Effectiveness of treating gestational syphilis in the last trimester on the incidence of congenital syphilis: a systematic review and meta-analysis

Objectives: To evaluate the effectiveness and safety of treatment for gestational syphilis during the third trimester on maternal and perinatal outcomes, according to the timing of administration relative to delivery, and assess the certainty of the body of evidence. Materials and methods: This systematic review included randomized controlled trials, quasiexperimental studies, cohort studies, and case series involving women diagnosed with GS at 28 weeks’ gestation or later, treated with penicillin or other antibiotics. Search was done in 2023 and updated on June 2025. Two researchers selected studies and extracted data. We assessed the incidence of Congenital Syphilis and maternal treatment failure. Outcomes are presented by maternal and perinatal endpoints and treatment regimen. Results: No randomized controlled trials were identified. Ten cohort studies comprising 5438 women with GS and three case series of Congenital Syphilis were included. Benzathine penicillin G administered during the third trimester might be associated with a cumulative incidence of Congenital Syphilis of 8% (95% CI: 2–13%). The effectiveness of treatment administered 4 weeks before delivery remains uncertain. Aminopenicillins were possibly associated with a 43% incidence of Congenital Syphilis. Safety data were limited. Case series of foetuses with hidrops fetalis associated with gestational syphilis to mothers treated with a 10-day course of intravenous aqueous crystalline penicillin G showed seven newborns with complete response, suggesting prevention of Congenital Syphilis. Conclusion: Treatment of GS with benzathine penicillin G during the third trimester is beneficial in reducing the risk of Congenital Syphilis. However, as its effectiveness is uncertain when administered fewer than 30 days before delivery, neonates born within this timeframe should continue to be managed in accordance with current guidelines for possible Congenital Syphilis. Aminopenicillins may be associated with a high rate of treatment failure. Alternative strategies to treat the fetus during the final four weeks of pregnancy are needed to reduce the risk of Congenital Syphilis.