European Journal of Obstetrics & Gynecology and Reproductive Biology 197 (2016) 63–71

Contents lists available at ScienceDirect

European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

Cigarette smoking and risk of uterine myoma: systematic review and

meta-analysis
Francesca Chiaffarino a,*, Elena Ricci a, Sonia Cipriani a, Vito Chiantera b, Fabio Parazzini a,c
a
Dipartimento della donna, del bambino e del neonato, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
b
Department of Gynecology, Charitè Universitätsmedizin, Charitestraße 1, 10117 Berlin, Germany
c
Dipartimento di Scienze Cliniche e di Comunità, Università degli studi di Milano, Milan, Italy

A R T I C L E I N F O A B S T R A C T

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.

Introduction advances have been made in the understanding of the hormonal

Uterine myomas are the most common benign tumors derived
from smooth muscle cells in the uterine myometrium. In an online
survey the self-reported prevalence of myoma, in the age group of
40–49 years, ranged from 9.4% in United Kingdom to 17.4% in Italy
[1], but many tumors are asymptomatic and may not be diagnosed.
Although the etiology of uterine myoma is still not well known,
* Corresponding author at: Via Commenda, 12-20122 Milano, Italy.
Tel.: +39 02 55032318; fax: +39 02 550320252.
E-mail address: francesca.chiaffarino@alice.it (F. Chiaffarino).
factors, genetic factors and growth factors of these tumors [2]. They
have considered a hormonal-dependent pathological condition,
where growth is thought to depend on ovarian hormones. Both
estrogen and progesterone appear to promote the development of
myomas. Factors that increase exposure to estrogen, such as
obesity and early menarche, increase the incidence [2]. On the
other hand, exercise and increased parity, which decreased
exposure to estrogen, appear to be protective [3].
Smoking is a modifiable risk factor that may affect endogenous
levels of hormones and women who smoke have lower urinary
estrogen levels during the luteal phase of the menstrual cycle than
non-smokers [4]. Nicotine can reduce androgens conversion to

http://dx.doi.org/10.1016/j.ejogrb.2015.11.023
0301-2115/ß 2015 Elsevier Ireland Ltd. All rights reserved.

