Accepted Manuscript

Syphilis During Pregnancy: A Preventable Threat to Maternal-Fetal Health

Martha W.F. Rac, MD, Paula A. Revell, PhD, Catherine S. Eppes, MD, MPH

PII: S0002-9378(16)32167-6
DOI: 10.1016/j.ajog.2016.11.1052
Reference: YMOB 11431

To appear in: American Journal of Obstetrics and Gynecology

Received Date: 8 September 2016

Revised Date: 17 November 2016
Accepted Date: 30 November 2016

Please cite this article as: Rac MWF, Revell PA, Eppes CS, Syphilis During Pregnancy: A Preventable
Threat to Maternal-Fetal Health, American Journal of Obstetrics and Gynecology (2017), doi: 10.1016/
j.ajog.2016.11.1052.

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1 Syphilis During Pregnancy: A Preventable Threat to Maternal-Fetal Health

3 Martha W.F. RAC, MD1

4 Paula A. REVELL, PhD2

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5 Catherine S. EPPES, MD, MPH1

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7 Baylor College of Medicine

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8 1Department of Obstetrics and Gynecology

9 2Departments of Pathology and Pediatrics

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10 Houston, Texas

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12 Address corresponding to:

13 Martha Rac, MD
14 Baylor College of Medicine
15 Department of Obstetrics & Gynecology
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16 1504 Taub Loop

17 Houston, Texas 77030
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18 Phone: 713-873-8794
19 Fax: 713-790-0108
20 Email: Martha.Rac@bcm.edu
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22 The authors report no conflicts of interest.

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24 Abstract word count: 355
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25 Total word count: 4680

26 Short Title: Syphilis During Pregnancy
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27 Review
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29 Abstract
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31 Syphilis remains the most common congenital infection worldwide and has

32 tremendous consequences for the mother and her developing fetus if left untreated.

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33 Recently, there has been an increase in the number congenital syphilis cases in the

34 United States. Thus, recognition and appropriate treatment of reproductive age

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35 women must be a priority. Testing should be performed at initiation of prenatal

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36 care and twice during the third trimester in high-risk patients. There are two

37 diagnostic algorithms available and physicians should be aware of which algorithm

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38 is utilized by their testing laboratory. Women testing positive for syphilis should
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39 undergo a history and physical exam as well as testing for other sexually

40 transmitted infections, including HIV. Serofast syphilis can occur in patients with
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41 previous adequate treatment but persistent low non-treponemal titers (<1:8).

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42 Syphilis can infect the fetus in all stages of the disease regardless of trimester and
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43 can sometimes be detected with ultrasound after 20 weeks. The most common

44 findings include hepatomegaly and placentomegaly, but also elevated peak systolic
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45 velocity in the middle cerebral artery [indicative of fetal anemia], ascites and

46 hydrops fetalis. Pregnancies with ultrasound abnormalities are at higher risk of

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47 compromise during syphilotherapy as well as fetal treatment failure. Thus, we

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48 recommend a pre-treatment ultrasound in viable pregnancies when feasible. The

49 only recommended treatment during pregnancy is benzathine penicillin G (BPG)

50 and it should be administered according to maternal stage of infection per Centers

51 for Disease Control (CDC) guidelines. Women with a penicillin allergy should be

52 desensitized and then treated with penicillin appropriate for their stage of syphilis.
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53 The Jarisch-Herxheimer reaction occurs in up to 44% of gravidas and can cause

54 contractions, fetal heart rate abnormalities and even stillbirth in the most severely

55 affected pregnancies. We recommend all viable pregnancies receive the first dose of

56 BPG on Labor and Delivery under continuous fetal monitoring for at least 24 hours.

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57 Thereafter, the remaining BPG doses can be given in an outpatient setting. The rate

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58 of maternal titer decline is not tied to pregnancy outcomes. Therefore, after

59 adequate syphilotherapy, maternal titers should be checked monthly to ensure they

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60 are not increasing, as this may indicate reinfection or treatment failure.

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62 Key Words: congenital syphilis, fetal syphilis, syphilis during pregnancy

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64 Condensation

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66 Syphilis remains a threat to maternal-fetal health and adequate screening and

67 treatment should be a priority for all obstetrician-gynecologists.

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68

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69 Short Title: Syphilis during pregnancy

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70
71 Introduction

72 Syphilis is an ancient infection that has plagued populations for centuries. Penicillin

73 revolutionized the treatment of syphilis and drastically decreased the rates of

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74 syphilis across all stages of disease. Yet, despite an available cure for over 70 years,

75 it remains a significant global health concern. On November 13, 2015 the Centers

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76 for Disease Control reported a 38% increase in the rate of congenital syphilis (CS)

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77 cases in the United States from 2012-2014 (1). This coincided with a 22% national

78 increase in rates of primary and secondary syphilis in women during the same

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79 period. Reasons for the rise in rates are not entirely clear, but demonstrate the
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80 immediate need for obstetricians and gynecologists to recognize, diagnose and treat

81 syphilis. The purpose of this document is to review the presentation, diagnosis and
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82 management of syphilis during pregnancy.

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83
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85 Epidemiology
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86 Syphilis is caused by treponema pallidum, a highly motile, spiral-shaped, gram-

87 negative bacterium and is the most common congenital infection worldwide (2,3,4).
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88 The economic and reproductive costs are enormous, as 25% of pregnancies may
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89 result in stillbirth or miscarriage or other adverse pregnancy outcomes (4).

90 However, CS is largely a preventable disease, requiring safe sex practices,

91 recognition, testing, and timely treatment during pregnancy.

