BACKGROUND Globally syphilis is an important yet preventable cause of stillbirth, neonatal mortality and morbidity. OBJECTIVES This review sought to estimate the effect of detection and treatment of active syphilis in pregnancy with at least 2.4 MU benzathine penicillin (or equivalent) on syphilis-related stillbirths and neonatal mortality. METHODS We conducted a systematic literature review of multiple databases to identify relevant studies. Data were abstracted into standardised tables and the quality of evidence was assessed using adapted GRADE criteria. Where appropriate, meta-analyses were undertaken. RESULTS Moderate quality evidence (3 studies) supports a reduction in the incidence of clinical congenital syphilis of 97% (95% c.i 93 - 98%) with detection and treatment of women with active syphilis in pregnancy with at least 2.4 MU penicillin. The results of meta-analyses suggest that treatment with penicillin is associated with an 82% reduction in stillbirth (95% c.i. 67 - 90%) (8 studies), a 64% reduction in preterm delivery (95% c.i. 53 - 73%) (7 studies) and an 80% reduction in neonatal deaths (95% c.i. 68 - 87%) (5 studies). Although these effect estimates were large and remarkably consistent across studies, few of the studies adjusted for potential confounding factors and thus the overall quality of the evidence was considered low. However, given these large observed effects and a clear biological mechanism for effectiveness the GRADE recommendation is strong. CONCLUSION Detection and appropriate, timely penicillin treatment is a highly effective intervention to reduce adverse syphilis-related pregnancy outcomes. More research is required to identify the most cost-effective strategies for achieving maximum coverage of screening for all pregnant women, and access to treatment if required.