Syphilis Infection During Pregnancy: Screening -- Asymptomatic pregnant women

Importance

Syphilis is an infection that is primarily sexually transmitted. Untreated syphilis infection during pregnancy can be passed to the fetus, causing congenital syphilis. Congenital syphilis is associated with premature birth, low birth weight, stillbirth, neonatal death, and significant abnormalities in the infant such as deformed bones, anemia, enlarged liver and spleen, jaundice, brain and nerve problems (eg, permanent vision or hearing loss), and meningitis.¹ In 2023, there were 3882 cases of congenital syphilis in the US, including 279 congenital syphilis–related stillbirths and neonatal/infant deaths,² the highest number reported in more than 30 years.

Rates of new syphilis cases have continued to rise over the past 3 decades, especially in women. Although men account for the majority of syphilis cases, the change in incidence among women was 2 to 4 times higher than that among men between 2017 and 2021.³ Consequently, cases of congenital syphilis have also increased. Congenital syphilis increased more than 10-fold over a recent decade, from 334 cases in 2012 to 3882 cases in 2023.^2,4 It is estimated that almost 90% of new congenital syphilis cases could have been prevented with timely testing and treatment.⁴

Certain racial and ethnic groups in the US are disproportionately affected by syphilis. Based on 2023 sexually transmitted infection surveillance data from the Centers for Disease Control and Prevention (CDC), congenital syphilis rates were 9.3 cases per 100,000 live births in Asian women, 222.0 cases per 100,000 live births in Black women, 125.0 cases per 100,000 live births in Hispanic or Latina women, 680.8 cases per 100,000 live births in Native American/Alaska Native women, 295.6 live births per 100,000 live births in Native Hawaiian/Pacific Islander women, 82.2 cases per 100,000 live births in multiracial women, and 57.3 cases per 100 000 live births in White women.⁵ Reviews of medical, public health, and social science literature have reported that social context and disparities in social factors such as poverty, neighborhood opportunities, incarceration rates, segregation, and ratio of men to women may influence sexual behavior and sexual networks, likely contributing to the observed racial disparities in sexually transmitted infection rates.^6-8

USPSTF Assessment of Magnitude of Net Benefit

In 2018, the US Preventive Services Task Force (USPSTF) reviewed the evidence for screening for syphilis infection in asymptomatic pregnant women and issued an A recommendation.⁹ The USPSTF has decided to use a reaffirmation deliberation process to update this recommendation. The USPSTF uses the reaffirmation process for well-established, evidence-based standards of practice in current primary care practice for which only a very high level of evidence would justify a change in the grade of the recommendation.¹⁰ In its deliberation of the evidence, the USPSTF considers whether the new evidence is of sufficient strength and quality to change its previous conclusions about the evidence.

Using a reaffirmation process, the USPSTF concludes with high certainty that screening for syphilis infection in pregnancy has a substantial net benefit.

See Table 1 for more information on the USPSTF recommendation rationale and assessment. For more details on the methods the USPSTF uses to determine the net benefit, see the USPSTF Procedure Manual.¹⁰

Table 1. Summary of USPSTF Rationale

Abbreviation: USPSTF, US Preventive Services Task Force.

Practice Considerations

Patient Population Under Consideration

This recommendation applies to all adolescents and adults who are pregnant, whether or not risk factors for syphilis are present.

Screening Tests

Screening for syphilis involves a blood test that detects antibodies that may reflect infection with Treponema pallidum, the organism that causes syphilis. Treponemal tests, such as the T pallidum particle agglutination (TP-PA) test, detect an antibody response to antigens specific to T pallidum.¹¹ Nontreponemal tests, such as the Venereal Disease Research Laboratory or rapid plasma reagin test, detect antibodies that may reflect tissue damage from T pallidum infection or tissue damage from other conditions that can cause the release of lipoidal antigens. Because of high false-positive rates associated with nontreponemal tests alone, especially in pregnancy, a 2-step process is used to improve diagnostic accuracy. A traditional screening algorithm is a 2-step process that begins with a nontreponemal test (eg, Venereal Disease Research Laboratory or rapid plasma reagin) followed by a confirmatory treponemal test (eg, TP-PA) for persons with positive nontreponemal test results. A reverse sequence algorithm uses an automated treponemal test (eg, enzyme-linked or chemiluminescence immunoassay) for the initial screening, followed by a nontreponemal test for reactive samples. Discordant results in the reverse sequence are resolved with a second confirmatory treponemal test (TP-PA preferred). The automated processes used in reverse sequence may be appropriate for high-volume laboratories.^1,11 

Point-of-care tests for antibodies to T pallidum are available that can be performed in a clinical setting or at home using fingerstick blood samples that do not require laboratory processing.¹² It is unclear how results from these tests alone, without additional confirmatory testing, should guide treatment decisions.

