SE M I N A R S I N P E R I N A T O L O G Y ] (]]]]) ]]]–]]]

Available online at www.sciencedirect.com

Seminars in Perinatology

www.seminperinat.com

Congenital syphilis
Joshua M. Cooper, MDa, and Pablo J. Sánchez, MDb,*
a
Department of Pediatrics, Division of Neonatology, Wake Forest School of Medicine, Medical Center Boulevard,
Winston-Salem, NC 27157
b
Department 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 abstra ct

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

https://doi.org/10.1053/j.semperi.2018.02.005
0146-0005/& 2018 Published by Elsevier Inc.
2 SE M I N A R S I N
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.
syphilis among women.6,7 However, the highest rates of
primary and secondary syphilis in adults has occurred among
men who have sex with men (MSM),8,9 and the contribution
of men who have sex with men and women (MSMW) to the
congenital syphilis epidemic remains unknown.
Transmission
Syphilis is transmitted to the fetus transplacentally following
maternal spirochetemia, although transmission to the new-
born could occur intrapartum by contact with maternal
genital lesion(s). Intrauterine transmission is supported by
the isolation of the organism from umbilical cord blood and
amniotic fluid by rabbit infectivity testing.10–12 The isolation
of T. pallidum from as many as 74% of amniotic fluid speci-
mens obtained from women with early syphilis also suggests
that the organism is capable of traversing the fetal mem-
branes, gain access to the amniotic fluid, and result in fetal
infection.11,13 Intrauterine transmission also is supported by
the finding of abnormalities consistent with congenital syph-
ilis both in utero and at birth,10 as well as by detection of
specific IgM antibodies to T. pallidum in fetal serum obtained
by cordocentesis and in neonatal serum obtained at birth.14–16
Vertical transmission increases as the stage of pregnancy
advances but can occur at any time in gestation. The theory
that the Langerhans cell layer of the cytotrophoblast forms a
placental barrier against fetal infection before the 18th week
of pregnancy was disproved by detection of spirochetes in
fetal tissue from spontaneous abortion as early as 9 and 10
weeks’ gestation17 and recovery of spirochetes from amniotic
fluid at 14 weeks of pregnancy by rabbit infectivity testing.11
Futhermore, electron microscopy has demonstrated the per-
sistence of the Langerhans cell layer throughout pregnancy.
Importantly, vertical transmission is related to the stage of
maternal syphilis, with the highest transmission rates seen
with early syphilis and specifically, secondary syphilis. In
1950, Ingraham reported that among 251 women with
untreated syphilis of less than 4 years’ duration, 41% of their
infants were born alive and had congenital syphilis, 25% were
stillborn, 14% died in the neonatal period, 21% had low birth
weight but no evidence of syphilis, and only 18% were normal
P E R I N A T O L O G Y ] (]]]]) ]]]–]]]
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
Clinical manifestations
Syphilis during pregnancy is associated with premature
delivery, spontaneous abortion, stillbirth, nonimmune
hydrops, perinatal death, and two characteristic syndromes
of clinical disease, early and late congenital syphilis.21 More-
over, the placenta of infants with congenital syphilis often is
large, thick, and pale. Histopathologic features include
necrotizing funisitis (“barber's pole” appearance), villous
enlargement, and acute villitis.22 Placental and umbilical cord
histopathology should be performed on every case of sus-
pected syphilis. The clinical, laboratory, and radiographic
abnormalities of congenital syphilis are a consequence of
active infection with T. pallidum and the resultant inflamma-
tory response induced in various body organs and tissues.
The majority of infants born to mothers with untreated
syphilis appear normal and have no clinical or laboratory
evidence of infection at birth, but may develop manifesta-
tions of disease months to years later if left untreated.23
Early congenital syphilis refers to those clinical manifestations
that appear in the first 2 years of age (Table 1). Hepatospleno-
megaly secondary to either extramedullary hematopoiesis or
hepatitis is frequent and may take months to resolve. The
hepatitis of congenital syphilis may worsen transiently after
initiation of penicillin therapy. Thrombocytopenia with pete-
chiae and purpura also occurs frequently and may be the sole
manifestation of congenital infection. Mucocutaneous lesions
are prominent manifestations that occur in 40–60% of affected
infants. The rash of congenital syphilis usually is oval and
maculopapular but becomes copper-colored with desquamation
mostly in the palms and soles (Fig. 2). A characteristic fluid-filled,
bullous eruption known as pemphigus syphiliticus may develop
with peeling and eventual crusting and skin wrinkling. Rarely,
mucous patches of the lips, tongue, and palate as well as white,
flat, moist, raised plaques known as condylomata lata in the
perioral and perianal areas may occur.
