Menstrual and reproductive factors and risk of breast cancer: A case-control study in the Fez region, Morocco

Abstract

Background

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.

Methods

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.

Results

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).

Conclusion

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.

About the Authors:

Mohamed Khalis

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliations Department of Epidemiology, Faculty of Medicine and Pharmacy, Fez, Morocco, University Claude Bernard Lyon1, Ifsttar, UMRESTTE, UMR T_9405, Lyon, France, Sidi Mohamed Ben Abdellah University, Fez, Morocco

ORCID logo http://orcid.org/0000-0003-4639-049X

Barbara Charbotel

Roles Formal analysis, Supervision, Writing – review & editing

Affiliation: University Claude Bernard Lyon1, Ifsttar, UMRESTTE, UMR T_9405, Lyon, France

Véronique Chajès

Roles Formal analysis, Writing – review & editing

Affiliation: Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France

Sabina Rinaldi

Roles Formal analysis, Writing – review & editing

Affiliation: Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France

Aurélie Moskal

Roles Formal analysis, Writing – review & editing

Affiliation: Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France

Carine Biessy

Roles Formal analysis, Writing – review & editing

Affiliation: Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France

Laure Dossus

Roles Formal analysis, Writing – review & editing

Affiliation: Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France

Inge Huybrechts

Roles Writing – review & editing

Affiliation: Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France

Emmanuel Fort

Roles Formal analysis, Writing – review & editing

Affiliation: University Claude Bernard Lyon1, Ifsttar, UMRESTTE, UMR T_9405, Lyon, France

Nawfel Mellas

Roles Conceptualization, Data curation, Writing – review & editing

Affiliation: Department of Oncology, Hassan II University Hospital of Fez, Fez, Morocco

Samira Elfakir

Roles Conceptualization, Investigation, Methodology, Writing – review & editing

Affiliations Department of Epidemiology, Faculty of Medicine and Pharmacy, Fez, Morocco, Sidi Mohamed Ben Abdellah University, Fez, Morocco

Hafida Charaka

Roles Conceptualization, Data curation, Methodology, Writing – review & editing

Affiliations Department of Epidemiology, Faculty of Medicine and Pharmacy, Fez, Morocco, Sidi Mohamed Ben Abdellah University, Fez, Morocco

Chakib Nejjari

Roles Conceptualization, Data curation, Investigation, Methodology, Supervision, Writing – review & editing

Affiliations Department of Epidemiology, Faculty of Medicine and Pharmacy, Fez, Morocco, Mohammed VI University of Health Sciences, Casablanca, Morocco

Isabelle Romieu

Roles Formal analysis, Writing – review & editing

Affiliation: Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France

Karima El Rhazi

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Writing – review & editing

Affiliations Department of Epidemiology, Faculty of Medicine and Pharmacy, Fez, Morocco, Sidi Mohamed Ben Abdellah University, Fez, Morocco

Introduction

Breast cancer is the most commonly diagnosed cancer in women worldwide [1]. 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 [6]. In Morocco, breast cancer remains the most common cancer in women, constituting about 35.8% of all new cancer diagnoses in women [7]. According to the most recent report of the cancer registry in Casablanca, the age-standardized 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 [2,11,12].

However, evidence suggests that international variation in the burden of breast cancer reflects differences in the patterns of risk factors [13]. 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.

Methods

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.

Study subjects

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 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 shown).

The participation rate in this study was 97.1% (237/244) for cases and 92.5% (237/256) for controls.

Ethical considerations

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) [14]. 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 [15]. 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 [16]. Definitions of these three domains are given in (WHO 2016) [16]. The Metabolic Equivalent (MET)-minutes per week were calculated based on the published GPAQ Analysis Guide [16]. 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 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 [17]. Women in the age range 45–54 years were assigned to an unknown menopausal status.

Statistical analysis

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.

[Figure omitted. See PDF.]

Table 1. Baseline characteristics of case and control subjects [number (percentage) or mean ± standard deviation].

https://doi.org/10.1371/journal.pone.0191333.t001

Results

Table 1 presents the baseline characteristics of the subjects by case–control status. The mean age of the study population (cases and controls) was 48.6 years. Compared with control subjects, cases were more likely to be postmenopausal, nulliparous, younger at menarche, and older at first pregnancy, to live in a rural area, and to have a higher BMI, a family history of breast cancer, a lower monthly household income, and a longer interval between age at menarche and age at first full-term pregnancy. Cases and control subjects did not show differences in marital status, educational level, occupation, passive smoking, intensity of physical activity, age at menopause, breastfeeding per child, or interval between age at menarche and age at menopause.

