ESPID Reports and Reviews

CONTENTS
Congenital Syphilis: Controversies and Questions

EDITORIAL BOARD
Editors: Emmanuel Roilides and Shamez Ladhani
Board Members

David Burgner (Melbourne, Cristiana Nascimento-Carvalho Tobias Tenenbaum (Mannhein, Germany)

Australia) (Bahia, Brazil) Marc Tebruegge (Southampton, UK)
Kow-Tong Chen (Tainan,Taiwan) Ville Peltola (Turku, Finland) Helen Groves (Junior ESPID Board
Luisa Galli (Florence, Italy) Ira Shah (Mumbai, India) Member, UK)
Steve Graham (Melbourne, George Syrogiannopoulos Fani Ladomenou (Junior ESPID Board
Australia) (Larissa, Greece) Member, Greece)

Congenital Syphilis: Controversies and Questions

A Global Perspective
Bridget Freyne, MBBchBAO, PhD,*† Clare Nourse, FRACP, MD,‡§ and Tony Walls, FRACP, MD¶‖

Key Words: gestational syphilis, epidemiology, of gestational syphilis was 0.69% (95% con- include tiered entrance onto the elimination
congenital syphilis fidence intervals: 0.57%–0.81%), which pathway. Successful elimination strategies
translated into an estimated rate of congenital were underpinned by political engagement,
syphilis of 473 (385–561)/100,000 live births. consistent health infrastructure, and engage-
BACKGROUND In the African region, these rates are 3 times ment with high risk populations.4 These les-
Syphilis, the infection caused by the the global average at 1.62% and 1377/100,000 sons will be important for HICs dealing with a
spirochete Treponema pallidum subsp. Palli- live births, respectively.2 Since these estimates resurgence of syphilis. The aim of this review
dum, has been a disease of public health con- were reported, there have been significant is to present a global perspective on several
cern for over 100 years. Gestational syphilis increases in syphilis notifications in high- key controversies in the prevention of mother
is the second leading infectious cause of still- income countries (HICs) which have included to child transmission of syphilis and to high-
birth worldwide after malaria. Untreated pri- proportional increases in women of childbear- light opportunities for global collaboration.
mary syphilis in pregnancy results in adverse ing age. In Australia, there was a 90% increase
birth outcome 50%–80% of affected pregnan- in reported syphilis cases between 2015 and
cies.1 Modeling of sentinel surveillance data 2020, with a 40% increase among women of CONTROVERSY 1: OPTIMIZING
in 2016 indicated that the global prevalence child bearing age. In the United States, a 21% DIAGNOSTIC ALGORITHMS FOR
increase total notifications between 2019 and MOTHERS AND INFANTS
2020 included a 21% increases in primary and Due to the limitations of serology-
Accepted for publication December 3, 2022
secondary syphilis among women aged 20–24 based diagnostics for syphilis, algorithms
From the *Department of Paediatric Infectious and a 32% increase among women aged combining treponemal tests, nontreponemal
Diseases, Children’s Health Ireland, Dublin, 25–30.3 Despite the widespread availability of tests, and clinical information are required to
Ireland; †Division of Women & Children’s affordable diagnostics and effective treatment, ascertain the stage of maternal syphilis and
Health, School of Medicine, University Col-
lege Dublin, Ireland; ‡Queensland Children’s
syphilis in pregnancy threatens the attain- guide treatment of both mother and infant.
Hospital, Brisbane, Australia; §Faculty of ment of the sustainable development goal for The diagnosis of congenital syphilis depends
Medicine, University of Queensland, Brisbane, reduction of child mortality through impact on on: (i) comparison of paired maternal and
Australia; ¶Department of Paediatrics, Univer- global preterm and stillbirth rates. neonatal nontreponemal titers (with a 4-fold
sity of Otago, Christchurch, New Zealand; and
‖Research for Children Aotearoa, New Zealand
In 2007, the World Health Organi- relative increase in neonatal titers compared
https://www.healthprecinct.org.nz/research-for- zation (WHO) launched a strategy for the with maternal titers being considered con-
children-aotearoa/. elimination of mother to child transmission genital infection) ± the presence of neonatal
The authors have no funding or conflicts of interest (EMTCT) of syphilis by 2030, which was IgM where available, (ii) evaluation of the
to disclose.
Address for correspondence: Tony Walls, FRACP,
expanded in 2014 to include HIV. Cuba and adequacy of maternal treatment [defined by
MD, Department of Paediatrics, University of Thailand became the first low and middle- stage appropriate dosing of penicillin (1–3
Otago, Christchurch, New Zealand. E-mail: tony. income countries (LMICs) to achieve WHO doses) at least 4 weeks before delivery and
walls@otago.ac.nz. validation goals for EMTCT of both HIV and a concomitant drop in nontreponemal titers
Copyright © 2023 Wolters Kluwer Health, Inc. All
rights reserved.
syphilis. In recognition of the high preva- where retesting is available] and (iii) no evi-
ISSN: 0891-3668/23/4205-e166 lence rates and implementation challenges for dence reinfection.3 In low-income settings,
DOI: 10.1097/INF.0000000000003808 LMICs, the roadmap was adapted in 2017 to the introduction of rapid screening tests

