Pediatrics

Congenital Syphilis

OVERVIEW: What every practitioner needs to know

Are you sure your patient has congenital syphilis? What are the typical findings for this disease?

Syphilis in children may occur as an acquired or congenital infection. Treponema pallidum subspecies pallidum is the causative microbe. This chapter focuses on congenital syphilis. Syphilis beyond early infancy is a sexually transmitted infection (STI). Congenital presentations range from asymptomatic to severe, multi-organ disease.

What are the clinical manifestations of syphilis during childhood?

Congenital syphilis early in gestation can lead to fetal demise with spontaneous abortion or later term stillbirth or premature delivery. Fetal infection is essentially equivalent to secondary syphilis, with widespread dissemination of infection. The timing of infection in utero or during birth impacts the degree of illness and range of symptoms and signs. Manifestations of congenital syphilis are divided into early signs (first two years of life) and late signs (onset after the second year of life). About two-thirds of infants with congenital syphilis are asymptomatic at birth.

The most common early manifestations of symptomatic congenital syphilis are bone involvement (periostitis, osteochondritis; 78%), leukocytosis (72%), hepatosplenomegaly (71%), rash (68%), Coombs-negative hemolytic anemia (58%), fever (42%), thrombocytopenia (40%), evidence of neurosyphilis (23%), pneumonitis (17%), renal involvement (proteinuria, hematuria; 16%), rhinitis (snuffles; 14%), and generalized adenopathy (14%).

Hepatic infection is associated with elevated concentrations of transaminases and alkaline phosphatase as well as hyperbilirubinemia. Many symptomatic infants are jaundiced. Prothrombin time may be prolonged.

Severe fetal hemolytic anemia can lead to hydrops. Leucopenia occurs in some cases. Hemolysis and liver disease may persist for weeks despite appropriate therapy.

Bone involvement may cause pain, which causes infants to refuse to move one or more affected extremities (pseudoparalysis of Parrot). The humerus and femur are most often involved, and the changes seen on plain films can be the only abnormality evident in some children with congenital syphilis. The serrated appearance at the epiphyseal margin of long bones is called Wegner sign. Demineralization of diaphyses and metaphyses is evident on plain radiographs. Characteristic wedge-shaped demineralization of the upper medial tibial metaphysis is known as Wimberger sign.

Skin findings may be present at birth or develop during the first few weeks of life. The primary rash, called pemphigus syphiliticus, consists of vesiculobullous lesions that may begin as copper-red papules similar to the classic rash of acquired secondary syphilis. Exudates from these lesions are highly contagious. Infants also may develop condyloma lata and mucous patches. Petechiae may be present with severe thrombocytopenia.

Most instances of neurosyphilis in neonates are asymptomatic, with diagnosis based on abnormal cerebrospinal fluid (CSF) results (see below). Progression of untreated congenital syphilis can result in meningitis, hydrocephalus, and cranial nerve injuries. Chorioretinitis and cataracts may develop.

Pneumonia is common and usually occurs as bilateral fluffy infiltrates. Other early findings include intrauterine growth retardation, failure to thrive (if untreated in the neonatal period), nephrotic syndrome, and myocarditis. Any organ system or body part can be affected.

Infection generally responds rapidly to treatment, although some manifestations may persist for a number of weeks. Severe cases may have permanent injuries from infection prior to therapy that heal with sequelae.

Late congenital syphilis

Late manifestations occur in about 40% of survivors of untreated congenital syphilis. These usually are the destructive results of early lesions. The saddle-nose deformity represents nasal cartilage destruction from early rhinitis. Prolonged periostitis and osteochondritis can lead to frontal bossing (olympian brow), thickening of the medial portion of the clavicle (Higoumenakis sign), thinning and bowing of the tibia (saber shins). Perforation of the hard palate can occur. Clutton joints are painless, symmetric, sterile effusions of the knees and sometimes other joints.

