Accepted Manuscript Progression of Ultrasound Findings of Fetal Syphilis Following Maternal Treatment Martha W.F. Rac , MD Stefanie N. Bryant , MD Donald D. McIntire , PhD Joseph B. Cantey , MD Diane M. Twickler , MD George D. Wendel Jr., MD Jeanne S. Sheffield , MD PII:
S0002-9378(14)00563-8
DOI:
10.1016/j.ajog.2014.05.049
Reference:
YMOB 9862
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 6 March 2014 Revised Date:
24 April 2014
Accepted Date: 31 May 2014
Please cite this article as: Rac MWF, Bryant SN, McIntire DD, Cantey JB, Twickler DM, Wendel Jr. GD, Sheffield JS, Progression of Ultrasound Findings of Fetal Syphilis Following Maternal Treatment, American Journal of Obstetrics and Gynecology (2014), doi: 10.1016/j.ajog.2014.05.049. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Rac |1 1
Progression of Ultrasound Findings of Fetal Syphilis Following Maternal Treatment
Martha W.F. RAC, MD1
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Stefanie N. BRYANT, MD1
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Donald D. McINTIRE, PhD1
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Joseph B. CANTEY, MD2
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Diane M. TWICKLER, MD1,3
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George D. WENDEL, Jr., MD1
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Jeanne S. SHEFFIELD, MD1
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University of Texas Southwestern Medical Center
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Department of Obstetrics and Gynecology1
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Department of Pediatrics2
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Department of Radiology3
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Dallas, Texas
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Martha Rac, MD University of Texas Southwestern Medical Center Department of Obstetrics & Gynecology 5323 Harry Hines Blvd. Dallas, TX 75390-9032 Phone: 214-648-3113 Fax: 214-648-7262 Email: [email protected]
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The authors report no conflicts of interest.
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Abstract: 248 Text: 3264
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Condensation
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Hepatomegaly is the most common ultrasound abnormality of fetal syphilis and is the last to
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resolve after maternal syphilotherapy.
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ACCEPTED MANUSCRIPT Rac |3 38 Abstract
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Objective: To evaluate ultrasound findings of fetal syphilis and describe their progression
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after maternal treatment.
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Study Design: This is a retrospective cohort study from September 1981 to June 2011 of
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seropositive women after 18 weeks of gestation who had an ultrasound prior to treatment
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to evaluate for fetal syphilis. Only those women receiving treatment after their initial
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ultrasound but before delivery were included. If the initial ultrasound was abnormal,
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serial sonography was performed until resolution of the abnormality or delivery. Patient
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demographics, ultrasound findings, stage of syphilis, delivery and infant outcomes were
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recorded. Standard statistical analyses were performed. Kaplan-Meier estimates were
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constructed to estimate time to resolution.
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Results: 235 women met inclusion criteria and 73 (30%) had evidence of fetal syphilis on
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initial ultrasound. Abnormalities included hepatomegaly (79%), placentomegaly (27%),
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polyhydramnios (12%), ascites (10%) and abnormal MCA Dopplers (33%). After
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treatment, MCA Doppler abnormalities, ascites and polyhydramnios resolved first, followed
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by placentomegaly and finally hepatomegaly. Infant outcomes were available for 173
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deliveries. 32(18%) were diagnosed with congenital syphilis. Congenital syphilis was more
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common when antenatal ultrasound abnormalities were present (39% vs. 12%, p 18 weeks who received an ultrasound prior to treatment to
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evaluate for evidence of fetal syphilis. Women not treated before delivery and those with
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serofast syphilis were excluded. Subjects were identified using an established database of
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patients diagnosed with syphilis during pregnancy. A secondary search of our
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departmental ultrasound database was then performed by searching for “syphilis” in the
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indication field.
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At our institution, women are tested for syphilis at three points during pregnancy: at entry
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into prenatal care, 28-32 weeks and again at delivery. A non-treponemal antibody test
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(Rapid Plasma Reagin (RPR) or Venereal Disease Research Laboratory (VDRL)) is used as
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the initial screening test and a positive result is confirmed using a treponemal serologic
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test (fluorescent treponemal antibody absorption (FTA-Abs) or the microhemagglutination
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assay for antibodies to Treponema pallidum (MHA-TP)). After a woman is identified as
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having syphilis, she is referred to our Infectious Disease Obstetrics Complications Clinic
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where a thorough medical history and clinical exam is performed. If the patient reports
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prior treatment for syphilis, the Dallas County Health Department is contacted for
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confirmation. Based on the history and physical exam, the patient is assigned a stage of
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syphilis in order to direct appropriate therapy. Maternal stage of syphilis is diagnosed
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using the Center for Disease Control and Prevention (CDC) guidelines.5 If the patient is at
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or beyond 18 weeks of gestation, a targeted ultrasound is performed specifically looking
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for the presence of hepatomegaly, placentomegaly, polyhydramnios, ascites and elevated
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ACCEPTED MANUSCRIPT Rac |8 middle cerebral artery velocimetry before maternal treatment is undertaken. If the patient
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is at or beyond 24 weeks and there is sonographic evidence of fetal infection, the patient is
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monitored in our labor and delivery suite while receiving treatment secondary to concern
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for a Jarisch-Herxheimer reaction. If the ultrasound is without evidence of fetal syphilis,
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the patient is treated during the same visit and discharged home with follow-up the next
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week.
