Volume 74, Number 9

OBSTETRICAL AND GYNECOLOGICAL SURVEY

Copyright © 2019 Wolters Kluwer Health,
Inc. All rights reserved. CME REVIEW ARTICLE
CHIEF EDITOR’S NOTE: This article is part of a series of continuing education activities in this Journal through which a total of
27
36 AMA PRA Category 1 Credits™ can be earned in 2019. Instructions for how CME credits can be earned appear on the last page
of the Table of Contents.

Syphilis in Pregnancy
Shelun Tsai, MD,* Michael Y. Sun, MD,† Jeffrey A. Kuller, MD,‡
Eleanor H. J. Rhee, MD,§ and Sarah Dotters-Katz, MD, MMHPE§
*Resident, Department of Obstetrics and Gynecology, Duke University; †Resident, Department of Psychiatry, Duke University;
‡Professor, Department of Obstetrics and Gynecology, Duke University, and Division of Maternal-Fetal Medicine, Duke
University Medical Center; and §Assistant Professor, Department of Obstetrics and Gynecology, Duke University, and Division
of Maternal-Fetal Medicine, Duke University Medical Center, Durham, NC

Importance: Since 2013, the United States has seen a rise in cases of congenital syphilis, culminating in a rel-
ative increase of 153% from 2013 to 2017 and 918 reported cases in 2017. In all, 50% to 80% of pregnant
women with syphilis experience an adverse pregnancy outcome including stillbirth or spontaneous abortion.
Objective: This article aims to review the current evidence and recommendations for management of syphilis
in pregnancy.
Evidence Acquisition: Original research articles, review articles, and guidelines on syphilis were reviewed.
Results: In pregnancy, routine screening for syphilis is recommended on initiation of prenatal care. In high-risk
populations, repeat testing is recommended in the early third trimester and at delivery. Penicillin remains the
recommended treatment in pregnancy. After treatment, nontreponemal titers should be repeated at minimum
during the early third trimester and at delivery to assess for serologic response. In high-risk populations, titers
should be repeated monthly.
Conclusion and Relevance: Routine screening in pregnancy is essential for identification of syphilis infection
and prevention of congenital syphilis. Subsequent adequate treatment with penicillin therapy more than 30 days
before delivery and at the correct dosages depending on the stage of infection should be incorporated into
clinical practice.
Target Audience: Obstetricians and gynecologists, family physicians
Learning Objectives: After completion of this educational activity, the obstetrician/gynecologist should be
better able to summarize current knowledge of how syphilis impacts maternal and neonatal outcomes; describe
the recommended screening and diagnostic tests for syphilis; and outline the treatment regimens and follow-up
recommendations for management of syphilis in pregnancy.

Twelve million new cases of syphilis occur globally
each year, including 2 million affected pregnancies,
making congenital syphilis the most common congeni-
tal infection worldwide.1 Syphilis in pregnancy carries
significant risks for adverse outcomes, with more than
25% of affected pregnancies ending in stillbirth or
spontaneous abortion.1 In the United States, while rates
of syphilis reached a historic low in 2001, they have
All authors, faculty, and staff in a position to control the content of
this CME activity and their spouses/life partners (if any) have disclosed
that they have no financial relationships with, or financial interests in,
any commercial organizations relevant to this educational activity.
Correspondence requests to: Shelun Tsai, MD, Duke University,
DUMC 3967, Durham, NC 27710. E-mail: shelun.tsai@duke.edu.
www.obgynsurvey.com | 557
increased almost every year since.2 The increase was
reflected in both males and females, all ethnicities,
and in 72% of states.2 Since 2013, the rates of congenital
syphilis have shown a marked increase with a year-
over-year rise that culminated in 918 reported cases of
congenital syphilis in 2017 (23.3 cases per 100,000 live
births).2 This represented a 153% relative increase over
rates seen in 2013. African American mothers and
mothers living in the Western United States were most
often affected.2 Of the congenital syphilis cases in
2017, 64 stillbirths were attributed to syphilis, and 13 ad-
ditional neonates died due to the infection.2
Many authors have attempted to better understand the
etiologies contributing to the dramatic rise in congenital

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

558 Obstetrical and Gynecological Survey
syphilis cases.3,4 According to a 2015 report by the
Centers for Disease Control and Prevention (CDC),
21.8% of mothers who gave birth to infants with congen-
ital syphilis received no prenatal care.3 Of mothers with
1 or more prenatal visits, 43% received no treatment for
syphilis during pregnancy, whereas another 30% re-
ceived inadequate treatment (late initiation <30 days
before delivery, nonpenicillin therapy, or incorrect dos-
age of penicillin).3 Mothers receiving inadequate treat-
ment were more likely to have poor outcomes.4,5 These
findings highlight the importance of addressing ade-
quate prenatal care, as well as screening, diagnosis,
and treatment of syphilis in pregnancy.
