Evaluating causal influence of maternal educational attainment on offspring birthweight via observational study and Mendelian randomization analyses

Background: Although extensive discussions on the influence of maternal educational attainment on offspring birthweight, the conclusion remains controversial, and it is challenging to comprehensively assess the causal association between them. Methods: To estimate effect of maternal educational attainment on the birthweight of first child, we first conducted an individual-level analysis with UK Biobank participants of white ancestry (n = 208,162). We then implemented Mendelian randomization (MR) methods including inverse variance weighted (IVW) MR and multivariable MR to assess the causal relation between maternal education and maternal-specific birthweight. Finally, using the UK Biobank parent-offspring trio data (n = 618), we performed a polygenic score based MR to simultaneously adjust for confounding effects of fetal-specific birthweight and paternal educational attainment. We also conducted simulations for power evaluation and sensitivity analyses for horizontal pleiotropy of instruments. Results: We observed that birthweight of first child was positively influenced by maternal education, with 7 years of maternal education as the reference, adjusted effect = 44.8 (95%CIs 38.0-51.6, P = 6.15 x 10- 38), 54.9 (95% CIs 47.6-62.2, P = 4.21 x 10-128), and 89.4 (95%CIs 82.1-96.7, P = 4.28 x 10-34) for 10, 15 and 20 years of maternal educational attainment, respectively. A causal relation between maternal education and offspring birthweight was revealed by IVW MR (estimated effect = 0.074 for one standard deviation increase in maternal education years, 95%CIs 0.054-0.093, P = 2.56 x 10-13) and by complementary MR methods. This connection was not substantially affected by paternal education or horizontal pleiotropy. Further, we found a positive but insignificant causal association (adjusted effect = 24.0, 95%CIs - 150.1-198.1, P = 0.787) between maternal education and offspring birthweight after simultaneously controlling for fetal genome and paternal education; this null causality was largely due to limited power of small sample sizes of parent-offspring trios. Conclusion: This study offers supportive evidence for a causal association between maternal education and offspring birthweight, highlighting the significance of enhancing maternal education to prevent low birthweight.