Expert Reviews ajog.

org

Syphilis during pregnancy: a preventable threat to

maternal-fetal health
Martha W. F. Rac, MD; Paula A. Revell, PhD; Catherine S. Eppes, MD, MPH

the same period. Reasons for the rise in

Syphilis remains the most common congenital infection worldwide and has tremendous rates are not entirely clear, but demon-
consequences for the mother and her developing fetus if left untreated. Recently, there has strate the immediate need for obstetri-
been an increase in the number of congenital syphilis cases in the United States. Thus, cians and gynecologists to recognize,
recognition and appropriate treatment of reproductive-age women must be a priority. diagnose, and treat syphilis. The purpose
Testing should be performed at initiation of prenatal care and twice during the third of this document is to review the pre-
trimester in high-risk patients. There are 2 diagnostic algorithms available and physicians sentation, diagnosis, and management of
should be aware of which algorithm is utilized by their testing laboratory. Women testing syphilis during pregnancy.
positive for syphilis should undergo a history and physical exam as well as testing for other
sexually transmitted infections, including HIV. Serofast syphilis can occur in patients with Epidemiology
previous adequate treatment but persistent low nontreponemal titers (<1:8). Syphilis can Syphilis is caused by Treponema pal-
infect the fetus in all stages of the disease regardless of trimester and can sometimes be lidum, a highly motile, spiral-shaped,
detected with ultrasound >20 weeks. The most common findings include hepatomegaly Gram-negative bacterium, and is the
and placentomegaly, but also elevated peak systolic velocity in the middle cerebral artery most common congenital infection
(indicative of fetal anemia), ascites, and hydrops fetalis. Pregnancies with ultrasound worldwide.2-4 The economic and repro-
abnormalities are at higher risk of compromise during syphilotherapy as well as fetal ductive costs are enormous, as 25% of
treatment failure. Thus, we recommend a pretreatment ultrasound in viable pregnancies pregnancies may result in stillbirth,
when feasible. The only recommended treatment during pregnancy is benzathine penicillin miscarriage, or other adverse pregnancy
G and it should be administered according to maternal stage of infection per Centers for outcomes.4 However, CS is largely a
Disease Control and Prevention guidelines. Women with a penicillin allergy should be preventable disease, requiring safe sex
desensitized and then treated with penicillin appropriate for their stage of syphilis. The practices, recognition, testing, and
Jarisch-Herxheimer reaction occurs in up to 44% of gravidas and can cause contractions, timely treatment during pregnancy.
fetal heart rate abnormalities, and even stillbirth in the most severely affected pregnancies. In 2007, the World Health Organi-
We recommend all viable pregnancies receive the first dose of benzathine penicillin G in a zation launched an initiative to elimi-
labor and delivery department under continuous fetal monitoring for at least 24 hours. nate CS by 2015 with goals to test 95%
Thereafter, the remaining benzathine penicillin G doses can be given in an outpatient of gravidas for syphilis and treat 95%
setting. The rate of maternal titer decline is not tied to pregnancy outcomes. Therefore, of seropositive gravidas.4 While coun-
after adequate syphilotherapy, maternal titers should be checked monthly to ensure they tries such as Cuba, Thailand, Armenia,
are not increasing four-fold, as this may indicate reinfection or treatment failure. Belarus, and the Republic of Moldova
Key words: congenital syphilis, fetal syphilis, syphilis during pregnancy have achieved elimination,5-7 rates of
CS in the United States have only
increased. In fact, the highest rates of
Introduction health concern. On Nov. 13, 2015, the CS since 2001 were reported in 2014,
Syphilis is an ancient infection that has Centers for Disease Control and Pre- with a total of 458 cases of CS and a
plagued populations for centuries. vention (CDC) reported a 38% increase rate of 11.6 cases per 100,000 live
Penicillin revolutionized the treatment in the rate of congenital syphilis (CS) births.1 This rise represented a 38%
of syphilis and drastically decreased the cases in the United States from 2012 increase in CS cases during 2013
rates of syphilis across all stages of dis- through 2014.1 This coincided with a through 2014, which mirrored the 23%
ease. Yet, despite an available cure for 22% national increase in rates of primary increase in primary or secondary
>70 years, it remains a significant global and secondary syphilis in women during syphilis rates in women during the
same period1 (Figure 1).
Substantial racial disparities are noted
From the Department of Obstetrics and Gynecology (Drs Rac and Eppes) and Pathology and in syphilis cases during pregnancy. Af-
Pediatrics (Dr Revell), Baylor College of Medicine, Houston, TX. rican American women represent the
Received Sept. 8, 2016; revised Nov. 17, 2016; accepted Nov. 30, 2016. most highly affected demographic.
The authors report no conflict of interest. Likewise, half of CS cases in 2014 were
Corresponding author: Martha W. F. Rac, MD. Martha.Rac@bcm.edu found in infants born to African Amer-
0002-9378/$36.00
ª 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2016.11.1052 ican women (38.2/100,000 live births, 10
times the rate in whites), and they

