MATERNAL-FETAL CASE STUDIES

Syphilis in Pregnancy: Fetal and

Neonatal Complications
Daniela Moino, MD,* Stephanie Ros, MD*
*Department of Obstetrics and Gynecology, University of South Florida, Tampa, FL

THE CASE
A 28-year-old gravida 2, para 1-0-0-1 woman with a history of a previous cesar-
ean delivery presented to a tertiary-care facility at 26.4 weeks’ gestation because
of preterm contractions. She had not yet initiated prenatal care. All standard pre-
natal laboratory tests were collected, including the Treponema pallidum antibody
test, the result of which was positive. The laboratory performed a reflex quantita-
tive nontreponemal test, the rapid plasma reagin (RPR), and the result showed a
titer of 1:32. The patient denied previous syphilis infection or treatment. All
other sexually transmitted infection screenings were negative, including gonor-
rhea, chlamydia, human immunodeficiency virus, hepatitis B surface antigen,
and hepatitis C antibody. Pelvic examination did not demonstrate condyloma
lata or a chancre. Based on her serologic findings, she was diagnosed with early
latent syphilis. She was given the first of 3 doses of 2.4 million units of intra-
muscular benzathine penicillin G (BPG) and was admitted to the antepartum
service for the evaluation of preterm labor and for 24 hours of continuous fetal
monitoring given the possibility of the Jarisch–Herxheimer reaction during ini-
tial treatment of syphilis.
During this admission, she remained afebrile. Fetal testing was reassuring.
Anatomic ultrasonography demonstrated fetal hepatomegaly and polyhydram-
nios concerning for fetal syphilis infection. No ascites, placentomegaly, or hy-
drops were noted on ultrasonography. Her contractions resolved, and she was
discharged from the hospital.

CASE PROGRESSION
The patient returned to the hospital for 2 more weekly doses of intramuscular
BPG. At 32 weeks’ gestation, 1 month after completion of her course of penicil-
lin, repeat RPR titers were 1:4. Ultrasonography showed hepatomegaly, poly-
hydramnios, and fetal growth restriction with a lagging abdominal circumference
at the 6th percentile. Umbilical artery Doppler flow was normal. Weekly biophysi-
AUTHOR DISCLOSURES Drs Moino and
cal profile ultrasonography demonstrated stable findings with polyhydramnios. Ros have disclosed no financial
Fetal biometry at 36 weeks’ gestation demonstrated persistent fetal growth restric- relationships relevant to this article. This
tion with interval growth. Two months after antibiotic treatment, serologic tests commentary does not contain a
discussion of an unapproved/
for syphilis demonstrated elevated RPR titers of 1:32, and the specific treponemal investigative use of a commercial
antibody test was positive. product/device.

