Congenital Syphilis

Effective prevention and detection of congenital syphilis depends on the identification of syphilis in pregnant women and, therefore, on the routine serologic screening of pregnant women during the first prenatal visit. Additional testing at 28 weeks’ gestation and again at delivery is warranted for women who are at increased risk or live in communities with increased prevalence of syphilis infection (442,450). Moreover, as part of the management of pregnant women who have syphilis, information concerning ongoing risk behaviors and treatment of sex partners should be obtained to assess the risk for reinfection. Routine screening of newborn sera or umbilical cord blood is not recommended, as diagnosis at this time does not prevent symptomatic congenital syphilis in some newborns. No mother or newborn infant should leave the hospital without maternal serologic status having been documented at least once during pregnancy, and preferably again at delivery if at risk.

Evaluation and Treatment of Neonates (Infants Aged <30 Days)

The diagnosis of congenital syphilis can be difficult, as maternal nontreponemal and treponemal IgG antibodies can be transferred through the placenta to the fetus, complicating the interpretation of reactive serologic tests for syphilis in neonates. Therefore, treatment decisions frequently must be made on the basis of 1) identification of syphilis in the mother; 2) adequacy of maternal treatment; 3) presence of clinical, laboratory, or radiographic evidence of syphilis in the neonate; and 4) comparison of maternal (at delivery) and neonatal nontreponemal serologic titers using the same test, preferably conducted by the same laboratory. Any neonate at risk for congenital syphilis should receive a full evaluation and testing for HIV infection.

All neonates born to mothers who have reactive nontreponemal and treponemal test results should be evaluated with a quantitative nontreponemal serologic test (RPR or VDRL) performed on the neonate’s serum, because umbilical cord blood can become contaminated with maternal blood and yield a false-positive result, and Wharton’s jelly within the umbilical cord can yield a false-negative result. Conducting a treponemal test (i.e., TP-PA, FTA-ABS, EIA, or CIA) on neonatal serum is not recommended because it is difficult to interpret. No commercially available immunoglobulin (IgM) test can be recommended.

All neonates born to women who have reactive serologic tests for syphilis should be examined thoroughly for evidence of congenital syphilis (e.g., nonimmune hydrops, jaundice, hepatosplenomegaly, rhinitis, skin rash, and pseudoparalysis of an extremity). Pathologic examination of the placenta or umbilical cord using specific staining (e.g., silver) or a T. pallidum PCR test using a CLIA-validated test should be considered; DFA-TP reagents are not available. Darkfield microscopic examination or PCR testing of suspicious lesions or body fluids (e.g., bullous rash and nasal discharge) also should be performed. In addition to these tests, for stillborn infants, skeletal survey demonstrating typical osseous lesions might aid in the diagnosis of congenital syphilis.

The following scenarios describe the congenital syphilis evaluation and treatment of neonates born to women who have reactive serologic tests for syphilis during pregnancy. Maternal history of infection with T. pallidum and treatment for syphilis must be considered when evaluating and treating the neonate for congenital syphilis in most scenarios, except when congenital syphilis is proven or highly probable (See Scenario 1).

Scenario 1: Proven or highly probable congenital syphilis

Any neonate with:

1. an abnormal physical examination that is consistent with congenital syphilis;
   OR
2. a serum quantitative nontreponemal serologic titer that is fourfold higher than the mother’s titer;^¶
   OR
3. a positive darkfield test or PCR of lesions or body fluid(s).

^¶ The absence of a fourfold or greater titer for a neonate does not exclude congenital syphilis.

Recommended Evaluation

• CSF analysis for VDRL, cell count, and protein **
• Complete blood count (CBC) and differential and platelet count
• Other tests as clinically indicated (e.g., long-bone radiographs, chest radiograph, liver-function tests, neuroimaging, ophthalmologic examination, and auditory brain stem response).

^**CSF test results obtained during the neonatal period can be difficult to interpret; normal values differ by gestational age and are higher in preterm infants. Values as high as 25 white blood cells (WBCs) /mm3 and/or protein of 150 mg/dL might occur among normal neonates; lower values (i.e., 5 WBCs/mm3 and protein of 40 mg/dL) might be considered the upper limits of normal. Other causes of elevated values should be considered when an infant is being evaluated for congenital syphilis.

