Causal Relationships Between Leukocyte Subsets and Adverse Fetal Outcomes: A Mendelian Randomization Study

Background: The tolerance and dynamic regulation of the maternal immune system during pregnancy are pivotal for ensuring fetal health. Immune cell subsets play a complex and crucial role in this process, closely linked to the neonatal health status. Despite recognizing the significance of dysregulation in the quantity and activity of immune cells in neonatal disease occurrence, their specific roles remain elusive, resulting in a dearth of clinically viable interventions for immune-mediated neonatal diseases. Materials and Methods: Employing two-sample Mendelian randomization (MR) methodology, this study systematically investigated 446 leukocyte features (N = 500,675), including leukocyte subsets, absolute cell (AC) counts, and morphological parameters (MP) and their correlation with seven adverse fetal outcomes (N = 1,100,458), encompassing fetal growth restriction (FGR), preterm birth (PTB), neonatal jaundice (NNJ), digestive system disorders of fetus and newborn (DSDFN), hemorrhagic and hematological disorders of fetus and newborn (HDFN), respiratory distress of newborn (RDN), and transitory disorders of metabolism specific to fetus and newborn (TDMSFN). Results: The results unveiled significant causal relationships between 301 leukocyte subsets and these seven adverse fetal outcomes, with 259, 245, 15, 44, 11, 32, and 68 pairs of notable associations for each adverse outcome, respectively. Furthermore, the study highlighted potential pathogenic mechanisms underlying the mutual influence among neonatal diseases. MR results indicated FGR as a robustly correlated risk factor for PTB and NNJ and showed a reciprocal causal relationship between NNJ and FGR. PTB exhibited a positive correlation with HDFN. Conclusions: This study provided profound insights into the intricate regulatory mechanisms of leukocyte subsets in neonatal diseases, paving the way for new avenues in the diagnosis and treatment of associated disorders.