In this hospital-based case–control study of Iranian women, multiparity was a strong protective factor for postmenopausal breast cancer. Family history of breast cancer, oral contraceptive use and increasing BMI were associated with increased risks of postmenopausal breast cancer, while there were no significant associations with age at menarche, age at first childbearing, height, education and breastfeeding. The estimated attributable fraction combined for parity less than 7 children and overweight/obesity (BMI > 25) accounted for approximately 64% of breast cancer among postmenopausal women in Iran.
To the best of our knowledge, this is the largest case–control study of postmenopausal breast cancer in Iran. Nonetheless, our study has some important limitations. Hospital-based case–control studies are particularly susceptible to selection bias . We are confident that our case-women were representative for all incident breast cancers in our study area. However, because population-based sampling of controls is not feasible in Iran, we had to rely on less optimal approaches for control selection. Although the indicators shown in Table 2 are reassuring, there is no mechanism whereby we can document that our controls were indeed representative for the prevalence of risk factors in the person-time that gave rise to our cases. Differential misclassification of exposure is another possible limitation. Such misclassification could arise both because cases and controls were interviewed by different nurses and because they recall or report differently. Reassuringly, however, our main findings were related to measured height and weight and to number of children, arguably factors with little opportunity for misclassification. Hence, we feel confident that the strong associations we found in relation to BMI and parity cannot possibly have arisen due to differential misclassification. In addition, we did not collect information about hormone replacement therapy (HRT), an established risk factor for breast cancer . However, similar to many Asian countries [20, 21], less than one per cent of Iranian women aged 50 years and older used HRT, often following surgical menopause . Thus, HRT is an unlikely confounder in our study. Previous studies focusing on the association between parity and breast cancer have primarily been conducted in high-risk western countries among women with generally low parity and therefore limited possibilities to explore the association between parity and breast cancer in detail. A population-based study in Finland found that women with at least five births had a significantly decreased risk of breast cancer (SIR = 0.55), especially postmenopausal breast cancer , and a similar reduction in risk was reported for women with at least seven childbirths in Nigeria . In our study, the protective effect of women with at least 7 childbirths was even stronger than the risk reductions reported from Finland and Nigeria. Socio-cultural differences may partly account for the differences of the parity-related reduced breast cancer risk between study populations.
We found that the grand multiparous women differed from those with fewer childbirths; they were less educated, had a younger age at first pregnancy, breastfed their children for longer periods and were less likely to use oral contraceptives. We find it likely that the protective effect of grand multiparity can to a large extent be explained by unmeasured lifestyle factors, which distort the association away from the null and strengthened it. For example, differences between women with high and low parity with respect to exposures to traditional low calorie high fiber diets, physical activity due to traditional way of life, early life events and conditions may play a role for the breast cancer risk in parous women . Further knowledge about such differences in Iranian women with high and low parity may provide important clues with respect to prevention of late onset breast cancer.
In most studies, the association between parity and breast cancer risk is modified by age at first pregnancy. MacMahon et al. discovered that younger age at first childbearing reduces the risk of breast cancer . This association is biologically plausible and has also been demonstrated in experimental rodent models . The protective effect of age at first full-term pregnancy might be stronger for premenopausal than postmenopausal breast cancer . Some epidemiological studies have, however, failed to reveal any relationship between breast cancer and age at first full-term pregnancy independent of parity [24, 29]. We found no independent association between age at first childbirth and breast cancer. In the present study age at first pregnancy was in a lower range than in most other studies. For example, 90 percent of our controls had their first pregnancy before 25 years of age compared with 35 and 68 percent respectively in studies in the US  and New Zealand .
We found no significant association between breastfeeding and risk of postmenopausal breast cancer. Results of a collaborative study, combining epidemiological data from 47 studies, found a protective role of breastfeeding on the risk of breast cancer . However, a meta-analysis  and several studies [32–34] have shown that the weak protective effect of lactation is confined to premenopausal breast cancer. In our previous study of premenopausal breast cancer in Iranian women, we found a protective effect of breast feeding .
We found no significant association between education and breast cancer after adjusting for other variables in multivariable analysis. In Iran, womens’ literacy rates increased from 57% to 97% between 1966 and 1996 in urban areas, while corresponding increase in rural areas was even more dramatic (from 5% to 86%) . In 1998, 52% of students admitted to the governmental universities were women, which increased to 65% in 2007 . Although education may have not directly affected breast cancer in Iran, the dramatic increasing rate of educated women is related to postponed marriage and childbearing, more oral contraceptive use and lower parity [12, 37].
The positive association between BMI and risk of postmenopausal breast cancer in our study is consistent with the results of other studies in high-risk and low-risk countries[38–40]. In stratified analysis, we also found that this association was restricted to older women, while there was no significant association between BMI and breast cancer diagnosed below 58 years. A recent national survey revealed that 67% of Iranian women in the age group 55 to 64 years are overweight or obese (BMI ≥ 25) . Among women aged 55 to 64 years, the prevalence of overweight and obesity was 64% among controls and 75% among cases (data not shown). In the report of International Obesity Task Force, Middle East has one of the highest prevalence rates of obesity in the world . Hence, along with aging of the population, obesity will play a growing role in the burden of postmenopausal breast cancer in Iran and other Middle Eastern countries the coming decades. The present study showed that about 25% of postmenopausal breast cancers in Iran could be prevented if all women had BMI ≤ 25.
Iran experienced a high fertility rate until the 1980s . In 1980, the total fertility rate was about seven children per women, which decreased to 2.8 children per woman in 1996 and 1.7 in 2007 [36, 37]. It is estimated that, with assuming consistency of age-specific rates, Iran will, only due to the demographic transition, face a doubling in the number of new cases of breast cancer in 2030 . However, this study indicates that 64% of postmenopausal breast cancer in Iran could be attributed to parity lower than 7 births and overweight/obesity (BMI > 25). Thus, with current decline in parity, increasing prevalence of obesity and social changes toward westernization, it is clear that due to increasing age-specific incidence we may expect an even more rapid growth, especially in postmenopausal women. Such trends may also be expected in other Middle Eastern and Asian countries with similar pattern of socio-cultural and demographic transitions. In addition to demographic differences, the declining parity in younger birth cohorts may also explain the current ten years lower mean age at onset of breast cancer in low- and middle-income countries compared with high-income countries [13, 43–45].