BACKGROUND: Congenital syphilis (CS) in the United States increased 10-fold in the last decade. At a large public hospital in Los Angeles, the numbers of infants born to birthing parents with untreated syphilis during pregnancy have continued to rise. METHODS: We compiled a retrospective case-series from all infant rapid plasma reagin (RPR) test results from 2022-2023 summarizing CS diagnosis and relevant diagnostic criteria. Chi-squared and Fisher's exact tests were used to examine associations between birthing parent risk factors and CS diagnosis. RESULTS: Birthing parent syphilis complicated 97 out of 2367 live births (4.1%) at our institution. Approximately 36% (n = 35) of infants born to birthing parents with a history of syphilis (n = 94) were born to a birthing parent with inadequately treated syphilis or concern for reinfection. Infants with exposure to birthing parent syphilis were mostly asymptomatic at birth but had a high frequency of abnormalities in laboratory and radiographic evaluation. Compared to infants with Less Likely or Unlikely CS, birthing parents with infants with Highly Probable or Possible CS were more likely to have methamphetamine use during pregnancy (41% vs. 69%, p = 0.02), cocaine use during pregnancy (2% vs. 14%, p = 0.03), opiate use during pregnancy (7% vs. 37%, p = <
0.001), and no prenatal care (7% vs. 40%, p ≤ 0.001). CONCLUSIONS: This case series identified birthing parent substance use and no prenatal care as risk factors for Highly Probable or Possible CS, underscoring the vulnerability of this population and informing future work in prevention of this disease.