In the 1940s and 1950s, a variety of penicillin-based clinical regimens were shown to effectively prevent neonatal transmission of syphilis.1–5 Today's guidelines still are based on the clinical experience from those studies.6,7 The Centers for Disease Control and Prevention (CDC) recommendations are thought to prevent congenital infection and treat maternal syphilis in 98% of cases.8 In the late 1980s there was a resurgence in infectious syphilis in adults, and the number of cases of congenital syphilis increased dramatically, peaking in 1990.9 In 1994 more than 2200 cases of congenital syphilis (under 1 year of age) were reported to the CDC, the highest rate since the 1950s.9 In retrospective series, as many as 20% of the infants with congenital syphilis were born to women whose syphilis had been treated before delivery.10,11 These maternal treatment failures raised questions about the adequacy of antepartum syphilis treatment to prevent congenital syphilis.
In July 1987, the CDC convened a panel of clinicians to discuss congenital syphilis and determine ways to solve the problem. There had been no major clinical trials to assess contemporary CDC treatment recommendations in pregnancy; particularly there was little information regarding efficacy of therapy in pregnancy for the different stages of disease. The recommendations of the consultants were published by the CDC as a set of Policy Guidelines in January 1988.6
The purpose of the present study was to evaluate the efficacy of the CDC recommendations for the treatment of syphilis in pregnancy for the eradication of maternal infection and prevention of congenital syphilis.
Materials and Methods
This was a prospective clinical trial from September 1, 1987, to August 31, 1989, including all women who delivered at Parkland Memorial Hospital in Dallas, Texas, approved by the University of Texas Southwestern Institutional Review Board. Subjects were identified through the Dallas County Hospital District prenatal system by maternal syphilis serologic screening (first prenatal visit, 28–32 weeks prenatal visit, and at delivery), the Parkland Memorial Hospital Emergency Room, or Dallas County Health Department Sexually Transmitted Diseases Clinic. Rapid plasma reagin test, VDRL test with titer and confirmatory microhemagglutinin assay for antibodies to Treponema pallidum were used to identify infected patients. All antepartum, delivery, and newborn serologic testing was performed in the Parkland Memorial Hospital laboratory. Patient demographics were obtained from their records. Confirmation of substance abuse was obtained from patient history or urine drug screening. Women considered at high risk were screened for human immunodeficiency virus (HIV).
Clinical stage was assigned by clinical examination and darkfield microscopy before treatment. Primary syphilis was diagnosed as a chancre at the site of infection. Secondary syphilis was diagnosed in women with typical dermatitis, mucocutaneous genital lesions (ie, condylomata lata), with evidence of first or secondary syphilis or adenopathy. Latent stage infection was diagnosed after physical examination and diligent review of available medical records; if latent infection could not be confirmed as early (less than 1 year duration), it was classified as late latent syphilis. Lumbar puncture for cerebrospinal fluid analysis was performed according to contemporary CDC guidelines.12 The diagnosis of sero-fast syphilis was determined in those women who had histories of previous treatment clearly documented with at least a fourfold decline in serologic antibody titers after treatment.
Treatment was administered following CDC recommendations.6 Primary, secondary or early latent (under 1 year duration) syphilis was treated with 2,400,000 units intramuscular (IM) benzathine penicillin G. Late latent syphilis (uncertain or longer than 1 year duration) was treated with 7,200,000 units IM benzathine penicillin G over 3 consecutive weeks. Monthly quantitative VDRL titers were measured subsequently at clinic visits and delivery. Clinical cure was defined by the resolution of symptoms in patients with primary or secondary syphilis and a fourfold decrease in titer over 3–4 months. In patients with latent syphilis, a fourfold decrease in titer over 6 months was considered a clinical cure. Treatment failure was defined as a persistent (longer than 1 month) fourfold increase in titer, or an unchanged titer 6 months after treatment. These patients underwent a second course of penicillin therapy.6
At delivery, all subjects were examined for maternal signs of recurrent infection and visible placental hydrops. Neonatal evaluation included a complete physical examination, quantitative VDRL from cord blood, complete blood count, platelet count, liver transaminase tests, and a long-bone radiographic survey. A lumbar puncture for cerebrospinal fluid VDRL, cell count, and protein was performed, if treatment occurred within 30 days of delivery, or if the infant had any physical findings of congenital syphilis.6 The diagnosis of congenital syphilis was based on the criteria established by Kaufmann.6,13 A definite case of congenital infection required identifying T pallidum specimens from lesions by darkfield microscopy or histologic examination. A probable case of congenital syphilis required clinical manifestation of disease, along with a confirmatory microhemagglutinen assay for antibodies to T pallidum, a rising VDRL over the first 3 months of life, or a persistent VDRL over the first 4 months of life. Infants were followed until syphilis serologic conversion to negative, according to contemporary CDC guidelines.6
Data were compared by χ2 or Mantel Haenszel test for trend using statistical software (SAS; SAS Institute Inc., Cary, NC). All tests were two sided, and P < .05 was considered significant. Odds ratios (ORs) and exact 95% confidence intervals (CIs) were reported in appropriate cases.