Syphilitic vasculitis can damage developing tooth buds, leading to peg-shaped, notched incisors (Hutchinson teeth) and multicusped first molars (mulberry molars). Deciduous teeth are not affected. Interstitial keratitis (usually not seen before 5 years of age), corneal scarring and glaucoma can develop. Untreated early neurosyphilis can lead to cranial nerve palsies, paresis, and optic atrophy. The constellation of Hutchinson teeth, interstitial keratitis, and eighth nerve deafness is the Hutchinson triad.

What other disease/condition shares some of these symptoms?

Manifestations of symptomatic congenital syphilis can have considerable overlap with other congenital infections caused by cytomegalovirus (CMV), toxoplasmosis, and rubella. It is less commonly confused with neonatal herpes simplex infection. It can also mimic blood group incompatibility and other neonatal conditions, depending on the constellation of symptomatic organ involvement.

What caused this disease to develop at this time?

How is syphilis transmitted?

Congenital syphilis usually results from transplacental passage of treponemas but can be acquired intrapartum from exposure to lesions in the birth canal or on the perineum. Postpartum acquisition from maternal (or wet nurse) infected lesions during breastfeeding also can occur. Syphilis can be transmitted from mother to fetus at any point during pregnancy. Vertical transmission risk is higher during early stages of syphilis than late latent infection.

Infants with congenital syphilis also can transmit the infection from infected skin lesions, which may manifest as vesicles or desquamating skin with purulent or serous exudate (syphilitic pemphigus), and from snuffles, which is infectious nasal discharge.

Young children with evidence of secondary syphilis potentially represent missed cases of congenital syphilis, especially if asymptomatic. However, post-natal acquisition also could be possible in children with secondary syphilis, and careful clinical and forensic investigation for possible child sexual abuse is required when a congenital origin of secondary syphilis cannot be reasonably ascertained.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Definitive diagnosis of syphilis is made by darkfield microscopy or tests that detect T. pallidum in lesion exudates or tissue specimens. PCR-based tests are available in some locations but are not commercially available. Presumptive diagnosis of syphilis is made by two types of serologic tests: 1) nontreponemal tests and 2) specific treponemal tests. Presumptive diagnosis is the most commonly used approach clinically.

Nontreponemal tests traditionally have been used and are still recommended by the CDC as the initial serologic test for diagnosis of syphilis, followed by treponemal tests when the nontreponemal test is positive. In infants with congenital syphilis, unless they are born so prematurely that the maternal transfer of IgG antibodies that occurs during the third trimester was minimal or absent, specific treponemal tests are expected to be positive. Thus, serologic evaluation of infants with suspected congenital infection relies on nontreponemal tests. Nontreponemal antibodies also may be of maternal origin but can be useful in that maternal and infant titers can be compared.

Serum treponemal tests based on enzyme immunoassays (EIA) and chemiluminescence immunoassays (CIA) recently have become the first step ("reverse sequence" testing) in many locales for laboratory diagnosis of syphilis for adult patients due to lower costs of these tests. Positive EIA or CIA tests require reflex to nontreponemal tests. Bypassing this step remains appropriate for serologic diagnosis of congenital syphilis when the mother is known to have (or have had) syphilis. Communication with the clinical laboratory may be needed.

Nontreponemal tests

Nontreponemal test titers usually correlate with disease activity. These tests detect antibodies that react with cardiolipin embedded in lecithin-cholesterol liposomes. The titers of these antibodies rise as the spirochetal infection progresses and then fall with eradication of infection by treatment or gradual immunologic control when untreated.

The two available nontreponemal assays are the Venereal Disease Research Laboratory (VDRL) and Rapid Plasma Reagin (RPR) tests. Most patients become nonreactive by these tests after successful treatment or spontaneous resolution of the infection. A minority of infected persons have persisting low titers (e.g. 1:4, 1:2) for months to years after resolution of infection (serofast reaction). Reinfection or relapse leads to a rise in titer. Four-fold changes in titer are considered indicative of response to treatment when decreasing (e.g. 1:32 to 1:8) or active infection when increasing (e.g. 1:4 to 1:16).

