Clinical Infectious Diseases Advance Access published November 19, Maternal Titers after Adequate Syphilotherapy during Pregnancy

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1 Clinical Infectious Diseases Advance Access published November 19, Maternal Titers after Adequate Syphilotherapy during Pregnancy Martha W. F. Rac 1, Stefanie N. Bryant 1, Joseph B. Cantey 2, Donald D. McIntire 1, George D. Wendel, Jr. 1, Jeanne S. Sheffield 1 1 University of Texas Southwestern Medical Center, Department of Obstetrics and Gynecology 2 Department of Pediatrics, Parkland Health and Hospital System, Dallas, Texas Corresponding Author: Martha Rac, MD, University of Texas Southwestern Medical Center, Department of Obstetrics & Gynecology, 5323 Harry Hines Blvd. Dallas, TX , Phone: , Fax: , Martha.Rac@utsouthwestern.edu Article Summary Less than half of women treated for syphilis after 18 weeks of gestation will achieve a four fold decline in titers by delivery. The Author Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e mail: journals.permissions@oup.com.

2 2 Abstract Background: To construct a timeline for non treponemal titer decline specific to pregnancy and evaluate factors associated with inadequate decline by delivery. Methods: This was a retrospective chart review from September 1984 to June 2011 of women diagnosed with syphilis after 18 weeks of gestation. Women were treated according to stage of syphilis per CDC guidelines. Patients with both pre treatment and delivery titers were included for data analysis. Demographics, stage of syphilis, maternal titers, delivery and infant outcomes were recorded. Standard statistical analyses were performed for categorical and continuous data. The titer decline was analyzed using mixed effects regression modeling. Results: A total of 166 patients met inclusion criteria. Mean gestational age at treatment was weeks and 93 (56%) women were diagnosed with early stage syphilis. For all stages of syphilis, maternal titers declined after syphilotherapy. Primary and secondary disease had higher pre treatment titers and declined more rapidly than latent stage disease and syphilis of unknown duration. Sixty three (38%) patients achieved a 4 fold decline by delivery. Patients without a four fold decline by delivery were older (24.6 vs 21.5 years, p<0.001), treated later in pregnancy (30.3 vs 27.3 weeks, p<0.001), diagnosed with latent syphils or syphilis of unknown duration, and had less time from treatment to delivery (7.8 vs 11.1 weeks, p <0.001). Conclusions: Maternal serologic response during pregnancy after adequate syphilotherapy varied by stage of disease. Failure to achieve a four fold decline in titers by delivery is more a reflection of treatment timing rather than treatment failure.

3 3 Introduction Despite the availability of penicillin for more than 70 years for the treatment of syphilis, questions still remain regarding adequate serologic response during pregnancy. A four fold decline in a non treponemal titer is considered an adequate serologic response after syphilotherapy (1). However, recommendations regarding time allotted to achieve an adequate decline in non treponemal titers are based on observational and randomized controlled trials from non pregnant populations (2,3,4). Serologic response also depends on stage of syphilis, initial pre treatment titer, HIV status and history of prior syphilitic infection. All studies used by the Centers for Disease Control and Prevention (CDC) when formulating the definition of adequate serologic response listed pregnancy as an exclusion criteria. It is unknown whether pregnant women have a similar non treponemal titer response after treatment as that observed in non gravid populations. For the non pregnant individual, the CDC recommends that 6 to 12 months in early stage disease (primary, secondary, and early latent syphilis) and 12 to 24 months in late stage disease (late latent syphilis or syphilis of unknown duration) is required to gauge adequate serologic response. In HIV positive patients, a full 12 and 24 months is allotted for early stage and late stage disease, respectively, as a slower serologic response has previously been described in this population (1,2,3,4,5). Physiologic changes during pregnancy may alter the rate of maternal serologic response to treatment. In the only other study that evaluated maternal serologic response in pregnancy, Galan et al found that only 55% of the 49 women treated for syphilis during pregnancy achieved a four fold decline by 3 months after

4 4 syphilotherapy leading them to question treatment adequacy during pregnancy (6). Knowledge of serologic response per stage of syphilis is important to develop guidelines specific to pregnancy and guide clinical management of both the mother and infant. The purpose of this study was to construct a timeline for nontreponemal titer decline specific to pregnancy and evaluate factors associated with and without a four fold decline in titer by delivery. Materials and Methods This is a secondary analysis of a retrospective cohort of women diagnosed with syphilis after 18 weeks gestation from September 1981 to December 2011 at our institution. All women received targeted sonography prior to treatment to evaluate for fetal syphilis, which is standard of care at our institution. Patients were treated according to the CDC treatment guidelines per stage of syphilis (1). For the purpose of this study, we included only those patients with both pre treatment and delivery non treponemal titers in an effort to establish trends in maternal serologic response after syphilotherapy. All patients in the cohort had a reactive non treponemal serology which was subsequently confirmed by a positive treponemal antibody test. Non treponemal serology was performed with either Venereal Disease Research Laboratory (VDRL) or Rapid Plasma Reagin (RPR). During the study period, our institution replaced VDRL with RPR for both screening and post treatment surveillance. However, all patients in the cohort had concordant non treponemal tests before and after treatment performed at our institution alone. Maternal demographic data, stage of syphilis at diagnosis, non treponemal titers (pre treatment and at delivery), delivery and infant outcomes were recorded. Data

