Syphilis, pregnancy and penicillin allergies: Challenges, strategies and desensitization
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Syphilis, an STI caused by the bacterium Treponema pallidum, has re-emerged as a major public health threat in the United States, with rates skyrocketing over the past decade.
According to the CDC, syphilis cases surged by 80% between 2018 and 2022, reaching levels not seen since the 1950s. Particularly concerning is the rise in congenital syphilis cases, which have increased by 10 times over the last decade, including 180% from 2018 to 2022, putting newborns at risk for severe health complications.
Although a recent CDC report indicated that the overall STI epidemic in the United States may be slowing, cases of congenital syphilis continued to increase. This epidemic underscores the urgent need for enhanced testing, targeted treatment and comprehensive preventive measures to reverse this public health emergency.
Screening and diagnosis
The CDC recommends that all pregnant individuals be screened for syphilis at their first prenatal visit. Early screening is crucial to ensure timely detection and treatment, minimizing risks for both mother and baby. Additional screening should be considered for individuals with increased risk factors, such as residing in areas with high syphilis prevalence, engaging in substance use or having a new sexual partner. The American College of Obstetricians and Gynecologists recommends routine testing at the first prenatal care visit, the third trimester and at the time of delivery.
Screening typically involves serologic tests, including nontreponemal tests such as the rapid plasma reagin (RPR) and Venereal Disease Research Laboratory tests and treponemal tests including enzyme immunoassays, fluorescent treponemal antibody absorption test and T. pallidum particle agglutination assay. These tests detect antibodies associated with syphilis infection and do not distinguish between an active infection and a past infection that has been treated. However, social determinants of health, including barriers to health care access and limited testing availability, contribute to inconsistent screening practices, underscoring the need for comprehensive public health efforts to ensure early and repeated testing for all at-risk populations.
Treatment
Treatment should be initiated as soon as syphilis infection is identified because transmission to the fetus can occur at any stage during pregnancy, with increasing risk as gestation progresses. Untreated maternal syphilis carries up to an 80% risk of fetal infection.
Currently, the only accepted treatment in the U.S. is benzathine penicillin G, administered as a single dose for early-stage infections or as three weekly doses over 3 weeks for later stages. Given the long history of this treatment, extensive data support its efficacy, with up to 98% prevention rates for congenital syphilis, backed by decades of clinical experience.
Recent disruptions in the benzathine penicillin G supply chain have led health officials to emphasize prioritizing this medication for pregnant individuals and newborns because it remains the only approved treatment option to prevent congenital syphilis.
Desensitization: The preferred solution
Penicillin allergy is reported by 5% to 10% of pregnant individuals. However, according to the American Academy of Allergy, fewer than 1% of the general population have a true, type-I (IgE mediated) allergic reaction to penicillin. Given this discrepancy, health care providers are encouraged to conduct thorough allergy histories and determine if a true allergy exists.
For patients determined to be low risk for serious reactions, an oral penicillin challenge may be safely administered in a controlled health care setting. Individuals with a moderate risk of hypersensitivity may benefit from penicillin skin testing (PST) to confirm their allergy status.
For those who tolerate an oral challenge or have a negative PST, penicillin allergy labeling should be removed and syphilis treatment should proceed with the appropriate penicillin product. For pregnant patients with a confirmed immediate allergy, penicillin desensitization is the recommended approach by the CDC to safely and effectively prevent congenital syphilis. Although generally well tolerated, desensitization is typically conducted in a hospital setting due to the necessity of close monitoring.
Desensitization remains essential for those with true penicillin allergies, given the lack of evidence for alternative treatments in this population.
Alternative considerations and future directions
Although doxycycline and ceftriaxone are alternative treatments for syphilis in nonpregnant individuals, they have limitations in pregnancy. Doxycycline, for example, is generally avoided due to risks of fetal teeth discoloration and bone development issues. Ceftriaxone, although safe for other infections in pregnancy and with a low cross-reactivity risk for penicillin allergies, is not recommended by the CDC because of limited data supporting its efficacy in preventing congenital syphilis.
