Ronald M. Ramus
History of present illness
A 20-year-old gravida 1 woman presents for urgent follow- up after initiation of prenatal care. She is now 12 weeks’
pregnant. Her medical history is unremarkable. She has never had surgery and her only medication is a prenatal vitamin. She has had four sexual partners in her lifetime but has never received any gynecologic care or sexually transmitted infection screening prior to her pregnancy.
A panel of routine prenatal laboratory studies were per- formed five days prior, including a rapid plasma reagin (RPR) test. Her test returns with a positive result, at a titer of 1 : 32. A confirmatory test for treponemal specific anti- bodies was also positive.
Physical examination
General appearance:Well-nourished woman with no discomfort
Vital signs:
Temperature: 37.0°C Pulse: 80 beats/min
Blood pressure: 120/70 mmHg Respiratory rate: 16 breaths/min HEENT:Unremarkable
Neck:Supple
Cardiovascular:Regular rate and rhythm without rubs, murmurs, or gallops
Lungs:Clear to auscultation bilaterally Abdomen:Soft, nontender
Extremities:No obvious lymphadenopathy. A faint erythematous rash is noted on her palms and soles Neurologic:Nonfocal
External genitalia:Multiple smooth, moist,flat lesions on the vulva and in the perianal region (Fig. 56.1)
Vagina:Unremarkable, scant discharge
Cervix:Nulliparous, no mucopurulent discharge Uterus:Approximately 12 weeks’size
Adnexa:Nontender, no masses Laboratory studies:
CBC: Normal
Negative for chlamydia, gonorrhea, hepatitis B, and HIV
How would you manage this patient?
The patient’s laboratory testing confirms a true syphilis infec- tion. The erythematous rash on her palms and soles, as well as the perianal condyloma lata lesions seen are consistent with a diagnosis of secondary syphilis.
The patient was given benzathine penicillin G (Bicillin®) 2.4 million units IM as a one-time dose, and will undergo retesting several weeks later to confirm adequate treatment (her RPR titer should drop at least fourfold). In addition, the RPR will be repeated monthly thereafter throughout the preg- nancy to look for evidence of reinfection.
Syphilis
Syphilis is a sexually transmitted disease caused by the spiro- chete Treponema pallidum. The Centers for Disease Control and Prevention (CDC) recommends screening for syphilis in pregnancy. This is typically done at thefirst prenatal visit, and is repeated in the third trimester in women at high risk for syphilis. High-risk women include sex workers, users of illicit drugs, individuals with HIV, infection with other sexually transmitted diseases, women living in an area with a high incidence of syphilis, a lack of regular prenatal care, uninsured women, poverty, or sexual promiscuity. The RPR test is the most common laboratory study used to screen for syphilis. It is ideally suited for this role due to its simplicity and low cost. An alternative nontreponemal specific screening assay is the VDRL (venereal disease research laboratory) test. The VDRL
Acute Care and Emergency Gynecology, ed. David Chelmow, Christine R. Isaacs and Ashley Carroll. Published by Cambridge University Press.
© Cambridge University Press 2015.
Fig. 56.1 Perianal condyloma lata. This is a commonfinding with secondary syphilis. The lesions areflat, raised, and moist. (Photograph courtesy of Nick Fiumara, MD.)
test was developed before World War 1 and has now largely been replaced by the RPR assay, as both tests use the same antigen but in the RPR test the antigen is bound to a carbon particle to allow visualization of the flocculation reaction (foaming in a test tube) that does not require a microscope.
Because the spirochete responsible for syphilis cannot be cul- tured in the laboratory, serologic testing is essential in making the diagnosis. It is important to remember, however, that the RPR test is notspecificto syphilis and there are many known false positive RPR associations. This includes connective tissue diseases such as lupus, Lyme disease, malaria, tuberculosis, certain types of pneumonia, intravenous drug use, HIV, and even pregnancy itself. It is estimated that 1–2% of the United States population has false positive nontreponemal specific test results [1]. Therefore, a positive RPR should always be followed by atreponemal specifictest, most commonly either FTA-ABS (fluorescent treponemal antibody absorption test), MHA-TP (microhemagglutination assay for T. pallidum), or TP-PA (T. pallidum particle agglutination assay) based on one’s local laboratory availability.
