REVIEW

CURRENT
OPINION The continuing threat of syphilis in pregnancy
Heather R. Moline and James F. Smith Jr

Purpose of review
Syphilis in pregnancy continues to be a worldwide threat to mothers and their fetuses, and in recent years
has been increasing in prevalence. The purpose of this short review is to address current issues in the
diagnosis and management of syphilis complicating pregnancies.
Recent findings
Maternal syphilis infections and congenital syphilis appear to be increasing in both high and low
resource settings. Treponema pallidum ssp. pallidum, the causative spirochete of syphilis, remains one
of the few human infectious pathogens that has not been successfully cultured, making identification
difficult and research in targeted antimicrobial therapies challenging. Fortunately, syphilis remains
sensitive to penicillin, which remains the foundational therapy for this infection. Patients with syphilis
and significant penicillin allergies remain a specific challenge in treatment. Of concern is the
emergence of T. pallidum resistant to macrolides such as azithromycin. This will limit options in patients
with penicillin allergies, and potentially contribute to suboptimal treatment. During pregnancy, penicillin
is the only known effective treatment for congenital syphilis, and pregnant patients with penicillin
allergy should be desensitized and treated with penicillin. Research focusing on protein expression of
the genome of T. pallidum may lead to more accurate screening and diagnosis and development of
novel antibiotic therapies.
Summary
Obstetric and pediatric providers, public health organizations, and governments should recognize the
re-emergence of syphilis globally and in their local healthcare environments. Screening of all pregnant
patients with robust treatment and follow-up represents the most effective method to reduce congenital
syphilis currently available.
Keywords
congenital syphilis, pregnancy, Treponema

INTRODUCTION CONGENITAL SYPHILIS

Syphilis, caused by Treponema pallidum ssp. pallidum,
is currently estimated to have infected more than
35 million humans, and annually results in more
than 11 million new cases [1]. It is estimated there
are about 1 million cases of congenital syphilis
worldwide. Furthermore, untreated congenital
syphilis will result in stillbirth or pregnancy loss
in a significant portion of cases [2]. Thus, syphilis
remains a significant contributor to human disease
burden, especially related to fetal and neonatal dis-
ease. Importantly, syphilis is considered endemic in
sub-Saharan Africa and southeast Asia and is now
showing increased rates in both high and low
resource areas around the globe [3]. The present
brief review is intended to reacquaint the reader
with this potentially devastating congenital infec-
tion, given its persistence and re-emergence as a
health threat.
Syphilis is concerning in pregnant women because
of the potentially devastating effects on the fetus.
Syphilis in pregnant women is transmitted to the
fetus via transplacental passage, and has an infec-
tion rate of 25–75% [4]. Paradoxically, the fetal
consequences of transplacental transmission of
syphilis exhibit an inverse relationship with the
length of maternal infection. The longer maternal
Department of Obstetrics and Gynecology, Creighton University School
of Medicine, Omaha, Nebraska, USA
Correspondence to James F. Smith, Jr, MD, MA, FACOG, Professor and
Chair, Department of Obstetrics and Gynecology, Creighton University
School of Medicine, 601 N. 30th Street, Suite 4700, Omaha, NE 68131,
USA. Tel: +1 402 280 4431; fax: +1 402 280 4315;
e-mail: jfsmith@creighton.edu
Curr Opin Obstet Gynecol 2016, 28:101–104
DOI:10.1097/GCO.0000000000000258

