Human immunodeficiency virus (HIV) is a single-stranded enveloped RNA retrovirus that was first described in the 1980s and is known for its severity of systemic immune dysregulation and associated opportunistic infections. It is transmitted through contact with blood or bodily fluids, and it can be transmitted vertically, most often at the time of delivery. Since the advent of antiretroviral therapy, the average life expectancy and natural course of HIV infection has improved notably.¹

In 2019, just over 1 million adults and adolescents in the United States were living with the diagnosis of HIV.² In the same year, the rate of new HIV diagnoses in the United States had stabilized at a rate of 13.2 new cases per 100,000 individuals.² Among this cohort, individuals identifying as females at birth accounted for 19% of the total population living with HIV.² Sexual contact was the most common route of transmission, followed by injection drug use—77% and 20%, respectively.²

It is important to note that the incidence and prevalence of HIV does not reflect the individuals who unknowingly are living with the disease. The disease burden associated with HIV infection and the availability of effective treatment modalities has led to the recommendation that all individuals undergo HIV screening at least once in their lifetime.³ Early identification of HIV infection is important to optimize the health of all individuals and future generations.

The interplay between high-risk sexual practices and the risk for HIV exposure and unintended pregnancy places the ObGyn at the forefront of HIV prevention and identification. Early diagnosis and standardized treatment with antiretroviral therapies have led to both a dramatic improvement in adult disease burden and a dramatic decrease in perinatal transmission.^4,5 In 2019, perinatal transmission accounted for less than 1% of HIV transmission in the United States.² This is a decrease of greater than 54% from 2014, which, again, emphasizes the role of the ObGyn in HIV management.⁶

Preconception care: Gynecologic screening, diagnosis, and management

The Centers for Disease Control and Prevention (CDC) recommends that an individual undergo HIV screening at least once in their lifetime.³ HIV screening algorithms have changed over the last 20 years to reduce the number of false-positive and/or false-negative results obtained through HIV antibody testing alone.⁷ HIV-1/2 antibody/antigen immunoassay is recommended as the initial screening test. If reactive, this should be followed by an HIV p24-specific antigen test. Reactivity for both the HIV-1/2 immunoassay and the HIV p24-specific antigen test confirms the diagnosis of HIV infection. However, if HIV p24-specific antigen testing is indeterminate or an acute HIV infection is suspected, an HIV nucleic acid test (NAT) should be performed.^7,8

Upon a positive diagnosis, a multidisciplinary team approach is recommended to address the mental, social, and physical care of the patient. Team members should include an adult medicine clinician, an infectious disease clinician, an ObGyn, social services staff, and behavioral health support to achieve the goal of obtaining and maintaining the patient’s optimal health status.

TABLE 1 lists the recommended initial laboratory assessments that should follow a new diagnosis of HIV infection. Based on the laboratory results, the indicated vaccinations, antibiotic prophylaxis for opportunistic infections, and optimal combined antiretroviral therapy (cART) can be determined.⁹ The vaccinations listed in TABLE 2 should be up to date.^10,11 Additionally, cervical cancer screening with cytology and human papillomavirus (HPV) testing and treatment should be performed in accordance with the 2019 American Society for Cervical Cancer Prevention (ASCCP) guidelines.¹²

Promptly initiating cART is of utmost importance; this decreases the rate of HIV transmission via sexual contact and decreases the rate of perinatal transmission.^5,13 Results of the initial laboratory assessment, hepatitis B status, and desire for pregnancy/contraception should be considered when initiating cART.^3,14,15

It is imperative to discuss sharing the positive diagnostic results with the patient’s partner. The CDC provides guidance for these discussions,¹⁶ which should address the use of preexposure prophylaxis (PrEP) if partner screening establishes partner serodiscordance (that is, HIV positivity in one partner and HIV negativity in the other partner). PrEP is a single pill approved by the US Food and Drug Administration (FDA) that combines tenofovir 300 mg and emtricitabine 200 mg daily¹⁷ and has been recommended since 2012.^18-20 PrEP also should be considered in sexually active individuals who have higher-risk behaviors within an area with high HIV prevalence.^18-21 Despite the CDC’s strong recommendations for PrEP use, lack of insurance coverage and high cost are barriers to universal use. The National Alliance of State and Territorial AIDS Directors (NASTAD) provides a list of patient and copayment assistance programs that can be found at the NASTAD website: https://nastad.org/prepcost-resources/prep-assitance-programs.

Continue to: Preconception considerations...

Preconception considerations

In individuals with known HIV infection, preconception consultation with an ObGyn or maternal-fetal medicine (MFM) specialist should be recommended prior to conception.²² Preconception recommendations include addressing optimization of maternal medical comorbidities, addressing routine health screening and vaccinations, performing sexually transmitted infection screening, and optimizing HIV disease status.^3,22,23

With the assistance of adult medicine and infectious disease clinicians, a cART regimen that is sufficient to reliably maintain viral suppression (that is, viral load < 50 copies/mL on 2 separate occasions at least 3 months apart) and is safe for use in pregnancy should be established.³ In serodiscordant couples, recommended mechanisms to prevent HIV transmission during conception include sustained viral suppression in the HIV-positive partner, PrEP use in the HIV-negative partner, and timing of unprotected intercourse during peak fertility only.³

Antepartum care

The initial prenatal visit

Women who have no prior screening for HIV or prior negative HIV results should undergo HIV screening at the first prenatal visit.³ Screening should be performed in accordance with the “opt out method.”⁶ Using this method, a woman without a known diagnosis of HIV infection is told that she will undergo HIV screening as a component of routine prenatal care unless she decides that she does not want this test performed.^6,24,25 At the time of screening, all pregnant women should be provided with comprehensive information regarding HIV screening, HIV screening results, and the implications of HIV infection on pregnancy.²⁶

In the pregnant patient with confirmed HIV infection, all preconception considerations should be addressed. If not already in place, referrals to appropriate providers (infectious disease specialist, ObGyn, MFM specialist) and ancillary support staff (social services, behavioral health support) should be arranged. All efforts should be implemented to optimize additional medical comorbidities. TABLE 3 lists additional prenatal testing requirements.²²

First and second trimester

Antiretroviral adherence and barriers to adherence should be addressed at every prenatal visit. If the patient is started on antiretroviral therapy in pregnancy or is switched to an alternative cART regimen, viral load assessment should be performed 2 to 4 weeks after the start or change in cART and then repeated monthly until undetectable levels are achieved.^3,26 If an undetectable viral load cannot be obtained, cART adherence should be thoroughly evaluated, and the patient should be referred to an infectious disease or HIV treatment specialist.²⁶

If the initial prenatal testing indicates an undetectable viral load, repeat viral load assessment can be performed every 3 months throughout the pregnancy.³ If initial prenatal testing indicates an undetectable HIV viral load and the T-lymphocyte count is greater than 200 cells/mm³, repeat viral load testing can be performed every 6 months to ensure stability.³

Early screening for gestational diabetes should be performed in patients receiving protease inhibitors because these agents may interfere with carbohydrate tolerance.^22,26

Continue to: Third trimester...

Third trimester

Women with negative HIV screening at the initial prenatal evaluation should undergo repeat HIV screening in the third trimester if they are at high risk for HIV exposure.²⁵ Factors that determine high-risk status are listed in TABLE 4.²⁷ Sexually transmitted infection screening should be repeated in the third trimester.²⁶

Repeat assessment of the viral load should be completed between 34 and 36 weeks’ gestation or sooner if additional indications for early term or late preterm delivery arise.³ Viral load assessments aid in determining delivery timing and route and the need for zidovudine (ZDV) treatment (FIGURE).

Studies that were performed prior to standardized cART use found higher rates of perinatal transmission associated with vaginal delivery when compared with cesarean delivery (CD).^28-30 However, these studies did not account for measures of viral load within their study populations.^28-30

In more recent studies performed in the era of standardized cART and viral load monitoring, CD does not provide protection from perinatal transmission when the maternal viral load is less than 1,000 copies/mL at the time of delivery.³¹ Similarly, delivery prior to 40 weeks’ gestation does not confer protection from perinatal transmission.³²

Alternatively, if the maternal viral load is 1,000 copies/mL or greater, CD should be considered to reduce the risk of perinatal transmission. A scheduled, elective CD at 38 weeks’ gestation is recommended in those with a maternal viral load of 1,000 copies/mL or greater and no medical indication for earlier delivery in order to decrease the likelihood of labor onset and/or rupture of membranes prior to delivery.^3,33

Intrapartum care

Rapid antigen testing (with follow-up confirmatory testing as indicated) is recommended in patients presenting to labor and delivery with no prior documentation of HIV status.^3,8,26

Despite a significant decrease in perinatal transmission rates over the last 30 years, a large proportion of perinatal transmission cases are thought to result from intrapartum fetal exposure. While the mechanism of transmission is not known, a correlation between maternal viral load and risk for perinatal transmission has been shown. A maternal viral load of less than 1,000 copies/mL has been associated with a perinatal transmission risk of less than 2%.^34,35 A maternal viral load between 50 and 999 copies/mL has been associated with a perinatal transmission rate of 1% to 2% compared with less than 1% for a maternal viral load of less than 50 copies/mL or undetectable measures.^5,36,37

These differences in perinatal transmission rates have prompted the recommendation for administration of ZDV for a minimum of 3 hours prior to delivery in mothers with a viral load of 1,000 copies/mL or greater.^4,38 The recommended ZDV dosing is: a 1-hour intravenous loading dose of 2 mg/kg followed by continuous infusion of 1 mg/kg per hour until delivery.^39,40 Patients who opt for vaginal delivery despite nonsuppressed viral loads (≥1,000 copies/mL) after thorough perinatal counseling should receive ZDV at the start of labor through delivery.³ All patients should be continued on cART throughout their intrapartum and postpartum course.

The duration of membrane rupture and the use of invasive fetal monitoring (that is, fetal scalp electrodes) have been assessed as mechanisms of perinatal transmission. Although they were performed prior to the standardized use of cART, several studies demonstrated that increased perinatal transmission rates were associated with invasive fetal monitoring.^34,41,42 While limited data have refuted this finding in women with suppressed viral loads (< 50 copies/mL), the American College of Obstetricians and Gynecologists recommends avoiding the use of invasive fetal monitoring in labor.²⁶

Pre-cART studies demonstrated increased rates of perinatal transmission with longer durations of membrane rupture prior to delivery.^43,44 More recent studies have reevaluated this association and determined that the increased perinatal transmission rates are more likely associated with higher maternal viral loads at the time of delivery rather than duration of membrane rupture.^45-47 No clear evidence describes when or if CD after the onset of labor or rupture of membranes provides protection from perinatal HIV transmission in pregnant women with HIV receiving no antiretroviral drugs or only ZDV during labor.^43,48 CD can be considered for patients in whom scheduled, pre-labor CD was planned who present in labor or with rupture of membranes prior to scheduled CD.²⁶ These, and additional intrapartum considerations, are listed in TABLE 5.^49,50

Appropriate personal protective equipment should be available and donned for all providers present throughout intrapartum management and at delivery.^23,26 Should any provider injury occur, immediate cleansing of the injury site should be performed, followed by referral to proper workplace supervisors for additional laboratory testing and antiretroviral prophylaxis.

Continue to: Postpartum care...

Postpartum care

Postpartum contraception should be offered and provided in accordance with patient request. Regardless of other birth control methods, strict condom use should be advised. PrEP should be discussed and offered for all partners of serodiscordant couples.

Upon outpatient follow-up, assessment and provision of routine health maintenance should be performed. Any abnormal cervical pathology encountered during prenatal care should be managed in accordance with ASCCP guidelines.¹² Follow-up care should be established with adult medicine, infectious disease, and ObGyn clinicians.²⁶

Neonatal considerations

Neonates born to mothers with positive or unknown HIV status should undergo expedited HIV testing.^51,52 Consultation should be conducted with pediatric or neonatology colleagues to determine the antiretroviral regimen and duration of therapy based on presumed HIV status of the neonate. Ideally, antiretroviral therapy should be initiated within 6 hours of delivery.^3,53

Formula feeding should be implemented as maternal HIV infection is one of the few contraindications to breastfeeding.^54,55 The risk of late breast milk transmission, defined as postnatal transmission that occurs after 1 month of age, may vary based on maternal viral load, but it has been reported as high as 8.9 transmissions per 100 person-years of breastfeeding.⁵⁶

Resources available

Care of the pregnant patient with HIV and the reduction of perinatal transmission both depend on early diagnosis of HIV and effective treatment with cART. Such patients benefit from a team-based care model that includes the ObGyn and/or MFM specialist, infectious disease clinician, pediatrician, and social worker. As guidelines evolve for care of these patients, a reference checklist, such as the examples provided at the Society for Maternal-Fetal Medicine website (smfm.org) or at HIV.gov, provide an outline for:

• management before, during, and after pregnancy
• suggestions for management teams of interest to successfully carry out the checklist requirements
• proposals for measurements of quality performance with the use of checklists in the management of HIV in pregnancy.

In addition, assistance with clinical decision making for patients with HIV in pregnancy can be obtained via telephone consultation with the National Clinician Consultation Center–Perinatal HIV/AIDS (888-448-8765), which is available 24 hours a day, 7 days a week. ●

Human immunodeficiency virus (HIV) is a single-stranded enveloped RNA retrovirus that was first described in the 1980s and is known for its severity of systemic immune dysregulation and associated opportunistic infections. It is transmitted through contact with blood or bodily fluids, and it can be transmitted vertically, most often at the time of delivery. Since the advent of antiretroviral therapy, the average life expectancy and natural course of HIV infection has improved notably.¹

In 2019, just over 1 million adults and adolescents in the United States were living with the diagnosis of HIV.² In the same year, the rate of new HIV diagnoses in the United States had stabilized at a rate of 13.2 new cases per 100,000 individuals.² Among this cohort, individuals identifying as females at birth accounted for 19% of the total population living with HIV.² Sexual contact was the most common route of transmission, followed by injection drug use—77% and 20%, respectively.²

It is important to note that the incidence and prevalence of HIV does not reflect the individuals who unknowingly are living with the disease. The disease burden associated with HIV infection and the availability of effective treatment modalities has led to the recommendation that all individuals undergo HIV screening at least once in their lifetime.³ Early identification of HIV infection is important to optimize the health of all individuals and future generations.

The interplay between high-risk sexual practices and the risk for HIV exposure and unintended pregnancy places the ObGyn at the forefront of HIV prevention and identification. Early diagnosis and standardized treatment with antiretroviral therapies have led to both a dramatic improvement in adult disease burden and a dramatic decrease in perinatal transmission.^4,5 In 2019, perinatal transmission accounted for less than 1% of HIV transmission in the United States.² This is a decrease of greater than 54% from 2014, which, again, emphasizes the role of the ObGyn in HIV management.⁶

Preconception care: Gynecologic screening, diagnosis, and management

The Centers for Disease Control and Prevention (CDC) recommends that an individual undergo HIV screening at least once in their lifetime.³ HIV screening algorithms have changed over the last 20 years to reduce the number of false-positive and/or false-negative results obtained through HIV antibody testing alone.⁷ HIV-1/2 antibody/antigen immunoassay is recommended as the initial screening test. If reactive, this should be followed by an HIV p24-specific antigen test. Reactivity for both the HIV-1/2 immunoassay and the HIV p24-specific antigen test confirms the diagnosis of HIV infection. However, if HIV p24-specific antigen testing is indeterminate or an acute HIV infection is suspected, an HIV nucleic acid test (NAT) should be performed.^7,8

Upon a positive diagnosis, a multidisciplinary team approach is recommended to address the mental, social, and physical care of the patient. Team members should include an adult medicine clinician, an infectious disease clinician, an ObGyn, social services staff, and behavioral health support to achieve the goal of obtaining and maintaining the patient’s optimal health status.

TABLE 1 lists the recommended initial laboratory assessments that should follow a new diagnosis of HIV infection. Based on the laboratory results, the indicated vaccinations, antibiotic prophylaxis for opportunistic infections, and optimal combined antiretroviral therapy (cART) can be determined.⁹ The vaccinations listed in TABLE 2 should be up to date.^10,11 Additionally, cervical cancer screening with cytology and human papillomavirus (HPV) testing and treatment should be performed in accordance with the 2019 American Society for Cervical Cancer Prevention (ASCCP) guidelines.¹²

Promptly initiating cART is of utmost importance; this decreases the rate of HIV transmission via sexual contact and decreases the rate of perinatal transmission.^5,13 Results of the initial laboratory assessment, hepatitis B status, and desire for pregnancy/contraception should be considered when initiating cART.^3,14,15

It is imperative to discuss sharing the positive diagnostic results with the patient’s partner. The CDC provides guidance for these discussions,¹⁶ which should address the use of preexposure prophylaxis (PrEP) if partner screening establishes partner serodiscordance (that is, HIV positivity in one partner and HIV negativity in the other partner). PrEP is a single pill approved by the US Food and Drug Administration (FDA) that combines tenofovir 300 mg and emtricitabine 200 mg daily¹⁷ and has been recommended since 2012.^18-20 PrEP also should be considered in sexually active individuals who have higher-risk behaviors within an area with high HIV prevalence.^18-21 Despite the CDC’s strong recommendations for PrEP use, lack of insurance coverage and high cost are barriers to universal use. The National Alliance of State and Territorial AIDS Directors (NASTAD) provides a list of patient and copayment assistance programs that can be found at the NASTAD website: https://nastad.org/prepcost-resources/prep-assitance-programs.

Continue to: Preconception considerations...

Preconception considerations

In individuals with known HIV infection, preconception consultation with an ObGyn or maternal-fetal medicine (MFM) specialist should be recommended prior to conception.²² Preconception recommendations include addressing optimization of maternal medical comorbidities, addressing routine health screening and vaccinations, performing sexually transmitted infection screening, and optimizing HIV disease status.^3,22,23

With the assistance of adult medicine and infectious disease clinicians, a cART regimen that is sufficient to reliably maintain viral suppression (that is, viral load < 50 copies/mL on 2 separate occasions at least 3 months apart) and is safe for use in pregnancy should be established.³ In serodiscordant couples, recommended mechanisms to prevent HIV transmission during conception include sustained viral suppression in the HIV-positive partner, PrEP use in the HIV-negative partner, and timing of unprotected intercourse during peak fertility only.³

Antepartum care

The initial prenatal visit

Women who have no prior screening for HIV or prior negative HIV results should undergo HIV screening at the first prenatal visit.³ Screening should be performed in accordance with the “opt out method.”⁶ Using this method, a woman without a known diagnosis of HIV infection is told that she will undergo HIV screening as a component of routine prenatal care unless she decides that she does not want this test performed.^6,24,25 At the time of screening, all pregnant women should be provided with comprehensive information regarding HIV screening, HIV screening results, and the implications of HIV infection on pregnancy.²⁶

In the pregnant patient with confirmed HIV infection, all preconception considerations should be addressed. If not already in place, referrals to appropriate providers (infectious disease specialist, ObGyn, MFM specialist) and ancillary support staff (social services, behavioral health support) should be arranged. All efforts should be implemented to optimize additional medical comorbidities. TABLE 3 lists additional prenatal testing requirements.²²

First and second trimester

Antiretroviral adherence and barriers to adherence should be addressed at every prenatal visit. If the patient is started on antiretroviral therapy in pregnancy or is switched to an alternative cART regimen, viral load assessment should be performed 2 to 4 weeks after the start or change in cART and then repeated monthly until undetectable levels are achieved.^3,26 If an undetectable viral load cannot be obtained, cART adherence should be thoroughly evaluated, and the patient should be referred to an infectious disease or HIV treatment specialist.²⁶

If the initial prenatal testing indicates an undetectable viral load, repeat viral load assessment can be performed every 3 months throughout the pregnancy.³ If initial prenatal testing indicates an undetectable HIV viral load and the T-lymphocyte count is greater than 200 cells/mm³, repeat viral load testing can be performed every 6 months to ensure stability.³

Early screening for gestational diabetes should be performed in patients receiving protease inhibitors because these agents may interfere with carbohydrate tolerance.^22,26

Continue to: Third trimester...

Third trimester

Women with negative HIV screening at the initial prenatal evaluation should undergo repeat HIV screening in the third trimester if they are at high risk for HIV exposure.²⁵ Factors that determine high-risk status are listed in TABLE 4.²⁷ Sexually transmitted infection screening should be repeated in the third trimester.²⁶

Repeat assessment of the viral load should be completed between 34 and 36 weeks’ gestation or sooner if additional indications for early term or late preterm delivery arise.³ Viral load assessments aid in determining delivery timing and route and the need for zidovudine (ZDV) treatment (FIGURE).

Studies that were performed prior to standardized cART use found higher rates of perinatal transmission associated with vaginal delivery when compared with cesarean delivery (CD).^28-30 However, these studies did not account for measures of viral load within their study populations.^28-30

In more recent studies performed in the era of standardized cART and viral load monitoring, CD does not provide protection from perinatal transmission when the maternal viral load is less than 1,000 copies/mL at the time of delivery.³¹ Similarly, delivery prior to 40 weeks’ gestation does not confer protection from perinatal transmission.³²

Alternatively, if the maternal viral load is 1,000 copies/mL or greater, CD should be considered to reduce the risk of perinatal transmission. A scheduled, elective CD at 38 weeks’ gestation is recommended in those with a maternal viral load of 1,000 copies/mL or greater and no medical indication for earlier delivery in order to decrease the likelihood of labor onset and/or rupture of membranes prior to delivery.^3,33

Intrapartum care

Rapid antigen testing (with follow-up confirmatory testing as indicated) is recommended in patients presenting to labor and delivery with no prior documentation of HIV status.^3,8,26

Despite a significant decrease in perinatal transmission rates over the last 30 years, a large proportion of perinatal transmission cases are thought to result from intrapartum fetal exposure. While the mechanism of transmission is not known, a correlation between maternal viral load and risk for perinatal transmission has been shown. A maternal viral load of less than 1,000 copies/mL has been associated with a perinatal transmission risk of less than 2%.^34,35 A maternal viral load between 50 and 999 copies/mL has been associated with a perinatal transmission rate of 1% to 2% compared with less than 1% for a maternal viral load of less than 50 copies/mL or undetectable measures.^5,36,37

These differences in perinatal transmission rates have prompted the recommendation for administration of ZDV for a minimum of 3 hours prior to delivery in mothers with a viral load of 1,000 copies/mL or greater.^4,38 The recommended ZDV dosing is: a 1-hour intravenous loading dose of 2 mg/kg followed by continuous infusion of 1 mg/kg per hour until delivery.^39,40 Patients who opt for vaginal delivery despite nonsuppressed viral loads (≥1,000 copies/mL) after thorough perinatal counseling should receive ZDV at the start of labor through delivery.³ All patients should be continued on cART throughout their intrapartum and postpartum course.

The duration of membrane rupture and the use of invasive fetal monitoring (that is, fetal scalp electrodes) have been assessed as mechanisms of perinatal transmission. Although they were performed prior to the standardized use of cART, several studies demonstrated that increased perinatal transmission rates were associated with invasive fetal monitoring.^34,41,42 While limited data have refuted this finding in women with suppressed viral loads (< 50 copies/mL), the American College of Obstetricians and Gynecologists recommends avoiding the use of invasive fetal monitoring in labor.²⁶

Pre-cART studies demonstrated increased rates of perinatal transmission with longer durations of membrane rupture prior to delivery.^43,44 More recent studies have reevaluated this association and determined that the increased perinatal transmission rates are more likely associated with higher maternal viral loads at the time of delivery rather than duration of membrane rupture.^45-47 No clear evidence describes when or if CD after the onset of labor or rupture of membranes provides protection from perinatal HIV transmission in pregnant women with HIV receiving no antiretroviral drugs or only ZDV during labor.^43,48 CD can be considered for patients in whom scheduled, pre-labor CD was planned who present in labor or with rupture of membranes prior to scheduled CD.²⁶ These, and additional intrapartum considerations, are listed in TABLE 5.^49,50

Appropriate personal protective equipment should be available and donned for all providers present throughout intrapartum management and at delivery.^23,26 Should any provider injury occur, immediate cleansing of the injury site should be performed, followed by referral to proper workplace supervisors for additional laboratory testing and antiretroviral prophylaxis.

Continue to: Postpartum care...

Postpartum care

Postpartum contraception should be offered and provided in accordance with patient request. Regardless of other birth control methods, strict condom use should be advised. PrEP should be discussed and offered for all partners of serodiscordant couples.

Upon outpatient follow-up, assessment and provision of routine health maintenance should be performed. Any abnormal cervical pathology encountered during prenatal care should be managed in accordance with ASCCP guidelines.¹² Follow-up care should be established with adult medicine, infectious disease, and ObGyn clinicians.²⁶

Neonatal considerations

Neonates born to mothers with positive or unknown HIV status should undergo expedited HIV testing.^51,52 Consultation should be conducted with pediatric or neonatology colleagues to determine the antiretroviral regimen and duration of therapy based on presumed HIV status of the neonate. Ideally, antiretroviral therapy should be initiated within 6 hours of delivery.^3,53

Formula feeding should be implemented as maternal HIV infection is one of the few contraindications to breastfeeding.^54,55 The risk of late breast milk transmission, defined as postnatal transmission that occurs after 1 month of age, may vary based on maternal viral load, but it has been reported as high as 8.9 transmissions per 100 person-years of breastfeeding.⁵⁶

Resources available

Care of the pregnant patient with HIV and the reduction of perinatal transmission both depend on early diagnosis of HIV and effective treatment with cART. Such patients benefit from a team-based care model that includes the ObGyn and/or MFM specialist, infectious disease clinician, pediatrician, and social worker. As guidelines evolve for care of these patients, a reference checklist, such as the examples provided at the Society for Maternal-Fetal Medicine website (smfm.org) or at HIV.gov, provide an outline for:

• management before, during, and after pregnancy
• suggestions for management teams of interest to successfully carry out the checklist requirements
• proposals for measurements of quality performance with the use of checklists in the management of HIV in pregnancy.

In addition, assistance with clinical decision making for patients with HIV in pregnancy can be obtained via telephone consultation with the National Clinician Consultation Center–Perinatal HIV/AIDS (888-448-8765), which is available 24 hours a day, 7 days a week. ●

Human immunodeficiency virus (HIV) is a single-stranded enveloped RNA retrovirus that was first described in the 1980s and is known for its severity of systemic immune dysregulation and associated opportunistic infections. It is transmitted through contact with blood or bodily fluids, and it can be transmitted vertically, most often at the time of delivery. Since the advent of antiretroviral therapy, the average life expectancy and natural course of HIV infection has improved notably.¹

In 2019, just over 1 million adults and adolescents in the United States were living with the diagnosis of HIV.² In the same year, the rate of new HIV diagnoses in the United States had stabilized at a rate of 13.2 new cases per 100,000 individuals.² Among this cohort, individuals identifying as females at birth accounted for 19% of the total population living with HIV.² Sexual contact was the most common route of transmission, followed by injection drug use—77% and 20%, respectively.²

It is important to note that the incidence and prevalence of HIV does not reflect the individuals who unknowingly are living with the disease. The disease burden associated with HIV infection and the availability of effective treatment modalities has led to the recommendation that all individuals undergo HIV screening at least once in their lifetime.³ Early identification of HIV infection is important to optimize the health of all individuals and future generations.