352 American Journal of Obstetrics & Gynecology APRIL 2017

ajog.org Expert Reviews

continue to have the highest rate of rise

FIGURE 1
in incidence of primary and secondary
syphilis among women.8
Congenital Syphilis: Reported Cases 2006e2015
Geographically, rates of CS have
increased across all regions with the
most substantial increases seen in the
Northeast (74%) and West (64%).
Despite a modest increase of 9% in the
South, this region continues to have the
highest disease burden in the United
States.8
Reasons for the rise in CS cases are not
clear but likely multifactorial. According
to data from the CDC, 21.8% of the 458
women who gave birth to infants with CS
in 2014 received no prenatal care. Of the
women who did receive prenatal care,
43% did not receive prenatal treatment
and 17% were treated <30 days prior to
delivery. Of women not treated despite
receiving prenatal care, 15.6% were
never tested, and 38.5% seroconverted
during pregnancy.8 These findings
highlight some of the major barriers to
reducing the rates of CS, including access
Cases of congenital syphilis (CS) according to year of birth compared to rates of primary and sec-
to prenatal care, lack of screening or
ondary (P&S) syphilis cases among women, 2006 through 2015.8 Image courtesy of the Centers for
diagnosis during pregnancy, and failure
Disease Control (www.cdc.gov).
to provide adequate treatment.
Rac. Syphilis during pregnancy. Am J Obstet Gynecol 2017.

Clinical presentation and stages of

syphilis
Syphilis is spread through sexual contact
and the spirochete penetrates mucous
membranes or abrasions in the skin to
disseminate systemically before clinical
disease appears. The incubation period
ranges from 21 days to 6 months. A pri-
mary lesion, or painless chancre, appears
at the site of inoculation. Without treat-
ment, spontaneous resolution of the
chancre will occur within 4-6 weeks on
average.9-11 Regional lymphadenopathy
can accompany primary disease and lasts
for months after the primary lesion has
healed. Lymph nodes are firm, non-
suppurative, and painless. Primary dis-
ease commonly goes unnoticed.
Secondary syphilis occurs 6-8 weeks
following untreated primary disease
and consists of systemic and local
mucocutaneous lesions with generalized
parenchymal and constitutional mani-
festations. These manifestations can be
subtle and some patients may enter the
latent phase without ever recognizing
secondary lesions. Table 1 illustrates the
numerous clinical symptoms of sec-
ondary syphilis. If left untreated, sec-
ondary syphilis spontaneously resolves
within 1-6 months.9-11
Thereafter, the patient enters the
latent phase of syphilis, characterized by
the absence of clinical symptoms but
positive serologic tests. Early latent
syphilis is latent disease <1 year duration
whereas late latent syphilis is 1 year
after infection. Syphilis of unknown
duration is latent disease with no
knowledge of infection duration. With
the exception of early latent syphilis,
latent disease is not sexually transmitted
but can be vertically transmitted. In
untreated early latent syphilis, up to 25%
of patients can experience a relapse of
secondary symptoms, thus sexual
transmission can still occur.
Tertiary syphilis can develop in up to
one third of untreated patients. This in-
cludes benign granulomatous lesions of
the skin, mucous membranes, skeleton,
and involvement of the aorta (cardio-
vascular syphilis). The majority of deaths
from tertiary syphilis are the result of
cardiovascular involvement.
Neurosyphilis can occur in any stage
of syphilis. Evaluation is based on clin-
ical suspicion, including mental status
changes in the context of positive syph-
ilis testing. Diagnosis requires a lumbar
puncture showing either a positive
venereal disease research laboratory test
result or elevated glucose and low pro-
tein without an alternative diagnosis.
Although cerebrospinal fluid abnormal-
ities have been documented in up to
30-40% of patients with secondary
syphilis, evaluation and treatment for
neurosyphilis is not recommended in the
absence of neurological symptoms.9-11
All HIV-positive patients should have a
thorough neurologic exam and those
diagnosed with neurosyphilis should be
tested for HIV.8
Pregnancy does not affect the course
of syphilis but syphilis can significantly
affect the course of pregnancy. Maternal
stages are not altered as a result of
pregnancy but >50% of infants will be

