CASE REPORT

Neonatal Cholestasis Secondary to Congenital Syphilis

April P. Padua-Zamora, MD,1 Ma. Patricia Riego de Dios, MD2 and Germana Emerita V. Gregorio, MD, MSc, PhD1

Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics,

1

College of Medicine and Philippine General Hospital, University of the Philippines Manila
2
Department of Pediatrics, College of Medicine and Philippine General Hospital, University of the Philippines Manila

ABSTRACT

We report two infants with neonatal cholestasis and hepatosplenomegaly secondary to congenital syphilis.
The onset of jaundice of the first infant was at six weeks of life and the second case on the 28th hour of life with
associated neurologic and bone involvement. The diagnosis was suspected based on a maternal history of untreated
syphilis, clinical findings, and a reactive rapid plasma reagin. Early recognition and treatment can lead to clinical
improvement but prevention by mandatory testing and treatment of maternal syphilis is a more effective strategy.

Keywords: congenital syphilis, neonatal cholestasis, rapid plasma reagin

INTRODUCTION
Syphilis is a highly contagious disease that causes serious
health problems if not treated. It is caused by Treponema
pallidum, a gram-negative spirochete that is detected in
Giemsa-stained smears of syphilitic lesions.1,2 Most cases
of syphilis are transmitted through sexual contact but they
may also be transmitted vertically depending on the stage
of syphilis in the pregnant woman. If the mother is in
the primary or secondary stage of syphilis, the probability
of transmission is > 80%.2 Maternal-to-child transmission
can be transplacental or through the exposure of the child
to the birth canal during delivery, a condition known as
congenital syphilis.3
In 2016, the estimated global burden of congenital
syphilis was at 661,000 children, or around 473 cases per
100,000 live births. The number has decreased from 748,000
cases in 2012, reflecting increased access to antenatal care
and syphilis screening worldwide.4 In the Philippines,
a search of the Philippine Pediatric Society’s registry of
diseases reported that out of 4.7 million cases from 2006
up to June 2021, 239 had congenital syphilis (A50.9), 185
of whom were reported in the last 5 years (2016 to 2020).5
Review of records of the Division of Infectious Disease
and Tropical Medicine of the UP PGH Department of
Pediatrics showed that there were a total of 73 cases of early
congenital syphilis who were referred from 2016-2020,
with an estimated incidence of 1-1.5 per 1,000 admissions
Corresponding author:
Germana Emerita V. Gregorio, MD, MSc, PhD
per year.
Division of Pediatric Gastroenterology, Hepatology and Congenital syphilis may present either as an early
Nutrition disease if diagnosed before two years of age, or as a late
Department of Pediatrics disease if it occurs after two years. Based on 310 cases of
College of Medicine and Philippine General Hospital
University of the Philippines Manila
congenital syphilis, early disease manifestations included
Taft Avenue, Ermita, Manila 1000, Philippines hepatomegaly in 100 cases (32%), skeletal deformities in 91
Email: gvgregorio@up.edu.ph (29%), splenomegaly in 56 (18%), low birth weight (< 2.5 kg)

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 Neonatal Cholestasis Secondary to Congenital Syphilis

