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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 symptomatology. We will also review the data collected for congenital syphilis
an infectious entity with complex pathophysiology. In this review, we from the CDC as this can manifest with stillbirth, neonatal death, and
highlighted the epidemiology and risk factors associated with syphilis. The nonimmune hydrops. The diagnosis of syphilis focuses on a combination of
incidence of syphilis in most populations showed a consistent upward trend nontreponemal and treponemal antibody tests with the CDC recommending a
until the 1940s with the introduction of penicillin as the preferred treatment. traditional algorithm from screening to confirmation. However, other agencies
The emergence of congenital syphilis and vertical transmission has been a have recently adopted the reverse testing algorithm which has outperformed
direct result of heterosexual syphilis transmission. We also explore the the traditional algorithm in certain populations. We finally focus on
microbiology and pathogenesis of Treponema pallidum as it directly correlates syphilotherapy and monitoring response to treatment with a specific emphasis
with its route of transmission and infectivity. The clinical features are best on pregnancy.
categorized into stages (primary, secondary, early, and late latent and
tertiary). The primary stage presents as a characteristic chancre and inguinal Birth Defects Research 109:347–352, 2017.
adenopathy, while the secondary “bacteremia” stage has a predilection to C 2017 Wiley Periodicals, Inc.
V
dermatologic manifestations and constitutional symptoms. The latent phase of
syphilis witnesses a quiescent period with variable relapse of symptoms and
Key words: congenital syphilis; reverse testing algorithm in syphilis; syphilis
finally, one-third of untreated patients undergo tertiary syphilis years after the
clinical features; syphilotherapy; Treponema pallidum pathogenesis
initial infection characterized by severe neurologic or cardiovascular

Introduction the bacteria loses its infectivity at higher temperatures. Thus


Syphilis is a chronic systemic infection caused by the spiro- fever is a rare manifestation of clinical syphilis. While ars-
chete Treponema pallidum. While its origin is fraught with phenamine was the first pharmacological agent used against
controversy, it was not recognized as a morbid entity until syphilis, its toxicity as a chemotherapeutic agent carried a
the end of the 15th century. The prevailing theory is that its high mortality (Karamanou et al., 2013). Not until the advent
introduction to the Old World from the Americas was of penicillin in the 1940s did a major breakthrough arise in
engendered by crewmembers of Christopher Columbus. syphilis treatment. Despite the clinical efficacy of penicillin,
Their return to Spain was concurrent with a great syphilis however, syphilis remains a significant worldwide public
pandemic (“The Great Pox”) which spread throughout health concern.
Europe from 1490 to 1500 (Sheffield and Wendel, 1999).
Syphilis was long believed to be a psychiatric disease Epidemiology and Risk Factors
as opposed to an infectious etiology. It was not until 1901 The general downward trend in syphilis from the 1940s
that Ilya Mechnikov, working at the Pasteur Institute in saw two brief setbacks. The first occurred in the late
Paris, successfully inoculated monkeys with T. pallidum. 1970s and early 1980s, attributed to the increase in men
The discovery confirmed the infectious transmission of having sex with men (MSM) population and the emergence
syphilis (Ilya Mecnikov, 1908). In 1937, US Surgeon Gener- of the HIV/AIDS epidemic. Second, the late 1980s was a
al Thomas Parran predicted that 10% of Americans would period of dramatic increase in primary and secondary
be infected by syphilis (Parran, 1937) suggesting not only syphilis cases, which peaked in 1990 at 20.3 cases per
its pervasiveness but also the recognition of the public 100,000 population (McFarlin et al., 1994; Sheffield and
health ramifications of screening and treatment. Wendel, 1999). Various factors contributing to this surge
With respect to early treatment, Julius Wagner-Jauregg were the exchange of crack and cocaine for sex, decreased
made initial strides experimenting with fever therapy to treat public health funding for syphilis control and syphilis mis-
neurosyphilis in 1917 with the introduction of the “heat box” management (e.g., unrecognized disease and inadequate
as the preferred treatment modality. His “treatment” led to a treatment). Unfortunately, this second peak in the United
better understanding of the pathophysiology of T. pallidum— States was in part due to a significant increase in hetero-
sexual syphilis transmission with a resultant increase in
congenital syphilis (CS) rates.
Johns Hopkins Medicine, Department of Gynecology and Obstetrics, The last decade has seen a slow but steady increase in
Baltimore, Maryland
syphilis rates again, first in the MSM population and then
*Correspondence to: Michael E. Tsimis, Johns Hopkins Medicine, Department during the last 2 years among women. The 2013 to 2014
Gynecology and Obstetrics, 600 N. Wolfe Street, Phipps 228, Baltimore, MD primary or secondary syphilis rate was 6.3 cases per
21287. E-mail: MST@jhu.edu
100,000 population, with an increase in women of 22.7%
Published online in Wiley Online Library (wileyonlinelibrary.com). from the year prior. This increase was reported in all
Doi: 10.1002/bdra.23562 regions of the country and in all races and ethnicities. The

