Pre-natal exposures and breast tissue composition: findings from a British pre-birth cohort of young women and a systematic review

Rachel Denholm, Bianca De Stavola, John H. Hipwell, Simon J. Doran, Marta C. Busana, Amanda Eng, Mona Jeffreys, Martin O. Leach, David Hawkes, Isabel dos Santos Silva

Breast density, the amount of fibroglandular tissue in the adult breast for a women's age and body mass index, is a strong biomarker of susceptibility to breast cancer, which may, like breast cancer risk itself, be influenced by events early in life. In the present study, we investigated the association between pre-natal exposures and breast tissue composition. A sample of 500 young, nulliparous women (aged approximately 21 years) from a U.K. pre-birth cohort underwent a magnetic resonance imaging examination of their breasts to estimate percent water, a measure of the relative amount of fibroglandular tissue equivalent to mammographic percent density. Information on pre-natal exposures was collected throughout the mothers' pregnancy and shortly after delivery. Regression models were used to investigate associations between percent water and pre-natal exposures. Mediation analysis, and a systematic review and meta-analysis of the published literature, were also conducted. Adjusted percent water in young women was positively associated with maternal height (p for linear trend [p t] = 0.005), maternal mammographic density in middle age (p t = 0.018) and the participant's birth size (p t < 0.001 for birthweight). A 1-SD increment in weight (473 g), length (2.3 cm), head circumference (1.2 cm) and Ponderal Index (4.1 g/cm(3)) at birth were associated with 3 % (95 % CI 2-5 %), 2 % (95 % CI 0-3 %), 3 % (95 % CI 1-4 %) and 1 % (95 % CI 0-3 %), respectively, increases in mean adjusted percent water. The effect of maternal height on the participants' percent water was partly mediated through birth size, but there was little evidence that the effect of birthweight was primarily mediated via adult body size. The meta-analysis supported the study findings, with breast density being positively associated with birth size. These findings provide strong evidence of pre-natal influences on breast tissue composition. The positive association between birth size and relative amount of fibroglandular tissue indicates that breast density and breast cancer risk may share a common pre-natal origin.