Reproductive factors and mammographic density within the International Consortium of Mammographic Density: A cross-sectional study

Abstract

Background: Elevated mammographic density (MD) for a woman's age and body mass index (BMI) is an established breast cancer risk factor. The relationship of parity, age at first birth, and breastfeeding with MD is less clear. We examined the associations of these factors with MD within the International Consortium of Mammographic Density (ICMD).

Methods: ICMD is a consortium of 27 studies with pooled individual-level epidemiological and MD data from 11,755 women without breast cancer aged 35-85 years from 22 countries, capturing 40 country-& ethnicity-specific population groups. MD was measured using the area-based tool Cumulus. Meta-analyses across population groups and pooled analyses were used to examine linear regression associations of square-root (√) transformed MD measures (percent MD (PMD), dense area (DA), and non-dense area (NDA)) with parity, age at first birth, ever/never breastfed and lifetime breastfeeding duration. Models were adjusted for age at mammogram, age at menarche, BMI, menopausal status, use of hormone replacement therapy, calibration method, mammogram view and reader, and parity and age at first birth when not the association of interest.

Results: Among 10,988 women included in these analyses, 90.1% (n = 9,895) were parous, of whom 13% (n = 1,286) had ≥ five births. The mean age at first birth was 24.3 years (Standard deviation = 5.1). Increasing parity (per birth) was inversely associated with √PMD (β: - 0.05, 95% confidence interval (CI): - 0.07, - 0.03) and √DA (β: - 0.08, 95% CI: - 0.12, - 0.05) with this trend evident until at least nine births. Women who were older at first birth (per five-year increase) had higher √PMD (β:0.06, 95% CI:0.03, 0.10) and √DA (β:0.06, 95% CI:0.02, 0.10), and lower √NDA (β: - 0.06, 95% CI: - 0.11, - 0.01). In stratified analyses, this association was only evident in women who were post-menopausal at MD assessment. Among parous women, no associations were found between ever/never breastfed or lifetime breastfeeding duration (per six-month increase) and √MD.

Conclusions: Associations with higher parity and older age at first birth with √MD were consistent with the direction of their respective associations with breast cancer risk. Further research is needed to understand reproductive factor-related differences in the composition of breast tissue and their associations with breast cancer risk.

Keywords: Age at first birth; Breastfeeding; Mammographic density; Parity; Reproductive factors.

Fig. 1

Flow chart of the study sample with reasons for exclusion in the grey boxes and the subsequent analytical samples in the dashed boxes for each exposure of interest – parity, age at first birth, ever/never breastfed, and lifetime breastfeeding duration. * This study was excluded from the ever/never breastfed analyses as 100% of women in the US-USC Asian population group reported never breastfeeding. This proportion may be as a result of the random sample selected from the study during the initial consortium development which may not reflect the true proportion of women who breastfed in this specific population group. Given this uncertainty, it was decided to exclude this study from the ever/never breastfed analyses

Fig. 2

Graph showing mean parity (blue), mean age at first birth (red), and mean lifetime breastfeeding duration (green) for the 40 country-ethnicity specific population groups included in this study

Fig. 3

a–b Forest plots showing the associations between parity and √MD measures (a: √PMD and b: √DA) for all women (parous and nulliparous) across the 40 country-ethnicity specific population groups in the ICMD sample. Analyses were adjusted for age at mammogram, BMI, menopausal status, use of hormone replacement therapy, age at menarche, age at first birth, and image parameters

Fig. 4

a–b Pooled analysis plots showing the associations between parity (categorical) and √MD measures (a: √PMD and b: √DA) for all women (parous and nulliparous) in the pooled ICMD sample. Analyses were adjusted for age at mammogram, BMI, menopausal status, use of hormone replacement therapy, age at menarche, age at first birth, and image parameters

Fig. 5

a–b Forest plot showing the associations between age at first birth and √MD measures (a: √PMD and b: √DA) among parous women across 39 country-ethnicity specific population groups in the ICMD sample. Analyses were adjusted for age at mammogram, BMI, menopausal status, use of hormone replacement therapy, age at menarche, parity, and image parameters

Fig. 6

a–b Pooled analysis plots showing the associations between age at first birth (categorical) and √MD measures (a: √PMD and b: √DA) among parous women in the pooled ICMD sample. Analyses were adjusted for age at mammogram, BMI, menopausal status, use of hormone replacement therapy, age at menarche, parity, and image parameters

Fig. 7

a–b Forest plot showing the associations between ever/never breastfed and √MD measures (a: √PMD and b: √DA) among parous women across 30 country-ethnicity specific population groups in the ICMD sample. Analyses were adjusted for age at mammogram, BMI, menopausal status, use of hormone replacement therapy, age at menarche, parity, age at first birth, and image parameters

Fig. 8

a–b Forest plot showing the associations between lifetime breastfeeding duration and √MD measures (a: √PMD and b: √DA) among parous women that breastfed across 28 country-ethnicity specific population groups in the ICMD sample. Analyses were adjusted for age at mammogram, BMI, menopausal status, use of hormone replacement therapy, age at menarche, parity, age at first birth, and image parameters

Fig. 9

a–b Pooled analysis plots showing the associations between lifetime breastfeeding duration (categorical) and √MD measures (a: √PMD and b: √DA) among parous women that breastfed in the pooled ICMD sample. Analyses were adjusted for age at mammogram, BMI, menopausal status, use of hormone replacement therapy, age at menarche, parity, age at first birth, and image parameters