Peer-reviewed
Diagnosis and treatment of “the great imitator” that has resurged.
Syphilis, known as the “the great imitator,” is a clinical disease with myriad manifestations and stages. Clinical illness results from infection with the spirochete Treponema pallidum, which enters at sites of sexual contact and by transmission across the placenta during pregnancy.
Maternal syphilis is associated with a 21% increased risk for stillbirth, 6% increased risk for preterm delivery, and 9% increased risk for neonatal death.1 Between 2014 and 2018, primary and secondary syphilis in women increased by 172% (to 3 cases per 100,000 females) in the United States.2
Congenital syphilis rates have paralleled this rise, increasing by 185% (to 33.1 cases per 100,000 live births) in the same years. Experts believe that recent upward trends are multifactorial,3-5 and the coronavirus disease 2019 pandemic certainly has disrupted ongoing efforts at reversing these trends, with closure of sexual health clinics and redirected public health efforts from a focus on sexually transmitted diseases to mitigating the COVID-19 crisis.6
As the pandemic rages on, we have yet to see how long-term effects of this generation-defining crisis will later manifest as “second waves” of other, neglected diseases such as syphilis. To prepare clinicians for what lies ahead, we review the diagnosis and management of syphilis in pregnancy.
All pregnant women should be screened for syphilis at the first prenatal visit or at first presentation to care.7-9 Screening and treatment early in pregnancy is associated with decreased incidence of congenital syphilis, preterm birth, low birth weight, stillbirth, and neonatal death.10,11
Repeat screening in the early third trimester, between 28 and 32 weeks of gestation, and again at delivery is recommended in women at high risk for syphilis or who live in areas with high syphilis prevalence.7,8 State laws differ with regard to required timing and frequency of testing, and clinicians should familiarize themselves with current state prenatal screening and reporting requirements. In some states, providers who fail to abide by syphilis screening laws may be subject to civil or criminal liabilities.12,13 Testing for maternal syphilis is recommended as part of the evaluation for stillbirth.14 HIV and other STI screening should be offered when syphilis is diagnosed.
Although some syphilis infections may come to the attention of providers after a patient reports symptoms or lesions, the most common pathway is for clinicians to make a laboratory diagnosis first, which must be followed by patient counseling along with a thorough history and physical (including pelvic) examination to complete a clinical staging evaluation.
Following all three of these elements (laboratory studies, thorough sexual history, and physical with pelvic examination), the clinical stage of syphilis is determined, any necessary fetal evaluation completed, and a treatment regimen may be prescribed.
Confusion commonly arises when abnormal laboratory evaluation is detected at an initial visit prior to complete history and physical examination – just because the patient’s laboratory values are abnormal for the first time does not mean that the patient has a diagnosis of primary syphilis.
Not all patients experience all symptomatic stages of syphilis, and unless physical signs of primary or secondary syphilis are clearly documented and supported by clinical history and laboratory studies, the assumption of recent infection should not be made.
Primary syphilis, which occurs around 3 weeks after initial infection by the spirochete through any site of sexual contact, is characterized by a painless chancre (Table).
Table: Clinical staging of primary, secondary, and latent syphilis
Because the site of the chancre may be located on the cervix or vagina, lesions may be missed without a thorough pelvic examination. Women with immunosuppression may experience multiple chancres or chancres that persist after secondary lesions appear.15 The chancre resolves within 4 to 6 weeks even without treatment (sooner if treated), although inadequate immune-mediated clearance results in systemic dissemination of organisms and later secondary manifestations of disease around 6 to 8 weeks later.
Classic symptoms of secondary syphilis are diffuse maculopapular skin rash (in up to 90%), generalized lymphadenopathy, and highly-contagious mucosal lesions including oral mucous patches16 and genital condyloma lata. Some women may describe systemic symptoms such as malaise, arthralgias, and fevers. Manifestations of secondary syphilis resolve after approximately 1 to 6 months regardless of treatment and typically resolve within a few weeks after adequate syphilotherapy.
