD-1 inhibitors represent a major advancement in the field of oncodermatology, real-world efficacy and safety data in the upcoming years will be important for elucidating their true benefit for patients with BCC.

Last year, our Update focused on the expansion of sequencing in prenatal diagnosis. This year, we are taking a step sideways to remember the many diagnoses we may miss if we rely on exome sequencing alone. A recent case report in Prenatal Diagnosis describes a pregnancy affected by fetal akinesia sequence and polyhydramnios in which sequencing did not reveal a diagnosis. Expansion of the differential to include congenital myotonic dystrophy and subsequent triplet repeat testing led the clinicians to the diagnosis and identification of a triplet repeat expansion in the DMPK gene. This case serves as our first example of how complementary testing and technologies should continue to help us make critical diagnoses. 

What is the yield of exome sequencing vs panels in nonimmune hydrops?

Rogers R, Moyer K, Moise KJ Jr. Congenital myotonic dystrophy: an overlooked diagnosis not amenable to detection by sequencing. Prenat Diagn. 2022;42:233-235. doi:10.1002/pd.6105.

Norton ME, Ziffle JV, Lianoglou BR, et al. Exome sequencing vs targeted gene panels for the evaluation of nonimmune hydrops fetalis. Am J Obstet Gynecol. 2021;28:S0002-9378(21)00828-0. doi:10.1016/j.ajog.2021.07.014.
 

We have had several illuminating discussions with our colleagues about the merits of exome sequencing (ES) versus panels and other modalities for fetal diagnosis. Many obstetricians practicing at the leading edge may feel like ES should be utilized uniformly for fetal anomalies with nondiagnostic karyotype or microarray. However, for well-defined phenotypes with clear and narrow lists of implicated genes (eg, skeletal dysplasias) or patients without insurance coverage, panel sequencing still has utility in prenatal diagnosis. The question of which phenotypes most benefit from ES versus panel sequencing is an area of interesting, ongoing research for several investigators.

Secondary analysis of nonimmune hydrops cohort

Norton and colleagues tackled one such cohort in a study presented in the American Journal of Obstetrics and Gynecology. They compared the proportion of diagnoses that would have been identified in commercial lab panels with their research of phenotype-driven ES in a cohort of 127 fetuses with features of nonimmune hydrops fetalis (NIHF). NIHF can be caused by a variety of single-gene disorders in addition to chromosomal disorders and copy number variants on chromosomal microarray. Patients were eligible for inclusion in the cohort if they had a nondiagnostic karyotype or microarray and any of the following features: nuchal translucency of 3.5 mm or greater, cystic hygroma, pleural effusion, pericardial effusion, ascites, or skin edema. Standard sequencing methods and variant analysis were performed. They assumed 100% analytical sensitivity and specificity of the panels for variant detection and collected cost information on the targeted gene panels.

Study outcomes

In the ES analysis of cases, 37 of 127 cases (29%) had a pathogenic or likely pathogenic variant in 1 of 29 genes, and another 12 of 127 cases (9%) had variants of uncertain significance that were strongly suspected to be the etiology during clinical analysis. The types of disorders that were identified are listed in the TABLE. In addition to a feature of NIHF, 50% of the cases had a structural anomaly.

There were 10 identified clinical panels from 7 clinical laboratories. These panels ranged in size from 11 to 128 genes. The highest simulated yield of any commercial panel was only 62% of the pathogenic variants identified by ES. The other commercial laboratory panels detection yield ranged from 11% to 62% of pathogenic variants detected by ES. For overall yield, the largest panel would have a diagnostic yield of 18% of diagnoses relative to the 29% diagnostic yield from ES.

The largest panel included 128 genes prior to the publication of the original cohort and was updated after publication to include 148 genes. The larger updated panel would have identified all of the patients in the ES cohort. However, many of the other panels listed would have identified a smaller fraction of the variants identified by ES (range, 11%-62%). At the time of publication, the cost of the panels ranged from $640 to $3,500, and the cost of prenatal ES ranged from $2,458 to $7,500.

Continue to: Strengths and limitations...

Strengths and limitations

Twenty-three percent of the patients who were sequenced had an increased fetal nuchal translucency or cystic hygroma, and another 17% had a single fetal effusion. This inclusivity makes this study more applicable to broader fetal anomaly populations. However, it is worth noting that only 61% of patients had NIHF by the definition of 2 or more fluid collections or skin thickening.

The authors assumed 100% sensitivity and specificity for the panel tests relative to diagnostic ES results, but this may not reflect real-life analysis. There is inherent subjectivity and subsequent differences in variant calling (deciding which genetic changes are pathogenic) between institutions and companies despite efforts to standardize this process. Due to the simulated nature of this study, these differences are not captured. Additionally, although the authors note that the research ES had at least 30 times the coverage (an adequate number of sequence reads for accurate testing) than did the commercial lab panels, some gene panels have additional sequencing of intronic regions, copy number analysis, and up to 10 times more coverage than ES, which could lead to more diagnoses.

Frequency of Beckwith-Widemann syndrome in prenatally diagnosed omphaloceles

Abbasi N, Moore A, Chiu P, et al. Prenatally diagnosed omphaloceles: report of 92 cases and association with Beckwith-Wiedemann syndrome. Prenat Diagn. 2021;41:798-816. doi:10.1002/pd.5930.

An omphalocele is diagnosed prenatally on ultrasound when an anterior midline mass, often containing abdominal contents, is seen herniating into the base of the umbilical cord. Omphaloceles are often associated with additional structural abnormalities and underlying genetic syndromes, thus a thorough fetal assessment is required for accurate prenatal counseling and neonatal care.

Identification of Beckwith-Widemann syndrome (BWS) in the setting of a prenatally diagnosed omphalocele is difficult because of its wide range of clinical features and its unique genetic basis. Unlike many genetic disorders that are caused by specific genetic variants, or spelling changes in the genes, BWS results from a change in the expression of one or more of the genes in a specific region of chromosome 11. A high index of clinical suspicion as well as an understanding of the various genetic and epigenetics alterations that cause BWS is required for prenatal diagnosis.

Retrospective cohort at a single center

The authors in this study reviewed all pregnancies in which an omphalocele was diagnosed prenatally at a single center between 2010 and 2015. They describe a standard prenatal evaluation following identification of an omphalocele including echocardiogram, detailed anatomic survey, and availability of an amniocentesis to facilitate aneuploidy screening and testing for BWS. This review also includes an overview of perinatal and long-term outcomes for cases of BWS diagnosed at their center between 2000 and 2015.

Study outcomes

Results of prenatal genetic testing in this cohort were divided between cases of an isolated omphalocele (without other structural changes) and cases of nonisolated omphaloceles. In the group of pregnancies with an isolated omphalocele, 2 of 27 pregnancies (7.4%) were found to have an abnormal karyotype, and 6 of 16 of the remaining pregnancies (37.5%) were diagnosed with BWS. Among the group of pregnancies with a nonisolated omphalocele, 23 of 59 pregnancies (39%) were found to have an abnormal karyotype, and 1 of 20 pregnancies (5%) were diagnosed with BWS.

Prenatal sonographic features associated with cases of BWS included polyhydramnios in 12 of 19 cases (63%) and macrosomia in 8 of 19 cases (42%). Macroglossia is another characteristic feature of the disorder, which was identified in 4 of 19 cases (21%) prenatally and in an additional 10 of 19 cases (52.6%) postnatally. Interestingly, only 1 of the cases of BWS was caused by a microdeletion at 11p15.4—a change that was identified on microarray. The additional 6 cases of BWS were caused by imprinting changes in the region, which are only detectable with a specific methylation-analysis technique.

Among the 19 cases of BWS identified over a 15-year period, there was 1 intrauterine demise. Preterm birth occurred in 10 of 19 cases (52.6%), including 8 of 19 cases (42.1%) of spontaneous preterm labor. Respiratory distress (27.8%), hypoglycemia (61%), and gastrointestinal reflux (59%) were common neonatal complications. Embryonal tumors were diagnosed in 2 of 16 patients (12.5%). Although neurodevelopmental outcomes were incomplete, their data suggested normal development in 75% of children. There were 2 neonatal deaths in this cohort and 1 childhood death at age 2 years.

Study strengths and limitations

As with many studies investigating a rare disorder, this study is limited by its retrospective nature and small sample size. Nevertheless, it adds an important cohort of patients with a prenatally diagnosed omphalocele to the literature and illuminates the utility of a standardized approach to testing for BWS in this population.

Continue to: Genetic diagnoses that could have been identified by expanded carrier screening...

 

 

Genetic diagnoses that could have been identified by expanded carrier screening

Stevens BK, Nunley PB, Wagner C, et al. Utility of expanded carrier screening in pregnancies with ultrasound abnormalities. Prenat Diagn. 2022;42:60-78. doi:10.1002/pd.6069.

This series is a thorough retrospective review of patients evaluated in a pediatric genetics clinic from 2014 through 2017. Patients were included if they were evaluated in the first 6 months of life and had a structural abnormality that might be detected on prenatal ultrasonography. The genetic testing results were analyzed and categorized according to types of genetic disorders, with the goal of identifying how many patients might have been identified by expanded carrier screening (ECS) panels.

Study outcomes

A total of 931 charts were reviewed, and 85% (791 of 931) of patients evaluated in the first 6 months of life were determined to have a structural anomaly that might be detected on prenatal ultrasonography. Of those patients, 691 went on to have genetic testing and 32.1% (222 of 691) of them had a diagnostic (pathogenic) genetic testing result related to the phenotype. The types of diagnostic testing results are shown in the FIGURE. Notably, 42 single-gene disorders were detected.

FIGURE Diagnostic test result in pediatric patients evaluated under age 6 months

Of those 222 patients with diagnostic results, there were 8 patients with autosomal recessive and X-linked conditions that could be detected using a 500-gene ECS panel. Five patients could be detected with a 271-gene panel. After nondiagnostic microarray, 11.3% of patients had a condition that could be detected by using a 500-gene ECS panel. The identified conditions included cystic fibrosis, CYP21‐related congenital adrenal hyperplasia, autosomal recessive polycystic kidney disease, Antley‐Bixler syndrome, and Morquio syndrome type A.

Furthermore, the authors conducted a literature review of 271 conditions and found that 32% (88 of 271) of conditions may be associated with ultrasound findings.

Study strengths and limitations

When applying these data to prenatal populations, the authors acknowledge several notable limitations. There is a selection bias toward less-severe phenotypes for many patients choosing to continue rather than to interrupt a pregnancy. Additionally, only 23% of the patients in the study had a microarray and ES, which may lead to an underrepresentation of single-gene disorders and an underestimation of the utility of ECS. Finally, a retrospective classification of structural abnormalities that may be detectable by ultrasonography may not always reflect what is actually reported in prenatal imaging.

However, the work that the authors put forth to evaluate and categorize 931 participants by the results of genetic testing and structural anomalies is appreciated, and the level of detail is impressive for this retrospective chart review. Additionally, the tables itemizing the authors’ review of 271 ECS disorders that may have ultrasonography findings categorized by disorder and system are helpful and quick diagnostic references for clinicians providing prenatal care. ●

Last year, our Update focused on the expansion of sequencing in prenatal diagnosis. This year, we are taking a step sideways to remember the many diagnoses we may miss if we rely on exome sequencing alone. A recent case report in Prenatal Diagnosis describes a pregnancy affected by fetal akinesia sequence and polyhydramnios in which sequencing did not reveal a diagnosis. Expansion of the differential to include congenital myotonic dystrophy and subsequent triplet repeat testing led the clinicians to the diagnosis and identification of a triplet repeat expansion in the DMPK gene. This case serves as our first example of how complementary testing and technologies should continue to help us make critical diagnoses. 

What is the yield of exome sequencing vs panels in nonimmune hydrops?

Rogers R, Moyer K, Moise KJ Jr. Congenital myotonic dystrophy: an overlooked diagnosis not amenable to detection by sequencing. Prenat Diagn. 2022;42:233-235. doi:10.1002/pd.6105.

Norton ME, Ziffle JV, Lianoglou BR, et al. Exome sequencing vs targeted gene panels for the evaluation of nonimmune hydrops fetalis. Am J Obstet Gynecol. 2021;28:S0002-9378(21)00828-0. doi:10.1016/j.ajog.2021.07.014.
 

We have had several illuminating discussions with our colleagues about the merits of exome sequencing (ES) versus panels and other modalities for fetal diagnosis. Many obstetricians practicing at the leading edge may feel like ES should be utilized uniformly for fetal anomalies with nondiagnostic karyotype or microarray. However, for well-defined phenotypes with clear and narrow lists of implicated genes (eg, skeletal dysplasias) or patients without insurance coverage, panel sequencing still has utility in prenatal diagnosis. The question of which phenotypes most benefit from ES versus panel sequencing is an area of interesting, ongoing research for several investigators.

Secondary analysis of nonimmune hydrops cohort

Norton and colleagues tackled one such cohort in a study presented in the American Journal of Obstetrics and Gynecology. They compared the proportion of diagnoses that would have been identified in commercial lab panels with their research of phenotype-driven ES in a cohort of 127 fetuses with features of nonimmune hydrops fetalis (NIHF). NIHF can be caused by a variety of single-gene disorders in addition to chromosomal disorders and copy number variants on chromosomal microarray. Patients were eligible for inclusion in the cohort if they had a nondiagnostic karyotype or microarray and any of the following features: nuchal translucency of 3.5 mm or greater, cystic hygroma, pleural effusion, pericardial effusion, ascites, or skin edema. Standard sequencing methods and variant analysis were performed. They assumed 100% analytical sensitivity and specificity of the panels for variant detection and collected cost information on the targeted gene panels.

Study outcomes

In the ES analysis of cases, 37 of 127 cases (29%) had a pathogenic or likely pathogenic variant in 1 of 29 genes, and another 12 of 127 cases (9%) had variants of uncertain significance that were strongly suspected to be the etiology during clinical analysis. The types of disorders that were identified are listed in the TABLE. In addition to a feature of NIHF, 50% of the cases had a structural anomaly.

There were 10 identified clinical panels from 7 clinical laboratories. These panels ranged in size from 11 to 128 genes. The highest simulated yield of any commercial panel was only 62% of the pathogenic variants identified by ES. The other commercial laboratory panels detection yield ranged from 11% to 62% of pathogenic variants detected by ES. For overall yield, the largest panel would have a diagnostic yield of 18% of diagnoses relative to the 29% diagnostic yield from ES.

The largest panel included 128 genes prior to the publication of the original cohort and was updated after publication to include 148 genes. The larger updated panel would have identified all of the patients in the ES cohort. However, many of the other panels listed would have identified a smaller fraction of the variants identified by ES (range, 11%-62%). At the time of publication, the cost of the panels ranged from $640 to $3,500, and the cost of prenatal ES ranged from $2,458 to $7,500.

Continue to: Strengths and limitations...

Strengths and limitations

Twenty-three percent of the patients who were sequenced had an increased fetal nuchal translucency or cystic hygroma, and another 17% had a single fetal effusion. This inclusivity makes this study more applicable to broader fetal anomaly populations. However, it is worth noting that only 61% of patients had NIHF by the definition of 2 or more fluid collections or skin thickening.

The authors assumed 100% sensitivity and specificity for the panel tests relative to diagnostic ES results, but this may not reflect real-life analysis. There is inherent subjectivity and subsequent differences in variant calling (deciding which genetic changes are pathogenic) between institutions and companies despite efforts to standardize this process. Due to the simulated nature of this study, these differences are not captured. Additionally, although the authors note that the research ES had at least 30 times the coverage (an adequate number of sequence reads for accurate testing) than did the commercial lab panels, some gene panels have additional sequencing of intronic regions, copy number analysis, and up to 10 times more coverage than ES, which could lead to more diagnoses.

