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Seminars in Perinatology

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Congenital syphilis Joshua M. Cooper, MDa, and Pablo J. Sánchez, MDb,* aDepartment of Pediatrics, Division of Neonatology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157 bDepartment of Pediatrics, Divisions of Neonatology and Pediatric Infectious Diseases, Center for Perinatal Research, Nationwide Children’s Hospital, The Ohio State University College of Medicine, 700 Children’s Drive, RB3, WB5245, Columbus, OH 43205-2664 article info abstract

Keywords: Congenital syphilis remains a major public health problem worldwide, and its incidence is Congenital syphilis increasing in the United States. This review highlights the ongoing problem of this congenital syphilis review preventable infection, and discusses vertical transmission and clinical manifestations congenital infection while providing a practical algorithm for the evaluation and management of infants born reverse syphilis screening to mothers with reactive serologic tests for syphilis. Every case of congenital syphilis must be seen as a failure of our public health system to provide optimal prenatal care to pregnant women, as congenital syphilis can be prevented by early and repeated prenatal serologic screening of mothers and penicillin treatment of infected women, their sexual partners, and their newborn infants. & 2018 Published by Elsevier Inc.

Congenital syphilis, a result of fetal infection with Treponema radiographic abnormalities. Using the revised case definition, pallidum,1 is an ancient disease that continues to plague there were 6383 cases of congenital syphilis reported to the infants worldwide. Despite wide understanding of the disease CDC from 1999 to 2013, with a neonatal mortality of 11.6/1000 and optimal preventive strategies, congenital syphilis births and a case fatality rate of 6.5%.4 Of the 418 deaths, 82% remains a major cause of fetal and neonatal mortality (n ¼ 342) were stillbirths. Importantly, the majority of deaths globally.2 The global burden of congenital syphilis is con- occurred among infants born to mothers with untreated or founded further by the high prevalence of co-infection with the inadequately treated syphilis, and 59% occurred by 31 weeks human immunodeficiency virus (HIV) in adults, as syphilis is a of gestation. Since 2012, there has been a steady increase in known risk factor for acquisition of HIV. cases of congenital syphilis reported to the CDC with 628 In 1988, the surveillance case definition for national report- cases (15.7/100,000 live births) reported in 2016 that included ing of congenital syphilis was broadened by the Centers for 41 syphilitic stillbirths (Fig. 1; https://www.cdc.gov/std/stats16/ Disease and Prevention (CDC) to include all liveborn and syphilis.htm).5 In 2016, rates of congenital syphilis were highest stillborn infants, irrespective of clinical findings, who had among Blacks (43.1/100,000 live births), followed by American reactive serologic tests for syphilis and delivered to women Indians/Alaska Natives (31.6/100,000 live births), Hispanics (20. with untreated or inadequately treated syphilis.3 This change 5/100,000 live births), Asians/Pacific Islanders (9.2/100,000 live resulted in a fourfold increase in reported cases of congenital births), and Whites (5.3/100,000 live births). syphilis when compared to the previously used Kaufman As has been observed historically, the increase in congen- criteria that included only infants with clinical, laboratory, or ital syphilis paralleled increases in primary and secondary

* Corresponding author. Tel.: þ1 614 355 6638/1 614 355 5724; fax: þ1 614.355.5899. E-mail address: [email protected] (P.J. Sánchez). https://doi.org/10.1053/j.semperi.2018.02.005 0146-0005/& 2018 Published by Elsevier Inc. 2 S EMINARS IN P ERINATOLOGY ] ( ]]]]) ]]]– ]]]

full term infants.18 Among mothers with late latent infection, only 2% of their infants had congenital syphilis. In 1952, Fiumara and colleagues19 reported that untreated maternal primary or secondary syphilis resulted in 50% of infants having congenital syphilis while the other 50% were stillborn, premature, or died in the neonatal period. With early and late latent infection, 40% and 10% of infants, respectively, had congenital syphilis. More recently, from 1988 to 1998 at Parkland Memorial Hospital, Dallas, Sheffield and colleagues reported vertical transmission rates of 29%, 59%, 50%, and 13% in mothers with primary, secondary, early latent, and late latent infection, respectively.20

