Menstrual and reproductive factors and risk of breast cancer: A case-control study in the Fez region, Morocco
Menstrual and reproductive factors and risk of breast cancer: A case-control study in the Fez region, Morocco
Mohamed Khalis 0 1 2
Barbara Charbotel 0 2
VeÂ ronique Chajès 0 2
Sabina Rinaldi 0 2
AureÂ lie Moskal 0 2
Carine Biessy 0 2
Laure Dossus 0 2
Inge Huybrechts 0 2
Emmanuel Fort 0 2
Nawfel Mellas 0 2
Samira Elfakir 0 1 2
Hafida Charaka 0 1 2
Chakib Nejjari 0 1 2
Isabelle Romieu 0 2
Karima El Rhazi 0 1 2
0 confidence interval; GPAQ, Global Physical Activity Questionnaire; MET , Metabolic equivalent; OR, odds ratios , USA
1 Department of Epidemiology, Faculty of Medicine and Pharmacy , Fez, Morocco, 2 University Claude Bernard Lyon1, Ifsttar, UMRESTTE, UMR T_9405, Lyon , France , 3 Sidi Mohamed Ben Abdellah University , Fez , Morocco , 4 Section of Nutrition and Metabolism, International Agency for Research on Cancer , Lyon , France , 5 Department of Oncology, Hassan II University Hospital of Fez, Fez, Morocco, 6 Mohammed VI University of Health Sciences , Casablanca , Morocco
2 Editor: Yi Li, Baylor College of Medicine , UNITED STATES
Data Availability Statement: All relevant data are
within the paper.
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
Breast cancer is the most common cancer in women worldwide. In the Moroccan context,
the role of well-known reproductive factors in breast cancer remains poorly documented.
The aim of this study was to explore the relationship between menstrual and reproductive
factors and breast cancer risk in Moroccan women in the Fez region.
A case±control study was conducted at the Hassan II University Hospital of Fez between
January 2014 and April 2015. A total of 237 cases of breast cancer and 237 age-matched
controls were included. Information on sociodemographic characteristics, menstrual and
reproductive history, family history of breast cancer, and lifestyle factors was obtained
through a structured questionnaire. Conditional logistic regression models were used to
estimate odds ratios and 95% confidence intervals for breast cancer by menstrual and
reproductive factors adjusted for potential confounders.
Early menarche (OR = 1.60, 95% CI: 1.08±2.38) and nulliparity (OR = 3.77, 95% CI: 1.98±
7.30) were significantly related to an increased risk of breast cancer, whereas an early age
at first full-term pregnancy was associated with a decreased risk of breast cancer (OR =
0.41, 95% CI: 0.25±0.65).
The results of this study confirm the role of established reproductive factors for breast
cancer in Moroccan women. It identified some susceptible groups at high risk of breast cancer.
Preventive interventions and screening should focus on these groups as a priority. These
results should be confirmed in a larger, multicenter study.
Breast cancer is the most commonly diagnosed cancer in women worldwide [
]. The etiology
of female breast cancer is multifactorial, and includes reproductive, genetic, lifestyle, and
environmental factors [2±5].
In North Africa, as in many regions that are either developing or in epidemiological
transition, breast cancer incidence rates have clearly risen [
]. In Morocco, breast cancer remains
the most common cancer in women, constituting about 35.8% of all new cancer diagnoses in
]. According to the most recent report of the cancer registry in Casablanca, the
agestandardized incidence rate of breast cancer increased from 35.0 to 49.5 per 100 000 women
between 2004 and 2012, showing an annual increase of 3.18%. The most widely proposed
explanations for this increase are changes in reproductive behaviors (smaller number of
children, shorter duration of breastfeeding, higher age at first pregnancy), and in lifestyle and
dietary habits (higher obesity rates) among Moroccan women in the past three decades [8±10].
Numerous epidemiological studies performed throughout the world have confirmed the
role of many reproductive factors, such as age at menarche, age at first pregnancy, age at
menopause, parity, and breastfeeding, in the etiology of breast cancer [
However, evidence suggests that international variation in the burden of breast cancer
reflects differences in the patterns of risk factors [
]. In the Moroccan context, the role of
well-known reproductive factors in breast cancer remains poorly documented, and it is
probable that unidentified exposures specific to Moroccan women may play an important role.
The aim of this case±control study was to explore the relationship between menstrual and
reproductive factors and breast cancer risk in Moroccan women in the Fez region. To the best
of our knowledge, this is one of the first epidemiological studies on risk factors for breast
cancer in Morocco.
Study design and setting
The Fez Breast Cancer Study is a case±control study, conducted at the Hassan II University
Hospital of Fez, ranked as one of the most important medical centers in Morocco, covering
more than 3 million people in the Fez region.
