Background Reproductive factors (RFs) in women, such as menarche and menopause, the age at which women start and stop having children, and the number of children they have, have been implicating in disease risk including, breast cancer, cardiovascular, respiratory diseases. While body mass index (BMI) has similarly been identified as a risk factor in such diseases. Studies have identified strong bidirectional associations between adulthood BMI and RFs in women, and higher body size in girls was reported to be associated with earlier age at menarche and menopause. Considering the evidence of interplay between BMI and RFs, it is important to consider causal relationships which may underlie these associations. This study aims to appraise causality between both childhood and adulthood adiposity and the RFs, as well as establishing the magnitude of any identified relationships and direction of causality.

Methods We used data from the UK Biobank and genetic consortia with data available for RFs and BMI. We then applied Mendelian randomization (MR) methods to estimate the causal relationships between RFs and BMI both in childhood and adulthood. Sensitivity analyses were used to investigate directionality of the effect observed, to test for evidence of pleiotropy and to account for any sample overlap.

Results MR revealed body size and BMI in childhood and adulthood respectively have potentially causal relationships with a number of RFs, as well as a number of reproductive having a potentially effect on BMI in adulthood. Notably higher body size during childhood appears to lead to an earlier age at menarche (Beta (B)=-0.65, 95% confidence intervals (CI)=-0.74, -0.56), age at first, (B=-0.07, CI=-0.12, -0.01) and last birth (B=-0.09, CI=-0.13, -0.04). While higher BMI during adulthood seems to lead to an earlier age at menopause (B=-0.53, CI=-0.82, -0.23), age at first live birth (B=-1.72, CI=-2.06, -1.39), age at last live birth (B=-1.40, CI=-1.68, -1.13), earlier age at first sexual intercourse (B=-1.09, CI=-1.39, -0.78) and increased likelihood of having children (OR=1.11, CI=1.01, 1.21). Finally, findings suggests that earlier menarche (B=-0.03, CI= -0.04, -0.03) and age at first birth (B=-0.05, CI=-0.06, -0.03) and age first had sexual intercourse (B=-0.03, CI=-0.04, -0.01) may lead to higher adulthood BMI.

Conclusion The findings of this study present strong evidence for causal interplay between adiposity and women’s RFs and future studies should consider adiposity when investigating risk of RFs, whether as a potential confounder or mediator, on disease risk.