The ESPID Reports and Reviews of Pediatric Infectious Diseases series topics, authors and contents are chosen and approved
independently by the Editorial Board of ESPID.

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 The Pediatric Infectious Disease Journal  •  Volume 42, Number 5, May 2023 Congenital Syphilis: A Global Perspective

(RSTs) has increased the coverage of syphilis However, this is associated with a heavy bur- recommended universal rescreening in the
testing at first antenatal visit and has proven den of clinical and laboratory capacity only 3rd trimester or at delivery. An alternative
cost-effective. The most widely used RSTs feasible in well-resourced systems. While this approach is to retest only high-risk popu-
are treponemal tests alone, which have high approach will prevent unnecessary treatment lations, defined as patients living in areas
specificity but are unable to differentiate the of mothers and infants and ensure adequate with rates of primary and secondary syphi-
stage of disease or success of prior treatment. follow-up, the converse challenge is high lis greater than 2/100,000, women who are
These have been chosen over traditional rates of biologic false positives requiring uninsured or low income, women who are
nontreponemal tests (rapid plasma regain or re-evaluation. In practice, in the absence of diagnosed with another sexually transmitted
Venereal Disease Research Laboratory test) adequate treatment information, most clini- infection during pregnancy or who sell sex
as they do not require phlebotomy, labora- cians in both HIC and LMIC settings will opt for money or drugs. The limitations of this
tory reagents or a microscope and results are to treat potentially exposed infants. approach include the dependence on adequate
available in real-time facilitating same day Investment in accurate, affordable identification of high-risk women who fre-
test and treat strategies.5 RSTs could substantially reduce over-treat- quently do not disclose or may not be aware
Figure  1 compares 3 WHO-recom- ment in LMICS and may have a role in reach- of the risks associated with certain practices.8
mended algorithms for diagnosis and man- ing vulnerable populations in HICs. Current Globally, universal rescreening at
agement of syphilis in pregnancy, which can areas of active research include RSTs which delivery serves 3 functions, the importance
be chosen by Ministries of Health depending combine both treponemal and nontreponemal of which vary depending on local epidemi-
on local availability of tests. Each algorithm components and rapid nucleic acid amplifi- ology and health systems challenges. First,
assumes over-treatment, with women who are cation tests on perinatal swabs and tissues. it ensures that women and infants affected
RST positive without documentation of treat- Prior collaborative Global Health initiatives by gestational syphilis and not yet tested are
ment automatically qualifying for retreatment for malaria and tuberculosis diagnostics can diagnosed and receive treatment, which can
with up to 3 doses of IM Benzathine Penicil- act as templates to advocate for development prevent late sequelae of congenital syphilis
lin (BPG).6 Over-treatment may be justified of these tools. not apparent at birth. Second, it will capture
in high prevalence settings given the afford- women who tested positive during antenatal
ability of BPG and the fact that 50%–80% of care but were unable to access treatment for
untreated pregnancies will end in an adverse CONTROVERSY 2: UNIVERSAL themselves and their partners. Finally, it will
birth outcome. By contrast, the algorithm RETESTING OF PREGNANT identify women who have become infected
from the Australian & New Zealand Paedi- WOMEN AFTER THE 3RD during pregnancy. In Malawi, modeling data
atric Infectious Diseases Group recommends TRIMESTER suggests that only 23% of pregnant women
an intensive diagnostic and follow-up testing Of the 62 national guidelines identi- may currently have access to service coverage
regimen with a higher threshold for treatment. fied in the review by Trinh et al,7 46 (81%) in line with EMTCT process outcomes and