Screening Timing and Intervals

All pregnant women should be tested for syphilis when they first present to care. Screening for syphilis should occur as early in pregnancy as possible. If early testing is not done, testing should occur at the first opportunity, which could be as late as at admission for delivery. A recent analysis of national data from 2022 found that 5% of congenital syphilis cases (197/3761 cases) occurred in late pregnancy after having had a negative syphilis screening result earlier in pregnancy.⁴ Similar to the disparities seen in the burden of syphilis, 40.6% of these cases occurred in Black women, 28.4% occurred in Hispanic or Latina women, and 19.8% occurred in White women.⁴ Some retrospective studies estimate that 25% to 50% of congenital syphilis cases could be prevented by repeat screening in the third trimester of pregnancy.^13-15 The CDC,16 Women’s Preventive Services Initiative (WPSI),¹⁷ American Academy of Pediatrics (AAP),¹⁸ and American College of Obstetricians and Gynecologists (ACOG)¹⁹ recommend repeat screening in the early third trimester (approximately 28 weeks of gestation) and again at delivery; however, these organizations differ in whether they recommend repeat screening for all pregnant women¹⁹ or just for those at high risk for syphilis infection. Women at high risk for syphilis infection include those who live in high-prevalence areas; have a history of HIV, incarceration, or multiple sexual partners; engage in sex in combination with drug use or commercial sex work; or are experiencing homelessness.^16,18 Clinicians should be aware of the prevalence of syphilis infection in the communities they serve and state mandates for syphilis screening. Most states mandate screening for syphilis in all pregnant women at the first prenatal visit, and some mandate repeat screening early in the third trimester and at delivery.²⁰

Treatment

The CDC recommends parenteral penicillin G as the only treatment with documented efficacy during pregnancy. Treatment protocols are specific to the stage of syphilis infection, with later-stage infection requiring longer duration of treatment. When syphilis is diagnosed during the second half of pregnancy, management should include a sonographic fetal evaluation for signs of congenital syphilis. Pregnant women with a penicillin allergy should be desensitized and then treated with penicillin. Approximately 10% of patients report a penicillin allergy, although the number of patients who are truly allergic may be much smaller.^16,21,22 Clinicians are encouraged to refer to the CDC’s “Sexually Transmitted Infection Treatment Guidelines” for the most up-to-date treatment guidance.¹⁶

Additional Tools and Resources

A list of state prenatal syphilis screening laws and regulations (https://www.cdc.gov/syphilis/hcp/prenatal-screening-laws/index.html) and county-level data on syphilis infection rates (https://www.cdc.gov/sti-statistics/county-level-syphilis-data/) are available from the CDC. The CDC also provides multilingual materials for patients on syphilis prenatal screening (https://www.cdc.gov/sti/php/communication-resources/syphilis-prenatal-screening-protect-your-baby.html).

Other Related USPSTF Recommendations

The USPSTF has issued recommendations on screening for syphilis in adults and adolescents who are not pregnant,²³ as well as screening for other sexually transmitted infections, including chlamydia and gonorrhea,²⁴ hepatitis B virus,^25,26 genital herpes,²⁷ and HIV.²⁸ The USPSTF has also issued a recommendation on counseling to prevent sexually transmitted infections.²⁹ Current versions of these and other related USPSTF recommendations are available at https://www.uspreventiveservicestaskforce.org/uspstf/.

Reaffirmation of Previous USPSTF Recommendation

This recommendation is a reaffirmation of the USPSTF 2018 reaffirmation recommendation statement. In 2018, the USPSTF reviewed the evidence for screening for syphilis infection during pregnancy and found that the benefits of screening substantially outweighed the harms.⁹ The USPSTF found no new substantial evidence that could change its recommendation and, therefore, reaffirms its recommendation to screen for syphilis infection during pregnancy.

Supporting Evidence

Scope of Review

To reaffirm its recommendation, the USPSTF commissioned a reaffirmation evidence update. The aim of the evidence update that supports the reaffirmation process is to identify “new and substantial evidence sufficient enough to justify a change in the grade of the recommendation.”¹⁰ The reaffirmation update focused on key questions on the benefits and harms of screening for syphilis infection in adolescents and adults who are pregnant.

Benefits of Early Detection and Treatment

The USPSTF found no new evidence that was inconsistent with the previously established benefits of screening for syphilis infection during pregnancy. No new studies were identified that evaluated the effectiveness of screening to decrease congenital syphilis rates or improve maternal health outcomes.^1,30 Evidence from previous reviews³¹ demonstrates fewer adverse pregnancy outcomes among pregnant women screened and treated for syphilis infection compared with those not treated. Treatment appears to be more beneficial when provided earlier rather than later in pregnancy.³¹ A 2014 systematic review of 54 observational studies found that the incidence of congenital syphilis, preterm birth, low birth weight, stillbirth, and neonatal death was dramatically reduced in pregnant women treated for syphilis during pregnancy compared with those who had untreated syphilis.³² The reduction in stillbirth and fetal loss was much smaller when treatment did not occur until the third trimester. The USPSTF previously reviewed evidence on the effects of implementing a free syphilis screening and treatment program for all pregnant women living in Shenzhen, China, from 2002 to 2012 (n = 2,441,237).³³ During follow-up, screening uptake increased from 89.8% to 97.2%, and the congenital syphilis case rate decreased from 109.3 to 9.4 cases per 100,000 live births. During the same time, the incidence of adverse pregnancy outcomes decreased from 42.7% to 19.2%, and the incidence of stillbirth or fetal loss decreased from 19.0% to 3.3%.