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Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Maternal fetal medicine
KEY POINTS
 Congenital syphilis appears to be increasing in both
high and low resource areas globally.
 Screening programs for syphilis appear most effective
when there is robust treatment follow-up.
 Syphilis remains sensitive to penicillin and this is
considered the most effective treatment to prevent
complications of congenital syphilis; for the penicillin-
allergic patient desensitization and treatment with
penicillin should occur.
 Macrolide-resistant syphilis is emerging as a new threat
in many areas of the globe.
infection is present, the less severe the sequelae
for neonate with respect to rate of transmission
and subsequent fetal damage. Recent studies
demonstrate that about 52% of pregnancies in
mothers with either untreated or suboptimally
treated syphilis result in some form of adverse preg-
nancy outcome [5,6]. These adverse outcomes
include early fetal loss or stillbirth (21–40%), neo-
natal death (9–20%), low birth weight, and preterm
delivery (6%). They also included congenital syph-
ilis in liveborns. Congenital syphilis is marked by
nonimmune hydrops fetalis, jaundice, deafness,
hepatosplenomegaly, rhinitis, skin rash, and pseu-
doparalysis of extremities [7].
Congenital syphilis is of increasing concern in
the United States. Although the case fatality rate has
remained stable from 1999 to 2013 [8], the overall
rate of congenital syphilis in the United States is
increasing. Between 2012 and 2014, cases increased
by 38% and the rate of congenital syphilis in the
United States is currently 11.6 cases per 100 000 live
&&
births [9 ]. This is disappointing, as the rate had
steadily declined in the 4 years preceding 2012. The
geographic distribution of cases of congenital syph-
ilis reflects the distribution of the disease across
races. Congenital syphilis rates are 10 and 3 times
higher among infants born to black and Hispanic
mothers (38.2 and 12.2 cases per 100 000 live births,
respectively) compared with white mothers
&&
(3.7 cases per 100 000 live births) [9 ]. At least half
of the cases of congenital syphilis will result in
adverse events if screening and treatment are not
efficiently performed [10].
TESTING FOR SYPHILIS
Testing for syphilis in the prenatal period is
complicated by several factors. T. pallidum has yet
to be successfully cultured [11]. It has complex
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nutritional and environment needs to survive that
have not been replicated in vitro. Therefore, testing
has remained by direct visualization of the spiro-
chete or serologic testing for treponemal and
nontreponemal antibodies. Although detection by
polymerase chain reaction (PCR) is attractive and
possible, this modality is expensive and sensitivity
and specificity vary based on tissue tested and genes
targeted [12]. PCR identification of syphilis has had
limited clinical utility to date.
Serologic testing remains the most common
testing globally but has its drawbacks as well. Non-
treponemal tests such as the rapid plasmin regain
(RPR) test are widely available but are also associated
with increased false-negative rates in primary and
&&
tertiary syphilis [13 ]. Furthermore, diagnosis may
be challenging in women who have previously been
infected with syphilis, have recurrent infection
marked by rising nontreponemal titers, and those
who are ‘serofast’ with persistently positive non-
treponemal titers despite treatment can be especi-
ally challenging [7].
Historically, a nontreponemal test found to be
positive was followed with a treponemal test. New
testing algorithms support ‘reverse testing’ in that
the treponemal test occurs first, then followed by
&&
nontreponemal testing if positive [13 ]. This is
particularly effective in high prevalence areas.
Although this method of testing may lead to an
increase in the number of false-positive results,
reverse testing allows for higher throughput, can
identify patients in all stages of disease, and has a
&&
higher sensitivity in early stages of the disease [13 ].
It may result in faster and more accurate diagnosis
and the potential for expedited treatment of the
mother and fetus [14,15]. The performance of this
strategy is relatively new and continues to be inves-
tigated in different populations at risk. Globally,
countries may vary in their approach to testing
for syphilis based on local resources.
Cost-effectiveness of testing and retesting for
populations at risk of acquiring syphilis during preg-
nancy has also been recently assessed. Using a
decision model, a recent study demonstrated that
retesting during third trimester care was not cost-
effective for populations at low risk for seroconver-
sion during pregnancy [16]. However, for high-risk
populations and for individuals with high-risk
behaviors, testing in the third trimester is reasonable
and becomes cost-effective when seroconversion
rates are 19-fold higher than national averages
for primary and secondary syphilis [16]. Especially
in emerging countries where syphilis is highly
prevalent, screening programs regardless of their
construct must be coordinated with effective treat-
ment opportunities to be cost-effective [17].
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TREATMENT
With the discovery of penicillin, syphilis has
become a highly curable infection, and congenital
syphilis is considered a preventable disease. A single
intramuscular injection of long-acting benzathine
penicillin G 2.4 million units will cure a person who
has primary, secondary, or early latent syphilis.
Three doses at weekly intervals are recommended
