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Article history: Objective: To review the literature on the relationship between smoking and the risk of uterine myoma,
Received 22 June 2015 we conducted a systematic review and a meta-analysis of published studies. In this meta-analysis, we
Received in revised form 11 November 2015 included all identified studies of association between smoking and uterine myoma where these were
Accepted 18 November 2015
case–control or cohort studies, reporting original data, ultrasound or histological confirmed diagnosis of
myomas and information on the association between tobacco smoking and myomas.
Keywords: Study design: We carried out a literature search on MEDLINE/EMBASE of all studies published as original
Smoking
articles in English up to October 2015, using the Medical Subject Heading terms and free search terms
Uterine myoma
about myoma and smoking.
Risk factor
We selected only studies published in English. Moreover, bibliographies of the retrieved papers were
reviewed, to identify any other relevant publication.
A total of 14 different studies were eligible for a qualitative synthesis and data extract from 10 studies
were combined in a meta-analysis.
Results: The summary OR of former compared to never smokers was 0.93 (0.88–0.99) with no
heterogeneity. The summary OR of current smokers compared to never smokers, was 0.83 (0.65–1.04),
even if the subtotal OR in cohort studies was 0.85 (0.73–0.98) with no heterogeneity. When sensitivity
analysis was performed the summary OR was 0.83 (0.71–0.97).
Conclusion: The primary meta-analyses found no significant effect of smoking on risk of uterine myoma.
Subgroup analysis for study design showed a small risk reduction for current and former smokers in
cohort studies. A sensitivity analysis showed an inverse association between ever smoking and uterine
myoma. However, given the limited number of studies in each sub-analysis, weak associations and the
absence of a dose dependent effect, caution should be paid in the interpretation of these findings and
further investigation are needed.
ß 2015 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ejogrb.2015.11.023
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64 F. Chiaffarino et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 197 (2016) 63–71
estrone secondary to inhibition of aromatase [5]. Thus, smoking is For some studies, we pooled estimates of different categories of
associated with impaired production and reduced levels of cases or controls using the method by Hamling et al. [18], thus
endogenous circulating estrogens [6]. taking into account their correlation.
Epidemiological studies investigating the role of tobacco Pooled estimates of the odds ratios (OR) and the corresponding
smoking have shown conflicting results: some have shown an 95% confidence intervals (CI) were calculated using fixed or, when
inverse relationship between cigarette smoking and risk of uterine significant heterogeneity among estimates emerged, random
myoma [7–10], but in others smoking increased the risk [11,12], effects models. Sensitivity analysis were also performed.
whereas in two cohort studies it was unrelated to myoma risk We assessed the heterogeneity among studies using the x2 test
[13,14]. [19] and quantified it using the I2 statistic, which represents the
Thus, in order to provide a summary of the available literature percentage of the total variation across studies that is attributable
on the relation between cigarette smoking and uterine myoma, we to heterogeneity rather than chance [20]. Results were defined as
conducted a systematic review and to allow an overall quantitative heterogeneous for p values less than 0.10 [19].
estimate of any such relation, we combined in a meta-analysis all We computed summary estimates for ever tobacco smokers,
published data on the issue. former smokers, current smokers, moderate current smokers, and
heavy current smokers, as compared to never smokers.
