By Ahizechukwu C. Eke, MD, PhD, MPH
Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
SYNOPSIS: Although syphilis screening during pregnancy is effective in identifying maternal syphilis, it is not without consequences. False-positive syphilis testing can result in unwarranted antibiotic therapy; re-screening based on risk is not always consistent, and among pregnant women who truly test positive to syphilis, treatment is not always optimized to prevent congenital syphilis.
SOURCE: O’Connor NP, Burke PC, Worley S, et al. Outcomes after positive syphilis screening. Pediatrics 2022;150:e2022056457.
In the United States, syphilis has seen a dramatic rebound, especially among women of reproductive age, where both primary and secondary syphilis rates more than tripled between 2011 and 2018. Congenital syphilis also has surged in the United States, from 8.4 to 33.1 cases per 100,000 live births between 2012 and 2018.1,2 Although syphilis is a sexually transmitted infection, certain behavioral patterns, including having multiple sexual partners, engaging in sexual activity while under the influence of illicit drugs, incarceration, and concurrent gonorrheal infection, increase the likelihood of syphilis infection during pregnancy.3,4
Screening and treatment for syphilis early in pregnancy has been associated with reduced rates of congenital syphilis, fetal hydrops, preterm birth, low birth weight, stillbirth, and neonatal demise.5,6 The effectiveness of syphilis screening has led to recommendations by the U.S. Preventive Services Task Force (USPSTF), the American College of Obstetricians and Gynecologists (ACOG), and the American Academy of Pediatrics (AAP) to begin screening for syphilis during the first prenatal visit (typically in the first trimester), and continue through the third trimester and the time of delivery in high-risk populations.4,7 Women diagnosed with syphilis are treated and their fetuses are followed for ultrasound stigmata of congenital syphilis syndrome. After delivery, the infants are evaluated for clinical or laboratory features of syphilis. Traditional and reverse algorithms for syphilis testing during pregnancy are performed with two different serial tests (a screening and a diagnostic test) because screening using a single test has been shown to be inadequate for detecting syphilis. Furthermore, additional testing always is needed to differentiate between true positive (TP) and false-positive (FP) results, with FP results being more common than TP results.8 Therefore, in this study, O’Connor and colleagues aimed to estimate the prevalence of TP, FP testing, and failure to complete the required maternal and neonatal evaluation following a positive syphilis screen in a sizable population.8
This was a population-based retrospective cohort study in the Cleveland Clinic’s Health System, located in northeastern Ohio, between June 1, 2014, and Feb. 28, 2021. All pregnant patients who were diagnosed and treated for syphilis during pregnancy met inclusion criteria. Pregnant participants were excluded from the study if no confirmatory testing for syphilis was available, or if the initial screen could not be adjudicated. Diagnosis of syphilis was accomplished by both traditional and reverse testing. The initial positive serum syphilis screen during pregnancy was classified as FP or TP based on laboratory-based criteria. A rapid plasma reagin (RPR) positive screen was validated with a fluorescent treponemal antibody absorption (FTA) test using the traditional approach, while for reverse screening, a positive or equivocal syphilis immunoglobulin (Ig) G or syphilis IgM and IgG was confirmed by an RPR, or, if the RPR was negative, by a positive Treponema pallidum antibody (TPA) test. If the RPR was positive but neither the FTA nor the TPA confirmed the result, the screen was considered FP under the traditional testing approach. Conversely, if a positive syphilis IgG or syphilis IgM and IgG assay was followed by a negative RPR and a negative TPA, the screen was considered FP.
Women with TP were categorized as having a “past diagnosis” if they had been diagnosed and treated for syphilis before the index pregnancy or a “new diagnosis” if syphilis was newly detected by screening. Women who had been treated for syphilis before becoming pregnant were considered to have a new diagnosis if their initial screening revealed signs of reinfection. Pregnant women were considered to have received adequate therapy for syphilis if they received stage-appropriate therapy at least four weeks before delivery. According to the Centers for Disease Control and Prevention (CDC) risk classification criteria, infants delivered to TP mothers were classified into one of four categories: confirmed or highly likely congenital syphilis; possible congenital syphilis; a lower likelihood of congenital syphilis; and no evidence of congenital syphilis. Statistical analysis was done using standard statistical tests.
Out of 75,056 pregnant women screened, 221 (183 FP and 38 TP) had a positive syphilis screen. The baseline characteristics were similar for women treated for syphilis before pregnancy and those with a new diagnosis. Infants born to TP mothers with past and new syphilis diagnoses had similar gestational ages and birth weights. The FP and TP rates were 243.8 cases per 100,000 births and 50.6 cases per 100,000 births, respectively. Seventeen (45%) of the TP women were newly diagnosed, while 21 (55%) had a past diagnosis (28.0 cases per 100,000). The false discovery rate was 0.83 (95% confidence interval [CI], 0.78-0.88). False discovery rates were similar for traditional (0.83; 95% CI, 0.72, 0.94) and reverse syphilis testing (0.83; 95% CI, 0.77, 0.88). FP syphilis screening led to antibiotic therapy in two women and one infant. One infant was diagnosed with congenital syphilis at birth. Fourteen TP results were obtained in women who were newly diagnosed with syphilis before the end of the third trimester of pregnancy. Half of these mothers did not have their infants classified as having optimal syphilis treatment because of concerns about reinfection, treatment failure, inadequate treatment or follow-up care, or late therapy.