C 2017 Wiley Periodicals, Inc.


V
348 UPDATE ON SYPHILIS AND PREGNANCY

highest rate of syphilis in women is in the reproductive age stage. Systemic dissemination of spirochetes to any organ sys-
group, 15 to 44 years of age. As expected, the 2013 to 2014 tem is witnessed during this stage, which can appear 4 to 10
congenital syphilis rate also increased 27.5% from the year weeks after the chancre appears. The dermatologic presenta-
before 11.6 cases per 100,000 live births (CDC, 2015). tion tends to be the most prevalent, affecting 90% of infected
Risk factors associated with syphilis transmission women, followed by constitutional symptoms, manifesting in
during pregnancy include young age, African-American 70% of women with secondary syphilis. The central nervous
and Hispanic ethnicity, low socioeconomic status, less system is also a common target at this stage with approximate-
education, inadequate prenatal care, prostitution and sub- ly 40% of adults having evidence of cerebral spinal fluid abnor-
stance abuse (Sheffield and Wendel, 1999). The emergence malities (Lukehard et al., 1988). Constitutional symptoms are
of syphilis as a public health issue has made pregnancy a also common including low-grade fever, pharyngitis, malaise,
quintessential time for screening and proper treatment of arthralgias, and myalgias.
syphilis. The most common manifestations include: (1) A macu-
lopapular rash, usually nonpruritic, starting on the trunk
Microbiology and Pathogenesis and extending to the proximal extremities with spread to
Treponema pallidum subsp. pallidum is a motile spirochete, the entire body including palmar and plantar target-like
approximately 5 to 15 lm in length and 0.15 lm in width, lesions. (2) Mucous patches which are silver to gray super-
appearing tightly coiled in a helix but has a flat wave mor- ficial erosions of the genital, anal, and/or oral mucosa. (3)
phology on electron microspcopy. It moves with a spiral Condylomata lata, which appear as gray plaques in moist
motion due to the rotation of flagellar filaments in the intertriginous areas such as the labia majora and minora.
periplasmic space. There are at least 57 subtypes, (4) Generalized lymphadenopathy.
although only a few cause most of the reported clinical While most women manifest the symptoms above, second-
disease. ary syphilis can affect any organ system lending to its name as
Sexual transmission of syphilis occurs when spiro- “The Great Imitator.” Hepatitis, gastritis, anterior and posterior
chetes gain access through an abrasion or break in the uveitis, interstitial keratitis, optic neuritis, otosyphilis, skeletal
vaginal or anal mucosal surfaces through oral-genital or involvement, and neurosyphilis have all been reported in wom-
genital-genital contact with an infected partner. Primary en with secondary syphilis.
and secondary stage disease carries the highest likelihood
of infection; a single sexual exposure to an individual car- LATENT SYPHILIS

