Syphilis is a chronic systemic infection caused by the motile spirochete Treponema pallidum. It is most commonly acquired through direct sexual contact. During pregnancy, infection can also occur via transplacental transmission. Exposure to open lesions containing the organisms facilitates transmission of the spirochete across mucous membranes or skin abrasions. The infection is acquired in 50–60% of partners after a single sexual exposure to an infected lesion. The tissue destruction observed in syphilis infections is a result of the immune response rather than a direct insult from the spirochete itself.
Although the incidence of syphilis steadily declined in the 1990s to early 2000s, there was a notable increase from 2003 to 2005. During this period, there was a parallel rise in the number of diagnosed cases of congenital syphilis (Fig. 15–4).
Congenital syphilis (CS) rate among infants age <1 year and rate of primary and secondary (P&S) syphilis among females age ≥10 years. (Reproduced from Centers for Disease Control and Prevention. National Electronic Telecommunication System for Surveillance, United States, 1995–2008. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5914a1.htm.)
Public health strategies, counseling, and education of patients on sexually transmitted infections can help reduce the risk of these infections. Although correct and consistent use of latex condoms may decrease the risk of syphilis transmission, sexual abstinence is the only guaranteed method to avoid transmission. Other risk factors associated with syphilis in pregnancy include poverty, sexual promiscuity, and illicit drug use. Avoiding activities leading to risky behavior, such as alcohol and drug use, may also help prevent transmission. The risk of syphilis can be further modified by early identification of infected patients, screening of high-risk populations, adequate treatment of patients and exposed individuals, and improved access to health care.
Congenital syphilis can be prevented by screening all pregnant women and treating those with evidence of infection. Patients should be encouraged to seek early prenatal care, and all pregnant women should undergo screening at the initial prenatal visit. High-risk patients should be rescreened in the third trimester, around 28 weeks of gestation, and in areas with high rates of congenital syphilis, rescreening upon admission in labor should be considered. Women with an intrauterine fetal demise after 20 weeks of gestation should also be evaluated for syphilis.
Syphilis is an infection that presents in different stages over a period of time if untreated. Early syphilis, which occurs within the first year after acquisition of the infection, includes primary and secondary syphilis. Latent syphilis refers to the absence of symptoms in the setting of positive serologies and often follows secondary syphilis. Tertiary or late syphilis, which involves the central nervous and cardiovascular systems, manifests years to decades after the initial infection. Table 15–5 summarizes the clinical manifestations of the various stages of syphilis.
Table 15–5. Clinical Manifestations of the Various Stages of Syphilis. ||Download (.pdf)
Table 15–5. Clinical Manifestations of the Various Stages of Syphilis.
|Primary||Secondary||Early latent (<1 year from initial infection)||Late latent (>1 year from initial infection)||Tertiary|
|Chancre||Maculopapular rash (trunk to distal extremities), myalgia|
|Cardiovascular disease (aortic aneurysms, aortic insufficiency, coronary stenosis)|
|Inguinal lymphadenopathy||Fever, myalgias||Neurosyphilis (paralysis, tabes dorsalis, dementia)|
|Generalized lymphadenopathy||Cutaneous lesions (gummas)|
The chancre, the characteristic lesion of primary syphilis, is a painless, nontender ulcer with an indurated base and raised border. The lesion is found at the site of inoculation. In women, it is most often found on the external genitalia, on the cervix, or in the vagina. Primary syphilis may also manifest with painless inguinal lymphadenopathy. The incubation period varies from 10–90 days, with a mean incubation time of 3 weeks. The primary chancre heals spontaneously in 3–6 weeks in the absence of treatment.
Secondary syphilis is a systemic process characterized by disseminated spread of the infection. This stage typically presents 6 weeks to 6 months after the onset of the primary chancre. Patients present with skin and mucous membrane lesions, along with flu-like symptoms (fever and myalgia) and generalized lymphadenopathy. The generalized maculopapular rash begins on the trunk and proximal extremities and spreads to the entire body, including the palms, soles, and scalp. Condyloma lata are wart-like lesions found in the genital area. The rash usually resolves spontaneously within 2–6 weeks. Patients then enter the latent stage of syphilis.
