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. 2012 Feb 26;27(5):1504–1509. doi: 10.1093/humrep/des046

Hypertension and risk of uterine leiomyomata in US black women

RG Radin 1,*, L Rosenberg 1, JR Palmer 1, YC Cozier 1, SK Kumanyika 2, LA Wise 1
PMCID: PMC3329191  PMID: 22371286

Abstract

BACKGROUND

Previous studies have found a positive association between hypertension and risk of hysterectomy-confirmed uterine leiomyomata (UL). The association of hypertension with UL confirmed by ultrasound or other surgery is less clear.

METHODS

The present study evaluated the association of hypertension with UL incidence according to confirmation method (hysterectomy, other surgery or ultrasound) in the Black Women's Health Study, 1997–2007. We collected prospective data every 2 years on physician-diagnosed hypertension and UL in 22 530 premenopausal women. Validation sub-studies confirmed 99 and 96% of hypertension and UL self-reported diagnoses, respectively. Cox regression was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the association of hypertension and UL, adjusting for potential confounders.

RESULTS

During 172 162 person-years of follow-up, there were 6447 incident cases of UL confirmed by ultrasound (n = 5111), hysterectomy (n = 670) or other surgery (n = 666). Treated hypertension was associated with UL confirmed by hysterectomy (IRR = 1.32, 95% CI: 1.06, 1.63), but it was not associated with UL confirmed by ultrasound (IRR = 1.05, 95% CI: 0.96, 1.16) or other surgery (IRR = 1.13, 95% CI: 0.88, 1.46).

CONCLUSIONS

Treated hypertension was associated with UL confirmed by hysterectomy, but not UL confirmed by other methods (other surgery or ultrasound). These data suggest it is premature to conclude that hypertension is related to an increased risk of UL. Additional studies are needed to assess whether the association with hysterectomy-confirmed UL can be explained by other sources of bias, such as patient or physician preferences for specific types of medical care.

Keywords: fibroids, uterine, hypertension, African Americans, epidemiology

Introduction

Uterine leiomyomata (UL), or fibroids, are a major source of gynecologic morbidity, particularly among black women in the USA, who are more likely than white women to present with multiple and symptomatic UL and to be diagnosed in their early 30s (Kjerulff et al., 1996; Marshall et al., 1997; Baird et al., 2003). Age-specific cumulative incidence estimates of clinically relevant UL in black women exceed 30% by age 36 and 50% by age 48 (Baird et al., 2003). UL are the leading indication for hysterectomy in the USA, although only a fraction of cases progress to surgery (Wu et al., 2007). Two cross-sectional studies (Luoto et al., 2001; Silver et al., 2005), two case–control studies (Faerstein et al., 2001; Takeda et al., 2008) and a prospective cohort study (Boynton-Jarrett et al., 2005) have shown a positive association between hypertension and UL. Risk of UL was more strongly associated with treated hypertension than with untreated hypertension (Faerstein et al., 2001; Boynton-Jarrett et al., 2005). Three of the five studies were confined to surgically confirmed cases: two based on cases confirmed by hysterectomy (Luoto et al., 2001; Silver et al., 2005), and one based on cases confirmed by hysterectomy or other surgery (Takeda et al., 2008). The two studies that included both ultrasound- and hysterectomy-confirmed UL (Faerstein et al., 2001; Boynton-Jarrett et al., 2005) were conducted before newer surgical procedures such as myomectomy became common for UL treatment (Viswanathan et al., 2007). Therefore, it is uncertain whether hypertension is associated with UL that do not require surgical treatment or that require less invasive forms of surgery.

In a large prospective cohort study of premenopausal black women in the USA, we evaluated whether physician-diagnosed hypertension was associated with risk of incident UL and whether the association varied by method of case confirmation—hysterectomy, other surgery or ultrasound.