Frequency of Beckwith-Widemann syndrome in prenatally diagnosed omphaloceles

Abbasi N, Moore A, Chiu P, et al. Prenatally diagnosed omphaloceles: report of 92 cases and association with Beckwith-Wiedemann syndrome. Prenat Diagn. 2021;41:798-816. doi:10.1002/pd.5930.

An omphalocele is diagnosed prenatally on ultrasound when an anterior midline mass, often containing abdominal contents, is seen herniating into the base of the umbilical cord. Omphaloceles are often associated with additional structural abnormalities and underlying genetic syndromes, thus a thorough fetal assessment is required for accurate prenatal counseling and neonatal care.

Identification of Beckwith-Widemann syndrome (BWS) in the setting of a prenatally diagnosed omphalocele is difficult because of its wide range of clinical features and its unique genetic basis. Unlike many genetic disorders that are caused by specific genetic variants, or spelling changes in the genes, BWS results from a change in the expression of one or more of the genes in a specific region of chromosome 11. A high index of clinical suspicion as well as an understanding of the various genetic and epigenetics alterations that cause BWS is required for prenatal diagnosis.

Retrospective cohort at a single center

The authors in this study reviewed all pregnancies in which an omphalocele was diagnosed prenatally at a single center between 2010 and 2015. They describe a standard prenatal evaluation following identification of an omphalocele including echocardiogram, detailed anatomic survey, and availability of an amniocentesis to facilitate aneuploidy screening and testing for BWS. This review also includes an overview of perinatal and long-term outcomes for cases of BWS diagnosed at their center between 2000 and 2015.

Study outcomes

Results of prenatal genetic testing in this cohort were divided between cases of an isolated omphalocele (without other structural changes) and cases of nonisolated omphaloceles. In the group of pregnancies with an isolated omphalocele, 2 of 27 pregnancies (7.4%) were found to have an abnormal karyotype, and 6 of 16 of the remaining pregnancies (37.5%) were diagnosed with BWS. Among the group of pregnancies with a nonisolated omphalocele, 23 of 59 pregnancies (39%) were found to have an abnormal karyotype, and 1 of 20 pregnancies (5%) were diagnosed with BWS.

Prenatal sonographic features associated with cases of BWS included polyhydramnios in 12 of 19 cases (63%) and macrosomia in 8 of 19 cases (42%). Macroglossia is another characteristic feature of the disorder, which was identified in 4 of 19 cases (21%) prenatally and in an additional 10 of 19 cases (52.6%) postnatally. Interestingly, only 1 of the cases of BWS was caused by a microdeletion at 11p15.4—a change that was identified on microarray. The additional 6 cases of BWS were caused by imprinting changes in the region, which are only detectable with a specific methylation-analysis technique.

Among the 19 cases of BWS identified over a 15-year period, there was 1 intrauterine demise. Preterm birth occurred in 10 of 19 cases (52.6%), including 8 of 19 cases (42.1%) of spontaneous preterm labor. Respiratory distress (27.8%), hypoglycemia (61%), and gastrointestinal reflux (59%) were common neonatal complications. Embryonal tumors were diagnosed in 2 of 16 patients (12.5%). Although neurodevelopmental outcomes were incomplete, their data suggested normal development in 75% of children. There were 2 neonatal deaths in this cohort and 1 childhood death at age 2 years.

Study strengths and limitations

As with many studies investigating a rare disorder, this study is limited by its retrospective nature and small sample size. Nevertheless, it adds an important cohort of patients with a prenatally diagnosed omphalocele to the literature and illuminates the utility of a standardized approach to testing for BWS in this population.

Continue to: Genetic diagnoses that could have been identified by expanded carrier screening...

 

 

Genetic diagnoses that could have been identified by expanded carrier screening

Stevens BK, Nunley PB, Wagner C, et al. Utility of expanded carrier screening in pregnancies with ultrasound abnormalities. Prenat Diagn. 2022;42:60-78. doi:10.1002/pd.6069.

This series is a thorough retrospective review of patients evaluated in a pediatric genetics clinic from 2014 through 2017. Patients were included if they were evaluated in the first 6 months of life and had a structural abnormality that might be detected on prenatal ultrasonography. The genetic testing results were analyzed and categorized according to types of genetic disorders, with the goal of identifying how many patients might have been identified by expanded carrier screening (ECS) panels.

Study outcomes

A total of 931 charts were reviewed, and 85% (791 of 931) of patients evaluated in the first 6 months of life were determined to have a structural anomaly that might be detected on prenatal ultrasonography. Of those patients, 691 went on to have genetic testing and 32.1% (222 of 691) of them had a diagnostic (pathogenic) genetic testing result related to the phenotype. The types of diagnostic testing results are shown in the FIGURE. Notably, 42 single-gene disorders were detected.

FIGURE Diagnostic test result in pediatric patients evaluated under age 6 months

Of those 222 patients with diagnostic results, there were 8 patients with autosomal recessive and X-linked conditions that could be detected using a 500-gene ECS panel. Five patients could be detected with a 271-gene panel. After nondiagnostic microarray, 11.3% of patients had a condition that could be detected by using a 500-gene ECS panel. The identified conditions included cystic fibrosis, CYP21‐related congenital adrenal hyperplasia, autosomal recessive polycystic kidney disease, Antley‐Bixler syndrome, and Morquio syndrome type A.

Furthermore, the authors conducted a literature review of 271 conditions and found that 32% (88 of 271) of conditions may be associated with ultrasound findings.

Study strengths and limitations

When applying these data to prenatal populations, the authors acknowledge several notable limitations. There is a selection bias toward less-severe phenotypes for many patients choosing to continue rather than to interrupt a pregnancy. Additionally, only 23% of the patients in the study had a microarray and ES, which may lead to an underrepresentation of single-gene disorders and an underestimation of the utility of ECS. Finally, a retrospective classification of structural abnormalities that may be detectable by ultrasonography may not always reflect what is actually reported in prenatal imaging.

However, the work that the authors put forth to evaluate and categorize 931 participants by the results of genetic testing and structural anomalies is appreciated, and the level of detail is impressive for this retrospective chart review. Additionally, the tables itemizing the authors’ review of 271 ECS disorders that may have ultrasonography findings categorized by disorder and system are helpful and quick diagnostic references for clinicians providing prenatal care. ●

Last year, our Update focused on the expansion of sequencing in prenatal diagnosis. This year, we are taking a step sideways to remember the many diagnoses we may miss if we rely on exome sequencing alone. A recent case report in Prenatal Diagnosis describes a pregnancy affected by fetal akinesia sequence and polyhydramnios in which sequencing did not reveal a diagnosis. Expansion of the differential to include congenital myotonic dystrophy and subsequent triplet repeat testing led the clinicians to the diagnosis and identification of a triplet repeat expansion in the DMPK gene. This case serves as our first example of how complementary testing and technologies should continue to help us make critical diagnoses. 

What is the yield of exome sequencing vs panels in nonimmune hydrops?

Rogers R, Moyer K, Moise KJ Jr. Congenital myotonic dystrophy: an overlooked diagnosis not amenable to detection by sequencing. Prenat Diagn. 2022;42:233-235. doi:10.1002/pd.6105.

Norton ME, Ziffle JV, Lianoglou BR, et al. Exome sequencing vs targeted gene panels for the evaluation of nonimmune hydrops fetalis. Am J Obstet Gynecol. 2021;28:S0002-9378(21)00828-0. doi:10.1016/j.ajog.2021.07.014.
 

We have had several illuminating discussions with our colleagues about the merits of exome sequencing (ES) versus panels and other modalities for fetal diagnosis. Many obstetricians practicing at the leading edge may feel like ES should be utilized uniformly for fetal anomalies with nondiagnostic karyotype or microarray. However, for well-defined phenotypes with clear and narrow lists of implicated genes (eg, skeletal dysplasias) or patients without insurance coverage, panel sequencing still has utility in prenatal diagnosis. The question of which phenotypes most benefit from ES versus panel sequencing is an area of interesting, ongoing research for several investigators.

Secondary analysis of nonimmune hydrops cohort

Norton and colleagues tackled one such cohort in a study presented in the American Journal of Obstetrics and Gynecology. They compared the proportion of diagnoses that would have been identified in commercial lab panels with their research of phenotype-driven ES in a cohort of 127 fetuses with features of nonimmune hydrops fetalis (NIHF). NIHF can be caused by a variety of single-gene disorders in addition to chromosomal disorders and copy number variants on chromosomal microarray. Patients were eligible for inclusion in the cohort if they had a nondiagnostic karyotype or microarray and any of the following features: nuchal translucency of 3.5 mm or greater, cystic hygroma, pleural effusion, pericardial effusion, ascites, or skin edema. Standard sequencing methods and variant analysis were performed. They assumed 100% analytical sensitivity and specificity of the panels for variant detection and collected cost information on the targeted gene panels.

Study outcomes

In the ES analysis of cases, 37 of 127 cases (29%) had a pathogenic or likely pathogenic variant in 1 of 29 genes, and another 12 of 127 cases (9%) had variants of uncertain significance that were strongly suspected to be the etiology during clinical analysis. The types of disorders that were identified are listed in the TABLE. In addition to a feature of NIHF, 50% of the cases had a structural anomaly.

There were 10 identified clinical panels from 7 clinical laboratories. These panels ranged in size from 11 to 128 genes. The highest simulated yield of any commercial panel was only 62% of the pathogenic variants identified by ES. The other commercial laboratory panels detection yield ranged from 11% to 62% of pathogenic variants detected by ES. For overall yield, the largest panel would have a diagnostic yield of 18% of diagnoses relative to the 29% diagnostic yield from ES.

The largest panel included 128 genes prior to the publication of the original cohort and was updated after publication to include 148 genes. The larger updated panel would have identified all of the patients in the ES cohort. However, many of the other panels listed would have identified a smaller fraction of the variants identified by ES (range, 11%-62%). At the time of publication, the cost of the panels ranged from $640 to $3,500, and the cost of prenatal ES ranged from $2,458 to $7,500.

Continue to: Strengths and limitations...

Strengths and limitations

Twenty-three percent of the patients who were sequenced had an increased fetal nuchal translucency or cystic hygroma, and another 17% had a single fetal effusion. This inclusivity makes this study more applicable to broader fetal anomaly populations. However, it is worth noting that only 61% of patients had NIHF by the definition of 2 or more fluid collections or skin thickening.

The authors assumed 100% sensitivity and specificity for the panel tests relative to diagnostic ES results, but this may not reflect real-life analysis. There is inherent subjectivity and subsequent differences in variant calling (deciding which genetic changes are pathogenic) between institutions and companies despite efforts to standardize this process. Due to the simulated nature of this study, these differences are not captured. Additionally, although the authors note that the research ES had at least 30 times the coverage (an adequate number of sequence reads for accurate testing) than did the commercial lab panels, some gene panels have additional sequencing of intronic regions, copy number analysis, and up to 10 times more coverage than ES, which could lead to more diagnoses.

Frequency of Beckwith-Widemann syndrome in prenatally diagnosed omphaloceles

Abbasi N, Moore A, Chiu P, et al. Prenatally diagnosed omphaloceles: report of 92 cases and association with Beckwith-Wiedemann syndrome. Prenat Diagn. 2021;41:798-816. doi:10.1002/pd.5930.

An omphalocele is diagnosed prenatally on ultrasound when an anterior midline mass, often containing abdominal contents, is seen herniating into the base of the umbilical cord. Omphaloceles are often associated with additional structural abnormalities and underlying genetic syndromes, thus a thorough fetal assessment is required for accurate prenatal counseling and neonatal care.

Identification of Beckwith-Widemann syndrome (BWS) in the setting of a prenatally diagnosed omphalocele is difficult because of its wide range of clinical features and its unique genetic basis. Unlike many genetic disorders that are caused by specific genetic variants, or spelling changes in the genes, BWS results from a change in the expression of one or more of the genes in a specific region of chromosome 11. A high index of clinical suspicion as well as an understanding of the various genetic and epigenetics alterations that cause BWS is required for prenatal diagnosis.

Retrospective cohort at a single center

The authors in this study reviewed all pregnancies in which an omphalocele was diagnosed prenatally at a single center between 2010 and 2015. They describe a standard prenatal evaluation following identification of an omphalocele including echocardiogram, detailed anatomic survey, and availability of an amniocentesis to facilitate aneuploidy screening and testing for BWS. This review also includes an overview of perinatal and long-term outcomes for cases of BWS diagnosed at their center between 2000 and 2015.

Study outcomes

Results of prenatal genetic testing in this cohort were divided between cases of an isolated omphalocele (without other structural changes) and cases of nonisolated omphaloceles. In the group of pregnancies with an isolated omphalocele, 2 of 27 pregnancies (7.4%) were found to have an abnormal karyotype, and 6 of 16 of the remaining pregnancies (37.5%) were diagnosed with BWS. Among the group of pregnancies with a nonisolated omphalocele, 23 of 59 pregnancies (39%) were found to have an abnormal karyotype, and 1 of 20 pregnancies (5%) were diagnosed with BWS.

Prenatal sonographic features associated with cases of BWS included polyhydramnios in 12 of 19 cases (63%) and macrosomia in 8 of 19 cases (42%). Macroglossia is another characteristic feature of the disorder, which was identified in 4 of 19 cases (21%) prenatally and in an additional 10 of 19 cases (52.6%) postnatally. Interestingly, only 1 of the cases of BWS was caused by a microdeletion at 11p15.4—a change that was identified on microarray. The additional 6 cases of BWS were caused by imprinting changes in the region, which are only detectable with a specific methylation-analysis technique.

Among the 19 cases of BWS identified over a 15-year period, there was 1 intrauterine demise. Preterm birth occurred in 10 of 19 cases (52.6%), including 8 of 19 cases (42.1%) of spontaneous preterm labor. Respiratory distress (27.8%), hypoglycemia (61%), and gastrointestinal reflux (59%) were common neonatal complications. Embryonal tumors were diagnosed in 2 of 16 patients (12.5%). Although neurodevelopmental outcomes were incomplete, their data suggested normal development in 75% of children. There were 2 neonatal deaths in this cohort and 1 childhood death at age 2 years.

Study strengths and limitations

As with many studies investigating a rare disorder, this study is limited by its retrospective nature and small sample size. Nevertheless, it adds an important cohort of patients with a prenatally diagnosed omphalocele to the literature and illuminates the utility of a standardized approach to testing for BWS in this population.

Continue to: Genetic diagnoses that could have been identified by expanded carrier screening...

 

 

Genetic diagnoses that could have been identified by expanded carrier screening

Stevens BK, Nunley PB, Wagner C, et al. Utility of expanded carrier screening in pregnancies with ultrasound abnormalities. Prenat Diagn. 2022;42:60-78. doi:10.1002/pd.6069.

This series is a thorough retrospective review of patients evaluated in a pediatric genetics clinic from 2014 through 2017. Patients were included if they were evaluated in the first 6 months of life and had a structural abnormality that might be detected on prenatal ultrasonography. The genetic testing results were analyzed and categorized according to types of genetic disorders, with the goal of identifying how many patients might have been identified by expanded carrier screening (ECS) panels.

Study outcomes

A total of 931 charts were reviewed, and 85% (791 of 931) of patients evaluated in the first 6 months of life were determined to have a structural anomaly that might be detected on prenatal ultrasonography. Of those patients, 691 went on to have genetic testing and 32.1% (222 of 691) of them had a diagnostic (pathogenic) genetic testing result related to the phenotype. The types of diagnostic testing results are shown in the FIGURE. Notably, 42 single-gene disorders were detected.

FIGURE Diagnostic test result in pediatric patients evaluated under age 6 months

Of those 222 patients with diagnostic results, there were 8 patients with autosomal recessive and X-linked conditions that could be detected using a 500-gene ECS panel. Five patients could be detected with a 271-gene panel. After nondiagnostic microarray, 11.3% of patients had a condition that could be detected by using a 500-gene ECS panel. The identified conditions included cystic fibrosis, CYP21‐related congenital adrenal hyperplasia, autosomal recessive polycystic kidney disease, Antley‐Bixler syndrome, and Morquio syndrome type A.

