Update on Syphilis and Pregnancy
Michael E. Tsimis* and Jeanne S. Sheffield
While the origins of syphilis remain unknown, it has long been recognized as
an infectious entity with complex pathophysiology. In this review, we
highlighted the epidemiology and risk factors associated with syphilis. The
incidence of syphilis in most populations showed a consistent upward trend
until the 1940s with the introduction of penicillin as the preferred treatment.
The emergence of congenital syphilis and vertical transmission has been a
direct result of heterosexual syphilis transmission. We also explore the
microbiology and pathogenesis of Treponema pallidum as it directly correlates
with its route of transmission and infectivity. The clinical features are best
categorized into stages (primary, secondary, early, and late latent and
tertiary). The primary stage presents as a characteristic chancre and inguinal
adenopathy, while the secondary “bacteremia” stage has a predilection to
dermatologic manifestations and constitutional symptoms. The latent phase of
syphilis witnesses a quiescent period with variable relapse of symptoms and
finally, one-third of untreated patients undergo tertiary syphilis years after the
initial infection characterized by severe neurologic or cardiovascular
Introduction
Syphilis is a chronic systemic infection caused by the spiro-
chete Treponema pallidum. While its origin is fraught with
controversy, it was not recognized as a morbid entity until
the end of the 15th century. The prevailing theory is that its
introduction to the Old World from the Americas was
engendered by crewmembers of Christopher Columbus.
Their return to Spain was concurrent with a great syphilis
pandemic (“The Great Pox”) which spread throughout
Europe from 1490 to 1500 (Sheffield and Wendel, 1999).
Syphilis was long believed to be a psychiatric disease
as opposed to an infectious etiology. It was not until 1901
that Ilya Mechnikov, working at the Pasteur Institute in
Paris, successfully inoculated monkeys with T. pallidum.
The discovery confirmed the infectious transmission of
syphilis (Ilya Mecnikov, 1908). In 1937, US Surgeon Gener-
al Thomas Parran predicted that 10% of Americans would
be infected by syphilis (Parran, 1937) suggesting not only
its pervasiveness but also the recognition of the public
health ramifications of screening and treatment.
With respect to early treatment, Julius Wagner-Jauregg
made initial strides experimenting with fever therapy to treat
neurosyphilis in 1917 with the introduction of the “heat box”
as the preferred treatment modality. His “treatment” led to a
better understanding of the pathophysiology of T. pallidum—
Johns Hopkins Medicine, Department of Gynecology and Obstetrics,
Baltimore, Maryland
*Correspondence to: Michael E. Tsimis, Johns Hopkins Medicine, Department
Gynecology and Obstetrics, 600 N. Wolfe Street, Phipps 228, Baltimore, MD
21287. E-mail: MST@jhu.edu
Published online in Wiley Online Library (wileyonlinelibrary.com).
Doi: 10.1002/bdra.23562
C 2017 Wiley Periodicals, Inc.
V
symptomatology. We will also review the data collected for congenital syphilis
from the CDC as this can manifest with stillbirth, neonatal death, and
nonimmune hydrops. The diagnosis of syphilis focuses on a combination of
nontreponemal and treponemal antibody tests with the CDC recommending a
traditional algorithm from screening to confirmation. However, other agencies
have recently adopted the reverse testing algorithm which has outperformed
the traditional algorithm in certain populations. We finally focus on
syphilotherapy and monitoring response to treatment with a specific emphasis
on pregnancy.
Birth Defects Research 109:347–352, 2017.
C 2017 Wiley Periodicals, Inc.
V
Key words: congenital syphilis; reverse testing algorithm in syphilis; syphilis
clinical features; syphilotherapy; Treponema pallidum pathogenesis
the bacteria loses its infectivity at higher temperatures. Thus
fever is a rare manifestation of clinical syphilis. While ars-
phenamine was the first pharmacological agent used against
syphilis, its toxicity as a chemotherapeutic agent carried a
high mortality (Karamanou et al., 2013). Not until the advent
of penicillin in the 1940s did a major breakthrough arise in
syphilis treatment. Despite the clinical efficacy of penicillin,
however, syphilis remains a significant worldwide public
health concern.
