Syphilis in Pregnancy

1. What every clinician should know

Syphilis is a systemic bacterial infection caused by the spirochete Treponema pallidum. The World Health Organization (WHO) estimates that 1.3 million pregnant women annually have active syphilis infection, resulting in a substantial burden of preventable morbidity and mortality. The CDC estimates that 55,400 people in the United States get new syphilis infections annually. Syphilis during pregnancy can cause stillbirth and fetal loss, resulting in over 90,000 neonatal deaths annually worldwide. In the United States, there were 360 reports of children with congenital syphilis in 2011.

Syphilis is most commonly transmitted sexually, though vertical transmission can also occur. If untreated during pregnancy, syphilis can cause infection of the fetus leading to spontaneous abortion, late-term stillbirth, premature birth, low birth weight, neonatal death or congenital disease, and long-term sequelae, such as neurologic impairment and deafness.

The individuals the most at risk of syphilis in pregnancy are those who have had direct sexual contact with an individual who has primary or secondary syphilis (transmission occurs in up to 50% of cases), are aged 25 to 29, are affected by poverty, lack health insurance, have a history of sexual promiscuity, are a sex worker, have a history of use of illicit drugs, have infection with another sexually transmitted disease (STD), or are living in an area with high syphilis mortality. The Centers for Disease Control and Prevention (CDC) has reported that greater than 80% of reported cases of congenital syphilis occur because mothers received either no penicillin treatment or inadequate treatment, and no prenatal care occurred in more than one third of cases.

The risk of acquisition for the fetus is directly related to the stage of maternal syphilis during pregnancy. Transmission usually occurs in utero and affects the placenta, umbilical cord and fetus. The incubation period is from 10 to 90 days, with a mean of 3 weeks. Individuals with primary secondary or early latent syphilis (up to 1 year) have replicating treponemal organisms and are capable of transmitting syphilis to susceptible hosts.

2. Diagnosis and differential diagnosis

Screening

All women should be screened at the time of their first prenatal visit.
Re-screen: during third trimester at28 to 32 weeks and again at delivery in women who are at high risk (see above), live in high areas of syphilis morbidity, are previously untested, or had a positive screening in the first trimester.
Women who have stillborn deliveries after 20 weeks gestational age.

Diagnosis

T. pallidum cannot be cultured in the laboratory setting, so diagnosis relies upon direct visualization or serologic testing.

Direct visualization: Using dark-field microscopy, identification of spirochetes from nonoral lesions or body secretions.

Serology: A recent change in the traditional order of screening and confirmatory tests for syphilis has taken place. Two types of tests are generally used: (1) nonspecific treponemal tests for regain-type antibodies, such as the Rapid Plasma Reagin (RPR) test and the Venereal Disease Research Laboratory (VDRL) test and (2) treponemal-specific antibody tests such as the T. pallidum particle agglutination (TP-PA), the fluorescent treponemal antibody absorbed (FTS-ABS) and newer enzyme immunoassay (EIA) tests. Of note, treponemal-specific antibody tests appear earlier than nontreponemal antibodies and they are usually detectable for life (even after successful treatment), therefore cannot distinguish between treated and untreated infections. The order of testing is as follows:

Step 1: Test with a treponemal-specific test, automated enzyme immunoassays (EIAs) or immunochemiluminescence test.

If results are positive, move to second step.

If results are negative, there is no syphilis diagnosis, though recent infection cannot be ruled out.
Step 2: Obtain a nontreponemal antibody test: RPR or VDRL

If results are positive, diagnosis of syphilis can be made, old or new. Treatment is usually indicated, unless the patient has been previously treated. Retreatment indicated if titer has increased fourfold or more.

If results are negative, probably old treated syphilis. Treatment might be indicated if not previously treated. If false-positive screening treponemal test result suspected, or if not previously treated retest with a different treponemal test.
Step 3: Obtain second treponemal test with T. pallidum particle agglutination (TP-PA) or with fluorescent treponemal antibody test (FTP-ABS)

If results are positive: treat for late latent syphilis

If results are negative: no further treatment or testing is indicated

Additional testing and monitoring after treatment

Seropositive pregnant women should be considered infected unless documented treatment history is obtained in medical record and serologic tests have declined appropriately.
It takes 4 to 6 weeks after exposure for both of these types of tests to become positive. It is important to note that when a syphilitic chancre appears, both the nonspecific antibody tests, as well as the treponema-specific tests will be negative, and the lesion should be sampled for dark-field examination.
If new diagnosis is made, be sure to have recently tested for other STDs: HIV, gonorrhea, and chlamydia.
Monitoring after treatment is performed using nontreponemal tests, such as VDRL and RPR, which are reported as a titer of antibody and can be used to follow patient treatment response (see schedule below). Titers should decrease and become negligible within 6 to 12 months after successful therapy for early syphilis, and 1 to 18 months with late syphilis of more than 1 year of duration.
Rising titers indicate need for further diagnostic measures, such as cerebrospinal fluid (CSF) sampling and subsequent appropriate treatment.