Fig. 1 – Congenital syphilis—Reported cases by year of birth and rates of reported cases of primary and secondary – syphilis among woman, United States, 2007 2016. Clinical manifestations

Syphilis during pregnancy is associated with premature syphilis among women.6,7 However, the highest rates of delivery, spontaneous abortion, stillbirth, nonimmune primary and secondary syphilis in adults has occurred among hydrops, perinatal death, and two characteristic syndromes men who have sex with men (MSM),8,9 and the contribution of clinical disease, early and late congenital syphilis.21 More- of men who have sex with men and women (MSMW) to the over, the placenta of infants with congenital syphilis often is congenital syphilis epidemic remains unknown. large, thick, and pale. Histopathologic features include necrotizing funisitis (“barber's pole” appearance), villous enlargement, and acute villitis.22 Placental and umbilical cord Transmission histopathology should be performed on every case of sus- pected syphilis. The clinical, laboratory, and radiographic Syphilis is transmitted to the fetus transplacentally following abnormalities of congenital syphilis are a consequence of maternal spirochetemia, although transmission to the new- active infection with T. pallidum and the resultant inflamma- born could occur intrapartum by contact with maternal tory response induced in various body organs and tissues. genital lesion(s). Intrauterine transmission is supported by The majority of infants born to mothers with untreated the isolation of the organism from umbilical cord blood and syphilis appear normal and have no clinical or laboratory – amniotic fluid by rabbit infectivity testing.10 12 The isolation evidence of infection at birth, but may develop manifesta- of T. pallidum from as many as 74% of amniotic fluid speci- tions of disease months to years later if left untreated.23 mens obtained from women with early syphilis also suggests Early congenital syphilis refers to those clinical manifestations that the organism is capable of traversing the fetal mem- that appear in the first 2 years of age (Table 1). Hepatospleno- branes, gain access to the amniotic fluid, and result in fetal megaly secondary to either extramedullary hematopoiesis or infection.11,13 Intrauterine transmission also is supported by hepatitis is frequent and may take months to resolve. The the finding of abnormalities consistent with congenital syph- hepatitis of congenital syphilis may worsen transiently after ilis both in utero and at birth,10 as well as by detection of initiation of penicillin therapy. Thrombocytopenia with pete- specific IgM antibodies to T. pallidum in fetal serum obtained chiaeandpurpuraalsooccursfrequentlyandmaybethesole – by cordocentesis and in neonatal serum obtained at birth.14 16 manifestation of congenital infection. Mucocutaneous lesions Vertical transmission increases as the stage of pregnancy are prominent manifestations that occur in 40–60% of affected advances but can occur at any time in gestation. The theory infants. The rash of congenital syphilis usually is oval and that the Langerhans cell layer of the cytotrophoblast forms a maculopapular but becomes copper-colored with desquamation placental barrier against fetal infection before the 18th week mostly in the palms and soles (Fig. 2). A characteristic fluid-filled, of pregnancy was disproved by detection of spirochetes in bullous eruption known as pemphigus syphiliticus may develop fetal tissue from spontaneous abortion as early as 9 and 10 with peeling and eventual crusting and skin wrinkling. Rarely, weeks’ gestation17 and recovery of spirochetes from amniotic mucous patches of the lips, tongue, and palate as well as white, fluid at 14 weeks of pregnancy by rabbit infectivity testing.11 flat,moist,raisedplaquesknownascondylomata lata in the Futhermore, electron microscopy has demonstrated the per- perioral and perianal areas may occur. sistence of the Langerhans cell layer throughout pregnancy. Some affected infants may develop rhinitis (“snuffles”), a nasal Importantly, vertical transmission is related to the stage of discharge that is initially watery but may become thick, purulent, maternal syphilis, with the highest transmission rates seen and blood-tinged. Both the nasal discharge and bullous fluid with early syphilis and specifically, secondary syphilis. In contain large concentrations of spirochetes and are highly 1950, Ingraham reported that among 251 women with infectious. Other less common manifestations include anemia, untreated syphilis of less than 4 years’ duration, 41% of their ocular findings (chorioretinitis, cataract, glaucoma, and uveitis), infants were born alive and had congenital syphilis, 25% were pneumonitis, pneumonia alba, nephrotic syndrome, myocarditis, stillborn, 14% died in the neonatal period, 21% had low birth pancreatitis, and inflammation and fibrosis of the gastrointesti- weight but no evidence of syphilis, and only 18% were normal nal tract leading to malabsorption and diarrhea. S EMINARS IN P ERINATOLOGY ] ( ]]]]) ]]]– ]]] 3

