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Syphilis is on the increase: the implications for
child health
Rana Chakraborty and Suzanne Luck
Arch. Dis. Child. 2008;93;105-109
doi:10.1136/adc.2006.103515
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Leading article
Syphilis is on the increase: the
implications for child health
Rana Chakraborty, Suzanne Luck
Regardless of origins, syphilis has affected
Europeans over many centuries. The first
well-documented outbreak occurred in
Naples in 1494, rapidly swept throughout
Europe and was associated with a myriad
of presenting signs and symptoms and a
high mortality rate.1 The condition was
once a leading cause of dementia and in
the pre-antibiotic era caused one out of
five of all admissions to psychiatric
institutions in the USA.2 In 1943
Mahoney and co-workers first treated
cases of syphilis with penicillin. This drug
has remained the mainstay of treatment
since that time.3
TRANSMISSION
Horizontal transmission among adolescents and adults is primarily sexual,
although anecdotal reports cite kissing,
contact with infected secretions and
blood transfusion as potential sources of
acquisition and transmission.4
Transmission to the fetus is usually via
the placenta, but may occur during
delivery in the presence of maternal
genital lesions. The risk of vertical transmission of syphilis from an infected
untreated mother decreases as maternal
disease progresses, ranging from 70–100%
for primary syphilis and 40% for early
latent syphilis to 10% for late latent
disease (early and late latent syphilis
occurring less than or more than 1 year
after initial infection in adults, respectively).3 5 Although unusual, transmission
to newborns from mothers with tertiary
syphilis has also been reported.6 Thus, the
longer the interval between infection and
pregnancy, the more benign is the outcome in the infant (Kassowitz’s law).6
EPIDEMIOLOGY
Syphilis is common in the developing
world with localised prevalence in pregnant women varying widely from 2.5% in
Burkina Faso to 17.4% in Cameroon.7
Department of Child Health, St George’s Hospital,
London, UK
Correspondence to: Dr R Chakraborty, Department
of Child Health, St George’s Hospital, 5th Floor,
Lanesborough Wing, Blackshaw Road, Tooting,
London SW17 0QT, UK; rchakrab@sgul.ac.uk
Arch Dis Child February 2008 Vol 93 No 2
However, such data may be skewed by
high numbers of false-positive assays.
Data on sexually transmitted infections
have been collected in the UK since 1917;
such infections are currently reported by
genitourinary medicine (GUM) clinics to
the Health Protection Agency (HPA) by
KC60 statutory notification in England,
Wales and Northern Ireland and by
ISD(D)5/STISS returns in Scotland.
These official figures may therefore be
an underestimation of the burden of
congenital syphilis if diagnoses are made
outside the GUM setting. Since 1998 a
sharp increase in syphilis diagnoses has
been documented among heterosexual
populations8 9 and men who have sex
with men (MSM) (fig 1). In Manchester
and London, this increase resulted in the
introduction of enhanced surveillance in
1999 and 2001, respectively, which was
subsequently extended nationally.
Among women, syphilis primarily
affects 16–34-year-olds who are also those
most likely to conceive (fig 2), mandating
screening for
syphilis
antenatally.
Localised outbreaks in the UK have been
associated with sex workers and cocaine
usage.8 10 An earlier study performed by
the British Paediatric Surveillance Unit
(BPSU) commented on an over-representation of pregnant women from ethnic
minorities born outside the UK treated for
syphilis in the Thames region.11 Recent
reports have raised concerns that current
antenatal testing may be inadequate for
the identification and treatment of
women at risk.11–13 These concerns are
reinforced by recent data from the HPA,
which identified 36 cases of congenital
syphilis in the UK in 2005, the highest
number in 10 years.14
CLINICAL MANIFESTATIONS
In pregnant women untreated or inadequately treated syphilis is associated with
prematurity, low birth weight, nonimmune hydrops and intrauterine death.
It has been estimated that at least twothirds of all fetuses of mothers with
infectious syphilis are in some way
affected.15 The WHO estimates that
1 million pregnancies are affected by
syphilis worldwide. Of these 460 000 will
result in abortion or perinatal death,
270 000 infants will be born prematurely
or with low birth weight, and 270 000
will be born with stigmata of congenital
syphilis.16 Most affected infants are
asymptomatic at birth with two-thirds
developing symptoms by 3–8 weeks.