Materials and Methods

Study population

The Black Women's Health Study (BWHS) is an ongoing US prospective cohort study of 59 000 black women aged 21–69 years at baseline (1995). Participants were recruited from mailing lists of Essence magazine, black professional organizations and personal contacts of early respondents. Baseline data on medical and reproductive history, demographics and lifestyle factors were collected by self-administered mailed questionnaire, and follow-up questionnaires are mailed to participants every 2 years to update exposures and illnesses. Cohort retention through 2007 was 80%. The Institutional Review Board of Boston University Medical Center approved the study protocol.

Assessment of hypertension

The baseline and follow-up questionnaires asked whether the participant had been diagnosed with hypertension and whether she took diuretics or other blood pressure medications. Participants indicated a diagnosis of ‘high blood pressure (not during pregnancy)’ on the baseline and first two follow-up questionnaires (1997, 1999), and ‘hypertension (high blood pressure)’ on subsequent follow-up questionnaires (2001, 2003, 2005). We classified hypertension as ‘untreated’ if medications were not used and as ‘treated’ if the participant reported taking ‘diuretics (water pills)’, in addition to a hypertension diagnosis, or ‘blood pressure medication’.

We allowed exposure classification to vary over time: new information from follow-up questionnaires enabled participants to change from ‘no hypertension’ to ‘untreated hypertension’ or ‘treated hypertension’, or from ‘untreated hypertension’ to ‘treated hypertension’. In a validation study of treated hypertension in which we obtained medical records for 139 women, we confirmed the self-reported diagnosis in 99% of women. Confirmation was based on medical record evidence of initial systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg, or prescription for antihypertensive medication (Cozier et al., 2007). A question about ‘year of first diagnosis’ was included on all questionnaires, with the exception of the 1995 questionnaire on which women reported their age at diagnosis in categories (<30, 30–39, 40–49 and ≥50 years) and the 1997 questionnaire on which women reported a diagnosis before or after 1 March 1995.

Assessment of covariates

Information on age, state of residence, marital status, weight, parity, menopausal status, female hormone use, cigarette smoking, alcohol consumption, oral contraceptive use and medical history was collected on the 1995 and each follow-up questionnaire. Height, occupation and age at menarche were collected on the 1995 questionnaire.

Assessment of UL incidence

The follow-up questionnaires from 1999 to 2007 included a question on ‘uterine fibroids’ diagnosis in the previous 2 years (or ‘ever’ on the 2005 questionnaire), the year of the first diagnosis, and the diagnostic method. The 1999 questionnaire asked whether the diagnosis was confirmed by ‘pelvic exam’ and/or by ‘ultrasound/hysterectomy’; the 2001 questionnaire asked whether the diagnosis was confirmed by ‘pelvic exam’ and/or by ‘ultrasound or laparoscopy’; the 2003, 2005 and 2007 questionnaires asked whether the diagnosis was confirmed by ‘ultrasound’ and/or by ‘surgery (e.g. hysterectomy)’.

UL cases in the present analysis were defined as participants who indicated a diagnosis confirmed by ultrasound or surgery and a year of diagnosis ≥1997. Ultrasound, the standard used to confirm diagnoses in US clinical practice (Stewart, 2001), has high sensitivity (99%) and specificity (91%) relative to histologic evidence (Loutradis et al., 1990; Dueholm et al., 2002). Cases were classified according to the diagnostic method recorded on the questionnaire when they first reported their diagnosis. A surgically confirmed case was further classified as hysterectomy-confirmed if the participant reported a hysterectomy under a separate question on that survey. The main questionnaire did not elicit data on type of surgery for ‘other surgery’ cases. However, based on data from 4003 cases who completed a supplemental questionnaire in 2007–2009, the three most common surgeries reported by ‘other surgery’ cases were myomectomy (57%), dilatation and curettage (26%) and uterine artery embolization (17%). The index date was taken to be the midpoint of the reported calendar year of the diagnosis. Cases diagnosed by pelvic exam only (n = 525) were analyzed as non-cases because of the uncertainty of this diagnostic method (Stewart, 2001). We conducted a validation study of self-reported UL confirmed by ultrasound or surgery in 248 randomly selected cases and verified the self-report in 96% of the 127 women for whom we obtained medical records (Wise et al., 2005a).