Table 1 – Clinical, laboratory, and radiographic findings in congenital syphilis. However, the majority of infected newborns have a normal physical examination and no laboratory or radiographic abnormalities.

Early congenital syphilis (o 2 years of age): Physical examination findings: Stillborn Preterm Nonimmune hydrops fetalis Intrauterine growth restriction / small for gestational age Hepatomegalya with or without jaundice Splenomegalya Skin rash (Figure 2)a Adenopathy (characteristically palpable epitrochlear nodes) Rhinitis (snuffles) Mucus patch Condylomata lata Pseudoparalysis of Parrot Eye: chorioretinitis, cataract Central nervous system: asymptomatic invasion,a cranial nerve palsies, seizures Laboratory findings: Anemia Thrombocytopeniaa Hypoglycemia Cerebrospinal fluid pleocytosis, elevated protein content Liver transaminitis and direct hyperbilirubinemia Radiographic findings: Bone abnormalities: periostitis, osteochondritisa Fig. 2 – Newborn with peeling bullous lesions of congenital Pneumonia alba syphilis (Courtesy of Dr. Mario del Barco of the Hospital Other: Materno Infantil, Salta, Argentina and Dr. Liliana Vázquez, Nephrotic syndrome, pancreatitis, myocarditis, fever, Buenos Aires, Argentina). gastrointestinal malabsorption, hypopituitarism (diabetes insipidus) Late congenital syphilis (42 years of age): Dentition: Hutchinson’s teeth,b Mulberry molars involves the metaphysis and is visualized on the long bone Eye: interstitial keratitis,b healed chorioretinitis radiographs approximately 5 weeks after fetal infection. b Eighth nerve deafness Bilateral demineralization and osseous destruction of the Rhagades proximal medial tibial metaphysis is referred to as Wimberger Central nervous system: mental retardation, hydrocephalus, sign. Periostitis requires 16 weeks for roentgenographic dem- seizures, optic nerve atrophy, juvenile general paresis, cranial nerve palsies onstration and consists of multiple layers of periosteal new fl Bone/Joint: frontal bossing, saddle nose deformity, protuberant bone formation in response to diaphyseal in ammation. mandible, short maxilla, high palatal arch, saber shin, The bone lesions heal after several months, even without sternoclavicular joint thickening (Higouménakis sign), Clutton antibiotic therapy. joints

Adapted from Syphilis. Velaphi S and Sánchez PJ. in Infectious Disease: Congenital and Perinatal Infections: A Concise Guide to Diag- nosis. Edited by: C. Hutto © Humana Press Inc., Totowa, NJ, 2005. aProminent feature bComprise Hutchinson’s Triad that is specific for congenital syphilis.

Radiographic abnormalities consisting of osteochondritis and periostitis occur in 60–80% of infants with clinical signs of congenital syphilis and 20% of well-appearing, congenitally infected infants (Fig. 3). In stillborn infants, skeletal survey demonstrating typical oseous lesions may aid in the diag- nosis of congenital syphilis. These abnormalities tend to involve the long bones (tibia, humerus, and femur), ribs, and cranium, and are usually symmetric, with the lower extremities involved more often than the upper extremities. Fig. 3 – Bone radiographs of infant with early congenital The bone lesions may be painful and result in subepiphyseal syphilis demonstrating periostitis of femur and fracture and epiphyseal dislocation with pseudoparalysis of osteochondritis of femur, tibia, and ulna (“saw-tooth” the affected limb (pseudoparalysis of Parrot). Osteochondritis pattern). 4 S EMINARS IN P ERINATOLOGY ] ( ]]]]) ]]]– ]]]