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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
associated with impaired production and reduced levels of
endogenous circulating estrogens [6].
Epidemiological studies investigating the role of tobacco
smoking have shown conflicting results: some have shown an
inverse relationship between cigarette smoking and risk of uterine
myoma [7–10], but in others smoking increased the risk [11,12],
whereas in two cohort studies it was unrelated to myoma risk
[13,14].
Thus, in order to provide a summary of the available literature
on the relation between cigarette smoking and uterine myoma, we
conducted a systematic review and to allow an overall quantitative
estimate of any such relation, we combined in a meta-analysis all
published data on the issue.
Materials and methods
The review and the meta-analysis were performed according
to PRISMA (preferred reporting items for systematic reviews and
meta-analyses) [15] and MOOSE (Meta-analysis of Observational
Studies in Epidemiology) guidelines [16]. We executed a MED-
LINE/EMBASE search of papers published until October 10, 2015,
using the Medical Subject Heading terms in free research
‘‘myoma’’ or ‘‘leiomyoma’’ combined with ‘‘smoking’’ and
‘‘tobacco’’ and free search terms ‘‘tobacco’’ or ‘‘smoking’’ or
‘‘smok*’’ or ‘‘cigarette*’’ in combination with ‘‘fibroids’’ or ‘‘uterine
fibroids’’ or ‘‘myoma’’ or ‘‘uterine myoma’’ or ‘‘leiomyoma’’ or
‘‘uterine leiomyoma’’.
We selected only studies on humans, published as full-length
papers in English. Moreover, bibliographies of the retrieved papers
were reviewed, to identify any other relevant publication.
In the review we included all identified studies of association of
smoking and uterine myoma, whereas studies were included in the
meta-analysis only if: they were case–control or cohort studies,
reporting original data; diagnosis of myomas was ultrasound or
histological confirmed and/or clinically based; studies reported
information on the association between tobacco smoking and
myomas, including estimates of the relative risk (RR) or the odds
ratio (OR), with the corresponding 95% confidence interval (CI), or
frequency distribution to calculate them.
When we found more than one publication based on the same
study population and data, we included only the one with most
detailed information, or published most recently.
Data extraction and selection of eligible studies was carried out
in duplicate by two investigators (FC and ER). Disagreements were
solved by discussing and reviewing the respective issue. Cross-
referencing of selected articles revealed no further eligible records.
From each publication we extracted the following information:
country of origin; study design; number and characteristics of
subjects (cases, controls or cohort size); age, if available;
categories of tobacco smoking (smoking status, smoking intensity
and duration of smoking, if available); measures of association (RR
or OR) of myomas and corresponding 95% CI for every category of
tobacco smoking, or frequency distribution to calculate them;
confounding variables allowed for in the statistical analysis.
When more than one regression model was provided, estimates
adjusted for the largest number of confounding variables were
considered.
The quality of the studies included in the meta-analysis were
assessed using the Newcastle–Ottawa scale. This instrument was
developed to assess the quality of nonrandomized studies,
specifically cohort and case–control studies [17]. Studies were
judged based on three broad categories: selection of study groups,
comparability of study groups, and assessment of outcome (cohort
studies) or ascertainment of exposure (case–control studies).
Maximum score was 9.
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For some studies, we pooled estimates of different categories of
cases or controls using the method by Hamling et al. [18], thus
taking into account their correlation.
Pooled estimates of the odds ratios (OR) and the corresponding
95% confidence intervals (CI) were calculated using fixed or, when
significant heterogeneity among estimates emerged, random
effects models. Sensitivity analysis were also performed.
We assessed the heterogeneity among studies using the x2 test
[19] and quantified it using the I2 statistic, which represents the
percentage of the total variation across studies that is attributable
to heterogeneity rather than chance [20]. Results were defined as
heterogeneous for p values less than 0.10 [19].
We computed summary estimates for ever tobacco smokers,
former smokers, current smokers, moderate current smokers, and
heavy current smokers, as compared to never smokers.
Among the selected studies, six reported more categories of
current smokers, thus we could calculate separate estimates for
moderate and heavy current smokers but we were able to combine
data from four studies because two studies considered ever
smokers and not only current ones. Moreover, different cut-points
for moderate and heavy smoking were chosen, depending on those
shown in the papers: thus the cut-point for moderate smoking was
less than 10 cigarettes per day in two studies [8,14], less than
15 cigarettes per day in one study [13] and less than 1 pack/day in
another [11]. For heavy current smokers the cut-point was more
than 19 cigarettes per day in two studies [11,14], more than 24 in
one study [13] and more than 10 in another one [8].
Publication bias was evaluated using funnel plot [21].
Results
From the literature search we identified 345 articles, after the
exclusion of 170 as duplicates. 331 studies were excluded for the
reason shown in Fig. 1 and 14 articles describing 14 different
studies were eligible for a qualitative synthesis and data extract
from 10 studies were combined in a meta-analysis.
The main characteristics of identified papers are presented in
Table 1: eight case control studies, four cohort studies and two
cross-sectional. Of the selected studies, 8 were from USA, 3 from
Europe and 3 from Asia. The articles were published between
1986 and 2012.
The effect estimates according to smoking exposure published
in the selected articles were summarized in Table 2.
In the meta-analysis we excluded two cross-sectional studies
[12,22], since in this study design exposure and disease are
recorded at the same time: we could not determine whether the
exposure preceded the occurrence of uterine myoma.
Moreover, two studies were excluded because the categories of
smoking exposure were not clear [23,24] and in the American
cohort study the presence of myoma was self-reported without
any other diagnosis confirmation [24]. Overall, data from ten
studies, including 374,212 women, 7612 with uterine myoma,
were used in the meta-analysis.
Ever smokers
In qualitative analysis seven studies reported information on
ever smokers (Table 2). Among these, three of them, two case–
control studies and one cohort study, showed no effect of ever
smoking. Two case–control studies showed a protective effect of
ever smoking [7,9] and in the American study was dose dependent
[9] whereas the exposure to cigarette smoking increased the risk of
myoma in Iranian premenopausal women and in Slovenian women
[23,25].
In quantitative analysis the Iranian study was excluded because
the categories of smoking exposure were not clear. In the random
 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
two studies [7,26] reported the adjusted OR of ever smokers
compared to never smokers; in the study by Pakiz we calculated
the OR from published frequency distribution; seven studies did
not compare ever versus never smokers, thus we calculated the OR
or RR, as appropriate, combining former and current smokers or
more categories of ever smokers in one ever smokers category.
Consequently, these estimates were not adjusted. The summary
OR (95% CI) of myoma for ever smokers, compared to never
smokers, was 0.86 (0.73–1.01) with significant heterogeneity
(x2 = 76.92, p = 0.00001), similarly to both OR obtained from
cohort and from case–control studies separately, as shown in Fig. 2.
Moreover, as regards the case–control studies on the relationship
between ever smoking and uterine myoma, it becomes immedi-
ately evident, that the OR in the study by Pakiz [25] was completely
different. It should take into account that this Slovenian study [25]
regarded a small sample of women with higher age range when
compared with other studies and the estimate, included in the
meta-analysis, was not adjusted. Furthermore, tobacco smoking
was not the main topic of the paper. In sensitivity analysis, when a
Slovenian study [25] was dropped, the OR of myoma for ever
smokers in case–control studies subgroup was 0.75 (0.62–0.92),
and the summary OR for ever smokers as compared to never
smokers was 0.83 (0.71–0.97) with significant heterogeneity
(x2 = 18.02, p = 0.003).
Current smokers
A cohort study [10] and a case–control study [8], including pre-
and post-menopausal women, showed an inverse association
between myoma and smoking. On the contrary, in a Chinese case–
control study, current smoking of one or more packs of cigarettes
per day was associated with an increasing risk for White women,
but not for African-American women [11]. Moreover, in a cross-
sectional study, smoking was positively associated with diffuse
myomas, with similar patterns between African-American and
Caucasians women, but was not associated with submucosal or
intramural/subserosal myoma [12]. In a case–control [27] and two
cohort studies [13,14] current smoking was not associated with
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,
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.