False positive nontreponemal test results occur in about 1% of adults. False positive results can occur in association with Epstein-Barr virus infection, hepatitis, varicella, measles, tuberculosis, malaria, HIV, and endocarditis. Lymphoma, rheumatologic conditions (especially systemic lupus erythematosus), injection drug abuse, immunizations (e.g., MMR, influenza, smallpox), and even pregnancy also can cause false-positive results. Wharton jelly contamination of cord blood specimens can cause false-positive results. Maternal Lyme disease would not cause a false positive result.

Late congenital syphilis represents a period of minimal microbial replication, such that VDRL and RPR tests are typically negative during these periods.

False-negative nontreponemal test results can occur if an infant has a very high concentration of reactive antibodies, which may prevent the flocculation of test antigen required to produce a positive result. This situation is called the prozone phenomenon. Dilution of the serum specimen prior to testing can overcome this inhibition and permits the appropriate positive reaction. Clinicians should request testing of diluted specimens when the clinical presentation suggests congenital syphilis infection and the nontreponemal test result is unexpectedly negative. The prozone phenomenon does not occur with specific treponemal tests.

Treponemal tests

Several specific treponemal tests are available: 1) fluorescent treponemal antibody absorbed (FTA-ABS) tests; 2) T. pallidum passive particle agglutination (TP-PA); 3) various enzyme immunofluorescence assays (EIAs), and 4) chemiluminescence assays (CIAs). A positive specific test in an infant cannot distinguish between maternal and infant infection. If specific treponemal antibodies are of maternal origin and the infant is not infected, these likely will disappear by 18 months of age or sooner. Persistence at 18 months or beyond indicates congenital or acquired syphilis, depending on the clinical circumstances.

Neurosyphilis

Diagnosis of neurosyphilis requires cerebrospinal fluid (CSF) analysis. The diagnosis ultimately is based on a combination of results of serum and CSF tests and clinical symptoms and signs (e.g., cranial nerve dysfunction, auditory or ophthalmic abnormalities, meningitis, stroke, altered mental status, and loss of vibration sense). CSF protein is usually elevated above age-related norms and pleocytosis is usually present. The CSF white blood cell count may be less informative in persons with HIV infection, who may have lower cell counts with neurosyphilis than HIV-negative persons.

The VDRL test is the nontreponemal test used for spinal fluid. It has high specificity but is relatively insensitive. The VDRL can be falsely positive in neonates born to mothers with syphilis due to transplacental and trans blood:CSF barrier passage of maternal antibodies. Some experts prefer the FTA-ABS test for CSF. The FTA-ABS test on CSF is highly sensitive but less specific. A negative CSF FTA-ABS makes neurosyphilis highly unlikely.

Additional considerations

Infants with congenital syphilis seldom have nontreponemal test titers higher than their mothers. However, a neonatal titer equal to or greater than four-fold the maternal titer obtained at the same time indicates active infection of the infant.

Pregnant women with persistently negative nontreponemal tests have a very low risk of transmitting syphilis to their infants.

Mothers of infants with congenital syphilis should be evaluated for other STIs, including Chlamydia trachomatis, gonococcal, HIV, hepatitis B and possibly hepatitis C infections.

Management of syphilis during pregnancy should include ultrasound evaluation of the fetus for congenital syphilis. Presence of hydrops, hepatomegaly, ascites, or thickened placenta among other signs suggest a higher risk of fetal treatment failure. Evidence to recommend specific therapy in these cases is insufficient.

Congenital syphilis can cause fetal demise. When any pregnancy results in stillbirth after 20 weeks gestation, the mother should be tested for syphilis.

What is the diagnostic approach to congenital syphilis?

Infants born to mothers who have reactive nontreponemal and treponemal tests should be evaluated with a quantitative nontreponemal test (i.e., VDRL or RPR) performed on infant serum. Cord blood should not be used due to potential contamination with maternal blood. Treponemal titers are not necessary on the infant unless maternal test results cannot be obtained.