Almost all exhibit symptoms by 3 months
of age.17
The pathological features in all stages of
syphilis reflect vasculitis and its consequences, namely necrosis and fibrosis. The
gummatous stage is characterised by
chronic granulomatous inflammation. The
syndromes of congenital syphilis can be
classified as either early or late. Early
features are similar to the manifestations
of secondary syphilis in adults; late onset is
defined as symptoms developing in children
older than 2 years of age and characterised
by gumma formation in tissues including
bone, cardiac and the nervous system.
The early manifestations of congenital
syphilis
The symptoms of early syphilis can be
varied. ‘‘Snuffles’’ or persistent rhinitis is
often the earliest presenting symptom,
occurring in 4–22% of newborns.18 This
discharge can take many forms and is
highly infectious. Necrotising funisitis, a
deep-seated infection of the umbilical cord,
was considered to be diagnostic of congenital syphilis. It almost always occurs in
premature neonates and is associated with a
high incidence of intrauterine or perinatal
death.19 Other common, but often nonspecific, symptoms of congenital syphilis
include non-tender generalised lymphadenopathy, conjugated hyperbilirubinaemia
and hepatosplenomegaly (table 1).20 21
Glomerulonephritis resulting in nephrotic
syndrome may also occur. The rash in early
syphilis is classically a vesiculobullous or
maculopapular rash occurring on the palms
and soles and may be associated with
desquamation. Other rashes including
erythema
multiforme
have
been
reported.20 22 Asymptomatic cerebrospinal
fluid changes (elevated protein, positive
Venereal Disease Research Laboratory test
(VDRL)) may be found in 80% of infants,23
but acute syphilitic meningitis occurs
rarely.24
Bony lesions occur commonly and
present in the first 8 months of life.
Radiographic abnormalities may be seen
in 20% of babies with asymptomatic
infection necessitating prompt radiological assessment of all exposed infants. The
bones most often affected include the
tibia, the tubular bones of the hands and
feet and, more rarely, the skull and
105
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Leading article
Figure 1 Numbers of diagnoses of syphilis (primary, secondary and early latent) by sex, GUM
clinics, England, Wales and Scotland, 1931–2005. Equivalent Scottish data are not available prior to
1945. Northern Ireland data from 1931 to 2000 are incomplete and have been excluded. Data
source: KC60 statutory returns and ISD(D)5\STISS data. GUM, genitourinary medicine.
clavicles. Radiographic examination of
bones can reveal irregular epiphyseal lines,
decalcification of subchondral bone, cupping of the diaphysis, irregularity of
cartilage adjacent to the epiphysis and
periosteal
thickening.
The
typical
Wimberger’s lines seen during early syphilis reflect metaphyseal destruction secondary to focal erosion of the inner aspect
of the proximal tibia.21 25 Osteochondritis
or Parrot’s pseudo-paralysis is the most
common and earliest lesion characterised
by an asymmetric, painful, flaccid paralysis of the upper limbs and knees which
can be confused with Erb’s palsy.26
Diaphyseal periostitis is asymptomatic
and radiographic changes are often not
seen until after 3 months of age.
The late manifestations of congenital
syphilis
Late congenital syphilis occurs in children
over the age of 2, but most often presents
in puberty.15 Late syphilis can affect many
organ systems, although the sites most
often involved include the bones, teeth
and nervous system. A poor response to
intensive treatment is often documented
during the management of these late
manifestations.27
Some 25–33% of infants with untreated
congenital syphilis have asymptomatic
neurosyphilis once they are more than
2 years old.24 Symptomatic neurosyphilis,
tabes dorsalis and cerebrovascular lesions
develop rarely, with juvenile paresis developing in 1–5% of children/adolescents
with congenital syphilis.24 When symptomatic, neurosyphilis can result in eighth
nerve deafness. The onset of deafness is
generally sudden and occurs at 8–10 years
of age; associated with notched incisors
and interstitial keratitis it forms part of
the classical Hutchinson’s triad. Other
ocular lesions include iridocyclitis and
chorioretinitis.
Following the changes seen in early
syphilis, granulation tissue replaces bone
marrow cortex and pathological fractures
may result later in the disease. Early bony
changes can be completely reversed with
timely treatment but if untreated the
characteristic permanent deformities associated with congenital syphilis develop,
such as saddle nose, palatal erosions, short
maxillae, protruding mandible, frontal
bossing, and sabre tibia. Clutton’s joints
(hydrarthrosis) involving the knees or
elbows may develop between 8 and
15 years of age.
Other characteristic signs of congenital
syphilis are mulberry molars and fissuring
around the mouth (rhagades). Rashes can
also be seen in late onset congenital
syphilis but are more localised in nature
and morphologically distinct from those
seen in early syphilis, consisting of
nodules and gummata.