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93 In 2007, the World Health Organization launched an initiative to eliminate CS by

94 2015 with goals to test 95% of gravidas for syphilis and treat 95% of seropositive

95 gravidas (4). While countries such as Cuba, Thailand, Armenia, Belarus and the

96 Republic of Moldova have achieved elimination, (5,6,7), rates of CS in the United

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97 States have only increased. In fact, the highest rates of CS since 2001 were reported

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98 in 2014, with a total of 458 cases of CS and a rate of 11.6 cases per 100,0000 live

99 births (1). This rise represented a 28% increase in CS cases during 20132014,

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100 which mirrored the 23% increase in primary or secondary syphilis rates in women

101 during the same period (1) (Figure 1).

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103 Substantial racial disparities are noted in syphilis cases during pregnancy. African
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104 American women represent the most highly affected demographic. Likewise, half of

105 CS cases in 2014 were found in infants born to African American women (38.2 per
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106 100,000 live births, 10 times the rate in whites), and they continue to have the
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107 highest rate of rise in incidence of primary and secondary syphilis among women

108 (8).
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109
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110 Geographically, rates of CS have increased across all regions with the most
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111 substantial increases seen in the Northeast (74%) and West (64%). Despite a

112 modest increase of 9% in the South, this region continues to have the highest

113 disease burden in the United States (8).

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115 Reasons for the rise in CS cases are not clear but likely multifactorial. According to

116 data from the CDC, 21.8% of the 458 women who gave birth to infants with CS in

117 2014 received no prenatal care. Of the women who did receive prenatal care, 43%

118 did not receive prenatal treatment and 17% were treated <30 days prior to delivery.

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119 Of women not treated despite receiving prenatal care, 15.6% were never tested and

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120 38.5% seroconverted during pregnancy (8). These findings highlight some of the

121 major barriers to reducing the rates of congenital syphilis, including access to

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122 prenatal care, lack of screening or diagnosis during pregnancy and failure to provide

123 adequate treatment.

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125 Clinical presentation and stages of syphilis

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126 Syphilis is spread through sexual contact and the spirochete penetrates mucous

127 membranes or abrasions in the skin to disseminate systemically before clinical

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128 disease appears. The incubation period ranges from 21 days to 6 months. A
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129 primary lesion, or painless chancre, appears at the site of inoculation. Without

130 treatment, spontaneous resolution of the chancre will occur within 4-6 weeks on
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131 average (9,10,11). Regional lymphadenopathy can accompany primary disease and
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132 lasts for months after the primary lesion has healed. Lymph nodes are firm,
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133 nonsuppurative and painless. Primary disease commonly goes unnoticed.

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135 Secondary syphilis occurs 6 to 8 weeks following untreated primary disease and

136 consists of systemic and local mucocutaneous lesions with generalized parenchymal

137 and constitutional manifestations. These manifestations can be subtle and some
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138 patients may enter the latent phase without ever recognizing secondary lesions.

139 Table 1 illustrates the numerous clinical symptoms of secondary syphilis.

140 If left untreated, secondary syphilis spontaneously resolves within 1-6 months

141 (9,10,11).

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142

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143 Thereafter, the patient enters the latent phase of syphilis, characterized by the

144 absence of clinical symptoms but positive serologic tests. Early latent syphilis is

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145 latent disease < 1 years duration where as late latent syphilis is >1 year after

146 infection. Syphilis of unknown duration is latent disease with no knowledge of

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147 infection duration. With the exception of early latent syphilis, latent disease is not

148 sexually transmitted but can be vertically transmitted. In untreated early latent
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149 syphilis, up to 25% of patients can experience a relapse of secondary symptoms,

150 thus sexual transmission can still occur.

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151
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152

153 Tertiary syphilis can develop in up to one-third of untreated patients. This includes
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154 benign granulomatous lesions of the skin, mucous membranes, skeleton, and
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155 involvement of the aorta (cardiovascular syphilis). The majority of deaths from
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156 tertiary syphilis are the result of cardiovascular involvement.

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158 Neurosyphilis can occur in any stage of syphilis. Evaluation is based on clinical

159 suspicion, including mental status changes in the context of positive syphilis testing.

160 Diagnosis requires a lumbar puncture showing either a positive VDRL or elevated
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161 glucose and low protein without other diagnosis. Although CSF abnormalities have

162 been documented in up to 30-40% of patients with secondary syphilis, evaluation

163 and treatment for neurosyphilis is not recommended in the absence of neurological

164 symptoms (9,10,11). All HIV positive patients should have a thorough neurologic

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165 exam and those diagnosed with neurosyphilis should be tested for HIV (8).

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166

167 Pregnancy does not affect the course of syphilis but syphilis can significantly affect

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168 the course of pregnancy. Maternal stages are not altered as a result of pregnancy

169 but >50% of infants will be clinically affected in untreated early syphilis and 35% in

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170 latent disease (9,12). Adverse pregnancy outcomes are twelve times more likely in

171 untreated pregnancies (13). In a recent systematic review, adverse pregnancy

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172 outcomes occurred in 76.8% of untreated pregnancies compared to 13.7% of

173 uninfected pregnancies (14). Even after treatment, there remains a significantly
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174 higher risk of adverse pregnancy outcomes compared to uninfected pregnancies

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175 (15).

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178
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179 Testing

180 Infection with Treponema pallidum has always posed unique diagnostic challenges.

181 T. pallidum cannot be cultivated in vitro or visualized by bright field microscopy.

182 Additionally, no FDA-cleared molecular assays for detection are available. Although

183 direct organism detection with dark field microscopy can provide presumptive
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184 diagnosis early in infection, darkfield microscopy is not widely available and the

185 vast majority of syphilis cases encountered in clinical practice are asymptomatic.

186 Given these unique challenges, syphilis diagnostics have relied on serologic tests as

187 the mainstay of laboratory diagnosis. Serologic tests for syphilis include detection

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188 of both non-treponemal antibodies and treponemal specific antibodies.

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189 Non-treponemal tests (NTTs) include the rapid plasma reagin (RPR) and the

190 venereal disease research laboratory (VDRL) test, which detects both IgM and IgG

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191 antibodies against cardiolipins released from host cell damage during infection.

