Expert Reviews
org
Syphilis in pregnancy: an ongoing public health
threat
Catherine S. Eppes, MD, MPH; Irene Stafford, MD; Martha Rac, MD
Introduction and epidemiology of
congenital syphilis in the United
States
Syphilis is a pathogenic treponeme that
is acquired sexually, hematogenously or
via vertical transmission from mother to
infant. Despite the availability of peni-
cillin for over 70 years and evidence-
based curative treatment options, it re-
mains a public health threat. Since 2001,
primary and secondary syphilis rates
among reproductive-age women have
been steadily increasing (Figure 1). By
2014, rates of congenital syphilis (CS)
rose to the highest rates observed since
2001 (11.6/100,000), and on November
13, 2015 the Centers for Disease Control
and Prevention (CDC) published a
Morbidity and Mortality Weekly Report
(MMWR) alerting the public about this
public health crisis and calling for im-
mediate action.1 Unfortunately, CS
continues to increase nationally. The
number of reported CS cases in the
United States increased by 261% from
2013 to 2018, from 362 to 1306 cases.2 In
2019, there were 1870 cases of CS,
increasing to 2022 cases in 2020.2
Figure 2 shows the increase in CS cases
since 2011.
An interesting correlation has been
noted between the rise of opioid use and
methamphetamines in reproductive-
From the Baylor College of Medicine,
Department of OB/Gyn, Division of Maternal
Fetal Medicine, Houston, TX (Drs Eppes and
Rac); and The University of Texas Health
Science Center Houston, Department of OB/
Gyn, Division of Maternal Fetal Medicine,
Houston, TX (Dr Stafford).
Received March 11, 2022; revised July 8, 2022;
accepted July 18, 2022.
The authors report no conflict of interest.
Corresponding author: Catherine S. Eppes, MD,
MPH. Catherine.eppes@bcm.edu
0002-9378/$36.00
ª 2022 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ajog.2022.07.041
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ajog.
Syphilis is a treponemal infection that can be acquired sexually, hematogenously, or via
vertical transmission from mother to infant. Despite evidence-based curative treatment
options with penicillin, it remains a public health threat with increasing prevalence over
recent years. Congenital syphilis, a condition where a fetus acquires the infection during
pregnancy, can lead to stillbirth, miscarriage, preterm birth, birth defects, and lifelong
physical or neurologic changes. Congenital syphilis rates in the United States increased
by 261% from 2013 to 2018 and continue to increase in 2021. The only recommended
treatment for syphilis in pregnancy is benzathine penicillin G because evidence of
decreased risk of congenital syphilis with other modalities is lacking. Testing for syphilis
is complex and includes either the reverse-sequence algorithm or the traditional algo-
rithm. Determination of the clinical stage of syphilis includes incorporation of the previous
treatment sequence and physical examination. The goal of this review was to discuss the
current evidence about optimal treatment and testing during pregnancy to optimize
maternal health and prevent congenital syphilis.
Key words: congenital syphilis, fetal syphilis, reverse sequence, syphilis during preg-
nancy, syphilis testing, syphilis treatment, traditional algorithm, treponemal testing
aged women and primary and second- rates of health insurance, and inadequate
ary syphilis. A MMWR published in access to health care only serve to worsen
2019 reported that the use of injection disparities observed with syphilis.5,6 In-
drugs, methamphetamine, and heroin terventions addressing social and struc-
doubled in women and heterosexual tural factors associated with disparities
men diagnosed with primary and sec- should be tailored to different age groups
ondary syphilis between 2013 and 2017, and regions across the United States.
highlighting the link between these 2 In 2018, the CDC performed a review
intersecting epidemics.3 Linkages be- to identify missed prevention opportu-
tween programs that treat patients with nities that may have contributed to CS
substance use disorder and sexual dis- cases.7 They found that the most com-
ease control programs may be important mon gaps included:
to address these concurrent conditions.
There are several stark healthcare 1. Lack of timely prenatal care with no
disparities related to syphilis infections, timely syphilis testing (28.2%)
with higher incidences in Black, Amer- 2. Lack of timely syphilis testing despite
ican Indian, and Pacific Islander pop- timely prenatal care
ulations and in the Southern United 3. Lack of adequate maternal treatment
States. Historic events, such as the un- despite a timely syphilis diagnosis
ethical Tuskegee study, likely played a (30.7%)
role in these disparities. In this 1932 4. Late identification of seroconversion
study, 399 Black men were longitudinally during pregnancy (identified <30
followed without their consent to days before delivery)
observe the natural history of syphilis.
Once penicillin became available, treat- This review describes the pathophysi-
ment was purposely withheld from the ology, clinical manifestations, and best evi-
participants, adversely affecting their dence on the management of syphilis
health and generations to come.4 The during pregnancy. We also focus on recog-
effects of systemic racism, poverty, low nized gaps and proposed interventions for
ajog.org
some of the previously mentioned missed
opportunities, and discuss future directions
that could help us overcome challenges to
the elimination of CS.
Syphilis as a stealth pathogen
Treponema pallidum subspecies pal-
lidum, a spirochete of 5- to 15-mm length,
is the causative agent of syphilis. Sir
William Osler once famously labeled
syphilis “the great imitator” because of
the myriad of clinical manifestations in all
stages, particularly late stages, that mimic
“almost every disease known to man.” T
pallidum is a peculiar bacterium with
certain notable characteristics that have
contributed to its ability to evade eradi-
cation. First, the organism is narrow and
difficult to stain (“pallidum” meaning
“pale”) and cannot be directly visualized
with light microscopy. Therefore, dark-
field microscopy must be used for direct
visualization. Secondly, the outer mem-
brane is relatively devoid of protein tar-
gets that can be recognized by the host
immune system or targeted for diagnostic
purposes. Thirdly, T pallidum has limited
metabolic capabilities and is entirely
dependent on a mammalian host for
sustained growth.8 Historically, efforts to
culture and maintain T pallidum for a
meaningful amount of time in a labora-
tory setting were unsuccessful.9e11
Therefore, research of these organisms
relied on live rabbits, greatly hampering
scientific advancement. In 2018,
Edmonson et al12 reported successful
culture and maintenance of T pallidum
for >180 days with full retention of
infectivity, structural integrity, and
motility. This was followed by a paper in
2021 from the same authors12 reporting
ongoing growth of T pallidum for >3
years. Although in vitro cell culture of T
pallidum may have limited clinical
utility owing to a long doubling time
(30e50 hours), the importance of this
breakthrough cannot be overstated.
Applications of this cell culture system
will lead to a better grasp of the organ-
ism’s growth and replication character-
istics, gene expression, genetics and
mutagenesis, targets for diagnostic
testing, susceptibility to antimicrobials
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FIGURE 1
Primary and secondary syphilis—rates by sex, United States
(2011e2021)
The asterisk denotes reported 2021 primary and seconday syphilis data are preliminary as of March
9, 2022.
Adapted from Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2020. Atlanta: U.S. Department of
Health and Human Services; 2022.
Eppes. Syphilis in pregnancy. Am J Obstet Gynecol 2022.
and vaccine development, to name a
few,12 all leading to improved preg-
nancy outcomes.
Syphilis testing in pregnancy
Timing of testing in pregnancy
In 2018, the United States Preventive
Services Task Force statement regarding
testing at initiation of prenatal care
reinforced the need for early and timely
maternal treatment.2 The CDC, Amer-
ican Academy of Pediatrics, American
College of Obstetricians and Gynecolo-
gists, and other medical organizations
echoed this recommendation and added
that repeated screening in the third
trimester and at delivery should be per-
formed for individuals residing in high-
prevalence regions. With the ongoing
rise in CS rates nationwide, coupled with
a common pattern of delayed or un-
available maternal testing leading to
missed opportunities, many experts have
advocated for repeated screening in the
third trimester and during admission
for labor as a universal national
standard.13,14
DECEMBER 2022 American Journal of Obstetrics & Gynecology
Expert Reviews
Current gaps in testing during
pregnancy
Diagnostic recommendations and algo-
rithms for syphilis are complex and often
misinterpreted, exacerbating the challenge
of perinatal syphilis management. Stafford
et al16 reported that 18 of 73 (25%)
mothers with syphilis were inadequately
treated between 2014 and 2017 in a
southeastern region of the United States,
and that 11 of 73 (15%) of their newborns
were misdiagnosed as false-negative CS
cases.15 A 3-year prospective cohort study
of 26 infected mothereinfant dyads from
the Southwestern region of the United
States demonstrated that the rate of
appropriate posttreatment surveillance
was only 35%.16 Poor adherence to
appropriate surveillance was found to
occur in those who spoke a language other
than English (relative risk [RR], 2.6; 95%
confidence interval [CI], 0.74e24.10),
lacked sufficient prenatal care (RR, 1.5;
95% CI, 0.47e10.61), and experienced
unstable housing (RR, 1.5; 95% CI,
0.06e4.67). No obstetrical or neonatal risk
factors such as gestational age at delivery,
mode of delivery, neonatal intensive care
823
Expert Reviews
FIGURE 2
Congenital syphilis—cases by birth year, United States (2011e2021)
The asterisk denotes reported 2021 congenital syphilis data are preliminary as of March 9, 2022.
Adapted from Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2020. Atlanta: U.S. Department of
Health and Human Services; 2022.
Eppes. Syphilis in pregnancy. Am J Obstet Gynecol 2022.
unit admission, or length of hospital stay
affected adherence to clinical follow-up.17
Testing algorithms
One major challenge in the management
of syphilis during pregnancy is the
absence of a test that distinguishes newly
acquired syphilis from past infection. This
is further complicated by the presence of
the serofast state, a state of low, persistent
nontreponemal titer fluctuation (usually

