The detection of widespread contamination of human breastmilk with environmental pollutants has raised concerns regarding potential adverse health effects.1,2 A number of exogenous chemicals in breastmilk exhibit carcinogenic or xenoestrogenic activity; these chemicals include polychlorinated biphenyls (PCBs), chlorinated dioxins, chlorinated furans, polybrominated diphenylethers, polycyclic aromatic hydrocarbons, dichlorodiphenyltrichloroethane and other pesticides.3–6
Due to the persistence and accumulation of these chemicals in the human body, maternal age is an important predictor of contaminant levels in breastmilk.7 Many of these contaminants are poorly metabolized, leaving breast-feeding as the primary means of excretion.2,8 Parity has been inversely associated with breastmilk contaminant levels; first-born infants generally consume higher levels of contaminants relative to later siblings.7,9,10
Breastmilk consumption has been associated with greater levels of PCBs and related organochlorines in adipose tissue samples from children age 1–2 years.11 Studies among adults have hypothesized that organochlorine levels in adipose tissue may be related to increased breast cancer risk,12,13 although evidence is currently insufficient to support an association.14 It is unknown whether exposure to contaminants in breastmilk has the potential to increase cancer risk in adulthood.
A considerable volume of epidemiologic research has examined breastmilk consumption in infancy, birth order, and maternal age as risk factors for adult breast cancer,15–55 but no consensus has emerged. Some studies show modest decreases in breast cancer risk associated with having been breast-fed, with higher birth order, and with younger maternal age, while other studies find no association.
We explored whether maternal age and birth order associations for breast cancer risk vary according to exposure to breastmilk in infancy. We hypothesized that, due to less exposure to environmental contaminants in breastmilk, increasing birth order and younger maternal age would be associated with decreased adult breast cancer risk only among women who were breast-fed in infancy. We investigated this relation in a population-based case-control study of women in Wisconsin, USA.
Selection of Cases
We selected as cases women living in Wisconsin age 20–69 years with an incident diagnosis of invasive breast cancer in 2002–2006 reported to the state-mandated cancer registry. Those who had a listed telephone number and who reported that they had a driver’s license were eligible for participation. Telephone interviews were conducted according to institutionally approved protocols from May 2004 to November 2006. Of 2633 eligible breast cancer cases, 55 (2%) were deceased, 93 (4%) could not be located and 469 (18%) refused participation. Therefore, 2016 (77%) women were interviewed.
Selection of Controls
Using lists of licensed drivers from the Wisconsin Department of Transportation, controls were randomly selected within 5-year age strata to yield an age distribution similar to the cases. Inclusion criteria required no personal history of breast cancer and a publicly available telephone number. Of the 2781 potential controls, 7 (0.2%) were deceased, 140 (5%) could not be located, and 673 (24%) refused to participate. Interviews were obtained for 1961 (71%) of these women. Data for one interviewed control was considered unreliable by the interviewer. Hence, 1960 controls were available for analysis.
In structured telephone interviews, study participants self-reported whether they were breast-fed in infancy, how old their mother was when they were born, the number of children their mother gave birth to, and their birth order among siblings (including any deceased or half-siblings). The 35-minute interview also elicited information on reproductive history, physical activity, alcohol consumption, height and weight, oral contraceptive and postmenopausal hormone use, personal and family medical history, and demographic factors.
For each case, a reference date was defined as the registry-supplied date of invasive breast cancer diagnosis. For comparability, control subjects interviewed contemporaneously with cases were assigned an individual reference date, based on the normal distribution of days from diagnosis to interview in the cases already interviewed. Only exposures that occurred prior to the assigned reference date were included in analyses.
Odds ratios (ORs) and 95% confidence intervals (CIs) for breast cancer were computed using multivariable logistic regression models. Variables that were associated with breast cancer risk (P ≤ 0.05) in preliminarily age-adjusted models were included in multivariable models. All final models included the following covariates: age, birth order, age at menarche, age at first birth, parity, menopausal status, age at menopause, postmenopausal hormone use, family history of breast cancer in a mother or sister, height, weight at age 20, weight gain since age 20 and mammography screening. When evaluating the effect of birth order or maternal age, both variables were included in the fully adjusted model. We evaluated effect modification by including cross-product interaction terms in logistic models. All analyses were performed using SAS version 9.1 software (SAS Institute, Inc., Cary, NC).