The interplay between high-risk sexual practices and the risk for HIV exposure and unintended pregnancy places the ObGyn at the forefront of HIV prevention and identification. Early diagnosis and standardized treatment with antiretroviral therapies have led to both a dramatic improvement in adult disease burden and a dramatic decrease in perinatal transmission.^4,5 In 2019, perinatal transmission accounted for less than 1% of HIV transmission in the United States.² This is a decrease of greater than 54% from 2014, which, again, emphasizes the role of the ObGyn in HIV management.⁶

Preconception care: Gynecologic screening, diagnosis, and management

The Centers for Disease Control and Prevention (CDC) recommends that an individual undergo HIV screening at least once in their lifetime.³ HIV screening algorithms have changed over the last 20 years to reduce the number of false-positive and/or false-negative results obtained through HIV antibody testing alone.⁷ HIV-1/2 antibody/antigen immunoassay is recommended as the initial screening test. If reactive, this should be followed by an HIV p24-specific antigen test. Reactivity for both the HIV-1/2 immunoassay and the HIV p24-specific antigen test confirms the diagnosis of HIV infection. However, if HIV p24-specific antigen testing is indeterminate or an acute HIV infection is suspected, an HIV nucleic acid test (NAT) should be performed.^7,8

Upon a positive diagnosis, a multidisciplinary team approach is recommended to address the mental, social, and physical care of the patient. Team members should include an adult medicine clinician, an infectious disease clinician, an ObGyn, social services staff, and behavioral health support to achieve the goal of obtaining and maintaining the patient’s optimal health status.

TABLE 1 lists the recommended initial laboratory assessments that should follow a new diagnosis of HIV infection. Based on the laboratory results, the indicated vaccinations, antibiotic prophylaxis for opportunistic infections, and optimal combined antiretroviral therapy (cART) can be determined.⁹ The vaccinations listed in TABLE 2 should be up to date.^10,11 Additionally, cervical cancer screening with cytology and human papillomavirus (HPV) testing and treatment should be performed in accordance with the 2019 American Society for Cervical Cancer Prevention (ASCCP) guidelines.¹²

Promptly initiating cART is of utmost importance; this decreases the rate of HIV transmission via sexual contact and decreases the rate of perinatal transmission.^5,13 Results of the initial laboratory assessment, hepatitis B status, and desire for pregnancy/contraception should be considered when initiating cART.^3,14,15

It is imperative to discuss sharing the positive diagnostic results with the patient’s partner. The CDC provides guidance for these discussions,¹⁶ which should address the use of preexposure prophylaxis (PrEP) if partner screening establishes partner serodiscordance (that is, HIV positivity in one partner and HIV negativity in the other partner). PrEP is a single pill approved by the US Food and Drug Administration (FDA) that combines tenofovir 300 mg and emtricitabine 200 mg daily¹⁷ and has been recommended since 2012.^18-20 PrEP also should be considered in sexually active individuals who have higher-risk behaviors within an area with high HIV prevalence.^18-21 Despite the CDC’s strong recommendations for PrEP use, lack of insurance coverage and high cost are barriers to universal use. The National Alliance of State and Territorial AIDS Directors (NASTAD) provides a list of patient and copayment assistance programs that can be found at the NASTAD website: https://nastad.org/prepcost-resources/prep-assitance-programs.

Continue to: Preconception considerations...

Preconception considerations

In individuals with known HIV infection, preconception consultation with an ObGyn or maternal-fetal medicine (MFM) specialist should be recommended prior to conception.²² Preconception recommendations include addressing optimization of maternal medical comorbidities, addressing routine health screening and vaccinations, performing sexually transmitted infection screening, and optimizing HIV disease status.^3,22,23

With the assistance of adult medicine and infectious disease clinicians, a cART regimen that is sufficient to reliably maintain viral suppression (that is, viral load < 50 copies/mL on 2 separate occasions at least 3 months apart) and is safe for use in pregnancy should be established.³ In serodiscordant couples, recommended mechanisms to prevent HIV transmission during conception include sustained viral suppression in the HIV-positive partner, PrEP use in the HIV-negative partner, and timing of unprotected intercourse during peak fertility only.³

Antepartum care

The initial prenatal visit

Women who have no prior screening for HIV or prior negative HIV results should undergo HIV screening at the first prenatal visit.³ Screening should be performed in accordance with the “opt out method.”⁶ Using this method, a woman without a known diagnosis of HIV infection is told that she will undergo HIV screening as a component of routine prenatal care unless she decides that she does not want this test performed.^6,24,25 At the time of screening, all pregnant women should be provided with comprehensive information regarding HIV screening, HIV screening results, and the implications of HIV infection on pregnancy.²⁶

In the pregnant patient with confirmed HIV infection, all preconception considerations should be addressed. If not already in place, referrals to appropriate providers (infectious disease specialist, ObGyn, MFM specialist) and ancillary support staff (social services, behavioral health support) should be arranged. All efforts should be implemented to optimize additional medical comorbidities. TABLE 3 lists additional prenatal testing requirements.²²

First and second trimester

Antiretroviral adherence and barriers to adherence should be addressed at every prenatal visit. If the patient is started on antiretroviral therapy in pregnancy or is switched to an alternative cART regimen, viral load assessment should be performed 2 to 4 weeks after the start or change in cART and then repeated monthly until undetectable levels are achieved.^3,26 If an undetectable viral load cannot be obtained, cART adherence should be thoroughly evaluated, and the patient should be referred to an infectious disease or HIV treatment specialist.²⁶

If the initial prenatal testing indicates an undetectable viral load, repeat viral load assessment can be performed every 3 months throughout the pregnancy.³ If initial prenatal testing indicates an undetectable HIV viral load and the T-lymphocyte count is greater than 200 cells/mm³, repeat viral load testing can be performed every 6 months to ensure stability.³

Early screening for gestational diabetes should be performed in patients receiving protease inhibitors because these agents may interfere with carbohydrate tolerance.^22,26

Continue to: Third trimester...

Third trimester

Women with negative HIV screening at the initial prenatal evaluation should undergo repeat HIV screening in the third trimester if they are at high risk for HIV exposure.²⁵ Factors that determine high-risk status are listed in TABLE 4.²⁷ Sexually transmitted infection screening should be repeated in the third trimester.²⁶

Repeat assessment of the viral load should be completed between 34 and 36 weeks’ gestation or sooner if additional indications for early term or late preterm delivery arise.³ Viral load assessments aid in determining delivery timing and route and the need for zidovudine (ZDV) treatment (FIGURE).

Studies that were performed prior to standardized cART use found higher rates of perinatal transmission associated with vaginal delivery when compared with cesarean delivery (CD).^28-30 However, these studies did not account for measures of viral load within their study populations.^28-30

In more recent studies performed in the era of standardized cART and viral load monitoring, CD does not provide protection from perinatal transmission when the maternal viral load is less than 1,000 copies/mL at the time of delivery.³¹ Similarly, delivery prior to 40 weeks’ gestation does not confer protection from perinatal transmission.³²

Alternatively, if the maternal viral load is 1,000 copies/mL or greater, CD should be considered to reduce the risk of perinatal transmission. A scheduled, elective CD at 38 weeks’ gestation is recommended in those with a maternal viral load of 1,000 copies/mL or greater and no medical indication for earlier delivery in order to decrease the likelihood of labor onset and/or rupture of membranes prior to delivery.^3,33

Intrapartum care

Rapid antigen testing (with follow-up confirmatory testing as indicated) is recommended in patients presenting to labor and delivery with no prior documentation of HIV status.^3,8,26

Despite a significant decrease in perinatal transmission rates over the last 30 years, a large proportion of perinatal transmission cases are thought to result from intrapartum fetal exposure. While the mechanism of transmission is not known, a correlation between maternal viral load and risk for perinatal transmission has been shown. A maternal viral load of less than 1,000 copies/mL has been associated with a perinatal transmission risk of less than 2%.^34,35 A maternal viral load between 50 and 999 copies/mL has been associated with a perinatal transmission rate of 1% to 2% compared with less than 1% for a maternal viral load of less than 50 copies/mL or undetectable measures.^5,36,37

These differences in perinatal transmission rates have prompted the recommendation for administration of ZDV for a minimum of 3 hours prior to delivery in mothers with a viral load of 1,000 copies/mL or greater.^4,38 The recommended ZDV dosing is: a 1-hour intravenous loading dose of 2 mg/kg followed by continuous infusion of 1 mg/kg per hour until delivery.^39,40 Patients who opt for vaginal delivery despite nonsuppressed viral loads (≥1,000 copies/mL) after thorough perinatal counseling should receive ZDV at the start of labor through delivery.³ All patients should be continued on cART throughout their intrapartum and postpartum course.

The duration of membrane rupture and the use of invasive fetal monitoring (that is, fetal scalp electrodes) have been assessed as mechanisms of perinatal transmission. Although they were performed prior to the standardized use of cART, several studies demonstrated that increased perinatal transmission rates were associated with invasive fetal monitoring.^34,41,42 While limited data have refuted this finding in women with suppressed viral loads (< 50 copies/mL), the American College of Obstetricians and Gynecologists recommends avoiding the use of invasive fetal monitoring in labor.²⁶

Pre-cART studies demonstrated increased rates of perinatal transmission with longer durations of membrane rupture prior to delivery.^43,44 More recent studies have reevaluated this association and determined that the increased perinatal transmission rates are more likely associated with higher maternal viral loads at the time of delivery rather than duration of membrane rupture.^45-47 No clear evidence describes when or if CD after the onset of labor or rupture of membranes provides protection from perinatal HIV transmission in pregnant women with HIV receiving no antiretroviral drugs or only ZDV during labor.^43,48 CD can be considered for patients in whom scheduled, pre-labor CD was planned who present in labor or with rupture of membranes prior to scheduled CD.²⁶ These, and additional intrapartum considerations, are listed in TABLE 5.^49,50

Appropriate personal protective equipment should be available and donned for all providers present throughout intrapartum management and at delivery.^23,26 Should any provider injury occur, immediate cleansing of the injury site should be performed, followed by referral to proper workplace supervisors for additional laboratory testing and antiretroviral prophylaxis.

Continue to: Postpartum care...

Postpartum care

Postpartum contraception should be offered and provided in accordance with patient request. Regardless of other birth control methods, strict condom use should be advised. PrEP should be discussed and offered for all partners of serodiscordant couples.

Upon outpatient follow-up, assessment and provision of routine health maintenance should be performed. Any abnormal cervical pathology encountered during prenatal care should be managed in accordance with ASCCP guidelines.¹² Follow-up care should be established with adult medicine, infectious disease, and ObGyn clinicians.²⁶

Neonatal considerations

Neonates born to mothers with positive or unknown HIV status should undergo expedited HIV testing.^51,52 Consultation should be conducted with pediatric or neonatology colleagues to determine the antiretroviral regimen and duration of therapy based on presumed HIV status of the neonate. Ideally, antiretroviral therapy should be initiated within 6 hours of delivery.^3,53

Formula feeding should be implemented as maternal HIV infection is one of the few contraindications to breastfeeding.^54,55 The risk of late breast milk transmission, defined as postnatal transmission that occurs after 1 month of age, may vary based on maternal viral load, but it has been reported as high as 8.9 transmissions per 100 person-years of breastfeeding.⁵⁶

Resources available

Care of the pregnant patient with HIV and the reduction of perinatal transmission both depend on early diagnosis of HIV and effective treatment with cART. Such patients benefit from a team-based care model that includes the ObGyn and/or MFM specialist, infectious disease clinician, pediatrician, and social worker. As guidelines evolve for care of these patients, a reference checklist, such as the examples provided at the Society for Maternal-Fetal Medicine website (smfm.org) or at HIV.gov, provide an outline for:

• management before, during, and after pregnancy
• suggestions for management teams of interest to successfully carry out the checklist requirements
• proposals for measurements of quality performance with the use of checklists in the management of HIV in pregnancy.

In addition, assistance with clinical decision making for patients with HIV in pregnancy can be obtained via telephone consultation with the National Clinician Consultation Center–Perinatal HIV/AIDS (888-448-8765), which is available 24 hours a day, 7 days a week. ●

Abdel-Fattah M, Cooper D, Davidson T, et al. Single-incision mini-slings for stress urinary incontinence in women. N Engl J Med. 2022;386:1230-1243.

EXPERT COMMENTARY

A joint society position statement by the American Urogynecologic Society and the Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction published in December 2021 declared synthetic midurethral slings, first cleared for use in the United States in the early 1990s, the most extensively studied anti-incontinence operation and the standard of care for the treatment of female stress urinary incontinence.¹ Full-length retropubic and transobturator (out-in and in-out) slings have been extensively evaluated for safety and efficacy in well-conducted randomized trials.² Single-incision mini-slings (SIMS) were first cleared for use in 2006, but they lack the long-term safety and comparative effectiveness data of full-length standard midurethral slings (SMUS).³ Furthermore, several iterations of the mini-slings have come to market but have been withdrawn or modified to allow for adjustability.

The SIMS trial by Abdel-Fattah and colleagues, published recently in the New England Journal of Medicine, is one of the few randomized trials with long-term (3 year) subjective and objective outcome data based on comparison of adjustable single-incision mini-slings versus standard full-length midurethral slings.

Details of the study

The SIMS trial is a noninferiority multicenter randomized controlled trial funded by the National Institute for Health Research at 21 hospitals in the United Kingdom that compared adjustable mini-sling procedures performed under local anesthesia with full-length retrotropubic and transobturator sling procedures performed under general anesthesia. Patients and surgeons were not masked to study group assignment because of the differences in anesthesia, and patients with greater than stage 2 prolapse were excluded from the trial.

The primary outcome was Patient Global Impression of Improvement (PGI-I) based on a 7-point Likert scale, with success defined as very much improved or much improved at 15 months and failure defined as all other responses (improved, same, worse, much worse, and very much worse). A noninferiority margin was set at 10 percentage points at 15 months.

Secondary outcomes and adverse events at 36 months included postoperative pain, return to normal activities, objective success based on a 24-hour pad test weight of less than 8 g, and tape exposure, organ injury, new or worsening urinary urgency, dyspareunia, and need for prolonged catheterization.

A total of 596 women were enrolled in the study, 298 in the mini-sling arm and 298 in the standard midurethral sling arm. Baseline characteristics were similar in both groups with most sling procedures being performed by general consultant gynecologists (>60%) versus subspecialist urogynecologists.

Results. Success at 15 months, based on the PGI-I responses of very much better or much better, was noted in 79.1% of patients in the mini-sling group (212/268) versus 75.6% in the full-length sling group (189/250). The authors deemed mini-slings noninferior to standard full-length slings (adjusted risk difference, 4.6 percentage points; 95% confidence interval [CI], -2.7 to 11.8; P<.001 for noninferiority). Success rates declined but remained similar in both groups at 36 months: 72% in the mini-sling group (177/246) and 66.8% (157/235) in the full-length sling group.

More than 70% of mini-incision slings were Altis (Coloplast) and 22% were Ajust (CR Bard; since withdrawn from the market). The majority of standard midurethral full-length slings were transobturator slings (52.9%) versus retropubic slings (35.6%).

While blood loss, organ injury, and 36-month objective 24-hour pad test did not differ between groups, there were significant differences in other secondary outcomes. Dyspareunia and coital incontinence were more common with mini-slings at 15 and 36 months, reported in 11.7% of the mini-sling group and 4.8% of the full-length group (P<.01). Groin or thigh pain did not differ significantly between groups at 36 months (14.1% in mini-sling and 14.9% in full-length sling group, P = .61). Mesh exposure was noted in 3.3% of those with mini-slings and 1.9% of those with standard midurethral slings. The need for surgical intervention to treat recurrent stress incontinence or mesh removal for voiding dysfunction, pain, or mesh exposure also did not differ between groups (8.7% of the mini-sling group and 4.6% of the midurethral sling group; P = .12).

Study strengths and limitations

The strengths of this pragmatic randomized trial are in the use of clinically important and validated patient-reported subjective and objective outcomes in an adequately powered multisite trial of long duration (36 months). This study is important in demonstrating noninferiority of the mini-sling procedure compared with full-length slings, especially given this trial’s timing when there was a pause or suspension of sling mesh use in the United Kingdom beginning in 2018.

Study limitations include the loss to follow-up with diminished response rate of 87.1% at 15 months and 81.4% at 36 months and the inability to adequately assess for the uncommon outcomes, such as mesh-related complications and groin pain.

Further analysis needed

The high rate of dyspareunia (11.7%) with mini-slings deserves further analysis and consideration of whether or not to implant them in patients who are sexually active. Groin or thigh pain did not differ at 36 months but reported pain coincided with the higher percentage of transobturator slings placed over retropubic slings. Prior randomized trials of transobturator versus retropubic midurethral slings have demonstrated this same phenomenon of increased groin pain with the transobturator approach.² Furthermore, this study by Abdel-Fattah and colleagues excluded patients with advanced anterior or apical prolapse, but one trial is currently underway in the United States.⁴

In conclusion, this trial suggests some advantages of single-incision mini-slings—ability to perform the procedure under local anesthesia, less synthetic mesh implantation with theoretically decreased risk of bladder perforation or bowel injury, and potential for easier removal compared with full-length slings. Disadvantages include dyspareunia and mesh exposure, which could be significant trade-offs for patients. ●

Abdel-Fattah M, Cooper D, Davidson T, et al. Single-incision mini-slings for stress urinary incontinence in women. N Engl J Med. 2022;386:1230-1243.

EXPERT COMMENTARY

A joint society position statement by the American Urogynecologic Society and the Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction published in December 2021 declared synthetic midurethral slings, first cleared for use in the United States in the early 1990s, the most extensively studied anti-incontinence operation and the standard of care for the treatment of female stress urinary incontinence.¹ Full-length retropubic and transobturator (out-in and in-out) slings have been extensively evaluated for safety and efficacy in well-conducted randomized trials.² Single-incision mini-slings (SIMS) were first cleared for use in 2006, but they lack the long-term safety and comparative effectiveness data of full-length standard midurethral slings (SMUS).³ Furthermore, several iterations of the mini-slings have come to market but have been withdrawn or modified to allow for adjustability.

The SIMS trial by Abdel-Fattah and colleagues, published recently in the New England Journal of Medicine, is one of the few randomized trials with long-term (3 year) subjective and objective outcome data based on comparison of adjustable single-incision mini-slings versus standard full-length midurethral slings.

Details of the study

The SIMS trial is a noninferiority multicenter randomized controlled trial funded by the National Institute for Health Research at 21 hospitals in the United Kingdom that compared adjustable mini-sling procedures performed under local anesthesia with full-length retrotropubic and transobturator sling procedures performed under general anesthesia. Patients and surgeons were not masked to study group assignment because of the differences in anesthesia, and patients with greater than stage 2 prolapse were excluded from the trial.

The primary outcome was Patient Global Impression of Improvement (PGI-I) based on a 7-point Likert scale, with success defined as very much improved or much improved at 15 months and failure defined as all other responses (improved, same, worse, much worse, and very much worse). A noninferiority margin was set at 10 percentage points at 15 months.

Secondary outcomes and adverse events at 36 months included postoperative pain, return to normal activities, objective success based on a 24-hour pad test weight of less than 8 g, and tape exposure, organ injury, new or worsening urinary urgency, dyspareunia, and need for prolonged catheterization.

A total of 596 women were enrolled in the study, 298 in the mini-sling arm and 298 in the standard midurethral sling arm. Baseline characteristics were similar in both groups with most sling procedures being performed by general consultant gynecologists (>60%) versus subspecialist urogynecologists.

Results. Success at 15 months, based on the PGI-I responses of very much better or much better, was noted in 79.1% of patients in the mini-sling group (212/268) versus 75.6% in the full-length sling group (189/250). The authors deemed mini-slings noninferior to standard full-length slings (adjusted risk difference, 4.6 percentage points; 95% confidence interval [CI], -2.7 to 11.8; P<.001 for noninferiority). Success rates declined but remained similar in both groups at 36 months: 72% in the mini-sling group (177/246) and 66.8% (157/235) in the full-length sling group.

More than 70% of mini-incision slings were Altis (Coloplast) and 22% were Ajust (CR Bard; since withdrawn from the market). The majority of standard midurethral full-length slings were transobturator slings (52.9%) versus retropubic slings (35.6%).

While blood loss, organ injury, and 36-month objective 24-hour pad test did not differ between groups, there were significant differences in other secondary outcomes. Dyspareunia and coital incontinence were more common with mini-slings at 15 and 36 months, reported in 11.7% of the mini-sling group and 4.8% of the full-length group (P<.01). Groin or thigh pain did not differ significantly between groups at 36 months (14.1% in mini-sling and 14.9% in full-length sling group, P = .61). Mesh exposure was noted in 3.3% of those with mini-slings and 1.9% of those with standard midurethral slings. The need for surgical intervention to treat recurrent stress incontinence or mesh removal for voiding dysfunction, pain, or mesh exposure also did not differ between groups (8.7% of the mini-sling group and 4.6% of the midurethral sling group; P = .12).

Study strengths and limitations

The strengths of this pragmatic randomized trial are in the use of clinically important and validated patient-reported subjective and objective outcomes in an adequately powered multisite trial of long duration (36 months). This study is important in demonstrating noninferiority of the mini-sling procedure compared with full-length slings, especially given this trial’s timing when there was a pause or suspension of sling mesh use in the United Kingdom beginning in 2018.

Study limitations include the loss to follow-up with diminished response rate of 87.1% at 15 months and 81.4% at 36 months and the inability to adequately assess for the uncommon outcomes, such as mesh-related complications and groin pain.

Further analysis needed

The high rate of dyspareunia (11.7%) with mini-slings deserves further analysis and consideration of whether or not to implant them in patients who are sexually active. Groin or thigh pain did not differ at 36 months but reported pain coincided with the higher percentage of transobturator slings placed over retropubic slings. Prior randomized trials of transobturator versus retropubic midurethral slings have demonstrated this same phenomenon of increased groin pain with the transobturator approach.² Furthermore, this study by Abdel-Fattah and colleagues excluded patients with advanced anterior or apical prolapse, but one trial is currently underway in the United States.⁴

In conclusion, this trial suggests some advantages of single-incision mini-slings—ability to perform the procedure under local anesthesia, less synthetic mesh implantation with theoretically decreased risk of bladder perforation or bowel injury, and potential for easier removal compared with full-length slings. Disadvantages include dyspareunia and mesh exposure, which could be significant trade-offs for patients. ●

Abdel-Fattah M, Cooper D, Davidson T, et al. Single-incision mini-slings for stress urinary incontinence in women. N Engl J Med. 2022;386:1230-1243.

EXPERT COMMENTARY

A joint society position statement by the American Urogynecologic Society and the Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction published in December 2021 declared synthetic midurethral slings, first cleared for use in the United States in the early 1990s, the most extensively studied anti-incontinence operation and the standard of care for the treatment of female stress urinary incontinence.¹ Full-length retropubic and transobturator (out-in and in-out) slings have been extensively evaluated for safety and efficacy in well-conducted randomized trials.² Single-incision mini-slings (SIMS) were first cleared for use in 2006, but they lack the long-term safety and comparative effectiveness data of full-length standard midurethral slings (SMUS).³ Furthermore, several iterations of the mini-slings have come to market but have been withdrawn or modified to allow for adjustability.

The SIMS trial by Abdel-Fattah and colleagues, published recently in the New England Journal of Medicine, is one of the few randomized trials with long-term (3 year) subjective and objective outcome data based on comparison of adjustable single-incision mini-slings versus standard full-length midurethral slings.

Details of the study

The SIMS trial is a noninferiority multicenter randomized controlled trial funded by the National Institute for Health Research at 21 hospitals in the United Kingdom that compared adjustable mini-sling procedures performed under local anesthesia with full-length retrotropubic and transobturator sling procedures performed under general anesthesia. Patients and surgeons were not masked to study group assignment because of the differences in anesthesia, and patients with greater than stage 2 prolapse were excluded from the trial.

The primary outcome was Patient Global Impression of Improvement (PGI-I) based on a 7-point Likert scale, with success defined as very much improved or much improved at 15 months and failure defined as all other responses (improved, same, worse, much worse, and very much worse). A noninferiority margin was set at 10 percentage points at 15 months.

Secondary outcomes and adverse events at 36 months included postoperative pain, return to normal activities, objective success based on a 24-hour pad test weight of less than 8 g, and tape exposure, organ injury, new or worsening urinary urgency, dyspareunia, and need for prolonged catheterization.

A total of 596 women were enrolled in the study, 298 in the mini-sling arm and 298 in the standard midurethral sling arm. Baseline characteristics were similar in both groups with most sling procedures being performed by general consultant gynecologists (>60%) versus subspecialist urogynecologists.

Results. Success at 15 months, based on the PGI-I responses of very much better or much better, was noted in 79.1% of patients in the mini-sling group (212/268) versus 75.6% in the full-length sling group (189/250). The authors deemed mini-slings noninferior to standard full-length slings (adjusted risk difference, 4.6 percentage points; 95% confidence interval [CI], -2.7 to 11.8; P<.001 for noninferiority). Success rates declined but remained similar in both groups at 36 months: 72% in the mini-sling group (177/246) and 66.8% (157/235) in the full-length sling group.

More than 70% of mini-incision slings were Altis (Coloplast) and 22% were Ajust (CR Bard; since withdrawn from the market). The majority of standard midurethral full-length slings were transobturator slings (52.9%) versus retropubic slings (35.6%).

While blood loss, organ injury, and 36-month objective 24-hour pad test did not differ between groups, there were significant differences in other secondary outcomes. Dyspareunia and coital incontinence were more common with mini-slings at 15 and 36 months, reported in 11.7% of the mini-sling group and 4.8% of the full-length group (P<.01). Groin or thigh pain did not differ significantly between groups at 36 months (14.1% in mini-sling and 14.9% in full-length sling group, P = .61). Mesh exposure was noted in 3.3% of those with mini-slings and 1.9% of those with standard midurethral slings. The need for surgical intervention to treat recurrent stress incontinence or mesh removal for voiding dysfunction, pain, or mesh exposure also did not differ between groups (8.7% of the mini-sling group and 4.6% of the midurethral sling group; P = .12).

Study strengths and limitations

The strengths of this pragmatic randomized trial are in the use of clinically important and validated patient-reported subjective and objective outcomes in an adequately powered multisite trial of long duration (36 months). This study is important in demonstrating noninferiority of the mini-sling procedure compared with full-length slings, especially given this trial’s timing when there was a pause or suspension of sling mesh use in the United Kingdom beginning in 2018.

Study limitations include the loss to follow-up with diminished response rate of 87.1% at 15 months and 81.4% at 36 months and the inability to adequately assess for the uncommon outcomes, such as mesh-related complications and groin pain.