DIAGNOSIS
The gold standard for diagnosis of syphilis
is the rabbit infectivity test (RIT)
whereby the body fluid of a person with
suspected infection is injected into a
rabbit. Only one organism needs to be
present to confirm diagnosis, however
this test has obvious limitations and is
not used routinely in clinical practice in
the UK. Definitive diagnosis of syphilis
more usually involves viewing the classical spirochaetes of Treponema pallidum on
darkfield microscopy of mucosal lesions,
exudates, lymph nodes or placental tissue.
This test has a low sensitivity (,105
organisms/ml), however, and relies on
fresh, good quality specimens. In addition,
it is not specific when used for examining
oral lesions where treponemal species are
part of the normal oral flora.
The use of polymerase chain reaction
(PCR) to detect T pallidum in orogenital
lesions and CSF offers the possibility of a
more sensitive and specific means of
diagnosing syphilis.28 29 Neonates have
been reported to be more likely to have
syphilis detectable in the blood or CSF,
making PCR to detect T pallidum of
interest for the future diagnosis of congenital syphilis, and in particular early
detection of neurosyphilis.30
Antenatal testing
Figure 2 Rates of diagnoses of infectious syphilis (primary and secondary) by sex and age group,
GUM clinics, United Kingdom, 1996–2005. Data source: KC60 statutory returns and ISD(D)\5 data.
106
Guidelines have recently been published
relating to the diagnosis of syphilis in
adults and serology remains the mainstay
of laboratory testing for syphilis.31
Effective prevention of congenital syphilis
depends on the identification of active
infection in pregnant women by routine
Arch Dis Child February 2008 Vol 93 No 2
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Leading article
Table 1 Incidence of symptoms in early and
late congenital syphilis
Percentage of cases20 21
Early
Abnormal bone x ray
Hepatomegaly
Splenomegaly
Petechiae
Skin lesions
Anaemia
Lymphadenopathy
Jaundice
Pseudoparalysis
Snuffles
CSF abnormalities
Late
Frontal bossing
Palatal deformation
Dental dystrophies
Interstitial keratitis
Abnormal bone x ray
Nasal deformity
Eighth nerve deafness
Neurosyphilis
Joint disorder
33–95%
51–56%
49%
41%
35–44%
34%
32%
30%
28%
23%
25%
30–87%
76%
55%
20–50%
30–46%
10–30%
3–4%
1–5%
1–3%
screening during antenatal visits and near
the time of delivery with a non-treponemal test (VDRL or rapid plasma reagin
(RPR)). These tests are quantitative and
correlate with disease activity and
response to therapy.
Non-treponemal tests can be falsely
negative with early primary syphilis,
latent acquired syphilis of long duration
and late congenital syphilis. A non-treponemal test performed on serum samples
containing high concentrations of antibody against T pallidum can be weakly
reactive or falsely negative; this reaction is
termed the prozone phenomenon. Falsepositive results can be secondary to viral
infections (infectious mononucleosis,
hepatitis, varicella, measles), lymphoma,
tuberculosis, malaria, endocarditis, connective tissue disease, pregnancy, laboratory
error,
or
Wharton
jelly
contamination when cord blood specimens are used.32
For women treated during pregnancy,
follow-up serological testing is necessary
to assess the efficacy of therapy demonstrated by a fourfold decrease in nontreponemal titres. These usually become
non-reactive 1 year after prompt treatment of primary or secondary infection if
the initial titre is low (,1:8) and within
2 years with congenital infection or if the
initial titre is high. Differentiating treated
syphilis from active (re)infection may be
difficult in the absence of increasing titres.
To exclude a false-positive non-treponemal test, serology should be sent for
Arch Dis Child February 2008 Vol 93 No 2
confirmatory treponemal antibody detection by fluorescent treponemal antibody
absorption (FTA-ABS) or T pallidum particle agglutination (TPPA). Treatment
should not be delayed while awaiting
the results of the treponemal test if the
patient is symptomatic or at high risk of
infection. Treponemal test antibody titres
remain reactive for life even after successful therapy, correlate poorly with disease
activity and should therefore not be used
to assess response to therapy. Treponemal
tests may not be specific for syphilis, since
positive reactions variably occur in
patients with other spirochetal infections,
including yaws, pinta, leptospirosis, ratbite fever, relapsing fever and Lyme
disease.