The standardized questionnaire used in this study was also used in 2 other case-control studies conducted in 1992–1995 and 1997–2001.37,40 In these previous investigations, sequential samples of study participants were reinterviewed to evaluate the reliability of the questionnaire. Intraclass correlation coefficients and 95% confidence intervals were estimated for continuous questionnaire items, and Cohen’s kappa (κ) was used with categorical variables.56 For the breastmilk exposure status question, κ = 0.88 (95% CI = 0.79–0.97) among controls and κ = 0.96 (0.90–1.00) among cases. The intraclass correlation coefficients was 0.88 (0.86–0.90) for maternal age at the study participant’s birth among control women. Reproducibility information for the maternal age question was not available for case participants.
Table 1 presents odds ratios for breast cancer associations with established risk factors. Odds ratios decreased with older age at menarche and increasing parity, and increased with later age at first birth, later age at menopause, use of postmenopausal hormones containing estrogen plus progestin, family history of breast cancer, greater weight gain since age 20, and frequent mammographic examinations.
Table 2 displays odds ratios for breast cancer according to early life factors. In multivariable-adjusted models, maternal age (OR = 0.99 per 5-year increase [95% CI = 0.93–1.05]) and birth order (OR = 0.98 per 1-sibling increase [0.94–1.03]) were not associated with breast cancer risk.
In our study sample, 634 (31%) cases and 681 (35%) control women self-reported having been breast-fed in infancy. After multivariable adjustment, the odds ratio for breast cancer associated with exposure to breastmilk in infancy was 0.83 (CI = 0.72–0.96) compared with women who were not breast-fed (Table 2). In analyses restricted to first-born women (n = 557 cases, 514 controls), breastmilk exposure in infancy was not associated with breast cancer risk in either age-adjusted or multivariable-adjusted models (OR = 1.00 [CI = 0.77–1.31] and OR = 0.97 [0.74–1.29], respectively).
According to our a priori hypotheses, we performed birth order and maternal age analyses stratified according to whether the participant was breast-fed in infancy (Table 3). In multivariable models restricted to women who were not breast-fed, we observed a reduced risk of breast cancer associated with older maternal age (OR = 0.90 per 5-year increase [0.82–1.00]). Compared with women whose mothers were age 20–24 years at the respondent’s birth, women whose mothers were age 35 years or older had an odds ratio of 0.64 for breast cancer (95% CI = 0.45–0.92). Maternal age did not appear related to breast cancer risk among women who reported being breast-fed in infancy OR = 1.09 per 5-year increase [0.96–1.23]). In the test for interaction for breastmilk exposure by maternal age (continuous), P = 0.20 (χ2 = 1.65, 1 degree of freedom).
We observed an inverse association between breast cancer risk and increasing birth order among women who reported having been breast-fed in infancy, but not among women who were not breast-fed. Among breast-fed women, the odds ratio for breast cancer associated with each one-child increase in birth order was 0.91 (CI = 0.84–0.99). Women with 3 or more older siblings had 0.58 (0.39–0.86) times the odds of breast cancer compared with first-born women. For the interaction test of breastmilk exposure by birth order (first, second or third, fourth or higher), P = 0.28 (χ2 = 2.53, 2 degrees of freedom). We repeated the analyses in Tables 2 and 3 after excluding individuals with missing data on the variables of interest (maternal age, birth order, and breast-feeding status in infancy); odds ratios and confidence intervals remained virtually unchanged.
