Syphilis in Pregnancy - UpToDate

13/6/23, 19:22 Syphilis in pregnancy - UpToDate
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Syphilis in pregnancy
AUTHORS: Errol R Norwitz, MD, PhD, MBA, Charles B Hicks, MD
SECTION EDITORS: Charles J Lockwood, MD, MHCM, Jeanne Marrazzo, MD, MPH, FACP, FIDSA
DEPUTY EDITORS: Vanessa A Barss, MD, FACOG, Jennifer Mitty, MD, MPH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2023.

This topic last updated: Sep 16, 2022.
INTRODUCTION
Syphilis is a systemic infection caused by the spirochete Treponema pallidum. Infection is of

particular concern during pregnancy because of the risk of transplacental transmission to the
fetus. Congenital infection can be associated with several adverse outcomes, including
perinatal death.
Issues related to syphilis during pregnancy will be reviewed here. Syphilis in children and
nonpregnant adults are discussed separately:
● (See "Congenital syphilis: Clinical manifestations, evaluation, and diagnosis".)

● (See "Congenital syphilis: Management and outcome".)
● (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients
without HIV".)
● (See "Syphilis: Treatment and monitoring".)
PREVALENCE
● United States – The rate of primary and secondary syphilis in United States females
overall has been increasing in recent years and more than doubled from 2015 to 2019,
increasing by 179 percent [1]. The highest rates among females were in those 20 to 24
years of age (11.6 cases per 100,000 females) and 25 to 29 years of age (11.8 cases per
100,000 females). The number of syphilis cases among pregnant individuals increased
61 percent between 2012 and 2016 (from 1561 to 2508 cases), and this increase was
seen across all races and ethnicities, across the reproductive age range (15 to 45 years),
and across all regions of the country [2].
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After a steady decline, the rate of congenital syphilis has also been increasing during
this time period, corresponding to the increasing incidence in reproductive-aged
females. In 2020, 2022 cases of congenital syphilis were reported, and 139 (6.9 percent)
involved death related to the infection [3].
● Globally – Globally, the estimated prevalence of maternal syphilis in 2016 was 0.69
percent (95% CI 0.57-0.81), resulting in a global congenital syphilis rate of 473 (95% CI
385-561) per 100,000 live births [4].
EPIDEMIOLOGY
Syphilis occurs with equal frequency in males and females worldwide [5], but males are more
commonly infected in the United States. However, the male-to-female rate ratio in the United
States is declining because, although infection rates in both males and females are
increasing, the infection rate in females is increasing faster than that in males [1].
The infection is more common among pregnant people from vulnerable populations. Specific
risk factors include residence in a community with high syphilis rates, misusing drugs, having
a sexually transmitted infection [STI] during pregnancy, having more than one or a new sex
partner, having a sex partner with an STI, having sex in conjunction with drug use or
transactional sex, entering prenatal care during the second trimester or later or no prenatal
care, being incarcerated or having a partner who is incarcerated, or having unstable housing
or homelessness [2,6]. However, in one study, approximately 50 percent of pregnant people
with syphilis in the United States had none of 16 traditional risk factors for the disease [2].
The epidemiology of congenital syphilis is reviewed in more detail separately. (See

"Congenital syphilis: Clinical manifestations, evaluation, and diagnosis", section on
'Epidemiology'.)
MATERNAL ACQUISITION OF INFECTION
Sexual transmission requires exposure to open lesions in which microorganisms are present.
The spirochetes pass from the lesion across intact non-keratinized epithelium or abraded skin
into the new host. The efficiency of sexual (horizontal) transmission is estimated to be
approximately 30 percent [7]. The incubation period varies from 10 to 90 days (average
approximately three weeks); larger inocula shorten this incubation period [8]. (See "Syphilis:
Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section
on 'Transmission'.)
MATERNAL CLINICAL MANIFESTATIONS

The clinical manifestations of syphilis are not affected by the pregnant state. (See "Syphilis:
Epidemiology, pathophysiology, and clinical manifestations in patients without HIV".)
MATERNAL SCREENING
Universal antepartum screening is widely recommended because screening followed by

treatment with appropriate antibiotics usually prevents adverse maternal and offspring
outcomes ( algorithm 1) [9-11]. Screening is performed using a serologic test; either a
treponemal or nontreponemal test can be used. All of the tests have similar sensitivity and
specificity, so preference is based on other factors (eg, cost, time, personnel requirements).
(See 'Serologic testing' below.)
Candidates and timing of initial and repeat screening
● All pregnant people: screen at the first prenatal encounter

● Pregnant people at high risk of infection: repeat screening at 28 to 32 weeks and at
delivery
● Pregnant people who have not been screened in pregnancy or who give birth to a
stillborn after 20 weeks of gestation: screen at delivery
The United States Centers for Disease Control and Prevention (CDC) and many other global
and national organizations recommend screening all pregnant people for syphilis at the first
prenatal visit [12-17]. The cost and morbidity associated with screening for syphilis are low
and the benefit of detecting and treating the disease is high for both mother and child.
Universal screening for syphilis has the advantage of removing the stigma of testing since all
pregnant people are screened, not just those considered to be at higher risk. The major harm
of screening is the anxiety associated with a false-positive result [18,19]. (See 'False-positive
serologic tests in pregnancy' below.)
For pregnant people who are at high risk for acquiring syphilis (see 'Epidemiology' above),
the CDC recommends repeating screening during the third trimester at 28 to 32 weeks and
again at delivery [20]. Local prevalence rates are available from the CDC, which annually
publishes prevalence rates in the United States based on variables such as county, sex, age
group, ethnicity, and sexual behavior, but not pregnancy status. Routinely rescreening all
pregnant people in the third trimester and/or at delivery was cost-effective in some modeling
studies but not in others [21-23]
Opportunities for screening outside of traditional prenatal care — Screening for syphilis
should be considered when a pregnancy is diagnosed in a nonobstetric setting, such as a
drug treatment center, prison, emergency medicine department, or outreach program, given
that pregnant people with syphilis are less likely to receive prenatal care.

Rapid point of care tests are less accurate than standard nontreponemal and treponemal
tests [24], but can be helpful in guiding initial treatment decisions in patients in whom return
for follow-up is uncertain and thus reduce the risk of adverse outcomes from congenital
syphilis [25]. (See "Syphilis: Screening and diagnostic testing", section on 'Rapid serologic
tests'.)
Concurrent HIV screening — All pregnant people should be offered HIV counseling and
testing using an opt-out approach [26]. HIV testing is strongly recommended for those
known to have a sexually transmitted disease, such as syphilis, due to the high risk of
coexistent disease. HIV testing should be repeated at the time of repeat syphilis screening.
(See "Prenatal care: Initial assessment", section on 'HIV'.)
DIAGNOSIS
Serologic testing — For most patients, the diagnosis of syphilis is made through serologic
testing of blood specimens. Methods that detect the organism directly (eg, darkfield
microscopy) are not generally available.
Serologic testing to diagnose syphilis should include the use of both treponemal and
nontreponemal tests:
● Specific treponemal tests include fluorescent treponemal antibody absorption (FTA-