In this review, we will summarize the current knowl-
edge of how syphilis infection in pregnancy impacts
maternal and neonatal outcomes. We will survey the
different screening tests and algorithms for diagnosing
syphilis. Lastly, we will provide recommendations for
treatment and management of syphilis in pregnancy.
Clinical Presentation
Syphilis is caused by the bacterium Treponema
pallidum, which is highly motile, spiral-shaped, and
gram-negative. Infection occurs through sexual contact
when the spirochete penetrates mucus membranes or
through a break in the skin. Risk of transmission is
greatest during early syphilis (ie, primary and secondary
syphilis) when patients have the heaviest spirochete
load. The most commonly associated risk factors in
pregnant women are a history of sexually transmitted
diseases, more than 1 sex partner in the past year, incar-
ceration, and substance use.6 Clinical subtypes of syph-
ilis include primary, secondary, latent, and tertiary
syphilis. Additionally, neurosyphilis can develop con-
current to any of the above stages.
After syphilis transmission, there is an incubation pe-
riod of approximately 21 days before onset of clinical
symptoms.1 Primary syphilis is characterized by 1 or
more painless ulcerative lesions (ie, chancre) that appear
on the genitalia at the site of inoculation. This initial
stage of syphilis was observed in approximately only
6% of patients diagnosed with syphilis in 2017.2 Ulcera-
tive lesions may be accompanied by painless regional
lymphadenopathy. Lesions may spontaneously resolve
within 4 to 6 weeks with or without treatment.2,7,8
Approximately 25% of patients with untreated pri-
mary syphilis will experience progression to secondary
syphilis after 6 to 8 weeks. In 2017 data, 15% of patients
who received an initial diagnosis of syphilis were found
to have secondary syphilis.2 Manifestations of secondary
syphilis include mucocutaneous lesions, generalized
lymphadenopathy, condyloma lata, and general malaise.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
The systemic and localized lesions of secondary
syphilis may also resolve without treatment within 1
to 6 months.2,7,8 Thus, patients may enter the latent
stage of syphilis without having recognized any signs
or symptoms of the previous stages.
The latent phase of syphilis is defined by a lack of
clinical signs or symptoms despite positive serologies.
It is subdivided into early latent syphilis (<12 months
after initial infection) and late latent syphilis (≥12 months
after initial infection).2,7,8 With early or late latent syph-
ilis, maternal-to-fetal transmission is still possible.
The transition to tertiary syphilis is marked by the
onset of inflammatory lesions involving the cardiovas-
cular (eg, aortitis), skin (eg, gummas), and/or skeletal
(eg, osteitis) systems, generally occurring after 15 to
30 years of untreated syphilis infection. Involvement
of the central nervous system is termed neurosyphilis.
It may present as meningitis, cranial nerve palsy, cognitive
dysfunction, dementia, and/or tabes dorsalis (diminished
proprioception and vibratory sensation). There may also
be ocular involvement, such as anterior uveitis, optic
neuritis, and/or Argyll-Robertson pupils (light-near
dissociation).2,7,8
Pregnant women with any stage of syphilis risk ex-
posing their fetus to T. pallidum. Vertical transmission
most frequently occurs transplacentally or more rarely
during the delivery process due to direct contact of the
neonate with a genital lesion.9,10 Breastfeeding does
not result in transmission unless the neonate comes into
direct contact with an active syphilitic breast lesion.10
The risk of vertical transmission is largely dependent
on stage and duration of maternal disease, which corre-
late with spirochete load.10,11 As such, the rate of verti-
cal transmission of untreated early maternal syphilis is
higher than that of late maternal syphilis: 50% for pri-
mary and secondary syphilis, 40% for early latent
syphilis, and 10% for late latent syphilis and tertiary
syphilis.12,13 In addition, the risk of vertical transmis-
sion increases with higher maternal nontreponemal ti-
ters. In one study, mothers with higher nontreponemal
titers (≥1:8) had a 25% rate of congenital syphilis com-
pared with 4% in mothers with lower titers (<1:8).14
The subsequent presentation of congenital syphilis
varies widely. Some neonates born with congenital
syphilis do not go on to exhibit any signs or symptoms.