Patients with latent syphilis are usually asymptomatic with no findings on physical examination. Serologic tests continue to be positive during this time. Latent syphilis is further divided into early and late latent syphilis. If latent infection occurs within 1 year of the initial infection, it is defined as early latent syphilis. Late latent syphilis refers to infection that occurs 1 year after the time of initial infection. A patient can remain in the latent stage for many years.
About one-third of individuals with untreated syphilis will progress to the tertiary stage. Widespread tissue destruction in the tertiary stage results in cardiovascular disease, neurosyphilis, and cutaneous and osseous lesions. Obliterative endarteritis occurs as the spirochete develops a predilection for arterioles. Cardiovascular syphilis manifests with aortic aneurysms, aortic insufficiency, and coronary stenosis. Neurosyphilis is characterized by paralysis, paresthesias, tabes dorsalis, blindness, gait abnormalities, confusion, and dementia.
The Argyll-Robertson pupil (pupil that does not react to light but is able to accommodate) is pathognomonic for tertiary syphilis. Gummas are classic dermatologic manifestations. These gummas consist of necrosis surrounded by an inflammatory infiltrate encapsulated by proliferating connective tissue and form reddish-brown nodular lesions in the skin.
Testing for syphilis can be performed either with direct visualization of the organism or by direct serologic testing. Using dark field microscopy, spirochetes can be identified in bodily fluid or lesions. More recently, direct fluorescent antibody stains have replaced dark field microscopy, but technicians still require a fluorescent microscope to visualize the organism. Serologic tests may initially return negative in the early stages of chancre formation. Therefore, these lesions should be sampled for detection of spirochetes and undergo dark field examination.
Serologic testing consists of a nonspecific screening test followed by a confirmatory treponemal antibody test. The nontreponemal screening tests include the Venereal Disease Research Laboratories (VDRL) test, rapid plasma reagin (RPR) test, or automated reagin test. Reported as a titer, these tests use cardiolipin antigens to detect circulating antibodies and can be used to follow response to treatment. In certain patients, however, a low titer may persist for a long period of time. Due to the nonspecific nature of these tests, false-positive results are not uncommon (0.2–3.2%) and may occur in a multitude of settings including various infections, malignancies, connective tissue diseases, and chronic liver disease.
The fluorescent treponemal antibody absorption test (FTA-ABS) is the most commonly used confirmatory test that detects antibodies specifically directed to treponemal cellular components. Because these tests remain positive even after treatment, they are not used to follow response to treatment. In pregnancy, seropositive women should be considered infected unless a treatment history is well documented and subsequent serologic antibody titers have declined.
Less than 10% of patients with untreated syphilis progress to symptomatic late neurosyphilis. In the absence of clinical signs or symptoms of neurologic involvement, the CDC does not recommend routine lumbar puncture in primary and secondary syphilis. However, in patients with latent syphilis, lumbar puncture should be performed if there are signs of neurologic involvement, evidence of active tertiary syphilis, treatment failure, or HIV infection. The diagnosis of neurosyphilis depends on a combination of tests including reactive serologies, abnormal cerebrospinal fluid (CSF) cell count, elevated protein, and/or reactive CSF VDRL.
Serial quantitative VDRL titers facilitate the diagnosis of reinfection or persistence of active syphilis. With adequate treatment, VDRL titers decrease and become negative within 6–12 months in early syphilis and within 12–24 months in late syphilis. Further diagnostic tests (such as lumbar puncture) and appropriate treatment are needed if titers continue to rise.
