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Sexually Transmitted Diseases:
doi: 10.1097/01.olq.0000246314.35047.91
Article

Occurrence of Congenital Syphilis After Maternal Treatment With Azithromycin During Pregnancy

Zhou, Pingyu MD, PhD*; Qian, Yihong MD*; Xu, Jinhua MD†; Gu, Zhiying MD‡; Liao, Kanghuang MD†

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From the *Department of STD Institute, Shanghai Skin & STD Hospital, Shanghai, China; the †Department of Dermatology, Huashan Hospital of Fudan University, Shanghai, China; and the ‡Department of STD, Dongfang Hospital of Tongji University, Shanghai, China

The authors thank Dr. A. C. Chu from Hammersmith Hospital, London, and Mr. Shun Lv from Fudan University, Shanghai, for their helpful comments on writing the paper.

Correspondence: Pingyu Zhou, MD, PhD, 196 Wuyi Road, Shanghai, China, 200050. E-mail: zpyls@yahoo.com, zhoupingyu@medmail.com.cn.

Received for publication May 12, 2006, and accepted August 27, 2006.

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Abstract

Objective: To evaluate the efficacy of azithromycin in preventing congenital syphilis.

Method: Five pregnant women with syphilis who were allergic to penicillin were given azithromycin, 1 g daily orally or intravenously, in different hospitals. The duration of the therapy ranged from 1 day to 10 days. A second course of therapy was provided at 28 weeks gestation. The babies were given a physical examination and blood test for serum rapid plasma reagin test (RPR), treponema pallidum hemagglutination test (TPHA), and fluorescent treponemal antibody adsorption test (FTA-ABS-19-sIgM) within three months after birth.

Results: Five infants born to these mothers developed skin rashes. Four of the infants had hepatomegaly and one showed osteochondritis. The tests RPR, TPHA, and FTA-ABS-19-sIgM were positive. The RPR titers varied from 1:64 to 1:256 and the babies were diagnosed with congenital syphilis. They were successfully treated with penicillin.

Conclusions: Successful therapy for syphilis during pregnancy demands maternal care as well as prevention or cure of congenital infection. The failure of azithromycin in preventing congenital syphilis in our report suggests that azithromycin should not be recommended as an alternative in treating syphilitic pregnant women or fetal syphilis.

CONGENITAL SYPHILIS HAS BEEN INCREASING dramatically in China since 1998. Only 185 cases were reported in 1998, whereas 2,035 cases were reported in 2004. Congenital syphilis is of particular concern in Shanghai, which, in 2004, had one of the highest rates in China.1 Successful therapy of syphilis during pregnancy demands maternal cure as well as prevention or cure of congenital infection. So far, penicillin remains the most effective treatment in treating antepartum syphilis and preventing or curing congenital syphilis. However, the pregnant woman with syphilis who is allergic to penicillin is in a dilemma. We report 5 cases of congenital syphilis delivered from patients with maternal syphilis treated with azithromycin.

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Baseline Characteristics of Babies and Mothers

Five women had syphilis during their pregnancy and were treated with azithromycin in different hospitals because of allergy to penicillin. They received no additional antibiotics during pregnancy or after delivery. The median patient age was 24 years (range, 22–28 years). One woman had a rash and was diagnosed with secondary syphilis in her 22nd week of gestation, and after treatment, the rash disappeared within 2 weeks. The other women had no symptoms when they had their prenatal visit and found that their serum rapid plasma regain (RPR), Treponema pallidum hemagglutination test (TPHA) were positive, and their HIV-negative (All these tests were done in different hospitals.). Three of these 4 patients recalled that months earlier, they had developed a rash on their trunks and palms and were diagnosed with early latent syphilis. The other patient did not know when she acquired the disease and was diagnosed as having latent syphilis. The 5 mothers were treated with azithromycin at diagnosis and 3 of the mothers were treated a second time at 28 to 32 weeks gestation, respectively (see Table 1). Ultrasonic examination at or after 20 weeks gestation indicated that the fetuses were anatomically normal. Four patients stated they had no sex throughout their pregnancy after treatment; the other one had sex with her husband. There was no evidence showing reinfection when the mothers were retested 3 months after treatment or in the puerperium. All their sex partners had syphilis and were fully treated with penicillin.