Central nervous system invasion by T. pallidum occurs in congenital syphilis have nontreponemal serologic titers that about 50% of infants with clinical, laboratory, or radiographic are the same or one to two dilutions less than the maternal signs of congenital syphilis.24 Clinical signs of neurosyphilis titer. are rare in the neonatal period but pituitary gland dysfunc- Serologic tests for syphilis are classified into nontrepone- tion with hypoglycemia and diabetes insipidus has been mal and treponemal tests. Nontreponemal tests include the reported.25,26 Other manifestations include bulging fonta- Venereal Disease Research Laboratory (VDRL) test and the nelle, seizures, leptomeningitis, cranial nerve palsies, hydro- rapid plasma reagin (RPR) test. The same nontreponemal test cephalus, and cerebral infarction. should be performed on the mother and infant so that Clinical disease that occurs after 2 years of age is desig- accurate comparisons can be made. No commercially avail- nated as late congenital syphilis (Table 1) and results from able immunoglobulin M (IgM) test including the fluorescent persistent inflammation or scars caused by infection of early treponemal antibody absorption (FTA-ABS)-IgM test or total congenital syphilis.27 Dental stigmata include Hutchinson’s IgM determination is recommended. Treponemal tests teeth where the permanent upper central incisors are small, include the T. pallidum particle agglutination (TP-PA) test, widely spaced, barrel shaped, and notched, and mulberry the fluorescent treponemal antibody-absorption (FTA-ABS) molars where the first lower molar has many small cusps test, treponemal enzyme immunoassay (EIA), and chemilu- instead of the usual four. Osteochondritis affecting the otic minescence immunoassay (CIA). The treponemal tests capsule may result in eighth nerve deafness. Late ocular become reactive before the nontreponemal tests in individu- manifestations include uveitis and interstitial keratitis. The als with syphilis, and they have been used to confirm its constellation of interstitial keratitis, eight cranial nerve deaf- diagnosis. ness, and Hutchinson’s teeth is known as Hutchinson’s triad. Recently, many clinical laboratories are using the EIA or CIA The sequela of periostitis of the skull is frontal bossing, of treponemal tests for syphilis screening (“reverse sequence” the tibia is saber shins, and of the clavicle is Higouménakis screening) since these are automated tests that can be performed sign with sternoclavicular thickening. Clutton joints, or pain- simultaneously on multiple serum specimens from many indi- – less synovitis and hydrarthrosis, are rare. The sequelae of viduals30 33 (Fig. 4). If the EIA or CIA is positive, then a quanti- syphilitic rhinitis include rhagades and short maxilla with a tative nontreponemal test (e.g., RPR) is performed which if also high palatal arch. If the inflammation of the nasal mucosa reactive, confirms the diagnosis of syphilis. However, if the RPR extends to the underlying cartilage and bone, perforation of test is nonreactive, then a second treponemal test (TP-PA the palate and nasal septum occurs, resulting in a “saddle preferred) is performed, preferably on the same specimen. If nose” deformity. Sequelae of central nervous system infec- the second treponemal test is reactive, current or past syphilis tion include mental retardation, hydrocephalus, seizure infection is confirmed. For