Epidemiology and Risk Factors
The general downward trend in syphilis from the 1940s
saw two brief setbacks. The first occurred in the late
1970s and early 1980s, attributed to the increase in men
having sex with men (MSM) population and the emergence
of the HIV/AIDS epidemic. Second, the late 1980s was a
period of dramatic increase in primary and secondary
syphilis cases, which peaked in 1990 at 20.3 cases per
100,000 population (McFarlin et al., 1994; Sheffield and
Wendel, 1999). Various factors contributing to this surge
were the exchange of crack and cocaine for sex, decreased
public health funding for syphilis control and syphilis mis-
management (e.g., unrecognized disease and inadequate
treatment). Unfortunately, this second peak in the United
States was in part due to a significant increase in hetero-
sexual syphilis transmission with a resultant increase in
congenital syphilis (CS) rates.
The last decade has seen a slow but steady increase in
syphilis rates again, first in the MSM population and then
during the last 2 years among women. The 2013 to 2014
primary or secondary syphilis rate was 6.3 cases per
100,000 population, with an increase in women of 22.7%
from the year prior. This increase was reported in all
regions of the country and in all races and ethnicities. The
348
highest rate of syphilis in women is in the reproductive age
group, 15 to 44 years of age. As expected, the 2013 to 2014
congenital syphilis rate also increased 27.5% from the year
before 11.6 cases per 100,000 live births (CDC, 2015).
Risk factors associated with syphilis transmission
during pregnancy include young age, African-American
and Hispanic ethnicity, low socioeconomic status, less
education, inadequate prenatal care, prostitution and sub-
stance abuse (Sheffield and Wendel, 1999). The emergence
of syphilis as a public health issue has made pregnancy a
quintessential time for screening and proper treatment of
syphilis.
Microbiology and Pathogenesis
Treponema pallidum subsp. pallidum is a motile spirochete,
approximately 5 to 15 lm in length and 0.15 lm in width,
appearing tightly coiled in a helix but has a flat wave mor-
phology on electron microspcopy. It moves with a spiral
motion due to the rotation of flagellar filaments in the
periplasmic space. There are at least 57 subtypes,
although only a few cause most of the reported clinical
disease.
Sexual transmission of syphilis occurs when spiro-
chetes gain access through an abrasion or break in the
vaginal or anal mucosal surfaces through oral-genital or
genital-genital contact with an infected partner. Primary
and secondary stage disease carries the highest likelihood
of infection; a single sexual exposure to an individual car-
rying early stage disease carries a 50 to 60% risk of
acquiring syphilis. It is important to note, however, that
transmission may occur after the mucosal lesions have
resolved. Transmission may also occur transplacentally or
at the time of delivery through vertical transmission. The
mean incubation time after transmission is 21 days (range,
10–90 days) (Sweet and Gibbs, 2002).
Clinical Features
PRIMARY SYPHILIS
The primary stage is characterized by the “classic” chan-
cre: a painless, nontender, ulcerated lesion with a flat base
and a raised, red firm border whose diameter ranges from
0.5 to 2 cm. Multiple chancres can occur, predominantly in
HIV-infected individuals. In females, the chancre localizes
to the point of entry into the genital tract and can be
accompanied by painless nonsuppurative inguinal adenop-
athy in 80% of women, often regional in origin. Due to the
painless nature of the chancre and the location of most
chancres, they are often not detected in women.
Even without treatment, the chancre spontaneously
heals in 3 to 6 weeks, an indicator of an adequate host
immunologic response (Sheffield and Wendel, 1999).
SECONDARY SYPHILIS
The untreated woman with primary syphilis progresses to sec-
ondary syphilis, also known as the spirochetemia (bacteremia)
UPDATE ON SYPHILIS AND PREGNANCY
stage. Systemic dissemination of spirochetes to any organ sys-
tem is witnessed during this stage, which can appear 4 to 10
weeks after the chancre appears. The dermatologic presenta-
tion tends to be the most prevalent, affecting 90% of infected
women, followed by constitutional symptoms, manifesting in
70% of women with secondary syphilis. The central nervous
system is also a common target at this stage with approximate-
ly 40% of adults having evidence of cerebral spinal fluid abnor-
malities (Lukehard et al., 1988). Constitutional symptoms are
also common including low-grade fever, pharyngitis, malaise,
arthralgias, and myalgias.