ABS), microhemagglutination test for antibodies to T. pallidum (MHA-TP), T. pallidum
particle agglutination assay (TPPA), T. pallidum enzyme immunoassay (TP-EIA), and
chemiluminescence immunoassay (CIA). The TP-EIA is a commonly performed
treponemal test because it allows inexpensive volume testing of blood samples with
minimal time requirements for laboratory personnel.
● Nontreponemal tests include Rapid Plasma Reagin (RPR), Venereal Disease Research
Laboratory (VDRL), and Toluidine Red Unheated Serum Test (TRUST). The RPR and VDRL
are the most commonly performed nontreponemal tests.
Either test can be used as the initial screening test, depending on the preference of the
laboratory performing the test ( algorithm 1). Most laboratories use a testing strategy that
screens with a treponemal assay (most often an enzyme immunoassay) and then use a
nontreponemal test (RPR or VDRL) for confirmatory testing. Confirmatory testing is necessary
due to the potential for a false-positive screening test result. (See "Syphilis: Screening and
diagnostic testing", section on 'Serologic testing algorithms'.)
The diagnostic interpretation of syphilis serology, including interpretation of testing in

patients with prior syphilis, is the same as in nonpregnant individuals. As an example, in a
patient without prior syphilis, a diagnosis of syphilis is made when both treponemal tests and

nontreponemal tests are reactive. A more detailed discussion of how to interpret serologic
testing is presented elsewhere. (See "Syphilis: Screening and diagnostic testing", section on
'Interpretation of serologic testing'.)
False-positive serologic tests in pregnancy
● Prevalence – Biologic false-positive nontreponemal and treponemal results are

relatively common among pregnant people with an initial positive screening test. In a
study of 75,056 pregnancies, 221 patients (0.29 percent) had an initial positive screening
test and 183 of these patients (83 percent) were subsequently found to have a false-
positive test (false-positive rate: 244 cases per 100,000 pregnancies) [27]. False-positive
rates did not differ between traditional algorithms starting with a nontreponemal test
and reverse algorithms starting with a treponemal test.
● Patient evaluation during pregnancy – Given the high risk that an initial positive test
is a false-positive, testing algorithms should include confirmatory testing
( algorithm 1) [28]. When an initial treponemal screening test is positive but the
follow-up nontreponemal result is negative, treponemal reflexive testing is performed.
If reflex testing is also positive, the negative nontreponemal test may be secondary to a
prozone effect. (See "Syphilis: Screening and diagnostic testing", section on 'Prozone
reaction'.)
A positive (reactive) low titer nontreponemal screening test can be considered a

transient biologic false-positive result due to pregnancy if the follow-up treponemal test
is negative and the patient is asymptomatic and at low risk of acute syphilis. False-
positive nontreponemal test results can also be related to an acute event, such as an
acute febrile illness or recent immunization (including a COVID-19 vaccine [29]). Test
abnormalities attributed to these conditions are usually transitory, typically lasting for
six months or less. In addition to pregnancy, conditions associated with a false-positive
CIA treponemal test include advanced age (>50 years), tumor, dialysis, autoimmune
disease, and systemic infections unrelated to syphilis (eg, tuberculosis, rickettsial
diseases, endocarditis) [30], while a false-positive EIA has been associated with
advanced age (≥40 years) [31].
● Follow-up after delivery – All patients with biologic false-positives attributed to

pregnancy or another transient event should undergo follow-up testing at least four to
six weeks after giving birth. If the discordancy persists, then the need for further
evaluation can be determined on a case-by-case basis, taking into account factors such
as symptoms (eg, signs/symptoms of autoimmune disease) and risk of syphilis infection
[28,30-34]. (See "Syphilis: Screening and diagnostic testing", section on 'Positive
nontreponemal/negative treponemal'.)

STAGING
The stage of syphilis is clinically important because it impacts the treatment regimen and the
risk of vertical transmission. (See 'Vertical transmission' below.) Patients whose screening test
for syphilis is positive should be staged based on history and physical examination. Each
stage of syphilis has characteristic clinical findings that are not altered by pregnancy. A
synopsis is provided below and in the table ( table 1). A detailed discussion of staging,
including photographs of lesions, can be found separately. (See "Syphilis: Epidemiology,
pathophysiology, and clinical manifestations in patients without HIV", section on 'Clinical
manifestations' and "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in
patients without HIV", section on 'Stages of disease'.)
● Primary syphilis — When symptomatic, the first manifestation of syphilis is a skin

lesion that may be macular initially but typically evolves into a painless papule at the site
of inoculation. This soon ulcerates to produce the classic chancre(s) of primary syphilis,
a 1 to 2 centimeter painless ulcer with a raised, indurated margin that may be genital or
extragenital. The ulcer is associated with mild to moderate regional lymphadenopathy
that may be bilateral. Chancres heal spontaneously within three to six weeks, even in
the absence of treatment. The primary stage of syphilis may not be noticed if the lesion
is on the vaginal or cervical epithelium. (See "Syphilis: Epidemiology, pathophysiology,
and clinical manifestations in patients without HIV", section on 'Primary syphilis
(chancre)'.)
● Secondary syphilis — Secondary syphilis is a disseminated systemic process that

occurs in approximately 25 percent of untreated patients, usually beginning six weeks
to six months after the appearance of the chancre of primary syphilis. A generalized
maculopapular skin rash involving the palms and soles and mucous membranes is
characteristic of this stage of the infection. Generalized lymphadenopathy may
accompany the rash. Additional clinical features may include fever, pharyngitis, weight
loss, and condylomata lata. Although spirochetes can be found in the cerebrospinal fluid
(CSF) of around 40 to 50 percent of patients with early syphilis [35], neurologic
manifestations are uncommon. The rash of secondary syphilis typically resolves
spontaneously within two to six weeks. (See "Syphilis: Epidemiology, pathophysiology,
and clinical manifestations in patients without HIV", section on 'Secondary syphilis'.)
● Latent syphilis — In the United States, latent syphilis is defined as "early latent" when it
is possible to document a nonreactive syphilis serology within the past year or a history
of symptoms of early syphilis within the past year. Otherwise, the disease is considered
"late latent". Latent syphilis is by definition asymptomatic. If untreated, a small
proportion of patients will develop signs and symptoms of secondary or late syphilis,
but many will remain asymptomatic. People with latent syphilis can transmit the
infection to sexual partners, or the fetus; however, this is considerably less common in
late latent syphilis. (See "Syphilis: Epidemiology, pathophysiology, and clinical
manifestations in patients without HIV", section on 'Latent syphilis (asymptomatic)' and
'Vertical transmission' below.)
● Tertiary (late) syphilis — Tertiary syphilis is infrequently diagnosed and is

characterized by slowly progressive signs and symptoms. Clinical manifestations include
gumma formation and cardiovascular disease. Such manifestations usually develop 5 to
20 years after the disease has become latent. (See "Syphilis: Epidemiology,
pathophysiology, and clinical manifestations in patients without HIV", section on 'Late
syphilis'.)
● Neurosyphilis — Early in the course of syphilis infection, T. pallidum can enter the
central nervous system and subsequently produce a variety of signs and symptoms
during both early and late syphilis. Neurosyphilis is described in detail separately. (See
"Neurosyphilis".)
MATERNAL TREATMENT
Treatment setting — The authors administer treatment for syphilis in an outpatient setting,
and counsel patients about potential side effects and when to contact their provider. Others
may choose to administer the first dose of penicillin in a labor and delivery unit with
continuous fetal monitoring for at least 24 hours in pregnancies that have reached a
gestational age when intervention would be considered in case of Jarisch-Herxheimer
reaction and its potential sequelae (eg, preterm labor, nonreassuring fetal heart rate pattern)
[6]. There is no consensus regarding the best approach; both are acceptable. (See 'Potential
complications of treatment: Jarisch-Herxheimer reaction' below.)
Preferred regimen: penicillin
Key principles
● Penicillin G benzathine is the standard for the treatment of syphilis in both pregnant
and nonpregnant individuals. No clinically relevant penicillin-resistant strains of T.
pallidum have been identified to date. Penicillin G benzathine therapy is effective for
treating maternal disease, preventing transmission to the fetus, and treating
established fetal disease.
● Pregnant people with penicillin allergy should be desensitized and treated with
penicillin G benzathine because penicillin G benzathine is considered the only
appropriate treatment of syphilis during pregnancy. Desensitization may be performed
in the outpatient or inpatient setting, depending on the severity of the past reaction and

available resources. (See "Rapid drug desensitization for immediate hypersensitivity

reactions", section on 'Risk stratification' and "Rapid drug desensitization for immediate
hypersensitivity reactions", section on 'Setting and staffing'.)
● The appropriate penicillin G benzathine regimen depends on the stage of disease