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Ultrasound reports and available images from the targeted exam were reviewed.
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Hepatomegaly was defined as a liver length greater than the 95th percentile for gestational
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age12 Placentomegaly was defined as a placental thickness exceeding the mean plus two
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standard deviations for gestational age as established by Hoddick.13 Ultrasound reports
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from exams performed before 1985 were reviewed for stigmata of fetal syphilis diagnosed
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by an experienced faculty radiologist or maternal fetal medicine specialist .
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Polyhydramnios was defined as an amniotic fluid index greater than 250mm.14 Middle
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cerebral artery peak systolic velocimetry greater than 1.5 multiples of the median was
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considered abnormal.15 After the year 2000, this parameter consistently became part of
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our ultrasound protocol for fetal syphilis to indirectly evaluate for fetal anemia.
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After the initial ultrasound, all women were treated with benzathine penicillin G (BPG)
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intramuscularly according to their stage of syphilis as per CDC treatment guidelines.5 In
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August 1992, we began to treat women with early stage syphilis using two injections of 2.4
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million units of BPG one week apart to maintain treponemocidal levels.16 Women with an
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abnormal pre-treatment ultrasound were given serial follow-up ultrasounds until
ACCEPTED MANUSCRIPT Rac |9 resolution of the sonographic abnormalities or delivery, whichever occurred first. Delivery
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and infant outcomes were recorded if available. Neonatal physical examination and
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laboratory findings were recorded as was placental pathology. Hepatomegaly was defined
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as a palpable liver 2cm or more below the costal margin. Congenital syphilis was
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diagnosed using CDC diagnostic criteria.5
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Standard life table methods were calculated to estimate time to resolution of ultrasound
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abnormalities after adequate maternal syphilotherapy. Kaplan-Meier estimates were
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constructed for each ultrasound abnormality. Student’s t-test was used to evaluate
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continuous variables and a χ2 test was used for frequencies. P < 0.05 was considered
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significant. This study was approved by the Institutional Review Board at the University of
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Texas Southwestern Medical Center.
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ACCEPTED MANUSCRIPT R a c | 10 Results
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During the study period, 235 women were diagnosed with syphilis > 18 weeks of gestation
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and received an ultrasound before treatment. Seventy three (31%) women had > 1
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ultrasound abnormality. The most common ultrasound abnormality identified was
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hepatomegaly (79%), followed by placentomegaly (27%), polyhydramnios (12%) and
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ascites (10%). Of the fifty-two women who had MCA PSV performed, 17(33%) were
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elevated (Table 1).
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Women with an abnormal pre-treatment ultrasound were compared to those with a
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normal pre-treatment ultrasound. Patient characteristics of the two groups are described
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in Table 2. There were no differences in age, race or parity between the two groups. There
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was also no difference in stage of maternal disease (p=0.9). Although the majority of
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women were diagnosed with early stage disease, this did not correlate with an abnormal
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pre-treatment ultrasound (58% vs. 57%, respectively, p=0.9). Consistent with known risk
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factors for vertical transmission, women with an abnormal pre-treatment ultrasound were
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diagnosed later in pregnancy (27.3 + 5.3 weeks vs 25.4 vs 6.5 week, p=0.03), had fewer
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prenatal visits (7.1 + 3.7 vs 8.4 + 4.2, p=0.03), and were treated later in pregnancy,
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although this last comparison did not reach statistical significance. Only one patient in
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each group was HIV positive.
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Delivery outcomes were available for 194 pregnancies. Of the 41 women lost to follow-up,
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no significant differences were noted in maternal stage of syphilis, gestational age at
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diagnosis and treatment, or ultrasound abnormalities when compared to women who were
ACCEPTED MANUSCRIPT R a c | 11 not lost to follow-up. Women with an abnormal pre-treatment ultrasound delivered
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significantly earlier than those with a normal pre-treatment ultrasound (37.3 + 3.7 weeks
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vs 38.5 + 2.4 weeks, p=0.01) and in particularly, there were significantly more women who
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had an abnormal pre-treatment ultrasound who delivered earlier than 32 weeks (7% vs.
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1% respectively, p=0.01). In women who delivered < 37 weeks, indications for delivery
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were analyzed and were not significantly different between the two groups. Time from
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treatment to delivery was shorter in women with an abnormal pre-treatment ultrasound
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(7.1 + 4.7 weeks vs 9.8 + 5.3 weeks, p98% efficacious for eradicating maternal infection and preventing congenital
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infection,31 identification of maternal syphilis in a timely manner is perhaps the largest
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barrier to eradicating infant infection from a public health
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standpoint. 26
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Interestingly, twelve percent of neonates with clinical evidence of congenital syphilis at
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birth had a normal antepartum pre-treatment ultrasound. None of the women in the
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cohort required re-treatment for syphilis and only 2 women were co-infected with HIV,
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both conditions that have been shown to be associated with infant infection.32 Our cohort
ACCEPTED MANUSCRIPT R a c | 17 did extend over a 30 year time period when ultrasound resolution was rapidly improving.