Further analysis needed

The high rate of dyspareunia (11.7%) with mini-slings deserves further analysis and consideration of whether or not to implant them in patients who are sexually active. Groin or thigh pain did not differ at 36 months but reported pain coincided with the higher percentage of transobturator slings placed over retropubic slings. Prior randomized trials of transobturator versus retropubic midurethral slings have demonstrated this same phenomenon of increased groin pain with the transobturator approach.² Furthermore, this study by Abdel-Fattah and colleagues excluded patients with advanced anterior or apical prolapse, but one trial is currently underway in the United States.⁴

In conclusion, this trial suggests some advantages of single-incision mini-slings—ability to perform the procedure under local anesthesia, less synthetic mesh implantation with theoretically decreased risk of bladder perforation or bowel injury, and potential for easier removal compared with full-length slings. Disadvantages include dyspareunia and mesh exposure, which could be significant trade-offs for patients. ●

In the uterus, coordinated myometrial cell contraction is not triggered by neural activation; instead, myometrial cells work together as a contractile syncytium through cell-to-cell gap junction connections permitting the intercellular sharing of small molecules, which in turn facilitates activation of the actin-myosin contractile apparatus and coordinated uterine contraction. In myometrial cells, connexin 43 (Cx43) is the main gap junction protein. Cx43 permits the passage of small hydrophilic molecules (ATP) and ions (calcium) cell to cell. Estradiol increases Cx43 synthesis in human myometrial cells.¹ Progesterone decreases Cx43 synthesis effectively isolating myometrial cells, reducing cell-to-cell sharing of chemicals that stimulate contraction, blocking coordinated uterine contraction.² Progesterone suppression of Cx43 synthesis helps to prevent premature uterine contraction during pregnancy. At term, decreases in progesterone levels result in an increase in Cx43 synthesis, facilitating the onset of effective labor. In myometrial cells, antiprogestins, including mifepristone, increase the number of gap junction connections, facilitating a coordinated contractile signal in response to misoprostol or oxytocin.^3,4

It takes time for antiprogestins to stimulate myometrial cell production of Cx43. In the rat myometrium the administration of mifepristone results in a 2.5-fold increase of Cx43 mRNA transcripts within 9 hours and a 5.6-fold increase in 24 hours.³ Hence, most mifepristone treatment protocols involve administering mifepristone and waiting 24 to 48 hours before administering an agent that stimulates myometrial contraction, such as misoprostol. Antiprogestins also increase the sensitivity of myometrial cells to oxytocin stimulation of uterine contractions by increasing Cx43 concentration.⁴

Progesterone also regulates other important biological processes in the cervix, decidua, placenta, and cervix. Antiprogestins can facilitate cervical ripening and disrupt decidual function, interfering with the attachment of pregnancy tissue.⁵ In the cervix, antiprogestins increase matrix metalloproteinase expression, disrupting collagen organization, decreasing cervical tensile strength and leading to cervical ripening.⁶

Pharmacology of mifepristone

Mifepristone is an antiprogestin and antiglucocorticoid with high-affinity binding to both the progesterone and glucocorticoid receptors (FIGURE 1). The phenylaminodimethyl group at C-11 of mifepristone changes the positional equilibrium of helix 12 of the progesterone receptor, reducing the ability of the receptor to bind required co-activators, limiting receptor binding to DNA, resulting in an antiprogesterone effect.⁷ At the low, single-dose used for treatment of miscarriage and fetal demise (200 mg one dose), mifepristone is an antiprogestin. At the high, daily dose used for the treatment of hyperglycemia caused by Cushing disease (≥ 300 mg daily), mifepristone is also an antiglucocorticoid.

Although mifepristone is a powerful antiglucocorticoid, in patients with an intact hypothalamic-pituitary-adrenal axis, mifepristone does not cause adrenal insufficiency. In people with an intact hypothalamic-pituitary-adrenal axis, daily administration of mifepristone (≥ 200 mg) for 7 days or longer results in an increase in pituitary secretion of ACTH and adrenal secretion of cortisol, largely overcoming the antiglucocorticoid action of mifepristone.^8-10 This compensatory increase in ACTH and cortisol is not possible in patients who have had a hypophysectomy or bilateral adrenalectomy or have adrenal suppression due to long-term treatment with high doses of glucocorticoids. Mifepristone is contraindicated for patients with these conditions because it may cause glucocorticoid insufficiency by blocking glucocorticoid receptors.

The terminal half-life of mifepristone is 18 hours.¹¹ Following oral administration of a single dose of mifepristone 200 mg the peak circulating concentration is reached in 90 minutes. Mifepristone is metabolized by CYP3A4 and is also a strong inhibitor of CYP3A4. Contraindications to the use of mifepristone include adrenal failure, porphyria, hemorrhagic diseases, anticoagulation, an IUD in the uterus, ectopic pregnancy, long-term glucocorticoid administration, and an undiagnosed adnexal mass.

Continue to: Mifepristone-misoprostol for the treatment of early missed miscarriage with a gestational sac...

Mifepristone-misoprostol for the treatment of early missed miscarriage with a gestational sac

For patients with a miscarriage, the treatment options to resolve the pregnancy loss are expectant management, medication, or surgery.¹² Joint decision-making is recommended to establish a management plan that supports the patient’s values. Expectant management is most likely to result in a multi-week process to achieve completion of the miscarriage. A surgical procedure is most likely to result in rapid resolution of the miscarriage with the greatest rate of success. Surgical evacuation of the uterus may be the preferred option for patients who have excessive uterine bleeding or concerning vital signs. Both medical and surgical management are more likely than expectant management to successfully resolve the miscarriage.¹³

In the past, the standard approach to medication management of a miscarriage was the administration of one or more doses of misoprostol, a synthetic prostaglandin E1. However, two large trials have reported that the dual-medication sequence of mifepristone followed 24 to 48 hours later by misoprostol is more effective than misoprostol alone for resolving a miscarriage.^14,15 This is probably due to mifepristone making the uterus more responsive to the effects of misoprostol.

Schreiber and colleagues¹⁴ reported a study of 300 patients with an anembryonic gestation or embryonic demise, between 5 and 12 completed weeks of gestation, who were randomly assigned to treatment with mifepristone (200 mg) followed in 24 to 48 hours with vaginal misoprostol (800 µg) or vaginal misoprostol (800 µg) alone. Ultrasonography was performed 1 to 4 days after misoprostol administration. Successful treatment was defined as expulsion of the gestational sac plus no additional surgical or medical intervention within 30 days after treatment. In this study, the dual-medication regimen of mifepristone-misoprostol was more successful than misoprostol alone in resolving the miscarriage, 84% and 67%, respectively (relative risk [RR], 1.25; 95% confidence interval [CI], 1.09–1.43).

Surgical evacuation of the uterus occurred less often with mifepristone-misoprostol treatment than with misoprostol monotherapy—9% and 24%, respectively (RR, 0.37; 95% CI, 0.21–0.68). Pelvic infection occurred in 2 patients (1.3%) in each group. Uterine bleeding managed with blood transfusion occurred in 3 patients who received mifepristone-misoprostol and 1 patient who received misoprostol alone. In this study, clinical factors including active bleeding, parity, and gestational age did not influence treatment success with the mifepristone-misoprostol regimen.¹⁶ The mifepristone-misoprostol regimen was reported to be more cost-effective than misoprostol alone.¹⁷

Chu and colleagues¹⁵ reported a study of medication treatment of missed miscarriage that included more than 700 patients randomly assigned to treatment with mifepristone-misoprostol or placebo-misoprostol. Missed miscarriage was diagnosed by an ultrasound demonstrating a gestational sac and a nonviable pregnancy. The doses of mifepristone and misoprostol were 200 mg and 800 µg, respectively. In this study the misoprostol was administered 48 hours following mifepristone or placebo using a vaginal, oral, or buccal route, but 90% of patients used the vaginal route. Treatment was considered successful if the patient passed the gestational sac as determined by an ultrasound performed 7 days after entry into the study. If the gestational sac was passed, the patients were asked to do a urine pregnancy test 3 weeks after entering the study to conclude their care episode. If patients did not pass the gestational sac, they were offered a second dose of misoprostol or surgical evacuation. In this study, mifepristone-misoprostol resulted in fewer patients who did not pass the gestational sac within 7 days after entry into the study than placebo (mifepristone-misoprostol, 17% vs placebo-misoprostol, 24% (P=.043). Surgical intervention was performed in 25% of patients treated with placebo-misoprostol and 17% of patients treated with mifepristone-misoprostol (RR, 0.73; 95% CI, 0.53–0.95; P=.021). A cost-effectiveness analysis of the trial results reported that the combination of mifepristone-misoprostol was less costly than misoprostol alone for the management of missed miscarriages.¹⁸

Misoprostol can be administered by an oral, buccal, rectal, or vaginal route.^19,20 Vaginal administration results in higher circulating concentrations of misoprostol than buccal administration, but both routes of administration produce similar mean uterine tone and mean uterine activity as measured by an intrauterine pressure transducer over 5 hours.²¹ Hence, at our institution, we most often use buccal administration of misoprostol. To assess effectiveness of mifepristone-misoprostol treatment, 1 week after treatment with a pelvic ultrasound to detect expulsion of the gestational sac. Alternatively, a urine pregnancy test can be performed 3 weeks following medication treatment. The mifepristone-misoprostol regimen is not approved by the US Food and Drug Administration for the treatment of miscarriage.

Continue to: Mifepristone-misoprostol for the treatment of fetal demise...

Mifepristone-misoprostol for the treatment of fetal demise

Fetal loss in the second or third trimesters is a devastating experience for most patients, painfully echoing in the heart and mind for years. Empathic and effective treatment of fetal loss may reduce the adverse impact of the event. Multiple studies have reported that combinations of mifepristone and misoprostol reduced the time from initiation of labor contractions to birth compared with misoprostol alone.^22-28 In addition, the combination of mifepristone-misoprostol reduced the amount of misoprostol needed to achieve delivery.^22,23

In one clinical trial, 66 patients with fetal demise between 14 and 28 weeks’ gestation were randomized to receive mifepristone 200 mg or placebo.²² Twenty-four to 48 hours later, misoprostol for induction of labor was initiated. Among the patients from 14 to 23 completed weeks of gestation, the misoprostol dose was 400 µg vaginally every 6 hours. For patients from 24 to 28 weeks gestation, the misoprostol dose was 200 µg vaginally every 4 hours. The median times from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups were 6.8 hours and 10.5 hours (P=.002).

Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required fewer doses of misoprostol (2.1 vs 3.4; P=.002) and a lower total dose of misoprostol (768 µg vs 1,182 µg; P=.003). All patients in the mifepristone group delivered within 24 hours. By contrast, 13% of the patients in the placebo group delivered more than 24 hours after the initiation of misoprostol treatment. Five patients were readmitted with retained products of conception needing suction curettage—4 in the placebo group and 1 in the mifepristone group.²²

In a second clinical trial, 110 patients with fetal demise after 20 weeks of gestation were randomized to receive mifepristone 200 mg or placebo.²³ Thirty-six to 48 hours later, misoprostol for induction of labor was initiated. Among the patients from 20 to 25 completed weeks of gestation, the misoprostol dose was 100 µg vaginally every 6 hours for a maximum of 4 doses. For patients ≥26 weeks gestation, the misoprostol dose was 50 µg vaginally every 4 hours for a maximum of 6 doses. The median times from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups were 9.8 hours and 16.3 hours. (P=.001).

Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required a lower total dose of misoprostol (110 µg vs 198 µg, P<.001).

Delivery within 24 hours following initiation of misoprostol occurred in 93% and 73% of the patients in the mifepristone and placebo groups, respectively (P<.001). Compared with patients in the mifepristone group, shivering occurred more frequently among the patients in the placebo group (7.5% vs 19.2%; P=.09), likely because they received greater doses of misoprostol.²³

Miscarriage and fetal demise frequently cause patients to experience a range of emotions including denial, numbness, grief, anger, guilt, and depression. It may take months or years for people to progress to a tentative acceptance of the loss, refocusing on future aspirations. Empathic care and timely and effective medical intervention to resolve the pregnancy loss optimize outcomes. For medication treatment of miscarriage and fetal demise, mifepristone is an important agent because it improves the success rate for resolution of miscarriage without surgery and it shortens the time of labor for inductions for fetal demise. Obstetrician-gynecologists are the specialists leading advances in treatment of miscarriage and fetal demise. I encourage you to use mifepristone in your care of appropriate patients with miscarriage and fetal demise. ●

In the uterus, coordinated myometrial cell contraction is not triggered by neural activation; instead, myometrial cells work together as a contractile syncytium through cell-to-cell gap junction connections permitting the intercellular sharing of small molecules, which in turn facilitates activation of the actin-myosin contractile apparatus and coordinated uterine contraction. In myometrial cells, connexin 43 (Cx43) is the main gap junction protein. Cx43 permits the passage of small hydrophilic molecules (ATP) and ions (calcium) cell to cell. Estradiol increases Cx43 synthesis in human myometrial cells.¹ Progesterone decreases Cx43 synthesis effectively isolating myometrial cells, reducing cell-to-cell sharing of chemicals that stimulate contraction, blocking coordinated uterine contraction.² Progesterone suppression of Cx43 synthesis helps to prevent premature uterine contraction during pregnancy. At term, decreases in progesterone levels result in an increase in Cx43 synthesis, facilitating the onset of effective labor. In myometrial cells, antiprogestins, including mifepristone, increase the number of gap junction connections, facilitating a coordinated contractile signal in response to misoprostol or oxytocin.^3,4

It takes time for antiprogestins to stimulate myometrial cell production of Cx43. In the rat myometrium the administration of mifepristone results in a 2.5-fold increase of Cx43 mRNA transcripts within 9 hours and a 5.6-fold increase in 24 hours.³ Hence, most mifepristone treatment protocols involve administering mifepristone and waiting 24 to 48 hours before administering an agent that stimulates myometrial contraction, such as misoprostol. Antiprogestins also increase the sensitivity of myometrial cells to oxytocin stimulation of uterine contractions by increasing Cx43 concentration.⁴

Progesterone also regulates other important biological processes in the cervix, decidua, placenta, and cervix. Antiprogestins can facilitate cervical ripening and disrupt decidual function, interfering with the attachment of pregnancy tissue.⁵ In the cervix, antiprogestins increase matrix metalloproteinase expression, disrupting collagen organization, decreasing cervical tensile strength and leading to cervical ripening.⁶

Pharmacology of mifepristone

Mifepristone is an antiprogestin and antiglucocorticoid with high-affinity binding to both the progesterone and glucocorticoid receptors (FIGURE 1). The phenylaminodimethyl group at C-11 of mifepristone changes the positional equilibrium of helix 12 of the progesterone receptor, reducing the ability of the receptor to bind required co-activators, limiting receptor binding to DNA, resulting in an antiprogesterone effect.⁷ At the low, single-dose used for treatment of miscarriage and fetal demise (200 mg one dose), mifepristone is an antiprogestin. At the high, daily dose used for the treatment of hyperglycemia caused by Cushing disease (≥ 300 mg daily), mifepristone is also an antiglucocorticoid.

Although mifepristone is a powerful antiglucocorticoid, in patients with an intact hypothalamic-pituitary-adrenal axis, mifepristone does not cause adrenal insufficiency. In people with an intact hypothalamic-pituitary-adrenal axis, daily administration of mifepristone (≥ 200 mg) for 7 days or longer results in an increase in pituitary secretion of ACTH and adrenal secretion of cortisol, largely overcoming the antiglucocorticoid action of mifepristone.^8-10 This compensatory increase in ACTH and cortisol is not possible in patients who have had a hypophysectomy or bilateral adrenalectomy or have adrenal suppression due to long-term treatment with high doses of glucocorticoids. Mifepristone is contraindicated for patients with these conditions because it may cause glucocorticoid insufficiency by blocking glucocorticoid receptors.

The terminal half-life of mifepristone is 18 hours.¹¹ Following oral administration of a single dose of mifepristone 200 mg the peak circulating concentration is reached in 90 minutes. Mifepristone is metabolized by CYP3A4 and is also a strong inhibitor of CYP3A4. Contraindications to the use of mifepristone include adrenal failure, porphyria, hemorrhagic diseases, anticoagulation, an IUD in the uterus, ectopic pregnancy, long-term glucocorticoid administration, and an undiagnosed adnexal mass.

Continue to: Mifepristone-misoprostol for the treatment of early missed miscarriage with a gestational sac...

Mifepristone-misoprostol for the treatment of early missed miscarriage with a gestational sac

For patients with a miscarriage, the treatment options to resolve the pregnancy loss are expectant management, medication, or surgery.¹² Joint decision-making is recommended to establish a management plan that supports the patient’s values. Expectant management is most likely to result in a multi-week process to achieve completion of the miscarriage. A surgical procedure is most likely to result in rapid resolution of the miscarriage with the greatest rate of success. Surgical evacuation of the uterus may be the preferred option for patients who have excessive uterine bleeding or concerning vital signs. Both medical and surgical management are more likely than expectant management to successfully resolve the miscarriage.¹³

In the past, the standard approach to medication management of a miscarriage was the administration of one or more doses of misoprostol, a synthetic prostaglandin E1. However, two large trials have reported that the dual-medication sequence of mifepristone followed 24 to 48 hours later by misoprostol is more effective than misoprostol alone for resolving a miscarriage.^14,15 This is probably due to mifepristone making the uterus more responsive to the effects of misoprostol.

Schreiber and colleagues¹⁴ reported a study of 300 patients with an anembryonic gestation or embryonic demise, between 5 and 12 completed weeks of gestation, who were randomly assigned to treatment with mifepristone (200 mg) followed in 24 to 48 hours with vaginal misoprostol (800 µg) or vaginal misoprostol (800 µg) alone. Ultrasonography was performed 1 to 4 days after misoprostol administration. Successful treatment was defined as expulsion of the gestational sac plus no additional surgical or medical intervention within 30 days after treatment. In this study, the dual-medication regimen of mifepristone-misoprostol was more successful than misoprostol alone in resolving the miscarriage, 84% and 67%, respectively (relative risk [RR], 1.25; 95% confidence interval [CI], 1.09–1.43).

Surgical evacuation of the uterus occurred less often with mifepristone-misoprostol treatment than with misoprostol monotherapy—9% and 24%, respectively (RR, 0.37; 95% CI, 0.21–0.68). Pelvic infection occurred in 2 patients (1.3%) in each group. Uterine bleeding managed with blood transfusion occurred in 3 patients who received mifepristone-misoprostol and 1 patient who received misoprostol alone. In this study, clinical factors including active bleeding, parity, and gestational age did not influence treatment success with the mifepristone-misoprostol regimen.¹⁶ The mifepristone-misoprostol regimen was reported to be more cost-effective than misoprostol alone.¹⁷

Chu and colleagues¹⁵ reported a study of medication treatment of missed miscarriage that included more than 700 patients randomly assigned to treatment with mifepristone-misoprostol or placebo-misoprostol. Missed miscarriage was diagnosed by an ultrasound demonstrating a gestational sac and a nonviable pregnancy. The doses of mifepristone and misoprostol were 200 mg and 800 µg, respectively. In this study the misoprostol was administered 48 hours following mifepristone or placebo using a vaginal, oral, or buccal route, but 90% of patients used the vaginal route. Treatment was considered successful if the patient passed the gestational sac as determined by an ultrasound performed 7 days after entry into the study. If the gestational sac was passed, the patients were asked to do a urine pregnancy test 3 weeks after entering the study to conclude their care episode. If patients did not pass the gestational sac, they were offered a second dose of misoprostol or surgical evacuation. In this study, mifepristone-misoprostol resulted in fewer patients who did not pass the gestational sac within 7 days after entry into the study than placebo (mifepristone-misoprostol, 17% vs placebo-misoprostol, 24% (P=.043). Surgical intervention was performed in 25% of patients treated with placebo-misoprostol and 17% of patients treated with mifepristone-misoprostol (RR, 0.73; 95% CI, 0.53–0.95; P=.021). A cost-effectiveness analysis of the trial results reported that the combination of mifepristone-misoprostol was less costly than misoprostol alone for the management of missed miscarriages.¹⁸

Misoprostol can be administered by an oral, buccal, rectal, or vaginal route.^19,20 Vaginal administration results in higher circulating concentrations of misoprostol than buccal administration, but both routes of administration produce similar mean uterine tone and mean uterine activity as measured by an intrauterine pressure transducer over 5 hours.²¹ Hence, at our institution, we most often use buccal administration of misoprostol. To assess effectiveness of mifepristone-misoprostol treatment, 1 week after treatment with a pelvic ultrasound to detect expulsion of the gestational sac. Alternatively, a urine pregnancy test can be performed 3 weeks following medication treatment. The mifepristone-misoprostol regimen is not approved by the US Food and Drug Administration for the treatment of miscarriage.

Continue to: Mifepristone-misoprostol for the treatment of fetal demise...

Mifepristone-misoprostol for the treatment of fetal demise

Fetal loss in the second or third trimesters is a devastating experience for most patients, painfully echoing in the heart and mind for years. Empathic and effective treatment of fetal loss may reduce the adverse impact of the event. Multiple studies have reported that combinations of mifepristone and misoprostol reduced the time from initiation of labor contractions to birth compared with misoprostol alone.^22-28 In addition, the combination of mifepristone-misoprostol reduced the amount of misoprostol needed to achieve delivery.^22,23

In one clinical trial, 66 patients with fetal demise between 14 and 28 weeks’ gestation were randomized to receive mifepristone 200 mg or placebo.²² Twenty-four to 48 hours later, misoprostol for induction of labor was initiated. Among the patients from 14 to 23 completed weeks of gestation, the misoprostol dose was 400 µg vaginally every 6 hours. For patients from 24 to 28 weeks gestation, the misoprostol dose was 200 µg vaginally every 4 hours. The median times from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups were 6.8 hours and 10.5 hours (P=.002).

Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required fewer doses of misoprostol (2.1 vs 3.4; P=.002) and a lower total dose of misoprostol (768 µg vs 1,182 µg; P=.003). All patients in the mifepristone group delivered within 24 hours. By contrast, 13% of the patients in the placebo group delivered more than 24 hours after the initiation of misoprostol treatment. Five patients were readmitted with retained products of conception needing suction curettage—4 in the placebo group and 1 in the mifepristone group.²²

In a second clinical trial, 110 patients with fetal demise after 20 weeks of gestation were randomized to receive mifepristone 200 mg or placebo.²³ Thirty-six to 48 hours later, misoprostol for induction of labor was initiated. Among the patients from 20 to 25 completed weeks of gestation, the misoprostol dose was 100 µg vaginally every 6 hours for a maximum of 4 doses. For patients ≥26 weeks gestation, the misoprostol dose was 50 µg vaginally every 4 hours for a maximum of 6 doses. The median times from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups were 9.8 hours and 16.3 hours. (P=.001).

Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required a lower total dose of misoprostol (110 µg vs 198 µg, P<.001).

Delivery within 24 hours following initiation of misoprostol occurred in 93% and 73% of the patients in the mifepristone and placebo groups, respectively (P<.001). Compared with patients in the mifepristone group, shivering occurred more frequently among the patients in the placebo group (7.5% vs 19.2%; P=.09), likely because they received greater doses of misoprostol.²³

Miscarriage and fetal demise frequently cause patients to experience a range of emotions including denial, numbness, grief, anger, guilt, and depression. It may take months or years for people to progress to a tentative acceptance of the loss, refocusing on future aspirations. Empathic care and timely and effective medical intervention to resolve the pregnancy loss optimize outcomes. For medication treatment of miscarriage and fetal demise, mifepristone is an important agent because it improves the success rate for resolution of miscarriage without surgery and it shortens the time of labor for inductions for fetal demise. Obstetrician-gynecologists are the specialists leading advances in treatment of miscarriage and fetal demise. I encourage you to use mifepristone in your care of appropriate patients with miscarriage and fetal demise. ●

In the uterus, coordinated myometrial cell contraction is not triggered by neural activation; instead, myometrial cells work together as a contractile syncytium through cell-to-cell gap junction connections permitting the intercellular sharing of small molecules, which in turn facilitates activation of the actin-myosin contractile apparatus and coordinated uterine contraction. In myometrial cells, connexin 43 (Cx43) is the main gap junction protein. Cx43 permits the passage of small hydrophilic molecules (ATP) and ions (calcium) cell to cell. Estradiol increases Cx43 synthesis in human myometrial cells.¹ Progesterone decreases Cx43 synthesis effectively isolating myometrial cells, reducing cell-to-cell sharing of chemicals that stimulate contraction, blocking coordinated uterine contraction.² Progesterone suppression of Cx43 synthesis helps to prevent premature uterine contraction during pregnancy. At term, decreases in progesterone levels result in an increase in Cx43 synthesis, facilitating the onset of effective labor. In myometrial cells, antiprogestins, including mifepristone, increase the number of gap junction connections, facilitating a coordinated contractile signal in response to misoprostol or oxytocin.^3,4

It takes time for antiprogestins to stimulate myometrial cell production of Cx43. In the rat myometrium the administration of mifepristone results in a 2.5-fold increase of Cx43 mRNA transcripts within 9 hours and a 5.6-fold increase in 24 hours.³ Hence, most mifepristone treatment protocols involve administering mifepristone and waiting 24 to 48 hours before administering an agent that stimulates myometrial contraction, such as misoprostol. Antiprogestins also increase the sensitivity of myometrial cells to oxytocin stimulation of uterine contractions by increasing Cx43 concentration.⁴

Progesterone also regulates other important biological processes in the cervix, decidua, placenta, and cervix. Antiprogestins can facilitate cervical ripening and disrupt decidual function, interfering with the attachment of pregnancy tissue.⁵ In the cervix, antiprogestins increase matrix metalloproteinase expression, disrupting collagen organization, decreasing cervical tensile strength and leading to cervical ripening.⁶

Pharmacology of mifepristone

Mifepristone is an antiprogestin and antiglucocorticoid with high-affinity binding to both the progesterone and glucocorticoid receptors (FIGURE 1). The phenylaminodimethyl group at C-11 of mifepristone changes the positional equilibrium of helix 12 of the progesterone receptor, reducing the ability of the receptor to bind required co-activators, limiting receptor binding to DNA, resulting in an antiprogesterone effect.⁷ At the low, single-dose used for treatment of miscarriage and fetal demise (200 mg one dose), mifepristone is an antiprogestin. At the high, daily dose used for the treatment of hyperglycemia caused by Cushing disease (≥ 300 mg daily), mifepristone is also an antiglucocorticoid.

Although mifepristone is a powerful antiglucocorticoid, in patients with an intact hypothalamic-pituitary-adrenal axis, mifepristone does not cause adrenal insufficiency. In people with an intact hypothalamic-pituitary-adrenal axis, daily administration of mifepristone (≥ 200 mg) for 7 days or longer results in an increase in pituitary secretion of ACTH and adrenal secretion of cortisol, largely overcoming the antiglucocorticoid action of mifepristone.^8-10 This compensatory increase in ACTH and cortisol is not possible in patients who have had a hypophysectomy or bilateral adrenalectomy or have adrenal suppression due to long-term treatment with high doses of glucocorticoids. Mifepristone is contraindicated for patients with these conditions because it may cause glucocorticoid insufficiency by blocking glucocorticoid receptors.

The terminal half-life of mifepristone is 18 hours.¹¹ Following oral administration of a single dose of mifepristone 200 mg the peak circulating concentration is reached in 90 minutes. Mifepristone is metabolized by CYP3A4 and is also a strong inhibitor of CYP3A4. Contraindications to the use of mifepristone include adrenal failure, porphyria, hemorrhagic diseases, anticoagulation, an IUD in the uterus, ectopic pregnancy, long-term glucocorticoid administration, and an undiagnosed adnexal mass.

Continue to: Mifepristone-misoprostol for the treatment of early missed miscarriage with a gestational sac...

Mifepristone-misoprostol for the treatment of early missed miscarriage with a gestational sac

For patients with a miscarriage, the treatment options to resolve the pregnancy loss are expectant management, medication, or surgery.¹² Joint decision-making is recommended to establish a management plan that supports the patient’s values. Expectant management is most likely to result in a multi-week process to achieve completion of the miscarriage. A surgical procedure is most likely to result in rapid resolution of the miscarriage with the greatest rate of success. Surgical evacuation of the uterus may be the preferred option for patients who have excessive uterine bleeding or concerning vital signs. Both medical and surgical management are more likely than expectant management to successfully resolve the miscarriage.¹³

In the past, the standard approach to medication management of a miscarriage was the administration of one or more doses of misoprostol, a synthetic prostaglandin E1. However, two large trials have reported that the dual-medication sequence of mifepristone followed 24 to 48 hours later by misoprostol is more effective than misoprostol alone for resolving a miscarriage.^14,15 This is probably due to mifepristone making the uterus more responsive to the effects of misoprostol.