women with a history of adequately disorder, cranial nerve palsies, paralysis, and optic nerve treated syphilis, no further evaluation or treatment is necessary. atrophy. However, as many as 40% of adults and 80% of pregnant women Infants with late congenital syphilis are not infective. Devel- will have discordant results (reactive EIA/CIA, nonreactive RPR opment of the characteristic lesions is prevented by treatment test, and nonreactive TP-PA test) which are more prevalent in during pregnancy or within the first 3 months of age. populations with low prevalence of syphilis, suggesting a false- positive EIA/CIA screen.31,32 Further supporting the occurrence of false-positive EIA/CIA test results is the finding that about 50% of pregnant women with discordant results will have a subsequent Diagnosis and management negative CIA test result after delivery.32 A practical approach to the management of infants born to The diagnosis of congenital syphilis is established by the mothers with reactive serologic tests for syphilis is presented in observation of spirochetes in body fluids or tissue and Fig. 5.34 All pregnant women who have syphilis and their sexual suggested by serologic test results. T. pallidum may be iden- partner(s) should be tested for coinfection with HIV, although tified by dark field microscopy, polymerase chain reaction infants born to mothers coinfected with syphilis and HIV do not (PCR) testing, and fluorescent antibody or silver staining of require different evaluation, therapy, or follow-up. Infants born mucocutaneous lesions, nasal discharge, vesicular fluid, to mothers with reactive serologic test results for syphilis should amniotic fluid, placenta, umbilical cord, or tissue obtained have a serum quantitative nontreponemal test performed and be at autopsy. In research laboratories, the diagnosis also can be carefully examined for physical signs of congenital syphilis. established by inoculation of body fluids into rabbit testes In neonates who have a normal physical examination and a with resultant syphilitic infection of the rabbit (“rabbit infec- serum quantitative nontreponemal serologic titer that is less tivity testing”).15,28,29 From a clinical standpoint, however, the than fourfold the maternal titer, evaluation and treatment diagnosis usually is only inferred since maternal nontrepo- depends on the maternal treatment history. If the mother has nemal and treponemal IgG antibodies are transferred trans- untreated syphilis or the treatment is undocumented or inad- placentally to the fetus, complicating the interpretation of equate (o4 weeks before delivery or with any nonpenicillin G reactive serologic tests for syphilis in infants up to 18 months regimen), a complete evaluation consisting of cerebrospinal fluid of age. The unusual finding of an infant’s serum quantitative (CSF) analysis, long bone radiographs, and complete blood cell nontreponemal serologic titer that is fourfold higher than the (CBC) and platelet counts should be performed to guide optimal mother’s titer is confirmatory of congenital infection.15 How- therapy. The evaluation must be completely normal if the infant ever, the absence of such a finding does not exclude a is to be treated with a single intramuscular dose of benzathine diagnosis of congenital syphilis as most infants with penicillin G. Almost none of these infants will have central S EMINARS IN P ERINATOLOGY ] ( ]]]]) ]]]– ]]] 5