The most common manifestations include: (1) A macu-
lopapular rash, usually nonpruritic, starting on the trunk
and extending to the proximal extremities with spread to
the entire body including palmar and plantar target-like
lesions. (2) Mucous patches which are silver to gray super-
ficial erosions of the genital, anal, and/or oral mucosa. (3)
Condylomata lata, which appear as gray plaques in moist
intertriginous areas such as the labia majora and minora.
(4) Generalized lymphadenopathy.
While most women manifest the symptoms above, second-
ary syphilis can affect any organ system lending to its name as
“The Great Imitator.” Hepatitis, gastritis, anterior and posterior
uveitis, interstitial keratitis, optic neuritis, otosyphilis, skeletal
involvement, and neurosyphilis have all been reported in wom-
en with secondary syphilis.
LATENT SYPHILIS
In the absence of treatment, the symptomatology of second-
ary syphilis resolves within 2 to 6 weeks, at which point the
latent phase begins. Latent syphilis has been subdivided into
early latent (<12 months) and late latent (>12 months)
phases. In the early latent phase, recrudescence can occur in
approximately 20 to 25% of women. In contrast, relapses
during the late latent phase are uncommon and patients are
not considered contagious by means of sexual transmission
(Sheffield and Wendel, 1999). Vertical transmission has
been reported in women with both early and late latent
syphilis, although transmission rates are significantly lower
than in primary and secondary syphilis. Serologic tests are
positive, but there are no clinical manifestations during the
latent stages.
TERTIARY SYPHILIS
Tertiary syphilis occurs in approximately one third of patients
who go untreated and develops years after the initial infec-
tion (Youmans, 1964). Secondary to public health measures
and slow disease progression, the evolution to tertiary syphi-
lis is understandably rare in reproductive age women. Of the
patients who manifest tertiary syphilis, half of those have late
benign syphilis, whose characteristic feature is the gumma, a
locally destructive granulomatous lesion affecting multiple
organ systems such as skin and bone. Of the remaining half,
one fourth exhibit cardiovascular syphilis, diagnosed by medi-
al necrosis of the aorta contributing to saccular aneurysms.
BIRTH DEFECTS RESEARCH 109:347–352 (2017)
The remaining quarter of patients with tertiary syphilis will
suffer from neurosyphilis, which produces general paresis,
tabes dorsalis, optic atrophy, and meningovascular syphilis.
The Argyll-Robertson pupil, in which the pupil does not react
to light but accommodates, is pathognomonic for this stage.
The pathogenesis seems to be related to obliteration and
inflammation of arteries supplying target tissues causing
their eventual destruction. While neurosyphilis is classified as
a subset of tertiary syphilis, the presentation of neurosyphilis
can present at any stage of syphilis infection (Sheffield and
Wendel, 1999; Duff, 2014).
CONGENITAL SYPHILIS
Congenital syphilis occurs with the vertical transmission
from an infected mother to her fetus during the course of
pregnancy. The CDC has analyzed national surveillance
data tracking the rate of CS for various time periods in the
United States. During the 1990s, the United States saw a
decrease in syphilis and as a corollary, CS cases between
1991 and 2005 witnessed a steady decrease in prevalence.
The period of 2005 to 2008 marked a slight increase in
CS, from 8.2 to 10.1 cases per 100,000 live births (CDC,
2014). The data from 2008 to 2012 show the rate of
reported CS decreased from 10.5 to 8.4 cases per 100,000
live births only to see it increase in the two subsequent
years to 11.6, a rate not attained since 2001. This increase
mirrors the 22% increased rate of primary and secondary
syphilis among women during the same time period. Rea-
sons for this increase are the absolute increased rate of
primary and secondary syphilis, reinfection of women
from untreated male partners, no prenatal care, and inade-
quate treatment (CDC, 2015). With these trends, it is
imperative that the reduction of CS be approached from
different facets including dissemination of accurate infor-
mation, proper screening and adequate treatment among
reproductive age women and heterosexual men, alike.