Infants with reactive nontreponemal titers should be examined carefully for physical signs of congenital syphilis. Pathologic examination of the placenta or umbilical cord using specific fluorescent antitreponemal antibody staining is recommended when possible. Darkfield microscopy of specimens from any infant lesions or exudates should be performed. Additional evaluation of the infant depends on the clinical presentation plus maternal and infant serologic results.

Infants with proven or highly probable disease based on the above information who have 1) any abnormal physical examination findings suggestive of congenital syphilis; 2) serum nontreponemal titer four-fold or greater than the maternal titer should undergo a full evaluation. This includes a complete blood count (with differential and platelet count) and CSF analysis for cell count, protein, and VDRL (some experts also recommend the FTA-ABS as well). CSF WBC >25 cells/mm3 and protein concentrations >150 mg/dL are considered compatible with congenital neurosyphilis. (Of note, higher thresholds for abnormal values of both tests may be allowable for preterm infants, and some experts recommend lower thresholds for term infants of 5 cells/mm3 and 40 mg/dL for protein.)

Other tests are ordered based on clinical findings or diagnostic considerations. Long bone radiographs (periostitis, osteochondritis) are highly sensitive for diagnosis of congenital syphilis. These may be obtained when the diagnosis is uncertain by other means or when pseudoparalysis or other extremity signs are present.

Liver function tests should be obtained for infants with jaundice or hepatosplenomegaly. Chest radiography is obtained for signs of lower respiratory tract infection (pneumonia alba). Urinalysis may be obtained for concerns about renal function but is unlikely to influence management.

Ophthalmologic examination should be considered when there is other evidence of CNS or external ocular involvement. CNS imaging studies are usually needed only to evaluate the extent of severe congenital infection (e.g., evidence of hydrocephalus, microcephaly) or to help differentiate between syphilis and other congenital infections.

Infants with possible or confirmed congenital syphilis who have abnormal hearing screenings (now part of routine newborn care) should undergo auditory brain stem response testing.

Infants with no abnormal physical findings and serum nontreponemal titers that are less than four-hold higher than maternal serum titers require CSF and CBC studies as above as well as long bone radiographs if the mother 1) was not treated, treated inadequately, or has no documentation of treatment; 2) was treated with a nonpenicillin regimen; or 3) received treatment with completion up to 4 weeks prior to delivery.

CSF evaluation is not mandatory if a 10 day parenteral course of penicillin is planned, but such evaluation may reveal findings that prompt closer follow-up and repeat CSF studies at 6 months of age (see follow-up below). If any part of this evaluation is not performed or cannot be interpreted, the infant should be managed as if CNS infection is present (see treatment below).

Infants with no abnormal physical findings and serum nontreponemal titers that are less than four-hold higher than maternal serum titers do not require any evaluation if the mother 1) was treated with an adequate penicillin regimen during pregnancy that was completed up to 4 weeks prior to delivery and 2) has no evidence of reinfection or relapse. This is true also for such infants born to mothers treated adequately for syphilis before pregnancy and whose nontreponemal titers have remained low or stable during pregnancy and at delivery (i.e., VDRL <1;2, RPR <1:4).

Would imaging studies be helpful? If so, which ones?

See descriptions of skeletal lesions.

If you are able to confirm that the patient has syphilis, what treatment should be initiated?

Penicillin G, parenterally administered, is the preferred agent for treating all stages and types of syphilis. The stage of disease and clinical manifestations determine the preparation, dosage and length of treatment.

Neonates with proven or highly probable congenital syphilis should be treated either with 1) aqueous penicillin G, 50,000 units/kg per dose, with two doses administered per day every 12 hours during the first 7 days of life and then three doses per day every 8 hours thereafter, for a total of 10 days; or 2). procaine penicillin G, 50,000 units/kg per dose IM once daily for 10 days. If more than one day of therapy is missed, the full course is restarted. In general, any doses of ampicillin administered as part of initial treatment for suspected sepsis should not be counted towards the course of penicillin therapy.

