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\begin{document}

\title{Secondary syphilis in the third trimester of pregnancy}



\author[1]{Ryosuke Tajiri}%
\author[1]{Emi Kondo}%
\author[1]{Yuma Saito}%
\author[1]{Mao Sekimata}%
\author[1]{Yasuyuki Kinjo}%
\author[1]{Hiroshi Mori}%
\author[1]{Kiyoshi Yoshino}%
\affil[1]{University of Occupational and Environmental Health Japan}%


\vspace{-1em}



  
  \date{May 22, 2024}


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\textbf{Secondary syphilis in the third trimester of pregnancy}

Ryosuke Tajiri, Emi Kondo, Yuma Saito, Mao Sekimata, Yasuyuki Kinjo,
Hiroshi Mori, Kiyoshi Yoshino

Facilities: Department of Obstetrics and Gynecology, School of Medicine,
University of Occupational and Environmental Health, Japan

Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.

Corresponding author: Dr. Ryosuke Tajiri

Department of Obstetrics and Gynecology, School of Medicine, University
of Occupational and Environmental Health. Japan, 1-1 Iseigaoka,
Yahatanishi-ku, Kitakyushu 807-8555, Japan.

Tel: +81-93-603-1611, Fax: +81-93-691-8892

e-mail:\emph{r-tajiri@med.uoeh-u.ac.jp}

Consent statement: Written informed consent was obtained from the
patient to publish this report in accordance with the journal's patient
consent policy.

\emph{Abstract:}

Screening tests for syphilis are performed during early pregnancy in
Japan. However, syphilis may develop after the second trimester, and
remain undiagnosed due to the current screening methods. Moreover, no
guidelines have been established for management of syphilis in the third
trimester. We present the case of syphilis in the third trimester of a
32-year-old primipara female, which was managed successfully. Her early
pregnancy screening tests were negative for syphilis. In the third
trimester, she was diagnosed with second-stage syphilis. Treatment with
penicillin G resulted in gross resolution of the ulcer and the skin
rash. However, the risk of peripartum infection could not be ruled out.
Therefore, caesarean section was performed at 38 weeks of gestation.
Guidelines should be established for management of syphilis and mode of
delivery during the second and third trimesters of pregnancy, which
would aid in successful disease management and prevention of perinatal
death or disability.

\emph{Key words:} Cesarian Section/Pregnancy/Pregnancy Complications,
Infectious/ Syphilis, Congenital

\emph{Introduction:}

Syphilis is an infectious disease caused by \emph{Treponema
pallidum}(TP), a member of the Spirochaetaceae family. It is one of the
most common sexually transmitted diseases. According to the World Health
Organization (WHO) estimates, approximately 17.7 million people all over
the world between the ages of 15 and 49 years had syphilis in the year
2012, and this number reportedly increases by an estimated 5.6 million
every year (1). The estimated prevalence and incidence of syphilis
varies with region and country. The highest prevalence of syphilis has
been reported in Africa, with more than 60\% of new cases occur in
developing countries (1). Gestational syphilis reportedly occurs most
frequently in Africa, accounting for more than 60\% of the global
estimates (2). Syphilis is a Category 5 infectious disease in Japan
according to the Infectious Diseases Law, and the number of syphilis
cases has been gradually increasing since 2013 (3). Syphilis, especially
among young people, has become a concern in the recent years. Syphilis
in pregnant women and congenital syphilis have become public health
issues worldwide (4). In Japan, the haematology test for syphilis is
performed at public expense as a screening test in the first trimester
of pregnancy during antenatal health examination. In some foreign
countries, syphilis screening tests are also conducted in the second and
third trimesters of pregnancy (5). However, in Japan, screening tests
for syphilis are not conducted after the initial examination.

Herein, we report a case in which a vulvar ulcer at 37 weeks of
gestation led to the diagnosis of syphilis after a negative screening
test during early pregnancy.

