Treatment of Syphilis in Pregnancy and Congenital Syphilis: Current Evidence, Challenges, and Future Directions

Syphilis remains a global public health concern, with maternal infection posing a substantial risk for congenital syphilis, a preventable condition associated with severe morbidity and mortality. Penicillin, particularly benzathine penicillin G, remains the cornerstone of treatment and the only therapy with proven efficacy in preventing vertical transmission during pregnancy. However, recurrent global shortages, limited manufacturing capacity, mislabeling of penicillin allergy, and the absence of validated alternative regimens for pregnant women and neonates threaten progress toward elimination goals. This review summarizes current evidence on the treatment of syphilis in pregnancy and congenital syphilis, highlighting the established maternal and neonatal regimens, diagnostic and therapeutic challenges, and clinical consequences of delayed or inadequate treatment. We examine the scope and drivers of benzathine penicillin G shortages, the overestimation of penicillin allergy and its impact on care, and the role of neonatal management when maternal therapy is suboptimal. Emerging data on alternative antimicrobial agents, including cephalosporins, tetracyclines, lipoglycopeptides, and novel compounds are discussed considering recent advances in Treponema pallidum culture and susceptibility testing. While several non-penicillin agents show promise for non-pregnant populations, robust evidence supporting their use during pregnancy and for the prevention of congenital syphilis is lacking. Addressing these gaps through coordinated supply chain strategies, guideline harmonization, and targeted clinical research is essential to ensure resilient and equitable syphilis control and advance global efforts toward the elimination of congenital syphilis.