Blissful ignorance when managing pregnant women with syphilis and nonreactive nontreponemal tests?

The use of the reverse sequence syphilis algorithm has identified a population with serodiscordant test results: nonreactive nontreponemal tests and confirmed reactive treponemal tests. This is a heterogeneous population. Most individuals have treated syphilis resulting in a decline in nontreponemal antibody titers after therapy. Others have early infection (testing preceded the development of detectable antibodies or was affected by the prozone phenomenon), and subsequent nontreponemal tests are usually found to be reactive. Nontreponemal antibody titers may also decline over time even in the absence of therapy, so asymptomatic individuals with persistently nonreactive nontreponemal tests and no history of syphilis treatment may have late syphilis. In the antibiotic era, several important clinical and public health questions arise in individuals with serodiscordant test results without documented past syphilis treatment. What are the clinical risks of progression to tertiary syphilis? What are the public health risks of (a) sexual transmission and (b) vertical transmission from mother to infant? In this issue of Sexually Transmitted Diseases, Peterman and colleagues try to address the question of vertical transmission of syphilis in women with persistently nonreactive nontreponemal tests. They reviewed public health reports over a 28-year period to determine if any cases of congenital syphilis could be identified. Their data suggest that vertical transmission in these women is very unlikely. Are their conclusions justified? The probability of vertical transmission from an untreated mother depends on the duration of the infection in the mother and the stage of pregnancy (reviewed by Wicher and Wicher). Transmission is 70% to 100% in primary and secondary syphilis, 40% in early latent syphilis, and 10% in late latent disease. In 1922, Williams reported that 50 of 109 infants born to 50 seronegative mothers (of which 46 had never received treatment for syphilis) had probable (n = 7) or definitive (n = 43) congenital syphilis (also reviewed by Moore). Although the study suggests the possibility of vertical transmission among untreated seronegative women with syphilis, there are several issues worth highlighting. The study offered limited data on the persistence of seronegativity (thus, early infection could not be ruled out). Nontreponemal tests used in the modern antibiotic era are more sensitive than those used in the preantibiotic era. Finally, routine exposures to A-lactam antibiotics, tetracyclines, and macrolides for indications other than syphilis in the modern era further complicate historical comparisons. Modern reports of vertical transmission of syphilis in seronegative women, when not caused by seronegative early infection in the mother or the prozone phenomenon yielding false-negative nontreponemal test results, are often incompletely documented. As such, the current study by Peterman, despite its limitations, deserves attention. The major strength of this study is the large number (n = 23,863) of case reports of congenital syphilis collected over a 28-year period. This study has several limitations that mostly pertain to the quality of the data collected from public health records and are discussed by the authors. A few are worth highlighting. The screening of pregnant women during the study period was mainly conducted using the traditional syphilis testing algorithm, which consists of screening for the presence of nontreponemal antibodies followed, if positive, by a confirmatory treponemal test. In the setting of a negative nontreponemal test result, only clinical suspicion would dictate whether a treponemal test was ordered. Given that congenital syphilis is rare and may not manifest at the time of delivery, clinicians with limited experience may miss the diagnosis when the nontreponemal test is nonreactive (a form of outcome identification bias). In addition, the missing data on public health case-report forms introduce another source for potential misclassification. For example, missing data made it difficult to definitively classify the outcome in an infant whose mother had persistently nonreactive nontreponemal tests and whose bone radiographs were suggestive of congenital syphilis. Although the Peterman study correctly EDITORIAL