Congenital syphilis_ Clinical features and diagnosis - UpToDate

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10/08/2019

Congenital syphilis: Clinical features and diagnosis - UpToDate Official reprint from UpToDate® www.uptodate.com ©2019 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Congenital syphilis: Clinical features and diagnosis Author: Simon R Dobson, MD, FRCP(C) Section Editors: Sheldon L Kaplan, MD, Leonard E Weisman, MD Deputy Editor: Carrie Armsby, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jul 2019. | This topic last updated: Jan 29, 2019.

INTRODUCTION Congenital syphilis occurs when the spirochete Treponema pallidum is transmitted from a pregnant woman to her fetus. Infection can result in stillbirth, prematurity, or a wide spectrum of clinical manifestations; only severe cases are clinically apparent at birth [1]. The clinical features and diagnosis of congenital syphilis will be discussed here. The evaluation, management, and prevention of congenital syphilis are discussed separately. (See "Congenital syphilis: Evaluation, management, and prevention".) Syphilis in pregnancy and acquired syphilis also are discussed separately:

● ● ● ● ● ●

(See "Syphilis in pregnancy".) (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in HIV-uninfected patients".) (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in HIV-uninfected patients", section on 'Clinical manifestations'.) (See "Syphilis: Treatment and monitoring".) (See "Neurosyphilis".) (See "Syphilis: Screening and diagnostic testing".)

CASE DEFINITION The Centers for Disease Control and Prevention (CDC) case definition for congenital syphilis is provided in the table (table 1) [1]. Other case definitions may differ slightly from the CDC definition [2]. In general, case definitions for congenital syphilis require only one of two criteria:

● The child has physical, laboratory, or radiographic signs of congenital syphilis (confirmed/highly probable congenital syphilis), or ● The child was born to a mother with untreated, inadequately, or suboptimally treated syphilis (presumed congenital syphilis) (table 2) Some experts would also presume infants to have congenital syphilis if their mothers had contact with a person with primary or secondary syphilis within 90 days before delivery and were not treated or were inadequately treated [3,4].

EPIDEMIOLOGY Congenital syphilis is a significant public health problem, complicating an estimated one million pregnancies per year throughout the world [5]. The incidence of congenital syphilis reflects the rate of syphilis in women of childbearing age [6]. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in HIV-uninfected patients", section on 'Epidemiology'.) Most cases develop because the mother received no prenatal care or insufficient treatment for syphilis before or during pregnancy (table 2) [7-10]. Among women with untreated early syphilis, 40 percent of pregnancies result in spontaneous abortion [11]. (See "Syphilis in pregnancy", section on 'Prevalence'.) In the United States, the rate of congenital syphilis among infants 150 percent compared with 2013. As is expected, the increase in rates of congenital syphilis parallels increases in primary and secondary syphilis among all women and reproductive-aged women during this period (figure 1) [8,12,13]. Poor access to prenatal care is an important risk factor for congenital syphilis. Among the 458 cases of congenital syphilis reported to the Centers for Disease Control and Prevention in 2014, nearly one-quarter were born to mothers who did not receive prenatal care [12]. Among the 314 cases in which the mother received prenatal care, 135 (43 percent) received no treatment for syphilis during the pregnancy and 94 (30 percent) received inadequate treatment. Similarly, in a report by the New York City Department of Health and Mental Hygiene of 578 syphilis infections reported in pregnant women during 2010 to 2016, >85 percent did not result in congenital infection, presumably because of early screening and treatment [14]. https://www.uptodate.com/contents/congenital-syphilis-clinical-features-and-diagnosis/print?source=history_widget

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Of the 68 cases of congenital syphilis that occurred, 31 percent were born to women who received no prenatal care or did not have a syphilis test ≥45 days before delivery. In addition, of the women who had appropriate testing during pregnancy, 15 percent received no or inadequate treatment. Obstacles to accessing health care identified in this report included substance use, mental health disorders, recent arrival in the United States, unstable housing, and lack of health care coverage. The rate of congenital syphilis is increased among infants born to mothers with HIV infection. However, the contribution of maternal coinfection with syphilis and HIV to vertical transmission of either syphilis or HIV is not completely understood. (See "Syphilis in the HIV-infected patient", section on 'Effect of syphilis on HIV'.) The rate of congenital syphilis is generally low among children adopted internationally; however it is relatively increased among those adopted from Africa (table 3). Given the difficulty in confirming adequate treatment/treatment response of the birth mother and the risk of long-term sequelae in untreated children, we recommend screening international adoptees for congenital syphilis (regardless of the country of origin). (See "International adoption: Infectious disease aspects", section on 'Syphilis'.)

