What is the recommended management of primary syphilis in a pregnant woman, including treatment regimen, follow‑up serology, partner therapy, and neonatal care, and how should a reported penicillin allergy be addressed?

Primary Syphilis in Pregnancy

Treat all pregnant women with primary syphilis using benzathine penicillin G 2.4 million units IM as a single dose, followed by a second dose of 2.4 million units IM exactly one week later, as this is the only proven therapy to prevent congenital syphilis and maternal-to-fetal transmission. 1, 2

Treatment Regimen for Primary Syphilis

For primary syphilis in pregnancy, administer benzathine penicillin G 2.4 million units IM immediately, then repeat with a second dose of 2.4 million units IM one week after the initial dose. 1, 3, 2

• The two-dose regimen is particularly critical for women in the third trimester or those with secondary syphilis features, as single-dose therapy has been associated with treatment failure. 1, 2, 4
• Research from South Africa demonstrated that treponemicidal coverage of 3 weeks or less (essentially one injection) resulted in significantly decreased birth weight (2,748 vs. 3,130 g), with relative risks of 8.5 for prematurity, 20.5 for perinatal mortality, and 2.0 for congenital syphilis compared to longer coverage. 4
• Each injection must be spaced exactly 7 days apart to ensure adequate treponemicidal coverage, ideally administered 4 weeks or more before delivery. 3, 4

Management of Penicillin Allergy

Pregnant women with reported penicillin allergy must undergo skin testing to confirm allergy status, followed by desensitization and treatment with penicillin—there are no acceptable alternatives. 1, 3, 2

• The CDC explicitly states that no alternative antimicrobial regimen is acceptable for treating syphilis in pregnancy; penicillin remains mandatory even with confirmed allergy. 3, 2
• Desensitization can be performed safely during pregnancy with careful monitoring, as demonstrated in case reports of successful intravenous penicillin desensitization. 5
• Never use tetracycline, doxycycline, or erythromycin: tetracyclines cause maternal hepatotoxicity and fetal bone/tooth staining, while erythromycin does not reliably cure fetal infection or prevent congenital syphilis. 1, 3, 2

Follow-Up Serology Protocol

Repeat serologic titers in the third trimester and at delivery to monitor treatment response. 1, 2

• Check titers monthly until delivery in women at high risk for reinfection or in areas with high syphilis prevalence. 1, 2
• Most women will deliver before the serologic response to treatment can be definitively evaluated, making close monitoring essential. 3
• Do not compare titers between different test types (VDRL vs. RPR), as they are not directly comparable. 3

Monitoring for Jarisch-Herxheimer Reaction

Counsel patients to seek immediate obstetric attention if they experience fever, uterine contractions, or decreased fetal movements within 24 hours after treatment. 3, 2

• Women treated during the second half of pregnancy are at risk for premature labor and/or fetal distress if treatment precipitates a Jarisch-Herxheimer reaction. 6
• For gestations beyond 20 weeks, consider fetal and uterine-contraction monitoring for 24 hours after initiating therapy, especially when ultrasound suggests possible fetal infection. 3
• Never delay treatment due to fear of Jarisch-Herxheimer reaction—untreated maternal syphilis poses far greater risk to the fetus than the reaction itself. 3, 2

Fetal Assessment

Perform pretreatment ultrasound in viable pregnancies when feasible, particularly after 20 weeks gestation. 1, 3

• Sonographic signs of fetal syphilis include hepatomegaly, placentomegaly, ascites, hydrops, and elevated middle cerebral artery peak systolic velocity. 1, 3
• Pregnancies with ultrasound abnormalities indicating fetal syphilis have greater risk for treatment failure and should be managed in consultation with obstetric specialists. 6
• Ultrasound findings should not delay therapy—treatment must proceed immediately regardless of imaging results. 6

Partner Management

Treat sexual partners exposed within 90 days of diagnosis presumptively with benzathine penicillin G 2.4 million units IM, even if seronegative. 1, 3

• Offer HIV testing to all patients with syphilis, as co-infection increases the risk of perinatal transmission and may affect treatment response. 1, 3, 2
• Long-term sexual partners should be clinically and serologically evaluated. 2

Neonatal Care Considerations

No newborn should be discharged without documented maternal syphilis screening at least once during pregnancy, preferably with confirmation at delivery. 1, 3, 2

• If the mother received adequate treatment more than 4 weeks before delivery and has no evidence of reinfection, the infant may require only benzathine penicillin G 50,000 units/kg IM as a single dose. 6
• If maternal treatment was inadequate, given less than 4 weeks before delivery, or if the infant shows signs of congenital syphilis, the infant requires full evaluation (CSF analysis, long-bone radiographs, CBC with platelets) and 10 days of parenteral penicillin therapy. 6
• Infants born to mothers with untreated primary syphilis at delivery should receive 10 days of parenteral therapy. 6

Critical Pitfalls to Avoid

• Do not use single-dose therapy alone—research demonstrates significantly worse outcomes with inadequate treponemicidal coverage. 4, 7
• Do not substitute non-penicillin antibiotics (azithromycin, ceftriaxone, erythromycin)—these are ineffective and do not prevent congenital infection. 3, 2
• Do not discharge a newborn without documented maternal screening—this represents a critical systems failure. 1, 3, 2
• Do not delay treatment for ultrasound results—imaging should inform prognosis but never postpone therapy. 6