Once the treponemal specific test confirms the diagnosis of syphilis, as in the case of this patient, the next step is to perform a physical examination to look for any clinical symptoms of infection. Clinical findings will vary based on the stage of syphilis present (Table 56.1). Primary syphilis is associated with a painless chancre and regional lymphadenopathy. The chancre can be on the vulva, vagina, or cervix and typically spontaneously resolves in three to six weeks. Secondary syphilis is typically apparent anywhere from six weeks to six months after the initial infection. It is associated with a diffuse erythematous rash known to occur all over the body, and notably appears at times on the palms and soles. There may also be evidence of condy- loma lata, (flat, moist, nontender lesions on the perineum or perianal regions) and diffuse lymphadenopathy. The rash of secondary syphilis is usually apparent for two to six weeks, but may be subtle and not obvious to the patient or health- care provider. If there are no clinicalfindings of syphilis the patient likely has latent disease. Patients with latent disease are typically divided into two groups: early versus late latent disease. Early latent disease is diagnosed when a negative RPR test was noted less than a year prior in the patient’s personal history. If there is no evidence to support a
duration of infection of less than a year, the patient is presumed to have late latent syphilis.
Prior to making a diagnosis of latent syphilis one must determine if there is a history of syphilis treatment in the past.
A recent study found that 34% of patients appropriately treated for syphilis will have persistent serologic evidence of the disease one year after treatment [2] even though their syphilis has been cured; a condition called“serofast syphilis.”
Ideally confirmation of this diagnosis requires documentation of appropriate treatment in the past, typically tracked by ones local Health Department. If confirmation of prior treatment is obtained and the RPR titer remains low (typically 1 : 4 or less) then retreatment is not necessary and the patient is considered serofast. If proof of prior treatment is not available, or the titer is 1 : 8 or higher, it is appropriate to presume latent disease or reinfection and to treat accordingly. Untreated infection after many years of latency can lead to tertiary disease, or neurosy- philis. Fortunately, this is extremely rare in pregnancy as gravid women are typically too young to present with signs and symptoms suggestive of a longstanding syphilis infection.
AsTable 56.1indicates, the treatment for syphilis in preg- nancy is penicillin. A long-acting penicillin is required, so the typical formulation is benzathine penicillin G (Bicillin), given as a 2.4 million unit dose IM. Penicillin is the clear preferred agent in pregnancy, as none of the alternative antibiotics used to treat syphilis (such as azithromycin, ceftriaxone, or erythro- mycin) have been shown to be effective in crossing the placenta and treating fetal infection. The CDC currently recommends a single dose of Bicillin for the treatment of primary, secondary, and early latent syphilis in pregnancy [3]; however, many authorities in the field recommend a second dose of Bicillin one week later to provide better treatment for the fetus [4].
Late latent disease requires three doses of Bicillin given at weekly intervals.
Many patients claim to have a penicillin allergy. Since penicillin is the only safe and effective agent to treat syphilis in pregnancy, it is mandatory to perform skin testing to determine if a true allergy exists. If an allergic reaction is documented then one must proceed with a desensitization algorithm prior to penicillin treatment. There are both oral and intravenous regimens to perform desensitization [5], and this is typically done in an inpatient setting in consultation with an Allergy/Immunology specialist.
Table 56.1 The stages of syphilis seen in pregnancy, with characteristic findings and treatment recommendations
Stage Clinicalfindings RPR titer Treatment
Primary Genital chancre, regional lymphadenopathy High Bicillin®2.4 million units × 1 Secondary Condyloma lata, palmar erythema, generalized
lymphadenopathy High Bicillin®2.4 million units × 1
Early latent None Usually low Bicillin®2.4 million units × 1
Late latent None Usually low Bicillin®2.4 million units × 3 doses weekly
RPR, rapid plasma reagin.