Other neonates may suffer hepatosplenomegaly, skele-
tal abnormalities, anemia, skin rash, blindness, or deaf-
ness. Still others do not have clinical symptoms at birth
but may develop symptoms a few weeks or even years
later.5 In addition, congenital syphilis may complicate
the course of pregnancy and lead to miscarriage and
stillbirth in 25% of affected pregnancies.1 The risk of
fetal loss is higher when the syphilis infection occurs
 Syphilis in Pregnancy • CME Review Article
earlier in pregnancy.15 When infection occurs later in
the third trimester, fetal immunocompetence and the
fetal-placental immune response protect against fetal
loss and increase the chance of asymptomatic disease.16
Diagnostic Testing
The diagnosis of syphilis is uniquely challenging, as
T. pallidum cannot be cultured and is not visible under
standard light microscopy. As such, serological testing
is the cornerstone of laboratory diagnosis of syphilis.
The 2 general categories of serological testing are trep-
onemal and nontreponemal. A combination of the 2 is
employed in the diagnostic algorithms for syphilis infec-
tions (Fig. 1). At an increasing number of institutions,
traditional algorithms are being supplanted by so-called
“reverse” algorithms made possible by advances in
high-throughput automation.17,18 In other words, trepo-
nemal testing is increasingly being performed as the ini-
tial screening test for syphilis. This has led to some
confusion among interpreting clinicians.
Treponemal tests refer to assays that specifically de-
tect T. pallidum–related antibodies. These antibodies
are generated in the course of the immune response to
T. pallidum and continue to circulate throughout an in-
dividual's life, even after eradication of the disease. A
positive treponemal assay suggests that an individual
either currently harbors an active infection or was pre-
viously treated for an active infection.17,19 Studies have
shown that antitreponemal immunoglobulin M anti-
body production begins approximately 2 weeks after
exposure to T. pallidum, followed by another 2 weeks
FIG. 1. Traditional and reverse algorithm for diagnosis of syphilis.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
559
later by immunoglobulin G antibodies.20 Clinically,
this may correlate with detectable antibody levels
within 3 days of lesion onset in primary syphilis.21
Historically, treponemal testing referred to manual
assays such as fluorescent treponemal antibody absorp-
tion and T. pallidum particle agglutination (TP-PA).
More recently, treponemal testing has become more
rapid and automated, as exemplified in enzyme-linked
immunosorbent assays (EIAs) and chemiluminescence
immunoassays (CIAs).17,22 The newer tests have
comparable sensitivities (95%–99%) and specificities
(95%–99%) but outperform the older treponemal tests
for individuals with primary syphilis.22–26
In contrast, nontreponemal testing detects antibodies
released in response to cell damage (eg, cardiolipin,
lecithins) starting approximately 6 weeks after initial
infection.20 Rapid plasma reagin (RPR) and venereal
disease research laboratory (VDRL) are examples of
nontreponemal tests. The specificity of nontreponemal
testing is comparable to treponemal testing (98%).
However, the sensitivity varies depending on the stage
of syphilis infection. Sensitivities range from 78% to
80% in primary syphilis to 100% in secondary syphilis,
96% to 98% in latent syphilis, and 71% to 73% in ter-
tiary syphilis.22–26 Nontreponemal tests are particularly
valuable as quantitative measures for monitoring dis-
ease, as titers increase with active disease and decrease
with treatment. Typically, a 4-fold change in titer values
is considered clinically significant—equivalent to 2 di-
lutions, such as from 1:16 to 1:4.19,27 Comparisons be-
tween titer values should be made using the same
method (ie, VDRL or RPR) and preferably the same
560 Obstetrical and Gynecological Survey

laboratory, as the 2 tests cannot be directly compared.27 Recommended Screening in Pregnancy

Although useful, nontreponemal tests are more labor-
The United States Preventative Services Task Force
intensive, need to be performed manually, and require
(USPSTF) recommends screening all pregnant women
a knowledgeable clinician to interpret the results.
