European Journal of Obstetrics & Gynecology and Reproductive Biology 259 (2021) 207–210

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European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

Syphilis in pregnancy: The impact of “the Great Imitator”

Alison Ukua,* , Zahraa Albujasima , Tina Dwivedib , Zana Ladipoc, Justin C. Konjed
a
Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton Under Lyne, OL6 9RW, UK
b
Sexual Health Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, FY3 9ES, UK
c
Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, FY3 9ES, UK
d
Weill Cornell Medicine Doha, Qatar

A R T I C L E I N F O A B S T R A C T

Article history: Syphilis remains a common congenital infection over the globe. There has been a tremendous rise in the
Received 29 October 2020 number of congenital syphilis cases worldwide in the last 20 years. It affects large numbers of pregnant
Received in revised form 28 December 2020 mothers in high burden regions causing a significantly high perinatal mortality and morbidity, which can
Accepted 8 January 2021
be easily prevented by early antenatal screening and treatment.
Diagnosis of maternal syphilis in pregnancy mainly based on clinical symptoms, serological tests and
Keywords: direct identification of treponemes in clinical samples. However, the diagnosis can be challenging due to
Syphilis
the relapsing-remitting nature of the disease. The early stage of the infection is usually symptomatic
Treponema pallidum
Congenital syphilis
which is commonly followed by an asymptomatic latent phase but infectious and as a result serological
tests will be positive. The risk of transplacental transmission is high during the second and third
trimester.
Obstetric complications of syphilis include spontaneous miscarriage, non-immune hydrops, stillbirth,
preterm labour, low birth weight, increased neonatal mortality and congenital syphilis among neonates.
Penicillin is the drug of choice for treatment and should be commenced immediately. Babies born to
mothers with syphilis should also be treated with penicillin. Early detection and prompt intervention are
the key to the prevention and successful control of congenital syphilis. The aim of this review is to
highlight the impact of syphilis infection on pregnancy and discuss the current trends in diagnosis and
management of maternal and congenital syphilis.
© 2021 Published by Elsevier B.V.

Introduction
Syphilis is believed to be one of the oldest diseases, first
discovered at the end of 15th century. In the past, syphilis was
thought to be a psychiatric rather than an infectious disease. In
1901 IIya Mechnikov discovered the infectious nature of the
disease when he inoculated monkeys with T. pallidum [1].
Around 10–12 million new syphilis infections emerge world-
wide each year according to the World Health Organization (WHO).
The infection rates vary significantly between different countries
and different demographic subcategories of populations [2].
Generally, the infection rate among pregnant mothers is low in
high-income countries (HIC). It is estimated to be around 0.02
%–4.5 % in Europe and the United States respectively.
There was a significant rise in the number of diagnosed
congenital syphilis cases in parts of Eastern Europe and Central
* Corresponding author.
E-mail addresses: Alisonuku@doctors.org.uk, Alison.Uku@tgh.nhs.uk (A. Uku).
Asia. Africa has a consistently high rate of syphilis infection among
pregnant women at around 3–18 % [4].
The incidence of syphilis in the UK has witnessed a big rise since
2013. Over the last decade syphilis cases have risen by 162 % with
more than half of the cases reported in London [3,5,6]. Nearly 1 in
700 to 1 in 7000 pregnant women screened positive for syphilis
between 2008 and 2018. However, only 25 % of these women had
acquired the infection during pregnancy, most had either been
inadequately treated or had a false positive result. Overall, only
over a third of patients who tested positive required antibiotics
therapy [6,7].
Microbiology of syphilis
Though the disease itself, had been around from centuries
before, syphilis was eventually found to be caused by the
spirochaete Treponema pallidum, which was identified for the first
time by Schaudinn and Hoffmann in 1905 [8]. T. pallidum is a
bacterium that measures approximately 0.10 to 0.18 micrometers
in diameter and 6–20 micrometers in length [10]. Currently, there
is no reliable culture media to grow this bacterium. It is also not

https://doi.org/10.1016/j.ejogrb.2021.01.010
0301-2115/© 2021 Published by Elsevier B.V.
A. Uku, Z. Albujasim, T. Dwivedi et al. European Journal of Obstetrics & Gynecology and Reproductive Biology 259 (2021) 207–210

possible to observe it by direct microscopy, however, techniques

like darkfield microscopy are used to visualize it [11,12]. T. pallidum
pallidum is one of four subspecies of T. pallidum, which cause
diseases such as Bejel, Yaws, and Pinta [13]. A 50 -flanking region of
a 15-kDa lipoprotein gene which was recently discovered is being
currently used to distinguish between the four pathogenic strains
[14,15].

Transmission

Syphilis is acquired sexually in most cases by direct inoculation

via skin-to-skin contact with active primary or secondary lesions.
The risk of transmission within 30 days of sexual exposure is up to
30 % [16,17]. T. pallidium can also readily cross the placenta and
infect the fetus. This can occur at any stage during pregnancy;
however, the manifestations of congenital syphilis are dependent
on the gestational age, stage of maternal syphilis and treatment
[13]. Syphilis can rarely be transmitted by blood transfusion [18].
Risk factors for the transmission of syphilis in pregnant mothers
include young age, multiple sexual partners, low socioeconomic
and educational status, drug abuse, unprotected sex and a previous
history of STIs [19,4].