1:8) that can occur after adequately
treated syphilis. Therefore, the results of a
patient’s syphilis test should always be
interpreted in combination with a thor-
ough history and physical examination,
and the information corroborated from
public health data.
The ideal diagnostic tests, including
rabbit infectivity studies, dark-field mi-
croscopy, and polymerase chain reaction
(PCR) technology are not readily avail-
able for use in clinical practice.18e20
Consequently, diagnosis of maternal
and neonatal syphilis relies on serologic
assays to detect nontreponemal-specific
and treponemal-specific antibodies.
Treponemal-specific tests (TTs) detect
immunoglobulin (Ig) G and/or IgM an-
tibodies (as observed with some enzyme-
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linked immunosorbent assays [EIA] and
chemiluminescence immunoassays
[CIA]) specific to T pallidum. These tests
are used to confirm a positive non-
treponemal antibody test (NTT) result
but cannot differentiate previous treated
infection from active disease because they
remain positive indefinitely. Commonly
used TTs include the T pallidum particle
agglutination assay (TP-PA) and the
fluorescent treponemal antibody absorp-
tion assay (FTA-ABS). Newer treponemal
tests include EIA and CIA, which are
equally specific as TP-PA and FTA-ABS
but have better sensitivity for primary
syphilis. They are also automated, allow-
ing for high-throughput testing.
NTTs detect IgG antibodies against
lecithin, cholesterol, and cardiolipin
released from cell wall damage after
infection. These tests are nonspecific and
include the rapid plasma reagin (RPR)
and the venereal disease research labo-
ratory (VDRL) test. They can be quali-
tative but are commonly reported as
titers (1:x) that fluctuate according to
disease activity and in response to
treatment. Higher NTT values are
observed in early syphilis, particularly
primary and secondary syphilis, relative
ajog.org
to latent disease. After adequate syph-
ilotherapy, NTT values will decline to
negative in most patients, and NTTs can
be followed for treatment response.21
They are also the preferred test in pa-
tients with a known history of syphilis
infection given that treponemal-specific
antibodies remain positive for life. The
sensitivity of NTTs for the diagnosis of
syphilis depends on stage of infection.
The highest sensitivity is observed with
secondary syphilis and then wanes with
very early or late syphilis. The positive
and negative predictive values depend on
the population being tested and should
be incorporated in the decision to
treat.22 False-positive NTTs are defined
as a positive NTT but negative TT and
have been reported in up to 28% of
gravidas screened during pregnancy.23
Two diagnostic algorithms are avail-
able that use both NTTs and TTs. It is
important to note that no single test or
combination thereof can definitively di-
agnose and stage syphilis in the absence
of a comprehensive history and physical
examination. The “traditional algo-
rithm” starts with a NTT (typically RPR)
and reflexes to a TT to rule out false-
positive results. If both the NTT and
TT are positive, the patient is deemed to
have current or past syphilis. A thorough
history and physical examination should
be performed using local health records
to determine the stage of syphilis. In
patients with low titers (
1:8), the
serofast state must be considered in the
setting of previous infection and known
adequate syphilotherapy. Because the
“traditional algorithm” begins with an
NTT, limitations include varying titer
interpretations between laboratories and
potential for false-negative results in
primary and tertiary syphilis because of
lower sensitivity.24
In 2009, a new algorithm, known as
the “reverse algorithm,” was proposed.26
This algorithm begins with a
treponemal-specific test (CIA or multi-
plex bead EIA) followed by a NTT (RPR)
if positive. Because TTs remains positive
for life, including EIA and CIA,
discrepant results (CIA/EIAþ, RPR)
occur. In this scenario, another
treponemal-specific test (typically TP-
PA) is performed to determine disease
ajog.org Expert Reviews