( table 2). The pregnant state does not affect the maternal response to treatment.
(See 'Patients with immediate type allergic reactions to penicillin' below.)
● Bicillin L-A must be distinguished from Bicillin C-R – Penicillin G benzathine (long-
acting intramuscular) is marketed under the trade name Bicillin L-A. This agent should
only be given via the intramuscular route since intravenous administration has been
associated with cardiopulmonary arrest and death.
Bicillin L-A must be distinguished from Bicillin C-R (which contains equal concentrations
of intermediate-acting procaine and long-acting benzathine penicillin) and
should not be used to treat patients with syphilis.
Treatment of primary, secondary, or early latent disease and post-exposure

prophylaxis
● A single dose of penicillin G benzathine 2.4 million units intramuscularly is appropriate

for patients with primary, secondary, or early latent disease and for post-exposure
prophylaxis after sexual contact with a partner with known or suspected syphilis
( table 2) (see 'Staging' above).
Some clinicians administer an additional dose of penicillin G benzathine 2.4 million units one
week after the first dose to patients with primary, secondary, or early latent disease [6],
based in part on evidence of efficacy [36-38] and on pharmacokinetic data of altered penicillin
levels in pregnant people [39,40]. There is no harm to giving a second dose, but it has not
been recommended in guidelines from national organizations because the value of a second
dose has not been evaluated in a randomized trial and there have been shortages of
penicillin G benzathine in some countries. A second dose of penicillin is not administered to
nonpregnant patients with primary, secondary, or early latent disease. (See "Syphilis:
Treatment and monitoring", section on 'Treatment of early syphilis'.)
Treatment of late latent and tertiary disease
● Three doses of penicillin G benzathine 2.4 million units intramuscularly at weekly

intervals are recommended for late latent and tertiary syphilis ( table 2).
Pregnant people whose scheduled dose is delayed by >9 days should repeat the full course of
therapy [20]. (See "Syphilis: Treatment and monitoring", section on 'Treatment of late
syphilis'.)

If an asymptomatic patient with suspected latent syphilis was previously treated for syphilis
but receipt of an appropriate treatment regimen cannot be verified, then the full three-dose
penicillin regimen recommended for late latent syphilis should be administered. Diagnosis of
treatment failure is discussed below. (See 'Interpretation of response to therapy and
diagnosis of treatment failure' below.)
Treatment of neurosyphilis — Treatment of neurosyphilis is parenteral and typically

requires inpatient administration ( table 2). (See "Syphilis: Treatment and monitoring",
section on 'Treatment of neuro/ocular/otic syphilis'.)
Patients with immediate type allergic reactions to penicillin — For pregnant people with
syphilis and a history of an immediate type allergic reaction to penicillin, the only satisfactory
treatment is desensitization followed by penicillin therapy [20].
Penicillin allergy is reported by 5 to 10 percent of pregnant people [41]; however, serious

allergic reactions to penicillin are rare. It is important to verify the history of "allergy," since
the patient may incorrectly assume a nonallergic side effect (eg, nausea or vomiting) to be
allergic in origin. The major symptoms of concern are immunoglobulin E (IgE)-mediated
(immediate) responses, such as urticaria, angioedema or anaphylaxis with airway
obstruction, bronchospasm or hypotension ( table 3).
Referral — Patients who report symptoms suggestive of a past immediate allergy to a

penicillin should be evaluated with penicillin skin testing, if possible. In most cases, this
involves referral to an allergist, as skin testing requires some expertise to perform and
interpret. In addition, allergists can perform rapid drug desensitization protocols if
appropriate. (See 'Desensitization' below.)
Many patients may give a vague history of a mild reaction, such as rash, which is difficult to
classify with any precision. We suggest consulting an allergist in such cases, but if an allergist
is not available and the clinician believes the risk of a significant reaction is minimal, a test
dose or graded challenge may be performed. Test dosing is discussed elsewhere. (See "An
approach to the patient with drug allergy", section on 'Graded challenge'.)
Skin testing — Penicillin skin testing takes approximately one hour to perform and can
determine if the patient has an immediate penicillin allergy.
Individuals who had a true IgE-mediated reaction to penicillin in the distant past with no
reexposure may lose their sensitivity over time. Approximately 80 percent of patients with a
history of IgE-mediated penicillin allergy that occurred ≥10 years in the past will now have a
negative skin test and can safely take penicillin. (See "Penicillin allergy: Immediate reactions",
section on 'Penicillin skin testing' and "Penicillin allergy: Immediate reactions", section on
'Time elapsed since the reaction'.)

● Positive test – Pregnant people with a positive skin test are at significant risk of a
reaction to penicillin; two-thirds develop some allergic symptoms and a subset of those
will have a life-threatening anaphylactic reaction [41]. Penicillin desensitization is
recommended for pregnant people with a positive skin test who require penicillin
therapy. (See "Penicillin allergy: Immediate reactions", section on 'Desensitization'.)
● Negative test – Pregnant people with negative skin test results are at no greater risk
for a reaction to penicillin than the general population and can receive the drug.
However, the first dose should be given under medical supervision because the
negative predictive value of skin testing, while high, is not 100 percent.
Desensitization — It is strongly recommended that desensitizations be performed by

allergy specialists.
Penicillin desensitization involves exposing the patient to a small amount of penicillin and
gradually increasing the dose until an effective level is reached, followed by the appropriate
therapeutic penicillin regimen. Penicillin desensitization can be achieved either orally or
intravenously. Oral desensitization is simpler and safer. The procedure requires
approximately four hours to accomplish and requires close patient monitoring. Most adverse
reactions can be managed without discontinuation of the desensitization protocol.
Desensitizations are usually performed in the hospital and often in the intensive care setting
because it is critical to have the staffing and equipment available to manage anaphylaxis.
However, oral desensitization to penicillin has been performed by allergy specialists in the
outpatient setting, with one-on-one nursing and intravenous access.
Protocols for intravenous desensitizations are reviewed separately. (See "Penicillin allergy:
Immediate reactions", section on 'Desensitization' and "Rapid drug desensitization for
immediate hypersensitivity reactions".)
Role of nonpenicillin regimens — During pregnancy, nonpenicillin antibiotic regimens used

for syphilis treatment in males and nonpregnant females are either contraindicated (eg,
tetracycline), lack sufficient data regarding efficacy (eg, ceftriaxone), or do not cross the
placental barrier completely so the fetus is not effectively treated (eg, erythromycin,
azithromycin). Therefore, they are not recommended for pregnant people. Nonpenicillin
regimens should only be considered when penicillin cannot be obtained or for
penicillin-allergic patients when penicillin desensitization is not possible. (See 'Patients
with immediate type allergic reactions to penicillin' above.)
● World Health Organization (WHO) regimens – In parts of the world where penicillin
desensitization is not possible [42]:
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• For nonpenicillin treatment of early syphilis (ie, primary, secondary, or latent <2
years [WHO definition]) in pregnancy, administer one of the following alternative
regimens:
- Erythromycin 500 mg orally four times daily for 14 days, or

