Limitations Background:

Although not recommended by the American Academy of Pediatrics (AAP) for pregnant women, some laboratories are using “reverse screening

(RS)” for the serologic screening for syphilis. This method of testing starts with a treponemal specific enzyme immunoassay (EIA) or

chemiluminescence immunoassay (CIA) screening test followed by a nontreponemal test (i.e. RPR) if the EIA or CIA is positive. Discordant

treponemal and nontreponemal results may occur, prompting the need for a “tie-breaker” treponemal test such as a Treponema pallidum particle

agglutination assay (TPPA).

RS may identify mothers with no history of syphilis or syphilis treatment, but with a reactive treponemal test and a nonreactive nontreponemal test.

Such discordant results have resulted in uncertainty in management of the neonate, creating maternal serologic scenarios for which there are

currently no guidelines or algorithms to guide the evaluation and management of these neonates. The AAP provides no guidance for neonates

born to mothers with discordant results using reverse screening. The Centers for Disease Control (CDC) provides some guidance in the evaluation

of suspected congenital syphilis (CS), but they are not specific to RS.

Methods:

We reviewed the literature for RS in pregnant women and developed a draft algorithm for management of neonates. We posed clinical scenarios to

specialists with extensive pediatric syphilis experience. The proposed algorithm is a conservative approach to the management of these infants

and reflects a synthesis of approaches, but the final algorithm may not reflect the approach of each contributing author.

Results:

A proposed algorithm was developed for the evaluation and treatment of infants born to mothers with reactive tests for syphilis using reverse

screening.

Conclusion:

Current AAP and CDC guidelines for CS are not tailored to reverse screening. Evidence-based data for evaluating these neonates is limited. We

have developed a conservative proposed algorithm for the management of neonates born to mothers with discordant serology using RS.

Congenital Syphilis: Management Dilemmas using Reverse Screening

Michelle Sewnarine MD1,2, Sujatha Rajan MD1,2, Geoffrey A. Weinberg MD3,4, Kenneth Bromberg MD5,6, Sunil Sood MD1,2, Lorry Rubin MD1,2

1Cohen Children’s Medical Center of New York of the Northwell Health System, New Hyde Park, NY 2Hofstra Northwell School of Medicine at Hofstra University, Hempstead, NY

3Golisano Children’s Hospital, Rochester, NY 4University of Rochester School of Medicine and Dentistry, Rochester, NY

5Brooklyn Hospital Center, Brooklyn, NY 6Icahn School of Medicine at Mount Sinai, New York, NY

Background • Diagnosis of congenital syphilis (CS) can be difficult. Many neonates with suspected CS are asymptomatic or exhibit non-specific clinical

findings. In addition, it may be difficult to interpret reactive syphilis serology in neonates, given the passive transfer of maternal antibodies to the

neonate.

• The traditional screening test for syphilis is a nontreponemal serologic test (e.g. RPR, VDRL), followed by a specific treponemal test (e.g.

Treponema pallidum particle agglutination [TPPA] or fluorescent treponemal antibody-absorption test [FTA-ABS]) if the former is positive.

• Recently, several laboratories are performing reverse sequence screening for the diagnosis of syphilis. The initial test is a treponemal specific

enzyme immunoassay (EIA) or chemiluminescence immunoassay (CLIA) followed by a nontreponemal test if the EIA or CIA is positive.

- A discordant screening treponemal test and nontreponemal test result may occur, prompting the need for a “tie-breaker” confirmatory

treponemal test such as a TPPA or FTA-ABS test.

• The use of reverse screening (RS) poses a diagnostic dilemma and treatment challenge for pediatricians evaluating newborns born to mothers

with discordant results.

- A positive CIA/EIA screening test followed by a nonreactive nontreponemal test and a nonreactive confirmatory treponemal test may

represent early primary syphilis or a false-positive result in low-risk women with no history of treated syphilis.

- Another challenging situation is when a pregnant woman has a negative result using a traditional nontreponemal test in the prenatal period

and a reverse screening test is performed in the peripartum period that shows a positive result. The peripartum period may be the first time

the woman is tested with a treponemal test. If the nontreponemal test is negative, this result may be interpreted as early primary syphilis, the

prozone effect, late latent syphilis, latent syphilis of unknown duration, or treated syphilis. Other than past appropriately treated syphilis,

transmission to the neonate is possible in all of the above stages of syphilis infection.

- Maternal treatment for latent syphilis in the peripartum or postpartum period may influence the decision to evaluate and treat the neonate.

• Currently, there are no guidelines for the evaluation and management of newborns born to mothers with reactive serologic tests for syphilis using

RS.

Abstract

M. Sewnarine

269-01 76th Avenue

New Hyde Park, NY 11040

P (718) 470-3480

F (718) 470-0887

msewnarine@northwell.edu

• We reviewed the literature for RS in pregnant women and found it lacking in providing guidance to clinicians evaluating newborns. The literature

provided an interpretation of the various combinations of serologies which may be encountered with RS. However, it did not provide information

about management of the neonate. We posed clinical scenarios to specialists with extensive pediatric syphilis experience. Therefore, based on

expert consensus, we developed a draft algorithm for management of neonates. The proposed algorithm is a conservative approach to the

management of these infants and reflects a synthesis of approaches, but the final algorithm may not reflect the approach of each contributing

author.