Congenital syphilis is diagnosed easily in the setting of a fetus with clinical manifestations of syphilis, placentomegaly, and positive laboratory studies confirming the infection. However, many neonates do not manifest signs and symptoms of congenital infection. Although cord blood may return positive for nonspecific tests for syphilis, the diagnosis is difficult due to the transplacental transfer of maternal nontreponemal and treponemal IgG antibodies to the fetus. In these complicated situations, treatment must be based on the diagnosis of syphilis in the mother, treatment status of the mother, comparison of maternal and infant nontreponemal serologic titers at the time of delivery, and presence of clinical findings of syphilis in the infant. Infants with positive VDRL tests results with no clinical evidence of syphilis should have monthly VDRL titers for at least 9 months; rising titers indicate the need for therapy.
In addition to the aforementioned manifestations of the various stages of syphilis, complications of congenital syphilis result in significant neonatal morbidity. Although vertical transmission can occur at any time during pregnancy and at any stage of syphilis, the risk of congenital infection is greater in the earlier stages of the disease. Women with primary or secondary syphilis are more likely to transmit the disease to their fetuses than are women with latent disease. Maternal primary syphilis and secondary syphilis are associated with a 50% risk of congenital syphilis, whereas early latent syphilis carries a 40% risk of congenital syphilis. The risk of congenital syphilis is even lower, close to 10%, among patients with late latent syphilis. Although serious adverse outcomes are more likely to occur with transmission in the earlier stages, most pregnant women are in the latent stage of syphilis at the time of diagnosis and have had the infection for more than 1 year.
Although the spirochete can cross the placenta and infect the fetus as early as the sixth week of gestation, clinical manifestations do not appear until after the 16th week. By this time, the fetal immune system has matured and can respond to the spirochete. It is the immune reaction to the infection that is responsible for tissue destruction rather than direct injury by the spirochete. The risk of congenital syphilis is increased with infection late in pregnancy, treatment less than 30 days before delivery, inappropriate treatment of the mother, and the lack of prenatal serologic testing.
Untreated syphilis is associated with significant adverse effects on the pregnancy including spontaneous abortion, intrauterine growth restriction, fetal demise, congenital anomalies, preterm delivery, and neonatal death. Stillbirth rates range from 10–35%. Fetuses with congenital infections exhibit hepatosplenomegaly, ascites, polyhydramnios, placental thickening, and hydrops.
Congenital syphilis is divided into 2 clinical syndromes: early and late congenital syphilis (Table 15–6). Early congenital syphilis refers to the manifestations of syphilis within the first 2 years of life. These infants can present with a maculopapular rash, snuffles (flu-like syndrome associated with nasal discharge), mucous lesions, hepatosplenomegaly, jaundice, anemia, lymphadenopathy, chorioretinitis, and iritis. Late congenital syphilis presents after 2 years of age. Findings consistent with late congenital syphilis include frontal bossing, short maxilla, saddle nose, saber shins, high palatal arch, Hutchinson teeth, interstitial keratitis, and eighth nerve deafness. Infants may also have other neurologic manifestations such as mental retardation, hydrocephalus, and optic nerve atrophy.
Table 15–6. Signs and Symptoms of Congenital Syphilis. ||Download (.pdf)
Table 15–6. Signs and Symptoms of Congenital Syphilis.
|Early (Symptoms within 2 Years of Life)||Late (Symptoms after 2 Years of Life)|
|Maculopapular rash||Frontal bossing|
|Mucous lesions||Saddle nose|
|Jaundice||High palatal arch|
|Chorioretinitis||Eighth nerve deafness|
Pregnant women with a history of sexual contact with a person with documented syphilis, positive dark field microscopic visualization of spirochetes, positive serologies via a specific treponemal test, or evidence of reinfection should be treated. Penicillin G is the treatment of choice for all stages of syphilis and is effective in treating maternal disease, preventing fetal transmission, and treating fetal disease (Table 15–7). Although alternatives to penicillin are available to treat nonpregnant penicillin-allergic patients, parenteral penicillin G is the only therapy with documented efficacy for syphilis during pregnancy because it crosses the placenta in adequate amounts, effectively treating the fetus. Therefore, it is recommended that patients with known penicillin allergy undergo desensitization followed by subsequent treatment with penicillin. Although erythromycin was previously used for treatment of syphilis in pregnancy, its efficacy for treatment of the fetus and prevention of transmission is inadequate. Doxycycline and tetracycline may be used to treat nonpregnant patients. The efficacy of antibiotics such as ceftriaxone and azithromycin is currently under investigation.