- Ceftriaxone 1 g intramuscularly once daily for 10 to 14 days, or
- Azithromycin 2 g once orally (when local susceptibility to azithromycin is likely)
• For nonpenicillin treatment of late syphilis, administer erythromycin 500 mg orally

four times daily for 30 days.
• Infants born to individuals who were treated during pregnancy with nonpenicillin
regimens should receive penicillin treatment because erythromycin and
azithromycin do not cross the placental barrier completely so the fetus is not
effectively treated.
- Aqueous benzyl penicillin 100,000 to 150,000 U/kg/day intravenously for 10 to 15

days, or
- Procaine penicillin 50,000 U/kg/day single dose intramuscularly for 10 to 15 days
A small study in China evaluated the use of ceftriaxone for treatment of early syphilis in 11
pregnant people with a history of penicillin allergy [43]. Preliminary results were encouraging,
RPR titers fell and there were no clinical manifestations of congenital syphilis in the infants. A
large scale trial of this treatment strategy is planned as an alternative to desensitization. Until
the results of such trials are available, penicillin desensitization followed by penicillin
treatment should be regarded as "standard of care" for the management of penicillin-allergic
pregnant people with syphilis.
POTENTIAL COMPLICATIONS OF TREATMENT: JARISCH-HERXHEIMER

REACTION
Treatment of syphilis may precipitate the Jarisch-Herxheimer reaction. The risk of occurrence
of Jarisch-Herxheimer reaction is not a contraindication to syphilis treatment. However, all
patients should be counseled about the risks and clinical features of this febrile reaction, and
told to contact their provider if symptoms occur.
● Signs and symptoms – Clinical manifestations include an acute febrile reaction

accompanied by headache, myalgia, rash, and hypotension [44]. The reaction begins
within one to two hours of treatment, peaks at eight hours, and typically resolves within
24 to 48 hours. In one series, 15 out of 33 pregnant people treated for syphilis on a high
risk pregnancy unit at Parkland Hospital had a Jarisch-Herxheimer reaction, including 3

out of 3 with primary syphilis, 12 out of 20 with secondary syphilis, and 0 out of 10 with
latent syphilis [44]. The reaction may be more common in people with HIV.
Management is supportive care (eg, antipyretics, intravenous fluids).
The clinical findings are thought to result from the release of large amounts of
treponemal lipopolysaccharide from dying spirochetes and an increase in circulating
cytokine levels (tumor necrosis factor alpha [TNF-alpha], interleukin-6, interleukin-8).
● Complications – The Jarisch-Herxheimer reaction may precipitate uterine contractions,

preterm labor, and/or nonreassuring fetal heart rate tracings in pregnant people
treated in the second half of pregnancy [44,45]. Patients should report symptoms of
labor or decreased fetal activity to their provider immediately; evaluation and treatment
are according to usual obstetric standards.
● Role of premedication – The authors do not premedicate patients. Premedication with

corticosteroids [46] or TNF-alpha antibodies [47,48] appears to prevent the reaction, but
is not widely used given limited data of the relative risks and benefits of this approach,
with no data in pregnant people. In a study of 22 nonpregnant patients with primary
syphilis treated with penicillin for three days, 15 patients were given penicillin alone
while the other 7 received 20, 40, or 60 mg of oral prednisolone on the first and second
day of antibiotic administration [46]. Jarisch-Herxheimer reactions (defined as
temperature ≥38°C) occurred more frequently in the control group (93 versus 12
percent) and in no patient who received 60 mg of prednisolone. Nonfebrile
manifestations of the reaction were not evaluated.
Premedication with acetaminophen or meptazinol may reduce the severity or duration

of symptoms, but the reaction itself is not prevented [49]; premedication with
pentoxifylline has not been effective [50].
POST-TREATMENT MATERNAL FOLLOW-UP
Clinical follow-up — Patients with early syphilis should be assessed clinically for resolution of
symptoms (eg, rash, ulcer). However, for patients with late stage cardiovascular or
noncutaneous gummatous disease, a significant change in symptoms is unlikely. Monitoring
is described in detail separately. (See "Syphilis: Treatment and monitoring", section on
'Clinical assessment'.)
Frequency of nontreponemal titers — Pregnant people treated for early syphilis should
have a nontreponemal titer checked at the time of treatment to establish a baseline against
which to monitor response to treatment, since this titer may differ from that of the initial
diagnostic test due to elapsed time between diagnosis and initiation of therapy. The

subsequent frequency of monitoring is the same as in nonpregnant patients and depends

upon the stage of disease and presence of HIV coinfection.
When monitoring nontreponemal titers, the same test should be performed each time (ie,
serial rapid plasma antigen or serial Venereal Disease Research Laboratory) and ideally at the
same laboratory. (See "Syphilis: Treatment and monitoring", section on 'How often to
monitor'.)
Interpretation of response to therapy and diagnosis of treatment failure
● A fourfold increase in the nontreponemal titer after treatment is evidence of treatment

failure.
● A fourfold decline in the titer, equivalent to a change of two dilutions (eg, from 1:16 to
1:4 or from 1:32 to 1:8), is considered to be an acceptable response to syphilis therapy.
A decline in maternal nontreponemal serologic titers following treatment does not

guarantee that fetal treatment has been adequate. Thus, neonates should be evaluated
for congenital syphilis after delivery. (See "Congenital syphilis: Management and
outcome" and "Congenital syphilis: Clinical manifestations, evaluation, and diagnosis".)
There is wide patient-to-patient variability in the rate of decline in nontreponemal titers,

which can be influenced by factors such as previous episodes of syphilis, HIV infection, stage
of syphilis, and the level of the titer at the time of diagnosis. If the diagnostic titer is low (eg,
1:4), it is common for the rate of decline to be slower than if the diagnostic titer is high (eg,
1:128). In nonpregnant patients, an adequate response to therapy is expected by 12 months
for patients with early syphilis and 24 months for patients with late syphilis, but the authors
are willing to avoid retreatment as long as the titer is declining, even if the pace is slower
than expected. However, in pregnancy, it is probably prudent to err on the side of
overtreatment for early or late syphilis, so retreatment is reasonable if a fourfold decline from
pretreatment titer has not occurred by six months.
Seroreversion and serofast states — The loss of antibodies over time (seroreversion) in a
patient who has been treated for syphilis is considered consistent with clinical cure. The
majority of patients who are treated for syphilis will experience seroreversion over time.
Issues regarding the serofast state are reviewed separately. (See "Syphilis: Treatment and
monitoring", section on 'Serologic testing' and "Syphilis: Treatment and monitoring", section
on 'Persons with an inadequate response to treatment'.)
POTENTIAL ADVERSE PREGNANCY OUTCOMES

Pregnancies complicated by syphilis are at increased risk of several adverse outcomes from
placental and fetal infection [35,51-56]. Maternal treatment reduces the risk of adverse
outcomes, but preterm labor can be precipitated by the Jarisch-Herxheimer reaction (see
'Potential complications of treatment: Jarisch-Herxheimer reaction' above). Adverse outcomes
include:
● Pregnancy loss
● Preterm birth
● Stillbirth
● Impaired fetal growth
● Congenital infection ( table 4)
● Neonatal mortality
VERTICAL TRANSMISSION
Inadequate maternal screening and/or inadequate maternal treatment can result in

congenital syphilis. Screening failures occur primarily among pregnant people who do not
receive prenatal care or have late entry into prenatal care and in high-risk patients who are
not rescreened in the third trimester and at delivery [18,57].
Pathogenesis of congenital infection — T. pallidum readily infects the placenta.