nervous system invasion by T. pallidum if their complete evalua- tion is normal.24 Alternatively, a complete evaluation is not necessary if 10 days of parenteral penicillin therapy is provided. The diagnosis of congenital neurosyphilis is difficult to estab- lish since the majority of infants with congenital syphilis do not manifest any abnormalities on neurologic examination. Central nervous system invasion by T. pallidum is only inferred from CSF abnormalities such as a reactive VDRL test, pleocytosis (greater than 18–25 white blood cells per microliter), and elevated protein content (4150 mg/dL; 4170 mg/dL if infant is premature). How- ever, a reactive CSF VDRL test in neonates may be caused by passive transfer of nontreponemal IgG antibodies from serum into the CSF.35 By rabbit infectivity testing utilizing neonatal CSF, Michelow and coworkers24 found that invasion of the central nervous system with T. pallidum occurs in 41% of infants who have clinical, laboratory, or radiographic abnormalities of con- genital syphilis and in 60% of those who have an abnormal physical examination consistent with a diagnosis of congenital syphilis. The sensitivity and specificity of a reactive CSF VDRL test, pleocytosis, and elevated protein content were 53% and 90%, 38% and 88%, and 56% and 78%, respectively. Therefore, if clinical, laboratory or radiographic evaluation supports a diagnosis of congenital syphilis, then therapy effective against central nervous system disease is warranted irrespective of the results of CSF analyses. Older infants and children aged ≥1 month who are identified as having reactive serologic tests for syphilis should have maternal serology and records reviewed to assess whether they have congenital or acquired syphilis.34 This often is problematic among international adoptees in whom neither the results of previous maternal or infant serologic testing or treatment history is known or documented. These children should have CSF analysis for VDRL, cell count, and protein as well as a complete CBC and platelet counts. Other tests should be performed Fig. 4 – The figure shows the recommended algorithm for as clinically indicated (e.g., long-bone radiographs, chest radio- reverse sequence syphilis screening (treponemal test graph, liver function tests, abdominal ultrasound, ophthalmo- screening followed by nontreponemal test confirmation). logic examination, neuroimaging, and auditory brain stem The CDC recommends that a specimen with reactive EIA/CIA response). results be tested reflexively with a quantitative nontreponemal test (e.g., RPR or VDRL). If test results are discordant, the specimen should be tested reflexively using Treatment the TP-PA test as a confirmatory treponemal test. (MMWR Morb Mortal Wkly Rep. 2011 Feb 11;60(5):133-7.) Penicillin is the only known effective antimicrobial agent for Abbreviations: CDC ¼ Center for Disease Control and prevention of vertical transmission of syphilis and treatment of Prevention; EIA/CIA ¼ enzyme immunoassay/ fetal infection and congenital syphilis.34,36 Pregnant women with chemiluminescence immunoassay; RPR ¼ rapid plasma syphilis should receive the penicillin regimen appropriate for reagin; TP-PA ¼ Treponema pallidum particle agglutination. the stage of infection.34 Pregnant women who have a history *Despite these recommendations for reverse sequence of penicillin allergy should be desensitized and treated with screening, CDC continues to recommend the traditional penicillin.37 algorithm with reactive nontreponemal tests confirmed by The decision to treat an infant for congenital syphilis is † treponemal testing. If incubating or primary syphilis is based on the clinical presentation, previous serologic test suspected, treat with benzathine penicillin G 2.4 million results and treatment of the mother, and the results of units intramuscularly in a single dose. §Evaluate clinically, serologic testing of the infant and mother at the time of determine whether treated for syphilis in the past, assess delivery (Fig. 5). Neonates with proven or highly probable risk for infection, and administer therapy according to disease since they have (1) an abnormal physical examina- CDC’s 2010 STD Treatment Guidelines (available at http:// tion that is consistent with congenital syphilis; (2) a serum ¶ www.cdc.gov/std/treatment/2010). If at risk for syphilis, quantitative nontreponemal serologic titer that is fourfold repeat RPR in several weeks. higher than the mother’s titer; or (3) a positive darkfield test 6 S EMINARS IN P ERINATOLOGY ] ( ]]]]) ]]]– ]]]