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Thus, subtle findings identified with contemporary technology may not have been seen
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with earlier imaging. In addition, diagnostic criteria for congenital syphilis consist of both
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exam findings and laboratory abnormalities, some of which do not correlate with antenatal
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ultrasound findings. Although antenatal ultrasound is a useful tool in the evaluation of a
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pregnant woman with syphilis and an abnormal finding may affect the management of the
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infected mother, a normal ultrasound does not rule out a congenitally infected infant.
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Our study has several strengths and limitations. The strength of this study is the large
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patient population of pregnant women with syphilis identified and treated at a single
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center with a standardized treatment protocol. Limitations include the retrospective
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design, limited availability and resolution of images for review as well as overall attrition
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rate from treatment to delivery. Compliance and poor follow-up is a known problem in
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similar high-risk populations. Lago et al attempted to follow infants diagnosed with
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congenital syphilis up to 5 years of age. Only 50% of infants returned for 1 visit, and of
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those, only 21% were seen at 3 and 5 years old.18 Similarly, Rawstron et al only had 17%
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of infants initially treated for congenital syphilis at Kings County Hospital in Brooklyn, New
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York return for follow-up.33 Thus, our follow-up rate of 198 (84%) delivery outcomes and
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173 (74%) infant outcomes from the initial cohort of 235 treated mothers is actually quite
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remarkable.
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Despite these limitations, our study closes over a decade long gap of knowledge pertaining
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to the pathophysiology of fetal syphilis. We found that ultrasound abnormalities associated
ACCEPTED MANUSCRIPT R a c | 18 with fetal syphilis were found in thirty-one percent of gravidas diagnosed with syphilis
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after 18 weeks of gestation and were not associated with stage of maternal disease.
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Hepatomegaly developed early and resolved last after adequate antepartum treatment.
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Sonographic evidence of fetal syphilis was strongly associated with a diagnosis of
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congenital syphilis at delivery for all maternal stages. Additionally, a normal ultrasound
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did not necessarily eliminate the possibility of congenital syphilis at delivery. Future
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studies are needed to clarify whether persistence of hepatomegaly is secondary to
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treatment failure or prolonged resolution in the setting of adequate maternal and fetal
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syphilotherapy.
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4. Hollier LM, Cox S. Syphilis. Seminars in Perinatology, 1998; 22(4): 323-331.
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7. Hollier LM, Harstad TW, Sanchez PJ, Twickler DM, Wendel GD. Fetal Syphilis:
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10. Daffos F, Forestier F, Grangeot-Keros L, Capella-Pavlovsky M, Lebon P, Chartier M, et al. Prenatal Diagnosis of Congenital Rubella. Lancet 1984;2:1-3. 11. Hira SK, Bhat GJ, Patel JB, Din SN, Atilli RV, Patel MI, Baskamathan S, Hira RS, Andu
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14. Moore TR, Cayle JE. The Amniotic Fluid Index in Normal Human Pregnancy. Am J Obstet Gynecol 1990 May;162(5):1168-73.
15. Mari G, Deter RL, Carpenter RL, et al. Noninvasive Diagnosis by Doppler Ultrasonography of Fetal Anemia due to Maternal Red-Cell Alloimmunization. N
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16. Lawrence N, Bawdon RE, Sidawi E, Stettler RW, McIntire DD, Wendel GD. Penicillin Levels Following the Administration of Benzathine Penicillin G in Pregnancy. Obstet
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18. Lago EG, Vaccari A, Fiori R. Clinical Features and Follow-up of Congenital Syphilis. Sex Trans Dis Feb 2012;40(2):85-94.
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19. Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong CY. Williams Obstetrics, 23rd edition. New York: McGraw-Hill Medical, 2010. Print. 20. Kim CH. Homeostatic and Pathologic Extramedullary Hematopoiesis. Journal of Blood Medicine 2010;1:13-19.
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21. Long WA, Ulshen MH, Lawson EE. Clinical Manifestations of Congenital Syphilitic Hepatitis: Implications for Pathogenesis. J Pediatr Gastroenterol Nutr 1984
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22. Anand NK, Chellani HK, Wadhwa A, Prasanna SB, Mohan M. Congenital Syphilitic Hepatitis. Indian Pediatrics 1991;28(2):157-9.
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23. Ricci JM, Fojaco RM, O’Sullivan MJ. Congenital Syphilis: The University of
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Miami/Jackson Memorial Medical Center Experience, 1986-1988. Obstet Gynecol
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24. Hawkes SJ, Gomez GB, Broutet N. Early Antenatal Care: Does it Make a Difference to
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25. Qin JB, Feng TJ, Yang TB, et al. Risk Factors for Congenital Syphilis and Adverse
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26. Liu JB, Hong FC, Pan P, et al. A Risk Model for Congenital Syphilis in Infants Born to
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Transm Infect 2010;86:292-296.