in 51 (16%), anemia in 50 (16%), skin lesions in 45 (15%) Due to the persistence of jaundice, the patient was
and hyperbilirubinemia in 40 (13%). Other less common brought to our institution. At this time, stools were pale-
manifestations seen in less than 10% of cases included CSF colored (stool color #2–3) based on a standard infant stool
pleocytosis, nephritis, chorioretinitis, and failure to thrive.6,7 color card.10 Physical examination revealed stable vital signs
Late manifestations result from scarring in early with no wasting (weight for length, 50th percentile) but
congenital syphilis and most commonly include frontal with severe stunting (length for age < 3rd percentile) and
bossing (87%), short maxilla (84%), high palatal arch (76%), microcephaly (head circumference < 3rd percentile). The
and Hutchinson triad (75%). The latter includes interstitial patient was jaundiced with icteric sclerae. The liver was
keratitis, eighth nerve deafness, and Hutchinson's teeth, firm, palpable 5 cm below the right costal margin, and with
which are abnormal permanent peg-shaped and notched smooth edges. The spleen was palpable 3 cm below the left
upper central incisors.6,7 costal margin. There were no gross bone deformities or skin
There have been very few local reports of early lesions. The assessment was neonatal cholestasis probably
congenital syphilis both in the local and foreign literature neonatal hepatitis, etiology undetermined.
and these present mainly with jaundice. In 1948, “congenital Laboratory investigations showed anemia [87 g/L
hepatoptosis” or displacement of the liver was reported in (normal value: 105–140)], normal white cell count [WBC:
an autopsy of a six-week-old infant diagnosed with syphilis 13 x109 cells/L (nv 6­ –14 x 109)] but with lymphocytic
who also had intestinal stenosis and died of subdural predominance (74%) and normal platelet count [222 x 109
hematoma.8 Liver histology of this infant showed diffuse cells/L (nv 150–450)]. Direct hyperbilirubinemia [Total
interstitial hepatitis. In 1954, the Department of Social 10.18 mg/dl (normal value: 0.2-1.3); direct bilirubin 7.67
Hygiene of the Manila Health Department reported 300 mg/dL (nv: 0.0-0.4)] was noted with elevated liver enzymes
cases of congenital syphilis, 85% of whom were described [AST 454 U/L (nv: 17–59); ALT 169 IU/L (nv: <50); GGT
to have a negative Kahn titer after one and half years.9 No of 150 U/L (nv: 15–73)]. Albumin (32 g/L nv: 19–49)
recent local studies were reported after these. In this report, and prothrombin time (1.16, nv: 1–1.2) levels were within
we describe two infants with neonatal cholestasis secondary normal. The HBsAg was non-reactive. Ultrasound of the liver
to early congenital syphilis, one with the onset of jaundice at showed hepatosplenomegaly with unremarkable bile ducts
six weeks of life and another on the 28th hour of life. Both and gall bladder. Due to the maternal history of multiple
mothers were informed and gave oral consent for the cases sexual partners, a rapid plasma reagin (RPR) qualitative test
to be reported. was done on the patient which was noted to be reactive. A
lumbar tap was subsequently performed to exclude CNS
Cases involvement and analysis showed a WBC count of 6 x 106/L
(Polymorphonuclear cells 2, lymphocytes 4), which was not
Case 1 compatible with neurosyphilis. There was an insufficient
The patient is a 2-month-old boy, born full term to a amount of specimen to send for CSF protein and VDRL
32-year-old G3P2 (2-0-0-2) mother via spontaneous vaginal testing. The CSF culture was negative. The patient was
delivery at a local hospital. The mother had seven prenatal managed as neonatal cholestasis secondary to congenital
consults at a local health center, where she underwent syphilis and was started on penicillin G treatment.
ultrasound imaging but had no other laboratory tests such After four days of penicillin, the stool color was noted
as screening for hepatitis B and syphilis. During pregnancy, to improve. Jaundice gradually decreased in intensity
she had intermittent bouts of headache and dizziness that with total bilirubin from 10.2 to 6.6 mg/dl on the 9th day
were relieved with paracetamol. She also had an intake of of penicillin G treatment. The patient was sent home after
ferrous sulfate and calcium supplements while pregnant. completing 10 days of treatment and advised to take ursode-
There were no other maternal illnesses. She has had three oxycholic acid as choleretic and multivitamin supplements.
sexual partners, with unknown sexual practices. Unfortunately, the patient was lost to follow up during the
The patient was meconium stained at birth, with an COVID-19 pandemic.
Apgar score of 8, 9 and birthweight of 2.62 kg, with no other During the patient’s confinement, a qualitative rapid
feto-maternal complications. He was discharged with good plasma reagin test was done on the mother and the test
suck and activity and without jaundice after two days in the was also reactive. Quantitative RPR and treponemal tests
hospital. He was exclusively breastfed for two months, after were not done as these were unavailable in our institution.
which he was given milk formula. He was well until the 6th Maternal HIV was non-reactive. The mother was also
day of life when jaundice was noted but no consult was done. advised to undergo penicillin G treatment.
At 1 ½ month, the patient was brought to the local
health center for routine vaccination. He was noted again Case 2
to be jaundiced with increasing abdominal girth and tea- The patient is a newborn girl, born preterm (34 weeks
colored urine. He was advised to undergo sunlight exposure. by pediatric aging) to a 16- year-old G2P0 (0-0-1-0) woman
via low segment cesarean section due to bleeding placenta