False-positive tests

False positives of nontreponemal tests can occur with viral infections, autoimmune diseases (systemic lupus erythematous, sarcoidosis, rheumatoid arthritis), narcotic abuse, and pregnancy. Women with biologic false-positive tests that are attributed to pregnancy should have repeat testing 4 to 6 weeks after delivery. Women with persistent false positives of nontreponemal tests ought to be referred for rheumatologic evaluation.
False positives of treponema-specific tests, which detect antibodies specific to T. pallidum, can occur in the presence of other treponemal subspecies (e.g., pertenue, which causes yaws, and carateum, which causes pinta), though these subspecies are rare in the United States.

Diagnosis and management in the newborn born to women with reactive serologic tests

Most infected newborns are asymptomatic at birth. Maternal transfer of antibodies leads to difficulty in interpreting reactive serologic tests.
Infants born to mothers who have reactive nontreponemal and treponemal tests should be evaluated with quantitative RPR or VDRL.
Thorough examination of the newborn should be performed to rule out evidence of congenital syphilis (nonimmune hydrops, jaundice, hepatosplenomegaly, rhinitis, rash), along with pathologic examination of the placenta or umbilical cord.

Prenatal diagnosis and monitoring

Ultrasound should be obtained if maternal syphilis is diagnosed to identify fetal hydrops, hepatosplenomegaly, and placentomegaly.
Amniocentesis has been used to identify the presence of T. pallidum by using dark-field microscopy or antitreponemal antibody immunofluorescence assays.

Immunocompromised patients: HIV positive individuals may have unusual serologic responses, including both false-negative results and serologic titers that are higher than expected. HIV positive patients have higher rates of treatment failure and might be at increased risk of neurologic complications.

On Exam

Clinical features of syphilis are not changed by pregnancy status.

Primary syphilis: a chancre lesion is characteristic of primary syphilis, occurring at site of initial inoculation of T. pallidum. This is a painlessround, slightly elongated ulcer, 1 to 2 cm across with indurated margin, and base is clear without exudate. External genital chancres are easy to identify. More commonly, though, vaginal or cervical lesions are present and speculum examination is needed for their identification. Check for local adenopathy. Lesion heals spontaneously, usually within 3 to 6 weeks. Multiple chancres occur in 30% of individuals. Identification of primary syphilis in women is uncommon.

Secondary syphilis: a systemic self-limiting disease with possible flulike syndrome, fever and/or myalgias, which may last 2 to 6 weeks. Almost every organ system can be affected. Development of a maculopapular rash can occur, affecting palms and soles of feet, as well as scalp. Diffuse painless adenopathy may be present. The CNS is invaded by spirochetes in approximately 40% of cases. Skin may reveal condyloma lata (raised wartlike lesions found in warm, moist areas) and mucous membranes may reveal mucosal ulcers. Other complications such as alopecia, optic neuritis, uveitis, hepatitis, hepatosplenomegaly glomerulonephritis, osteitis, and meningitis may occur.

Tertiary syphilis: occurs in up to 30% to 40% of untreated individuals and may begin years to decades after infection. Manifestations are exhibited more among individuals coinfected with HIV. Features may include:

Gumma: characteristic nodular lesion on skin, reddish-brown, and variable in size, may drain. This is a reaction to the organism.
Neurosyphilis: meningitis, cerebrovascular abnormalities, and paresis.
Cardiovascular syphilis: although uncommon, can lead to aortic aneurysm, aortic insufficiency, coronary stenosis, and myocarditis.

Latent syphilis: Absence of symptoms with positive serology.

Early latent: less than 1 year from initial symptoms. Secondary syphilis may recur.
Late latent: more than 1 year from initial symptoms. Patients are not usually infectious by sexual transmission, but the spirochete may still be transplacentally transmitted to the fetus.
All patients with latent syphilis should be evaluated clinically for evidence of tertiary syphilis, such as aortitis and gumma, as well as syphilitic ocular disease.