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27. Zhu L, Qin M, Du L, Xie R, Wong T, Wen SW. Maternal and Congenital Syphilis in Shanghai, China, 2002 to 2006. Int J Infect Dis 2010;12S:e45-e48.
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28. Ortiz-Lopez N, Diez M, Diaz O, Simon F, Diaz A. Epidemiological Surveillance of
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Congenital Syphilis in Spain, 2000-2010. Pediatr Infect Dis J 2012;31(9):988-990.
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29. Carles G, Lochet S, Youssef M, et al. Syphilis and Pregnancy. J Gynecol Obstet Biol
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Reprod (Paris) Jun 2008;37(4):353-7.
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30. Sheffield JS, Sanchez PJ, Morris G, Maberry M, Zeray F, McIntire DD, Wendel GD. Congenital syphilis after maternal treatment for syphilis during pregnancy. Am J
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Obstet Gynecol March 2002;186(3):569-573.
447 448
31. Alexander JM, Sheffield JS, Sanchez PJ, Mayfield J, Wendel GD. Efficacy of Treatment for Syphilis in Pregnancy. Obstet Gynecol 2001;93(1)1:5-8.
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32. Rolfs RT, Joesoef MR, Hendershot EF, et al; The Syphilis and HIV Study Group. A randomized trial of enhanced therapy for early syphilis in patients with and without
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human immunodeficiency virus infection. N Engl J Med 1997;337:307–14.
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33. Rawstron SA, Mehta S, Marcellino L, et al. Congenital Syphilis and Flourescent
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Treponemal Antibody Test Reactivity After the Age of 1 Year. Sex Transm Dis
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2001;28:412-416.
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Figure 1: Timeline to resolution of abnormal ultrasound findings
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syphilotherapy.
Figure Legends
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463
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Table 1. Frequency of ultrasound abnormalities present in the 73 women with an
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abnormal pre-treatment ultrasound
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Ultrasound
Abnormality* 58(79)
Placentomegaly
20(27)
Polyhydramnios
9(12)
Ascites
7(10)
Elevated MCA PSV
17/52 (33)
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Data reported as N(%)
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*more than one abnormality can be present
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ACCEPTED MANUSCRIPT R a c | 25 Table 2. Patient Characteristics Abnormal Ultrasound n=73 23.6 + 5.5
Age
Normal Ultrasound n=162 23.4 + 5.3
P-value 0.79 0.66
93(57)
White
3(4)
7(4)
25(34)
59(36)
0
3(2)
19(26)
49(30)
Hispanic Other Nulliparity Stage of Syphilis
Primary
3(4)
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Race
0.51 0.91
10(6)
17(23)
Early Latent
22(30)
Late Latent
23(32)
56(34)
Unknown Duration
8(12)
14(9)
42(58)
92(57)
0.92
27.3 + 5.3
25.4 + 6.6
0.03
7.1 + 3.7
8.4 + 4.2
0.03
29.8 + 4.0
28.6 + 4.8
0.06
Gestational Age at
Diagnosis (weeks)
Number of Prenatal
Visits
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Gestational Age at
Initial Ultrasound
38(23) 44(27)
ACCEPTED MANUSCRIPT R a c | 26 and Treatment
(weeks)
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Data reported as N(%) or mean ± SD
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Table 3. Initial infant physical exam findings and placental pathology of those infants
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diagnosed with congenital syphilis
Ultrasound
n=17
n=15
Hepatomegaly
11 (65)
9 (60)
Ascites
3 (18)
1 (7)
Anemia
1 (6)
1 (7)
Placentomegaly
5 (29)
1 (7)
Data reported as N(%)
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P-value
0.78 0.35
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Normal
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Abnormal
0.93 0.10
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S0002-9378(14)00563-8
DOI:
10.1016/j.ajog.2014.05.049
Reference:
YMOB 9862
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 6 March 2014 Revised Date:
24 April 2014
Accepted Date: 31 May 2014
Please cite this article as: Rac MWF, Bryant SN, McIntire DD, Cantey JB, Twickler DM, Wendel Jr. GD, Sheffield JS, Progression of Ultrasound Findings of Fetal Syphilis Following Maternal Treatment, American Journal of Obstetrics and Gynecology (2014), doi: 10.1016/j.ajog.2014.05.049. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Rac |1 1
Progression of Ultrasound Findings of Fetal Syphilis Following Maternal Treatment
Martha W.F. RAC, MD1
4
Stefanie N. BRYANT, MD1
5
Donald D. McINTIRE, PhD1
6
Joseph B. CANTEY, MD2
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Diane M. TWICKLER, MD1,3
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George D. WENDEL, Jr., MD1
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Jeanne S. SHEFFIELD, MD1
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University of Texas Southwestern Medical Center
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Department of Obstetrics and Gynecology1
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Department of Pediatrics2
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Department of Radiology3
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Dallas, Texas
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18 19 20 21 22 23 24 25 26 27 28 29
Martha Rac, MD University of Texas Southwestern Medical Center Department of Obstetrics & Gynecology 5323 Harry Hines Blvd. Dallas, TX 75390-9032 Phone: 214-648-3113 Fax: 214-648-7262 Email: [email protected]
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The authors report no conflicts of interest.