Furthermore, the authors conducted a literature review of 271 conditions and found that 32% (88 of 271) of conditions may be associated with ultrasound findings.

Study strengths and limitations

When applying these data to prenatal populations, the authors acknowledge several notable limitations. There is a selection bias toward less-severe phenotypes for many patients choosing to continue rather than to interrupt a pregnancy. Additionally, only 23% of the patients in the study had a microarray and ES, which may lead to an underrepresentation of single-gene disorders and an underestimation of the utility of ECS. Finally, a retrospective classification of structural abnormalities that may be detectable by ultrasonography may not always reflect what is actually reported in prenatal imaging.

However, the work that the authors put forth to evaluate and categorize 931 participants by the results of genetic testing and structural anomalies is appreciated, and the level of detail is impressive for this retrospective chart review. Additionally, the tables itemizing the authors’ review of 271 ECS disorders that may have ultrasonography findings categorized by disorder and system are helpful and quick diagnostic references for clinicians providing prenatal care. ●

The transition to menopause begins with ovarian fluctuation and hormonal changes, often beginning before significant changes in menstruation. Reproductive aging with loss of follicular activity progresses over a wide age range (42 to 58 years) with an average onset at approximately age 47, ranging from 4 to 8 years. Although most women have heard about menopause, defined as 12 months after the last period, they often lack understanding about perimenopause or that the menopausal transition usually begins 5 years before menopause.¹

Perimenopause, defined as early and late menopause transition stages, may be viewed as a window of potential vulnerability for women who develop or have worsening menstrual-related mood disorders. Over time, hormonal fluctuations often lead to menstrual cycle irregularity (either shorter or longer). Changes occurring during perimenopause may be confusing as it may not be clear whether symptoms are related to menopause, aging, or stress. Often not recognized or treated adequately, perimenopausal symptoms may be challenging to navigate for both women and clinicians.

The perimenopausal process is often even more confusing for women with early menopause—whether due to bilateral oophorectomy, chemotherapy or radiation therapy, genetics, or an autoimmune process—because of lack of recognition that an early menopausal transition is occurring or what solutions are available for symptoms. While there is support in the workplace for women during pregnancy and breastfeeding, there remains little support or recognition for the oft challenging perimenopausal transition leading to menopause.

Perimenopause: Common symptoms and treatments

Symptoms may be related to either estrogen level deficiency or excess during perimenopause, and these level changes may even occur within the same cycle.

Cyclic breast tenderness may develop, worsened by caffeine or high salt intake (which can be potentially improved, although without clinical trial evidence, with decreased caffeine or a trial of evening primrose oil or vitamin E).

Changes in menstrual flow and frequency of menses are typical. Flow may be lighter or heavier, longer or shorter, and there may be cycle variability, missed menses, or midcycle spotting.² Bleeding may be heavy, with or without cramping. In addition to imaging with vaginal ultrasonography or hysteroscopy to identify structural issues, symptoms may be managed with nonsteroidal anti-inflammatory drugs (NSAIDs), hormonal therapy (HT) with short hormone-free interval contraceptives, oral progestogens, or progestin intrauterine systems. Newer medical treatments include antifibrinolytic drugs and selective progesterone-receptor modulators. Uterine ablation to decrease or stop bleeding is effective if there are no structural abnormalities, such as fibroids or polyps or the presence of adenomyosis, where glands will regrow into the endometrium after ablation. Endometrial biopsy is indicated for persistent abnormal uterine bleeding or those with risk factors such as chronic anovulation.

Worsening headaches or menstrual migraines may be triggered by hormonal changes, which may respond to NSAIDs; dihydroergotamine; triptans; the combination of aspirin, acetaminophen, and caffeine; or estrogen the week before menses. For women taking oral contraceptives (OCPs), adding estradiol the week before menses, or using the OCP continuously, may decrease headache frequency. These short-term prophylactic strategies during the perimenstrual time are often effective. If not, preventive therapy is available for women with frequent, severe headaches.

Mood complaints and poor sleep are independently associated with menstrual irregularity, and can lead to fatigue or anxiety, worsening premenstrual syndrome, or depressive moods. Sleep is disrupted premenstrually for up to one-third of women, and sleep disruption is particularly prevalent in those with premenstrual mood disorders and worsens during perimenopause.³

Reproductive hormones act on the neurotransmitter systems in the brain involved in mood regulation and emotion. The fluctuating hormones occurring during perimenopause may exacerbate pre-existing menstrual-related mood disorders. A subset of women experience depressive moods due to perimenopausal elevations in ovarian hormones.⁴ Others may exhibit increased mood sensitivity with the ovarian hormone withdrawal accompanying late menopause transition and early postmenopausal phase.⁵ There is significant comorbidity between premenstrual mood disorder (PMDD) and postpartum depression.⁶ During perimenopause and early menopause, clinicians should ask about prior hormonally-related depression (puberty, postpartum) and recognize that current or past premenstrual syndrome may worsen into a more severe premenstrual dysphoric disorder. Evidence-based treatments for PMDD include selective serotonin reuptake inhibitors (SSRIs); either taken continuously or only during the luteal phase; drospirenone-containing oral contraceptives, often with shorter pill-free intervals; GnRH analogues with or without hormone add-back; and cognitive behavioral therapy.⁷ For women whose perimenopausal moods improve with HT or develop worsened mood sensitivity with ovarian hormone withdrawal, clinicians should recognize that mood may worsen when treatment is ceased.⁵

Continue to: Menopausal symptoms...

 

 

Menopausal symptoms

Vasomotor symptoms (VMS), hot flashes, or night sweats occur in up to 75% of women as they develop more menstrual irregularity and move closer to their final period and menopause.

Hot flashes are transient episodes of flushing with the sensation of warmth (up to intense heat) on the upper body and face or head, often associated with sweating, chills or flushing, an increase in heart rate, and lowered blood pressure. Hot flashes can sometimes be preceded by an intense feeling of dread, followed by rapid heat dissipation. The etiology of hot flashes is still not clear, but the neurokinin receptors are involved. They are related to small fluctuations in core body temperature superimposed on a narrow thermoneutral zone in symptomatic women. Hot flashes are triggered when core body temperature rises above the upper (sweating) threshold. Shivering occurs if the core body temperature falls below the lower threshold. Sleep may be disrupted, with less rapid eye movement (REM) sleep, and associated with throwing covers on and off or changing sheets or nightclothes. On average, hot flashes last 7.2 years,⁸ and they are more bothersome if night sweats interfere with sleep or disrupt performance during the day.

In the Stages of Reproductive Aging Workshop (STRAW + 10), women reported VMS within 1-3 years after the menopausal transition.⁸ Four trajectories of hot flashes were identified in the Study of Women’s Health Across the Nation (SWAN) trial,⁹ including low levels throughout the menopause transition, early onset, late onset, and a group which had frequent hot flashes, starting early and lasting longer. Serum estrogen levels were not predictive of hot flash frequency or severity.

Hot flashes have been associated with low levels of exercise, cigarette smoking, high follicle-stimulating hormone levels and low estradiol levels, increasing body mass index, ethnicity (with hot flashes more common among Black and Hispanic women), low socioeconomic status, prior PMDD, anxiety, perceived stress, and depression.⁸ Women with a history of premenstrual syndrome, stress, sexual dysfunction, physical inactivity, or hot flashes are more vulnerable to depressive symptoms during perimenopause and early menopause.⁵

Depression may co-occur or overlap with menopause symptoms. Diagnosis involves menopausal stage, co-occurring psychiatric and menopause symptoms, psychosocial stressors, and a validated screening tool such as PQ9. Treatments for perimenopausal depression, such as antidepressants, psychotherapy, or cognitive behavioral therapy, are recommended first line for perimenopausal depression. Estrogen therapy has not been approved to treat perimenopausal depression but appears to have antidepressant effects in perimenopausal women, particularly those with bothersome vasomotor symptoms.⁵

Anxiety can worsen during menopause, and may respond to calming apps, meditation, cognitive behavioral therapy, hypnosis, yoga or tai chi, HT, or antianxiety medications.

Weight gain around the abdomen (ie, belly fat) is a common complaint during the menopausal transition, despite women reporting not changing their eating or exercise patterns. Increasing exercise or bursts of higher intensity, decreasing portion sizes or limiting carbohydrates and alcohol may help.

Memory and concentration problems, described as brain fog, tend to be more of an issue in perimenopause and level out after menopause. Counsel midlife women that these changes are not due to dementia but are related to normal aging, hormonal changes, mood, stress, or other life circumstances. Identifying and addressing sleep issues and mood disorders may help mitigate brain fog, as can advising women to avoid excess caffeine, alcohol, nicotine, and eating before bed. Improvements in memory, cognition, and health have been found with the Mediterranean diet, regular exercise, avoiding multitasking, and engaging in mentally stimulating activities.

Sleeping concerns in peri- and postmenopausal women include sleeping less and more frequent insomnia. Women are more likely to use prescription sleeping aids during these times of their lives. The data from SWAN⁸ show that the menopausal transition is related to self-reported difficulty sleeping, independent of age. Sleep latency interval is increased while REM sleep decreases. Night sweats can trigger awakenings in the first half of the night. The perceived decline in sleep quality also may be attributed to general aging effects, nocturnal urination, sleep-related disorders such as sleep apnea or restless legs, or chronic pain, stress, or depression.¹⁰ Suggestions for management include sleep apps, cognitive behavioral therapy, low-dose antidepressant therapy, addressing sleep routines, and HT. Hypnotics should be avoided.

Sexuality issues are common complaints during the menopausal transition. Cross-sectional data reported from a longitudinal, population-based Australian cohort of women aged 45 to 55 years, found a decrease in sexual responsivity, sexual frequency, libido, vaginal dyspareunia, and more partner problems.¹¹ Low libido may be related to relationship issues, dyspareunia with vaginal narrowing, loss of lubrication, levator spasm, stress, anxiety, exhaustion or mood disorder, lowered hormone levels, excess alcohol intake, underlying health concerns, or a side effect of medications for depression or pain. There is no direct correlation between testosterone levels and libido.

When HT at menopause may be helpful

For healthy symptomatic women without contraindications who are younger than age 60, or within 10 years of menopause onset, the benefits of initiating HT most likely outweigh the risks to relieve bothersome hot flashes and night sweats.^12-17 For older women, or for those further from menopause, the greater absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia, in general, outweigh the potential benefits.^12-17 Extended durations of HT have less safety and efficacy data and should be considered primarily for those with persistent menopausal symptoms, with periodic re-evaluation.^13,14 For bothersome genitourinary syndrome of menopause symptoms that do not respond to vaginal moisturizers or lubricants, low-dose vaginal HTs are encouraged.^13-17

Continue to: Early-onset menopause...

Early-onset menopause

According to observational studies,¹⁸ early menopause is associated with a higher risk of osteoporosis, coronary heart disease, cognitive changes, vaginal dryness, loss of libido, and mood changes. Studies have shown that women with early menopause who take HT, without contraindications, to the average age of menopause (age 52) decrease the health risks of early menopause (bone loss, heart disease, mood, and cognition changes).^13,14,18

Women with early menopause, whether spontaneous or following bilateral oophorectomy or cancer treatment, should be counseled to get adequate calcium (dietary recommended over supplementation) and vitamin D intake, eat a healthy diet, and exercise regularly. Evaluation should include risk for bone loss, heart disease, mood changes, and vaginal changes.

Extended use of HT

Up to 8% of women have hot flashes for 20 years or more after menopause.¹⁹ The decision to continue or to stop HT is not always clear for women:

• with persistent hot flashes after a trial period of HT discontinuation
• with bone loss that cannot be treated with bone-specific medications
• who request continuation for quality of life.

Extended use of HT should include an ongoing assessment of its risks and benefits, periodic trials off of HT, and documentation of rationale and informed discussions about continuing. Lower doses and transdermal therapies appear safer, as does micronized progesterone instead of more potent synthetic progestins.^13-17

Genitourinary syndrome of menopause

Once women are further into menopause, they may notice vaginal dryness, vulvar itching or burning, bothersome vaginal discharge, or urinary urgency or frequency. The development of painful intercourse frequently occurs, a combination of the loss of estrogen with thinning of the vaginal mucosa, a loss of the acidic vaginal milieu with less elasticity, and spasm of the levator muscles. Some women develop urinary tract infections after intercourse or have more frequent reoccurrences. First-line therapy is often vaginal moisturizers and lubricants. Vaginal therapies (estradiol, conjugated estrogen, or dehydroepiandrosterone) or oral selective estrogen-receptor modulators (SERMs; ospemifene) improve vaginal dryness and dyspareunia.^13,14 Pelvic therapy has also proved valuable for incontinence, pelvic floor dysfunction, and levator spasms.²⁰

Where are there gaps in clinician knowledge?

Studies on emotional health, mood, and sleep need to incorporate measures of menstrual timing into data collection and analyses. Does the sleep disruption occurring premenstrually during perimenopause disproportionately contribute to a woman’s vulnerability to depressive disorders? The risk of clinically significant depressive symptoms increases 1.5- to 2.9-fold in the menopause transition.⁵ Research into premenstrual dysphoria during the menopause transition may identify different trajectories in the timing of symptoms related to either cycle itself or the ovarian hormone fluctuations or both.²¹ Gamma-aminobutyric acid (GABA)-modulating drugs, such as sepranolone, which blocks allopregnanolone’s actions at the GABAA receptor, may allow treatment of menstrual-related mood disorders without the need for hormonal interventions.²¹

Despite extended observational trial data, more data are needed to inform us about the long-term risks and benefits of using menopausal HT, particularly when initiated at menopause and to help address the timing of HT discontinuation. Furthermore, there are many unanswered questions. For instance:

• How much safer are lower dose and transdermal therapies?
• Do untreated hot flashes increase the risk of cardiovascular disease or dementia?
• Will newer non-HT options, such as the neurokinin receptor antagonists that are in testing but are not yet available, lower cardiovascular or dementia risks?
• What will be the risks and benefits for the newer estrogen in testing (estetrol, or E4), considered a natural estrogen and which appears to have lower thrombotic risks?
• What will be the role of intravaginal energy-based therapies, such as vaginal laser or radiofrequency devices?
• How do we address diverse populations and the effects of menopause on race, gender, culture, prior trauma, and socioeconomic status?

Lack of recognition of menopausal symptoms, particularly in the workplace

Clinicians need to understand the varied physical and emotional symptoms that may occur with hormonal changes as women traverse perimenopause and early menopause. We need to recognize that the lack of discussion about women’s health during this time may make women feel ashamed and fearful of bringing up their symptoms due to fear of being dismissed or stigmatized.²² Women may not seek help until a crisis at home or work occurs, as they may fear that admitting symptoms or a need for help or time away from work will threaten how they are viewed at work or affect their chances of promotion. Although there are economic costs around menopause for appointments, tests, therapies, and missed time at work, not addressing menopausal health leads to poorer performance, workplace absences, and additional medical costs.²²

Conclusion

Menopause occurs naturally as a part of a woman’s life cycle. However, women need assistance navigating perimenopausal hormonal fluctuations and decisions about HT once in menopause. Increased awareness and education about perimenopause and menopause will allow compassionate, individualized, informed care, including lifestyle changes, behavioral or complementary strategies, or medical therapies, hormonal or nonhormonal.²⁷ As a medical society, we need to challenge the stigma associated with aging and menopause and educate ourselves and our patients to help women navigate this challenging time. ●

The transition to menopause begins with ovarian fluctuation and hormonal changes, often beginning before significant changes in menstruation. Reproductive aging with loss of follicular activity progresses over a wide age range (42 to 58 years) with an average onset at approximately age 47, ranging from 4 to 8 years. Although most women have heard about menopause, defined as 12 months after the last period, they often lack understanding about perimenopause or that the menopausal transition usually begins 5 years before menopause.¹

Perimenopause, defined as early and late menopause transition stages, may be viewed as a window of potential vulnerability for women who develop or have worsening menstrual-related mood disorders. Over time, hormonal fluctuations often lead to menstrual cycle irregularity (either shorter or longer). Changes occurring during perimenopause may be confusing as it may not be clear whether symptoms are related to menopause, aging, or stress. Often not recognized or treated adequately, perimenopausal symptoms may be challenging to navigate for both women and clinicians.