Restriction criteria

Premenopausal women free of UL constituted the population at risk because UL are rare after menopause (Stewart, 2001). Follow-up began with the start of the second questionnaire cycle in 1997 because the 1999 questionnaire was the first to elicit information on method of UL diagnosis. Of 25 225 participants who completed the 1997 questionnaire and were at risk for UL, we excluded women who did not report a blood pressure screening in the previous 2 years (n = 938) or were missing data on hypertensive status (n = 37); cases with missing data on UL diagnosis method (n = 112) or year (n = 139); women who refused participation or were lost-to-follow-up after 1997 (n = 915) and women with missing covariate data (n = 554), leaving 22 530 women for analysis. Excluded participants had lower educational attainment (mean number of years = 14.3 versus 14.9) and were more likely to smoke currently (18 versus 14%), but were similar to included participants with respect to risk factors for UL such as age, parity, years since last birth and BMI. Comparison of hypertension prevalence would be uncertain due to the substantial proportion of excluded participants who did not report a recent screening for high blood pressure.

Data analysis

We estimated incidence rate ratios (IRR) and 95% confidence intervals (95% CI) for hypertension and UL risk using Cox regression models stratified by age and questionnaire cycle. Participants contributed person-time from 1 March 1997 until they either reported a UL diagnosis or were censored due to menopause, loss to follow-up, death or the end of follow-up (1March 2007). A covariate was included in multivariable analyses if it was an established risk factor for UL based on the literature or if it was a suspected risk factor that was associated with the exposure at baseline. The multivariable model controlled for age (years), questionnaire cycle (1997–1999, 1999–2001, 2001–2003, 2003–2005 and 2005–2007), parity status (parous, nulliparous), age at first birth (years), years since last birth (<5, 5–9, 10–14, 15–19 and ≥20), ever use of oral contraceptives (no, yes), age at first oral contraceptive use (years), ever use of female hormones (no, yes), age at menarche (years), BMI (<20, 20–24, 25–29, 30–34 and ≥35 kg/m2), type 2 diabetes (no, yes), cigarette smoking (never, current and former), current alcohol consumption (<1, 1–6 and ≥7 drinks/week), US region of residence (West, Northeast, South, Midwest and other), marital status (married/living as married, single and divorced/separated/widowed), occupation (white collar, not white collar, unemployed and missing) and education (≤12, 13–15, 16 and ≥17 years). Time-varying covariates were updated using an Anderson-Gill data structure (Therneau, 1997).

Based on previous evidence that the association between diastolic blood pressure and UL was stronger among women with BMI ≥27 kg/m2 (Boynton-Jarrett et al., 2005), we examined obesity as an effect modifier. Statistical interaction on the multiplicative scale was assessed using the likelihood ratio test, comparing models with and without two cross-product terms: treated hypertension with BMI ≥30 kg/m2 and untreated hypertension with BMI ≥30 kg/m2 (Hosmer and Lemeshow, 1989). Also, we examined the risk of UL in relation to categories of years since diagnosis of hypertension (<2, 2–4, 5–9 and ≥10 years). The midpoint of each category of years since diagnosis was modeled as a linear variable to calculate a two-sided test for linear trend. Statistical analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC, USA).

Results

At baseline, treated hypertension was positively correlated with age, BMI, parity, time since last birth, living in the South and Midwest, smoking, female hormone use and type 2 diabetes, and inversely associated with age at first birth, vigorous exercise, ever use of oral contraceptives, white-collar occupation and marital status (Table I). Correlations between untreated hypertension and baseline characteristics were generally similar, but weaker in magnitude. Of the 1454 women with untreated hypertension at baseline, 32% changed their status to treated hypertension over follow-up.

Table I.

Characteristics of 22 530 premenopausal women according to report of hypertension at baseline: BWHS, USA, 1997a.