Materials and methods Among the selected studies, six reported more categories of
current smokers, thus we could calculate separate estimates for
The review and the meta-analysis were performed according moderate and heavy current smokers but we were able to combine
to PRISMA (preferred reporting items for systematic reviews and data from four studies because two studies considered ever
meta-analyses) [15] and MOOSE (Meta-analysis of Observational smokers and not only current ones. Moreover, different cut-points
Studies in Epidemiology) guidelines [16]. We executed a MED- for moderate and heavy smoking were chosen, depending on those
LINE/EMBASE search of papers published until October 10, 2015, shown in the papers: thus the cut-point for moderate smoking was
using the Medical Subject Heading terms in free research less than 10 cigarettes per day in two studies [8,14], less than
‘‘myoma’’ or ‘‘leiomyoma’’ combined with ‘‘smoking’’ and 15 cigarettes per day in one study [13] and less than 1 pack/day in
‘‘tobacco’’ and free search terms ‘‘tobacco’’ or ‘‘smoking’’ or another [11]. For heavy current smokers the cut-point was more
‘‘smok*’’ or ‘‘cigarette*’’ in combination with ‘‘fibroids’’ or ‘‘uterine than 19 cigarettes per day in two studies [11,14], more than 24 in
fibroids’’ or ‘‘myoma’’ or ‘‘uterine myoma’’ or ‘‘leiomyoma’’ or one study [13] and more than 10 in another one [8].
‘‘uterine leiomyoma’’. Publication bias was evaluated using funnel plot [21].
We selected only studies on humans, published as full-length
papers in English. Moreover, bibliographies of the retrieved papers Results
were reviewed, to identify any other relevant publication.
In the review we included all identified studies of association of From the literature search we identified 345 articles, after the
smoking and uterine myoma, whereas studies were included in the exclusion of 170 as duplicates. 331 studies were excluded for the
meta-analysis only if: they were case–control or cohort studies, reason shown in Fig. 1 and 14 articles describing 14 different
reporting original data; diagnosis of myomas was ultrasound or studies were eligible for a qualitative synthesis and data extract
histological confirmed and/or clinically based; studies reported from 10 studies were combined in a meta-analysis.
information on the association between tobacco smoking and The main characteristics of identified papers are presented in
myomas, including estimates of the relative risk (RR) or the odds Table 1: eight case control studies, four cohort studies and two
ratio (OR), with the corresponding 95% confidence interval (CI), or cross-sectional. Of the selected studies, 8 were from USA, 3 from
frequency distribution to calculate them. Europe and 3 from Asia. The articles were published between
When we found more than one publication based on the same 1986 and 2012.
study population and data, we included only the one with most The effect estimates according to smoking exposure published
detailed information, or published most recently. in the selected articles were summarized in Table 2.
Data extraction and selection of eligible studies was carried out In the meta-analysis we excluded two cross-sectional studies
in duplicate by two investigators (FC and ER). Disagreements were [12,22], since in this study design exposure and disease are
solved by discussing and reviewing the respective issue. Cross- recorded at the same time: we could not determine whether the
referencing of selected articles revealed no further eligible records. exposure preceded the occurrence of uterine myoma.
From each publication we extracted the following information: Moreover, two studies were excluded because the categories of
country of origin; study design; number and characteristics of smoking exposure were not clear [23,24] and in the American
subjects (cases, controls or cohort size); age, if available; cohort study the presence of myoma was self-reported without
categories of tobacco smoking (smoking status, smoking intensity any other diagnosis confirmation [24]. Overall, data from ten
and duration of smoking, if available); measures of association (RR studies, including 374,212 women, 7612 with uterine myoma,
or OR) of myomas and corresponding 95% CI for every category of were used in the meta-analysis.
tobacco smoking, or frequency distribution to calculate them;
confounding variables allowed for in the statistical analysis. Ever smokers
When more than one regression model was provided, estimates
adjusted for the largest number of confounding variables were In qualitative analysis seven studies reported information on
considered. ever smokers (Table 2). Among these, three of them, two case–
The quality of the studies included in the meta-analysis were control studies and one cohort study, showed no effect of ever
assessed using the Newcastle–Ottawa scale. This instrument was smoking. Two case–control studies showed a protective effect of
developed to assess the quality of nonrandomized studies, ever smoking [7,9] and in the American study was dose dependent
specifically cohort and case–control studies [17]. Studies were [9] whereas the exposure to cigarette smoking increased the risk of
judged based on three broad categories: selection of study groups, myoma in Iranian premenopausal women and in Slovenian women
comparability of study groups, and assessment of outcome (cohort [23,25].