FIGURE 3
Timeline of syphilis testing positivity and testing algorithms

DECEMBER 2022 American Journal of Obstetrics & Gynecology 825

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Expert Reviews
status. If TP-PA is negative (CIA/
EIAþ, RPR, TP-PA), then 2 pos-
sibilities exist: early primary syphilis
or false-positive EIA or CIA. During
pregnancy, discrepant results can
represent biologic false-positives in up
to 53% of cases; thus, it is reasonable
to repeat testing within 4 weeks if
clinical suspicion of syphilis is low.20
If TP-PA is positive, then the patient
is considered to have current or past
syphilis. It is important that labora-
tories establish which algorithm to use
and reflex each test appropriately. It is
equally important that the provider
understand the nature of each test
result and ensure that the appropriate
follow-up test was ordered. Figure 3
shows both algorithms and a timeline
of positivity for each serologic test
component.27
Newborn testing
TTs can be positive in newborns because
of passive transfer of maternal IgG anti-
bodies and persist for >15 months.
Therefore, this testing modality has not
been widely adopted as a clinical diag-
nostic measure for the newborn.18e20
Several IgM platforms including the IgM
19S FTA-ABS tests, IgM immunoblots,
and IgM enzyme-linked immunoassays
have been used to detect T pallidum in
neonates; however, like immunofluores-
cence, PCR and dark-field microscopy
may be negative in early infection.18e20
Given the paucity of diagnostic tools for
the newborn, the NTTs, the VDRL test,
and the RPR test are currently used for
diagnosis of CS in the newborn, regardless
of the poor testing performance of these
serologic tests, with reported sensitivity of
only 14%.13,18,20
Syphilis course in pregnancy
The course and presentation of syphilis
infection in pregnant individuals
mirror those observed in nonpregnant
adults (Table 1). Primary syphilis pre-
sents with an ulcer or painless lesion at
=
Adapted from Rac et al.13
FTA-ABS, fluorescent treponemal antibody absorption assay; Ig, immunoglobulin; RPR, rapid plasma reagin; TPHA, Treponema pallidum hemagglutination; TP-PA, Treponema pallidum particle agglutination
assay; VDRL, venereal disease research laboratory.
Eppes. Syphilis in pregnancy. Am J Obstet Gynecol 2022.
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the site of infection within 3 weeks of
exposure; however, multiple painful
lesions have also been described.
Approximately 2 to 6 weeks after res-
olution of the primary lesion, second-
ary syphilis manifestations occur,
representing systemic infection.
Symptoms of secondary syphilis
include a plantar, palmar, or dissemi-
nated skin rash characterized by
brown discoloration. This rash is often
flat but can be raised, with
sores measuring <2 cm. Other muco-
cutaneous lesions can present along
with lymphadenopathy, alopecia, and
leukoplakia in some cases. Two to 3
months after resolution of secondary
symptoms, infected individuals enter
latent infection, which is characterized
by a lack of clinical symptoms despite
positive serologic testing. When latent
infection is acquired within the pre-
ceding 12 months, it is referred to as
early latent syphilis. All other cases of
latent syphilis are classified as late
latent syphilis or syphilis of unknown
duration.13 These latter 2 stages of
asymptomatic infection can persist for
years, during which syphilis is mini-
mally infectious to nonpregnant in-
dividuals; however, it continues to
carry a risk of in utero transmission to
the fetus.13,25,28,29 Tertiary syphilis may
present at any time during the lifetime
of the infected, untreated individual.
Complications of this phase include
cardiovascular infection, gummata and
neurosyphilis. Early neurologic clinical
manifestations can present within the
first years of infection, with late
neurologic manifestations occurring
up to 30 years after infection. Infection
of the visual or auditory system can
occur at any stage of syphilis, presents
with or without additional central
nervous system (CNS) involvement,
and can lead to permanent vision loss.
Other neurologic symptoms observed
include memory loss and personality
changes.7
ajog.org
The temporary nature of the painless
chancre, vague symptomatology of sec-
ondary syphilis, and the asymptomatic
nature of latent syphilis all contribute to
the potential for delayed diagnosis. In
fact, approximately 50% of infected
mothers who present with latent syphilis
are discovered through routine testing
rather than self-reported complaints of
primary or secondary syphilis manifes-
tations.7,13,17 A high index of suspicion is
encouraged to improve timely diagnosis
and treatment.
Syphilis treatment during pregnancy
In 2018, lack of adequate maternal
syphilotherapy replaced inadequate
prenatal care as the most common
missed opportunity.4 Evidence is clear
that treatment of syphilis improves
pregnancy outcomes. When compared
with noninfected patients, untreated
gravidas are 12 times more likely to
experience stillbirth, preterm birth, and
congenital infection.30,31 The risk of CS
correlates with stage of syphilis and
gestational age at treatment. Primary
and secondary syphilis, early latent, and
late latent syphilis are associated with a
50%, 40%, and 10% risk of CS, respec-
tively.32 Contemporaneous estimates of
congenital infection, preterm birth, and
stillbirth according to maternal stage of
syphilis are lacking, and most of our
understanding of the adverse pregnancy
outcomes of untreated syphilis during
pregnancy comes from meta-analyses
and systematic review estimates31,33
(Table 2). In a meta-analysis of 11,398
gravidas with syphilis, treatment in the
third trimester was associated with a
w41% risk of CS vs a risk of approxi-
mately 18% in the second trimester and
10% in the first trimester.34 Other
studies have also showed lower rates of
adverse pregnancy outcomes when
screening and treatment of positive
gravidas occurred in the first and second
trimester vs the third trimester.34
Therefore, treatment of syphilis should
ajog.org
TABLE 1
Clinical course and symptom presentation of syphilis
Stage of syphilis
Primary syphilis
Secondary syphilis
Tertiary syphilis
Neurosyphilis
13
Reprinted from Rac et al .
CNS, central nervous system.
Eppes. Syphilis in pregnancy. Am J Obstet Gynecol 2022.
occur as early in the pregnancy as
possible.
Benzathine penicillin G (BPG) is the
only recommended treatment for syph-
ilis during pregnancy. It is 98.7% effec-
tive in treating maternal infection and
preventing CS.33 Alternative antimicro-
bials exist that are active against T pal-
lidum and used in nonpregnant patients,
such as ceftriaxone, doxycycline, tetra-
cycline, azithromycin, erythromycin,
and amoxicillin. However, evidence in
pregnant patients is insufficient to
recommend their use. In fact, no treat-
ment trials exist in pregnancy that
directly compare alternative antimicro-
bials with BPG. This lack of high-quality
evidence can be problematic in areas of
the world where supply of BPG is
compromised and alternative antimi-
crobials are the only available treatment
option. In these instances, the use of
alternative treatments has been associ-
ated with higher rates of CS.33
But there may be promise on the ho-
rizon. Cefixime is a third-generation
cephalosporin that is administered
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Clinical findings
Chancre lymphadenopathy
Rash (Figure 3, A)
Patchy alopecia
Condyloma lata (Figure 3, B)
Mucous patches
Generalized symptoms
Parenchymal effects (less common)
Granulomatous lesions
Cardiovascular
CNS
Opthalmologic
orally, crosses the placenta, and is active
against T pallidum with a low side-effect
profile.35,36 In a randomized, open-label,
noncomparative pilot study of cefixime
vs BPG as a treatment for early syphilis in
men and nonpregnant women, Stafylis
et al35 found that 87% of patients who
received cefixime were successfully
treated, with a 4-fold decline in RPR ti-
ters by 6 months. Taylor et al36 are
currently conducting a phase II trial
evaluating the efficacy of cefixime in
nonpregnant women with RPR titers
>1:16 that, if favorable, could serve as
guidance for similar trials in pregnancy.
Until more data becomes available, the
use of alternative antimicrobials during
pregnancy is not recommended. BPG
supply should be prioritized to pregnant
patients. If a pregnant patient is allergic
to penicillin, it is recommended that she
undergo penicillin desensitization to
safely receive treatment with BPG ac-
cording to her clinical stage. Oral
desensitization protocols are available
for review, but we recommend that
desensitization of the infected gravida be
DECEMBER 2022 American Journal of Obstetrics & Gynecology
Expert Reviews
Location/characterization
Distributed widely, commonly involving palms and
soles.Macular, papular, papulosquamous, pustular,
and nonpruritic
Scalp hair or eyebrows
Warm/moist intertriginous areas such as vulva, inner
thighs, axillae, perineum, skin under breasts
Mouth, throat, or genital areas
Fever, sore throat, weight loss, malaise, anorexia,
meningismus
Hepatitis, gastrointestinal symptoms, nephrotic
syndrome, arthritis, periostitis, optic neuritis
Skin, mucous membranes, skeleton
Typically aortic lesions
Cognitive dysfunction, motor or sensory deficits,
auditory symptoms, cranial nerve palsies, meningitis,
stroke, tabes dorsalis (syphilitic myelopathy)
Uveitis, retinitis, optic neuritis, Argyll Robertson pupils
performed in collaboration with an al-
lergy specialist.37
Treatment of syphilis is administered
according to the clinical stage of disease
(Table 3, Figure 4). The acceptable in-
terval between multiple doses is un-
known. Currently, the CDC
recommends that multiple doses of BPG
be administered within 9 days, and if this
is not achieved, the entire treatment
regimen should be restarted.7,39 Some
experts suggest a second dose of BPG be
administered (within 9 days) in early
syphilis. This is somewhat controversial
given the worldwide shortage of BPG,
and no randomized controlled trial has
been performed that establishes superi-
ority of 2 doses relative to a single dose of
BPG for early syphilis. However, theo-
retical advantages exist. Studies in preg-
nant patients near term receiving BPG
for group B streptococcal prophylaxis
showed that 4.8 million units main-
tained treponemocidal levels (defined as
a serum concentration 0.018 ug/mL)
for 100 days in most patients.39 This was
compared with similar patients who
827
Expert Reviews ajog.org

