MDedge ObGyn

CASE Pregnant woman with positive Treponema pallidum antibody test

A 30-year-old primigravida at 10 weeks and 4 days of gestation by her last menstrual period presents to your office for her initial prenatal visit. She expresses no concerns. You order the standard set of laboratory tests, including a sexually transmitted infection (STI) screening panel. Consistent with your institution’s use of the reverse algorithm for syphilis screening, you obtain a Treponema pallidum antibody test, which reflexes to the rapid plasma reagin (RPR) test. Three days later, you receive a notification that this patient’s T pallidum antibody result was positive, followed by negative RPR test results. The follow-up T pallidum particle agglutination (TP-PA) test also was negative. Given these findings, you consider:

• What is the correct interpretation of the patient’s sequence of test results?
• Is she infected, and does she require treatment?

Meet our perpetrator

Syphilis has plagued society since the late 15th century, although its causative agent, the spirochete T pallidum, was not recognized until 1905.^1,2T pallidum bacteria are transmitted via sexual contact, as well as through vertical transmission during pregnancy or delivery. Infection with syphilis is reported in 50% to 60% of sexual partners after a single exposure to an infected individual with early syphilis, and the mean incubation period is 21 days.³T pallidum can cross the placenta and infect a fetus as early as the sixth week of gestation.³ Congenital syphilis infections occur in the neonates of 50% to 80% of women with untreated primary, secondary, or early latent syphilis infections; maternal syphilis is associated with a 21% increased risk of stillbirth, a 6% increased risk of preterm delivery, and a 9% increased risk of neonatal death.^4,5 Additionally, syphilis infection is associated with a high risk of HIV infection, as well as coinfection with other STIs.¹

Given the highly infective nature of T pallidum, as well as the severity of the potential consequences of infection for both mothers and babies, primary prevention, education of at-risk populations, and early recognition of clinical features of syphilis infection are of utmost importance in preventing morbidity and mortality. In this article, we review the epidemiology and extensive clinical manifestations of syphilis, as well as current screening recommendations and treatment for pregnant women.

The extent of the problem today

Although US rates of syphilis have ebbed and flowed for the past several decades, the current incidence has grown exponentially in recent years, with the number of cases reported to the Centers for Disease Control and Prevention (CDC) increasing by 71% from 2014 to 2018.⁶ During this time period, reported cases of primary and secondary syphilis in women more than doubled (172.7% and 165.4%, respectively) according to CDC data, accompanied by a parallel rise in reported cases of congenital syphilis in both live and stillborn infants.⁶ In 2018, the CDC reported a national rate of congenital syphilis of 33.1 cases per 100,000 live births, a 39.7% rise compared with data from 2017.⁶

Those most at risk. Risk factors for syphilis infection include age younger than 30 years, low socioeconomic status, substance abuse, HIV infection, concurrent STIs, and high-risk sexual activity (sex with multiple high-risk partners).³ Additionally, reported rates of primary and secondary syphilis infections, as well as congenital syphilis infections, are more elevated among women who identify as Black, American Indian/Alaska Native, and/or Hispanic.⁶ Congenital infections in the United States are correlated with a lack of prenatal care, which has been similarly linked with racial and socioeconomic disparities, as well as with untreated mental health and substance use disorders and recent immigration to the United States.^5,7

Continue to: The many phases of syphilis...

The many phases of syphilis

The characteristic lesion of primary syphilis is a chancre, which is a painless, ulcerative lesion with raised borders and a clean, indurated base appearing at the site of spirochete entry (FIGURE 1). Chancres most commonly appear in the genital area, with the most frequent sites in females being within the vaginal canal or on the cervix. Primary chancres tend to heal spontaneously within 3 to 6 weeks, even without treatment, and frequently are accompanied by painless inguinal lymphadenopathy. Given that the most common chancre sites are not immediately apparent, primary infections in women often go undetected.³ In fact, it is essential for clinicians to recognize that, in our routine practice, most patients with syphilis will not be symptomatic at all, and the diagnosis will only be made by serologic screening.

Following resolution of the primary phase, the patient may enter the secondary stage of T pallidum infection. During this stage, spirochetes may disseminate throughout the bloodstream to infect all major organ systems. The principal manifestations of secondary syphilis include a diffuse maculopapular rash that begins on the trunk and proximal extremities and spreads to include the palms and soles (FIGURE 2); mucosal lesions, such as mucous patches and condyloma lata (FIGURE 3); nonscarring alopecia; periostitis; generalized lymphadenopathy; and, in some cases, hepatitis or nephritis.^1,3

Untreated, about 40% of patients will progress to the tertiary stage of syphilis, which is characterized by gummas affecting the skin and mucous membranes (FIGURE 4) and cardiovascular manifestations including arterial aneurysms and aortic insufficiency.³

Neurologic manifestations of syphilis may arise during any of the above stages, though the most characteristic manifestations tend to appear decades after the primary infection. Early neurosyphilis may present as meningitis, with or without concomitant ocular syphilis (uveitis, retinitis) and/or as otic syphilis (hearing loss, persistent tinnitus).^1,5 Patients with late (tertiary) neurosyphilis tend to exhibit meningovascular symptoms similar to stroke (aphasia, hemiplegia, seizures) and/or parenchymal effects such as general paresis. Tabes dorsalis (manifestations of which include urinary and rectal incontinence, lightning pains, and ataxia) is a late-onset manifestation.^1,3

Congenital syphilis can be subdivided into an early and late stage. The first stage, in which clinical findings occur within the first 2 years of life, commonly features a desquamating rash, hepatomegaly, and rhinitis. Anemia, thrombocytopenia, periostitis, and osteomyelitis also have been documented.⁵ Of note, two-thirds of infants are asymptomatic at birth and may not develop such clinical manifestations for 3 to 8 weeks.³ If untreated, early congenital infection may progress to late manifestations, such as Hutchinson teeth, mulberry molars, interstitial keratitis, deafness, saddle nose, saber shins, and such neurologic abnormalities as developmental delay and general paresis.³

Continue to: Prenatal screening and diagnosis...

Prenatal screening and diagnosis

Current recommendations issued by the CDC and the American College of Obstetricians and Gynecologists state that all pregnant women should be screened for syphilis infection at their first presentation to care, with repeat screening between 28 and 32 weeks of gestation and at birth, for women living in areas with a high prevalence of syphilis and/or with any of the aforementioned risk factors.^3,5 Given that providers may be unfamiliar with the prevalence of syphilis in their area, and that patients may acquire or develop an infection later on in their pregnancy, researchers have begun to investigate the feasibility of universal third-trimester screening. While the cost-effectiveness of such a protocol is disputed, recent studies suggest that it may result in a substantial decrease in adverse maternal and fetal outcomes.^8,9

Diagnostic tests

The traditional algorithm for the diagnosis of syphilis infection begins with a nontreponemal screening test, such as the RPR or the Venereal Disease Research Laboratory test. If positive, these screening tests are followed by a confirmatory treponemal test, such as the fluorescent treponemal antibody (FTA) test or the TP-PA (FIGURE 5).

The “reverse” screening algorithm begins with the FTA and, if positive, reflexes to the RPR. A reactive RPR indicates an active infection, and the patient should be treated. A negative RPR should be followed by the TP-PA to rule out a false-positive immunoglobulin G test. If the TP-PA test result is positive, the diagnosis of syphilis is confirmed (FIGURE 6). It is crucial to understand, however, that treponemal antibodies will remain positive for a patient’s lifetime, and someone who may have been treated for syphilis in the past also will screen positive. Once 2 treponemal tests are positive, physicians should take a careful history to assess prior infection risk and treatment status. A negative TP-PA excludes a diagnosis of syphilis.

Advantages of the reverse screening algorithm. Nontreponemal tests are inexpensive and easy to perform, and titers allow for identification of a baseline to evaluate response to treatment.¹¹ However, given the fluctuation of RPR sensitivity (depending on stage of disease and a decreased ability to detect primary and latent stages of syphilis), there has been a resurgence of interest in the reverse algorithm.¹¹ While reverse screening has been found to incur higher costs, and may result in overtreatment and increased stress due to false-positive results,¹² there is evidence to suggest that this algorithm is more sensitive for primary and latent infections.^8,11,13-15

Given the rise in prevalence of syphilis infections in the United States over the past decade, and therefore a higher pretest probability of syphilis in the population, we favor the reverse screening algorithm in obstetrics, particularly given the risks of adverse maternal and fetal outcomes.

Treating syphilis in pregnancy

Parenteral benzathine penicillin G is the only currently recommended medication for the treatment of syphilis in pregnancy. This drug is effective in treating maternal infection and in preventing fetal infections, as well as in treating established fetal infections.^3,5 Regimens differ depending on the stage of syphilis infection (TABLE). Treatment for presumed early syphilis is recommended for women who have had sexual contact with a partner diagnosed with primary, secondary, or early latent syphilis within 3 months of their current pregnancy.⁵ Any patient with diagnosed syphilis who demonstrates clinical signs of neurologic involvement should undergo lumbar puncture to assess for evidence of neurosyphilis.³ CDC guidelines recommend that patients who report an allergy to penicillin undergo desensitization therapy in a controlled setting, as other antibiotics that have been investigated in the treatment of syphilis are either not appropriate due to teratogenicity or due to suboptimal fetal treatment.^3,5

Syphilotherapy may lead to the Jarisch-Herxheimer reaction, which is an acute systemic reaction to inflammatory cytokines produced in response to lipopolysaccharide released by dying spirochetes.⁵ This reaction is characterized by fever, chills, myalgia, headache, hypotension, and worsening of cutaneous lesions. Preterm labor and delivery and fetal heart rate tracing abnormalities also have been documented in pregnant women experiencing this reaction, particularly during the second half of pregnancy.¹⁶ Prior to the start of treatment, a detailed sonographic assessment should be performed to assess the fetus for signs of early syphilis, including hepatomegaly, elevated peak systolic velocity of the middle cerebral artery (indicative of fetal anemia), polyhydramnios, placentomegaly, or hydrops.^5,7

CASE Resolved

The combination of the patient’s test results—positive FTA, negative RPR, and negative TP-PA—suggest a false-positive treponemal assay. This sequence of tests excludes a diagnosis of syphilis; therefore, no treatment is necessary. Depending on the prevalence of syphilis in the patient’s geographic location, as well as her sexual history, rescreening between 28 and 32 weeks may be warranted. ●

CASE Pregnant woman with positive Treponema pallidum antibody test

A 30-year-old primigravida at 10 weeks and 4 days of gestation by her last menstrual period presents to your office for her initial prenatal visit. She expresses no concerns. You order the standard set of laboratory tests, including a sexually transmitted infection (STI) screening panel. Consistent with your institution’s use of the reverse algorithm for syphilis screening, you obtain a Treponema pallidum antibody test, which reflexes to the rapid plasma reagin (RPR) test. Three days later, you receive a notification that this patient’s T pallidum antibody result was positive, followed by negative RPR test results. The follow-up T pallidum particle agglutination (TP-PA) test also was negative. Given these findings, you consider:

• What is the correct interpretation of the patient’s sequence of test results?
• Is she infected, and does she require treatment?

Meet our perpetrator

Syphilis has plagued society since the late 15th century, although its causative agent, the spirochete T pallidum, was not recognized until 1905.^1,2T pallidum bacteria are transmitted via sexual contact, as well as through vertical transmission during pregnancy or delivery. Infection with syphilis is reported in 50% to 60% of sexual partners after a single exposure to an infected individual with early syphilis, and the mean incubation period is 21 days.³T pallidum can cross the placenta and infect a fetus as early as the sixth week of gestation.³ Congenital syphilis infections occur in the neonates of 50% to 80% of women with untreated primary, secondary, or early latent syphilis infections; maternal syphilis is associated with a 21% increased risk of stillbirth, a 6% increased risk of preterm delivery, and a 9% increased risk of neonatal death.^4,5 Additionally, syphilis infection is associated with a high risk of HIV infection, as well as coinfection with other STIs.¹

Given the highly infective nature of T pallidum, as well as the severity of the potential consequences of infection for both mothers and babies, primary prevention, education of at-risk populations, and early recognition of clinical features of syphilis infection are of utmost importance in preventing morbidity and mortality. In this article, we review the epidemiology and extensive clinical manifestations of syphilis, as well as current screening recommendations and treatment for pregnant women.

The extent of the problem today

Although US rates of syphilis have ebbed and flowed for the past several decades, the current incidence has grown exponentially in recent years, with the number of cases reported to the Centers for Disease Control and Prevention (CDC) increasing by 71% from 2014 to 2018.⁶ During this time period, reported cases of primary and secondary syphilis in women more than doubled (172.7% and 165.4%, respectively) according to CDC data, accompanied by a parallel rise in reported cases of congenital syphilis in both live and stillborn infants.⁶ In 2018, the CDC reported a national rate of congenital syphilis of 33.1 cases per 100,000 live births, a 39.7% rise compared with data from 2017.⁶

Those most at risk. Risk factors for syphilis infection include age younger than 30 years, low socioeconomic status, substance abuse, HIV infection, concurrent STIs, and high-risk sexual activity (sex with multiple high-risk partners).³ Additionally, reported rates of primary and secondary syphilis infections, as well as congenital syphilis infections, are more elevated among women who identify as Black, American Indian/Alaska Native, and/or Hispanic.⁶ Congenital infections in the United States are correlated with a lack of prenatal care, which has been similarly linked with racial and socioeconomic disparities, as well as with untreated mental health and substance use disorders and recent immigration to the United States.^5,7

Continue to: The many phases of syphilis...

The many phases of syphilis

The characteristic lesion of primary syphilis is a chancre, which is a painless, ulcerative lesion with raised borders and a clean, indurated base appearing at the site of spirochete entry (FIGURE 1). Chancres most commonly appear in the genital area, with the most frequent sites in females being within the vaginal canal or on the cervix. Primary chancres tend to heal spontaneously within 3 to 6 weeks, even without treatment, and frequently are accompanied by painless inguinal lymphadenopathy. Given that the most common chancre sites are not immediately apparent, primary infections in women often go undetected.³ In fact, it is essential for clinicians to recognize that, in our routine practice, most patients with syphilis will not be symptomatic at all, and the diagnosis will only be made by serologic screening.

Following resolution of the primary phase, the patient may enter the secondary stage of T pallidum infection. During this stage, spirochetes may disseminate throughout the bloodstream to infect all major organ systems. The principal manifestations of secondary syphilis include a diffuse maculopapular rash that begins on the trunk and proximal extremities and spreads to include the palms and soles (FIGURE 2); mucosal lesions, such as mucous patches and condyloma lata (FIGURE 3); nonscarring alopecia; periostitis; generalized lymphadenopathy; and, in some cases, hepatitis or nephritis.^1,3

Untreated, about 40% of patients will progress to the tertiary stage of syphilis, which is characterized by gummas affecting the skin and mucous membranes (FIGURE 4) and cardiovascular manifestations including arterial aneurysms and aortic insufficiency.³

Neurologic manifestations of syphilis may arise during any of the above stages, though the most characteristic manifestations tend to appear decades after the primary infection. Early neurosyphilis may present as meningitis, with or without concomitant ocular syphilis (uveitis, retinitis) and/or as otic syphilis (hearing loss, persistent tinnitus).^1,5 Patients with late (tertiary) neurosyphilis tend to exhibit meningovascular symptoms similar to stroke (aphasia, hemiplegia, seizures) and/or parenchymal effects such as general paresis. Tabes dorsalis (manifestations of which include urinary and rectal incontinence, lightning pains, and ataxia) is a late-onset manifestation.^1,3

Congenital syphilis can be subdivided into an early and late stage. The first stage, in which clinical findings occur within the first 2 years of life, commonly features a desquamating rash, hepatomegaly, and rhinitis. Anemia, thrombocytopenia, periostitis, and osteomyelitis also have been documented.⁵ Of note, two-thirds of infants are asymptomatic at birth and may not develop such clinical manifestations for 3 to 8 weeks.³ If untreated, early congenital infection may progress to late manifestations, such as Hutchinson teeth, mulberry molars, interstitial keratitis, deafness, saddle nose, saber shins, and such neurologic abnormalities as developmental delay and general paresis.³

Continue to: Prenatal screening and diagnosis...

Prenatal screening and diagnosis

Current recommendations issued by the CDC and the American College of Obstetricians and Gynecologists state that all pregnant women should be screened for syphilis infection at their first presentation to care, with repeat screening between 28 and 32 weeks of gestation and at birth, for women living in areas with a high prevalence of syphilis and/or with any of the aforementioned risk factors.^3,5 Given that providers may be unfamiliar with the prevalence of syphilis in their area, and that patients may acquire or develop an infection later on in their pregnancy, researchers have begun to investigate the feasibility of universal third-trimester screening. While the cost-effectiveness of such a protocol is disputed, recent studies suggest that it may result in a substantial decrease in adverse maternal and fetal outcomes.^8,9

Diagnostic tests

The traditional algorithm for the diagnosis of syphilis infection begins with a nontreponemal screening test, such as the RPR or the Venereal Disease Research Laboratory test. If positive, these screening tests are followed by a confirmatory treponemal test, such as the fluorescent treponemal antibody (FTA) test or the TP-PA (FIGURE 5).

The “reverse” screening algorithm begins with the FTA and, if positive, reflexes to the RPR. A reactive RPR indicates an active infection, and the patient should be treated. A negative RPR should be followed by the TP-PA to rule out a false-positive immunoglobulin G test. If the TP-PA test result is positive, the diagnosis of syphilis is confirmed (FIGURE 6). It is crucial to understand, however, that treponemal antibodies will remain positive for a patient’s lifetime, and someone who may have been treated for syphilis in the past also will screen positive. Once 2 treponemal tests are positive, physicians should take a careful history to assess prior infection risk and treatment status. A negative TP-PA excludes a diagnosis of syphilis.

Advantages of the reverse screening algorithm. Nontreponemal tests are inexpensive and easy to perform, and titers allow for identification of a baseline to evaluate response to treatment.¹¹ However, given the fluctuation of RPR sensitivity (depending on stage of disease and a decreased ability to detect primary and latent stages of syphilis), there has been a resurgence of interest in the reverse algorithm.¹¹ While reverse screening has been found to incur higher costs, and may result in overtreatment and increased stress due to false-positive results,¹² there is evidence to suggest that this algorithm is more sensitive for primary and latent infections.^8,11,13-15

Given the rise in prevalence of syphilis infections in the United States over the past decade, and therefore a higher pretest probability of syphilis in the population, we favor the reverse screening algorithm in obstetrics, particularly given the risks of adverse maternal and fetal outcomes.

Treating syphilis in pregnancy

Parenteral benzathine penicillin G is the only currently recommended medication for the treatment of syphilis in pregnancy. This drug is effective in treating maternal infection and in preventing fetal infections, as well as in treating established fetal infections.^3,5 Regimens differ depending on the stage of syphilis infection (TABLE). Treatment for presumed early syphilis is recommended for women who have had sexual contact with a partner diagnosed with primary, secondary, or early latent syphilis within 3 months of their current pregnancy.⁵ Any patient with diagnosed syphilis who demonstrates clinical signs of neurologic involvement should undergo lumbar puncture to assess for evidence of neurosyphilis.³ CDC guidelines recommend that patients who report an allergy to penicillin undergo desensitization therapy in a controlled setting, as other antibiotics that have been investigated in the treatment of syphilis are either not appropriate due to teratogenicity or due to suboptimal fetal treatment.^3,5

Syphilotherapy may lead to the Jarisch-Herxheimer reaction, which is an acute systemic reaction to inflammatory cytokines produced in response to lipopolysaccharide released by dying spirochetes.⁵ This reaction is characterized by fever, chills, myalgia, headache, hypotension, and worsening of cutaneous lesions. Preterm labor and delivery and fetal heart rate tracing abnormalities also have been documented in pregnant women experiencing this reaction, particularly during the second half of pregnancy.¹⁶ Prior to the start of treatment, a detailed sonographic assessment should be performed to assess the fetus for signs of early syphilis, including hepatomegaly, elevated peak systolic velocity of the middle cerebral artery (indicative of fetal anemia), polyhydramnios, placentomegaly, or hydrops.^5,7

CASE Resolved

The combination of the patient’s test results—positive FTA, negative RPR, and negative TP-PA—suggest a false-positive treponemal assay. This sequence of tests excludes a diagnosis of syphilis; therefore, no treatment is necessary. Depending on the prevalence of syphilis in the patient’s geographic location, as well as her sexual history, rescreening between 28 and 32 weeks may be warranted. ●

CASE Pregnant woman with positive Treponema pallidum antibody test

A 30-year-old primigravida at 10 weeks and 4 days of gestation by her last menstrual period presents to your office for her initial prenatal visit. She expresses no concerns. You order the standard set of laboratory tests, including a sexually transmitted infection (STI) screening panel. Consistent with your institution’s use of the reverse algorithm for syphilis screening, you obtain a Treponema pallidum antibody test, which reflexes to the rapid plasma reagin (RPR) test. Three days later, you receive a notification that this patient’s T pallidum antibody result was positive, followed by negative RPR test results. The follow-up T pallidum particle agglutination (TP-PA) test also was negative. Given these findings, you consider:

• What is the correct interpretation of the patient’s sequence of test results?
• Is she infected, and does she require treatment?