5 5 were analyzed by comparing women with a four fold decline in non treponemal titers by delivery to those who did not achieve a four fold decline. Time from treatment to delivery was also analyzed with regards to serologic response and measured from treatment initiation in women who required more than one penicillin injection. Congenital syphilis was diagnosed using CDC diagnostic criteria per the attending neonatologist (1). Student s t test was used to evaluate continuous variable and χ 2 squared was used for frequencies. Logistic regression analysis was used to adjust for gestational age at treatment as a linear effect modifier. The absolute decrease in non treponemal titer by stage as well as comparison of the rate of change by stage was performed using analysis of variance and mixed effects regression model with unstructured variance/covariance. Pairwise comparisons between the stages were made using regression contrasts with p values adjusted for multiple testing by the method of Tukey Kramer. P < 0.05 was considered significant and all tests were two tailed. This study was approved by the Institutional Review Board at the University of Texas Southwestern Medical Center. Results Two hundred and thirty five women were included in the original cohort and 166 (71%) had both pre treatment and delivery non treponemal titers available for review. Table 1 details the patient characteristics of these 166 patients. Mean gestational age at treatment was weeks and 93 (56%) were diagnosed with early stage syphilis. Of the 147 infant outcomes available, 27 (18%) required treatment for congenital syphilis. Figure 1 depicts the maternal serologic response

6 6 per stage of syphilis after appropriate syphilotherapy. For all stages of syphilis, maternal non treponemal titers declined by delivery. Secondary syphilis was associated with the highest titers at diagnosis followed by primary syphilis, syphilis of unknown duration, late latent syphilis and finally early latent syphilis (P<0.001). Titers from women with primary and secondary syphilis declined more rapidly after treatment than titers from women with latent stage disease (p<0.001). There was no significant difference in titers at delivery between all stages of syphilis (P=0.054). Overall, sixty three (38%) patients achieved a 4 fold decline by delivery. Table 2 shows the characteristics of the cohort divided into those with and without a four fold non treponemal titer decline by delivery. There were no differences noted in race or parity. Maternal age, stage of maternal syphilis and timing of treatment was significantly different between the two groups. Maternal stage of syphilis remained significant after adjusting for treatment timing (p=0.003). Patients with secondary syphilis were most likely to achieve a four fold titer decline by delivery (p=0.02). Patients not achieving a four fold decline in titers by delivery tended to be older ( vs years, p<0.001), treated later in pregnancy ( vs weeks, p<0.001), and were diagnosed with early and late latent stage disease or syphilis of unknown duration (87(84) vs 35(55), p<0.001). Only one patient in the cohort was HIV infected, and she achieved a fourfold titer decline by delivery. There was no significant difference in gestational age at delivery between those women with and without a four fold decline in titer (38.4 ±2.9 vs ± 2.6, respectively). However, women not achieving a four fold decline in titers by delivery had less time from treatment to delivery (7.8± 5 vs 11.1± 5.1

7 7 weeks, p <0.001), with 22 percent delivering < 4 weeks after treatment. Of the 147 available infant outcomes, the diagnosis of congenital syphilis was similar between those patients with and without a four fold titer decline (9(16) vs. 18(20), p=0.63). No women in the cohort required retreatment with penicillin for a treatment failure defined as an 4 fold increase in non treponemal titer. Comment This study provides data on the serologic response rates per stage of syphilis in pregnancies diagnosed at or beyond 18 weeks of gestation. We found that syphilis titers were highest in primary and secondary syphilis and the rate of titer decline was greatest in these women. Overall, less than half of the women diagnosed with syphilis after 18 weeks of gestation achieved a four fold decline in non treponemal titers by delivery. While lack of a four fold titer decline by delivery was associated with older maternal age, latent syphilis and less time from treatment to delivery, the risk of having an infant needing treatment for congenital syphilis did not correlate with the four fold titer decline by delivery. There are several important considerations in the interpretation of maternal serologic response resulting from our data. First, serologic response is similar in the pregnant and non pregnant population. Romanowski and colleagues reviewed 882 non pregnant patients with syphilis <1 year duration and found that titer decline was dependent on stage of syphilis. Patients with primary and secondary syphilis achieved a four fold titer decline sooner than those with early latent syphilis (2). In our cohort, women treated for primary and secondary syphilis also had a more