The combination of non-treponemal
and treponemal tests provides sensitive
and specific screening for all stages of
syphilis but requires subjective interpretation and cannot readily be automated.33
With the recent commercial availability of
enzyme immunoassays (EIAs), the nontreponemal and treponemal combination
is increasingly being replaced in UK
diagnostic microbiology laboratories by
assays detecting treponemal IgG or IgG
and IgM. Advantages include the production of objective results, the ability to link
EIA plate readers directly to laboratory
computer systems, and the facility for
automation.34 A quantitative non-treponemal test and serology for specific antitreponemal IgM provides a baseline for
monitoring the effect of therapy. IgM
becomes undetectable within 3–9 months
after adequate treatment of early syphilis
but may persist for up to 18 months after
treatment of late disease.35 Although the
treponemal IgG EIA has not been as
widely adopted in the USA,31 there are
published data showing that screening
with recombinant antigen-based treponemal IgG and IgM has comparable sensitivity and specificity compared to the
non-treponemal and treponemal combination,36–38 and may be useful for detecting treponemal antibody in HIV-infected
patients.39
Evaluation of newborn infants with
perinatal exposure to syphilis
All infants born to seropositive mothers
should be considered to be exposed to
syphilis unless full investigation of the
mother shows other explanations for the
serological findings and/or evidence of
complete treatment and response to this
treatment. Where possible the placenta
and/or umbilical cord should be sent for
pathological examination and dark
ground microscopy, if this is available.
Serology should be sent for quantitative
non-treponemal tests using the same
assay as that performed on the mother
to enable comparison of titres. Cord blood
is inadequate for screening since sera can
be non-reactive even when the mother is
seropositive and contamination with
maternal blood may occur.40 A guide for
interpretation of the results of nontreponemal and treponemal serological
tests is given in table 2.41 Where combinations of diagnostic tests other than those
referred to above are being used, we
recommend local collaboration and discussion antenatally regarding planned
follow-up for the neonate.
Anti-treponemal IgG measured in the
infant can be transplacentally acquired
from the mother and persist for up to
18 months, and so is not of use in the
initial evaluation of an infant for congenital infection.
Detection of specific anti-treponemal
IgM may also be useful in the diagnosis of
congenital infection, but a negative result
around the time of delivery does not
exclude congenital infection. Serological
follow-up is indicated and should include
repeat IgM testing, and quantitative nontreponemal and treponemal serology to
demonstrate loss of passive maternal
antibody.
An exposed infant should be evaluated
for active syphilis and considered at high
risk for infection if:
1.
2.
3.
4.
5.
6.
7.
The infant is symptomatic.
Titre of maternal non-treponemal
serology (eg, VDRL, RPR) has
increased fourfold.
Infant non-treponemal titre is fourfold greater than maternal titre.
Maternal syphilis was untreated or
inadequately treated during pregnancy with insufficient serological
follow-up.
Maternal syphilis was treated with a
non-penicillin regimen.
After treatment of maternal syphilis
(with an appropriate penicillin regimen), the expected decrease in nontreponemal antibody titre after therapy did not occur.
Treatment for maternal syphilis was
commenced less than 1 month
before delivery.
If the situation is unclear, then repeat
maternal and infant bloods should be
taken at birth, a full evaluation of the
baby carried out and serious consideration
given to treatment of the neonate while
results are awaited. If treatment is not
instituted, clinicians should be certain
107
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Leading article
Table 2 Guide for interpretation of syphilis serological test results of mothers and their infants
Non-treponemal test
(VDRL, RPR, EIA, ART)
Treponemal test
(MHA-TP, FTA-ABS)
Mother
Infant
Mother
Infant
Interpretation
–
+
+
–
+
+/–
–
–
+
–
–
+
+
–
+
–
+
+
+
+
No syphilis or incubating syphilis in the mother and infant
No syphilis in mother (false-positive non-treponemal test with passive transfer to infant)
Maternal syphilis with possible infant infection; or mother treated for syphilis during pregnancy; or mother with
latent syphilis and possible infection of the infant
Recent or previous syphilis in the mother; possible infection in the infant
Mother successfully treated for syphilis before or early in pregnancy; or mother with Lyme disease, yaws or pinta
(ie, false–positive serology)
ART, automated reagin test; EIA, enzyme immunoassay; FTA-ABS, fluorescent treponemal antibody absorbed; MHA-TP, microhaemagglutination assay – Treponema pallidum; RPR, rapid plasma
reagin; VDRL, Venereal Disease Research Laboratory.
that rigorous follow-up will be possible
and attendance ensured. In women who
come from areas where other treponemal
infections are endemic (such as pinta or
yaws), babies should be treated as if they
have congenital syphilis since it is impossible using standard serological tests to
differentiate between these infections. If
maternal HIV is present, then the risk of
transmission of syphilis should be considered to be even greater and a lower
threshold for treatment adopted.