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Expert Reviews
FIGURE 2
Palmar and plantar lesions of secondary syphilis
A, Palmar and B, plantar hyperpigmented, annular papulosquamous syphilids. Reprinted with permission from78.
Rac. Syphilis during pregnancy. Am J Obstet Gynecol 2017.
clinically affected in untreated early
syphilis and 35% in latent disease.9,12
Adverse pregnancy outcomes are 12
times more likely in untreated
FIGURE 3
Condyloma lata of secondary
syphilis
Condyloma lata of perineal region. Reprinted
with permission from78.
Rac. Syphilis during pregnancy. Am J Obstet Gynecol 2017.
354 American Journal of Obstetrics & Gynecology APRIL 2017
pregnancies.13 In a recent systematic
review, adverse pregnancy outcomes
occurred in 76.8% of untreated preg-
nancies compared to 13.7% of unin-
fected pregnancies.14 Even after
treatment, there remains a significantly
higher risk of adverse pregnancy out-
comes compared to uninfected
pregnancies.15
Testing
Infection with T pallidum has always
posed unique diagnostic challenges. T
pallidum cannot be cultivated in vitro or
visualized by bright-field microscopy.
Additionally, no Food and Drug
Administrationecleared molecular as-
says for detection are available. Although
direct organism detection with dark-
field microscopy can provide presump-
tive diagnosis early in infection,
dark-field microscopy is not widely
available and the vast majority of syphilis
cases encountered in clinical practice are
asymptomatic. Given these unique
challenges, syphilis diagnostics have
relied on serologic tests as the mainstay
of laboratory diagnosis. Serologic
ajog.org
tests for syphilis include detection of
both nontreponemal antibodies and
treponemal-specific antibodies.
Nontreponemal tests (NTTs) include
rapid plasma reagin (RPR) and the ve-
nereal disease research laboratory test,
which detects both IgM and IgG anti-
bodies against cardiolipins released from
host cell damage during infection. These
tests can be qualitative or quantitative
with titers that increase with active dis-
ease and decrease following adequate
therapy. Higher NTT titers are seen in
primary and secondary syphilis as
compared to latent syphilis. Most in-
dividuals convert to nonreactive
following adequate treatment, although
some patients will remain serofast. This
is a condition of persistent low NTT ti-
ters (<1:8) without active disease and is
more common with latent infection.16,17
The sensitivities of the NTTs are com-
parable and vary depending on stage of
infection. Lower sensitivity is seen in
very early and very late infection and
highest sensitivity is seen in secondary
syphilis.18 The positive and negative
predictive value of the NTTs depends on
ajog.org
the population being tested; impor-
tantly, false-positive NTT reactions have
been associated with pregnancy.19,20 The
US Preventive Services Task Force
recently reported sensitivity, specificity,
and positive and negative predictive
value of each NTT and treponemal test
(TT) according to stage of syphilis.18
TTs include all assays that detect IgM
and IgG antibodies specific to T pal-
lidum. While these tests can confirm
previous T pallidum infection, they
cannot differentiate individuals who
have been treated from those with an
active disease. Generally, TTs remain
reactive for life following eradication of
the infection. Historically the most
commonly used TTs were the T pallidum
particle agglutination assay (TP-PA) and
the fluorescent treponemal antibody
absorption assay (FT-ABS). Recent ad-
vances in the detection of T pallidum
antibodies have resulted in several
TTs that are highly sensitive and specific
and are automated to accommodate
high-throughput testing. These include
enzyme-linked immunosorbent assay,
chemiluminescence immunoassay
(CIA), and multiplex bead enzyme
immunoassay (EIA) formats. The spec-
ificity of these assays are comparable to
the TP-PA and FT-ABS but have better
sensitivity for early primary syphilis that
is sometimes missed by TP-PA, FT-ABS,
and NTTs.18
Due to the limitations of each avail-
able laboratory test for syphilis, no single
test can be used to diagnose syphilis.
As such, a diagnostic algorithm
composed of multiple tests is used
to diagnose syphilis. The algorithm
used for decades, referred to as the
“traditional algorithm,” initiates NTT
screening, such as an RPR, followed by
confirmation of reactive specimens with
a treponemal-specific test to rule out
false-positive results. In 2009 a new al-
gorithm was proposed and designated
the “reverse algorithm.”21,22 This algo-
rithm initiates screening with a
treponemal-specific test (EIA or CIA);
reactive samples are tested by quantita-
tive RPR and discrepant samples (those
that test RPR nonreactive) are tested by
TP-PA to aid in determination of disease
and treatment status. If the TP-PA is
Expert Reviews
TABLE 1
Clinical presentation and stages of syphilis9,10
Stage of
syphilis Clinical findings Location/characterization
Primary Chancre
syphilis Lymphadenopathy
Secondary Rash (Figure 2) Distributed widely, commonly involve palms
syphilis and soles
Macular, papular, papulosquamous, pustular,
and nonpruritic
Patchy alopecia
Scalp hair or eyebrows
Condyloma lata (Figure 3)
Mucous patches
Generalized symptoms Warm/moist intertriginous areas such as
vulva, inner thighs, axillae, perineum, skin
under breasts
Parenchymal effects (less Mouth, throat, or genital areas
common) Fever, sore throat
Weight loss, malaise
Anorexia, meningismus
Hepatitis, gastrointestinal symptoms,
nephrotic syndrome, arthritis
Periostitis, optic neuritis
Tertiary Granulomatous lesions Skin, mucous membranes, skeleton
syphilis Cardiovascular Typically aortic lesions
Neurosyphilis CNS Cognitive dysfunction, motor or sensory
Ophthalmologic deficits, auditory symptoms, cranial nerve
palsies, meningitis, stroke, tabes dorsalis
(syphilitic myelopathy)
Uveitis, neuroretinitis, optic neuritis, Argyll
Robertson pupils
CNS, central nervous system.
Rac. Syphilis during pregnancy. Am J Obstet Gynecol 2017.
negative (þEIA/CIA, eRPR, eTP-PA), risk populations, it is critical that the
that may reflect very early disease or ordering physician understand the na-
false-positive EIA/CIA results. In fact, a ture of the test being ordered. Many
study out of Kaiser Permanente showed laboratories offer the reverse diagnostic
that 53% of discrepant results (CIAþ/ algorithm and will reflex tests appro-
eRPR/eTP-PA) during pregnancy were priately, however, if the laboratory does
false positives on repeated testing (con- not automatically reflex to the appro-
verted to eCIA/eRPR/eTP-PA).23 priate confirmatory tests following a
However, in high-prevalence pop- positive treponemal-specific test it is
ulations or if clinical suspicion is high, incumbent on the physician to do so.
discrepant results are more likely to Figure 4 shows the timeline of testing
represent early syphilis and we recom- components and a flow chart for both
mend treatment during pregnancy in the traditional and reverse sequence
lieu of repeated testing.24 Further, pa- algorithms.
tients with possible latent syphilis but Each of the 2 algorithms has strengths
negative RPR who otherwise would be and weaknesses, and importantly labo-
screen negative using the traditional al- ratories establish which algorithm best
gorithm can be detected with the reverse suits the needs of their population.
algorithm.18 Due to the risk for false- Typically, high-volume laboratories will
positive test results, particularly in low- utilize the reverse algorithm to take
APRIL 2017 American Journal of Obstetrics & Gynecology 355
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FIGURE 4
Serologic components of syphilis testing and comparison of screening algorithms