The clinical spectrum of CS encompasses stillbirth, neona-
tal death, and nonimmune hydrops. Additionally, the clinical
signs of syphilis during the first 2 years of life is termed early
congenital syphilis while late congenital syphilis describes
the clinical stigmata thereafter (Fiumara et al., 1952; Sheffield
and Wendel, 1999). The risk of congenital syphilis correlates
with the degree of maternal spirochetemia and duration of
disease with primary and secondary syphilis conferring the
highest risk of adverse pregnancy outcomes. Up to 60% of
infants born to untreated mothers are diagnosed with con-
genital syphilis either after a stillbirth evaluation or by means
of a neonatal diagnosis at birth. While fetuses before 16 weeks
gestation rarely become infected owing to their inability to
mount an immune response, spirochetes have been found in
aborti specimens.
Early congenital syphilis includes a maculopapular rash
progressing to desquamation, hepatosplenomegaly, osteochon-
dritis, snuffles (flu-like syndrome with nasal discharge) and
iritis. In cases where CS goes undiagnosed or incompletely
349
treated, late congenital syphilis can present with the classic tri-
ad of Hutchinson’s teeth, interstitial keratitis, and eighth-nerve
deafness. Associated signs may also include saddle nose, saber
shins, seizures, and mental retardation (Ingall et al., 2006).
Diagnosis
Treponema pallidum cannot be grown and sustained for pro-
longed periods in vitro. As a result, screening and diagnostic
tests have aimed at identifying the spirochete by means of
other mechanisms. There are two main testing schema that
clinicians rely on for laboratory diagnosis: direct detection
methods and serologic tests.
DIRECT OBSERVATION
The most sensitive method of diagnosing syphilis is by
means of the rabbit infectivity test (RIT). The test consists of
an intratesticular injection of infectious tissue or fluid into a
rabbit and if seropositive, the serial passage of lymphatic
product to a second rabbit. Infection in this second animal is
required to confirm T. pallidum spirochetes (Larsen et al.,
1995). The Darkfield microscopic examination is useful
primarily in early stage disease using exudate from lesions;
the spirochetes are identified using a Darkfield condenser.
The direct fluorescent antibody test of lesions is per-
formed using touch preparations with immunostaining. More
recently, polymerase chain reaction (PCR) of lesion exudates
is being used for diagnosis and in primary lesions, was found
to have higher diagnostic accuracy than dark-field detection
(Gayet-Ageron et al., 2015). The utility of PCR in other speci-
mens including blood and cerebrospinal fluid is still under
investigation.
SEROLOGIC TESTS
Nontreponemal antibody tests. The Venereal Disease Research
Laboratory (VDRL) slide test and the rapid plasma reagin
(RPR) card test constitute the nonspecific antibody tests,
both used for screening. These serologic tests will measure
antibodies relative to a standard antigen mixture containing
breakdown products from damaged host cells such as cardio-
lipin, cholesterol and lecithin. The specificity for both tests
ranges from 97 to 99%, irrespective of the stage (Larsen
et al., 1995). These tests are reported as titers; RPR titers are
usually higher than VDRL titers. Titers should be followed by
the same lab using the same nontreponemal test for consis-
tency and when following titers, one test (either VDRL or
RPR) should be chosen throughout without switching over
for the interpretation to be valid. Of note, RPR is more sensi-
tive and specific with blood tests with respect to VDRL.
A prozone reaction occurs when nontreponemal anti-
body levels are so high that they prevent the agglutination
reaction, resulting in a false negative tests. This can be
prevented by diluting the sample out at least 16 dilutions.
False positive results can occur with bacterial or viral
infections, malignancy, drug use, pregnancy, autoimmune
disorders, and aging.
350
TABLE 1. Treatment Regimen of Syphilis in Pregnancy as Recommended by CDC
Diagnosis
Primary, secondary, and early latent syphilis (<1 yr)
Late latent syphilis (>1 yr), latent syphilis of
unknown duration, and tertiary syphilis
Neurosyphilis
Penicillin allergic
TREPONEMAL ANTIBODY TESTS
The treponemal serologic tests use antibodies specific for
Treponema pallidum making them well-suited for confir-
matory testing. These treponemal-specific tests include the
fluorescent treponemal antibody absorption test and the T.
pallidum particle agglutination (TP-PA) test. Both tests
also approach the 97 to 99% specificity range although
they are nonquantitative. The tests are more expensive
and more difficult to perform, limiting their use in screen-
ing. More recently, automated treponemal enzyme and
chemiluminescence immunoassays (CIA) have been devel-
oped. The automation allows for high-volume, low cost
testing and is being used in the “reverse algorithm” testing
described below.