The perimenopausal process is often even more confusing for women with early menopause—whether due to bilateral oophorectomy, chemotherapy or radiation therapy, genetics, or an autoimmune process—because of lack of recognition that an early menopausal transition is occurring or what solutions are available for symptoms. While there is support in the workplace for women during pregnancy and breastfeeding, there remains little support or recognition for the oft challenging perimenopausal transition leading to menopause.

Perimenopause: Common symptoms and treatments

Symptoms may be related to either estrogen level deficiency or excess during perimenopause, and these level changes may even occur within the same cycle.

Cyclic breast tenderness may develop, worsened by caffeine or high salt intake (which can be potentially improved, although without clinical trial evidence, with decreased caffeine or a trial of evening primrose oil or vitamin E).

Changes in menstrual flow and frequency of menses are typical. Flow may be lighter or heavier, longer or shorter, and there may be cycle variability, missed menses, or midcycle spotting.² Bleeding may be heavy, with or without cramping. In addition to imaging with vaginal ultrasonography or hysteroscopy to identify structural issues, symptoms may be managed with nonsteroidal anti-inflammatory drugs (NSAIDs), hormonal therapy (HT) with short hormone-free interval contraceptives, oral progestogens, or progestin intrauterine systems. Newer medical treatments include antifibrinolytic drugs and selective progesterone-receptor modulators. Uterine ablation to decrease or stop bleeding is effective if there are no structural abnormalities, such as fibroids or polyps or the presence of adenomyosis, where glands will regrow into the endometrium after ablation. Endometrial biopsy is indicated for persistent abnormal uterine bleeding or those with risk factors such as chronic anovulation.

Worsening headaches or menstrual migraines may be triggered by hormonal changes, which may respond to NSAIDs; dihydroergotamine; triptans; the combination of aspirin, acetaminophen, and caffeine; or estrogen the week before menses. For women taking oral contraceptives (OCPs), adding estradiol the week before menses, or using the OCP continuously, may decrease headache frequency. These short-term prophylactic strategies during the perimenstrual time are often effective. If not, preventive therapy is available for women with frequent, severe headaches.

Mood complaints and poor sleep are independently associated with menstrual irregularity, and can lead to fatigue or anxiety, worsening premenstrual syndrome, or depressive moods. Sleep is disrupted premenstrually for up to one-third of women, and sleep disruption is particularly prevalent in those with premenstrual mood disorders and worsens during perimenopause.³

Reproductive hormones act on the neurotransmitter systems in the brain involved in mood regulation and emotion. The fluctuating hormones occurring during perimenopause may exacerbate pre-existing menstrual-related mood disorders. A subset of women experience depressive moods due to perimenopausal elevations in ovarian hormones.⁴ Others may exhibit increased mood sensitivity with the ovarian hormone withdrawal accompanying late menopause transition and early postmenopausal phase.⁵ There is significant comorbidity between premenstrual mood disorder (PMDD) and postpartum depression.⁶ During perimenopause and early menopause, clinicians should ask about prior hormonally-related depression (puberty, postpartum) and recognize that current or past premenstrual syndrome may worsen into a more severe premenstrual dysphoric disorder. Evidence-based treatments for PMDD include selective serotonin reuptake inhibitors (SSRIs); either taken continuously or only during the luteal phase; drospirenone-containing oral contraceptives, often with shorter pill-free intervals; GnRH analogues with or without hormone add-back; and cognitive behavioral therapy.⁷ For women whose perimenopausal moods improve with HT or develop worsened mood sensitivity with ovarian hormone withdrawal, clinicians should recognize that mood may worsen when treatment is ceased.⁵

Continue to: Menopausal symptoms...

 

 

Menopausal symptoms

Vasomotor symptoms (VMS), hot flashes, or night sweats occur in up to 75% of women as they develop more menstrual irregularity and move closer to their final period and menopause.

Hot flashes are transient episodes of flushing with the sensation of warmth (up to intense heat) on the upper body and face or head, often associated with sweating, chills or flushing, an increase in heart rate, and lowered blood pressure. Hot flashes can sometimes be preceded by an intense feeling of dread, followed by rapid heat dissipation. The etiology of hot flashes is still not clear, but the neurokinin receptors are involved. They are related to small fluctuations in core body temperature superimposed on a narrow thermoneutral zone in symptomatic women. Hot flashes are triggered when core body temperature rises above the upper (sweating) threshold. Shivering occurs if the core body temperature falls below the lower threshold. Sleep may be disrupted, with less rapid eye movement (REM) sleep, and associated with throwing covers on and off or changing sheets or nightclothes. On average, hot flashes last 7.2 years,⁸ and they are more bothersome if night sweats interfere with sleep or disrupt performance during the day.

In the Stages of Reproductive Aging Workshop (STRAW + 10), women reported VMS within 1-3 years after the menopausal transition.⁸ Four trajectories of hot flashes were identified in the Study of Women’s Health Across the Nation (SWAN) trial,⁹ including low levels throughout the menopause transition, early onset, late onset, and a group which had frequent hot flashes, starting early and lasting longer. Serum estrogen levels were not predictive of hot flash frequency or severity.

Hot flashes have been associated with low levels of exercise, cigarette smoking, high follicle-stimulating hormone levels and low estradiol levels, increasing body mass index, ethnicity (with hot flashes more common among Black and Hispanic women), low socioeconomic status, prior PMDD, anxiety, perceived stress, and depression.⁸ Women with a history of premenstrual syndrome, stress, sexual dysfunction, physical inactivity, or hot flashes are more vulnerable to depressive symptoms during perimenopause and early menopause.⁵

Depression may co-occur or overlap with menopause symptoms. Diagnosis involves menopausal stage, co-occurring psychiatric and menopause symptoms, psychosocial stressors, and a validated screening tool such as PQ9. Treatments for perimenopausal depression, such as antidepressants, psychotherapy, or cognitive behavioral therapy, are recommended first line for perimenopausal depression. Estrogen therapy has not been approved to treat perimenopausal depression but appears to have antidepressant effects in perimenopausal women, particularly those with bothersome vasomotor symptoms.⁵

Anxiety can worsen during menopause, and may respond to calming apps, meditation, cognitive behavioral therapy, hypnosis, yoga or tai chi, HT, or antianxiety medications.

Weight gain around the abdomen (ie, belly fat) is a common complaint during the menopausal transition, despite women reporting not changing their eating or exercise patterns. Increasing exercise or bursts of higher intensity, decreasing portion sizes or limiting carbohydrates and alcohol may help.

Memory and concentration problems, described as brain fog, tend to be more of an issue in perimenopause and level out after menopause. Counsel midlife women that these changes are not due to dementia but are related to normal aging, hormonal changes, mood, stress, or other life circumstances. Identifying and addressing sleep issues and mood disorders may help mitigate brain fog, as can advising women to avoid excess caffeine, alcohol, nicotine, and eating before bed. Improvements in memory, cognition, and health have been found with the Mediterranean diet, regular exercise, avoiding multitasking, and engaging in mentally stimulating activities.

Sleeping concerns in peri- and postmenopausal women include sleeping less and more frequent insomnia. Women are more likely to use prescription sleeping aids during these times of their lives. The data from SWAN⁸ show that the menopausal transition is related to self-reported difficulty sleeping, independent of age. Sleep latency interval is increased while REM sleep decreases. Night sweats can trigger awakenings in the first half of the night. The perceived decline in sleep quality also may be attributed to general aging effects, nocturnal urination, sleep-related disorders such as sleep apnea or restless legs, or chronic pain, stress, or depression.¹⁰ Suggestions for management include sleep apps, cognitive behavioral therapy, low-dose antidepressant therapy, addressing sleep routines, and HT. Hypnotics should be avoided.

Sexuality issues are common complaints during the menopausal transition. Cross-sectional data reported from a longitudinal, population-based Australian cohort of women aged 45 to 55 years, found a decrease in sexual responsivity, sexual frequency, libido, vaginal dyspareunia, and more partner problems.¹¹ Low libido may be related to relationship issues, dyspareunia with vaginal narrowing, loss of lubrication, levator spasm, stress, anxiety, exhaustion or mood disorder, lowered hormone levels, excess alcohol intake, underlying health concerns, or a side effect of medications for depression or pain. There is no direct correlation between testosterone levels and libido.

When HT at menopause may be helpful

For healthy symptomatic women without contraindications who are younger than age 60, or within 10 years of menopause onset, the benefits of initiating HT most likely outweigh the risks to relieve bothersome hot flashes and night sweats.^12-17 For older women, or for those further from menopause, the greater absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia, in general, outweigh the potential benefits.^12-17 Extended durations of HT have less safety and efficacy data and should be considered primarily for those with persistent menopausal symptoms, with periodic re-evaluation.^13,14 For bothersome genitourinary syndrome of menopause symptoms that do not respond to vaginal moisturizers or lubricants, low-dose vaginal HTs are encouraged.^13-17

Continue to: Early-onset menopause...

Early-onset menopause

According to observational studies,¹⁸ early menopause is associated with a higher risk of osteoporosis, coronary heart disease, cognitive changes, vaginal dryness, loss of libido, and mood changes. Studies have shown that women with early menopause who take HT, without contraindications, to the average age of menopause (age 52) decrease the health risks of early menopause (bone loss, heart disease, mood, and cognition changes).^13,14,18

Women with early menopause, whether spontaneous or following bilateral oophorectomy or cancer treatment, should be counseled to get adequate calcium (dietary recommended over supplementation) and vitamin D intake, eat a healthy diet, and exercise regularly. Evaluation should include risk for bone loss, heart disease, mood changes, and vaginal changes.

Extended use of HT

Up to 8% of women have hot flashes for 20 years or more after menopause.¹⁹ The decision to continue or to stop HT is not always clear for women:

• with persistent hot flashes after a trial period of HT discontinuation
• with bone loss that cannot be treated with bone-specific medications
• who request continuation for quality of life.

Extended use of HT should include an ongoing assessment of its risks and benefits, periodic trials off of HT, and documentation of rationale and informed discussions about continuing. Lower doses and transdermal therapies appear safer, as does micronized progesterone instead of more potent synthetic progestins.^13-17

Genitourinary syndrome of menopause

Once women are further into menopause, they may notice vaginal dryness, vulvar itching or burning, bothersome vaginal discharge, or urinary urgency or frequency. The development of painful intercourse frequently occurs, a combination of the loss of estrogen with thinning of the vaginal mucosa, a loss of the acidic vaginal milieu with less elasticity, and spasm of the levator muscles. Some women develop urinary tract infections after intercourse or have more frequent reoccurrences. First-line therapy is often vaginal moisturizers and lubricants. Vaginal therapies (estradiol, conjugated estrogen, or dehydroepiandrosterone) or oral selective estrogen-receptor modulators (SERMs; ospemifene) improve vaginal dryness and dyspareunia.^13,14 Pelvic therapy has also proved valuable for incontinence, pelvic floor dysfunction, and levator spasms.²⁰

Where are there gaps in clinician knowledge?

Studies on emotional health, mood, and sleep need to incorporate measures of menstrual timing into data collection and analyses. Does the sleep disruption occurring premenstrually during perimenopause disproportionately contribute to a woman’s vulnerability to depressive disorders? The risk of clinically significant depressive symptoms increases 1.5- to 2.9-fold in the menopause transition.⁵ Research into premenstrual dysphoria during the menopause transition may identify different trajectories in the timing of symptoms related to either cycle itself or the ovarian hormone fluctuations or both.²¹ Gamma-aminobutyric acid (GABA)-modulating drugs, such as sepranolone, which blocks allopregnanolone’s actions at the GABAA receptor, may allow treatment of menstrual-related mood disorders without the need for hormonal interventions.²¹

Despite extended observational trial data, more data are needed to inform us about the long-term risks and benefits of using menopausal HT, particularly when initiated at menopause and to help address the timing of HT discontinuation. Furthermore, there are many unanswered questions. For instance:

• How much safer are lower dose and transdermal therapies?
• Do untreated hot flashes increase the risk of cardiovascular disease or dementia?
• Will newer non-HT options, such as the neurokinin receptor antagonists that are in testing but are not yet available, lower cardiovascular or dementia risks?
• What will be the risks and benefits for the newer estrogen in testing (estetrol, or E4), considered a natural estrogen and which appears to have lower thrombotic risks?
• What will be the role of intravaginal energy-based therapies, such as vaginal laser or radiofrequency devices?
• How do we address diverse populations and the effects of menopause on race, gender, culture, prior trauma, and socioeconomic status?

Lack of recognition of menopausal symptoms, particularly in the workplace

Clinicians need to understand the varied physical and emotional symptoms that may occur with hormonal changes as women traverse perimenopause and early menopause. We need to recognize that the lack of discussion about women’s health during this time may make women feel ashamed and fearful of bringing up their symptoms due to fear of being dismissed or stigmatized.²² Women may not seek help until a crisis at home or work occurs, as they may fear that admitting symptoms or a need for help or time away from work will threaten how they are viewed at work or affect their chances of promotion. Although there are economic costs around menopause for appointments, tests, therapies, and missed time at work, not addressing menopausal health leads to poorer performance, workplace absences, and additional medical costs.²²

Conclusion

Menopause occurs naturally as a part of a woman’s life cycle. However, women need assistance navigating perimenopausal hormonal fluctuations and decisions about HT once in menopause. Increased awareness and education about perimenopause and menopause will allow compassionate, individualized, informed care, including lifestyle changes, behavioral or complementary strategies, or medical therapies, hormonal or nonhormonal.²⁷ As a medical society, we need to challenge the stigma associated with aging and menopause and educate ourselves and our patients to help women navigate this challenging time. ●

The transition to menopause begins with ovarian fluctuation and hormonal changes, often beginning before significant changes in menstruation. Reproductive aging with loss of follicular activity progresses over a wide age range (42 to 58 years) with an average onset at approximately age 47, ranging from 4 to 8 years. Although most women have heard about menopause, defined as 12 months after the last period, they often lack understanding about perimenopause or that the menopausal transition usually begins 5 years before menopause.¹

Perimenopause, defined as early and late menopause transition stages, may be viewed as a window of potential vulnerability for women who develop or have worsening menstrual-related mood disorders. Over time, hormonal fluctuations often lead to menstrual cycle irregularity (either shorter or longer). Changes occurring during perimenopause may be confusing as it may not be clear whether symptoms are related to menopause, aging, or stress. Often not recognized or treated adequately, perimenopausal symptoms may be challenging to navigate for both women and clinicians.

The perimenopausal process is often even more confusing for women with early menopause—whether due to bilateral oophorectomy, chemotherapy or radiation therapy, genetics, or an autoimmune process—because of lack of recognition that an early menopausal transition is occurring or what solutions are available for symptoms. While there is support in the workplace for women during pregnancy and breastfeeding, there remains little support or recognition for the oft challenging perimenopausal transition leading to menopause.

Perimenopause: Common symptoms and treatments

Symptoms may be related to either estrogen level deficiency or excess during perimenopause, and these level changes may even occur within the same cycle.

Cyclic breast tenderness may develop, worsened by caffeine or high salt intake (which can be potentially improved, although without clinical trial evidence, with decreased caffeine or a trial of evening primrose oil or vitamin E).