Meet our perpetrator

Syphilis has plagued society since the late 15th century, although its causative agent, the spirochete T pallidum, was not recognized until 1905.^1,2T pallidum bacteria are transmitted via sexual contact, as well as through vertical transmission during pregnancy or delivery. Infection with syphilis is reported in 50% to 60% of sexual partners after a single exposure to an infected individual with early syphilis, and the mean incubation period is 21 days.³T pallidum can cross the placenta and infect a fetus as early as the sixth week of gestation.³ Congenital syphilis infections occur in the neonates of 50% to 80% of women with untreated primary, secondary, or early latent syphilis infections; maternal syphilis is associated with a 21% increased risk of stillbirth, a 6% increased risk of preterm delivery, and a 9% increased risk of neonatal death.^4,5 Additionally, syphilis infection is associated with a high risk of HIV infection, as well as coinfection with other STIs.¹

Given the highly infective nature of T pallidum, as well as the severity of the potential consequences of infection for both mothers and babies, primary prevention, education of at-risk populations, and early recognition of clinical features of syphilis infection are of utmost importance in preventing morbidity and mortality. In this article, we review the epidemiology and extensive clinical manifestations of syphilis, as well as current screening recommendations and treatment for pregnant women.

The extent of the problem today

Although US rates of syphilis have ebbed and flowed for the past several decades, the current incidence has grown exponentially in recent years, with the number of cases reported to the Centers for Disease Control and Prevention (CDC) increasing by 71% from 2014 to 2018.⁶ During this time period, reported cases of primary and secondary syphilis in women more than doubled (172.7% and 165.4%, respectively) according to CDC data, accompanied by a parallel rise in reported cases of congenital syphilis in both live and stillborn infants.⁶ In 2018, the CDC reported a national rate of congenital syphilis of 33.1 cases per 100,000 live births, a 39.7% rise compared with data from 2017.⁶

Those most at risk. Risk factors for syphilis infection include age younger than 30 years, low socioeconomic status, substance abuse, HIV infection, concurrent STIs, and high-risk sexual activity (sex with multiple high-risk partners).³ Additionally, reported rates of primary and secondary syphilis infections, as well as congenital syphilis infections, are more elevated among women who identify as Black, American Indian/Alaska Native, and/or Hispanic.⁶ Congenital infections in the United States are correlated with a lack of prenatal care, which has been similarly linked with racial and socioeconomic disparities, as well as with untreated mental health and substance use disorders and recent immigration to the United States.^5,7

Continue to: The many phases of syphilis...

The many phases of syphilis

The characteristic lesion of primary syphilis is a chancre, which is a painless, ulcerative lesion with raised borders and a clean, indurated base appearing at the site of spirochete entry (FIGURE 1). Chancres most commonly appear in the genital area, with the most frequent sites in females being within the vaginal canal or on the cervix. Primary chancres tend to heal spontaneously within 3 to 6 weeks, even without treatment, and frequently are accompanied by painless inguinal lymphadenopathy. Given that the most common chancre sites are not immediately apparent, primary infections in women often go undetected.³ In fact, it is essential for clinicians to recognize that, in our routine practice, most patients with syphilis will not be symptomatic at all, and the diagnosis will only be made by serologic screening.

Following resolution of the primary phase, the patient may enter the secondary stage of T pallidum infection. During this stage, spirochetes may disseminate throughout the bloodstream to infect all major organ systems. The principal manifestations of secondary syphilis include a diffuse maculopapular rash that begins on the trunk and proximal extremities and spreads to include the palms and soles (FIGURE 2); mucosal lesions, such as mucous patches and condyloma lata (FIGURE 3); nonscarring alopecia; periostitis; generalized lymphadenopathy; and, in some cases, hepatitis or nephritis.^1,3

Untreated, about 40% of patients will progress to the tertiary stage of syphilis, which is characterized by gummas affecting the skin and mucous membranes (FIGURE 4) and cardiovascular manifestations including arterial aneurysms and aortic insufficiency.³

Neurologic manifestations of syphilis may arise during any of the above stages, though the most characteristic manifestations tend to appear decades after the primary infection. Early neurosyphilis may present as meningitis, with or without concomitant ocular syphilis (uveitis, retinitis) and/or as otic syphilis (hearing loss, persistent tinnitus).^1,5 Patients with late (tertiary) neurosyphilis tend to exhibit meningovascular symptoms similar to stroke (aphasia, hemiplegia, seizures) and/or parenchymal effects such as general paresis. Tabes dorsalis (manifestations of which include urinary and rectal incontinence, lightning pains, and ataxia) is a late-onset manifestation.^1,3

Congenital syphilis can be subdivided into an early and late stage. The first stage, in which clinical findings occur within the first 2 years of life, commonly features a desquamating rash, hepatomegaly, and rhinitis. Anemia, thrombocytopenia, periostitis, and osteomyelitis also have been documented.⁵ Of note, two-thirds of infants are asymptomatic at birth and may not develop such clinical manifestations for 3 to 8 weeks.³ If untreated, early congenital infection may progress to late manifestations, such as Hutchinson teeth, mulberry molars, interstitial keratitis, deafness, saddle nose, saber shins, and such neurologic abnormalities as developmental delay and general paresis.³

Continue to: Prenatal screening and diagnosis...

Prenatal screening and diagnosis

Current recommendations issued by the CDC and the American College of Obstetricians and Gynecologists state that all pregnant women should be screened for syphilis infection at their first presentation to care, with repeat screening between 28 and 32 weeks of gestation and at birth, for women living in areas with a high prevalence of syphilis and/or with any of the aforementioned risk factors.^3,5 Given that providers may be unfamiliar with the prevalence of syphilis in their area, and that patients may acquire or develop an infection later on in their pregnancy, researchers have begun to investigate the feasibility of universal third-trimester screening. While the cost-effectiveness of such a protocol is disputed, recent studies suggest that it may result in a substantial decrease in adverse maternal and fetal outcomes.^8,9

Diagnostic tests

The traditional algorithm for the diagnosis of syphilis infection begins with a nontreponemal screening test, such as the RPR or the Venereal Disease Research Laboratory test. If positive, these screening tests are followed by a confirmatory treponemal test, such as the fluorescent treponemal antibody (FTA) test or the TP-PA (FIGURE 5).

The “reverse” screening algorithm begins with the FTA and, if positive, reflexes to the RPR. A reactive RPR indicates an active infection, and the patient should be treated. A negative RPR should be followed by the TP-PA to rule out a false-positive immunoglobulin G test. If the TP-PA test result is positive, the diagnosis of syphilis is confirmed (FIGURE 6). It is crucial to understand, however, that treponemal antibodies will remain positive for a patient’s lifetime, and someone who may have been treated for syphilis in the past also will screen positive. Once 2 treponemal tests are positive, physicians should take a careful history to assess prior infection risk and treatment status. A negative TP-PA excludes a diagnosis of syphilis.

Advantages of the reverse screening algorithm. Nontreponemal tests are inexpensive and easy to perform, and titers allow for identification of a baseline to evaluate response to treatment.¹¹ However, given the fluctuation of RPR sensitivity (depending on stage of disease and a decreased ability to detect primary and latent stages of syphilis), there has been a resurgence of interest in the reverse algorithm.¹¹ While reverse screening has been found to incur higher costs, and may result in overtreatment and increased stress due to false-positive results,¹² there is evidence to suggest that this algorithm is more sensitive for primary and latent infections.^8,11,13-15

Given the rise in prevalence of syphilis infections in the United States over the past decade, and therefore a higher pretest probability of syphilis in the population, we favor the reverse screening algorithm in obstetrics, particularly given the risks of adverse maternal and fetal outcomes.

Treating syphilis in pregnancy

Parenteral benzathine penicillin G is the only currently recommended medication for the treatment of syphilis in pregnancy. This drug is effective in treating maternal infection and in preventing fetal infections, as well as in treating established fetal infections.^3,5 Regimens differ depending on the stage of syphilis infection (TABLE). Treatment for presumed early syphilis is recommended for women who have had sexual contact with a partner diagnosed with primary, secondary, or early latent syphilis within 3 months of their current pregnancy.⁵ Any patient with diagnosed syphilis who demonstrates clinical signs of neurologic involvement should undergo lumbar puncture to assess for evidence of neurosyphilis.³ CDC guidelines recommend that patients who report an allergy to penicillin undergo desensitization therapy in a controlled setting, as other antibiotics that have been investigated in the treatment of syphilis are either not appropriate due to teratogenicity or due to suboptimal fetal treatment.^3,5

Syphilotherapy may lead to the Jarisch-Herxheimer reaction, which is an acute systemic reaction to inflammatory cytokines produced in response to lipopolysaccharide released by dying spirochetes.⁵ This reaction is characterized by fever, chills, myalgia, headache, hypotension, and worsening of cutaneous lesions. Preterm labor and delivery and fetal heart rate tracing abnormalities also have been documented in pregnant women experiencing this reaction, particularly during the second half of pregnancy.¹⁶ Prior to the start of treatment, a detailed sonographic assessment should be performed to assess the fetus for signs of early syphilis, including hepatomegaly, elevated peak systolic velocity of the middle cerebral artery (indicative of fetal anemia), polyhydramnios, placentomegaly, or hydrops.^5,7

CASE Resolved

The combination of the patient’s test results—positive FTA, negative RPR, and negative TP-PA—suggest a false-positive treponemal assay. This sequence of tests excludes a diagnosis of syphilis; therefore, no treatment is necessary. Depending on the prevalence of syphilis in the patient’s geographic location, as well as her sexual history, rescreening between 28 and 32 weeks may be warranted. ●

People with a history of heart failure – no matter the type – face more complications and death than their peers without HF once hospitalized with COVID-19, a new observational study shows.

A history of HF was associated with a near doubling risk of in-hospital mortality and ICU care and more than a tripling risk of mechanical ventilation despite adjustment for 18 factors including race, obesity, diabetes, previous treatment with renin-angiotensin-aldosterone system (RAAS) inhibitors, and severity of illness.

Adverse outcomes were high regardless of whether patients had HF with a preserved, mid-range, or reduced left ventricular ejection fraction (HFpEF/HFmrEF/HFrEF).

“That for me was the real zinger,” senior author Anuradha Lala, MD, said in an interview . “Because as clinicians, oftentimes, and wrongly so, we think this person has preserved ejection fraction, so they’re not needing my heart failure expertise as much as someone with heart failure with reduced ejection fraction.”

In the peak of the pandemic, that may have meant triaging patients with HFpEF to a regular floor, whereas those with HFrEF were seen by the specialist team.

“What this alerted me to is to take heart failure as a diagnosis very seriously, regardless of ejection fraction, and that is very much in line with all of the emerging data about heart failure with preserved ejection fraction,” said Dr. Lala, from the Icahn School of Medicine at Mount Sinai, New York.

“Now when I see patients in the clinic, I incorporate part of our visit to talking about what they are doing to prevent COVID, which I really wasn’t doing before. It was like ‘Oh yeah, what crazy times we’re dealing with’ and then addressing their heart failure as I normally would,” she said. “But now, interwoven into every visit is: Are you wearing a mask, what’s your social distancing policy, who are you living with at home, has anyone at home or who you’ve interacted with been sick? I’m asking those questions just as a knee-jerk reaction for these patients because I know the repercussions. We have to keep in mind these are observational studies, so I can’t prove causality but these are observations that are, nonetheless, quite robust.”

Although cardiovascular disease, including HF, is recognized as a risk factor for worse outcomes in COVID-19 patients, data are sparse on the clinical course and prognosis of patients with preexisting HF.

“I would have expected that there would have been a gradation of risk from the people with very low ejection fractions up into the normal range, but here it didn’t seem to matter at all. So that’s an important point that bad outcomes were independent of ejection fraction,” commented Lee Goldberg, MD, professor of medicine and chief of advanced heart failure and cardiac transplant at the University of Pennsylvania, Philadelphia.

The study also validated that there is no association between use of RAAS inhibitors and bad outcomes in patients with COVID-19, he said.

Although this has been demonstrated in several studies, concerns were raised early in the pandemic that ACE inhibitors and angiotensin receptor blockers could facilitate infection with SARS-CoV-2 and increase the risk of severe or lethal COVID-19.  

“For most clinicians that question has been put to bed, but we’re still getting patients that will ask during office visits ‘Is it safe for me to stay on?’ They still have that doubt [about] ‘Are we doing the right thing?’ ” Dr. Goldberg said.

“We can reassure them now. A lot of us are able to say there’s nothing to that, we’re very clear about this, stay on the meds. If anything, there’s data that suggest actually it may be better to be on an ACE inhibitor; that the hospitalizations were shorter and the outcomes were a little bit better.”  

For the current study, published online Oct. 28 in the Journal of the American College of Cardiology, the investigators analyzed 6,439 patients admitted for COVID-19 at one of five Mount Sinai Health System hospitals in New York between Feb. 27 and June 26. Their mean age was 65.3 years, 45% were women, and one-third were treated with RAAS inhibitors before admission.

Using ICD-9/10 codes and individual chart review, HF was identified in 422 patients (6.6%), of which 250 patients had HFpEF (≥50%), 44 had HFmrEF (41%-49%), and 128 had HFrEF (≤40%).

Patients with HFpEF were older, more frequently women with a higher body mass index and history of lung disease than patients with HFrEF, whereas those with HFmrEF fell in between.

The HFpEF group was also treated with hydroxychloroquine or macrolides and noninvasive ventilation more frequently than the other two groups, whereas antiplatelet and neurohormonal therapies were more common in the HFrEF group.

Patients with a history of HF had significantly longer hospital stays than those without HF (8 days vs. 6 days), increased need for intubation (22.8% vs. 11.9%) and ICU care (23.2% vs. 16.6%), and worse in-hospital mortality (40% vs. 24.9%).

After multivariable regression adjustment, HF persisted as an independent risk factor for ICU care (odds ratio, 1.71; 95% CI, 1.25-2.34), intubation and mechanical ventilation (OR, 3.64; 95% CI, 2.56-5.16), and in-hospital mortality (OR, 1.88; 95% CI, 1.27-2.78).

“I knew to expect higher rates of adverse outcomes but I didn’t expect it to be nearly a twofold increase,” Dr. Lala said. “I thought that was pretty powerful.”

No significant differences were seen across LVEF categories in length of stay, need for ICU care, intubation and mechanical ventilation, acute kidney injury, shock, thromboembolic events, arrhythmias, or 30-day readmission rates.

However, cardiogenic shock (7.8% vs. 2.3% vs. 2%) and HF-related causes for 30-day readmissions (47.1% vs. 0% vs. 8.6%) were significantly higher in patients with HFrEF than in those with HFmrEF or HFpEF.

Also, mortality was lower in those with HFmrEF (22.7%) than with HFrEF (38.3%) and HFpEF (44%). The group was small but the “results suggested that patients with HFmrEF could have a better prognosis, because they can represent a distinct and more favorable HF phenotype,” the authors wrote.

The statistical testing didn’t show much difference and the patient numbers were very small, noted Dr. Goldberg. “So they might be overreaching a little bit there.”

“To me, the take-home message is that just having the phenotype of heart failure, regardless of EF, is associated with bad outcomes and we need to be vigilant on two fronts,” he said. “We really need to be doing prevention in the folks with heart failure because if they get COVID their outcomes are not going to be as good. Second, as clinicians, if we see a patient presenting with COVID who has a history of heart failure we may want to be much more vigilant with that individual than we might otherwise be. So I think there’s something to be said for kind of risk-stratifying people in that way.”

Dr. Goldberg pointed out that the study had many “amazing strengths,” including a large, racially diverse population, direct chart review to identify HF patients, and capturing a patient’s specific HF phenotype.  

Weaknesses are that it was a single-center study, so the biases of how these patients were treated are not easily controlled for, he said. “We also don’t know when the hospital system was very strained as they were making some decisions: Were the older patients who had advanced heart and lung disease ultimately less aggressively treated because they felt they wouldn’t survive?”

Dr. Lala has received personal fees from Zoll, outside the submitted work. Dr. Goldberg reported research funding with Respicardia and consulting fees from Abbott.

This article first appeared on Medscape.com.

People with a history of heart failure – no matter the type – face more complications and death than their peers without HF once hospitalized with COVID-19, a new observational study shows.

A history of HF was associated with a near doubling risk of in-hospital mortality and ICU care and more than a tripling risk of mechanical ventilation despite adjustment for 18 factors including race, obesity, diabetes, previous treatment with renin-angiotensin-aldosterone system (RAAS) inhibitors, and severity of illness.

Adverse outcomes were high regardless of whether patients had HF with a preserved, mid-range, or reduced left ventricular ejection fraction (HFpEF/HFmrEF/HFrEF).

“That for me was the real zinger,” senior author Anuradha Lala, MD, said in an interview . “Because as clinicians, oftentimes, and wrongly so, we think this person has preserved ejection fraction, so they’re not needing my heart failure expertise as much as someone with heart failure with reduced ejection fraction.”

In the peak of the pandemic, that may have meant triaging patients with HFpEF to a regular floor, whereas those with HFrEF were seen by the specialist team.

“What this alerted me to is to take heart failure as a diagnosis very seriously, regardless of ejection fraction, and that is very much in line with all of the emerging data about heart failure with preserved ejection fraction,” said Dr. Lala, from the Icahn School of Medicine at Mount Sinai, New York.

“Now when I see patients in the clinic, I incorporate part of our visit to talking about what they are doing to prevent COVID, which I really wasn’t doing before. It was like ‘Oh yeah, what crazy times we’re dealing with’ and then addressing their heart failure as I normally would,” she said. “But now, interwoven into every visit is: Are you wearing a mask, what’s your social distancing policy, who are you living with at home, has anyone at home or who you’ve interacted with been sick? I’m asking those questions just as a knee-jerk reaction for these patients because I know the repercussions. We have to keep in mind these are observational studies, so I can’t prove causality but these are observations that are, nonetheless, quite robust.”

Although cardiovascular disease, including HF, is recognized as a risk factor for worse outcomes in COVID-19 patients, data are sparse on the clinical course and prognosis of patients with preexisting HF.

“I would have expected that there would have been a gradation of risk from the people with very low ejection fractions up into the normal range, but here it didn’t seem to matter at all. So that’s an important point that bad outcomes were independent of ejection fraction,” commented Lee Goldberg, MD, professor of medicine and chief of advanced heart failure and cardiac transplant at the University of Pennsylvania, Philadelphia.

The study also validated that there is no association between use of RAAS inhibitors and bad outcomes in patients with COVID-19, he said.

Although this has been demonstrated in several studies, concerns were raised early in the pandemic that ACE inhibitors and angiotensin receptor blockers could facilitate infection with SARS-CoV-2 and increase the risk of severe or lethal COVID-19.  

“For most clinicians that question has been put to bed, but we’re still getting patients that will ask during office visits ‘Is it safe for me to stay on?’ They still have that doubt [about] ‘Are we doing the right thing?’ ” Dr. Goldberg said.

“We can reassure them now. A lot of us are able to say there’s nothing to that, we’re very clear about this, stay on the meds. If anything, there’s data that suggest actually it may be better to be on an ACE inhibitor; that the hospitalizations were shorter and the outcomes were a little bit better.”  

For the current study, published online Oct. 28 in the Journal of the American College of Cardiology, the investigators analyzed 6,439 patients admitted for COVID-19 at one of five Mount Sinai Health System hospitals in New York between Feb. 27 and June 26. Their mean age was 65.3 years, 45% were women, and one-third were treated with RAAS inhibitors before admission.

Using ICD-9/10 codes and individual chart review, HF was identified in 422 patients (6.6%), of which 250 patients had HFpEF (≥50%), 44 had HFmrEF (41%-49%), and 128 had HFrEF (≤40%).

Patients with HFpEF were older, more frequently women with a higher body mass index and history of lung disease than patients with HFrEF, whereas those with HFmrEF fell in between.

The HFpEF group was also treated with hydroxychloroquine or macrolides and noninvasive ventilation more frequently than the other two groups, whereas antiplatelet and neurohormonal therapies were more common in the HFrEF group.

Patients with a history of HF had significantly longer hospital stays than those without HF (8 days vs. 6 days), increased need for intubation (22.8% vs. 11.9%) and ICU care (23.2% vs. 16.6%), and worse in-hospital mortality (40% vs. 24.9%).

After multivariable regression adjustment, HF persisted as an independent risk factor for ICU care (odds ratio, 1.71; 95% CI, 1.25-2.34), intubation and mechanical ventilation (OR, 3.64; 95% CI, 2.56-5.16), and in-hospital mortality (OR, 1.88; 95% CI, 1.27-2.78).

“I knew to expect higher rates of adverse outcomes but I didn’t expect it to be nearly a twofold increase,” Dr. Lala said. “I thought that was pretty powerful.”

No significant differences were seen across LVEF categories in length of stay, need for ICU care, intubation and mechanical ventilation, acute kidney injury, shock, thromboembolic events, arrhythmias, or 30-day readmission rates.

However, cardiogenic shock (7.8% vs. 2.3% vs. 2%) and HF-related causes for 30-day readmissions (47.1% vs. 0% vs. 8.6%) were significantly higher in patients with HFrEF than in those with HFmrEF or HFpEF.

Also, mortality was lower in those with HFmrEF (22.7%) than with HFrEF (38.3%) and HFpEF (44%). The group was small but the “results suggested that patients with HFmrEF could have a better prognosis, because they can represent a distinct and more favorable HF phenotype,” the authors wrote.

The statistical testing didn’t show much difference and the patient numbers were very small, noted Dr. Goldberg. “So they might be overreaching a little bit there.”

“To me, the take-home message is that just having the phenotype of heart failure, regardless of EF, is associated with bad outcomes and we need to be vigilant on two fronts,” he said. “We really need to be doing prevention in the folks with heart failure because if they get COVID their outcomes are not going to be as good. Second, as clinicians, if we see a patient presenting with COVID who has a history of heart failure we may want to be much more vigilant with that individual than we might otherwise be. So I think there’s something to be said for kind of risk-stratifying people in that way.”

Dr. Goldberg pointed out that the study had many “amazing strengths,” including a large, racially diverse population, direct chart review to identify HF patients, and capturing a patient’s specific HF phenotype.  