Clinical manifestation
Syphilis is a chronic sexually transmitted infection character-
ized by systemic manifestations. There are four stages of acquired
syphilis: primary, secondary, latent and tertiary syphilis [21].
Primary syphilis
Fig. 2. A typical papular rash that was dispersed over her truck region and arms. In
the case of secondary syphilis [37].
anterior uveitis, meningitis, cranial nerve palsies, hepatitis,
splenomegaly, periostitis and glomerulonephritis are less com-
mon at this stage (Fig. 2).

The first stage of syphilis is classically characterized by the Latent syphilis

appearance of primary syphilitic ulcer (chancre) at the site of
inoculation within 10–90 days form infection Fig. 1.
The chancre maybe single or multiple with induration and a
clear base, discharging clear serum. It usually resolves within 3–6
weeks without treatment. Regional rubbery lymphadenopathy is
also common at this stage.
Secondary syphilis
This appears within 2–6 weeks after the disappearance of the
chancre. It has multisystemic manifestations and is characterized
by a generalized maculopapular rash which often affects the palms
and soles [8].
Cutaneous lesions including patchy alopecia and condylomata
lata which is generally reddish-brown or purple, flat-topped and
moist commonly seen in the anogenital area. Generalized
lymphadenopathy is also common. Other features such as
Fig. 1. A primary anal syphilitic chancre on the anal region [36].
This stage of syphilis is asymptomatic, but serological tests are
positive. It results from untreated primary and secondary syphilis.
It has 2 phases early latent syphilis (within the first 2 years of
infection) and late latent syphilis after 2 years of infection.
Tertiary syphilis
Used synonymously with late symptomatic syphilis; may
develop in approximately a third of individuals. It manifests
months or years after the primary infection. It is non-infectious but
can lead to irreversible cardiovascular, neurological and granulo-
matous lesions that affect various body organs [5].
Syphilis in pregnancy
If left untreated primary or secondary maternal syphilis,
increases the likelihood of vertical transmission to the fetus. This
may be as high as 60–80 %. In contrast, the risk of transplacental
transmission of latent or tertiary syphilis is only around 20 %.
The fetal risk increases with increase gestational age. Spirochetes
cross the placenta and infect the fetus as early as 14 gestational
weeks [21].
Untreated syphilis in pregnant mothers is associated with
adverse pregnancy outcome. This include early fetal loss,
prematurity, stillbirth, congenital infections, neonatal and infant
death. Maternal syphilis is responsible for 460 000 miscarriages or
stillbirth and 270 000 low birth weight or premature babies
worldwide according the WHO. These numbers exceeded those of
other neonatal infections caused by HIV and tetanus [3].
In the UK, the coverage of antenatal screening for syphilis is
over 99 %. However, the incidence of congenital syphilis is still
below the WHO elimination target of 0.5/1000 live births [38] In
addition to routine antenatal screening for syphilis in the first