Latent syphilis is characterized by positive diagnostic testing in a patient without objective findings. Clinically, latent syphilis is divided into early and late (or unknown duration) latent stages, depending on the timing of initial infection based on a detailed history of exposure and reported symptoms.
In 2018, the Centers for Disease Control and Prevention (CDC) began using the surveillance term “syphilis, early non-primary non-secondary” rather than “early latent syphilis” to clarify that some clinical manifestations such as neurosyphilis may occur during any stage.17 From a clinical perspective, however, either name represents asymptomatic infection, which is clearly documented based on laboratory seroconversion to have occurred within the previous 12 months.
In a woman with early latent syphilis, secondary lesions may recur in 25% of patients. In late latent syphilis, now known as “unknown duration or late syphilis” from a surveillance perspective, infection duration is either unknown or greater than one year. Late latent syphilis is relatively less contagious to sexual partners but still transmissible to the fetus in pregnancy, with an approximate 10% risk of fetal infection.18
Tertiary syphilis, which occurs in up to 40% of individuals with untreated syphilis, refers to benign gummas and cardiovascular syphilis, but not to neurosyphilis. It is rare in a reproductive-aged population.
Neurosyphilis is clinically described as early or late neurosyphilis, as manifestations may occur at any time during the course of infection. Early neurologic involvement may include meningitis, uveitis or retinitis, or stroke-like symptoms, and occurs in approximately 1% of patients with secondary syphilis.19 Late neurosyphilis occurs a decade or more after initial diagnosis, and may occur along with other manifestations of tertiary syphilis.
Congenital syphilis may result from maternal syphilis infection prior to or during pregnancy, or when maternal syphilis is diagnosed at delivery.
Diagnosis of congenital syphilis following delivery is challenging, and involves assessment of maternal history and laboratory studies, complete physical, laboratory and radiologic evaluation of a neonate, and may include pathologic evaluation of the placenta.
Risk of congenital infection is related to the stage of maternal infection, and occurs in approximately 50-80% of women with untreated primary, secondary, or early latent syphilis, and up to 10% of women with late latent syphilis. Syphilitic stillbirths also are included as cases of congenital syphilis for national reporting purposes.2
Neonatal manifestations of congenital syphilis are divided into two characteristic syndromes. Early congenital syphilis is diagnosed in the first two years of life, and may involve clinical symptoms similar to those in adult secondary syphilis.
Classically, hepatosplenomegaly, desquamating skin rash, rhinitis (“snuffles”), anemia, thrombocytopenia, and osteochondritis may be observed.20 Late congenital syphilis manifests after two years of life, and may be characterized by notched teeth (Hutchinson’s teeth), deafness, and interstitial keratitis of the eye; together, these are known as Hutchinson’s Triad. Central nervous system involvement with developmental delay, hydrocephalus, seizures, and nerve palsies, as well as bone deformities, may occur.
At delivery, the placenta itself may have gross and histopathologic characteristics of T pallidum infection. On gross examination, the placenta appears large, pale, and hydropic.
On microscopic examination, terminal villi appear enlarged and densely cellular, with evidence of chronic villitis.21 Umbilical cord sections demonstrate necrotizing funisitis, characterized by perivascular rings of necrotic debris surrounding the large vessels.
These findings are not specific to syphilis infection, however. In some laboratories, T pallidum may be directly detected by immunohistochemistry in either placenta or umbilical cord specimens in a woman with untreated or inadequately treated syphilis. This evaluation should be encouraged when feasible, as the direct detection of T pallidum facilitates accurate reporting and optimal maternal and neonatal care.
T pallidum is difficult to visualize or directly detect with common methods available in most laboratories (such as culture or polymerase chain reaction [PCR]). Clinicians usually rely on serologic testing, which allows only indirect diagnosis of infection, and must be combined with complete history and physical (with pelvic) examination.
Two algorithms are used, and require slightly different interpretation (Figure).
