Alternative Treatments for Syphilis During Pregnancy

Abstract

SYPHILIS IN PREGNANCY Syphilis in pregnancy continues to be a problem worldwide. In the United States, the rate of congenital syphilis continues to rapidly rise with the highest number of cases reported in 2017 since 1997.1 In fact, congenital syphilis is among the most common neonatal infections contributing to early infant mortality. There are more cases of congenital syphilis than perinatally acquired human immunodeficiency virus infection.2 If a pregnant woman is infected with syphilis and not properly treated, the fetus has up to an 80% likelihood of being infected.1 Syphilis infection during pregnancy is associated with miscarriage, stillbirth, or neonatal death shortly after delivery in 30% of cases.3 If the fetus survives, the pregnancy may be complicated by preterm birth, low birth weight, and congenital syphilis.2,3 Early congenital syphilis is associated with bone deformities, rashes, jaundice, lethargy, and anemia.4 Later consequences of congenital syphilis include neurological impairment, sensorineural deafness, and blindness due to interstitial keratitis.4 The current standard of care for the treatment of syphilis acquired during pregnancy is benzathine penicillin G, as a single intramuscular injection of 2.4 million units.5 Benzathine penicillin G treatment is highly effective. The success of benzathine penicillin G treatment is as high as 98.2% in the prevention of congenital syphilis.6 In nonpregnant patients, doxycycline7 and ceftriaxone8 are accepted alternative treatments; however, benzathine penicillin G is the only recommended treatment for syphilis in pregnancy.5 In the case of penicillin allergy, the only treatment recommendation is penicillin desensitization followed by treatment with benzathine penicillin G.5 One third or more pregnant women may undergo allergic reactions during desensitization procedures9; therefore, the desensitization process requires close monitoring by experienced personnel.9 Another challenge for the treatment of syphilis during pregnancy is the access to benzathine penicillin G. There have been stockouts and shortages of benzathine penicillin G globally and multiple disruptions in manufacturing and the supply chain.10,11 Additionally, in many settings, it may be preferable to administer oral medications instead of injections. New and alternative treatments are urgently needed. Therefore, to assess the current evidence for alternative treatments and describe the path forward, we reviewed published alternative treatments for pregnant women diagnosed with syphilis. REVIEW OF PRIOR EXPERIENCE WITH ALTERNATIVE TREATMENTS We searched 3 databases: PubMed, Embase, and Scopus between the dates of January 1, 1970, and December 31, 2018. We examined cases of nonpenicillin treatments of syphilis in pregnant patients and excluded studies involving only penicillin. We defined successful maternal treatment as both a 4-fold decline in maternal rapid plasma reagin (RPR) titer from the time of diagnosis compared with the time of delivery and the resolution of presenting clinical findings. Congenital syphilis prevention was defined as the absence of congenital syphilis. We identified 6 publications between 1970 and 2018 that described alternative treatments for syphilis in a total of 21 pregnant patients (see Table 1). There were no publications reporting more than 15 cases or any randomized or comparative controlled trials that investigated alternative treatments for syphilis during pregnancy.TABLE 1: Alternative Options to Penicillin for Treatment of Syphilis During PregnancyAmoxicillin In a case series by Katanami et al.12 in Japan, the authors reported 2 case patients treated with oral amoxicillin as an alternative to penicillin. Although, in Japan, benzathine penicillin G is the recommended treatment for syphilis in pregnancy, the authors report that benzathine penicillin G is not routinely available, and they typically use benzylpenicillin benzathine hydrate, amoxicillin, or ampicillin as alternatives.12 In their case series, one mother at 13 weeks of gestation received oral amoxicillin 6 g and probenecid 1 g daily for a 14-day course.12 The second case patient at 6 weeks of gestation received oral amoxicillin 1.5 g with probenecid 750 mg daily for treatment days 1 to 3, oral amoxicillin 3 g daily with probenecid 750 mg daily for treatment days 4 to 6, and intramuscular ceftriaxone 2 g daily for treatment days 7 to 14.12 Case patient 1 had a decline in RPR titer from 1:16 to 1:4 6 months after treatment. Case patient 2 had a decline in RPR titer from 1:32 to 1:4 6 months after treatment. The newborns had no evidence of congenital syphilis.12 Cephalosporin Antibiotics As reported above, one of the Katanami et al12 cases described the successful use of intramuscular ceftriaxone in conjunction with oral amoxicillin for the treatment of syphilis during pregnancy with the prevention of congenital syphilis. Zhou et al13 reported 11 pregnant women with primary or secondary syph