Hypertensive status
No Yes, untreated Yes, treated with medication
Number 19 233 1454 1843
Age, years (mean) 33.8 34.3 39.6
Married (%) 40 37 35
Education, years (mean) 14.9 14.6 14.6
White-collar occupation (%) 55 49 51
Region of residence in USA (%)
 West 18 18 16
 Midwest 22 22 25
 Northeast 27 29 24
 South 33 31 36
BMI, kg/m2 (mean) 27.2 30.6 33.1
Age at menarche, years (mean) 12.4 12.3 12.1
Parous (%) 57 55 59
Age at first birth, years (mean)b 23.3 22.8 22.4
Time since last birth, years (mean)b 9.3 9.5 10.3
Ever used oral contraceptives (%) 82 80 77
Age, first oral contraceptives use (mean)c 18.9 18.9 18.9
Ever used female hormones (%) 4 5 8
Engage in vigorous exercise (%) 63 59 50
Current smoker (%) 14 16 16
Alcohol intake, drinks/week (mean) 1.3 1.6 1.4
Type 2 diabetes (%) 2 3 9
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aMeans and percentages are standardized to the age distribution of the cohort in 1997.

bRestricted to 12 720 participants who were parous at baseline.

cRestricted to 18 328 participants who reported having used oral contraceptives at baseline.

During 172 162 person-years of follow-up, there were 6447 incident cases of UL confirmed by ultrasound (n = 5111), hysterectomy (n = 670) or other surgery (n = 666) (Table II). Overall, there was a weak positive association between treated hypertension and risk of UL (IRR = 1.08, 95% CI: 1.00, 1.16). The association was stronger among cases confirmed by hysterectomy (IRR = 1.32, 95% CI: 1.06, 1.63), but was consistent with the null hypothesis among cases confirmed by ultrasound (IRR = 1.05, 95% CI: 0.96, 1.16) or other surgery (IRR = 1.13, 95% CI: 0.88, 1.36). Untreated hypertension was positively associated with risk of UL confirmed by ultrasound, but not by other methods (ultrasound: IRR = 1.17, 95% CI: 1.04, 1.30; hysterectomy: IRR = 0.71, 95% CI: 0.49, 1.03; other surgery: IRR = 1.13, 95% CI: 0.88, 1.36). No association was observed between years since hypertension diagnosis and UL risk (data not shown).

Table II.

Hypertension in relation to incident UL: BWHS, USA, 1997–2007.

Cases Person-years Model 1 IRR (95% CI)a Model 2 IRR (95% CI)b
All cases 6447 172 162 — —
 No hypertension 5121 138 750 1.00c 1.00c
 Untreated hypertension 453 11 359 1.08 (0.98, 1.19) 1.09 (0.99, 1.20)
 Treated hypertension 873 22 052 1.08 (1.00, 1.16) 1.08 (1.00, 1.16)
 Cases confirmed by hysterectomy 670 172 162
  No hypertension 488 138 750 1.00c 1.00c
  Untreated hypertension 32 11 359 0.76 (0.53, 1.09) 0.71 (0.49, 1.03)
  Treated hypertension 150 22 052 1.44 (1.19, 1.73) 1.32 (1.06, 1.63)
 Cases confirmed by other surgery 666 171 404
  No hypertension 531 138 188 1.00c 1.00c
  Untreated hypertension 47 11 322 1.09 (0.81, 1.47) 1.06 (0.78, 1.45)
  Treated hypertension 88 21 895 1.15 (0.91, 1.45) 1.13 (0.88, 1.46)
 Cases confirmed by ultrasound only 5111 170 635
  No hypertension 4102 137 568 1.00c 1.00c
  Untreated hypertension 374 11 264 1.12 (1.00, 1.24) 1.17 (1.04, 1.30)
  Treated hypertension 635 21 803 1.01 (0.93, 1.10) 1.05 (0.96, 1.16)
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aIRR and 95% CIs adjusted for age and questionnaire cycle.

bIRR and 95% CI adjusted for age, questionnaire cycle, parity status, age at first birth, years since last birth, ever use of oral contraceptives, age at first oral contraceptives use, ever use of female hormones, age at menarche, BMI, type 2 diabetes, cigarette smoking, current alcohol consumption, US region of residence, marital status, occupation and education.

cReference group.