second dose in early syphilis theoretically

TABLE 2 advantageous.
Summary estimates of adverse pregnancy outcomes in untreated After complete treatment, non-
maternal syphilis treponemal titers should be followed to
Qin et al (2014)33 Summary estimate (95% CI) ensure a 4-fold decline (for example,
All adverse pregnancy outcomes 76.8% (68.8e83.2) NNT 1:64/1:16). The amount of time
allowed to achieve this 4-fold decline in
Congenital syphilis 36.0% (28.0e44.9)
nontreponemal titers differs according
Preterm birth 23.2% (18.1e29.3) to the initial stage of syphilis. The CDC
Low birthweight 23.4% (12.8e38.6) suggests the following amount of time
Miscarriage 14.9% (11.4e19.4) per stage of syphilis to observe a 4-fold
decline:
Stillbirth or fetal loss 26.4% (21.9e31.4)
Neonatal death 16.2% (10.1e25.1)  Early syphilis: 6 to 12 months
Gomez et al (2013)31  Late syphilis or unknown duration:
All adverse pregnancy outcomes 66.5% (58.0e74.1) up to 24 months
 HIV positivity: up to 24 months
Clinical evidence of syphilis 15.5% (7.5e29.0)
regardless of stage of syphilis
Prematurity or low birthweight 12.1% (3.9e31.8)
Stillbirth and fetal loss 25.6% (18.5e34.2) If a 4-fold decline is not observed after
Neonatal death 12.3% (9.3e16.2)
these time frames, then treatment failure
33 31
or reinfection must be considered.
Adapted from Qin et al, and Gomez et al.
Studies looking at titer decline after
CI, confidence interval.
syphilotherapy during pregnancy are
Eppes. Syphilis in pregnancy. Am J Obstet Gynecol 2022.
lacking but stress the importance of
treatment timing. Rac et al41 reviewed
the charts of 166 women treated for
syphilis during pregnancy. They found
received only 1 dose of BPG, with only occur.5,13,41 This, in addition to the that titers declined across all stages of
36% of them maintaining treponemo- physiological changes of pregnancy that syphilis, most rapidly after primary and
cidal levels at 7 days postinjection.40 increase drug elimination and lower secondary syphilis. However, only 66
These data are important to consider effective drug concentration (including (38%) gravidas achieved a 4-fold decline
because we know that spirochetemia is increase in glomerular filtration rates, in NTTs before delivery, and those that
highest during the early stages of syphilis cardiac output, and circulating blood did not achieve such decline tended to be
when treatment failure is more likely to volume), makes the consideration of a older, have latent syphilis, and be treated
later in pregnancy. On average, women
who did not achieve a 4-fold NTT
decline by delivery had less time between
TABLE 3 treatment and delivery (P<.001), with
Treatment of syphilis during pregnancy7 22% of patients delivering <4 weeks af-
Stage of syphilis Treatment ter treatment. Despite this, pregnancy
outcomes, including rates of CS, were
Primary syphilis BPG 2.4 million units IM once
similar between the groups. Thus,
Secondary syphilis achieving an adequate titer decline by
Early latent syphilis Expert opinion recommends a second dose of BPG delivery is more a reflection of treatment
of 2.4 million units IM, 1 week after the initial dose timing rather than an indication of
(total of 4.8 million units) treatment adequacy.41 It is important to
Late latent syphilis BPG of 7.2 million units total, given as 3 doses of note that patients with a pretreatment
2.4 million units IM, each at 1-week intervalsa NTT titer <1:8 may not achieve a 4-fold
Syphilis of unknown duration
decline despite adequate allowed time.
Reinfection
In this case, investigating the correlation
Adapted from Workkowski et al.38
with clinical history and physical exam-
BPG, benzathine penicillin G; IM, intramuscularly.
ination is recommended to determine if
a
An interval of >9 days between doses is unacceptable during pregnancy, and if present the treatment regimen should be
restarted. retreatment is indicated.
Eppes. Syphilis in pregnancy. Am J Obstet Gynecol 2022. It is our practice to check NTT titers
every 4 weeks in patients who have

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ajog.org Expert Reviews

FIGURE 4
Management algorithm for patients with positive treponemal and nontreponemal antibodies

Perform history and

physical examinaon

History of syphilis No history of syphilis

Treatment history
Treatment history Physicial exam with
indicates inadequate Physicial exam
indicates previously signs/sx syphilis*
treatment or no negave (latent)
treated adequately
previous treatment

Physical exam posive Physical exam posive

Physical exam Physical exam
with signs/sx syphilis* with signs/symptoms
negave negave (latent)
of syphilis*

Treat with benzathine penicillin

G for likely reinfecon with Likely serofast and no
primary, secondary, or terary treatment needed.
syphilis. Consider checking RPR
every 4 weeks
throughout
pregnancy.
If early latent: 1–2 Treat with benzathine If early Treat with
doses of benzathine penicillin G for likely latent: 1–2 benzathine
penicillin G. If reinfecon with doses of penicillin G for
unknown duraon or primary, secondary, or benzathine primary, secondary
late latent: 3 doses of terary syphilis. penicillin G. If or terary syphilis.
benzathine penicillin unknown
G duraon or
late latent: 3
doses of
benzathine
penicillin G.