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A. Uku, Z. Albujasim, T. Dwivedi et al.
trimester, a repeat screening is recommended at 28 weeks
gestation in high- risk groups [39].
Congenital syphilis
Congenital syphilis has continued to be a problem worldwide
particularly in low-income countries. It can result miscarriages,
stillbirths, low birth weight, preterm birth, fetal hydrops and
neonatal morbidity and mortality. The risk of vertical transmission
of syphilis depend on the stage of maternal syphilis, gestational age
and maternal treatment [25,26]. An untreated woman has an
estimated 70 % risk of vertical transmission to cause fetal infection
during the first 4 years of infection [27].
Congenital syphilis is considered early congenital syphilis if
develops in the first 2 years after birth. It typically presents with a
maculopapular rash, hepatosplenomegaly, osteochondritis and a
flu like syndrome. Misdiagnosis or inadequate treatment of early
congenital syphilis may lead to late congenital syphilis, which has
the classical triad of triad of Hutchinson's teeth, interstitial
keratitis and eighth-nerve deafness. Other pathognomonic signs
include saddle nose, saber shins, seizures, and mental retardation
[1,34]. Clinical signs and symptoms of ECS result from active
infection and inflammation while clinical manifestations of late
congenital syphilis are malformations that represent the scaring
caused by chronic inflammation [27]. Around 60 % of new-borns
are asymptomatic. In fact, a third of cases of CS presents with low
birth weight, which could be the only sign at birth [27].
Diagnosis
There are many techniques to test for syphilis. These are tests
used to confirm the presence of disease by direct detection
methods (i.e. dark-field microscopy, direct fluorescent antibody
test and nucleic acid amplification test) and serological tests such
as the treponemal and non-treponemal tests.
Dark field microscopic examination is useful to diagnose the
early stage syphilis using the exudate from syphilitic lesions. PCR
maybe used on oral or other lesions where contamination with
commensal treponemes is likely. Owing to limited availability and
the time taken to obtain a result, this is not a replacement for dark-
field microscopy in the clinic setting. It may be helpful in diagnosis
by demonstrating T. pallidum in tissue samples, vitreous fluid, and
cerebrospinal fluid (CSF). Recently, polymerase chain reaction of
lesion exudates has been found to have a higher accuracy rate than
dark field detection [1].
Serological diagnosis for syphilis is based on the detection of
both nontreponemal and treponemal-specific antibodies. Trepo-
nemal serological tests must be confirmed by further serology.
The most commonly used non-treponemal tests are the
microscopic Venereal Diseases Research Laboratory (VDRL) and
the macroscopic rapid plasma reagin (RPR) tests. RPR tests can be
performed within an hour. These tests detect anti-lipid immuno-
globin M or G (IgM or IgG) antibodies. The downside of using these
tests is the high rate of false positive results as these antibodies can
be found in other pathologies such as acute viral infections and
chronic autoimmune diseases [1]. Moreover, these tests can be
affected by a prozone reaction which is a false negative response
resulting from high antibody titer in a specimen. Therefore, repeat
testing at two and four weeks is recommended to exclude syphilis
[20]. A quantitative VDRL/RPR is also used to monitor response to
treatment and therefore should be performed on a specimen taken
on the day of treatment.
Treponemal tests include Treponemal enzyme immunoassay
(EIA), the Treponema pallidum haemagglutination assay (TPHA),
the Treponema pallidum particle agglutination assay (TPPA) and the
fluorescent treponemal antibody absorption (FTAABS) tests. These
European Journal of Obstetrics & Gynecology and Reproductive Biology 259 (2021) 207–210
tests are highly specific because they detect antibodies against
treponemal-specific antigens; however, they do not differentiate
venereal syphilis from endemic syphilis (the latter includes Yaws
and Pinta). Ideally, one of these tests is used as a confirmatory test
following a positive non- treponemal test. Treponemal tests
usually remain positive (85 %) for the patient’s lifetime, regardless
of treatment. Thus, a positive treponemal test does not distinguish
between active infection and infection that has been previously
treated [11].
Rapid Syphilis Tests (RSTS) are on-site tests that usually provide
a quick result within 1015 min. They work on the same principle
as the specific treponemal tests by detecting treponemal specific
antibodies. These test for IgM and IgG antibodies and detect
disease activity through these antibodies level. They are available
in combination with the treponemal RSTs, providing both a
screening (RPR/VDRL equivalent) and confirmatory (TPHA/TPPA
equivalent) component [20].
Treatment
Management of syphilis in pregnancy requires a multidisci-
plinary team input of an obstetrician, fetal medicine physician,
midwives, paediatrician, GUM and primary care physicians and
microbiologists. Management should also involve antibiotics,
partner notification, testing and screening for other STIs, and
advice regarding safe sexual practice.
In pregnant women, a single dose of benzathine penicillin G 2.4
mu is the treatment recommended by the WHO. A second dose is
advisable when the diagnosis is made in the third trimester as the
physiological changes in pregnancy results in a low level of
penicillin concentrations.
In patients with penicillin allergy, there is limited evidence on
using other non-penicillin alternative such as ceftriaxone, azi-
thromycin or erythromycin as there are insufficient studies
evaluating azithromycin in pregnancy and there are reported
treatment failures with erythromycin. Therefore, de-sensitization
to penicillin with immediate penicillin treatment in patients with
reported allergy should be considered [20].
One important side effect (reaction) of the treatment with
penicillin of patients with syphilis is the Jarisch– Herxheimer
reaction, resulting from large numbers of bacteria death after the
antimicrobial is given leading to the release cytokines which
induce an acute inflammatory reaction. It can be found in 40–45 %
of pregnant women treated for syphilis especially if treatment is
given in the second half on the pregnancy. This typically occurs
within the first 24 h of treatment and symptoms include fever,
rigors and a skin rash. Preterm uterine contractions and fetal
distress have been reported, therefore admission to the hospital
and symptomatic treatment is therefore advisable [1].
Conclusion
Syphilis complicating pregnancy may result in adverse out-
comes. Antenatal screening and timely penicillin therapy are
crucial measures to reduce the risk of vertical transmission to
prevent congenital syphilis.
While early detection and appropriate treatment can greatly
reduce syphilis complications, the major limitation has been
failure to diagnose and treat infected mothers. Routine screening in
recommended for all pregnant mothers in the first trimester and a
repeat screening every 3 months for high-risk women as advised
by the BASHH/PHE guidance [20].
The prevention of syphilis in pregnancy goes beyond early
prenatal screening. Health education, treating partners, advice on
safe sexual practice and identifying high risk behaviors are other
important aspects to combat this avoidable infection.
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Declaration of Competing Interest
The authors report no declarations of interest.
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