During the 2-year study period, 28,552 women delivered at Parkland Memorial Hospital. Seven hundred forty-six had positive serologic tests for syphilis, and 298 of these were identified as having sero-fast serologic tests. Four hundred forty-eight women (1.6% of the population) had untreated syphilis, of those 340 (75.9%) received prenatal care and antepartum therapy (Table 1).
The mean age of women with untreated syphilis was 24 years, and the mean gestational age at diagnosis was 32 weeks. The majority of the population was black (59%) and Hispanic (30%). The incidence of drug abuse was 13% and HIV infection 1.5%. Table 2 shows the stages of untreated syphilis at the time of diagnosis. The majority of patients (71%) were in the latent phase of infection. The distribution of disease stage was similar in those treated antepartum and postpartum.
In the antepartum treatment group, current CDC treatment recommendations prevented congenital syphilis in all of the 27 maternal primary and the 136 maternal late latent infections and 100 of 102 maternal early latent infections. There were four fetal treatment failures in 75 cases of secondary syphilis (94.7% success rate), significantly different in the other groups (P = .03). The success of treatment in the three most infectious stages combined (primary, secondary, and early latent infection) was 198 of 204 (97.1%; 95% CI: 93.7, 98.9). Overall, we found a 98.2% success rate for preventing congenital syphilis (Table 3). Of the six fetal treatment failures, four delivered within 2 weeks of treatment. Two infants were stillborn with congenital syphilis. Two treatment failures were born to crack cocaine users. There was only one maternal treatment failure among the 340 women treated antepartum (99.7%, 95% CI 98.4, 100). This woman's pregnancy was complicated by HIV infection, and she had asymptomatic neurosyphilis at delivery. Her infant had no signs of congenital syphilis and did not develop HIV infection.
Maternal treatment was uniformly successful at all gestational ages. There were no differences in fetal treatment findings based on gestational age (Table 4), nor were there any differences in treatment efficacy in women with HIV infection or antepartum drug abuse.
A resurgence of congenital syphilis in the 1980s led to questions about the adequacy of the CDC guidelines for treatment of maternal syphilis and prevention of neonatal infection. Several factors contributed to the increase in congenital syphilis, including increased incidence of maternal disease, failure to detect maternal disease, noncompliance with treatment recommendations, and fetal treatment failure. Lack of prenatal care leading to failure to identify and treat maternal infection accounted for many cases of congenital syphilis.
We were concerned that a significant number of cases of congenital syphilis might be due to fetal treatment failures. The efficacy of penicillin for treating syphilis in immunocompetent adults generally was agreed to be approximately 95%.8,14 The current treatment recommendations have not been studied prospectively in pregnancy, but their efficacy has been estimated to be approximately 98%.14 Many studies of syphilis in pregnancy were conducted in the 1940s and 1950s, with a variety of older penicillin preparations and treatment regimens.1–5 Although they showed efficacy in treatment, older studies did not provide adequate information on prenatal care, gestational age at treatment, and pharmacokinetics. Many of the women in those studies were in later stages of the disease, and few data exist on the efficacy of treatment in early disease.
Adding to our concerns about efficacy of current treatment recommendations are retrospective series describing fetal treatment failures.10,11 These failures were more common in women with HIV and women who delivered soon after treatment. Distinguishing between maternal treatment failure and maternal reinfection can further complicate interpretation of retrospective studies. Most recent studies do not consistently confirm the stage of maternal disease at the time of treatment.8
In our obstetric population, the prevalence of untreated syphilis diagnosed in pregnancy was 1.6%, and 76% of these women received antepartum care and treatment before delivery. Our attendance for prenatal care in the general obstetric population during this time was approximately 90%. Treatment was based on contemporary CDC guidelines and prevented congenital syphilis 98% of the time. Six cases of congenital syphilis occurred, and we believe two important observations follow. First, four of six failures occurred in women with secondary syphilis. Although maternal treatment of secondary syphilis was successful with 2,400,000 units of benzathine penicillin G, the fetus might be at higher risk for treatment failures. Longer durations of maternal infection and higher treponemal load might contribute to these failures. Second, four of six failures occurred in women who delivered within 14 days of treatment. These cases might be associated with maternal Jarisch-Herxheimer reactions,15 incompletely treated fetal infections, or the infants may be uninfected with resolving congenital syphilis. Our fetal treatment failures were not associated with HIV infection; however, there were only seven women with HIV in our study population, limiting any conclusions about syphilis therapy and HIV. Our only maternal treatment failure was an HIV-infected woman.