Maternal Screening: Reactive TP Assay (EIA/CIA) Maternal Screening: Reactive RPR/VDRL

+ + Nonreactive Reactive maternal RPR/VDR Reactive maternal TP-PA/FTA-ABS/EIA/CIA maternal RPR/VDRL

Nonreactive maternal TP- + Nonreactive Reactive maternal TP-PA PA/FTA-ABS/EIA/CIA maternal TP- PA Infant RPR/VDRL False-positive reaction: no further evaluation False-positive reaction: no further evaluation Infant RPR/VDRL <4 times maternal RPR/VDRL Infant RPR/VDRL ≥4 times maternal RPR/VDRL

Infant physical exam normal* Infant physical exam abnormal

Maternal Maternal penicillin Maternal treatment: None, # Evaluate; treatment before treatment during or undocumented, or ≤ 4 § Treatment (1) pregnancy pregnancy and >4 weeks before delivery, or weeks before non-penicillin drug, or delivery maternal evidence of reinfection or relapse (≥ 4- fold increase in titers)

No evaluation No evaluation; ‡ Evaluate or treatment Treatment (2)

Normal Abnormal, not done, or evaluation incomplete evaluation

Treatment (2) Treatment (1)

+ Test for HIV-antibody. Infants of HIV-infected mothers do not require different evaluation or treatment. * If the infant’s RPR/VDRL is nonreactive AND the mother has had no treatment, undocumented treatment, treatment during pregnancy, or evidence of reinfection or relapse (≥ 4-fold increase in titers), THEN treat infant with a single IM injection of benzathine penicillin (50,000 U/kg). No additional evaluation is needed. § Women who maintain a VDRL titer ≤1:2 (RPR ≤ 1:4) beyond 1 year following successful treatment are considered serofast. # Evaluation consists of CBC, platelet count; CSF examination for cell count, protein, and quantitative VDRL. Other tests as clinically indicated: long-bone x-rays, neuroimaging, auditory brainstem response, eye exam, chest x-ray, liver function tests. ‡ CBC, platelet count; CSF examination for cell count, protein, and quantitative VDRL; long-bone x-rays TREATMENT: (1) Aqueous penicillin G 50,000 U/kg IV q 12 hr (≤1 wk of age), q 8 hr (>1 wk), or procaine penicillin G 50,000 U/kg IM single daily dose, x 10 days (2) Benzathine penicillin G 50,000 U/kg IM x 1 dose

Fig. 5 – Algorithm for evaluation and treatment of infants born to mothers with reactive serologic tests for syphilis. of body fluid(s) should receive either aqueous crystalline counts, and long bone radiographs are normal.39 Although penicillin G (50,000 U/kg intravenously every 12 hours for failure of a single injection of benzathine penicillin in the the first week of age, followed by every 8 hours beyond 7 days treatment of congenital syphilis has been reported in infants of age) or aqueous procaine penicillin G (50,000 U/kg intra- born to mothers with untreated syphilis, none had received a muscularly once daily) for 10 days. Neonates with possible complete evaluation to ascertain that it was normal.40 Treat- congenital syphilis who have a normal physical examination ment failure also may have been due to the inability of a but their evaluation (CBC and platelet counts, CSF analysis, single dose of benzathine penicillin to adequately penetrate and long bone radiographs) is abnormal or incomplete, and achieve treponemicidal concentrations in certain sites should also receive a 10 day course of penicillin therapy. If such as the aqueous humor and central nervous system. more than 1 day of therapy is missed, the entire course Normal neonates born to mothers adequately treated should be restarted. Data are insufficient regarding the use of during pregnancy and greater than 4 weeks before delivery other antimicrobial agents such as ampicillin. should be considered as a “close contact” and receive a single Neonates who have a normal physical examination and a intramuscular injection of benzathine penicillin G (50,000 U/ serum quantitative nontreponemal serologic titer less than kg), although no evaluation is required or recom- fourfold the maternal titer and one of the following: (1) mended.20,34,41,42 Similarly, normal infants who have a non- mother was not treated, inadequately treated, or has no reactive serum nontreponemal test result but are born to documentation of having received treatment; or (2) mother mothers with untreated or inadequately syphilis can receive was treated with a nonpenicillin G regimen38; or (3) mother a single dose of intramuscular benzathine penicillin G received recommended treatment o4 weeks before delivery, (50,000 U/kg) without evaluation—an increasingly common can receive a single intramuscular injection of benzathine scenario with the use of reverse sequence syphilis screening penicillin G (50,000 U/kg) if CSF studies, CBC and platelet during pregnancy. Newborns with normal physical S EMINARS IN P ERINATOLOGY ] ( ]]]]) ]]]– ]]] 7