Schreiber and colleagues¹⁴ reported a study of 300 patients with an anembryonic gestation or embryonic demise, between 5 and 12 completed weeks of gestation, who were randomly assigned to treatment with mifepristone (200 mg) followed in 24 to 48 hours with vaginal misoprostol (800 µg) or vaginal misoprostol (800 µg) alone. Ultrasonography was performed 1 to 4 days after misoprostol administration. Successful treatment was defined as expulsion of the gestational sac plus no additional surgical or medical intervention within 30 days after treatment. In this study, the dual-medication regimen of mifepristone-misoprostol was more successful than misoprostol alone in resolving the miscarriage, 84% and 67%, respectively (relative risk [RR], 1.25; 95% confidence interval [CI], 1.09–1.43).

Surgical evacuation of the uterus occurred less often with mifepristone-misoprostol treatment than with misoprostol monotherapy—9% and 24%, respectively (RR, 0.37; 95% CI, 0.21–0.68). Pelvic infection occurred in 2 patients (1.3%) in each group. Uterine bleeding managed with blood transfusion occurred in 3 patients who received mifepristone-misoprostol and 1 patient who received misoprostol alone. In this study, clinical factors including active bleeding, parity, and gestational age did not influence treatment success with the mifepristone-misoprostol regimen.¹⁶ The mifepristone-misoprostol regimen was reported to be more cost-effective than misoprostol alone.¹⁷

Chu and colleagues¹⁵ reported a study of medication treatment of missed miscarriage that included more than 700 patients randomly assigned to treatment with mifepristone-misoprostol or placebo-misoprostol. Missed miscarriage was diagnosed by an ultrasound demonstrating a gestational sac and a nonviable pregnancy. The doses of mifepristone and misoprostol were 200 mg and 800 µg, respectively. In this study the misoprostol was administered 48 hours following mifepristone or placebo using a vaginal, oral, or buccal route, but 90% of patients used the vaginal route. Treatment was considered successful if the patient passed the gestational sac as determined by an ultrasound performed 7 days after entry into the study. If the gestational sac was passed, the patients were asked to do a urine pregnancy test 3 weeks after entering the study to conclude their care episode. If patients did not pass the gestational sac, they were offered a second dose of misoprostol or surgical evacuation. In this study, mifepristone-misoprostol resulted in fewer patients who did not pass the gestational sac within 7 days after entry into the study than placebo (mifepristone-misoprostol, 17% vs placebo-misoprostol, 24% (P=.043). Surgical intervention was performed in 25% of patients treated with placebo-misoprostol and 17% of patients treated with mifepristone-misoprostol (RR, 0.73; 95% CI, 0.53–0.95; P=.021). A cost-effectiveness analysis of the trial results reported that the combination of mifepristone-misoprostol was less costly than misoprostol alone for the management of missed miscarriages.¹⁸

Misoprostol can be administered by an oral, buccal, rectal, or vaginal route.^19,20 Vaginal administration results in higher circulating concentrations of misoprostol than buccal administration, but both routes of administration produce similar mean uterine tone and mean uterine activity as measured by an intrauterine pressure transducer over 5 hours.²¹ Hence, at our institution, we most often use buccal administration of misoprostol. To assess effectiveness of mifepristone-misoprostol treatment, 1 week after treatment with a pelvic ultrasound to detect expulsion of the gestational sac. Alternatively, a urine pregnancy test can be performed 3 weeks following medication treatment. The mifepristone-misoprostol regimen is not approved by the US Food and Drug Administration for the treatment of miscarriage.

Continue to: Mifepristone-misoprostol for the treatment of fetal demise...

Mifepristone-misoprostol for the treatment of fetal demise

Fetal loss in the second or third trimesters is a devastating experience for most patients, painfully echoing in the heart and mind for years. Empathic and effective treatment of fetal loss may reduce the adverse impact of the event. Multiple studies have reported that combinations of mifepristone and misoprostol reduced the time from initiation of labor contractions to birth compared with misoprostol alone.^22-28 In addition, the combination of mifepristone-misoprostol reduced the amount of misoprostol needed to achieve delivery.^22,23

In one clinical trial, 66 patients with fetal demise between 14 and 28 weeks’ gestation were randomized to receive mifepristone 200 mg or placebo.²² Twenty-four to 48 hours later, misoprostol for induction of labor was initiated. Among the patients from 14 to 23 completed weeks of gestation, the misoprostol dose was 400 µg vaginally every 6 hours. For patients from 24 to 28 weeks gestation, the misoprostol dose was 200 µg vaginally every 4 hours. The median times from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups were 6.8 hours and 10.5 hours (P=.002).

Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required fewer doses of misoprostol (2.1 vs 3.4; P=.002) and a lower total dose of misoprostol (768 µg vs 1,182 µg; P=.003). All patients in the mifepristone group delivered within 24 hours. By contrast, 13% of the patients in the placebo group delivered more than 24 hours after the initiation of misoprostol treatment. Five patients were readmitted with retained products of conception needing suction curettage—4 in the placebo group and 1 in the mifepristone group.²²

In a second clinical trial, 110 patients with fetal demise after 20 weeks of gestation were randomized to receive mifepristone 200 mg or placebo.²³ Thirty-six to 48 hours later, misoprostol for induction of labor was initiated. Among the patients from 20 to 25 completed weeks of gestation, the misoprostol dose was 100 µg vaginally every 6 hours for a maximum of 4 doses. For patients ≥26 weeks gestation, the misoprostol dose was 50 µg vaginally every 4 hours for a maximum of 6 doses. The median times from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups were 9.8 hours and 16.3 hours. (P=.001).

Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required a lower total dose of misoprostol (110 µg vs 198 µg, P<.001).

Delivery within 24 hours following initiation of misoprostol occurred in 93% and 73% of the patients in the mifepristone and placebo groups, respectively (P<.001). Compared with patients in the mifepristone group, shivering occurred more frequently among the patients in the placebo group (7.5% vs 19.2%; P=.09), likely because they received greater doses of misoprostol.²³

Miscarriage and fetal demise frequently cause patients to experience a range of emotions including denial, numbness, grief, anger, guilt, and depression. It may take months or years for people to progress to a tentative acceptance of the loss, refocusing on future aspirations. Empathic care and timely and effective medical intervention to resolve the pregnancy loss optimize outcomes. For medication treatment of miscarriage and fetal demise, mifepristone is an important agent because it improves the success rate for resolution of miscarriage without surgery and it shortens the time of labor for inductions for fetal demise. Obstetrician-gynecologists are the specialists leading advances in treatment of miscarriage and fetal demise. I encourage you to use mifepristone in your care of appropriate patients with miscarriage and fetal demise. ●

CASE Pregnant woman’s husband is ill after traveling

A 29-year-old primigravid woman at 18 weeks’ gestation just returned from a 10-day trip to Nigeria with her husband. While in Nigeria, the couple went on safari. On several occasions during the safari, they consumed bushmeat prepared by their guides. Her husband now has severe malaise, fever, chills, myalgias, cough, and prominent submandibular, cervical, and inguinal adenopathy. In addition, he has developed a diffuse papular-vesicular rash on his trunk and extremities.

• What is the most likely diagnosis?
• Does this condition pose a danger to his wife?
• What treatment is indicated for his wife?

What we know

In recent weeks, the specter of another poorly understood biological threat has emerged in the medical literature and lay press: monkeypox. This article will first review the epidemiology, clinical manifestations, and diagnosis of this infection, followed by a discussion of how to prevent and treat the condition, with special emphasis on the risks that this infection poses in pregnant women.

Virology

The monkeypox virus is a member of the orthopoxvirus genus. The variola (smallpox) virus and vaccinia virus are included in this genus. It is one of the largest of all viruses, measuring 200-250 nm. It is enveloped and contains double-stranded DNA. Its natural reservoir is probably African rodents. Two distinct strains of monkeypox exist in different geographical regions of Africa: the Central African clade and the West African clade. The Central African clade is significantly more virulent than the latter, with a mortality rate approaching 10%, versus 1% in the West African clade. The incubation period of the virus ranges from 4-20 days and averages 12 days.^1,2

Epidemiology

Monkeypox was first discovered in 1958 by Preben von Magnus in a colony of research monkeys in Copenhagen, Denmark. The first case of monkeypox in humans occurred in the Democratic Republic of Congo in 1970 in a 9-year-old boy. Subsequently, cases were reported in the Ivory Coast, Liberia, Nigeria, and Sierra Leone. The infection was limited to the rain forests of central and western Africa until 2003. At that time, the first cases in the United States were reported. The US cases occurred in the Midwest and were traced to exposure to pet prairie dogs. These animals all came from a single distributor, and they apparently were infected when they were housed in the same space with Gambian rats, which are well recognized reservoirs of monkeypox in their native habitat in Africa.^1-3

A limited outbreak of monkeypox occurred in the United Kingdom in 2018. Seventy-one cases, with no fatalities, were reported. In 2021 another US case of monkeypox was reported in Dallas, Texas, in an individual who had recently traveled to the United States from Nigeria. A second US case was reported in November 2021 from a patient in Maryland who had returned from a visit to Nigeria. Those were the only 2 reported cases of monkeypox in the United States in 2021.^1-3

Then in early May 2022, the United Kingdom reported 9 cases of monkeypox. The first infected patient had recently traveled to Nigeria and, subsequently, infected 2 members of his family.⁴ On May 18, the Massachusetts Department of Public Health confirmed a case of monkeypox in an adult man who had recently traveled to Canada. As of July 7, 6,027 cases have been reported from at least 39 countries.⁵ Eight states in the United States reported cases. To date, 73 deaths have occurred in this recent outbreak of infections (case fatality rate, 4.5%).^4-6

The current outbreak is unusual in that, previously, almost all cases occurred in western and central Africa in remote tropical rain forests. Infection usually resulted from close exposure to rats, rabbits, squirrels, monkeys, porcupines, and gazelles. Exposure occurred when persons captured, slaughtered, prepared, and then ate these animals for food without properly cooking the flesh.

The leading theory is that the present outbreak originated among men who had sex with men at 2 raves held in Spain and Belgium. The virus appears to have been spread by skin-to-skin contact, by respiratory droplets, by contact with contaminated bedding, and probably by sperm.^2,4,6

Continue to: Clinical manifestations...

Clinical manifestations

Monkeypox evolves through 2 stages: a pre-eruptive stage and an eruptive stage. Prodromal symptoms include malaise, severe headache, myalgias, fever, drenching sweats, backache, fatigue, sore throat, dyspnea, and cough. Within 2-3 days, the characteristic skin eruption develops. The lesions usually begin on the face and then spread in a centrifugal manner to the trunk and extremities, including the palms of the hands and soles of the feet. The lesions typically progress from macules to papules to vesicles to pustules. They then crust and scab over. An interesting additional finding is the presence of prominent lymphadenopathy behind the ear, beneath the mandible, in the neck, and in the groin.¹

Several different illnesses must be considered in the differential diagnosis of monkeypox infection. They include measles, scabies, secondary syphilis, and medication-associated allergic reactions. However, the 2 conditions most likely to be confused with monkeypox are chickenpox (varicella) and smallpox. Lymphadenopathy is much more prominent in monkeypox compared with chickenpox. Moreover, with monkeypox, all lesions tend to be at the same stage of evolution as opposed to appearing in crops as they do in chickenpox. Smallpox would be extremely unlikely in the absence of a recognized laboratory accident or a bioterrorism incident.⁷

Diagnosis

The presumptive diagnosis of monkeypox infection is made primarily based on clinical examination. However, laboratory testing is indicated to definitively differentiate monkeypox from other orthopoxvirus infections such as varicella and smallpox.

In specialized laboratories that employ highly trained personnel and maintain strict safety precautions, the virus can be isolated in mammalian cell cultures. Electron microscopy is a valuable tool for identifying the characteristic brick-shaped poxvirus virions. Routine histologic examination of a lesion will show ballooning degeneration of keratinocytes, prominent spongiosis, dermal edema, and acute inflammation, although these findings are not unique to monkeypox.¹

The Centers for Disease Control and Prevention (CDC) has developed serologic tests that detect immunoglobulin (Ig) M- and IgG-specific antibody. However, the most useful and practical diagnostic test is assessment of a skin scraping by polymerase chain reaction (PCR). This test is more sensitive than assessment of serum PCR.¹

When the diagnosis of monkeypox is being considered, the clinician should coordinate testing through the local and state public health departments and through the CDC. Effective communication with all agencies will ensure that laboratory specimens are processed in a timely and efficient manner. The CDC website presents information on specimen collection.⁸

How do we manage monkeypox?

Prevention

The first step in prevention of infection is to isolate infected individuals until all lesions have dried and crusted over. Susceptible people should avoid close contact with skin lesions, respiratory and genital secretions, and bedding of patients who are infected.

The ultimate preventive measure, however, is vaccination of susceptible people either immediately before exposure (eg, military personnel, first responders, infection control investigators, health care workers) or immediately after exposure (general population). Older individuals who received the original smallpox vaccine likely have immunity to monkeypox infection. Unfortunately, very few women who currently are of reproductive age received this vaccine because its use was discontinued in the United States in the early 1970s. Therefore, the vast majority of our patients are uniquely susceptible to this infection and should be vaccinated if there is an outbreak of monkeypox in their locality.^7,9

The current preferred vaccine for prevention of both smallpox and monkeypox is the Jynneos (Bavarian Nordic A/S) vaccine.¹⁰ This agent incorporates a replication-deficient live virus and does not pose the same risk for adverse events as the original versions of the smallpox vaccine. Jynneos is administered subcutaneously rather than by scarification. Two 0.5-mL doses, delivered 28 days apart, are required for optimal effect. The vaccine must be obtained from local and state health departments, in consultation with the CDC.^7,9

There is very little published information on the safety of the Jynneos vaccine in pregnant or lactating women, although animal data are reassuring. Moreover, the dangers of monkeypox infection are significant, and in the event of an outbreak, vaccination of susceptible individuals, including pregnant women, is indicated.

Continue to: Treatment...

Treatment

Infected pregnant women should receive acetaminophen 1,000 mg orally every 8 hours, to control fever and provide analgesia. An antihistamine such as diphenhydramine 25 mg orally every 6-8 hours, may be used to control pruritus and provide mild sedation. Adequate fluid intake and optimal nutrition should be encouraged. Skin lesions should be inspected regularly to detect signs of superimposed bacterial infections. Small, localized bacterial skin infections can be treated with topical application of mupirocin ointment 2%, 3 times daily for 7-14 days. For diffuse and more severe bacterial skin infections, a systemic antibiotic may be necessary. Reasonable choices include amoxicillin-clavulanate 875 mg/125 mg orally every 12 hours, or trimethoprim-sulfamethoxazole double strength 800 mg/160 mg orally every 12 hours.¹¹ The latter agent should be avoided in the first trimester of pregnancy because of potential teratogenic effects.

Several specific agents are available through the CDC for treatment of orthopoxvirus infections such as smallpox and monkeypox. Information about these agents is summarized in the TABLE.^12-16

Unique considerations in pregnancy

Because monkeypox is so rare, there is very little information about the effects of this infection in pregnant women. The report most commonly cited in the literature is that by Mbala et al, which was published in 2017.¹⁷ These authors described 4 pregnant patients in the Democratic Republic of Congo who contracted monkeypox infection over a 4-year period. All 4 women were hospitalized and treated with systemic antibiotics, antiparasitic medications, and analgesics. One patient delivered a healthy infant. Two women had spontaneous abortions in the first trimester. The fourth patient experienced a stillbirth at 22 weeks’ gestation. At postmortem examination, the fetus had diffuse cutaneous lesions, prominent hepatomegaly, and hydrops. No structural malformations were noted. The placenta demonstrated numerous punctate hemorrhages, and high concentrations of virus were recovered from the placenta and from fetal tissue.

Although the information on pregnancy outcome is quite limited, it seems clear that the virus can cross the placenta and cause adverse effects such as spontaneous abortion and fetal death. Accordingly, I think the following guidelines are a reasonable approach to a pregnant patient who has been exposed to monkeypox or who has developed manifestations of infection.^3,7,9

• In the event of a community outbreak, bioterrorism event, or exposure to a person with suspected or confirmed monkeypox infection, the pregnant patient should receive the Jynneos vaccine.
• The pregnant patient should be isolated from any individual with suspected or confirmed monkeypox.
• If infection develops despite these measures, the patient should be treated with either tecovirimat or vaccinia immune globulin IV. Hospitalization may be necessary for seriously ill individuals.

• Within 2 weeks of infection, a comprehensive ultrasound examination should be performed to assess for structural abnormalities in the fetus.

• Subsequently, serial ultrasound examinations should be performed at intervals of 4-6 weeks to assess fetal growth and re-evaluate fetal anatomy.
• Following delivery, a detailed neonatal examination should be performed to assess for evidence of viral injury. Neonatal skin lesions and neonatal serum can be assessed by PCR for monkeypox virus. The newborn should be isolated from the mother until all the mother’s lesions have dried and crusted over.

CASE Resolved

Given the husband’s recent travel to Nigeria and consumption of bushmeat, he most likely has monkeypox. The infection can be spread from person to person by close contact; thus, his wife is at risk. The couple should isolate until all of his lesions have dried and crusted over. The woman also should receive the Jynneos vaccine. If she becomes symptomatic, she should be treated with tecovirimat or vaccinia immune globulin IV. ●

CASE Pregnant woman’s husband is ill after traveling

A 29-year-old primigravid woman at 18 weeks’ gestation just returned from a 10-day trip to Nigeria with her husband. While in Nigeria, the couple went on safari. On several occasions during the safari, they consumed bushmeat prepared by their guides. Her husband now has severe malaise, fever, chills, myalgias, cough, and prominent submandibular, cervical, and inguinal adenopathy. In addition, he has developed a diffuse papular-vesicular rash on his trunk and extremities.

• What is the most likely diagnosis?
• Does this condition pose a danger to his wife?
• What treatment is indicated for his wife?

What we know

In recent weeks, the specter of another poorly understood biological threat has emerged in the medical literature and lay press: monkeypox. This article will first review the epidemiology, clinical manifestations, and diagnosis of this infection, followed by a discussion of how to prevent and treat the condition, with special emphasis on the risks that this infection poses in pregnant women.

Virology

The monkeypox virus is a member of the orthopoxvirus genus. The variola (smallpox) virus and vaccinia virus are included in this genus. It is one of the largest of all viruses, measuring 200-250 nm. It is enveloped and contains double-stranded DNA. Its natural reservoir is probably African rodents. Two distinct strains of monkeypox exist in different geographical regions of Africa: the Central African clade and the West African clade. The Central African clade is significantly more virulent than the latter, with a mortality rate approaching 10%, versus 1% in the West African clade. The incubation period of the virus ranges from 4-20 days and averages 12 days.^1,2

Epidemiology

Monkeypox was first discovered in 1958 by Preben von Magnus in a colony of research monkeys in Copenhagen, Denmark. The first case of monkeypox in humans occurred in the Democratic Republic of Congo in 1970 in a 9-year-old boy. Subsequently, cases were reported in the Ivory Coast, Liberia, Nigeria, and Sierra Leone. The infection was limited to the rain forests of central and western Africa until 2003. At that time, the first cases in the United States were reported. The US cases occurred in the Midwest and were traced to exposure to pet prairie dogs. These animals all came from a single distributor, and they apparently were infected when they were housed in the same space with Gambian rats, which are well recognized reservoirs of monkeypox in their native habitat in Africa.^1-3

A limited outbreak of monkeypox occurred in the United Kingdom in 2018. Seventy-one cases, with no fatalities, were reported. In 2021 another US case of monkeypox was reported in Dallas, Texas, in an individual who had recently traveled to the United States from Nigeria. A second US case was reported in November 2021 from a patient in Maryland who had returned from a visit to Nigeria. Those were the only 2 reported cases of monkeypox in the United States in 2021.^1-3

Then in early May 2022, the United Kingdom reported 9 cases of monkeypox. The first infected patient had recently traveled to Nigeria and, subsequently, infected 2 members of his family.⁴ On May 18, the Massachusetts Department of Public Health confirmed a case of monkeypox in an adult man who had recently traveled to Canada. As of July 7, 6,027 cases have been reported from at least 39 countries.⁵ Eight states in the United States reported cases. To date, 73 deaths have occurred in this recent outbreak of infections (case fatality rate, 4.5%).^4-6

The current outbreak is unusual in that, previously, almost all cases occurred in western and central Africa in remote tropical rain forests. Infection usually resulted from close exposure to rats, rabbits, squirrels, monkeys, porcupines, and gazelles. Exposure occurred when persons captured, slaughtered, prepared, and then ate these animals for food without properly cooking the flesh.

The leading theory is that the present outbreak originated among men who had sex with men at 2 raves held in Spain and Belgium. The virus appears to have been spread by skin-to-skin contact, by respiratory droplets, by contact with contaminated bedding, and probably by sperm.^2,4,6

Continue to: Clinical manifestations...

Clinical manifestations

Monkeypox evolves through 2 stages: a pre-eruptive stage and an eruptive stage. Prodromal symptoms include malaise, severe headache, myalgias, fever, drenching sweats, backache, fatigue, sore throat, dyspnea, and cough. Within 2-3 days, the characteristic skin eruption develops. The lesions usually begin on the face and then spread in a centrifugal manner to the trunk and extremities, including the palms of the hands and soles of the feet. The lesions typically progress from macules to papules to vesicles to pustules. They then crust and scab over. An interesting additional finding is the presence of prominent lymphadenopathy behind the ear, beneath the mandible, in the neck, and in the groin.¹

Several different illnesses must be considered in the differential diagnosis of monkeypox infection. They include measles, scabies, secondary syphilis, and medication-associated allergic reactions. However, the 2 conditions most likely to be confused with monkeypox are chickenpox (varicella) and smallpox. Lymphadenopathy is much more prominent in monkeypox compared with chickenpox. Moreover, with monkeypox, all lesions tend to be at the same stage of evolution as opposed to appearing in crops as they do in chickenpox. Smallpox would be extremely unlikely in the absence of a recognized laboratory accident or a bioterrorism incident.⁷

Diagnosis

The presumptive diagnosis of monkeypox infection is made primarily based on clinical examination. However, laboratory testing is indicated to definitively differentiate monkeypox from other orthopoxvirus infections such as varicella and smallpox.

In specialized laboratories that employ highly trained personnel and maintain strict safety precautions, the virus can be isolated in mammalian cell cultures. Electron microscopy is a valuable tool for identifying the characteristic brick-shaped poxvirus virions. Routine histologic examination of a lesion will show ballooning degeneration of keratinocytes, prominent spongiosis, dermal edema, and acute inflammation, although these findings are not unique to monkeypox.¹

The Centers for Disease Control and Prevention (CDC) has developed serologic tests that detect immunoglobulin (Ig) M- and IgG-specific antibody. However, the most useful and practical diagnostic test is assessment of a skin scraping by polymerase chain reaction (PCR). This test is more sensitive than assessment of serum PCR.¹

When the diagnosis of monkeypox is being considered, the clinician should coordinate testing through the local and state public health departments and through the CDC. Effective communication with all agencies will ensure that laboratory specimens are processed in a timely and efficient manner. The CDC website presents information on specimen collection.⁸

How do we manage monkeypox?

Prevention

The first step in prevention of infection is to isolate infected individuals until all lesions have dried and crusted over. Susceptible people should avoid close contact with skin lesions, respiratory and genital secretions, and bedding of patients who are infected.

The ultimate preventive measure, however, is vaccination of susceptible people either immediately before exposure (eg, military personnel, first responders, infection control investigators, health care workers) or immediately after exposure (general population). Older individuals who received the original smallpox vaccine likely have immunity to monkeypox infection. Unfortunately, very few women who currently are of reproductive age received this vaccine because its use was discontinued in the United States in the early 1970s. Therefore, the vast majority of our patients are uniquely susceptible to this infection and should be vaccinated if there is an outbreak of monkeypox in their locality.^7,9

The current preferred vaccine for prevention of both smallpox and monkeypox is the Jynneos (Bavarian Nordic A/S) vaccine.¹⁰ This agent incorporates a replication-deficient live virus and does not pose the same risk for adverse events as the original versions of the smallpox vaccine. Jynneos is administered subcutaneously rather than by scarification. Two 0.5-mL doses, delivered 28 days apart, are required for optimal effect. The vaccine must be obtained from local and state health departments, in consultation with the CDC.^7,9

There is very little published information on the safety of the Jynneos vaccine in pregnant or lactating women, although animal data are reassuring. Moreover, the dangers of monkeypox infection are significant, and in the event of an outbreak, vaccination of susceptible individuals, including pregnant women, is indicated.

Continue to: Treatment...

Treatment

Infected pregnant women should receive acetaminophen 1,000 mg orally every 8 hours, to control fever and provide analgesia. An antihistamine such as diphenhydramine 25 mg orally every 6-8 hours, may be used to control pruritus and provide mild sedation. Adequate fluid intake and optimal nutrition should be encouraged. Skin lesions should be inspected regularly to detect signs of superimposed bacterial infections. Small, localized bacterial skin infections can be treated with topical application of mupirocin ointment 2%, 3 times daily for 7-14 days. For diffuse and more severe bacterial skin infections, a systemic antibiotic may be necessary. Reasonable choices include amoxicillin-clavulanate 875 mg/125 mg orally every 12 hours, or trimethoprim-sulfamethoxazole double strength 800 mg/160 mg orally every 12 hours.¹¹ The latter agent should be avoided in the first trimester of pregnancy because of potential teratogenic effects.

Several specific agents are available through the CDC for treatment of orthopoxvirus infections such as smallpox and monkeypox. Information about these agents is summarized in the TABLE.^12-16

Unique considerations in pregnancy

Because monkeypox is so rare, there is very little information about the effects of this infection in pregnant women. The report most commonly cited in the literature is that by Mbala et al, which was published in 2017.¹⁷ These authors described 4 pregnant patients in the Democratic Republic of Congo who contracted monkeypox infection over a 4-year period. All 4 women were hospitalized and treated with systemic antibiotics, antiparasitic medications, and analgesics. One patient delivered a healthy infant. Two women had spontaneous abortions in the first trimester. The fourth patient experienced a stillbirth at 22 weeks’ gestation. At postmortem examination, the fetus had diffuse cutaneous lesions, prominent hepatomegaly, and hydrops. No structural malformations were noted. The placenta demonstrated numerous punctate hemorrhages, and high concentrations of virus were recovered from the placenta and from fetal tissue.

Although the information on pregnancy outcome is quite limited, it seems clear that the virus can cross the placenta and cause adverse effects such as spontaneous abortion and fetal death. Accordingly, I think the following guidelines are a reasonable approach to a pregnant patient who has been exposed to monkeypox or who has developed manifestations of infection.^3,7,9

• In the event of a community outbreak, bioterrorism event, or exposure to a person with suspected or confirmed monkeypox infection, the pregnant patient should receive the Jynneos vaccine.
• The pregnant patient should be isolated from any individual with suspected or confirmed monkeypox.
• If infection develops despite these measures, the patient should be treated with either tecovirimat or vaccinia immune globulin IV. Hospitalization may be necessary for seriously ill individuals.

• Within 2 weeks of infection, a comprehensive ultrasound examination should be performed to assess for structural abnormalities in the fetus.

• Subsequently, serial ultrasound examinations should be performed at intervals of 4-6 weeks to assess fetal growth and re-evaluate fetal anatomy.
• Following delivery, a detailed neonatal examination should be performed to assess for evidence of viral injury. Neonatal skin lesions and neonatal serum can be assessed by PCR for monkeypox virus. The newborn should be isolated from the mother until all the mother’s lesions have dried and crusted over.

