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Congenital Syphilis: A U.S. Perspective

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Review

Congenital Syphilis: A U.S. Perspective

Alvaro E. Galvis 1,2 and Antonio Arrieta 1,2,*
1 Children’s Hospital of Orange County, Department of Infectious Diseases. Orange, CA, USA
2 University of California, Irvine School of Medicine. Irvine, CA, USA
* Correspondence: [email protected];

Abstract: Congenital syphilis still represents a worldwide public health problem. If left untreated,
can lead to fetal demise and high neonatal morbidity and mortality. Unfortunately, in the last
decade there has been a resurgence of cases in the US. This review discusses the ongoing problem
of this preventable congenital infection, vertical transmission and clinical manifestations while
providing a guidance for the evaluation and management of infants born to mothers with reactive
serologic tests for syphilis

Keywords: syphilis; Treponema pallidum; congenital infection

1. Introduction

Congenital syphilis (CS) occurs when Treponema pallidum infects the fetus of a woman typically
affected by primary or secondary syphilis. Despite the wide understanding of the disease, ability to
treat and optimal preventive strategies, CS remains a major cause of fetal and neonatal mortality
globally. The global burden of CS is exacerbated by the high prevalence of co-infection with human
immunodeficiency virus in adults.
Mother to child transmission (MTCT) can occur at any time during gestation, risk of
transmission in relation to maternal stage of infection is highest during secondary syphilis while fetal
infection during late latent infection is uncommon. In 1988 the surveillance case definition for
national reporting of CS was broadened by the Centers for Disease Control and Prevention (CDC) to
include: 1) a condition affecting stillbirths and infants born to mothers with untreated or inadequately
treated syphilis regardless of signs in the infant or 2) a condition affecting an infant with clinical
evidence of congenital syphilis including direct detection of Treponema pallidum or a reactive
nontreponemal syphilis test with signs on physical examination, radiographs, or cerebrospinal fluid
analysis[1]
CS is the second most common cause worldwide of preventable stillbirth[2]. It could also result in
prematurity and low birth weight. It may be clinically apparent immediately after birth or it can
remain asymptomatic for months or years. Newborns can be successfully treated with appropriate
antibiotics started early after delivery, but this requires a high index of suspicion and appropriate
diagnosis which may at times be difficult[3]
Testing during prenatal care (PNC) visits and timely treatment with appropriate antibiotics for
maternal stage of syphilis will prevent most cases of CS. Still close to a third of CS cases were
diagnosed in newborns who’s mothers were tested during pregnancy and may have acquired
infection after initial testing, emphasizing the need for multiple testing of pregnant women in areas
of high prevalence of primary and secondary syphilis or in women at high risk for acquiring infection
[4]

© 2020 by the author(s). Distributed under a Creative Commons CC BY license.

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Focus on prevention of CS is important but it must start with understanding of the socio-
economic circumstances that place young women at risk for acquiring syphilis. Poverty is the
common denominator for homelessness, drug use, exchange of sex for drugs or money, incarceration
and low education level; all features for increased risk for syphilis. Efforts to overcome these
inequities are under way, meanwhile, focus on expanding care for pregnant women and
understanding the missed opportunities for prevention and implementation of interventions tailored
to local experience will help halt the continued increase of CS.

2. Epidemiology

Worldwide, more than half a million cases of CS were diagnosed in 2016 (rate 472 cases per
100,000 live births) resulting in over 200,000 stillbirths and early neonatal deaths [5]. Estimated
adverse birth outcomes decreased slightly but not statistically significantly from 397,000 cases in 2012
to 355,000 (which excluded 306,000 asymptomatic cases) in 2016[5] In 2007 the World Health
Organization (WHO), launched a global initiative for the elimination of MTCT of syphilis and human
immune deficiency virus (HIV) with three simple interventions a) reach at least 95% of at least 1 PNC
visit, b) 95% of women receiving PNC tested for syphilis and c) at least 95% of women treated
adequately and timely for syphilis.
Recently the CDC reported that CS cases had increased each year in the United States (US) since
2012 which as expected coincided with the increase rate of primary and secondary syphilis in women
of childbearing age[6] (see figure 1) In 2017 there were 918 babies born with CS in the US and the
national CS rate was 23.3 cases per 100,000 live births, the highest rate reported since 1997, an increase
of 153.3% relative to 2013 and to 1,306 in 2018 (increase of 261%)[7].CS rates were 6.4 times and 3.3
times higher among infants born to black and Hispanic mothers (86.6 and 44.7 cases per 100,000 live
births) respectively, compared to white mothers (13.5 cases per 100,000 live births). Significant ethnic,
socioeconomic and geographic differences affect the risk for primary or secondary syphilis in women
of childbearing age[4]