Table 2 shows crude and adjusted ORs and 95% CIs for breast cancer by menstrual and reproductive factors. After adjustment for potential confounders, women who reached menarche at age ≤13 years had a significantly higher risk of breast cancer, compared with women who reached menarche after age 13 years (OR = 1.60, 95% CI: 1.08–2.38). Nulliparous women had a significantly higher risk of breast cancer compared with parous women (OR = 3.77, 95% CI: 1.98–7.30). Women who were younger than 20 years at their first full-term pregnancy had a significantly lower risk of developing breast cancer, compared with women who were older than 20 years at their first full-term pregnancy (OR = 0.41, 95% CI: 0.25–0.65).

[Figure omitted. See PDF.]

Table 2. Association between menstrual and reproductive factors and breast cancer risk.

https://doi.org/10.1371/journal.pone.0191333.t002

Finally, there was no significant association with breast cancer risk for irregularity of menstrual cycle, age at menopause, history of miscarriages and abortions, breastfeeding per child, or history of oral contraceptive use.

Discussion

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 full-term pregnancy (<20 years) was associated with a significantly decreased risk of breast cancer.

Consistent with findings from other epidemiological studies in Morocco [18] 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 [23]. This 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 [24].

In most studies in the literature, nulliparity was one of the strongest risk factors for breast cancer [21,25,26]. 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 [27,28]. Further investigations are needed to explore the mechanisms underlying the positive association between nulliparity and breast cancer risk reported in our study.

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 full-term 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 [33].

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 [28]. Our result were in line with the findings of previously published studies in other populations [26,29,34,35].

There is evidence suggesting that breastfeeding may have a protective effect on breast cancer risk [36]. 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 breastfeeding [36]. 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 [12]. Numerous studies [22,30,34,44] 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 significant association [19,45]. 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 [12].

In agreement with results from another case–control study in the region [20], 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 [46,47]. 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 study.

The relationship between history of abortions and breast cancer risk is controversial [48]. 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 [49]. However, a recent meta-analysis conducted in China reported a positive association between breast cancer risk and induced abortion [50]. More details about abortion (number, age at abortion) may provide important information on the relationship between abortion and breast cancer risk.

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 [8,10] 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.

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.

Acknowledgments

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 Müller for English editing.

Citation: Khalis M, Charbotel B, Chajès V, Rinaldi S, Moskal A, Biessy C, et al. (2018) Menstrual and reproductive factors and risk of breast cancer: A case-control study in the Fez region, Morocco. PLoS ONE 13(1): e0191333. https://doi.org/10.1371/journal.pone.0191333

References

1. Ferlay J, Héry C, Autier P, Sankaranarayanan R. Global burden of breast cancer. In: Breast cancer epidemiology. Springer, New York; 2010. p. 1–19

2. Key TJ, Verkasalo PK, Banks E. Epidemiology of breast cancer. The Lancet Oncology. 2001 Mar;2(3):133–40. pmid:11902563

3. MacMahon B. Epidemiology and the causes of breast cancer. Int J Cancer. 2006 May 15;118(10):2373–8. pmid:16358260

4. Easton DF, Narod SA, Ford D, Steel M. The genetic epidemiology of BRCA1. Breast Cancer Linkage Consortium. Lancet. 1994 Sep 10;344(8924):761 pmid:7915813

5. Coughlin SS, Smith SA. The Impact of the Natural, Social, Built, and Policy Environments on Breast Cancer. J Environ Health Sci. 2015;1(3). pmid:26457327

6. Gray J, Evans N, Taylor B, Rizzo J, Walker M. State of the evidence: the connection between breast cancer and the environment. Int J Occup Environ Health. 2009;15(1):43–78. pmid:19267126

7. Lalla Salma Foundation, Prevention, Detection and Treatment of Cancers. Registry of Greater Casablanca 2008–2012. Rabat: 2017. http://www.contrelecancer.ma/fr/documents/registre-des-cancers-de-la-region-du-grand-casab-2/

8. Corbex M, Bouzbid S, Boffetta P. Features of breast cancer in developing countries, examples from North-Africa. European Journal of Cancer. 2014 Jul;50(10):1808–18. pmid:24767469

9. Bouchbika Z, Haddad H, Benchakroun N, Eddakaoui H, Kotbi S, Megrini A, et al. Cancer incidence in Morocco: report from Casablanca registry 2005–2007. Pan African Medical Journal. 2013;16:31. pmid:24570792

10. Khalis M, El Rhazi K, Charaka H, Chajès V, Rinaldi S, Nejjari C, et al. Female Breast Cancer Incidence and Mortality in Morocco: Comparison with Other Countries. Asian Pac J Cancer Prev. 2016 01;17(12):5211–6. pmid:28125863

11. Kelsey JL, Gammon MD, John EM. Reproductive factors and breast cancer. Epidemiol Rev. 1993;15(1):36–47. pmid:8405211

12. Parsa P, Parsa B. Effects of reproductive factors on risk of breast cancer: a literature review. Asian Pac J Cancer Prev. 2009 Dec;10(4):545–50 pmid:19827866