192 These tests can be qualitative or quantitative with titers that increase with active

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193 disease and decrease following adequate therapy. Higher NTT titers are seen in

194 primary and secondary syphilis as compared to latent syphilis. Most individuals
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195 convert to nonreactive following adequate treatment, although some patients will

196 remain serofast. This is a condition of persistent low NTT titers (<1:8) without
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197 active disease and is more common with latent infection (16,17). The sensitivities
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198 of the NTTs are comparable and vary depending on stage of infection. Lower

199 sensitivity is seen in very early and very late infection and highest sensitivity is seen
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200 in secondary syphilis (18). The positive and negative predictive value of the NTTs
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201 depends on the population being tested; importantly false positive NTT reactions
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202 have been associated with pregnancy (19,20). The U.S Preventive Services Task

203 Force recently reported sensitivity, specificity, positive and negative predictive

204 value of each NTT and TT according to stage of syphilis (18).

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206 Treponemal tests (TTs) include all assays that detect IgM and IgG antibodies specific

207 to T. pallidum. While these tests can confirm previous T. pallidum infection, they

208 cannot differentiate individuals who have been treated from those with current

209 disease. Generally, TTs remain reactive for life following eradication of the

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210 infection. Historically the most commonly used TTs were the T. pallidum particle

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211 agglutination assay (TP-PA) and the fluorescent treponemal antibody absorption

212 assay (FT-ABS). Recent advances in the detection of T. pallidum antibodies have

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213 resulted in several TTs that are highly sensitive and specific and are automated to

214 accommodate high throughput testing. These include enzyme-linked

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215 immunosorbent assay (ELISA), chemilluminescence immunoassay (CIA), and

216 multiplex bead enzyme immunoassay (EIA) formats. The specificity of these assays
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217 are comparable to the TP-PA and FT-ABS but have better sensitivity for early

218 primary syphilis that is sometimes missed by TP-PA, FT-ABS and NTTs (18).
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219
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220 Due to the limitations of each available laboratory test for syphilis, no single

221 diagnostic test can be used to diagnose syphilis. As such, a diagnostic algorithm
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222 composed of multiple tests is used to diagnose syphilis. The algorithm used for
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223 decades, referred to as the traditional algorithm, initiates screening with a NTT
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224 screen, such as an RPR, followed by confirmation of reactive specimens with a

225 treponemal specific test to rule out false-positive results. In 2009 a new algorithm

226 was proposed and designated the reverse algorithm (21,22). This algorithm

227 initiates screening with a treponemal specific test (EIA or CIA); reactive samples are

228 tested by quantitative RPR and discrepant samples (those that test RPR non-
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229 reactive) are tested by TP-PA to aid in determination of disease and treatment

230 status. If the TP-PA is negative (+EIA/CIA, -RPR, -TP-PA), that may reflect very early

231 disease or false positive EIA/CIA results. In fact, a study out of Kaiser Permanente

232 showed that 53% of discrepant results (CIA+/-RPR/-TP-PA) during pregnancy were

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233 false positives on repeat testing (converted to CIA/-RPR/-TP-PA) (23). However, in

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234 high prevalence populations or if clinical suspicion is high, discrepant results are

235 more likely to represent early syphilis and we recommend treatment during

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236 pregnancy in lieu of repeat testing (24). Further, patients with possible latent

237 syphilis but negative RPR can be detected with the reverse algorithm who otherwise

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238 would be screen negative using the traditional algorithm (18). Due to the risk for

239 false positive test results, particularly in low risk populations, it is critical that the
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240 ordering physician understand the nature of the test being ordered. Many

241 laboratories offer the reverse diagnostic algorithm and will reflex tests
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242 appropriately, however, if the laboratory does not automatically reflex to the
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243 appropriate confirmatory tests following a positive treponemal specific test it is

244 incumbent on the physician to do so. Figure 4 shows the timeline of testing
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245 components and a flowchart for both the traditional and reverse sequence
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246 algorithms.
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247

248 Each of the two algorithms has strengths and weaknesses, and importantly

249 laboratories establish which algorithm best suits the needs of their population.

250 Typically, high volume laboratories will utilize the reverse algorithm to take

251 advantage of the high sample throughput, automation and objective test
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252 interpretation. In low volume settings, the traditional algorithm may be more cost

253 effective despite the requirement for manual operation and subjective

254 interpretation.

255

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256 Both testing algorithms (described later in the review) do not distinguish between

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257 previously treated versus untreated syphilis. Therefore, when patients have both

258 positive treponemal specific and nonspecific test results, in the absence of clinical

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259 symptoms, the differential diagnosis is serofast (previously treated syphilis with

260 persistent low RPR titers) versus latent syphilis. Previous treatment history and

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261 prior RPR titers will help distinguish between the two diagnoses, and can often be

262 obtained from State or Local Departments of Public Health. In the presence of
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263 previous inadequate treatment or no known treatment and unknown timing of

264 infection, we recommend treating pregnant patients as syphilis of unknown

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265 duration.
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266

267
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268 Prevention and identification of CS depends on careful maternal screening. Syphilis

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269 testing is recommended at initiation of prenatal care in all women, but only select
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270 states have mandatory third trimester testing and providers should be familiar with

271 their state laws regarding frequency of testing (25). Selective screening based on

272 state laws, geographic prevalence and patient risk factors follows regulatory

273 guidelines and CDC recommendations, however without universal third trimester

274 testing the true prevalence of syphilis will not be recognized. In women at high risk
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275 for acquiring syphilis, testing should occur at 28-32 weeks and again at delivery

276 (11) (Table 2). In addition, all women who present with a stillbirth >20 weeks

277 gestation should be tested and all patients diagnosed with syphilis should also be

278 tested for HIV. Syphilis is a nationally notifiable condition and requirements for

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279 reporting vary by state. State laws regarding reporting requirements can be found

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280 at http://www.cdc.gov/std/program/final-std-statutesall-states-5june-2014.pdf.

