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Annals of Epidemiology 23 (2013) 286e290

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Annals of Epidemiology

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Self-reported family history of leiomyoma: not a reliable marker of high risk

Tina Marie Saldana PhD a, Malana Moshesh MDb, Donna Day Baird PhD b,*

a Social & Scientific Systems, Inc., Durham, NCbNational Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC

a r t i c l e i n f o

Article history:Received 5 December 2012Accepted 6 March 2013

Keywords:Uterine leiomyomaFibroidsFamily historyEpidemiologyGeneticsEpidemiology

* Corresponding author. Epidemiology, NationalHealth Sciences, NIH, 111 T.W. Alexander Dr., Research

E-mail address: baird@niehs.nih.gov (D.D. Baird).

1047-2797/$ e see front matter Published by Elsevierhttp://dx.doi.org/10.1016/j.annepidem.2013.03.003

a b s t r a c t

Purpose: To examine the importance of self-reported family history of uterine leiomyoma (fibroids) asa marker of risk.Methods: Women, aged 35 to 49, were randomly selected from the membership of a large, urban healthplan. Participants completed a self-administered questionnaire about family history of fibroids. Ultra-sound screening for fibroids followed, regardless of whether participants had been previously diagnosed(660 black, 412 white). Data for each ethnic group were analyzed separately using Poisson regression.Results: In both ethnic groups, women who reported a family history of fibroids had an elevated risk offibroids compared with those without family history. However, no elevated risk was apparent for caseswho did not know they had fibroids when they reported the family history information.Conclusions: Many women may first learn about their family history of fibroids when discussing theirown clinical diagnosis with family members. Such bias would invalidate self-reported family history asa predictor of fibroid risk. As new pharmacologic treatments for fibroids are developed, women at highrisk of fibroids would benefit from early screening and pharmacologic treatment to delay development oflarge fibroids and reduce the need for invasive treatments. Self-reported family history is not useful foridentifying high-risk women.

Published by Elsevier Inc.

Introduction

Fibroids are the most common reproductive tract tumor inwomen, and the leading indication for hysterectomy in the UnitedStates [1, 2]. Fibroids contribute to many common gynecologicproblems, including pelvic pain, and menorrhagia, the latter ofwhich can lead to life-threatening anemia [3]. U.S. medical costsassociated with this condition are estimated at $4 to $10 billionannually [4]. The tumors are clonal in growth [5], and a minoritydevelop specific cyctogenetic changes. Despite the strides inetiologic research, this condition remains understudied [6, 7], andestablished risk factors are few [7]. Although a premenopausalhormonal milieu is needed, what triggers tumor initiation andregulates growth remains a mystery. However, there has beena welcome research push for new, noninvasive treatments [8, 9].As these become available, it will be important to identify high-risk women so that disease can be detected early.

For many conditions, family history is used as a marker of highrisk [10]. For example, breast cancer in first-degree relatives is one

Institute of EnvironmentalTriangle Park, NC 27709.

Inc.

of the items of the Gail score, a set of questions used to predictbreast cancer risk [11]. However, few studies have investigated thepredictive value of family history data for fibroids [12e14] (Table 1).These previous studies reported significant associations betweenself-reported family history of fibroids and fibroid risk, but noneincluded risk estimates for African Americans, the group in theUnited States with the highest prevalence of fibroids [7]. AfricanAmericanwomen are more likely thanwhites to develop fibroids ata younger age [15], and they have a greater risk of significantsymptoms leading to surgery [16, 17]. In addition, they may be lesslikely thanwhites to benefit from regression of their disease duringthe perimenopausal years [18]. Reasons for these ethnic differencesare largely unknown, and many believe that genetics may bea contributing factor.

Genetic causes of fibroids are largely unknown, except forfumarate hydratase gene mutations, which are seen in rare familialsyndromes, but account for only a small fraction of the huge burdenof fibroid tumors in women [19]. Twin studies suggest significantheritability of fibroids [20e22], two genome-wide associationstudies implicate possible loci [23, 24], and a linkage study indicatesthat HMGA-2 is a candidate gene [25], but findings have not beenreplicated. Thus, although there are certainly heritable contribu-tions to development of common, nonsyndromic fibroids, thereare no clinically available markers at this time.

Table 1Summary of studies evaluating association between family history and fibroids

Study Study design Racial make up Fibroid definition Family history definition Model adjusted OR or RR (95% CI)

Templeman et al. [12] Prospective cohort80,204 eligible participantsn ¼ 1790 surgical casesafter 11-yr follow-up

White-81%*

Black-4%Latina-7.4%Asian-3%.