Transplacental transmission to the fetus can occur from approximately the 9th to 10th week of
gestation [58] and at any stage of maternal disease. Importantly, the manifestations of
congenital infection are influenced by the gestational age, state of maternal syphilis,
maternal treatment, and immunological response of the fetus.
Fetal abnormalities result from a robust inflammatory response to T. pallidum; thus, they are
most pronounced after 20 weeks of gestation since the fetal immunologic response is poorly
developed in the first half of pregnancy [6]. After the placenta is infected, transplacental
passage of spirochetes to the fetal circulation leads to fetal hepatic infection and dysfunction,
followed by amniotic fluid infection, fetal hematologic abnormalities (anemia,
thrombocytopenia), ascites, hydrops, and fetal immunoglobulin M (IgM) production [59].
Hepatomegaly is thought to be caused by inflammation, extramedullary hematopoiesis, and
hepatic congestion [6].
Neonates can also become infected during birth from contact with maternal secretions or
blood containing spirochetes.
Factors influencing frequency of vertical transmission — In two systematic reviews, 15

and 36 percent of infants of mothers with untreated syphilis had clinical evidence of
congenital syphilis [60,61]. Factors that increase the risk of congenital infection include:

● Early stage syphilis – The risk of congenital infection is extremely high in the first four
years after maternal acquisition of infection, when spirochetemia is common in the
absence of treatment [62-64]. When looked at by stage, the risk of congenital infection
in term infants has been reported to be 50 percent for primary and secondary untreated
syphilis, 40 percent for early latent untreated syphilis, and 10 percent for late untreated
syphilis [65]. When looked at by baseline titer, the risk of congenital syphilis in offspring
of patients with nontreponemal titer ≥8 versus <8 was 26 and 4 percent, respectively, in
one systematic review [61].
● Maternal acquisition of infection later rather than earlier in gestation – The

frequency of vertical transmission increases with increasing gestational age at
acquisition of maternal infection.
● Failure to appropriately identify and treat maternal infection – Reviews of

congenital syphilis cases generally reveal that most could have been prevented [66]. The
majority of cases occurred because of:
• Lack of maternal screening (often because of lack of prenatal care, sometimes

because high-risk patients may not be identified if providers are uncomfortable
asking questions about sexual behavior)
• Lack of third-trimester rescreening in high-risk patients
• Lack of screening at delivery in high-risk patients and pregnant people who did not
receive prenatal care
• Lack of appropriate follow-up and treatment
Globally, many undetected maternal cases are also due to lack of adequate antenatal
care services. Although 88 percent of pregnant people globally had at least one prenatal
care visit, among syphilis-infected mothers, only 51 percent of those who had a prenatal
visit were adequately treated [4]. Pregnant people who received some prenatal care but
were not diagnosed or diagnosed but not treated accounted for 74 percent of the global
congenital syphilis burden. Point-of-care testing and same-day treatment could be
effective in antenatal care settings where loss to follow-up for test results and treatment
is common.
In New York City, 68 individuals gave birth to an infant with congenital syphilis in 2010 to
2016 [67]. Of these individuals, approximately one-third did not receive prenatal care or
a syphilis test ≥45 days before delivery; another one-third had a time-appropriate,
nonreactive test at the first prenatal visit and subsequently acquired syphilis during
pregnancy, but it was not diagnosed in most of this group because they did not have
repeat testing at 28 to 32 weeks; and many of the remaining individuals had a reactive

syphilis test ≥45 days before delivery but had inadequate maternal treatment because
treatment was initiated too late or not at all.
Prenatal (fetal) diagnosis — Fetal infection should be suspected if there are characteristic
findings on ultrasound examination after 20 weeks of gestation in a pregnant person with
untreated or inadequately treated syphilis. Before 18 to 20 weeks, fetal abnormalities are not
usually seen because of fetal immunologic immaturity. (See 'Pathogenesis of congenital
infection' above.)
Findings on ultrasound are nonspecific and included the following in one review [68]:
● Hepatomegaly, defined as liver length >95th percentile for gestational age (83 percent)
● Anemia, based on Doppler middle cerebral artery peak systolic velocity >1.5 multiples of
the median (38 percent)
● Placentomegaly, defined as placental thickness >2 standard deviations above mean for
gestational age (34 percent)
● Growth restriction (14 percent)
● Hydrops (12 percent)
• Skin edema 7 percent, pericardial effusion 2 percent, ascites 19 percent
● Polyhydramnios (11 percent), oligohydramnios (9 percent)
Hepatomegaly and placentomegaly are early findings. Anemia, ascites, and hydrops occur
later in the course of infection.
An abnormal ultrasound is not diagnostic of fetal infection and a normal ultrasound does not
exclude fetal infection. In one series, congenital syphilis was diagnosed in 39 percent of
infants of seropositive mothers who had a pretreatment fetal ultrasound with one or more of
the above findings and in 12 percent of infants when the ultrasound examination was normal
[69]. Some manifestations of congenital disease are subtle and/or not seen on prenatal
ultrasound examination (eg, ocular and osseous abnormalities). (See "Congenital syphilis:
Clinical manifestations, evaluation, and diagnosis", section on 'Early congenital syphilis' and
"Congenital syphilis: Management and outcome".)
Diagnostic testing of amniotic fluid or fetal blood definitively establishes intrauterine

infection, but invasive procedures to obtain these specimens can be associated with
complications, do not change management, and thus are not recommended. Potential fetal
laboratory manifestations of infection were illustrated in a series of 24 pregnant people with
primary, secondary, or early latent syphilis diagnosed after 24 weeks of gestation who
underwent funipuncture [59]. The following abnormalities were noted: abnormal liver
chemistries (88 percent), thrombocytopenia (35 percent), anemia (26 percent), and positive
fetal antitreponemal IgM (13 percent).
Fetal treatment and treatment failure — Maternal penicillin treatment is curative for fetal
infection in most cases. Although fetal anemia is one of the adverse sequelae of congenital
infection, intrauterine transfusion is rarely necessary as appropriate treatment of maternal
infection generally reverses the anemia [6].
Congenital infection has been diagnosed in 1 to 2 percent of offspring of mothers adequately

treated during pregnancy compared with 70 to 100 percent of offspring of untreated
mothers. The WHO estimates that treatment reduces early fetal deaths or stillbirths by 82
percent, preterm or low birth weight by 65 percent, neonatal deaths by 80 percent, and
clinical disease in infants by 97 percent [70].
In an observational series of 43 treatment failures, the following characteristics were more

likely in adequately treated patients who went on to have congenitally infected infants [64]:
● High nontreponemal titer at treatment and delivery

● Birth ≤36 weeks
● Early stage infection
● Short interval (≤30 days) between treatment and giving birth
The authors hypothesized that high treponemal load, altered penicillin pharmacokinetics in
pregnancy, and inadequate time for fetal therapeutic response may have accounted for the
treatment failures.
Newborn evaluation and treatment — The clinical manifestations, diagnosis, treatment,

and prognosis of congenital syphilis in the neonate are discussed separately. (See "Congenital
syphilis: Management and outcome" and "Congenital syphilis: Clinical manifestations,
evaluation, and diagnosis".)
PREGNANCY MANAGEMENT
Pregnancies in people with syphilis should be comanaged by obstetric and infectious disease
specialists.
Ultrasound examination — At least one ultrasound examination after 20 weeks of gestation

should be performed to look for signs of congenital infection. In pregnancies with a
presumptive sonographic diagnosis of congenital syphilis, ultrasound examinations should
be performed every one or two weeks to assess fetal well-being and the fetal response to
treatment.