Definitions:

• High-risk mother: History of HIV and/or other STIs, inadequate prenatal care, unprotected sexual intercourse with several partners, new sexual

partners during pregnancy, mother is a sex worker, mother has signs and/or symptoms of syphilis, has a partner with clinical or serologic

evidence of syphilis, or follow-up is uncertain.

• Low-risk mother: Not fulfilling the criteria of a high-risk mother.

#707

• Current AAP and CDC guidelines for the evaluation of congenital syphilis are not tailored to reverse screening.

• Evidence-based data for evaluating these neonates is limited.

• We have developed a conservative proposed algorithm for the management of neonates born to mothers with discordant syphilis serology using

reverse sequence screening.

• There is a need for studies to validate the safety and efficacy of this approach.

Conclusions

References

1. CDC, Sexually Transmitted Diseases Treatment Guidelines, 2015. MMWR Morb Mortal Wkly Rep. 2015;64(3):45-48.

2. Kimberlin DW (Ed.) Red Book®: 2015 Report of the Committee on Infectious Diseases. Syphilis. 30th ed. Elk Grove Village, IL: American

Academy of Pediatrics; 2015:755-768.

3. Mmeje O, Chow J, Davidson L, Shieh J, Schapiro J, Park I. Discordant Syphilis Immunoassays in Pregnancy: Perinatal Outcomes and

Implications for Clinical Management. Clinical Infectious Diseases 2015; 61(7):1049-53.

4. Patel SJ, Klinger R, O’Toole D, Schillinger J. Missed Opportunities for Preventing Congenital Syphilis Infection in New York City. Obstetrics &

Gynecology 2012; 120:882-8.

5. Park I, Chow J, Bolan G, Stanley M, Shieh J, Schapiro J. Screening for Syphilis with the Treponemal Immunoassay: Analysis of Discordant

Serology Results and Implications for Clinical Management. The Journal of Infectious Diseases 2011; 204:1297-304.

6. Peterman T, Newman D, Davis D, Su J. Do Women with Persistently Negative Nontreponemal Test Results Transmit Syphilis During

Pregnancy? Sexually Transmitted Diseases 2012; 40:311-315.

7. Wicher V, Wicher K. Pathogenesis of Maternal-Fetal Syphilis Revisited. Clinical Infectious Diseases 2001; 33:354-363.

• This algorithm represents expert consensus, but is not yet validated.

• The algorithm is a conservative approach and neonates may receive unnecessary evaluation and/or treatment due to lack of evidence-based

data.

Mother’s Serology Interpretation of Serology Results in a Mother with No History of Treatment

CIA/EIA+, RPR -, TPPA+ Early primary syphilis, the prozone effect, late latent syphilis, or latent syphilis of unknown duration

CIA/EIA+, RPR -, TPPA- Early primary syphilis or false-positive CIA/EIA

CIA/EIA+, RPR -, TPPA equivocal Early primary syphilis, the prozone effect, late latent syphilis, latent syphilis of unknown duration, or false-positive CIA/EIA and/or TPPA

Results

Methods

Maternal CIA/EIA

CIA/EIA + CIA/EIA -

RPR + RPR -

Evaluate and treat

per American

Academy of

Pediatrics (AAP)

recommendations

TPPA + TPPA - or TPPA equivocal

Documented

appropriately treated

syphilis before or

during pregnancy?

Low-risk mother2

No evaluation and

no treatment of

baby. Recheck

mother’s serology

within 4 weeks.

High-risk

mother1

Yes No

Follow AAP algorithm

recommendations *

AAP full evaluation3 of baby and

PCN pending results4

Baby’s RPR - and

negative evaluation

Baby’s RPR ≥ 1:1 or

positive evaluation (abnormal exam or

abnormal/incomplete results)

Treatment:

b-PCN x 1 dose or PCN x 10 days Treatment:

PCN x 10 days

No further

evaluation

Proposed algorithm for evaluation and treatment of

infants born to mothers with reactive serologic tests for

syphilis using “reverse screening”

1 Modified from CDC

criteria of high-risk mother:

History of HIV and/or other

STIs, inadequate prenatal

care, unprotected sexual

intercourse with several

partners, new sexual partners

during pregnancy, mother is a

sex worker, mother has signs

and/or symptoms of syphilis,

has a partner with clinical or

serologic evidence of syphilis,

or follow-up is uncertain.

2 Low-risk mother: Not

fulfilling the criteria of a high-

risk mother.

3 AAP full evaluation: RPR,

CBC, CSF analysis for cell

count, protein, and VDRL,

and testing for HIV infection.

Other tests as clinically

indicated: e.g. LFTs, chest

x-ray, long bone x-rays, eye

exam, neuroimaging, and

auditory brainstem response.

4 If baby’s RPR is nonreactive

and the provider determines

mother’s risk of untreated

syphilis is low, treatment with

b-PCN x 1 dose can be

considered without an

evaluation.

PCN = penicillin (aqueous

penicillin G or procaine

penicillin G)

b-PCN = benzathine penicillin

Mother CIA/EIA+, RPR-, TPPA+ and documented appropriately treated syphilis before or during pregnancy = past treated syphilis

If no evidence of clinical reinfection/relapse in mother + baby’s RPR < fourfold mother’s + baby’s exam normal No evaluation +/- b-PCN x 1

*