Weaknesses are that it was a single-center study, so the biases of how these patients were treated are not easily controlled for, he said. “We also don’t know when the hospital system was very strained as they were making some decisions: Were the older patients who had advanced heart and lung disease ultimately less aggressively treated because they felt they wouldn’t survive?”

Dr. Lala has received personal fees from Zoll, outside the submitted work. Dr. Goldberg reported research funding with Respicardia and consulting fees from Abbott.

This article first appeared on Medscape.com.

People with a history of heart failure – no matter the type – face more complications and death than their peers without HF once hospitalized with COVID-19, a new observational study shows.

A history of HF was associated with a near doubling risk of in-hospital mortality and ICU care and more than a tripling risk of mechanical ventilation despite adjustment for 18 factors including race, obesity, diabetes, previous treatment with renin-angiotensin-aldosterone system (RAAS) inhibitors, and severity of illness.

Adverse outcomes were high regardless of whether patients had HF with a preserved, mid-range, or reduced left ventricular ejection fraction (HFpEF/HFmrEF/HFrEF).

“That for me was the real zinger,” senior author Anuradha Lala, MD, said in an interview . “Because as clinicians, oftentimes, and wrongly so, we think this person has preserved ejection fraction, so they’re not needing my heart failure expertise as much as someone with heart failure with reduced ejection fraction.”

In the peak of the pandemic, that may have meant triaging patients with HFpEF to a regular floor, whereas those with HFrEF were seen by the specialist team.

“What this alerted me to is to take heart failure as a diagnosis very seriously, regardless of ejection fraction, and that is very much in line with all of the emerging data about heart failure with preserved ejection fraction,” said Dr. Lala, from the Icahn School of Medicine at Mount Sinai, New York.

“Now when I see patients in the clinic, I incorporate part of our visit to talking about what they are doing to prevent COVID, which I really wasn’t doing before. It was like ‘Oh yeah, what crazy times we’re dealing with’ and then addressing their heart failure as I normally would,” she said. “But now, interwoven into every visit is: Are you wearing a mask, what’s your social distancing policy, who are you living with at home, has anyone at home or who you’ve interacted with been sick? I’m asking those questions just as a knee-jerk reaction for these patients because I know the repercussions. We have to keep in mind these are observational studies, so I can’t prove causality but these are observations that are, nonetheless, quite robust.”

Although cardiovascular disease, including HF, is recognized as a risk factor for worse outcomes in COVID-19 patients, data are sparse on the clinical course and prognosis of patients with preexisting HF.

“I would have expected that there would have been a gradation of risk from the people with very low ejection fractions up into the normal range, but here it didn’t seem to matter at all. So that’s an important point that bad outcomes were independent of ejection fraction,” commented Lee Goldberg, MD, professor of medicine and chief of advanced heart failure and cardiac transplant at the University of Pennsylvania, Philadelphia.

The study also validated that there is no association between use of RAAS inhibitors and bad outcomes in patients with COVID-19, he said.

Although this has been demonstrated in several studies, concerns were raised early in the pandemic that ACE inhibitors and angiotensin receptor blockers could facilitate infection with SARS-CoV-2 and increase the risk of severe or lethal COVID-19.  

“For most clinicians that question has been put to bed, but we’re still getting patients that will ask during office visits ‘Is it safe for me to stay on?’ They still have that doubt [about] ‘Are we doing the right thing?’ ” Dr. Goldberg said.

“We can reassure them now. A lot of us are able to say there’s nothing to that, we’re very clear about this, stay on the meds. If anything, there’s data that suggest actually it may be better to be on an ACE inhibitor; that the hospitalizations were shorter and the outcomes were a little bit better.”  

For the current study, published online Oct. 28 in the Journal of the American College of Cardiology, the investigators analyzed 6,439 patients admitted for COVID-19 at one of five Mount Sinai Health System hospitals in New York between Feb. 27 and June 26. Their mean age was 65.3 years, 45% were women, and one-third were treated with RAAS inhibitors before admission.

Using ICD-9/10 codes and individual chart review, HF was identified in 422 patients (6.6%), of which 250 patients had HFpEF (≥50%), 44 had HFmrEF (41%-49%), and 128 had HFrEF (≤40%).

Patients with HFpEF were older, more frequently women with a higher body mass index and history of lung disease than patients with HFrEF, whereas those with HFmrEF fell in between.

The HFpEF group was also treated with hydroxychloroquine or macrolides and noninvasive ventilation more frequently than the other two groups, whereas antiplatelet and neurohormonal therapies were more common in the HFrEF group.

Patients with a history of HF had significantly longer hospital stays than those without HF (8 days vs. 6 days), increased need for intubation (22.8% vs. 11.9%) and ICU care (23.2% vs. 16.6%), and worse in-hospital mortality (40% vs. 24.9%).

After multivariable regression adjustment, HF persisted as an independent risk factor for ICU care (odds ratio, 1.71; 95% CI, 1.25-2.34), intubation and mechanical ventilation (OR, 3.64; 95% CI, 2.56-5.16), and in-hospital mortality (OR, 1.88; 95% CI, 1.27-2.78).

“I knew to expect higher rates of adverse outcomes but I didn’t expect it to be nearly a twofold increase,” Dr. Lala said. “I thought that was pretty powerful.”

No significant differences were seen across LVEF categories in length of stay, need for ICU care, intubation and mechanical ventilation, acute kidney injury, shock, thromboembolic events, arrhythmias, or 30-day readmission rates.

However, cardiogenic shock (7.8% vs. 2.3% vs. 2%) and HF-related causes for 30-day readmissions (47.1% vs. 0% vs. 8.6%) were significantly higher in patients with HFrEF than in those with HFmrEF or HFpEF.

Also, mortality was lower in those with HFmrEF (22.7%) than with HFrEF (38.3%) and HFpEF (44%). The group was small but the “results suggested that patients with HFmrEF could have a better prognosis, because they can represent a distinct and more favorable HF phenotype,” the authors wrote.

The statistical testing didn’t show much difference and the patient numbers were very small, noted Dr. Goldberg. “So they might be overreaching a little bit there.”

“To me, the take-home message is that just having the phenotype of heart failure, regardless of EF, is associated with bad outcomes and we need to be vigilant on two fronts,” he said. “We really need to be doing prevention in the folks with heart failure because if they get COVID their outcomes are not going to be as good. Second, as clinicians, if we see a patient presenting with COVID who has a history of heart failure we may want to be much more vigilant with that individual than we might otherwise be. So I think there’s something to be said for kind of risk-stratifying people in that way.”

Dr. Goldberg pointed out that the study had many “amazing strengths,” including a large, racially diverse population, direct chart review to identify HF patients, and capturing a patient’s specific HF phenotype.  

Weaknesses are that it was a single-center study, so the biases of how these patients were treated are not easily controlled for, he said. “We also don’t know when the hospital system was very strained as they were making some decisions: Were the older patients who had advanced heart and lung disease ultimately less aggressively treated because they felt they wouldn’t survive?”

Dr. Lala has received personal fees from Zoll, outside the submitted work. Dr. Goldberg reported research funding with Respicardia and consulting fees from Abbott.

This article first appeared on Medscape.com.

Carvalho Gazarra LB, Bonacordi CL, Yela DA, et al. Bone mass in women with premature ovarian insufficiency: a comparative study between hormone therapy and combined oral contraceptives. Menopause. 2020;27:1110-1116.

EXPERT COMMENTARY

Premature ovarian insufficiency (POI) refers to a condition in women in whom ovarian function ceases prior to age 40 years. Although hormone therapy (HT) is a mainstay of treatment for women with POI, it is uncertain which approach to HT is most effective in terms of bone mineral density (BMD). Investigators recently published their results of an observational study that aimed to evaluate the use of combined oral contraceptives (COCs) for preserving BMD in women with POI.

Details of the study

At an academic center in Brazil, Carvalho Gazarra and colleagues identified women with POI who had undergone 2 or more BMD assessments performed 2 or more years apart.¹ HT regimens (all of which were taken continuously) employed the following: a COC with ethinyl estradiol (EE) 30 µg and levonorgestrel; low-dose estrogen plus progestin therapy (EPT, conjugated equine estrogen [CEE] 0.625 mg with medroxyprogesterone acetate or estradiol 1.0 mg with norethindrone acetate); or high-dose estrogen plus progestin (CEE 1.25 mg or estradiol 2.0 mg combined with the same progestins).

Results. Among 119 evaluable women with POI (mean age, 30.3 years), the use of COC was associated with the most positive BMD trends. For women using COC or high-dose EPT, BMD at the lumbar spine increased. By contrast, BMD of the lumbar spine declined in women who used no treatment or low-dose EPT.¹

Other studies’ take on dose, route of administration, and cost considerations

Sequelae of POI include infertility, bothersome hot flashes, vaginal dryness, sexual dysfunction, mood disorders, and an elevated risk of cardiovascular disease, dementia, Parkinson’s disease, and osteoporosis. Importantly, clinicians and patients need to understand that the results from the Women’s Health Initiative studies do not apply to women with POI.² Physiologic doses of HT (that is, doses higher than those used to treat menopausal symptoms in women with normal/spontaneous menopause) are appropriate for women with POI, at least until they reach the normal age of menopause (51 to 52 years).

A clinical trial conducted in Scotland in women with POI found that high-dose transdermal estrogen (application of one to two 0.1-mg estradiol patches) daily had an impact on BMD that was more positive than that of an oral contraceptive formulated with EE 30 µg.³ Likewise, a trial in the United States found that, among oligo-amenorrheic athletes, a hormone replacement regimen using a 0.1-mg estradiol patch had a more positive impact on BMD than an oral contraceptive formulated with EE 30 µg.⁴

Although Carvalho Gazarra and colleagues acknowledged awareness of reports suggesting the skeletal health benefits of high-dose estradiol patches, in the Brazilian public health system oral hormone therapy is less expensive and oral contraceptives are available at no charge.¹ ●

Carvalho Gazarra LB, Bonacordi CL, Yela DA, et al. Bone mass in women with premature ovarian insufficiency: a comparative study between hormone therapy and combined oral contraceptives. Menopause. 2020;27:1110-1116.

EXPERT COMMENTARY

Premature ovarian insufficiency (POI) refers to a condition in women in whom ovarian function ceases prior to age 40 years. Although hormone therapy (HT) is a mainstay of treatment for women with POI, it is uncertain which approach to HT is most effective in terms of bone mineral density (BMD). Investigators recently published their results of an observational study that aimed to evaluate the use of combined oral contraceptives (COCs) for preserving BMD in women with POI.

Details of the study

At an academic center in Brazil, Carvalho Gazarra and colleagues identified women with POI who had undergone 2 or more BMD assessments performed 2 or more years apart.¹ HT regimens (all of which were taken continuously) employed the following: a COC with ethinyl estradiol (EE) 30 µg and levonorgestrel; low-dose estrogen plus progestin therapy (EPT, conjugated equine estrogen [CEE] 0.625 mg with medroxyprogesterone acetate or estradiol 1.0 mg with norethindrone acetate); or high-dose estrogen plus progestin (CEE 1.25 mg or estradiol 2.0 mg combined with the same progestins).

Results. Among 119 evaluable women with POI (mean age, 30.3 years), the use of COC was associated with the most positive BMD trends. For women using COC or high-dose EPT, BMD at the lumbar spine increased. By contrast, BMD of the lumbar spine declined in women who used no treatment or low-dose EPT.¹

Other studies’ take on dose, route of administration, and cost considerations

Sequelae of POI include infertility, bothersome hot flashes, vaginal dryness, sexual dysfunction, mood disorders, and an elevated risk of cardiovascular disease, dementia, Parkinson’s disease, and osteoporosis. Importantly, clinicians and patients need to understand that the results from the Women’s Health Initiative studies do not apply to women with POI.² Physiologic doses of HT (that is, doses higher than those used to treat menopausal symptoms in women with normal/spontaneous menopause) are appropriate for women with POI, at least until they reach the normal age of menopause (51 to 52 years).

A clinical trial conducted in Scotland in women with POI found that high-dose transdermal estrogen (application of one to two 0.1-mg estradiol patches) daily had an impact on BMD that was more positive than that of an oral contraceptive formulated with EE 30 µg.³ Likewise, a trial in the United States found that, among oligo-amenorrheic athletes, a hormone replacement regimen using a 0.1-mg estradiol patch had a more positive impact on BMD than an oral contraceptive formulated with EE 30 µg.⁴

Although Carvalho Gazarra and colleagues acknowledged awareness of reports suggesting the skeletal health benefits of high-dose estradiol patches, in the Brazilian public health system oral hormone therapy is less expensive and oral contraceptives are available at no charge.¹ ●

Carvalho Gazarra LB, Bonacordi CL, Yela DA, et al. Bone mass in women with premature ovarian insufficiency: a comparative study between hormone therapy and combined oral contraceptives. Menopause. 2020;27:1110-1116.

EXPERT COMMENTARY

Premature ovarian insufficiency (POI) refers to a condition in women in whom ovarian function ceases prior to age 40 years. Although hormone therapy (HT) is a mainstay of treatment for women with POI, it is uncertain which approach to HT is most effective in terms of bone mineral density (BMD). Investigators recently published their results of an observational study that aimed to evaluate the use of combined oral contraceptives (COCs) for preserving BMD in women with POI.

Details of the study

At an academic center in Brazil, Carvalho Gazarra and colleagues identified women with POI who had undergone 2 or more BMD assessments performed 2 or more years apart.¹ HT regimens (all of which were taken continuously) employed the following: a COC with ethinyl estradiol (EE) 30 µg and levonorgestrel; low-dose estrogen plus progestin therapy (EPT, conjugated equine estrogen [CEE] 0.625 mg with medroxyprogesterone acetate or estradiol 1.0 mg with norethindrone acetate); or high-dose estrogen plus progestin (CEE 1.25 mg or estradiol 2.0 mg combined with the same progestins).

Results. Among 119 evaluable women with POI (mean age, 30.3 years), the use of COC was associated with the most positive BMD trends. For women using COC or high-dose EPT, BMD at the lumbar spine increased. By contrast, BMD of the lumbar spine declined in women who used no treatment or low-dose EPT.¹

Other studies’ take on dose, route of administration, and cost considerations

Sequelae of POI include infertility, bothersome hot flashes, vaginal dryness, sexual dysfunction, mood disorders, and an elevated risk of cardiovascular disease, dementia, Parkinson’s disease, and osteoporosis. Importantly, clinicians and patients need to understand that the results from the Women’s Health Initiative studies do not apply to women with POI.² Physiologic doses of HT (that is, doses higher than those used to treat menopausal symptoms in women with normal/spontaneous menopause) are appropriate for women with POI, at least until they reach the normal age of menopause (51 to 52 years).

A clinical trial conducted in Scotland in women with POI found that high-dose transdermal estrogen (application of one to two 0.1-mg estradiol patches) daily had an impact on BMD that was more positive than that of an oral contraceptive formulated with EE 30 µg.³ Likewise, a trial in the United States found that, among oligo-amenorrheic athletes, a hormone replacement regimen using a 0.1-mg estradiol patch had a more positive impact on BMD than an oral contraceptive formulated with EE 30 µg.⁴

Although Carvalho Gazarra and colleagues acknowledged awareness of reports suggesting the skeletal health benefits of high-dose estradiol patches, in the Brazilian public health system oral hormone therapy is less expensive and oral contraceptives are available at no charge.¹ ●

Surprisingly, in the United States, the most common cancer associated with human papillomavirus (HPV) is oropharyngeal squamous cell cancer (SCC), with one study reporting 15,479 cases among men and 3,428 cases among women in 2015.¹ In the same year, the investigators reported 11,788 cases of cervical cancer.¹ A public health concern is that cases of oropharyngeal SCC are increasing, while cases of cervical cancer are decreasing. From 1999 to 2015, the rate of oropharyngeal SCC increased annually among both men and women, at rates of 2.7% and 0.8% per year, respectively. By contrast, the rate of cervical cancer decreased by 1.6% per year.¹

Although the incidence of HPV-negative oropharyngeal SCC (cases associated with cigarette smoking) has declined by 50% from 1988 to 2004, the incidence of HPV-positive oropharyngeal SCC has increased by 225%, with much of the increase occurring among young, white men.² HPV infection is a major cause of oropharyngeal SCC at the base of the tongue and tonsils, but not in the soft palate or oropharyngeal walls.³

Most physicians and parents recognize that the 9-valent (9v)HPV vaccine prevents the majority of cervical cancers and precancers in women. Far fewer people realize that there is an important opportunity to prevent a large number of oropharyngeal cancers by improving 9vHPV vaccination in men and women.

Which HPV types are associated with oropharyngeal cancer?

HPV16 is the most common HPV type associated with oropharyngeal SCC. Among these cancer types, greater than 80% harbor HPV16, with greater than 90% harboring HPV16 or 18 and less than 10% of tumors associated with HPV types 31, 33, 45, 52, or 58.^4-7

The high prevalence of HPV16 in patients with oropharyngeal cancer raises the question of the HPV status of the intimate partner of the index patient. In one study of 164 people with HPV detected in their oropharyngeal, the partner of the index patient had a low prevalence of high-risk HPV types (1.2%) in oral rinse and gargle samples, similar to the rate in the general population (1.3%).⁷ This finding is reassuring and suggests that intimate partners of patients with HPV-positive oropharyngeal cancer effectively clear high-risk HPV virus from the oropharynx. The HPV status of the genital tissue of the intimate partner of an index patient with oropharyngeal SCC has not been adequately studied.

Men are more likely than women to harbor oral HPV

Among a sample of 5,501 men and women aged 14 to 69 years from the National Health and Nutrition Examination Survey, oral rinses were obtained and analyzed for the presence of HPV.⁸ The prevalence of any oral HPV and any oral high-risk HPV was 6.9% and 3.7%, respectively. Oral HPV-16 was detected in 1.6% of men and 0.3% of women. The prevalence of HPV was higher among current smokers, heavy alcohol drinkers, and people with a history of a greater number of sexual partners. In men and women reporting more than 20 lifetime sexual partners, the prevalence of oral HPV was 20%.

In a study of 2,627 men and women aged 18 to 33 years, the prevalence of oral HPV 16/18/6/11 was lower among those vaccinated versus those unvaccinated (0.11% and 1.6%, respectively; P = .008).⁹ Among men, oral HPV 16/18/6/11 was lower among those vaccinated versus unvaccinated (0.0% and 2.13%, respectively; P = .007).⁹ The results of this observational study support the important role of vaccination in reducing oral HPV infection.

Continue to: Vaccinate boys and girls to prevent cancer...

Vaccinate boys and girls to prevent cancer

Most population studies report that males are less likely to receive an HPV vaccine than females. For example, based on the National Health Interview Survey of people aged 18 to 26, the percentage of women who self-reported receiving at least one dose of HPV vaccine was 37% in 2013 and 54% in 2018.¹⁰ By contrast, among men, the rates of self-reported vaccination were much lower—8% in 2013 and 27% in 2018.¹⁰

The percentage of women who received the recommended number of doses of HPV vaccine (see “9vHPV vaccine: Indications and immunization schedule”) was 26% in 2013 and 35% in 2018.¹⁰ For men, these percentages were 2% in 2013 and 9% in 2018.¹⁰ These data indicate that, compared with women, men are less likely to receive an HPV vaccination and far less likely to have received the recommended number of doses.

It is heartening that there has been a slow and steady increase in the prevalence of HPV vaccination. In fact, increasing the HPV vaccination rate among both boys and girls has the potential to markedly reduce the incidence of oropharyngeal cancer.

The reasons for the female-male gap in vaccination rates are not fully characterized. For one, parental awareness of the importance of HPV vaccination to prevent cancer among men is limited, and represents an important opportunity for additional public health education. In a qualitative interview study of mothers with children aged 11 to 19, the investigators reported that most mothers were aware that HPV vaccination could prevent cervical cancer in women, but most mothers did not know that HPV causes cancer of the mouth and that vaccination could prevent oropharyngeal cancer in boys and girls.¹¹ Because of this lack of knowledge, the mothers did not think their sons needed to have an HPV vaccine. The research report is aptly titled, “I don’t think he needs the HPV vaccine cause boys can’t have cervical cancer.”¹¹

Clinicians are highly influential in guiding parents to accept HPV vaccination of their children. Offering consistent messaging to parents that HPV vaccination prevents cancer in both women and men, and reducing the out-of-pocket cost of vaccination surely will result in an increase in the vaccination rate of boys and girls. ●

Surprisingly, in the United States, the most common cancer associated with human papillomavirus (HPV) is oropharyngeal squamous cell cancer (SCC), with one study reporting 15,479 cases among men and 3,428 cases among women in 2015.¹ In the same year, the investigators reported 11,788 cases of cervical cancer.¹ A public health concern is that cases of oropharyngeal SCC are increasing, while cases of cervical cancer are decreasing. From 1999 to 2015, the rate of oropharyngeal SCC increased annually among both men and women, at rates of 2.7% and 0.8% per year, respectively. By contrast, the rate of cervical cancer decreased by 1.6% per year.¹

Although the incidence of HPV-negative oropharyngeal SCC (cases associated with cigarette smoking) has declined by 50% from 1988 to 2004, the incidence of HPV-positive oropharyngeal SCC has increased by 225%, with much of the increase occurring among young, white men.² HPV infection is a major cause of oropharyngeal SCC at the base of the tongue and tonsils, but not in the soft palate or oropharyngeal walls.³

Most physicians and parents recognize that the 9-valent (9v)HPV vaccine prevents the majority of cervical cancers and precancers in women. Far fewer people realize that there is an important opportunity to prevent a large number of oropharyngeal cancers by improving 9vHPV vaccination in men and women.

Which HPV types are associated with oropharyngeal cancer?