Diagnosis of asymptomatic neurosyphilis:

Cerebrospinal fluid examination (CSF) examination should be considered for those who have neurologic or ophthalmic signs or symptoms, evidence of active tertiary syphilis (aortitis and gumma), treatment failure or HIV infection with late latent syphilis or syphilis of unknown duration. This includes pregnant women.
Some clinicians will perform a CSF examination on all patients who have latent syphilis and a nontreponemal serologic titer of greater than, or equal to 1:32, or if the patient has a CD4 count of <350.
There is no single test that can be used to diagnose neurosyphilis. CSF VDRL is diagnostic of neurosyphilis, but it may be nonreactive in the presence of neurosyphilis.

Differential Diagnosis

The differential diagnosis for primary syphilis, or a chancre, is broad and includes chancroid, granuloma inguinale (Donovanosis), herpes simplex, herpes zoster, HIV, lymphogranuloma venereum (LGV), and Yaws.

For secondary syphilis, the differential diagnosis includes rocky mountain spotted fever, lichen planus, pityriasis rosea, guttate psoriasis, and exanthematous drug/viral eruptions. Gummas seen in tertiary syphilis can mimic basal cell carcinoma.

3. Management

Consult services

If a provider has questions regarding syphilis and pregnancy, a maternal fetal medicine (high-risk obstetrics) doctor should be consult reatmentTreatment is medical and does not differ during the antepartum, intrapartum, or postpartum periods. Treatment is recommended in those with:

A history of sexual contact with a person with documented syphilis, or either a positive dark-field examination or serologic evidence of syphilis with a specific treponemal test
A diagnosis that cannot be ruled out with certainty
Previous treatment but evidence of reinfection:

A fourfold rise in titer of a quantitative nontreponemal test

A dark-field positive lesion

Parenteral penicillin G (PCG) is the only agent with documented efficacy against syphilis during pregnancy. Penicillin therapy is effective in treating maternal disease, preventing maternal transmission of syphilis to the fetus, as well as treating fetal disease. All women with syphilis in pregnancy should be treated with the PCG regimen below, according to their stage of infection.

If a woman is allergic to penicillin, desensitization is recommended. Doxycycline and tetracycline should not be used in pregnancy, due to fetal side effects, and erythromycin is not reliable because of unpredictable placental transfer. Patients can have allergy testing to penicillin, if available. If skin testing is not possible and patients have a history of anaphylaxis, angioedema, bronchospasm, or urticarial (suggestive of an IgE-mediated reaction), they should be desensitized in a hospital setting. Oral desensitization to penicillin is safe in pregnancy.

Primary, secondary, or early latent syphilis: Benzathine PCG 2.4 million U IM one time (some institutions recommend administration of a second dose of Benzathine PCG 2.4 million U IM 1 week later)
Tertilary, late latent, or latent syphilis of unknown duration: Benzathine PCG 2.4 million U IM once weekly for 3 weeks
Neurosyphilis: Aqueous PCG 3 to 4 million U IV q4h or as a continuous infusion for 10 to 14 days

Maternal Follow-up

Remember that rate of treatment failure may be increased in pregnant patients with secondary syphilis.
After treatment, nontreponemal antibody serologic titers (such as RPR and VDRL) should continue to be monitored at 1, 3, 6, 12, and 24 months. Titers should continue to decrease, with a fourfold decrease by 6 months posttreatment, and be nonreactive by 12 to 24 months.
If titers increase fourfold or if a titer initially greater than 1:32 fails to decline fourfold within 12 to 24 months, or if the patient develops signs or symptoms of syphilis, the patient should be evaluated for neurosyphilis and treated appropriately.
If CSF pleocytosis ispresent on initial lumbar puncture, CSF examination should be repeated every 6 months until cell count is normal. If no improvement after 6 months or if CSF has not normalized by 2 years, then retreatment should take place.

Treatment of infants with presumed congenital syphilis

Infants should be treated for presumed congenital syphilis if born to mothers who meet any of the following criteria:

Untreated syphilis at the time of delivery or treated for syphilis <1 month prior to delivery.
Serologic evidence of relapse or reinfection after treatment (fourfold or greater increase in nontreponemal antibody titer).
Treated with nonpenicillin regimen for syphilis during pregnancy.
Syphilis treatment history is not well-documented.
Treated for early syphilis with appropriate regimen, but nontreponemal antibody titers did not decrease fourfold.
Treated appropriately before pregnancy but had insufficient serologic follow-up ensuring adequate treatment and lack of current infection.

4. Complications

Complications of syphilis/consequence of condition

T. pallidum can be transferred across the placenta as early as 6 weeks of gestational age and risk of transmission is present throughout pregnancy and during labor and delivery. As gestation advances, the frequency of vertical transmission increases. The severity of fetal infection decreases with infection later in pregnancy. Approximately 80% of children born to mothers with untreated syphilis will be affected.
Syphilis adversely affects pregnancy. Untreated syphilis can cause spontaneous abortion, stillbirth, nonimmune hydrops, preterm delivery and perinatal death.
Early congenital syphilis, as well as the classic stigmata of late congenital syphilis, can occur (see below).