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 MATERNAL OUTCOME both femurs. A formal hearing assessment with auditory brain-
At 37 weeks’ gestation, the patient presented with prelabor stem response and an ophthalmologic examination were per-
rupture of membranes. The patient elected for a repeat cesar- formed, both of which were normal. He remained at the hospital
ean delivery, which was uncomplicated. At delivery, the pla- for 2 weeks and was treated with intravenous aqueous crystalline
centa appeared enlarged and pale. Histopathologic analysis of penicillin G 200,000 to 300,000 units/kg, administered as
the placenta demonstrated enlarged hypercellular immature 50,000 units/kg of body weight every 4 to 6 hours for 10 days.
villi, proliferative vascular changes, and chronic villitis. The
umbilical cord was inflamed with abscesslike foci of necrosis SYPHILIS IN PREGNANCY
within Wharton jelly, which was centered around the umbili- The rate of congenital syphilis is increasing, and the year 2022
cal vessels and consistent with necrotizing funisitis. had the highest rates of congenital syphilis in the United
States since 1991. (1) In 2022, a total of 3,755 cases of congeni-
NEONATAL OUTCOME tal syphilis were reported to the Centers for Disease Control
A liveborn male newborn was delivered and had appropriate and Prevention, including 282 cases of congenital syphilis as-
respiratory effort. His Apgar score was 7 and 8 at 1 and sociated with stillbirths and neonatal deaths. (1) The rate of
5 minutes of age, respectively. His birthweight was congenital and primary syphilis is demonstrated in Fig 1.
2,850 g (25th percentile). He had a diffuse erythematous Primary syphilis in adults presents with a painless, indu-
papular rash and desquamation of the feet and hands. rated ulcerative lesion known as a chancre at the site of in-
He was admitted to the NICU. Complete blood cell fection within 3 weeks of exposure via sexual contact. (2)
counts demonstrated normocytic normochromic anemia After resolution of the primary lesion, systemic secondary
(hemoglobin level of 8.7 g/dL [87 g/L]), leukocytosis syphilis manifestations occur within 2 to 6 weeks, including
(white blood cell count of 18,000/mL [18 × 109/L] with neutro- alopecia, lymphadenopathy, oral lesions, and a disseminated
phils 41%, lymphocytes 55%, monocytes 3%, eosinophils skin rash characterized by flat brown macular lesions that
1%), and thrombocytopenia (platelet count of 92 × 103/mL usually spreads to the palms and soles. (2) Upon resolution
[92 × 109/L]). His serum total protein level was 4.9 g/dL of these secondary findings, individuals will enter a period of
(49 g/L), with an albumin level of 2.9 g/dL (29 g/L). Com- latent infection termed “latent syphilis,” which is character-
prehensive metabolic panel showed normal liver function en- ized by a lack of clinical symptoms despite positive serologic
zymes including a normal total bilirubin and direct bilirubin. testing. (2)(3) If latent infection occurs within 12 months, it
Abdominal ultrasonography demonstrated ascites. He under- is referred to as early latent syphilis. (3) Tertiary syphilis
went paracentesis and a lumbar puncture, and the spinal may present any time later, with manifestations including
fluid confirmed congenital syphilis with a positive specific cardiovascular infection, gummas, and neurosyphilis. (3)
treponemal test confirming neurosyphilis. A complete skele-
tal survey showed transverse bands of increased density across SCREENING FOR SYPHILIS DURING PREGNANCY
the humeral metaphyses associated with patchy areas of bone Screening for syphilis in pregnancy is critically important to
destruction in the diaphysis. Additional irregular areas of in- minimize the risks of congenital syphilis. Serologic diagnosis
creased density with a “moth-eaten” appearance were noted in of syphilis follows the same sequence used in nonpregnant

Figure 1. Congenital syphilis (CS) cases with the primary and secondary (P&S) syphilis rates per 100,000 women aged 15 to 44 years in the United States
between 2013 and 2022 (source of numbers: National Overview of STIs, 2022, cdc.gov).

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 patients of either the reverse sequence or traditional screen- treatment during pregnancy. With timely screening and treat-
ing algorithm. (2) Regardless of the screening algorithm ment as early in the pregnancy as possible, the risk of congen-
used (Fig 2), an initial positive test must be confirmed by a ital syphilis is minimized. Syphilis during pregnancy is
reflexed nontreponemal test or a second treponemal-specific associated with preterm delivery, miscarriage, fetal demise,
test with different antigens. (4)(5) and nonimmune hydrops. (4) Syphilis is transmitted through
the placenta or by contact with genital lesions in the pregnant
person during delivery. (2)(4) Intrauterine transmission is also
RISKS OF SYPHILIS IN PREGNANCY supported by the detection of specific immunoglobulin M
The most important aspect of preventing congenital syphilis antibodies to T pallidum in fetal serum from cordocentesis
is early prenatal screening of the pregnant person and prompt and in neonatal blood collected after delivery. (2) The

Figure 2. Example of screening approach to test for syphilis infection. EIA5enzyme immunoassay, FTA-ABS5fluorescent treponemal antibody-
absorption, RPR5rapid plasma reagin, TP-PA5Treponema pallidum particle agglutination assay, VDRL5Venereal Disease Research Laboratory.