Our findings suggested no associations for maternal age and birth order in relation to adult breast cancer risk in the full study population. Breastmilk exposure in infancy was associated with a small decrease in the odds ratio for breast cancer overall. However, this relation was not observed among first-born women. Consistent with our initial hypotheses, higher birth order was associated with reduced breast cancer risk only among breast-fed women. However, maternal age had an unexpected inverse association with breast cancer risk among women who were not breast-fed. To our knowledge, no previous study has reported on potential interactions of birth order or maternal age with breastmilk exposure in determining adult breast cancer risk.
Previous reports have generally suggested a protective effect of younger maternal age in relation to adult breast cancer risk.21,25,26,28,43,46,50 However, an approximately equal number of reports detected weak or statistically nonsignificant positive trends24,27,33,36,52,54 or found no association.23,29,35,37,39,41,55 In 2005, Forman et al53 recalculated previous findings to create a uniform reference group of maternal age 20–24. Of 12 studies, only 2 detected a statistically significant increase in breast cancer risk among women with mothers older than 25 years43 or 35–39 years.26
Although many publications of the independent effects of birth order in relation to breast cancer risk have indicated null or statistically nonsignificant associations,17,21,24,25,29,35,36,43,47,48,50,51,54,55 at least 3 studies have shown inverse associations between birth order and breast cancer risk, either overall or among subgroups of premenopausal women.28,32,46
Within the substantial literature of breastmilk consumption in infancy in relation to adult breast cancer risk, 2 reviews42,53 and a meta-analysis57 suggest that women exposed to breastmilk as infants may have a 20%–35% reduction in breast cancer risk. A third review concluded that, while early viral etiology hypotheses58 have clearly not been upheld, results regarding the association between breastmilk exposure and breast cancer risk have been inconsistent.49
A predominant explanation for potential decreases in breast cancer incidence according to high birth order and younger maternal age is variation in the in utero hormonal environment and the potential creation of a “fertile soil” for breast carcinogenesis in adult life.59 Hormonal profiles differ according to parity with higher estrogen levels in first pregnancies.60,61 One early study also provided evidence of higher estrogen levels during pregnancy among women age 20–24 years compared with both younger and older women.62 However, a second, more recent study did not detect differences in estrogen levels during pregnancy according to maternal age.63
Another theory suggests that older maternal age results in a greater probability of genetic mutation and chromosomal aberrations; however, some controversy remains whether these effects are independent of paternal age.64 In our study, information about paternal age was not collected and was therefore unavailable for analysis.
Previous investigations of breastmilk exposure in infancy have highlighted differences relative to bottle-feeding in terms of nutrition, immunologic activity, and hormonal exposures. Some studies have indicated that environmental contaminant exposure is higher in breast-fed infants compared with formula-fed infants.65–69 Duration of breast-feeding has demonstrated a dose-response relation with PCB and dichlorodiphenyltrichloroethane exposure in the infant.11,69–72 Information on duration of breast-feeding in infancy was not available in our study.
Other limitations of our study should be considered. Birth order and maternal age were evaluated as proxies for potential relative concentration of persistent organic pollutants in breastmilk. The study questionnaire did not explicitly ask whether a participant’s older siblings were breast-fed in infancy. Therefore, our interpretation of the potential interaction between birth order and breast-feeding status is dependent on the assumption that if a woman was breast-fed in infancy, presumably her older siblings were breast-fed as well.
Confidence in our findings is strengthened by the high response rates, use of a standardized instrument with high reproducibility, and multivariable adjustment. Self-reported exposure to breast-milk in infancy has been highly correlated with mother’s reports (r = 0.74).73 Being breast-fed in infancy may also be correlated with the decision to breast-feed as an adult, a behavior known to reduce breast cancer risk.74 We additionally adjusted model estimates for duration of adult breast-feeding; odds ratios remained unchanged.
These findings suggest that maternal age and birth order associations with adult breast cancer risk may differ according to exposure to breastmilk in infancy.
We thank Henry Anderson, Patrick Remington, Laura Stephenson and the staff of the Wisconsin Cancer Reporting System, and the Wisconsin Women’s Health Study staff for assistance with data collection. We are especially grateful to the study participants, whose generosity made this research possible.
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