Changes in menstrual flow and frequency of menses are typical. Flow may be lighter or heavier, longer or shorter, and there may be cycle variability, missed menses, or midcycle spotting.² Bleeding may be heavy, with or without cramping. In addition to imaging with vaginal ultrasonography or hysteroscopy to identify structural issues, symptoms may be managed with nonsteroidal anti-inflammatory drugs (NSAIDs), hormonal therapy (HT) with short hormone-free interval contraceptives, oral progestogens, or progestin intrauterine systems. Newer medical treatments include antifibrinolytic drugs and selective progesterone-receptor modulators. Uterine ablation to decrease or stop bleeding is effective if there are no structural abnormalities, such as fibroids or polyps or the presence of adenomyosis, where glands will regrow into the endometrium after ablation. Endometrial biopsy is indicated for persistent abnormal uterine bleeding or those with risk factors such as chronic anovulation.

Worsening headaches or menstrual migraines may be triggered by hormonal changes, which may respond to NSAIDs; dihydroergotamine; triptans; the combination of aspirin, acetaminophen, and caffeine; or estrogen the week before menses. For women taking oral contraceptives (OCPs), adding estradiol the week before menses, or using the OCP continuously, may decrease headache frequency. These short-term prophylactic strategies during the perimenstrual time are often effective. If not, preventive therapy is available for women with frequent, severe headaches.

Mood complaints and poor sleep are independently associated with menstrual irregularity, and can lead to fatigue or anxiety, worsening premenstrual syndrome, or depressive moods. Sleep is disrupted premenstrually for up to one-third of women, and sleep disruption is particularly prevalent in those with premenstrual mood disorders and worsens during perimenopause.³

Reproductive hormones act on the neurotransmitter systems in the brain involved in mood regulation and emotion. The fluctuating hormones occurring during perimenopause may exacerbate pre-existing menstrual-related mood disorders. A subset of women experience depressive moods due to perimenopausal elevations in ovarian hormones.⁴ Others may exhibit increased mood sensitivity with the ovarian hormone withdrawal accompanying late menopause transition and early postmenopausal phase.⁵ There is significant comorbidity between premenstrual mood disorder (PMDD) and postpartum depression.⁶ During perimenopause and early menopause, clinicians should ask about prior hormonally-related depression (puberty, postpartum) and recognize that current or past premenstrual syndrome may worsen into a more severe premenstrual dysphoric disorder. Evidence-based treatments for PMDD include selective serotonin reuptake inhibitors (SSRIs); either taken continuously or only during the luteal phase; drospirenone-containing oral contraceptives, often with shorter pill-free intervals; GnRH analogues with or without hormone add-back; and cognitive behavioral therapy.⁷ For women whose perimenopausal moods improve with HT or develop worsened mood sensitivity with ovarian hormone withdrawal, clinicians should recognize that mood may worsen when treatment is ceased.⁵

Continue to: Menopausal symptoms...

 

 

Menopausal symptoms

Vasomotor symptoms (VMS), hot flashes, or night sweats occur in up to 75% of women as they develop more menstrual irregularity and move closer to their final period and menopause.

Hot flashes are transient episodes of flushing with the sensation of warmth (up to intense heat) on the upper body and face or head, often associated with sweating, chills or flushing, an increase in heart rate, and lowered blood pressure. Hot flashes can sometimes be preceded by an intense feeling of dread, followed by rapid heat dissipation. The etiology of hot flashes is still not clear, but the neurokinin receptors are involved. They are related to small fluctuations in core body temperature superimposed on a narrow thermoneutral zone in symptomatic women. Hot flashes are triggered when core body temperature rises above the upper (sweating) threshold. Shivering occurs if the core body temperature falls below the lower threshold. Sleep may be disrupted, with less rapid eye movement (REM) sleep, and associated with throwing covers on and off or changing sheets or nightclothes. On average, hot flashes last 7.2 years,⁸ and they are more bothersome if night sweats interfere with sleep or disrupt performance during the day.

In the Stages of Reproductive Aging Workshop (STRAW + 10), women reported VMS within 1-3 years after the menopausal transition.⁸ Four trajectories of hot flashes were identified in the Study of Women’s Health Across the Nation (SWAN) trial,⁹ including low levels throughout the menopause transition, early onset, late onset, and a group which had frequent hot flashes, starting early and lasting longer. Serum estrogen levels were not predictive of hot flash frequency or severity.

Hot flashes have been associated with low levels of exercise, cigarette smoking, high follicle-stimulating hormone levels and low estradiol levels, increasing body mass index, ethnicity (with hot flashes more common among Black and Hispanic women), low socioeconomic status, prior PMDD, anxiety, perceived stress, and depression.⁸ Women with a history of premenstrual syndrome, stress, sexual dysfunction, physical inactivity, or hot flashes are more vulnerable to depressive symptoms during perimenopause and early menopause.⁵

Depression may co-occur or overlap with menopause symptoms. Diagnosis involves menopausal stage, co-occurring psychiatric and menopause symptoms, psychosocial stressors, and a validated screening tool such as PQ9. Treatments for perimenopausal depression, such as antidepressants, psychotherapy, or cognitive behavioral therapy, are recommended first line for perimenopausal depression. Estrogen therapy has not been approved to treat perimenopausal depression but appears to have antidepressant effects in perimenopausal women, particularly those with bothersome vasomotor symptoms.⁵

Anxiety can worsen during menopause, and may respond to calming apps, meditation, cognitive behavioral therapy, hypnosis, yoga or tai chi, HT, or antianxiety medications.

Weight gain around the abdomen (ie, belly fat) is a common complaint during the menopausal transition, despite women reporting not changing their eating or exercise patterns. Increasing exercise or bursts of higher intensity, decreasing portion sizes or limiting carbohydrates and alcohol may help.

Memory and concentration problems, described as brain fog, tend to be more of an issue in perimenopause and level out after menopause. Counsel midlife women that these changes are not due to dementia but are related to normal aging, hormonal changes, mood, stress, or other life circumstances. Identifying and addressing sleep issues and mood disorders may help mitigate brain fog, as can advising women to avoid excess caffeine, alcohol, nicotine, and eating before bed. Improvements in memory, cognition, and health have been found with the Mediterranean diet, regular exercise, avoiding multitasking, and engaging in mentally stimulating activities.

Sleeping concerns in peri- and postmenopausal women include sleeping less and more frequent insomnia. Women are more likely to use prescription sleeping aids during these times of their lives. The data from SWAN⁸ show that the menopausal transition is related to self-reported difficulty sleeping, independent of age. Sleep latency interval is increased while REM sleep decreases. Night sweats can trigger awakenings in the first half of the night. The perceived decline in sleep quality also may be attributed to general aging effects, nocturnal urination, sleep-related disorders such as sleep apnea or restless legs, or chronic pain, stress, or depression.¹⁰ Suggestions for management include sleep apps, cognitive behavioral therapy, low-dose antidepressant therapy, addressing sleep routines, and HT. Hypnotics should be avoided.

Sexuality issues are common complaints during the menopausal transition. Cross-sectional data reported from a longitudinal, population-based Australian cohort of women aged 45 to 55 years, found a decrease in sexual responsivity, sexual frequency, libido, vaginal dyspareunia, and more partner problems.¹¹ Low libido may be related to relationship issues, dyspareunia with vaginal narrowing, loss of lubrication, levator spasm, stress, anxiety, exhaustion or mood disorder, lowered hormone levels, excess alcohol intake, underlying health concerns, or a side effect of medications for depression or pain. There is no direct correlation between testosterone levels and libido.

When HT at menopause may be helpful

For healthy symptomatic women without contraindications who are younger than age 60, or within 10 years of menopause onset, the benefits of initiating HT most likely outweigh the risks to relieve bothersome hot flashes and night sweats.^12-17 For older women, or for those further from menopause, the greater absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia, in general, outweigh the potential benefits.^12-17 Extended durations of HT have less safety and efficacy data and should be considered primarily for those with persistent menopausal symptoms, with periodic re-evaluation.^13,14 For bothersome genitourinary syndrome of menopause symptoms that do not respond to vaginal moisturizers or lubricants, low-dose vaginal HTs are encouraged.^13-17

Continue to: Early-onset menopause...

Early-onset menopause

According to observational studies,¹⁸ early menopause is associated with a higher risk of osteoporosis, coronary heart disease, cognitive changes, vaginal dryness, loss of libido, and mood changes. Studies have shown that women with early menopause who take HT, without contraindications, to the average age of menopause (age 52) decrease the health risks of early menopause (bone loss, heart disease, mood, and cognition changes).^13,14,18

Women with early menopause, whether spontaneous or following bilateral oophorectomy or cancer treatment, should be counseled to get adequate calcium (dietary recommended over supplementation) and vitamin D intake, eat a healthy diet, and exercise regularly. Evaluation should include risk for bone loss, heart disease, mood changes, and vaginal changes.

Extended use of HT

Up to 8% of women have hot flashes for 20 years or more after menopause.¹⁹ The decision to continue or to stop HT is not always clear for women:

• with persistent hot flashes after a trial period of HT discontinuation
• with bone loss that cannot be treated with bone-specific medications
• who request continuation for quality of life.

Extended use of HT should include an ongoing assessment of its risks and benefits, periodic trials off of HT, and documentation of rationale and informed discussions about continuing. Lower doses and transdermal therapies appear safer, as does micronized progesterone instead of more potent synthetic progestins.^13-17

Genitourinary syndrome of menopause

Once women are further into menopause, they may notice vaginal dryness, vulvar itching or burning, bothersome vaginal discharge, or urinary urgency or frequency. The development of painful intercourse frequently occurs, a combination of the loss of estrogen with thinning of the vaginal mucosa, a loss of the acidic vaginal milieu with less elasticity, and spasm of the levator muscles. Some women develop urinary tract infections after intercourse or have more frequent reoccurrences. First-line therapy is often vaginal moisturizers and lubricants. Vaginal therapies (estradiol, conjugated estrogen, or dehydroepiandrosterone) or oral selective estrogen-receptor modulators (SERMs; ospemifene) improve vaginal dryness and dyspareunia.^13,14 Pelvic therapy has also proved valuable for incontinence, pelvic floor dysfunction, and levator spasms.²⁰

Where are there gaps in clinician knowledge?

Studies on emotional health, mood, and sleep need to incorporate measures of menstrual timing into data collection and analyses. Does the sleep disruption occurring premenstrually during perimenopause disproportionately contribute to a woman’s vulnerability to depressive disorders? The risk of clinically significant depressive symptoms increases 1.5- to 2.9-fold in the menopause transition.⁵ Research into premenstrual dysphoria during the menopause transition may identify different trajectories in the timing of symptoms related to either cycle itself or the ovarian hormone fluctuations or both.²¹ Gamma-aminobutyric acid (GABA)-modulating drugs, such as sepranolone, which blocks allopregnanolone’s actions at the GABAA receptor, may allow treatment of menstrual-related mood disorders without the need for hormonal interventions.²¹

Despite extended observational trial data, more data are needed to inform us about the long-term risks and benefits of using menopausal HT, particularly when initiated at menopause and to help address the timing of HT discontinuation. Furthermore, there are many unanswered questions. For instance:

• How much safer are lower dose and transdermal therapies?
• Do untreated hot flashes increase the risk of cardiovascular disease or dementia?
• Will newer non-HT options, such as the neurokinin receptor antagonists that are in testing but are not yet available, lower cardiovascular or dementia risks?
• What will be the risks and benefits for the newer estrogen in testing (estetrol, or E4), considered a natural estrogen and which appears to have lower thrombotic risks?
• What will be the role of intravaginal energy-based therapies, such as vaginal laser or radiofrequency devices?
• How do we address diverse populations and the effects of menopause on race, gender, culture, prior trauma, and socioeconomic status?

Lack of recognition of menopausal symptoms, particularly in the workplace

Clinicians need to understand the varied physical and emotional symptoms that may occur with hormonal changes as women traverse perimenopause and early menopause. We need to recognize that the lack of discussion about women’s health during this time may make women feel ashamed and fearful of bringing up their symptoms due to fear of being dismissed or stigmatized.²² Women may not seek help until a crisis at home or work occurs, as they may fear that admitting symptoms or a need for help or time away from work will threaten how they are viewed at work or affect their chances of promotion. Although there are economic costs around menopause for appointments, tests, therapies, and missed time at work, not addressing menopausal health leads to poorer performance, workplace absences, and additional medical costs.²²

Conclusion

Menopause occurs naturally as a part of a woman’s life cycle. However, women need assistance navigating perimenopausal hormonal fluctuations and decisions about HT once in menopause. Increased awareness and education about perimenopause and menopause will allow compassionate, individualized, informed care, including lifestyle changes, behavioral or complementary strategies, or medical therapies, hormonal or nonhormonal.²⁷ As a medical society, we need to challenge the stigma associated with aging and menopause and educate ourselves and our patients to help women navigate this challenging time. ●

CASE Placenta accreta spectrum following uncomplicated vaginal delivery

Imagine you are an obstetric hospitalist taking call at a level II maternal level of care hospital. Your patient is a 35-year-old woman, gravida 2, para 1, with a past history of retained placenta requiring dilation and curettage and intravenous antibiotics for endomyometritis. This is an in vitro fertilization pregnancy that has progressed normally, and the patient labored spontaneously at 38 weeks’ gestation. Following an uncomplicated vaginal delivery, the placenta has not delivered, and you attempt a manual placental extraction after a 40-minute third stage. While there is epidural analgesia and you can reach the uterine fundus, you are unable to create a separation plane between the placenta and uterus.

What do you do next?

Placenta accreta spectrum (PAS) includes a broad range of clinical scenarios with abnormal placental attachment as their common denominator. The condition has classically been defined pathologically, with chorionic villi attaching directly to the myometrium (“accreta”) or extending more deeply into the myometrium (“increta”) or attaching to surrounding tissues and structures (“percreta”).¹ It is most commonly encountered in patients with low placental implantation on a prior cesarean section scar; indeed, placenta previa, particularly with a history of cesarean delivery, is the strongest risk factor for the development of PAS.² In addition to abnormal placental attachment, these placental attachments are often hypervascular and can lead to catastrophic hemorrhage if not managed appropriately. For this reason, patients with sonographic or radiologic signs of PAS should be referred to specialized centers for further workup, counseling, and delivery planning.³

Although delivery at a specialized PAS center has been associated with improved patient outcomes,⁴ not all patients with PAS will be identified in the antepartum period. Ultrasonography may miss up to 40% to 50% of PAS cases, particularly when the sonologist has not been advised to look for the condition,⁵ and not all patients with PAS will have a previa implanted in a prior cesarean scar. A recent study found that these patients with nonprevia PAS were identified by imaging less than 40% of the time and were significantly less likely to be managed by a specialized team of clinicians.⁶ Thus, it falls upon every obstetric care provider to be aware of this diagnosis, promptly recognize its unanticipated presentations, and have a plan to optimize patient safety.

Step 1: Recognition

While PAS is classically defined as a pathologic condition, no clinician has the luxury of histology in the delivery room. Researchers have variously defined PAS clinically, with the common trait of abnormal placental adherence.^7-9 The TABLE compares published definitions that have been used in the literature. While some definitions include hemorrhage, no clinician wants to induce significant hemorrhage to confirm their patient’s diagnosis. Thus, practically, the clinical PAS diagnosis comes down to abnormal placental attachment: If it is apparent that some or all of the placenta will not separate from the uterine wall with digital manipulation or careful curettage, then PAS should be suspected, and appropriate steps should be taken before further removal attempts.