The decreased efficacy of maternal treatment with secondary syphilis is concerning. Unfortunately, there are limited data, even in nonpregnant adults, to guide management when the perception of an increased risk of failure is present. For example, Rolfs et al16 were unable to show a clinical benefit to augmenting recommended benzathine penicillin G with oral amoxicillin and probenecid in the treatment of primary or secondary syphilis in adults with and without HIV infection. There are no data to support additional penicillin improving the adequacy of treatment when maternal secondary syphilis is present. Because most of the fetal treatment failures occurred soon after maternal therapy, we speculate that the fetuses were severely affected in utero. Perhaps sonographic evaluation before treatment might identify those affected fetuses at higher risk for treatment failure and better predict risk of failure than the maternal stage of disease.
1. Cole HN, Plotke F, Thomas EW, Jenkins KH. Penicillin in the treatment of syphilis in pregnancy. J Veneral Dis Information 1949;30:95–9.
2. Ingraham NR. The value of penicillin alone in the prevention and treatment of congenital syphilis. Acta Derm Venereol Suppl (Stockh) 1951;24:60–88.
3. Jackson FR, Vanderstoep EM, Knox JM, Desmond MM, Moore MB. Use of aqueous benzathine penicillin G in the treatment of syphilis in pregnant women. Am J Obstet Gynecol 1962;83:1389–92.
4. Bundesen HN, Rodriquez J, Aron HCS, Korman BF. Outcome of pregnancies of women treated with aqueous penicillin for early infectious syphilis. Arch Dermatol Syphilology 1950;62:230–6.
5. Wammock VS, Carrozzino OM, Ingraham NR, Clair NE. Penicillin therapy of the syphilitic pregnant woman: Its practical application to a large urban obstetrical service. Am J Obstet Gynecol 1950;59:806–19.
6. Centers for Disease Control. Policy guidelines for the prevention and control of congenital syphilis. MMWR Morb Mortal Wkly Rep 1988;37(S-1):1–13.
7. Centers for Disease Control and Prevention. 1998 guidelines for the treatment of sexually transmitted diseases. MMWR Morb Mortal Wkly Rep 1983;47:28–49.
8. Rolfs RT. Treatment of syphilis, 1993. Clin Infect Dis 1995;20(Supp 1):S23–38.
9. Nakashima AK, Rolfs RT, Flock ML, Kilmarz P, Greenspan JR. Epidemiology of syphilis in the United States, 1941–1993. Sex Transm Dis 1996;23:16–23.
10. McFarlin BL, Bottoms SF, Dock BS, Isada NB. Epidemic syphilis: Maternal factors associated with congenital infection. Am J Obstet Gynecol 1994;170:535–40.
11. Rawstron SA, Bromberg K. Failure of recommended maternal therapy to prevent congenital syphilis. Sex Transm Dis 1991;18:102–6.
12. Centers for Disease Control and Prevention. Guidelines for the prevention of sexually transmitted diseases. MMWR Morb Mortal Wkly Rep 1985;34(S-4):1–35.
13. Kaufman RE, Jones OG, Blount JH, Weisner PJ. Questionnaire survey of reported early congenital syphilis: Problems in diagnosis, prevention, and treatment. Sex Transm Dis 1977;4:135–9.
14. Zenker PN, Rolfs RT. Treatment of syphilis, 1989. Rev Infect Dis 1990;12:S590–S602.
15. Klein VR, Cox SM, Mitchell MD, Wendel GD Jr. The Jarisch-Herxheimer reaction complicating syphilotherapy in pregnancy. Obstet Gynecol 1990;75:375–80.
16. Rolfs RT, Joesoef MR, Hendershot EF, Rampalo AM, Augenbraum MH, Chiu MI, et al. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. N Engl J Med 1997;337:307–14.