studies) or ascertainment of exposure (case–control studies). In quantitative analysis the Iranian study was excluded because
Maximum score was 9. the categories of smoking exposure were not clear. In the random
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F. Chiaffarino et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 197 (2016) 63–71 65
Fig. 1. Flow chart of the selection of studies on cigarette smoking and risk of uterine myoma included in the systematic review and meta-analysis.
effects model of the meta-analysis, we considered ten studies. Only Slovenian study [25] was dropped, the OR of myoma for ever
two studies [7,26] reported the adjusted OR of ever smokers smokers in case–control studies subgroup was 0.75 (0.62–0.92),
compared to never smokers; in the study by Pakiz we calculated and the summary OR for ever smokers as compared to never
the OR from published frequency distribution; seven studies did smokers was 0.83 (0.71–0.97) with significant heterogeneity
not compare ever versus never smokers, thus we calculated the OR (x2 = 18.02, p = 0.003).
or RR, as appropriate, combining former and current smokers or
more categories of ever smokers in one ever smokers category. Current smokers
Consequently, these estimates were not adjusted. The summary
OR (95% CI) of myoma for ever smokers, compared to never A cohort study [10] and a case–control study [8], including pre-
smokers, was 0.86 (0.73–1.01) with significant heterogeneity and post-menopausal women, showed an inverse association
(x2 = 76.92, p = 0.00001), similarly to both OR obtained from between myoma and smoking. On the contrary, in a Chinese case–
cohort and from case–control studies separately, as shown in Fig. 2. control study, current smoking of one or more packs of cigarettes
Moreover, as regards the case–control studies on the relationship per day was associated with an increasing risk for White women,
between ever smoking and uterine myoma, it becomes immedi- but not for African-American women [11]. Moreover, in a cross-
ately evident, that the OR in the study by Pakiz [25] was completely sectional study, smoking was positively associated with diffuse
different. It should take into account that this Slovenian study [25] myomas, with similar patterns between African-American and
regarded a small sample of women with higher age range when Caucasians women, but was not associated with submucosal or
compared with other studies and the estimate, included in the intramural/subserosal myoma [12]. In a case–control [27] and two
meta-analysis, was not adjusted. Furthermore, tobacco smoking cohort studies [13,14] current smoking was not associated with
was not the main topic of the paper. In sensitivity analysis, when a risk of uterine myoma (Fig. 3).
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66
Table 1
Main characteristics of the studies on tobacco smoking and risk of uterine myoma.
Study and year Country Study design Cases Controls Sample size cases/ Age (ys) Smoking habit Confounding factors NOS
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controls Quality
score
Bidgoli et al., 2012 Iran Case–control Women with myomas Women without 138/138 Postmenopausal Active and passive
confirmed by myomas women were exposure to cigarettes
pathological reports excluded. smoke versus no
exposure
Chen et al., 2001 USA Case–control Women with myomas Women without White: 247–988, <44 were included. Never, former smoker, Age at sterilization and 6
F. Chiaffarino et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 197 (2016) 63–71
undergoing tubal myomas African-American: 70– White: 35.6–32.0 current smoker number of living
sterilization undergoing tubal 280 cases and controls African-American: smoking < or >1 children, education,
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8
The subtotal OR from cohort studies was 0.85 (0.73–0.98) with no
Former smokers
p = 0.67).
quitting
smoker.
25–84
20–54
for the highest class) versus never smokers: both ORs were not
201/1503
535/535
Duration of smoking
Women without
Women without
Women without
Women without
myomas
myomas
myomas
physician clinical
(ultrasound or
hysterectomy
quantitative synthesis.
confirmed)
confirmed)
diagnosis
Case–control
Comment
Cohort
Cohort
USA
USA
and
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68 F. Chiaffarino et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 197 (2016) 63–71
Table 2
Reported estimates in selected studies.