TRANSMISSION Humans are the only natural host of T. pallidum [15]. Congenital syphilis generally is acquired through transplacental transmission of spirochetes in the maternal bloodstream or, occasionally, through direct contact with an infectious lesion during birth [16-18]. (See "Syphilis in pregnancy", section on 'Vertical transmission'.) Transplacental transmission of T. pallidum can occur at any time during gestation but occurs with increasing frequency as gestation advances. Women with untreated primary or secondary syphilis are more likely to transmit syphilis to their fetuses than women with latent disease (60 to 90 versus 40 percent in early latent and 25 white blood cells [WBC]/microL for infants 5 WBC/microL).

● Elevated CSF protein (defined by consensus as >150 mg/dL in term infants 170 mg/dL in preterm infants 40 mg). However, none of these findings is highly sensitive or specific [38,40]. In an observational study that used the rabbit infectivity test as the reference standard for identification of spirochetes in the CSF, the sensitivity and specificity of reactive CSF VDRL, elevated CSF WBC, and elevated CSF protein were as follows [38]:

● Reactive CSF VDRL: sensitivity 54 percent; specificity 90 percent ● Elevated CSF WBC count: sensitivity 38 percent; specificity 88 percent ● Elevated CSF protein: sensitivity 56 percent; specificity 78 percent The significance of a reactive CSF VDRL in a neonate is not clear, since there may be false positives (related to maternal nontreponemal immunoglobulin G [IgG] antibodies that cross the placenta and diffuse into the fetal CSF or contamination of the CSF with blood from a traumatic lumbar puncture) and false negatives (neonates with initial nonreactive CSF VDRL may subsequently develop signs of neurosyphilis). (See 'Congenital neurosyphilis' below.) https://www.uptodate.com/contents/congenital-syphilis-clinical-features-and-diagnosis/print?source=history_widget

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Examination of the CSF for T. pallidum DNA by polymerase chain reaction may prove more useful for definitive diagnosis of congenital neurosyphilis [16,38,39], but this test is not widely available. (See 'Diagnostic tests' below.)

LATE CONGENITAL SYPHILIS Late congenital syphilis is arbitrarily defined by clinical manifestations with onset after two years of age [4]. Manifestations of late congenital syphilis are related to scarring or persistent inflammation from early infection and are characterized by gumma formation in various tissues [53]. Late congenital syphilis develops in approximately 40 percent of infants born to women with untreated syphilis during pregnancy. Some manifestations of late congenital syphilis can be prevented by treatment of the mother during pregnancy or treatment of the infant within the first three months of life [54,55]. However, other manifestations (eg, keratitis, saber shins) may occur or progress despite appropriate therapy [56]. Manifestations of late congenital syphilis include (table 5) [1,21,55,57,58]:

● Facial features – Frontal bossing (picture 3), saddle nose, short maxilla, protuberant mandible. ● Eyes – Interstitial keratitis (picture 4) (bilateral, usually occurs around puberty, but can occur anytime between 4 and 30 years), secondary glaucoma, corneal scarring, optic atrophy.

● Ears – Sensorineural hearing loss associated with late congenital syphilis typically develops suddenly at 8 to 10 years of age and often accompanies interstitial keratitis. The higher frequencies are affected first; normal conversational tones are affected later. Syphilis-associated hearing loss may respond to long-term glucocorticoid therapy [59].

● Oropharynx – Hutchinson teeth (hypoplastic, notched, widely spaced permanent teeth [upper central incisors most commonly affected] (picture 5); before eruption, Hutchinson teeth are visible on dental radiographs), mulberry molars (maldevelopment of the cusps of the first molars) (picture 6), and perforation of the hard palate (picture 7) (virtually pathognomonic for congenital syphilis).

● Cutaneous – Rhagades (perioral fissures or a cluster of scars radiating around the mouth) (picture 8), gummas (granulomatous inflammatory response to spirochetes) in the skin or mucous membranes.