In this study, a total of 474 women (237 cases and 237 age-matched controls) were recruited
between January 2014 and April 2015.
Cases were patients recently diagnosed with histologically confirmed breast cancer (all
consecutive cases), admitted during the study period to the Medical Oncology Center at the
University Hospital of Fez, which is a referral center for breast cancer in the region.
Controls were healthy women with no history of cancer, who accompanied patients to the
consultations department at the University Hospital of Fez. This department provides health
consultations to patients for various medical and surgical specialties. Women who
accompanied patients with any type of cancer were excluded from this study. Control subjects were
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individually matched to cases by age (age at cancer diagnosis ± 3 years), and they were
recruited at approximately the same time as the recruitment of cases.
Because of the difficulty of recruiting some controls aged 60 years or older among the
women accompanying patients to the hospital, women randomly selected at the consultations
department were asked whether they could provide the telephone numbers and addresses of
other, older women, who could potentially be recruited. Women meeting the age requirement
were called by telephone, checked for inclusion criteria, and invited to participate in this
study. The socioeconomic characteristics such as income and education level of controls
recruited with this method are approximately the same as those of other controls (data not
The participation rate in this study was 97.1% (237/244) for cases and 92.5% (237/256) for
This study was approved by the Ethics Committee of the Hassan II University Hospital of Fez.
Participation in this study was strictly voluntary, and all subjects were informed about the
right to withdraw at any time without giving an explanation. All information collected from
participants was kept confidential. The Fez Breast Cancer Study was conducted according to
the guidelines of the Declaration of Helsinki. Written informed consent to participate in the
study was obtained from all study participants before the interviews were conducted.
Data collection and measurements
Data were collected through face-to-face interviews by six trained interviewers. The pre-tested
structured questionnaire included information on sociodemographic characteristics (e.g., age,
educational level, marital status, area of residence, occupation, monthly household income),
menstrual and reproductive history (e.g., age at menarche, regularity of menstrual cycle, age at
menopause, parity, age at first full-term pregnancy, history of abortions, history of
miscarriages, use of oral contraceptives, breastfeeding, postmenopausal hormone use), family history
of breast cancer in first- and second-degree relatives, alcohol consumption, smoking, and
passive smoking (the inhalation of tobacco smoke from people who are smoking nearby in the
home or at work).
Current weight and height were measured by the interviewers according to the
recommendations of Lohman et al. (1988) [
]. Body mass index (BMI) was calculated as the weight in
kilograms divided by the square of the height in meters. BMI was classified using cut-off points
recommended by WHO . The categories underweight (<18.5 kg/m2) and normal weight
(18.5±24.9 kg/m2) were grouped into one category (<25 kg/m2), due to the low number of
women in these categories. Information on physical activity was obtained using a Global
Physical Activity Questionnaire (GPAQ2), which includes estimates of physical activity in three
domains (activity at work, activity travelling to and from places, recreational activities) as well
as sedentary behavior . Definitions of these three domains are given in (WHO 2016) .
The Metabolic Equivalent (MET)-minutes per week were calculated based on the published
GPAQ Analysis Guide . The intensity of physical activity was classified into three
categories: light intensity (<600 MET-minutes per week), moderate intensity (600±3000
MET-minutes per week), and vigorous intensity ( 3000 MET-minutes per week).
To determine menopausal status at recruitment, women were considered to be
premenopausal if they reported regular menstrual cycles over the previous 12 months and
postmenopausal in case of absence of menstruation in the last 12 months. Women who had missing data
on menopausal status were considered to be premenopausal if they were younger than 45
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years, and postmenopausal if they were older than 54 years, because in a previous study
conducted in Moroccan women, the median age at menopause was estimated to be 50.25 years
]. Women in the age range 45±54 years were assigned to an unknown menopausal status.
Frequencies (percentages) for qualitative variables and mean values (± standard deviation) for
continuous variables were calculated. Conditional logistic regression models were used to
identify the reproductive factors associated with breast cancer. Multivariate adjusted odds
ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated, adjusting for
area of residence (urban, rural), monthly household income ( 2000, >2000 Moroccan
Dirham), age at menarche (continuous), menopausal status and age at menopause combined
(premenopausal, postmenopausal <46.5 years, postmenopausal 46.5 years, missing), parity
(parous, nulliparous), age at first full-term pregnancy (nulliparous, <20 years, 20 years),
family history of breast cancer (yes/no), and BMI (<25, 25±29, 30 kg/m2). None of other
potential confounders listed in Table 1 changed our risk estimates by 10% or more. Median
values in controls were used as cut-off points for age at menarche, age at menopause, age at
first full-term pregnancy, and breastfeeding per child. BMI information was missing for three
controls, and these missing values were replaced with the median value in controls. Data
analysis was performed using Stata/IC 14.1 software.