Pathologic diagnosis Mother or sister hadfibroidsSelf-administratedquestionnaire

Race and age RR: 1.42 (1.25e1.61)

Sato et al. [13] Hospital basedn ¼ 144 surgicallydiagnosed cases; n ¼ 288controls recruited fromcancer screening program

100% Japanese Pathologic diagnosis First-degree relatives hadfibroidsSelf-administratedquestionnaire

Stratified by parity <2 birthsOR: 5.81 (2.32e14.57)�2 birthsOR: 2.11 (1.19e3.74)

Van Voorhis et al. [14] Hospital basedn ¼ 81 casesn ¼ 103 controlsRecruited women whounderwent hysterectomy

95% white Pathologic diagnosis Mother had fibroidsSelf-administratedquestionnaire

Parity and age OR: 2.85 (1.25e6.52)

CI ¼ confidence interval; OR ¼ odds ratio; RR ¼ relative risk.* Racial breakdown for cohort obtained from Fertil Steril 2009;92(4):1436e46.

Fig. 1. Population step-down for analysis sample.

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We have examined the evidence that self-reported familyhistory of fibroids is associated with presence of fibroids in a largesample of black and white women [26]. This study also offers anopportunity to investigate possible bias in family history studies offibroids. Biased reporting could arise because a diagnosis of fibroidsmay lead women to seek out information from family membersabout their own experiences with fibroids, while womenwho havenever been diagnosed may remain unaware of a family history. TheNational Institute of Environmental Health Sciences Uterine FibroidStudy included a questionnaire that asked women about theirfamily history of fibroids and subsequently screened them forfibroids with standardized ultrasound examinations regardless ofany prior diagnosis. This allows us to evaluate the effects of possibledifferential self-report that could arise depending on knowledge ofone’s fibroids.

Methods

Study population

The National Institute of Environmental Health Sciences UterineFibroid Study was designed to determine the prevalence of fibroidsbased on ultrasound screening. Study staff enrolled randomlyselected women, 35 to 49 years old, who were members ofa prepaid health plan [26]. For this analysis, women were excludedif they did not self-identify as African American/black or white, ifthey did not complete a mail questionnaire that included the familyhistory questions, and if fibroid status was missing. The resultingsample included 1072 women (660 African American, 412 white;Fig. 1). The research was approved by the National Institute ofEnvironmental Health Sciences and George Washington UniversityHuman Subject Review Boards. Participants gave informed consent.

Fibroid status assessment

To assess fibroid status, premenopausal women were asked toundergo transvaginal and transabdominal ultrasonography as partof the enrollment clinic visit. Experienced sonographers weretrained for the protocol and worked under the direct supervision ofa radiologist. Fibroids of 0.5 cm or greater diameter were identified.Participants who had recently undergone an ultrasound examina-tion at the clinic for clinical purposes were not asked to repeat anexamination for the study. For these women, data on presence offibroids and size of largest were abstracted from the clinic radiologyreports. Of the 913 ultrasound examinations (85% of the totalsample of 1072), 198 were recent clinic examinations (18% of the

total sample). In addition, 93 women had had a prior uterinesurgery, and we abstracted fibroid status data from pathologyrecords for these women (9% of the total sample). For 65 partici-pants who did not complete ultrasound screening examinationsand for 1 woman whose examination was indeterminate, weaccepted their self-report of a prior diagnosis (6% of the totalsample). Self-report of “no fibroids” was not accepted becauseundiagnosed fibroids were common [26]. Primary statistical anal-yses were repeated without women whose fibroid status relied onself-report, and results were essentially unchanged.

Family history assessment

Participants were asked whether either their mother or a sisterhad fibroids. Those with a positive response for either wereconsidered to have a positive family history.

Table 2Characteristics of participants in the family history analysis of the uterine fibroidstudy

Characteristic African Americans(n ¼ 660)

Whites(n ¼ 412)

No. % No. %

Fibroid statusNo 151 23 193 47Yes (newly detected fibroids) 177 27 132 32Yes (self-reported and study

confirmed fibroids)332 50 87 21

Age (yrs)35e39 215 32 128 3140e44 228 35 137 3345e49 217 33 147 36

Education�High school or some college 461 70 49 12College degree 76 11 65 16College plus additional 52 8 72 17Postgraduate 71 11 226 55

Age at menarche (yrs)<11 79 12 19 511 115 17 62 1512 178 27 111 2713 149 23 138 3314 60 9 48 12>14 76 12 32 8Missing 3 2

ParityNo 139 21 238 58Yes 521 79 174 42

No. of full-term pregnancies delivered after age 24 years0 339 51 264 641 205 31 58 14�2 116 18 90 22