Some affected infants may develop rhinitis (“snuffles”), a nasal
discharge that is initially watery but may become thick, purulent,
and blood-tinged. Both the nasal discharge and bullous fluid
contain large concentrations of spirochetes and are highly
infectious. Other less common manifestations include anemia,
ocular findings (chorioretinitis, cataract, glaucoma, and uveitis),
pneumonitis, pneumonia alba, nephrotic syndrome, myocarditis,
pancreatitis, and inflammation and fibrosis of the gastrointesti-
nal tract leading to malabsorption and diarrhea.
 SE M I N A R S I N P E R I N A T O L O G Y ] (]]]]) ]]]–]]] 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.
Eighth nerve deafnessb 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
Bone/Joint: frontal bossing, saddle nose deformity, protuberant bone formation in response to diaphyseal inflammation.
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.
a
Prominent feature
b
Comprise 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 SE M I N A R S I N P E R I N A T O L O G Y
Central nervous system invasion by T. pallidum occurs in
about 50% of infants with clinical, laboratory, or radiographic
signs of congenital syphilis.24 Clinical signs of neurosyphilis
are rare in the neonatal period but pituitary gland dysfunc-
tion with hypoglycemia and diabetes insipidus has been
reported.25,26 Other manifestations include bulging fonta-
nelle, seizures, leptomeningitis, cranial nerve palsies, hydro-
cephalus, and cerebral infarction.
Clinical disease that occurs after 2 years of age is desig-
nated as late congenital syphilis (Table 1) and results from
persistent inflammation or scars caused by infection of early
congenital syphilis.27 Dental stigmata include Hutchinson’s
teeth where the permanent upper central incisors are small,
widely spaced, barrel shaped, and notched, and mulberry
molars where the first lower molar has many small cusps
instead of the usual four. Osteochondritis affecting the otic
capsule may result in eighth nerve deafness. Late ocular
manifestations include uveitis and interstitial keratitis. The
constellation of interstitial keratitis, eight cranial nerve deaf-
ness, and Hutchinson’s teeth is known as Hutchinson’s triad.
The sequela of periostitis of the skull is frontal bossing, of
the tibia is saber shins, and of the clavicle is Higouménakis
sign with sternoclavicular thickening. Clutton joints, or pain-
less synovitis and hydrarthrosis, are rare. The sequelae of
syphilitic rhinitis include rhagades and short maxilla with a
high palatal arch. If the inflammation of the nasal mucosa
extends to the underlying cartilage and bone, perforation of
the palate and nasal septum occurs, resulting in a “saddle
nose” deformity. Sequelae of central nervous system infec-
tion include mental retardation, hydrocephalus, seizure
disorder, cranial nerve palsies, paralysis, and optic nerve
atrophy.
Infants with late congenital syphilis are not infective. Devel-
opment of the characteristic lesions is prevented by treatment
during pregnancy or within the first 3 months of age.
Diagnosis and management
The diagnosis of congenital syphilis is established by the
observation of spirochetes in body fluids or tissue and
suggested by serologic test results. T. pallidum may be iden-
tified by dark field microscopy, polymerase chain reaction
(PCR) testing, and fluorescent antibody or silver staining of
mucocutaneous lesions, nasal discharge, vesicular fluid,
amniotic fluid, placenta, umbilical cord, or tissue obtained
at autopsy. In research laboratories, the diagnosis also can be
established by inoculation of body fluids into rabbit testes
with resultant syphilitic infection of the rabbit (“rabbit infec-
tivity testing”).15,28,29 From a clinical standpoint, however, the
diagnosis usually is only inferred since maternal nontrepo-
nemal and treponemal IgG antibodies are transferred trans-
placentally to the fetus, complicating the interpretation of
reactive serologic tests for syphilis in infants up to 18 months
of age. The unusual finding of an infant’s serum quantitative
nontreponemal serologic titer that is fourfold higher than the
mother’s titer is confirmatory of congenital infection.15 How-
ever, the absence of such a finding does not exclude a
diagnosis of congenital syphilis as most infants with
] (]]]]) ]]]–]]]
congenital syphilis have nontreponemal serologic titers that
are the same or one to two dilutions less than the maternal
titer.