for individuals with late latent syphilis or latent
syphilis of unknown duration. The growth of
T. pallidum is slow, with a doubling time of only
30–33 h [11]. Thus, extended exposure to penicillin
is necessary for cure. Alternative therapies used for
penicillin-allergic individuals are not used during
pregnancy because of the either inconsistent pla-
cental transfer (erythromycin or azithromicin) or
the potential for adverse fetal effects (tetracycline
and doxycycline). Desensitization and treatment
with penicillin is therefore necessary for those preg-
nant women with penicillin allergies. A single oral
2 g dose of azithromycin is considered a suitable
alternative for the penicillin-allergic nonpregnant
&&
patient with early syphilis [18 ]. Importantly,
T. pallidum is demonstrating increasing rates of
&& &
resistance to macrolides [18 ,19 ]. This must be
considered in all treatment schemes. It is important
to remember that although treatment with penicil-
lin during pregnancy will eradicate syphilis and
prevent further damage, it will not have prevented
fetal harm that has already occurred. Early screen-
ing and robust treatment policies continue to offer
the most optimistic outcomes for fetuses and
newborns.
CURRENT CONSIDERATIONS
The resurgence of syphilis among pregnant women
presents many challenges to the obstetric provider.
Rates are rising both nationally and internationally,
and epidemiologic factors are being assessed in
attempts to reduce these rates. Demographic
analysis of rising syphilis rates demonstrates rates
rising highest in the population identifying them-
&&
selves men who have sex with men (MSM) [20 ].
Although complete epidemiologic studies are
ongoing regarding the sexual behaviors of bisexual
MSM, such studies are demonstrating lower rates of
condom use among MSM who then engage in sexual
&&
acts with women [20 ]. This behavior puts women
and their potential current/future fetuses at risk.
Thus, prenatal care must continue its focus on
screening and treatment of syphilis. Early identifi-
cation of the infected pregnant woman with ante-
natal screening at the first visit (and later in
pregnancy for high-risk individuals) is the corner-
stone of reducing congenital syphilis. Performing
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Continuing threat of syphilis in pregnancy Moline and Smith
point-of-care testing with same-day treatment of
infected women may offer advantages in some
populations [21]. Identifying and treating sexual
partners to reduce re-infection risk, high-risk behav-
ior modification, and promoting access to antenatal
healthcare will likely all contribute to reducing the
rate of infection.
In addition to epidemiologic and behavioral
research, translational research related to syphilis
is occurring and may offer advances in the future. As
an example, the genome of T. Pallidum spp. pallidum
has been sequenced and 1087 genes are present [22].
These encode for 1027 proteins, of which about 550
have had their function defined. There are 444
proteins that are considered ‘hypothetical’ and
research is ongoing in determining their presence
and function. This research is important for several
reasons. First, identification of protein function may
lead to the development of effective new antibiotics.
Second, these proteins may be useful in developing
targeted vaccines for syphilis [22]. Third, investi-
gation of proteins may lead to improved serodiag-
&
nosis of syphilis [23 ]. Finally, it is possible that
understanding protein function will assist in the
successful culture of T. pallidum.
In 2007, the WHO began its initiative for Global
Elimination of Congenital Syphilis [24]. This was
followed by the additional partnerships with the
Pan American Health Organization and Joint
United Nations Program on HIV/AIDS to evaluate
progress and areas of opportunity in the efforts to
eliminate maternal and neonatal syphilis and HIV
infections. More than 40 countries involved in the
initiative were testing 95% or more pregnant
women in prenatal care by the year 2014. Efforts
to improve prenatal care have included increased
access, early screening for syphilis in the first
trimesters (and later in pregnancy for high-risk
individuals), screening of pregnant women in
emergency departments, on-site testing with rapid
point-of-care screening tests, same-day treatments
for women and partners, and high-risk behavior
modification. As evidence of the potential success
of coordinated efforts, Cuba has been recognized in
2015 as the first nation to end maternal-to-child
transmission of both syphilis and HIV. Despite the
challenges in eradicating congenital syphilis, coor-
dinated and intentional interventions to test and
treat for syphilis are promising [24].
CONCLUSION
Despite our ability to screen and treat for syphilis in
pregnancy, syphilis affecting women and their preg-
nancies appears to be increasing. This is noted in
both high and low resource areas around the globe.
www.co-obgyn.com 103
Maternal fetal medicine
Coordinated efforts to increase effective screening
programs, and importantly effective treatment pro-
tocols, appear to offer the best defense against the
potential harmful effects of this persistent sexually
transmitted infection. Epidemiologic, behavioral,
and translational research hold promise in defining
optimal, and perhaps novel, screening and treat-
ment paradigms.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
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& of special interest
&& of outstanding interest
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For providers in the United States, this publication should be a ‘call to arms’ to
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