for syphilis as early as possible.32 Legally, most states
Traditional algorithms relied on nontreponemal testing
mandate screening, and 14 have instituted penalties
as the initial screen followed by a confirmatory treponemal
for clinicians who fail to screen.34 Only 6 states do
test to rule out false-positive results. In 2009, the re-
not require prenatal syphilis screening. Furthermore,
verse algorithm was proposed,28 in which treponemal
17 states require repeat screening during the third tri-
testing was utilized as the initial screen with nontreponemal
mester, and 8 states require additional screening at time
testing used to clarify disease status. Newer treponemal
of delivery.
tests (EIA, CIA) have become more cost-effective than
While there are no studies evaluating the effective-
nontreponemal testing due to advances in automation,
ness of repeat syphilis testing in pregnancy, the CDC,
making the reverse algorithm more cost-effective than
American Academy of Pediatrics, and the American
the traditional algorithm, as well. Studies comparing
College of Obstetricians and Gynecologists recommend
the reverse and traditional algorithms suggest that while
repeat screening in the early third trimester and at delivery
reverse algorithms have a higher false-positive rate in both
in high-risk populations.7,35 High-risk populations
low- and high-prevalence areas, they detect additional
include women who live in high-prevalence areas,
cases of syphilis that would have been missed by tradi-
women who are human immunodeficiency virus–
tional testing.17,29–31
positive, women diagnosed with a sexually transmitted
Discordance between treponemal and nontreponemal
disease during pregnancy, and women who have a his-
testing can be caused by seroconversion of nontreponemal
tory of incarceration or commercial sex work.17,32
antibodies, false-positive treponemal test results, or
Hersh et al36 constructed a model to gauge the cost-
early primary syphilis in which nontreponemal antibod-
effectiveness of repeat screening during the third trimester
ies have yet to develop.17,28 Discordant results are sub-
compared with screening only once during pregnancy.
sequently evaluated with a second treponemal test (eg,
The model showed that repeat screening in the third tri-
TP-PA) to determine disease status. For example, a re-
mester would result in fewer adverse maternal and neona-
active treponemal immunoassay (EIA, CIA) followed
tal outcomes. Specifically, 41 cases of congenital syphilis,
by a nonreactive nontreponemal assay (VDRL, RPR)
73 cases of intrauterine fetal demise, and 27 cases of
would warrant further investigation with TP-PA. Reac-
neonatal deaths would be averted. The cost savings
tivity suggests a current or past infection. A nonreactive
were estimated to be $52 million. Furthermore, 4000
second treponemal test indicates that either the initial
additional quality-adjusted life-years would be gener-
immunoassay was a false positive or that the patient
ated. While prior analyses came to different conclu-
has early primary syphilis. As expected, locations with
sions about the cost-effectiveness of screening,37,38
low prevalence of disease exhibit greater proportions of
Hersh and colleagues'36 model was the only one to in-
discordant results representing false-positives.28,29,31
corporate mortality and long-term morbidity of affected
Of note, neither algorithm can distinguish between
neonates. Thus, the conclusion that repeat screening
active and previously treated infection in a patient with
can be cost-effective follows from the relative inexpen-
positive treponemal and nontreponemal testing. Treat-
siveness of screening and treatment compared with the
ment history and prior nontreponemal titer levels are
very high costs of adverse outcomes.36
helpful to differentiate between these 2 possibilities.17,32
While nontreponemal antibodies typically decline
Impact of Syphilis on Neonatal Outcomes
with treatment, approximately 15% to 20% of patients
with early syphilis will have persistent low RPR titers Vertical transmission of syphilis can occur at any
for 6 to 12 months or longer. This is known as the stage of disease and any trimester of pregnancy. The
serofast state.24,27 The serofast state can lead to confu- T. pallidum spirochete has been shown to cross the pla-
sion for a clinician trying to distinguish this state from centa as early as 8 to 9 weeks' gestation.39,40 Untreated
treatment failure and reinfection. In a study, even syphilis has severe consequences in pregnancy. A meta-
retreatment of serofast patients resulted in a greater than analysis of 6 case-control studies showed that fetal loss
4-fold decline in RPR titers in only 13% of study partic- and stillbirth were 21% more likely in women with
ipants.24,33 Patients with higher nontreponemal titers at syphilis compared with healthy controls.41 The World
baseline (≥1:32) were more likely to exhibit a greater Health Organization estimates that 50% to 80% of preg-
than 4-fold decline.24,33 The optimal management strat- nancies affected by syphilis end in stillbirth, miscar-
egy of serofast patients remains unclear.24,33 riage, or other adverse pregnancy outcomes.1

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 Syphilis in Pregnancy • CME Review Article
Historically, amniocentesis and percutaneous umbili-
cal blood sampling were used to document fetal infec-
tion,40,42,43 whereas today, fetal ultrasound has become
the most commonly used modality, given its noninvasive
nature. Characteristic ultrasound findings of fetal syphi-
lis infection are caused by the inflammatory response
to T. pallidum. As a result, detection of fetal syphilis in-
fection via ultrasound prior to 20 weeks is rare because
the fetal immune system reaches maturation only after
approximately 20 weeks gestation.44,45
The progression of ultrasonographic findings in un-
treated fetal syphilis infection was described by Hollier
et al46 in 2001; later, Rac et al47 in 2014 described the
resolution of sonographic findings after treatment.