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Abstract: 248 Text: 3264
ACCEPTED MANUSCRIPT Rac |2 32
Condensation
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Hepatomegaly is the most common ultrasound abnormality of fetal syphilis and is the last to
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resolve after maternal syphilotherapy.
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ACCEPTED MANUSCRIPT Rac |3 38 Abstract
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Objective: To evaluate ultrasound findings of fetal syphilis and describe their progression
41
after maternal treatment.
42
Study Design: This is a retrospective cohort study from September 1981 to June 2011 of
43
seropositive women after 18 weeks of gestation who had an ultrasound prior to treatment
44
to evaluate for fetal syphilis. Only those women receiving treatment after their initial
45
ultrasound but before delivery were included. If the initial ultrasound was abnormal,
46
serial sonography was performed until resolution of the abnormality or delivery. Patient
47
demographics, ultrasound findings, stage of syphilis, delivery and infant outcomes were
48
recorded. Standard statistical analyses were performed. Kaplan-Meier estimates were
49
constructed to estimate time to resolution.
50
Results: 235 women met inclusion criteria and 73 (30%) had evidence of fetal syphilis on
51
initial ultrasound. Abnormalities included hepatomegaly (79%), placentomegaly (27%),
52
polyhydramnios (12%), ascites (10%) and abnormal MCA Dopplers (33%). After
53
treatment, MCA Doppler abnormalities, ascites and polyhydramnios resolved first, followed
54
by placentomegaly and finally hepatomegaly. Infant outcomes were available for 173
55
deliveries. 32(18%) were diagnosed with congenital syphilis. Congenital syphilis was more
56
common when antenatal ultrasound abnormalities were present (39% vs. 12%, p 18 weeks who received an ultrasound prior to treatment to
133
evaluate for evidence of fetal syphilis. Women not treated before delivery and those with
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serofast syphilis were excluded. Subjects were identified using an established database of
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patients diagnosed with syphilis during pregnancy. A secondary search of our
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departmental ultrasound database was then performed by searching for “syphilis” in the
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indication field.
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At our institution, women are tested for syphilis at three points during pregnancy: at entry
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into prenatal care, 28-32 weeks and again at delivery. A non-treponemal antibody test
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(Rapid Plasma Reagin (RPR) or Venereal Disease Research Laboratory (VDRL)) is used as
142
the initial screening test and a positive result is confirmed using a treponemal serologic
143
test (fluorescent treponemal antibody absorption (FTA-Abs) or the microhemagglutination
144
assay for antibodies to Treponema pallidum (MHA-TP)). After a woman is identified as
145
having syphilis, she is referred to our Infectious Disease Obstetrics Complications Clinic
146
where a thorough medical history and clinical exam is performed. If the patient reports
147
prior treatment for syphilis, the Dallas County Health Department is contacted for
148
confirmation. Based on the history and physical exam, the patient is assigned a stage of
149
syphilis in order to direct appropriate therapy. Maternal stage of syphilis is diagnosed
150
using the Center for Disease Control and Prevention (CDC) guidelines.5 If the patient is at
151
or beyond 18 weeks of gestation, a targeted ultrasound is performed specifically looking
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for the presence of hepatomegaly, placentomegaly, polyhydramnios, ascites and elevated
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ACCEPTED MANUSCRIPT Rac |8 middle cerebral artery velocimetry before maternal treatment is undertaken. If the patient
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is at or beyond 24 weeks and there is sonographic evidence of fetal infection, the patient is
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monitored in our labor and delivery suite while receiving treatment secondary to concern
156
for a Jarisch-Herxheimer reaction. If the ultrasound is without evidence of fetal syphilis,
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the patient is treated during the same visit and discharged home with follow-up the next
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week.
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Ultrasound reports and available images from the targeted exam were reviewed.
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Hepatomegaly was defined as a liver length greater than the 95th percentile for gestational
162
age12 Placentomegaly was defined as a placental thickness exceeding the mean plus two
163
standard deviations for gestational age as established by Hoddick.13 Ultrasound reports
164
from exams performed before 1985 were reviewed for stigmata of fetal syphilis diagnosed
165
by an experienced faculty radiologist or maternal fetal medicine specialist .
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Polyhydramnios was defined as an amniotic fluid index greater than 250mm.14 Middle
167
cerebral artery peak systolic velocimetry greater than 1.5 multiples of the median was
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considered abnormal.15 After the year 2000, this parameter consistently became part of
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our ultrasound protocol for fetal syphilis to indirectly evaluate for fetal anemia.
