Syphilis in Pregnancy

Contributors:
Valerie Cacciatore, DO – PGY4
Maternal-Fetal Medicine

Last Update: 8/2024

Syphilis is a sexually transmitted systemic infection caused by a spirochete, Treponema pallidum and is diagnosed with serologic testing, clinical history and a detailed physical exam. Since reaching a historic low in 2000 and 2001, the rate of primary and secondary syphilis has increased almost every year, and by as much as 11.2% during 2018–2019. In the US, 129K new cases of all stage syphilis were diagnosed in 2019. In SC, there were 516 new cases of primary and secondary syphilis. SC is 20^th highest state for prevalence of syphilis at any stage. Primary and secondary syphilis are most infectious stages.

Unfortunately, the above means that congenital syphilis is also on the rise. There’s been a 41.4% increase from 2018 to 2019 and nearly a 300% increase from 2015 to 2019.

Public Health Crisis

21% increased risk for stillbirth

6% increased risk for preterm delivery

9% increased risk for neonatal death

Strongly associated with acquisition of HIV

Screening

Traditional syphilis screening approach: The CDC published guidelines in 1990s with the first-line test being a nontreponemal assay, such as VDRL and RPR. If positive, the second-line confirmatory test was a treponemal test, such as fluorescent treponemal antibody absorption tests or the T. pallidum passive particle agglutination (TP-PA) test. The treponemal tests typically remain positive for life. The VDRL or RPR false positive rate can be as high as 2% which can be due to viral illnesses such as hepatitis, connective tissue disorders, heroin use, malaria, antiphospholipid syndromes, and even normal pregnancy.

**In 2008, the CDC issued the current syphilis screening approach. A treponemal test is used as the first-line test, and if positive, reflexes to the nontreponemal test.

• When the treponemal test (Treponema Ab screen) is positive, it will reflex to qualitative RPR
  • If RPR is positive, it will reflex to RPR titer to determine the disease timeline and guide treatment
  • If the RPR is negative, it will reflex to a second treponemal test for confirmation (TPPA)
• Test to order: “Syphilis screen with reflex to confirmation.” Lab11006

Because of the high prevalence of syphilis in SC, all pregnant women should be screened at the following intervals:

1.  First prenatal visit

2.  With late-second-trimester labs (ie GDM screening)

3.  Upon admission for delivery

4.  If presenting with an IUFD after 20 weeks gestation

Classification and Presentation:

Primary: Identification of characteristic painless chancre, raised with firm border. This is self-limited and appears approximately 3 weeks after infection

• If suspected, polymerase chain reaction (PCR) can be collected from the lesion, though clinically there is rarely the opportunity to do so.
  • Quest code 16595 “Treponema pallidum quantitative PCR”
• Dark field microscopy is largely replaced by PCR
• Usually resolves in 6-8 weeks.

Secondary: Dissemination of spirochetes 4-10 weeks after the chancre appears. Mostly dermatologic abnormalities including macular rash, plantar and palmar rashes, patchy alopecia, and condylomata lata due to replication of spirochetes at a lower body temperature

• RPR titers 1:32 or higher are usually indicative of secondary syphilis. 
• Resolves in 1-6 months

Early Latent: No clinical manifestations. Results when primary or secondary syphilis was not treated and is discovered serologically within 12 months of original infection

• Should have negative screening test within the past year to confirm early latent diagnosis

Late latent: No clinical manifestations. Serologically discovered beyond 12 months of original infection

Tertiary: Comprises syphilitic disease of multiple organ systems 10-30 years after infection

• CV: Aortic aneurysms, aortic insufficiency, coronary stenosis, and myocarditis is made by symptoms, physical examination, EKG, ECHD, and angiography.
• MSK: Charcot’s joints, gummas
• Ophthalmologic: light sensitivity, pain, blindness

Neurosyphilis:  

• Early Neurosyphilis: may occur with any stage
  • Aseptic meningitis, cranial nerve palsies
• Late Neurosyphilis: occurs decades after initial infection
  • Paresis, dementia, psychiatric symptoms, tabes dorsalis, Argyll-Robertson pupils
• Diagnose with lumbar puncture demonstrating a positive VDRL, increased cell count, and increased protein.
  • Indications for LP:
    • Any stage of syphilis + HIV
    • Aortitis, gumma, or iritis in setting of positive serology
    • 4-fold rise of VDRL/RPR after treatment
    • Failure of 4-fold decline in VDRL or RPR following treatment
    • Presence of CNS symptoms AND positive serology

Treatment:

Primary/secondary/early latent: 2.4 million Penicillin G (1.2 in each buttock) every week for 2 doses

Late latent/tertiary/unknown: 2.4 million Penicillin G (1.2 million in each buttock) every week for 3 weeks

• If a dose is missed for more than 9 days, then the full 3 dose course should be restarted

Neuro: Aqueous crystalline Penicillin G 18-24 million per day as 3-4 million units IV q 4 hours or continuous over 24 hours for 10-14 days

Post-exposure prophylaxis: Penicillin G 2.4 million IM in single dose (1.2 in each buttock)

For those with a penicillin allergy in pregnancy, you must desensitize. This is done in the ICU setting at GMH. Call inpatient pharmacy at 864-455-8815 as they will place orders per their protocol. For non-pregnant patients with a penicillin allergy, doxycycline, tetracycline and ceftriaxone may be acceptable alternatives. There is limited evidence for use of ceftriaxone in treatment for neurosyphilis.