HPV16 is the most common HPV type associated with oropharyngeal SCC. Among these cancer types, greater than 80% harbor HPV16, with greater than 90% harboring HPV16 or 18 and less than 10% of tumors associated with HPV types 31, 33, 45, 52, or 58.^4-7

The high prevalence of HPV16 in patients with oropharyngeal cancer raises the question of the HPV status of the intimate partner of the index patient. In one study of 164 people with HPV detected in their oropharyngeal, the partner of the index patient had a low prevalence of high-risk HPV types (1.2%) in oral rinse and gargle samples, similar to the rate in the general population (1.3%).⁷ This finding is reassuring and suggests that intimate partners of patients with HPV-positive oropharyngeal cancer effectively clear high-risk HPV virus from the oropharynx. The HPV status of the genital tissue of the intimate partner of an index patient with oropharyngeal SCC has not been adequately studied.

Men are more likely than women to harbor oral HPV

Among a sample of 5,501 men and women aged 14 to 69 years from the National Health and Nutrition Examination Survey, oral rinses were obtained and analyzed for the presence of HPV.⁸ The prevalence of any oral HPV and any oral high-risk HPV was 6.9% and 3.7%, respectively. Oral HPV-16 was detected in 1.6% of men and 0.3% of women. The prevalence of HPV was higher among current smokers, heavy alcohol drinkers, and people with a history of a greater number of sexual partners. In men and women reporting more than 20 lifetime sexual partners, the prevalence of oral HPV was 20%.

In a study of 2,627 men and women aged 18 to 33 years, the prevalence of oral HPV 16/18/6/11 was lower among those vaccinated versus those unvaccinated (0.11% and 1.6%, respectively; P = .008).⁹ Among men, oral HPV 16/18/6/11 was lower among those vaccinated versus unvaccinated (0.0% and 2.13%, respectively; P = .007).⁹ The results of this observational study support the important role of vaccination in reducing oral HPV infection.

Continue to: Vaccinate boys and girls to prevent cancer...

Vaccinate boys and girls to prevent cancer

Most population studies report that males are less likely to receive an HPV vaccine than females. For example, based on the National Health Interview Survey of people aged 18 to 26, the percentage of women who self-reported receiving at least one dose of HPV vaccine was 37% in 2013 and 54% in 2018.¹⁰ By contrast, among men, the rates of self-reported vaccination were much lower—8% in 2013 and 27% in 2018.¹⁰

The percentage of women who received the recommended number of doses of HPV vaccine (see “9vHPV vaccine: Indications and immunization schedule”) was 26% in 2013 and 35% in 2018.¹⁰ For men, these percentages were 2% in 2013 and 9% in 2018.¹⁰ These data indicate that, compared with women, men are less likely to receive an HPV vaccination and far less likely to have received the recommended number of doses.

It is heartening that there has been a slow and steady increase in the prevalence of HPV vaccination. In fact, increasing the HPV vaccination rate among both boys and girls has the potential to markedly reduce the incidence of oropharyngeal cancer.

The reasons for the female-male gap in vaccination rates are not fully characterized. For one, parental awareness of the importance of HPV vaccination to prevent cancer among men is limited, and represents an important opportunity for additional public health education. In a qualitative interview study of mothers with children aged 11 to 19, the investigators reported that most mothers were aware that HPV vaccination could prevent cervical cancer in women, but most mothers did not know that HPV causes cancer of the mouth and that vaccination could prevent oropharyngeal cancer in boys and girls.¹¹ Because of this lack of knowledge, the mothers did not think their sons needed to have an HPV vaccine. The research report is aptly titled, “I don’t think he needs the HPV vaccine cause boys can’t have cervical cancer.”¹¹

Clinicians are highly influential in guiding parents to accept HPV vaccination of their children. Offering consistent messaging to parents that HPV vaccination prevents cancer in both women and men, and reducing the out-of-pocket cost of vaccination surely will result in an increase in the vaccination rate of boys and girls. ●

Surprisingly, in the United States, the most common cancer associated with human papillomavirus (HPV) is oropharyngeal squamous cell cancer (SCC), with one study reporting 15,479 cases among men and 3,428 cases among women in 2015.¹ In the same year, the investigators reported 11,788 cases of cervical cancer.¹ A public health concern is that cases of oropharyngeal SCC are increasing, while cases of cervical cancer are decreasing. From 1999 to 2015, the rate of oropharyngeal SCC increased annually among both men and women, at rates of 2.7% and 0.8% per year, respectively. By contrast, the rate of cervical cancer decreased by 1.6% per year.¹

Although the incidence of HPV-negative oropharyngeal SCC (cases associated with cigarette smoking) has declined by 50% from 1988 to 2004, the incidence of HPV-positive oropharyngeal SCC has increased by 225%, with much of the increase occurring among young, white men.² HPV infection is a major cause of oropharyngeal SCC at the base of the tongue and tonsils, but not in the soft palate or oropharyngeal walls.³

Most physicians and parents recognize that the 9-valent (9v)HPV vaccine prevents the majority of cervical cancers and precancers in women. Far fewer people realize that there is an important opportunity to prevent a large number of oropharyngeal cancers by improving 9vHPV vaccination in men and women.

Which HPV types are associated with oropharyngeal cancer?

HPV16 is the most common HPV type associated with oropharyngeal SCC. Among these cancer types, greater than 80% harbor HPV16, with greater than 90% harboring HPV16 or 18 and less than 10% of tumors associated with HPV types 31, 33, 45, 52, or 58.^4-7

The high prevalence of HPV16 in patients with oropharyngeal cancer raises the question of the HPV status of the intimate partner of the index patient. In one study of 164 people with HPV detected in their oropharyngeal, the partner of the index patient had a low prevalence of high-risk HPV types (1.2%) in oral rinse and gargle samples, similar to the rate in the general population (1.3%).⁷ This finding is reassuring and suggests that intimate partners of patients with HPV-positive oropharyngeal cancer effectively clear high-risk HPV virus from the oropharynx. The HPV status of the genital tissue of the intimate partner of an index patient with oropharyngeal SCC has not been adequately studied.

Men are more likely than women to harbor oral HPV

Among a sample of 5,501 men and women aged 14 to 69 years from the National Health and Nutrition Examination Survey, oral rinses were obtained and analyzed for the presence of HPV.⁸ The prevalence of any oral HPV and any oral high-risk HPV was 6.9% and 3.7%, respectively. Oral HPV-16 was detected in 1.6% of men and 0.3% of women. The prevalence of HPV was higher among current smokers, heavy alcohol drinkers, and people with a history of a greater number of sexual partners. In men and women reporting more than 20 lifetime sexual partners, the prevalence of oral HPV was 20%.

In a study of 2,627 men and women aged 18 to 33 years, the prevalence of oral HPV 16/18/6/11 was lower among those vaccinated versus those unvaccinated (0.11% and 1.6%, respectively; P = .008).⁹ Among men, oral HPV 16/18/6/11 was lower among those vaccinated versus unvaccinated (0.0% and 2.13%, respectively; P = .007).⁹ The results of this observational study support the important role of vaccination in reducing oral HPV infection.

Continue to: Vaccinate boys and girls to prevent cancer...

Vaccinate boys and girls to prevent cancer

Most population studies report that males are less likely to receive an HPV vaccine than females. For example, based on the National Health Interview Survey of people aged 18 to 26, the percentage of women who self-reported receiving at least one dose of HPV vaccine was 37% in 2013 and 54% in 2018.¹⁰ By contrast, among men, the rates of self-reported vaccination were much lower—8% in 2013 and 27% in 2018.¹⁰

The percentage of women who received the recommended number of doses of HPV vaccine (see “9vHPV vaccine: Indications and immunization schedule”) was 26% in 2013 and 35% in 2018.¹⁰ For men, these percentages were 2% in 2013 and 9% in 2018.¹⁰ These data indicate that, compared with women, men are less likely to receive an HPV vaccination and far less likely to have received the recommended number of doses.

It is heartening that there has been a slow and steady increase in the prevalence of HPV vaccination. In fact, increasing the HPV vaccination rate among both boys and girls has the potential to markedly reduce the incidence of oropharyngeal cancer.

The reasons for the female-male gap in vaccination rates are not fully characterized. For one, parental awareness of the importance of HPV vaccination to prevent cancer among men is limited, and represents an important opportunity for additional public health education. In a qualitative interview study of mothers with children aged 11 to 19, the investigators reported that most mothers were aware that HPV vaccination could prevent cervical cancer in women, but most mothers did not know that HPV causes cancer of the mouth and that vaccination could prevent oropharyngeal cancer in boys and girls.¹¹ Because of this lack of knowledge, the mothers did not think their sons needed to have an HPV vaccine. The research report is aptly titled, “I don’t think he needs the HPV vaccine cause boys can’t have cervical cancer.”¹¹

Clinicians are highly influential in guiding parents to accept HPV vaccination of their children. Offering consistent messaging to parents that HPV vaccination prevents cancer in both women and men, and reducing the out-of-pocket cost of vaccination surely will result in an increase in the vaccination rate of boys and girls. ●

CASE Concerning finding on repeat CD

A 30-year-old woman with a history of 1 prior cesarean delivery (CD) presents to labor and delivery at 38 weeks of gestation with symptoms of mild cramping. Her prenatal care was uncomplicated. The covering team made a decision to proceed with a repeat CD. A Pfannenstiel incision is made to enter the abdomen, and inspection of the lower uterine segment is concerning for a placenta accreta spectrum (PAS) (FIGURE).

What would be your next steps?

Placenta accreta spectrum describes the range of disorders of placental implantation, including placenta accreta, increta, and percreta. PAS is a significant cause of severe maternal morbidity and mortality, primarily due to massive hemorrhage at the time of delivery. The incidence of PAS continues to rise along with the CD rate. The authors of a recent meta-analysis reported a pooled prevalence rate of 1 in 588 women.¹ Notably, in women with PAS, the rate of hysterectomy is 52.2%, and the transfusion-dependent hemorrhage rate is 46.9%.¹

Ideally, PAS should be diagnosed or at least suspected antenatally during prenatal ultrasonography, leading to delivery planning by a multidisciplinary team.² The presence of a multidisciplinary team—in addition to the primary obstetric and surgical teams—composed of experienced anesthesiologists, a blood bank able to respond to massive transfusion needs, critical care specialists, and interventional radiologists is associated with improved outcomes.^3-5

Occasionally, a patient is found to have an advanced PAS (increta or percreta) at the time of delivery. In these situations, it is paramount that the appropriate resources be assembled as expeditiously as possible to optimize maternal outcomes. Surgical management can be challenging even for experienced pelvic surgeons, and appropriate resuscitation cannot be provided by a single anesthesiologist working alone. A cavalier attitude of proceeding with the delivery “as usual” in the face of an unexpected PAS situation can lead to disastrous consequences, including maternal death.

In this article, we review the important steps to take when faced with the unexpected situation of a PAS at the time of CD.

Continue to: Stop and collect your multidisciplinary team...

Stop and collect your multidisciplinary team

Once the diagnosis of an advanced PAS is suspected, the first step is to stop and request the presence of your institution’s multidisciplinary surgical team. This team typically includes a maternal-fetal specialist or, if not available, an experienced obstetrician, and an expert pelvic surgeon, which varies by institution (gynecologic oncologist, trauma surgeon, urologist, urogynecologist, vascular surgeon). An interventional radiology team is an additional useful resource that can assist with the control of pelvic hemorrhage using embolization techniques.

In our opinion, it is not appropriate to have a surgical backup team available only as needed at a certain distance from the hospital or even in the building. Because of the acuity and magnitude of bleeding that can occur in a short time, the most appropriate approach is to have your surgical team scrubbed and ready to assist or take over the procedure immediately if indicated.

Additional support staff also may be required. A single circulating nurse may not be sufficient, and available nursing staff may need to be called. The surgical technician scrubbed on the case may be familiar only with uncomplicated CDs and can be overwhelmed during a PAS case. Having a more experienced surgical technologist can optimize the availability of the appropriate instruments for the surgical team.

If a multidisciplinary surgical team with PAS management expertise is not available at your institution and the patient is stable, it is appropriate to consider transferring her to the nearest center that can meet the high-risk needs of this situation.⁶

Prepare for resuscitation

While you are calling your multidisciplinary team members, implement plans for resuscitation by notifying the anesthesiologist about the PAS findings. This will allow the gathering of needed resources that may include calling on additional anesthesiologists with experience in high-risk obstetrics, trauma, or critical care.

Placing large-bore intravenous lines or a central line to allow rapid transfusion is essential. Strongly consider inserting an arterial line for hemodynamic monitoring and intraoperative blood draws to monitor blood loss, blood gases, electrolytes, and coagulation parameters, which can guide resuscitative efforts and replacement therapies.

Simultaneously, inform the blood bank to prepare blood and blood products for possible activation of a massive transfusion protocol. It is imperative to have the products available in the operating room (OR) prior to proceeding with the surgery. Our current practice is to have 10 units of packed red blood cells and fresh frozen plasma available in the OR for all our prenatally diagnosed electively planned PAS cases.

Optimize exposure of the surgical field

Appropriate exposure of the surgical field is essential and should include exposure of the uterine fundus and the pelvic sidewalls. The uterine incision should avoid the placenta; typically it is placed at the level of the uterine fundus. Exposure of the pelvic sidewalls is needed to open the retroperitoneum and identify the ureter and the iliac vessels.

Vertical extension of the fascial incision probably will be needed to achieve appropriate exposure. Although at times this can be done without a concomitant vertical skin incision, often an inverted T incision is required. Be mindful that PAS is a life-threatening condition and that aesthetics are not a priority. After extending the fascial incision, adequate exposure can be achieved with any of the commonly used retractors or wound protectors (depending on institutional availability and surgeon preference) or by the surgical assistants using body wall retractors.

We routinely place the patient in lithotomy position. This allows us to monitor for vaginal bleeding (often a site of unrecognized massive hemorrhage) during the surgery, facilitate retrograde bladder filling, and provide a vaginal access to the pelvis. In addition, the lithotomy position allows for cystoscopy and placement of ureteral stents, which can be performed before starting the surgery to help prevent urinary tract injuries or at the end of the procedure in case one is suspected.⁷

Continue to: Performing the hysterectomy...

 

 

Performing the hysterectomy

A complete review of all surgical techniques for managing PAS is beyond the scope of this article. However, we briefly cover important procedural steps and offer suggestions on how to minimize the risk of bleeding.

In our experience. The areas with the highest risk of massive bleeding that can be difficult to control include the pelvic sidewall when there is lateral extension of the PAS, the vesicouterine space, and placenta previa vaginally. Be mindful of these areas at risk and have a plan in place in case of bleeding.

Uterine incision

Avoid the placenta when making the uterine incision, which is typically done in the fundal part of the uterus. Cut and tie the cord and return it to the uterine cavity. Close the incision in a single layer. Use of a surgical stapler can be used for the hysterotomy and can decrease the amount of blood loss.⁸

Superior attachments of the uterus

The superior attachments of the uterus include the round ligament, the utero-ovarian ligament, and the fallopian tubes. With meticulous dissection, develop an avascular space underneath these structures and, in turn, individually divide and suture ligate; this is typically achieved with minimal blood loss.

In addition, isolate the engorged veins of the broad ligament and divide them in a similar fashion.

In our experience. Use of a vessel-sealing device can facilitate division of all the former structures. Simply excise the fallopian tubes with the vessel-sealing device either at this time or after the uterus is removed.

Pelvic sidewall

Once the superior attachments of the uterus have been divided, the next step involves exposing the pelvic sidewall structures, that is, the ureter and the pelvic vessels. Expose the ureter from the pelvic brim to the level of the uterine artery. The hypogastric artery is exposed as well in this process and the pararectal space developed.

When the PAS has extended laterally, perform stepwise division of the lateral attachments of the placenta to the pelvic sidewall using a combination of electrocautery, hemoclips, and the vessel-sealing device. In laterally extended PAS cases, it often is necessary to divide the uterine artery either at its origin or at the level of the ureter to allow for the completion of the separation of the placenta from the pelvic sidewall.

In our experience. During this lateral dissection, significant bleeding may be encountered from the neovascular network that has developed in the pelvic sidewall. The bleeding may be diffuse and difficult to control with the methods described above. In this situation, we have found that placing hemostatic agents in this area and packing the sidewall with laparotomy pads can achieve hemostasis in most cases, thus allowing the surgery to proceed.

Continue to: Bladder dissection...

Bladder dissection

The next critical part of the surgery involves developing the vesicovaginal space to mobilize the bladder. Prior to initiating the bladder dissection, we routinely retrograde fill the bladder with 180 to 240 mL of saline mixed with methylene blue. This delineates the superior edge of the bladder and indicates the appropriate level to start the dissection. Then slowly develop the vesicouterine space using a combination of electrocautery and a vessel-sealing device until the bladder is mobilized to the level of the anterior vaginal wall. Many vascular connections are encountered at that level, and meticulous dissection and patience is required to systematically divide them all.

In our experience. This part of the surgery presents several challenges. The bladder wall may be invaded by the placenta, which will lead to an increased risk of bleeding and cystotomy during the dissection. In these cases, it might be preferable to create an intentional cystotomy to guide the dissection; at times, a limited excision of the involved bladder wall may be required. In other cases, even in the absence of bladder wall invasion, the bladder may be densely adherent to the uterine wall (usually due to a history of prior CDs), and bladder mobilization may be complicated by bleeding from the neovascular network that has developed between the placenta and bladder.

Uterine arteries and cervix

Once the placenta is separated from its lateral attachments and the bladder is mobilized, the next steps are similar to those in a standard abdominal hysterectomy. If the uterine arteries were not yet divided during the pelvic sidewall dissection, they are clamped, divided, and suture ligated at the level of the uterine isthmus. The decision whether to perform a supracervical or total hysterectomy depends on the level of cervical involvement by the placenta, surgeon preference, anatomic distortion, and bleeding from the cervix and anterior vaginal wall.

Responding to massive bleeding

Not uncommonly, and despite the best efforts to avoid it, massive bleeding may develop from the areas at risk as noted above. If the bleeding is significant and originates from multiple areas (including vaginal bleeding from placenta previa), we recommend proceeding with an expeditious hysterectomy to remove the specimen, and then reassess the pelvic field for hemostatic control and any organ damage that may have occurred.

The challenge of PAS

Surgical management of PAS is one the most challenging procedures in pelvic surgery. Successful outcomes require a multidisciplinary team approach and an experienced team dedicated to the management of this condition.⁹ By contrast, proceeding “as usual” in the face of an unexpected PAS situation can lead to disastrous consequences in terms of maternal morbidity and mortality. ●

CASE Concerning finding on repeat CD

A 30-year-old woman with a history of 1 prior cesarean delivery (CD) presents to labor and delivery at 38 weeks of gestation with symptoms of mild cramping. Her prenatal care was uncomplicated. The covering team made a decision to proceed with a repeat CD. A Pfannenstiel incision is made to enter the abdomen, and inspection of the lower uterine segment is concerning for a placenta accreta spectrum (PAS) (FIGURE).

What would be your next steps?

Placenta accreta spectrum describes the range of disorders of placental implantation, including placenta accreta, increta, and percreta. PAS is a significant cause of severe maternal morbidity and mortality, primarily due to massive hemorrhage at the time of delivery. The incidence of PAS continues to rise along with the CD rate. The authors of a recent meta-analysis reported a pooled prevalence rate of 1 in 588 women.¹ Notably, in women with PAS, the rate of hysterectomy is 52.2%, and the transfusion-dependent hemorrhage rate is 46.9%.¹

Ideally, PAS should be diagnosed or at least suspected antenatally during prenatal ultrasonography, leading to delivery planning by a multidisciplinary team.² The presence of a multidisciplinary team—in addition to the primary obstetric and surgical teams—composed of experienced anesthesiologists, a blood bank able to respond to massive transfusion needs, critical care specialists, and interventional radiologists is associated with improved outcomes.^3-5

Occasionally, a patient is found to have an advanced PAS (increta or percreta) at the time of delivery. In these situations, it is paramount that the appropriate resources be assembled as expeditiously as possible to optimize maternal outcomes. Surgical management can be challenging even for experienced pelvic surgeons, and appropriate resuscitation cannot be provided by a single anesthesiologist working alone. A cavalier attitude of proceeding with the delivery “as usual” in the face of an unexpected PAS situation can lead to disastrous consequences, including maternal death.

In this article, we review the important steps to take when faced with the unexpected situation of a PAS at the time of CD.

Continue to: Stop and collect your multidisciplinary team...

Stop and collect your multidisciplinary team

Once the diagnosis of an advanced PAS is suspected, the first step is to stop and request the presence of your institution’s multidisciplinary surgical team. This team typically includes a maternal-fetal specialist or, if not available, an experienced obstetrician, and an expert pelvic surgeon, which varies by institution (gynecologic oncologist, trauma surgeon, urologist, urogynecologist, vascular surgeon). An interventional radiology team is an additional useful resource that can assist with the control of pelvic hemorrhage using embolization techniques.

In our opinion, it is not appropriate to have a surgical backup team available only as needed at a certain distance from the hospital or even in the building. Because of the acuity and magnitude of bleeding that can occur in a short time, the most appropriate approach is to have your surgical team scrubbed and ready to assist or take over the procedure immediately if indicated.

Additional support staff also may be required. A single circulating nurse may not be sufficient, and available nursing staff may need to be called. The surgical technician scrubbed on the case may be familiar only with uncomplicated CDs and can be overwhelmed during a PAS case. Having a more experienced surgical technologist can optimize the availability of the appropriate instruments for the surgical team.

If a multidisciplinary surgical team with PAS management expertise is not available at your institution and the patient is stable, it is appropriate to consider transferring her to the nearest center that can meet the high-risk needs of this situation.⁶

Prepare for resuscitation

While you are calling your multidisciplinary team members, implement plans for resuscitation by notifying the anesthesiologist about the PAS findings. This will allow the gathering of needed resources that may include calling on additional anesthesiologists with experience in high-risk obstetrics, trauma, or critical care.