8 8 rapid rate of decline irrespective of treatment timing and these women were more likely to achieve a four fold titer decline by delivery. Older age has been demonstrated previously in non pregnant patients to be associated with slower serologic response to syphilotherapy (7) and was a risk factor in our pregnant series. Immune senescence has been suggested as a cause of slower serologic response in older patients (7 ). There is also evidence that repeat infections affect the rate of titer decline in both non pregnant and gravid populations (2,6). Although we did not collect information regarding multiple repeat infections, it is possible that older age could serve as a surrogate for the prior infection versus first episode phenomenon. HIV status has been shown to influence the rate of titer decline in non pregnant populations in both retrospective and prospective series (3,4). Patients with HIV co infection have higher rates of serologic treatment failures when compared to HIV negative patients, although clinical treatment failures are similar (3,4,8). There was only one patient co infected with HIV in our cohort limiting our ability to draw conclusions regarding the effect HIV has on the maternal serologic response. However, it is worth mentioning that she achieved a four fold titer decline by delivery. It is clear from previous studies in non pregnant populations that time from treatment is the most important variable in achieving an adequate serologic response. We found that less than half of women diagnosed and treated for syphilis after 18 weeks of gestation achieved a four fold titer decline by delivery. Since CDC recommendations regarding adequate serologic response state that treatment

9 9 failure should not be considered until 6 to 12 months after therapy in early stage disease or 12 to 24 months in late stage disease (1), it appears that the normal length of the human gestation is insufficient in length to achieve an adequate serologic response. In our cohort, the average gestational age at treatment was 29 weeks limiting our ability to draw conclusions regarding treatment failures based on a 6 12 month timeframe. However, late prenatal care is a known problem in seropositive women (9,10,11,12,13,14,15) making the results of our cohort more clinically applicable to the majority of women who contract syphilis while pregnant. Inadequate maternal serologic response is not necessarily indicative of inadequate treatment however, as equal rates of congenital syphilis were seen in those women with and without a four fold titer decline. In the only other study to evaluate the serologic response during pregnancy, Galan et al in 1997 found that only 47% of seropositive gravidas achieved a four fold titer decline 3 months after maternal treatment, which was considered an adequate amount of time to achieve a serologic response per CDC recommendations in 1997 (6,16). As a result, they questioned whether syphilis was undertreated during pregnancy. However, infant outcomes were not reviewed, limiting their ability to correlate maternal serologic response to vertical transmission rates. Well designed prospective studies have shown the recommended penicillin treatment regimens for syphilis(1) to be 98% efficacious for eradicating both maternal and fetal infection (17). Our study provides additional data to suggest that the risk of congenital syphilis in the neonate is more dependent on the time interval from treatment until delivery, a known risk factor for presumed

10 10 treatment failures (9), than on whether a four fold decline in titer by delivery was documented. Several study limitations should be acknowledged. This study was retrospective and required review of medical records. However, all women were treated at a single institution using a standardized protocol. Infant outcomes were also incomplete. Out of 166 pregnancies, we had available 147 infant outcomes for a follow up rate of 89%. Additionally, since serologic response is measured in 3 to 6 month epochs, not including women before 18 weeks of gestation could have underestimated the number of women that achieved a four fold titer decline by delivery. However, late prenatal care, poor compliance and inadequate follow up are known problems in seropositive gravidas (10,18,19) making our results applicable to the majority of pregnancies afflicted with syphilis. Despite these limitations, this is the largest cohort describing the serologic response to syphilotherapy during pregnancy. We have shown that decline in maternal titers during pregnancy after adequate syphilotherapy varied by stage of disease with a more rapid rate of decline noted in women with primary and secondary syphilis. Of women diagnosed and treated for syphilis after 18 weeks, less than half will achieve a four fold decline in non treponemal titer by delivery. That being said, the diagnosis of congenital syphilis did not correlate with maternal serological response to syphilotherapy. The assumption of inadequate maternal treatment based solely on adequate titer decline at delivery will result in an excess of both women being retreated and infants being treated unnecessarily for syphilis. A prospective study

11 11 across all stages of pregnancy would be prudent to complete the maternal serologic response to syphiliotherapy and establish national guidelines. The authors have no reported conflicts of interest related to the content of this manuscript. References 1. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines Atlanta (GA); U.S. Department of Health and Human Services; Romanowski B, Sutherland R, Fick GH, Mooney D, Love EJ. Serologic Response to treatment of infectious syphilis. Ann Intern Med 1991;114: Ghanem KG, Erbelding EJ, Wiener ZS, et al. Serological response to syphilis treatment in HIV positive and HIV negative patients attending sexually transmitted diseases clinics. Sex Transm Infect 2007;83: 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 human immunodeficiency virus infection. N Engl J Med 1997;337: Cohen SE, Klausner JD, Engleman J, Philip S. Syphilis in the Modern Era: An update for physicians. Infect Dis Clin N Am 2013;27: Galan HL, Montalvo JF, Deaver J. Retrospective analysis of the serologic response to the treatment of syphilis during pregnancy. Infectious Diseases in Obstetrics and Gynecology 1997 May;5:23 28.