Neonates who have normal physical examination (asymptomatic) and have serum nontreponemal serologic titers equal to or less than four-fold higher than the maternal titer and whose mother 1) was not treated, inadequately, treated, or has no documentation of treatment; 2) was treated with a non-penicillin regimen; or 3) received a recommended penicillin regimen up to 4 weeks prior to delivery may be treated as above for symptomatic congenital syphilis or given a single dose of benzathine penicillin G, 50,000 units/kg IM. If such infants have any abnormal CSF or other laboratory findings or part of the recommended evaluation could not be performed or interpreted, a 10-day regimen should be administered.

Some experts recommend a full 10-day course of penicillin G for those neonates born to women with untreated early syphilis at delivery because of their high risk of congenital infection even if examination and evaluation are normal.

Neonates who have a normal physical examination and serum nontreponemal serologic titers the same or less than four-fold higher than the maternal titer and whose mother 1) was treated with a recommended penicillin regimen during pregnancy with completion up to 4 weeks prior to delivery and 2) has no evidence of reinfection or relapse may be treated with a single dose of benzathine penicillin G IM as above. Alternatively, if the maternal nontreponemal titer decreased four-fold or more after appropriate treatment for early syphilis or remained stably low (defined as VDRL <1:2 or RPR <1:4) after appropriate treatment for late syphilis, the infant may be observed without treatment if close serologic follow-up is assured.

Infants born to mothers with HIV and syphilis co-infection

At this time, infants born to such mothers are evaluated according to the guidelines for each individual infection. Although false-negative maternal syphilis serologic results have been reported with HIV-coinfection, screening all infants born to HIV-positive mothers for syphilis with no evidence of maternal syphilis is not recommended.

Despite a lack of specific regimen for HIV pregnant woman, all should be evaluated for syphilis and receive standard therapy if infected. There is an increased risk for perinatal transmission of HIV in those who have placental inflammation from congenital infection. The neonates born to these mothers should be carefully evaluated.

Management during periods of penicillin shortage

Penicillin shortages have been a problem in recent years and could be again in the future. Procaine penicillin G, if available, IM once a day can be substituted for some or all daily doses of aqueous penicillin G IV. Ceftriaxone may be considered as a substitute in consultation with a specialist.

What are the adverse effects associated with each treatment option?

Allergic reactions (e.g., rashes, hives, anaphylaxis) are the primary side effects that can occur with administration of antibiotics to treat syphilis.

The Jarisch-Herxheimer reaction is an acute febrile event that usually occurs within 2 to 12 hours after initiation of any therapy for syphilis. It is characterized by headache, fever, myalgia, and diaphoresis. It occurs predominately in early stages of syphilis (primary or secondary) when organism burdens are highest. It is likely due to release of treponemal endotoxin-like compounds as the microbes lyse. It is rare in newborns but has been described in later infancy and beyond.

What are the possible outcomes of syphilis?

All infants who are seroreactive (or born to mothers seroreactive at delivery), whether treated or observed, should be re-evaluated at 1, 2, 3, 6, and 12 months of age. Nontreponemal tests should be obtained every 2 to 3 months until negative. Uninfected infants and those adequately treated for congenital syphilis should demonstrate declining nontreponemal titers by 3 months of age and should become seronegative by 6 months of age.

Infants treated beyond the neonatal period may have slower decline in titers. Titers that are stable beyond 6 months of age or increasing indicate the need for re-evaluation and retreatment with a 10-day course of parenteral penicillin G.

Infants with any findings of neurosyphilis (e.g., abnormal CSF findings or reactive VDRL serology) should undergo repeat lumbar puncture for CSF evaluation every 6 months until all findings, including VDRL test results, are normal or nonreactive. A reactive CSF VDRL at any examination is an indication for retreatment. Failure of CSF WBC counts to decline steadily on determination or to normalize by age 2 years also is an indication for retreatment. CNS imaging studies such as magnetic resonance imaging should be considered in children with persisting CSF abnormalities.