Table 15–7. CDC-Recommended Treatment of Syphilis during Pregnancy. ||Download (.pdf)
Table 15–7. CDC-Recommended Treatment of Syphilis during Pregnancy.
1. Primary, secondary, and early latent syphilis (<1 year)
Benzathine penicillin G, 2.4 MU IM in a single dose
2. Late latent syphilis (>1 year), latent syphilis of unknown duration, and tertiary syphilis
Benzathine penicillin G, 7.2 MU total, administered as 3 doses of 2.4 MU IM each at 1-week intervals
Aqueous crystalline penicillin G, 18–24 MU per day administered as 3–4 MU IV every 4 hours or by continuous infusion for 10–14 days
Procaine penicillin, 2.4 MU IM daily, plus probenecid 500 mg PO qid, both for 10–14 days
|4. Penicillin-allergic||Pregnant women with a history of penicillin allergy should have allergy confirmed and then be desensitized|
Desensitization can occur in an oral or intravenous manner. Regardless of the route, patients should undergo desensitization in a hospital setting due to potential serious IgE-mediated allergic reactions.
Early disease, with documentation that the initial infection occurred within the past year, is treated with a single dose of benzathine penicillin. Because of treatment failures even after adherence to recommended guidelines, some experts recommend additional therapy with a second dose of penicillin G 1 week after the initial dose. Despite adequate therapy, risk factors for treatment failure include high VDRL titers at the time of diagnosis, unknown duration of infection, treatment within 4 weeks of delivery, and ultrasound signs of fetal syphilis.
Late latent syphilis, latent syphilis of unknown duration, and tertiary syphilis should be treated with 3 doses of benzathine penicillin at weekly intervals. Neurosyphilis requires more intensive treatment with high doses of intravenous aqueous crystalline penicillin or intramuscular procaine penicillin for 10–14 days.
Patients may develop the Jarisch-Herxheimer reaction within several hours after treatment. Symptoms last for 12–24 hours and include fever, chills, myalgias, vasodilation, mild hypotension, and tachycardia. In addition to the symptoms present in nonpregnant individuals, women undergoing treatment in the second trimester are at risk for preterm contractions, preterm labor (highest risk 48 hours after treatment), decreased fetal movement, fetal distress, and fetal death. Patients improve with supportive therapy because the Jarisch-Herxheimer reaction is usually self-limited and resolves by 24–36 hours.
Response to therapy should be monitored with clinical and serologic examination at 1, 3, 6, 12, and 24 months after treatment. Titers usually decline at least 4-fold within 12–24 months of treatment. Patients with persistent clinical symptoms or with sustained 4-fold increases in the nontreponemal test titer have either failed therapy or become reinfected. These patients need retreatment, CSF analysis, and HIV testing. Pregnant women treated for syphilis need repeat serologic titers at 28–32 weeks of gestation and at delivery. Women at high risk for reinfection may have serologies checked monthly.
After adequate treatment, nontreponemal serologic tests often become negative. The treponemal test results usually remain positive for life. Certain patients may have positive nontreponemal tests despite treatment. In these cases, titers are usually not higher than 1:8.
The number of cases of early syphilis has recently been rising, particularly among intravenous drug users and the HIV population. The syphilis rate among women increased from 1.1 cases per 100,000 females in 2007 to 1.5 cases per 100,000 females in 2008. Women of reproductive age make up 80% of the female population with syphilis. Therefore, syphilis is an important health concern. Serious sequelae for the fetus and neonate are due to the failure to diagnose or adequately treat maternal disease.
The efficacy of penicillin for treatment of syphilis in pregnancy ranges from 95–100%. Prognosis is usually favorable once the patient is adequately treated. However, pregnant patients require close follow-up because treatment failure may result in a congenitally infected fetus and neonate.
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