Figure 1: Reported Cases by Year of Birth and Rates of Reported Cases of Primary and Secondary Syphilis
Among Females Aged 15-44 Years, United States, 2009-2018, Adapted from the CDC Sexually Transmitted
Disease Surveillance 2018 [6]
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3. Biology of Treponema Pallidum

Syphilis is a chronic infection caused by Treponema pallidum subspecies pallidum (hence referred
as T. pallidum) which belongs to the family of spiral-shaped bacteria, the Spirochaetaceace commonly
referred to as the spirochetes. Other members of this order include the genera Borrelia and Leptosira.
T. pallidum is related to other pathogenic treponemes which are all morphologically identical to
each other and cause nonvenereal diseases including T. pallidum endemiccum (bejel), T pallidum
pertenue (yaws), and T carateum (pinta) which can be differentiated from one another by their
clinical manifestations and genetic differences.[8, 9]
The T. pallidum cellular structure is composed of a fragile outer membrane that lacks
liposaccharides (LPS), an inner cytoplastic membrane and a thin layer of peptidoglycan between
the membranes that provides structural stability. The endoflagella and organelles that allow for the
characteristic corkscrew mobility are located in the periplasmic space [10]
The genome of T pallidum is 1.14 Mb which is strikingly smaller than most conventional gram-
negative and gram positive bacteria such as Escherichia coli which is 4.6 Mb and Staphylococcus
aureus which is about 2.8 Mb[11]. The lack of genetic sequence therefore, leads T. pallidum to have a
limited metabolic capacity and hence requires macromolecules from the host environment for most
of its nutritional requirements. Analysis carried out by the Genome Sequencing Project
demonstrated that T. pallidum is capable of carrying out glycolysis and carries the ability to
interconvert amino acids and fatty acids. However, the organism lacks the ability for using
alternative carbon sources for energy and de novo synthesis of enzyme cofactors or nucleotides.
Instead the genome encodes for the various transporters needed to obtain the vast majority of
essential macromolecules.[9, 10]

3. Clinical Manifestations
As discussed above, CS occurs when syphilis during pregnancy goes untreated, is treated late
(< 4 weeks before delivery) or inadequately (incomplete regimen for stage of disease, treatment
with an agent other than penicillin); it may result in death (6.5% of cases) of which more than 80%
are stillbirths. Prematurity and low birth weight were strongly associated with death among
neonates born with CS [12, 13].
Most newborns born to mothers with untreated syphilis appear normal and may have no
clinical or laboratory manifestations of CS [14] Diagnosis and treatment decisions may be difficult
and not free of controversy particularly with interpretation of recent establishment of reverse
sequence algorithm (see diagnosis section) [15, 16]

3.1 Early Congenital Syphilis.

Early CS is diagnosed when children develop manifestations of disease within the first 2 years
of life. These are typically systemic reflecting the inflammatory process taking place at one or many
of the organs that became affected during transplacental infection. [3, 17, 18]) (See table 1)
Mucocutaneous lesions are common, affecting 40% - 60% of infants with CS. Characteristic rash
is typically maculo-papular, prominently distributed on the palms and soles and similar to that of
secondary syphilis, it evolves from erythematous to copper in color; pemphigus syphyliticus is unique
to newborns and consists of vesicobulous lesions which may peel and eventually crust and heal with
noticeable skin wrinkling; occasionally mucous lesions which are elevated and flat, may develop in
perioral and perianal regions and go unrecognized [19] (See figure 2). Some infants may develop
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rhinitis, characterized by a copious nasal discharge which may become purulent if untreated.
Condylomatous and bullous lesions as well as nasal discharge contain large amounts of T pallidum
and are highly contagious.
.