Serologic tests for syphilis are classified into nontrepone-
mal and treponemal tests. Nontreponemal tests include the
Venereal Disease Research Laboratory (VDRL) test and the
rapid plasma reagin (RPR) test. The same nontreponemal test
should be performed on the mother and infant so that
accurate comparisons can be made. No commercially avail-
able immunoglobulin M (IgM) test including the fluorescent
treponemal antibody absorption (FTA-ABS)-IgM test or total
IgM determination is recommended. Treponemal tests
include the T. pallidum particle agglutination (TP-PA) test,
the fluorescent treponemal antibody-absorption (FTA-ABS)
test, treponemal enzyme immunoassay (EIA), and chemilu-
minescence immunoassay (CIA). The treponemal tests
become reactive before the nontreponemal tests in individu-
als with syphilis, and they have been used to confirm its
diagnosis.
Recently, many clinical laboratories are using the EIA or CIA
treponemal tests for syphilis screening (“reverse sequence”
screening) since these are automated tests that can be performed
simultaneously on multiple serum specimens from many indi-
viduals30–33 (Fig. 4). If the EIA or CIA is positive, then a quanti-
tative nontreponemal test (e.g., RPR) is performed which if also
reactive, confirms the diagnosis of syphilis. However, if the RPR
test is nonreactive, then a second treponemal test (TP-PA
preferred) is performed, preferably on the same specimen. If
the second treponemal test is reactive, current or past syphilis
infection is confirmed. For women with a history of adequately
treated syphilis, no further evaluation or treatment is necessary.
However, as many as 40% of adults and 80% of pregnant women
will have discordant results (reactive EIA/CIA, nonreactive RPR
test, and nonreactive TP-PA test) which are more prevalent in
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
negative CIA test result after delivery.32
A practical approach to the management of infants born to
mothers with reactive serologic tests for syphilis is presented in
Fig. 5.34 All pregnant women who have syphilis and their sexual
partner(s) should be tested for coinfection with HIV, although
infants born to mothers coinfected with syphilis and HIV do not
require different evaluation, therapy, or follow-up. Infants born
to mothers with reactive serologic test results for syphilis should
have a serum quantitative nontreponemal test performed and be
carefully examined for physical signs of congenital syphilis.
In neonates who have a normal physical examination and a
serum quantitative nontreponemal serologic titer that is less
than fourfold the maternal titer, evaluation and treatment
depends on the maternal treatment history. If the mother has
untreated syphilis or the treatment is undocumented or inad-
equate (o4 weeks before delivery or with any nonpenicillin G
regimen), a complete evaluation consisting of cerebrospinal fluid
(CSF) analysis, long bone radiographs, and complete blood cell
(CBC) and platelet counts should be performed to guide optimal
therapy. The evaluation must be completely normal if the infant
is to be treated with a single intramuscular dose of benzathine
penicillin G. Almost none of these infants will have central
 SE M I N A R S I N
Fig. 4 – The figure shows the recommended algorithm for
reverse sequence syphilis screening (treponemal test
screening followed by nontreponemal test confirmation).
The CDC recommends that a specimen with reactive EIA/CIA
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
the TP-PA test as a confirmatory treponemal test. (MMWR
Morb Mortal Wkly Rep. 2011 Feb 11;60(5):133-7.)
Abbreviations: CDC ¼ Center for Disease Control and
Prevention; EIA/CIA ¼ enzyme immunoassay/
chemiluminescence immunoassay; RPR ¼ rapid plasma
reagin; TP-PA ¼ Treponema pallidum particle agglutination.
