Sexually Transmitted Diseases:
Prevalence and Risk Factors for Herpes Simplex Virus Type 2 Infection Among Pregnant Women in Israel
DAN, MICHAEL MD*; SADAN, OSCAR MD†; GLEZERMAN, MAREK MD†; RAVEH, DAVID MD‡; SAMRA, ZMIRA PhD§
*Infectious Diseases Unit and the †Department of Obstetrics and Gynecology, the E. Wolfson Hospital, Holon, and the ‡Infectious Diseases Unit, Shaare Zedek Medical Center, Jerusalem; and the §Department of Microbiology, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel
Correspondence: Michael Dan, MD, Wolfson Hospital, Holon 58100, Israel. E-mail: firstname.lastname@example.org
Received for publication February 18, 2003,
revised May 29, 2003, and accepted May 30, 2003.
Background: Although usually a nuisance to the adult patient, herpes simplex virus type 2 (HSV-2) infection can have devastating consequences on the infected newborn. It is thus important to document the prevalence and risk factors of this infection among pregnant women in a defined population. The availability of the new type-specific assays that provide accurate serologic results prompted us to study the seroprevalence of HSV-2 infection among pregnant women in Israel.
Study Design: In a cross-sectional descriptive study, 512 pregnant women were tested. The study population included Israeli-born Jewish and Arab women, and new immigrants from the former Soviet Union. A competition-based enzyme-linked immunosorbent assay (ELISA) was used to detect type-specific HSV-1 and HSV-2 antibodies. Univariate and multivariate analyses were performed to identify risk factors for HSV-2 seropositivity.
Results: The prevalence of HSV-2 infection was 13.3% (95% confidence interval, 10.5–16.5%) and that of HSV-1 was 94.9%. History of genital or labial herpes was reported by 1.3% and 26.8% of the participants, respectively. The HSV-2 infection rate was 3-fold higher among immigrants from the former Soviet Union (27.5%) than among Israeli-born Jewish and Arab women (9%). The only risk factor independently associated with HSV-2 seropositivity was multiple lifetime sexual partners.
Conclusion: We have documented a relatively low seroprevalence of HSV-2 infection in a demographically mixed group of pregnant women in Israel. The role of high-risk sexual behavior in the spread of the infection has been reconfirmed.
THE MOST SEVERE CONSEQUENCE of herpes simplex virus type 2 (HSV-2) infection is related to its transmission from the mother to the newborn during delivery. 1 In the adult patient, genital herpes could have significant psychosocial repercussions. HSV-2 infection has also gained attention as a possible causal factor in the transmission of HIV. 2
The recent development of accurate type-specific serologic assays allows identification of carriers of HSV-2 infection in individuals with or without preexisting antibodies to HSV-1. 3 These tests are important epidemiologic tools that can be used in HSV-2 seroprevalence studies. HSV-2 seropositivity provides an objective marker for sexual risk behavior in cross-sectional surveys. Very little is known about the true prevalence of HSV-2 infection in Israel and the risk factors for its acquisition. 4
Study Design and Population
This cross-sectional, descriptive, prospective study was conducted in the obstetric department at the E. Wolfson Hospital, Holon, Israel, between July 2000 and April 2001. The study population consisted of unselected pregnant women admitted for delivery. A questionnaire was administered by a trained nurse covering demographic details and risk factors for genital herpes, including age, country of birth, years of schooling, number of pregnancies, number of deliveries, contraceptive methods used, age at first sexual intercourse, lifetime number of sexual partners, history of labial herpes, history of genital herpes, and symptoms suggestive of this condition (vesicles, ulcers, fissures, and irritation in the genital area, vaginal discharge, and dysuria), history of other sexually transmitted diseases (STDs), and knowledge about genital herpes. Blood samples were collected into tubes without anticoagulant and allowed to clot at room temperature for 30 minutes. Serum was separated after centrifugation and stored in polypropylene tubes at -20°C until assayed. The hospital ethics committee approved the study.
Type-specific immunoglobulin G antibodies to HSV-1 and HSV-2 were detected using a competition-based enzyme-linked immunosorbent assay (SeroHSV1 and SeroHSV2; Savyon Diagnostics Ltd, Ashdod, Israel). Sensitivity and specificity of the assay were previously found to be >94% and >92%, respectively. 5 The test uses microtiter plates coated with partially purified viral proteins from HSV-1 (Macintyre strain) and HSV-2 (G strain). The serum to be tested is diluted with serum diluent containing either HSV-1- or HSV-2-specific monoclonal antibodies (MAbs) raised against either HSV-1 or HSV-2 glycoprotein G major immunodominant epitopes, and incubated with either SeroHSV1 or SeroHSV2 plates. If human HSV-1 or HSV-2 antibodies are present in the sample, they will compete with the respective MAbs. If, however, there are no specific HSV-1 or HSV-2 antibodies in the human sample, only HSV-1 or HSV-2 MAbs will be bound on the respective plates. The tests were performed as recommended by the manufacturer's instruction manual and described elsewhere. 5 Positive and equivocal HSV-2 results by the competition-based ELISA were retested by the MRL Diagnostics HSV-2 ELISA IgG assay (MRL Diagnostics, Cypress, CA). Screening for syphilis was done by rapid plasma reagent or VDRL, Treponema pallidum hemagglutination, and the fluorescent treponemal antibody absorption test.
Statistical analysis was performed using the EpiInfo 6.04 days software (Centers for Disease Control and Prevention, Atlanta, GA), PEPI (J. H. Abramson and P. M. Gahlinger, Sagebrush Press, 2001), and SPSS version 10.0 for windows (SPSS, Inc, Chicago, IL). Univariate and binary logistic regression analyses were performed to establish which demographic and behavioral risk factors were associated with HSV-2 seropositivity.