At cesarean delivery, the PAS diagnosis may be aided by visual cues. With placenta previa, the lower uterine segment may bulge and take on a bluish hue, distinctly different from the upper healthy myometrium. PAS may also manifest with neovascularization, particularly behind the bladder. As with vaginal births, the placenta will fail to separate after the delivery, and controlled traction on the umbilical cord can produce a “dimple sign,” or visible myometrial retraction at the site of implantation (FIGURE 1). Finally, if the diagnosis is still in doubt, attempts to gently form a cleavage plane between the placenta and myometrium will be unsuccessful if PAS is present.⁸

Step 2: Initial management—pause, plan

Most importantly, do not attempt to forcibly remove the placenta. It can be left attached to the uterus until appropriate resources are secured. Efforts to forcibly remove an adherent placenta may well lead to major hemorrhage, and thus it falls on the patient’s care team to pause and plan for PAS care at this point. FIGURE 2 displays an algorithm for patient management. Further steps depend primarily on whether or not the patient is already hemorrhaging. In a stable situation, the patient should be counseled regarding the abnormal findings and the suspected PAS diagnosis. This includes the possibility of further procedures, blood transfusion, and hysterectomy. Local resources, including nursing, anesthesia, and the blood bank, should be notified about the situation and for the potential to call in specialized services. If on-site experienced specialists are not available, then patient transfer to a PAS specialty center should be strongly considered. While awaiting additional help or transport, the patient requires close monitoring for gross and physiologic signs of hemorrhage. If pursued, transport to a PAS specialty center should be expedited.

If the patient is already hemorrhaging or unstable, then appropriate local resources must be activated. At a minimum, this requires an obstetrician and anesthesiologist at the bedside and activation of hemorrhage protocols (eg, a massive transfusion protocol). If blood products are unavailable, consider whether they can be transported from other nearby blood banks, and start that process promptly. Next, contact backup services. Based on local resources and clinical severity, this may include maternal-fetal medicine specialists, pelvic surgeons, general and trauma surgeons, intensivists, interventional radiologists, and transfusion specialists. Even if the patient cannot be safely transferred to another hospital, the obstetrician can call an outside PAS specialist to discuss next steps in care and begin transfer plans, assuming the patient can be stabilized. Based on the Maternal Levels of Care definitions published by the American College of Obstetricians and Gynecologists and the Society of Maternal-Fetal Medicine,¹⁰ patients with PAS should be managed at level III or level IV centers. However, delivery units at every level of maternal care should have a protocol for securing local help and reaching an appropriate consultant if a PAS case is encountered. Know which center in your area specializes in PAS so that when an unanticipated case arises, you know who to call.

Continue to: Step 3: Ultimate management—mobilize and prepare for bleeding...

Step 3: Ultimate management—mobilize and prepare for bleeding

If diagnosis occurs intraoperatively at a PAS specialty center, or if safe transport is not possible, then the team should mobilize for the possibility of hysterectomy and prepare for massive bleeding, which can occur regardless of the treatment chosen. Many patients require or will opt for hysterectomy. For example, a patient who has finished childbearing may consent to a hysterectomy upon hearing she likely has PAS. In patients with suspected PAS who are actively hemorrhaging or are unstable, hysterectomy is required.

Uterine conservation may be considered in stable patients who strongly desire future childbearing or uterine retention. This often requires leaving densely adherent placental tissue in situ and thus requires thorough counseling regarding the risks of delayed hemorrhage, infection, and emergent hysterectomy.¹¹ This may not be desirable or safe for some patients, so informed consent is crucial. In such cases, we strongly recommend consultation with a PAS specialist, even if that requires immediate control of the placental blood supply (such as with arterial embolization), and transfer to a PAS specialty center.

Clinical scenarios

Vaginal delivery

The patient in the opening case was never expected to have PAS given her normal placental location and absence of a uterine scar. Even though she had some possible PAS risk factors (past retained placenta with instrumentation and in vitro fertilization), her absolute risk for the condition was low. Nevertheless, inability to create a separation plane should be considered PAS until proven otherwise. Although at this point many obstetricians would move to an operating room for uterine curettage, we recommend that the care team pause and put measures in place for possible PAS and hemorrhage. This involves notification of the blood bank, crossmatching of blood products, alerting the anesthesia team, and having a clear plan in place should a major hemorrhage ensue. This may involve use of balloon tamponade, activation of an interventional radiology team, or possible laparotomy with arterial ligations or hysterectomy. Avoidance of a prolonged third stage should be balanced against the need for preparation with these cases.

It is important for clinicians to bear in mind, and communicate to the patient, that hysterectomy is the standard of care for PAS. Significant delays in performing an indicated hysterectomy can lead to coagulopathy and patient instability. Timeliness is key; we find that delays in the decision to perform an indicated hysterectomy are often at the root of the cause for worsened morbidity in patients with unanticipated PAS. With an unscarred uterus and no placenta previa, a postpartum hysterectomy can be performed by many obstetrician-gynecologists experienced in this abdominal procedure.

Cesarean delivery

Undiagnosed PAS may present at cesarean delivery with or without placenta previa and a prior uterine scar. With this combination, PAS is often visually apparent upon opening the abdominal cavity (TABLE and FIGURE 1). Such surgical findings call for a clinical pause, as further actions at this point can lead to catastrophic hemorrhage. The obstetrician should consider a series of questions:

1. Are appropriate surgical and transfusion resources immediately available? If yes, they should be notified in case they are needed urgently. If not, then the obstetrician should ask whether the delivery must occur now.

2. Is this a scheduled delivery with a stable patient and fetus? If so, then closing the abdominal incision, monitoring the patient and fetus, and either transferring the patient to a PAS center or awaiting appropriate local specialists may be a lifesaving step.

3. Is immediate delivery required? If the fetus must be delivered, then it is imperative to create a hysterotomy out of the way of the placenta. Disrupting the adherent placenta with either an incision or manual manipulation may trigger a massive hemorrhage and should be avoided. This may require rectus muscle transection or creating a “T” incision on the skin to reach the uterine fundus and creating a hysterotomy over the top or even the back of the uterus. Once the fetus is delivered and lack of uterine hemorrhage confirmed (both abdominally and vaginally), the hysterotomy and abdomen can be closed with anticipation of urgent patient transfer to a PAS team or center.

4. Is the patient hemorrhaging? If the patient is hemorrhaging and closure is not an option, then recruitment of local emergent surgical teams is warranted, even if that requires packing the abdomen until an appropriate surgeon can arrive.

Diagnosis at cesarean delivery requires expedited and complex patient counseling. A patient who is unstable or hemorrhaging needs to be told that hysterectomy is lifesaving in this situation. For patients who are stable, it may be appropriate to close the abdomen and leave the placenta in situ, perform comprehensive counseling, and assess the possibility of transfer to a specialty center.

Summary

All obstetric care providers should be familiar with the clinical presentation of undiagnosed accreta spectrum. While hemorrhage is often part of the diagnosis, recognition of abnormal placental adherence and PAS-focused management should ideally be undertaken before this occurs. Once PAS is suspected, avoidance of further placental disruption may save significant morbidity, even if that means leaving the placenta attached until appropriate resources can be obtained. A local protocol for consultation, emergency transfer, and deployment of local resources should be part of every delivery unit’s emergency preparedness plan.

CASE Outcome

This patient is stabilized, with an adherent, retained placenta and no signs of hemorrhage. You administer uterotonics and notify your anesthesiologist and backup obstetrician that you have a likely case of accreta spectrum. A second intravenous line is placed, and blood products are crossmatched. The closest level III hospital is called, and they accept your patient for transfer. There, she is counseled about PAS, and she expresses no desire for future childbearing. After again confirming no placental separation in the operating room, the patient is moved immediately to perform laparotomy and total abdominal hysterectomy through a Pfannenstiel incision. She does not require a blood transfusion, and the pathology returns with grade I placenta accreta spectrum. ●

CASE Placenta accreta spectrum following uncomplicated vaginal delivery

Imagine you are an obstetric hospitalist taking call at a level II maternal level of care hospital. Your patient is a 35-year-old woman, gravida 2, para 1, with a past history of retained placenta requiring dilation and curettage and intravenous antibiotics for endomyometritis. This is an in vitro fertilization pregnancy that has progressed normally, and the patient labored spontaneously at 38 weeks’ gestation. Following an uncomplicated vaginal delivery, the placenta has not delivered, and you attempt a manual placental extraction after a 40-minute third stage. While there is epidural analgesia and you can reach the uterine fundus, you are unable to create a separation plane between the placenta and uterus.

What do you do next?

Placenta accreta spectrum (PAS) includes a broad range of clinical scenarios with abnormal placental attachment as their common denominator. The condition has classically been defined pathologically, with chorionic villi attaching directly to the myometrium (“accreta”) or extending more deeply into the myometrium (“increta”) or attaching to surrounding tissues and structures (“percreta”).¹ It is most commonly encountered in patients with low placental implantation on a prior cesarean section scar; indeed, placenta previa, particularly with a history of cesarean delivery, is the strongest risk factor for the development of PAS.² In addition to abnormal placental attachment, these placental attachments are often hypervascular and can lead to catastrophic hemorrhage if not managed appropriately. For this reason, patients with sonographic or radiologic signs of PAS should be referred to specialized centers for further workup, counseling, and delivery planning.³

Although delivery at a specialized PAS center has been associated with improved patient outcomes,⁴ not all patients with PAS will be identified in the antepartum period. Ultrasonography may miss up to 40% to 50% of PAS cases, particularly when the sonologist has not been advised to look for the condition,⁵ and not all patients with PAS will have a previa implanted in a prior cesarean scar. A recent study found that these patients with nonprevia PAS were identified by imaging less than 40% of the time and were significantly less likely to be managed by a specialized team of clinicians.⁶ Thus, it falls upon every obstetric care provider to be aware of this diagnosis, promptly recognize its unanticipated presentations, and have a plan to optimize patient safety.

Step 1: Recognition

While PAS is classically defined as a pathologic condition, no clinician has the luxury of histology in the delivery room. Researchers have variously defined PAS clinically, with the common trait of abnormal placental adherence.^7-9 The TABLE compares published definitions that have been used in the literature. While some definitions include hemorrhage, no clinician wants to induce significant hemorrhage to confirm their patient’s diagnosis. Thus, practically, the clinical PAS diagnosis comes down to abnormal placental attachment: If it is apparent that some or all of the placenta will not separate from the uterine wall with digital manipulation or careful curettage, then PAS should be suspected, and appropriate steps should be taken before further removal attempts.

At cesarean delivery, the PAS diagnosis may be aided by visual cues. With placenta previa, the lower uterine segment may bulge and take on a bluish hue, distinctly different from the upper healthy myometrium. PAS may also manifest with neovascularization, particularly behind the bladder. As with vaginal births, the placenta will fail to separate after the delivery, and controlled traction on the umbilical cord can produce a “dimple sign,” or visible myometrial retraction at the site of implantation (FIGURE 1). Finally, if the diagnosis is still in doubt, attempts to gently form a cleavage plane between the placenta and myometrium will be unsuccessful if PAS is present.⁸

Step 2: Initial management—pause, plan

Most importantly, do not attempt to forcibly remove the placenta. It can be left attached to the uterus until appropriate resources are secured. Efforts to forcibly remove an adherent placenta may well lead to major hemorrhage, and thus it falls on the patient’s care team to pause and plan for PAS care at this point. FIGURE 2 displays an algorithm for patient management. Further steps depend primarily on whether or not the patient is already hemorrhaging. In a stable situation, the patient should be counseled regarding the abnormal findings and the suspected PAS diagnosis. This includes the possibility of further procedures, blood transfusion, and hysterectomy. Local resources, including nursing, anesthesia, and the blood bank, should be notified about the situation and for the potential to call in specialized services. If on-site experienced specialists are not available, then patient transfer to a PAS specialty center should be strongly considered. While awaiting additional help or transport, the patient requires close monitoring for gross and physiologic signs of hemorrhage. If pursued, transport to a PAS specialty center should be expedited.

If the patient is already hemorrhaging or unstable, then appropriate local resources must be activated. At a minimum, this requires an obstetrician and anesthesiologist at the bedside and activation of hemorrhage protocols (eg, a massive transfusion protocol). If blood products are unavailable, consider whether they can be transported from other nearby blood banks, and start that process promptly. Next, contact backup services. Based on local resources and clinical severity, this may include maternal-fetal medicine specialists, pelvic surgeons, general and trauma surgeons, intensivists, interventional radiologists, and transfusion specialists. Even if the patient cannot be safely transferred to another hospital, the obstetrician can call an outside PAS specialist to discuss next steps in care and begin transfer plans, assuming the patient can be stabilized. Based on the Maternal Levels of Care definitions published by the American College of Obstetricians and Gynecologists and the Society of Maternal-Fetal Medicine,¹⁰ patients with PAS should be managed at level III or level IV centers. However, delivery units at every level of maternal care should have a protocol for securing local help and reaching an appropriate consultant if a PAS case is encountered. Know which center in your area specializes in PAS so that when an unanticipated case arises, you know who to call.

Continue to: Step 3: Ultimate management—mobilize and prepare for bleeding...

Step 3: Ultimate management—mobilize and prepare for bleeding

If diagnosis occurs intraoperatively at a PAS specialty center, or if safe transport is not possible, then the team should mobilize for the possibility of hysterectomy and prepare for massive bleeding, which can occur regardless of the treatment chosen. Many patients require or will opt for hysterectomy. For example, a patient who has finished childbearing may consent to a hysterectomy upon hearing she likely has PAS. In patients with suspected PAS who are actively hemorrhaging or are unstable, hysterectomy is required.

Uterine conservation may be considered in stable patients who strongly desire future childbearing or uterine retention. This often requires leaving densely adherent placental tissue in situ and thus requires thorough counseling regarding the risks of delayed hemorrhage, infection, and emergent hysterectomy.¹¹ This may not be desirable or safe for some patients, so informed consent is crucial. In such cases, we strongly recommend consultation with a PAS specialist, even if that requires immediate control of the placental blood supply (such as with arterial embolization), and transfer to a PAS specialty center.

Clinical scenarios

Vaginal delivery

The patient in the opening case was never expected to have PAS given her normal placental location and absence of a uterine scar. Even though she had some possible PAS risk factors (past retained placenta with instrumentation and in vitro fertilization), her absolute risk for the condition was low. Nevertheless, inability to create a separation plane should be considered PAS until proven otherwise. Although at this point many obstetricians would move to an operating room for uterine curettage, we recommend that the care team pause and put measures in place for possible PAS and hemorrhage. This involves notification of the blood bank, crossmatching of blood products, alerting the anesthesia team, and having a clear plan in place should a major hemorrhage ensue. This may involve use of balloon tamponade, activation of an interventional radiology team, or possible laparotomy with arterial ligations or hysterectomy. Avoidance of a prolonged third stage should be balanced against the need for preparation with these cases.

It is important for clinicians to bear in mind, and communicate to the patient, that hysterectomy is the standard of care for PAS. Significant delays in performing an indicated hysterectomy can lead to coagulopathy and patient instability. Timeliness is key; we find that delays in the decision to perform an indicated hysterectomy are often at the root of the cause for worsened morbidity in patients with unanticipated PAS. With an unscarred uterus and no placenta previa, a postpartum hysterectomy can be performed by many obstetrician-gynecologists experienced in this abdominal procedure.

Cesarean delivery

Undiagnosed PAS may present at cesarean delivery with or without placenta previa and a prior uterine scar. With this combination, PAS is often visually apparent upon opening the abdominal cavity (TABLE and FIGURE 1). Such surgical findings call for a clinical pause, as further actions at this point can lead to catastrophic hemorrhage. The obstetrician should consider a series of questions:

1. Are appropriate surgical and transfusion resources immediately available? If yes, they should be notified in case they are needed urgently. If not, then the obstetrician should ask whether the delivery must occur now.

2. Is this a scheduled delivery with a stable patient and fetus? If so, then closing the abdominal incision, monitoring the patient and fetus, and either transferring the patient to a PAS center or awaiting appropriate local specialists may be a lifesaving step.