Figure: Traditional and reverse sequence syphilis screening algorithms
In a traditional screening algorithm, presumptive serologic diagnosis of syphilis requires two tests: an initial nontreponemal test followed by a confirmatory treponemal-specific test.8 The rapid plasma reagin is the most commonly used nontreponemal antibody in the United States. This test measures antibody to cardiolipin, which is thought to be contained within T pallidum, as well as in the damaged host cell membrane.22 A confirmatory test is required because false-positive nontreponemal tests occur, and the false-positive rate for a rapid plasma reagin is about 1% in pregnant women.23 When reactive, the nontreponemal test is quantified as a titer, which typically correlates with disease activity and is used to follow treatment response.
The reverse sequence algorithm begins with a treponemal antibody test, typically an automated enzyme or chemiluminescent immunoassays (EIA or CIA).
The advantage to this test is in the laboratory through-put: for high volume laboratories, the ability to perform automated testing has proposed cost advantages.24 The sensitivity of available treponemal immunoassays ranges between 97% and 100%, depending on clinical stage and the specific assay used.25,26
However, false-positive rates are as high as 40 to 80%, and thus reflex testing is still required.27 When reactive, a treponemal immunoassay is reflexed to a nontreponemal test, which then (if reactive) must be interpreted as presumptive active syphilis or (if nonreactive) reflexed to a second treponemal test (typically Treponema pallidum particle agglutination test, or TP-PA).
With either algorithm, a detailed clinical history and physical exam are needed to establish risk factors for syphilis, confirm previous treatment regimens, and document any physical evidence of early-stage infection. If no previous treatment can be confirmed in an asymptomatic patient with laboratory evidence of syphilis, initiation of a full course of treatment for latent syphilis is recommended following consultation with a specialist and fetal evaluation, if indicated.
Congenital infection is presumed in all cases of maternal syphilis infection during pregnancy. When present, sonographic findings consistent with congenital infection represent severely infected fetuses.
Ultrasound findings of congenital infection typically are not manifest until after approximately 18 to 20 weeks of gestation due to relative immaturity of the fetal immune response. Findings may include placentomegaly (thickness exceeding 4cm), hepatomegaly, polyhydramnios, ascites, and non-immune hydrops.28
Detailed sonography is indicated with performance of middle cerebral artery Doppler studies to evaluate for fetal anemia when maternal syphilis is diagnosed.29 When ultrasound findings of congenital syphilis are identified after fetal viability, initial treatment in an inpatient setting with monitoring of the mother and fetus are recommended to detect possible fetal distress or preterm labor.
Optimal treatment of syphilis during pregnancy is estimated to reduce the risk of congenital syphilis by 97%, stillbirth by 82%, preterm birth by 64%, and neonatal mortality by 80%.30
Long-acting parenteral penicillin G is the only currently recommended treatment for syphilis in pregnancy.28,31 For early-stage syphilis, including primary, secondary, and early latent (early non-primary non-secondary), a single intramuscular dose of 2.4 million units of benzathine penicillin G is necessary.
Some experts recommend two weekly doses of 2.4 million units of benzathine penicillin G for women diagnosed with early clinical stage infection, because congenital syphilis may still occur despite treatment with a single dose, particularly with high nontreponemal titers common to early maternal stage syphilis.31 Our practice is to routinely administer two doses of 2.4 million units intramuscular benzathine penicillin G over 2 consecutive weeks to all women with early-stage syphilis, with an interval of no more than 10 days between injections.
Have you been witnessing a rise in syphilis cases among your patients? How do you think increasing telehealth appointments could benefit your patients? Let us know what you think by sending an email to COGeditorial@mmhgroup.com or via Twitter @ContempOBGYN.