A total of 512 pregnant women at delivery were tested. Their mean age was 28.3 ± 5.4 years (median, 28 y; range, 16–44 y). Complete demographic and behavioral data were available for 440 women (86%). Partial collection of data was generally the result of precipitated discharge from the hospital, usually over the weekends or holydays. Only 1.3% of the tested women refused to furnish any information. Data on the demographic and sexual behavior characteristics of the study population are shown in Table 1 (“No. Tested,” second column). The mean age at first intercourse was 19.4 ± 2.9 years; 2.5% had intercourse before the age of 16 years, and 1.1% refused to answer the question or stated not remembering the age at which they became sexually active. The mean number of lifetime sexual partners was 1.9 ± 2.2; 1.5% refused to respond specifically to this question. History of STD was reported by 4.9% of women, the most common being genital herpes (1.3%), genital warts (human papillomavirus virus [HPV] infection), and pelvic inflammatory disease. History of orolabial herpes was reported by 26.8% of the women.
Of the 512 serum samples tested for HSV-2 antibodies by the competition-based ELISA, 67 were positive (all tested positive on the MRL Diagnostics HSV-2 ELISA IgG test), 17 gave an equivocal result, and 428 were negative. The retesting of the equivocal sera by the MRL Diagnostics HSV-2 ELISA IgG test gave a positive result in one sample and negative results in 16 samples. HSV-2 seroprevalence for the entire study population was 13.3% based on 68 HSV-2-positive results in 512 women tested (95% confidence interval [CI], 10.46–16.53%). Two of the 6 women who reported a history of genital herpes were HSV-2-seronegative; hence, only 6% of the HSV-2-seropositive women had a history of genital herpes. The HSV-1 seroprevalence was 94.9% (95% CI, 92.65–96.66%); all participants but one reporting a history of orolabial herpes had antibodies to HSV-1. Results of screening for syphilis were available for 504 women and only one (0.2%) had positive serology; she was HSV-2-seronegative and did not report other STDs.
Table 1 presents the HSV-2 seropositivity rate according to various demographic and sexual behavior characteristics. The prevalence of HSV-2 antibodies was significantly higher among immigrants than among Israeli-born women (P <0.0001). The difference in the rates of HSV-2 seropositivity in the different age groups was of borderline significance (P = 0.06); however, the mean age of seropositive women, 29.8 ± 5.5 years, was significantly higher than that (28.0 ± 5.4 y) of the seronegative women (P <0.05). HSV-2 seroprevalence was significantly associated with the number of lifetime sexual partners (P <0.0001) and history of sexually transmitted infections (P <0.0005). On univariate analysis, 4 variables came out in the order of significance: lifetime number of sex partners, woman's origin, history of prior STD, and woman's age. On multivariate analysis, the number of lifetime sexual partners was the only significant independent variable (P <0.001).
The results of the current study reemphasize the primary role of sexual risk behavior in the acquisition of HSV-2 infection. 6 In agreement with other studies, 6–8 we show that HSV-2 seropositivity is associated with a greater number of lifetime sexual partners and history of other STDs. Although HSV-2 seroprevalence was almost 2-fold higher in women who became sexually active before the age of 20 years (16.6%) than in those whose age of onset of sexual activity was 20 years or above (9%), the difference did not reach statistical significance. Our findings support the use of HSV-2 serology as a marker of lifetime sexual risk. On the other hand, they validate the reliability of self-reported information regarding sexual behavior. Several studies showed an association between the prevalence of HSV-2 infection and ethnicity. 7–11 However, the impact of risky sexual behavior was not always evaluated. 9–11 In the current study, HSV-2 seroprevalence was significantly associated with emigration from the former Soviet Union; this association, however, was not independent and was abolished when the number of lifetime sexual partners was considered. Age was previously reported in most, 7,8,10–13 but not all, 14 studies to be an independent risk factor for HSV-2 infection. Our findings support the association between HSV-2 seroprevalence and increasing age, yet the interaction was not independent. Few of the seropositive women reported ever having genital herpes, suggesting a high level of asymptomatic infection or unrecognized signs and symptoms. The high rate of asymptomatic HSV-2 infection in our study population might be explained, at least partially, by the high prevalence of concomitant HSV-1 seropositivity. 15 Although many women with HSV-2 infection develop unrecognized genital symptoms, 16 we could not confirm the assumption that nonspecific vulvovaginal symptoms would be reported more often by the seropositive participants than by those not harboring the virus. This might be the result of the substantial overlap in the clinical manifestations of genital herpes with those of other more common conditions such as cervicovaginal infections, urinary tract infections, and dermatoses that can affect the genitals. 17 The prevalence of HSV-2 infection among pregnant women as documented in the current study has a 2-fold significance. Compared with the situation in European countries with a prevalence range of 9–33%, 9,14,18,19 the infection rate in our pregnant population places it on the lower part of the scale, with a low chance of neonatal transmission from reactivated genital herpes. On the other hand, the majority of our pregnant population is susceptible to HSV-2 infection and might acquire it during pregnancy with potentially severe neonatal repercussions. It has been suggested that pregnant women and their partners should be screened for HSV-2 using the type-specific serology, and HSV-discordant couples should be counseled about the risk of specific sexual practices. 17
Our study has a few limitations. Because of budgetary considerations, we had to limit our sample size to approximately 500 women, a fact that reduced the power of the study. Furthermore, in 14% of the participants data collection was incomplete. Most of the women with lacking information delivered on weekends or holydays, which should not bias our findings.
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