If more than 1 day of therapy is missed, the entire course should be restarted. Data are insufficient regarding the use of other antimicrobial agents (e.g., ampicillin). When possible, a full 10-day course of penicillin is preferred, even if ampicillin was initially provided for possible sepsis. The use of agents other than penicillin requires close serologic follow-up to assess adequacy of therapy.

Scenario 2: Possible Congenital Syphilis

Any neonate who has a normal physical examination and a serum quantitative nontreponemal serologic titer equal to or less than fourfold the maternal titer and one of the following:

1. mother was not treated, inadequately treated, or has no documentation of having received treatment;
   OR
2. mother was treated with erythromycin or a regimen other than those recommended in these guidelines (i.e., a nonpenicillin G regimen);^††
   OR
3. mother received recommended treatment <4 weeks before delivery.

^†† A women treated with a regimen other than recommended in these guidelines should be considered untreated.

Recommended Evaluation

• CSF analysis for VDRL, cell count, and protein**
• CBC, differential, and platelet count
• Long-bone radiographs

A complete evaluation is not necessary if 10 days of parenteral therapy is administered, although such evaluations might be useful. For instance, a lumbar puncture might document CSF abnormalities that would prompt close follow-up. Other tests (e.g., CBC, platelet count, and bone radiographs) can be performed to further support a diagnosis of congenital syphilis.

^**CSF test results obtained during the neonatal period can be difficult to interpret; normal values differ by gestational age and are higher in preterm infants. Values as high as 25 white blood cells (WBCs) /mm3 and/or protein of 150 mg/dL might occur among normal neonates; lower values (i.e., 5 WBCs/mm3 and protein of 40 mg/dL) might be considered the upper limits of normal. Other causes of elevated values should be considered when an infant is being evaluated for congenital syphilis.

Before using the single-dose benzathine penicillin G regimen, the complete evaluation (i.e., CSF examination, long-bone radiographs, and CBC with platelets) must be normal, and follow-up must be certain. If any part of the infant’s evaluation is abnormal or not performed, if the CSF analysis is uninterpretable because of contamination with blood, or if follow-up is uncertain, a 10-day course of penicillin G is required. If the neonate’s nontreponemal test is nonreactive and the provider determines that the mother’s risk of untreated syphilis is low, treatment of the neonate with a single IM dose of benzathine penicillin G 50,000 units/kg for possible incubating syphilis can be considered without an evaluation.

Neonates born to mothers with untreated early syphilis at the time of delivery are at increased risk for congenital syphilis, and the 10-day course of penicillin G may be considered even if the complete evaluation is normal and follow-up is certain.

Scenario 3: Congenital Syphilis less likely

Any neonate who has a normal physical examination and a serum quantitative nontreponemal serologic titer equal to or less than fourfold the maternal titer and both of the following are true:

1. mother was treated during pregnancy, treatment was appropriate for the stage of infection, and treatment was administered >4 weeks before delivery and
2. mother has no evidence of reinfection or relapse.

Recommended Evaluation

No evaluation is recommended.

Scenario 4: Congenital Syphilis unlikely

Any neonate who has a normal physical examination and a serum quantitative nontreponemal serologic titer equal to or less than fourfold the maternal titer and both of the following are true:

1. mother’s treatment was adequate before pregnancy and
2. mother’s nontreponemal serologic titer remained low and stable (i.e., serofast) before and during pregnancy and at delivery (VDRL <1:2; RPR <1:4).

Recommended Evaluation

No evaluation is recommended.