rying early stage disease carries a 50 to 60% risk of In the absence of treatment, the symptomatology of second-
acquiring syphilis. It is important to note, however, that ary syphilis resolves within 2 to 6 weeks, at which point the
transmission may occur after the mucosal lesions have latent phase begins. Latent syphilis has been subdivided into
resolved. Transmission may also occur transplacentally or early latent (<12 months) and late latent (>12 months)
at the time of delivery through vertical transmission. The phases. In the early latent phase, recrudescence can occur in
mean incubation time after transmission is 21 days (range, approximately 20 to 25% of women. In contrast, relapses
10–90 days) (Sweet and Gibbs, 2002). during the late latent phase are uncommon and patients are
not considered contagious by means of sexual transmission
Clinical Features (Sheffield and Wendel, 1999). Vertical transmission has
PRIMARY SYPHILIS been reported in women with both early and late latent
The primary stage is characterized by the “classic” chan- syphilis, although transmission rates are significantly lower
cre: a painless, nontender, ulcerated lesion with a flat base than in primary and secondary syphilis. Serologic tests are
and a raised, red firm border whose diameter ranges from positive, but there are no clinical manifestations during the
0.5 to 2 cm. Multiple chancres can occur, predominantly in latent stages.
HIV-infected individuals. In females, the chancre localizes
TERTIARY SYPHILIS
to the point of entry into the genital tract and can be
Tertiary syphilis occurs in approximately one third of patients
accompanied by painless nonsuppurative inguinal adenop-
who go untreated and develops years after the initial infec-
athy in 80% of women, often regional in origin. Due to the
tion (Youmans, 1964). Secondary to public health measures
painless nature of the chancre and the location of most
and slow disease progression, the evolution to tertiary syphi-
chancres, they are often not detected in women.
lis is understandably rare in reproductive age women. Of the
Even without treatment, the chancre spontaneously
patients who manifest tertiary syphilis, half of those have late
heals in 3 to 6 weeks, an indicator of an adequate host
benign syphilis, whose characteristic feature is the gumma, a
immunologic response (Sheffield and Wendel, 1999).
locally destructive granulomatous lesion affecting multiple
SECONDARY SYPHILIS organ systems such as skin and bone. Of the remaining half,
The untreated woman with primary syphilis progresses to sec- one fourth exhibit cardiovascular syphilis, diagnosed by medi-
ondary syphilis, also known as the spirochetemia (bacteremia) al necrosis of the aorta contributing to saccular aneurysms.
BIRTH DEFECTS RESEARCH 109:347–352 (2017) 349