Figure 2. A) Perirectal lesion on a 6 months-old infant with an RPR of 1:512. B) Histological staining of a biopsy
from the perirectal mass demonstrates high amount of spirochetes. [19]. From Arrieta, A.C. and J. Singh,
Congenital Syphilis. 381(22): p. 2157-2157. Copyright © 2019 Massachusetts Medical Society. Reprinted with
permission.

Liver and spleen are frequently involved with hepatosplenomegaly a common feature on
physical exam which may take months to resolve after treatment. Liver enzymes, direct bilirubin and
alkaline phosphatase are typically elevated. Hematological abnormalities are common; anemia is
noticed in 75% of patients and 50% will have an elevated white blood cell count with monocytosis.
Thrombocytopenia and petechia occurs frequently and may be the only manifestation of CS. Skeletal
manifestations are present radiographically in > 95% of symptomatic and 25% of asymptomatic CS
infants. Lesions are typically symmetric and involve primarily long bones.
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Table 1. Clinical manifestations of early and late congenital syphilis

Early Congenital Syphilis Late Congenital Syphilis

Prenatal Dentition

Nonimmune hydrops Hutchinson’s teeth

Intrauterine growth retardation Mulberry molars

Stillbirth Eye

Hematological/ Interstitial keratitis

Reticuloendothelial

Hepatosplenomegaly Ear

Lymphadenopathy Eight nerve deafness

Thrombocytopenia Nose/Face

Anemia Saddle nose

Leukopenia/Leukocytosis Impaired maxillary growth

(monocytosis)

Mucocutaneous Cutaneous

Rhinitis (sniffles) Rhagades

Rash (papulovesicular, Skeletal

prominent in palms and sole;
pemphigus syphiliticus)

Mucous patches Frontal bossing

Skeletal Saber shins

Long bone lesions (Weinberger Clavicle (sternal end)

sign in tibial protuberance) hypertrophy
(Higoumenakis’ sign)

Periostitis (pseudoparalysis) Clutton’s joints (knees)

Neurological Neurological

Aseptic meningitis Aseptic

meningitis/asymptomatic
neurosyphilis

Ocular Other*

Retinitis (rare, also cataracts and

keratitis)
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Destruction of tribal tubercle (Weinberger sign) is highly suggestive of CS [20](See figure 3).
Periostitis of the metaphysis of the long bones results in pseudoparalysis (pseudoparalysis of
Parrot) and distinctive radiographic features (see figure 3)
CNS involvement is common, cerebrospinal fluid (CSF) abnormalities consistent with aseptic
meningitis are present in > 50% of symptomatic and 10% of asymptomatic infants. Often is the only
finding elicited during the work up for sepsis in young febrile infants [14]. Non treponemal tests
should be considered in all febrile infants with CSF pleocytosis and no microbiological diagnosis.
Other manifestations of CS include pulmonary involvement (pneumonia alba), immune complex
mediated nephrotic syndrome, lymphadenopathy, ocular findings (retinitis, uveitis or cataracts),
pancreatitis and myocarditis may be present with less frequency.

A B

C D

Figure 3. Neonate born to mother without prenatal care highlights importance of testing of pregnant
women without prenatal care (PNC) and complete evaluation as not all tests are abnormal. Patient was born
at 29 weeks gestation to a G7 P3033 homeless woman without PNC. Tested positive for methamphetamine. No
hepatosplenomegaly was identified on exam She had at a + RPR (1:16); positive TP-PA. Her newborn infant
had a + RPR (1:256) Her skeletal survey showed extensive periostitis and destruction of the distal metaphysis
both femur Her WBC was 66.2 K/UL; Hgb 9.1 g/dl. Liver enzymes (AST = 77/ALT = 10) were normal, alkaline
phosphatase = 322 U/L, direct bilirubin = 0.3. CSF had a protein of 201 mg/dl, glucose 57 mg/dl, WBC = 1/mm3,
VDRL + Ophthalmological exam showed interstitial keratitis. Weinberger sign (A). Periostitis of the long bones
(B). Rib notch associated with CS. (C). Epiphyseal dislocation with pseudoparalysis of the affected limb (D)
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3.2 Late Congenital Syphilis.