3. Is immediate delivery required? If the fetus must be delivered, then it is imperative to create a hysterotomy out of the way of the placenta. Disrupting the adherent placenta with either an incision or manual manipulation may trigger a massive hemorrhage and should be avoided. This may require rectus muscle transection or creating a “T” incision on the skin to reach the uterine fundus and creating a hysterotomy over the top or even the back of the uterus. Once the fetus is delivered and lack of uterine hemorrhage confirmed (both abdominally and vaginally), the hysterotomy and abdomen can be closed with anticipation of urgent patient transfer to a PAS team or center.

4. Is the patient hemorrhaging? If the patient is hemorrhaging and closure is not an option, then recruitment of local emergent surgical teams is warranted, even if that requires packing the abdomen until an appropriate surgeon can arrive.

Diagnosis at cesarean delivery requires expedited and complex patient counseling. A patient who is unstable or hemorrhaging needs to be told that hysterectomy is lifesaving in this situation. For patients who are stable, it may be appropriate to close the abdomen and leave the placenta in situ, perform comprehensive counseling, and assess the possibility of transfer to a specialty center.

Summary

All obstetric care providers should be familiar with the clinical presentation of undiagnosed accreta spectrum. While hemorrhage is often part of the diagnosis, recognition of abnormal placental adherence and PAS-focused management should ideally be undertaken before this occurs. Once PAS is suspected, avoidance of further placental disruption may save significant morbidity, even if that means leaving the placenta attached until appropriate resources can be obtained. A local protocol for consultation, emergency transfer, and deployment of local resources should be part of every delivery unit’s emergency preparedness plan.

CASE Outcome

This patient is stabilized, with an adherent, retained placenta and no signs of hemorrhage. You administer uterotonics and notify your anesthesiologist and backup obstetrician that you have a likely case of accreta spectrum. A second intravenous line is placed, and blood products are crossmatched. The closest level III hospital is called, and they accept your patient for transfer. There, she is counseled about PAS, and she expresses no desire for future childbearing. After again confirming no placental separation in the operating room, the patient is moved immediately to perform laparotomy and total abdominal hysterectomy through a Pfannenstiel incision. She does not require a blood transfusion, and the pathology returns with grade I placenta accreta spectrum. ●

CASE Placenta accreta spectrum following uncomplicated vaginal delivery

Imagine you are an obstetric hospitalist taking call at a level II maternal level of care hospital. Your patient is a 35-year-old woman, gravida 2, para 1, with a past history of retained placenta requiring dilation and curettage and intravenous antibiotics for endomyometritis. This is an in vitro fertilization pregnancy that has progressed normally, and the patient labored spontaneously at 38 weeks’ gestation. Following an uncomplicated vaginal delivery, the placenta has not delivered, and you attempt a manual placental extraction after a 40-minute third stage. While there is epidural analgesia and you can reach the uterine fundus, you are unable to create a separation plane between the placenta and uterus.

What do you do next?

Placenta accreta spectrum (PAS) includes a broad range of clinical scenarios with abnormal placental attachment as their common denominator. The condition has classically been defined pathologically, with chorionic villi attaching directly to the myometrium (“accreta”) or extending more deeply into the myometrium (“increta”) or attaching to surrounding tissues and structures (“percreta”).¹ It is most commonly encountered in patients with low placental implantation on a prior cesarean section scar; indeed, placenta previa, particularly with a history of cesarean delivery, is the strongest risk factor for the development of PAS.² In addition to abnormal placental attachment, these placental attachments are often hypervascular and can lead to catastrophic hemorrhage if not managed appropriately. For this reason, patients with sonographic or radiologic signs of PAS should be referred to specialized centers for further workup, counseling, and delivery planning.³

Although delivery at a specialized PAS center has been associated with improved patient outcomes,⁴ not all patients with PAS will be identified in the antepartum period. Ultrasonography may miss up to 40% to 50% of PAS cases, particularly when the sonologist has not been advised to look for the condition,⁵ and not all patients with PAS will have a previa implanted in a prior cesarean scar. A recent study found that these patients with nonprevia PAS were identified by imaging less than 40% of the time and were significantly less likely to be managed by a specialized team of clinicians.⁶ Thus, it falls upon every obstetric care provider to be aware of this diagnosis, promptly recognize its unanticipated presentations, and have a plan to optimize patient safety.

Step 1: Recognition

While PAS is classically defined as a pathologic condition, no clinician has the luxury of histology in the delivery room. Researchers have variously defined PAS clinically, with the common trait of abnormal placental adherence.^7-9 The TABLE compares published definitions that have been used in the literature. While some definitions include hemorrhage, no clinician wants to induce significant hemorrhage to confirm their patient’s diagnosis. Thus, practically, the clinical PAS diagnosis comes down to abnormal placental attachment: If it is apparent that some or all of the placenta will not separate from the uterine wall with digital manipulation or careful curettage, then PAS should be suspected, and appropriate steps should be taken before further removal attempts.

At cesarean delivery, the PAS diagnosis may be aided by visual cues. With placenta previa, the lower uterine segment may bulge and take on a bluish hue, distinctly different from the upper healthy myometrium. PAS may also manifest with neovascularization, particularly behind the bladder. As with vaginal births, the placenta will fail to separate after the delivery, and controlled traction on the umbilical cord can produce a “dimple sign,” or visible myometrial retraction at the site of implantation (FIGURE 1). Finally, if the diagnosis is still in doubt, attempts to gently form a cleavage plane between the placenta and myometrium will be unsuccessful if PAS is present.⁸

Step 2: Initial management—pause, plan

Most importantly, do not attempt to forcibly remove the placenta. It can be left attached to the uterus until appropriate resources are secured. Efforts to forcibly remove an adherent placenta may well lead to major hemorrhage, and thus it falls on the patient’s care team to pause and plan for PAS care at this point. FIGURE 2 displays an algorithm for patient management. Further steps depend primarily on whether or not the patient is already hemorrhaging. In a stable situation, the patient should be counseled regarding the abnormal findings and the suspected PAS diagnosis. This includes the possibility of further procedures, blood transfusion, and hysterectomy. Local resources, including nursing, anesthesia, and the blood bank, should be notified about the situation and for the potential to call in specialized services. If on-site experienced specialists are not available, then patient transfer to a PAS specialty center should be strongly considered. While awaiting additional help or transport, the patient requires close monitoring for gross and physiologic signs of hemorrhage. If pursued, transport to a PAS specialty center should be expedited.

If the patient is already hemorrhaging or unstable, then appropriate local resources must be activated. At a minimum, this requires an obstetrician and anesthesiologist at the bedside and activation of hemorrhage protocols (eg, a massive transfusion protocol). If blood products are unavailable, consider whether they can be transported from other nearby blood banks, and start that process promptly. Next, contact backup services. Based on local resources and clinical severity, this may include maternal-fetal medicine specialists, pelvic surgeons, general and trauma surgeons, intensivists, interventional radiologists, and transfusion specialists. Even if the patient cannot be safely transferred to another hospital, the obstetrician can call an outside PAS specialist to discuss next steps in care and begin transfer plans, assuming the patient can be stabilized. Based on the Maternal Levels of Care definitions published by the American College of Obstetricians and Gynecologists and the Society of Maternal-Fetal Medicine,¹⁰ patients with PAS should be managed at level III or level IV centers. However, delivery units at every level of maternal care should have a protocol for securing local help and reaching an appropriate consultant if a PAS case is encountered. Know which center in your area specializes in PAS so that when an unanticipated case arises, you know who to call.

Continue to: Step 3: Ultimate management—mobilize and prepare for bleeding...

Step 3: Ultimate management—mobilize and prepare for bleeding

If diagnosis occurs intraoperatively at a PAS specialty center, or if safe transport is not possible, then the team should mobilize for the possibility of hysterectomy and prepare for massive bleeding, which can occur regardless of the treatment chosen. Many patients require or will opt for hysterectomy. For example, a patient who has finished childbearing may consent to a hysterectomy upon hearing she likely has PAS. In patients with suspected PAS who are actively hemorrhaging or are unstable, hysterectomy is required.

Uterine conservation may be considered in stable patients who strongly desire future childbearing or uterine retention. This often requires leaving densely adherent placental tissue in situ and thus requires thorough counseling regarding the risks of delayed hemorrhage, infection, and emergent hysterectomy.¹¹ This may not be desirable or safe for some patients, so informed consent is crucial. In such cases, we strongly recommend consultation with a PAS specialist, even if that requires immediate control of the placental blood supply (such as with arterial embolization), and transfer to a PAS specialty center.

Clinical scenarios

Vaginal delivery

The patient in the opening case was never expected to have PAS given her normal placental location and absence of a uterine scar. Even though she had some possible PAS risk factors (past retained placenta with instrumentation and in vitro fertilization), her absolute risk for the condition was low. Nevertheless, inability to create a separation plane should be considered PAS until proven otherwise. Although at this point many obstetricians would move to an operating room for uterine curettage, we recommend that the care team pause and put measures in place for possible PAS and hemorrhage. This involves notification of the blood bank, crossmatching of blood products, alerting the anesthesia team, and having a clear plan in place should a major hemorrhage ensue. This may involve use of balloon tamponade, activation of an interventional radiology team, or possible laparotomy with arterial ligations or hysterectomy. Avoidance of a prolonged third stage should be balanced against the need for preparation with these cases.

It is important for clinicians to bear in mind, and communicate to the patient, that hysterectomy is the standard of care for PAS. Significant delays in performing an indicated hysterectomy can lead to coagulopathy and patient instability. Timeliness is key; we find that delays in the decision to perform an indicated hysterectomy are often at the root of the cause for worsened morbidity in patients with unanticipated PAS. With an unscarred uterus and no placenta previa, a postpartum hysterectomy can be performed by many obstetrician-gynecologists experienced in this abdominal procedure.

Cesarean delivery

Undiagnosed PAS may present at cesarean delivery with or without placenta previa and a prior uterine scar. With this combination, PAS is often visually apparent upon opening the abdominal cavity (TABLE and FIGURE 1). Such surgical findings call for a clinical pause, as further actions at this point can lead to catastrophic hemorrhage. The obstetrician should consider a series of questions:

1. Are appropriate surgical and transfusion resources immediately available? If yes, they should be notified in case they are needed urgently. If not, then the obstetrician should ask whether the delivery must occur now.

2. Is this a scheduled delivery with a stable patient and fetus? If so, then closing the abdominal incision, monitoring the patient and fetus, and either transferring the patient to a PAS center or awaiting appropriate local specialists may be a lifesaving step.

3. Is immediate delivery required? If the fetus must be delivered, then it is imperative to create a hysterotomy out of the way of the placenta. Disrupting the adherent placenta with either an incision or manual manipulation may trigger a massive hemorrhage and should be avoided. This may require rectus muscle transection or creating a “T” incision on the skin to reach the uterine fundus and creating a hysterotomy over the top or even the back of the uterus. Once the fetus is delivered and lack of uterine hemorrhage confirmed (both abdominally and vaginally), the hysterotomy and abdomen can be closed with anticipation of urgent patient transfer to a PAS team or center.

4. Is the patient hemorrhaging? If the patient is hemorrhaging and closure is not an option, then recruitment of local emergent surgical teams is warranted, even if that requires packing the abdomen until an appropriate surgeon can arrive.

Diagnosis at cesarean delivery requires expedited and complex patient counseling. A patient who is unstable or hemorrhaging needs to be told that hysterectomy is lifesaving in this situation. For patients who are stable, it may be appropriate to close the abdomen and leave the placenta in situ, perform comprehensive counseling, and assess the possibility of transfer to a specialty center.

Summary

All obstetric care providers should be familiar with the clinical presentation of undiagnosed accreta spectrum. While hemorrhage is often part of the diagnosis, recognition of abnormal placental adherence and PAS-focused management should ideally be undertaken before this occurs. Once PAS is suspected, avoidance of further placental disruption may save significant morbidity, even if that means leaving the placenta attached until appropriate resources can be obtained. A local protocol for consultation, emergency transfer, and deployment of local resources should be part of every delivery unit’s emergency preparedness plan.

CASE Outcome

This patient is stabilized, with an adherent, retained placenta and no signs of hemorrhage. You administer uterotonics and notify your anesthesiologist and backup obstetrician that you have a likely case of accreta spectrum. A second intravenous line is placed, and blood products are crossmatched. The closest level III hospital is called, and they accept your patient for transfer. There, she is counseled about PAS, and she expresses no desire for future childbearing. After again confirming no placental separation in the operating room, the patient is moved immediately to perform laparotomy and total abdominal hysterectomy through a Pfannenstiel incision. She does not require a blood transfusion, and the pathology returns with grade I placenta accreta spectrum. ●

Lupus erythematosus tumidus (LET) is a rare photosensitive dermatosis¹ that previously was considered a subtype of chronic cutaneous lupus erythematosus; however, the clinical course and favorable prognosis of LET led to its reclassification into another category, called intermittent cutaneous lupus erythematosus.² Although known about for more than 100 years, the association of LET with systemic lupus erythematosus (SLE), its autoantibody profile, and its prognosis are not well characterized. The purpose of this study was to describe the demographics, clinical characteristics, autoantibody profile, comorbidities, and treatment of LET based on a retrospective review of patients with LET.

Methods

A retrospective review was conducted in patients with histologically diagnosed LET who presented to the Department of Dermatology at the Wake Forest School of Medicine (Winston-Salem, North Carolina) over 6 years (July 2012 to July 2018). Inclusion criteria included males or females aged 18 to 75 years with clinical and histopathology-proven LET, which was defined as a superficial and deep lymphocytic infiltrate with abundant mucin deposition in the reticular dermis and absent or focal dermoepidermal junction alterations. Exclusion criteria included males or females younger than 18 years or older than 75 years or patients without clinical and histopathologically proven LET. Medical records were evaluated for demographics, clinical characteristics, diagnoses, autoantibodies, treatment, and recurrence. Photosensitivity was confirmed by clinical history. This study was approved by the Wake Forest School of Medicine institutional review board.

Results

Twenty-five patients were included in the study (eTable). The mean age (SD) at diagnosis was 46 (10.9) years, with a male to female ratio of 1:4. Twenty-two (88%) patients were White non-Hispanic, whereas 3 (12%) were Black. Lupus erythematosus tumidus most commonly affected the trunk (18/25 [72%]) and upper extremities (18/25 [72%]), followed by the head and neck (15/25 [60%]) and lower extremities (8/25 [32%])(Figure 1). The most common morphologies were plaques (18/25 [72%]), papules (17/25 [68%]), and nodules (6/25 [24%])(Figures 2 and 3). Most patients experienced painful (14/25 [56%]) or pruritic (13/25 [52%]) lesions as well as photosensitivity (13/25 [52%]). Of all measured autoantibodies, 5 of 22 (23%) patients had positive antinuclear antibody (ANA) titers greater than 1:80, 1 of 14 (7%) patients had positive anti-Ro (anti-SSA), 1 of 14 (7%) had positive anti-La (anti-SSB), 2 of 10 (20%) had positive anti–double-stranded DNA, and 0 of 6 (0%) patients had positive anti-Smith antibodies. Four (16%) patients with SLE had skin and joint involvement, whereas 1 had lupus nephritis. One (4%) patient had discoid lupus erythematosus (DLE). Seventeen (68%) patients reported recurrences or flares. The mean duration of symptoms (SD) was 28 (44) months.

Topical corticosteroids (21/25 [84%]) and hydroxychloroquine (20/25 [80%]) were the most commonly prescribed treatments. Hydroxychloroquine monotherapy achieved clearance or almost clearance in 12 (60%) patients. Four patients were prescribed thalidomide after hydroxychloroquine monotherapy failed; 2 achieved complete clearance with thalidomide and hydroxychloroquine, 1 achieved complete clearance with thalidomide monotherapy, and 1 improved but did not clear. Four patients were concurrently started on quinacrine (mepacrine) after hydroxychloroquine monotherapy failed; 1 patient had no clearance, 1 discontinued because of allergy, 1 improved, and 1 cleared. Four patients had short courses of prednisone lasting 1 to 4 weeks. Three of 4 patients treated with methotrexate discontinued because of adverse effects, and 1 patient improved. Other prescribed treatments included topical calcineurin inhibitors (10/25 [40%]), dapsone (1/25 [4%]), and clofazimine (1/25 [4%]).