Table 1
Table 1
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From October 1998 to May 2004, 5 infants born to these mothers were referred to our hospital because of skin rashes (see photographs). On examination, 4 of the infants had hepatomegaly. Four of the babies were female and one male. They ranged in age from 49 to 67 days. The tests for serum RPR, TPHA, and fluorescent treponemal antibody adsorption test (FTA-ABS-19-sIgM) were performed and results were positive. The RPR titers varied from 1:64 to 1:256. Three of the babies were performed bone x-ray and one showed osteochondritis. Routine blood test was done and the details are shown in Table 2. The evaluation of cerebrospinal fluid was only done in one baby and it showed normal. The criteria for diagnosis of congenital syphilis was based on 1) the infants’ mothers had syphilis during pregnancy; 2) presence of clinical, laboratory, or radiographic evidence of syphilis in the infants; 3) a positive serum RPR test, which was confirmed by TPHA; 4) a serum quantitative RPR titer that was 4-fold greater than the mother’s titer at the same laboratory; or 5) a positive FTA-ABS- 19-sIgM. Their sera were HIV-negative. The babies were treated with 14 days of intravenous penicillin (100,000 U/kg every 8 hours) or intramuscularly (50,000 U/kg per day) and recovered without further complications at a follow-up visit to our hospital 8 weeks later.

Table 2
Table 2
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Although congenital syphilis has been studied for many years, our understanding of the pathophysiology of maternal transmission of T. pallidum is still incomplete. Lack of knowledge of fetal syphilis and difficulty in assessing the severity of fetal infection has limited our knowledge of the successful treatment of fetal infection. Also, poor prenatal care represents a major risk factor for the development of congenital syphilis. Penicillin has proven its effectiveness in treating antepartum syphilis and preventing or curing congenital syphilis in the last 50 years, although the possibility of occasional treatment failures may occur.2,3 To penicillin-allergic pregnant women with syphilis, the therapeutic approach is always difficult. Tetracyclines are contraindicated during pregnancy,4,5 and the effect of erythromycin on preventing congenital syphilis has been variable.6,7 Although penicillin desensitization is a proven therapy, desensitization regent is hardly available in China. To those allergic to penicillin, erythromycin is recommended as an alternative in China, especially for pregnant women. Azithromycin is a macrolide antibiotic that is structurally similar to erythromycin8,9 and is therefore naturally accepted as another alternative to penicillin. The principal mechanism of azithromycin is through binding with the 50S ribosomal subunit and inhibition of messenger RNA-directed polypeptide synthesis. Perhaps because azithromycin can be given orally with a single dose in treating syphilis, and some studies have been shown early syphilis to be successfully treated with a single dose of azithromycin,10,11 azithromycin emerged as an attractive alternative to penicillin therapy for syphilis in the 1990s. However, the 5 infants were born with congenital syphilis in our report despite the fact that their mothers’ syphilis had been treated with azithromycin as soon as they were diagnosed. The mothers were given different doses of azithromycin, each exceeding 1 g. Several small studies have documented the efficacy of a 1-g single oral dose of azithromycin in the treatment of nonpregnant patients not infected with HIV during the incubation period of syphilis and at an early stage of the infection.10 There is no evidence that larger doses of azithromycin should be given to pregnant women compared with nonpregnant women. The decline in RPR titers of the mothers and monthly follow-up of the clinical and laboratory findings after using azithromycin did not indicate whether the maternal treatment was successful or not, because time period for serologic assessment of maternal treatment for most women before delivery was insufficient. In addition, maternal RPR titers are not a precise parameter for signifying the risk of fetal infection because there is no evidence that any maternal serologic response predicts successful fetal treatment. The mothers’ sex history and clinical and laboratory parameters did not suggest reinfection with T. pallidum later in pregnancy, which might have resulted in fetal treatment failure. The precise reason for the failure of azithromycin to prevent congenital syphilis in our patients is unknown, but it has been reported that the pharmacokinetics of orally administered azithromycin in the term-gravid woman showed that umbilical arterial and venous serum azithromycin levels were low during the first 72 hours. Amniotic fluid levels were highest at 6 hours and declined rapidly. Fetal serum levels of azithromycin were low (approximately 20–50% less than maternal serum levels).12 This may partially account for the failure of azithromycin in preventing congenital syphilis.