Once adequate treatment is administered, the nonspe-
cific antibody tests become nonreactive after treatment
with a small cohort of patients having a persistent low
titer for a variable period of time (“serofast syphilis”). In
contrast, once the specific treponemal tests are positive,
85% will remain positive for life (Larsen et al., 1995).
DIAGNOSTIC ALGORITHMS
All pregnant women initially presenting for prenatal care
should be screened and in high-risk populations, retested
at 28 weeks and again at delivery. The US Centers for Dis-
ease Control and Prevention (CDC) recommends the
“traditional” algorithm for the diagnosis of syphilis. In
these paradigm, syphilis serologic testing begins with a
nontreponemal test (e.g., VDRL, RPR) and if reactive, fol-
lowed by confirmatory testing using a treponemal anti-
body test. Recently, however, the Association of Public
Health Laboratories, the UK Health Protection Agency and
the International Union Against Sexually Transmitted
Infections have proposed the use of the reverse algorithm
that begins with a treponemal assay. A reactive treponemal
assay then reflexes to a quantitative nontreponemal assay.
In cases in which the specific treponemal assay is reactive
UPDATE ON SYPHILIS AND PREGNANCY
Treatment
Benzathine penicillin G, 2.4 million units IM in single dose
Benzathine penicillin G, 2.4 million units IM for three doses
(each 1 week apart)
 Aqueous crystalline penicillin G, 3-4 million units IV every 4 hours
or via continuous infusion for 10-14 days
OR
 Procaine penicillin, 2.4 million units IM daily plus probenecid
500 mg PO qid both for 10-14 days
Confirm allergy and desensitize, then appropriate treatment as above
and the nontreponemal test is nonreactive, a second but
different treponemal test is used to resolve the discordan-
cy. In a study reviewing testing discordance in pregnant
women using the reverse algorithm with a CIA as the
screening treponemal test, 80% were CIA1/RPR-/TP-PA-.
More than half of these on retesting were CIA-, suggesting
a false positive result (Larsen et al., 1995).
Reflexive testing with another treponemal test such as
TP-PA is important and will help clarify the clinical inter-
pretation. While interpretation of reverse testing results in
pregnancy is difficult, the reverse algorithm has outper-
formed the traditional algorithm in sensitivity, specificity
and diagnostic accuracy in other populations (Tong et al.,
2014). The confirmatory tests within the reverse algorithm
should not be used, however, in cases of previously con-
firmed syphilis because these tests can remain positive for
life. The traditional algorithm is recommended in this situ-
ation. Various institutions have implemented their own
version of protocols based on their specific population but
all broadly fall into the traditional or reverse technique.
ANTENATAL DIAGNOSIS OF CONGENITAL SYPHILIS
Ultrasound evaluation is a useful tool for the diagnosis of
congenital syphilis before delivery. A recent report describ-
ing the use of serial ultrasonography in 235 women diag-
nosed with syphilis after 18 weeks found that 31% had
abnormal findings on their initial ultrasound. The findings
included hepatomegaly (79%), placentomegaly (27%),
polyhydramnios (12%), ascites (10%), and abnormal
Doppler velocimetry of the middle cerebral artery (33%).
Commencement of treatment coincided with a specific
sequence of resolution for each abnormal finding starting
with the MCA Doppler, the ascites and the polyhydramnios.
Placentomegaly and hepatomegaly resolved last after ade-
quate syphilotherapy. Congential syphilis was diagnosed at
birth in 39% of infants with abnormal ultrasound findings
BIRTH DEFECTS RESEARCH 109:347–352 (2017)
(Rac et al., 2014). The study shows that ultrasound may
serve as an adjunct not only to identify more severely
affected fetuses, but also its use as a gauge to monitor
effectiveness of maternal syphilotherapy.