CASE Resolved

Given the husband’s recent travel to Nigeria and consumption of bushmeat, he most likely has monkeypox. The infection can be spread from person to person by close contact; thus, his wife is at risk. The couple should isolate until all of his lesions have dried and crusted over. The woman also should receive the Jynneos vaccine. If she becomes symptomatic, she should be treated with tecovirimat or vaccinia immune globulin IV. ●

CASE Pregnant woman’s husband is ill after traveling

A 29-year-old primigravid woman at 18 weeks’ gestation just returned from a 10-day trip to Nigeria with her husband. While in Nigeria, the couple went on safari. On several occasions during the safari, they consumed bushmeat prepared by their guides. Her husband now has severe malaise, fever, chills, myalgias, cough, and prominent submandibular, cervical, and inguinal adenopathy. In addition, he has developed a diffuse papular-vesicular rash on his trunk and extremities.

• What is the most likely diagnosis?
• Does this condition pose a danger to his wife?
• What treatment is indicated for his wife?

What we know

In recent weeks, the specter of another poorly understood biological threat has emerged in the medical literature and lay press: monkeypox. This article will first review the epidemiology, clinical manifestations, and diagnosis of this infection, followed by a discussion of how to prevent and treat the condition, with special emphasis on the risks that this infection poses in pregnant women.

Virology

The monkeypox virus is a member of the orthopoxvirus genus. The variola (smallpox) virus and vaccinia virus are included in this genus. It is one of the largest of all viruses, measuring 200-250 nm. It is enveloped and contains double-stranded DNA. Its natural reservoir is probably African rodents. Two distinct strains of monkeypox exist in different geographical regions of Africa: the Central African clade and the West African clade. The Central African clade is significantly more virulent than the latter, with a mortality rate approaching 10%, versus 1% in the West African clade. The incubation period of the virus ranges from 4-20 days and averages 12 days.^1,2

Epidemiology

Monkeypox was first discovered in 1958 by Preben von Magnus in a colony of research monkeys in Copenhagen, Denmark. The first case of monkeypox in humans occurred in the Democratic Republic of Congo in 1970 in a 9-year-old boy. Subsequently, cases were reported in the Ivory Coast, Liberia, Nigeria, and Sierra Leone. The infection was limited to the rain forests of central and western Africa until 2003. At that time, the first cases in the United States were reported. The US cases occurred in the Midwest and were traced to exposure to pet prairie dogs. These animals all came from a single distributor, and they apparently were infected when they were housed in the same space with Gambian rats, which are well recognized reservoirs of monkeypox in their native habitat in Africa.^1-3

A limited outbreak of monkeypox occurred in the United Kingdom in 2018. Seventy-one cases, with no fatalities, were reported. In 2021 another US case of monkeypox was reported in Dallas, Texas, in an individual who had recently traveled to the United States from Nigeria. A second US case was reported in November 2021 from a patient in Maryland who had returned from a visit to Nigeria. Those were the only 2 reported cases of monkeypox in the United States in 2021.^1-3

Then in early May 2022, the United Kingdom reported 9 cases of monkeypox. The first infected patient had recently traveled to Nigeria and, subsequently, infected 2 members of his family.⁴ On May 18, the Massachusetts Department of Public Health confirmed a case of monkeypox in an adult man who had recently traveled to Canada. As of July 7, 6,027 cases have been reported from at least 39 countries.⁵ Eight states in the United States reported cases. To date, 73 deaths have occurred in this recent outbreak of infections (case fatality rate, 4.5%).^4-6

The current outbreak is unusual in that, previously, almost all cases occurred in western and central Africa in remote tropical rain forests. Infection usually resulted from close exposure to rats, rabbits, squirrels, monkeys, porcupines, and gazelles. Exposure occurred when persons captured, slaughtered, prepared, and then ate these animals for food without properly cooking the flesh.

The leading theory is that the present outbreak originated among men who had sex with men at 2 raves held in Spain and Belgium. The virus appears to have been spread by skin-to-skin contact, by respiratory droplets, by contact with contaminated bedding, and probably by sperm.^2,4,6

Continue to: Clinical manifestations...

Clinical manifestations

Monkeypox evolves through 2 stages: a pre-eruptive stage and an eruptive stage. Prodromal symptoms include malaise, severe headache, myalgias, fever, drenching sweats, backache, fatigue, sore throat, dyspnea, and cough. Within 2-3 days, the characteristic skin eruption develops. The lesions usually begin on the face and then spread in a centrifugal manner to the trunk and extremities, including the palms of the hands and soles of the feet. The lesions typically progress from macules to papules to vesicles to pustules. They then crust and scab over. An interesting additional finding is the presence of prominent lymphadenopathy behind the ear, beneath the mandible, in the neck, and in the groin.¹

Several different illnesses must be considered in the differential diagnosis of monkeypox infection. They include measles, scabies, secondary syphilis, and medication-associated allergic reactions. However, the 2 conditions most likely to be confused with monkeypox are chickenpox (varicella) and smallpox. Lymphadenopathy is much more prominent in monkeypox compared with chickenpox. Moreover, with monkeypox, all lesions tend to be at the same stage of evolution as opposed to appearing in crops as they do in chickenpox. Smallpox would be extremely unlikely in the absence of a recognized laboratory accident or a bioterrorism incident.⁷

Diagnosis

The presumptive diagnosis of monkeypox infection is made primarily based on clinical examination. However, laboratory testing is indicated to definitively differentiate monkeypox from other orthopoxvirus infections such as varicella and smallpox.

In specialized laboratories that employ highly trained personnel and maintain strict safety precautions, the virus can be isolated in mammalian cell cultures. Electron microscopy is a valuable tool for identifying the characteristic brick-shaped poxvirus virions. Routine histologic examination of a lesion will show ballooning degeneration of keratinocytes, prominent spongiosis, dermal edema, and acute inflammation, although these findings are not unique to monkeypox.¹

The Centers for Disease Control and Prevention (CDC) has developed serologic tests that detect immunoglobulin (Ig) M- and IgG-specific antibody. However, the most useful and practical diagnostic test is assessment of a skin scraping by polymerase chain reaction (PCR). This test is more sensitive than assessment of serum PCR.¹

When the diagnosis of monkeypox is being considered, the clinician should coordinate testing through the local and state public health departments and through the CDC. Effective communication with all agencies will ensure that laboratory specimens are processed in a timely and efficient manner. The CDC website presents information on specimen collection.⁸

How do we manage monkeypox?

Prevention

The first step in prevention of infection is to isolate infected individuals until all lesions have dried and crusted over. Susceptible people should avoid close contact with skin lesions, respiratory and genital secretions, and bedding of patients who are infected.

The ultimate preventive measure, however, is vaccination of susceptible people either immediately before exposure (eg, military personnel, first responders, infection control investigators, health care workers) or immediately after exposure (general population). Older individuals who received the original smallpox vaccine likely have immunity to monkeypox infection. Unfortunately, very few women who currently are of reproductive age received this vaccine because its use was discontinued in the United States in the early 1970s. Therefore, the vast majority of our patients are uniquely susceptible to this infection and should be vaccinated if there is an outbreak of monkeypox in their locality.^7,9

The current preferred vaccine for prevention of both smallpox and monkeypox is the Jynneos (Bavarian Nordic A/S) vaccine.¹⁰ This agent incorporates a replication-deficient live virus and does not pose the same risk for adverse events as the original versions of the smallpox vaccine. Jynneos is administered subcutaneously rather than by scarification. Two 0.5-mL doses, delivered 28 days apart, are required for optimal effect. The vaccine must be obtained from local and state health departments, in consultation with the CDC.^7,9

There is very little published information on the safety of the Jynneos vaccine in pregnant or lactating women, although animal data are reassuring. Moreover, the dangers of monkeypox infection are significant, and in the event of an outbreak, vaccination of susceptible individuals, including pregnant women, is indicated.

Continue to: Treatment...

Treatment

Infected pregnant women should receive acetaminophen 1,000 mg orally every 8 hours, to control fever and provide analgesia. An antihistamine such as diphenhydramine 25 mg orally every 6-8 hours, may be used to control pruritus and provide mild sedation. Adequate fluid intake and optimal nutrition should be encouraged. Skin lesions should be inspected regularly to detect signs of superimposed bacterial infections. Small, localized bacterial skin infections can be treated with topical application of mupirocin ointment 2%, 3 times daily for 7-14 days. For diffuse and more severe bacterial skin infections, a systemic antibiotic may be necessary. Reasonable choices include amoxicillin-clavulanate 875 mg/125 mg orally every 12 hours, or trimethoprim-sulfamethoxazole double strength 800 mg/160 mg orally every 12 hours.¹¹ The latter agent should be avoided in the first trimester of pregnancy because of potential teratogenic effects.

Several specific agents are available through the CDC for treatment of orthopoxvirus infections such as smallpox and monkeypox. Information about these agents is summarized in the TABLE.^12-16

Unique considerations in pregnancy

Because monkeypox is so rare, there is very little information about the effects of this infection in pregnant women. The report most commonly cited in the literature is that by Mbala et al, which was published in 2017.¹⁷ These authors described 4 pregnant patients in the Democratic Republic of Congo who contracted monkeypox infection over a 4-year period. All 4 women were hospitalized and treated with systemic antibiotics, antiparasitic medications, and analgesics. One patient delivered a healthy infant. Two women had spontaneous abortions in the first trimester. The fourth patient experienced a stillbirth at 22 weeks’ gestation. At postmortem examination, the fetus had diffuse cutaneous lesions, prominent hepatomegaly, and hydrops. No structural malformations were noted. The placenta demonstrated numerous punctate hemorrhages, and high concentrations of virus were recovered from the placenta and from fetal tissue.

Although the information on pregnancy outcome is quite limited, it seems clear that the virus can cross the placenta and cause adverse effects such as spontaneous abortion and fetal death. Accordingly, I think the following guidelines are a reasonable approach to a pregnant patient who has been exposed to monkeypox or who has developed manifestations of infection.^3,7,9

• In the event of a community outbreak, bioterrorism event, or exposure to a person with suspected or confirmed monkeypox infection, the pregnant patient should receive the Jynneos vaccine.
• The pregnant patient should be isolated from any individual with suspected or confirmed monkeypox.
• If infection develops despite these measures, the patient should be treated with either tecovirimat or vaccinia immune globulin IV. Hospitalization may be necessary for seriously ill individuals.

• Within 2 weeks of infection, a comprehensive ultrasound examination should be performed to assess for structural abnormalities in the fetus.

• Subsequently, serial ultrasound examinations should be performed at intervals of 4-6 weeks to assess fetal growth and re-evaluate fetal anatomy.
• Following delivery, a detailed neonatal examination should be performed to assess for evidence of viral injury. Neonatal skin lesions and neonatal serum can be assessed by PCR for monkeypox virus. The newborn should be isolated from the mother until all the mother’s lesions have dried and crusted over.

CASE Resolved

Given the husband’s recent travel to Nigeria and consumption of bushmeat, he most likely has monkeypox. The infection can be spread from person to person by close contact; thus, his wife is at risk. The couple should isolate until all of his lesions have dried and crusted over. The woman also should receive the Jynneos vaccine. If she becomes symptomatic, she should be treated with tecovirimat or vaccinia immune globulin IV. ●

Recently Sermo had an interesting case report. A young woman, a few hours after undergoing cupping and acupuncture to her upper back, developed dyspnea and presented to the emergency department. There she was found to have a pneumothorax requiring chest tube placement.

I’m certainly not an expert on pneumothoraces, cupping, or acupuncture. Maybe the occurrence is coincidental, though it certainly is temporally concerning.

If I were to cause a pneumothorax doing an electromyography and nerve conduction velocity of the chest wall or upper back, I’m sure I’d have a lot to answer for. Beyond just arranging care for the patient and explaining things to her and her family members, I’d probably have to deal with a board investigation and/or malpractice claim.

Yet, in my experience, people who provide such services rarely face legal accountability, whereas their counterparts in allopathic medicine regularly do so. How many late-night TV attorney ads have you seen that say “have you been injured by an acupuncturist?”

Me, neither.

I’m not going to go into the questions of whether acupuncture, or even cupping, do anything at all. But this case also raises the point that people tend to think of “alternative” medical treatments as things that, while of unclear benefit, are generally harmless.

The fact is that there is no such thing as a risk-free medical procedure. There probably never will be. No matter how well trained and intentioned the person doing it is, there is always the chance of something going wrong. Human error, mechanical failure, bad luck. As they say, dung happens.

In medicine we think about the risk-benefit ratio and proceed accordingly. But the risk, no matter how low, is never zero. People need to understand this applies to pretty much everything health-related. Even over-the-counter supplements, no matter how great their claims may sound (also unproven) have their issues.

Caveat emptor.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Recently Sermo had an interesting case report. A young woman, a few hours after undergoing cupping and acupuncture to her upper back, developed dyspnea and presented to the emergency department. There she was found to have a pneumothorax requiring chest tube placement.

I’m certainly not an expert on pneumothoraces, cupping, or acupuncture. Maybe the occurrence is coincidental, though it certainly is temporally concerning.

If I were to cause a pneumothorax doing an electromyography and nerve conduction velocity of the chest wall or upper back, I’m sure I’d have a lot to answer for. Beyond just arranging care for the patient and explaining things to her and her family members, I’d probably have to deal with a board investigation and/or malpractice claim.

Yet, in my experience, people who provide such services rarely face legal accountability, whereas their counterparts in allopathic medicine regularly do so. How many late-night TV attorney ads have you seen that say “have you been injured by an acupuncturist?”

Me, neither.

I’m not going to go into the questions of whether acupuncture, or even cupping, do anything at all. But this case also raises the point that people tend to think of “alternative” medical treatments as things that, while of unclear benefit, are generally harmless.

The fact is that there is no such thing as a risk-free medical procedure. There probably never will be. No matter how well trained and intentioned the person doing it is, there is always the chance of something going wrong. Human error, mechanical failure, bad luck. As they say, dung happens.

In medicine we think about the risk-benefit ratio and proceed accordingly. But the risk, no matter how low, is never zero. People need to understand this applies to pretty much everything health-related. Even over-the-counter supplements, no matter how great their claims may sound (also unproven) have their issues.

Caveat emptor.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Recently Sermo had an interesting case report. A young woman, a few hours after undergoing cupping and acupuncture to her upper back, developed dyspnea and presented to the emergency department. There she was found to have a pneumothorax requiring chest tube placement.

I’m certainly not an expert on pneumothoraces, cupping, or acupuncture. Maybe the occurrence is coincidental, though it certainly is temporally concerning.

If I were to cause a pneumothorax doing an electromyography and nerve conduction velocity of the chest wall or upper back, I’m sure I’d have a lot to answer for. Beyond just arranging care for the patient and explaining things to her and her family members, I’d probably have to deal with a board investigation and/or malpractice claim.

Yet, in my experience, people who provide such services rarely face legal accountability, whereas their counterparts in allopathic medicine regularly do so. How many late-night TV attorney ads have you seen that say “have you been injured by an acupuncturist?”

Me, neither.

I’m not going to go into the questions of whether acupuncture, or even cupping, do anything at all. But this case also raises the point that people tend to think of “alternative” medical treatments as things that, while of unclear benefit, are generally harmless.

The fact is that there is no such thing as a risk-free medical procedure. There probably never will be. No matter how well trained and intentioned the person doing it is, there is always the chance of something going wrong. Human error, mechanical failure, bad luck. As they say, dung happens.

In medicine we think about the risk-benefit ratio and proceed accordingly. But the risk, no matter how low, is never zero. People need to understand this applies to pretty much everything health-related. Even over-the-counter supplements, no matter how great their claims may sound (also unproven) have their issues.

Caveat emptor.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

The use of laparoscopic power morcellators for minimally invasive hysterectomy has significantly decreased, and while the use of containment bags increased after the U.S. Food and Drug Administration’s 2014 safety warning about power morcellators, most procedures employing them are still performed without bags, according to a large database study in Obstetrics & Gynecology.

Containment bags are thought to limit the dissemination of potentially pathologic tissue, including unsuspected cancerous cells.

Rates of uterine cancer in women having morcellation were similar before and after the 2014 FDA guidance, and containment bags were used in only a small proportion of women with uterine cancer, according to findings from a research group led by Jason D. Wright, MD, of the division of gynecologic oncology at Columbia University, New York.

“Despite warnings from professional societies and regulatory agencies, as well as intense public scrutiny after the FDA warnings, the majority of morcellated uterine cancers occurred with uncontained laparoscopic power morcellation,” Dr. Wright and associates wrote, adding that the findings have important policy implications. First, efforts are needed to ensure morcellation is avoided in women with pathologic abnormalities. Second, despite regulatory approval, the safety and efficacy of containment bags remain uncertain, and the use and outcomes of these devices should be monitored closely.

The authors noted that laparoscopic power morcellation with a containment bag actually carries a small but significant increase in the risk of complications, compared with uncontained morcellation.

The study

Drawing on the Premier Healthcare Database, the researchers looked at deidentified patients aged 18 years or older who underwent laparoscopic supracervical hysterectomy from 2010 to 2018. The largest age group having the procedure consisted of women aged 40-49.

Patients were stratified based on use of laparoscopic power morcellators.

The cohort was further stratified as either pre–FDA guidance (2010 quarter 1 to 2014 quarter 1) or post–FDA guidance (2014 quarter 2 to 2018 quarter 2).

In the final cohort of 67,115 patients, laparoscopic power morcellator use decreased from 66.7% in 2013 quarter 4 to 13.3% by 2018 quarter 2. The likelihood of using this device decreased by 9.5% for each quarter elapsed in the post–FDA warning period (risk ratio, 0.91; 95% confidence interval, 0.90-0.91).

In other findings, containment bag use rose from 5.2% in 2013 quarter 4 to 15.2% by 2018 quarter 2. The likelihood of containment bag use rose by 3% for each quarter elapsed in the post–FDA warning period (RR, 1.03; 95% CI, 1.02-1.05).

Among women who underwent surgery with laparoscopic power morcellator use, uterine cancers or sarcomas were identified in 54 (0.17%) before the FDA guidance, compared with 7 (0.12%) after the guidance (P = .45).

Containment bags were used in 11.1% of women with uterine cancers or sarcomas before the FDA guidance, compared with 14.3% after the guidance (P = .12). The perioperative complication rate was 3.3% among women who had laparoscopic power morcellator use without a containment bag, compared with 4.5% (P = .001) in those with a containment bag (adjusted RR, 1.35; 95% CI, 1.12-1.64).

A related editorial argued that the backlash against power morcellation was unwarranted and an example of “reactionary medicine.”

Ben A. Abdu, MD, and Cameron Lowry, MD, of the department of obstetrics and gynecology at the University of Tennessee Health Science Center in Memphis, noted that with the known advantages of laparoscopy over laparotomy – decreased blood loss, decreased pain, and fewer wound complications and infections – it is of paramount importance to continue to offer minimally invasive surgery whenever possible. After the FDA raised safety concerns, there was a rise in the rate of open abdominal hysterectomy, which was accompanied by an increase in surgical morbidity. “Perhaps for now we should avoid throwing the baby out with the bath water,” they wrote.

The editorialists pointed out that any surgery may entail unintended complications. “It is also important to remember that there is a risk of dissemination of malignant tissue whether or not power morcellation is used, and it has even been observed in laparotomy,” they stated, noting that bag rupture and tissue spillage can occur even when the containment bag remains intact.

The downward trend in the use of power morcellators observed by Dr. Wright’s group is of serious concern, the commentators added, especially because the FDA communication was made in response to a rare occurrence and possibly resting on an overestimation of risk. “Based on their review of the medical literature at the time, the FDA cited prevalence estimates of 1 in 352 for any uterine sarcoma and 1 in 498 for leiomyosarcoma,” they wrote. “Many authors have expressed concern that the FDA data review was overestimated.” For example, they cite a meta-analysis using prospective data in which the prevalence of occult leiomyosarcoma was estimated at 1 in 8,300. Despite this extremely low prevalence, there has been an almost total nationwide hospital moratorium on the use of power morcellation, which will likely continue. Some manufacturers have ceased or limited production, distribution, and sales of these devices, they noted.

According to Dr. Michael L. Nimaroff, MD, however, chief of minimally invasive gynecologic surgery at Northwell Health in New Hyde Park, N.Y., the general post–FDA-guidance backlash did not have much effect on expert practitioners in this surgical field. “Those of us who specialize in minimally invasive gynecologic surgery, which has many benefits for the patients, never pivoted,” he told this news organization. “We continued to perform it but more conscientiously and with more concern for safety.”

As for morcellator use, added Dr. Nimaroff, specialists were so accustomed to doing these surgeries before the containment systems were made available that they don’t miss the power morcellator. “We actually retrieve tissue manually, and most of our morcellations, if they’re not contained manually, are retrieved vaginally or through a slightly bigger incision. So patients still benefit from minimally invasive surgery, and in some cases these techniques actually shorten the operation.”

This study received no external funding. Dr. Wright is editor in chief of Obstetrics & Gynecology. He reported royalties from UpToDate and has received research support from Merck. Coauthor Dr. Hou has served as a consultant for Foundation Medicine and Natera. Dr. Abdu and Dr. Lowry disclosed no competing interests, as did Dr. Nimaroff.

The use of laparoscopic power morcellators for minimally invasive hysterectomy has significantly decreased, and while the use of containment bags increased after the U.S. Food and Drug Administration’s 2014 safety warning about power morcellators, most procedures employing them are still performed without bags, according to a large database study in Obstetrics & Gynecology.

Containment bags are thought to limit the dissemination of potentially pathologic tissue, including unsuspected cancerous cells.

Rates of uterine cancer in women having morcellation were similar before and after the 2014 FDA guidance, and containment bags were used in only a small proportion of women with uterine cancer, according to findings from a research group led by Jason D. Wright, MD, of the division of gynecologic oncology at Columbia University, New York.

“Despite warnings from professional societies and regulatory agencies, as well as intense public scrutiny after the FDA warnings, the majority of morcellated uterine cancers occurred with uncontained laparoscopic power morcellation,” Dr. Wright and associates wrote, adding that the findings have important policy implications. First, efforts are needed to ensure morcellation is avoided in women with pathologic abnormalities. Second, despite regulatory approval, the safety and efficacy of containment bags remain uncertain, and the use and outcomes of these devices should be monitored closely.

The authors noted that laparoscopic power morcellation with a containment bag actually carries a small but significant increase in the risk of complications, compared with uncontained morcellation.

The study

Drawing on the Premier Healthcare Database, the researchers looked at deidentified patients aged 18 years or older who underwent laparoscopic supracervical hysterectomy from 2010 to 2018. The largest age group having the procedure consisted of women aged 40-49.

Patients were stratified based on use of laparoscopic power morcellators.

The cohort was further stratified as either pre–FDA guidance (2010 quarter 1 to 2014 quarter 1) or post–FDA guidance (2014 quarter 2 to 2018 quarter 2).

In the final cohort of 67,115 patients, laparoscopic power morcellator use decreased from 66.7% in 2013 quarter 4 to 13.3% by 2018 quarter 2. The likelihood of using this device decreased by 9.5% for each quarter elapsed in the post–FDA warning period (risk ratio, 0.91; 95% confidence interval, 0.90-0.91).

In other findings, containment bag use rose from 5.2% in 2013 quarter 4 to 15.2% by 2018 quarter 2. The likelihood of containment bag use rose by 3% for each quarter elapsed in the post–FDA warning period (RR, 1.03; 95% CI, 1.02-1.05).

Among women who underwent surgery with laparoscopic power morcellator use, uterine cancers or sarcomas were identified in 54 (0.17%) before the FDA guidance, compared with 7 (0.12%) after the guidance (P = .45).

Containment bags were used in 11.1% of women with uterine cancers or sarcomas before the FDA guidance, compared with 14.3% after the guidance (P = .12). The perioperative complication rate was 3.3% among women who had laparoscopic power morcellator use without a containment bag, compared with 4.5% (P = .001) in those with a containment bag (adjusted RR, 1.35; 95% CI, 1.12-1.64).

A related editorial argued that the backlash against power morcellation was unwarranted and an example of “reactionary medicine.”

Ben A. Abdu, MD, and Cameron Lowry, MD, of the department of obstetrics and gynecology at the University of Tennessee Health Science Center in Memphis, noted that with the known advantages of laparoscopy over laparotomy – decreased blood loss, decreased pain, and fewer wound complications and infections – it is of paramount importance to continue to offer minimally invasive surgery whenever possible. After the FDA raised safety concerns, there was a rise in the rate of open abdominal hysterectomy, which was accompanied by an increase in surgical morbidity. “Perhaps for now we should avoid throwing the baby out with the bath water,” they wrote.

The editorialists pointed out that any surgery may entail unintended complications. “It is also important to remember that there is a risk of dissemination of malignant tissue whether or not power morcellation is used, and it has even been observed in laparotomy,” they stated, noting that bag rupture and tissue spillage can occur even when the containment bag remains intact.

The downward trend in the use of power morcellators observed by Dr. Wright’s group is of serious concern, the commentators added, especially because the FDA communication was made in response to a rare occurrence and possibly resting on an overestimation of risk. “Based on their review of the medical literature at the time, the FDA cited prevalence estimates of 1 in 352 for any uterine sarcoma and 1 in 498 for leiomyosarcoma,” they wrote. “Many authors have expressed concern that the FDA data review was overestimated.” For example, they cite a meta-analysis using prospective data in which the prevalence of occult leiomyosarcoma was estimated at 1 in 8,300. Despite this extremely low prevalence, there has been an almost total nationwide hospital moratorium on the use of power morcellation, which will likely continue. Some manufacturers have ceased or limited production, distribution, and sales of these devices, they noted.

According to Dr. Michael L. Nimaroff, MD, however, chief of minimally invasive gynecologic surgery at Northwell Health in New Hyde Park, N.Y., the general post–FDA-guidance backlash did not have much effect on expert practitioners in this surgical field. “Those of us who specialize in minimally invasive gynecologic surgery, which has many benefits for the patients, never pivoted,” he told this news organization. “We continued to perform it but more conscientiously and with more concern for safety.”

As for morcellator use, added Dr. Nimaroff, specialists were so accustomed to doing these surgeries before the containment systems were made available that they don’t miss the power morcellator. “We actually retrieve tissue manually, and most of our morcellations, if they’re not contained manually, are retrieved vaginally or through a slightly bigger incision. So patients still benefit from minimally invasive surgery, and in some cases these techniques actually shorten the operation.”

This study received no external funding. Dr. Wright is editor in chief of Obstetrics & Gynecology. He reported royalties from UpToDate and has received research support from Merck. Coauthor Dr. Hou has served as a consultant for Foundation Medicine and Natera. Dr. Abdu and Dr. Lowry disclosed no competing interests, as did Dr. Nimaroff.

The use of laparoscopic power morcellators for minimally invasive hysterectomy has significantly decreased, and while the use of containment bags increased after the U.S. Food and Drug Administration’s 2014 safety warning about power morcellators, most procedures employing them are still performed without bags, according to a large database study in Obstetrics & Gynecology.

Containment bags are thought to limit the dissemination of potentially pathologic tissue, including unsuspected cancerous cells.

Rates of uterine cancer in women having morcellation were similar before and after the 2014 FDA guidance, and containment bags were used in only a small proportion of women with uterine cancer, according to findings from a research group led by Jason D. Wright, MD, of the division of gynecologic oncology at Columbia University, New York.