Treatment Effect

• Repeat RPR titers if reinfection is suspected
• Repeat RPR titers at 28-32 weeks and at time of delivery
  • Defer this if less than 8 weeks since treatment
• Coordinate repeat RPR titers at 6 and 12 months for primary, secondary and early latent syphilis
• Coordinate repeat titers at 6, 12, and 24 months for late latent and tertiary syphilis

Success of treatment is inferred via monitoring of RPR or VDRL titers

• Aim for 4-fold decline in titers over 6-12 months

• More likely to occur with higher baseline titers, younger age and earlier stage

Treatment failure:

• No 4-fold decrease
• Subsequent increase after initial decrease
• Consider re-infection

Serofast state: Patients who have at least a 4-fold decline in titers but whose nontreponemal titers do not serorevert or continue to fall after 24 months of monitoring

• Occurs in 15-20% of patients with early syphilis and as high as 35% in those with late latent syphilis
• All serofast individuals should be tested for HIV
• After identifying a patient as serofast, repeat nontreponemal tests every six months for one to two years then annually to assess for late failure or reinfection.

Treatment Outcomes

• 97% reduction in congenital syphilis
• 82% reduction in stillbirth
• 64% reduction in preterm birth
• 80% reduction in neonatal mortality

Jarish-Herxheimer Reaction: phagocytosis and release of immune complexes from breakdown of spirochetes

• Occurs within 1^st 24 hours of treatment in up to 35% of cases, most commonly in treatment of early syphilis
• Characterized by self-limited fever, headache, myalgias, hypotension, and rash. Rarely meningitis, respiratory distress, seizures, and uterine contractions can occur
• Cannot prevent it but may use Tylenol and/or NSAIDs for symptomatic relief

Effect of disease on pregnancy:

Transmission

• Transplacental transmission occurs as early as the 9^th-10^th week.
  • Rate of transmission increases the later maternal infection occurs.
• Transmission at delivery through direct contact with lesions

Fetal infection

• Occurs in 50-80% of women with untreated primary, secondary or early latent syphilis
• Can cause miscarriage, preterm birth, FGR, congenital infection and neonatal mortality

Effect on placenta

• T. pallidum infects the placenta causing placentomegaly. At delivery, placenta may appear pale because of diminished number of vessels and increased vascular resistance in uterine and umbilical arteries.

Maternal syphilis can cause fetal infection by several routes.

• Incubation period is 3-4 weeks. 
• Spirochetes readily cross placenta to cause congenital infection.
• Neonates can also encounter spirochetes through direct contact with lesions at delivery.

Fetal effects

Most pronounced after 20 weeks of gestation since fetal immunologic response is poorly developed before this point.

Presents as a continuum: fetal hepatic infection (hepatomegaly), anemia, ascites, hydrops, death

• With successful treatment, middle cerebral arterial doppler abnormalities, ascites, and polyhydramnios resolve first (usually within one month), followed by placentomegaly, and lastly hepatomegaly. Hepatomegaly can take months to resolve after maternal treatment.

Care plan

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, twice weekly testing should be done to assess fetal well-being and the fetal response to treatment.

Late preterm delivery for neonatal treatment is warranted when there is a high risk of treatment failure such as progressive worsening of signs of congenital syphilis on ultrasound or hydrops.

If treatment failure/congenital syphilis is suspected, patient should be transferred from outside facilities to GMH for delivery and/or treatment of the neonate.

At delivery, pediatric providers should be notified of 1) maternal syphilis stage 2) treatment status, and 3) fetal ultrasound findings.

Notify pathology that placenta is being submitted because of syphilis diagnosis. MUST BE WRITTEN ON REQUISITION

Neonatal effects

Jaundice, petechiae, purpuric skin lesions, lymphadenopathy, rhinitis, pneumonia, myocarditis, nephrosis, long bone involvement, and congenital deafness.

Postpartum follow up

Follow up after pregnancy is typically through the health department though appointments cannot be schedule out > 1 week. Alternatively, you can get the patient follow up with PCP who may finish therapy and schedule titer follow up.

Resources

1. Centers for Disease Control and Prevention. 2015 STD Treatment Guidelines. 2015;64(3):140. Available at: https://www.cdc.gov/std/tg2015/default.htm
2. Hollier LM, Harstad TW, Sanchez PJ, et al. Fetal syphilis: clinical and laboratory characteristics. Obstet Gynecol 2001; 97:947.
3. Rac MW, Revell PA, Eppes CS. Syphilis during pregnancy: a preventable threat to maternal-fetal health. Am J Obstet Gynecol 2017; 216:352.
4. 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 
5. Adhikari EH. Syphilis in Pregnancy. Obstet Gynecol. 2020 May;135(5):1121-1135. doi: 10.1097/AOG.0000000000003788. PMID: 32282589.

LabCorp Screening Cascade

Reverse algorithm used by Prisma Health Laboratories

CDC Syphilis Pocket Guide for Providers