examination and nonreactive nontreponemal test results are after therapy might be slower for infants and children treated unlikely to have abnormalities detected on conventional after the neonatal period. If serologic nontreponemal titers laboratory and radiographic testing.43,44 increase fourfold at any timeorremainstableafter12–18 Infants and children aged ≥1 month who have reactive months, the child should be evaluated and (re)-treated with a serologic tests for syphilis and confirmed or likely congenital 10-day course of parenteral penicillin G. A reactive treponemal syphilis should receive aqueous crystalline penicillin G test beyond 18 months of age when the child has lost all (200,000–300,000 units/kg/day IV, administered as 50,000 maternal IgG antibodies confirms the diagnosis of congenital units/kg every 4–6 hours for 10 days). If the child has no syphilis. If the child was not previously treated, then treatment is clinical manifestations of congenital syphilis and the evalua- indicated as for late congenital syphilis. As many as 30% of tion (including the CSF examination) is normal, treatment children who had confirmed congenital syphilis (detection of with up to 3 weekly doses of benzathine penicillin G spirochetes in blood/CSF by RIT) and received appropriate (50,000 U/kg IM) is a suitable alternative. A single dose of penicillin treatment have nonreactive treponemal tests at 418 benzathine penicillin G (50,000 units/kg IM) can be considered months of age. after the 10-day course of IV aqueous penicillin to provide Infants with abnormal CSF findings should have a repeat more comparable duration of treatment as those who have lumbar puncture performed at 6 months after therapy. A no clinical manifestations and normal CSF. reactive CSF VDRL test result or an abnormal protein content If the availability of aqueous or procaine pencillin G is or cell count that cannot be attributed to other ongoing compromised, ceftriaxone for 10 days can be considered with illness at that time is an indication for re-treatment. careful clinical and serologic follow-up, including CSF evaluation (see http://www.cdc.gov/nchstp/dstd/penicillinG.htm).34 Ceftriax- one should not be adminstered with calcium-containing prod- ucts in neonates as it can increase the risk of lethal precipitates Prevention forming in the lungs and kidneys. In addition, ceftriaxone must be used with caution in infants with jaundice as it can theoret- Congenital syphilis is effectively prevented by prenatal ically displace bilirubin from albumin-binding sites. Research serologic screening of mothers and penicillin treatment of efforts are needed urgently to evaluate whether other antibiotics infected women, their sexual partners, and their newborn 47 such as ampicillin can treat effectively congenital syphilis. infants. All pregnant women should have a serologic test fi fi Sinilarly, infants and children who require treatment for for syphilis performed at the rst prenatal visit in the rst – ’ syphilis but who have a history of penicillin allergy or develop trimester, and in high risk areas, again at 28 32 weeks 34 an allergic reaction presumed secondary to penicillin should be gestation and delivery. Serologic screening tests should be desensitized, if necessary, and then treated with penicillin. If a performed on mothers and not on infants, because the infant nonpenicillin agent is used, close serologic and CSF follow-up are may have a nonreactive serologic test result if the maternal indicated. titer is reactive at a low dilution. No mother or newborn Within 24 hours of initiation of pencillin therapy, a small should leave the hospital without the maternal serologic percentage of infants and children who have congenital syphilis status documented at least once during the pregnancy, and may develop a Jarisch-Herxheimer reaction, an acute inflamma- preferably again at delivery if in a high risk area. tory response likely due to the rapid killing of spirochetes. It is Infants with suspected or proven congenital syphilis are characterized by fever, tachypnea, tachycardia, hypotension, cared for with standard precautions only. If the infant has accentuation of cutaneous lesions, or even death due to cardi- cutaneous lesions or mucous membrane involvement, then ovascular collapse. A similar reaction can occur in women contact precautions with gloves should be instituted until 24 treated for syphilis during thesecondhalfofpregnancyand hours of treatment has been completed. may precipitate premature labor and/or fetal distress.45,46 Corti- All cases of syphilis must be reported to the local public costeroid therapy has not been shown to alter or prevent the health department so contact investigation can be performed fi reaction, and treatment is supportive care only. with identi cation of core environments and populations. The public health impact of syphilis in pregnancy and infancy remains substantial, and only through optimal pre- Follow-up natal healthcare services will elimination of maternal-to- child transmission of syphilis become a reality. Although data are lacking on neurodevelopmental outcomes of infants with congenital syphilis, the majority of these infants who are treated in early infancy do well without Financial disclosure any long-term complications due to syphilis. Infants with reactive serologic test results or born to mothers who were The authors have no financial relationships relevant to this seroreactive at delivery should have serial quantitative non- article to disclose. treponemal tests performed every 2–3 months until preferably the test becomes nonreactive or the titer has decreased fourfold. In infants with congenital syphilis, nontreponemal serologic tests should decline fourfold and become nonreactive within 6– Funding source 12 months after adequate treatment. Uninfected infants usually become seronegative by 6 months of age. The serologic response No funding was required for this manuscript. 8 S EMINARS IN P ERINATOLOGY ] ( ]]]]) ]]]– ]]]

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