Placing large-bore intravenous lines or a central line to allow rapid transfusion is essential. Strongly consider inserting an arterial line for hemodynamic monitoring and intraoperative blood draws to monitor blood loss, blood gases, electrolytes, and coagulation parameters, which can guide resuscitative efforts and replacement therapies.

Simultaneously, inform the blood bank to prepare blood and blood products for possible activation of a massive transfusion protocol. It is imperative to have the products available in the operating room (OR) prior to proceeding with the surgery. Our current practice is to have 10 units of packed red blood cells and fresh frozen plasma available in the OR for all our prenatally diagnosed electively planned PAS cases.

Optimize exposure of the surgical field

Appropriate exposure of the surgical field is essential and should include exposure of the uterine fundus and the pelvic sidewalls. The uterine incision should avoid the placenta; typically it is placed at the level of the uterine fundus. Exposure of the pelvic sidewalls is needed to open the retroperitoneum and identify the ureter and the iliac vessels.

Vertical extension of the fascial incision probably will be needed to achieve appropriate exposure. Although at times this can be done without a concomitant vertical skin incision, often an inverted T incision is required. Be mindful that PAS is a life-threatening condition and that aesthetics are not a priority. After extending the fascial incision, adequate exposure can be achieved with any of the commonly used retractors or wound protectors (depending on institutional availability and surgeon preference) or by the surgical assistants using body wall retractors.

We routinely place the patient in lithotomy position. This allows us to monitor for vaginal bleeding (often a site of unrecognized massive hemorrhage) during the surgery, facilitate retrograde bladder filling, and provide a vaginal access to the pelvis. In addition, the lithotomy position allows for cystoscopy and placement of ureteral stents, which can be performed before starting the surgery to help prevent urinary tract injuries or at the end of the procedure in case one is suspected.⁷

Continue to: Performing the hysterectomy...

 

 

Performing the hysterectomy

A complete review of all surgical techniques for managing PAS is beyond the scope of this article. However, we briefly cover important procedural steps and offer suggestions on how to minimize the risk of bleeding.

In our experience. The areas with the highest risk of massive bleeding that can be difficult to control include the pelvic sidewall when there is lateral extension of the PAS, the vesicouterine space, and placenta previa vaginally. Be mindful of these areas at risk and have a plan in place in case of bleeding.

Uterine incision

Avoid the placenta when making the uterine incision, which is typically done in the fundal part of the uterus. Cut and tie the cord and return it to the uterine cavity. Close the incision in a single layer. Use of a surgical stapler can be used for the hysterotomy and can decrease the amount of blood loss.⁸

Superior attachments of the uterus

The superior attachments of the uterus include the round ligament, the utero-ovarian ligament, and the fallopian tubes. With meticulous dissection, develop an avascular space underneath these structures and, in turn, individually divide and suture ligate; this is typically achieved with minimal blood loss.

In addition, isolate the engorged veins of the broad ligament and divide them in a similar fashion.

In our experience. Use of a vessel-sealing device can facilitate division of all the former structures. Simply excise the fallopian tubes with the vessel-sealing device either at this time or after the uterus is removed.

Pelvic sidewall

Once the superior attachments of the uterus have been divided, the next step involves exposing the pelvic sidewall structures, that is, the ureter and the pelvic vessels. Expose the ureter from the pelvic brim to the level of the uterine artery. The hypogastric artery is exposed as well in this process and the pararectal space developed.

When the PAS has extended laterally, perform stepwise division of the lateral attachments of the placenta to the pelvic sidewall using a combination of electrocautery, hemoclips, and the vessel-sealing device. In laterally extended PAS cases, it often is necessary to divide the uterine artery either at its origin or at the level of the ureter to allow for the completion of the separation of the placenta from the pelvic sidewall.

In our experience. During this lateral dissection, significant bleeding may be encountered from the neovascular network that has developed in the pelvic sidewall. The bleeding may be diffuse and difficult to control with the methods described above. In this situation, we have found that placing hemostatic agents in this area and packing the sidewall with laparotomy pads can achieve hemostasis in most cases, thus allowing the surgery to proceed.

Continue to: Bladder dissection...

Bladder dissection

The next critical part of the surgery involves developing the vesicovaginal space to mobilize the bladder. Prior to initiating the bladder dissection, we routinely retrograde fill the bladder with 180 to 240 mL of saline mixed with methylene blue. This delineates the superior edge of the bladder and indicates the appropriate level to start the dissection. Then slowly develop the vesicouterine space using a combination of electrocautery and a vessel-sealing device until the bladder is mobilized to the level of the anterior vaginal wall. Many vascular connections are encountered at that level, and meticulous dissection and patience is required to systematically divide them all.

In our experience. This part of the surgery presents several challenges. The bladder wall may be invaded by the placenta, which will lead to an increased risk of bleeding and cystotomy during the dissection. In these cases, it might be preferable to create an intentional cystotomy to guide the dissection; at times, a limited excision of the involved bladder wall may be required. In other cases, even in the absence of bladder wall invasion, the bladder may be densely adherent to the uterine wall (usually due to a history of prior CDs), and bladder mobilization may be complicated by bleeding from the neovascular network that has developed between the placenta and bladder.

Uterine arteries and cervix

Once the placenta is separated from its lateral attachments and the bladder is mobilized, the next steps are similar to those in a standard abdominal hysterectomy. If the uterine arteries were not yet divided during the pelvic sidewall dissection, they are clamped, divided, and suture ligated at the level of the uterine isthmus. The decision whether to perform a supracervical or total hysterectomy depends on the level of cervical involvement by the placenta, surgeon preference, anatomic distortion, and bleeding from the cervix and anterior vaginal wall.

Responding to massive bleeding

Not uncommonly, and despite the best efforts to avoid it, massive bleeding may develop from the areas at risk as noted above. If the bleeding is significant and originates from multiple areas (including vaginal bleeding from placenta previa), we recommend proceeding with an expeditious hysterectomy to remove the specimen, and then reassess the pelvic field for hemostatic control and any organ damage that may have occurred.

The challenge of PAS

Surgical management of PAS is one the most challenging procedures in pelvic surgery. Successful outcomes require a multidisciplinary team approach and an experienced team dedicated to the management of this condition.⁹ By contrast, proceeding “as usual” in the face of an unexpected PAS situation can lead to disastrous consequences in terms of maternal morbidity and mortality. ●

CASE Concerning finding on repeat CD

A 30-year-old woman with a history of 1 prior cesarean delivery (CD) presents to labor and delivery at 38 weeks of gestation with symptoms of mild cramping. Her prenatal care was uncomplicated. The covering team made a decision to proceed with a repeat CD. A Pfannenstiel incision is made to enter the abdomen, and inspection of the lower uterine segment is concerning for a placenta accreta spectrum (PAS) (FIGURE).

What would be your next steps?

Placenta accreta spectrum describes the range of disorders of placental implantation, including placenta accreta, increta, and percreta. PAS is a significant cause of severe maternal morbidity and mortality, primarily due to massive hemorrhage at the time of delivery. The incidence of PAS continues to rise along with the CD rate. The authors of a recent meta-analysis reported a pooled prevalence rate of 1 in 588 women.¹ Notably, in women with PAS, the rate of hysterectomy is 52.2%, and the transfusion-dependent hemorrhage rate is 46.9%.¹

Ideally, PAS should be diagnosed or at least suspected antenatally during prenatal ultrasonography, leading to delivery planning by a multidisciplinary team.² The presence of a multidisciplinary team—in addition to the primary obstetric and surgical teams—composed of experienced anesthesiologists, a blood bank able to respond to massive transfusion needs, critical care specialists, and interventional radiologists is associated with improved outcomes.^3-5

Occasionally, a patient is found to have an advanced PAS (increta or percreta) at the time of delivery. In these situations, it is paramount that the appropriate resources be assembled as expeditiously as possible to optimize maternal outcomes. Surgical management can be challenging even for experienced pelvic surgeons, and appropriate resuscitation cannot be provided by a single anesthesiologist working alone. A cavalier attitude of proceeding with the delivery “as usual” in the face of an unexpected PAS situation can lead to disastrous consequences, including maternal death.

In this article, we review the important steps to take when faced with the unexpected situation of a PAS at the time of CD.

Continue to: Stop and collect your multidisciplinary team...

Stop and collect your multidisciplinary team

Once the diagnosis of an advanced PAS is suspected, the first step is to stop and request the presence of your institution’s multidisciplinary surgical team. This team typically includes a maternal-fetal specialist or, if not available, an experienced obstetrician, and an expert pelvic surgeon, which varies by institution (gynecologic oncologist, trauma surgeon, urologist, urogynecologist, vascular surgeon). An interventional radiology team is an additional useful resource that can assist with the control of pelvic hemorrhage using embolization techniques.

In our opinion, it is not appropriate to have a surgical backup team available only as needed at a certain distance from the hospital or even in the building. Because of the acuity and magnitude of bleeding that can occur in a short time, the most appropriate approach is to have your surgical team scrubbed and ready to assist or take over the procedure immediately if indicated.

Additional support staff also may be required. A single circulating nurse may not be sufficient, and available nursing staff may need to be called. The surgical technician scrubbed on the case may be familiar only with uncomplicated CDs and can be overwhelmed during a PAS case. Having a more experienced surgical technologist can optimize the availability of the appropriate instruments for the surgical team.

If a multidisciplinary surgical team with PAS management expertise is not available at your institution and the patient is stable, it is appropriate to consider transferring her to the nearest center that can meet the high-risk needs of this situation.⁶

Prepare for resuscitation

While you are calling your multidisciplinary team members, implement plans for resuscitation by notifying the anesthesiologist about the PAS findings. This will allow the gathering of needed resources that may include calling on additional anesthesiologists with experience in high-risk obstetrics, trauma, or critical care.

Placing large-bore intravenous lines or a central line to allow rapid transfusion is essential. Strongly consider inserting an arterial line for hemodynamic monitoring and intraoperative blood draws to monitor blood loss, blood gases, electrolytes, and coagulation parameters, which can guide resuscitative efforts and replacement therapies.

Simultaneously, inform the blood bank to prepare blood and blood products for possible activation of a massive transfusion protocol. It is imperative to have the products available in the operating room (OR) prior to proceeding with the surgery. Our current practice is to have 10 units of packed red blood cells and fresh frozen plasma available in the OR for all our prenatally diagnosed electively planned PAS cases.

Optimize exposure of the surgical field

Appropriate exposure of the surgical field is essential and should include exposure of the uterine fundus and the pelvic sidewalls. The uterine incision should avoid the placenta; typically it is placed at the level of the uterine fundus. Exposure of the pelvic sidewalls is needed to open the retroperitoneum and identify the ureter and the iliac vessels.

Vertical extension of the fascial incision probably will be needed to achieve appropriate exposure. Although at times this can be done without a concomitant vertical skin incision, often an inverted T incision is required. Be mindful that PAS is a life-threatening condition and that aesthetics are not a priority. After extending the fascial incision, adequate exposure can be achieved with any of the commonly used retractors or wound protectors (depending on institutional availability and surgeon preference) or by the surgical assistants using body wall retractors.

We routinely place the patient in lithotomy position. This allows us to monitor for vaginal bleeding (often a site of unrecognized massive hemorrhage) during the surgery, facilitate retrograde bladder filling, and provide a vaginal access to the pelvis. In addition, the lithotomy position allows for cystoscopy and placement of ureteral stents, which can be performed before starting the surgery to help prevent urinary tract injuries or at the end of the procedure in case one is suspected.⁷

Continue to: Performing the hysterectomy...

 

 

Performing the hysterectomy

A complete review of all surgical techniques for managing PAS is beyond the scope of this article. However, we briefly cover important procedural steps and offer suggestions on how to minimize the risk of bleeding.

In our experience. The areas with the highest risk of massive bleeding that can be difficult to control include the pelvic sidewall when there is lateral extension of the PAS, the vesicouterine space, and placenta previa vaginally. Be mindful of these areas at risk and have a plan in place in case of bleeding.

Uterine incision

Avoid the placenta when making the uterine incision, which is typically done in the fundal part of the uterus. Cut and tie the cord and return it to the uterine cavity. Close the incision in a single layer. Use of a surgical stapler can be used for the hysterotomy and can decrease the amount of blood loss.⁸

Superior attachments of the uterus

The superior attachments of the uterus include the round ligament, the utero-ovarian ligament, and the fallopian tubes. With meticulous dissection, develop an avascular space underneath these structures and, in turn, individually divide and suture ligate; this is typically achieved with minimal blood loss.

In addition, isolate the engorged veins of the broad ligament and divide them in a similar fashion.

In our experience. Use of a vessel-sealing device can facilitate division of all the former structures. Simply excise the fallopian tubes with the vessel-sealing device either at this time or after the uterus is removed.

Pelvic sidewall

Once the superior attachments of the uterus have been divided, the next step involves exposing the pelvic sidewall structures, that is, the ureter and the pelvic vessels. Expose the ureter from the pelvic brim to the level of the uterine artery. The hypogastric artery is exposed as well in this process and the pararectal space developed.

When the PAS has extended laterally, perform stepwise division of the lateral attachments of the placenta to the pelvic sidewall using a combination of electrocautery, hemoclips, and the vessel-sealing device. In laterally extended PAS cases, it often is necessary to divide the uterine artery either at its origin or at the level of the ureter to allow for the completion of the separation of the placenta from the pelvic sidewall.

In our experience. During this lateral dissection, significant bleeding may be encountered from the neovascular network that has developed in the pelvic sidewall. The bleeding may be diffuse and difficult to control with the methods described above. In this situation, we have found that placing hemostatic agents in this area and packing the sidewall with laparotomy pads can achieve hemostasis in most cases, thus allowing the surgery to proceed.

Continue to: Bladder dissection...

Bladder dissection

The next critical part of the surgery involves developing the vesicovaginal space to mobilize the bladder. Prior to initiating the bladder dissection, we routinely retrograde fill the bladder with 180 to 240 mL of saline mixed with methylene blue. This delineates the superior edge of the bladder and indicates the appropriate level to start the dissection. Then slowly develop the vesicouterine space using a combination of electrocautery and a vessel-sealing device until the bladder is mobilized to the level of the anterior vaginal wall. Many vascular connections are encountered at that level, and meticulous dissection and patience is required to systematically divide them all.

In our experience. This part of the surgery presents several challenges. The bladder wall may be invaded by the placenta, which will lead to an increased risk of bleeding and cystotomy during the dissection. In these cases, it might be preferable to create an intentional cystotomy to guide the dissection; at times, a limited excision of the involved bladder wall may be required. In other cases, even in the absence of bladder wall invasion, the bladder may be densely adherent to the uterine wall (usually due to a history of prior CDs), and bladder mobilization may be complicated by bleeding from the neovascular network that has developed between the placenta and bladder.

Uterine arteries and cervix

Once the placenta is separated from its lateral attachments and the bladder is mobilized, the next steps are similar to those in a standard abdominal hysterectomy. If the uterine arteries were not yet divided during the pelvic sidewall dissection, they are clamped, divided, and suture ligated at the level of the uterine isthmus. The decision whether to perform a supracervical or total hysterectomy depends on the level of cervical involvement by the placenta, surgeon preference, anatomic distortion, and bleeding from the cervix and anterior vaginal wall.

Responding to massive bleeding

Not uncommonly, and despite the best efforts to avoid it, massive bleeding may develop from the areas at risk as noted above. If the bleeding is significant and originates from multiple areas (including vaginal bleeding from placenta previa), we recommend proceeding with an expeditious hysterectomy to remove the specimen, and then reassess the pelvic field for hemostatic control and any organ damage that may have occurred.

The challenge of PAS

Surgical management of PAS is one the most challenging procedures in pelvic surgery. Successful outcomes require a multidisciplinary team approach and an experienced team dedicated to the management of this condition.⁹ By contrast, proceeding “as usual” in the face of an unexpected PAS situation can lead to disastrous consequences in terms of maternal morbidity and mortality. ●

The coronavirus disease 2019 (COVID-19) pandemic has upended the traditional 2020–2021 application season for ObGyn residency programs. In May 2020, the 2 national ObGyn education organizations, the Association of Professors of Gynecology and Obstetrics (APGO) and Council on Resident Education in ObGyn (CREOG), issued guidelines to ensure a fair and equitable application process.¹ These guidelines are consistent with recommendations from the Association of American Medical Colleges (AAMC) and the Coalition for Physician Accountability. Important recommendations include:

• limiting away rotations
• being flexible in the number of specialty-specific letters of recommendation required
• encouraging residency programs to develop alternate means of conveying information about their curriculum.

In addition, these statements provide timing on when programs should release interview offers and when to begin interviews. Finally, programs are required to commit to online interviews and virtual visits for all applicants, including local students, rather than in-person interviews.

Here, we focus on identifying apps that students can use to help them with the application process—apps for the nuts and bolts of applying and interviewing and apps to learn more about individual programs.

Students must use the Electronic Residency Application Service (ERAS) platform from AAMC to enter their information and register with the National Resident Matching Program (NRMP). Students also must use the ERAS to submit their applications to their selected residency programs. The ERAS platform does not include an app to aid in the completion or submission of an application. The NRMP has developed the MATCH PRISM app, but this does not allow students to register for the match or submit their rank list. To learn about how to schedule interviews, residency programs may use one of the following sources: ERAS, Interview Broker, or Thalamus. Moreover, APGO/CREOG has partnered with Thalamus for the upcoming application cycle, which provides residency programs and applicants tools for application management, interview scheduling, and itinerary building. Thalamus offers a free app.

This year offers some unique challenges. The application process for ObGyn residencies is likely to be more competitive, and students face the added stress of having to navigate the interview season:

• without away rotations (audition interviews)
• without in-person visits of the city/hospital/program or social events before or after interview day
• with an all-virtual interview day.

Continue to: To find information on individual residency programs...

To find information on individual residency programs, the APGO website lists the FREIDA and APGO Residency Directories, which are not apps. Students are also aware of the Doximity Residency Navigator, which does include an app. The NRMP MATCH PRISM app is another resource, as it provides students with a directory of residency programs and information about each program.

The American College of Obstetricians and Gynecologists (ACOG) recognizes that residency program websites and social media will be crucial in helping applicants learn about individual programs, faculty, and residents. As such, ACOG hosted a Virtual Residency Showcase in September 2020 in which programs posted content on Instagram and Twitter using the hashtag #ACOG-ResWeek20.² Similarly, APGO and CREOG produced a report containing a social media directory, which lists individual residency programs and whether or not they have a social media handle/account.³ In a recent webinar,⁴ Drs. Sarah Santiago and Elizabeth Southworth noted that the number of residency programs that have an Instagram account more than doubled (from 60 to 128) between May and September 2020.

The coronavirus disease 2019 (COVID-19) pandemic has upended the traditional 2020–2021 application season for ObGyn residency programs. In May 2020, the 2 national ObGyn education organizations, the Association of Professors of Gynecology and Obstetrics (APGO) and Council on Resident Education in ObGyn (CREOG), issued guidelines to ensure a fair and equitable application process.¹ These guidelines are consistent with recommendations from the Association of American Medical Colleges (AAMC) and the Coalition for Physician Accountability. Important recommendations include:

• limiting away rotations
• being flexible in the number of specialty-specific letters of recommendation required
• encouraging residency programs to develop alternate means of conveying information about their curriculum.

In addition, these statements provide timing on when programs should release interview offers and when to begin interviews. Finally, programs are required to commit to online interviews and virtual visits for all applicants, including local students, rather than in-person interviews.

Here, we focus on identifying apps that students can use to help them with the application process—apps for the nuts and bolts of applying and interviewing and apps to learn more about individual programs.

Students must use the Electronic Residency Application Service (ERAS) platform from AAMC to enter their information and register with the National Resident Matching Program (NRMP). Students also must use the ERAS to submit their applications to their selected residency programs. The ERAS platform does not include an app to aid in the completion or submission of an application. The NRMP has developed the MATCH PRISM app, but this does not allow students to register for the match or submit their rank list. To learn about how to schedule interviews, residency programs may use one of the following sources: ERAS, Interview Broker, or Thalamus. Moreover, APGO/CREOG has partnered with Thalamus for the upcoming application cycle, which provides residency programs and applicants tools for application management, interview scheduling, and itinerary building. Thalamus offers a free app.

This year offers some unique challenges. The application process for ObGyn residencies is likely to be more competitive, and students face the added stress of having to navigate the interview season:

• without away rotations (audition interviews)
• without in-person visits of the city/hospital/program or social events before or after interview day
• with an all-virtual interview day.

Continue to: To find information on individual residency programs...

To find information on individual residency programs, the APGO website lists the FREIDA and APGO Residency Directories, which are not apps. Students are also aware of the Doximity Residency Navigator, which does include an app. The NRMP MATCH PRISM app is another resource, as it provides students with a directory of residency programs and information about each program.

The American College of Obstetricians and Gynecologists (ACOG) recognizes that residency program websites and social media will be crucial in helping applicants learn about individual programs, faculty, and residents. As such, ACOG hosted a Virtual Residency Showcase in September 2020 in which programs posted content on Instagram and Twitter using the hashtag #ACOG-ResWeek20.² Similarly, APGO and CREOG produced a report containing a social media directory, which lists individual residency programs and whether or not they have a social media handle/account.³ In a recent webinar,⁴ Drs. Sarah Santiago and Elizabeth Southworth noted that the number of residency programs that have an Instagram account more than doubled (from 60 to 128) between May and September 2020.

