Herpes Simplex Virus Type 2 Seroprevalence and Ultrasound-diagnosed Uterine Fibroids in a Large Population of Young African-American Women

Kristen R. Moore; Jennifer S. Smith; Stephen R. Cole; Victor J. Schoenbach; Katherine Schlusser; Charlotte A. Gaydos; Donna D. Baird*

Disclosures

Am J Epidemiol. 2016;183(11):961-968. 

In This Article

Discussion

Our study did not show an association between HSV-2 and the presence of fibroids or the size, number, or total volume of fibroids. Even among women who were seropositive and had genital herpes severe enough to warrant reporting a clinical diagnosis, there was no association with fibroids. In addition, the lack of an association was consistent across various sensitivity analyses: excluding women with cervical treatment and stratifying by size of the largest fibroid, age, and number of sexual partners before age 20 years.

Our findings are consistent with a previous study on this same population that evaluated several self-reported RTIs, showing no association of genital herpes with fibroids.[17] Two other studies have investigated the association between self-reported genital herpes and the presence of fibroids.[4,16] A clinic-based case-control study of premenopausal women (aged 18–55 years) showed no association of genital herpes with clinically detected fibroids.[16] The Uterine Fibroid Study,[4] a cross-sectional study that used ultrasound to screen randomly selected members of an urban health plan aged 35–49 years for fibroids, found suggestions of a positive association of self-reported genital herpes with fibroids in both African-American and white women.[4] However, these findings were not precise enough to rule out associations due to chance. A small pilot study investigated whether pathogens were present in fibroid tissue; specimens from 20 Uterine Fibroid Study participants who had reported a history of sexually transmitted disease or multiple sexual partners were tested for viral DNA matching HSV-1, HSV-2, cytomegalovirus, human herpes virus (types 6, 7, and 8), and Epstein-Barr virus using polymerase chain reaction.[4] None of these pathogens was detected in the tumor samples.

Our study had several limitations. It was a cross-sectional analysis. Thus, the timing of acquisition of HSV-2 infection in relation to fibroid development is unknown. However, it is likely that exposure occurred before disease onset for most women. More than half the women who self-reported genital herpes reported that their first diagnosis was before the age of 22 years, and approximately 45% of new HSV-2 infections in the United States are among persons aged 15–24 years.[23] Also, most of the fibroids were small, suggesting relatively recent development, and fibroid development in African Americans appears to be infrequent before the mid-20s.[18,41] Finally, the median amount of time between the first self-reported HSV-2 diagnosis and study enrollment was 6 years, and because antibody titers persist for years after infection,[34] even exposure to HSV-2 multiple years prior to enrollment should have been captured.

We did not use the Western blot test, the gold standard method for HSV-2 serology.[35,42] However, the HerpeSelect 2 assay we used[38] has been found to perform very well for HSV-2 infections, with sensitivity between 96% and 100% and specificity between 97% and 98%[43,44] in comparison with the Western blot. The Western blot technique is not approved by the US Food and Drug Administration and is more complex, more costly, less time-efficient, and much less widely available than the enzyme-linked immunosorbent assay.[45] In addition, we did not capture persons who had a very recent infection, because it can take weeks to months after infection for immunoglobulin G antibodies to be detected. However, because we seek to measure past exposure, ideally at the time of fibroid development, low sensitivity for very recent infections did not jeopardize our assessment of cumulative exposure to HSV-2.

In addition, HSV-2 seroprevalence alone underestimates the prevalence of genital herpes simplex virus infection due to the omission of genital infections caused solely by HSV-1, which are increasing in incidence.[46] However, because HSV-1 also causes orolabial infections, which are very prevalent,[46] a large proportion of the population will have antibodies to HSV-1, and we would not be able to distinguish orolabial HSV-1 infection from genital HSV-1 infection. Thus, the value of the added information to be gained from measuring HSV-1 is unclear.

Finally, our sample was a volunteer sample of women. However, the seroprevalence of HSV-2 in our cohort (47%) was very similar to the seroprevalence of 50% for African-American women in the United States.[24] Furthermore, 22% of the women in our cohort had fibroids at ultrasound screening, which falls within the range of prior US studies that conducted ultrasound screening.[2,4,41,47]

Our study also had several strengths. This was, to our knowledge, the first study to investigate the relationship between HSV-2 and fibroids using an immunological measure of exposure. Our blinded quality-control samples demonstrated low measurement error in HSV-2 serostatus. Previous studies have used only self-reported diagnosis of genital herpes as the exposure measurement, which is problematic due to the high prevalence of asymptomatic infection. Furthermore, we used a standard and valid measure of fibroid status based on systematic ultrasound screening rather than fibroids clinically detected because of symptoms or incidental detection. The number, diameter, and volume of the fibroids were systematically measured, which enabled us to examine associations with these separate characteristics. Our sample size was sufficient to provide good precision for the main hypotheses. In addition, most women with a history of HSV-2 are unaware of their exposure status, making it very unlikely that women without fibroids who had a history of HSV-2 exposure would be more likely to enroll in the study than those without HSV-2; thus, there was limited potential for selection bias. Our study also had extensive data with which to assess potential confounding and minimal missing data. In addition, we conducted sensitivity analyses to evaluate potential bias.

Overall, based on our findings in a large cohort of young (ages 23–34 years) African-American women, HSV-2 seropositivity does not appear to be a risk factor for fibroids in this group. However, this does not suggest that other RTIs do not play a role in fibroid development. Further study of other serologically measured RTIs is still warranted, as are prospective studies of the relationship between RTIs and fibroid growth.

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