In a pregnant woman with a non‑treponemal syphilis titer (VDRL/RPR) of 1:4 that has not decreased after two months of appropriate benzathine penicillin G therapy, what is the recommended next step in management?

Management of Pregnant Woman with Persistent 1:4 Syphilis Titer

A pregnant woman with a non-treponemal titer of 1:4 that has not decreased after two months of appropriate benzathine penicillin G therapy should receive re-treatment with a second dose of benzathine penicillin G 2.4 million units IM, particularly because she is in pregnancy and the adequacy of maternal treatment cannot be confirmed by the expected fourfold titer decline. 1

Critical Context: Why This Titer Pattern Matters in Pregnancy

The 1:4 titer represents a low-level serologic response, but the lack of fourfold decline after appropriate treatment is the key concern 1. In pregnancy, this pattern triggers specific management protocols because:

• Failure to achieve a fourfold decline in nontreponemal titers after treatment for early syphilis indicates inadequate treatment response, which places the fetus at risk for congenital syphilis 1
• The CDC specifically identifies pregnant women whose titers "did not decrease sufficiently after therapy to indicate an adequate response (≥fourfold decrease)" as requiring their infants to undergo full evaluation for congenital syphilis 1
• Some experts recommend additional therapy (a second dose of benzathine penicillin 2.4 million units IM) 1 week after the initial dose, particularly for women in the third trimester and women who have secondary syphilis during pregnancy 1

Immediate Re-Treatment Protocol

Administer benzathine penicillin G 2.4 million units IM immediately 1, 2:

• This second dose should be given without delay, as the two-month window has already passed without adequate serologic response 1
• The 2009 HIV/AIDS guidelines note that "certain specialists recommend a second injection 1 week after the initial injection for pregnant women with early syphilis" due to treatment failures reported after single injections 1
• For HIV-infected pregnant women, a second injection should be strongly considered due to additional concerns about treatment efficacy 1

Essential Concurrent Evaluation

Determine Stage of Maternal Infection

• Review the original diagnosis: Was this primary, secondary, or early latent syphilis? 1
• Timing of initial treatment: Treatment given <4 weeks before delivery is considered inadequate for preventing congenital syphilis 1
• Initial titer at diagnosis: Higher baseline titers (>1:8) may require longer to decline 1

HIV Testing

• All pregnant women with syphilis must be tested for HIV infection 1, 2, 3
• HIV co-infection significantly affects serologic response patterns and increases the risk of treatment failure 1, 2, 3
• HIV-infected patients may have "unusually low, high, or fluctuating titers" 1, 2

Rule Out Reinfection

• A fourfold increase in titer would indicate reinfection or relapse, requiring full re-treatment 1
• Evaluate for new sexual exposures during pregnancy 2
• Sexual partners from the past 6 months should be identified, tested, and treated presumptively 2

Follow-Up Monitoring Strategy

Serologic Monitoring

• Check quantitative nontreponemal titers monthly throughout pregnancy until adequacy of treatment is assured 1
• Use the same test method (RPR or VDRL) from the same laboratory for all serial measurements 2, 3
• Treatment success is defined as a fourfold decline in titer within 6 months for early syphilis 2, 4

Expected Serologic Response After Re-Treatment

• After re-treatment, titers should decline fourfold within 6-12 months for early syphilis 2, 4
• Some patients become "serofast" with persistent low titers (≤1:8) despite adequate treatment—this does not necessarily indicate treatment failure 2, 5
• A recent 2025 study of 584 pregnant women with serofast syphilis found that 92% had normal pregnancy outcomes, with no cases of congenital syphilis among 462 newborns followed 5

Implications for the Newborn

Because the mother's titers did not decrease fourfold after appropriate therapy, the infant will require comprehensive evaluation at birth 1:

Mandatory Infant Evaluation Components

• CSF analysis for VDRL, cell count, and protein 1
• Complete blood count with differential and platelet count 1
• Long-bone radiographs 1
• Quantitative nontreponemal serologic test on infant's serum (not cord blood) 1

Infant Treatment Decision Algorithm

If the infant's evaluation is completely normal AND follow-up is certain:

• Single dose of benzathine penicillin G 50,000 units/kg IM 1

If any part of the evaluation is abnormal, incomplete, or follow-up is uncertain:

• Full 10-day course of aqueous crystalline penicillin G 100,000-150,000 units/kg/day IV (administered as 50,000 units/kg every 12 hours during first 7 days, then every 8 hours) 1
• OR procaine penicillin G 50,000 units/kg IM daily for 10 days 1

Critical Pitfalls to Avoid

Do Not Delay Re-Treatment

• Waiting beyond two months without serologic response places the fetus at continued risk 1, 6
• A 2019 retrospective study of 1,187 pregnant women with syphilis found that treatment after 28 weeks of pregnancy was associated with significantly higher rates of adverse outcomes (adjusted RR = 2.34) compared to treatment before 28 weeks 6

Penicillin Allergy Is Not an Excuse

• There are no proven alternatives to penicillin for treating syphilis in pregnancy 1, 2
• Pregnant women with penicillin allergy must undergo desensitization and receive penicillin 1, 2
• Erythromycin, tetracycline, and doxycycline are contraindicated—they cannot reliably cure fetal infection 1

Monitor for Jarisch-Herxheimer Reaction

• Women treated during the second half of pregnancy are at risk for premature labor or fetal distress if treatment precipitates a Jarisch-Herxheimer reaction 1, 7
• Advise the patient to seek immediate medical attention if she notices any change in fetal movements or experiences contractions 1, 7
• This reaction is "a complex allergic response to antigens released from dead micro-organisms, which can cause fetal distress and uterine contractions" 7

Prozone Phenomenon

• In rare cases (5.3%), very high antibody levels can cause false-negative RPR results 8
• If clinical suspicion is high despite negative or low titers, request serial dilutions of the serum 8
• This phenomenon is particularly important in secondary syphilis and in areas of high syphilis prevalence 8

Special Consideration: Serofast State in Pregnancy

• The 2025 prospective study found that among 568 women with serofast syphilis, 74.7% maintained stable titers throughout pregnancy, and re-treatment did not significantly improve seroreversion rates (aOR 1.43,95% CI 0.76-2.71) 5
• However, this evidence applies to women with documented adequate prior treatment and stable low titers—not to women whose titers have failed to decline after recent treatment 5
• The current scenario (lack of fourfold decline after initial treatment) represents inadequate treatment response, not serofast state 1