With successful fetal treatment, middle cerebral arterial Doppler abnormalities, ascites, and
polyhydramnios resolve first (usually within approximately one month), followed by
placentomegaly, and lastly hepatomegaly. Hepatomegaly can take months to resolve after
maternal treatment [69].
Delivery issues
● Late preterm delivery for neonatal treatment is indicated when there is a high risk of
fetal treatment failure (eg, progressive worsening signs of congenital syphilis on
ultrasound examination, hydrops) [6,59].
● If the patient first presents for pregnancy care when they are in labor and their
nontreponemal or treponemal test is positive, maternal evaluation and treatment for
syphilis are performed as described above; intrapartum care and procedures are not
impacted.
● At delivery, pediatric providers should be notified about maternal syphilis stage and
treatment, and fetal ultrasound findings. (See "Congenital syphilis: Management and
outcome" and "Congenital syphilis: Clinical manifestations, evaluation, and diagnosis".)
Placenta — The placenta/fetal membranes should be sent for histopathologic examination.

The pathologist should be notified about maternal syphilis stage and treatment.
The placenta in people with untreated syphilis is typically large and edematous. Characteristic
placental findings include ( picture 1):
● Hydrops placentalis
● Chronic villitis (plasma cells, mixed acute and chronic infiltrate)
● Perivillous fibrous proliferation (onion skin vessels)
● Normoblastemia
● Necrotizing funisitis
● Acute chorioamnionitis
● Plasma cell deciduitis
These pathological changes can adversely affect fetoplacental exchange of oxygen and
nutrients, which may account, at least in part, for some adverse fetal outcomes [6].
Silver stain should reveal the spirochetes, but they are often very difficult to identify. The best
yield is often in the decidua basalis or capsularis where there are plasma cells or, in cases of
fetal death, in the vitreous.
SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Sexually transmitted
infections".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles on
a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Congenital syphilis (The Basics)")
SUMMARY AND RECOMMENDATIONS
● Clinical findings – Each stage of syphilis has characteristic maternal clinical features
that are not altered by pregnancy ( table 1). (See 'Staging' above.)
● Diagnosis – Diagnostic evaluation for maternal syphilis is the same in pregnant and
nonpregnant individuals. A maternal diagnosis of syphilis is made when both
nontreponemal and treponemal tests are reactive. (See 'Diagnosis' above.)
● Screening – We recommend screening pregnant people for syphilis (Grade 1B) (See
'Maternal screening' above.).
• All pregnant people: screen at the first prenatal encounter
• Pregnant people at high risk of infection: repeat screening at 28 to 32 weeks and at

delivery
• Pregnant people who have not been screened in pregnancy or who deliver a stillborn
after 20 weeks of gestation: screen at delivery

● False-positive screening tests – False-positive screening tests may be more common in

the setting of pregnancy. Confirmatory testing must be performed ( algorithm 1). (See
'False-positive serologic tests in pregnancy' above.)
● Treatment – Penicillin G benzathine is the standard for the treatment of syphilis
• Penicillin G benzathine therapy is effective for treating maternal disease, preventing

transmission to the fetus, and treating established fetal disease. The long-acting
intramuscular formulation must be used (Bicillin L-A); Bicillin C-R (which contains
equal concentrations of intermediate-acting procaine and long-acting benzathine
penicillin) should not be used to treat patients with syphilis. (See 'Maternal
treatment' above.)
• The appropriate penicillin G benzathine regimen depends on the stage of disease

( table 2).
- Primary, secondary, or early latent disease: a single dose of penicillin G

benzathine 2.4 million units intramuscularly. Some clinicians administer an
additional dose of penicillin G benzathine 2.4 million units one week after the
first dose. (See 'Treatment of primary, secondary, or early latent disease and
post-exposure prophylaxis' above.)
- Late latent, tertiary, and disease of unknown duration: three doses of

penicillin G benzathine 2.4 million unit intramuscularly at weekly intervals. If a
dose is missed for more than 14 days, the full three dose course of therapy
should be started again. (See 'Treatment of late latent and tertiary disease'
above.)
If an asymptomatic patient with what could be latent syphilis was previously

treated for syphilis but receipt of an appropriate treatment regimen cannot be
verified, the full three-dose penicillin regimen recommended for late latent
syphilis should be administered.
● Desensitization in penicillin allergy – We recommend desensitization for penicillin-

allergic pregnant patients followed by penicillin G benzathine therapy (Grade 1B).
Alternative drugs are not as safe for the pregnant person or fetus or not as effective for
prevention of congenital syphilis. (See 'Patients with immediate type allergic reactions to
penicillin' above and 'Role of nonpenicillin regimens' above.)
● Jarisch-Herxheimer reaction – Treatment of syphilis may precipitate the Jarisch-

Herxheimer reaction, which may precipitate uterine contractions, preterm labor, and/or
nonreassuring fetal heart rate tracing in pregnant people treated in the second half of
pregnancy. Maternal discomfort is treated with supportive care and pregnancy

complications are managed by standard obstetric protocols. (See 'Potential

complications of treatment: Jarisch-Herxheimer reaction' above.)
● Maternal follow-up
• Pregnant people treated for early syphilis should have a titer checked just before
treatment, since it is not uncommon for this titer to be higher than that of the initial
diagnostic titer due to elapsed time between diagnosis and therapy. The subsequent
frequency of monitoring is the same as in nonpregnant patients and depends upon
the stage of disease and presence of HIV coinfection. When monitoring
nontreponemal titers, the same test, preferably the rapid plasmin regain (RPR),
should be performed each time and at the same laboratory. (See 'Frequency of
nontreponemal titers' above.)
• A fourfold increase in the nontreponemal titer after treatment is always abnormal. A

fourfold decline in the titer, equivalent to a change of two dilutions (eg, from 1:16 to
1:4 or from 1:32 to 1:8), is considered to be an acceptable response to syphilis
therapy; however, this can take months to achieve. A fall in maternal titers does not
guarantee that fetal treatment has been adequate. (See 'Interpretation of response
to therapy and diagnosis of treatment failure' above and 'Ultrasound examination'
above.)
● Vertical transmission
• Frequency – The frequency of vertical transmission is higher with early stage than
late stage syphilis. Among people who acquire syphilis during pregnancy, the risk of
vertical transmission increases with increasing gestational age at acquisition of
maternal infection. (See 'Vertical transmission' above.)
• Prenatal diagnosis – Fetal infection should be suspected if there are characteristic

findings on ultrasound examination after 20 weeks of gestation in a patient with
untreated or inadequately treated syphilis. Hepatomegaly and placentomegaly are
early sonographic findings suggestive of congenital syphilis. Anemia, ascites, and
hydrops occur later in the course of fetal infection. An abnormal ultrasound is not
diagnostic of fetal infection and a normal ultrasound does not exclude fetal infection.
(See 'Prenatal (fetal) diagnosis' above.)
• Treatment – Maternal penicillin G benzathine treatment is curative for fetal infection

in most cases. Maternal treatment ≤30 days before delivery is a risk factor for
congenital infection. (See 'Fetal treatment and treatment failure' above.)
Use of UpToDate is subject to the Terms of Use.

Topic 4794 Version 78.0

GRAPHICS
Screening and diagnosis of syphilis in pregnant women without prior syphilis
STI: sexually transmitted infection.
* The initial type of screening test (treponemal versus nontreponemal) is typically dictated by the clinical
¶ Nontreponemal tests include the rapid plasma reagin (RPR), the Venereal Disease Research Laboratory
toluidine red unheated serum test (TRUST).