sterilization respectively 34.1–29.5 cases cigarettes pack/day heavy menstrual flow,

and controls irregular cycles, cycle
respectively length
Dragomir et al., 2010 USA Cross-sectional Women with myomas Women without Caucasian: 203–202, 35–49 Never, ever smokers Age, age at menarche,
(ultrasound confirmed) myomas African-American: full term pregnancies,
419–162 cases and BMI, Physical activity,
controls respectively ethnicity
Faerstein et al., 2001 USA Case–control Women with myomas Women without 318/394 42.3  6.4 20–55 Never, former, current Age, clinic, etnicity, 6
(surgically or myomas cases; 39.8  6.0 smoker. Tertile of education and marital
sonographically 18–53 controls. duration and pack/ status
confirmed) Postmenopausal years
women were
excluded.
Lambertino et al., 2011 USA Cohort Women with self Women without 95 cases Mean age women % cigarette smoking N.A.
reported myomas myomas with myoma:
54.7. w/o
myoma:52.7
Lumbiganon et al., 1995 Thailand Case–control Women with myomas Women without 910/2709 87.5% and 82.7% never, ever smokers Control for potential 6
who required surgical myomas cases and controls counfounding factors,
treatment respectively were but not otherwise
(histopathologically <50 age. specified
confirmed)
Marshall et al., 1998 USA Cohort Women with myomas Women without 2967 new cases among 25–42 Never, current, former Age, race, marital 8
(ultrasound/ myomas 94,095 premenopausal smokers, n. cigarettes/ status, age at
hysterectomy women day menarche, BMI, age at
confirmed) first birth, years since
last birth, history of
infertility and age at
first oral contraceptive
use
Nagata et al., 2009 Japan Cross-sectional Women with myomas Women without 54/231 Postmenopausal Never, current, former N.A.
(ultrasound/ myomas women were smokers
hysterectomy excluded
confirmed)
Pakiz et al., 2010 Slovenia Case–control Women with myomas Women 50 + 56/41 Age range. Cases: smoking and duration N.A. 5
(histologically undergoing vaginal 42.4–53.5 Controls: of smoking (mean)
confirmed) hysterectomy for 57.2–64.2
pelvic organ
prolapse
Parazzini et al., 1995 Italy Case–control Women with myomas Women admitted 476/1283 <55 years Never, current, former Age, education, 6
(histologically to the hospitals for smokers, no. of menopausal status,
confirmed) acute, non- cigarettes/day, BMI, parity, oral
gynecologic, duration of smoking contraceptive use
nonhormonal, (years)
nonneoplastic
conditions
 F. Chiaffarino et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 197 (2016) 63–71 67