356 American Journal of Obstetrics & Gynecology APRIL 2017

ajog.org
advantage of the high sample
throughput, automation, and objective
test interpretation. In low-volume set-
tings, the traditional algorithm may be
more cost-effective despite the require-
ment for manual operation and subjec-
tive interpretation of NTTs.
Neither testing algorithm (described
later in the review) can distinguish
between previously treated vs untreated
syphilis. Therefore, when patients have
both positive treponemal-specific and
-nonspecific test results, in the absence of
clinical symptoms, the differential diag-
nosis is serofast (previously treated syph-
ilis with persistent low RPR titers) vs
latent syphilis. Treatment history and
prior RPR titers will help distinguish
between the 2 diagnoses, and can
often be obtained from local or state
departments of public health. In the
presence of previous inadequate treat-
ment or no known treatment and
unknown timing of infection, we recom-
mend treating pregnant patients as syph-
ilis of unknown duration.
Prevention and identification of CS
depends on careful maternal screening.
Syphilis testing is recommended at
initiation of prenatal care in all
women, but only select states have
mandatory third-trimester testing and
providers should be familiar with their
state laws regarding frequency of
testing.25 Selective screening based on
state laws, geographic prevalence, and
patient risk factors follows regulatory
guidelines and CDC recommendations;
however, without universal third-
trimester testing, the true prevalence
of syphilis will not be recognized. In
women at high risk for acquiring
syphilis, testing should occur at 28-32
weeks and again at delivery11 (Table 2).
In addition, all women who present
with a stillbirth >20 weeks’ gestation
=
A, Timeline of syphilis testing components and B, comparison of traditional and reverse sequence algorithms.21,22,95 aIgM by enzyme-linked immu-
nosorbent assay or fluorescent treponemal antibody absorption assay (FTA-Abs) 195 or immunoblot Treponema pallidum hemagglutination assay
(TPHA), which is specific treponemal assay used to confirm positive screening test. Similar treponemal assays are T pallidum particle agglutination assay
(TP-PA), FTA-Abs, and microhemagglutination assay for treponema pallidum (MHA-TP). Figure 4, A, adapted from Peeling and Ye.95 Used with
permission.
RPR, rapid plasma reagin; VDRL, venereal disease research laboratory test.
Rac. Syphilis during pregnancy. Am J Obstet Gynecol 2017.
should be tested and all patients diag-
nosed with syphilis should also be
tested for HIV. Syphilis is a nationally
notifiable condition and requirements
for reporting vary by state. State laws
regarding reporting requirements can
be found at http://www.cdc.gov/std/
program/final-std-statutesall-states-5june
-2014.pdf.
Multiple studies have demonstrated
cost-effectiveness of syphilis screening at
the initiation of prenatal care.26-30
Recently, the cost-effectiveness of
repeat testing has been evaluated.29,30
These studies utilized lower rates of
primary and secondary syphilis, which
are not applicable to all geographic re-
gions. The incidence of syphilis may also
be underrecognized in regions that
either do not perform repeat testing, or
have higher rates of CS discordant from
rates of primary and secondary syphilis.
In addition, the model attributed a low
rate of preterm delivery related to
syphilis, and even lower rates of pre-
sumed CS in women with early syphilis.
Contemporary studies are lacking that
evaluate seroconversion rates during
pregnancy, making the models highly
contingent on older, less accurate data.
For these reasons, we encourage
repeated third-trimester testing in all
women during pregnancy.
Ultrasound findings and
pathophysiology of fetal syphilis
Vertical transmission of syphilis occurs in
all stages of syphilis and in each trimester
of pregnancy.31-35 Fetal infection occurs
in >50% of untreated early syphilis and
35% of untreated latent disease.9,12
Amniocentesis and percutaneous umbil-
ical blood sampling were previously used
to document fetal infection, but
comprehensive fetal ultrasound is now
the most common method used to
APRIL 2017 American Journal of Obstetrics & Gynecology
Expert Reviews
TABLE 2
High-risk characteristics for
acquiring syphilis during
pregnancy that require testing
twice during third trimester
(at 28e32 weeks and delivery)11
High morbidity area (rates of primary and
secondary syphilis of 2 per 100,000)
No evidence of prior testing
Uninsured or low income
Diagnosed with STD during pregnancy
Exchange sex for money or drugs
STD, sexually transmitted disease.
Rac. Syphilis during pregnancy. Am J Obstet Gynecol
2017.
evaluate for fetal infection.32-34,36,37
Characteristic fetal abnormalities seen
with ultrasound are the result of a robust
inflammatory response to T pallidum and
typically not seen <20 weeks as the result
of fetal immunologic immaturity.32,38
Pregnancies with evidence of fetal infec-
tion by ultrasound have higher rates of
fetal compromise during treatment as
well as fetal treatment failures.35,39 Before
20 weeks, ultrasound abnormalities are
usually not seen and treatment is uni-
formly successful.32,39-41
Ultrasound abnormalities suggestive
of fetal syphilis can be seen >20 weeks
and in all stages of maternal syphilis.
One study found that 31% of infected
gravidas had evidence of fetal syphilis on
pretreatment ultrasound. These abnor-
malities, in decreasing frequencies,
include34-36:

hepatomegaly (80%).

elevated peak systolic velocity of the
middle cerebral artery (MCA) by
Doppler ultrasound indicative of fetal
anemia (33%).

placentomegaly (27%).
357
Expert Reviews
FIGURE 5
Progression of ultrasound abnormalities
Progression of ultrasound abnormalities before and after maternal and fetal syphilotherapy.34,35
Reprinted with permission from35.
Rac. Syphilis during pregnancy. Am J Obstet Gynecol 2017.

polyhydramnios (12%).

ascites (10%) and fetal hydrops.
The pathophysiology of fetal syphilis
was first described by Hollier et al34 in
2001 and completed in 2014 by Rac
et al.35 Fetal syphilis is a continuum
characterized by early hepatic and
placental involvement followed by am-
niotic fluid infection, hematologic
FIGURE 6
Hepatomegaly and ascites in
fetal syphilis
Hepatomegaly and ascites in fetus with syphilis.
Dotted lines and crossbars demonstrate correct
measurement of fetal liver length. Fetal liver
should be measured from right hemidiaphragm
to tip of right lobe. Fetus should be in back down
position with right side up.
Rac. Syphilis during pregnancy. Am J Obstet Gynecol 2017.
358 American Journal of Obstetrics & Gynecology APRIL 2017
dysfunction, and finally ascites and fetal
IgM production. As maternal stage of
syphilis progresses untreated, more ab-
normalities develop.34 After adequate
syphilotherapy, findings of late fetal
syphilitic infection (MCA Doppler ab-
normalities, ascites) resolve first and
findings thought to occur early, such as
placentomegaly and hepatomegaly, are
the last to resolve35 (Figure 5).
Due to the prevalence of ultrasound
abnormalities in fetuses, the following
are recommended structures/compo-
nents to be visualized and documented
during comprehensive ultrasound in
women with active syphilis:

liver length (Figure 6).

placental thickness.

peak systolic velocity of the MCA.

amniotic fluid index.

evaluation for ascites or hydrops.
Suggested nomograms and definitions
of abnormal are shown in Table 3.
The manifestations of fetal syphilis are
poorly understood but likely the result of
multiple physiologic processes, and their
etiologies may lend insight into the
morbidities observed clinically. Hepato-
megaly is thought to result from acute
syphilitic hepatitis, exaggerated extra-
medullary hematopoiesis, cardiogenic
hepatic congestion, or even a therapeutic
ajog.org
paradox as seen in postnatal studies after
syphilotherapy.42-44 Placentomegaly
results from inflammation and enlarge-
ment of the placental villi as a result of
syphilitic infection.45-47 These histo-
pathologic changes lead to increased
uteroplacental resistance that correlates
with degree of fetal infection.48 Syph-
ilotherapy induces acute vascular perfu-
sion changes, possibly secondary to the
Jarisch-Herxheimer (JH) reaction, of-
fering an explanation as to why maternal
treatment may be intolerable to the most
severely affected fetuses.48
Notable hematologic aberrations of
fetal syphilis include anemia and throm-
bocytopenia. Both appear to be specific to
the developing fetus and neonate, and
may result from the difference in prop-
erties of the fetal and adult red blood cell
compounded by an alteration in fetal
hematopoiesis induced by fetal infec-
tion.49 We do not recommend an intra-
uterine transfusion as adequate treatment
with benzathine penicillin G (BPG) re-
verses the hematologic abnormalities of
fetal syphilis.35,50
Lastly, a normal ultrasound does
not necessarily rule out congenital
infection. Rac et al35 found that w12%
of neonates with a normal pretreatment
ultrasound during pregnancy required
treatment for CS at delivery. It is
important to keep in mind that certain
manifestations of CS, such as osseous
lesions, are not detected by ultrasound.
Patient counseling should include the
limitations of ultrasound and the
importance of a vigilant physical exam at
delivery to rule out neonatal infection
regardless of maternal treatment history.
Treatment of syphilis during
pregnancy
Benzathine penicillin G (BPG) is highly
efficacious during pregnancy and remains
the only recommended treatment for
maternal syphilis and prevention of CS.
Studies have found the efficacy of BPG to
be 99.7% for eradicating maternal disease
during pregnancy and 98.2% for pre-
venting CS across all stages of syphilis.51
Maternal treatment should occur as
early in pregnancy as possible and
comply with the recommended regimen
per stage of syphilis as determined by the
ajog.org Expert Reviews