Δ Treponemal tests include the fluorescent treponemal antibody absorption (FTA-ABS), the Treponema pal
agglutination (TPPA), the T. pallidum enzyme immunoassay (TP-EIA), or chemiluminescence immunoassay
treponemal tests target different antigens.
◊ Refer to the topic that discusses syphilis and pregnancy for treatment regimens.
§ A reactive low titer nontreponemal screening test can be considered a transient biologic false-positive r
if the confirmatory treponemal test is negative and the patient is asymptomatic and at low risk of acute sy
nontreponemal test results can also be related to an acute event, such as an acute febrile illness or recen
abnormalities attributed to these conditions are usually transitory and typically last for 6 months or less.
¥ If at 28 to 32 weeks gestation a screening nontreponemal test (eg, RPR) is reactive and the confirmatory
FTA-ABS) is nonreactive, treatment is usually the best option rather than repeating a confirmatory trepon
weeks. If at 28 to 32 weeks a screening treponemal test is reactive and the confirmatory nontreponemal t
second treponemal test that targets different antigens should be performed; if positive, serology is consi
if negative, syphilis is unlikely. However, if there is diagnostic uncertainty (eg, a second treponemal test ca
the setting of pregnancy, we prefer to treat.
‡ Testing performed at delivery is used to help inform the pediatrician regarding screening/treatment of t
of the mother at delivery does not prevent transmission.
Graphic 116084 Version 4.0

Clinical manifestation of syphilis
Stage Clinical manifestations
Primary syphilis Single painless ulcer (chancre) at site of inoculation, regional

adenopathy
Secondary syphilis Rash (disseminated and/or involving the palms and soles), fever,
malaise, mucocutaneous lesions, hepatitis, arthritis,
glomerulonephritis, condyloma lata, pharyngitis, alopecia
Latent syphilis Asymptomatic
Early latent (<1 year

after initial infection)
Late latent (>1 year after

initial infection)
Tertiary (late) syphilis
Gummatous disease Granulomatous disease of the skin and subcutaneous tissues,

bones, or viscera
Cardiovascular disease Aortic aneurysm, aortic insufficiency
Central nervous system Tabes dorsalis, Argyll-Robertson pupils, paresis, seizures, subtle
disease (neurosyphilis) psychiatric manifestations, dementia. May be asymptomatic.
Neurosyphilis (can occur at any time during the course of infection)
Early Asymptomatic meningitis, symptomatic meningitis, or, less

commonly, meningovascular disease (ie, meningitis and stroke).
Vision or hearing loss with or without concomitant meningitis may
also be present, and ocular/otologic syphilis is treated as
neurosyphilis.
Late Most common forms involve the brain and spinal cord (dementia
[general paresis] and tabes dorsalis).

Treatment of syphilis in pregnancy
Stage of syphilis Treatment
Primary/secondary/early Penicillin G benzathine (Bicillin L-A) 2.4 million units IM in a single dose
latent (usually administered as 1.2 million units in each buttock)*
Late Penicillin G benzathine (Bicillin L-A) 2.4 million units IM once weekly
latent/tertiary/unknown (usually administered as 1.2 million units in each buttock) for 3 weeks
duration (7.2 million units total dose) ¶
Neurosyphilis (including Aqueous crystalline penicillin G (intravenous) 18 to 24 million units per

ocular syphilis) Δ day, administered as 3 to 4 million units IV every 4 hours or as a
continuous infusion over 24 hours for 10 to 14 days
OR
Penicillin G procaine 2.4 million units IM once daily (usually

administered as 1.2 million units in each buttock) plus probenecid 500
mg PO 4 times daily, both for 10 to 14 days
Post-exposure Penicillin G benzathine (Bicillin L-A) 2.4 million units IM in a single dose
prophylaxis (usually administered as 1.2 million units in each buttock)
Pregnant women are treated with the penicillin regimen appropriate for their stage of
infection. Parenteral (IM or IV) penicillin G is the only therapy with documented safety and
efficacy for both mother and fetus during pregnancy. Pregnant women with a history of
penicillin allergy should be desensitized and treated with penicillin. Refer to the relevant topic
review for further guidance on management of pregnant patients with penicillin allergy.
If penicillin desensitization is not possible for treatment of early syphilis (primary, secondary,
or latent <2 years), the World Health Organization (WHO) suggests using, with caution,
erythromycin 500 mg 4 times daily for 14 days, ceftriaxone 1 g IM once daily for 10 to 14 days,
or azithromycin 2 g once orally (when local susceptibility to azithromycin is likely). If penicillin
desensitization is not possible for treatment of late syphilis, the WHO recommends treatment
with erythromycin 500 mg orally 4 times daily for 30 days. Macrolides (eg, erythromycin) do
not completely cross the placental barrier; therefore, the WHO also recommends that infants
born to women treated with non-penicillin regimens receive a 10 to 15 day course of
parenteral penicillin treatment.
IM: intramuscular; IV: intravenous; PO: oral.
* If serologic failure is detected at follow-up and additional follow-up cannot be assured, consider
retreating with penicillin G benzathine 2.4 million units IM once weekly for 3 weeks. Prompt
cerebrospinal fluid examination is recommended.
¶ If a dose is missed for more than 14 days, then the full 3 dose course of therapy should be
restarted.
Δ Penicillin G benzathine 2.4 million units IM once per week for up to 3 weeks may be
administered after completion of IV penicillin G treatment to provide a comparable total duration
of therapy as latent syphilis.
Data from:
1. Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually transmitted diseases treatment
guidelines, 2015. MMWR Recomm Rep 2015; 64:1.
2. World Health Organization guidelines for treatment of Treponema pallidum (syphilis), 2016.
http://apps.who.int/iris/bitstream/10665/249572/1/9789241549806-eng.pdf?ua=1 (Accessed on August 15, 2018).

Classification of allergic reactions (Gell and Coombs)
Clinical
Type Description Mechanism
features
I Anaphylactic, Antigen exposure causes release of Anaphylaxis

immediate-type vasoactive substances, such as
Immediate Angioedema
hypersensitivity histamine, prostaglandins, and
reaction (30 to
leukotrienes from mast cells or Bronchospasm
60 min)
basophils. This response is usually, but Urticaria (hives)
Accelerated not always, IgE-dependent.
reaction (1 to
72 hours)
II Antibody- An antigen or hapten that is intimately Hemolytic

dependent associated with a cell binds to antibody, anemia
cytotoxicity leading to cell or tissue injury.
Interstitial
nephritis
III Immune complex Damage is caused by formation or Serum sickness

disease deposition of antigen-antibody
complexes in vessels or tissue.
IV Cell-mediated or Antigen exposure sensitizes T cells, Contact

delayed which then mediate tissue injury. dermatitis
hypersensitivity
V Uncertain, but probably involving T cell Maculopapular

cytotoxicity. rash
(>72 hours)
IgE: immunoglobulin E.
Adapted from: Weiss ME, Adkinson NF. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clin
Allergy 1988; 18:515.