In the meta-analyses of three cohort and three case–control

studies combined, the summary OR of current smokers was 0.83
(0.65–1.04) with significant heterogeneity (x2 = 24.48, p = 0.0004).
6

8
The subtotal OR from cohort studies was 0.85 (0.73–0.98) with no

Age, time period, age at

menarche, parity, age at
frequency pap test, age

education, BMI, OC use

feeding, race, BMI, oral
heterogeneity (x2 = 3.60, p = 0.16). If data were published in
Menopausal status,

first and last birth,

education, breast-

contraceptive use classes of cigarettes per day or pack/years, we included the

estimates of the highest dose class in the analyses.
at menarche,

Former smokers

Six studies reported information on former smokers (Table 2)

smoker. Cigarettes/day,

and only a cohort study [10] found a small significant protective

Never, former, current

Never, former, current

No. of cigarettes/day

effect of former smoking on myoma risk. In the meta-analysis the

smoking, y. since

summary OR of former compared to never smokers (see Fig. 4) was

pack/years, y. of

0.93 (0.88–0.99) with not significant heterogeneity (x2 = 4.03,

Never, ever

p = 0.67).
quitting
smoker.

Moderate and heavy current smokers

Among the selected studies, six reported more categories of

premenopausal

current smokers, thus we could calculate separate estimates for

moderate and heavy current smokers but we were able to combine
data from four studies because two studies considered ever
women
25–39

25–84
20–54

smokers and not only current ones. Moreover, different cut-points

Only

for moderate and heavy smoking were chosen, depending on those

shown in the papers (see Materials and Methods).
Fig. 5A and B reported respectively the results of the meta-
1790 cases among

analyses of low-moderate (including the risk estimates for the

133,000 women

lowest class) and heavy current smokers (including the estimates

2177 cases

for the highest class) versus never smokers: both ORs were not
201/1503
535/535

statistically significant with borderline heterogeneity.

Duration of smoking
Women without

Women without

Women without

Women without

Only three studies reported effect measures for the relationship

between duration of smoking and myoma risk. Two of them found
no association, whereas no clear association emerged between
myomas

myomas

myomas

myomas

years of smoking and risk of myoma in our previous [8]: women

with less than twenty years of smoking, had approximately a 50%
reduced risk of myoma requiring surgery, but this protection was
reported myomas with
Women with myomas

Women with myomas

Women with myomas

(surgically confirmed)

not found in women with twenty or more years of smoking. Since

information on smoking habit duration was even more heteroge-
Women with self-

physician clinical

neous than that on cigarettes dose, we decided not to try a

(pathologically

(ultrasound or
hysterectomy

quantitative synthesis.
confirmed)

confirmed)
diagnosis

Funnel plot, reported in Fig. 6, is a graphical tool for the

assessment of publication bias. Its interpretation is largely
subjective [28] and can be supported by Egger’s test for assessing
asymmetry. In the present study the Egger’s test result (p = 0.35)
suggested no presence of publication bias thought, because of the
lower power of the test, bias cannot be excluded [29].
Case–control

Case–control

Comment
Cohort

Cohort

Epidemiological studies investigating the role of smoking on risk

of myoma have shown conflicting results but to our knowledge, this
Scotland
England

is the first systematic review and meta-analysis on that topic. The

primary meta-analysis found no significant effect of smoking on
USA

USA

USA
and

risk of myoma. Subgroup analysis for study design showed a small,

but significant, risk reduction for current and former smokers in
Templeman et al., 2009

cohort studies. The absence of statistical significance in ever

Samadi et al., 1996

smokers and in the subgroup of case–control studies could be

Wise et al., 2004
Ross et al., 1986

due to the analysis, which was based, in most studies, in absence of

adjusted OR, on raw estimates. Moreover, as regards the case–
control studies on the relationship between ever smoking and
myoma, a sensitivity analysis, dropping the study by Pakiz [25],
showed an inverse association between ever smoking and myoma.

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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.