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Neonatal Cholestasis Secondary to Congenital Syphilis

B C

A D E

Figure 1. Skeletal survey showed findings consistent with congenital syphilis (see arrows). (A) Rugger jersey spine with
characteristic prominent endplate densities at multiple contiguous vertebral levels, producing an alternating
sclerotic-lucent-sclerotic appearance. (B) Demineralized calvarium and signs of subtle molding consistent with
craniotabes. (C to E) Bilateral periostitis of the bony pelvis, bilateral diaphyseal, and metaphyseal periostitis of
the long bones with transverse metaphyseal hypodense bands.

previa. The mother’s first pregnancy was a spontaneous before emergency cesarean section due to the occurrence of
abortion at 20 weeks age of gestation for which she profuse vaginal bleeding. Upon delivery, the placenta was
underwent dilatation and curettage 10 months before her noted to be abnormally enlarged and weighed 600 grams.
admission. For this pregnancy, the mother had three prenatal The patient was born with good cry and activity, with
consults at their local health center but did not undergo any an Apgar score of 8,9. Her weight of 2.5 kg was appropriate
prenatal screening tests. She was admitted to our institution for gestational age but the length of 42 cm and head
due to preterm labor and on examination, she was found to circumference of 30 cm was less than the 10th and the 25th
have two discrete, non-tender, hypopigmented ulcerations, percentile, respectively. The fontanels were soft and flat.
approximately 1 x 1 cm around the perianal region with There was no jaundice. The abdomen was distended with the
no associated inguinal lymphadenopathy. Sexual history liver palpable 2 cm below the right costal margin and the
revealed that she was sexually abused at 13 years old and spleen 3.5 cm below the left costal margin. There were no
has one sexual partner who denied promiscuity. Work-up skin lesions.
revealed a reactive RPR quantitative test (1:64), moderately The patient had respiratory distress (respiratory rate of
positive fluorescent treponemal antibody absorption (FTA- 60 breaths per minute) and desaturation (oxygen saturation
ABS) test (1:10), and fetal hepatomegaly on congenital of 90–92%) on her 4th minute of life, hence she was placed
anomaly scan. Work-up for hepatitis B, HIV, and TORCH on continuous positive airway pressure and was eventually
(Toxoplasma IgM, rubella IgM, and cytomegalovirus IgM) shifted to non-invasive positive pressure ventilation due
showed negative results. She was assessed to have primary to persistent respiratory distress. A babygram confirmed
syphilis and was started on intramuscular benzathine the presence of reticular opacities in both inner lung zones
penicillin G 2.4 million IU, given approximately 4 hours consistent with neonatal pneumonia.

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 Neonatal Cholestasis Secondary to Congenital Syphilis

Table 1. Comparison of clinical and diagnostic features of two patients diagnosed with congenital syphilis
Case 1 Case 2
Demographic characteristics
Age/Sex 2 months/M Newborn/F
Clinical presentation Jaundice Respiratory distress
Onset of symptom 6 weeks old 4th minute of life
Onset of jaundice 6 weeks 28th hour of life
Maternal history Multiple sexual partners; Seven prenatal consults Sexual abuse at 13 years old; Three prenatal consults
Birth weight < 2500 g Absent Absent
Physical examination
Length < 3rd percentile < 10th percentile
Head circumference < 3rd percentile 25th percentile
Skin lesions Absent Absent
Jaundice Present Present
Hepato- and/or splenomegaly Present Present
Hematologic Investigations
Anemia Present Present
Leucopenia/Leucocytosis Absent Absent
Lymphocytic predominance Present Present
Thrombocytopenia Absent Present
CSF study
Protein Not done* Elevated
WBC Normal Normal
Ultrasound of Liver Hepatosplenomegaly Normal liver size; splenomegaly
Skeletal survey Not done Craniotabes, rugger jersey spine, and periostitis of the
bony pelvis and long bones
* Inadequate specimen