The asterisk represents that if at any point in the evaluation, clinical evidence of neurologic infection is observed, a cerebrospinal fluid examination to rule
out neurosyphilis should be considered.
RPR, rapid plasma reagin.
Eppes. Syphilis in pregnancy. Am J Obstet Gynecol 2022.

undergone treatment or are deemed
serofast. Frequent testing of NTT titers
allows early identification of inappro-
priate NTT titer decline, such as NTT
titer plateau or slowly rising titers, even
without a 4-fold rise (defined as a
clinically significant NTT titer rise),
and thus earlier evaluation and
retreatment if deemed clinically
appropriate. It is true that there is no
evidence to prove that this approach is
superior to checking titers at the
appropriate follow-up mark defined by
the CDC per above criteria. However,
evidence suggests that acquired immu-
nity from previous syphilis infection
can blunt the presentation and course
of reinfection. Studies in nonpregnant
patients have shown lower bacterial and
cerebrospinal fluid syphilis burden in
patients with repeated episodes of
syphilis, and these patients were less
likely to manifest symptoms. Thus, in
high-risk populations, frequent testing
of NTT titers may provide more data to
aid in the detection of asymptomatic
reinfection.31

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Expert Reviews
Effective clinical management of
gravidas with syphilis requires treatment
of their sexual partner to prevent rein-
fection and adverse pregnancy out-
comes. Partner treatment was a central
concept in the original implementation
efforts to prevent and eradicate syphilis
in the 1940s. Unfortunately, rates of
partner treatment are disappointingly
low. One study from Uganda40 reported
only a 18.3% rate of partner treatment
during pregnancy. There are no studies
from the United States addressing the
rate of partner treatment for syphilis
during pregnancy. Partner notification
of most sexually transmitted infections
(STIs) is often done by the infected
pregnant patient. This can be hampered
by limited knowledge about the STIs,
fear of domestic violence, lack of
communication, and stigma associated
with certain STIs. An added challenge
with syphilis is that, because BPG is an
intramuscular injection, a face-to-face
assessment is often needed for treat-
ment. Therefore, the partner must pre-
sent for treatment to ultimately receive
it. Studies evaluating ways to improve
partner engagement have been mixed. In
the same Ugandan study,40 text
messaging and/or telephone call notifi-
cation to partners did not improve
partner treatment rates. Another study
from Mongolia42 found that rapid
syphilis testing with same-day treatment
increased partner treatment during
pregnancy to 94.6% vs 55.2% with
standard off-site testing, and reduced the
rate of CS by 93.5%. More studies are
needed, particularly in higher-resourced
countries, to improve partner engage-
ment in care and syphilis treatment
during pregnancy.
JarischeHerxheimer reaction
The JarischeHerxheimer (JH) reaction is
an acute systemic reaction that can occur
during treatment for syphilis. This reac-
tion results from the rapid killing of spi-
rochetes, causing release of copious
amounts of endotoxins, lipopolysaccha-
rides, prostaglandins, and cytokines,
leading to an acute inflammatory
response.43e45 Reported symptoms of the
JH reaction include worsening of skin
lesions (if present), temperature
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elevation, chills, tachycardia, arthralgias,
pharyngitis, headaches, and leukocytosis.
The JH reaction is more likely to occur
in early syphilis than in late syphilis.
Rates of the JH reaction in nonpregnant
patients are reported to be 95% to 100%
in primary syphilis, 60% to 95% in sec-
ondary syphilis, 50% in syphilis of un-
known duration, 12% to 75% in
neurosyphilis, and rarely in late
syphilis.22,46e49 Clinical manifestations
appear 2 to 8 hours after treatment
initiation and abate by 24 hours.49
Treatment is supportive. The use of
corticosteroids has not been shown to
prevent the JH reaction, and thus is not
recommended. Furthermore, incre-
mental dosing of BPG does not mitigate
the JH reaction.50
Evidence is limited regarding the JH
reaction during pregnancy. Two studies
(total N¼83) have reported on the
incidence and clinical manifestations of
the JH reaction during pregnancy. In
both studies, the JH reaction was re-
ported in 40% to 45% of gravidas un-
dergoing treatment. When broken down
by stages, the JH reaction occurred most
frequently following treatment of pri-
mary and secondary syphilis and syphilis
of unknown duration (50%e100%) vs
after treatment for late latent syphilis,
when no cases were reported. The
symptomatology of the JH reaction
during pregnancy was the same as that of
the nonpregnant population. In addi-
tion, preterm contractions, fetal heart
rate changes (tachycardia and/or de-
celerations), and decreased fetal move-
ment also occurred.22,47 In severely
infected pregnancies such as those with
abnormalities seen with ultrasound,
these changes may progress to preterm
labor or even stillbirth.51e57 For this
reason, it is our practice for viable
pregnancies to administer the first dose
of BPG during labor and delivery under
continuous fetal monitoring for at least
24 hours. All subsequent doses (if
needed) are given in an outpatient
setting. If the JH reaction is observed,
supportive care and intrauterine resus-
citation are initiated. The decision to
deliver should be individualized and
based on gestational age and response to
intrauterine resuscitation. If inpatient
ajog.org
monitoring during the first dose of
syphilotherapy is not feasible, the patient
should be informed of the JH reaction
symptomatology and told to present to
the hospital if decreased fetal movement,
fevers, or preterm labor symptoms are
experienced.
Ultrasound findings of fetal syphilis
Vertical infection occurs in all stages of
syphilis and across all trimesters, with
the highest risk observed in early syphilis
(w50%) compared with latent disease
(w35%).79,53e57 Although T pallidum
has been isolated from fetal tissue as
early as at 9 weeks of gestation,54,55
sonographic evidence of infection
cannot be detected until after 20 weeks
of pregnancy, when the fetal immune
system is able to generate the robust
immune-mediated injury responsible
for the observed ultrasound abnormal-
ities. Transmission of syphilis in utero
starts with placental infection, followed
by widespread dissemination to virtually
every organ system. The most common
ultrasound abnormalities reported, in
decreasing frequency, include hepato-
megaly (80%), fetal anemia as evident by
an elevated peak systolic velocity of the
middle cerebral artery (MCA) (33%),
placentomegaly (27%), polyhydramnios
(12%), and ascites and fetal hydrops
(10%).58 Splenomegaly and car-
diomegaly have also been reported,
albeit less commonly. Two publica-
tions7,39 have elucidated the complete
pathophysiology of fetal infection. Fetal
syphilis is a cumulative continuum
characterized by early placental infection
followed by amniotic fluid infection,
hematologic dysfunction, ascites, and
lastly IgM production. After treatment,
findings of late fetal syphilis (MCA
Doppler abnormalities and hydrops)
resolve first, and findings thought to
occur early, such as placentomegaly and
hepatomegaly, persist the longest
(Figure 4).55,58
Performing a pretreatment compre-
hensive ultrasound in all women at >20
weeks of gestation who are diagnosed
with syphilis should be considered. Fe-
tuses with detectable ultrasound stig-
mata of syphilis are considered severely
infected and at higher risk of the JH
ajog.org
reaction, preterm labor, fetal heart rate
decelerations, intrauterine fetal demise,
and treatment failure. These possibilities
should be included in patient
counseling.47,54,55,60,61
It is our practice to document the
following during the comprehensive
ultrasound:
 Liver length (Tables 4 and 5)
 Placental thickness (Table 4,
Figure 6)
 Peak systolic velocity of the MCA
(Tables 4 and 6)
 Evaluation for ascites or hydrops
(Figure 5, Table 4)
Suggested nomograms and definitions
of normal values are shown in Figure 6
and Tables 4 and 6. In our practice, the
presence of abnormal ultrasound findings
prompts serial sonography until resolu-
tion or delivery. Persistence of abnor-
malities and expected resolution sequence
should be communicated to neonatology
and incorporated into the evaluation of
the newborn. The sensitivity of ultra-
sound to detect symptomatic congenital
infection at delivery is limited and de-
pends on clinical suspicion, provider
experience, and inherent limitations of
ultrasound technology. One study re-
ported a 12% rate of CS at delivery in 162
fetuses who had no sonographic stigmata
of congenital infection during pretreat-
ment ultrasound.56 It is important to
remember that certain stigmata of fetal
syphilis, such as osseous lesions or
rhinitis, are not visible on prenatal
ultrasound.
Other risk factors for fetal treatment
failure include nontreponemal titers
1:32 and treatment in the third
trimester or
28 days before delivery.37
Congenital syphilis
CS at birth mostly results from maternal
intrapartum infection; however, rarely
exposure to maternal genital lesions dur-
ing delivery may result in newborn
infection. Infection of syphilis in the fetus
or neonate is uniquely aggressive relative
to other perinatal infections, with activa-
tion of inflammation involving multiple
organ systems, leading to profound organ
damage and resultant neonatal
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TABLE 4
Suggested nomograms for sonographic markers of fetal syphilis
(AJOG 2016)
Structure/component
Liver length
Placental thickness
MCA Dopplers
Evaluation for ascites or
gross hydrops
EGA, estimated gestational age; MCA, middle cerebral artery; MoM, multiples of the median; SMFM, Society for Maternal-Fetal
Medicine.
Eppes. Syphilis in pregnancy. Am J Obstet Gynecol 2022.
complications. In addition to a 30% to
40% stillbirth risk, newborns of infected
mothers are often born preterm or with
low birthweight (10%e40%).18,62 Fetuses
exposed in utero often have significant
hematologic abnormalities, hepatobiliary
dysfunction (33%e100%), blistering
skin rashes (40%), and potential neuro-
logic and orthopedic sequelae (75%), all
of which result in prolonged neonatal
intensive care unit stay, with significant
morbidity and adverse long-term
outcomes.18e20,47,62e64 The most
serious complication is CNS involve-
ment, which occurs in up to 40% of
newborns with symptomatic CS. When
chronic, CNS involvement can result in
neurodevelopmental (ND) delay and
seizures. Detailed data on the long-
term ND outcomes of newborns
exposed to maternal syphilis are lack-
ing. Future studies should focus on
long-term follow-up of exposed neo-
nates to determine best-practice sur-
veillance and early interventions.
Diagnostic criteria and treatment for
congenital syphilis
The algorithm for the diagnosis of CS at
birth relies on a complicated amalgam of
factors:
1. Change in newborn NTTs relative
to maternal titers
2. Maternal treatment status
(adequately treated, suboptimally
treated, untreated)
Expert Reviews
Nomogram for
reference Definition of abnormal
Vintzileos et al 91
Hepatomegaly defined as a liver length >95th
percentile for EGA
Hoddick et al95, Placental thickness that exceeds 2 standard
1985 deviations for EGA
Mari et al94 MCA >1.5 MoM
Norton SMFM Ascites: free fluid within the fetal abdominal
2014 cavity
Hydrops: 2 cavities with abnormal fluid
collections
3. Duration of maternal treatment
(< or > 28 days before birth)
4. Newborn signs and symptoms
5. Placental pathologic evaluation
Current neonatal treatment algo-
rithms are complex, and can result in
delayed or missed diagnosis of CS in the
asymptomatic newborn with equivocal
nontreponemal titers.17,21 One of the key
challenges in adequate diagnosis and
treatment is the high rate of asymp-
tomatic CS at birth, estimated to be as
high as 60%.13,16,28,29,43 According to
published surveillance data from the
CDC, the current newborn algorithm
fails to detect CS in 5% to 10% of
exposed newborns, illustrating the
challenges of identifying true infection
when a fetus is at risk.3,16
Regardless of treatment strategies
used at birth, current CDC guidelines
still require follow-up of the exposed
newborn every 2 to 3 months for up to
18 months to conclusively determine
infection status by nontreponemal eval-
uations and exams, adding to the public
health burden.13,17 Loss-to-follow-up
rates have been estimated at 70% in
published data, increasing the risk of
missed or delayed diagnosis and excess
neonatal morbidity.13,17 If congenital
infection remains undetected, up to 40%
of neonates will develop stigmata of late
CS, such as Hutchinson’s teeth, intersti-
tial keratitis, eighth-nerve deafness,
DECEMBER 2022 American Journal of Obstetrics & Gynecology 831
Expert Reviews ajog.org