13. DeSantis CE, Bray F, Ferlay J, Lortet-Tieulent J, Anderson BO, Jemal A. International Variation in Female Breast Cancer Incidence and Mortality Rates. Cancer Epidemiology Biomarkers & Prevention. 2015 Oct 1;24(10):1495–506. pmid:26359465

14. Lohman TG, Roche AF, Martorell R. Anthropometric standardization reference manual. Human kinetics books; 1988

15. World Health Organization, “Obesity: preventing and managing the global epidemic,” WHO Technical Report Series 894, WHO, Geneva, Switzerland, 2000;894:i–xii, 1–253

16. World Health Organization. Global Physical Activity Questionnaire (GPAQ). http://www.who.int/chp/steps/GPAQ/en/. Accessed February 25, 2016

17. Loukid M, Hilali MK, Bernis C. Age at natural menopause in Marrakech, Morocco and prevalence of menopausal symptoms. Bull Mem Soc Anthropol Paris 2007; 19:65–75

18. Laamiri FZ, Bouayad A, Hasswane N, Ahid S, Mrabet M, Amina B. Risk Factors for Breast Cancer of Different Age Groups: Moroccan Data? Open Journal of Obstetrics and Gynecology. 2015;5(02):79.

19. Xu YL, Sun Q, Shan GL, Zhang J, Liao HB, Li SY, et al. A case-control study on risk factors of breast cancer in China. Arch Med Sci. 2012;8(2):303–9. pmid:22662004

20. Msolly A, Gharbi O, Ben Ahmed S. Impact of menstrual and reproductive factors on breast cancer risk in Tunisia: a case-control study. Med Oncol. 2013;30(1):480. pmid:23377925

21. Gao YT, Shu XO, Dai Q, Potter JD, Brinton LA, Wen W, et al. Association of menstrual and reproductive factors with breast cancer risk: results from the Shanghai Breast Cancer Study. Int J Cancer. 2000 Jul 15;87(2):295–300 pmid:10861490

22. Hsieh CC, Trichopoulos D, Katsouyanni K, Yuasa S. Age at menarche, age at menopause, height and obesity as risk factors for breast cancer: associations and interactions in an international case-control study. Int J Cancer. 1990 Nov 15;46(5):796–800 pmid:2228308

23. Collaborative Group on Hormonal Factors in Breast Cancer. Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. The Lancet Oncology. 2012 Nov;13(11):1141–51. pmid:23084519

24. Clavel-Chapelon F, E3N Group. Cumulative number of menstrual cycles and breast cancer risk: results from the E3N cohort study of French women. Cancer Causes Control. 2002 Nov;13(9):831–8 pmid:12462548

25. Huo D, Adebamowo CA, Ogundiran TO, Akang EE, Campbell O, Adenipekun A, et al. Parity and breastfeeding are protective against breast cancer in Nigerian women. British Journal of Cancer. 2008 Mar 11;98(5):992–6. pmid:18301401

26. Ewertz M, Duffy SW, Adami HO, Kvale G, Lund E, Meirik O, et al. Age at first birth, parity and risk of breast cancer: a meta-analysis of 8 studies from the Nordic countries. Int J Cancer. 1990 Oct 15;46(4):597–603 pmid:2145231

27. Lee E, Ma H, McKean-Cowdin R, Van Den Berg D, Bernstein L, Henderson BE, et al. Effect of reproductive factors and oral contraceptives on breast cancer risk in BRCA1/2 mutation carriers and noncarriers: results from a population-based study. Cancer Epidemiol Biomarkers Prev. 2008 Nov 1;17(11):3170–8. pmid:18990759

28. Russo J, Moral R, Balogh GA, Mailo D, Russo IH. The protective role of pregnancy in breast cancer. Breast Cancer Res. 2005 Jun;7(3):131–42. pmid:15987443

29. Nagata C, Hu YH, Shimizu H. Effects of menstrual and reproductive factors on the risk of breast cancer: meta-analysis of the case-control studies in Japan. Jpn J Cancer Res. 1995 Oct;86(10):910–5 pmid:7493908

30. Kawai M, Minami Y, Kuriyama S, Kakizaki M, Kakugawa Y, Nishino Y, et al. Reproductive factors, exogenous female hormone use and breast cancer risk in Japanese: the Miyagi Cohort Study. Cancer Causes Control. 2010 Jan;21(1):135–45. pmid:19816778

31. Lambe M, Hsieh CC, Chan HW, Ekbom A, Trichopoulos D, Adami HO. Parity, age at first and last birth, and risk of breast cancer: a population-based study in Sweden. Breast Cancer Res Treat. 1996;38(3):305–11 pmid:8739084