*Despite these recommendations for reverse sequence
screening, CDC continues to recommend the traditional
algorithm with reactive nontreponemal tests confirmed by
treponemal testing. †If incubating or primary syphilis is
suspected, treat with benzathine penicillin G 2.4 million
units intramuscularly in a single dose. §Evaluate clinically,
determine whether treated for syphilis in the past, assess
risk for infection, and administer therapy according to
CDC’s 2010 STD Treatment Guidelines (available at http://
www.cdc.gov/std/treatment/2010). ¶If at risk for syphilis,
repeat RPR in several weeks.
P E R I N A T O L O G Y ] (]]]]) ]]]–]]] 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
as clinically indicated (e.g., long-bone radiographs, chest radio-
graph, liver function tests, abdominal ultrasound, ophthalmo-
logic examination, neuroimaging, and auditory brain stem
response).
Treatment
Penicillin is the only known effective antimicrobial agent for
prevention of vertical transmission of syphilis and treatment of
fetal infection and congenital syphilis.34,36 Pregnant women with
syphilis should receive the penicillin regimen appropriate for
the stage of infection.34 Pregnant women who have a history
of penicillin allergy should be desensitized and treated with
penicillin.37
The decision to treat an infant for congenital syphilis is
based on the clinical presentation, previous serologic test
results and treatment of the mother, and the results of
serologic testing of the infant and mother at the time of
delivery (Fig. 5). Neonates with proven or highly probable
disease since they have (1) an abnormal physical examina-
tion that is consistent with congenital syphilis; (2) a serum
quantitative nontreponemal serologic titer that is fourfold
higher than the mother’s titer; or (3) a positive darkfield test
6 SE M I N A R S I N P E R I N A T O L O G Y ] (]]]]) ]]]–]]]

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
penicillin G (50,000 U/kg intravenously every 12 hours for
the first week of age, followed by every 8 hours beyond 7 days
of age) or aqueous procaine penicillin G (50,000 U/kg intra-
muscularly once daily) for 10 days. Neonates with possible
congenital syphilis who have a normal physical examination
but their evaluation (CBC and platelet counts, CSF analysis,
and long bone radiographs) is abnormal or incomplete,
should also receive a 10 day course of penicillin therapy. If
more than 1 day of therapy is missed, the entire course
should be restarted. Data are insufficient regarding the use of
other antimicrobial agents such as ampicillin.
Neonates who have a normal physical examination and a
serum quantitative nontreponemal serologic titer less than
fourfold the maternal titer and one of the following: (1)
mother was not treated, inadequately treated, or has no
documentation of having received treatment; or (2) mother
was treated with a nonpenicillin G regimen38; or (3) mother
received recommended treatment o4 weeks before delivery,
can receive a single intramuscular injection of benzathine
penicillin G (50,000 U/kg) if CSF studies, CBC and platelet
counts, and long bone radiographs are normal.39 Although
failure of a single injection of benzathine penicillin in the
treatment of congenital syphilis has been reported in infants
born to mothers with untreated syphilis, none had received a
complete evaluation to ascertain that it was normal.40 Treat-
ment failure also may have been due to the inability of a
single dose of benzathine penicillin to adequately penetrate
and achieve treponemicidal concentrations in certain sites
such as the aqueous humor and central nervous system.
Normal neonates born to mothers adequately treated
during pregnancy and greater than 4 weeks before delivery
should be considered as a “close contact” and receive a single
intramuscular injection of benzathine penicillin G (50,000 U/
kg), although no evaluation is required or recom-
mended.20,34,41,42 Similarly, normal infants who have a non-
reactive serum nontreponemal test result but are born to
mothers with untreated or inadequately syphilis can receive
a single dose of intramuscular benzathine penicillin G
(50,000 U/kg) without evaluation—an increasingly common
scenario with the use of reverse sequence syphilis screening
during pregnancy. Newborns with normal physical
 SE M I N A R S I N P E R I N A T O L O G Y
examination and nonreactive nontreponemal test results are
unlikely to have abnormalities detected on conventional
laboratory and radiographic testing.43,44
Infants and children aged ≥1 month who have reactive
serologic tests for syphilis and confirmed or likely congenital
syphilis should receive aqueous crystalline penicillin G
(200,000–300,000 units/kg/day IV, administered as 50,000
units/kg every 4–6 hours for 10 days). If the child has no
clinical manifestations of congenital syphilis and the evalua-
tion (including the CSF examination) is normal, treatment
with up to 3 weekly doses of benzathine penicillin G
(50,000 U/kg IM) is a suitable alternative. A single dose of
benzathine penicillin G (50,000 units/kg IM) can be considered
after the 10-day course of IV aqueous penicillin to provide
more comparable duration of treatment as those who have
no clinical manifestations and normal CSF.