281

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283 Multiple studies have demonstrated cost-effectiveness of syphilis screening at the

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284 initiation of prenatal care (26,27,28,29,30). Recently, the cost-effectiveness of

285 repeat testing has been evaluated (29,30). These studies utilized lower rates of
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286 primary and secondary syphilis, which are not applicable to all geographic regions.

287 The incidence of syphilis may also be under recognized in regions that either do not
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288 perform repeat testing, or have higher rates of CS discordant from high rates of
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289 primary and secondary syphilis. In addition the model attributed a low rate of

290 preterm delivery related to syphilis, and even lower rates of presumed CS in women
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291 with early syphilis. Contemporary studies are lacking that evaluate seroconversion
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292 rates during pregnancy, making the models highly contingent on older less accurate
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293 data. For these reasons, we encourage repeat third trimester testing in all women

294 during pregnancy.

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296 Ultrasound findings and pathophysiology of fetal syphilis

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298 Vertical transmission of syphilis occurs in all stages of syphilis and in each trimester

299 of pregnancy (31,32,33,34,35). Fetal infection occurs in >50% of untreated early

300 syphilis and 35% of untreated latent disease (9,12). Amniocentesis and

301 percutaneous umbilical blood sampling were previously used to document fetal

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302 infection, but comprehensive fetal ultrasound is now the most common method

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303 used to evaluate for fetal infection (32,33,34,36,37). Characteristic fetal

304 abnormalities seen with ultrasound are the result of a robust inflammatory

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305 response to T. pallidum and typically not seen before 20 weeks as the result of fetal

306 immunologic immaturity (32,38). Pregnancies with evidence of fetal infection by

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307 ultrasound have higher rates of fetal compromise during treatment as well as fetal

308 treatment failures (35,39). Before 20 weeks, ultrasound abnormalities are usually
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309 not seen and treatment is uniformly successful (32,39,40,41).

310
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311 Ultrasound abnormalities suggestive of fetal syphilis can be seen after 20 weeks and
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312 in all stages of maternal syphilis. One study found that 31% of infected gravidas had

313 evidence of fetal syphilis on pretreatment ultrasound. These abnormalities, in

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314 decreasing frequencies, include (34,35,36):

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315 Hepatomegaly (80%)

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316 Elevated peak systolic velocity (PSV) of the middle cerebral artery (MCA) by

317 Doppler ultrasound indicative of fetal anemia (33%)

318 Placentomegaly (27%)

319 Polyhydramnios (12%)

320 Ascites (10%) and fetal hydrops

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321

322 The pathophysiology of fetal syphilis was first described by Hollier et al in 2001 and

323 completed in 2014 by Rac et al. Fetal syphilis is a continuum characterized by early

324 hepatic and placental involvement followed by amniotic fluid infection, hematologic

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325 dysfunction and finally ascites and fetal IgM production. As maternal stage of

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326 syphilis progresses untreated, more abnormalities develop (34). After adequate

327 syphilotherapy, findings of late fetal syphilitic infection (MCA Doppler

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328 abnormalities, ascites) resolve first and findings thought to occur early, such as

329 placentomegaly and hepatomegaly, are the last to resolve (35)(Figure 5).

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331 Due to the prevalence of ultrasound abnormalities in fetuses, the following are
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332 recommended structures/components to be visualized and documented during

333 comprehensive ultrasound in women with active syphilis:

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334 liver length (figure 6)

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335 placental thickness

336 peak systolic velocity of the middle cerebral artery (MCA)

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337 amniotic fluid index

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338 Evaluation for ascites or hydrops.

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339 Suggested nomograms and definitions of abnormal are shown in table 3.

340 The manifestations of fetal syphilis are poorly understood but likely the result of

341 multiple physiologic processes, and their etiologies may lend insight into the

342 morbidities observed clinically. Hepatomegaly is thought to result fro, acute

343 syphilitic hepatitis, exaggerated extramedullary hematopoiesis, cardiogenic hepatic

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344 congestion or even a therapeutic paradox as seen in postnatal studies after

345 syphilotherapy (42,43,44). Placentomegaly results from inflammation and

346 enlargement of the placental villi as a result of syphilitic infection (45,46,47). These

347 histopathologic changes lead to increased utero-placental resistance that correlates

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348 with degree of fetal infection (48). Syphilotherapy induces acute vascular perfusion

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349 changes, possibly secondary to the Jarisch Herxheimer reaction, offering an

350 explanation as to why maternal treatment may be intolerable to the most severely

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351 affected fetuses (48).

352

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353 Notable hematologic aberrations of fetal syphilis include anemia and

354 thrombocytopenia. Both appear to be specific to the developing fetus and neonate,
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355 and may result from the difference in properties of the fetal and adult RBC

356 compounded by an alteration in fetal hematopoiesis induced by fetal infection (49).

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357 We do not recommend an intrauterine transfusion as adequate treatment with

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358 Benzathine Penicillin G reverses the hematologic abnormalities of fetal syphilis.

359 (35,50).
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361 Lastly, a normal ultrasound does not necessarily rule out congenital infection. Rac et
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362 al found that ~12% of neonates with a normal pretreatment ultrasound during

363 pregnancy required treatment for congenital syphilis at delivery (35). It is

364 important to keep in mind that certain manifestations of congenital syphilis, such as

365 osseous lesions, are not detected by ultrasound. Patient counseling should include
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366 the limitations of ultrasound and the importance of a vigilant physical exam in the

367 nursery to rule out neonatal infection regardless of maternal treatment history.