\emph{Case report:}

A 32-year-old primipara female was referred to our hospital for painless
delivery. Prenatal history included one prior spontaneous miscarriage in
a year ago. The patient had a history of smoking, which she had stopped
after the discovery of pregnancy. She had a history of panic disorder
and bipolar disorder, for which she was on medication. However, she
self-interrupted her medication and hospital visits after discovering
her pregnancy. Pregnancy was spontaneous and was managed at a primary
care facility. The initial screening test performed at 12 weeks of
gestation was negative for rapid plasma reagin (RPR) and TP antibodies.
No abnormalities were observed in other laboratory results. At 22 weeks
of gestation, she developed vulvovaginal and vaginal itching, which was
diagnosed as vulvovaginal candidiasis by vaginal culture and treated
with oxenazole vaginal suppositories. She was referred to our hospital
at 33 weeks of pregnancy, which has a comprehensive perinatal mother and
childcare centre, because she wanted to have a painless delivery.
Thereafter, the patient continued antenatal care at the hospital. She
had persistent vulvar itching and white tinea versicolor discharge. She
continued the treatment for vulvar candidiasis with an oxazol vaginal
suppository, but the treatment was refractory. At the time of her visit
at 37 weeks and 2 days of pregnancy, painless induration and ulcerative
lesions were observed on the vulva, and a blood test was performed on
the suspicion of syphilis. Early in the morning of the next day, 37
weeks and 3 days after conception, she developed fever and pain during
urination and was urgently admitted to the hospital on the same day.

On admission, the patient had a fever of 37.5\selectlanguage{ngerman}°C. On examination,
rice-sized erythematous plaques were observed on the palms, along with
pale oedematous erythematous plaques with infiltrates on the right
forearm and trunk, and numerous rice-sized painless ulcerative lesions
on the vulva (Figure1). Internal examination revealed no bleeding or
water breakage, and the cervix was closed. Uterine tenderness was not
observed. Blood tests revealed a white blood cell count of 9000/\selectlanguage{greek}µ\selectlanguage{english}l
(84.6\% neutrophils); C-reactive protein (CRP), 10.47 mg/dl; PT, 13 s,
and APTT, 64 s. Cardiotocography (CTG) findings on admission were 145
bpm at baseline, moderate baseline fibrillation, transient tachycardia,
no transient bradycardia, and no uterine contractions. Transabdominal
ultrasonography showed that the foetus was growing at a rate equivalent
to the number of weeks. None of the findings were suggestive of
congenital syphilis, such as obvious foetal hepatomegaly, ascites,
foetal oedema, or placental thickening.

Based on positive RPR and TP antibodies, along with clinical symptoms,
such as painless ulceration of the vulva and a generalized rose rash,
she was diagnosed with second-stage syphilis. Subsequent detailed
interviews revealed that her husband had used a sex establishment at
around 15 weeks of gestation, and also had sexual intercourse with her
during the same time. The patient's husband was treated with oral
benzylpenicillin. After discussing the treatment plan with the
Department of Infectious Diseases, the patient was treated for
neurosyphilis with 4 million units of penicillin G six times a day for
10 days. The patient was in full-term labour at the time of treatment
initiation. No Jarisch-Herxheimer reaction was observed. Although the
generalized rosacea and vulvar hard chancre had resolved, the blood
tests were positive for RPR and TP quantitative tests (RPR: 11.58 R.U.
and TP antibody: 188.5 COI). No specific guidelines have been
established for the mode of delivery in cases of syphilis diagnosed in
the third trimester of pregnancy. Since the patient remained positive
for RPR and TP antibodies, and the risk of peripartum infection could
not be assessed, we opted for a caesarean section. An emergency
caesarean section was performed under spinal anaesthesia at 38 weeks and
3 days of gestation due to the onset of labour pain. A girl child
weighing 2908 g, with an Apgar score of 8/9 and an umbilical artery
blood pH of 7.280, was delivered. The first cry was rather weak, and
prompt resuscitation was initiated. Since spontaneous respiration was
weak, Continuous Postive Airway Pressure (CPAP) and oxygen were
administered, after which the respiratory condition improved. Based on
the maternal condition, the patient was admitted to the NICU for close
examination and treatment of congenital syphilis. Blood test at birth
showed a negative RPR of 0.49 R.U., positive TP antibody of 18.3 COI,
and FTA-Abs-IgM of less than 5. Although there were no findings
suggestive of congenital syphilis on physical examination, a dose of 50,
000 U/kg/dose of penicillin G was started after birth to prevent
congenital syphilis. Vital signs of the new-born remained stable after
the start of treatment. No obvious signs of infection were observed, and
penicillin G administration was terminated on the 10th day of life.
Early congenital syphilis test was negative, and the patient was
discharged on the 19th day of life.