Comparison First author Year Study design Published Published Published

estimates estimates estimates
(95% CI) All (95% CI) (95% CI)
White women African-American
women

Ever versus never smokers

Samadi [a] 1996 Case–control 0.8 (0.5–1.1)
Lumbiganon [b] 1996 Case–control 0.63 (0.40–0.99)
Bidgoli [c] 2012 Case–control 2.09 (1.29–3.37)
Pakiz [d] 2010 Case–control 0.198 (0.075–0.52)
1–14 cigarettes/day Ross [e] 1986 Case–control 0.74
15 cigarettes/day Ross [e] 1986 Case–control 0.65
<5 pack/year Faerstein [f] 2001 Case–control 1.0 (0.6–1.6)
5–13 pack/year Faerstein [f] 2001 Case–control 0.8 (0.5–1.4)
13.2–58 pack/year Faerstein [f] 2001 Case–control 0.9 (0.5–1.4)
<2.0 pack/year Wise [g] 2004 Cohort 0.94 (0.79–1.12)
2.0–5.9 pack/year Wise [g] 2004 Cohort 0.97 (0.81–1.16)
6.0–12.4 pack/year Wise [g] 2004 Cohort 0.88 (0.73–1.04)
12.5 pack/year Wise [g] 2004 Cohort 0.93 (0.79–1.11)

Current versus never smokers

Faerstein [f] 2001 Case–control 0.7 (0.4–1.3)
Dragomir [h] 2010 Cross-sectional 2.13 (1.29–3.53) 3.00 (1.07–8.38) 1.97 (1.11–3.51)
Dragomir [h] 2010 Cross-sectional 1.24 (0.74–2.07) 1.60 (0.52–4.98) 1.13 (0.64–2.01)
Dragomir [h] 2010 Cross-sectional 0.87 (0.58–1.32) 0.63 (0.23–1.74) 0.89 (0.56–1.40)
Wise [g] 2004 Cohort 0.88 (0.77–1.01)
Templeman [i] 2009 Cohort 0.65 (0.50–0.85)
1–9 cigarettes/day Parazzini [l] 1996 Case–control 0.5 (0.3–0.7)
10 cigarettes/day Parazzini [l] 1996 Case–control 0.5 (0.4–0.8)
1–14 cigarettes/day Marshall [m] 1998 Cohort 0.84 (0.70–1.01)
15–24 cigarettes/day Marshall [m] 1998 Cohort 0.89 (0.75–1.06)
25 cigarettes/day Marshall [m] 1998 Cohort 0.93 (0.73–1.19)
<1 pack/day Chen [n] 2001 Case–control 0.9 (0.6–1.5) 1.2 (0.6–2.3)
1 pack/day Chen [n] 2001 Case–control 1.6 (1.1–2.3) 0.7 (0.2–1.7)
<10cigarettes/day Wise [g] 2004 Cohort 1.06 (0.86–1.30)
10–19 cigarettes/day Wise [g] 2004 Cohort 0.82 (0.68–0.98)
20 cigarettes/day Wise [g] 2004 Cohort 0.87 (0.78–1.12)

Former versus never smokers

Parazzini [l] 1996 Case–control 1.2 (0.9–1.8)
Chen [n] 2001 Case–control 1.1 (0.7–1.6) 0.9 (0.4–2.2)
Faerstein [f] 2001 Case–control 0.9 (0.6–1.4)
Wise [g] 2004 Cohort 0.95 (0.84–1.08)
Templeman [i] 2009 Cohort 0.87 (0.77–0.97)
Quit < 1 year Marshall [m] 1998 Cohort 1.17 (0.95–1.44)
Quit  1 year Marshall [m] 1998 Cohort 0.95 (0.87–1.05)
Duration
<20 years Parazzini [l] 1996 Case–control 0.5 (0.3–0.6)
20 years Parazzini [l] 1996 Case–control 0.6 (0.4–1.0)
<10 years Faerstein [f] 2001 Case–control 1.1 (0.7–1.9)
10–18 years Faerstein [f] 2001 Case–control 0.9(0.6–1.4)
19–34 years Faerstein [f] 2001 Case–control 0.6 (0.4–1.1)
<10 years Wise [g] 2004 Cohort 0.94 (0.82–1.09)
10–19 years Wise [g] 2004 Cohort 0.93 (0.80–1.08)
 20 years Wise [g] 2004 Cohort 0.89 (0.74–1.06)