Late onset disease is seen in children older than 2 years of age and is not contagious. The features
of late onset CS are the consequence of protracted inflammation of organs and tissues resulting in
permanent scars or destruction of affected organs [21, 22])
Dental manifestations are seen in permanent teeth; Hutchinson’s teeth are small, widely
separated, barrel shaped and notched; Mulberry molars refer to the presence of many small cusps on
the first lower molar instead of the usual four cusps. Treatment of CS in utero or during the first 3
months of life prevents dental changes.
Interstitial keratitis usually appears in puberty, severe inflammation usually presents in one eye
later becoming bilateral; it is not seen in children who received treatment before 3 months of age.
Eight nerve deafness occurs in only 3% of patients with late CS and typically presents in the first
decade of life. Spirochetes are not found in children with deafness or keratitis, and these may respond
to steroids. The simultaneous presence of interstitial keratitis, eighth nerve deafness and
Hutchinson’s teeth is known as Hutchinson’s triad.
Rhagades are linear scarring lesions radiating from the mouth [23]. Saddle nose is the late
sequela of cartilage and bone destruction in children with CS rhinitis. Saddle nose is often associated
with failure of the maxilla to grow fully, with relative protuberance of the mandible and associated
high palatal arch.
Skeletal sequelae including frontal bossing, saber shins and thickening of the sternal end of the
clavicle are the consequence of protracted periostitis. Symmetric, chronic, painless swelling of the
knees (Clutton joints) is a rare manifestation of CS.
Incidence of neurological manifestations in CS varies in different reports but may affect as much
as a third of patients with abnormal findings in spinal fluid. Developmental delay, hydrocephalus,
seizures and cranial nerve involvement have been reported but are rare now.
Late CS is rare in the US these days and represents a failure to diagnose and treat CS early. This is
more common in asymptomatic neonates in who the risks or infectious status of the mother were not
well evaluated.