use has been noted, primarily related to

TABLE 5 synthetic opioids (fentanyl). Opioid-
Nomograms for liver length (Vintzileos et al). Ultrasound measurements related deaths have increased by 38.4%
in mean length (–SD) of fetal liver length in 221 normal pregnancies from in the 12 months leading up to May
20 weeks until term 2020.71 As mentioned previously, an as-
Gestational age sociation exists between methamphet-
(wk) Number of measurements Arithmetic mean (mm) –2 SD (mm) amine and opioid use and CS rates.
20 8 27.3 6.4 Therefore, further increase in synthetic
21 2 28.0 1.5 opioid use will most likely negatively
affect the rates of primary and secondary
22 4 30.6 6.7
syphilis in women, and ultimately
23 13 30.9 4.5 worsen the rates of CS.
24 10 32.9 6.7
25 14 33.6 5.3
Social determinants of health and
26 10 35.7 6.3 access-to-care barriers
27 20 36.6 3.3 Timeliness of prenatal care is a consis-
28 14 38.4 4.0 tent area of opportunity identified in
many cases of CS. Pregnant persons face
29 13 39.1 5.0
many barriers in accessing care, often
30 10 38.7 5.0 related to social determinants of health,
31 13 39.6 5.7 such as transportation, housing, and
32 11 42.7 7.5 childcare. A 2018 review of cases in
Indiana looked at 23 consecutive cases
33 14 43.8 6.6
from 2013 to 2017, including qualitative
34 11 44.8 7.1 analyses and maternal interviews that
35 14 47.8 9.1 explored social vulnerability factors such
36 10 49.0 8.4
as poverty, violence, inequality, trans-
portation, medical insurance, and
37 10 52.0 6.8 housing.72 Notably, 21 of the 23 patients
38 12 52.9 4.2 had health insurance (86% Medicaid or
39 5 55.4 6.7 Affordable Care Act Marketplace plan),
but >34.7% (n¼8) had no prenatal care.
40 1 59.0
In those with prenatal care, a median of 4
41 2 49.3 2.4 visits was reported. The most common
Adapted from Vintzileos et al.91 risk factors noted included social
SD, standard deviation. vulnerability, lack of engagement in
Eppes. Syphilis in pregnancy. Am J Obstet Gynecol 2022. healthcare, and having a male sex part-
ner. As an example, of the cases with CS,
6 pregnant persons were homeless at the
time of their syphilis diagnosis, and 3
had an “unstable” living scenario. Eight
other cosmetic manifestations, and ND programs have added COVID-19 mothers reported that they or their
delays, all of which are irreversible with tracking efforts to their prioritized partner were incarcerated. Furthermore,
antibiotic treatment.46,65e67 STD-HIV caseloads. This has resulted in women in this study reported that they
significant delays in STD surveillance found it difficult to carry out physician-
Pandemic-related effects on syphilis response, reportedly for up to several ordered off-site syphilis testing because
in pregnancy weeks, even for perinatal syphilis.22,68e70 of “issues such as transportation, cost,
During the COVID-19 pandemic, the Undoubtedly, a reduction in federal and employment conflicts, or competing
focus was understandably on reducing state STD prevention workforce efforts family responsibilities.”
spread, which led to a decrease in pa- has contributed to the rising rates of Strategies to reduce perinatal and CS
tients attending public sexual and infectious diseases like syphilis, which that include improvements in timeli-
reproductive health visits.22,68 According remains largely dependent on longitu- ness of testing or treatment of positive
to published data from the National dinal surveillance.16,22,23,70 results will need to include in-
Coalition of STD directors, 98% of Finally, during the COVID-19 terventions to address the barriers
sexually transmitted disease (STD) pandemic, a further increase in opioid involved in access to care.