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369

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370 Treatment of Syphilis During Pregnancy

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371 Benzathine penicillin G (BPG) is highly efficacious during pregnancy and remains

372 the only recommended treatment for maternal syphilis and prevention of congenital

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373 syphilis. Studies have found the efficacy of to be 99.7% for eradicating maternal

374 disease during pregnancy and 98.2% for preventing congenital syphilis across all

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375 stages of syphilis (51).

376
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377 Maternal treatment should occur as early in pregnancy as possible and comply with

378 the recommended regimen per stage of syphilis as determined by the Centers for
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379 Disease Control STD guidelines (11,52,53) (Table 4). Evidence has consistently
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380 shown that early and adequate maternal treatment during pregnancy confers the

381 lowest rates of congenital syphilis and adverse pregnancy outcomes (52,53). If any
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382 dose of BPG is missed or a lapse of >10 days occurs between any dose, the entire
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383 regimen should be restarted (54,55,56,57). Similarly, if a gravida is treated with

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384 any regimen other than penicillin or adequate treatment cannot be verified,

385 retreatment with the appropriate penicillin regimen is recommended.

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387 In primary, secondary and early latent syphilis, an additional dose of BPG has

388 traditionally been recommended on the basis of expert opinion and clinical
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389 experience (11). Recently, this has come into question given a national shortage of

390 BPG. Although no randomized controlled trials have been conducted to evaluate 1

391 dose versus 2 doses for early syphilis during pregnancy (58), theoretic

392 pharmacologic benefits exist to support additional doses. Nathan et al studied the

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393 serum concentrations of BPG in 25 women at term and found the number of women

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394 with a serum concentration >0.018ug/mL (the desired treponemocidal

395 concentration) significantly declined over the course of a week. By day 7, 36% had

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396 serum concentrations lower than the needed treponemocidal concentration (57).

397 Weeks et al demonstrated that 4.8 million units BPG given near term for GBS

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398 prophylaxis provided at least 30 days and in the majority of patients up to 100 days

399 of treponemocidal concentrations (59). There is also observational evidence to

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400 suggest that multiple BPG doses may be associated with more favorable pregnancy

401 outcomes (31,53,60,61,62). We continue to recommend an additional dose of BPG

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402 with early syphilis, especially beyond 20 weeks, however acknowledge that more
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403 research is needed to establish the most efficacious treatment during pregnancy,

404 particularly in the context of a national shortage of BPG.

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405
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406 Maternal NTT titers should be rechecked at the time of treatment in order gauge
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407 appropriate titer decline after syphilotherapy as some women will be treated on a

408 different day than their initial diagnostic testing. After maternal syphilotherapy,

409 follow-up NTT titers are performed monthly to ensure they are not increasing. We

410 state it this way to highlight two important points. First, titer decline will vary by

411 stage of maternal disease and treatment timing during pregnancy (Figure 7), with
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412 only 38% of gravidas achieving a 4-fold decline by delivery in a recent retrospective

413 review (63). Thus, the length of human gestation is likely insufficient to gauge

414 adequate maternal serologic response to syphilotherapy. If patients NTT titers

415 have not decreased four-fold by delivery, ongoing serologic surveillance per CDC

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416 guidelines should continue post-partum according to the structure of your local

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417 health care system. Secondly and most importantly, the rate of maternal titer

418 decline after adequate syphilotherapy is not predictive of fetal treatment failures

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419 (63). If NTT titers increase four-fold or symptoms persist or recur then re-infection

420 or maternal treatment failure should be considered. Patients should be evaluated

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421 for neurosyphilis and re-treated with 3 doses of Bicillin. If neurosyphilis is

422 diagnosed then the patient should be treated accordingly (8).

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424 Treatment Failures

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425 Fetal treatment failure is defined as the diagnosis of congenital syphilis despite
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426 adequate maternal treatment. Risk factors for fetal treatment failure include

427 (34,53,64):
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428 early syphilis (< 1 year)

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429 ultrasound abnormalities suggestive of fetal syphilis

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430 treatment late in pregnancy

431 Timing of treatment does not impact maternal cure rates, but does impact rates of

432 congenital syphilis (CS). Higher rates of CS have been observed with shorter

433 intervals between treatment and delivery, particularly if treatment occurs <30 days

434 from delivery (51,65,66,67,68). As a result, adequacy of maternal treatment is

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435 measured not only by the number of BPG doses received in accordance with stage of

436 disease, but also whether or not treatment occurred >30 days before delivery (11).

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438 Penicillin Allergy

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439 Women with a penicillin allergy should be desensitized and subsequently treated

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440 with the appropriate penicillin regimen. Both oral and intravenous desensitization

441 regimens have been described (69,70). Desensitization may be managed by the

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442 obstetrician/gynecologist with experience in desensitization, or concurrently with a

443 specialist in the field of Allergy and Immunology. An oral desensitization protocol

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444 used in pregnancy can be found in the CDC STD treatment guidelines 2015 (11,69).

445
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446 There is insufficient evidence that alternative antibiotics are efficacious for the

447 treatment of syphilis during pregnancy. Doxycycline and tetracycline are both
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448 contraindicated during pregnancy and macrolides have been associated with
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449 treatment failure during pregnancy, inconsistent placental transfer as well as

450 treponemal resistance (62,71). Ceftriaxone is highly treponemocidal with good

EP

451 placental transfer and was found to be 100% efficacious in 11 gravidas with primary
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452 or secondary syphilis treated before 20 weeks (72). Although promising, this study
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453 provides no applicable information on the majority of gravidas with syphilis

454 encountered in clinical practice, that is, the third trimester patient with latent

455 syphilis (35,62,64). More evidence is needed to establish the efficacy for ceftriaxone

456 in all stages of syphilis across all trimesters of pregnancies before it can be

457 considered a safe alternative.