4.Diagnostic Tests and Management

Definitive diagnosis of CS is made when spirochetes are identified by darkfield microscopy
examination of the body fluids or tissue, however, most clinical settings lack the capacity to perform
direct detection. T. pallidum can be detected by polymerase chain reaction assays, but to date no assays
are approved by the US Food and Drug Administration (FDA) for clinical diagnosis. Direct
fluorescent antibodies (DFA) were historically used but are no longer available in the US. Instead
most clinical laboratories utilize serological testing to infer a diagnosis of CS since maternal non-
treponemal and treponemal IgG antibodies are transferred trans-placentally to the fetus. The
finding of an infant’s serum quantitative non-treponemal titer that is four-fold higher than the
maternal titer is confirmatory for CS. However, the absence of such finding does not exclude the
diagnosis as most infants with CS have titers that are equal to or less than the maternal titer.[24, 25]
Two algorithms of serological testing are commonly used for the diagnosis of CS, and both
require two-step testing (see figure 4) . These algorithms utilize both non-treponemal and treponemal
serological tests and only vary in the order in which the tests are performed. [16, 24, 26] The same
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non-treponemal tests must be performed on mother and infant so that an accurate comparison can
be made. The traditional algorithm starts with a quantitative non-treponemal test such as the rapid
plasma reagin (RPR) or Venereal Disease Research Laboratory (VDRL) followed by a confirmatory
treponemal-specific test such as fluorescent treponemal antibody absorption (FT-ABS) or T pallidum
particle agglutination test (TP-PA) if the non-treponemal test is positive. With development of high-
throughput automated treponemal-specific immunoassays, many clinical laboratories have opted for
the reverse sequence algorithm (RS) for CS screening. The RS starts with a treponemal test such as
the treponemal enzyme immunoassay (EIA) or chemiluminescence immunoassay (CIA). If positive,
then a quantitative non-treponemal test such as RPR is performed, which if also positive, it confirms
a diagnosis of syphilis in the mother. Then a comparison is made in between the non-treponemal
titers of the mother and infant to determine the diagnosis of confirmed or probable CS. If, however,
the non-treponemal test is negative then a second treponemal test (TP-PA is the preferred) is
performed. If the second treponemal test is negative then the initial positive result is deemed as a
false-positive. However, if the second treponemal test is positive then the diagnosis of previous or
current syphilis infection is made on the mother [27, 28]. . Infants born to women who have a previous
history of adequate treatment for syphilis, longer than 4 weeks before delivery and evidence of 4-fold
declining non-treponemal titer, require no further evaluation if appropriate follow of the infant is
likely.
All Infants born to mothers with reactive serological test for syphilis require quantitative non-
treponemal testing and should be carefully examined for signs of CS if the mother has no history of
adequate treatment. Moreover, given the high rate of co-infection with HIV, these women should be
screened for HIV infection as well. If mother is unavailable for testing, the newborn must be screened
utilizing HIV DNA PCR. Appropriate prophylaxis or treatment should be considered. In neonates
who have a normal physical examination and a serum quantitative non-treponemal serologic titer
that is less than four-fold the maternal titer, evaluation and treatment depends on maternal treatment
history. If the mother has untreated syphilis or the treatment is undocumented or inadequate (see
above), a complete evaluation consisting of cerebrospinal fluid (CSF) analysis, long bone
radiographs, liver enzymes and bilirubin and complete blood cell (CBC) and platelet counts should
be performed to guide optimal therapy. If the evaluation is completely normal but follow up is
questionable, the infant should be treated with a single intramuscular dose of benzathine penicillin
G[25]. Alternatively, if any abnormality is encountered, the infant should receive a 10-day course of
parenteral treatment with crystalline penicillin G or procaine penicillin.[3]
Congenital neurosyphilis (CN) is a very difficult diagnosis to derive as most babies with CS have
a normal physical and neurological examination. CN can be suspected based on CSF findings which
includes a reactive VDRL test, pleocytosis (defined by the CDC as greater than 5 white blood cells
per microliter, although this value in itself can be found in a normal neonate[29] ), and elevated
protein content (45 mg/dL; 170mg/dL if infant is premature). Hence, if the physical exam, laboratory
and radiographic results support the diagnosis of CS, treatment must be inclusive of CN regardless
of CSF findings.[3, 24, 25]
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Traditional

Reverse Sequence

F
FIGURE 4. Traditional and reverse sequence algorithms for maternal serologies. NTT=Non-treponemal test
TT= Treponemal test *=The confirmatory TT must be different from the initial TT. Ɨ= The likely or most likely
interpretation of the test results.
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5. Treatment and Follow Up.

Parenteral penicillin G remains as the only antibiotic capable of preventing MTCT and CS.
Pregnant women with syphilis should receive the penicillin regimen appropriate for the stage of
infection. Pregnant women who have a history of penicillin allergy must be desensitized and treated
with penicillin. The decision to treat an infant is dependent on whether the infant has proven or
probable CS, has possible CS, or considered less likely or unlikely to have CS (see figure 5) The
treatment of infants with CS based on the CDC and Red Book guidelines as detailed on figure5. Note
that if more than one dose of penicillin is missed the entire course should be restarted [3, 25].
After discharge, an infant is followed every 2-3 months with repeat nontreponemal titers. Infants
with CS who are adequately treated should have a four-fold decrease on non-treponemal titers within
6 months and become non-reactive by 12 months. Uninfected infants who had maternal-fetal
transmission of IgG non-treponemal antibodies should be seronegative by 6 months. If the non-
treponemal tiers increase four-fold at any time or remain stable after 12 months, the infant must be
re-evaluated and re-treated with an additional 10-day course of parenteral penicillin G. If the infant
at initial evaluation had a positive VDRL consistent with NS, then a repeat lumbar puncture is
performed at 6 months of age [3, 30]