● Neurologic – Intellectual disability, arrested hydrocephalus, cranial nerve palsies ● Skeletal – Anterior bowing of the shins ("saber shins") (picture 9), enlargement of the sternoclavicular portion of the clavicle (Higoumenakis sign), painless arthritis of the knees ("Clutton joints") (picture 10), and, rarely, other joints.

● Hematologic – Paroxysmal cold hemoglobinuria (see "Paroxysmal cold hemoglobinuria"). Among these manifestations, Hutchinson triad (Hutchinson teeth, interstitial keratitis, and sensorineural hearing loss), mulberry molars, and Clutton joints are relatively specific for congenital syphilis [21,57].

DIFFERENTIAL DIAGNOSIS The manifestations of congenital syphilis in neonates may be similar to those of other neonatal infections or newborn conditions, including:

● Toxoplasmosis infection (see "Toxoplasmosis and pregnancy", section on 'Fetal infection' and "Congenital toxoplasmosis: Clinical features and diagnosis", section on 'Clinical features')

● Rubella virus infection (see "Congenital rubella syndrome: Clinical features and diagnosis", section on 'Evaluation and diagnosis') ● Cytomegalovirus infection (see "Congenital cytomegalovirus infection: Clinical features and diagnosis", section on 'Clinical manifestations') ● Herpes simplex virus infection (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Evaluation and diagnosis')

● Neonatal sepsis (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Evaluation and initial management')

● Neonatal hepatitis (see "Causes of cholestasis in neonates and young infants") ● Hydrops fetalis (see "Nonimmune hydrops fetalis", section on 'Etiology and prenatal management of disorders associated with hydrops' and "Postnatal diagnosis and management of hemolytic disease of the fetus and newborn", section on 'Diagnosis')

● Long-bone abnormalities (eg, osteomyelitis, rickets, physical abuse) or failure to move an extremity (see "Differential diagnosis of the orthopedic manifestations of child abuse" and "Brachial plexus syndromes", section on 'Neonatal brachial plexus palsy')

● Vesicular lesions (see "Vesicular, pustular, and bullous lesions in the newborn and infant") Historical features, additional findings, and/or laboratory testing usually differentiate these conditions from congenital syphilis.

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DIAGNOSTIC TESTS The diagnosis of syphilis is complicated by the absence of a method to culture T. pallidum on laboratory media. In clinical settings, the diagnosis of syphilis may be established by:

● Direct visualization of T. pallidum by darkfield microscopy (picture 11) or fluorescent antibody staining of infected body fluids or lesions, placenta, or umbilical cord

● Demonstration of the T. pallidum by special stains (picture 12) or histopathologic examination [60,61] ● Demonstration of serologic reactions typical of syphilis Tests that may be used to establish the diagnosis of congenital syphilis in research settings include:

● Animal inoculation (ie, rabbit infectivity test) ● Detection of T. pallidum DNA in a clinical specimen (eg, polymerase chain reaction [PCR]) [16,38,39,62] These testing methods are discussed in detail separately. (See "Syphilis: Screening and diagnostic testing", section on 'Diagnostic tests'.) Darkfield microscopy can be performed on body fluids (eg, nasal discharge) or moist skin lesions [63]. Darkfield microscopy enables demonstration of thin, delicate, corkscrew-shaped organisms with rigid, tightly wound spirals (picture 11). A positive darkfield slide illustrates the characteristic motility associated with T. pallidum: a forward and backward motion with rotation about the longitudinal axis [63]. Soft side-to-side bending and twisting may also be seen. Failure to identify spirochetes with darkfield microscopy does not exclude the diagnosis of syphilis. Darkfield microscopy depends upon the direct visualization of live, active spirochetes, characteristics that are rapidly destroyed by the previous use of antibiotics. Serologic testing can establish a diagnosis of proven/highly probable, at-risk, or unlikely congenital syphilis infection (see 'Interpretation' below). Serologic tests include nontreponemal tests (eg, Venereal Disease Research Laboratory or rapid plasma reagin [RPR]) and treponemal tests (eg, fluorescent treponemal antibody absorption [FTA-ABS], T. pallidum particle agglutination, enzyme immunoassay, chemiluminescence immunoassay, microhemagglutination test for T. pallidum [MHA-TP]) [1]. Nontreponemal tests are inexpensive and rapidly performed. They are sensitive, but not specific. Nontreponemal tests generally are used in the evaluation of neonates with possible congenital syphilis because they provide quantitative results, which can be compared with simultaneously obtained maternal results to categorize neonatal infection [50]. The neonate's nontreponemal titer usually is one to two dilutions less than that of the mother [64]. When the mother's titer is low, the neonate may have nonreactive serology but remains at risk for congenital syphilis. (See 'Congenital syphilis less likely' below.) Serologic tests for immunoglobulin G [IgG] antibodies are problematic because it is not possible to differentiate between passively acquired maternal antibody and endogenous antibody produced by the fetus/neonate. The ability to detect immunoglobulin M [IgM] antibodies, which do not cross the placenta, would confirm fetal infection. Unfortunately, a sufficiently sensitive and specific IgM assay is not available for routine use in the assessment of congenital syphilis [49]. The fluorescent anti-treponemal IgM antibody test IgM FTA-ABS was used in the past, but because of lack of sensitivity [65,66], the Centers for Disease Control and Prevention suspended its use for diagnostic testing of infants. The rabbit infectivity test (RIT), which involves the inoculation of cerebrospinal fluid [CSF] or other body fluids into rabbits to determine the presence of viable T. pallidum, is the reference standard test for congenital syphilis [21,23,53]. However, routine use of RIT is not practical because it involves animal testing and is not widely available. PCR has been used on neonatal blood and CSF for diagnosis of congenital syphilis, but these tests are not widely available [16,38,39,67]. Compared with isolation of the spirochetes by rabbit infectivity testing, the sensitivity and specificity of PCR on cerebrospinal fluid was 65 to 71 percent and 97 to 100 percent, respectively [38,39]. Among 17 infants who had spirochetes detected in CSF by rabbit inoculation, blood PCR was the best predictor of central nervous system infection with T. pallidum [38].

APPROACH TO DIAGNOSIS The vagaries of the maternal history and signs or lack of signs in the newborn in combination with the potential consequences of delayed or missed diagnosis of congenital syphilis demand a "safety first" approach to both diagnosis and treatment [4]. The Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics (AAP) Committee on Infectious Diseases provide guidelines for the evaluation and management of congenital syphilis (algorithm 1 and table 6) [49,50]. Maternal nontreponemal test results are required for entry into the algorithm. The CDC and AAP guidelines recommend that maternal samples be screened according to the traditional algorithm (ie, a nontreponemal test followed by a treponemal test if the nontreponemal test is positive). However, some laboratories screen samples in reverse (ie, a treponemal test before the nontreponemal test) [68]. Interpretation of results with reverse sequence screening is discussed separately. (See "Syphilis: Screening and diagnostic testing", section on 'Serologic testing algorithms'.) Point-of-care testing (usually linked with HIV testing) using immunochromatographic strips provides an alternative to laboratory testing that is particularly useful in resource-limited settings. These tests can be done during antenatal visits, do not require the laboratory infrastructure necessary https://www.uptodate.com/contents/congenital-syphilis-clinical-features-and-diagnosis/print?source=history_widget

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for conventional tests, and can be performed on finger-stick blood samples. They are easy to perform, it is easy to interpret their results, and they have a quick turnaround time of 20 minutes or so. They have good sensitivity and specificity, comparable to those of conventional treponemal and nontreponemal tests [68,69]. Clinical suspicion — The diagnosis of congenital syphilis should be suspected in all infants born to women who have reactive nontreponemal and treponemal tests for syphilis; the treponemal test is necessary to exclude a false-positive nontreponemal test (see "Syphilis in pregnancy"). The diagnosis of congenital syphilis also should be suspected in infants born to women who are identified clinically or through contact tracing as having early syphilis during the three months after delivery [4]. In addition, the possibility of congenital syphilis should be considered in infants and children with the following nonspecific clinical findings, particularly in infants born to women with a history of syphilis or risk factors for syphilis (see "Syphilis in pregnancy", section on 'Prevalence'):

● ● ● ● ● ● ● ● ● ● ● ● ●

Unexplained prematurity (