The remaining quarter of patients with tertiary syphilis will treated, late congenital syphilis can present with the classic tri-
suffer from neurosyphilis, which produces general paresis, ad of Hutchinson’s teeth, interstitial keratitis, and eighth-nerve
tabes dorsalis, optic atrophy, and meningovascular syphilis. deafness. Associated signs may also include saddle nose, saber
The Argyll-Robertson pupil, in which the pupil does not react shins, seizures, and mental retardation (Ingall et al., 2006).
to light but accommodates, is pathognomonic for this stage.
The pathogenesis seems to be related to obliteration and Diagnosis
inflammation of arteries supplying target tissues causing Treponema pallidum cannot be grown and sustained for pro-
their eventual destruction. While neurosyphilis is classified as longed periods in vitro. As a result, screening and diagnostic
a subset of tertiary syphilis, the presentation of neurosyphilis tests have aimed at identifying the spirochete by means of
can present at any stage of syphilis infection (Sheffield and other mechanisms. There are two main testing schema that
Wendel, 1999; Duff, 2014). clinicians rely on for laboratory diagnosis: direct detection
CONGENITAL SYPHILIS
methods and serologic tests.
Congenital syphilis occurs with the vertical transmission DIRECT OBSERVATION
from an infected mother to her fetus during the course of The most sensitive method of diagnosing syphilis is by
pregnancy. The CDC has analyzed national surveillance means of the rabbit infectivity test (RIT). The test consists of
data tracking the rate of CS for various time periods in the an intratesticular injection of infectious tissue or fluid into a
United States. During the 1990s, the United States saw a rabbit and if seropositive, the serial passage of lymphatic
decrease in syphilis and as a corollary, CS cases between product to a second rabbit. Infection in this second animal is
1991 and 2005 witnessed a steady decrease in prevalence. required to confirm T. pallidum spirochetes (Larsen et al.,
The period of 2005 to 2008 marked a slight increase in 1995). The Darkfield microscopic examination is useful
CS, from 8.2 to 10.1 cases per 100,000 live births (CDC, primarily in early stage disease using exudate from lesions;
2014). The data from 2008 to 2012 show the rate of the spirochetes are identified using a Darkfield condenser.
reported CS decreased from 10.5 to 8.4 cases per 100,000 The direct fluorescent antibody test of lesions is per-
live births only to see it increase in the two subsequent formed using touch preparations with immunostaining. More
years to 11.6, a rate not attained since 2001. This increase recently, polymerase chain reaction (PCR) of lesion exudates
mirrors the 22% increased rate of primary and secondary is being used for diagnosis and in primary lesions, was found
syphilis among women during the same time period. Rea- to have higher diagnostic accuracy than dark-field detection
sons for this increase are the absolute increased rate of (Gayet-Ageron et al., 2015). The utility of PCR in other speci-
primary and secondary syphilis, reinfection of women mens including blood and cerebrospinal fluid is still under
from untreated male partners, no prenatal care, and inade- investigation.
quate treatment (CDC, 2015). With these trends, it is
imperative that the reduction of CS be approached from SEROLOGIC TESTS
different facets including dissemination of accurate infor- Nontreponemal antibody tests. The Venereal Disease Research
mation, proper screening and adequate treatment among Laboratory (VDRL) slide test and the rapid plasma reagin
reproductive age women and heterosexual men, alike. (RPR) card test constitute the nonspecific antibody tests,
The clinical spectrum of CS encompasses stillbirth, neona- both used for screening. These serologic tests will measure
tal death, and nonimmune hydrops. Additionally, the clinical antibodies relative to a standard antigen mixture containing
signs of syphilis during the first 2 years of life is termed early breakdown products from damaged host cells such as cardio-
congenital syphilis while late congenital syphilis describes lipin, cholesterol and lecithin. The specificity for both tests
the clinical stigmata thereafter (Fiumara et al., 1952; Sheffield ranges from 97 to 99%, irrespective of the stage (Larsen
and Wendel, 1999). The risk of congenital syphilis correlates et al., 1995). These tests are reported as titers; RPR titers are
with the degree of maternal spirochetemia and duration of usually higher than VDRL titers. Titers should be followed by
disease with primary and secondary syphilis conferring the the same lab using the same nontreponemal test for consis-
highest risk of adverse pregnancy outcomes. Up to 60% of tency and when following titers, one test (either VDRL or
infants born to untreated mothers are diagnosed with con- RPR) should be chosen throughout without switching over
genital syphilis either after a stillbirth evaluation or by means for the interpretation to be valid. Of note, RPR is more sensi-
of a neonatal diagnosis at birth. While fetuses before 16 weeks tive and specific with blood tests with respect to VDRL.
gestation rarely become infected owing to their inability to A prozone reaction occurs when nontreponemal anti-
mount an immune response, spirochetes have been found in body levels are so high that they prevent the agglutination
aborti specimens. reaction, resulting in a false negative tests. This can be
Early congenital syphilis includes a maculopapular rash prevented by diluting the sample out at least 16 dilutions.
progressing to desquamation, hepatosplenomegaly, osteochon- False positive results can occur with bacterial or viral
dritis, snuffles (flu-like syndrome with nasal discharge) and infections, malignancy, drug use, pregnancy, autoimmune
iritis. In cases where CS goes undiagnosed or incompletely disorders, and aging.
350 UPDATE ON SYPHILIS AND PREGNANCY