Despite the recent use of azithromycin in syphilis management, macrolide-resistant T. pallidum had previously been reported. The first molecular confirmation of macrolide resistance in T. pallidum was obtained in the 1970s from a penicillin-allergic patient with secondary syphilis who did not respond to 45 days of erythromycin treatment.13 Eight different mutations of bacterial 23S rRNA genes have been described that confer macrolide resistance by altering the site at which the drug interacts with the ribosome.14 In 2004, Lukehart et al published a report on the molecular biology of 12 T. pallidum isolates containing the A2058G (which is the most common mutation identified in macrolide-resistant pathogens) mutation from San Francisco and another 20 from Seattle, Baltimore, and Dublin (Ireland) from 1998 through 2003.15 A T. pallidum isolate with this mutation was shown to be resistant to erythromycin and azithromycin treatment in vivo using test rabbits. Most recently, Mitchell reported that azithromycin-resistant T. pallidum was widespread in San Francisco.16 No reports have been found regarding whether azithromycin succeeds in treating syphilitic pregnant women and preventing congenital syphilis. The presented cases here are not sufficient to ascertain the optimal regimen of azithromycin for treating pregnant syphilitic women and preventing fetal infections. The decline in RPR titers of the mothers did not indicate whether the maternal treatment was successful or not because time period for serologic assessment of maternal treatment for most women before delivery was insufficient. According to the syphilitic fetus, we can speculate that these mothers might not be successfully treated. This may be coursed by the fact that the prevalence of azithromycin-resistant T. pallidum increased in recent years.16 Therefore, azithromycin might not be an option in treating syphilitic pregnant women or fetus syphilis.

Inadequately treated maternal disease often results in serious sequelae for the fetus and newborn. Thus, infants whose mothers were treated for syphilis not using penicillin during pregnancy, retreatment of the baby should be strongly recommended,17 and they must be closely followed up with clinical and serologic evaluation for evidence of congenital syphilis.

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Fig. 2
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References

1. Chinese Center for Disease Prevention and Control; Center for STI and AIDS Prevention and Control. 2004 report on STD epidemic analysis in China. Bulletin for STI Prevention and Control 2005; 19:2–8.

2. Conover CS, Rend CA, Miller GB, et al. Congenital syphilis after treatment of maternal syphilis with a penicillin regimen exceeding CDC guidelines. Infect Dis Obstet Gynecol 1998; 6:134–137.

3. Rawstrom SA, Bromberg K. Failure of recommended maternal therapy to prevent congenital syphilis. Sex Transm Dis 1991; 18:102–106.

4. Kline AH, Blattner RJ, Lunin M. Transplacental effect of tetracyclines on teeth. JAMA 1964; 188:178–180.

5. Smilack JD. The tetracyclines. Mayo Clin Proc 1999; 74:727–729.

6. Fenton LJ, Light IJ. Congenital syphilis after maternal treatment with erythromycin. Obstet Gynecol 1976; 47:492–494.

7. Hashisaki P, Wertzberger GG, Conrad GL, et al. Erythromycin failure in the treatment of syphilis in a pregnant woman. Sex Transm Dis 1983; 10:36–38.

8. Lalak NJ, Morris DL. Azithromycin clinical pharmacokinetics. Clin Pharmacokinet 1993; 25:370–374.

9. Drew RH, Gallis HA. Azithromycin: spectrum of activity, pharmacokinetics, and clinical applications. Pharmacotherapy 1992; 12:161–173.

10. Hook EW III, Martin DH, Stephens J, et al. A randomized, comparative pilot study of azithromycin versus benzathine penicillin G for treatment of early syphilis. Sex Transm Dis 2002; 29:486–490.

11. Rekart ML, Patrick DM, Chakraborty B, et al. Targeted mass treatment for syphilis with oral azithromycin. Lancet 2003; 361:313–314.

12. Ramsey PS, Vaules MB, Vasdev GM, et al. Maternal and transplacental pharmacokinetics of azithromycin. Am J Obstet Gynecol 2003; 188:714–718.

13. Stapleton JT, Stamm LV, Bassford PJ Jr. Potential for development of antibiotic resistance in pathogenic treponemes. Rev Infect Dis 1985; 7(suppl 2):S314–317.

14. Vester B, Douthwaite S. Macrolide resistance conferred by base substitutions in 23S rRNA. Antimicrob Agents Chemother 2001; 45:1–12.

15. Lukehart S, Godornes C, Molini BJ, et al. Macrolide resistance in Treponema pallidum in the United States and Ireland. N Engl J Med 2004; 351:154–158.

16. Mitchell SJ, Engelman J, Kent CK, et al. Azithromycin-resistant syphilis infection: San Francisco, California, 2000–2004. Clin Infect Dis 2006; 42:337–345.

17. Diagnostic criteria and management of syphilis. In: Standardization Administration of the People’s Republic of China. China’s Compulsory National Standard Collecting, the Vol. 5 of Labour Protection, Medical and Health, 3rd ed. Beijing: Standards Press of China, 2003:218–226.

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