Causal Effects of Maternal BMI on Pregnancy Outcomes: A Mendelian Randomisation Study Investigating the Mediating Role of Blood Counts

Background Pregnancy requires a delicate balance between the maternal immune system and inflammatory responses. Elevated maternal body mass index (BMI) significantly compromises the immune system and increases systemic inflammation. High maternal BMI is associated with adverse pregnancy outcomes, including an increased risk of both pre-eclampsia and preterm birth, which may be mediated through immune-related blood cell changes. Methods This study used Mendelian randomisation (MR) to investigate the causal relationship between maternal BMI and pregnancy outcomes, including birth weight, placental weight, gestational duration, and pre-eclampsia. We applied two-step MR to assess whether immune-related blood counts, such as neutrophils, lymphocytes, and platelets, mediate these relationships. Single nucleotide polymorphism (SNP) effect estimates for maternal BMI and pregnancy outcomes were sourced from publicly available genome-wide association studies (GWAS), with pregnancy outcomes partitioned into maternal genetic effects to proxy genetic effects on the intrauterine environment. Results We found that elevated maternal BMI causally increased placental weight (βIVW = 0.164sd, P = 2.92 x 10-7) and risk of pre-eclampsia (ORiVW  1.75, P = 6.3 x 10-30). The effect of maternal BMI on placental weight was larger than its effect on birth weight. Mediation analysis found no evidence of the involvement of immune-related blood counts in these relationships. Conclusions Maternal BMI has a significant impact on pregnancy outcomes, particularly by increasing placental weight and the risk of pre-eclampsia. These findings highlight BMI-driven placental adaptations as key contributors to pregnancy complications.