TABLE 1. Treatment Regimen of Syphilis in Pregnancy as Recommended by CDC

Diagnosis Treatment

Primary, secondary, and early latent syphilis (<1 yr) Benzathine penicillin G, 2.4 million units IM in single dose

Late latent syphilis (>1 yr), latent syphilis of Benzathine penicillin G, 2.4 million units IM for three doses

unknown duration, and tertiary syphilis (each 1 week apart)

Neurosyphilis  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

Penicillin allergic Confirm allergy and desensitize, then appropriate treatment as above

TREPONEMAL ANTIBODY TESTS and the nontreponemal test is nonreactive, a second but
The treponemal serologic tests use antibodies specific for different treponemal test is used to resolve the discordan-
Treponema pallidum making them well-suited for confir- cy. In a study reviewing testing discordance in pregnant
matory testing. These treponemal-specific tests include the women using the reverse algorithm with a CIA as the
fluorescent treponemal antibody absorption test and the T. screening treponemal test, 80% were CIA1/RPR-/TP-PA-.
pallidum particle agglutination (TP-PA) test. Both tests More than half of these on retesting were CIA-, suggesting
also approach the 97 to 99% specificity range although a false positive result (Larsen et al., 1995).
they are nonquantitative. The tests are more expensive Reflexive testing with another treponemal test such as
and more difficult to perform, limiting their use in screen- TP-PA is important and will help clarify the clinical inter-
ing. More recently, automated treponemal enzyme and pretation. While interpretation of reverse testing results in
chemiluminescence immunoassays (CIA) have been devel- pregnancy is difficult, the reverse algorithm has outper-
oped. The automation allows for high-volume, low cost formed the traditional algorithm in sensitivity, specificity
testing and is being used in the “reverse algorithm” testing and diagnostic accuracy in other populations (Tong et al.,
described below.
2014). The confirmatory tests within the reverse algorithm
Once adequate treatment is administered, the nonspe-
should not be used, however, in cases of previously con-
cific antibody tests become nonreactive after treatment
firmed syphilis because these tests can remain positive for
with a small cohort of patients having a persistent low
life. The traditional algorithm is recommended in this situ-
titer for a variable period of time (“serofast syphilis”). In
ation. Various institutions have implemented their own
contrast, once the specific treponemal tests are positive,
version of protocols based on their specific population but
85% will remain positive for life (Larsen et al., 1995).
all broadly fall into the traditional or reverse technique.
DIAGNOSTIC ALGORITHMS
ANTENATAL DIAGNOSIS OF CONGENITAL SYPHILIS
All pregnant women initially presenting for prenatal care
should be screened and in high-risk populations, retested Ultrasound evaluation is a useful tool for the diagnosis of
at 28 weeks and again at delivery. The US Centers for Dis- congenital syphilis before delivery. A recent report describ-
ease Control and Prevention (CDC) recommends the ing the use of serial ultrasonography in 235 women diag-
“traditional” algorithm for the diagnosis of syphilis. In nosed with syphilis after 18 weeks found that 31% had
these paradigm, syphilis serologic testing begins with a abnormal findings on their initial ultrasound. The findings
nontreponemal test (e.g., VDRL, RPR) and if reactive, fol- included hepatomegaly (79%), placentomegaly (27%),
lowed by confirmatory testing using a treponemal anti- polyhydramnios (12%), ascites (10%), and abnormal
body test. Recently, however, the Association of Public Doppler velocimetry of the middle cerebral artery (33%).
Health Laboratories, the UK Health Protection Agency and Commencement of treatment coincided with a specific
the International Union Against Sexually Transmitted sequence of resolution for each abnormal finding starting
Infections have proposed the use of the reverse algorithm with the MCA Doppler, the ascites and the polyhydramnios.
that begins with a treponemal assay. A reactive treponemal Placentomegaly and hepatomegaly resolved last after ade-
assay then reflexes to a quantitative nontreponemal assay. quate syphilotherapy. Congential syphilis was diagnosed at
In cases in which the specific treponemal assay is reactive birth in 39% of infants with abnormal ultrasound findings
BIRTH DEFECTS RESEARCH 109:347–352 (2017) 351