Body mass index<30 158 24 242 5930e35 195 30 96 23�35 304 46 74 18

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Statistical analysis

All analyses were conducted separately for blacks and whites.Descriptive statistics (percentages) were calculated for categoricalvariables. Because of the high prevalence of fibroids, although oddsratios (ORs) can be used to evaluate the significance of an associ-ation, they overestimate relative risk [27, 28]. Log-binomial modelscan be used to provide risk estimates but sometimes these modelsdo not converge [28, 29], as was the case with our data. We useda recommended alternative, the modified Poisson model withrobust error variances [30], to estimate the relative risk associatedwith reported family history. Risk ratios (RR) and 95% confidenceintervals (CI) were calculated. Estimates were adjusted for age andother factors previously found to be associated with fibroids in thisstudy population (age at menarche, parity after age 24, body massindex, physical activity) [31]. To investigate how family historyestimates might be affected by participant’s knowledge of her ownfibroid status, we subdivided the cases into two groups dependingon whether or not they had had a clinical diagnosis of fibroidsbefore reporting the family history information. To investigate howfamily history associations might be affected by severity of thecondition, we limited cases to those with fibroids under 4 cm inlargest diameter (numbers were not sufficient to examine womenwith fibroids �4 cm). Within that group of women with relativelyhomogeneous severity, we again compared associations for thetwo case groups based on whether or not they had had a clinicaldiagnosis of fibroids before reporting the family history informa-tion. Additional sensitivity analyses were conducted to investigatethe influence of “opportunity” for a positive family history basedon having a mother still living or having at least one sister overage 30 (an age at which fibroids might potentially have beendiagnosed). All analyses were conducted using SAS 9.2.1 (SAS, Inc.,Cary, NC).

Missing 3Smoking statusNever 315 47 238 58Past 156 24 144 35Current 189 29 30 7

Physical activityLow (<185) 249 38 107 26Medium 212 32 144 35High 101 16 83 20Very high 94 14 77 19Missing 4 1

Family history of fibroidsNone 319 48 211 51Yes 253 38 108 26Missing 88 14 93 23

Results

Of the 1072 women included in this analysis, there were 660African Americans and 412 whites (Table 2). Seventy-seven percentof African American women and 53% of white women had fibroids.Many of the cases were newly identified by study screening (35% ofAfrican American cases and 60% of white cases). These cases did notknow they had fibroids when they provided family history data.Thirty-eight percent of African Americans and 26% of whitesreported a family history of fibroids.

The age-adjusted relative risk of fibroids associated with self-reported family history was significantly elevated for both AfricanAmericans (RR, 1.2; 95% CI, 1.1e1.3) and whites (RR, 1.3; 95% CI,1.1e1.6). Adjusting estimates further for age at menarche, parityafter 24 years of age, body mass index, and physical activity showedlittle change (Table 3).

We then looked at the family history associations after sub-dividing the cases according to whether women knew they had

Table 3Associations of self-reported family history of fibroids and fibroids

Family history* African Americans

No.y RR 95% CI aRR 95

None 226:93 1.00 Ref. 1.0 ReYes 211:42 1.2 1.1e1.3 1.2 1.1Missing 72:16 1.2 1.0e1.3 1.2 1.0

aRR ¼ adjusted for age, age at menarche, parity after age 24 years, body mass index, phy* Family history: Mother or sister or both had fibroids.y Number of women with fibroids: Number of women without fibroids, the multivaria

covariate data.

fibroids when providing family history information. The adjustedRRs for the two groups are shown in Figure 2. There was a strongfamily history association when cases included those with priorknowledge of their fibroids, but no evidence of a family historyassociation when cases were limited to those who reported family

Whites

% CI No.y RR 95% CI aRR 95% CI

f. 101:110 1.0 Ref. 1.0 Ref.e1.3 69:39 1.3 1.1e1.6 1.3 1.1e1.5e1.3 49:44 1.1 0.9e1.4 1.1 0.9e1.4

sical activity; Ref. ¼ reference group; RR ¼ relative risk adjusted for age of woman.

ble-adjusted analysis included 10 fewer blacks and 3 fewer whites owing to missing

Fig. 2. The association between self-reported family history of fibroids stratified byprior knowledge of fibroids status among black and white women.

T.M. Saldana et al. / Annals of Epidemiology 23 (2013) 286e290 289

history before learning that they had fibroids (cases without priorknowledge). This pattern was seen for both African American andwhite women.