Treatment with three weekly doses of 2.4 million units intramuscular benzathine penicillin G is necessary for late latent (unknown duration or late syphilis) in pregnancy. Currently the CDC acknowledges that an interval of 7-9 days between doses may be optimal based on pharmacokinetic studies, but clinical experience suggests that an interval of 10-14 days between doses may be acceptable.8 A conservative practice is to allow an interval of up to 10 days between intramuscular injections for treatment of late latent syphilis in pregnancy. If a patient misses a scheduled dose, the treatment course is restarted.
For pregnant women reporting a penicillin allergy, a thorough clinical history should be taken to determine whether the reported reaction is moderate to high risk for anaphylaxis or other life-threatening drug reaction.32 In women with a clinical history consistent with a moderate to high-risk allergic reaction, formal evaluation for possible penicillin allergy testing in a setting with clinicians trained in recognition and treatment of hypersensitivity reactions is recommended.
For women with verified IgE-mediated hypersensitivity reactions, penicillin desensitization is indicated.33 Fortunately, this is rarely necessary. Importantly, in women with IgE-mediated allergy who undergo desensitization and treatment with penicillin and are later reinfected, repeat allergy testing and desensitization is necessary because IgE antibodies may reform.
Symptoms of primary or secondary syphilis should resolve within a few weeks after treatment is initiated. In the first 24 hours following initial treatment, some women may experience a Jarisch-Herxheimer reaction, an acute febrile reaction characterized by myalgia, fever, headache, and potentially preterm labor and fetal heart rate tracing abnormalities in pregnant women.
Before treatment, women should be counseled about the potential for these symptoms, as well as on appropriate management with antipyretics. Because fetal heart rate tracing abnormalities may occur in a severely affected fetus, initial treatment at a center with the capability for emergent delivery and neonatal stabilization is recommended for women with ultrasound evidence of congenital infection in a potentially viable fetus. Subsequent doses are administered in the outpatient setting as appropriate for the clinical stage of infection.
In general, a nontreponemal titer may be repeated if maternal re-exposure to an untreated partner is suspected, although the decision to retreat is a clinical one. There is little evidence supporting the benefit of repeating monthly nontreponemal titers following adequate therapy.
In all women, we inquire about partner treatment and potential for re-exposure at each prenatal visit after maternal diagnosis, and repeat a rapid plasma reagin test at 28-32 weeks or sooner if the clinical history suggests re-exposure or reinfection. If clinical symptoms persist or recur, or when nontreponemal titer increases by fourfold (2-dilution) or greater for more than 2 weeks, reinfection should be considered and retreatment initiated.8
Some patients may have a persistent low nontreponemal titer known as “serofast” despite complete treatment (typically <1:8).
A serofast rapid plasma reagin is more common with lower initial rapid plasma reagin titers and latent syphilis at the time of diagnosis.34,35 When past treatment has been confirmed and there is no suspicion of re-exposure in a patient with serofast rapid plasma reagin or venereal disease research laboratory test, no additional treatment is indicated.
A final nontreponemal titer is repeated at the time of delivery for all women diagnosed with syphilis during pregnancy, and for all women in some states.
This confirms maternal treatment response (or lack thereof) and allows for a direct comparison of the neonatal nontreponemal titer, which may reflect maternal antibody levels or neonatal response to congenital infection.
Despite near elimination of syphilis in the United States only two decades ago, maternal and congenital syphilis have made an unwelcome return, even as we face new challenges with the COVID-19 pandemic.
Ob/gyns should be well-informed about current guidelines for syphilis screening and management in pregnancy. Ultimately, virtual collaboration among physicians, scientists, public health facilities, and political leaders will be needed to increase public and physician awareness, facilitate access to early prenatal care in underserved communities, and reverse the current epidemic.
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References
S4E1: New RNA platform can predict pregnancy complications
February 11th 2022In this episode of Pap Talk, Contemporary OB/GYN® sat down with Maneesh Jain, CEO of Mirvie, and Michal Elovitz, MD, chief medical advisor at Mirvie, a new RNA platform that is able to predict pregnancy complications by revealing the biology of each pregnancy. They discussed recently published data regarding the platform's ability to predict preeclampsia and preterm birth.
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