New York State Addendum for Congenital Syphilis Treatment Guidelines

The New York State Bureau of Sexually Transmitted Disease Control has issued an addendum to the Centers for Disease Control and Prevention, Sexually Transmitted Diseases Treatment Guidelines 2006. These modified guidelines, presented below, reflect the Bureau's policy and procedures specifically for the evaluation and management of pregnant women with syphilis, and of infants at risk for congenital syphilis. Clinical providers are encouraged to refer to this addendum for guidance on the evaluation and treatment of syphilis in pregnant women and at-risk infants. The Centers for Disease Control and Prevention, Sexually Transmitted Diseases Treatment Guidelines 2006 are referred to throughout this document.

Syphilis During Pregnancy

New York State Regulations for Screening During Pregnancy

  1. All women must be screened serologically for syphilis at the time pregnancy is first diagnosed. In communities and populations with high syphilis prevalence or for patients at high risk New York State surveillance data indicates that repeat infection and infection acquired late in pregnancy are not uncommon events; therefore, women from these settings should be screened repeatedly throughout pregnancy (perhaps monthly in some instances e.g., high risk women who continue to be sexually active).
  2. New York State law mandates screening at delivery for all infants. In addition, any woman who delivers a stillborn infant after 20 weeks gestation must be tested for syphilis. No infant should leave the hospital without the serologic status of the infant's mother having been determined at least once during pregnancy.

Diagnostic Considerations

Seropositive pregnant women should be considered infected unless treatment history is documented clearly in a medical or health department record and sequential serologic antibody titers have appropriately declined. Serofast low antibody titers might not require treatment; however, persistent higher titer antibody tests might indicate reinfection and require treatment.

Treatment

Penicillin is effective for preventing transmission to fetuses and for treating established infection among fetuses. Evidence is insufficient, however, to determine whether the specific, recommended penicillin regimens are optimal.

Recommended Regimens

Treatment during pregnancy should be the penicillin regimen appropriate for the woman's stage of syphilis. Some experts recommend additional therapy (e.g., a second dose of benzathine penicillin 2.4 million units IM) one week after the initial dose, particularly for those women in the third trimester of pregnancy and for women who have secondary syphilis during pregnancy.

Other Management Considerations

Women who are treated for syphilis during the second half of pregnancy are at risk for premature labor or fetal distress, or both, if their treatment precipitates the Jarisch-Herxheimer reaction. These women should be advised to seek medical attention following treatment if they notice any decrease in fetal movements or if they have contractions. Stillbirth is a rare complication of treatment; however, since therapy is necessary to prevent further fetal damage, that concern should not delay treatment. All patients with syphilis should be tested for HIV.

Follow-Up

Serologic titers should be checked monthly until adequacy of treatment has been assured. The antibody response should be appropriate for the stage of disease.

Management of Sex Partners

Refer to General Principles, Management of Sex Partners (CDC guidelines, page 24.)

Special Considerations

Penicillin Allergy

There are no proven alternatives to penicillin. A pregnant woman with a history of penicillin allergy should be treated with penicillin, after desensitization, if necessary. Skin testing may be helpful for some patients and in some settings (CDC guidelines, page 33, Management of Patients Who Have a History of Penicillin Allergy). Tetracycline and doxycycline are contraindicated during pregnancy. Erythromycin should not be used because it cannot be relied upon to cure an infected fetus. Data are insufficient to recommend azithromycin or ceftriaxone for treatment of maternal infection and prevention of congenital syphilis.

Congenital Syphilis

Evaluation and Treatment of Infants During the First Month of Life

Who Should Be Evaluated

Infants should be evaluated for congenital syphilis if they were born to seropositive (nontreponemal test confirmed by treponemal test) women who meet the following criteria:

  • Have untreated syphilis; or
  • Were treated for syphilis during pregnancy with a non-recommended therapy (including erythromycin, doxycycline, tetracycline or a nonrecommended penicillin regimen); or
  • Were treated for syphilis less than 1 month before delivery; or
  • Were treated for syphilis during pregnancy with the appropriate penicillin regimen, but nontreponemal antibody titers did not decrease sufficiently after therapy to indicate an adequate response (greater than or equal to fourfold decrease); or
  • Do not have a well-documented history of treatment for syphilis; or
  • Were treated appropriately before pregnancy but had insufficient serologic follow-up to assure that they had responded appropriately to treatment and are not currently infected (greater than or equal to fourfold decrease for patients treated for early syphilis; stable or declining titers less than or equal to 1:4 for other patients).