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After the initial ultrasound, all women were treated with benzathine penicillin G (BPG)
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intramuscularly according to their stage of syphilis as per CDC treatment guidelines.5 In
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August 1992, we began to treat women with early stage syphilis using two injections of 2.4
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million units of BPG one week apart to maintain treponemocidal levels.16 Women with an
175
abnormal pre-treatment ultrasound were given serial follow-up ultrasounds until
ACCEPTED MANUSCRIPT Rac |9 resolution of the sonographic abnormalities or delivery, whichever occurred first. Delivery
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and infant outcomes were recorded if available. Neonatal physical examination and
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laboratory findings were recorded as was placental pathology. Hepatomegaly was defined
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as a palpable liver 2cm or more below the costal margin. Congenital syphilis was
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diagnosed using CDC diagnostic criteria.5
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Standard life table methods were calculated to estimate time to resolution of ultrasound
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abnormalities after adequate maternal syphilotherapy. Kaplan-Meier estimates were
184
constructed for each ultrasound abnormality. Student’s t-test was used to evaluate
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continuous variables and a χ2 test was used for frequencies. P < 0.05 was considered
186
significant. This study was approved by the Institutional Review Board at the University of
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Texas Southwestern Medical Center.
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ACCEPTED MANUSCRIPT R a c | 10 Results
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During the study period, 235 women were diagnosed with syphilis > 18 weeks of gestation
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and received an ultrasound before treatment. Seventy three (31%) women had > 1
193
ultrasound abnormality. The most common ultrasound abnormality identified was
194
hepatomegaly (79%), followed by placentomegaly (27%), polyhydramnios (12%) and
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ascites (10%). Of the fifty-two women who had MCA PSV performed, 17(33%) were
196
elevated (Table 1).
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Women with an abnormal pre-treatment ultrasound were compared to those with a
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normal pre-treatment ultrasound. Patient characteristics of the two groups are described
200
in Table 2. There were no differences in age, race or parity between the two groups. There
201
was also no difference in stage of maternal disease (p=0.9). Although the majority of
202
women were diagnosed with early stage disease, this did not correlate with an abnormal
203
pre-treatment ultrasound (58% vs. 57%, respectively, p=0.9). Consistent with known risk
204
factors for vertical transmission, women with an abnormal pre-treatment ultrasound were
205
diagnosed later in pregnancy (27.3 + 5.3 weeks vs 25.4 vs 6.5 week, p=0.03), had fewer
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prenatal visits (7.1 + 3.7 vs 8.4 + 4.2, p=0.03), and were treated later in pregnancy,
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although this last comparison did not reach statistical significance. Only one patient in
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each group was HIV positive.
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Delivery outcomes were available for 194 pregnancies. Of the 41 women lost to follow-up,
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no significant differences were noted in maternal stage of syphilis, gestational age at
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diagnosis and treatment, or ultrasound abnormalities when compared to women who were
ACCEPTED MANUSCRIPT R a c | 11 not lost to follow-up. Women with an abnormal pre-treatment ultrasound delivered
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significantly earlier than those with a normal pre-treatment ultrasound (37.3 + 3.7 weeks
215
vs 38.5 + 2.4 weeks, p=0.01) and in particularly, there were significantly more women who
216
had an abnormal pre-treatment ultrasound who delivered earlier than 32 weeks (7% vs.
217
1% respectively, p=0.01). In women who delivered < 37 weeks, indications for delivery
218
were analyzed and were not significantly different between the two groups. Time from
219
treatment to delivery was shorter in women with an abnormal pre-treatment ultrasound
220
(7.1 + 4.7 weeks vs 9.8 + 5.3 weeks, p98% efficacious for eradicating maternal infection and preventing congenital
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infection,31 identification of maternal syphilis in a timely manner is perhaps the largest
328
barrier to eradicating infant infection from a public health
329
standpoint. 26
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Interestingly, twelve percent of neonates with clinical evidence of congenital syphilis at
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birth had a normal antepartum pre-treatment ultrasound. None of the women in the
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cohort required re-treatment for syphilis and only 2 women were co-infected with HIV,
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both conditions that have been shown to be associated with infant infection.32 Our cohort
ACCEPTED MANUSCRIPT R a c | 17 did extend over a 30 year time period when ultrasound resolution was rapidly improving.
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Thus, subtle findings identified with contemporary technology may not have been seen
337
with earlier imaging. In addition, diagnostic criteria for congenital syphilis consist of both
338
exam findings and laboratory abnormalities, some of which do not correlate with antenatal
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ultrasound findings. Although antenatal ultrasound is a useful tool in the evaluation of a
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pregnant woman with syphilis and an abnormal finding may affect the management of the
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infected mother, a normal ultrasound does not rule out a congenitally infected infant.