Maternal pathway Infant pathway

RST only +ve treat

-ve discharge
WHO strategies

Treat infant 10-15 days IV BP / IM PP if:

⁻ Symptomatic congenital syphilis
⁻ Maternal treatment < 30 days prior to delivery or
+ve treat
RPR only incomplete
-ve discharge
Treat infant stat dose IM BPG if:
⁻ Uncertainty regarding maternal treatment OR above
treatment not feasible
RPR+ve treat with 2
+ve treat and RPR further doses if duration
RST first
-ve discharge of syphils > 2 years or NK
RPR -ve discharge

Symptomatic OR
serology/placenta abnormal:
⁻ Treat 10-15 days
Retest high risk at ⁻ Follow-up serology at
Desensitise if
28-32 wks & if ⁻ Infant IgM & Paired 1,2,4,6,12 months or until
ANZPID strategy

Both tests -ve penicillin allergy.

+ve evaluate as RPR non-reactive x 2
syphilis Treat as per stage:
Non-treponemal - Early: IM BPG x 1 ⁻ Clinical examinaon ⁻ If neurosyphilis repeat LP
(RPR OR VDRL) Both tests +ve - Late: IM BPG x 3 (+/- LP, eyes, radiograph 6m
AND Treponemal OR Trep +ve - RPR weekly until ⁻ Placental histology + ⁻ Retreatment if required
(TPPA/TPHA/EIA) delivery PCR
Repeat at 4 weeks Test & Treat partners
Non-trep +ve
& if remains +ve Normal serology and examinaon
AND Trep -ve
evaluate as syphilis repeat serology at 3 & 6 mth

FIGURE 1.  Comparison of potential recommended strategies for the diagnosis, management and follow-up of pregnancies affected
by syphilis in LMIC (WHO) and HIC (Australian & New Zealand Paediatric Infectious Diseases Group ANZPID). BP indicates aqueous
benzylpenicillin; IM BPG, intra-muscular benzathine penicillin; EIA, enzyme immunoassay antibody test; LP, lumbar puncture;
NK, not known; PCR, polymerase chain reaction; PP, procaine penicillin; RPR, rapid plasma regain; TPHA, Treponema Pallidum
Hemagglutinin Test; TPPA, Treponema Pallidum Particle Agglutination Test; VDRL, Venereal Disease Research Laboratory test.

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Freyne et al The Pediatric Infectious Disease Journal  •  Volume 42, Number 5, May 2023