On the patient’s 28th hour of life, she was noted to The latter required prolonged nothing-per-orem and the use
have jaundice up to the chest and bilirubin levels showed of total parenteral nutrition. She eventually succumbed on
cholestasis [Total bilirubin 7.83 mg/dL (nv 1–10.5), Direct the 45th day of life to multiple organ dysfunction syndrome
bilirubin 4.94 mg/dL (nv 0–0.6)]. The transaminase [ALT 9 (cardiovascular, respiratory, hematologic, renal, and hepatic)
IU/L (nv 6–40)] and the prothrombin time (INR 0.91) levels secondary to multi-drug resistant Acinetobacter baumanii
were normal. Further laboratory work-ups revealed anemia sepsis.
(Hemoglobin 120 g/L, nv 150–240) and thrombocytopenia
(platelet count 50 x 109/L, nv 84–478) with normal WBC Discussion
count (WBC 29.70 x 109/L, nv 9.1–34) but with lymphocytic
predominance (65%) The quantitative serum RPR was We presented two infants with neonatal cholestasis
positive at 1:256 and titers were 4-fold higher than the secondary to congenital syphilis, one of whom had onset of
mother at 1:64. The CSF analysis showed elevated protein jaundice at six weeks of life and another on the 28th hour
for age (164 mg/dL, nv <150), a normal white cell count of life associated with neurologic and bone involvement.
[WBC 6 x106/L (PMN 2, lymphocytes 4)]. CSF VDRL Neonatal cholestasis secondary to congenital syphilis in our
test was not available at the time of testing. The blood and institution has not been reported in the last 15 years.11 A
CSF cultures were sterile. The whole abdominal ultrasound comparison of the patients’ clinical and diagnostic features
showed a normal liver size and echogenicity, splenomegaly, is presented in Table 1.
and small-for-age but morphologically intact kidneys. The The first case had jaundice and hepatosplenomegaly,
skeletal survey demonstrated craniotabes, rugger jersey anemia, with no skin, bone, or neurologic manifestations of
spine, and periostitis of the bony pelvis and long bones syphilis. The second case had jaundice and splenomegaly with
suggestive of congenital syphilis (Figure 1). There was also anemia, thrombocytopenia, elevated CSF protein suggestive
an incidental finding of basioccipital fracture on the skeletal of CNS involvement, and presence of microcephaly, sclerotic
survey but was not confirmed on craniocervical CT scan. vertebrae, and periostitis of the long bones on the skeletal
She was treated with a meningitic dose of aqueous survey. The diagnosis of congenital syphilis was suspected
crystalline penicillin G at 75,000IU/kg/dose every 12 based on the sexual history of their mothers and by a
hours for the first 7 days, then every 8 hours until day 14. positive RPR test. For the first case, the two-month-old boy
During the hospital stay, no improvement in the bilirubin had a therapeutic response to penicillin G administration
levels was noted as other factors aggravated the cholestasis with a decrease in intensity of jaundice and improvement
including nosocomial sepsis and necrotizing enterocolitis. in stool color. However, for the second case, the presence

