Elevated maternal body mass index (BMI) and pregnancy induced chronic inflammation impact maternal immune related blood parameters, such as absolute counts of lymphocyte (LAC) and monocyte blood cells (MAC). Additionally, epidemiological studies demonstrate associations between elevated maternal BMI, altered blood parameters and offspring birth weight (BW). In this study, we aim to ascertain whether there is a causal link between high maternal BMI during pregnancy and BW, exploring potential mediation by maternal blood parameters.
We employed two-sample Mendelian randomisation (MR) to assess the causal relationship between maternal BMI (exposure) and BW (outcome), and between maternal LAC or MAC (exposures) on BW (outcome). Single nucleotide polymorphism(SNP)-exposures and SNP-outcome effect estimates were sourced from publicly available genome-wide association studies, with BW partitioned into maternal genetic effects (proxy intrauterine effects). Elevated maternal BMI causally increased BW (βIVW= 0.12 per standard deviation of BMI/ per standard deviation of BW (BWSD), SE=0.01, P=4.45E-34), with evidence of pleiotropy. Elevated LAC and MAC causally decreased BW (βIVW= -0.04LAC/BWSD, SE=0.01, P=0.004 & βIVW= -0.02MAC/BWSD, SE=0.01, P=0.04, respectively), again with evidence of pleiotropy. Under the hypothesis that the pleiotropy in the maternal BMI-BW relationship could be (partially) explained by the effect of maternal BMI on LAC and/or MAC, we conducted a mediation analysis using multivariable MR (MVMR). This attenuated the causal association between LAC/MAC and BW to the null, but the BMI-BW causal relationship remained. Sensitivity analyses using MR-Egger and weighted median MVMR indicated the BMI-BW causal relationship remained after accounting for pleiotropy. Our study unveils causal associations between maternal BMI, blood counts, and BW. However, MVMR found no strong evidence of a mediation effect of BMI on BW through blood counts.