The U.S. Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specific preventive care services for patients without obvious related signs or symptoms.

It bases its recommendations on the evidence of both the benefits and harms of the service, and an assessment of the balance. The USPSTF does not consider the costs of providing a service in this assessment.

The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decisionmaking to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms.

Importance

Untreated syphilis infection in pregnant women can be transmitted to the fetus (congenital syphilis) and is associated with stillbirth, neonatal death, and significant morbidity (e.g., bone deformities and neurologic impairment) in infants born with congenital syphilis.¹

Detection

The USPSTF found adequate evidence that screening tests can accurately detect syphilis infection in pregnant women.

Benefits of Detection and Early Treatment

The USPSTF found convincing evidence that universal screening for syphilis infection in pregnant women reduces the incidence of congenital syphilis and the adverse outcomes of pregnancy associated with maternal infection.

Harms of Detection and Early Treatment

Screening for syphilis infection in pregnant women may result in potential harms, including anxiety and harms of treatment with antibiotic medications. However, the USPSTF concluded that these harms of screening are no greater than small.

USPSTF Assessment

The USPSTF concludes with high certainty that the net benefit of screening for syphilis infection in pregnant women is substantial.

Patient Population Under Consideration

This recommendation applies to all pregnant women.

Screening Intervals

All pregnant women should be tested as early as possible when they first present to care, whether it is at the first prenatal visit or at delivery, if the patient has not received prenatal care. For pregnant women at high risk for infection, many organizations recommend repeat serologic testing in the third trimester and again at delivery.^{2, 3} According to the Centers for Disease Control and Prevention (CDC), pregnant women at high risk for syphilis infection who warrant repeat testing include women with a history of syphilis infection, incarceration, or drug use; women with multiple or concurrent sex partners; and women who live in high-prevalence areas.⁴ The American Academy of Pediatrics (AAP) and the American College of Obstetricians and Gynecologists (ACOG) recommend repeat screening in communities and populations with a high prevalence of disease. Clinicians should be aware of the prevalence of infection in the communities they serve.⁵ Persons with a diagnosed sexually transmitted disease may be more likely than others to engage in high-risk behavior, which places them at increased risk for syphilis infection. Most states mandate screening in all pregnant women at some point during pregnancy, and many mandate screening at the time of delivery.

Screening Tests

Current screening tests for syphilis rely on detection of antibodies rather than direct detection of the organism. Screening for syphilis infection is a two-step process involving an initial nontreponemal test (Venereal Disease Research Laboratory or rapid plasma reagin [RPR] test) followed by a confirmatory treponemal antibody detection test (fluorescent treponemal antibody absorption or Treponema pallidum particle agglutination test). A reverse sequence screening algorithm has been developed in which an automated treponemal test (such as enzyme-linked, chemiluminescence, or multiplex flow immunoassays) is performed first, followed by a nontreponemal test. If the test results are discordant in the reverse sequence algorithm, a second treponemal test (preferably using a different treponemal antibody) is performed. The USPSTF found no studies comparing the test accuracy of the traditional screening algorithm versus the reverse sequence screening algorithm.

Treatment

The CDC provides guidance on the appropriate treatment of syphilis in pregnant women. In its 2015 guidelines on the treatment of sexually transmitted diseases, the CDC recommends parenteral benzathine penicillin G for the treatment of syphilis in pregnant women.² Evidence on the efficacy or safety of alternative antibiotic medications in pregnancy is limited; therefore, women who report a penicillin allergy should be evaluated for penicillin allergy and, if present, desensitized and treated with penicillin. Because the CDC updates these recommendations regularly, clinicians are encouraged to access the CDC Web site to obtain the most up-to-date information.

Additional Approaches to Prevention

Trends in incidence rates of congenital syphilis are closely related to trends in primary and secondary syphilis infection rates in women. Screening for syphilis in nonpregnant populations is an important public health approach to preventing the sexual transmission of syphilis and subsequent vertical transmission of congenital syphilis. The USPSTF recommends screening for syphilis in nonpregnant adolescents and adults at increased risk for infection.⁶

Useful Resources

The USPSTF has made recommendations on screening for other sexually transmitted diseases, including chlamydia and gonorrhea,⁷ hepatitis B virus,⁸ genital herpes,⁹ and HIV.¹⁰ National-, state-, and county-level data on syphilis infection rates are also available from the CDC.⁵

Research Needs and Gaps

Although the benefits of screening for syphilis infection in pregnant women to prevent congenital syphilis are well established, additional studies on the use of different screening algorithms in pregnant women, as well as studies to help identify optimal rescreening intervals and populations to rescreen during pregnancy, could help inform implementation of screening programs. Studies on treatment options besides penicillin could also be helpful.