The mother continued postoperative penicillin G infusion until
postoperative day 5, after which she was discharged. The patient is
currently receiving treatment on an outpatient basis. Histopathological
examination of the placenta revealed necrotizing funisitis (Figure 2).
In addition, immunohistochemical staining for TP antibodies showed
slightly positive organisms (Figure 2).

\emph{Discussion:}

There is insufficient literature on delivery of pregnant women with
syphilis. No specific guidelines have been established regarding
treatment methods or modes of delivery in syphilis patients.
Consequently, treatment policies and modes of delivery vary from one
medical facility to another. We reviewed the literature on management of
pregnancies complicated by syphilis that occurred in the third trimester
of pregnancy.

\emph{Syphilis Treponema} is a bacillus of the genus \emph{Treponema} ,
with a width of approximately 100-200 nm and a length of 10-20 \selectlanguage{greek}μ\selectlanguage{english}m (6).
It is a sexually transmitted disease that can be transmitted via contact
with mucous membranes and skin (6). It is also known that untreated
syphilis infection during pregnancy can lead to vertical infection and
congenital syphilis in the child (6,7). Clinical manifestations result
from a local inflammatory reaction caused by proliferating spirochetes
in the tissues. In general, early syphilis refers to infections that can
be sexually transmitted and is synonymous with infectious syphilis. The
WHO defines early syphilis as infections of less than 2 years duration
(8). Patients with first episode of syphilis present with a single
chancre or multiple lesions at the site of genital or sexual contact and
regional lymphadenopathy, approximately three weeks after infection (6).
Secondary symptoms such as fever, headache, and maculopapular rash on
the flanks, shoulders, arms, chest, and back appear. The rashes often
involve the palms of the hands and the soles of the feet (6).
Mother-to-child transmission primarily occurs during the primary and
secondary infection periods, followed by the early incubation period
(5,6,9). Infants born to infected mothers are often born premature, have
low birth weight, and clinical signs that mimic neonatal sepsis (such as
poor feeding, lethargy, rash, jaundice, hepatosplenomegaly, and
anaemia)(10,11).

Majority of syphilis cases in infants occur due to in utero
transmission, although mother-to-infant transmission of syphilis may
occur at the time of delivery. Spirochetes have reportedly been detected
in placental or umbilical cord samples as early as 9--10 weeks of
gestation, which substantiates transplacental transmission to the foetus
(12).

Syphilis often presents with diverse symptoms and is difficult to
diagnose clinically. Painless lesions in hidden exposed sites, such as
the cervix and rectum, are often missed. In addition, secondary syphilis
eruptions and other lesions may appear hazy or could be mistaken for
other diseases. Diagnosis of syphilis is often based on the medical
history and the results of blood and other laboratory investigations.
Serology is the most common method for diagnosing syphilis in both
symptomatic and non-symptomatic individuals who are screened.

Screening for syphilis is universally recommended for pregnant women,
regardless of previous exposure, because it is a highly effective
preventive intervention against vertical transmission during
pregnancy(5). Most national guidelines recommend screening for syphilis
during the first antenatal visit, ideally during the first trimester.
Some countries recommend that high-risk women should be screened again
in the third trimester of pregnancy and at the time of delivery to
identify new infections.

In the present case, syphilis screening test in the first trimester of
pregnancy was negative, but symptoms such as hard chancre confirmed
syphilis infection in the third trimester of pregnancy. A detailed
history after the onset of the disease suggested that she had sexually
transmitted syphilis from her husband immediately before or after
conceiving. Therefore, it was assumed that the initial screening test
result was negative because of pre-infection or early infection. She was
in full-term labour when the infection was discovered. Penicillin G
infusion to prevent congenital syphilis was administered for 10 days, as
per the package insert. The vulvar and skin lesions were confirmed to
have disappeared. However, lesions on the vaginal wall and cervix were
difficult to identify with the naked eye, and the possibility of trans
natal vaginal infection could not be ruled out. Therefore, we elected to
perform a caesarean section. There is no clear description of the mode
of delivery for syphilis cases in late pregnancy in the guidelines, and
this may be considered controversial. We also believe that screening for
syphilis during the second trimester of pregnancy should be considered
in the future.