Early ultrasound abnormalities include fetal hepatomeg-
aly (80% of affected pregnancies) and placentomegaly
(27%), which are correlated with hepatic dysfunction
and placental involvement, respectively.46,47 Hepato-
megaly (also the most common finding in postnatal stud-
ies5) is thought to result directly from syphilitic hepatitis
or secondary to increased extramedullary hematopoiesis
and/or hepatic congestion from fetal heart failure.5,47
Placentomegaly is believed to result from inflammation
as a result of the syphilis infection.48
The above early abnormalities are followed by
hematologic dysfunction. On ultrasound, this may
be suggested by elevated peak systolic velocity of the
middle cerebral artery (MCA) by Doppler ultrasound
(33%) indicative of fetal anemia and polyhydramnios
(12%).46,47,49,50 The etiology of fetal anemia is likely
multifactorial; hemolysis, altered hematopoiesis, hypers-
plenism, and/or nutritional deficiency are thought to be
involved.50 Lastly, in advanced disease, the fetus may
develop ascites (10%) and/or hydrops.46,47
Given the natural history of fetal syphilis infection
previously described, standard components of an ultra-
sound evaluation of a pregnant woman with an active
syphilis infection should include liver length, placental
thickness, peak systolic velocity of the MCA, amniotic
fluid volume assessment, and evaluation for hydrops.
Importantly, the absence of fetal ultrasound abnormal-
ities does not rule out congenital syphilis infection, as ap-
proximately 12% of neonates with normal ultrasound
findings during pregnancy still require treatment for con-
genital syphilis after delivery.47 In addition, certain clin-
ical features of congenital syphilis may not be detected
by fetal ultrasound, such as skeletal abnormalities.
Even so, the further the progression of sonographic
findings, the greater the risk of fetal treatment failure.51
However, if treatment is successful, sonographic find-
ings resolve in reverse order.8,47 In other words, sono-
graphic findings such as MCA Doppler abnormalities,
ascites, and polyhydramnios resolve first, followed by
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
561
placentomegaly and hepatomegaly.47 Because sequelae
of fetal syphilis generally resolve with adequate treat-
ment of the infection, other treatments such as intrauter-
ine transfusions for fetal anemia are generally not
recommended.47 No formal guidelines exist regarding
antenatal testing following diagnosis of syphilis in
pregnancy. If there is no evidence of fetal disease,
monthly ultrasound assessment to assess for evidence
of fetal disease is reasonable. Once fetal infection has
been identified, closer monitoring is indicated. The ex-
act frequency will depend on infection severity, pres-
ence of hydrops, and gestational age. As with most
causes of hydrops at early gestational ages, outcomes
are better with in utero resolution than delivery if the fe-
tal status is reassuring.
Treatment not only reverses ultrasound findings but
also significantly improves pregnancy outcomes, in-
cluding the incidence of congenital syphilis (14% with
treatment vs 36% without treatment), preterm birth
(9.9% vs 23.2%), stillbirth (4.5% vs 26.4%), and neona-
tal death (3.2% vs 16.2%).14 The reduction in adverse
pregnancy and neonatal outcomes is more prominent
when treatment occurs prior to the third trimester, al-
though a slight reduction is still observed in women
who receive treatment in the third trimester compared
with women who do not receive treatment at all (adverse
pregnancy outcomes of 64.4% after third-trimester treat-
ment vs 76.8% without treatment).14
Treatment of Syphilis
Since its discovery in the early 20th century, penicil-
lin remains one of the only recommended treatments for
syphilis infection and the only treatment recommended
in pregnant women.7 One study estimated that penicil-
lin is 98.2% effective for treatment of syphilis in preg-
nant women.52 Treatment should begin as soon as
possible after diagnosis. Clinicians should also consider
expedited partner therapy as a means to treat sexual
partners and minimize the risk of reinfection.53 Cases
and potential partners should be reported to the local
health department. Although timing does not generally
affect maternal cure rates, it has a significant impact on
rates of congenital syphilis.14,52 Multiple studies show
that treatment occurring less than 30 days from delivery
is correlated with higher rates of congenital syphi-
lis.7,14,52,54 In a study, Sheffield et al54 found 67% of
pregnancies resulting in congenital syphilis were
treated less than 30 days before delivery compared with
29% of pregnancies resulting in normal infants, even af-
ter adjusting for stage of syphilis and gestational age at
treatment. However, these findings may have been con-
founded by late prenatal care, treatment failure, and se-
verity of fetal syphilis infection.