In analyses stratified by BMI, the association between treated hypertension and hysterectomy-confirmed UL appeared stronger among women with BMI ≥30 than in women with BMI <30, although there was no significant statistical interaction (Table III). In separate analyses, UL confirmed by other surgery or ultrasound were not associated with treated hypertension, regardless of BMI (Table III).

Table III.

Hypertension in relation to incident UL, stratified by BMI: BWHS, USA, 1997–2007.

Cases Person-years Model 1 IRR (95% CI)a Model 2 IRR (95% CI)b P-value, interactiond
Cases confirmed by ultrasound or other surgery 5777 171 404
 BMI <30
  No hypertension 3260 97 478 1.00c 1.00c P= 0.93
  Untreated hypertension 218 5 788 1.12 (0.98, 1.29) 1.13 (0.99, 1.30)
  Treated hypertension 297 8907 1.03 (0.92, 1.17) 1.04 (0.92, 1.18)
 BMI ≥30
  No hypertension 1373 41 272 1.00c 1.00c
  Untreated hypertension 203 5571 1.11 (0.96, 1.29) 1.12 (0.97, 1.30)
  Treated hypertension 426 13 145 1.03 (0.92, 1.15) 1.05 (0.94, 1.18)
Cases confirmed by hysterectomy 670 172 162
 BMI <30
  No hypertension 338 97 478 1.00c 1.00c P= 0.19
  Untreated hypertension 17 5788 0.79 (0.49, 1.29) 0.79 (0.48, 1.31)
  Treated hypertension 53 8907 1.25 (0.93, 1.68) 1.16 (0.84, 1.58)
 BMI ≥30
  No hypertension 150 41 272 1.00c 1.00c
  Untreated hypertension 15 5571 0.73 (0.43, 1.24) 0.62 (0.36, 1.08)
  Treated hypertension 97 13 145 1.56 (1.20, 2.03) 1.38 (1.01, 1.86)
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aIRR and 95% CI adjusted for age and questionnaire cycle.

bIRR and 95% CI adjusted for age, questionnaire cycle, parity status, age at first birth, years since last birth, ever use of oral contraceptives, age at first oral contraceptives use, ever use of female hormones, age at menarche, BMI, type 2 diabetes, cigarette smoking, current alcohol consumption, US region of residence, marital status, occupation and education.

cReference group.

dLikelihood ratio test with two degrees of freedom comparing Model 2 with a model additionally adjusted for two variables indicating the cross-products of treated hypertension and BMI ≥30 and untreated hypertension and BMI ≥30.

Discussion

In this prospective cohort study of black women in the USA, there was a small positive association between hypertension treated with medication and risk of UL overall. However, when we examined the association according to method of confirmation, only hysterectomy-confirmed UL was positively associated with treated hypertension. No association was found between treated hypertension and UL confirmed by other surgery or ultrasound.

The positive association between treated hypertension and hysterectomy-confirmed UL agrees with results from previous cross-sectional (Luoto et al., 2001; Silver et al., 2005), case–control (Faerstein et al., 2001; Takeda et al., 2008) and prospective cohort (Boynton-Jarrett et al., 2005) studies. The association of hypertension with UL confirmed by ultrasound only has not been assessed previously. Two studies investigated the association of hypertension with risk of UL detected by either ultrasound or hysterectomy, and both found a positive association (Faerstein et al., 2001; Boynton-Jarrett et al., 2005). A stronger association with hysterectomy-confirmed UL (IRR = 1.50, 95% CI: 1.26, 1.78) appeared to drive the overall association with ultrasound- or hysterectomy-confirmed UL (IRR = 1.24, 95% CI: 1.13, 1.40) in the study of Boynton-Jarrett et al. (2005). The proportion of cases confirmed by hysterectomy in our study (12%) was lower than those reported by Faerstein et al. (2001) (27%) and Boynton-Jarrett et al. (2005) (22%), which may explain why we observed only a weak positive association between hypertension and UL confirmed by all methods.