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 likelihood of vertical transmission increases with advancing monthly or within 8 weeks after treatment to ensure that
gestational age and the duration of exposure. The rate of they are not increasing; a fourfold increase is considered a
transmission also corresponds to the stage of syphilis in the clinically significant titer change. A sustained titer increase
pregnant person, with the highest rate of transmission found may represent treatment failure or reinfection and requires
in pregnant patients with early syphilis and, particularly, sec- repeat treatment. (2) In contrast, titer decline will vary by
ondary syphilis. (2)(4) In a meta-analysis of 11,398 pregnant stage of disease in the pregnant person and treatment tim-
patients with syphilis, treatment during the third trimester ing during pregnancy. Rac et al (8) showed that only 38%
was associated with an 41% risk of congenital syphilis com- of pregnant individuals achieved a fourfold decline by deliv-
pared to a risk of 18% in the second trimester and 10% in ery. Thus, the duration of pregnancy is likely insufficient to
the first trimester. (5) Untreated infected pregnant patients are gauge adequate serologic response of the pregnant person.
12 times more likely than noninfected patients to have compli- Penicillin is the only antibiotic demonstrated to appreciably
cations such as stillbirth or preterm birth secondary to con- cross the placenta for bactericidal activity against T pallidum in
genital infection. (3)(4) pregnancy; therefore, alternative antibiotic treatments are not
MANAGEMENT OF SYPHILIS DURING PREGNANCY recommended. Pregnant patients with a penicillin allergy need
to undergo desensitization and subsequently receive treatment
Evidence shows that timely treatment of syphilis reduces the
with the appropriate penicillin regimen. (6)
likelihood of adverse pregnancy outcomes. (1)(2)(3)(4) Timely
antibiotic treatment is highly effective at preventing congenital
ULTRASONOGRAPHIC FINDINGS
syphilis. (1) In addition, the risk of congenital syphilis corre-
lates with the stage of syphilis and gestational age at treat- Ultrasonographic evidence indicative of an intrauterine
ment. Effective treatment of syphilis in pregnancy consists of syphilis infection can be detected after 18 weeks’ gestation
benzathine penicillin G (BPG) administered intramuscularly. once the fetus is able to mount an immune response. The
The dose and duration of the intramuscular BPG depend absence of any ultrasonographic findings does not exclude
on the clinical stage (Table 1). congenital syphilis infection. Indeed, the prevalence of
Studies have found that BPG efficacy is high (99.7%) congenital syphilis at delivery ranges from 12% to 15%
for eradicating disease in the pregnant person and 98.2% among at-risk fetuses with no ultrasonographic anomalies
for preventing congenital syphilis for all stages of syphilis. indicative of congenital infection. (2) However, if fetal
(6) The Jarisch-Herxheimer reaction occurs in up to 40% ultrasonographic abnormalities are noted, the fetus should
of pregnant individuals treated for syphilis (2) secondary be monitored serially to inform the pediatric care team
to the release of proinflammatory treponemal lipoproteins about prospective complications. Ultrasonographic find-
from dying syphilis treponemes after antibiotic treatment. ings are listed in Table 2.
(7) This reaction is characterized by transient constitutional Fetal anemia and related hydrops tend to resolve within
symptoms including pyrexia, chills, headache, myalgias, 3 weeks after the treatment of syphilis infection during
and potential exacerbation of existing cutaneous lesions. (7) pregnancy, with subsequent normalization of fetal liver
As such, continuous fetal heart rate monitoring for 12 to 24 and placental measurements. (2) Regardless, early detection
hours after treatment is typically recommended to confirm and adequate treatment before the third trimester allow
fetal well-being. (2) ultrasonographic abnormalities to resolve entirely in some
Quantitative nontreponemal titers such as the RPR titer cases. (2) Given the associated placentomegaly with syphilis
are used to monitor disease activity and the response to infection, the placenta should be sent for histopathologic
therapy in pregnant patients. RPR titers are performed review after delivery. (4)

Table 1. Recommended Treatment of Syphilis in Pregnancy Based on Stage.

Stage of Syphilis During Pregnancy Treatment
Primary syphilis BPG 2.4 million units IM once
Secondary syphilis In pregnant patients, some evidence suggests the benefit of a second dose of BPG
Early latent syphilis 2.4 million units IM 1 wk after initial dose
Late latent syphilis BPG 7.2 million units total administered as 3 doses of 2.4 million units IM each at
Syphilis of unknown duration 1-wk intervals
Tertiary syphilis Aqueous crystalline penicillin G 18 24 million units/d administered as 3 4 million
Neurosyphilis units intravenously every 4 hours or continuous infusion for 10 14 days

IM5intramuscular, BPG, benzathine penicillin G.