In conclusion, we encountered a case of a pregnant woman with
second-stage syphilis complication that developed in the third trimester
of pregnancy. Incidence of syphilis has been on the increase among young
people in the recent years, and we anticipate that similar cases may
increase in the future. Therefore, it is desirable to establish
guidelines for management and mode of delivery of patients with syphilis
in the second and trimesters of pregnancy.

\emph{Acknowledgements:} Informed consent for publication of this report
was obtained from the patient in our hospital. We appreciate Editage
(www.editage.com) for English language editing.

\emph{References:}

1. Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N,
et al. Global estimates of the prevalence and incidence of four curable
sexually transmitted infections in 2012 based on systematic review and
global reporting. PLoS One. 2015 ;10(12):e0143304.

2. Wijesooriya NS, Rochat RW, Kamb ML, Turlapati P, Temmerman M, Broutet
N, et al. Global burden of maternal and congenital syphilis in 2008 and
2012: a health systems modelling study. Lancet Glob Health.
2016;4(8):e525-33.

3. National Institute of Infectious Diseases, Japan. Notification Trends
Among Syphilis Cases in Japan {[}Internet{]}. Notification Trends Among
Syphilis Cases in Japan. 2021. Available from:
https://www.niid.go.jp/niid/ja/syphilis-m/syphilis-trend.html

4. Simms I, Bell G, Hughes G. Infectious syphilis in young
heterosexuals: responding to an evolving epidemic. Int J STD AIDS.
2011;22(9):481--2.

5. Adhikari EH. Syphilis in Pregnancy. Obstet Gynecol.
2020;135(5):1121--35.

6. Peeling RW, Mabey D, Kamb ML, Chen X-S, Radolf JD, Benzaken AS.
Syphilis. Nat Rev Dis Primers. 2017;3:17073.

7. Oswal S, Lyons G. Syphilis in pregnancy. Contin Educ Anaesth Crit
Care Pain. 2008;8(6):224--7.

8. WHO Guideline on Syphilis Screening and Treatment for Pregnant Women.
Geneva: World Health Organization; 2018. Available from
https://www.who.int/publications/i/item/9789241550093

9. Lopez A, Lee SJ, Bullard J. Syphilis in pregnancy and infant outcomes
in Manitoba. Paediatr Child Health {[}Internet{]}. 2022. Available from:
http://dx.doi.org/10.1093/pch/pxab099

10. S\selectlanguage{ngerman}ánchez PJ, Wendel GD Jr, Grimprel E, Goldberg M, Hall M,
Arencibia-Mireles O, et al. Evaluation of molecular methodologies and
rabbit infectivity testing for the diagnosis of congenital syphilis and
neonatal central nervous system invasion by Treponema pallidum. J Infect
Dis. 1993;167(1):148--57.

11. Watson-Jones D, Changalucha J, Gumodoka B, Weiss H, Rusizoka M,
Ndeki L, et al. Syphilis in pregnancy in Tanzania. I. Impact of maternal
syphilis on outcome of pregnancy. J Infect Dis. 2002;186(7):940--7.

12. Harter C, Benirschke K. Fetal syphilis in the first trimester. Am J
Obstet Gynecol. 1976;124(7):705--11.

\emph{Figure legends:}

\emph{Figure 1. A. Rice-sized erythematous plaques on the palms. B. Pale
oedematous erythema of the abdomen. C. Pale oedematous erythema on the
back. D. Numerous rice-sized painless ulcerative lesions on the vulva.}

\emph{Figure 2. A. Gross findings of the placenta and the umbilical
cord. B. Necrotizing funisitis (H\&E). Low power showing scattered
inflammatory cells in the vessel wall. C. Necrotizing funisitis (H\&E).
Medium power showing scattered inflammatory cells in the vessel wall and
an outer band of mild coagulation necrosis with cellular debris. D.
Immunohistochemical staining for TP antibodies. High power showing
slightly positive organisms.}\selectlanguage{english}
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