Comment

Prevalence of LET—Although other European LET case series reported a male predominance or equal male to female ratio, our case series reported female predominance (1:4).^1,3-5 Our male to female ratio resembles similar ratios in DLE and subacute lupus erythematosus, whereas relative to our study, SLE male to female ratios favored females over males.^6,7

Clinical Distribution of LET—In one study enrolling 24 patients with LET, 79% (19/24) of patients had facial involvement, 50% (12/24) had V-neck involvement, 50% (12/24) had back involvement, and 46% (11/24) had arm involvement,² whereas our study reported 72% involvement of the trunk, 72% involvement of the upper extremities, 60% involvement of the head and neck region, and 32% involvement of the lower extremities. Although our study reported more lower extremity involvement, the aforementioned study used precise topographic locations, whereas we used more generalized topographic locations. Therefore, it was difficult to compare disease distribution between both studies.²

Presence of Autoantibodies and Comorbidities—Of the 22 patients tested for ANA, 23% reported titers greater than 1:80, similar to the 20% positive ANA prevalence in an LET case series of 25 patients.⁵ Of 4 patients diagnosed with SLE, 3 had articular and skin involvement, and 1 had renal involvement. These findings resemble a similar LET case series.² Nonetheless, given the numerous skin criteria in the American College of Rheumatology SLE classification criteria, patients with predominant skin disease and positive autoantibodies are diagnosed as having SLE without notable extracutaneous involvement.² Therefore, SLE diagnosis in the setting of LET could be reassessed periodically in this population. One patient in our study was diagnosed with DLE several years later. It is uncommon for LET to be reported concomitantly with DLE.⁸

Treatment of LET—Evidence supporting efficacious treatment options for LET is limited to case series. Sun protection is recommended in all patients with LET. Earlier case series reported a high response rate with sun protection and topical corticosteroids, with 19% to 55% of patients requiring subsequent systemic antimalarials.^3,4 However, one case series presented a need for systemic antimalarials,⁵ similar to our study. Hydroxychloroquine 200 to 400 mg daily is considered the first-line systemic treatment for LET. Its response rate varies among studies and may be influenced by dosage.^1,3 Second-line treatments include methotrexate 7.5 to 25 mg once weekly, thalidomide 50 to 100 mg daily, and quinacrine. However, quinacrine is not currently commercially available. Thalidomide and quinacrine represented useful alternatives when hydroxychloroquine monotherapy failed. As with other immunomodulators, adverse effects should be monitored periodically.

Conclusion

Lupus erythematosus tumidus is characterized by erythematous papules and plaques that may be tender or pruritic. It follows an intermittent course and rarely is associated with SLE. Hydroxychloroquine is considered the first-line systemic treatment; however, recalcitrant disease could be managed with other immunomodulators, including methotrexate, thalidomide, or quinacrine.

Lupus erythematosus tumidus (LET) is a rare photosensitive dermatosis¹ that previously was considered a subtype of chronic cutaneous lupus erythematosus; however, the clinical course and favorable prognosis of LET led to its reclassification into another category, called intermittent cutaneous lupus erythematosus.² Although known about for more than 100 years, the association of LET with systemic lupus erythematosus (SLE), its autoantibody profile, and its prognosis are not well characterized. The purpose of this study was to describe the demographics, clinical characteristics, autoantibody profile, comorbidities, and treatment of LET based on a retrospective review of patients with LET.

Methods

A retrospective review was conducted in patients with histologically diagnosed LET who presented to the Department of Dermatology at the Wake Forest School of Medicine (Winston-Salem, North Carolina) over 6 years (July 2012 to July 2018). Inclusion criteria included males or females aged 18 to 75 years with clinical and histopathology-proven LET, which was defined as a superficial and deep lymphocytic infiltrate with abundant mucin deposition in the reticular dermis and absent or focal dermoepidermal junction alterations. Exclusion criteria included males or females younger than 18 years or older than 75 years or patients without clinical and histopathologically proven LET. Medical records were evaluated for demographics, clinical characteristics, diagnoses, autoantibodies, treatment, and recurrence. Photosensitivity was confirmed by clinical history. This study was approved by the Wake Forest School of Medicine institutional review board.

Results

Twenty-five patients were included in the study (eTable). The mean age (SD) at diagnosis was 46 (10.9) years, with a male to female ratio of 1:4. Twenty-two (88%) patients were White non-Hispanic, whereas 3 (12%) were Black. Lupus erythematosus tumidus most commonly affected the trunk (18/25 [72%]) and upper extremities (18/25 [72%]), followed by the head and neck (15/25 [60%]) and lower extremities (8/25 [32%])(Figure 1). The most common morphologies were plaques (18/25 [72%]), papules (17/25 [68%]), and nodules (6/25 [24%])(Figures 2 and 3). Most patients experienced painful (14/25 [56%]) or pruritic (13/25 [52%]) lesions as well as photosensitivity (13/25 [52%]). Of all measured autoantibodies, 5 of 22 (23%) patients had positive antinuclear antibody (ANA) titers greater than 1:80, 1 of 14 (7%) patients had positive anti-Ro (anti-SSA), 1 of 14 (7%) had positive anti-La (anti-SSB), 2 of 10 (20%) had positive anti–double-stranded DNA, and 0 of 6 (0%) patients had positive anti-Smith antibodies. Four (16%) patients with SLE had skin and joint involvement, whereas 1 had lupus nephritis. One (4%) patient had discoid lupus erythematosus (DLE). Seventeen (68%) patients reported recurrences or flares. The mean duration of symptoms (SD) was 28 (44) months.

Topical corticosteroids (21/25 [84%]) and hydroxychloroquine (20/25 [80%]) were the most commonly prescribed treatments. Hydroxychloroquine monotherapy achieved clearance or almost clearance in 12 (60%) patients. Four patients were prescribed thalidomide after hydroxychloroquine monotherapy failed; 2 achieved complete clearance with thalidomide and hydroxychloroquine, 1 achieved complete clearance with thalidomide monotherapy, and 1 improved but did not clear. Four patients were concurrently started on quinacrine (mepacrine) after hydroxychloroquine monotherapy failed; 1 patient had no clearance, 1 discontinued because of allergy, 1 improved, and 1 cleared. Four patients had short courses of prednisone lasting 1 to 4 weeks. Three of 4 patients treated with methotrexate discontinued because of adverse effects, and 1 patient improved. Other prescribed treatments included topical calcineurin inhibitors (10/25 [40%]), dapsone (1/25 [4%]), and clofazimine (1/25 [4%]).

Comment

Prevalence of LET—Although other European LET case series reported a male predominance or equal male to female ratio, our case series reported female predominance (1:4).^1,3-5 Our male to female ratio resembles similar ratios in DLE and subacute lupus erythematosus, whereas relative to our study, SLE male to female ratios favored females over males.^6,7

Clinical Distribution of LET—In one study enrolling 24 patients with LET, 79% (19/24) of patients had facial involvement, 50% (12/24) had V-neck involvement, 50% (12/24) had back involvement, and 46% (11/24) had arm involvement,² whereas our study reported 72% involvement of the trunk, 72% involvement of the upper extremities, 60% involvement of the head and neck region, and 32% involvement of the lower extremities. Although our study reported more lower extremity involvement, the aforementioned study used precise topographic locations, whereas we used more generalized topographic locations. Therefore, it was difficult to compare disease distribution between both studies.²

Presence of Autoantibodies and Comorbidities—Of the 22 patients tested for ANA, 23% reported titers greater than 1:80, similar to the 20% positive ANA prevalence in an LET case series of 25 patients.⁵ Of 4 patients diagnosed with SLE, 3 had articular and skin involvement, and 1 had renal involvement. These findings resemble a similar LET case series.² Nonetheless, given the numerous skin criteria in the American College of Rheumatology SLE classification criteria, patients with predominant skin disease and positive autoantibodies are diagnosed as having SLE without notable extracutaneous involvement.² Therefore, SLE diagnosis in the setting of LET could be reassessed periodically in this population. One patient in our study was diagnosed with DLE several years later. It is uncommon for LET to be reported concomitantly with DLE.⁸

Treatment of LET—Evidence supporting efficacious treatment options for LET is limited to case series. Sun protection is recommended in all patients with LET. Earlier case series reported a high response rate with sun protection and topical corticosteroids, with 19% to 55% of patients requiring subsequent systemic antimalarials.^3,4 However, one case series presented a need for systemic antimalarials,⁵ similar to our study. Hydroxychloroquine 200 to 400 mg daily is considered the first-line systemic treatment for LET. Its response rate varies among studies and may be influenced by dosage.^1,3 Second-line treatments include methotrexate 7.5 to 25 mg once weekly, thalidomide 50 to 100 mg daily, and quinacrine. However, quinacrine is not currently commercially available. Thalidomide and quinacrine represented useful alternatives when hydroxychloroquine monotherapy failed. As with other immunomodulators, adverse effects should be monitored periodically.

Conclusion

Lupus erythematosus tumidus is characterized by erythematous papules and plaques that may be tender or pruritic. It follows an intermittent course and rarely is associated with SLE. Hydroxychloroquine is considered the first-line systemic treatment; however, recalcitrant disease could be managed with other immunomodulators, including methotrexate, thalidomide, or quinacrine.

Lupus erythematosus tumidus (LET) is a rare photosensitive dermatosis¹ that previously was considered a subtype of chronic cutaneous lupus erythematosus; however, the clinical course and favorable prognosis of LET led to its reclassification into another category, called intermittent cutaneous lupus erythematosus.² Although known about for more than 100 years, the association of LET with systemic lupus erythematosus (SLE), its autoantibody profile, and its prognosis are not well characterized. The purpose of this study was to describe the demographics, clinical characteristics, autoantibody profile, comorbidities, and treatment of LET based on a retrospective review of patients with LET.

Methods

A retrospective review was conducted in patients with histologically diagnosed LET who presented to the Department of Dermatology at the Wake Forest School of Medicine (Winston-Salem, North Carolina) over 6 years (July 2012 to July 2018). Inclusion criteria included males or females aged 18 to 75 years with clinical and histopathology-proven LET, which was defined as a superficial and deep lymphocytic infiltrate with abundant mucin deposition in the reticular dermis and absent or focal dermoepidermal junction alterations. Exclusion criteria included males or females younger than 18 years or older than 75 years or patients without clinical and histopathologically proven LET. Medical records were evaluated for demographics, clinical characteristics, diagnoses, autoantibodies, treatment, and recurrence. Photosensitivity was confirmed by clinical history. This study was approved by the Wake Forest School of Medicine institutional review board.

Results

Twenty-five patients were included in the study (eTable). The mean age (SD) at diagnosis was 46 (10.9) years, with a male to female ratio of 1:4. Twenty-two (88%) patients were White non-Hispanic, whereas 3 (12%) were Black. Lupus erythematosus tumidus most commonly affected the trunk (18/25 [72%]) and upper extremities (18/25 [72%]), followed by the head and neck (15/25 [60%]) and lower extremities (8/25 [32%])(Figure 1). The most common morphologies were plaques (18/25 [72%]), papules (17/25 [68%]), and nodules (6/25 [24%])(Figures 2 and 3). Most patients experienced painful (14/25 [56%]) or pruritic (13/25 [52%]) lesions as well as photosensitivity (13/25 [52%]). Of all measured autoantibodies, 5 of 22 (23%) patients had positive antinuclear antibody (ANA) titers greater than 1:80, 1 of 14 (7%) patients had positive anti-Ro (anti-SSA), 1 of 14 (7%) had positive anti-La (anti-SSB), 2 of 10 (20%) had positive anti–double-stranded DNA, and 0 of 6 (0%) patients had positive anti-Smith antibodies. Four (16%) patients with SLE had skin and joint involvement, whereas 1 had lupus nephritis. One (4%) patient had discoid lupus erythematosus (DLE). Seventeen (68%) patients reported recurrences or flares. The mean duration of symptoms (SD) was 28 (44) months.

Topical corticosteroids (21/25 [84%]) and hydroxychloroquine (20/25 [80%]) were the most commonly prescribed treatments. Hydroxychloroquine monotherapy achieved clearance or almost clearance in 12 (60%) patients. Four patients were prescribed thalidomide after hydroxychloroquine monotherapy failed; 2 achieved complete clearance with thalidomide and hydroxychloroquine, 1 achieved complete clearance with thalidomide monotherapy, and 1 improved but did not clear. Four patients were concurrently started on quinacrine (mepacrine) after hydroxychloroquine monotherapy failed; 1 patient had no clearance, 1 discontinued because of allergy, 1 improved, and 1 cleared. Four patients had short courses of prednisone lasting 1 to 4 weeks. Three of 4 patients treated with methotrexate discontinued because of adverse effects, and 1 patient improved. Other prescribed treatments included topical calcineurin inhibitors (10/25 [40%]), dapsone (1/25 [4%]), and clofazimine (1/25 [4%]).

Comment

Prevalence of LET—Although other European LET case series reported a male predominance or equal male to female ratio, our case series reported female predominance (1:4).^1,3-5 Our male to female ratio resembles similar ratios in DLE and subacute lupus erythematosus, whereas relative to our study, SLE male to female ratios favored females over males.^6,7

Clinical Distribution of LET—In one study enrolling 24 patients with LET, 79% (19/24) of patients had facial involvement, 50% (12/24) had V-neck involvement, 50% (12/24) had back involvement, and 46% (11/24) had arm involvement,² whereas our study reported 72% involvement of the trunk, 72% involvement of the upper extremities, 60% involvement of the head and neck region, and 32% involvement of the lower extremities. Although our study reported more lower extremity involvement, the aforementioned study used precise topographic locations, whereas we used more generalized topographic locations. Therefore, it was difficult to compare disease distribution between both studies.²

Presence of Autoantibodies and Comorbidities—Of the 22 patients tested for ANA, 23% reported titers greater than 1:80, similar to the 20% positive ANA prevalence in an LET case series of 25 patients.⁵ Of 4 patients diagnosed with SLE, 3 had articular and skin involvement, and 1 had renal involvement. These findings resemble a similar LET case series.² Nonetheless, given the numerous skin criteria in the American College of Rheumatology SLE classification criteria, patients with predominant skin disease and positive autoantibodies are diagnosed as having SLE without notable extracutaneous involvement.² Therefore, SLE diagnosis in the setting of LET could be reassessed periodically in this population. One patient in our study was diagnosed with DLE several years later. It is uncommon for LET to be reported concomitantly with DLE.⁸

Treatment of LET—Evidence supporting efficacious treatment options for LET is limited to case series. Sun protection is recommended in all patients with LET. Earlier case series reported a high response rate with sun protection and topical corticosteroids, with 19% to 55% of patients requiring subsequent systemic antimalarials.^3,4 However, one case series presented a need for systemic antimalarials,⁵ similar to our study. Hydroxychloroquine 200 to 400 mg daily is considered the first-line systemic treatment for LET. Its response rate varies among studies and may be influenced by dosage.^1,3 Second-line treatments include methotrexate 7.5 to 25 mg once weekly, thalidomide 50 to 100 mg daily, and quinacrine. However, quinacrine is not currently commercially available. Thalidomide and quinacrine represented useful alternatives when hydroxychloroquine monotherapy failed. As with other immunomodulators, adverse effects should be monitored periodically.

Conclusion

Lupus erythematosus tumidus is characterized by erythematous papules and plaques that may be tender or pruritic. It follows an intermittent course and rarely is associated with SLE. Hydroxychloroquine is considered the first-line systemic treatment; however, recalcitrant disease could be managed with other immunomodulators, including methotrexate, thalidomide, or quinacrine.