Several case reports evaluated alternative therapies for pregnant people with syphilis. One notable report in a 37-year-old female with a history of Stevens-Johnson syndrome reaction to penicillin, where penicillin desensitization would be contraindicated, saw positive results with antenatal treatment with ceftriaxone. She was diagnosed with early latent syphilis with an RPR titer of 1:64. She was treated with ceftriaxone 1 g IV daily at week 12 of pregnancy for 10 days, followed by another 10-day course of ceftriaxone 250 mg IM daily in the outpatient setting beginning at week 28 of pregnancy. At time of delivery, her RPR titer had decreased to 1:16, indicating successful treatment. The infant had a positive syphilis screen (enzyme immunoassay) and negative RPR on day 1 of life. The baby was treated with one dose of benzathine penicillin G, according to American Academy of Pediatrics guidelines. At 2-month follow-up, there were no concerns for congenital syphilis or allergy sequela in the mother or neonate.
A single-center retrospective study in Latvia assessed the safety and efficacy of ceftriaxone for preventing congenital syphilis in 79 pregnant women, where benzathine penicillin G is challenging to procure. Most participants were referred early in the second trimester, and 67.1% had early latent syphilis. Ceftriaxone was administered as 250 to 500 mg IM daily for a 10-day duration depending on the clinical stage of syphilis. Clinical and serological improvement was observed, with secondary syphilis cases achieving faster serological resolution (mean 6.1 months) than early latent cases (mean 7.5 months). Two early latent cases required an additional ceftriaxone course due to serologic relapse, although no clinical relapses or resistance were noted. Overall, this study suggests ceftriaxone may be a safe and effective alternative in settings where benzathine penicillin G is inaccessible, although further research is essential to substantiate any practice changes.
Oral cefixime, a third-generation cephalosporin with high transplacental transfer, is currently being studied as an oral alternative for early syphilis treatment in nonpregnant people with the intention of eventually evaluating safety and efficacy in pregnant patients.
Currently, no randomized trials have evaluated alternative syphilis treatments during pregnancy due to ethical considerations with research in vulnerable groups and the proven efficacy of penicillin. Case reports on ceftriaxone show promise but vary widely in treatment protocols and lack robust data. Although alternatives are effective in nonpregnant individuals, limited evidence in pregnant populations keeps penicillin desensitization the preferred approach for patients with allergies, underscoring the critical need for further research in accessible and effective treatment options.
References:
- 2022 U.S. syphilis cases reach highest numbers since 1050s. https://www.cdc.gov/nchhstp/newsroom/releases/2024/STI-Surveillance-Report-2022.html. Published Jan. 30, 2024. Accessed Nov. 25, 2024.
- CDC. Sexually transmitted infections treatment guidelines, 2021. Syphilis during pregnancy. https://www.cdc.gov/std/treatment-guidelines/syphilis-pregnancy.htm. Last reviewed July 22, 2021. Accessed Nov. 25, 2024.
- Coyle M, et al. Case Rep Womens Health. 2022;doi:10.1016/j.crwh.2022.e00446.
- Hartmane I, et al. Int J STD AIDS. 2024;doi:10.1177/09564624231206845.
- Hu F, et al. Biomed Res Int. 2020;doi:10.1155/2020/7626274.
- Joint Task Force on Practice Parameters. Ann Allergy Asthma Immunol. 2010; doi:10.1016/j.anai.2010.08.002.
- Katanami Y, et al. Emerg Infect Dis. 2017;doi:10.3201/eid2305.161936.
- Roberts CP, et al. Sex Transm Dis. 2019;doi:10.1097/OLQ.0000000000001050.
- U.S. syphilis cases in newborns continue to increase: A 10-times increase over a decade. https://www.cdc.gov/media/releases/2023/s1107-newborn-syphilis.html. Published Nov. 7, 2023. Accessed Nov. 25, 2024.
For more information:
Michelle Reyes, PharmD, is a PGY-1 pharmacy resident at Denver Health Medical Center.
Kati Shihadeh, PharmD, BCIDP, is a clinical pharmacy specialist in infectious diseases at Denver Health Medical Center. Shihadeh can be reached at katherine.shihadeh@dhha.org.
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