The purpose of this study was to explore the relationship between menstrual and reproductive
factors and breast cancer risk among Moroccan women in the Fez region.
The results from this case±control showed that early menarche ( 13 years) and nulliparity
were significantly associated with an increased risk of breast cancer, whereas an early age at first
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PLOS ONE | https://doi.org/10.1371/journal.pone.0191333
(n = 237)
full-term pregnancy (<20 years) was associated with a significantly decreased risk of breast
Consistent with findings from other epidemiological studies in Morocco [
] and other
countries [19±22], we found a significant association between early age at menarche and an
increased risk of breast cancer. A meta-analysis of 117 epidemiological studies confirmed that
young age at menarche is associated with increased risk of breast cancer [
meta-analysis showed that for every year of younger age at menarche, breast cancer risk increased by a
factor of 1.05 (95% CI: 1.04±1.05). The biological explanation for this association is based on
the early and prolonged exposure of the breast epithelium to estrogens produced during the
period of activity of the ovaries [
In most studies in the literature, nulliparity was one of the strongest risk factors for breast
]. In line with these studies, we also found a positive association between
nulliparity and breast cancer risk. Several mechanisms have been proposed to explain the potential
protective effect of pregnancy on breast cancer, such as decreased levels of estrogen and
progesterone, increased levels of sex hormone-binding globulin, and pregnancy-induced
differentiation of breast tissue [
]. Further investigations are needed to explore the mechanisms
underlying the positive association between nulliparity and breast cancer risk reported in our
In addition, a decrease in breast cancer risk with an increasing number of live births has
been reported by many studies [29±32]. Clavel-Chapelon and Gerber indicated that each
fullterm pregnancy leads to a 3% reduction in the risk of breast cancer diagnosed early or in
premenopausal women, while this reduction reaches 12% for cancers diagnosed in
postmenopausal women [
In our study, an early age at first full-term pregnancy was associated with a reduced risk of
breast cancer. Women who were younger than 20 years at first full-term pregnancy had a
significant decreased risk of breast cancer compared with women who were older than 20 years.
This finding may be explained by the fact that, at the first birth, the mammary epithelial cells,
which have a high degree of terminal differentiation, are capable of metabolizing carcinogens
and can repair DNA damage more efficiently [
]. Our result were in line with the findings of
previously published studies in other populations [
There is evidence suggesting that breastfeeding may have a protective effect on breast
cancer risk [
]. A meta-analysis including 50 302 women with breast cancer and 96 973
controls found that the relative risk of breast cancer decreased by 4.3% for every 12 months of
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Crude OR (95% CI)
Adjusted ORa (95% CI)
OR: odds ratio; CI: confidence interval.
aOdds ratios adjusted for area of residence (urban, rural), monthly household income ( 2000, >2000 Moroccan Dirham), age at menarche (continuous), menopausal
status and age at menopause combined (premenopausal, postmenopausal <46.5 years, postmenopausal 46.5 years, missing), parity (parous, nulliparous), age at first
full-term pregnancy (nulliparous, <20 years, 20 years), family history of breast cancer (yes/no), and body mass index (<25, 25±29, 30 kg/m2);
bAmong postmenopausal women;
cAmong breastfeeding women.
]. Other studies also supported the inverse relationship between breastfeeding
and breast cancer [25,37±39]. In our study, there is a lack of significant association between
breastfeeding and breast cancer risk. This may be related to the prolonged breastfeeding
practiced by both cases and controls in our study population and, more generally, in the region.
The distinct exposure pattern of our population should be considered in the interpretation. In
this study, we assessed the relationship between breastfeeding and breast cancer risk without
considering hormone receptor status. Some studies have suggested that the effect of
breastfeeding may differ by breast cancer subtypes [40±43]. Therefore, further studies are required
to explore probable differences by tumor subtypes in our population.