“Despite warnings from professional societies and regulatory agencies, as well as intense public scrutiny after the FDA warnings, the majority of morcellated uterine cancers occurred with uncontained laparoscopic power morcellation,” Dr. Wright and associates wrote, adding that the findings have important policy implications. First, efforts are needed to ensure morcellation is avoided in women with pathologic abnormalities. Second, despite regulatory approval, the safety and efficacy of containment bags remain uncertain, and the use and outcomes of these devices should be monitored closely.

The authors noted that laparoscopic power morcellation with a containment bag actually carries a small but significant increase in the risk of complications, compared with uncontained morcellation.

The study

Drawing on the Premier Healthcare Database, the researchers looked at deidentified patients aged 18 years or older who underwent laparoscopic supracervical hysterectomy from 2010 to 2018. The largest age group having the procedure consisted of women aged 40-49.

Patients were stratified based on use of laparoscopic power morcellators.

The cohort was further stratified as either pre–FDA guidance (2010 quarter 1 to 2014 quarter 1) or post–FDA guidance (2014 quarter 2 to 2018 quarter 2).

In the final cohort of 67,115 patients, laparoscopic power morcellator use decreased from 66.7% in 2013 quarter 4 to 13.3% by 2018 quarter 2. The likelihood of using this device decreased by 9.5% for each quarter elapsed in the post–FDA warning period (risk ratio, 0.91; 95% confidence interval, 0.90-0.91).

In other findings, containment bag use rose from 5.2% in 2013 quarter 4 to 15.2% by 2018 quarter 2. The likelihood of containment bag use rose by 3% for each quarter elapsed in the post–FDA warning period (RR, 1.03; 95% CI, 1.02-1.05).

Among women who underwent surgery with laparoscopic power morcellator use, uterine cancers or sarcomas were identified in 54 (0.17%) before the FDA guidance, compared with 7 (0.12%) after the guidance (P = .45).

Containment bags were used in 11.1% of women with uterine cancers or sarcomas before the FDA guidance, compared with 14.3% after the guidance (P = .12). The perioperative complication rate was 3.3% among women who had laparoscopic power morcellator use without a containment bag, compared with 4.5% (P = .001) in those with a containment bag (adjusted RR, 1.35; 95% CI, 1.12-1.64).

A related editorial argued that the backlash against power morcellation was unwarranted and an example of “reactionary medicine.”

Ben A. Abdu, MD, and Cameron Lowry, MD, of the department of obstetrics and gynecology at the University of Tennessee Health Science Center in Memphis, noted that with the known advantages of laparoscopy over laparotomy – decreased blood loss, decreased pain, and fewer wound complications and infections – it is of paramount importance to continue to offer minimally invasive surgery whenever possible. After the FDA raised safety concerns, there was a rise in the rate of open abdominal hysterectomy, which was accompanied by an increase in surgical morbidity. “Perhaps for now we should avoid throwing the baby out with the bath water,” they wrote.

The editorialists pointed out that any surgery may entail unintended complications. “It is also important to remember that there is a risk of dissemination of malignant tissue whether or not power morcellation is used, and it has even been observed in laparotomy,” they stated, noting that bag rupture and tissue spillage can occur even when the containment bag remains intact.

The downward trend in the use of power morcellators observed by Dr. Wright’s group is of serious concern, the commentators added, especially because the FDA communication was made in response to a rare occurrence and possibly resting on an overestimation of risk. “Based on their review of the medical literature at the time, the FDA cited prevalence estimates of 1 in 352 for any uterine sarcoma and 1 in 498 for leiomyosarcoma,” they wrote. “Many authors have expressed concern that the FDA data review was overestimated.” For example, they cite a meta-analysis using prospective data in which the prevalence of occult leiomyosarcoma was estimated at 1 in 8,300. Despite this extremely low prevalence, there has been an almost total nationwide hospital moratorium on the use of power morcellation, which will likely continue. Some manufacturers have ceased or limited production, distribution, and sales of these devices, they noted.

According to Dr. Michael L. Nimaroff, MD, however, chief of minimally invasive gynecologic surgery at Northwell Health in New Hyde Park, N.Y., the general post–FDA-guidance backlash did not have much effect on expert practitioners in this surgical field. “Those of us who specialize in minimally invasive gynecologic surgery, which has many benefits for the patients, never pivoted,” he told this news organization. “We continued to perform it but more conscientiously and with more concern for safety.”

As for morcellator use, added Dr. Nimaroff, specialists were so accustomed to doing these surgeries before the containment systems were made available that they don’t miss the power morcellator. “We actually retrieve tissue manually, and most of our morcellations, if they’re not contained manually, are retrieved vaginally or through a slightly bigger incision. So patients still benefit from minimally invasive surgery, and in some cases these techniques actually shorten the operation.”

This study received no external funding. Dr. Wright is editor in chief of Obstetrics & Gynecology. He reported royalties from UpToDate and has received research support from Merck. Coauthor Dr. Hou has served as a consultant for Foundation Medicine and Natera. Dr. Abdu and Dr. Lowry disclosed no competing interests, as did Dr. Nimaroff.

Time-restricted eating during the earlier part of the day (eTRE) may promote weight loss and reduce blood pressure, new findings suggest.

Previous studies have produced mixed results regarding the weight-loss potential for intermittent fasting, the practice of alternating eating with extended fasting, and the “time-restricted eating” format, where eating is restricted to a specific, often 10-hour, time window during the day.

In a new randomized clinical trial of 90 people with obesity in which that time window was 7 AM through 3 PM, so 8 hours long, researchers report that “eTRE was more effective for losing weight and lowering diastolic blood pressure than was eating over a period of 12 or more hours at 14 weeks. The eTRE intervention may therefore be an effective treatment for both obesity and hypertension.” The study, by Humaira Jamshed, PhD, of the department of nutrition sciences, University of Alabama at Birmingham, and colleagues, was published in JAMA Internal Medicine.

In an accompanying invited commentary, Shalender Bhasin, MBBS, points out that the study findings differ from those of a previous trial published in April of 139 adults conducted in China, which did not find a significant weight loss benefit with TRE versus ad lib eating.

“The scientific premise and the preclinical data of the effects of TRE are promising, but the inconsistency among studies renders it difficult to draw strong inferences from these well-conducted but relatively small trials,” notes Dr. Bhasin, of Harvard Medical School, Boston.
 

Need for larger and longer trials of TRE

Dr. Bhasin says – and the study authors also acknowledge – that much larger randomized clinical trials of longer duration are needed “to comprehensively evaluate the hypothesized benefits and risks of long-term TRE of calorically restricted diets in adults.”

Commenting on the study for the U.K. Science Media Centre, Simon Steenson, PhD, nutrition scientist, British Nutrition Foundation, said “one of the strengths of this new study is the trial design and the number of people who were recruited compared to many of the previous trials to date.”

However, Dr. Steenson also pointed to the prior Chinese research as evidence that the inconsistencies across studies highlight the need for larger and longer trials, with cardiovascular as well as weight-loss endpoints.

Still, Dr. Steenson said, “For individuals who may find that this pattern of eating fits better with their lifestyle and preferences, time-restricted feeding is one option for reducing overall calorie intake that might be a suitable approach for some. Ultimately, it is about finding the best approach to moderate calorie intake that works for each person, as successful and sustained weight loss is about ensuring the diet is feasible to follow in the long-term.”
 

Differences in weight loss, diastolic BP, but not all measures

The study population included 90 adults seen at the Weight Loss Medicine clinic at the University of Alabama at Birmingham between August 2018 and December 2019. Participants had a body mass index of 30-60 kg/m², and none had diabetes. 

They were randomized to eTRE with the 7 AM to PM eating window or a control schedule with eating across 12 hours or more, mimicking U.S. median mealtimes, at least 6 days a week. All participants received 30-minute weight-loss counseling sessions at baseline and at weeks 2, 6, and 10 and were advised to follow a diet of 500 kcal/day below their resting energy expenditure and exercise 75-150 minutes per week.

The eTRE group adhered with their schedule a mean of 6 days per week, lower than the 6.3 days among controls (P = .03), and adherence declined by about 0.4 days per week in the eTRE group over the 14 weeks (P = .001).  

At 14 weeks, both the eTRE group and controls had lost clinically meaningful amounts of weight, at –6.3 kg and –4.0 kg, respectively, but the –2.3 kg difference was significant (P = .002).

However, there was no difference in absolute fat loss (P = .09) or ratio of fat loss to weight loss (P = .43). There were also no significant differences in changes in other body composition parameters, including visceral fat and waist circumference.

Diastolic blood pressure was lowered by an additional 4 mmHg in the eTRE group, compared with controls at 14 weeks (P = .04), but there were no significant differences in systolic blood pressure, heart rate, glucose, A1c levels, insulin levels, measures of insulin resistance, or plasma lipids.

There were no differences between the two groups in self-reported physical activity, energy intake, or dietary macronutrient composition either. However, weight-loss modeling in 77 participants with at least two weight measurements indicated that the eTRE group reduced their intake by about 214 kcal/day, compared with controls (P = .04).

Those in the eTRE group also showed greater improvements in measures of mood disturbance, vigor-activity, fatigue-inertia, and depression-dejection. Other mood and sleep endpoints were similar between groups.

In a secondary analysis of just the 59 participants who completed the study, eTRE was also more effective at reducing body fat (P = .047) and trunk fat (P = .03).

About 41% of the eTRE completers planned to continue the practice after the study concluded.

The study was supported by grants from the National Center for Advancing Translational Sciences of the National Institutes of Health and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Jamshed has reported no relevant financial relationships. Dr. Bhasin has reported receiving grants to his institution for research on which Dr. Bhasin is the principal investigator from AbbVie and MIB, receiving personal fees from OPKO and Aditum and holding equity interest in FPT and XYOne. Dr. Steenson has declared funding in support of the British Nutrition Foundation that comes from a range of sources.

A version of this article first appeared on Medscape.com.

Time-restricted eating during the earlier part of the day (eTRE) may promote weight loss and reduce blood pressure, new findings suggest.

Previous studies have produced mixed results regarding the weight-loss potential for intermittent fasting, the practice of alternating eating with extended fasting, and the “time-restricted eating” format, where eating is restricted to a specific, often 10-hour, time window during the day.

In a new randomized clinical trial of 90 people with obesity in which that time window was 7 AM through 3 PM, so 8 hours long, researchers report that “eTRE was more effective for losing weight and lowering diastolic blood pressure than was eating over a period of 12 or more hours at 14 weeks. The eTRE intervention may therefore be an effective treatment for both obesity and hypertension.” The study, by Humaira Jamshed, PhD, of the department of nutrition sciences, University of Alabama at Birmingham, and colleagues, was published in JAMA Internal Medicine.

In an accompanying invited commentary, Shalender Bhasin, MBBS, points out that the study findings differ from those of a previous trial published in April of 139 adults conducted in China, which did not find a significant weight loss benefit with TRE versus ad lib eating.

“The scientific premise and the preclinical data of the effects of TRE are promising, but the inconsistency among studies renders it difficult to draw strong inferences from these well-conducted but relatively small trials,” notes Dr. Bhasin, of Harvard Medical School, Boston.
 

Need for larger and longer trials of TRE

Dr. Bhasin says – and the study authors also acknowledge – that much larger randomized clinical trials of longer duration are needed “to comprehensively evaluate the hypothesized benefits and risks of long-term TRE of calorically restricted diets in adults.”

Commenting on the study for the U.K. Science Media Centre, Simon Steenson, PhD, nutrition scientist, British Nutrition Foundation, said “one of the strengths of this new study is the trial design and the number of people who were recruited compared to many of the previous trials to date.”

However, Dr. Steenson also pointed to the prior Chinese research as evidence that the inconsistencies across studies highlight the need for larger and longer trials, with cardiovascular as well as weight-loss endpoints.

Still, Dr. Steenson said, “For individuals who may find that this pattern of eating fits better with their lifestyle and preferences, time-restricted feeding is one option for reducing overall calorie intake that might be a suitable approach for some. Ultimately, it is about finding the best approach to moderate calorie intake that works for each person, as successful and sustained weight loss is about ensuring the diet is feasible to follow in the long-term.”
 

Differences in weight loss, diastolic BP, but not all measures

The study population included 90 adults seen at the Weight Loss Medicine clinic at the University of Alabama at Birmingham between August 2018 and December 2019. Participants had a body mass index of 30-60 kg/m², and none had diabetes. 

They were randomized to eTRE with the 7 AM to PM eating window or a control schedule with eating across 12 hours or more, mimicking U.S. median mealtimes, at least 6 days a week. All participants received 30-minute weight-loss counseling sessions at baseline and at weeks 2, 6, and 10 and were advised to follow a diet of 500 kcal/day below their resting energy expenditure and exercise 75-150 minutes per week.

The eTRE group adhered with their schedule a mean of 6 days per week, lower than the 6.3 days among controls (P = .03), and adherence declined by about 0.4 days per week in the eTRE group over the 14 weeks (P = .001).  

At 14 weeks, both the eTRE group and controls had lost clinically meaningful amounts of weight, at –6.3 kg and –4.0 kg, respectively, but the –2.3 kg difference was significant (P = .002).

However, there was no difference in absolute fat loss (P = .09) or ratio of fat loss to weight loss (P = .43). There were also no significant differences in changes in other body composition parameters, including visceral fat and waist circumference.

Diastolic blood pressure was lowered by an additional 4 mmHg in the eTRE group, compared with controls at 14 weeks (P = .04), but there were no significant differences in systolic blood pressure, heart rate, glucose, A1c levels, insulin levels, measures of insulin resistance, or plasma lipids.

There were no differences between the two groups in self-reported physical activity, energy intake, or dietary macronutrient composition either. However, weight-loss modeling in 77 participants with at least two weight measurements indicated that the eTRE group reduced their intake by about 214 kcal/day, compared with controls (P = .04).

Those in the eTRE group also showed greater improvements in measures of mood disturbance, vigor-activity, fatigue-inertia, and depression-dejection. Other mood and sleep endpoints were similar between groups.

In a secondary analysis of just the 59 participants who completed the study, eTRE was also more effective at reducing body fat (P = .047) and trunk fat (P = .03).

About 41% of the eTRE completers planned to continue the practice after the study concluded.

The study was supported by grants from the National Center for Advancing Translational Sciences of the National Institutes of Health and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Jamshed has reported no relevant financial relationships. Dr. Bhasin has reported receiving grants to his institution for research on which Dr. Bhasin is the principal investigator from AbbVie and MIB, receiving personal fees from OPKO and Aditum and holding equity interest in FPT and XYOne. Dr. Steenson has declared funding in support of the British Nutrition Foundation that comes from a range of sources.

A version of this article first appeared on Medscape.com.

Time-restricted eating during the earlier part of the day (eTRE) may promote weight loss and reduce blood pressure, new findings suggest.

Previous studies have produced mixed results regarding the weight-loss potential for intermittent fasting, the practice of alternating eating with extended fasting, and the “time-restricted eating” format, where eating is restricted to a specific, often 10-hour, time window during the day.

In a new randomized clinical trial of 90 people with obesity in which that time window was 7 AM through 3 PM, so 8 hours long, researchers report that “eTRE was more effective for losing weight and lowering diastolic blood pressure than was eating over a period of 12 or more hours at 14 weeks. The eTRE intervention may therefore be an effective treatment for both obesity and hypertension.” The study, by Humaira Jamshed, PhD, of the department of nutrition sciences, University of Alabama at Birmingham, and colleagues, was published in JAMA Internal Medicine.

In an accompanying invited commentary, Shalender Bhasin, MBBS, points out that the study findings differ from those of a previous trial published in April of 139 adults conducted in China, which did not find a significant weight loss benefit with TRE versus ad lib eating.

“The scientific premise and the preclinical data of the effects of TRE are promising, but the inconsistency among studies renders it difficult to draw strong inferences from these well-conducted but relatively small trials,” notes Dr. Bhasin, of Harvard Medical School, Boston.
 

Need for larger and longer trials of TRE

Dr. Bhasin says – and the study authors also acknowledge – that much larger randomized clinical trials of longer duration are needed “to comprehensively evaluate the hypothesized benefits and risks of long-term TRE of calorically restricted diets in adults.”

Commenting on the study for the U.K. Science Media Centre, Simon Steenson, PhD, nutrition scientist, British Nutrition Foundation, said “one of the strengths of this new study is the trial design and the number of people who were recruited compared to many of the previous trials to date.”

However, Dr. Steenson also pointed to the prior Chinese research as evidence that the inconsistencies across studies highlight the need for larger and longer trials, with cardiovascular as well as weight-loss endpoints.

Still, Dr. Steenson said, “For individuals who may find that this pattern of eating fits better with their lifestyle and preferences, time-restricted feeding is one option for reducing overall calorie intake that might be a suitable approach for some. Ultimately, it is about finding the best approach to moderate calorie intake that works for each person, as successful and sustained weight loss is about ensuring the diet is feasible to follow in the long-term.”
 

Differences in weight loss, diastolic BP, but not all measures

The study population included 90 adults seen at the Weight Loss Medicine clinic at the University of Alabama at Birmingham between August 2018 and December 2019. Participants had a body mass index of 30-60 kg/m², and none had diabetes. 

They were randomized to eTRE with the 7 AM to PM eating window or a control schedule with eating across 12 hours or more, mimicking U.S. median mealtimes, at least 6 days a week. All participants received 30-minute weight-loss counseling sessions at baseline and at weeks 2, 6, and 10 and were advised to follow a diet of 500 kcal/day below their resting energy expenditure and exercise 75-150 minutes per week.

The eTRE group adhered with their schedule a mean of 6 days per week, lower than the 6.3 days among controls (P = .03), and adherence declined by about 0.4 days per week in the eTRE group over the 14 weeks (P = .001).  

At 14 weeks, both the eTRE group and controls had lost clinically meaningful amounts of weight, at –6.3 kg and –4.0 kg, respectively, but the –2.3 kg difference was significant (P = .002).

However, there was no difference in absolute fat loss (P = .09) or ratio of fat loss to weight loss (P = .43). There were also no significant differences in changes in other body composition parameters, including visceral fat and waist circumference.

Diastolic blood pressure was lowered by an additional 4 mmHg in the eTRE group, compared with controls at 14 weeks (P = .04), but there were no significant differences in systolic blood pressure, heart rate, glucose, A1c levels, insulin levels, measures of insulin resistance, or plasma lipids.

There were no differences between the two groups in self-reported physical activity, energy intake, or dietary macronutrient composition either. However, weight-loss modeling in 77 participants with at least two weight measurements indicated that the eTRE group reduced their intake by about 214 kcal/day, compared with controls (P = .04).

Those in the eTRE group also showed greater improvements in measures of mood disturbance, vigor-activity, fatigue-inertia, and depression-dejection. Other mood and sleep endpoints were similar between groups.

In a secondary analysis of just the 59 participants who completed the study, eTRE was also more effective at reducing body fat (P = .047) and trunk fat (P = .03).

About 41% of the eTRE completers planned to continue the practice after the study concluded.

The study was supported by grants from the National Center for Advancing Translational Sciences of the National Institutes of Health and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Jamshed has reported no relevant financial relationships. Dr. Bhasin has reported receiving grants to his institution for research on which Dr. Bhasin is the principal investigator from AbbVie and MIB, receiving personal fees from OPKO and Aditum and holding equity interest in FPT and XYOne. Dr. Steenson has declared funding in support of the British Nutrition Foundation that comes from a range of sources.

A version of this article first appeared on Medscape.com.

In October 2020, Medicare released an updated guidance to reduce Mohs micrographic surgery (MMS) reimbursement issues,¹ which initially was released in 2013. This guidance defines the latest performance and documentation requirements that Medicare requires for MMS. Understanding these requirements and making sure that your Mohs surgical reports have all the needed documentation details are critical because auditors from not only Medicare Administrative Contractors (MACs) but also private insurers and Medicare Advantage plans have adopted these standards and will deny payment for Mohs surgical codes if they are not met. This article provides a review of the updated Medicare requirements to make sure your MMS procedure notes are audit proof.

Notes Must Indicate Mohs Is the Most Appropriate Treatment

I review many of my colleagues’ Mohs notes and can tell you that some of the requirements laid out in the updated guidance typically are already reported by Mohs surgeons in their notes, including the location, number, and size of the lesion or lesions treated and the number of stages performed. However, there are some new requirements that often are not reported by Mohs surgeons that now need to be included. The guidance indicates the following:

The majority of skin cancers can be managed by simple excision or destruction techniques. The medical record of a patient undergoing MMS should clearly show that this procedure was chosen because of the complexity (eg, poorly defined clinical borders, possible deep invasion, prior irradiation), size or location (eg, maximum conservation of tumor-free tissue is important). Medicare will consider reimbursement for MMS for accepted diagnoses and indications, which you must document in the patient’s medical record as being appropriate for MMS and that MMS is the most appropriate choice for the treatment of a particular lesion.¹

In my experience, most Mohs notes include some statement that the skin cancer treated is appropriate based on the Mohs appropriate use criteria (AUC) or the AUC score. However, notes should make clear not just that the lesion treated is “appropriate” for MMS but also that it is the most appropriate treatment (eg, why the lesion was not managed by standard excision or destruction technique).

Mohs Surgeon Must Perform the Surgery and Interpret Slides

The updated guidance clearly indicates that MMS may only be performed by a physician who is specifically trained and highly skilled in Mohs techniques and pathologic identification: “Medicare will only reimburse for MMS services when the Mohs surgeon acts as both surgeon and pathologist.”¹ Mohs micrographic surgery codes may not be billed if preparation or interpretation of the pathology slides is performed by a physician other than the Mohs surgeon. Operative notes and pathology documentation in the patient’s medical record should clearly show that MMS was performed using an accepted MMS technique in which the physician acts in 2 integrated and distinct capacities—surgeon and pathologist—thereby confirming that the procedure meets the definition of the Current Procedural Terminology code(s).

Furthermore, the Mohs operative report should detail “the number of specimens per stage.”¹ I interpret this statement to indicate that the Mohs surgeon should document the number of tissue blocks examined in each stage of Mohs surgery. For example, a statement in the notes such as “the specimen from the first Mohs stage was oriented, mapped, and divided into 4 blocks” should suffice to meet this requirement.

Histologic Description Must Be Included in Mohs Notes

Medicare will require the Mohs surgeon to document “the histology of the specimens taken. That description should include depth of invasion, pathological pattern, cell morphology, and, if present, perineural invasion or presence of scar tissue.”¹ Although this histologic description requirement appears daunting, it is common for Mohs surgeons to indicate their pathologic findings on their Mohs map such as “NBCC” next to a red area to indicate “nodular basal cell carcinoma visualized.” A template-based system to translate typical pathologic findings can be employed to rapidly and accurately populate a Mohs note with histologic description such as “NBBC=nodular aggregates of palisaded basaloid epithelial tumor arising from the epidermis forming a palisade with a cleft forming from the adjacent mucinous stroma extending to the mid dermis. Centrally the nuclei become crowded with scattered mitotic figures and necrotic bodies evident.”

Recent Improvement for 1-Stage Mohs Surgeries

The most notable improvement in the 2020 MMS reimbursement requirements vs the prior version is that, “If tumor is visualized on stage one, you must describe the histology of the specimens taken.”¹ This indicates that if no tumor is visualized in the first stage, then no description of the tumor is possible or necessary. This is a much-needed improvement, as I have observed that some auditors have denied 1-stage Mohs surgeries due to lack of tumor histology description.

Final Thoughts

Overall, the updated Medicare guidance provides important details in the requirements for performance and documentation of Mohs surgery cases. However, additional critical information will be found in Mohs coverage policies and local coverage determinations (LCDs) from MACs and private insurers.^2-4 Each LCD and insurer Mohs payment policy has unique wording and requirements. Coverage of MMS for specific malignant diagnoses, histologic subtypes, locations, and clinical scenarios varies between LCDs; most are based directly on the Mohs AUC, while others have a less specific coverage criteria. To understand the specific documentation and coverage requirements of the MAC for a particular region or private insurer, Mohs surgeons are encouraged to familiarize themselves with the Mohs surgery LCD of their local MAC and coverage policies of their insurers and to ensure their documentation substantiates these requirements. Making sure that your MMS documentation is accurate and complies with Medicare and insurer requirements will keep you out of hot water with auditors and allow reimbursement for this critical skin cancer procedure.

In October 2020, Medicare released an updated guidance to reduce Mohs micrographic surgery (MMS) reimbursement issues,¹ which initially was released in 2013. This guidance defines the latest performance and documentation requirements that Medicare requires for MMS. Understanding these requirements and making sure that your Mohs surgical reports have all the needed documentation details are critical because auditors from not only Medicare Administrative Contractors (MACs) but also private insurers and Medicare Advantage plans have adopted these standards and will deny payment for Mohs surgical codes if they are not met. This article provides a review of the updated Medicare requirements to make sure your MMS procedure notes are audit proof.

Notes Must Indicate Mohs Is the Most Appropriate Treatment

I review many of my colleagues’ Mohs notes and can tell you that some of the requirements laid out in the updated guidance typically are already reported by Mohs surgeons in their notes, including the location, number, and size of the lesion or lesions treated and the number of stages performed. However, there are some new requirements that often are not reported by Mohs surgeons that now need to be included. The guidance indicates the following:

The majority of skin cancers can be managed by simple excision or destruction techniques. The medical record of a patient undergoing MMS should clearly show that this procedure was chosen because of the complexity (eg, poorly defined clinical borders, possible deep invasion, prior irradiation), size or location (eg, maximum conservation of tumor-free tissue is important). Medicare will consider reimbursement for MMS for accepted diagnoses and indications, which you must document in the patient’s medical record as being appropriate for MMS and that MMS is the most appropriate choice for the treatment of a particular lesion.¹

In my experience, most Mohs notes include some statement that the skin cancer treated is appropriate based on the Mohs appropriate use criteria (AUC) or the AUC score. However, notes should make clear not just that the lesion treated is “appropriate” for MMS but also that it is the most appropriate treatment (eg, why the lesion was not managed by standard excision or destruction technique).

Mohs Surgeon Must Perform the Surgery and Interpret Slides

The updated guidance clearly indicates that MMS may only be performed by a physician who is specifically trained and highly skilled in Mohs techniques and pathologic identification: “Medicare will only reimburse for MMS services when the Mohs surgeon acts as both surgeon and pathologist.”¹ Mohs micrographic surgery codes may not be billed if preparation or interpretation of the pathology slides is performed by a physician other than the Mohs surgeon. Operative notes and pathology documentation in the patient’s medical record should clearly show that MMS was performed using an accepted MMS technique in which the physician acts in 2 integrated and distinct capacities—surgeon and pathologist—thereby confirming that the procedure meets the definition of the Current Procedural Terminology code(s).

Furthermore, the Mohs operative report should detail “the number of specimens per stage.”¹ I interpret this statement to indicate that the Mohs surgeon should document the number of tissue blocks examined in each stage of Mohs surgery. For example, a statement in the notes such as “the specimen from the first Mohs stage was oriented, mapped, and divided into 4 blocks” should suffice to meet this requirement.

Histologic Description Must Be Included in Mohs Notes

Medicare will require the Mohs surgeon to document “the histology of the specimens taken. That description should include depth of invasion, pathological pattern, cell morphology, and, if present, perineural invasion or presence of scar tissue.”¹ Although this histologic description requirement appears daunting, it is common for Mohs surgeons to indicate their pathologic findings on their Mohs map such as “NBCC” next to a red area to indicate “nodular basal cell carcinoma visualized.” A template-based system to translate typical pathologic findings can be employed to rapidly and accurately populate a Mohs note with histologic description such as “NBBC=nodular aggregates of palisaded basaloid epithelial tumor arising from the epidermis forming a palisade with a cleft forming from the adjacent mucinous stroma extending to the mid dermis. Centrally the nuclei become crowded with scattered mitotic figures and necrotic bodies evident.”