If syphilis is diagnosed in the second half of pregnancy, fetal ultrasound evaluation should be performed prior to treat- ment. Congenital infection leads to hydrops fetalis (ascites, pleural effusions, pericardial effusions, subcutaneous edema with placentomegaly, and polyhydramnios), which is seen with ultrasound and is associated with stillbirth, preterm birth, and neonatal death. The risk of congenital infection is related to the stage of disease; perinatal transmission occurs in about 50% of cases of primary or secondary syphilis, but is reduced to 40%
with early latent disease and 10% with late latent disease [6].
If there is ultrasound evidence of fetal infection there is a higher risk of the Jarisch–Herxheimer reaction with treatment.
The lysis of spirochetes associated with the treatment of syph- ilis leads to the release of large amounts of lipopolysaccharide (LPS) and endotoxins. These substances elevate circulating cytokine levels, and can cause fever, chills, hypotension, head- ache, tachycardia, vasodilation, tachypnea, myalgias, and con- tractions in the mother. In addition, a fetus undergoing the Jarisch–Herxheimer reaction is more likely to have fetal heart rate decelerations or even fetal death. Because of these poten- tial complications with treatment, pregnancies undergoing penicillin therapy for syphilis with evidence of congenital infection in the third trimester are often treated in a Labor and Delivery unit to facilitate monitoring the fetus and delivery if there are any signs of fetal compromise.
Once treatment has been completed, the CDC recom- mends that repeat serologic titers be obtained at 28–32 weeks’
gestation and again at delivery on women treated earlier in pregnancy. If there is a fourfold or higher rise in titers during
surveillance following treatment, then one must presume reinfection and retreat the patient. For women at high risk of reinfection or in geographic areas in which the prevalence of syphilis is high, monthly serologic titers may be appropriate.
Given the rarity and potential severity of congenital syphilis, many experts consider any pregnant woman diagnosed with syphilis during pregnancy at high risk for re-infection [3].
Key teaching points
Treponemal specific testing for syphilis is required when a positive screening test (RPR) is obtained. A positive treponemal specific test confirms a true syphilis infection.
If syphilis testing is positive, one must review the patient’s history and any documentation of prior syphilis treatment to confirm if the diagnosis is“serofast syphilis.”
With no history of prior treatment, penicillin is the antibiotic necessary to achieve bacteriocidal levels in the fetus. If the patient has a suspected penicillin allergy, proceed with skin testing for confirmation of such an allergy. If the patient is truly allergic to penicillin, a desensitization protocol is necessary.
The stage of syphilis determines the risk to the fetus and the appropriate antibiotic treatment regimen.
Fetal infections may become apparent on ultrasound as evidenced by hydropic fetal changes. Treatment of an infected fetus may lead to a Jarisch–Herxheimer reaction, and because of such, requires appropriate fetal monitoring during treatment.
References
1. Larsen SA. Syphilis.Clin Lab Med1989:
9:545–57.
2. Tong ML, Lin LR, Liu GL, et al.
Factors associated with serological cure and the serofast state of HIV-negative patients with primary, secondary, latent, and tertiary syphilis.PLoS One2013;8(7):
e70102.
3. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2010.
MMWR2010;59(RR-12):26–40.
4. Kingston M, French P, Goh B, et al. UK national guidelines on the management of syphilis 2008.Intl J STD & AIDS 2008:19:729–40.
5. Wendel GD, Stark BJ, Jamison RB, Molina RD, Sullivan TJ. Penicillin
allergy and desensitization in serious infections during pregnancy.N Engl J Med1985;312:1229–32.
6. Sanchez PJ, Wendel GD, Grimprel E, et al. Evaluation of molecular methodologies and rabbit infectivity testing for the diagnosis of congenital syphilis and neonatal central nervous system invasion byTreponema pallidum.
J Infect Dis1993;167(1):148–57.
Case 56: Positive RPR on initial prenatal labs