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 Table 2. Frequency of Ultrasonographic Findings in may affect multiple organ systems and result in subsequent
Fetuses with Syphilis Infection prematurity, stillbirth, and neonatal death. This case report re-
Ultrasonography Findings Likelihood of Finding views the manifestations of congenital syphilis during preg-
Normal ultrasonography 12% 15%
nancy that resulted from delayed initiation of prenatal care.
Hepatomegaly 80% This case emphasizes the importance of early detection of
Placentomegaly 27%
Polyhydramnios
syphilis during pregnancy and prompt treatment with BPG.
12%
Nonimmune hydrops 10%
Fetal growth restriction 14%

American Board of Pediatrics

NEWBORN FINDINGS Neonatal-Perinatal Content
Many infants born to persons with untreated syphilis appear Specification
normal and have no clinical evidence of infection at birth, • Know the effects on the fetus and/or newborn
though they may subsequently develop manifestations of dis- infant of other maternal infections (eg, malaria)
ease. Early congenital syphilis refers to those clinical signs that and their management.
appear in the first 24 months of age. Common manifestations
include hepatosplenomegaly, thrombocytopenia, mucocutane-
ous lesions, rash, and bone lesions. (2)(4) Hepatosplenomegaly
originates from extramedullary hematopoiesis secondary to fetal References
anemia or hepatitis. Skin lesions present as petechiae from
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thrombocytopenia or widespread rash with copper-toned macu-
STIs, 2022. https://www.cdc.gov/std/statistics/2022/overview.
lopapular spots and notable peeling that localizes mostly to the htm#Syphilis. Accessed March 13, 2024
palms and soles. In addition, pemphigus syphilitics may arise, 2. Stafford IA, Workowski KA, Bachmann LH. Syphilis complicating
which is characterized by a fluid-filled, bullous eruption with pregnancy and congenital syphilis. N Eng. N Engl J Med.
subsequent peeling and crusting. Some newborns also develop 2024;390(3):242–253
snuffles, a type of rhinitis characterized by nasal watery and 3. Eppes CS, Stafford I, Rac M. Syphilis in pregnancy: an ongoing
purulent discharge. Both the nasal leakage and fluid from the public health threat. Am J Obstet Gynecol. 2022;227(6):822–838

bullous lesions comprise large concentrations of spirochetes 4. Cooper JM, Sanchez PJ. Congenital syphilis. Semin Perinatol.
2018;42(3):176–184
and are thus highly infectious. (4) In addition, bone lesions
5. Nurse-Findlay S, Taylor MM, Savage M, et al. Shortages of
including osteochondritis and periostitis are identified via
benzathine penicillin for prevention of mother-to-child transmission
radiographic images and occur in 60% to 80% of infants of syphilis: an evaluation from multi-country surveys and stakeholder
with clinical signs of congenital syphilis and 20% of well-ap- interviews. PLoS Med. 2017;14(12):e1002473
pearing, congenitally infected infants. (2) These abnormali- 6. Rac MW, Revell PA, Eppes CS. Syphilis during pregnancy:
ties tend to be symmetric and involve the long bones such a preventable threat to maternal-fetal health. Am J Obstet Gynecol.
as the tibia, humerus, and femur, with the lower extremities 2017;216(4):352–363
involved more often than the upper extremities. (4) 7. Belum GR, Belum VR, Chaitanya Arudra SK, Reddy BSN. The
Jarisch-Herxheimer reaction: revisited. Travel Med Infect Dis.
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CONCLUSION
8. Rac MW, Bryant SN, Cantey JB, McIntire DD, Wendel GD Jr,
The effect of untreated syphilis on pregnancy and infant health Sheffield JS. Maternal titers after adequate syphilotherapy during
outcomes is profound as the sequelae of congenital syphilis pregnancy. Clin Infect Dis. 2015;60(5):686–690

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