6. Conclusion
Syphilis infection during pregnancy still represents a worldwide public health problem. If left
untreated, can lead to fetal demise and high neonatal morbidity and mortality. CS can be effectively
prevented by prenatal serologic screening of mothers and penicillin treatment of infected women,
their sexual partners, and when indicated, their newborn infants. The CDC and the USPSTF both
recommend screening all pregnant women during the first trimester and high-risk mothers at 28
weeks gestation and delivery[7, 16]. A study done in Florida and Louisiana following the guidelines
in high risk pregnant women was able to pick up an additional 5% of CS cases by screening at 28
weeks and delivery for an additional treatment of 30 patients over first trimester screening only [31]
However, despite the available data and clinical knowledge, the rates in the US and worldwide
continue to rise and predominantly affects disadvantaged communities that have issues with
poverty, substance abuse and lack of health care access. To date the US does not have a national
program to mandate screening all pregnant women for CS, in fact there are still six states where there
is no requirement and only a third of states require a third trimester screening [32] . Worldwide the
WHO continues to implement prenatal screening programs that includes syphilis testing coupled
with appropriate, prompt penicillin treatment for pregnant women, These programs have been able
to demonstrate decrease cases of CS and moreover, are cost effective in comparison to dealing with
the long term sequela of untreated CS[30]. Unfortunately, there are many regions in the world where
the infrastructure is not available to scale up syphilis screening programs. To meet these
challenges increased awareness of on the risks, evaluation and treatment of syphilis in mother and
newborn is critically important as is educate legislators policy makers on the needs of disadvantage
populations who often cannot advocate for themselves.
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Figure 5, Algorithm for treatment of congenital syphilis. Figure produced by the California Department of
Public Health[33]
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Author Contributions: Alvaro E. Galvis- Writing- original draft preparation, review and editing, visualization.
Antonio Arrieta- Conceptualization, supervision, writing- original draft preparation, review and editing.

Funding: This research received no external funding

Acknowledgments: The authors would like to thank Dr. Matthew Zahn at the Orange County Department of
Public Health for his guidance.

Conflicts of Interest: The authors declare no conflict of interest.

References

1. CDC, Congenital syphilis--New York City, 1986-1988. MMWR Morb Mortal Wkly Rep, 1989(0149-2195
(Print)): p. 825-829.
2. Lawn, J.E., et al., Stillbirths: rates, risk factors, and acceleration towards 2030. The Lancet, 2016. 387(10018):
p. 587-603.
3. Cooper, J.M. and P.J. Sanchez, Congenital syphilis. Semin Perinatol, 2018. 42(3): p. 176-184.
4. Kimball A, T.E., Miele K, Bachmann L, Thorpe, P,, Weinstock H., Bowen V., Missed Opportunities for
Prevention of Congenital Syphilis MMWR Morb Mortal Wkly Rep, 2020. 69: p. 661–665.
5. Korenromp, E.L., et al., Global burden of maternal and congenital syphilis and associated adverse birth
outcomes-Estimates for 2016 and progress since 2012. PLoS One, 2019. 14(2): p. e0211720.
6. Prevention., C.f.D.C.a., Sexually Transmitted Disease Surveillance 2018. U.S. Department of Health and
Human Services, 2019.
7. Prevention, C.f.D.C.a., Sexually Transmitted Disease Surveillance 2018. 2019, U.S. Department of Health
and Human Services.
8. Peeling, R.W. and E.W. Hook, The pathogenesis of syphilis: the Great Mimicker, revisited. The Journal of
Pathology, 2006. 208(2): p. 224-232.
9. Šmajs, D., M. Strouhal, and S. Knauf, Genetics of human and animal uncultivable treponemal pathogens.
Infection, Genetics and Evolution, 2018. 61: p. 92-107.
10. Radolf, J.D., et al., Treponema pallidum, the syphilis spirochete: making a living as a stealth pathogen. Nature
Reviews Microbiology, 2016. 14(12): p. 744-759.
11. Wang, J., et al., Whole-Genome Sequence of Staphylococcus aureus Strain LCT-SA112. Journal of
Bacteriology, 2012. 194(15): p. 4124-4124.
12. Gust DA, L.W., St. Louis ME; Braxton J, AS; and Berman SM., Mortality Associated With Congenital
Syphilis in the United States, 1992–1998. Pediatrics, 2002. 109;e79.
13. Su, J.R., et al., Congenital syphilis: trends in mortality and morbidity in the United States, 1999 through 2013.
Am J Obstet Gynecol, 2016. 214(3): p. 381 e1-9.
14. Dorfman, D.G.J., Congenital Syphilis Presenting in infants after the newborn period. The New England
Journal of Medicine, 1990. 323(19): p. 1299-1302.
15. Wozniak, P.S., et al., Congenital syphilis in neonates with nonreactive nontreponemal test results. J Perinatol,
2017. 37(10): p. 1112-1116.
16. Force, U.S.P.S.T., et al., Screening for Syphilis Infection in Pregnant Women: US Preventive Services Task
Force Reaffirmation Recommendation Statement. JAMA, 2018. 320(9): p. 911-917.
17. Follett, Resurgence of Congenital Syphilis: Diagnosis and Treatment. Neonatal network : NN., 2011. 30(5):
p. 320.
18. Long, S.S., C.G. Prober, and M. Fischer. Principles and practice of pediatric infectious diseases. 2018;
Available from: https://www.clinicalkey.com/dura/browse/bookChapter/3-s2.0-C20130190204.
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 October 2020 doi:10.20944/preprints202010.0056.v1