A late age at menopause is a well-established risk factor for breast cancer [
] have shown a significant association between a later age at menopause
and increased risk of breast cancer, while other studies, including ours, failed to report a
7 / 12
significant association [
]. The higher risk of developing breast cancer in women with a
late age at menopause may be explained by both longer duration of and higher level of
exposure to estrogen and progesterone experienced by these women [
In agreement with results from another case±control study in the region [
], our study did
not find a statistically significant association between oral contraceptive use and risk of breast
cancer. However, some previous studies found that oral contraceptive use was associated with
an increased risk of breast cancer [
]. Age at starting oral contraceptive use might be
determinant in the association between oral contraceptive use and breast cancer risk; however, we
did not have information on that variable, so we were unable to further assess its effect in our
The relationship between history of abortions and breast cancer risk is controversial
]. In the current study, we found that history of abortions is not significantly associated
with breast cancer risk. This result is in line with a meta-analysis of 53 epidemiological
studies, including 83 000 women with breast cancer from 16 countries [
]. However, a
recent meta-analysis conducted in China reported a positive association between breast
cancer risk and induced abortion [
]. More details about abortion (number, age at abortion)
may provide important information on the relationship between abortion and breast cancer
Our study has some limitations. First, due to the retrospective nature of this study, most of
our data were self-reported by women, and could be subject to recall bias. However, women
were not aware of potential risk factors for breast cancer, and therefore measurement error is
most likely to be random (non-differential misclassification). Another limitation is the
relatively small number of cases and controls, which impaired stratified analysis by menopausal
status, and factors with small effect on breast cancer risk may have been missed because of low
statistical power. In addition, considering that cases were significantly more likely to live in a
rural area and to have a lower monthly household income, compared with controls, the
possibility of selection bias cannot be ruled out in this study.
The probable explanation is that controls were recruited from a consultations department
located in an urban area, and those accompanying patients to this department are more likely
to reside in an urban area and consequently their socioeconomic status may have been
relatively high. The epidemiological transition and the rise of chronic diseases associated with
urban lifestyles that are beginning to be seen among Moroccan women of lower
socioeconomic status may be another possible explanation for this difference. It is therefore particularly
important to explore the relationship between the socioeconomic level and breast cancer risk
in the Moroccan context.
Moreover, in this study some variables were excluded from the analysis, due to the low
number of women with certain habits in the region of the study (the frequency of
postmenopausal hormone use was 1.68% in cases and 0.84% in controls, the frequency of smoking was
4.64% in cases and 0.42% in controls, and the frequency of alcohol consumption was 0.00% in
cases and 0.42% in controls).
This study has several strengths, including an age-matched case±control design, a high
participation rate in cases and controls, and histological confirmation of breast cancer. Moreover,
this is the first epidemiological study to investigate the relationship between reproductive
factors and risk of breast cancer in the Fez region.
Our study confirms the role of established reproductive factors for breast cancer in
Moroccan women. Studies exploring changes in the pattern of breast cancer risk factors in Morocco
] suggest that adoption of a Western lifestyle, birth-control policies, and changes in
dietary habits might have resulted in earlier age at menarche, later age of marriage and first
pregnancy, and a decline in fertility.
8 / 12
Finally, the results of this study identified some susceptible groups at high risk of breast
cancer. Preventive interventions and screening should focus on these groups as a priority. These
results should be confirmed in a larger, multicenter study to support the generalization of the
results to all Moroccan women.
Rhazi. The authors would like to thank the staff of the consultations department at the University Hospital of Fez, for their assistance in data collection, and all the women who participated in this study. Special thanks also to Dr Karen MuÈller for English editing.
Conceptualization: Mohamed Khalis, Nawfel Mellas, Samira Elfakir, Hafida Charaka, Chakib
Nejjari, Karima El Rhazi.
Data curation: Mohamed Khalis, Nawfel Mellas, Hafida Charaka, Chakib Nejjari, Karima El
Formal analysis: Mohamed Khalis, Barbara Charbotel, VeÂronique Chajès, Sabina Rinaldi,
AureÂlie Moskal, Carine Biessy, Laure Dossus, Emmanuel Fort, Isabelle Romieu, Karima El
Investigation: Mohamed Khalis, Samira Elfakir, Chakib Nejjari, Karima El Rhazi.
Methodology: Mohamed Khalis, Samira Elfakir, Hafida Charaka, Chakib Nejjari, Karima El
Supervision: Barbara Charbotel, Chakib Nejjari, Karima El Rhazi.
Writing ± original draft: Mohamed Khalis.
Writing ± review & editing: Mohamed Khalis, Barbara Charbotel, VeÂronique Chajès, Sabina
Rinaldi, AureÂlie Moskal, Carine Biessy, Laure Dossus, Inge Huybrechts, Emmanuel Fort,
Nawfel Mellas, Samira Elfakir, Hafida Charaka, Chakib Nejjari, Isabelle Romieu, Karima El
9 / 12
World Health Organization, ªObesity: preventing and managing the global epidemic,º WHO Technical
Report Series 894, WHO, Geneva, Switzerland, 2000;894:i±xii, 1±253
World Health Organization. Global Physical Activity Questionnaire (GPAQ). http://www.who.int/chp/
steps/GPAQ/en/. Accessed February 25, 2016
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