The coronavirus disease 2019 (COVID-19) pandemic has upended the traditional 2020–2021 application season for ObGyn residency programs. In May 2020, the 2 national ObGyn education organizations, the Association of Professors of Gynecology and Obstetrics (APGO) and Council on Resident Education in ObGyn (CREOG), issued guidelines to ensure a fair and equitable application process.¹ These guidelines are consistent with recommendations from the Association of American Medical Colleges (AAMC) and the Coalition for Physician Accountability. Important recommendations include:

• limiting away rotations
• being flexible in the number of specialty-specific letters of recommendation required
• encouraging residency programs to develop alternate means of conveying information about their curriculum.

In addition, these statements provide timing on when programs should release interview offers and when to begin interviews. Finally, programs are required to commit to online interviews and virtual visits for all applicants, including local students, rather than in-person interviews.

Here, we focus on identifying apps that students can use to help them with the application process—apps for the nuts and bolts of applying and interviewing and apps to learn more about individual programs.

Students must use the Electronic Residency Application Service (ERAS) platform from AAMC to enter their information and register with the National Resident Matching Program (NRMP). Students also must use the ERAS to submit their applications to their selected residency programs. The ERAS platform does not include an app to aid in the completion or submission of an application. The NRMP has developed the MATCH PRISM app, but this does not allow students to register for the match or submit their rank list. To learn about how to schedule interviews, residency programs may use one of the following sources: ERAS, Interview Broker, or Thalamus. Moreover, APGO/CREOG has partnered with Thalamus for the upcoming application cycle, which provides residency programs and applicants tools for application management, interview scheduling, and itinerary building. Thalamus offers a free app.

This year offers some unique challenges. The application process for ObGyn residencies is likely to be more competitive, and students face the added stress of having to navigate the interview season:

• without away rotations (audition interviews)
• without in-person visits of the city/hospital/program or social events before or after interview day
• with an all-virtual interview day.

Continue to: To find information on individual residency programs...

To find information on individual residency programs, the APGO website lists the FREIDA and APGO Residency Directories, which are not apps. Students are also aware of the Doximity Residency Navigator, which does include an app. The NRMP MATCH PRISM app is another resource, as it provides students with a directory of residency programs and information about each program.

The American College of Obstetricians and Gynecologists (ACOG) recognizes that residency program websites and social media will be crucial in helping applicants learn about individual programs, faculty, and residents. As such, ACOG hosted a Virtual Residency Showcase in September 2020 in which programs posted content on Instagram and Twitter using the hashtag #ACOG-ResWeek20.² Similarly, APGO and CREOG produced a report containing a social media directory, which lists individual residency programs and whether or not they have a social media handle/account.³ In a recent webinar,⁴ Drs. Sarah Santiago and Elizabeth Southworth noted that the number of residency programs that have an Instagram account more than doubled (from 60 to 128) between May and September 2020.

Biologic therapy for psoriasis may protect against severe COVID-19, according to two large observational studies from Italy and France presented at the virtual annual congress of the European Academy of Dermatology and Venereology.

“Biologics seem to be very protective against severe, poor-prognosis COVID-19, but they do not prevent infection with the virus,” reported Giovanni Damiani, MD, a dermatologist at the University of Milan.

This apparent protective effect of biologic agents against severe and even fatal COVID-19 is all the more impressive because the psoriasis patients included in the Italian study – as is true of those elsewhere throughout the world – had relatively high rates of obesity, smoking, and chronic obstructive pulmonary disease, known risk factors for severe COVID-19, he added.

He presented a case-control study including 1,193 adult psoriasis patients on biologics or apremilast (Otezla) at Milan’s San Donato Hospital during the period from Feb. 21 to April 9, 2020. The control group comprised more than 10 million individuals, the entire adult population of the Lombardy region, of which Milan is the capital. This was the hardest-hit area in all of Italy during the first wave of COVID-19.

Twenty-two of the 1,193 psoriasis patients experienced confirmed COVID-19 during the study period. Seventeen were quarantined at home because their disease was mild. Five were hospitalized. But no psoriasis patients were placed in intensive care, and none died.

Psoriasis patients on biologics were significantly more likely than the general Lombardian population to test positive for COVID-19, with an unadjusted odds ratio of 3.43. They were at 9.05-fold increased risk of home quarantine for mild disease, and at 3.59-fold greater risk than controls for hospitalization for COVID-19. However, they were not at significantly increased risk of ICU admission. And while they actually had a 59% relative risk reduction for death, this didn’t achieve statistical significance.

Forty-five percent of the psoriasis patients were on an interleukin-17 (IL-17) inhibitor, 22% were on a tumor necrosis factor–alpha inhibitor, and 20% were taking an IL-12/23 inhibitor. Of note, none of 77 patients on apremilast developed COVID-19, even though it is widely considered a less potent psoriasis therapy than the injectable monoclonal antibody biologics.

The French experience

Anne-Claire Fougerousse, MD, and her French coinvestigators conducted a study designed to address a different question: Is it safe to start psoriasis patients on biologics or older conventional systemic agents such as methotrexate during the pandemic?

She presented a French national cross-sectional study of 1,418 adult psoriasis patients on a biologic or standard systemic therapy during a snapshot in time near the peak of the first wave of the pandemic in France: the period from April 27 to May 7, 2020. The group included 1,188 psoriasis patients on maintenance therapy and 230 who had initiated systemic treatment within the past 4 months. More than one-third of the patients had at least one risk factor for severe COVID-19.

Although testing wasn’t available to confirm all cases, 54 patients developed probable COVID-19 during the study period. Only five required hospitalization. None died. The two hospitalized psoriasis patients admitted to an ICU had obesity as a risk factor for severe COVID-19, as did another of the five hospitalized patients, reported Dr. Fougerousse, a dermatologist at the Bégin Military Teaching Hospital in Saint-Mandé, France. Hospitalization for COVID-19 was required in 0.43% of the French treatment initiators, not significantly different from the 0.34% rate in patients on maintenance systemic therapy. A study limitation was the lack of a control group.

Nonetheless, the data did answer the investigators’ main question: “This is the first data showing no increased incidence of severe COVID-19 in psoriasis patients receiving systemic therapy in the treatment initiation period compared to those on maintenance therapy. This may now allow physicians to initiate conventional systemic or biologic therapy in patients with severe psoriasis on a case-by-case basis in the context of the persistent COVID-19 pandemic,” Dr. Fougerousse concluded.


 

Proposed mechanism of benefit

The Italian study findings that biologics boost the risk of infection with the SARS-CoV-2 virus in psoriasis patients while potentially protecting them against ICU admission and death are backed by a biologically plausible albeit as yet unproven mechanism of action, Dr. Damiani asserted.

He elaborated: A vast body of high-quality clinical trials data demonstrates that these targeted immunosuppressive agents are associated with modestly increased risk of viral infections, including both skin and respiratory tract infections. So there is no reason to suppose these agents would offer protection against the first phase of COVID-19, involving SARS-CoV-2 infection, nor protect against the second (pulmonary phase), whose hallmarks are dyspnea with or without hypoxia. But progression to the third phase, involving hyperinflammation and hypercoagulation – dubbed the cytokine storm – could be a different matter.

“Of particular interest was that our patients on IL-17 inhibitors displayed a really great outcome. Interleukin-17 has procoagulant and prothrombotic effects, organizes bronchoalveolar remodeling, has a profibrotic effect, induces mitochondrial dysfunction, and encourages dendritic cell migration in peribronchial lymph nodes. Therefore, by antagonizing this interleukin, we may have a better prognosis, although further studies are needed to be certain,” Dr. Damiani commented.
 

Publication of his preliminary findings drew the attention of a group of highly respected thought leaders in psoriasis, including James G. Krueger, MD, head of the laboratory for investigative dermatology and codirector of the center for clinical and investigative science at Rockefeller University, New York.

The Italian report prompted them to analyze data from the phase 4, double-blind, randomized ObePso-S study investigating the effects of the IL-17 inhibitor secukinumab (Cosentyx) on systemic inflammatory markers and gene expression in psoriasis patients. The investigators demonstrated that IL-17–mediated inflammation in psoriasis patients was associated with increased expression of the angiotensin-converting enzyme 2 (ACE2) receptor in lesional skin, and that treatment with secukinumab dropped ACE2 expression to levels seen in nonlesional skin. Given that ACE2 is the chief portal of entry for SARS-CoV-2 and that IL-17 exerts systemic proinflammatory effects, it’s plausible that inhibition of IL-17–mediated inflammation via dampening of ACE2 expression in noncutaneous epithelia “could prove to be advantageous in patients with psoriasis who are at risk for SARS-CoV-2 infection,” according to Dr. Krueger and his coinvestigators in the Journal of Allergy and Clinical Immunology.

Dr. Damiani and Dr. Fougerousse reported having no financial conflicts regarding their studies. The secukinumab/ACE2 receptor study was funded by Novartis.
 

bjancin@mdedge.com

Biologic therapy for psoriasis may protect against severe COVID-19, according to two large observational studies from Italy and France presented at the virtual annual congress of the European Academy of Dermatology and Venereology.

“Biologics seem to be very protective against severe, poor-prognosis COVID-19, but they do not prevent infection with the virus,” reported Giovanni Damiani, MD, a dermatologist at the University of Milan.

This apparent protective effect of biologic agents against severe and even fatal COVID-19 is all the more impressive because the psoriasis patients included in the Italian study – as is true of those elsewhere throughout the world – had relatively high rates of obesity, smoking, and chronic obstructive pulmonary disease, known risk factors for severe COVID-19, he added.

He presented a case-control study including 1,193 adult psoriasis patients on biologics or apremilast (Otezla) at Milan’s San Donato Hospital during the period from Feb. 21 to April 9, 2020. The control group comprised more than 10 million individuals, the entire adult population of the Lombardy region, of which Milan is the capital. This was the hardest-hit area in all of Italy during the first wave of COVID-19.

Twenty-two of the 1,193 psoriasis patients experienced confirmed COVID-19 during the study period. Seventeen were quarantined at home because their disease was mild. Five were hospitalized. But no psoriasis patients were placed in intensive care, and none died.

Psoriasis patients on biologics were significantly more likely than the general Lombardian population to test positive for COVID-19, with an unadjusted odds ratio of 3.43. They were at 9.05-fold increased risk of home quarantine for mild disease, and at 3.59-fold greater risk than controls for hospitalization for COVID-19. However, they were not at significantly increased risk of ICU admission. And while they actually had a 59% relative risk reduction for death, this didn’t achieve statistical significance.

Forty-five percent of the psoriasis patients were on an interleukin-17 (IL-17) inhibitor, 22% were on a tumor necrosis factor–alpha inhibitor, and 20% were taking an IL-12/23 inhibitor. Of note, none of 77 patients on apremilast developed COVID-19, even though it is widely considered a less potent psoriasis therapy than the injectable monoclonal antibody biologics.

The French experience

Anne-Claire Fougerousse, MD, and her French coinvestigators conducted a study designed to address a different question: Is it safe to start psoriasis patients on biologics or older conventional systemic agents such as methotrexate during the pandemic?

She presented a French national cross-sectional study of 1,418 adult psoriasis patients on a biologic or standard systemic therapy during a snapshot in time near the peak of the first wave of the pandemic in France: the period from April 27 to May 7, 2020. The group included 1,188 psoriasis patients on maintenance therapy and 230 who had initiated systemic treatment within the past 4 months. More than one-third of the patients had at least one risk factor for severe COVID-19.

Although testing wasn’t available to confirm all cases, 54 patients developed probable COVID-19 during the study period. Only five required hospitalization. None died. The two hospitalized psoriasis patients admitted to an ICU had obesity as a risk factor for severe COVID-19, as did another of the five hospitalized patients, reported Dr. Fougerousse, a dermatologist at the Bégin Military Teaching Hospital in Saint-Mandé, France. Hospitalization for COVID-19 was required in 0.43% of the French treatment initiators, not significantly different from the 0.34% rate in patients on maintenance systemic therapy. A study limitation was the lack of a control group.

Nonetheless, the data did answer the investigators’ main question: “This is the first data showing no increased incidence of severe COVID-19 in psoriasis patients receiving systemic therapy in the treatment initiation period compared to those on maintenance therapy. This may now allow physicians to initiate conventional systemic or biologic therapy in patients with severe psoriasis on a case-by-case basis in the context of the persistent COVID-19 pandemic,” Dr. Fougerousse concluded.


 

Proposed mechanism of benefit

The Italian study findings that biologics boost the risk of infection with the SARS-CoV-2 virus in psoriasis patients while potentially protecting them against ICU admission and death are backed by a biologically plausible albeit as yet unproven mechanism of action, Dr. Damiani asserted.

He elaborated: A vast body of high-quality clinical trials data demonstrates that these targeted immunosuppressive agents are associated with modestly increased risk of viral infections, including both skin and respiratory tract infections. So there is no reason to suppose these agents would offer protection against the first phase of COVID-19, involving SARS-CoV-2 infection, nor protect against the second (pulmonary phase), whose hallmarks are dyspnea with or without hypoxia. But progression to the third phase, involving hyperinflammation and hypercoagulation – dubbed the cytokine storm – could be a different matter.

“Of particular interest was that our patients on IL-17 inhibitors displayed a really great outcome. Interleukin-17 has procoagulant and prothrombotic effects, organizes bronchoalveolar remodeling, has a profibrotic effect, induces mitochondrial dysfunction, and encourages dendritic cell migration in peribronchial lymph nodes. Therefore, by antagonizing this interleukin, we may have a better prognosis, although further studies are needed to be certain,” Dr. Damiani commented.
 

Publication of his preliminary findings drew the attention of a group of highly respected thought leaders in psoriasis, including James G. Krueger, MD, head of the laboratory for investigative dermatology and codirector of the center for clinical and investigative science at Rockefeller University, New York.

The Italian report prompted them to analyze data from the phase 4, double-blind, randomized ObePso-S study investigating the effects of the IL-17 inhibitor secukinumab (Cosentyx) on systemic inflammatory markers and gene expression in psoriasis patients. The investigators demonstrated that IL-17–mediated inflammation in psoriasis patients was associated with increased expression of the angiotensin-converting enzyme 2 (ACE2) receptor in lesional skin, and that treatment with secukinumab dropped ACE2 expression to levels seen in nonlesional skin. Given that ACE2 is the chief portal of entry for SARS-CoV-2 and that IL-17 exerts systemic proinflammatory effects, it’s plausible that inhibition of IL-17–mediated inflammation via dampening of ACE2 expression in noncutaneous epithelia “could prove to be advantageous in patients with psoriasis who are at risk for SARS-CoV-2 infection,” according to Dr. Krueger and his coinvestigators in the Journal of Allergy and Clinical Immunology.

Dr. Damiani and Dr. Fougerousse reported having no financial conflicts regarding their studies. The secukinumab/ACE2 receptor study was funded by Novartis.
 

bjancin@mdedge.com

Biologic therapy for psoriasis may protect against severe COVID-19, according to two large observational studies from Italy and France presented at the virtual annual congress of the European Academy of Dermatology and Venereology.

“Biologics seem to be very protective against severe, poor-prognosis COVID-19, but they do not prevent infection with the virus,” reported Giovanni Damiani, MD, a dermatologist at the University of Milan.

This apparent protective effect of biologic agents against severe and even fatal COVID-19 is all the more impressive because the psoriasis patients included in the Italian study – as is true of those elsewhere throughout the world – had relatively high rates of obesity, smoking, and chronic obstructive pulmonary disease, known risk factors for severe COVID-19, he added.

He presented a case-control study including 1,193 adult psoriasis patients on biologics or apremilast (Otezla) at Milan’s San Donato Hospital during the period from Feb. 21 to April 9, 2020. The control group comprised more than 10 million individuals, the entire adult population of the Lombardy region, of which Milan is the capital. This was the hardest-hit area in all of Italy during the first wave of COVID-19.

Twenty-two of the 1,193 psoriasis patients experienced confirmed COVID-19 during the study period. Seventeen were quarantined at home because their disease was mild. Five were hospitalized. But no psoriasis patients were placed in intensive care, and none died.

Psoriasis patients on biologics were significantly more likely than the general Lombardian population to test positive for COVID-19, with an unadjusted odds ratio of 3.43. They were at 9.05-fold increased risk of home quarantine for mild disease, and at 3.59-fold greater risk than controls for hospitalization for COVID-19. However, they were not at significantly increased risk of ICU admission. And while they actually had a 59% relative risk reduction for death, this didn’t achieve statistical significance.

Forty-five percent of the psoriasis patients were on an interleukin-17 (IL-17) inhibitor, 22% were on a tumor necrosis factor–alpha inhibitor, and 20% were taking an IL-12/23 inhibitor. Of note, none of 77 patients on apremilast developed COVID-19, even though it is widely considered a less potent psoriasis therapy than the injectable monoclonal antibody biologics.

The French experience

Anne-Claire Fougerousse, MD, and her French coinvestigators conducted a study designed to address a different question: Is it safe to start psoriasis patients on biologics or older conventional systemic agents such as methotrexate during the pandemic?

She presented a French national cross-sectional study of 1,418 adult psoriasis patients on a biologic or standard systemic therapy during a snapshot in time near the peak of the first wave of the pandemic in France: the period from April 27 to May 7, 2020. The group included 1,188 psoriasis patients on maintenance therapy and 230 who had initiated systemic treatment within the past 4 months. More than one-third of the patients had at least one risk factor for severe COVID-19.

Although testing wasn’t available to confirm all cases, 54 patients developed probable COVID-19 during the study period. Only five required hospitalization. None died. The two hospitalized psoriasis patients admitted to an ICU had obesity as a risk factor for severe COVID-19, as did another of the five hospitalized patients, reported Dr. Fougerousse, a dermatologist at the Bégin Military Teaching Hospital in Saint-Mandé, France. Hospitalization for COVID-19 was required in 0.43% of the French treatment initiators, not significantly different from the 0.34% rate in patients on maintenance systemic therapy. A study limitation was the lack of a control group.

Nonetheless, the data did answer the investigators’ main question: “This is the first data showing no increased incidence of severe COVID-19 in psoriasis patients receiving systemic therapy in the treatment initiation period compared to those on maintenance therapy. This may now allow physicians to initiate conventional systemic or biologic therapy in patients with severe psoriasis on a case-by-case basis in the context of the persistent COVID-19 pandemic,” Dr. Fougerousse concluded.


 

Proposed mechanism of benefit

The Italian study findings that biologics boost the risk of infection with the SARS-CoV-2 virus in psoriasis patients while potentially protecting them against ICU admission and death are backed by a biologically plausible albeit as yet unproven mechanism of action, Dr. Damiani asserted.

He elaborated: A vast body of high-quality clinical trials data demonstrates that these targeted immunosuppressive agents are associated with modestly increased risk of viral infections, including both skin and respiratory tract infections. So there is no reason to suppose these agents would offer protection against the first phase of COVID-19, involving SARS-CoV-2 infection, nor protect against the second (pulmonary phase), whose hallmarks are dyspnea with or without hypoxia. But progression to the third phase, involving hyperinflammation and hypercoagulation – dubbed the cytokine storm – could be a different matter.

“Of particular interest was that our patients on IL-17 inhibitors displayed a really great outcome. Interleukin-17 has procoagulant and prothrombotic effects, organizes bronchoalveolar remodeling, has a profibrotic effect, induces mitochondrial dysfunction, and encourages dendritic cell migration in peribronchial lymph nodes. Therefore, by antagonizing this interleukin, we may have a better prognosis, although further studies are needed to be certain,” Dr. Damiani commented.
 

Publication of his preliminary findings drew the attention of a group of highly respected thought leaders in psoriasis, including James G. Krueger, MD, head of the laboratory for investigative dermatology and codirector of the center for clinical and investigative science at Rockefeller University, New York.

The Italian report prompted them to analyze data from the phase 4, double-blind, randomized ObePso-S study investigating the effects of the IL-17 inhibitor secukinumab (Cosentyx) on systemic inflammatory markers and gene expression in psoriasis patients. The investigators demonstrated that IL-17–mediated inflammation in psoriasis patients was associated with increased expression of the angiotensin-converting enzyme 2 (ACE2) receptor in lesional skin, and that treatment with secukinumab dropped ACE2 expression to levels seen in nonlesional skin. Given that ACE2 is the chief portal of entry for SARS-CoV-2 and that IL-17 exerts systemic proinflammatory effects, it’s plausible that inhibition of IL-17–mediated inflammation via dampening of ACE2 expression in noncutaneous epithelia “could prove to be advantageous in patients with psoriasis who are at risk for SARS-CoV-2 infection,” according to Dr. Krueger and his coinvestigators in the Journal of Allergy and Clinical Immunology.

Dr. Damiani and Dr. Fougerousse reported having no financial conflicts regarding their studies. The secukinumab/ACE2 receptor study was funded by Novartis.
 

bjancin@mdedge.com

The Pharmaceutical Research and Manufacturers of America led the health sector in spending on lobbying through the first three quarters of 2020, and health care as a whole spent more than any of the other 12 sectors of the U.S. economy, according to the Center for Responsive Politics.

PhRMA spent $20.7 million on lobbying through the end of September, good enough for third on the overall list of U.S. companies and organizations. Three other members of the health sector made the top 10: the American Hospital Association ($18.3 million), BlueCross/BlueShield ($16.3 million), and the American Medical Association ($15.2 million), the center reported.

Total spending by the health sector was $464 million from Jan. 1 to Sept. 30, topping the finance/insurance/real estate sector at $403 million, and miscellaneous business at $371 million. Miscellaneous business is the home of the U.S. Chamber of Commerce, the annual leader in such spending for the last 20 years, based on data from the Senate Office of Public Records.

The largest share of health sector spending came from pharmaceuticals/health products, with a total of almost $233 million, just slightly more than the sector’s four other constituents combined: hospitals/nursing homes ($80 million), health services/HMOs ($75 million), health professionals ($67 million), and miscellaneous health ($9.5 million), the center said on OpenSecrets.org.