Although validation of self-reported UL and hypertension diagnoses in our cohort indicated high accuracy of self-report (96 and 99%, respectively), we cannot rule out the possibility that misclassification of exposure and outcome affected our results. However, numerous features of the study helped to minimize the impact of misclassification on the results. To reduce potential for undiagnosed hypertension in the ‘unexposed’ (reference) group, we restricted the analytic sample to women who reported a recent blood pressure screening. We classified treated hypertension (primary exposure) separately from untreated hypertension, and compared both groups with a common referent group of no physician-diagnosed hypertension. Given the high accuracy of self-reported hypertension, the study's prospective design (i.e. hypertension reported prior to the diagnosis of UL), and the blood pressure screening restriction, misclassification of hypertension is likely to be small and non-differential. Although non-differential misclassification is expected to attenuate results by decreasing study power (Goldberg, 1975), the large study size provided excellent power to detect small effect sizes. Finally, by requiring confirmation of UL by ultrasound or surgery, we increased the specificity of our outcome variable. With very high specificity of outcome classification, false negatives will have a negligible impact on the rate ratio in the presence of non-differential misclassification (Rothman et al., 2008).

A proposed biological mechanism similar to that of atherogenesis motivated initial epidemiologic studies of the association of hypertension and UL (Ross, 1986; Stewart and Nowak, 1998; Faerstein et al., 2001; Flake et al., 2003; Arslan et al., 2005). If hypertension contributes to abnormal vasculature (Stewart and Nowak, 1996) and UL growth (Wegienka et al., 2003), this may lead to increased severity of UL and therefore to hysterectomy. It is also possible that hypertension's effect on symptomatic UL may be stronger in the presence of obesity, which was also positively associated with hysterectomy-confirmed UL in this sample (Wise et al., 2005a). If obesity contributes to UL growth by increasing the concentration of circulating sex hormones (Dorgan et al., 1995; Schwartz et al., 2000; Yakar et al., 2006) and cytokines (Hotamisligil, 2006), this might explain the observed association between hypertension and hysterectomy-confirmed UL among obese women. However, we would have expected to find increased risks for all surgically confirmed cases, not only the hysterectomy-confirmed cases.

Alternatively, surveillance bias may explain the association of hypertension with incidence of hysterectomy-confirmed UL. Participants were not systematically screened for UL, and it was not possible to ascertain the time of tumor onset (Schwartz, 2001). Frequent office visits to monitor blood pressure would increase the opportunity for detection of UL in women with treated hypertension. The recommended frequency of doctor's visits for treated hypertension varies, from once monthly for hypertension that is not well-controlled, to every three to 6 months for hypertension that is controlled (Chobanian et al., 2003). If women with BMI ≥30 were more likely to have undiagnosed UL at baseline, this may explain the stronger association of treated hypertension and hysterectomy-confirmed UL among obese women. We were not able to assess the potential for surveillance bias because we did not collect data on the frequency of doctor's office visits per year.

Greater opportunity for and acceptance of invasive UL treatment is another potential explanation for the association of treated hypertension with hysterectomy-confirmed UL. An evaluation of whether this bias explains the observed results would have required data on case severity and other factors that influence the physician's case management and the participant's decision for undergoing hysterectomy.

In conclusion, treated hypertension was positively associated with incidence of UL confirmed by hysterectomy, but not by other surgery or ultrasound. These data suggest it is premature to conclude that hypertension is related to an increased risk UL. More consistent evidence from several studies is needed. It would be desirable for future studies to assess whether the association with hysterectomy-confirmed UL is related to other sources of bias, such as patient or physician preferences for specific types of medical care.

Authors’ roles

R.G.R., L.R., J.R.P., Y.C.C., S.K.K. and L.A.W.: study design; L.R., J.R.P., Y.C.C. and L.A.W.: study execution; R.G.R. and L.A.W.: analysis; R.G.R.: manuscript drafting; R.G.R., L.R., J.R.P., Y.C.C., S.K.K. and L.A.W.: critical review.

Funding

This project was supported by NIH grants CA058420 and HD055211. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflict of interest

None declared.

Acknowledgements

We gratefully acknowledge the contributions of BWHS participants and staff. This paper was presented as an abstract at the 43rd Annual Meeting of the Society for Epidemiologic Research in Seattle, Washington, 23–26 June 2010.

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