CDC sexually transmitted disease

guidelines11,52,53 (Table 4). Evidence has TABLE 3
consistently shown that early and Suggested nomograms for sonographic markers of fetal syphilis90-94
adequate maternal treatment during Structure/component Nomogram for reference Definition of abnormal
pregnancy confers the lowest rates of CS Liver length Vintzileos et al 90
Hepatomegaly defined as liver length
and adverse pregnancy outcomes.52,53 If >95th percentile for EGA
any dose of BPG is missed or a lapse of Placental thickness Hoddick et al91 Placental thickness >2 SD for EGA
10 days occurs between any dose, the
MCA Doppler Mari et al 92
MCA >1.5 MoM
entire regimen should be restarted.54-57
Similarly, if a gravida is treated with Amniotic fluid index Moore and Cayle 93
>250 mm
any regimen other than BPG or adequate Evaluation for ascites Society for Maternal-Fetal Ascites: free fluid within fetal
treatment cannot be verified, retreat- or gross hydrops Medicine et al94 abdominal cavity
ment with the appropriate penicillin Hydrops: 2 cavities with abnormal
fluid collections
regimen is recommended.
In primary, secondary, and early latent EGA, estimated gestational age; MCA, middle cerebral artery; MoM, multiples of median; SD, standard deviation.

syphilis, an additional dose of BPG has Rac. Syphilis during pregnancy. Am J Obstet Gynecol 2017.

traditionally been recommended on the

basis of expert opinion and clinical
experience.11 Recently, this has come
into question given a national shortage
of BPG. Although no randomized
controlled trials have been conducted to
evaluate 1 vs 2 doses for early syphilis
during pregnancy,58 theoretic pharma-
cologic benefits exist to support addi-
tional doses. Nathan et al57 studied the
serum concentrations of BPG in 25
women at term and found the number of
women with a serum concentration
0.018 mg/mL (the desired treponemo-
cidal concentration) significantly declined
over the course of a week. By day 7, 36%
had serum concentrations lower than the
needed treponemocidal concentration.57
Weeks et al59 demonstrated that 4.8
million units BPG given near term for
group B streptococcus prophylaxis pro-
vided at least 30 days and in the majority
of patients up to 100 days of treponemo-
cidal concentrations. There is also obser-
vational evidence to suggest that multiple
BPG doses may be associated with more
favorable pregnancy outcomes.31,53,60-62
We continue to recommend an addi-
tional dose of BPG with early syphilis,
especially >20 weeks, however acknowl-
edge that more research is needed to
establish the most efficacious treatment
during pregnancy, particularly in the
context of a national shortage of BPG.
Maternal NTT titers should be
rechecked at the time of treatment to
gauge appropriate titer decline after
syphilotherapy as some women will be
treated on a different day than their initial
diagnostic testing. After maternal
syphilotherapy, follow-up NTT titers are
performed monthly to ensure they are not
increasing four-fold, which is considered a
clinically significant titer change. We state
it this way to highlight 2 important points.
First, titer decline will vary by stage of
maternal disease and treatment timing
during pregnancy (Figure 7), with only
38% of gravidas achieving a 4-fold decline
by delivery in a recent retrospective re-
view.63 Thus, the length of human gesta-
tion is likely insufficient to gauge adequate
maternal serologic response to syph-
ilotherapy. If patients NTT titers have not
decreased 4-fold by delivery, ongoing
serologic surveillance per CDC guidelines
should continue postpartum according to
the structure of the local health care
TABLE 4
Treatment of syphilis during pregnancy according stage of disease11
Stage of syphilis
Primary syphilis
Secondary syphilis
Early latent syphilis
Late latent syphilis
Syphilis of unknown duration
Tertiary syphilis
Neurosyphilis
BPG, benzathine penicillin G; IM, intramuscular; IV, intravenous.
Rac. Syphilis during pregnancy. Am J Obstet Gynecol 2017.
system. Secondly and most importantly,
the rate of maternal titer decline after
adequate syphilotherapy is not predictive
of fetal treatment failures.63 If NTT titers
increase 4-fold or symptoms persist or
recur then reinfection or maternal treat-
ment failure should be considered. Sus-
pected treatment failures should be
evaluated for neurosyphilis and retreated
with 3 doses of BPG. If neurosyphilis is
diagnosed then the patient should be
treated accordingly.8
Treatment failures
Fetal treatment failure is defined as
the diagnosis of CS despite adequate
maternal treatment. Risk factors for fetal
treatment failure include34,53,64:
Treatment
BPG 2.4 million units IM once
Some evidence suggests that additional therapy is
beneficial for pregnant women; for women who have
primary, secondary, or early latent syphilis, second
dose of BPG 2.4 million units IM can be administered 1
week after initial dose (total 4.8 million units)
BPG 7.2 million units total, administered as 3 doses of
2.4 million units IM each at 1-week intervals
Aqueous crystalline penicillin G 18e24 million units/
day, administered as 3e4 million units IV every 4 hours
or continuous infusion, for 10e14 days