Taking one step down from the sector level, that $233 million made pharmaceuticals/health products the highest spending of about 100 industries in 2020, nearly doubling the efforts of electronics manufacturing and equipment ($118 million), which came a distant second. Hospitals/nursing homes was eighth on the industry list, the center noted.

rfranki@mdedge.com

The Pharmaceutical Research and Manufacturers of America led the health sector in spending on lobbying through the first three quarters of 2020, and health care as a whole spent more than any of the other 12 sectors of the U.S. economy, according to the Center for Responsive Politics.

PhRMA spent $20.7 million on lobbying through the end of September, good enough for third on the overall list of U.S. companies and organizations. Three other members of the health sector made the top 10: the American Hospital Association ($18.3 million), BlueCross/BlueShield ($16.3 million), and the American Medical Association ($15.2 million), the center reported.

Total spending by the health sector was $464 million from Jan. 1 to Sept. 30, topping the finance/insurance/real estate sector at $403 million, and miscellaneous business at $371 million. Miscellaneous business is the home of the U.S. Chamber of Commerce, the annual leader in such spending for the last 20 years, based on data from the Senate Office of Public Records.

The largest share of health sector spending came from pharmaceuticals/health products, with a total of almost $233 million, just slightly more than the sector’s four other constituents combined: hospitals/nursing homes ($80 million), health services/HMOs ($75 million), health professionals ($67 million), and miscellaneous health ($9.5 million), the center said on OpenSecrets.org.

Taking one step down from the sector level, that $233 million made pharmaceuticals/health products the highest spending of about 100 industries in 2020, nearly doubling the efforts of electronics manufacturing and equipment ($118 million), which came a distant second. Hospitals/nursing homes was eighth on the industry list, the center noted.

rfranki@mdedge.com

The Pharmaceutical Research and Manufacturers of America led the health sector in spending on lobbying through the first three quarters of 2020, and health care as a whole spent more than any of the other 12 sectors of the U.S. economy, according to the Center for Responsive Politics.

PhRMA spent $20.7 million on lobbying through the end of September, good enough for third on the overall list of U.S. companies and organizations. Three other members of the health sector made the top 10: the American Hospital Association ($18.3 million), BlueCross/BlueShield ($16.3 million), and the American Medical Association ($15.2 million), the center reported.

Total spending by the health sector was $464 million from Jan. 1 to Sept. 30, topping the finance/insurance/real estate sector at $403 million, and miscellaneous business at $371 million. Miscellaneous business is the home of the U.S. Chamber of Commerce, the annual leader in such spending for the last 20 years, based on data from the Senate Office of Public Records.

The largest share of health sector spending came from pharmaceuticals/health products, with a total of almost $233 million, just slightly more than the sector’s four other constituents combined: hospitals/nursing homes ($80 million), health services/HMOs ($75 million), health professionals ($67 million), and miscellaneous health ($9.5 million), the center said on OpenSecrets.org.

Taking one step down from the sector level, that $233 million made pharmaceuticals/health products the highest spending of about 100 industries in 2020, nearly doubling the efforts of electronics manufacturing and equipment ($118 million), which came a distant second. Hospitals/nursing homes was eighth on the industry list, the center noted.

rfranki@mdedge.com

Encouraging trends abound in the management of ovarian cancer. As rates of ovarian disease continue to decline, there has also been a notable increase in tools for detecting it earlier in its course.

To better understand these developments, this news organization reached out to Rebecca Stone, MD, an ovarian cancer expert and associate professor of gynecologic oncology at Johns Hopkins University, in Baltimore, Maryland. This interview has been edited for length and clarity.

There has been a decline in the rates of ovarian cancer in recent years. What are the possible causes of this?Dr. Stone: The number of new cases in the United States has actually been declining over the past 2 decades. This is thought to be attributable to the increased prescribing of oral contraceptive pills in the late 1990s and the uptake of preventive measures, such as risk-reducing gynecologic surgery for women with genetic predisposition to ovarian cancer, as well as opportunistic salpingectomy in the general population. Opportunistic salpingectomy was introduced about 10 years ago. It is a surgical means for primary prevention of tubo-ovarian cancer by removing both fallopian tubes at the time of elective surgery for women who have completed childbearing or in lieu of “tying the tubes” for women who desire permanent surgical sterility.

What can you tell us about a recent study suggesting that high-grade serous epithelial ovarian cancer may be detected earlier in the course of the disease by testing for TP53 clonal variants in DNA from Papanicolaou (Pap) tests performed during cervical cancer screening?

The idea here is that early mutational events that ultimately result in the development of epithelial ovarian cancer can be detected by performing gene sequencing on genetic material collected at the time of routine Pap smear screening done for cervical cancer. Pap tests are known to contain cells and genetic material shed from the fallopian tubes, where the precancerous lesions thought to give rise to epithelial ovarian cancer, predominantly serous epithelial ovarian cancers, start.

p53 gene mutations are thought to occur early in the evolution of ovarian cancer. There are data indicating that these mutations actually occur in cells lining the fallopian tubes. Polymerase chain reaction–based DNA/gene sequencing performed on cervical fluid collected by Pap smears could detect these p53-mutated cells shed from the fallopian tubes.

A strength of this study is that it included healthy controls. None of their Pap smears screened positive for the p53 mutations, unlike the Pap smears of women predating their diagnosis of ovarian cancer. Limitations of the study include the fact that it had a small sample size. Findings will need to be confirmed in a larger patient population.

Also, the study only looked for p53 gene mutations. Ovarian cancers, like other cancers, are largely thought to occur when there is a buildup of mutations in critical genes that result in uncontrolled cell growth and division. These genetic changes/mutations are acquired during a person’s lifetime. Thus, there are likely early genetic changes/mutations that occur in addition to p53 mutations that ultimately lead to the development of ovarian cancer. Detecting these along with p53 mutations could improve the sensitivity/detection rate of the screening strategy that the authors are investigating.

Finally, this screening strategy may not prove effective for the early detection of all histologic subtypes of epithelial ovarian cancer or for nonepithelial ovarian cancers.

What other recent developments in the diagnosis of ovarian cancer should clinicians be aware of?

Liquid biopsies using circulating tumor DNA (ctDNA) have shown promising results for cancer detection and management, including ovarian cancer. However, further clarification is needed to define the minimum tumor size/burden detectable using ctDNA-based approaches. Moreover, large prospective studies are needed to determine the clinical utility of ctDNA detection for early diagnosis of ovarian cancer and its impact on patient outcomes.

DNA methylation is an early event in carcinogenesis and can be detected in blood plasma samples from cancer patients. Data related to the discovery and validation of discriminated methylated DNA marker candidates extracted from ovarian cancer tissues were presented at the American Society of Clinical Oncology meeting this year. Findings were subsequently evaluated in plasma from women with and without ovarian cancer.

In addition to blood, peritoneal fluid and uterine lavage have been used to obtain cell pellets that are used for the identification of common mutant genes – TP53, BRCA1, and BRCA2. These body fluids have also been shown as the source of tumor-derived material that can be used to differentiate between ovarian cancer patients and healthy individuals.

Further studies are needed to determine the sensitivity and specificity of other noninvasive tests for the diagnosis of ovarian cancer.

The American Cancer Society issued a statement that the human papillomavirus (HPV) test is the preferred cervical cancer screening tool. Why do they prefer the HPV test over the Pap test?

The American Cancer Society recommends that cervical cancer testing (screening) begin at age 25 years. Women aged 25-65 years should have a primary HPV test every 5 years. If primary HPV testing is not available, screening may be done with either a co-test that combines an HPV test with a Pap test every 5 years or a Pap test alone every 3 years.

The HPV test is widely available. The cost of an HPV test is approximately $44 (unit cost, 2014 USD). The cost of a Pap test is approximately $30 (unit cost, 2014 USD).

The HPV test is preferred over cytologic testing (Pap) for several reasons.

Firstly, in well-designed studies, the sensitivity of a single Pap smear for detecting high-grade precancer of the cervix is around 50%, which is less than optimal for a cancer screening test. Sensitivity means the chance that, if you have the disease (in this case, high-grade precancer of the cervix), the test will detect it. In particular, cytology is known to have an even more limited ability to detect glandular precancers, which arise in the endocervical canal rather than on or in close proximity to the exterior surface of the cervix (ectocervix). Thus, HPV-based screening programs hold the promise of improving detection of cervical adenocarcinoma.

Secondly, to function reliably, cytology programs require substantial infrastructure, highly qualified human resources, and a well‐defined quality-control system, which have proved to be costly and difficult to implement. This results in global disparities in cytology-based cervical cancer screening programs.

Thirdly, although co‐testing with both cytology and HPV tests is an option for screening programs, studies have confirmed that there is limited benefit from adding cytology to HPV screening. Long‐term studies from Kaiser Permanente that included over 1 million women found that HPV testing has a very high negative predictive value for precancerous lesions. Women with negative HPV tests were very unlikely to develop precancerous lesions in the following 5 years. The 5‐year risk of high-grade precancer or cancer of the cervix following a negative HPV test was 0.14%, whereas for women with a negative cytology, it was 0.31%. The screening benefit of co‐testing is largely driven by HPV testing and not cytology.

So, in summary, HPV testing is preferred over cytologic screening for cervical cancer, given its improved sensitivity and quality assurance, the opportunity to automate testing, and ultimately, its prospect of reducing the overall number of lifetime screenings for women.


Dr. Stone has disclosed no relevant financial relationships.

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

Encouraging trends abound in the management of ovarian cancer. As rates of ovarian disease continue to decline, there has also been a notable increase in tools for detecting it earlier in its course.

To better understand these developments, this news organization reached out to Rebecca Stone, MD, an ovarian cancer expert and associate professor of gynecologic oncology at Johns Hopkins University, in Baltimore, Maryland. This interview has been edited for length and clarity.

There has been a decline in the rates of ovarian cancer in recent years. What are the possible causes of this?Dr. Stone: The number of new cases in the United States has actually been declining over the past 2 decades. This is thought to be attributable to the increased prescribing of oral contraceptive pills in the late 1990s and the uptake of preventive measures, such as risk-reducing gynecologic surgery for women with genetic predisposition to ovarian cancer, as well as opportunistic salpingectomy in the general population. Opportunistic salpingectomy was introduced about 10 years ago. It is a surgical means for primary prevention of tubo-ovarian cancer by removing both fallopian tubes at the time of elective surgery for women who have completed childbearing or in lieu of “tying the tubes” for women who desire permanent surgical sterility.

What can you tell us about a recent study suggesting that high-grade serous epithelial ovarian cancer may be detected earlier in the course of the disease by testing for TP53 clonal variants in DNA from Papanicolaou (Pap) tests performed during cervical cancer screening?

The idea here is that early mutational events that ultimately result in the development of epithelial ovarian cancer can be detected by performing gene sequencing on genetic material collected at the time of routine Pap smear screening done for cervical cancer. Pap tests are known to contain cells and genetic material shed from the fallopian tubes, where the precancerous lesions thought to give rise to epithelial ovarian cancer, predominantly serous epithelial ovarian cancers, start.

p53 gene mutations are thought to occur early in the evolution of ovarian cancer. There are data indicating that these mutations actually occur in cells lining the fallopian tubes. Polymerase chain reaction–based DNA/gene sequencing performed on cervical fluid collected by Pap smears could detect these p53-mutated cells shed from the fallopian tubes.

A strength of this study is that it included healthy controls. None of their Pap smears screened positive for the p53 mutations, unlike the Pap smears of women predating their diagnosis of ovarian cancer. Limitations of the study include the fact that it had a small sample size. Findings will need to be confirmed in a larger patient population.

Also, the study only looked for p53 gene mutations. Ovarian cancers, like other cancers, are largely thought to occur when there is a buildup of mutations in critical genes that result in uncontrolled cell growth and division. These genetic changes/mutations are acquired during a person’s lifetime. Thus, there are likely early genetic changes/mutations that occur in addition to p53 mutations that ultimately lead to the development of ovarian cancer. Detecting these along with p53 mutations could improve the sensitivity/detection rate of the screening strategy that the authors are investigating.

Finally, this screening strategy may not prove effective for the early detection of all histologic subtypes of epithelial ovarian cancer or for nonepithelial ovarian cancers.

What other recent developments in the diagnosis of ovarian cancer should clinicians be aware of?

Liquid biopsies using circulating tumor DNA (ctDNA) have shown promising results for cancer detection and management, including ovarian cancer. However, further clarification is needed to define the minimum tumor size/burden detectable using ctDNA-based approaches. Moreover, large prospective studies are needed to determine the clinical utility of ctDNA detection for early diagnosis of ovarian cancer and its impact on patient outcomes.

DNA methylation is an early event in carcinogenesis and can be detected in blood plasma samples from cancer patients. Data related to the discovery and validation of discriminated methylated DNA marker candidates extracted from ovarian cancer tissues were presented at the American Society of Clinical Oncology meeting this year. Findings were subsequently evaluated in plasma from women with and without ovarian cancer.

In addition to blood, peritoneal fluid and uterine lavage have been used to obtain cell pellets that are used for the identification of common mutant genes – TP53, BRCA1, and BRCA2. These body fluids have also been shown as the source of tumor-derived material that can be used to differentiate between ovarian cancer patients and healthy individuals.

Further studies are needed to determine the sensitivity and specificity of other noninvasive tests for the diagnosis of ovarian cancer.

The American Cancer Society issued a statement that the human papillomavirus (HPV) test is the preferred cervical cancer screening tool. Why do they prefer the HPV test over the Pap test?

The American Cancer Society recommends that cervical cancer testing (screening) begin at age 25 years. Women aged 25-65 years should have a primary HPV test every 5 years. If primary HPV testing is not available, screening may be done with either a co-test that combines an HPV test with a Pap test every 5 years or a Pap test alone every 3 years.

The HPV test is widely available. The cost of an HPV test is approximately $44 (unit cost, 2014 USD). The cost of a Pap test is approximately $30 (unit cost, 2014 USD).

The HPV test is preferred over cytologic testing (Pap) for several reasons.

Firstly, in well-designed studies, the sensitivity of a single Pap smear for detecting high-grade precancer of the cervix is around 50%, which is less than optimal for a cancer screening test. Sensitivity means the chance that, if you have the disease (in this case, high-grade precancer of the cervix), the test will detect it. In particular, cytology is known to have an even more limited ability to detect glandular precancers, which arise in the endocervical canal rather than on or in close proximity to the exterior surface of the cervix (ectocervix). Thus, HPV-based screening programs hold the promise of improving detection of cervical adenocarcinoma.

Secondly, to function reliably, cytology programs require substantial infrastructure, highly qualified human resources, and a well‐defined quality-control system, which have proved to be costly and difficult to implement. This results in global disparities in cytology-based cervical cancer screening programs.

Thirdly, although co‐testing with both cytology and HPV tests is an option for screening programs, studies have confirmed that there is limited benefit from adding cytology to HPV screening. Long‐term studies from Kaiser Permanente that included over 1 million women found that HPV testing has a very high negative predictive value for precancerous lesions. Women with negative HPV tests were very unlikely to develop precancerous lesions in the following 5 years. The 5‐year risk of high-grade precancer or cancer of the cervix following a negative HPV test was 0.14%, whereas for women with a negative cytology, it was 0.31%. The screening benefit of co‐testing is largely driven by HPV testing and not cytology.

So, in summary, HPV testing is preferred over cytologic screening for cervical cancer, given its improved sensitivity and quality assurance, the opportunity to automate testing, and ultimately, its prospect of reducing the overall number of lifetime screenings for women.


Dr. Stone has disclosed no relevant financial relationships.

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

Encouraging trends abound in the management of ovarian cancer. As rates of ovarian disease continue to decline, there has also been a notable increase in tools for detecting it earlier in its course.

To better understand these developments, this news organization reached out to Rebecca Stone, MD, an ovarian cancer expert and associate professor of gynecologic oncology at Johns Hopkins University, in Baltimore, Maryland. This interview has been edited for length and clarity.

There has been a decline in the rates of ovarian cancer in recent years. What are the possible causes of this?Dr. Stone: The number of new cases in the United States has actually been declining over the past 2 decades. This is thought to be attributable to the increased prescribing of oral contraceptive pills in the late 1990s and the uptake of preventive measures, such as risk-reducing gynecologic surgery for women with genetic predisposition to ovarian cancer, as well as opportunistic salpingectomy in the general population. Opportunistic salpingectomy was introduced about 10 years ago. It is a surgical means for primary prevention of tubo-ovarian cancer by removing both fallopian tubes at the time of elective surgery for women who have completed childbearing or in lieu of “tying the tubes” for women who desire permanent surgical sterility.

What can you tell us about a recent study suggesting that high-grade serous epithelial ovarian cancer may be detected earlier in the course of the disease by testing for TP53 clonal variants in DNA from Papanicolaou (Pap) tests performed during cervical cancer screening?

The idea here is that early mutational events that ultimately result in the development of epithelial ovarian cancer can be detected by performing gene sequencing on genetic material collected at the time of routine Pap smear screening done for cervical cancer. Pap tests are known to contain cells and genetic material shed from the fallopian tubes, where the precancerous lesions thought to give rise to epithelial ovarian cancer, predominantly serous epithelial ovarian cancers, start.

p53 gene mutations are thought to occur early in the evolution of ovarian cancer. There are data indicating that these mutations actually occur in cells lining the fallopian tubes. Polymerase chain reaction–based DNA/gene sequencing performed on cervical fluid collected by Pap smears could detect these p53-mutated cells shed from the fallopian tubes.

A strength of this study is that it included healthy controls. None of their Pap smears screened positive for the p53 mutations, unlike the Pap smears of women predating their diagnosis of ovarian cancer. Limitations of the study include the fact that it had a small sample size. Findings will need to be confirmed in a larger patient population.

Also, the study only looked for p53 gene mutations. Ovarian cancers, like other cancers, are largely thought to occur when there is a buildup of mutations in critical genes that result in uncontrolled cell growth and division. These genetic changes/mutations are acquired during a person’s lifetime. Thus, there are likely early genetic changes/mutations that occur in addition to p53 mutations that ultimately lead to the development of ovarian cancer. Detecting these along with p53 mutations could improve the sensitivity/detection rate of the screening strategy that the authors are investigating.

Finally, this screening strategy may not prove effective for the early detection of all histologic subtypes of epithelial ovarian cancer or for nonepithelial ovarian cancers.

What other recent developments in the diagnosis of ovarian cancer should clinicians be aware of?

Liquid biopsies using circulating tumor DNA (ctDNA) have shown promising results for cancer detection and management, including ovarian cancer. However, further clarification is needed to define the minimum tumor size/burden detectable using ctDNA-based approaches. Moreover, large prospective studies are needed to determine the clinical utility of ctDNA detection for early diagnosis of ovarian cancer and its impact on patient outcomes.

DNA methylation is an early event in carcinogenesis and can be detected in blood plasma samples from cancer patients. Data related to the discovery and validation of discriminated methylated DNA marker candidates extracted from ovarian cancer tissues were presented at the American Society of Clinical Oncology meeting this year. Findings were subsequently evaluated in plasma from women with and without ovarian cancer.

In addition to blood, peritoneal fluid and uterine lavage have been used to obtain cell pellets that are used for the identification of common mutant genes – TP53, BRCA1, and BRCA2. These body fluids have also been shown as the source of tumor-derived material that can be used to differentiate between ovarian cancer patients and healthy individuals.

Further studies are needed to determine the sensitivity and specificity of other noninvasive tests for the diagnosis of ovarian cancer.

The American Cancer Society issued a statement that the human papillomavirus (HPV) test is the preferred cervical cancer screening tool. Why do they prefer the HPV test over the Pap test?

The American Cancer Society recommends that cervical cancer testing (screening) begin at age 25 years. Women aged 25-65 years should have a primary HPV test every 5 years. If primary HPV testing is not available, screening may be done with either a co-test that combines an HPV test with a Pap test every 5 years or a Pap test alone every 3 years.

The HPV test is widely available. The cost of an HPV test is approximately $44 (unit cost, 2014 USD). The cost of a Pap test is approximately $30 (unit cost, 2014 USD).

The HPV test is preferred over cytologic testing (Pap) for several reasons.

Firstly, in well-designed studies, the sensitivity of a single Pap smear for detecting high-grade precancer of the cervix is around 50%, which is less than optimal for a cancer screening test. Sensitivity means the chance that, if you have the disease (in this case, high-grade precancer of the cervix), the test will detect it. In particular, cytology is known to have an even more limited ability to detect glandular precancers, which arise in the endocervical canal rather than on or in close proximity to the exterior surface of the cervix (ectocervix). Thus, HPV-based screening programs hold the promise of improving detection of cervical adenocarcinoma.

Secondly, to function reliably, cytology programs require substantial infrastructure, highly qualified human resources, and a well‐defined quality-control system, which have proved to be costly and difficult to implement. This results in global disparities in cytology-based cervical cancer screening programs.

Thirdly, although co‐testing with both cytology and HPV tests is an option for screening programs, studies have confirmed that there is limited benefit from adding cytology to HPV screening. Long‐term studies from Kaiser Permanente that included over 1 million women found that HPV testing has a very high negative predictive value for precancerous lesions. Women with negative HPV tests were very unlikely to develop precancerous lesions in the following 5 years. The 5‐year risk of high-grade precancer or cancer of the cervix following a negative HPV test was 0.14%, whereas for women with a negative cytology, it was 0.31%. The screening benefit of co‐testing is largely driven by HPV testing and not cytology.

So, in summary, HPV testing is preferred over cytologic screening for cervical cancer, given its improved sensitivity and quality assurance, the opportunity to automate testing, and ultimately, its prospect of reducing the overall number of lifetime screenings for women.


