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The distribution and trends of syphilis are influenced by biologic factors, sexual behaviors, biomedical technology, availability of and access to health care, public health efforts, changes in population dynamics, and sociocultural factors. The objective of this article is to review the epidemiology of syphilis in the United States during the period 1941–1993 in the context of some of these factors.Surveillance data on cases of syphilis and congenital syphilis reported by state and city health departments to the Centers for Disease Control and Prevention were analyzed to show distribution and trends by geographic location, racial and ethnic groups, gender, and age.Historically, syphilis was distributed widely throughout the country and declined rapidly after the introduction of penicillin therapy and broad-based public health programs, attaining its lowest levels in the 1950s. However, in recent years, the disease has returned and become focused in the southern region and in urban areas outside that region. Rates of syphilis have remained highest in black Americans, and the most recent national epidemic of syphilis primarily involved them. Rates in white men were at intermediate levels during the early 1980s but have declined to low rates in the 1990s, possibly because of changes in behavior in response to the AIDS epidemic. Rates in white women and other racial and ethnic groups have remained low throughout the 1980s and 1990s.Syphilis remains a significant problem in the United States, and its epidemiology is influenced by a complex combination of factors. To prevent and control syphilis effectively, public health practitioners must understand these factors and design programs and interventions that address the disease in the context of these factors.