[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
smoking.
The present meta-analysis may be affected by limitations and
biases intrinsic in the observational studies included in the meta-
analysis. Smoking is self-reported information, thus some mis-
classification may have occurred. However, information on
tobacco smoking in observational studies has been shown to be
satisfactorily reproducible and valid [30,31].
An important limitation is that, in some of our meta-analysis
estimates, we found large heterogeneity, that could be explained by
several reasons: the study design, the absence (at least in ever smokers
analysis) of adjusted OR and other characteristics such as different
race and the age range of the women included in the studies. As regard
the study design, some heterogeneity remained among case–control
and cohort studies. Different women race were enrolled in the
selected studies and because of sample size limitations, not in all
studies were conducted race restricted analyses. Risk factors for
myoma may vary by race like as the incidence of disease [32], number
and size of myomas: in an American cross-sectional study of women
undergoing premenopausal hysterectomy, African-American women
showed higher prevalence of risk factors, such as obesity and
hypertension, when compared with White women [33]. In an
American case–control study, including White and African-American
women, smoking of one or more packs per day increased myoma risk
but only for White women [11]. Moreover, there were evidence that
premenopausal African-American women have higher ovarian
hormone levels than White women [34].
In order to focus on a population most likely to develop uterine
myoma, several studies included only premenopausal women
[22,23,27] or selected specific age range to cover the reproductive
years [9,11–13], but not all. It is possible that menopausal status
may modify the relation between smoking and myoma.
Furthermore, a small protection in smokers could be explained
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.

In conclusion, despite these limitations, we believe that this

study could be informative about the relationship between
cigarette smoking and uterine myoma. As a matter of fact, the
overall estimates showed the same direction of no significant
association, except for a weak protection that, given the limited
number of studies and the absence of a dose dependent effect,
deserves further investigations.

References

[1] Zimmermann A, Bernuit D, Gerlinger C, Schaefers M, Geppert K. Prevalence,

Fig. 6. Funnel-plot of studies on tobacco smoking and risk of uterine myoma. OR:
odds ratios for ever smokers versus non smokers; CI: confidence interval; s.e.:
standard error.
symptoms and management of uterine fibroids: an international internet-
based survey of 21,746 women. BMC Womens Health 2012;12:6.
[2] Parker WH. Etiology, symptomatology, and diagnosis of uterine myomas. Fertil
Steril 2007;87:725–36.
[3] Cook JD, Walker CL. Treatment strategies for uterine leiomyoma: the role of
hormonal modulation. Semin Reprod Med 2004;22:105–11.
[4] MacMahon B, Trichopoulos D, Cole P, Brown J. Cigarette smoking and urinary
estrogens. N Engl J Med 1982;307:1062–5.
[5] Biegon A, Alia-Klein N, Fowler JS. Potential contribution of aromatase inhibi-
tion to the effects of nicotine and related compounds on the brain. Front
Pharmacol 2012;3:185.