COMMENTARY
Screening for syphilis and treatment of a positive syphilis test has its benefits (treatment of maternal syphilitic infection with improved health outcomes; prevention of maternal sequelae of syphilis infection, including progression to tertiary syphilis; and prevention of congenital syphilis).9 However, screening pregnant participants for syphilis also has its potential harms, including anxiety following a positive screening test (before confirmatory results are available), cost of additional testing, and mislabeling of test results.10 Several studies have reported that FP screening can occur when pregnant women are screened for syphilis.11,12 Some acute or chronic infections (such as tuberculosis, hepatitis, malaria, and early human immunodeficiency virus infection), autoimmune illnesses (systemic lupus or rheumatoid arthritis), injection drug use, and prior vaccinations (such as smallpox or measles, mumps, and rubella) might cause an FP result in pregnancy, making it critical to confirm an FP result with confirmatory testing prior to therapy.
After the diagnosis of maternal syphilis by clinical history and physical examination, followed by laboratory testing using direct (immunohistochemistry, dark field microscopy, polymerase chain reaction, fluorescent antibody testing for Treponema pallidum) or indirect/serologic traditional or reverse testing methods (TPA, FTA, micro-hemagglutination assays), treatment with penicillin usually is first-line in pregnancy.4 At present, long-acting parenteral penicillin G (benzathine penicillin) remains the only recommended therapy for the treatment of syphilis during pregnancy. Late latent syphilis (i.e., undetermined duration or late syphilis) in pregnancy is treated with three weekly doses of 2.4 million units of intramuscular benzathine penicillin G.
Congenital syphilis can be difficult to diagnose using both direct and indirect laboratory testing because of the poor sensitivity of these tests in amniotic fluid. As such, if a pregnant mother is diagnosed with syphilis, congenital syphilis is presumed until ruled out.4 This requires a high index of suspicion even with the use of ultrasound features suggestive of congenital syphilis, such as polyhydramnios, bowel abnormalities, placentomegaly, ascites, hepatomegaly, and fetal hydrops.13 These ultrasound features usually are not seen until after the 20th week of gestation.4 Benzathine penicillin G 2.4 million units administered intramuscularly has a 98% success rate in preventing congenital infection. However, pregnant women who develop early stage syphilis, deliver shortly (within 30 days) after starting treatment, and who have one or more ultrasound features of congenital syphilis are more likely to have neonates with congenital syphilis despite maternal treatment.4
In summary, syphilitic infection during pregnancy remains a significant public health problem. While treatment with benzathine penicillin G remains the cornerstone of therapy during pregnancy, congenital syphilis can be difficult to diagnose and treat. ACOG recommends screening all pregnant women at their initial prenatal visit, and rescreening women at high risk of contracting syphilis at the time of delivery.
REFERENCES
- Bowen V, Su J, Torrone E, et al. Increase in incidence of congenital syphilis – United States, 2012-2014. MMWR Morb Mortal Wkly Rep 2015;64:1241-1245.
- Torrone EA, Miller WC. Congenital and heterosexual syphilis: Still part of the problem. Sex Transm Dis 2018;45(9S Suppl 1):S20-S22.
- Gulersen M, Lenchner E, Eliner Y, et al. Risk factors and adverse outcomes associated with syphilis infection during pregnancy. Am J Obstet Gynecol MFM 2023;5:100957.
- Adhikari EH. Syphilis in pregnancy. Obstet Gynecol 2020;135:1121-1135.
- Qin J, Yang T, Xiao S, et al. Reported estimates of adverse pregnancy outcomes among women with and without syphilis: A systematic review and meta-analysis. PloS One 2014;9:e102203.
- Matthias JM, Rahman MM, Newman DR, Peterman TA. Effectiveness of prenatal screening and treatment to prevent congenital syphilis, Louisiana and Florida, 2013-2014. Sex Transm Dis 2017;44:498-502.
- US Preventive Services Task Force; Curry SJ, Krist AH, Owens DK, et al. Screening for syphilis infection in pregnant women: US Preventive Services Task Force Reaffirmation Recommendation Statement. JAMA 2018;320:911-917.
- O’Connor NP, Burke PC, Worley S, et al. Outcomes after positive syphilis screening. Pediatrics 2022;150:e2022056457.
- Lin JS, Eder ML, Bean SI. Screening for syphilis infection in pregnant women: Updated evidence report and systematic review for the US Preventive Services Task Force. JAMA 2018;320:918-925.
- US Preventive Services Task Force (USPSTF); Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Screening for syphilis infection in nonpregnant adults and adolescents: US Preventive Services Task Force Recommendation Statement. JAMA 2016;315:2321-2327.
- Mmeje O, Chow JM, Davidson L, et al. Discordant syphilis immunoassays in pregnancy: Perinatal outcomes and implications for clinical management. Clin Infect Dis 2015;61:1049-1053.
- Williams JEP, Bazan JA, Turner AN, et al. Reverse sequence syphilis screening and discordant results in pregnancy. J Pediatr 2020;219:263-266.e1.
- David M, Hcini N, Mandelbrot L, et al. Fetal and neonatal abnormalities due to congenital syphilis: A literature review. Prenat Diagn 2022;42:643-655.