[a] OR for menopausal status, frequency of Pap smears, age at menarche, education, breast-feeding, race, BMI and oral contraceptive use.
[b] OR(unconditional stepwise logistic regression analysis) adjusted for age at menarche, age at first and last delivery, parity, number of abortion, age at first marriage,
education, breast-feeding, occupation, BMI, family history of myoma, oral contraceptive use and tubal ligation.
[c] OR of exposed to the cigarette smoke.
[d] OR of never smokers in comparison with ever smokers estimates by univariate logistic regression models.
[e] RR. p = 0.018 for linear trend in logistic model.
[f] OR adjusted for age, clinic (used for frequency-matching of the study groups), ethnicity, education and marital status.
[g] IRR (incidence rate ratios) adjusted for age, time period, age at menarche, parity, age at the first birth, years since last birth, use of oral contraceptives, education, caffeine
intake and BMI.
[h] OR adjusted for age, age at menarche, full-term pregnancies, BMI and physical activity. First row referred to diffuse myomas, second row referred to submucosal myomas
and the third row referred to intramural/subserosal myomas.
[i] RR adjusted for race and family history of fibroids and stratified by age.
[l] RR adjusted for age, education, parity, contraceptive use and Quetelet’s index.
[m] RR adjusted for age, race, marital status, age at menarche, BMI, age at first birth, years since last birth, history of infertility and age at first oral contraceptive use.
[n] OR () adjusted for age at sterilization and number of living children. The same results in white women, were obtained in multivariate analysis (adjusted for age, education,
heavy menstrual flow, irregular cycles, duration of bleeding, cycle length, number of living children, years since last delivery).
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F. Chiaffarino et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 197 (2016) 63–71 69
Fig. 2. Study-specific and summary odds ratios (OR) of uterine myoma for ever smokers versus non smokers. CI: confidence interval.
Finally, no effect was found for moderate and heavy tobacco myoma may vary by race like as the incidence of disease [32], number
smoking. and size of myomas: in an American cross-sectional study of women
The present meta-analysis may be affected by limitations and undergoing premenopausal hysterectomy, African-American women
biases intrinsic in the observational studies included in the meta- showed higher prevalence of risk factors, such as obesity and
analysis. Smoking is self-reported information, thus some mis- hypertension, when compared with White women [33]. In an
classification may have occurred. However, information on American case–control study, including White and African-American
tobacco smoking in observational studies has been shown to be women, smoking of one or more packs per day increased myoma risk
satisfactorily reproducible and valid [30,31]. but only for White women [11]. Moreover, there were evidence that
An important limitation is that, in some of our meta-analysis premenopausal African-American women have higher ovarian
estimates, we found large heterogeneity, that could be explained by hormone levels than White women [34].
several reasons: the study design, the absence (at least in ever smokers In order to focus on a population most likely to develop uterine
analysis) of adjusted OR and other characteristics such as different myoma, several studies included only premenopausal women
race and the age range of the women included in the studies. As regard [22,23,27] or selected specific age range to cover the reproductive
the study design, some heterogeneity remained among case–control years [9,11–13], but not all. It is possible that menopausal status
and cohort studies. Different women race were enrolled in the may modify the relation between smoking and myoma.
selected studies and because of sample size limitations, not in all Furthermore, a small protection in smokers could be explained
studies were conducted race restricted analyses. Risk factors for by anti-estrogenic effects of tobacco smoking.
Fig. 3. Study-specific and summary odds ratios (OR) of uterine myoma for current smokers versus non smokers. CI: confidence interval.
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70 F. Chiaffarino et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 197 (2016) 63–71
Fig. 4. Study-specific and summary odds ratios (OR) of uterine myoma for former smokers versus non smokers. CI: confidence interval.
Fig. 5. Study-specific and summary odds ratios (OR) of uterine myoma for moderate (A) and heavy (B) current smokers versus non smokers. CI: confidence interval.
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