(Rac et al., 2014). The study shows that ultrasound may TITER RESPONSE AFTER TREATMENT
serve as an adjunct not only to identify more severely Follow-up of pregnant women after treatment for syphilis
affected fetuses, but also its use as a gauge to monitor consists of nontreponemal antibody serologic titers at 1, 3,
effectiveness of maternal syphilotherapy. 6, 12, and 24 months. Titers are expected to decrease four-
fold by 6 months, eventually becoming nonreactive by 12 to
Treatment 24 months. In a recent report, Rac and colleagues (2015)
All pregnant women who have sexual contact with a per- found that 38% of women treated for syphilis during preg-
son known to have syphilis, who have direct visualization nancy achieved a fourfold decline by delivery. Those not
of spirochetes or who have serologic evidence consistent achieving an appropriate decline tended to be older, treated
with current infection should be treated. In cases in which later in pregnancy, diagnosed with latent syphilis or syphilis
the evidence is not clear to confirm infection or if there is of unknown duration, and tended to have a shorter time-
suspicion of reinfection, prompt treatment should also be frame from treatment to delivery (Rac et al. 2015). Treat-
initiated. The treatment schedules for syphilis by the CDC ment failure or reinfection should be suspected in patients
are shown in Table 1 (Workowski and Bolan, 2015). who, at any point, have persistent symptoms or a sustained
The administration of parenteral benzathine penicillin G fourfold increase in nontreponemal test titers. In cases of
provides a long-acting formulation that lasts greater than 1 treatment failure, CSF evaluation may be warranted with
week for nonpregnant patients and given the altered phar- either neurologic symptoms or HIV co-infection with CD4
macokinetics in pregnancy, lower analogous concentrations cell counts below 350 cells/ll (Ghanem et al., 2009).
in pregnancy. Therefore, there is a recommendation to add a Because the patient response to treatment may be idiosyn-
second injection of benzathine penicillin G 1 week after the cratic, it may be difficult to ascertain between treatment fail-
initial dose for early stage disease (Wendel et al., 2002). The ure and reinfection. Either case would merit a retreatment
efficacy of treatment is contingent upon the stage of syphilis of the patient with another course of therapy.
and the gestational age at the time of treatment. With CONCLUSIONS
respect to primary, late latent and tertiary stage, the treat- The overall decline in syphilis cases in the United States
ment efficacy approaches 100%. Secondary and early latent between 2008 and 2012 has now been offset by the
stage disease has a 95% effectiveness rate. Treatment initi- increased rate from 2012 to 2014. Worldwide syphilis infec-
ated before 18 to 20 weeks also has an efficacy approaching tion during pregnancy remains a significant cause of stillbirth
100% due to immunocompromised fetal status (Sheffield and long-term morbidity for infected neonates. Importantly,
and Wendel, 1999). While there are alternate antibiotics for there is also a strong association between syphilis infection
syphilotherapy in the nonpregnant population, penicillin and HIV transmission and acquisition. In an era in which
remains the only recommended therapy for pregnant wom- modern medicine grows at an exponential rate, we must be
en, HIV infected patients and neurosyphilis. Erythromycin conscientious in our efforts for continued public health
has been associated with an approximately 10% failure rate awareness and in our commitment to identify and treat of
as its transplacental passage is mercurial and, therefore, its syphilis for the health of both mothers and their offspring.
effectiveness is attenuated. Women with a documented aller-
gy to penicillin should undergo penicillin desensitization.
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