Dr. Stone has disclosed no relevant financial relationships.

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

Within minutes of her arrival at Community North Hospital in Indianapolis, Ramya Yeleti’s vital signs plummeted; her pulse was at 45 beats per minute and her ejection fraction was hovering near 10%. “I definitely thought there was a chance I would close my eyes and never open them again, but I only had a few seconds to process that,” she recalled. Then everything went black. Ramya fell unconscious as shock pads were positioned and a swarm of clinicians prepared to insert an Impella heart pump through a catheter into her aorta.

The third-year medical student and aspiring psychiatrist had been doing in-person neurology rotations in July when she began to experience fever and uncontrolled vomiting. Her initial thought was that she must have caught the flu from a patient.

After all, Ramya, along with her father Ram Yeleti, MD, mother Indira, and twin sister Divya, had all weathered COVID-19 in previous months and later tested positive for SARS-CoV-2 antibodies. The only family member who had been spared was her younger brother Rohith.

Indira suffered a severe case, requiring ICU care for 2 days but no ventilator; the others experienced mostly mild symptoms. Ramya — who was studying for her third-year board exams after classes at Marian University College of Osteopathic Medicine in Indianapolis went virtual in March — was left with lingering fatigue; however, her cough and muscle aches abated and her sense of taste and smell returned. When she started rotations, she thought her life was getting back to normal.

Ramya’s flu symptoms did not improve. A university-mandated rapid COVID test came back negative, but 2 more days of vomiting started to worry both her and her father, who is a cardiologist and chief physician executive at Community Health Network in Indianapolis. After Ramya felt some chest pain, she asked her father to listen to her heart. All sounded normal, and Ram prescribed ondansetron for her nausea.

But the antiemetic didn’t work, and by the next morning both father and daughter were convinced that they needed to head to the emergency department.

“I wanted to double-check if I was missing something about her being dehydrated,” Ram told Medscape Medical News. “Several things can cause protracted nausea, like hepatitis, appendicitis, or another infection. I feel terribly guilty I didn’t realize she had a heart condition.”
 

A surprising turn for the worst

Ramya’s subtle symptoms quickly gave way to the dramatic cardiac crisis that unfolded just after her arrival at Community North. “Her EKG looked absolutely horrendous, like a 75-year-old having a heart attack,” Ram said.

As a cardiologist, he knew his daughter’s situation was growing dire when he heard physicians shouting that the Impella wasn’t working and she needed extracorporeal membrane oxygenation (ECMO).

“At that point, I didn’t think she’d survive,” her father recalled. “We had 10 physicians in the room who worked on her for 5 hours to get her stabilized.”

“It was especially traumatic because, obviously, I knew exactly what was happening,” he added. “You can’t sugarcoat anything.”

After being connected to the heart–lung equipment, Ramya was transferred to IU Health Methodist Hospital, also in Indianapolis, where she was tested again for COVID-19. Unlike the rapid test administered just days earlier, the PCR assay came back positive.

“I knew she had acute myocarditis, but coronavirus never crossed my mind,” said Ram.

“As we were dealing with her heart, we were also dealing with this challenge: she was coming back positive for COVID-19 again,” said Roopa Rao, MD, the heart failure transplant cardiologist at IU Health who treated Ramya.

“We weren’t sure whether we were dealing with an active infection or dead virus” from her previous infection, Rao said, “so we started treating her like she had active COVID-19 and gave her remdesivir, convalescent plasma, and steroids, which was the protocol in our hospital.”

A biopsy of Ramya’s heart tissue, along with blood tests, indicated a past parvovirus infection. It’s possible that Ramya’s previous coronavirus infection made her susceptible to heart damage from a newer parvovirus infection, said Rao. Either virus, or both together, could have been responsible for the calamity.

Although it was unheard of during Ramya’s cardiac crisis in early August, evolving evidence now raises the possibility that she is one of a handful of people in the world to be reinfected with SARS-CoV-2. Also emerging are cases of COVID-related myocarditis and other extreme heart complications, particularly in young people.

“At the time, it wasn’t really clear if people could have another infection so quickly,” Rao told Medscape Medical News. “It is possible she is one of these rare individuals to have COVID-19 twice. I’m hoping at some point we will have some clarity.”

“I would favor a coinfection as probably the triggering factor for her sickness,” she said. “It may take some time, but like any other disease — and it doesn’t look like COVID will go away magically — I hope we’ll have some answers down the road.”
 

Another wrinkle

The next 48 hours brought astonishing news: Ramya’s heart function had rebounded to nearly normal, and her ejection fraction increased to about 45%. Heart transplantation wouldn’t be necessary, although Rao stood poised to follow through if ECMO only sustained, rather than improved, Ramya’s prognosis.

“Ramya was so sick that if she didn’t recover, the only option would be a heart transplant,” said Rao. “But we wanted to do everything to keep that heart.”

After steroid and COVID treatment, Ramya’s heart started to come back. “It didn’t make sense to me,” said Rao. “I don’t know what helped. If we hadn’t done ECMO, her heart probably wouldn’t have recovered, so I would say we have to support these patients and give them time for the heart to recover, even to the point of ECMO.”

Despite the good news, Ramya’s survival still hung in the balance. When she was disconnected from ECMO, clinicians discovered that the Impella device had caused a rare complication, damaging her mitral valve. The valve could be repaired surgically, but both Rao and Ram felt great trepidation at the prospect of cardiopulmonary bypass during the open-heart procedure.

“They would need to stop her heart and restart it, and I was concerned it would not restart,” Ram explained. “I didn’t like the idea of open-heart surgery, but my biggest fear was she was not going to survive it because of a really fresh, sick heart.”

The cardiologists’ fears did, in fact, come to pass: it took an hour to coax Ramya’s heart back at the end of surgery. But, just as the surgeon was preparing to reconnect Ramya to ECMO in desperation, “her heart recovered again,” Rao reported.

“Some things you never forget in life,” she said. “I can’t describe how everyone in the OR felt, all taking care of her. I told Ramya, ‘you are a fighter’.”
 

New strength

Six days would pass before Ramya woke up and learned of the astounding series of events that saved her. She knew “something was really wrong” because of the incision at the center of her chest, but learning she’d been on ECMO and the heart transplant list drove home how close to death she’d actually come.

“Most people don’t get off ECMO; they die on it,” she said. “And the chances of dying on the heart transplant list are very high. It was very strange to me that this was my story all of a sudden, when a week and a half earlier I was on rotation.”

Ongoing physical therapy over the past 3 months has transformed Ramya from a state of profound physical weakness to a place of relative strength. The now-fourth-year med student is turning 26 in November and is hungry to restart in-person rotations. Her downtime has been filled in part with researching myocarditis and collaborating with Rao on her own case study for journal publication.

But the mental trauma from her experience has girded her in ways she knows will make her stronger personally and professionally in the years ahead.

“It’s still very hard. I’m still recovering,” she acknowledged. “I described it to my therapist as an invisible wound on my brain.”

“When I came out of the hospital, I still had ECMO wounds, deep gashes on my legs that affected how fast and how long I could walk,” she said. “I felt like the same thing was going on my brain — a huge cut no one could see.”

Her intention to specialize in psychiatry has become more pressing now that Ramya has realized the impact of trauma on mental health.

“My body failing me was awful, but I could handle it,” she said. “Losing any part of my mind would have been way worse. I want to take care of that in my patients.”

This article first appeared on Medscape.com.

Within minutes of her arrival at Community North Hospital in Indianapolis, Ramya Yeleti’s vital signs plummeted; her pulse was at 45 beats per minute and her ejection fraction was hovering near 10%. “I definitely thought there was a chance I would close my eyes and never open them again, but I only had a few seconds to process that,” she recalled. Then everything went black. Ramya fell unconscious as shock pads were positioned and a swarm of clinicians prepared to insert an Impella heart pump through a catheter into her aorta.

The third-year medical student and aspiring psychiatrist had been doing in-person neurology rotations in July when she began to experience fever and uncontrolled vomiting. Her initial thought was that she must have caught the flu from a patient.

After all, Ramya, along with her father Ram Yeleti, MD, mother Indira, and twin sister Divya, had all weathered COVID-19 in previous months and later tested positive for SARS-CoV-2 antibodies. The only family member who had been spared was her younger brother Rohith.

Indira suffered a severe case, requiring ICU care for 2 days but no ventilator; the others experienced mostly mild symptoms. Ramya — who was studying for her third-year board exams after classes at Marian University College of Osteopathic Medicine in Indianapolis went virtual in March — was left with lingering fatigue; however, her cough and muscle aches abated and her sense of taste and smell returned. When she started rotations, she thought her life was getting back to normal.

Ramya’s flu symptoms did not improve. A university-mandated rapid COVID test came back negative, but 2 more days of vomiting started to worry both her and her father, who is a cardiologist and chief physician executive at Community Health Network in Indianapolis. After Ramya felt some chest pain, she asked her father to listen to her heart. All sounded normal, and Ram prescribed ondansetron for her nausea.

But the antiemetic didn’t work, and by the next morning both father and daughter were convinced that they needed to head to the emergency department.

“I wanted to double-check if I was missing something about her being dehydrated,” Ram told Medscape Medical News. “Several things can cause protracted nausea, like hepatitis, appendicitis, or another infection. I feel terribly guilty I didn’t realize she had a heart condition.”
 

A surprising turn for the worst

Ramya’s subtle symptoms quickly gave way to the dramatic cardiac crisis that unfolded just after her arrival at Community North. “Her EKG looked absolutely horrendous, like a 75-year-old having a heart attack,” Ram said.

As a cardiologist, he knew his daughter’s situation was growing dire when he heard physicians shouting that the Impella wasn’t working and she needed extracorporeal membrane oxygenation (ECMO).

“At that point, I didn’t think she’d survive,” her father recalled. “We had 10 physicians in the room who worked on her for 5 hours to get her stabilized.”

“It was especially traumatic because, obviously, I knew exactly what was happening,” he added. “You can’t sugarcoat anything.”

After being connected to the heart–lung equipment, Ramya was transferred to IU Health Methodist Hospital, also in Indianapolis, where she was tested again for COVID-19. Unlike the rapid test administered just days earlier, the PCR assay came back positive.

“I knew she had acute myocarditis, but coronavirus never crossed my mind,” said Ram.

“As we were dealing with her heart, we were also dealing with this challenge: she was coming back positive for COVID-19 again,” said Roopa Rao, MD, the heart failure transplant cardiologist at IU Health who treated Ramya.

“We weren’t sure whether we were dealing with an active infection or dead virus” from her previous infection, Rao said, “so we started treating her like she had active COVID-19 and gave her remdesivir, convalescent plasma, and steroids, which was the protocol in our hospital.”

A biopsy of Ramya’s heart tissue, along with blood tests, indicated a past parvovirus infection. It’s possible that Ramya’s previous coronavirus infection made her susceptible to heart damage from a newer parvovirus infection, said Rao. Either virus, or both together, could have been responsible for the calamity.

Although it was unheard of during Ramya’s cardiac crisis in early August, evolving evidence now raises the possibility that she is one of a handful of people in the world to be reinfected with SARS-CoV-2. Also emerging are cases of COVID-related myocarditis and other extreme heart complications, particularly in young people.

“At the time, it wasn’t really clear if people could have another infection so quickly,” Rao told Medscape Medical News. “It is possible she is one of these rare individuals to have COVID-19 twice. I’m hoping at some point we will have some clarity.”

“I would favor a coinfection as probably the triggering factor for her sickness,” she said. “It may take some time, but like any other disease — and it doesn’t look like COVID will go away magically — I hope we’ll have some answers down the road.”
 

Another wrinkle

The next 48 hours brought astonishing news: Ramya’s heart function had rebounded to nearly normal, and her ejection fraction increased to about 45%. Heart transplantation wouldn’t be necessary, although Rao stood poised to follow through if ECMO only sustained, rather than improved, Ramya’s prognosis.

“Ramya was so sick that if she didn’t recover, the only option would be a heart transplant,” said Rao. “But we wanted to do everything to keep that heart.”

After steroid and COVID treatment, Ramya’s heart started to come back. “It didn’t make sense to me,” said Rao. “I don’t know what helped. If we hadn’t done ECMO, her heart probably wouldn’t have recovered, so I would say we have to support these patients and give them time for the heart to recover, even to the point of ECMO.”

Despite the good news, Ramya’s survival still hung in the balance. When she was disconnected from ECMO, clinicians discovered that the Impella device had caused a rare complication, damaging her mitral valve. The valve could be repaired surgically, but both Rao and Ram felt great trepidation at the prospect of cardiopulmonary bypass during the open-heart procedure.

“They would need to stop her heart and restart it, and I was concerned it would not restart,” Ram explained. “I didn’t like the idea of open-heart surgery, but my biggest fear was she was not going to survive it because of a really fresh, sick heart.”

The cardiologists’ fears did, in fact, come to pass: it took an hour to coax Ramya’s heart back at the end of surgery. But, just as the surgeon was preparing to reconnect Ramya to ECMO in desperation, “her heart recovered again,” Rao reported.

“Some things you never forget in life,” she said. “I can’t describe how everyone in the OR felt, all taking care of her. I told Ramya, ‘you are a fighter’.”
 

New strength

Six days would pass before Ramya woke up and learned of the astounding series of events that saved her. She knew “something was really wrong” because of the incision at the center of her chest, but learning she’d been on ECMO and the heart transplant list drove home how close to death she’d actually come.

“Most people don’t get off ECMO; they die on it,” she said. “And the chances of dying on the heart transplant list are very high. It was very strange to me that this was my story all of a sudden, when a week and a half earlier I was on rotation.”

Ongoing physical therapy over the past 3 months has transformed Ramya from a state of profound physical weakness to a place of relative strength. The now-fourth-year med student is turning 26 in November and is hungry to restart in-person rotations. Her downtime has been filled in part with researching myocarditis and collaborating with Rao on her own case study for journal publication.

But the mental trauma from her experience has girded her in ways she knows will make her stronger personally and professionally in the years ahead.

“It’s still very hard. I’m still recovering,” she acknowledged. “I described it to my therapist as an invisible wound on my brain.”

“When I came out of the hospital, I still had ECMO wounds, deep gashes on my legs that affected how fast and how long I could walk,” she said. “I felt like the same thing was going on my brain — a huge cut no one could see.”

Her intention to specialize in psychiatry has become more pressing now that Ramya has realized the impact of trauma on mental health.

“My body failing me was awful, but I could handle it,” she said. “Losing any part of my mind would have been way worse. I want to take care of that in my patients.”

This article first appeared on Medscape.com.

Within minutes of her arrival at Community North Hospital in Indianapolis, Ramya Yeleti’s vital signs plummeted; her pulse was at 45 beats per minute and her ejection fraction was hovering near 10%. “I definitely thought there was a chance I would close my eyes and never open them again, but I only had a few seconds to process that,” she recalled. Then everything went black. Ramya fell unconscious as shock pads were positioned and a swarm of clinicians prepared to insert an Impella heart pump through a catheter into her aorta.

The third-year medical student and aspiring psychiatrist had been doing in-person neurology rotations in July when she began to experience fever and uncontrolled vomiting. Her initial thought was that she must have caught the flu from a patient.

After all, Ramya, along with her father Ram Yeleti, MD, mother Indira, and twin sister Divya, had all weathered COVID-19 in previous months and later tested positive for SARS-CoV-2 antibodies. The only family member who had been spared was her younger brother Rohith.

Indira suffered a severe case, requiring ICU care for 2 days but no ventilator; the others experienced mostly mild symptoms. Ramya — who was studying for her third-year board exams after classes at Marian University College of Osteopathic Medicine in Indianapolis went virtual in March — was left with lingering fatigue; however, her cough and muscle aches abated and her sense of taste and smell returned. When she started rotations, she thought her life was getting back to normal.

Ramya’s flu symptoms did not improve. A university-mandated rapid COVID test came back negative, but 2 more days of vomiting started to worry both her and her father, who is a cardiologist and chief physician executive at Community Health Network in Indianapolis. After Ramya felt some chest pain, she asked her father to listen to her heart. All sounded normal, and Ram prescribed ondansetron for her nausea.

But the antiemetic didn’t work, and by the next morning both father and daughter were convinced that they needed to head to the emergency department.

“I wanted to double-check if I was missing something about her being dehydrated,” Ram told Medscape Medical News. “Several things can cause protracted nausea, like hepatitis, appendicitis, or another infection. I feel terribly guilty I didn’t realize she had a heart condition.”
 

A surprising turn for the worst

Ramya’s subtle symptoms quickly gave way to the dramatic cardiac crisis that unfolded just after her arrival at Community North. “Her EKG looked absolutely horrendous, like a 75-year-old having a heart attack,” Ram said.

As a cardiologist, he knew his daughter’s situation was growing dire when he heard physicians shouting that the Impella wasn’t working and she needed extracorporeal membrane oxygenation (ECMO).

“At that point, I didn’t think she’d survive,” her father recalled. “We had 10 physicians in the room who worked on her for 5 hours to get her stabilized.”

“It was especially traumatic because, obviously, I knew exactly what was happening,” he added. “You can’t sugarcoat anything.”

After being connected to the heart–lung equipment, Ramya was transferred to IU Health Methodist Hospital, also in Indianapolis, where she was tested again for COVID-19. Unlike the rapid test administered just days earlier, the PCR assay came back positive.

“I knew she had acute myocarditis, but coronavirus never crossed my mind,” said Ram.

“As we were dealing with her heart, we were also dealing with this challenge: she was coming back positive for COVID-19 again,” said Roopa Rao, MD, the heart failure transplant cardiologist at IU Health who treated Ramya.

“We weren’t sure whether we were dealing with an active infection or dead virus” from her previous infection, Rao said, “so we started treating her like she had active COVID-19 and gave her remdesivir, convalescent plasma, and steroids, which was the protocol in our hospital.”

A biopsy of Ramya’s heart tissue, along with blood tests, indicated a past parvovirus infection. It’s possible that Ramya’s previous coronavirus infection made her susceptible to heart damage from a newer parvovirus infection, said Rao. Either virus, or both together, could have been responsible for the calamity.

Although it was unheard of during Ramya’s cardiac crisis in early August, evolving evidence now raises the possibility that she is one of a handful of people in the world to be reinfected with SARS-CoV-2. Also emerging are cases of COVID-related myocarditis and other extreme heart complications, particularly in young people.

“At the time, it wasn’t really clear if people could have another infection so quickly,” Rao told Medscape Medical News. “It is possible she is one of these rare individuals to have COVID-19 twice. I’m hoping at some point we will have some clarity.”

“I would favor a coinfection as probably the triggering factor for her sickness,” she said. “It may take some time, but like any other disease — and it doesn’t look like COVID will go away magically — I hope we’ll have some answers down the road.”
 

Another wrinkle

The next 48 hours brought astonishing news: Ramya’s heart function had rebounded to nearly normal, and her ejection fraction increased to about 45%. Heart transplantation wouldn’t be necessary, although Rao stood poised to follow through if ECMO only sustained, rather than improved, Ramya’s prognosis.

“Ramya was so sick that if she didn’t recover, the only option would be a heart transplant,” said Rao. “But we wanted to do everything to keep that heart.”

After steroid and COVID treatment, Ramya’s heart started to come back. “It didn’t make sense to me,” said Rao. “I don’t know what helped. If we hadn’t done ECMO, her heart probably wouldn’t have recovered, so I would say we have to support these patients and give them time for the heart to recover, even to the point of ECMO.”

Despite the good news, Ramya’s survival still hung in the balance. When she was disconnected from ECMO, clinicians discovered that the Impella device had caused a rare complication, damaging her mitral valve. The valve could be repaired surgically, but both Rao and Ram felt great trepidation at the prospect of cardiopulmonary bypass during the open-heart procedure.

“They would need to stop her heart and restart it, and I was concerned it would not restart,” Ram explained. “I didn’t like the idea of open-heart surgery, but my biggest fear was she was not going to survive it because of a really fresh, sick heart.”

The cardiologists’ fears did, in fact, come to pass: it took an hour to coax Ramya’s heart back at the end of surgery. But, just as the surgeon was preparing to reconnect Ramya to ECMO in desperation, “her heart recovered again,” Rao reported.

“Some things you never forget in life,” she said. “I can’t describe how everyone in the OR felt, all taking care of her. I told Ramya, ‘you are a fighter’.”
 

New strength

Six days would pass before Ramya woke up and learned of the astounding series of events that saved her. She knew “something was really wrong” because of the incision at the center of her chest, but learning she’d been on ECMO and the heart transplant list drove home how close to death she’d actually come.

“Most people don’t get off ECMO; they die on it,” she said. “And the chances of dying on the heart transplant list are very high. It was very strange to me that this was my story all of a sudden, when a week and a half earlier I was on rotation.”

Ongoing physical therapy over the past 3 months has transformed Ramya from a state of profound physical weakness to a place of relative strength. The now-fourth-year med student is turning 26 in November and is hungry to restart in-person rotations. Her downtime has been filled in part with researching myocarditis and collaborating with Rao on her own case study for journal publication.

But the mental trauma from her experience has girded her in ways she knows will make her stronger personally and professionally in the years ahead.

“It’s still very hard. I’m still recovering,” she acknowledged. “I described it to my therapist as an invisible wound on my brain.”

“When I came out of the hospital, I still had ECMO wounds, deep gashes on my legs that affected how fast and how long I could walk,” she said. “I felt like the same thing was going on my brain — a huge cut no one could see.”

Her intention to specialize in psychiatry has become more pressing now that Ramya has realized the impact of trauma on mental health.

“My body failing me was awful, but I could handle it,” she said. “Losing any part of my mind would have been way worse. I want to take care of that in my patients.”

This article first appeared on Medscape.com.