32. Magnusson CM, Persson IR, Baron JA, Ekbom A, Bergstrom R, Adami HO. The role of reproductive factors and use of oral contraceptives in the aetiology of breast cancer in women aged 50 to 74 years. Int J Cancer. 1999 Jan 18;80(2):231–6 pmid:9935204

33. Clavel-Chapelon F, Gerber M. Reproductive factors and breast cancer risk. Do they differ according to age at diagnosis? Breast Cancer Res Treat. 2002 Mar;72(2):107–15 pmid:12038701

34. Oran B, Celik I, Erman M, Baltali E, Zengin N, Demirkazik F, et al. Analysis of menstrual, reproductive, and life-style factors for breast cancer risk in Turkish women: a case-control study. Med Oncol. 2004;21(1):31–40. pmid:15034211

35. Chie WC, Hsieh C, Newcomb PA, Longnecker MP, Mittendorf R, Greenberg ER, et al. Age at any full-term pregnancy and breast cancer risk. Am J Epidemiol. 2000 Apr 1;151(7):715–22 pmid:10752799

36. Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet. 2002 Jul;360(9328):187–95. pmid:12133652

37. Awatef M, Olfa G, Imed H, Kacem M, Imen C, Rim C, et al. Breastfeeding reduces breast cancer risk: a case-control study in Tunisia. Cancer Causes Control. 2010 Mar;21(3):393–7. pmid:19921444

38. Tryggvadottir L, Tulinius H, Eyfjord JE, Sigurvinsson T. Breastfeeding and reduced risk of breast cancer in an Icelandic cohort study. Am J Epidemiol. 2001 Jul 1;154(1):37–42 pmid:11427403

39. Zhou Y, Chen J, Li Q, Huang W, Lan H, Jiang H. Association between breastfeeding and breast cancer risk: evidence from a meta-analysis. Breastfeed Med. 2015 Apr;10(3):175–82. pmid:25785349

40. Martinez ME, Wertheim BC, Natarajan L, Schwab R, Bondy M, Daneri-Navarro A, et al. Reproductive factors, heterogeneity, and breast tumor subtypes in women of mexican descent. Cancer Epidemiol Biomarkers Prev. 2013 Oct;22(10):1853–61. pmid:23950213

41. Turkoz FP, Solak M, Petekkaya I, Keskin O, Kertmen N, Sarici F, et al. Association between common risk factors and molecular subtypes in breast cancer patients. Breast. 2013 Jun;22(3):344–50. pmid:22981738

42. Redondo CM, Gago-Domínguez M, Ponte SM, Castelo ME, Jiang X, García AA, et al. Breast feeding, parity and breast cancer subtypes in a Spanish cohort. PLoS ONE. 2012;7(7):e40543. pmid:22792365

43. Palmer JR, Boggs DA, Wise LA, Ambrosone CB, Adams-Campbell LL, Rosenberg L. Parity and lactation in relation to estrogen receptor negative breast cancer in African American women. Cancer Epidemiol Biomarkers Prev. 2011 Sep;20(9):1883–91. pmid:21846820

44. La Vecchia C, Negri E, Bruzzi P, Dardanoni G, Decarli A, Franceschi S, et al. The role of age at menarche and at menopause on breast cancer risk: combined evidence from four case-control studies. Ann Oncol. 1992 Sep;3(8):625–9 pmid:1450044

45. Ebrahimi M, Vahdaninia M, Montazeri A. Risk factors for breast cancer in Iran: a case-control study. Breast Cancer Res. 2002;4(5):R10. pmid:12223127

46. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet. 1996 Jun 22;347(9017):1713–27 pmid:8656904

47. Rosenberg L, Zhang Y, Coogan PF, Strom BL, Palmer JR. A Case-Control Study of Oral Contraceptive Use and Incident Breast Cancer. Am J Epidemiol. 2008 Dec 13;169(4):473–9. pmid:19074777

48. Guo J, Huang Y, Yang L, Xie Z, Song S, Yin J, et al. Association between abortion and breast cancer: an updated systematic review and meta-analysis based on prospective studies. Cancer Causes Control. 2015 Jun;26(6):811–9. pmid:25779378

49. Beral V, Bull D, Doll R, Peto R, Reeves G. Breast cancer and abortion: collaborative reanalysis of data from 53 epidemiological studies, including 83 000 women with breast cancer from 16 countries. Lancet. 2004 Mar;363(9414):1007–16. pmid:15051280

50. Huang Y, Zhang X, Li W, Song F, Dai H, Wang J, et al. A meta-analysis of the association between induced abortion and breast cancer risk among Chinese females. Cancer Causes Control. 2014 Feb;25(2):227–36. pmid:24272196