832 American Journal of Obstetrics & Gynecology DECEMBER 2022

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ajog.org
Overcoming challenges to
elimination
Why is CS still a threat to pregnant
women in 2022? What follows is a dis-
cussion of the most pressing clinical
challenges and areas of opportunity that
we believe deserve immediate attention
and can be impactful in effecting change.
These areas of opportunity include:
1. Aligning syphilis management
across state lines
2. Improving provider knowledge
and access to syphilis experts
3. Improving public advocacy, visi-
bility, and representation
4. Increasing the availability of diag-
nostic tests
5. Addressing healthcare disparities
related to race and geography
6. Addressing social determinants of
health-related barriers to access to
timely prenatal care
Table 7 summarizes these
recommendations.
Aligning syphilis management across
state lines
The CDC recommends that “all women
should be screened serologically for
syphilis early in pregnancy.” However,
the legal mandate remains in control of
individual states (CDC STD). Eight
states (IA, MN, MS, NH, ND, WI, HI,
ME) do not require screening for syphilis
during pregnancy. Of these, Mississippi
had one of the highest rates of primary
and secondary syphilis cases in 2020, and
all the 8 states except Maine reported CS
cases in 2020.73 Lack of standardized
screening during pregnancy is also a
problem worldwide. In a review of
syphilis guidelines from 128 World
Health Organization (WHO) member
countries, Trinh et al74 found wide var-
iations in screening and treatment rec-
ommendations during pregnancy. First,
only 66% of WHO countries had
guidelines to review. Of those countries,
92% recommended universal screening
during pregnancy consistent with WHO
recommendations, and 95% recom-
mended BPG as first-line therapy.
However, 10% recommended a single
injection of BPG regardless of stage of
syphilis, a regimen that will undertreat
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FIGURE 5
Natural history of fetal syphilis before and after maternal treatment
Eppes. Syphilis in pregnancy. Am J Obstet Gynecol 2022.
most infected gravidas encountered in
clinical practice.58 Furthermore, 68% of
guidelines allowed alternative treat-
ments, and >50% of these did not spe-
cifically state the limitations of using
such alternative treatments during
pregnancy, namely the risk of fetal
treatment failures.74
One area that is particularly chal-
lenging is differentiating adequately
treated past infection from untreated
latent syphilis. This is particularly salient
in institutions that use the reverse algo-
rithm. As stated above, the reverse al-
gorithm initiates screening with
treponemal-specific antibodies, which
remain positive for life. Adequately
treated patients, who would otherwise
screen negative with the traditional al-
gorithm, screen positive with the reverse
algorithm. Although we advocate for
incorporation of local health depart-
ment data that can provide previous
nontreponemal titers and treatment
history, these data rely on provider and
institutional reporting, and as a result are
often incomplete. Furthermore, no na-
tional database is available, limiting the
utility of this service to within state lines.
Lessons can be learned from the national
response to increasing opioid abuse and
the development of prescription moni-
toring programs. These programs are
statewide electronic databases, accessible
to providers, that track all controlled
DECEMBER 2022 American Journal of Obstetrics & Gynecology
Expert Reviews
substances prescribed to a particular
patient. The use of these databases has
improved opioid prescribing practices
and lowered opioid overdoses.75,76
Standardization of medical care based
on best evidence is a well-known quality
initiative that improves outcomes and
lowers mortality.77,78 The lack of stan-
dardized policies and the inadequacy of
policies in some states result in missed
opportunities to identify infection in the
mother and provide appropriate and
timely antenatal treatment, contributing
to the ongoing rise in CS cases. We
consider that the development of federal
mandates for syphilis screening and
treatment during pregnancy are neces-
sary to identify all infected gravidas and
eliminate CS. In addition, the creation of
a database directly accessible to health-
care providers, preferably through a na-
tional data-sharing platform, would also
improve access to important diagnostic
information.
Improving provider knowledge and
access to syphilis experts
In the case of syphilis, being an ancient
disease does not equate to being an
obsolete disease. There are areas of the
United States where syphilis during
pregnancy may still be relatively un-
common, which can lead to clinical un-
familiarity and missed opportunities. As
stated previously, interpretation of
833
Expert Reviews ajog.org

community providers who may be un-

TABLE 6
Nomograms for expected peak systolic velocities of middle cerebral
artery according to gestational age, including median and multiples of
the median (MoM). Fetal anemia is suspected with peak systolic velocity
measures >1.5 MoM (Mari et al)
Week of gestation
18
20
22
24
26
28
30
32
34
36
38
40
94
Adapted from Mari et al.
Eppes. Syphilis in pregnancy. Am J Obstet Gynecol 2022.
syphilis serologic test results can be
challenging. Furthermore, many pro-
viders in practice today were taught the
traditional algorithm during their
training but now use the reverse algo-
rithm in clinical practice. Experts in the
diagnosis and management of syphilis
exist, but immediate access to these ex-
perts is limited. The structure of health
systems has been studied in an effort to
provide more “expert-level” care,
including centralized care of gravidas
with syphilis. This structure requires
referring a patient who screens positive
for syphilis to a syphilis expert or infec-
tious disease clinic where staging, treat-
ment, and follow-up are undertaken
with the aim of improved quality of care.
Although this health structure has been
successful in some medical institutions
such as centers of excellence for placenta
accreta spectrum disorders or fetal sur-
gery centers, the results of centralized
care of gravidas with syphilis are often
disappointing. Experience from Nairobi,
Kenya provides insight into the chal-
lenges of a centralized syphilis screening
program. Before 1992, women were
familiar with the appropriate manage-
ment of syphilis during pregnancy.
Another option is to bring expert care
to the bedside. This can be accom-
plished by creation of a national hotline
Multiples of the median staffed by specialists in syphilis care,
1.00 (median) 1.29 1.5 1.55 similar to what is available with HIV,
23.2 29.9 34.8 36.0
malaria, tuberculosis, and other infec-
tious disease management processes.
25.5 32.8 38.2 39.5 We consider that the combination of
27.9 36.0 41.9 43.3 improved community outreach and
30.7 39.5 46.0 47.5 creation of a national syphilis provider
hotline would help to improve provider
33.6 43.4 50.4 52.1
access to evidence- and experience-
36.9 47.6 55.4 57.2 based recommendations.
40.5 52.2 60.7 62.8
44.4 57.3 66.6 68.9 Improving public advocacy, visibility,
and representation
48.7 62.9 73.1 75.6
Advocacy and representation are needed
53.5 69.0 80.2 82.9 to change public perceptions of syphilis.
58.7 75.7 88.0 91.0 The stigma and shame associated with
64.4 83.0 96.6 99.8
syphilis often cause patients to remain
silent, preventing them from seeking
knowledge that facilitates self-advocacy
and protection. For many other in-
fections with similar perinatal morbidity
and mortality, national and global ini-
screened at their first prenatal visit and tiatives directed at wide dissemination of
samples sent to a centralized laboratory. information through education and
Results would return to the patient after visibility have been very effective in
2 to 4 weeks, after which positive pa- changing public perceptions and
tients would be referred to an STD reducing disease burden. For example,
referral clinic for subsequent manage- after the development of the hepatitis B
ment. Consequently, only 9.1% of RPR- vaccine in 1982, robust national efforts
positive patients received adequate were launched to reduce perinatal
treatment. After decentralizing syphilis transmission. With the support of the
screening and treatment to community federal government, the CDC, and other
prenatal clinics, 87.3% of RPR-positive medical organizations, prevention pro-
gravidas received timely treatment, as grams based on identification of infected
did 50% of their partners. Furthermore, mothers with subsequent vaccination of
this model was cost-effective relative to newborns and timely Ig administration
centralized care, theoretically prevent- successfully reduced hepatitis B trans-
ing 413 cases of CS.79 Although mission rates by >90%.80 In Harris
healthcare delivery systems differ be- County, Texas, similar public health
tween the United States and Nairobi, outreach programs have essentially
Kenya, similar socioeconomic chal- eliminated perinatal transmission of
lenges exist that affect follow-up among hepatitis B over the past 5 years. Pre-
infected gravidas. So how can we vention of perinatal HIV transmission is
improve access to “experts” in syphilis an even greater success story. The public
without delaying appropriate manage- health campaign to raise awareness of
ment? One option is to improve HIV, which included famous musicians,
dissemination of evidence-based artists, and other celebrities who openly
guidelines through outreach programs, talked about living with HIV/AIDS,
grand rounds, and continuing medical proved highly effective in disseminating
education requirements among information and bringing awareness

