Treatment of Congenital Syphilis
The treatment of congenital syphilis depends on the clinical scenario and maternal treatment history, with aqueous crystalline penicillin G 100,000-150,000 units/kg/day IV for 10 days being the preferred regimen for proven or highly probable cases. 1
Treatment Regimens by Clinical Scenario
Scenario 1: Proven or Highly Probable Congenital Syphilis
Infants requiring treatment include those with:
- Physical or radiographic evidence of active disease 1
- Reactive CSF VDRL or abnormal CSF parameters (>5 WBCs/mm³ or protein >40 mg/dL in term infants) 1
- Serum nontreponemal titer ≥4-fold higher than maternal titer 1
Recommended regimens: 1
- Aqueous crystalline penicillin G 100,000-150,000 units/kg/day IV, administered as 50,000 units/kg/dose every 12 hours during the first 7 days of life, then every 8 hours thereafter for a total of 10 days
- OR Procaine penicillin G 50,000 units/kg/dose IM once daily for 10 days
Critical caveat: If more than 1 day of therapy is missed, restart the entire 10-day course 1. Data are insufficient for alternative antimicrobials like ampicillin; when possible, complete the full 10-day penicillin course even if ampicillin was initially given for sepsis 1.
Scenario 2: Normal Examination but Inadequate Maternal Treatment
Infants with normal physical examination and serum titer ≤4-fold maternal titer, but whose mother was: 1
- Not treated, inadequately treated, or no documentation of treatment
- Treated with erythromycin or non-penicillin regimen
- Received treatment <4 weeks before delivery
Recommended regimens: 1
- Aqueous crystalline penicillin G 100,000-150,000 units/kg/day IV for 10 days (preferred)
- OR Procaine penicillin G 50,000 units/kg/dose IM daily for 10 days
- OR Benzathine penicillin G 50,000 units/kg/dose IM single dose (only if complete evaluation including CSF examination, long-bone radiographs, and CBC with platelets is normal and follow-up is certain) 1
Important note: If the mother has untreated early syphilis at delivery, 10 days of parenteral therapy should be strongly considered 1.
Scenario 3: Adequate Maternal Treatment >4 Weeks Before Delivery
Infants with normal examination, serum titer ≤4-fold maternal titer, and whose mother: 1
- Was treated during pregnancy with appropriate therapy for infection stage
- Received treatment >4 weeks before delivery
- Has no evidence of reinfection or relapse
Recommended regimen: 1
- Benzathine penicillin G 50,000 units/kg/dose IM single dose
Alternative approach: Some experts recommend close serologic follow-up without treatment if the mother's nontreponemal titers decreased 4-fold after appropriate therapy for early syphilis or remained stable/low for late syphilis 1.
Scenario 4: Maternal Treatment Before Pregnancy with Stable Titers
Infants with normal examination, serum titer ≤4-fold maternal titer, and whose mother: 1
- Was adequately treated before pregnancy
- Had stable low nontreponemal titers before, during pregnancy, and at delivery (VDRL <1:2; RPR <1:4)
Recommended approach: 1
- No treatment required
- However, benzathine penicillin G 50,000 units/kg IM single dose may be considered, particularly if follow-up is uncertain
Treatment of Older Infants and Children (>1 Month)
Children identified with reactive serologic tests after the neonatal period require: 1
- Review of maternal serology and treatment records
- Full evaluation including CSF analysis (VDRL, cell count, protein), CBC with differential and platelets, and other tests as clinically indicated (long-bone radiographs, chest radiograph, liver function tests, ophthalmologic examination, auditory brainstem response)
Recommended regimen: 1
- Aqueous crystalline penicillin G 200,000-300,000 units/kg/day IV, administered as 50,000 units/kg every 4-6 hours for 10 days
Special consideration: If the child has no clinical manifestations, normal CSF examination, and negative CSF VDRL, up to 3 weekly doses of benzathine penicillin G 50,000 units/kg IM can be considered 1. Some specialists suggest adding a single dose of benzathine penicillin G 50,000 units/kg IM following the 10-day IV course 1.
Evidence Quality and Comparative Effectiveness
High-quality evidence from a randomized trial (169 participants) demonstrated no differences between benzathine penicillin and procaine benzylpenicillin for absence of clinical manifestations (RR 1.00,95% CI 0.97-1.03) or serological cure (RR 1.00,95% CI 0.97-1.03), with no deaths in either group 2, 3. This supports either regimen as acceptable for asymptomatic congenital syphilis 3.
Critical Follow-Up Requirements
All seroreactive infants require: 1
- Follow-up examinations and nontreponemal testing every 2-3 months until nonreactive or titer decreases 4-fold
- Nontreponemal titers should decline by 3 months and be nonreactive by 6 months if adequately treated 1
- If titers are stable or increase after 6-12 months, perform CSF examination and retreat with 10-day parenteral penicillin 1
Infants with abnormal initial CSF require: 1
- Repeat lumbar puncture approximately every 6 months until normal
- Retreatment for neurosyphilis if CSF VDRL remains reactive or CSF indices remain abnormal 1
Common Pitfalls to Avoid
Do not use treponemal tests to evaluate treatment response - they remain positive despite effective therapy 1. Passively transferred maternal treponemal antibodies can persist until 15 months of age; a reactive treponemal test after 18 months is diagnostic of congenital syphilis 1.
CSF interpretation challenges: Normal CSF values differ by gestational age and are higher in preterm infants (up to 25 WBCs/mm³ and protein 150 mg/dL may be normal), though some experts recommend lower thresholds (5 WBCs/mm³, protein 40 mg/dL) 1.
No proven alternatives to penicillin exist for congenital syphilis 1. Infants with penicillin allergy should undergo desensitization if necessary 1. If non-penicillin agents are used, close serologic and CSF follow-up are mandatory 1.