Newly detected fibroids tend to be smaller than previouslydiagnosed fibroids [26], suggesting less severe disease. Therefore,we considered whether the lack of a family history associationamong the women with newly detected fibroids might be becausethey had less severe disease (i.e., family history might only beimportant in more severe disease). For this analysis, we excludedthose with the larger fibroids (those with more severe disease), andlimited analyses to those with fibroids smaller than 4 cm in diam-eter (a sample of women with less severe disease). Although thesample size is reduced, the same general pattern emerged. Thefamily history associationwas apparent when cases were limited tothose with prior knowledge, but there was no association whencases were limited to newly detected cases (cases who did notknow they had fibroids when they reported family history infor-mation; Fig. 3).

Finally, we considered the impact of “opportunity” for ob-taining family history information (having a living mother and/ora sister �30). The results changed little when we adjusted for theopportunity variables (living mother, sister �30) or when weexcluded the womenwith little opportunity (7.7% of whites, 5.3% ofblacks).

Discussion

A positive family history was associated with a 20% increasedrisk of having fibroids for African American and a 30% increased risk

Fig. 3. The association between self-reported family history of fibroids stratified byprior knowledge of fibroids status for less severe fibroids (<4 cm diameter) amongblack and white women.

for white women in our sample. However, knowledge of one’sfibroids seemed to influence self-report of family history. Theassociation was attenuated and no longer significant when theanalysis was limited to a case group that self-reported familyhistory before learning they had fibroids. Severity (inferred byfibroid size) did not seem to account for the observed attenuation ofeffect. Thus, it is possible that manywomen learn about their familyhistory of fibroids only after being diagnosed themselves. A diag-nosis may spur discussions with family members about thecondition, after which the family history is revealed. Women whohave not been diagnosed may be unaware of their family historyand thus underreport it.

Three previous studies have examined family history of fibroids[12e14] (Table 1). Our results from both black andwhite full modelswere similar to those from the prospective cohort study [12]. Forcomparison, we also calculated ORs with logistic regression. Bothblack (n ¼ 660) and white (n ¼ 412) women showed an approxi-mate two-fold elevated odds of fibroids for those self-reportingfamily history of fibroids compared with those with no familyhistory of fibroids (blacks: OR, 2.07 [95% CI, 1.4e3.2]; whites: OR,1.8[95% CI, 1.1e3.0]). These results are similar to the prior case-controlstudies [13, 14] (Table 1). Although all prior studies found signifi-cant associations, they could have suffered from the same bias aswe seemed to have observed in our data (i.e., nondiagnosed womenmay be less informed about their family history of fibroids thanwomen with a diagnosis).

Two small studies raise the possibility that more aggressive anddetailed assessments of family history data may yield informationuseful for assessing risk. A Russian study identified and studiedfamily members (mothers, sisters, daughters) of index fibroid cases.The index cases (n ¼ 97) that had at least two first-degree relativeswith fibroids had elevated levels of oncomarkers carbohydrateantigen 125 and carcinoembryonic antigen compared with indexcases with fewer than two first-degree relatives [32]. A more recentstudy also looked at clinical and molecular features associated withfamilial clustering of fibroid tumors. They found that cases with twofirst-degree relatives with fibroids had more severe disease thatincluded elevated vascular endothelial growth factor-A expressionin tumor tissue compared with cases with fewer than two first-degree relatives with fibroids [33].

Our study has both strengths andweaknesses. A unique strengthof our study is the ascertainment of fibroids by ultrasonography, sothere is little misclassification in disease outcome. Another is thatwe have a sufficiently large sample of African Americanwomen thatwe can report results for that group separately, which has not beendone before to our knowledge. The similarity of results for AfricanAmericans and whites suggests that our findings may be general-izable to a broad range of women. Limitations include the cross-sectional design and our reliance on self-report for family historyinformation (i.e., it was not verified by other sources). In addition,our data did not allow us to evaluate severity of fibroids for theparticipant’s mothers or sisters.

In light of the recent and anticipated advances in fibroid treat-ment [8, 9], better markers of who is likely to develop clinicallyburdensome tumors and who will remain asymptomatic willbecome critically important for counseling young women aboutfibroid-related health issues. Our data suggest that a simple self-report of family history of fibroids is unlikely to be a usefulmarker of high risk. Other approaches are needed.

Acknowledgments

The authors thank the NIEHS Uterine Fibroid Study researchteam for their dedicated studymanagement, data collection, qualitycontrol, and data management. They thank Dr. David Shore for

T.M. Saldana et al. / Annals of Epidemiology 23 (2013) 286e290290

statistical consultation and Drs. Stephanie London and HongleiChen for review of an earlier draft of the manuscript.

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