13 of 13

19. Arrieta, A.C. and J. Singh, Congenital Syphilis. New England Journal of Medicine, 2019. 381(22): p. 2157-
2157.
20. Stephens, J.R. and J. Arenth, Wimberger Sign in Congenital Syphilis. J Pediatr, 2015. 167(6): p. 1451.
21. Fiumara, N., Lessell S., Manifestations of Late Congenital Syphilis Arch Dermatol 1970. 102: p. 78-84.
22. De Santis, M., et al., Syphilis Infection during pregnancy: fetal risks and clinical management. Infect Dis
Obstet Gynecol, 2012. 2012: p. 430585.
23. Khetarpal, S., E. Kempf, and E. Mostow, Congenital syphilis: early- and late-stage findings of rhagades and
dental anomalies. Pediatr Dermatol, 2011. 28(4): p. 401-3.
24. Chen, M.W., et al., Evaluating congenital syphilis in a reverse sequence testing environment. J Perinatol, 2019.
39(7): p. 956-963.
25. American Academy of Pediatrics. Committee on Infectious, D., Red book : report of the Committee on
Infectious Diseases. 2018: Elk Grove Village, IL : American Academy of Pediatrics, c2018-.
26. Sena, A.C., B.L. White, and P.F. Sparling, Novel Treponema pallidum serologic tests: a paradigm shift in
syphilis screening for the 21st century. Clin Infect Dis, 2010. 51(6): p. 700-8.
27. CDC, Discordant results from reverse sequence syphilis screening--five laboratories, United States, 2006-2010.
Morb Mortal Wkly Rep, 2011(1545-861X (Electronic)).
28. Ghanem, K.G., S. Ram, and P.A. Rice, The Modern Epidemic of Syphilis. New England Journal of
Medicine, 2020. 382(9): p. 845-854.
29. Beeram, M., Chopde N.Dawood, Y., Siriboe S, Abedin M, , Lumbar puncture in the evaluation possible
asymptomatic congenital syphilis in neonates. The Journal of Pediatrics, 1996. 128(1).
30. Gomez, G.B., et al., Untreated maternal syphilis and adverse outcomes of pregnancy: a systematic review and
meta-analysis. Bull World Health Organ, 2013. 91(3): p. 217-26.
31. Matthias, J.M., et al., Effectiveness of Prenatal Screening and Treatment to Prevent Congenital Syphilis,
Louisiana and Florida, 2013-2014. Sex Transm Dis, 2017. 44(8): p. 498-502.
32. Stafford, I.A., P.J. Sanchez, and B.J. Stoll, Ending Congenital Syphilis. JAMA, 2019.
33. CDPH Congenital Syphilis Algorithm.
https://www.cdph.ca.gov/Programs/CID/DCDC/Pages/CongenitalSyphilis.aspx, 2019.

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