Note: Serologic tests for the mother and infant can be nonreactive at delivery if the mother was infected late during pregnancy.

Evaluation of the Infant

The clinical and laboratory evaluation of infants born to women described above should include the following:

  • A thorough physical examination for evidence of congenital syphilis;
  • A quantitative nontreponemal serologic test for syphilis performed on the infant's sera (not on cord blood);
  • CSF analysis for VDRL, cell count, and protein;
  • Long bone x-rays;
  • Other tests as clinically indicated (e.g., chest x-ray, complete blood count, differential and platelet count, liver function tests, cranial ultrasound, ophthalmologic exam, and auditory brainstem response);
  • For infants who have no evidence of congenital syphilis on the above evaluation, determination of presence of specific antitreponemal IgM antibody by a testing method recognized by CDC as having either provisional or standard status;
  • Pathologic examination of the placenta or amniotic cord using specific fluorescent antitreponemal antibody staining.

Treatment

Therapy Decisions

Infants should be treated for presumed congenital syphilis if they were born to mothers who, at delivery, 1) had untreated syphilis; 2) were treated with a nonrecommended antibiotic regimen; 3) were treated less than one month prior to delivery; or 4) had evidence of relapse or reinfection after treatment (CDC guidelines, page 30-32, Congenital Syphilis). Additional criteria for presumptively treating infants with congenital syphilis are as follows:

  • Physical evidence of active disease;
  • X-ray evidence of active disease;
  • A reactive VDRL-CSF or, for infants born to seroreactive mothers, an abnormal CSF white blood cell count or protein, regardless of CSF results;†
  • A serum quantitative nontreponemal serologic titer that is at least fourfold greater than the mother's titer;§
  • Specific antitreponemal IgM antibody detected by a testing method that has been given provisional or standard status by CDC;
  • If they meet the previously cited criteria for "Who Should Be Evaluated," but have not been fully evaluated (CDC guidelines, page 30, Congenital Syphilis).

Note: Infants with clinically evident congenital syphilis should have an ophthalmologic examination.

  • † In the immediate newborn period, interpretation of CSF test results may be difficult; normal values vary with gestational age and are higher in preterm infants. Other causes of elevated values also should be considered when an infant is being evaluated for congenital syphilis. Though values as high as 25 white blood cells (WBC) /mm3 and 150 mg protein/dL occur among normal neonates, some experts recommend that lower values (5 WBC/mm3 and 40 mg protein/dL) be considered the upper limits of normal. The infant should be treated if test results cannot exclude infection.
  • § The absence of a fourfold greater titer for an infant cannot be used as evidence against congenital syphilis.

Recommended Regimens

  • Aqueous crystalline penicillin G, 100,000-150,000 units/kg/day administered as 50,000 units/kg IV every 12 hours during the first 7 days of life and every 8 hours thereafter for a total of 10 days,
    or
  • Procaine penicillin G, 50,000 units/kg IM daily in a single dose for 10 days.

If more than one day of therapy is missed, the entire course should be restarted. When possible, a full 10-day course of penicillin is preferred, even if ampicillin was initially provided for possible sepsis.

Note: Due to reports of treatment failure of benzathine penicillin among newborns including cases among initially asymptomatic infants, the New York State Department of Health does not recommend use of benzathine penicillin G, 50,000 units/kg IM in a single dose for treatment of congenital syphilis. In some cases, infants with a normal complete evaluation for whom follow-up can be assured can be followed closely without treatment. If the decision is made to treat the baby, the standard 10-day therapy should be given.

Infants of Women Treated in the Third Trimester

Although there is uniform agreement that treatment of syphilis in early pregnancy is almost 100% effective in preventing congenital syphilis, the evidence is less certain for treatment in the last trimester. As indicated above (see CDC guidelines, Congenital Syphilis, scenarios page 31-32), if the mother was treated within one month of delivery, treatment of the infant is considered inadequate and the infant must be treated for congenital syphilis.