APRIL 2017 American Journal of Obstetrics & Gynecology 359

Expert Reviews
FIGURE 7
Nontreponemal titer decline
during pregnancy
Nontreponemal titer decline after adequate
maternal treatment according to stage of
syphilis. Reprinted with permission from63.
Rac. Syphilis during pregnancy. Am J Obstet Gynecol 2017.

early syphilis (<1 year).

ultrasound abnormalities suggestive
of fetal syphilis.

treatment late in pregnancy.
Timing of treatment does not impact
maternal cure rates, but does impact
rates of CS. Higher rates of CS have been
observed with shorter intervals between
treatment and delivery, particularly if
treatment occurs 30 days from de-
livery.51,65-68 As a result, adequacy of
maternal treatment is measured not only
by the number of BPG doses received
in accordance with stage of disease, but
also whether or not treatment occurred
>30 days before delivery.11
Penicillin allergy
Women with a penicillin allergy should
be desensitized and subsequently
treated with the appropriate penicillin
regimen. Both oral and intravenous
desensitization regimens have been
described.69,70 Desensitization may be
managed by the obstetrician/gynecolo-
gist with experience in desensitization,
or concurrently with a specialist in the
field of allergy and immunology. An
oral desensitization protocol used in
pregnancy can be found in the 2015
CDC sexually transmitted disease
treatment guidelines.11,69
There is insufficient evidence that
alternative antibiotics are efficacious for
360 American Journal of Obstetrics & Gynecology APRIL 2017
the treatment of syphilis during preg-
nancy. Doxycycline and tetracycline are
both contraindicated during pregnancy
and macrolides have been associated
with treatment failure during preg-
nancy, inconsistent placental transfer, as
well as treponemal resistance.62,71 Cef-
triaxone is highly treponemocidal with
good placental transfer and was found
to be 100% efficacious in 11 gravidas
with primary or secondary syphilis
treated <20 weeks.72 Although prom-
ising, this study provides no applicable
information on the majority of gravidas
with syphilis encountered in clinical
practice, that is, the third-trimester
patient with latent syphilis.35,62,64
More evidence is needed to establish
the efficacy for ceftriaxone in all stages
of syphilis across all trimesters of
pregnancies before it can be considered
a safe alternative.
JH reaction
Treatment of spirochete infections can
result in the JH reaction. This reaction is
thought to result from the rapid killing of
spirochetes causing copious release of
endotoxins, lipopolysaccharides, prosta-
glandins, and cytokines, leading to an
acute inflammatory response.73-75 In
nonpregnant patients, it occurs in 95%
of primary and secondary syphilis, but
rarely in latent syphilis due to lower
treponemal levels.76 In neurosyphilis, the
JH reaction is observed in 12-75% of
cases.77
Clinical symptoms are transient and
include systemic and local exacerbations
of the treponemal disease.73,78 Fever,
tachycardia, chills, arthralgia, pharyn-
gitis, headache, leukocytosis with lym-
phopenia, as well as worsening of
cutaneous lesions have been reported
and coined the “therapeutic paradox” of
syphilotherapy.35,73,78 Symptoms occur
2-8 hours after syphilotherapy is initi-
ated and abate by 24 hours.73
Treatment is supportive with the use
of antipyretics and intravenous fluid
therapy. Corticosteroids have been pro-
posed to decrease the intensity of the
reaction, but evidence of efficacy is
lacking, especially during pregnancy.39
Smaller, incremental dosing of peni-
cillin does not seem to lessen the
ajog.org
robustness of the reaction as the JH is an
all-or-nothing event provided the mini-
mum treponemocidal dose of 10 U/kg is
reached.79
The JH reaction occurs in up to 44%
of pregnant women and can precipitate
preterm labor, fetal heart rate abnor-
malities, and stillbirth.75,78,80-85 It occurs
in 100% of primary disease, 60% of
secondary disease, and more than half of
patients with syphilis of unknown
duration.80 Pregnancy-specific compli-
cations include uterine contractions (56-
67%), decreased fetal movement (67%),
and fetal heart rate decelerations
(50%).75,78,80 The majority of these
complications will resolve by 24 hours
after treatment although preterm birth
and stillbirth can occur in severely
affected pregnancies and despite normal
pretreatment ultrasounds.75,80,84,86,87
For these reasons, consideration should
be given to administering the first
dose of BPG in a labor and delivery
department under continuous fetal
monitoring for at least 24 hours in all
viable pregnancies. Fetal heart rate ab-
normalities present before or during
treatment, especially in the setting of
ultrasound abnormalities, may indicate a
severely affected fetus. If the JH reaction
induces preterm labor, management
should follow standard obstetric care.
In the setting of fetal heart rate abnor-
malities during treatment in the late
preterm period (34 weeks), specifically
recurrent late decelerations that do
not respond to intrauterine resuscita-
tion, we recommend delivery with
postnatal treatment of the infant (and
mother). Management of fetal heart
rate abnormalities in pregnancies
before this gestational age should be
individualized. The remainder of BPG
doses can be given in an outpatient
setting without concern for the JH
reaction.
Summary of recommendations
Management of syphilis during preg-
nancy requires a comprehensive
approach including results of testing,
treatment history, physical exam find-
ings, stage of disease, gestational age at
diagnosis and pretreatment ultrasound
findings. All women should have
ajog.org Expert Reviews