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458

459 Jarisch-Herxheimer Reaction

460 Treatment of spirochete infections can result in the Jarisch-Herxheimer (JH)

461 reaction. This reaction is thought to result from the rapid killing of spirochetes

PT
462 causing copious release of endotoxins, lipopolysaccharides, prostaglandins and

RI
463 cytokines, leading to an acute inflammatory response (73,74,75). In non-pregnant

464 patient, it occurs in 95% of primary and secondary syphilis, but rarely in latent

SC
465 syphilis due to lower treponemal levels (76). In neurosyphilis, the JH reaction is

466 observed in 12-75% of cases (77).

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467

468 Clinical symptoms are transient and include systemic and local exacerbations of the
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469 treponemal disease (73,78). Fever, tachycardia, chills, arthralgia, pharyngitis,

470 headache, leukocytosis with lymphopenia as well as worsening of cutaneous lesions

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471 have been reported and coined the therapeutic paradox of syphilotherapy
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472 (35,73,78). Symptoms occur 2-8 hours after syphilotherapy is initiated and abate

473 by 24 hours (73).

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474
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475 Treatment is supportive with the use of antipyretics and intravenous fluid therapy.
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476 Corticosteroids have been proposed to decrease the intensity of the reaction, but

477 evidence of efficacy is lacking, especially during pregnancy (39). Smaller,

478 incremental dosing of penicillin does not seem to lessen the robustness of the

479 reaction as the JH is an all-or-nothing event provided the minimum treponemocidal

480 dose of 10 U/kg is reached (79).

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481

482 The JH reaction occurs in up to 44% of pregnant women and can precipitate

483 preterm labor, fetal heart rate abnormalities and stillbirth (75,78,80,81,82,83,84). It

484 occurs in 100% of primary disease, 60% of secondary disease, and more than half of

PT
485 patients with syphilis of unknown duration (80). Pregnancy specific complications

RI
486 include uterine contractions (56-67%), decreased fetal movement (67%) and fetal

487 heart rate decelerations (50%) (75,78,80). The majority of these complications will

SC
488 resolve by 24 hours after treatment although preterm birth and stillbirth can occur

489 in severely affected pregnancies, despite normal pretreatment ultrasounds

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490 (75,80,84,86,87). For these reasons, consideration should be given to administering

491 the first dose of BPG on Labor and Delivery under continuous fetal monitoring for at
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492 least 24 hours in all viable pregnancies. Fetal heart rate abnormalities present

493 before or during treatment, especially in the setting of ultrasound abnormalities,

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494 may indicate a severely affected fetus. If the JH reaction induces preterm labor,
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495 management should follow standard obstetric care. In the setting of fetal heart rate

496 abnormalities during treatment in the late preterm period (>34 weeks), specifically
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497 recurrent late decelerations that do not respond to intrauterine resuscitation, we

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498 recommend delivery with post-natal treatment of the infant (and mother).
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499 Management of fetal heart rate abnormalities in pregnancies before this gestational

500 age should be individualized. The remainder of BPG doses can be given in an

501 outpatient setting without concern for the JH reaction.

502

503 Summary of Recommendations:

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504

505 Management of syphilis during pregnancy requires a comprehensive approach

506 including results of testing, prior treatment history, physical exam findings, stage of

507 disease, gestational age at diagnosis and pre-treatment ultrasound findings. All

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508 women should have testing performed at initiation of prenatal care. Repeat testing

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509 is recommended in the third trimester and again on labor and delivery in high-risk

510 populations.

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511

512 A positive test for syphilis requires knowledge of prior infection history, especially

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513 in women with low NTT titers (<1:8), as some of these women will be serofast. We

514 advocate development of a good working relationship with your local Health
M

515 department to verify treatment in women with prior infection. If treatment cannot

516 be verified, these women should be considered to have active infection. HIV testing
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517 should be performed in all women who test positive for syphilis.
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518

519 After active infection is confirmed, a physical exam is performed to determine stage
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520 of syphilis. Penicillin is the only recommended therapy during pregnancy and
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521 gravidas should be treated according to their stage of syphilis per CDC guidelines
AC

522 (table 5)(11). As stated previously, ultrasound abnormalities can be seen after 20

523 weeks. However, pregnancy management does not change until viability. Therefore

524 we recommend an ultrasound prior to maternal treatment in viable fetuses to

525 identify pregnancies at highest risk of complications from syphilotherapy.

526 Treatment should not be delayed if an ultrasound is not readily available. Viable
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527 pregnancies should receive their first dose of BPG on Labor and Delivery under

528 continuous fetal monitoring, regardless of sonographic findings. Additional doses of

529 BPG can be given as an outpatient. No evidence is available to weigh the risks and

530 benefits of antenatal syphilotherapy versus delivery with post-partum treatment in

PT
531 the late preterm period and this decision should be individualized. However,

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532 delivery with treatment in the nursery may be considered in the most severely

533 affected pregnancies (ultrasound abnormalities) to avoid complications of

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534 syphilotherapy.

535

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536 After maternal treatment, pregnancies with pre-treatment ultrasound abnormalities

537 should undergo serial ultrasound surveillance to follow resolution of abnormalities.

M

538 Follow-up NTT titers are performed monthly to ensure they are not increasing.

539 Women found to be serofast do not have an increased risk of adverse pregnancy
D

540 outcomes, but should also have monthly RPR titers as these patients represent a
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541 population at increased risk for re-infection (88). There are no studies evaluating

542 the benefit of antenatal testing in pregnancies treated for syphilis. However, low
EP

543 birth weight, preterm birth and stillbirth have been observed remote from
C

544 syphilotherapy, particularly during the third trimester, and even after adequate
AC

545 maternal treatment (52,53,61,75,80,88,89). For this reason, antenatal testing is a

546 reasonable intervention to consider.