Burden of Disease

Although national rates of syphilis infection in pregnant women are not currently available, the incidence rates of primary and secondary syphilis infection in women and congenital syphilis in infants have been increasing, despite consistent recommendations and legal mandates to screen for syphilis infection in pregnant women.¹¹ In 2012, the case rate for primary and secondary syphilis infection in women was 0.9 cases per 100,000 women, and for congenital syphilis was 8.4 cases per 100,000 live births.¹² In 2016, the case rate had increased to 1.9 cases of primary and secondary syphilis infection per 100,000 women and 15.7 cases of congenital syphilis per 100,000 live births. Late or limited prenatal care has been associated with congenital syphilis.¹¹ Although most cases of congenital syphilis occur among infants whose mother received prenatal care (almost 70% of infants with congenital syphilis are born to mothers who received prenatal care), detection and treatment of maternal syphilis often occurs too late to prevent transmission of congenital syphilis.¹² Recent data suggest that while screening rates for syphilis infection are generally high, the proportion of women who are screened earlier in pregnancy remains low (e.g., 20% of women are screened only at the time of delivery).¹³ Primary, secondary, and congenital syphilis rates differ by race/ethnicity. Case rates of primary, secondary, and congenital syphilis are higher in black, American Indian/Alaska Native, and Hispanic populations than in white populations. While rates of primary and secondary syphilis infection are lower in Asian women than in white women, rates of congenital syphilis are higher in Asian populations.¹¹ Syphilis rates also differ by geography, with generally higher rates of primary, secondary, and congenital syphilis in the West and South and lower rates in the Northeast and Midwest. However, clinicians should be aware of the prevalence of syphilis infection in their community, as rates can vary.¹¹

Syphilis can be transmitted to the fetus during all stages of maternal infection, although the risk is highest with primary and secondary syphilis maternal infection, which is why detection early in pregnancy is important.^{1, 2} Untreated syphilis infection during pregnancy greatly increases the risk of adverse pregnancy outcomes. A 2013 systematic review¹⁴ of six case-control studies found that compared with pregnancies that did not have maternal syphilis infection, untreated maternal syphilis infection during pregnancy was associated with an absolute difference of 21% for stillbirth or fetal loss, 9% for neonatal death, and 5% for prematurity or low birth weight. Infants born with congenital syphilis are often asymptomatic at birth, but most will develop signs within the first several weeks, which include rash, hemorrhagic rhinitis, lymphadenopathy, hepatosplenomegaly, and skeletal abnormalities.¹⁵ Additional sequelae include anemia, neurologic impairment such as blindness or deafness, and meningitis.¹⁶

Scope of Review

The USPSTF commissioned a targeted evidence review to determine whether to reaffirm its 2009 recommendation on screening for syphilis in pregnant women. The aim of this review was to identify any new and substantial evidence that would be sufficient to change the prior USPSTF recommendation. Given the established benefits and practice of screening for syphilis in pregnant women, the USPSTF focused its evidence review on the direct benefits of screening on the prevention of congenital syphilis morbidity and mortality and the harms of screening for and treatment of syphilis infection in pregnant women.

Benefits of Early Detection and Treatment

The USPSTF found no new evidence to refute the benefits of screening for syphilis infection in pregnant women. Evidence from observational studies demonstrates less adverse pregnancy outcomes in pregnant women who are screened and treated for syphilis infection compared with pregnant women who are not treated. In particular, treatment appears to be more beneficial when provided earlier rather than later in pregnancy.¹ A 2014 systematic review¹⁷ of 54 observational studies found that incidence of congenital syphilis, preterm birth, low birth weight, stillbirth, and neonatal death was dramatically improved in women treated for syphilis during pregnancy compared with women who had untreated syphilis. However, only a slight reduction in stillbirth or fetal loss was observed when women were only treated in the third trimester compared with women who had untreated syphilis. Extended followup of a study previously considered by the USPSTF for its 2009 recommendation reported 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).¹⁸ During this period, screening uptake increased from 89.8% to 97.2% and the number of congenital syphilis cases decreased from 109.3 to 9.4 cases per 100,000 live births. Additionally, over the same time period, 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%. The USPSTF found this evidence to be consistent with findings from its previous evidence review.