TABLE 5
Recommended management of syphilis during pregnancy

Test for syphilis at initiation of prenatal care, third trimester, and deliverya

For all positive results, conduct history and physical exam to stage disease

If patient is asymptomatic, check for past infection with adequate treatment, as patient may be serofast (NTT titers <1:8)

If adequate treatment cannot be verified or titers 4-fold higher, retreat (syphilis of unknown duration)

Treat according to maternal stage of disease; we recommend 2 doses of BPG in early syphilis (<1 years) for fetal benefit

If pregnancy is viable, perform comprehensive ultrasound to evaluate for fetal syphilis

If pregnancy is viable, give first dose of BPG in labor and delivery department under continuous fetal monitoring for 24 hours

Consider delivery with treatment in nursery during late preterm period if evidence of fetal heart rate abnormalities, with or without ultrasound
abnormalities or hydrops, appears before or during maternal treatment

Additional doses of BPG can be given as outpatient

Serial ultrasound surveillance for pregnancies with abnormal pretreatment ultrasound to monitor for resolution of abnormalities

Antenatal testing can be considered during third trimester

Notify neonatology at delivery for adequate neonatal evaluation

Send placenta to pathology for histologic evaluation
BPG, benzathine penicillin G; NTT, nontreponemal test.
a
Testing twice during third trimester is recommended in high-risk populations. Please see Table 3.
Rac. Syphilis during pregnancy. Am J Obstet Gynecol 2017.

testing performed at initiation of pre-
natal care. Repeated testing is recom-
mended in the third trimester and
again on labor and delivery in high-risk
populations.
A positive test for syphilis requires
knowledge of infection history, espe-
cially in women with low NTT titers
(1:8), as some of these women will be
serofast. We advocate development of a
good working relationship with your
local health department to verify treat-
ment in women with prior infection. If
treatment cannot be verified, these
women should be considered to have
active infection. HIV testing should be
performed in all women who test posi-
tive for syphilis.
After active infection is confirmed, a
physical exam is performed to determine
stage of syphilis. BPG is the only rec-
ommended therapy during pregnancy
and gravidas should be treated according
to their stage of syphilis per CDC
guidelines (Table 5).11 As stated previ-
ously, ultrasound abnormalities can be
seen >20 weeks. However, pregnancy
management does not change until
viability. Therefore, we recommend an
ultrasound prior to maternal treatment
in viable fetuses to identify pregnancies
at highest risk of complications from
syphilotherapy. Treatment should not be
delayed if an ultrasound is not readily
available. Viable pregnancies should
receive their first dose of BPG in a labor
and delivery department under contin-
uous fetal monitoring, regardless of
sonographic findings. Additional doses
of BPG can be given as an outpatient. No
evidence is available to weigh the risks
and benefits of antenatal syphilotherapy
vs delivery with postpartum treatment in
the late preterm period and this decision
should be individualized. However, de-
livery with treatment in the nursery may
be considered in the most severely
affected pregnancies (ultrasound ab-
normalities) to avoid complications of
syphilotherapy.
After maternal treatment, pregnan-
cies with pretreatment ultrasound
abnormalities should undergo serial
ultrasound surveillance to follow reso-
lution of abnormalities. Follow-up NTT
titers are performed monthly to ensure
they are not increasing four-fold.
Women found to be serofast do not
have an increased risk of adverse preg-
nancy outcomes, but should also have
monthly RPR titers as these patients
represent a population at increased risk
for reinfection.88 There are no studies
evaluating the benefit of antenatal
testing in pregnancies treated for
syphilis. However, low birthweight,
preterm birth, and stillbirth have been
observed remote from syphilotherapy,
particularly during the third trimester,
and even after adequate maternal
treatment.52,53,61,75,80,88,89 For this
reason, antenatal testing is a reasonable
intervention to consider.
Neonatology should be notified at de-
livery to ensure neonates are evaluated for
evidence of infection and treated appro-
priately if indicated. Although placental
histopathology is not required for the
diagnosis of CS, it has been shown to
improve detection in both liveborn and
stillborn infants and should be considered
in all gravidas diagnosed and treated for
syphilis.11,45 These recommendations are
summarized in Table 5. -
ACKNOWLEDGMENT
We would like to acknowledge George D.
Wendel Jr, MD, and Jeanne S. Sheffield, MD, for
their invaluable mentorship.
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