547

548 Neonatalogy should be notified at delivery to ensure neonates are evaluated for

549 evidence of infection and treated appropriately if indicated. Although placental

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550 histopathology is not required for the diagnosis of congenital syphilis, it has been

551 shown to improve detection in both liveborn and stillborn infants and should be

552 considered in all gravidas diagnosed and treated for syphilis (11,45). These

553 recommendations are summarized in Table 5.

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554

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555 References:

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559

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566 4. World Health Organization, Department of Reproductive Health and

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577 6. World Health Organization. Thailand is first country in Asia to eliminate

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648

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688 33. Wendel GD Jr., Sanchez PJ, Peters MT, Harstad TW, Potter LL, Norgard MV.

689 Identification of Treponema Pallidum in Amniotic Fluid and Fetal Blood from
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690 Pregnancies Complicated by Congenital Syphilis. Obstet Gynecol. 1991;78(5,

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711 39. Wendel GD Jr, Sheffield JS, Hollier LM, Hill JB, Ramsey PS, Sanchez PJ.

712 Treatment of syphilis in pregnancy and prevention of congenital syphilis.

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714

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721 42. Hira SK, Bhat GJ, Patel JB, Din SN, Atilli RV, Patel MI, Baskamathan S, Hira RS,
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732 45. Sheffield, JS, Sanchez PJ, Wendel GD Jr, Fong DWI, Margraf LR, Zeray F,

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774 spinal fluid after a single intramuscular injection of penicillin G benzathine.

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776
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861 and fetal monitoring changes in pregnant women treated for syphilis. Obstet

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864 81. Lentz JW, Ingraham NR, Beerman H, Stokes JH. Penicillin in the prevention

865 and treatment of congenital syphilis. JAMA 1944;126:408-13.

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866

867 82. Beerman IL, Ingraham NR. Recent advances in the management of the

868 syphilitic pregnant woman .Med Clin North Am 1945;9:1463-76.

869

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870 83. Ingraham NR, Stokes JH, Beerman H, Lentz JW, Wammock VS. Penicillin

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871 treatment of the syphilitic pregnant woman. JAMA 1946;130:683-8.

872

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873 84. Bowen JH, Cole HN, Driver JR, et al. Herxheimer reactions in penicillin

874 treatment of syphilis in pregnancy. Arch Dermatol Syphilol 1948;58:735-9.

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875

876 85. Cross JB, McCain JR, Herman A. The use of crystalline penicillin G in the
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877 treatment of syphnilis in pregnancy. Am J Obstet Gynecol 1949;57:461-5.

878
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879 86. Thompson SE. Treatment of syphilis in pregnancy. J Am Vener Dis Assoc
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880 1976;3:15966.

881
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882 87. Mascola L, Pelosi R, Blount JH, Alexander CE, Cates W Jr. Congenital syphilis
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883 revisted. Am J Dis Child. 1985 Jun;139(6):575-80.

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884

885 88. Wallace HE, Isitt CE, Broomhall HM, Perry AE, Wilson JD. Adverse pregnancy

886 outcomes following syphilis treatment in pregnancy in the UK. Int J STD and

887 AIDS. Sept 2015. Accessed August 21, 2016.

888
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889 89. Beksinska ME, Mullick S, Kunene B, Rees H, Deperthes B. A case study of

890 antenatal syphilis screening in South Africa: success and challenges. Sexually

891 Transmitted Diseases 2002;29:32-7.

892

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893 90. Vintzileos AM, Neckles S, Campbell WA et al. Fetal liver ultrasound

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894 measurements during normal pregnancy. Obstet Gynecol 1985;66:477-80.

895

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896 91. Hoddick WK, Mahoney BS, Callen PW, Filley RA. Placental Thickness. J

897 Ultrasound Med 1985;4:179-182.

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899 92. Mari G, Deter RL, Carpenter RL, et al. Noninvasive Diagnosis by Doppler
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900 Ultrasonography of Fetal Anemia due to Maternal Red-Cell Alloimmunization.

901 N Engl J Med 2000;342(1):9-14.

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902
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903 93. Moore TR, Cayle JE. The Amniotic Fluid Index in Normal Human Pregnancy.

904 Am J Obstet Gynecol 1990 May;162(5):1168-73.

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905
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906 94. Society for Maternal-Fetal Medicine (SMFM), Norton ME, Chauhan SP, Dashe
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907 JS. Society for maternal-fetal medicine (SMFM) clinical guideline #7:

908 nonimmune hydrops fetalis. An J Obstet Gynecol 2015 Feb;212(2):127-39.

909
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910 95. Peeling RW, Ye H. Diagnostic tools for preventing and managing maternal

911 and congenital syphilis: an overview. Bulletin of the World Health

912 Organization 2004;84:439-446.

913

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922

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928
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930
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932
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933
934
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936
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937
938
939
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940
941
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951

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955

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956 Table 1: Clinical presentation and stages of syphilis (9,10)

Stage of Syphilis Clinical findings Location/characterization

SC
Primary Syphilis Chancre

U
Lymphadenopathy
AN
Secondary Syphilis Rash (Figure 2). Distributed widely, commonly

involve the palms and soles.

M

Macular, papular,

papulosquamous, pustular
D

and nonpruritic.
TE

Patchy alopecia Scalp hair or eyebrows.