There are cases reported in the literature and to the Department of Health's surveillance system which suggest that treatment of the mother during the seventh and eighth month of pregnancy may also fail to treat the fetus. While this is an uncommon event, at present it is not possible to predict when treatment failure will occur. Therefore, if the mother is treated during the seventh or eighth month of pregnancy, both she and her infant must be followed especially closely. If these infants meet any of the criteria in "Evaluation & Treatment of Infants During the First Month of Life" (CDC guidelines, page 30, Congenital Syphilis), they should be given the standard 10-day therapy. For the baby who does not meet these treatment criteria, the mother should show an expected decrease in serologic titer. If this decrease cannot be documented, these infants should either be followed with repeat serologic testing over a one-year period or empirically treated with the standard 10- day therapy if follow-up cannot be assured.

Evaluation and Treatment of Older Infants and Children

After the newborn period (i.e., aged > 1 month), children diagnosed with syphilis should have a CSF examination to exclude neurosyphilis and records should be reviewed to assess whether the child has congenital or acquired syphilis (CDC guidelines, page 26, Primary and Secondary Syphilis and Latent Syphilis). Any child who is thought to have congenital syphilis or who has neurologic involvement should be treated with 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.

Follow-Up

A seroreactive infant (or an infant whose mother was seroreactive at delivery) who is not treated for congenital syphilis during the perinatal period should receive careful follow-up examinations at 1 month and at 2, 3, 6, and 12 months after therapy. Nontreponemal antibody titers should decline by 3 months of age and should be nonreactive by 6 months of age if the infant was not infected and the titers were the result of passive transfer of antibody from the mother. If these titers are found to be stable or increasing after 6 – 12 months, the child should be re-evaluated, including CSF examination, and fully treated. Passively transferred maternal treponemal antibodies may be present for as long as 1 year. If they are present greater than 1 year, the infant should be re-evaluated and treated for congenital syphilis. Treated infants also should be followed every 2-3 months to assure that nontreponemal antibody titers decline; these infants should have become nonreactive by 6 months of age (response may be slower for infants treated after the neonatal period). Treponemal tests should not be used to evaluate response to treatment because test results can remain positive despite effective therapy if the child was infected. Infants with CSF pleocytosis should undergo CSF examination every 6 months, or until the cell count is normal. If the cell count is still abnormal after 2 years, or if a downward trend is not present at each examination, the child should be re-treated. The VDRL-CSF also should be checked at 6 months; if still reactive, the infant should be re-treated.

Follow-up of children treated for congenital syphilis after the newborn period should be the same as that prescribed for congenital syphilis among neonates.

Special Considerations

Penicillin Allergy

Children who require treatment for syphilis after the newborn period (≥ 30 days), but who have a history of penicillin allergy, should be treated with penicillin after desensitization, if necessary. Skin testing may be helpful in some patients and settings (CDC guidelines, page 33, Management of Patients Who Have a History of Penicillin Allergy).

HIV Infection

Mothers of infants with congenital syphilis should be tested for HIV. Infants born to mothers who have HIV infection should be referred for evaluation and appropriate follow-up.

No data exist to suggest that infants with congenital syphilis whose mothers are co-infected with HIV require different evaluation, therapy, or follow-up for syphilis than is recommended for all infants.

Penicillin Shortage

During periods when the availability of penicillin is compromised, the following is recommended (see Alternatives to Intravenous Penicillin G for Specific Infections ):

  1. For infants (< 30 days of age) with clinical evidence of congenital syphilis, 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).
  2. For infants at risk of congenital syphilis without any clinical evidence of infection, use procaine penicillin G, 50,000 U/kg/dose IM a day in a single dose for 10 days. As stated previously, the New York State Department of Health does not recommend use of benzathine penicillin G, 50,000 units/kg IM in a single dose for treatment of congenital syphilis.
    Due to the lack of data, procaine penicillin is not recommended for treating infants ≥ 30 days old.
  3. For premature infants at risk of congenital syphilis but who have no other clinical evidence of infection and who might not tolerate IM injections because of decreased muscle mass, IV ceftriaxone may be considered only if careful clinical and serologic follow-up can be assured.

If aqueous or procaine penicillin G is not available, IV ampicillin (200 mg/kg a day in 4 divided doses for 10-14 days) or, alternatively, ceftriaxone may be considered with careful clinical and serologic follow-up. Ceftriaxone must be used with caution in jaundiced infants and dosed according to age and weight. For infants < 30 days old, use 75 mg/kg IV/IM a day in a single daily dose for 10-14 days. For older infants, this dose should be 100 mg/kg a day in a single daily dose. Studies that strongly support ampicillin or ceftriaxone for the treatment of congenital syphilis have not been done. As a result, their use requires management in consultation with an expert in the treatment of infants with congenital syphilis.