Harms of Screening and Treatment

Potential harms of screening for and treatment of syphilis infection include false-positive or discordant results from screening that require clinical evaluation, unnecessary anxiety to the patient, and harms of antibiotic medication use for treatment. The current reaffirmation review identified 5 studies (51,118 participants) that evaluated the harms of screening and 2 studies (130 participants) that evaluated the harms of treatment.^1,30 The 5 studies^34-38 that evaluated the harms of screening were all conducted in the US (1 study was conducted in the US and Argentina³⁸) and reported on false-positive rates of a single screening test. All 5 of these studies included participants from a variety of racial and ethnic backgrounds; however, only 2 studies^34,38 reported this information for their full study cohort. Black participants ranged from 18% to 67%, White participants ranged from 5% to 20%, and “Other” participants ranged from 0.2% to 13%. One of the studies additionally reported including 3% Asian participants and 75% Hispanic participants.³⁴ Two studies, conducted in Canada and Brazil, reported on the harms of treatment, which included rates of Jarisch-Herxhemier reactions (an acute, febrile reaction that often includes body aches, tachycardia, hypotension, and rash and can occur within the first 24 hours of antibiotic treatment of a spirochete infection^16,39) and immediate hypersensitivity reactions to penicillin.^40,41

For treatment harms, 1 small study (n = 39) reported that 5.1% of patients receiving penicillin therapy experienced Jarisch-Herxheimer reactions.⁴⁰ A second small study (n = 91) evaluated an algorithm to help guide penicillin desensitization among pregnant patients with syphilis who had a clinical history of immediate hypersensitivity reaction to penicillin.⁴¹ Among patients considered at  high risk for an immediate hypersensitivity reaction, 27.3% experienced it after oral desensitization and 2.5% experienced it after intravenous desensitization; 2.5% of patients considered at low risk for an immediate hypersensitivity reaction experienced it after penicillin provocation. Overall, the USPSTF found this evidence consistent with the previously known harms of syphilis screening and treatment during pregnancy.

Response to Public Comments

A draft version of this recommendation statement was posted for public comment on the USPSTF website from November 19 to December 23, 2024. A few comments were received asking that the USPSTF align with recommendations from other organizations and recommend repeat screening later in pregnancy. The USPSTF acknowledges that the recent rise of congenital syphilis cases is concerning and is dedicated to finding evidence-based strategies to prevent congenital syphilis. Due to limited available evidence, the USPSTF was not able to assess the effectiveness of screening more than once during pregnancy and is not making a recommendation for or against repeat screening. The USPSTF is calling for more research on the effectiveness of repeat screening during pregnancy and highlights this in the Research Needs and Gaps section. The USPSTF also describes other organizations’ approaches to repeat screening in the Practice Considerations section and Recommendations of Others section. Some comments also sought clarity on the specific time point when screening should be performed. Although a specific time point for screening could not be identified through the evidence, the USPSTF found that generally, reductions in congenital syphilis rates were greater when treatment was completed earlier in pregnancy rather than later. However, benefits were still seen when screening and treatment occurred later in pregnancy. Thus, the USPSTF recommends that screening occur as early in pregnancy as possible, even when this may be late in pregnancy or at delivery. This has been clarified in the recommendation. Last, a few comments sought clarification on who should be screened for syphilis during pregnancy. The USPSTF recommends universal syphilis screening in all adolescents and adults who are pregnant, whether or not risk factors for syphilis are present. Clarifying language has been added to the Practice Considerations section.

Research Needs and Gaps

See Table 2 for research needs and gaps related to screening for syphilis infection during pregnancy.

Recommendations of Others

This recommendation statement is consistent with those of other professional and public health organizations. The CDC,¹⁶ WSPI,¹⁷ AAP,¹⁸ and ACOG¹⁹ recommend initial screening for syphilis infection in all pregnant women at their first prenatal visit, even if previously tested. ACOG19 recommends universal rescreening during the third trimester and at birth and the CDC,¹⁶ WPSI,¹⁷ and AAP¹⁸ recommend rescreening at 28 weeks of gestation and again at delivery in women at high risk for acquiring syphilis. AAP¹⁸ and ACOG¹⁹ also recommend repeat screening after exposure to an infected partner. The American Academy of Family Physicians supports the 2018 USPSTF recommendation on screening for syphilis infection in pregnant women.⁴²

Table 2. Research Needs and Gaps for Screening for Syphilis Infection During Pregnancy

Abbreviations: USPSTF, US Preventive Services Task Force.

Supplement. eFigure. US Preventive Services Task Force (USPSTF) Grades and Levels of Evidence