C EP

Condyloma lata Warm/moist intertriginous

AC

(Figure 3) areas such as vulva, inner

thighs, axillae, perineum, skin

under breasts
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Mucous patches Mouth, throat or genital areas

Generalized Fever, Sore throat

symptoms Weight loss, Malaise

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Anorexia, Meningismus

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Parenchymal effects Hepatitis, Gastrointestinal

SC
(less common) symptoms, Nephrotic

syndrome, Arthritis

U
AN
Periostitis, Optic neuritis

Tertiary Syphilis Granulomatous Skin, mucous membranes,

M

lesions skeleton
D

Cardiovascular Typically Aortic lesions

TE

Neurosyphilis CNS Cognitive dysfunction, motor

or sensory deficits, auditory

EP

symptoms, cranial nerve

C

palsies, meningitis, stroke,

AC

Tabes Dorsalis (syphilitic

myelopathy)

Ophthalmologic Uveitis, neuroretinitis, optic

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neuritis, Argyll Robertson

pupils

957

958

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959

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960

961

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962
963
964

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965
966
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967
968
969
970
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971
972 Table 2. High-risk characteristics for acquiring syphilis during pregnancy that
973 require testing twice during the third trimester (at 28-32 weeks and delivery) (11).
D

974
High morbidity area (rates of primary and secondary syphilis of 2/100,000 or
TE

higher)
No evidence of prior testing
Uninsured or low income
Diagnosed with a STD during pregnancy
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Exchange sex for money or drugs

975
976
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977 Table 3: Suggested nomograms for sonographic markers of fetal syphilis

AC

978 (90,91,92,93,94)

Structure/component Nomogram for Definition of Abnormal

reference

liver length Vintzileos et al.(90) hepatomegaly defined as a liver

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length >95th % for EGA

placental thickness Hoddick et al.(91) placental thickness that exceeds

2 standard deviations for EGA

MCA dopplers Mari et al.(92) MCA >1.5 MoM

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amniotic fluid index Moore et al. (93) >250 mm

RI
(AFI)

Evaluation for ascites Norton SMFM Ascities: free fluid within the

SC
or gross hydrops 2014(94) fetal abdominal cavity

U
AN Hydrops: >2 cavities with

abnormal fluid collections

979 EGA: estimated gestational age

M

980 MoM: multiples of the median

981
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982
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983 Table 4: Treatment of syphilis during pregnancy according stage of disease (11)

Stage of Syphilis Treatment

EP

Primary Syphilis Benzathine penicillin G 2.4 million units

C

IM once
AC

Secondary Syphilis

* Some evidence suggests that additional

Early Latent Syphilis therapy is beneficial for pregnant

women. For women who have primary,

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secondary, or early latent syphilis, a

second dose of benzathine penicillin 2.4

million units IM can be administered 1

week after the initial dose (total 4.8

PT
million units)

RI
Late Latent Syphilis Benzathine penicillin G 7.2 million units

total, administered as 3 doses of 2.4

SC
Syphilis of Unknown Duration million units IM each at 1-week intervals

U
Tertiary Syphilis AN
Neurosyphilis Aqueous crystalline penicillin G18-24

million units per day, administered as 3-

M

4 million unit OV every 4 hours or

continuous infusion, for 10-14 days

D

984
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985 Table 5: Recommended Management of Syphilis During Pregnancy

Test for syphilis at initiation of prenatal care, third trimester and at delivery*
For all positive results, conduct history and physical exam to stage disease
EP

If patient asymptomatic, check for past infection with adequate treatment as

the patient may be serofast (NTT titers <1:8)
If adequate treatment cannot be verified or titers > 4 fold higher, retreat
C

(syphilis of unknown duration)

Treat according to maternal stage of disease. We recommend 2 doses of BPG
AC

in early syphilis (<1 year) for fetal benefit.

If pregnancy is viable, perform a comprehensive ultrasound to evaluate for
fetal syphilis
If pregnancy is viable, give first dose of BPG on Labor and Delivery under
continuous fetal monitoring for 24 hours
Consider delivery with treatment in the nursery during the late preterm
period if evidence of fetal heart rate abnormalities, with or without
ultrasound abnormalities or hydrops, appears before or during maternal
treatment
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Additional doses of BPG can be given as an outpatient.

Serial ultrasound surveillance for pregnancies with an abnormal pre-
treatment ultrasound to monitor for resolution of abnormalities
Antenatal testing can be considered during the third trimester
Notify neonatology at delivery for adequate neonatal evaluation
Send placenta to pathology for histologic evaluation

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986 *Testing twice during the third trimester is recommended in high-risk populations.
987 Please see Table 3.
988

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989

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990 Figure 1: Rates of congenital syphilis according to year of birth compared to the

991 rates of primary and secondary syphilis cases among women, 2006-2015 (8).

992

993 Figure 2: Palmar (A) and plantar (B) hyperpigmented, annular papulosquamous

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994 syphilids (78).

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995

996 Figure 3: Condyloma Lata of the perineal region(78)

SC
997

998 Figure 4: A timeline of syphilis testing components (A). and comparison of the

U
AN
999 traditional and reverse sequence algorithms (B) (21,22,95).

1000 aIgM by ELISA or FTA-ABS 195 or immunoblot

M

1001 TPHA T. pallidum haemagglutination assay which is a specific treponemal assay

1002 used to confirm a positive screening test. Similar treponemal assays are the TPPA,
D

1003 FTA-ABS and MHA-TP.

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1004 Figure 4a adapted from Peeling et al. Diagnostic tools for preventing and managing

1005 maternal and congenital syphilis: an overview. Bulletin of the World Health
EP

1006 Organization, June 2004, 82(6).

C

1007
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1008 Figure 5: Progression of ultrasound abnormalities before and after maternal and

1009 fetal syphilotherapy (34,35)

1010

1011 Figure 6: Hepatomegaly and ascites in a fetus with syphilis. The dotted lines and

1012 cross bars demonstrate correct measurement of the fetal liver length. The fetal liver
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1013 should be measured from the right hemidiaphragm to the tip of the right lobe. The

1014 fetus should be in a back down position with the right side up.

1015

1016

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1017 Figure 7: Non-treponemal titer (NTT) decline after adequate maternal treatment

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1018 according to stage of syphilis (63)

1019

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Congenital Syphilis Reported Cases by Year of Birth

and Rates of Primary and Secondary Syphilis Among
Women, United States, 20062015

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* CS = Congenital syphilis; P&S = Primary and secondary syphilis.
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