834 American Journal of Obstetrics & Gynecology DECEMBER 2022

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ajog.org Expert Reviews

about the disease to the public. The HIV

FIGURE 6
Champions of Change initiative
addressed the stigma and discrimination
Nomograms for placental thickness in 200 placentas from 9 weeks until
once surrounding this infection, and
term (Hoddick et al)95
through activism, media, and public
outreach, opinions and policy changed.
With federally mandated programs for
maternal testing, antiviral therapy, and
postnatal surveillance of infected women
and newborns, perinatal HIV trans-
mission declined by >90% after 1994,
with current rates of transmission as low
as 1% (HIV statistics from the CDC).
According to CDC surveillance data, 35
US children were diagnosed with peri-
natally acquired HIV in 2019.81 By
contrast, 1870 infants were diagnosed
with CS in 2019 in the United States.2
With limited public health campaigns
and few champions to advocate for the
disadvantaged populations predomi-
nantly affected, syphilis remains a
problem for mothers and infants. This
disease warrants legislation and social
support, starting with support for over-
burdened health departments and
extending to community outreach pro-
grams to educate clinicians on the front
lines, who may be confused by testing
guidelines and treatment recommenda-
tions. CS needs a strong public voice,
robust media coverage, and activism by
patient advocacy groups, community Adapted from Hoddick et al.95
leaders, state and local public health or- Eppes. Syphilis in pregnancy. Am J Obstet Gynecol 2022.
ganizations, professional societies, and
policy makers to change the public
perception and affect positive change.

Development of a clinically useful
diagnostic test
Given the limitations of the current
testing algorithms and poor longitudinal
follow-up of exposed neonates, the
development of a rapid, highly sensitive
diagnostic test is paramount to ensure
adequate identification of syphilis,
timely treatment, and complete elimi-
nation of CS.
Nucleic acid amplification testing
(NAAT) is a relatively new testing plat-
form used to diagnose agents that are
difficult to culture (including T pal-
lidum). Five different types of NAAT
have been evaluated, including routine
PCR, nested PCR, real-time PCR, reverse
TABLE 7
Suggested recommendations to improve management of syphilis during
pregnancy
Recommendations to improve identification and prevention of CS
1. Develop national mandates for syphilis screening and treatment during pregnancy
2. Improve access to expert-level care by creating a national provider hotline
3. Expand access of syphilis databases
4. Develop better neonatal diagnostic tests
5. Increase public advocacy, visibility, and awareness
6. Prioritize community outreach and continuing education to frontline providers
7. Target interventions to reduce racial, ethnic, and geographic disparities in CS
8. Address SDoH barriers to care and integrate these into prenatal care models
CS, congenital syphilis; SDoH, social determinants of health.
Eppes. Syphilis in pregnancy. Am J Obstet Gynecol 2022.

DECEMBER 2022 American Journal of Obstetrics & Gynecology 835

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Expert Reviews
transcriptase PCR, and loop-mediated
isothermal amplification assay.82e85
There are several T pallidumespecific
target genes for NAAT, including polA,
tpp47, bmp, 16S rRNA, tmpC, and
tmpA.83e86 The challenge that remains
with NAAT, and the reason why it has
not been more widely adopted, is that
the sensitivity and specificity vary
depending on the method used and the
stage of syphilis. Sensitivity and speci-
ficity of NAATare highest in primary and
secondary syphilis (89%e100%)
because a sample can be obtained from
the primary chancre or condyloma lata,
both of which contain high levels of
spirochetes, which improves detection.
Evaluation of blood, saliva, and urine
from patients with latent disease has
lower sensitivity and specificity. Stafford
et al87 assessed the performance of real-
time PCR in 6 mothereinfant dyads
exposed to syphilis. Whole blood and
serum were collected from all dyads at
birth. PCR results were compared with
syphilis diagnoses established according
to current CDC guidelines, including
longitudinal surveillance of the neonate.
The authors found that real-time PCR
was equally predictive of the final diag-
nosis based on the CDC-recommended
follow-up. Further development and
validation of PCR testing for the diag-
nosis of syphilis should be prioritized
given the potential for equivalent diag-
nostic performance but without the need
for longitudinal follow-up.
Rapid testing allows onsite testing,
improving timing and access to adequate
treatment. The Syphilis Health Check is
the only test approved by the US Food
and Drug Administration for use in the
United States, cleared in 2011 and
waived by Clinical Laboratory Improve-
ment Amendments (CLIA) in December
2014. The test is a qualitative rapid
membrane immunochromatographic
test that can detect antibodies to T pal-
lidum by fingerstick of whole blood,
serum, or plasma in approximately 10
minutes.20 However, the challenges of
this testing modality include that, as
other TTs, a nonreactive test cannot rule
out an infection acquired within the
preceding few months, thus potentially
missing primary or secondary syphilis,
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which have the highest rates of causing
fetal or CS. Because it is an antibody test,
a reactive result requires additional
testing using a nontreponemal test, and a
positive test may also indicate previous
infection.88
Addressing healthcare disparities
related to race and ethnicity,
geography, and social determinants of
health
As stated by the Institute of Medicine
with regard to “crossing the quality
chasm,” an essential pillar of quality care
is equity.89 Stated differently, we cannot
have quality without equity. Thus, given
the known racial and ethnic and
geographic disparities, it is essential that
communities, healthcare systems, and
public health departments use recog-
nized tools to improve equity, including
disaggregation of data on these in-
equities, respectful care models,
addressing implicit bias, and targeting
improvements in social determinants of
health.78,90,92,93
Conclusion
In summary, syphilis remains a threat to
maternal and child health despite a
curative treatment and >70 years of
public health surveillance. Elimination
of syphilis is possible but will require a
different approach that acknowledges
both the victories and the systemic fail-
ures over the decades. Only then can we
cultivate a novel approach to syphilis
elimination. -
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