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Syphilis in pregnancy

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
Literature review current through: Dec 2022. | 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 – Rates of syphilis infection among pregnant people in the United States are not available. 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).

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 [2].

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 [3].

EPIDEMIOLOGY — Syphilis occurs with equal frequency in males and females worldwide [4], 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 [5,6]. 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 [6].

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.)

Routinely rescreening all pregnant people in the third trimester and/or at delivery is not cost-effective [20]. 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 [21]. 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.

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 [22], 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 [23]. (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 [24]. 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) [25]. 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) [26]. 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 [27]). 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) [28], while a false-positive EIA has been associated with advanced age (≥40 years) [29].

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 [26,28-32]. (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 [33], 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) [5]. 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-RPenicillin 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 [5], based in part on evidence of efficacy [34-36] and on pharmacokinetic data of altered penicillin levels in pregnant people [37,38]. 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 [21]. (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 [21].

Penicillin allergy is reported by 5 to 10 percent of pregnant people [39]; 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 [39]. 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 [40]:

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 [41]. 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 [42]. 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 [42]. 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 [42,43]. 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 [44] or TNF-alpha antibodies [45,46] 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 [44]. 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 [47]; premedication with pentoxifylline has not been effective [48].

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 [33,49-53]. 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 [18,54].

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 [55] 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 [5]. 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 [56]. Hepatomegaly is thought to be caused by inflammation, extramedullary hematopoiesis, and hepatic congestion [5].

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 [57,58]. 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 [59-61]. 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 [62]. 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 [58].

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 [63]. 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 [3]. 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 [64]. 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 [65]:

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 [66]. 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 [56]. 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 [5].

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 [67].

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 [61]:

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 [66].

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) [5,56].

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 [5].

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.)

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References