Follow-Up

All neonates with reactive nontreponemal tests should receive careful follow-up examinations and serologic testing (i.e., a nontreponemal test) every 2–3 months until the test becomes nonreactive. In the neonate who was not treated because congenital syphilis was considered less likely or unlikely, nontreponemal antibody titers should decline by age 3 months and be nonreactive by age 6 months, indicating that the reactive test result was caused by passive transfer of maternal IgG antibody. At 6 months, if the nontreponemal test is nonreactive, no further evaluation or treatment is needed; if the nontreponemal test is still reactive, the infant is likely to be infected and should be treated. Treated neonates that exhibit persistent nontreponemal test titers by 6–12 months should be re-evaluated through CSF examination and managed in consultation with an expert. Retreatment with a 10-day course of a penicillin G regimen may be indicated. Neonates with a negative nontreponemal test at birth and whose mothers were seroreactive at delivery should be retested at 3 months to rule out serologically negative incubating congenital syphilis at the time of birth. Treponemal tests should not be used to evaluate treatment response because the results are qualitative and passive transfer of maternal IgG treponemal antibody might persist for at least 15 months.

Neonates whose initial CSF evaluations are abnormal should undergo a repeat lumbar puncture approximately every 6 months until the results are normal. A reactive CSF Venereal Disease Research Laboratory (VDRL) test or abnormal CSF indices that persist and cannot be attributed to other ongoing illness requires retreatment for possible neurosyphilis and should be managed in consultation with an expert.

Special Considerations

Penicillin Allergy

Infants and children who require treatment for congenital syphilis but who have a history of penicillin allergy or develop an allergic reaction presumed secondary to penicillin should be desensitized and then treated with penicillin (see Management of Persons with a History of Penicillin Allergy). Skin testing remains unavailable for infants and children because the procedure has not been standardized for this age group. Data are insufficient regarding the use of other antimicrobial agents (e.g., ceftriaxone) for congenital syphilis in infants and children. If a nonpenicillin G agent is used, close clinical, serologic, and CSF follow-up is required in consultation with an expert.

Penicillin Shortage

During periods when the availability of aqueous crystalline penicillin G is compromised, the following is recommended (see https://www.cdc.gov/std/treatment/drugnotices/penicilling.htm).

1. For neonates with clinical evidence of congenital syphilis (Scenario 1), check local sources for aqueous crystalline penicillin G (potassium or sodium). If IV penicillin G is limited, substitute some or all daily doses with procaine penicillin G (50,000 U/kg/dose IM a day in a single daily dose for 10 days).

If aqueous or procaine penicillin G is not available, ceftriaxone (in doses appropriate for birthweight) can be considered with careful clinical and serologic follow-up and in consultation with an expert, as evidence is insufficient to support the use of ceftriaxone for the treatment of congenital syphilis. Management might include a repeat CSF examination at age 6 months if the initial examination was abnormal. Ceftriaxone must be used with caution in infants with jaundice.

2. For neonates without any clinical evidence of congenital syphilis (Scenario 2 and Scenario 3), use

a. procaine penicillin G, 50,000 U/kg/dose IM a day in a single dose for 10 days

or

b. benzathine penicillin G, 50,000 U/kg IM as a single dose.

If any part of the evaluation for congenital syphilis is abnormal or was not performed, CSF examination is not interpretable, or follow-up is uncertain, procaine penicillin G is recommended. A single dose of ceftriaxone is inadequate therapy.

3. For premature infants who have no clinical evidence of congenital syphilis (Scenario 2 and Scenario 3) and might not tolerate IM injections because of decreased muscle mass, IV ceftriaxone can be considered with careful clinical and serologic follow-up and in consultation with an expert. Ceftriaxone dosing must be adjusted according to birthweight.

HIV Infection

Evidence is insufficient to determine whether neonates who have congenital syphilis and HIV or whose mothers have HIV infection require different therapy or clinical management than is recommended for all neonates. All neonates with congenital syphilis and HIV infection should be managed similarly as neonates with congenital syphilis who do not have HIV infection.

Evaluation and Treatment of Infants and Children with Congenital Syphilis

Infants and children aged ≥1 month who are identified as having reactive serologic tests for syphilis should be examined thoroughly and have maternal serology and records reviewed to assess whether they have congenital or acquired syphilis (see Primary and Secondary Syphilis and Latent Syphilis, Sexual Assault or Abuse of Children). Any infant or child at risk for congenital syphilis should receive a full evaluation and testing for HIV infection.

