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Learning From Temporal Relationships: Childbirth and Breast Cancer Risk

The relationship between childbirth and breast cancer risk is complex. Childbirth is an intrinsically multidimensional exposure, and understanding its effects requires disentangling age, parity, use of contraceptive and reproductive technology, and breastfeeding, among other factors. Given this complexity, the results of the large and sophisticated analysis by Nichols and colleagues (1) provide an important advance in this field. In this examination of nearly 900000 women aged younger than 55 years who were enrolled in studies of premenopausal breast cancer, risk for breast cancer peaked 5 years after childbirth and then gradually decreased for at least 2 decades. Because of the large study population, the investigators could also examine important subgroups: The effect was not seen for women who had only 1 child or had their first child before age 25 years, and it was greatest for estrogen receptornegative cancer and among women with a family history of breast cancer. Before considering the potential implications, we must recognize that these results come with several caveats. A randomized trial of time since childbirth is not feasible, and proving causality in an observational study remains challenging. The investigators made considerable analytic effort to isolate the effect of time since childbirth from that of other factors; however, the analyses are limited to the data collected, and the contribution of unmeasured factors (such as weight gain and breast cancer screening) to the observed association cannot be addressed. Because the most straightforward comparison reported is that of uniparous versus nulliparous women, the absence of a risk increase in uniparous women adds uncertainty about the association's validity in other subgroups. The results are based on incidence of premenopausal breast cancer, which is low in all women regardless of time since childbirth. Overall, the study estimated that 3 in 100 women will develop breast cancer between ages 41 and 50 years, a number that decreases to 2.8 for nulliparous women and increases to 3.1 for those who had a child 3 to 7 years earlier. Perhaps most important, although the analysis attempts to extricate the effect of time since birth from that of having given birth (that is, parity), these effects are highly dependent in real life. Increasing parity is known to be protective for breast cancer, and estimates in most studies are similar to those seen in this analysis (HR, 0.88 per birth) (Supplement Table 4 in the article [1]). Although these results suggest that the relationship between childbirth and breast cancer risk varies by time since birth, they do not change the current consensus that parity is associated with lower risk for breast cancer, particularly after a decade or so since last childbirth. Because most women have children in their 20s and 30s and breast cancer risk does not increase substantially until after age 50 years, the population effect of a transient increase in risk in the first decade after childbirth is likely to be substantially outweighed by the overall decrease in risk that comes from increasing parity. Despite these caveats, Nichols and colleagues' results add to a large body of evidence demonstrating a transient increase in breast cancer risk after childbirth (2, 3). Given the consistency of this finding across studies, should women who have recently had a child make different decisions about breast cancer diagnosis, screening, or prevention? The answer, in general, is no. Women with breast abnormalities should have a diagnostic evaluation regardless of time since childbirth. All women should pursue the healthy lifestyle behaviors, such as exercise and limiting alcohol intake, that reduce risk for breast canceragain, regardless of childbirth history. Current eligibility criteria for intensive interventions to reduce risk (for example, chemoprevention, screening by breast magnetic resonance imaging, or even prophylactic surgery) do not depend on time since childbirth. Perhaps the only situation in which time since childbirth might influence clinical decision making is when a woman in her 40s is on the fence about beginning mammography screening. In that setting, a multiparous woman who did not have a child before age 25 years and had a child in her late 30s might choose to begin screening at age 40 years instead of waiting until age 50 years. Eventually, time since last childbirth may be included in risk prediction models for breast cancer, thereby enabling a robust evaluation of whether the additional information increases the ability of the models to discriminate between women at clinically meaningful risk thresholds. Although the clinical implications of these findings are limited, the temporal relationship between childbirth and breast cancer risk offers an important clue for the ongoing effort to identify the mechanisms linking this risk with reproductive history. Much of this effort has focused on unraveling the physiologic changes in the breast after childbirth in the hope of identifying novel targets for risk reduction (4). However, childbirth brings maternal changes beyond breast tissue, including increased time stress, altered immune function and microbiota, and accelerated aging processes (59). Understanding how these factors change over time after childbirth in women who do and do not develop breast cancer could generate new insights into the molecular pathways driving breast cancer incidence and possibly lead to new targets for intervention. More than 100 years after the first experiments linking hormonal secretion to mammary tumor development, the cellular pathways underlying these processes have remained stubbornly resistant to elucidation (10). Perhaps a renewed focus on changes in risk over time will prove to be a missing piece of the puzzle.