HIV co-infection

HIV-infected infants with congenital syphilis may be at increased risk for treatment failure or development of neurosyphilis. Careful clinical and serological follow-up every 3 months, with retreatment as necessary is indicated by clinical findings and test results.

Prognosis

Congenital infection can lead to spontaneous abortion or fetal demise or stillbirth. These pregnancy complications are preventable through appropriate prenatal care. Congenital infection also can lead to premature birth and complications from this that are not directly related to syphilis.

What causes this disease and how frequent is it?

Pathogenesis

T. pallidum subspecies pallidum is one of several pathogenic Treponema in the family Spirochaetaceae, which also includes genera Borrelia and Leptospira. Treponemas are 5 to 15 µm in length and 0.1 to 0.5 µm in diameter with a helical coiled shape. The microbes are motile on the basis of a corkscrew motion from the actions of endoflagella that impart the coiled shape. The T. pallidum subspecies pallidum genome is 1.14 Mb, which encodes 1041 predicted proteins and is relatively small among bacteria. Treponema cannot be cultured directly in vitro.

Close but genetically distinct relatives include T. pallidum subspecies carateum, T. pallidum subspecies endemicum, and T. pallidum subspecies pertenue, the causes of pinta, bejel or endemic syphilis, and yaws, respectively. A number of nonpathogenic treponemal species are human oral and gastrointestinal commensals.

T. pallidum attaches to host cell surfaces by a ligand-receptor type process. The microbes are only able to replicate when attached to mammalian cells. Fetal and infant cells appear to support growth more than adult cells. The microbes spread in the bloodstream after initial infection and infiltrate into perivascular spaces. This may be aided by microbial hyaluronidase production. Host fibronectin coats the microbes and actually may inhibit phagocytosis and complement-mediated lysis.

IgG and IgM antibodies generally are present in the bloodstream by the time a chancre appears. Antibody production, however, does not appear to aid in control of infection. T. pallidum produces few surface-exposed proteins, but the Tpr K protein, which may serve as a porin, elicits an opsonic antibody response in a rabbit model of syphilis. Cell-mediated immunity is suppressed during primary and secondary syphilis. CD4+ T cells and macrophages predominate in chancres while CD8+ T cells predominate in lesions of secondary syphilis.

Prior syphilis infection may provide a modicum of protection upon re-exposure. Persons with untreated syphilis have relative resistance to reinfection but are not fully protected. Chancres usually do not develop upon re-infection, although these may occur with a high re-infecting inoculum. Antibody titers may rise in either case. Patients treated for syphilis during primary or secondary stages have only minor protection against re-infection and should be considered susceptible. Primary and secondary disease manifestations may not be as severe. Prior congenital syphilis does not protect against later acquired infection.

Syphilis pathologically is a systemic vasculitis. The microbes induce a perivascular cellular immune infiltration as they invade into tissues via capillaries. Immune complex deposition of anti-treponemal antibodies can lead to renal disease (acute syphilitic glomerulonephritis).

In congenital syphilis, the placenta is usually thickened. Villi are hypercellular with proliferative fetal vascular changes and acute and chronic inflammatory infiltrates. Spirochetes may be found in the walls of umbilical vessels.

Although variations in Human Leukocyte Antigen (HLA) genes may affect individual susceptibility to syphilis, at this time there is no role for genetic testing of any type with regard to prognosis or treatment decisions for patients with syphilis.

Epidemiology

Syphilis is primarily sustained in the population through sexual contact with infected persons. Recent national trends in the United States show the highest incidences of infection in the South and in urban areas of other parts of the country. Many new cases have occurred among persons with HIV infection. After steady declines through public health control measures during the last decades of the 1900s, syphilis rates in the U.S. increased annually from 2001 to 2014. Much of this overall increase has occurred among men who have sex with men. The proportion of cases among males has continued to increase.

Unfortunately, smaller increases in incidence have occurred also among females, with a corresponding increase in congenital syphilis rates to 11.6 per 100.000 live births in 2014 from the historical nadir of 8.2 per 100,000 live births in 2005 and the highest rate reported since 2001. Highest rates occur among males 20-29 years old and among females 25-29 years old. Rates in non-Hispanic blacks are higher than among other race/ethnicity groups in the U.S.