Recommended Evaluation

• CSF analysis for VDRL, cell count, and protein
• CBC, differential, and platelet count
• Other tests as clinically indicated (e.g., long-bone radiographs, chest radiograph, liver function tests, abdominal ultrasound, ophthalmologic examination, neuroimaging, and auditory brain-stem response)

If the infant or child has no clinical manifestations of congenital syphilis and the evaluation (including the CSF examination) is normal, treatment with up to 3 weekly doses of benzathine penicillin G, 50,000 U/kg IM can be considered. A single dose of benzathine penicillin G 50,000 units/kg IM up to the adult dose of 2.4 million units in a single dose can be considered after the 10-day course of IV aqueous penicillin to provide more comparable duration of treatment in those who have no clinical manifestations and normal CSF. All of the above treatment regimens also would be adequate for children who might have other treponemal infections.

Follow-Up

Careful follow-up examinations and serologic testing (i.e., a nontreponemal test) of infants and children treated for congenital syphilis after the neonatal period (30 days of age) should be performed every 3 months until the test becomes nonreactive or the titer has decreased fourfold. The serologic response after therapy might be slower for infants and children than neonates. If these titers increase at any point for more than 2 weeks or do not decrease fourfold after 12–18 months, the infant or child should be evaluated (e.g., through CSF examination), treated with a 10-day course of parenteral penicillin G, and managed in consultation with an expert. Treponemal tests should not be used to evaluate treatment response, because the results are qualitative and persist after treatment; further, passive transfer of maternal IgG treponemal antibody might persist for at least 15 months after delivery.

Infants or children whose initial CSF evaluations are abnormal should undergo a repeat lumbar puncture approximately every 6 months until the results are normal. After 2 years of follow-up, a reactive CSF VDRL test or abnormal CSF indices that persists and cannot be attributed to other ongoing illness requires retreatment for possible neurosyphilis and should be managed in consultation with an expert.

Special Considerations

Penicillin Allergy

Infants and children who require treatment for congenital syphilis but who have a history of penicillin allergy or develop an allergic reaction presumed secondary to penicillin should be desensitized and treated with penicillin (see Management of Persons with a History of Penicillin Allergy). Skin testing remains unavailable for infants and children because the procedure has not been standardized for this age group. Data are insufficient regarding the use of other antimicrobial agents (e.g., ceftriaxone) for congenital syphilis in infants and children. If a nonpenicillin G agent is used, close clinical, serologic, and CSF follow-up is required in consultation with an expert.

Penicillin Shortage

During periods when the availability of penicillin G is compromised, management options are similar to options for the neonate (see Evaluation and treatment of infants during the first month of life).

1. For infants and children with clinical evidence of congenital syphilis, procaine penicillin G (50,000 U/kg/dose IM up to the adult dose of 2.4 million units a day in a single daily dose for 10 days) is recommended. A single dose of benzathine penicillin G 50,000 units/kg IM up to the adult dose of 2.4 million units in a single dose can be considered after the 10-day course of procaine penicillin. If procaine or benzathine penicillin G is not available, ceftriaxone (in doses appropriate for age and weight) can be considered with careful clinical and serologic follow-up. Infants and children receiving ceftriaxone should be managed in consultation with an expert, as evidence is insufficient to support the use of ceftriaxone for the treatment of congenital syphilis in infants or children. For infants aged ≥30 days, use 75 mg/kg IV/IM of ceftriaxone a day in a single daily dose for 10–14 days (dose adjustment might be necessary based on current weight). For children, the dose should be 100 mg/kg of ceftriaxone a day in a single daily dose.

2. For infants and children without any clinical evidence of infection (see Scenario 2 and Scenario 3), use

a. procaine penicillin G, 50,000 U/kg/dose IM a day in a single dose for 10 days

or

b. benzathine penicillin G, 50,000 U/kg IM as a single dose.

If any part of the evaluation for congenital syphilis is abnormal or not performed, CSF examination is not interpretable, or follow-up is uncertain, procaine penicillin G is recommended.

HIV Infection

Evidence is insufficient to determine whether infants and children who have congenital syphilis and HIV or whose mothers have HIV infection require different therapy or clinical management than is recommended for all infants and children. All infants and children with congenital syphilis and HIV infection should be managed like infants and children without HIV infection.

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