Downloaded for Mahasiswa KTI UKDW (mhsktiukdw01@gmail.com) at Universitas Kristen Duta Wacana from ClinicalKey.com by Elsevier on August 24, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
 F. Chiaffarino et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 197 (2016) 63–71
[6] Baron JA, La Vecchia C, Levi F. The antiestrogenic effect of cigarette smoking in
women. Am J Obstet Gynecol 1990;162:502–14.
[7] Lumbiganon P, Rugpao S, Phandhu-fung S, Laopaiboon M, Vudhikamraksa N,
Werawatakul Y. Protective effect of depot-medroxyprogesterone acetate on
surgically treated uterine leiomyomas: a multicentre case–control study. Br
J146?Obstet Gynaecol 1996;103:909–14.
[8] Parazzini F, Negri E, La Vecchia C, et al. Uterine myomas and smoking. Results
from an Italian study. J Reprod Med 1996;41:316–20.
[9] Ross RK, Pike MC, Vessey MP, Bull D, Yeates D, Casagrande JT. Risk factors
for uterine fibroids: reduced risk associated with oral contraceptives. Br Med
J146?(Clin Res Ed) 1986;293:359–62.
[10] Templeman C, Marshall SF, Clarke CA, et al. Risk factors for surgically removed
fibroids in a large cohort of teachers. Fertil Steril 2009;92:1436–46.
[11] Chen CR, Buck GM, Courey NG, Perez KM, Wactawski-Wende J. Risk factors for
uterine fibroids among women undergoing tubal sterilization. Am J Epidemiol
2001;153:20–6.
[12] Dragomir AD, Schroeder JC, Connolly A, et al. Potential risk factors associated
with subtypes of uterine leiomyomata. Reprod Sci 2010;17:1029–35.
[13] Marshall LM, Spiegelman D, Manson JE, et al. Risk of uterine leiomyomata
among premenopausal women in relation to body size and cigarette smoking.
Epidemiology 1998;9:511–7.
[14] Wise LA, Palmer JR, Harlow BL, et al. Risk of uterine leiomyomata in relation to
tobacco, alcohol and caffeine consumption in the Black Women’s Health
Study. Hum Reprod 2004;19:1746–54.
[15] Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items
for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med
2009;6:e1000097.
[16] Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in
epidemiology: a proposal for reporting Meta-analysis Of Observational Stud-
ies in Epidemiology (MOOSE) group. JAMA 2000;283:2008–12.
[17] Wells GA. The Newcastle-Ottawa Scale (NOS) for assessing the quality of
nonrandomized studies in meta-analyses. http://www.ohri.ca/programs/
clinical_epidemiology/oxford.asp [Last accessed 20.10.15].
[18] Hamling J, Lee P, Weitkunat R, Ambuhl M. Facilitating meta-analyses by
deriving relative effect and precision estimates for alternative comparisons
from a set of estimates presented by exposure level or disease category. Stat
Med 2008;27:954–70.
[19] Greenland S. Quantitative methods in the review of epidemiologic literature.
Epidemiol Rev 1987;9:1–30.
[20] Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat
Med 2002;21:1539–58.
Downloaded for Mahasiswa KTI UKDW (mhsktiukdw01@gmail.com) at Universitas Kristen Duta Wacana from ClinicalKey.com by Elsevier on August 24, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
71
[21] Thornton A, Lee P. Publication bias in meta-analysis: its causes and conse-
quences. J Clin Epidemiol 2000;53:207–16.
[22] Nagata C, Nakamura K, Oba S, Hayashi M, Takeda N, Yasuda K. Association of
intakes of fat, dietary fibre, soya isoflavones and alcohol with uterine fibroids
in Japanese women. Br J Nutr 2009;101:1427–31.
[23] Bidgoli SA, Khorasani H, Keihan H, Sadeghipour A, Mehdizadeh A. Role of
endocrine disrupting chemicals in the occurrence of benign uterine leiomyo-
mata: special emphasis on AhR tissue levels. Asian Pac J Cancer Prev
2012;13:5445–50.
[24] Lambertino A, Turyk M, Anderson H, Freels S, Persky V. Uterine leiomyomata in
a cohort of Great Lakes sport fish consumers. Environ Res 2011;111:
565–72.
[25] Pakiz M, Potocnik U, But I. Solitary and multiple uterine leiomyomas among
Caucasian women: two different disorders. Fertil Steril 2010;94:2291–5.
[26] Samadi AR, Lee NC, Flanders WD, Boring 3rd JR, Parris EB. Risk factors for self-
reported uterine fibroids: a case-control study. Am J Public Health 1996;86:
858–62.
[27] Faerstein E, Szklo M, Rosenshein N. Risk factors for uterine leiomyoma: a
practice-based case-control study I. African-American heritage, reproductive
history, body size, and smoking. Am J Epidemiol 2001;153:1–10.
[28] Borenstein M. In: Rothstein HR, Sutton AJ, Borenstein M, editors. Publication
Bias in Meta-Analysis–Prevention Assessment and Adjustments. London, UK:
Wiley; Software for publication bias; 2005. p. 193–220.
[29] Cochrane. http://handbo ok.cochrane.org/ch apter_10/10_4_3_1_
recommendations_on_testing_for_funnel_plot_asymmetry.htm (Last
accessed 22.10.15).
[30] D’Avanzo B, La Vecchia C, Katsouyanni K, Negri E, Trichopoulos D. Reliability of
information on cigarette smoking and beverage consumption provided by
hospital controls. Epidemiology 1996;7:312–5.
[31] Patrick DL, Cheadle A, Thompson DC, Diehr P, Koepsell T, Kinne S. The validity
of self-reported smoking: a review and meta-analysis. Am J Public Health
1994;84:1086–93.
[32] Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative
incidence of uterine leiomyoma in black and white women: ultrasound
evidence. Am J Obstet Gynecol 2003;188:100–7.
[33] Moorman PG, Leppert P, Myers ER, Wang F. Comparison of characteristics of
fibroids in African American and white women undergoing premenopausal
hysterectomy. Fertil Steril 2013;99:768–76. e1.
[34] Haiman CA, Pike MC, Bernstein L, et al. Ethnic differences in ovulatory function
in nulliparous women. Br J Cancer 2002;86:367–71.