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of jaundice and pneumonia in the premature infant was Autopsy done on this patient revealed non-syndromic
confounded by the development of necrotizing enterocolitis paucity of intrahepatic bile ducts, which may explain the
and nosocomial sepsis. findings of pale- colored stool initially, similar to our first
Our diagnosis of a highly probable congenital syphilis case. In other reports on congenital syphilis, the development
was based on the Center for Disease Control guidelines,12 of jaundice was noted in patients while already admitted for
which define any neonate with the disease if there is: (1) a respiratory distress, with either concomitant maculopapular
mother who has untreated syphilis at delivery; (2) a reactive rash, pleural effusion, and ascites or purulent eye discharge
non-treponemal test such as the rapid plasma reagin test; and petechial rash.15,16 Our second patient developed
and (3) abnormal physical examination findings consistent jaundice on the 28th hour of life when the patient was already
with congenital syphilis. Both our patients had jaundice on ventilatory support secondary to neonatal pneumonia.
during their early neonatal period. Despite several prenatal Approximately 50% of infants with congenital syphilis
consultations, their mothers did not undergo screening with may present with pneumonia and the classic radiographic
RPR test, hence, failed to receive adequate treatment for appearance is complete opacification of both lung fields
syphilis at least four weeks before delivery. In centers with known as pneumonia alba or fluffy, diffuse infiltrate involving
quantitative RPR capacity, a patient’s RPR serologic titer all lung areas.6 In our patient, what was only seen on baby
that is fourfold higher than the mother is confirmatory as gram was reticular opacities in the inner lung field.
we have seen in our second case. Since RPR measures IgG Recognition and treatment of congenital syphilis are
antibody, the test does not distinguish between disease in important as penicillin G treatment will lead to improvement
the infant and maternally-derived antibody; hence, it is ideal of the patient. In our first patient, jaundice decreased and the
to determine the RPR ratio between the infant and mother. stool color improved during treatment and he was eventually
However, the absence of a fourfold titer does not exclude sent home. Our second patient was also treated for syphilis
the disease because the RPR titer ratio has low sensitivity but jaundice did not resolve due to the presence of other
(22%), but is highly specific (99%) in diagnosing congenital problems related to prematurity. Ideally, infants with reactive
syphilis.13 A treponemal test such as fluorescent treponemal nontreponemal tests should be thoroughly examined for
antibody absorption test (FTA-ABS) or treponemal pallidum late manifestations of congenital syphilis during follow up
hemagglutination assay (TPHA) on those with congenital (e.g., teeth abnormalities, interstitial keratitis, cranial nerve
syphilis is not recommended as it is difficult to interpret.12 palsy, deafness, bone, and joint changes) and serologic testing
Initially, the minimum required investigations for an (i.e., RPR or VDRL) repeated every 2–3 months until the
infant with cholestasis were done on both patients. These test becomes nonreactive. If tests remain reactive at 6–12
included a fractionated bilirubin, liver enzymes, and both months, repeat CSF evaluation and co-management with
serum albumin and prothrombin time, which are measures an infectious disease specialist are indicated.12
of the liver synthetic function. The results of their newborn Congenital syphilis is a preventable disease. The value
screening were also expedited as this would exclude metabolic of syphilis screening during antenatal check-ups should
disorders presenting with jaundice including galactosemia, be emphasized as a mother who is positive for the disease
hypothyroidism, and tyrosinemia. A fasting ultrasound was should already be treated during pregnancy; thus, preventing
also performed to identify the character of the bile duct, to transmission to the newborn. Among 355,000 estimated
visualize the presence of the gall bladder, and to assess the cases of congenital syphilis, adverse birth outcomes were
location of the liver and spleen. In both our patients, the noted in 57% of mothers who had prenatal check-ups but
ultrasound showed unremarkable bile ducts and gall bladder. were not screened, like our cases; 21% had no prenatal check-
It is also mandatory that the stool color is examined using ups, 16% had screening but were not treated, and only 6%
a stool color chart as the presence of pale or acholic stools were screened and treated.4 A 10-year study in China showed
will suggest an obstruction of bile ducts. In our first patient, that with the screening of pregnant women and treatment
the stool color was initially pale; hence, we could not exclude of those infected, the incidence of congenital syphilis
an obstructive cause at the onset. declined from 109.3 to 9.4 cases per 100 000 live births.17
After the initial investigation, a targeted evaluation In a meta-analysis with some studies with a high risk of
was done based on the maternal and family history and bias, the performance of the rapid immunochromatographic
the physical examination of the infant. Due to the mothers’ syphilis point-of-care for the antenatal clinic was assessed
high-risk sexual history, both infants were screened for using as reference standard the non-treponemal and
syphilis, which turned out positive. Other treatable disorders treponemal tests for active syphilis in pregnant women. The
that should be excluded, if indicated, include TORCH, immunochromatographic syphilis test was shown to have a
malaria, tuberculosis, and syphilis. pooled sensitivity and specificity for ICS of 0.85 (95% CrI:
Jaundice with hepatosplenomegaly, as the only 0.73 to 0.92) and 0.98 (95% CrI: 0.95 to 0.99), respectively.18
presentation of our first patient, is similar to the description In summary, we described two infants who had neonatal
of a two-week-old premature Japanese girl who presented cholestasis secondary to congenital syphilis whose mothers
solely with jaundice with no external malformation.14 had significant sexual histories, one who was sexually abused