Are additional laboratory studies available; even some that are not widely available?

PCR-based tests to detect T. pallidum and IgM serologic tests have been developed but are not available commercially and are not recommended at this point.

How can syphilis be prevented?

All pregnant women should be screened early in pregnancy. Additional maternal syphilis testing should be performed at delivery. In high risk populations, pregnant women also should be tested at 28 to 32 weeks gestation. No newborn infant should be discharged from the hospital without health care provider knowledge of the maternal serologic status for syphilis having been determined at least once during pregnancy.

Standard precautions are recommended for hospitalized infants with suspected or confirmed congenital syphilis. Open lesions, secretions, and possibly blood from such patients are contagious. Gloves should be worn during care of patients with congenital, primary and secondary syphilis with skin or mucous membrane lesions until 24 hours of effective therapy has been administered.

Persons, including health care workers, who have close unprotected contact with an infant with early congenital syphilis before 24 hours of effective antibiotic therapy is completed should be evaluated for evidence of syphilitic lesions 2 to 3 weeks after contact. Antibiotic prophylaxis should be considered for substantial exposures. Serologic testing should be conducted at baseline and 3 months later.

All cases of confirmed or suspected congenital syphilis should be reported to local health authorities to allow for follow-up of patients and appropriate contact investigations.

What is the evidence?

Workowski, KA, Bolan, GA. "Sexually transmitted diseases treatment guidelines, 2015". MMWR Recomm Rep. vol. 64. 2015.

(This guideline provides current national recommendations for the diagnosis and management of sexually transmitted diseases including syphilis in adults, adolescents, and children. This document was developed by CDC staff and national experts using systematic literature review, and it updates the 2010 version.)

Bowen, V, Su, J, Torrone, E, Kidd, S, Weinstock, H. "Increase in Incidence of Congenital Syphilis - United States, 2012-2014". MMWR. vol. 64. 2015. pp. 1241-1245.

Ghanem, KG. "Management of Adult Syphilis: Key Questions to Inform the 2015 Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines". Clin Infect Dis. vol. 61. 2015. pp. S818-S836.

(This study reviews several key questions asked to experts in the field in the management of adult syphilis. To answer those questions, the authors performed a systematic review with useful tables of evidence.)

"Sexually Transmitted Diseases Treatment Guidelines, 2010". MMWR. vol. 59. 2010. pp. 1-109.

(This guideline provides current national recommendations for diagnosis and treatment of acquired syphilis in adults and children and congenital syphilis. The guideline document was developed by CDC staff and national experts using systematic literature reviews for syphilis and other sexually transmitted diseases. It represents an update from the 2006 version of the guideline.)

Sena, AD, White, BL, Sparling, PF. "Novel Treponema pallidum serologic tests: A paradigm shift in syphilis screening for the 21st century". Clin Infect Dis. vol. 51. 2010. pp. 700-8.

(This study reviews the impact of reverse sequence screening for syphilis, where automated EIA/CIA-based treponemal tests are run first, followed by nontreponemal tests. The traditional approach, still recommended by the CDC, is to perform nontreponemal tests first.)

"Congenital syphilis-United States, 2003-2008". MMWR. vol. 59. 2010. pp. 413-7.

(This report reviews the most current epidemiology of congenital syphilis in the U.S., including the recent increase in cases that reflects increased prevalence of syphilis among pregnant women. This has reversed a long term declining trend.)

Ongoing controversies regarding etiology, diagnosis, treatment

Syphilis is uncommon among international adoptees, but congenital syphilis can go undiagnosed or may be inadequately treated in some countries.

Syphilis testing, both nontreponemal and treponemal, is recommended as part of evaluation of international children, regardless of any history of testing or treatment provided.

**The original source for this chapter was Dr Charles R. Woods. The chapter was revised for this program by Claudia M. Espinosa.

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