Prior evidence has demonstrated that screening in pregnancy is effective at detecting syphilis and that treatment is effective at preventing congenital syphilis and adverse pregnancy outcomes. The purpose of this review was to conduct a limited update of the evidence for the benefits and harms of screening and harms of treatment of syphilis during pregnancy for the US Preventive Services Task Force to reaffirm its 2018 recommendation.^1,2

An analytic framework and 3 key questions (KQs) guided the update (Figure). A literature search of Cochrane Library, Ovid MEDLINE, and trial registries was conducted from January 1, 2017, through July 25, 2023, with surveillance through March 21, 2025. Two investigators independently screened abstracts and articles and rated study quality using predefined criteria. Detailed methods and results are available in the full evidence review.⁴ The review also reported on a contextual question regarding the need for repeat screening during pregnancy; this question was not evaluated systematically.

For evidence on screening, eligible studies included asymptomatic pregnant adolescents and adults, screened using US Food and Drug Administration–approved tests that compared different 2-step serologic screening algorithms or compared single tests with a 2-step algorithm. Screening benefits included reduction in congenital syphilis and neonatal or maternal morbidity and mortality. Eligible screening harms included false-positive or false-negative results and psychosocial harms. The evidence review on harms of treatment was restricted to studies of syphilis treatment during pregnancy using penicillin. Eligible treatment harms included allergic reaction, premature labor, Jarisch-Herxheimer reaction, fetal harms, and other maternal harm

We found no new studies addressing the effectiveness of screening to reduce congenital syphilis or other adverse pregnancy outcomes (KQ1). Five new studies (51,118 participants) addressed the harms of screening (KQ2),and 2 studies (130 participants) addressed the harms of treatment (KQ3). A summary of the evidence is presented in the Table.

For screening harms, index test positivity across the 5 studies ranged between 1.0% and 4.8% and estimates of false-positive results ranged between 0% and 65%, varying by the index test evaluated and to which algorithm the index test was compared. One fair-quality, prospective study of traditional 2-step screening (nontreponemal test followed by treponemal test) reported a false-positive rate of 31% (11/35) for the initial nontreponemal test compared with the treponemal test. Five studies using a reverse-sequence, 2-step screening algorithm (treponemal test followed by nontreponemal test) reported false-positive rates that varied substantially (7%-65%). Three of those studies, all fair quality, were conducted prospectively, and 2 studies, 1 fair quality and 1 good quality, were conducted retrospectively. One study comparing a treponemal test with a nonstandard, composite 2-step screening algorithm reported no false-positives (0/15) and no false-negatives (0/301).

For treatment harms, 1 fair-quality study (n = 39) reported Jarisch-Herxheimer reaction in 5.1% of participants,and 1 good-quality study (n = 91) reported that 2.5% of participants had adverse reactions to standard penicillin provocation or desensitization protocols.

For the contextual question on repeat screening, we identified 3 retrospective cohort studies and 1 national registry. In a US national sample, approximately 5% of congenital syphilis cases occurred in pregnancies that initially screened negative for syphilis. Two of 3 cohort studies concluded that about one-half of congenital syphilis cases might be prevented with third-trimester repeat screening and adequate treatment, whereas the third study estimated that about one-fourth of cases might be preventable.

Although screening and early treatment for syphilis in pregnancy decreases adverse maternal and neonatal outcomes, optimal screening algorithms have not been identified. This limited review found evidence consistent with prior reviews on screening for syphilis in pregnancy that supports the need for 2-step serologic screening to reduce inaccurate screening results. Although based on small studies,we found estimates of penicillin treatment harms that could be used for bounding of potential harms. This review did not systematically address the accuracy of screening tests or comparative effectiveness of different screening algorithms, nor did it address the effectiveness of screening more than once during pregnancy. More information is needed regarding third trimester repeat screening.

Source: This article was published online in JAMA on May 13, 2025 (JAMA. doi:10.1001/jama.2025.1179).

Conflict of Interest Disclosures: None reported.

Funding/Support: This research was funded under contract 75Q80120D00007, Task Order 758Q0122F32006, from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services, under a contract to support the US Preventive Services Task Force (USPSTF

Role of the Funder/Sponsor: Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight, reviewed the evidence review to ensure that the analysis met methodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript findings. The opinions expressed in this document are those of the authors and do not reflect the official position of AHRQ or the US Department of Health and Hu

Additional Contributions: We gratefully acknowledge the following individuals for their contributions to this project, including former and current AHRQ staff (Brandy Peaker, MD, MPH; Tina Fan, MD, MPH; and Tracy Wolff, MD, MPH) and RTI International–University of North Carolina–Chapel Hill Evidence-based Practice Center (EPC) staff (Christiane E. Voisin, MSLS; Roberta Wines, MPH; Nila Sathe, MA, MLIS; Jessica Burch, BA; and Alexander Cone, BA). The USPSTF members, expert reviewers, and federal partner reviewers did not receive financial compensation for their contributions. EPC personnel received compensation for their roles in this project.

Additional Information: A draft version of the full evidence review underwent external peer review from 3 content experts (Catherine Squire Eppes, MD, MPH, Baylor College of Medicine; Peter Miksovsky, MD, Kaiser Permanente; and Jessica E. P. Williams, MD, Children’s National Hospital) and 5 individuals from 4 federal partner organizations (Eunice Kennedy Shriver National Institute of Child Health and Development; National Center for HIV, Viral Hepatitis, STD, and Tuberculosis Prevention; National Eye Institute; and Office of Research on Women’s Health). Comments from reviewers were presented to the USPSTF during its deliberation of the evidence and were considered in preparing the final evidence review. The USPSTF members and peer reviewers did not receive financial compensation for their contributions.

Evidence reviews for the US Preventive Services Task Force (USPSTF) use an analytic framework to visually display the key questions that the review will address to allow the USPSTF to evaluate the effectiveness and safety of a preventive service. The questions are depicted by linkages that relate to interventions and outcomes. Further details are available from the USPSTF Procedure Manual.³

Abbreviations: CIA, chemiluminescence immunoassay; EIA, enzyme immunoassay; IHR, immediate hypersensitivity reaction; JH, Jarisch-Herxheimer; NA, not applicable; RPR, rapid plasma reagin.