Clinical manifestations of early congenital syphilis*
Gestational/perinatal
Stillbirth
Prematurity
Birth weight <2500 g
Nonimmune hydrops fetalis
Placenta Large, thick, pale (send for pathologic/histologic

evaluation)
Umbilical cord Inflamed with abscess-like foci of necrosis within

Wharton's jelly, centered around the umbilical vessels
(necrotizing funisitis); barber-pole appearance (send for
pathologic/histologic evaluation)
Systemic
Fever May be more prominent in infants born to mothers who

are affected late in pregnancy and whose serology is
negative at delivery
Hepatomegaly Splenomegaly occurs in approximately one-half of

patients with hepatomegaly—isolated splenomegaly
does not occur
Generalized lymphadenopathy May be as large as 1 cm; generally nontender and firm
Failure to thrive
Edema Due to anemia/hydrops fetalis, nephrotic syndrome,

malnutrition
Mucocutaneous
Syphilitic rhinitis ("snuffles") Can be an early feature, developing after the first week
of life; contains spirochetes and is infectious (use
contact precautions)
Maculopapular rash Usually appears one to two weeks after rhinitis. Oval
lesions, initially red or pink and then coppery brown;
may be associated with superficial desquamation or
scaling, particularly on the palms or soles; more
common on the buttocks, back, posterior thighs, and
soles; contains spirochetes and is infectious (use
contact precautions).
Vesicular rash (pemphigus May be present at birth, most often develops in first four
syphiliticus) weeks; widely disseminated; vesicular fluid contains
spirochetes and is infectious (use contact
precautions)

Condylomata lata Single or multiple, flat, wartlike, moist lesions around the
mouth, nares, and anus and other areas of the skin
where there is moisture or friction; lesions contain
spirochetes and are infectious (use contact
precautions); frequently present without other signs of
infection
Jaundice Hyperbilirubinemia secondary to syphilitic hepatitis

and/or hemolysis
Hematologic
Anemia Newborn period: Hemolytic (Coomb's test [direct

antiglobulin test] negative); may persist after effective
treatment
After one month of age: May be chronic and

nonhemolytic
Thrombocytopenia May be associated with bleeding or petechiae; can be

the only manifestation of congenital infection
Leukopenia
Leukocytosis
Musculoskeletal
Pseudoparalysis of Parrot Lack of movement of an extremity because of pain

associated with bone lesion; affects upper extremities
more often than lower; usually unilateral; rarely present
at birth; poorly correlated with radiographic
abnormalities
Radiographic abnormalities: Most frequent abnormality in untreated early congenital

syphilis; not usually clinically discernible; typically
multiple and symmetric
Periostitis Irregular periosteal thickening; usually present at birth,

but may appear in the first few weeks of life
Wegner sign Metaphyseal serration or "sawtooth metaphysis"
Wimberger sign Demineralization and osseous destruction of the upper

medial tibial
Neurologic
CSF abnormalities Reactive CSF VDRL; elevated CSF white blood cell count;
elevated CSF protein
Acute syphilitic leptomeningitis Onset during the first year of life, usually between 3 and
6 months; presentation similar to bacterial meningitis
but CSF findings more consistent with aseptic meningitis
(mononuclear predominance); responds to penicillin
therapy

Chronic meningovascular syphilis Onset toward the end of the first year; hydrocephalus;
cranial nerve palsies; intellectual/neurodevelopmental
deterioration; cerebral infarction; protracted course
Miscellaneous
Pneumonia/pneumonitis/respiratory Complete opacification of both lung fields on chest

distress radiograph
Nephrotic syndrome Usually occurs at two to three months of age and

manifests with generalized edema and ascites
CSF: cerebrospinal fluid; VDRL: Venereal Disease Research Laboratory test.
* All of these findings may occur in other congenital infections; none is specific for congenital
syphilis.
Data from:
1. Ingall D, Sanchez PJ, Baker CH. Syphilis. In: Infectious Diseases of the Fetus and Newborn infant, 6th edition,
Remington JS, Klein JO, Wilson CB, Baker CJ (Eds), Elsevier Saunders, Philadelphia 2006. p.545.
2. Dobson SR, Sanchez PJ. Syphilis. In: Feigin and Cherry's Textbook of Pediatric Infectious Diseases, 7th, Cherry JD,
Harrison GJ, Kaplan SL, et al. (Eds), Elsevier Saunders, Philadelphia 2014. p.1761.
3. Woods CR. Syphilis in children: congenital and acquired. Semin Pediatr Infect Dis 2005; 16:245.
4. Saloojee H, Velaphi S, Goga Y, et al. The prevention and management of congenital syphilis: an overview and
recommendations. Bull World Health Organ 2004; 82:424.
5. Chakraborty R, Luck S. Syphilis is on the increase: the implications for child health. Arch Dis Child 2008; 93:105.
6. Rawstron SA. Treponema pallidum (Syphilis). In: Principles and Practice of Pediatric Infectious Diseases, 3rd
edition, Long SS, Pickering LK, Prober CG (Eds), Churchill Livingstone Elsevier, Philadelphia 2008. p.930.

Syphilis of the placenta
(A) Chronic villitis.
(B) Onion skin placental villi.
Courtesy of Drucilla J Roberts, MD.


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Literature review current through: May 2023.

Syphilis is a systemic infection caused by the spirochete Treponema pallidum. Infection is of

● (See "Congenital syphilis: Clinical manifestations, evaluation, and diagnosis".)

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The epidemiology of congenital syphilis is reviewed in more detail separately. (See

MATERNAL ACQUISITION OF INFECTION

MATERNAL CLINICAL MANIFESTATIONS

Universal antepartum screening is widely recommended because screening followed by

Candidates and timing of initial and repeat screening

● All pregnant people: screen at the first prenatal encounter

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● Specific treponemal tests include fluorescent treponemal antibody absorption (FTA-

The diagnostic interpretation of syphilis serology, including interpretation of testing in

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False-positive serologic tests in pregnancy

● Prevalence – Biologic false-positive nontreponemal and treponemal results are

A positive (reactive) low titer nontreponemal screening test can be considered a

● Follow-up after delivery – All patients with biologic false-positives attributed to

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● Primary syphilis — When symptomatic, the first manifestation of syphilis is a skin

● Secondary syphilis — Secondary syphilis is a disseminated systemic process that

● Tertiary (late) syphilis — Tertiary syphilis is infrequently diagnosed and is

Preferred regimen: penicillin

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available resources. (See "Rapid drug desensitization for immediate hypersensitivity

● The appropriate penicillin G benzathine regimen depends on the stage of disease

Treatment of primary, secondary, or early latent disease and post-exposure

● A single dose of penicillin G benzathine 2.4 million units intramuscularly is appropriate

Treatment of late latent and tertiary disease

● Three doses of penicillin G benzathine 2.4 million units intramuscularly at weekly

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Treatment of neurosyphilis — Treatment of neurosyphilis is parenteral and typically

Penicillin allergy is reported by 5 to 10 percent of pregnant people [41]; however, serious

Referral — Patients who report symptoms suggestive of a past immediate allergy to a

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Desensitization — It is strongly recommended that desensitizations be performed by

Role of nonpenicillin regimens — During pregnancy, nonpenicillin antibiotic regimens used

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- Erythromycin 500 mg orally four times daily for 14 days, or

• For nonpenicillin treatment of late syphilis, administer erythromycin 500 mg orally

- Aqueous benzyl penicillin 100,000 to 150,000 U/kg/day intravenously for 10 to 15

POTENTIAL COMPLICATIONS OF TREATMENT: JARISCH-HERXHEIMER

● Signs and symptoms – Clinical manifestations include an acute febrile reaction

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Management is supportive care (eg, antipyretics, intravenous fluids).

● Complications – The Jarisch-Herxheimer reaction may precipitate uterine contractions,

● Role of premedication – The authors do not premedicate patients. Premedication with

Premedication with acetaminophen or meptazinol may reduce the severity or duration

POST-TREATMENT MATERNAL FOLLOW-UP

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subsequent frequency of monitoring is the same as in nonpregnant patients and depends

Interpretation of response to therapy and diagnosis of treatment failure

● A fourfold increase in the nontreponemal titer after treatment is evidence of treatment

A decline in maternal nontreponemal serologic titers following treatment does not

There is wide patient-to-patient variability in the rate of decline in nontreponemal titers,

POTENTIAL ADVERSE PREGNANCY OUTCOMES

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Inadequate maternal screening and/or inadequate maternal treatment can result in

Pathogenesis of congenital infection — T. pallidum readily infects the placenta.

Factors influencing frequency of vertical transmission — In two systematic reviews, 15

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