the introduction of universal rescreening at Worldwide, notification strategies is not present. In these cases, however cli-
delivery would overcome some of these barri- include passive notification, which relies on nicians must assume that macrolides do not
ers. While universal retesting in LMICs with the pregnant woman informing her sexual cross the placenta effectively and that these
available treponemal RSTs will again lead to partner(s), and provider notification using infants have congenital syphilis. Phase I
over-treatment the risk benefit ratio remains phone or e-mail. The latter approach is and II trials of high dose amoxicillin and
favorable. Conversely, in HICs retesting at favored in high-income settings as it allows ceftriaxone in pregnant women have shown
delivery using the dual treponemal/nontre- ease of contact to multiple sexual partners, promising results although the participant
ponemal testing strategy in the mother and provides confidentiality for the index case numbers are small. Randomized controlled
infant may generate too many false positives and protects pregnant women from any studies of alternative agents such linezolid
in low-risk patients to be acceptable. threat of intimate partner violence when and oral cephalosporins including cefixime
The decision to adopt universal syphi- disclosing their diagnosis. The feasibility are actively recruiting nonpregnant patients
lis rescreening in the 3rd trimester is ulti- of this approach in LMICs is variable and and may provide efficacy data in poten-
mately dependent on local cost-effectiveness. efficacy studies from China and Uganda tially useful drugs for pregnant women and
A decision tree analysis of universal 3rd tri- showed that investment in provider notifi- infants.8 The use of innovative adaptive and
mester retesting in the United Kingdom con- cation did not translate into attendance for ecological trial designs as well as inclusion
cluded that the intervention would result in a treatment.10 Conversely, strategies aimed at of pregnant women in clinical trials with rig-
reduction of congenital syphilis cases of 5.5 inclusion of men more broadly in antenatal orous safety profiles should be employed to
(3.3–8.8)/yr with a cost of 1.8 million GBP clinic and MTCT services, which adapted assess the safety and efficacy of alternative
per life saved and was thus not cost-effective antenatal clinic service delivery to promote drugs with activity against T. pallidum in this
in that country.9 Similarly, a study done in the privacy and male attendance and which population.
United States in 2014 did not favor 3rd trimes- included nurse or video-led partner specific
ter testing. However, a repeat of this analysis education were more effective in promoting
in 2019 when the prevalence of primary and partner attendance for treatment following CONCLUSIONS AND
secondary syphilis had increased by 71.4% notification across a range of settings from RECOMMENDATIONS
indicated that the incidence of congenital Malawi to Thailand. In high-burden set- Gestational syphilis is responsible
syphilis had crossed the cost-effectiveness tings, optimizing strategies to treat sexual for a major preventable burden of adverse
threshold of 10/100,000 live births.8 This partners is an essential component of both perinatal outcomes globally and threatens
highlights that cost-effectiveness is dynamic the individual clinical and public health attainment of the sustainable development
and requires frequent review and potentially response to syphilis. goals on child mortality. Syphilis dispro-
even regional application. Retesting in the portionately affects vulnerable and mar-
3rd trimester may be a feasible intervention ginalized populations worldwide and is
to reduce the burden of community infection
CONTROVERSY 4: TREATMENT
exacerbated by cultural factors which affect
and the late sequelae of congenital infec- OPTIONS TO PREVENT female autonomy in care-seeking. Given
tion in asymptomatic infants. National and CONGENITAL SYPHILIS the recent dramatic rises in the incidence
regional data on the optimal strategies for BPG IM is the backbone of global of gestational syphilis in HICs, persistently
implementation of this strategy and the asso- EMTCT syphilis strategies. Determina- elevated and under-reported rates in LMICs
ciated cost-effectiveness are lacking globally, tion of the clinical stage of syphilis in and high rates of international migration, a
particularly in LMICS. the mother dictates the number of doses global approach to resolving the diagnostic,
required to adequately treat the infant. therapeutic and implementation controver-
Consistent delivery of this schedule is chal- sies in EMTCT of syphilis is warranted.
CONTROVERSY 3: THE lenging and failure to deliver or adequately
OPTIMAL APPROACH TO THE Global efforts to innovate against these
document the treatment schedule can result challenges for other endemic diseases of
MANAGEMENT OF SEXUAL in the need for additional investigations and public health concern such as HIV, tuber-
PARTNERS treatment in the infant. Global shortages culosis and malaria can provide a template
Management of the risk of reinfec- of BPG, which have disproportionately for success.
tion following successful antenatal treat- affected sub-Saharan Africa, Brazil, South
ment is an essential component of EMTCT East Asia and Australasia, have hampered REFERENCES
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