Potential Harms of Screening and Treatment

Potential harms of screening for and treatment of syphilis infection include false-positive results that require clinical evaluation, unnecessary anxiety to the patient, and harms of antibiotic medication use. Consistent with previous reviews, the current, targeted review¹ identified five studies^19-23 that reported on false-positive rates of various individual screening tests, and one study²⁴ that reported on false-negative RPR test results. Overall, these studies demonstrate that false-positive results with chemiluminescence or enzyme-linked immunoassay in pregnant women are common (false-positive rates ranged from 0% to 88.2%)^19-23 and that false-negative RPR test results can result from undiluted serum with high titers (known as the prozone effect).²⁴ Because of the high potential for false-positive results with individual tests, a two-step process for screening is recommended. The USPSTF found no studies that reported on the false-positive rate of the traditional or reverse sequence screening algorithm in pregnant women. Harms of treatment include rare adverse drug-related effects, such as anaphylaxis due to penicillin allergy and the Jarisch-Herxheimer reaction (febrile reaction with headache, myalgia, and other symptoms), which may occur within the first 24 hours after any type of syphilis therapy. The USPSTF found no studies that reported on harms to the fetus from treatment of syphilis infection.

Estimate of Magnitude of Net Benefit

Overall, the USPSTF found convincing evidence that screening for syphilis infection in pregnant women provides substantial benefit. Accurate screening algorithms are available to identify syphilis infection. Effective treatment with antibiotics can prevent congenital syphilis and significantly decrease adverse pregnancy outcomes, with small associated harms, providing an overall substantial health benefit.

This recommendation is a reaffirmation of the USPSTF 2009 recommendation statement. The USPSTF commissioned a targeted review of any substantial new evidence published since 2008 and determined that the net benefit of screening for syphilis infection in pregnant women continues to be well established. The USPSTF found no new substantial evidence that could change its recommendation, and therefore reaffirms its recommendation to screen for syphilis infection in all pregnant women.

This recommendation statement is consistent with those of other professional and public health organizations. The CDC recommends screening for syphilis infection in all pregnant women at their first prenatal visit.² AAP and ACOG recommend screening for syphilis infection in pregnant women as early as possible in pregnancy.³ The CDC, AAP, and ACOG also recommend repeat screening at 28 to 32 weeks of gestation and again at delivery in certain high-risk women. The CDC recommends repeat screening in pregnant women at high risk (including women with a history of syphilis infection, incarceration, or drug use; women with multiple or concurrent sex partners; and women who live in high-prevalence areas). AAP and ACOG recommend repeat screening in high-prevalence communities and populations. The American Academy of Family Physicians recommends screening for syphilis infection in all pregnant women.²⁵

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2. Centers for Disease Control and Prevention. 2015 Sexually Transmitted Diseases Treatment Guidelines. https://www.cdc.gov/std/tg2015/default.htm. Accessed January 16, 2018.
3. American Academy of Pediatrics and the American College of Obstetricians and Gynecologists. Guidelines for Perinatal Care. 8th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2017.
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16. Centers for Disease Control and Prevention. Congenital Syphilis—CDC Fact Sheet. https://www.cdc.gov/std/syphilis/stdfact-congenital-syphilis.htm. Accessed January 16, 2018.
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22. Henrich TJ, Yawetz S. Impact of age, gender, and pregnancy on syphilis screening using the Captia Syphilis-G assay. Sex Transm Dis. 2011;38(2):1126-30.
23. Wellinghausen N, Dietenberger H. Evaluation of two automated chemiluminescence immunoassays, the LIAISON Treponema Screen and the ARCHITECT Syphilis TP, and the Treponema pallidum particle agglutination test for laboratory diagnosis of syphilis. Chin Chem Lab Med. 2011;49(8):1375-7.
24. Liu LL, Lin LR, Tong ML, et al. Incidence and risk factors for the prozone phenomenon in serologic testing for syphilis in a large cohort. Clin Infect Dis. 2014;59(3):384-9.
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