Recent Improvement for 1-Stage Mohs Surgeries

The most notable improvement in the 2020 MMS reimbursement requirements vs the prior version is that, “If tumor is visualized on stage one, you must describe the histology of the specimens taken.”¹ This indicates that if no tumor is visualized in the first stage, then no description of the tumor is possible or necessary. This is a much-needed improvement, as I have observed that some auditors have denied 1-stage Mohs surgeries due to lack of tumor histology description.

Final Thoughts

Overall, the updated Medicare guidance provides important details in the requirements for performance and documentation of Mohs surgery cases. However, additional critical information will be found in Mohs coverage policies and local coverage determinations (LCDs) from MACs and private insurers.^2-4 Each LCD and insurer Mohs payment policy has unique wording and requirements. Coverage of MMS for specific malignant diagnoses, histologic subtypes, locations, and clinical scenarios varies between LCDs; most are based directly on the Mohs AUC, while others have a less specific coverage criteria. To understand the specific documentation and coverage requirements of the MAC for a particular region or private insurer, Mohs surgeons are encouraged to familiarize themselves with the Mohs surgery LCD of their local MAC and coverage policies of their insurers and to ensure their documentation substantiates these requirements. Making sure that your MMS documentation is accurate and complies with Medicare and insurer requirements will keep you out of hot water with auditors and allow reimbursement for this critical skin cancer procedure.

In October 2020, Medicare released an updated guidance to reduce Mohs micrographic surgery (MMS) reimbursement issues,¹ which initially was released in 2013. This guidance defines the latest performance and documentation requirements that Medicare requires for MMS. Understanding these requirements and making sure that your Mohs surgical reports have all the needed documentation details are critical because auditors from not only Medicare Administrative Contractors (MACs) but also private insurers and Medicare Advantage plans have adopted these standards and will deny payment for Mohs surgical codes if they are not met. This article provides a review of the updated Medicare requirements to make sure your MMS procedure notes are audit proof.

Notes Must Indicate Mohs Is the Most Appropriate Treatment

I review many of my colleagues’ Mohs notes and can tell you that some of the requirements laid out in the updated guidance typically are already reported by Mohs surgeons in their notes, including the location, number, and size of the lesion or lesions treated and the number of stages performed. However, there are some new requirements that often are not reported by Mohs surgeons that now need to be included. The guidance indicates the following:

The majority of skin cancers can be managed by simple excision or destruction techniques. The medical record of a patient undergoing MMS should clearly show that this procedure was chosen because of the complexity (eg, poorly defined clinical borders, possible deep invasion, prior irradiation), size or location (eg, maximum conservation of tumor-free tissue is important). Medicare will consider reimbursement for MMS for accepted diagnoses and indications, which you must document in the patient’s medical record as being appropriate for MMS and that MMS is the most appropriate choice for the treatment of a particular lesion.¹

In my experience, most Mohs notes include some statement that the skin cancer treated is appropriate based on the Mohs appropriate use criteria (AUC) or the AUC score. However, notes should make clear not just that the lesion treated is “appropriate” for MMS but also that it is the most appropriate treatment (eg, why the lesion was not managed by standard excision or destruction technique).

Mohs Surgeon Must Perform the Surgery and Interpret Slides

The updated guidance clearly indicates that MMS may only be performed by a physician who is specifically trained and highly skilled in Mohs techniques and pathologic identification: “Medicare will only reimburse for MMS services when the Mohs surgeon acts as both surgeon and pathologist.”¹ Mohs micrographic surgery codes may not be billed if preparation or interpretation of the pathology slides is performed by a physician other than the Mohs surgeon. Operative notes and pathology documentation in the patient’s medical record should clearly show that MMS was performed using an accepted MMS technique in which the physician acts in 2 integrated and distinct capacities—surgeon and pathologist—thereby confirming that the procedure meets the definition of the Current Procedural Terminology code(s).

Furthermore, the Mohs operative report should detail “the number of specimens per stage.”¹ I interpret this statement to indicate that the Mohs surgeon should document the number of tissue blocks examined in each stage of Mohs surgery. For example, a statement in the notes such as “the specimen from the first Mohs stage was oriented, mapped, and divided into 4 blocks” should suffice to meet this requirement.

Histologic Description Must Be Included in Mohs Notes

Medicare will require the Mohs surgeon to document “the histology of the specimens taken. That description should include depth of invasion, pathological pattern, cell morphology, and, if present, perineural invasion or presence of scar tissue.”¹ Although this histologic description requirement appears daunting, it is common for Mohs surgeons to indicate their pathologic findings on their Mohs map such as “NBCC” next to a red area to indicate “nodular basal cell carcinoma visualized.” A template-based system to translate typical pathologic findings can be employed to rapidly and accurately populate a Mohs note with histologic description such as “NBBC=nodular aggregates of palisaded basaloid epithelial tumor arising from the epidermis forming a palisade with a cleft forming from the adjacent mucinous stroma extending to the mid dermis. Centrally the nuclei become crowded with scattered mitotic figures and necrotic bodies evident.”

Recent Improvement for 1-Stage Mohs Surgeries

The most notable improvement in the 2020 MMS reimbursement requirements vs the prior version is that, “If tumor is visualized on stage one, you must describe the histology of the specimens taken.”¹ This indicates that if no tumor is visualized in the first stage, then no description of the tumor is possible or necessary. This is a much-needed improvement, as I have observed that some auditors have denied 1-stage Mohs surgeries due to lack of tumor histology description.

Final Thoughts

Overall, the updated Medicare guidance provides important details in the requirements for performance and documentation of Mohs surgery cases. However, additional critical information will be found in Mohs coverage policies and local coverage determinations (LCDs) from MACs and private insurers.^2-4 Each LCD and insurer Mohs payment policy has unique wording and requirements. Coverage of MMS for specific malignant diagnoses, histologic subtypes, locations, and clinical scenarios varies between LCDs; most are based directly on the Mohs AUC, while others have a less specific coverage criteria. To understand the specific documentation and coverage requirements of the MAC for a particular region or private insurer, Mohs surgeons are encouraged to familiarize themselves with the Mohs surgery LCD of their local MAC and coverage policies of their insurers and to ensure their documentation substantiates these requirements. Making sure that your MMS documentation is accurate and complies with Medicare and insurer requirements will keep you out of hot water with auditors and allow reimbursement for this critical skin cancer procedure.

James (Jim) R. Roberts, MD, whose 45-year career spanned the evolution of the field of emergency medicine (EM) as it grew into the flourishing specialty it is today, died on July 22, 2022, at the age of 76 years. Dr. Roberts was coauthor of the foundational EM text, Clinical Procedures in Emergency Medicine and Acute Care , and was among the first physicians in the world to be board certified in EM. He was a prominent member of the American College of Emergency Physicians, a long-time contributor and editorial board chair for Emergency Medicine News, and a founding member of the American College of Medical Toxicology. He previously served as chairman of the Mercy Catholic Medical Center emergency department in Philadelphia, and vice chairman of the department of emergency medicine at Drexel University, Philadelphia.

“Dr. Roberts was a prominent EM physician and a pioneer in emergency medicine,” said Robert Glatter, MD, assistant professor of emergency medicine at Hofstra University, Hempstead, N.Y.. “He is a revered and respected figure in emergency medicine.” This sentiment was echoed by his colleagues and former students across the EM world.

“How does one describe a unicorn?” Leslie Dye, MD, past president of the ACMT wrote in a tribute to Dr. Roberts on the ACMT website. “There are existing words, but he should have words that belong solely to him. Compassionate, irreverent, brilliant, funny, sarcastic, HUMBLE, modest, kind, inquisitive, and one of the best doctors I have ever met.” 

By all accounts, Dr. Roberts lived his life according to words he wrote in a 2018 column for Emergency Medicine News, “How to Be a Good EP.” “Emergency medicine is not just a job, it’s a lifestyle, but there is more to life than medicine. You can never make up a missed championship soccer game, anniversary, birthday, or chance to take your son or daughter fishing. In a heartbeat your children will be on their own and will likely have trouble finding time for you. Remember that you might need a shift off someday, so be ready to help a colleague with a similar request.”

He is survived by a large extended family, including his daughter Martha, son Matthew, and spouse of more than 40 years, Lydia Forte Roberts.

A version of this article first appeared on Medscape.com.

James (Jim) R. Roberts, MD, whose 45-year career spanned the evolution of the field of emergency medicine (EM) as it grew into the flourishing specialty it is today, died on July 22, 2022, at the age of 76 years. Dr. Roberts was coauthor of the foundational EM text, Clinical Procedures in Emergency Medicine and Acute Care , and was among the first physicians in the world to be board certified in EM. He was a prominent member of the American College of Emergency Physicians, a long-time contributor and editorial board chair for Emergency Medicine News, and a founding member of the American College of Medical Toxicology. He previously served as chairman of the Mercy Catholic Medical Center emergency department in Philadelphia, and vice chairman of the department of emergency medicine at Drexel University, Philadelphia.

“Dr. Roberts was a prominent EM physician and a pioneer in emergency medicine,” said Robert Glatter, MD, assistant professor of emergency medicine at Hofstra University, Hempstead, N.Y.. “He is a revered and respected figure in emergency medicine.” This sentiment was echoed by his colleagues and former students across the EM world.

“How does one describe a unicorn?” Leslie Dye, MD, past president of the ACMT wrote in a tribute to Dr. Roberts on the ACMT website. “There are existing words, but he should have words that belong solely to him. Compassionate, irreverent, brilliant, funny, sarcastic, HUMBLE, modest, kind, inquisitive, and one of the best doctors I have ever met.” 

By all accounts, Dr. Roberts lived his life according to words he wrote in a 2018 column for Emergency Medicine News, “How to Be a Good EP.” “Emergency medicine is not just a job, it’s a lifestyle, but there is more to life than medicine. You can never make up a missed championship soccer game, anniversary, birthday, or chance to take your son or daughter fishing. In a heartbeat your children will be on their own and will likely have trouble finding time for you. Remember that you might need a shift off someday, so be ready to help a colleague with a similar request.”

He is survived by a large extended family, including his daughter Martha, son Matthew, and spouse of more than 40 years, Lydia Forte Roberts.

A version of this article first appeared on Medscape.com.

James (Jim) R. Roberts, MD, whose 45-year career spanned the evolution of the field of emergency medicine (EM) as it grew into the flourishing specialty it is today, died on July 22, 2022, at the age of 76 years. Dr. Roberts was coauthor of the foundational EM text, Clinical Procedures in Emergency Medicine and Acute Care , and was among the first physicians in the world to be board certified in EM. He was a prominent member of the American College of Emergency Physicians, a long-time contributor and editorial board chair for Emergency Medicine News, and a founding member of the American College of Medical Toxicology. He previously served as chairman of the Mercy Catholic Medical Center emergency department in Philadelphia, and vice chairman of the department of emergency medicine at Drexel University, Philadelphia.

“Dr. Roberts was a prominent EM physician and a pioneer in emergency medicine,” said Robert Glatter, MD, assistant professor of emergency medicine at Hofstra University, Hempstead, N.Y.. “He is a revered and respected figure in emergency medicine.” This sentiment was echoed by his colleagues and former students across the EM world.

“How does one describe a unicorn?” Leslie Dye, MD, past president of the ACMT wrote in a tribute to Dr. Roberts on the ACMT website. “There are existing words, but he should have words that belong solely to him. Compassionate, irreverent, brilliant, funny, sarcastic, HUMBLE, modest, kind, inquisitive, and one of the best doctors I have ever met.” 

By all accounts, Dr. Roberts lived his life according to words he wrote in a 2018 column for Emergency Medicine News, “How to Be a Good EP.” “Emergency medicine is not just a job, it’s a lifestyle, but there is more to life than medicine. You can never make up a missed championship soccer game, anniversary, birthday, or chance to take your son or daughter fishing. In a heartbeat your children will be on their own and will likely have trouble finding time for you. Remember that you might need a shift off someday, so be ready to help a colleague with a similar request.”

He is survived by a large extended family, including his daughter Martha, son Matthew, and spouse of more than 40 years, Lydia Forte Roberts.

A version of this article first appeared on Medscape.com.

Keratinocyte carcinoma (KC), or nonmelanoma skin cancer, is the most commonly diagnosed cancer in the United States.¹ Basal cell carcinoma comprises the majority of all KCs.^2,3 Squamous cell carcinoma is the second most common skin cancer, representing approximately 20% of KCs and accounting for the majority of KC-related deaths.^4-7 Malignant melanoma represents the majority of all skin cancer–related deaths.⁸ The incidence of basal cell carcinoma, squamous cell carcinoma, and malignant melanoma in the United States is on the rise and carries substantial morbidity and mortality with notable social and economic burdens.^1,8-10

Prevention is necessary to reduce skin cancer morbidity and mortality as well as rising treatment costs. The most commonly used skin cancer screening method among dermatologists is the visual full-body skin examination (FBSE), which is a noninvasive, safe, quick, and cost-effective method of early detection and prevention.¹¹ To effectively confront the growing incidence and health care burden of skin cancer, primary care providers (PCPs) must join dermatologists in conducting FBSEs.^12,13

Despite being the predominant means of secondary skin cancer prevention, the US Preventive Services Task Force (USPSTF) issued an I rating for insufficient evidence to assess the benefits vs harms of screening the adult general population by PCPs.^14,15 A major barrier to studying screening is the lack of a standardized method for conducting and reporting FBSEs.¹³ Systematic thorough skin examination generally is not performed in the primary care setting.^16-18

We aimed to investigate what occurs during an FBSE in the primary care setting and how often they are performed. We examined whether there was potential variation in the execution of the examination, what was perceived by the patient vs reported by the physician, and what was ultimately included in the medical record. Miscommunication between patient and provider regarding performance of FBSEs has previously been noted,^17-19 and we sought to characterize and quantify that miscommunication. We hypothesized that there would be lower patient-reported FBSEs compared to physicians and patient medical records. We also hypothesized that there would be variability in how physicians screened for skin cancer.

METHODS

This study was cross-sectional and was conducted based on interviews and a review of medical records at secondary- and tertiary-level units (clinics and hospitals) across the United States. We examined baseline data from a randomized controlled trial of a Web-based skin cancer early detection continuing education course—the Basic Skin Cancer Triage curriculum. Complete details have been described elsewhere.¹² This study was approved by the institutional review boards of the Providence Veterans Affairs Medical Center, Rhode Island Hospital, and Brown University (all in Providence, Rhode Island), as well as those of all recruitment sites.

Data were collected from 2005 to 2008 and included physician online surveys, patient telephone interviews, and patient medical record data abstracted by research assistants. Primary care providers included in the study were general internists, family physicians, or medicine-pediatrics practitioners who were recruited from 4 collaborating centers across the United States in the mid-Atlantic region, Ohio, Kansas, and southern California, and who had been in practice for at least a year. Patients were recruited from participating physician practices and selected by research assistants who traveled to each clinic for coordination, recruitment, and performance of medical record reviews. Patients were selected as having minimal risk of melanoma (eg, no signs of severe photodamage to the skin). Patients completed structured telephone surveys within 1 to 2 weeks of the office visit regarding the practices observed and clinical questions asked during their recent clinical encounter with their PCP.

Measures

Demographics—Demographic variables asked of physicians included age, sex, ethnicity, academic degree (MD vs DO), years in practice, training, and prior dermatology training. Demographic information asked of patients included age, sex, ethnicity, education, and household income.

Physician-Reported Examination and Counseling Variables—Physicians were asked to characterize their clinical practices, prompted by questions regarding performance of FBSEs: “Please think of a typical month and using the scale below, indicate how frequently you perform a total body skin exam during an annual exam (eg, periodic follow-up exam).” Physicians responded to 3 questions on a 5-point scale (1=never, 2=sometimes, 3=about half, 4=often, 5=almost always).

Patient-Reported Examination Variables—Patients also were asked to characterize the skin examination experienced in their clinical encounter with their PCP, including: “During your last visit, as far as you could tell, did your physician: (1) look at the skin on your back? (2) look at the skin on your belly area? (3) look at the skin on the back of your legs?” Patient responses were coded as yes, no, don’t know, or refused. Participants who refused were excluded from analysis; participants who responded are detailed in Table 1. In addition, patients also reported the level of undress with their physician by answering the following question: “During your last medical exam, did you: 1=keep your clothes on; 2=partially undress; 3=totally undress except for undergarments; 4=totally undress, including all undergarments?”

Patient Medical Record–Extracted Data—Research assistants used a structured abstract form to extract the information from the patient’s medical record and graded it as 0 (absence) or 1 (presence) from the medical record.

Statistical Analysis

Descriptive statistics included mean and standard deviation (SD) for continuous variables as well as frequency and percentage for categorical variables. Logit/logistic regression analysis was used to predict the odds of patient-reported outcomes that were binary with physician-reported variables as the predictor. Linear regression analysis was used to assess the association between 2 continuous variables. All analyses were conducted using SPSS version 24 (IBM).²⁰ Significance criterion was set at α of .05.

RESULTS Demographics

The final sample included data from 53 physicians and 3343 patients. The study sample mean age (SD) was 50.3 (9.9) years for PCPs (n=53) and 59.8 (16.9) years for patients (n=3343). The physician sample was 36% female and predominantly White (83%). Ninety-one percent of the PCPs had an MD (the remaining had a DO degree), and the mean (SD) years practicing was 21.8 (10.6) years. Seventeen percent of PCPs were trained in internal medicine, 4% in internal medicine and pediatrics, and 79% family medicine; 79% of PCPs had received prior training in dermatology. The patient sample was 58% female, predominantly White (84%), non-Hispanic/Latinx (95%), had completed high school (94%), and earned more than $40,000 annually (66%).

Physician- and Patient-Reported FBSEs

Physicians reported performing FBSEs with variable frequency. Among PCPs who conducted FBSEs with greater frequency, there was a modest increase in the odds that patients reported a particular body part was examined (back: odds ratio [OR], 24.5% [95% CI, 1.18-1.31; P<.001]; abdomen: OR, 23.3% [95% CI, 1.17-1.30; P<.001]; backs of legs: OR, 20.4% [95% CI, 1.13-1.28; P<.001])(Table 1). The patient-reported level of undress during examination was significantly associated with physician-reported FBSE (β=0.16 [95% CI, 0.13-0.18; P<.001])(Table 2).

Because of the bimodal distribution of scores in the physician-reported frequency of FBSEs, particularly pertaining to the extreme points of the scale, we further repeated analysis with only the never and almost always groups (Table 1). Primary care providers who reported almost always for FBSE had 29.6% increased odds of patient-reported back examination (95% CI, 1.00-1.68; P=.048) and 59.3% increased odds of patient-reported abdomen examination (95% CI, 1.23-2.06; P<.001). The raw percentages of patients who reported having their back, abdomen, and backs of legs examined when the PCP reported having never conducted an FBSE were 56%, 40%, and 26%, respectively. The raw percentages of patients who reported having their back, abdomen, and backs of legs examined when the PCP reported having almost always conducted an FBSE were 52%, 51%, and 30%, respectively. Raw percentages were calculated by dividing the number of "yes" responses by participants for each body part examined by thetotal number of participant responses (“yes” and “no”) for each respective body part. There was no significant change in odds of patient-reported backs of legs examined with PCP-reported never vs almost always conducting an FBSE. In addition, a greater patient-reported level of undress was associated with 20.2% increased odds of PCPs reporting almost always conducting an FBSE (95% CI, 1.08-1.34; P=.001).

 

 

FBSEs in Patient Medical Records

When comparing PCP-reported FBSE and report of FBSE in patient medical records, there was a 39.0% increased odds of the patient medical record indicating FBSE when physicians reported conducting an FBSE with greater frequency (95% CI, 1.30-1.48; P<.001)(eTable 1). When examining PCP-reported never vs almost always conducting an FBSE, a report of almost always was associated with 79.0% increased odds of the patient medical record indicating that an FBSE was conducted (95% CI, 1.28-2.49; P=.001). The raw percentage of the patient medical record indicating an FBSE was conducted when the PCP reported having never conducted an FBSE was 17% and 26% when the PCP reported having almost always conducted an FBSE.

When comparing the patient-reported body part examined with patient FBSE medical record documentation, an indication of yes for FBSE on the patient medical record was associated with a considerable increase in odds that patients reported a particular body part was examined (back: 91.4% [95% CI, 1.59-2.31; P<.001]; abdomen: 75.0% [95% CI, 1.45-2.11; P<.001]; backs of legs: 91.6% [95% CI, 1.56-2.36; P<.001])(eTable 2). The raw percentages of patients who reported having their back, abdomen, and backs of legs examined vs not examined when the patient medical record indicated an FBSE was completed were 24% vs 14%, 23% vs 15%, and 26% vs 16%, respectively. An increase in patient-reported level of undress was associated with a 57.0% increased odds of their medical record indicating an FBSE was conducted (95% CI, 1.45-1.70; P<.001).

COMMENT How PCPs Perform FBSEs Varies

We found that PCPs performed FBSEs with variable frequency, and among those who did, the patient report of their examination varied considerably (Table 1). There appears to be considerable ambiguity in each of these means of determining the extent to which the skin was inspected for skin cancer, which may render the task of improving such inspection more difficult. We asked patients whether their back, abdomen, and backs of legs were examined as an assessment of some of the variety of areas inspected during an FBSE. During a general well-visit appointment, a patient’s back and abdomen may be examined for multiple reasons. Patients may have misinterpreted elements of the pulmonary, cardiac, abdominal, or musculoskeletal examinations as being part of the FBSE. The back and abdomen—the least specific features of the FBSE—were reported by patients to be the most often examined. Conversely, the backs of the legs—the most specific feature of the FBSE—had the lowest odds of being examined (Table 1).

In addition to the potential limitations of patient awareness of physician activity, our results also could be explained by differences among PCPs in how they performed FBSEs. There is no standardized method of conducting an FBSE. Furthermore, not all medical students and residents are exposed to dermatology training. In our sample of 53 physicians, 79% had reported receiving dermatology training; however, we did not assess the extent to which they had been trained in conducting an FBSE and/or identifying malignant lesions. In an American survey of 659 medical students, more than two-thirds of students had never been trained or never examined a patient for skin cancer.²¹ In another American survey of 342 internal medicine, family medicine, pediatrics, and obstetrics/gynecology residents across 7 medical schools and 4 residency programs, more than three-quarters of residents had never been trained in skin cancer screening.²² Our findings reflect insufficient and inconsistent training in skin cancer screening and underscore the need for mandatory education to ensure quality FBSEs are performed in the primary care setting.

Frequency of PCPs Performing FBSEs

Similar to prior studies analyzing the frequency of FBSE performance in the primary care setting,^16,19,23,24 more than half of our PCP sample reported sometimes to never conducting FBSEs. The percentage of physicians who reported conducting FBSEs in our sample was greater than the proportion reported by the National Health Interview Survey, in which only 8% of patients received an FBSE in the prior year by a PCP or obstetrician/gynecologist,¹⁶ but similar to a smaller patient study.¹⁹ In that study, 87% of patients, regardless of their skin cancer history, also reported that they would like their PCP to perform an FBSE regularly.¹⁹ Although some of our patient participants may have declined an FBSE, it is unlikely that that would have entirely accounted for the relatively low number of PCPs who reported frequently performing FBSEs.

Documentation in Medical Records of FBSEs

Compared to PCP self-reported performance of FBSEs, considerably fewer PCPs marked the patient medical record as having completed an FBSE. Among patients with medical records that indicated an FBSE had been conducted, they reported higher odds of all 3 body parts being examined, the highest being the backs of the legs. Also, when the patient medical record indicated an FBSE had been completed, the odds that the PCP reported an FBSE also were higher. The relatively low medical record documentation of FBSEs highlights the need for more rigorous enforcement of accurate documentation. However, among the cases that were recorded, it appeared that the content of the examinations was more consistent.

Benefits of PCP-Led FBSEs

Although the USPSTF issued an I rating for PCP-led FBSEs,¹⁴ multiple national medical societies, including the American Cancer Society,²⁵ American Academy of Dermatology,²⁶ and Skin Cancer Foundation,²⁷ as well as international guidelines in Germany,²⁸ Australia,^29,30 and New Zealand,³¹ recommend regular FBSEs among the general or at-risk population; New Zealand and Australia have the highest incidence and prevalence of melanoma in the world.⁸ The benefits of physician-led FBSEs on detection of early-stage skin cancer, and in particular, melanoma detection, have been documented in numerous studies.^30,32-38 However, the variability and often poor quality of skin screening may contribute in part to the just as numerous null results from prior skin screening studies,¹⁵ perpetuating the insufficient status of skin examinations by USPSTF standards.¹⁴ Our study underscores both the variability in frequency and content of PCP-administered FBSEs. It also highlights the need for standardization of screening examinations at the medical student, trainee, and physician level.

 

 

Study Limitations

The present study has several limitations. First, there was an unknown time lag between the FBSEs and physician self-reported surveys. Similarly, there was a variable time lag between the patient examination encounter and subsequent telephone survey. Both the physician and patient survey data may have been affected by recall bias. Second, patients were not asked directly whether an FBSE had been conducted. Furthermore, patients may not have appreciated whether the body part examined was part of the FBSE or another examination. Also, screenings often were not recorded in the medical record, assuming that the patient report and/or physician report was more accurate than the medical record.

Our study also was limited by demographics; our patient sample was largely comprised of White, educated, US adults, potentially limiting the generalizability of our findings. Conversely, a notable strength of our study was that our participants were recruited from 4 geographically diverse centers. Furthermore, we had a comparatively large sample size of patients and physicians. Also, the independent assessment of provider-reported examinations, objective assessment of medical records, and patient reports of their encounters provides a strong foundation for assessing the independent contributions of each data source.

CONCLUSION

Our study highlights the challenges future studies face in promoting skin cancer screening in the primary care setting. Our findings underscore the need for a standardized FBSE as well as clear clinical expectations regarding skin cancer screening that is expected of PCPs.

As long as skin cancer screening rates remain low in the United States, patients will be subject to potential delays and missed diagnoses, impacting morbidity and mortality.⁸ There are burgeoning resources and efforts in place to increase skin cancer screening. For example, free validated online training is available for early detection of melanoma and other skin cancers (https://www.visualdx.com/skin-cancer-education/).^39-42 Future directions for bolstering screening numbers must focus on educating PCPs about skin cancer prevention and perhaps narrowing the screening population by age-appropriate risk assessments.

Keratinocyte carcinoma (KC), or nonmelanoma skin cancer, is the most commonly diagnosed cancer in the United States.¹ Basal cell carcinoma comprises the majority of all KCs.^2,3 Squamous cell carcinoma is the second most common skin cancer, representing approximately 20% of KCs and accounting for the majority of KC-related deaths.^4-7 Malignant melanoma represents the majority of all skin cancer–related deaths.⁸ The incidence of basal cell carcinoma, squamous cell carcinoma, and malignant melanoma in the United States is on the rise and carries substantial morbidity and mortality with notable social and economic burdens.^1,8-10

Prevention is necessary to reduce skin cancer morbidity and mortality as well as rising treatment costs. The most commonly used skin cancer screening method among dermatologists is the visual full-body skin examination (FBSE), which is a noninvasive, safe, quick, and cost-effective method of early detection and prevention.¹¹ To effectively confront the growing incidence and health care burden of skin cancer, primary care providers (PCPs) must join dermatologists in conducting FBSEs.^12,13

Despite being the predominant means of secondary skin cancer prevention, the US Preventive Services Task Force (USPSTF) issued an I rating for insufficient evidence to assess the benefits vs harms of screening the adult general population by PCPs.^14,15 A major barrier to studying screening is the lack of a standardized method for conducting and reporting FBSEs.¹³ Systematic thorough skin examination generally is not performed in the primary care setting.^16-18

We aimed to investigate what occurs during an FBSE in the primary care setting and how often they are performed. We examined whether there was potential variation in the execution of the examination, what was perceived by the patient vs reported by the physician, and what was ultimately included in the medical record. Miscommunication between patient and provider regarding performance of FBSEs has previously been noted,^17-19 and we sought to characterize and quantify that miscommunication. We hypothesized that there would be lower patient-reported FBSEs compared to physicians and patient medical records. We also hypothesized that there would be variability in how physicians screened for skin cancer.

