The causal effect and impact of reproductive factors on breast cancer using super learner and targeted maximum likelihood estimation: a case-control study in Fars Province, Iran.

Objectives: The relationship between reproductive factors and breast cancer (BC) risk has been investigated in previous studies. Considering the discrepancies in the results, the aim of this study was to estimate the causal effect of reproductive factors on BC risk in a case-control study using the double robust approach of targeted maximum likelihood estimation. Methods: This is a causal reanalysis of a case-control study done between 2005 and 2008 in Shiraz, Iran, in which 787 confirmed BC cases and 928 controls were enrolled. Targeted maximum likelihood estimation along with super Learner were used to analyze the data, and risk ratio (RR), risk difference (RD), andpopulation attributable fraction (PAF) were reported. Results: Our findings did not support parity and age at the first pregnancy as risk factors for BC. The risk of BC was higher among postmenopausal women (RR = 3.3, 95 confidence interval (CI) = (2.3, 4.6)), women with the age at first marriage �20 years (RR = 1.6, 95 CI = (1.3, 2.1)), and the history of oral contraceptive (OC) use (RR = 1.6, 95 CI = (1.3, 2.1)) or breastfeeding duration �60 months (RR = 1.8, 95 CI = (1.3, 2.5)). The PAF for menopause status, breastfeeding duration, and OC use were 40.3 (95 CI = 39.5, 40.6), 27.3 (95 CI = 23.1, 30.8) and 24.4 (95 CI = 10.5, 35.5), respectively. Conclusions: Postmenopausal women, and women with a higher age at first marriage, shorter duration of breastfeeding, and history of OC use are at the higher risk of BC. © 2021, The Author(s).