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

Abstract and Introduction

Abstract

For decades reproductive tract infections (RTIs) have been hypothesized to play a role in uterine fibroid development. The few previous studies conducted used self-reported history of RTIs and had inconsistent findings. We investigated this hypothesis further using serological analysis, an immunological measure of past exposure. We focused on herpes simplex virus type 2 (HSV-2) because prior published data have suggested a possible association with fibroids, and serology for HSV-2 is much more sensitive than self-report. We used cross-sectional enrollment data from African-American women enrolled in a prospective study of fibroid incidence and growth (recruited 2010–2012) in the Detroit, Michigan, area. The women were aged 23–34 years and were screened for fibroids using a standardized ultrasound examination at their enrollment. Age- and multivariable-adjusted logistic regression models were used to estimate odds ratios. Of 1,696 participants, 1,658 had blood samples and HSV-2 serology results; 22% of participants with serology results had fibroids. There was no significant association between HSV-2 seropositivity and the presence of fibroids (multivariable-adjusted odds ratio = 0.94, 95% confidence interval: 0.73, 1.20), nor were there any associations with size of the largest fibroid, number of fibroids, or total fibroid volume. Our data provide no evidence for an influence of HSV-2 exposure on fibroid risk in young African-American women. Further study of other serologically measured RTIs is warranted.

Introduction

Uterine fibroids are among the most common gynecological conditions affecting women in the United States during their reproductive years.[1] Based on ultrasound screening of randomly selected women, the estimated cumulative incidence of fibroid tumors by age 50 years is more than 80% for African-American women and close to 70% for white women.[2] Symptoms resulting from fibroids (pain, severe bleeding, and reproductive problems) are the leading reason for hysterectomy in the United States, and the total annual costs of fibroids are as high as $34 billion.[3]

Fibroids are hormone-dependent, benign tumors of the uterine smooth muscle. Their etiological causes are largely unknown, but established risk factors include African-American heritage (African Americans are 2–3 times as likely as white women to have clinically recognized fibroids[2]), older age (up to the age of menopause), younger age at menarche, and nulliparity.[4–6] Three studies have found that progestin-only injectables (such as depot medroxyprogesterone acetate (DMPA)) are protective.[5,7,8] Heavier alcohol use may be a risk factor, although the number of studies is small.[9,10]

A hypothesis was raised decades ago that reproductive tract infections (RTIs) may play a role in fibroid development.[11] Both RTIs and fibroids disproportionately burden African-American women, and certain RTIs can lead to conditions such as chronic pelvic infection that could result in inflammatory reactions.[11] This hypothesis is consistent with another theorized mechanism of fibroid pathogenesis in which infection can stimulate an inflammatory immune response that can facilitate the initiation of tissue damage, resulting in tissue repair or regeneration (increased extracellular matrix, cell proliferation, decreased apoptosis), leading to the formation and growth of uterine fibroids.[12,13] Furthermore, fibroids were found to be associated with serologically determined Chagas disease (caused by a protozoan parasite),[14] and Epstein-Barr virus was found to infect smooth muscle cell tumors at sites outside of the uterus.[15]

However, the limited data on associations between RTIs and fibroid risk have yielded inconsistent findings.[4,16,17] One of the primary aims for undertaking the Study of Environment, Lifestyle, and Fibroids (SELF), a large study of fibroids in African-American women, was to fill this data gap.[18] The data from prior studies suggested positive associations between fibroids and pelvic inflammatory disease,[16] Chlamydia,[16] genital herpes,[4] trichomonas,[4] bacterial vaginosis,[4,17] and syphilis.[4] We recently published self-reported RTI data from SELF that showed no strong associations with fibroids.[17] We did find that women reporting a history of bacterial vaginosis had somewhat elevated odds of multiple fibroids (≥2) and larger total fibroid volume (≥2 cm3), and women reporting a history of chlamydia tended to have fewer and smaller fibroids.[17] However, all of these previous reports measured RTI history with questionnaire data, which can be plagued by recall error as well as misclassification due to the asymptomatic nature of most RTIs.[19–22] An immunological measure of exposure, namely serological analysis (diagnostic identification of antibodies in the serum that remain after infection), would provide a more accurate assessment of exposure than self-reported RTI history.

Herpes simplex virus type 2 (HSV-2), the main cause of genital and neonatal herpes, is a common RTI in the United States.[23] Compared with women of other racial/ethnic groups in the United States, African-American women have the highest seroprevalence of HSV-2 (50% for 14- to 49-year-olds between 2007 and 2010).[24] Other main risk factors for HSV-2 include higher numbers of sexual partners, heavy alcohol use, low socioeconomic status, being unpartnered rather than married or cohabiting, and lack of consistent condom use.[24–28] Also, DMPA use may increase risk of HSV-2 seroconversion,[29,30] and age at menarche has been found to be associated with HSV-2[31] and has been identified as a predictor of sexual behavior that is highly associated with HSV-2.[32,33]

HSV-2 antibodies have been shown to persist for years after infection,[34] and serological testing for HSV-2 can be done sensitively and specifically for past exposure to HSV-2.[35] Cell culture and polymerase chain reaction are the recommended laboratory tests for people who have active lesions or ulcers present.[36] However, most HSV-2 infections are asymptomatic or unrecognized (in a study by Fanfair et al.,[24] more than 85% of seropositive African-American women reported no history of diagnosis). Thus, seropositivity to HSV-2 is the best estimate of past, cumulative exposure.[24,25]

Building upon previous work, in which a positive association between self-reported HSV-2 and fibroids was found,[4] our primary aim was to investigate the relationship between HSV-2 and fibroids in a large cohort with ultrasound screening for fibroids and serological measurement of exposure. This study was, to our knowledge, the first to investigate the association of fibroids with HSV-2 exposure assessed serologically. We hypothesized that women seropositive for HSV-2 would have a higher prevalence of fibroids than women seronegative for HSV-2. We also explored the relationship between HSV-2 seropositivity and number, size, and total volume of fibroids.

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