562 Obstetrical and Gynecological Survey
The dosing regimen of penicillin depends on the stage
of syphilis (Table 1). Primary, secondary, and early latent
syphilis infections are treated with benzathine penicillin
G 2.4 million units intramuscular (IM) in a single dose.
For pregnant women, some studies recommend an ad-
ditional dose of penicillin 1 week after the initial
dose.7,51,55 Late latent syphilis and tertiary syphilis,
as well as syphilis of unknown duration, should be
treated with benzathine penicillin G 7.2 million units
total administered over 3 doses of 2.4 million units
IM each at 1-week intervals. The full regimen should
be repeated if any doses are missed, as the serum con-
centration of penicillin significantly declines over the
course of a week, resulting in inadequate bactericidal
levels by day 7.40 Neurosyphilis requires aqueous crystal-
line penicillin G 18 to 24 million units per day, adminis-
tered for 10 to 14 days either as 3 to 4 million units
intravenously (IV) every 4 hours or as a continuous infu-
sion.7 Alternative regimens consisting of doxycycline, tet-
racycline, azithromycin, and cephalosporins are not
adequate for use in pregnancy.7,56
Serological response to penicillin treatment is moni-
tored by serial nontreponemal titers. Outside preg-
nancy, nontreponemal titers are repeated 6 and
12 months after treatment of primary and secondary
syphilis; an additional test at 24 months is recom-
mended after the treatment of latent syphilis.7 Failure
of nontreponemal titers to decline 4-fold may represent
treatment failure or reinfection, and distinguishing be-
tween the 2 can be challenging. Additional history
should be obtained to assess the possibility of new ex-
posures and clinical manifestations suggestive of rein-
fection (eg, new chancre). Retreatment should be
considered.7 Furthermore, suspected treatment failures
warrant evaluation for neurosyphilis through lumbar
puncture and cerebrospinal fluid examination.7
The 9-month duration of pregnancy complicates
follow-up monitoring because most patients will not
have demonstrated serologic response to treatment over
TABLE 1
Dosages of Penicillin for Treatment of Each Stage of Syphilis
Stage of Syphilis
Primary syphilis
Secondary syphilis
Early latent syphilis
Late latent syphilis
Syphilis of unknown duration
Tertiary syphilis
Neurosyphilis
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
the gestational period.57 There are no targets for
nontreponemal titer decline specific to pregnant women
over the course of pregnancy. Rac et al57 found that only
38% of pregnant women achieve a 4-fold decline by de-
livery. At minimum, titers should be rechecked at
28 weeks' gestation and again at delivery.7 For women
who have a high risk of reinfection, serologic titers
should be checked monthly to monitor for significant ti-
ter changes.7 General follow-up recommendations for
nonpregnant women should be followed postpartum if
maternal titers have not decreased by 4-fold at the time
of delivery.7
Approximately 10% of patients report a penicillin al-
lergy.58 Pregnant women with syphilis and reported
penicillin allergies should be promptly referred for al-
lergy skin testing. Up to 90% of such patients are found
not to have a penicillin allergy after formal drug test-
ing,58 and penicillin skin testing is safe for pregnant
women.59 Even a confirmed penicillin allergy is not a
contraindication to penicillin therapy for syphilis in
pregnancy. Pregnant patients found to have an allergy
to penicillin should undergo penicillin desensitization,
which involves slow uptitration of diluted doses until
the target dose is achieved.7,58 This may be done with
either oral or IV regimens, which are equally effec-
tive.60 Either regimen takes approximately 4 to 12 hours
to complete. Desensitization should occur in the hospi-
tal setting due to the risk of anaphylaxis. During this
time, epinephrine and other medications for treatment
of anaphylaxis should be readily available. The desensi-
tization regimen should be repeated each time penicillin
is required in the future.