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Our study has several strengths and limitations. The strength of this study is the large
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patient population of pregnant women with syphilis identified and treated at a single
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center with a standardized treatment protocol. Limitations include the retrospective
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design, limited availability and resolution of images for review as well as overall attrition
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rate from treatment to delivery. Compliance and poor follow-up is a known problem in
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similar high-risk populations. Lago et al attempted to follow infants diagnosed with
349
congenital syphilis up to 5 years of age. Only 50% of infants returned for 1 visit, and of
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those, only 21% were seen at 3 and 5 years old.18 Similarly, Rawstron et al only had 17%
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of infants initially treated for congenital syphilis at Kings County Hospital in Brooklyn, New
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York return for follow-up.33 Thus, our follow-up rate of 198 (84%) delivery outcomes and
353
173 (74%) infant outcomes from the initial cohort of 235 treated mothers is actually quite
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remarkable.
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Despite these limitations, our study closes over a decade long gap of knowledge pertaining
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to the pathophysiology of fetal syphilis. We found that ultrasound abnormalities associated
ACCEPTED MANUSCRIPT R a c | 18 with fetal syphilis were found in thirty-one percent of gravidas diagnosed with syphilis
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after 18 weeks of gestation and were not associated with stage of maternal disease.
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Hepatomegaly developed early and resolved last after adequate antepartum treatment.
361
Sonographic evidence of fetal syphilis was strongly associated with a diagnosis of
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congenital syphilis at delivery for all maternal stages. Additionally, a normal ultrasound
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did not necessarily eliminate the possibility of congenital syphilis at delivery. Future
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studies are needed to clarify whether persistence of hepatomegaly is secondary to
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treatment failure or prolonged resolution in the setting of adequate maternal and fetal
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syphilotherapy.
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1. Centers for Disease Control. STD Surveillance 2012. http://www.cdc.gov/std/stats12/default.htm 2. Cohen SE, Klausner JD, Engleman J, Philip S. Syphilis in the Modern Era: An Update for Physicians. Infect Dis Clin N Am 2013; 27:705-722.
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3. Saloojee H, Velaphi S, Goga Y, Afadapa N, Steen R, Lincetto O. The Prevention and Mangement of Congenital Syphilis: An Overview and Recommendations. Bulletin of
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4. Hollier LM, Cox S. Syphilis. Seminars in Perinatology, 1998; 22(4): 323-331.
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5. Center for Disease Control. STD Treatment Guidelines 2010.
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6. Lawrence NL, Twickler DM, Peters MT, Sanchez PJ, Wendel GD. Fetal Syphilis: Correlation of Sonographic Findings and Rabbit Infectivity Testing of Amniotic Fluid.
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J Ultrasound Med 1993;2:97-101.
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7. Hollier LM, Harstad TW, Sanchez PJ, Twickler DM, Wendel GD. Fetal Syphilis:
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Clinical and Laboratory Characteristics. Obstet Gynecol. 2001; 97(6): 947-53.
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8. Wendel GD, Sheffield JS, Hollier LM, Hill JB, Ramsey PS, Sanchez PJ. Treatment of
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9. Nathan L, Bohoman VR, Sanchez PJ, Leos NK, Twickler DM, Wendel GD. In Utero
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Infection with Treponema Pallidium in Early Pregnancy. Prenatal Diagnosis
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10. Daffos F, Forestier F, Grangeot-Keros L, Capella-Pavlovsky M, Lebon P, Chartier M, et al. Prenatal Diagnosis of Congenital Rubella. Lancet 1984;2:1-3. 11. Hira SK, Bhat GJ, Patel JB, Din SN, Atilli RV, Patel MI, Baskamathan S, Hira RS, Andu
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NN. Early Congenital Syphilis: Clinico-Radiologic Features in 202 Patients. Sex
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12. Vintzileos AM, Neckles S, Campbell WA et al. Fetal liver ultrasound measurements
13. Hoddick WK, Mahoney BS, Callen PW, Filley RA. Placental Thickness. J Ultrasound Med 1985;4:179-182.
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14. Moore TR, Cayle JE. The Amniotic Fluid Index in Normal Human Pregnancy. Am J Obstet Gynecol 1990 May;162(5):1168-73.
15. Mari G, Deter RL, Carpenter RL, et al. Noninvasive Diagnosis by Doppler Ultrasonography of Fetal Anemia due to Maternal Red-Cell Alloimmunization. N
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16. Lawrence N, Bawdon RE, Sidawi E, Stettler RW, McIntire DD, Wendel GD. Penicillin Levels Following the Administration of Benzathine Penicillin G in Pregnancy. Obstet
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17. De Santis M, De Luca C, Mappa I, Spagnuolo T, Licameli A, Straface G, Scambia G.
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Syphilis Infection during Pregnancy: Fetal Risks and Clinical Management. Infect Dis
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Obstet Gynecol 2012:1-5.
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18. Lago EG, Vaccari A, Fiori R. Clinical Features and Follow-up of Congenital Syphilis. Sex Trans Dis Feb 2012;40(2):85-94.
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19. Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong CY. Williams Obstetrics, 23rd edition. New York: McGraw-Hill Medical, 2010. Print. 20. Kim CH. Homeostatic and Pathologic Extramedullary Hematopoiesis. Journal of Blood Medicine 2010;1:13-19.