12 12 7. Sena AC, Wolff M, Martin DH, et al. Predictors of serological cure and serofast state after treatment in HIV negative persons with early syphilis. Clin Infect Dis, 2011Dec;53(11): Horberg MA, Ranatunga DK, Quesenberry C, Klein DB, Silverberg MJ. Syphilis epidemiology and clinical outcomes in HIV infected and HIVuninfected patients in Kaiser Permanente Northern California. SexTransm Dis 2010; 37: 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 Obstet Gynecol March 2002;186(3): Ricci JM, Fojaco RM, O Sullivan MJ. Congenital Syphilis: The University of Miami/Jackson Memorial Medical Center Experience, Obstet Gynecol 1989;74(5): Liu JB, Hong FC, Pan P, et al. A Risk Model for Congenital Syphilis in Infants Born to Mothers with Syphilis Treated in Gestation: A Prospective Cohort Study. Sex Transm Infect 2010;86: Ortiz Lopez N, Diez M, Diaz O, Simon F, Diaz A. Epidemiological Surveillance of Congenital Syphilis in Spain, Pediatr Infect Dis J 2012;31(9): Zhu L, Qin M, Du L, Xie R, Wong T, Wen SW. Maternal and Congenital Syphilis in Shanghai, China, 2002 to Int J Infect Dis 2010;12S:e45 e Qin JB, Feng TJ, Yang TB, et al. Risk Factors for Congenital Syphilis and Adverse Pregnancy Outcomes in Offspring of Women with Syphilis in

13 13 Shenzhen, China: A Prospective Nested Case Control Study. Sex Trans Dis Jan 2014;41(1): Hawkes SJ, Gomez GB, Broutet N. Early Antenatal Care: Does it Make a Difference to Outcomes of Pregnancy Associated with Syphilis? A Systematic Review and Meta Analysis. PLOS ONE Feb 2013;8(2): Centers for Disease Control and Prevention Sexually transmitted diseases treatment guidelines. MMWR 1993;42(No. RR 14). 17. Alexander JM, Sheffield JS, Sanchez PJ, Mayfield J, Wendel GD. Efficacy of Treatment for Syphilis in Pregnancy. Obstet Gynecol 2001;93(1)1: Rawstron SA, Mehta S, Marcellino L, et al. Congenital Syphilis and Flourescent Treponemal Antibody Test Reactivity After the Age of 1 Year. Sex Transm Dis 2001;28: Lago EG, Vaccari A, Fiori R. Clinical Features and Follow up of Congenital Syphilis. Sex Trans Dis Feb 2012;40(2):85 94.

14 14 Table 1: Patient characteristics Age (years) Race Black White Hispanic Other 95 (57) 6 (4) 64 (39) 1 (0.01) Nulliparity 54 (33) Stage of Syphilis Primary Secondary Early Latent Late Latent Unknown Duration 6 (4) 38 (23) 49 (30) 57 (34) 16 (10) Gestational Age at Treatment (weeks) Gestational Age at Delivery (weeks) weeks from treatment to delivery 9.0 ± 5.3 < 4 weeks from treatment until delivery 31 (19) Congenital Syphilis a 27/147 (18) HIV positive 1 (0.01) Data presented as N(%) or Mean ± SD

15 15 a 147 infant outcomes available Table 2: Characteristics of those with and without a four fold decline in nontreponemal titers by delivery. No 4 fold decline N=103 4 fold decline N=63 P value Age (years) 24.6± ±4.4 <0.001 Race Black White Hispanic Other 54(52) 2(2) 46(45) 1(1) 41(65) 4(6) 18(29) 0(0) 0.09 Nulliparity 29(28) 25(40) 0.12 Stage of syphilis Primary Secondary Early Latent Late Latent Unknown Duration Gestational age at 2(2) 14(14) 37(36) 36(35) 14(14) 4(8) 24(38) 12(19) 21(33) 2(3) < a treatment (weeks) 30.3± ±4.2 <0.001

16 16 Gestational age at delivery 38.1± ± (weeks) Congenital syphilis b 18(20) 9(16) 0.63 Data presented as N(%) or Mean +SD a Adjusted for gestational age at treatment b 147 infant outcomes available

17 17 Figure Legend Figure 1: Non treponemal titer decline after treatment by stage of maternal syphilis