It is important to counsel patients on the adverse ef-
fects of treatment, including the Jarisch-Herxheimer re-
action, which presents with fever, headache, myalgia,
and worsening of cutaneous syphilitic lesions. It is esti-
mated to occur in 40% to 45% of treated syphilis in
pregnancy.61,62 The Jarisch-Herxheimer reaction is
due to the release of endotoxins and lipoproteins from
Treatment
Benzathine penicillin G 2.4 million units IM for 1 dose
Benzathine penicillin G 2.4 million units IM weekly for 3 doses
Aqueous crystalline penicillin G 18–24 million units
IV daily for 10–14 d. Can be administered as a
continuous infusion or 3–4 million units every 4 h
 Syphilis in Pregnancy • CME Review Article
the death of spirochetes, triggering an acute inflamma-
tory response.7,63 Symptoms typically begin 4 hours af-
ter initiation of penicillin treatment, peak at 8 hours, and
subside by 24 hours.63 It is more likely to occur during
treatment of primary and secondary syphilis due to
higher treponemal loads.61 Treatment is with supportive
therapies, and although there have been attempts to pre-
vent the Jarisch-Herxheimer reaction with corticoste-
roids, there is limited evidence suggesting efficacy.63
Currently, prophylactic treatment is not recommended.
In pregnancy, the Jarisch-Herxheimer reaction may
also result in preterm labor, decreased fetal movement,
and transient fetal heart rate abnormalities.61,62 These
complications typically resolve within 24 hours after
penicillin treatment. There have been cases of preterm
delivery following Jarisch-Herxheimer reactions, al-
though seemingly only in severely affected infants or
stillbirths.61,63 In fact, no cases of Jarisch-Herxheimer
reactions have resulted in preterm delivery of an unaf-
fected fetus. It is hypothesized that in severely affected
fetuses with poor hepatic function or a poor fetoplacental
environment the Jarisch-Herxheimer reaction acts as an
inciting event for preterm labor.61,64
At the time of delivery, the diagnosis of congenital
syphilis should be suspected in all neonates born to
women who have serological testing positive for syphi-
lis. The maternal diagnosis should be clearly communi-
cated between obstetrician and pediatrician to prepare
for anticipated delivery. Among the neonates who do
display clinical signs at birth, hepatomegaly is the most
common finding, consistent with antenatal ultrasound
findings.65,66 Other clinical signs include jaundice, rhini-
tis, rash, and lymphadenopathy, Suspicious lesions or
body fluids on the neonate should be sent for evaluation
by dark-field microscopy.27 Neonates should also have quan-
titative nontreponemal serologic testing performed on infant
serum. It is important to keep in mind that 60% to 90% of
live-born neonates who go on to develop clinical symptoms
of congenital syphilis do not display any signs at birth.66
Abnormalities in the placenta and umbilical cord can
also suggest potential syphilitic infection. The placenta
tends to appear large, thick, and pale.48 The placenta
should be sent to pathology for examination using specific
fluorescent antitreponemal antibody staining.27 The umbil-
ical cord may have a “barber's pole” appearance—spiral
streaks of red, light blue, and chalky white. The umbilical
cord may also appear inflamed with abscess-like necro-
sis within the Wharton jelly.67 Serologic testing on um-
bilical cord blood should not be performed because of
risk of contamination with maternal blood and a subse-
quent false-positive result.
The CDC has detailed guidelines for management of
neonatal congenital syphilis stratified by likelihood of
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
563
infection.27 Treatment with penicillin should be pro-
vided for infants with exposure to syphilis unless
congenital syphilis is unlikely (normal physical exami-
nation of infant, low infant titer, adequate maternal
treatment, low maternal titer).27
CONCLUSIONS
Syphilis is the most common congenital infection
worldwide and in recent years has seen a resurgence
in the United States. All pregnant women should be
screened for syphilis on initiation of prenatal care.
Penicillin treatment should be promptly provided for
patients with an active infection in order to prevent fur-
ther maternal and fetal sequelae of syphilis infection.
Nontreponemal titers and serial ultrasounds form the
basis of surveillance for syphilis infection and treatment
response. Pregnant patients should receive this compre-
hensive management approach of syphilis infection in
order to address rising rates of congenital syphilis.
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