In addition to blood for treponemal and
non-treponemal testing, the evaluation
should also include liver function tests, long
bone x rays, CSF specimen for VDRL test
and analysis for the detection of white cells
and elevated protein, and ophthalmic
assessment. A negative VDRL on CSF does
not exclude congenital neurosyphilis.
If a case of congenital syphilis is
suspected, evaluation of any previously
uninvestigated siblings should also be
considered.
TREATMENT
Parenteral penicillin G is the only documented effective therapy for patients who
have neurosyphilis, congenital syphilis or
syphilis during pregnancy. Aqueous crystalline penicillin G is preferred over
procaine penicillin G because adequate
CSF concentrations may not be achieved
with the latter. If more than 1 day of
therapy is missed, it has been recommended that the entire course should be
restarted, although there is no recent
evidence to support this recommendation.
Newborn infants
In newborn infants, the dose for aqueous
crystalline penicillin G is 100 000–
150 000 U/kg per day, administered as
50 000 U/kg per dose, intravenously,
every 12 h during the first 7 days of life
and every 8 h thereafter for a total of
10 days. Procaine penicillin G is administered in a single dose at 50 000 U/kg per
day, intramuscularly, for 10 days. These
108
recommendations are based on chronological, not gestational, age.
Older infants and children
Infants older than 4 weeks of age who
possibly have congenital syphilis or who
have neurological involvement should be
treated with aqueous crystalline penicillin, 200 000–300 000 U/kg per day, intravenously (administered every 6 h), for
10 days. This regimen also should be used
to treat children older than 1 year of age
who have late and previously untreated
congenital syphilis.41
During pregnancy
UK guidelines are already available and
patients should be treated with penicillin
according to the dosage schedules appropriate for the stage of syphilis as recommended for non-pregnant patients.42
Penicillin-allergic pregnant women should
be treated with penicillin after desensitisation. While awaiting penicillin desensitisation, erythromycin (or other nonpenicillin regimes) should be used.
Evidence that non-penicillin regimes are
effective in the treatment of congenital
syphilis is not currently available, however, meaning that infants should be
treated at birth as if mother had received
no treatment if such regimes are used.
FOLLOW-UP
Treated infants should be followed up at
3, 6 and 12 months of age until serologic
non-treponemal tests become non-reactive or the titre has decreased fourfold.
With adequate treatment or in cases
where antibody is transplacentally
acquired in the absence of congenital
infection, non-treponemal antibody titres
should decrease by 3 months of age and
be non-reactive by 6 months of age. At 6–
12 months of age previously treated
infants with increasing or persistent titres
should be evaluated, including CSF examination, and treated with a further 10-day
course of parenteral penicillin G.
Treated infants with congenital neurosyphilis should undergo repeated clinical
evaluation and CSF examination at 6month intervals until their CSF examination is normal. A persistently reactive
VDRL test of CSF is an indication for retreatment.41
In untreated babies with no symptoms
of congenital syphilis who are documented to have a non-treponemal antibody
titre at least fourfold less than their
mothers at birth and whose mother was
fully treated and evaluated antenatally
(including follow-up testing to confirm
successful treatment), no further followup is required. If there is any uncertainty
regarding the completeness of antenatal
follow-up or neonatal serology then the
baby should be reviewed and further
samples sent for non-treponemal antibody testing at 3 and 6 months of age.
A full re-evaluation should be carried out
if titres have not decreased by 6 months
of age. A sample for treponemal antibody
titres should then be sent at 12 months of
age; in most cases they will no longer be
detectable by this age if passively
acquired.
CONCLUSION
In this article we have reviewed the
management of maternal and congenital
syphilis. At a time when this disease has
re-emerged in the UK, we hope that the
review will assist clinicians in familiarising themselves again with the subtleties
of this age-old affliction. Despite the
introduction of effective treatment and
the availability of diagnostic testing in the
mid-20th century, syphilis still remains a
national health issue: ‘‘…(s)he who
knows syphilis knows the more things
change the more they stay the same’’!
Competing interests: None.
Accepted 4 September 2007
Arch Dis Child 2008;93:105–109.
doi:10.1136/adc.2006.103515
Arch Dis Child February 2008 Vol 93 No 2
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Leading article
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