METHODS

This study was cross-sectional and was conducted based on interviews and a review of medical records at secondary- and tertiary-level units (clinics and hospitals) across the United States. We examined baseline data from a randomized controlled trial of a Web-based skin cancer early detection continuing education course—the Basic Skin Cancer Triage curriculum. Complete details have been described elsewhere.¹² This study was approved by the institutional review boards of the Providence Veterans Affairs Medical Center, Rhode Island Hospital, and Brown University (all in Providence, Rhode Island), as well as those of all recruitment sites.

Data were collected from 2005 to 2008 and included physician online surveys, patient telephone interviews, and patient medical record data abstracted by research assistants. Primary care providers included in the study were general internists, family physicians, or medicine-pediatrics practitioners who were recruited from 4 collaborating centers across the United States in the mid-Atlantic region, Ohio, Kansas, and southern California, and who had been in practice for at least a year. Patients were recruited from participating physician practices and selected by research assistants who traveled to each clinic for coordination, recruitment, and performance of medical record reviews. Patients were selected as having minimal risk of melanoma (eg, no signs of severe photodamage to the skin). Patients completed structured telephone surveys within 1 to 2 weeks of the office visit regarding the practices observed and clinical questions asked during their recent clinical encounter with their PCP.

Measures

Demographics—Demographic variables asked of physicians included age, sex, ethnicity, academic degree (MD vs DO), years in practice, training, and prior dermatology training. Demographic information asked of patients included age, sex, ethnicity, education, and household income.

Physician-Reported Examination and Counseling Variables—Physicians were asked to characterize their clinical practices, prompted by questions regarding performance of FBSEs: “Please think of a typical month and using the scale below, indicate how frequently you perform a total body skin exam during an annual exam (eg, periodic follow-up exam).” Physicians responded to 3 questions on a 5-point scale (1=never, 2=sometimes, 3=about half, 4=often, 5=almost always).

Patient-Reported Examination Variables—Patients also were asked to characterize the skin examination experienced in their clinical encounter with their PCP, including: “During your last visit, as far as you could tell, did your physician: (1) look at the skin on your back? (2) look at the skin on your belly area? (3) look at the skin on the back of your legs?” Patient responses were coded as yes, no, don’t know, or refused. Participants who refused were excluded from analysis; participants who responded are detailed in Table 1. In addition, patients also reported the level of undress with their physician by answering the following question: “During your last medical exam, did you: 1=keep your clothes on; 2=partially undress; 3=totally undress except for undergarments; 4=totally undress, including all undergarments?”

Patient Medical Record–Extracted Data—Research assistants used a structured abstract form to extract the information from the patient’s medical record and graded it as 0 (absence) or 1 (presence) from the medical record.

Statistical Analysis

Descriptive statistics included mean and standard deviation (SD) for continuous variables as well as frequency and percentage for categorical variables. Logit/logistic regression analysis was used to predict the odds of patient-reported outcomes that were binary with physician-reported variables as the predictor. Linear regression analysis was used to assess the association between 2 continuous variables. All analyses were conducted using SPSS version 24 (IBM).²⁰ Significance criterion was set at α of .05.

RESULTS Demographics

The final sample included data from 53 physicians and 3343 patients. The study sample mean age (SD) was 50.3 (9.9) years for PCPs (n=53) and 59.8 (16.9) years for patients (n=3343). The physician sample was 36% female and predominantly White (83%). Ninety-one percent of the PCPs had an MD (the remaining had a DO degree), and the mean (SD) years practicing was 21.8 (10.6) years. Seventeen percent of PCPs were trained in internal medicine, 4% in internal medicine and pediatrics, and 79% family medicine; 79% of PCPs had received prior training in dermatology. The patient sample was 58% female, predominantly White (84%), non-Hispanic/Latinx (95%), had completed high school (94%), and earned more than $40,000 annually (66%).

Physician- and Patient-Reported FBSEs

Physicians reported performing FBSEs with variable frequency. Among PCPs who conducted FBSEs with greater frequency, there was a modest increase in the odds that patients reported a particular body part was examined (back: odds ratio [OR], 24.5% [95% CI, 1.18-1.31; P<.001]; abdomen: OR, 23.3% [95% CI, 1.17-1.30; P<.001]; backs of legs: OR, 20.4% [95% CI, 1.13-1.28; P<.001])(Table 1). The patient-reported level of undress during examination was significantly associated with physician-reported FBSE (β=0.16 [95% CI, 0.13-0.18; P<.001])(Table 2).

Because of the bimodal distribution of scores in the physician-reported frequency of FBSEs, particularly pertaining to the extreme points of the scale, we further repeated analysis with only the never and almost always groups (Table 1). Primary care providers who reported almost always for FBSE had 29.6% increased odds of patient-reported back examination (95% CI, 1.00-1.68; P=.048) and 59.3% increased odds of patient-reported abdomen examination (95% CI, 1.23-2.06; P<.001). The raw percentages of patients who reported having their back, abdomen, and backs of legs examined when the PCP reported having never conducted an FBSE were 56%, 40%, and 26%, respectively. The raw percentages of patients who reported having their back, abdomen, and backs of legs examined when the PCP reported having almost always conducted an FBSE were 52%, 51%, and 30%, respectively. Raw percentages were calculated by dividing the number of "yes" responses by participants for each body part examined by thetotal number of participant responses (“yes” and “no”) for each respective body part. There was no significant change in odds of patient-reported backs of legs examined with PCP-reported never vs almost always conducting an FBSE. In addition, a greater patient-reported level of undress was associated with 20.2% increased odds of PCPs reporting almost always conducting an FBSE (95% CI, 1.08-1.34; P=.001).

 

 

FBSEs in Patient Medical Records

When comparing PCP-reported FBSE and report of FBSE in patient medical records, there was a 39.0% increased odds of the patient medical record indicating FBSE when physicians reported conducting an FBSE with greater frequency (95% CI, 1.30-1.48; P<.001)(eTable 1). When examining PCP-reported never vs almost always conducting an FBSE, a report of almost always was associated with 79.0% increased odds of the patient medical record indicating that an FBSE was conducted (95% CI, 1.28-2.49; P=.001). The raw percentage of the patient medical record indicating an FBSE was conducted when the PCP reported having never conducted an FBSE was 17% and 26% when the PCP reported having almost always conducted an FBSE.

When comparing the patient-reported body part examined with patient FBSE medical record documentation, an indication of yes for FBSE on the patient medical record was associated with a considerable increase in odds that patients reported a particular body part was examined (back: 91.4% [95% CI, 1.59-2.31; P<.001]; abdomen: 75.0% [95% CI, 1.45-2.11; P<.001]; backs of legs: 91.6% [95% CI, 1.56-2.36; P<.001])(eTable 2). The raw percentages of patients who reported having their back, abdomen, and backs of legs examined vs not examined when the patient medical record indicated an FBSE was completed were 24% vs 14%, 23% vs 15%, and 26% vs 16%, respectively. An increase in patient-reported level of undress was associated with a 57.0% increased odds of their medical record indicating an FBSE was conducted (95% CI, 1.45-1.70; P<.001).

COMMENT How PCPs Perform FBSEs Varies

We found that PCPs performed FBSEs with variable frequency, and among those who did, the patient report of their examination varied considerably (Table 1). There appears to be considerable ambiguity in each of these means of determining the extent to which the skin was inspected for skin cancer, which may render the task of improving such inspection more difficult. We asked patients whether their back, abdomen, and backs of legs were examined as an assessment of some of the variety of areas inspected during an FBSE. During a general well-visit appointment, a patient’s back and abdomen may be examined for multiple reasons. Patients may have misinterpreted elements of the pulmonary, cardiac, abdominal, or musculoskeletal examinations as being part of the FBSE. The back and abdomen—the least specific features of the FBSE—were reported by patients to be the most often examined. Conversely, the backs of the legs—the most specific feature of the FBSE—had the lowest odds of being examined (Table 1).

In addition to the potential limitations of patient awareness of physician activity, our results also could be explained by differences among PCPs in how they performed FBSEs. There is no standardized method of conducting an FBSE. Furthermore, not all medical students and residents are exposed to dermatology training. In our sample of 53 physicians, 79% had reported receiving dermatology training; however, we did not assess the extent to which they had been trained in conducting an FBSE and/or identifying malignant lesions. In an American survey of 659 medical students, more than two-thirds of students had never been trained or never examined a patient for skin cancer.²¹ In another American survey of 342 internal medicine, family medicine, pediatrics, and obstetrics/gynecology residents across 7 medical schools and 4 residency programs, more than three-quarters of residents had never been trained in skin cancer screening.²² Our findings reflect insufficient and inconsistent training in skin cancer screening and underscore the need for mandatory education to ensure quality FBSEs are performed in the primary care setting.

Frequency of PCPs Performing FBSEs

Similar to prior studies analyzing the frequency of FBSE performance in the primary care setting,^16,19,23,24 more than half of our PCP sample reported sometimes to never conducting FBSEs. The percentage of physicians who reported conducting FBSEs in our sample was greater than the proportion reported by the National Health Interview Survey, in which only 8% of patients received an FBSE in the prior year by a PCP or obstetrician/gynecologist,¹⁶ but similar to a smaller patient study.¹⁹ In that study, 87% of patients, regardless of their skin cancer history, also reported that they would like their PCP to perform an FBSE regularly.¹⁹ Although some of our patient participants may have declined an FBSE, it is unlikely that that would have entirely accounted for the relatively low number of PCPs who reported frequently performing FBSEs.

Documentation in Medical Records of FBSEs

Compared to PCP self-reported performance of FBSEs, considerably fewer PCPs marked the patient medical record as having completed an FBSE. Among patients with medical records that indicated an FBSE had been conducted, they reported higher odds of all 3 body parts being examined, the highest being the backs of the legs. Also, when the patient medical record indicated an FBSE had been completed, the odds that the PCP reported an FBSE also were higher. The relatively low medical record documentation of FBSEs highlights the need for more rigorous enforcement of accurate documentation. However, among the cases that were recorded, it appeared that the content of the examinations was more consistent.

Benefits of PCP-Led FBSEs

Although the USPSTF issued an I rating for PCP-led FBSEs,¹⁴ multiple national medical societies, including the American Cancer Society,²⁵ American Academy of Dermatology,²⁶ and Skin Cancer Foundation,²⁷ as well as international guidelines in Germany,²⁸ Australia,^29,30 and New Zealand,³¹ recommend regular FBSEs among the general or at-risk population; New Zealand and Australia have the highest incidence and prevalence of melanoma in the world.⁸ The benefits of physician-led FBSEs on detection of early-stage skin cancer, and in particular, melanoma detection, have been documented in numerous studies.^30,32-38 However, the variability and often poor quality of skin screening may contribute in part to the just as numerous null results from prior skin screening studies,¹⁵ perpetuating the insufficient status of skin examinations by USPSTF standards.¹⁴ Our study underscores both the variability in frequency and content of PCP-administered FBSEs. It also highlights the need for standardization of screening examinations at the medical student, trainee, and physician level.

 

 

Study Limitations

The present study has several limitations. First, there was an unknown time lag between the FBSEs and physician self-reported surveys. Similarly, there was a variable time lag between the patient examination encounter and subsequent telephone survey. Both the physician and patient survey data may have been affected by recall bias. Second, patients were not asked directly whether an FBSE had been conducted. Furthermore, patients may not have appreciated whether the body part examined was part of the FBSE or another examination. Also, screenings often were not recorded in the medical record, assuming that the patient report and/or physician report was more accurate than the medical record.

Our study also was limited by demographics; our patient sample was largely comprised of White, educated, US adults, potentially limiting the generalizability of our findings. Conversely, a notable strength of our study was that our participants were recruited from 4 geographically diverse centers. Furthermore, we had a comparatively large sample size of patients and physicians. Also, the independent assessment of provider-reported examinations, objective assessment of medical records, and patient reports of their encounters provides a strong foundation for assessing the independent contributions of each data source.

CONCLUSION

Our study highlights the challenges future studies face in promoting skin cancer screening in the primary care setting. Our findings underscore the need for a standardized FBSE as well as clear clinical expectations regarding skin cancer screening that is expected of PCPs.

As long as skin cancer screening rates remain low in the United States, patients will be subject to potential delays and missed diagnoses, impacting morbidity and mortality.⁸ There are burgeoning resources and efforts in place to increase skin cancer screening. For example, free validated online training is available for early detection of melanoma and other skin cancers (https://www.visualdx.com/skin-cancer-education/).^39-42 Future directions for bolstering screening numbers must focus on educating PCPs about skin cancer prevention and perhaps narrowing the screening population by age-appropriate risk assessments.

Keratinocyte carcinoma (KC), or nonmelanoma skin cancer, is the most commonly diagnosed cancer in the United States.¹ Basal cell carcinoma comprises the majority of all KCs.^2,3 Squamous cell carcinoma is the second most common skin cancer, representing approximately 20% of KCs and accounting for the majority of KC-related deaths.^4-7 Malignant melanoma represents the majority of all skin cancer–related deaths.⁸ The incidence of basal cell carcinoma, squamous cell carcinoma, and malignant melanoma in the United States is on the rise and carries substantial morbidity and mortality with notable social and economic burdens.^1,8-10

Prevention is necessary to reduce skin cancer morbidity and mortality as well as rising treatment costs. The most commonly used skin cancer screening method among dermatologists is the visual full-body skin examination (FBSE), which is a noninvasive, safe, quick, and cost-effective method of early detection and prevention.¹¹ To effectively confront the growing incidence and health care burden of skin cancer, primary care providers (PCPs) must join dermatologists in conducting FBSEs.^12,13

Despite being the predominant means of secondary skin cancer prevention, the US Preventive Services Task Force (USPSTF) issued an I rating for insufficient evidence to assess the benefits vs harms of screening the adult general population by PCPs.^14,15 A major barrier to studying screening is the lack of a standardized method for conducting and reporting FBSEs.¹³ Systematic thorough skin examination generally is not performed in the primary care setting.^16-18

We aimed to investigate what occurs during an FBSE in the primary care setting and how often they are performed. We examined whether there was potential variation in the execution of the examination, what was perceived by the patient vs reported by the physician, and what was ultimately included in the medical record. Miscommunication between patient and provider regarding performance of FBSEs has previously been noted,^17-19 and we sought to characterize and quantify that miscommunication. We hypothesized that there would be lower patient-reported FBSEs compared to physicians and patient medical records. We also hypothesized that there would be variability in how physicians screened for skin cancer.

METHODS

This study was cross-sectional and was conducted based on interviews and a review of medical records at secondary- and tertiary-level units (clinics and hospitals) across the United States. We examined baseline data from a randomized controlled trial of a Web-based skin cancer early detection continuing education course—the Basic Skin Cancer Triage curriculum. Complete details have been described elsewhere.¹² This study was approved by the institutional review boards of the Providence Veterans Affairs Medical Center, Rhode Island Hospital, and Brown University (all in Providence, Rhode Island), as well as those of all recruitment sites.

Data were collected from 2005 to 2008 and included physician online surveys, patient telephone interviews, and patient medical record data abstracted by research assistants. Primary care providers included in the study were general internists, family physicians, or medicine-pediatrics practitioners who were recruited from 4 collaborating centers across the United States in the mid-Atlantic region, Ohio, Kansas, and southern California, and who had been in practice for at least a year. Patients were recruited from participating physician practices and selected by research assistants who traveled to each clinic for coordination, recruitment, and performance of medical record reviews. Patients were selected as having minimal risk of melanoma (eg, no signs of severe photodamage to the skin). Patients completed structured telephone surveys within 1 to 2 weeks of the office visit regarding the practices observed and clinical questions asked during their recent clinical encounter with their PCP.

Measures

Demographics—Demographic variables asked of physicians included age, sex, ethnicity, academic degree (MD vs DO), years in practice, training, and prior dermatology training. Demographic information asked of patients included age, sex, ethnicity, education, and household income.

Physician-Reported Examination and Counseling Variables—Physicians were asked to characterize their clinical practices, prompted by questions regarding performance of FBSEs: “Please think of a typical month and using the scale below, indicate how frequently you perform a total body skin exam during an annual exam (eg, periodic follow-up exam).” Physicians responded to 3 questions on a 5-point scale (1=never, 2=sometimes, 3=about half, 4=often, 5=almost always).

Patient-Reported Examination Variables—Patients also were asked to characterize the skin examination experienced in their clinical encounter with their PCP, including: “During your last visit, as far as you could tell, did your physician: (1) look at the skin on your back? (2) look at the skin on your belly area? (3) look at the skin on the back of your legs?” Patient responses were coded as yes, no, don’t know, or refused. Participants who refused were excluded from analysis; participants who responded are detailed in Table 1. In addition, patients also reported the level of undress with their physician by answering the following question: “During your last medical exam, did you: 1=keep your clothes on; 2=partially undress; 3=totally undress except for undergarments; 4=totally undress, including all undergarments?”

Patient Medical Record–Extracted Data—Research assistants used a structured abstract form to extract the information from the patient’s medical record and graded it as 0 (absence) or 1 (presence) from the medical record.

Statistical Analysis

Descriptive statistics included mean and standard deviation (SD) for continuous variables as well as frequency and percentage for categorical variables. Logit/logistic regression analysis was used to predict the odds of patient-reported outcomes that were binary with physician-reported variables as the predictor. Linear regression analysis was used to assess the association between 2 continuous variables. All analyses were conducted using SPSS version 24 (IBM).²⁰ Significance criterion was set at α of .05.

RESULTS Demographics

The final sample included data from 53 physicians and 3343 patients. The study sample mean age (SD) was 50.3 (9.9) years for PCPs (n=53) and 59.8 (16.9) years for patients (n=3343). The physician sample was 36% female and predominantly White (83%). Ninety-one percent of the PCPs had an MD (the remaining had a DO degree), and the mean (SD) years practicing was 21.8 (10.6) years. Seventeen percent of PCPs were trained in internal medicine, 4% in internal medicine and pediatrics, and 79% family medicine; 79% of PCPs had received prior training in dermatology. The patient sample was 58% female, predominantly White (84%), non-Hispanic/Latinx (95%), had completed high school (94%), and earned more than $40,000 annually (66%).

Physician- and Patient-Reported FBSEs

Physicians reported performing FBSEs with variable frequency. Among PCPs who conducted FBSEs with greater frequency, there was a modest increase in the odds that patients reported a particular body part was examined (back: odds ratio [OR], 24.5% [95% CI, 1.18-1.31; P<.001]; abdomen: OR, 23.3% [95% CI, 1.17-1.30; P<.001]; backs of legs: OR, 20.4% [95% CI, 1.13-1.28; P<.001])(Table 1). The patient-reported level of undress during examination was significantly associated with physician-reported FBSE (β=0.16 [95% CI, 0.13-0.18; P<.001])(Table 2).

Because of the bimodal distribution of scores in the physician-reported frequency of FBSEs, particularly pertaining to the extreme points of the scale, we further repeated analysis with only the never and almost always groups (Table 1). Primary care providers who reported almost always for FBSE had 29.6% increased odds of patient-reported back examination (95% CI, 1.00-1.68; P=.048) and 59.3% increased odds of patient-reported abdomen examination (95% CI, 1.23-2.06; P<.001). The raw percentages of patients who reported having their back, abdomen, and backs of legs examined when the PCP reported having never conducted an FBSE were 56%, 40%, and 26%, respectively. The raw percentages of patients who reported having their back, abdomen, and backs of legs examined when the PCP reported having almost always conducted an FBSE were 52%, 51%, and 30%, respectively. Raw percentages were calculated by dividing the number of "yes" responses by participants for each body part examined by thetotal number of participant responses (“yes” and “no”) for each respective body part. There was no significant change in odds of patient-reported backs of legs examined with PCP-reported never vs almost always conducting an FBSE. In addition, a greater patient-reported level of undress was associated with 20.2% increased odds of PCPs reporting almost always conducting an FBSE (95% CI, 1.08-1.34; P=.001).

 

 

FBSEs in Patient Medical Records

When comparing PCP-reported FBSE and report of FBSE in patient medical records, there was a 39.0% increased odds of the patient medical record indicating FBSE when physicians reported conducting an FBSE with greater frequency (95% CI, 1.30-1.48; P<.001)(eTable 1). When examining PCP-reported never vs almost always conducting an FBSE, a report of almost always was associated with 79.0% increased odds of the patient medical record indicating that an FBSE was conducted (95% CI, 1.28-2.49; P=.001). The raw percentage of the patient medical record indicating an FBSE was conducted when the PCP reported having never conducted an FBSE was 17% and 26% when the PCP reported having almost always conducted an FBSE.

When comparing the patient-reported body part examined with patient FBSE medical record documentation, an indication of yes for FBSE on the patient medical record was associated with a considerable increase in odds that patients reported a particular body part was examined (back: 91.4% [95% CI, 1.59-2.31; P<.001]; abdomen: 75.0% [95% CI, 1.45-2.11; P<.001]; backs of legs: 91.6% [95% CI, 1.56-2.36; P<.001])(eTable 2). The raw percentages of patients who reported having their back, abdomen, and backs of legs examined vs not examined when the patient medical record indicated an FBSE was completed were 24% vs 14%, 23% vs 15%, and 26% vs 16%, respectively. An increase in patient-reported level of undress was associated with a 57.0% increased odds of their medical record indicating an FBSE was conducted (95% CI, 1.45-1.70; P<.001).

COMMENT How PCPs Perform FBSEs Varies

We found that PCPs performed FBSEs with variable frequency, and among those who did, the patient report of their examination varied considerably (Table 1). There appears to be considerable ambiguity in each of these means of determining the extent to which the skin was inspected for skin cancer, which may render the task of improving such inspection more difficult. We asked patients whether their back, abdomen, and backs of legs were examined as an assessment of some of the variety of areas inspected during an FBSE. During a general well-visit appointment, a patient’s back and abdomen may be examined for multiple reasons. Patients may have misinterpreted elements of the pulmonary, cardiac, abdominal, or musculoskeletal examinations as being part of the FBSE. The back and abdomen—the least specific features of the FBSE—were reported by patients to be the most often examined. Conversely, the backs of the legs—the most specific feature of the FBSE—had the lowest odds of being examined (Table 1).

In addition to the potential limitations of patient awareness of physician activity, our results also could be explained by differences among PCPs in how they performed FBSEs. There is no standardized method of conducting an FBSE. Furthermore, not all medical students and residents are exposed to dermatology training. In our sample of 53 physicians, 79% had reported receiving dermatology training; however, we did not assess the extent to which they had been trained in conducting an FBSE and/or identifying malignant lesions. In an American survey of 659 medical students, more than two-thirds of students had never been trained or never examined a patient for skin cancer.²¹ In another American survey of 342 internal medicine, family medicine, pediatrics, and obstetrics/gynecology residents across 7 medical schools and 4 residency programs, more than three-quarters of residents had never been trained in skin cancer screening.²² Our findings reflect insufficient and inconsistent training in skin cancer screening and underscore the need for mandatory education to ensure quality FBSEs are performed in the primary care setting.

Frequency of PCPs Performing FBSEs

Similar to prior studies analyzing the frequency of FBSE performance in the primary care setting,^16,19,23,24 more than half of our PCP sample reported sometimes to never conducting FBSEs. The percentage of physicians who reported conducting FBSEs in our sample was greater than the proportion reported by the National Health Interview Survey, in which only 8% of patients received an FBSE in the prior year by a PCP or obstetrician/gynecologist,¹⁶ but similar to a smaller patient study.¹⁹ In that study, 87% of patients, regardless of their skin cancer history, also reported that they would like their PCP to perform an FBSE regularly.¹⁹ Although some of our patient participants may have declined an FBSE, it is unlikely that that would have entirely accounted for the relatively low number of PCPs who reported frequently performing FBSEs.

Documentation in Medical Records of FBSEs

Compared to PCP self-reported performance of FBSEs, considerably fewer PCPs marked the patient medical record as having completed an FBSE. Among patients with medical records that indicated an FBSE had been conducted, they reported higher odds of all 3 body parts being examined, the highest being the backs of the legs. Also, when the patient medical record indicated an FBSE had been completed, the odds that the PCP reported an FBSE also were higher. The relatively low medical record documentation of FBSEs highlights the need for more rigorous enforcement of accurate documentation. However, among the cases that were recorded, it appeared that the content of the examinations was more consistent.

Benefits of PCP-Led FBSEs

Although the USPSTF issued an I rating for PCP-led FBSEs,¹⁴ multiple national medical societies, including the American Cancer Society,²⁵ American Academy of Dermatology,²⁶ and Skin Cancer Foundation,²⁷ as well as international guidelines in Germany,²⁸ Australia,^29,30 and New Zealand,³¹ recommend regular FBSEs among the general or at-risk population; New Zealand and Australia have the highest incidence and prevalence of melanoma in the world.⁸ The benefits of physician-led FBSEs on detection of early-stage skin cancer, and in particular, melanoma detection, have been documented in numerous studies.^30,32-38 However, the variability and often poor quality of skin screening may contribute in part to the just as numerous null results from prior skin screening studies,¹⁵ perpetuating the insufficient status of skin examinations by USPSTF standards.¹⁴ Our study underscores both the variability in frequency and content of PCP-administered FBSEs. It also highlights the need for standardization of screening examinations at the medical student, trainee, and physician level.

 

 

Study Limitations

The present study has several limitations. First, there was an unknown time lag between the FBSEs and physician self-reported surveys. Similarly, there was a variable time lag between the patient examination encounter and subsequent telephone survey. Both the physician and patient survey data may have been affected by recall bias. Second, patients were not asked directly whether an FBSE had been conducted. Furthermore, patients may not have appreciated whether the body part examined was part of the FBSE or another examination. Also, screenings often were not recorded in the medical record, assuming that the patient report and/or physician report was more accurate than the medical record.

Our study also was limited by demographics; our patient sample was largely comprised of White, educated, US adults, potentially limiting the generalizability of our findings. Conversely, a notable strength of our study was that our participants were recruited from 4 geographically diverse centers. Furthermore, we had a comparatively large sample size of patients and physicians. Also, the independent assessment of provider-reported examinations, objective assessment of medical records, and patient reports of their encounters provides a strong foundation for assessing the independent contributions of each data source.

CONCLUSION

Our study highlights the challenges future studies face in promoting skin cancer screening in the primary care setting. Our findings underscore the need for a standardized FBSE as well as clear clinical expectations regarding skin cancer screening that is expected of PCPs.

As long as skin cancer screening rates remain low in the United States, patients will be subject to potential delays and missed diagnoses, impacting morbidity and mortality.⁸ There are burgeoning resources and efforts in place to increase skin cancer screening. For example, free validated online training is available for early detection of melanoma and other skin cancers (https://www.visualdx.com/skin-cancer-education/).^39-42 Future directions for bolstering screening numbers must focus on educating PCPs about skin cancer prevention and perhaps narrowing the screening population by age-appropriate risk assessments.