Strategies to lower risk of complications: Early identification, early treatment, appropriate monitoring, and regular care.

Complications of management

The Jarisch-Herxheimer reaction after treatment with penicillin can occur in up to 45% of pregnant women with syphilis. Cardinal features are fever, chills, myalgia, headache, hypotension, tachycardia, and transient accentuation of cutaneous lesions. This reaction typically starts within hours and can cause severe uterine contractions, premature labor, or fetal distress, usually resolving after 24 to 36 hours. Therefore, pregnant women should be counseled to seek immediate medical attention after syphilis treatment if fever, contractions, or decreased fetal movement develop. Pretreatment with corticosteroids has not been extensively evaluated and is not routinely recommended. Premedication with acetaminophen does not prevent the reaction from happening, but may reduce severity or duration of symptoms.

5. Prognosis and outcome

Pregnancy outcomes, maternal, and neonatal

The most severe effects on pregnancy outcome are with primary or secondary syphilis; however, the majority of women diagnosed during pregnancy are in the latent stage of syphilis.

Materno-fetal: non-immune hydrops, intrauterine growth restriction, preterm labor, and/or preterm delivery.

Neonatal/Child: neonatal death can occur, as well as early congenital syphilis and the possible development of the stigmata of late congenital syphilis.

Approximately two thirds of infants with early congenital syphilis are asymptomatic at birth and do not develop evidence of active disease for 3 to 8 weeks
Early congenital syphilis: onset is usually less than 2 years of age.

Maculopapular rash (with possible progression to desquamation or vesicular and bullae formation, snuffles, mucous patches in oral pharyngeal cavity, hepatosplenomegaly, jaundice, lymphadenopathy, “pseudoparalysis of Parrot” caused by osteochondritis, chorioretinitis, and iritis.
Late congenital syphilis:

Can occur if early congenital syphilis is untreated or incompletely treated.

May present as neurologic, dental, or a number of skeletal abnormalities: mental retardation, eighth-nerve deafness, hydrocephalus, general paresis, optic nerve atrophy, interstitial keratitis, Hutchinson teeth, mulberry molars, perioral fissures (rhagades), saddle nose, frontal bossing, saber shins, flaring scapulas, and bilateral knee effusions.

Hutchinson triad is pathognomonic for congenital syphilis: Hutchinson teeth, interstitial keratitis, and eighth-nerve deafness.

What would you tell a patient about the impact on her long-term health?

Discuss the importance of prevention of disease transmission with latex condom use. Educate patients that if a sore is outside the area covered by a condom, transmission is still possible.

6. What is the evidence for specific management and treatment recommendations

“Centers for Disease Control and Prevention (CDC)”. Sexually transmitted disease surveillance, 2011. 2012. (Pages 35-47 discuss epidemiology, demographics, and risk factors for syphilis.)

“Centers for Disease Control and Prevention (CDC). Syphilis testing algorithms using treponemal tests for initial screening—four laboratories, New York City, 2005-2006”. MMWR Morb Mortal Wkly Rep. vol. 57. 2008. pp. 872-5. (This link includes the new syphilis testing algorithm.)

“Centers for Disease Control and Prevention (CDC). Sexually transmitted disease treatment guidelines, 2010”. (Helpful link that outlines treatment regimens.)

De Santis, M, De Luca, C, Mappa, I. “Syphilis infection during pregnancy: fetal risks and clinical management”. Infect Dis Obstet Gynecol . 2012. pp. 430585(A comprehensive review of fetal risks and management, though it includes the old testing algorithm for syphilis diagnosis.)

Sweet, RL, Gibbs, RS. “”. Lippincott Williams & Wilkins.. 2009. (A comprehensive book chapter, addressing all aspects of syphilis in pregnancy.)

“U.S. Preventive Services Task Force. Screening for syphilis infection in pregnancy: U.S. Preventive Services Task Force reaffirmation recommendation statement”. Ann intern Med. 2009. pp. 150-705. (A good screening review, though it references the old testing algorithm.)

Workowski, KA, Berman, SM. “Centers for Disease Control and Prevention sexually transmitted disease treatment guidelines”. Clin Infec Dis. vol. 53. 2011. pp. s59-63. (A brief review of STIs, including syphilis.)

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Obstetrics and Gynecology

Syphilis in Pregnancy