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21. Long WA, Ulshen MH, Lawson EE. Clinical Manifestations of Congenital Syphilitic Hepatitis: Implications for Pathogenesis. J Pediatr Gastroenterol Nutr 1984
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22. Anand NK, Chellani HK, Wadhwa A, Prasanna SB, Mohan M. Congenital Syphilitic Hepatitis. Indian Pediatrics 1991;28(2):157-9.
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23. Ricci JM, Fojaco RM, O’Sullivan MJ. Congenital Syphilis: The University of
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Miami/Jackson Memorial Medical Center Experience, 1986-1988. Obstet Gynecol
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1989;74(5):687-693.
24. Hawkes SJ, Gomez GB, Broutet N. Early Antenatal Care: Does it Make a Difference to
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Outcomes of Pregnancy Associated with Syphilis? A Systematic Review and Meta-
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Analysis. PLOS ONE Feb 2013;8(2):1-7.
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25. Qin JB, Feng TJ, Yang TB, et al. Risk Factors for Congenital Syphilis and Adverse
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Prospective Nested Case-Control Study. Sex Trans Dis Jan 2014;41(1):13-23.
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26. Liu JB, Hong FC, Pan P, et al. A Risk Model for Congenital Syphilis in Infants Born to
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Mothers with Syphilis Treated in Gestation: A Prospective Cohort Study. Sex
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Transm Infect 2010;86:292-296.
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27. Zhu L, Qin M, Du L, Xie R, Wong T, Wen SW. Maternal and Congenital Syphilis in Shanghai, China, 2002 to 2006. Int J Infect Dis 2010;12S:e45-e48.
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28. Ortiz-Lopez N, Diez M, Diaz O, Simon F, Diaz A. Epidemiological Surveillance of
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Congenital Syphilis in Spain, 2000-2010. Pediatr Infect Dis J 2012;31(9):988-990.
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29. Carles G, Lochet S, Youssef M, et al. Syphilis and Pregnancy. J Gynecol Obstet Biol
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Reprod (Paris) Jun 2008;37(4):353-7.
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30. Sheffield JS, Sanchez PJ, Morris G, Maberry M, Zeray F, McIntire DD, Wendel GD. Congenital syphilis after maternal treatment for syphilis during pregnancy. Am J
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Obstet Gynecol March 2002;186(3):569-573.
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31. Alexander JM, Sheffield JS, Sanchez PJ, Mayfield J, Wendel GD. Efficacy of Treatment for Syphilis in Pregnancy. Obstet Gynecol 2001;93(1)1:5-8.
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32. Rolfs RT, Joesoef MR, Hendershot EF, et al; The Syphilis and HIV Study Group. A randomized trial of enhanced therapy for early syphilis in patients with and without
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human immunodeficiency virus infection. N Engl J Med 1997;337:307–14.
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33. Rawstron SA, Mehta S, Marcellino L, et al. Congenital Syphilis and Flourescent
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Treponemal Antibody Test Reactivity After the Age of 1 Year. Sex Transm Dis
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2001;28:412-416.
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Figure 1: Timeline to resolution of abnormal ultrasound findings
462
syphilotherapy.
Figure Legends
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463
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Table 1. Frequency of ultrasound abnormalities present in the 73 women with an
466
abnormal pre-treatment ultrasound
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Ultrasound
Abnormality* 58(79)
Placentomegaly
20(27)
Polyhydramnios
9(12)
Ascites
7(10)
Elevated MCA PSV
17/52 (33)
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Data reported as N(%)
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*more than one abnormality can be present
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ACCEPTED MANUSCRIPT R a c | 25 Table 2. Patient Characteristics Abnormal Ultrasound n=73 23.6 + 5.5
Age
Normal Ultrasound n=162 23.4 + 5.3
P-value 0.79 0.66
93(57)
White
3(4)
7(4)
25(34)
59(36)
0
3(2)
19(26)
49(30)
Hispanic Other Nulliparity Stage of Syphilis
Primary
3(4)
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0.51 0.91
10(6)
17(23)
Early Latent
22(30)
Late Latent
23(32)
56(34)
Unknown Duration
8(12)
14(9)
42(58)
92(57)
0.92
27.3 + 5.3
25.4 + 6.6
0.03
7.1 + 3.7
8.4 + 4.2
0.03
29.8 + 4.0
28.6 + 4.8
0.06
Gestational Age at
Diagnosis (weeks)
Number of Prenatal
Visits
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Early Stage Disease
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Gestational Age at
Initial Ultrasound
38(23) 44(27)
ACCEPTED MANUSCRIPT R a c | 26 and Treatment
(weeks)
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Data reported as N(%) or mean ± SD
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Table 3. Initial infant physical exam findings and placental pathology of those infants
487
diagnosed with congenital syphilis
Ultrasound
n=17
n=15
Hepatomegaly
11 (65)
9 (60)
Ascites
3 (18)
1 (7)
Anemia
1 (6)
1 (7)
Placentomegaly
5 (29)
1 (7)
Data reported as N(%)
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P-value
0.78 0.35
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Normal
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Abnormal
0.93 0.10
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