If the availability of aqueous or procaine pencillin G is
compromised, ceftriaxone for 10 days can be considered with
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
forming in the lungs and kidneys. In addition, ceftriaxone must
be used with caution in infants with jaundice as it can theoret-
ically displace bilirubin from albumin-binding sites. Research
efforts are needed urgently to evaluate whether other antibiotics
such as ampicillin can treat effectively congenital syphilis.
Sinilarly, infants and children who require treatment for
syphilis but who have a history of penicillin allergy or develop
an allergic reaction presumed secondary to penicillin should be
desensitized, if necessary, and then treated with penicillin. If a
nonpenicillin agent is used, close serologic and CSF follow-up are
indicated.
Within 24 hours of initiation of pencillin therapy, a small
percentage of infants and children who have congenital syphilis
may develop a Jarisch-Herxheimer reaction, an acute inflamma-
tory response likely due to the rapid killing of spirochetes. It is
characterized by fever, tachypnea, tachycardia, hypotension,
accentuation of cutaneous lesions, or even death due to cardi-
ovascular collapse. A similar reaction can occur in women
treated for syphilis during the second half of pregnancy and
may precipitate premature labor and/or fetal distress.45,46 Corti-
costeroid therapy has not been shown to alter or prevent the
reaction, and treatment is supportive care only.
Follow-up
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
any long-term complications due to syphilis. Infants with
reactive serologic test results or born to mothers who were
seroreactive at delivery should have serial quantitative non-
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–
12 months after adequate treatment. Uninfected infants usually
become seronegative by 6 months of age. The serologic response
] (]]]]) ]]]–]]] 7
after therapy might be slower for infants and children treated
after the neonatal period. If serologic nontreponemal titers
increase fourfold at any time or remain stable after 12–18
months, the child should be evaluated and (re)-treated with a
10-day course of parenteral penicillin G. A reactive treponemal
test beyond 18 months of age when the child has lost all
maternal IgG antibodies confirms the diagnosis of congenital
syphilis. If the child was not previously treated, then treatment is
indicated as for late congenital syphilis. As many as 30% of
children who had confirmed congenital syphilis (detection of
spirochetes in blood/CSF by RIT) and received appropriate
penicillin treatment have nonreactive treponemal tests at 418
months of age.
Infants with abnormal CSF findings should have a repeat
lumbar puncture performed at 6 months after therapy. A
reactive CSF VDRL test result or an abnormal protein content
or cell count that cannot be attributed to other ongoing
illness at that time is an indication for re-treatment.
Prevention
Congenital syphilis is effectively prevented by prenatal
serologic screening of mothers and penicillin treatment of
infected women, their sexual partners, and their newborn
infants.47 All pregnant women should have a serologic test
for syphilis performed at the first prenatal visit in the first
trimester, and in high risk areas, again at 28–32 weeks’
gestation and delivery.34 Serologic screening tests should be
performed on mothers and not on infants, because the infant
may have a nonreactive serologic test result if the maternal
titer is reactive at a low dilution. No mother or newborn
should leave the hospital without the maternal serologic
status documented at least once during the pregnancy, and
preferably again at delivery if in a high risk area.
Infants with suspected or proven congenital syphilis are
cared for with standard precautions only. If the infant has
cutaneous lesions or mucous membrane involvement, then
contact precautions with gloves should be instituted until 24
hours of treatment has been completed.
All cases of syphilis must be reported to the local public
health department so contact investigation can be performed
with identification of core environments and populations.
The public health impact of syphilis in pregnancy and
infancy remains substantial, and only through optimal pre-
natal healthcare services will elimination of maternal-to-
child transmission of syphilis become a reality.
Financial disclosure
The authors have no financial relationships relevant to this
article to disclose.
Funding source
No funding was required for this manuscript.
8 SE M I N A R S I N P E R I N A T O L O G Y
Potential conflicts of interest
The authors have no conflicts of interest relevant to this
article to disclose.
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