Treatment
All pregnant women who have sexual contact with a per-
son known to have syphilis, who have direct visualization
of spirochetes or who have serologic evidence consistent
with current infection should be treated. In cases in which
the evidence is not clear to confirm infection or if there is
suspicion of reinfection, prompt treatment should also be
initiated. The treatment schedules for syphilis by the CDC
are shown in Table 1 (Workowski and Bolan, 2015).
The administration of parenteral benzathine penicillin G
provides a long-acting formulation that lasts greater than 1
week for nonpregnant patients and given the altered phar-
macokinetics in pregnancy, lower analogous concentrations
in pregnancy. Therefore, there is a recommendation to add a
second injection of benzathine penicillin G 1 week after the
initial dose for early stage disease (Wendel et al., 2002). The
efficacy of treatment is contingent upon the stage of syphilis
and the gestational age at the time of treatment. With
respect to primary, late latent and tertiary stage, the treat-
ment efficacy approaches 100%. Secondary and early latent
stage disease has a 95% effectiveness rate. Treatment initi-
ated before 18 to 20 weeks also has an efficacy approaching
100% due to immunocompromised fetal status (Sheffield
and Wendel, 1999). While there are alternate antibiotics for
syphilotherapy in the nonpregnant population, penicillin
remains the only recommended therapy for pregnant wom-
en, HIV infected patients and neurosyphilis. Erythromycin
has been associated with an approximately 10% failure rate
as its transplacental passage is mercurial and, therefore, its
effectiveness is attenuated. Women with a documented aller-
gy to penicillin should undergo penicillin desensitization.
JARISCH-HERXHEIMER REACTION
The treatment of syphilis may precipitate the Jarisch-
Herxheimer reaction, characterized by an acute febrile ill-
ness associated with headaches, myalgia, rash and hypoten-
sion. The underlying pathophysiology stems from release of
treponemal polysaccharides from the destruction of spiro-
chetes with a concomitant increase in proinflammatory cyto-
kines including tumor necrosis factor-alpha, interleukin-6,
and interleukin-8 (Klein et al., 1990). The reaction occurs
1 to 2 hr after medication administration but generally
resolves within 24 to 48 hr and can affect up to 40% of
syphilitic pregnancies. From an obstetric standpoint,
preterm contractions, preterm labor, and nonreassuring
fetal heart rate tracings are known complications of syphilo-
therapy in the second half of pregnancy and may require
inpatient monitoring and symptomatic treatment (Myles
et al., 1998).
351
TITER RESPONSE AFTER TREATMENT
Follow-up of pregnant women after treatment for syphilis
consists of nontreponemal antibody serologic titers at 1, 3,
6, 12, and 24 months. Titers are expected to decrease four-
fold by 6 months, eventually becoming nonreactive by 12 to
24 months. In a recent report, Rac and colleagues (2015)
found that 38% of women treated for syphilis during preg-
nancy achieved a fourfold decline by delivery. Those not
achieving an appropriate decline tended to be older, treated
later in pregnancy, diagnosed with latent syphilis or syphilis
of unknown duration, and tended to have a shorter time-
frame from treatment to delivery (Rac et al. 2015). Treat-
ment failure or reinfection should be suspected in patients
who, at any point, have persistent symptoms or a sustained
fourfold increase in nontreponemal test titers. In cases of
treatment failure, CSF evaluation may be warranted with
either neurologic symptoms or HIV co-infection with CD4
cell counts below 350 cells/ll (Ghanem et al., 2009).
Because the patient response to treatment may be idiosyn-
cratic, it may be difficult to ascertain between treatment fail-
ure and reinfection. Either case would merit a retreatment
of the patient with another course of therapy.
CONCLUSIONS
The overall decline in syphilis cases in the United States
between 2008 and 2012 has now been offset by the
increased rate from 2012 to 2014. Worldwide syphilis infec-
tion during pregnancy remains a significant cause of stillbirth
and long-term morbidity for infected neonates. Importantly,
there is also a strong association between syphilis infection
and HIV transmission and acquisition. In an era in which
modern medicine grows at an exponential rate, we must be
conscientious in our efforts for continued public health
awareness and in our commitment to identify and treat of
syphilis for the health of both mothers and their offspring.
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