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 Neonatal Cholestasis Secondary to Congenital Syphilis

and another with multiple sexual partners. The disease 5. Philippine Pediatric Society, Inc. ICD 10 Registry. [Internet]. [cited
should be included in the differential diagnosis of an infant 2021 Mar 1]. Available from: https://pps.org.ph/icd-10-registry/
6. Dobson S, Sanchez P. Syphilis. In: Feigin and Cherry’s Textbook of
presenting with jaundice if maternal history is suggestive Pediatric Infectious Diseases. 8th ed. Philadelphia, PA: Elsevier; 2019.
of high-risk sexual behaviors and after exclusion of other 7. Darville T. Syphilis. Pediatr Rev. 1999 May; 20(5):160-4, quiz 165.
treatable causes of cholestasis. Continued maternal screening 8. Menes S, Ramos A, Guerrero R. Congenital hepatoptosis and subdural
for syphilis among pregnant patients is recommended and hematoma. Sto Tomas J Med. 1948 Sep;
9. Roda A, Pilapil Z, Laqui E, Ibarra L. Kahn reaction of syphilitics
should be emphasized during prenatal visits. after a certain routine treatment. J Philipp Federation Private Med
Practitioners. 1954 Dec;
Acknowledgment 10. Perinatal Services BC. BC Infant Stool Colour Card [Internet].
We would like to acknowledge the Division of Infectious [cited 2021 Jun 1]. Available from: https://med.ubc.ca/files/2013/07/
BCInfantStoolColourCard.pdf
and Tropical Medicine of the UP PGH Department of 11. Vitug JLD, Avila JMC, Gregorio GV. Histological pattern and
Pediatrics for the data on the number of early congenital outcome of Filipino children with liver disease who underwent
syphilis cases referred to the department. percutaneous liver biopsy: a five-year survey. Acta Med Philipp. 2015
Dec 31; 49(4):12-7.
12. Congenital Syphilis - 2015 STD Treatment Guidelines [Internet].
Statement of Authorship [cited 2020 Apr 8]. Available from: https://www.cdc.gov/std/tg2015/
All authors contributed in the conceptualization of congenital.htm
work, acquisition and analysis of data, drafting and revising, 13. Gong X, Wu M, Zhao L. P760 Sensitivity and specificity of the
and approved the final version to be published. quantitative test for TPPA and RPR for diagnosis of congenital syphilis
in neonates. Sex Transm Infect. 2019 Jul 1; 95(Suppl 1):A326-7.
14. Sugiura H, Hayashi M, Koshida R, Watanabe R, Nakanuma Y, Ohta
Author Disclosure G. Nonsyndromatic paucity of intrahepatic bile ducts in congenital
All authors declared no conflicts of interest. syphilis. A case report. Acta Pathol Jpn. 1988 Aug; 38(8):1061-8.
15. Filippi L, Serafini L, Dani C, Bertini G, Pezzati M, Tronchin M.
Congenital syphilis: unique clinical presentation in three preterm
Funding Source newborns. J Perinat Med. 2004 Jun; 32(1):90-4.
The study has no funding support. 16. Sood V, Cheilani H, Arya S. Congenital syphilis as neonatal cholestasis
syndrome - an extinct entity? Journal of Pediatric Sciences. 2014;
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