Association between blood mitochondrial DNA copy number and adverse pregnancy outcomes: a Mendelian randomization analysis

ObjectiveTo investigate the relationship between blood mitochondrial DNA (mtDNA) copy number and adverse pregnancy outcomes using a Mendelian randomization (MR) approach.MethodsData were obteined from the IEU OpenGWAS project. A Mendelian randomization (MR) approach was conducted, with single nucleotide polymorphisms (SNPs) associated with blood mtDNA copy number being used as instrumental variables. Firstly, the causal relationship between blood mtDNA copy number and adverse pregnancy outcomes was evaluated through univariate MR analysis. Further conduct multivariate MR analysis and adjust lactate levels to eliminate confounding effects of lactate metabolism. Finally, conduct reverse MR analysis to explore the reverse effect of adverse pregnancy outcomes on blood mtDNA copy number. Inverse variance weighted (IVW) was used as the primary analysis method, supplemented by MR-Egger regression, weighted median, simple mode, and weighted mode. Sensitivity analyses including MR-Egger intercept test, Cochran's Q test, MR-PRESSO, and leave-one-out analysis were conducted to ensure robustness. Multivariable MR was performed to adjust for lactate levels. Reverse MR analysis was also carried out.ResultsIn forward univariable MR, genetically predicted blood mtDNA copy number was causally associated with gestational hypertension (OR=0.719, 95%CI: 0.538–0.961, P < 0.05), pregnancy complicated with chronic hypertension (OR=0.719, 95%CI: 0.538–0.961, P < 0.05), preeclampsia (OR=0.616, 95% CI: 0.412–0.922, P< 0.05), and premature rupture of membranes (OR = 1.478, 95% CI: 1.008–2.168, P < 0.05). Multivariable MR adjusting for lactate levels showed that these causal effects remained significant, with effect sizes comparable to univariate estimates. Reverse MR indicated that premature rupture of membranes (β = 0.009, 95% CI: 0.001–0.017, P < 0.05), excessive vomiting during pregnancy (β = –0.004, 95% CI: –0.007–0.000, P < 0.05), and early pregnancy bleeding (β=0.008, 95%CI: 0.002–0.015, P < 0.01) were associated with blood mtDNA copy number. Sensitivity analyses confirmed the reliability of these findings.ConclusionBlood mtDNA copy number is causally related to gestational hypertension, chronic hypertension in pregnancy, preeclampsia, and premature rupture of membranes, independent of lactate metabolism. Additionally, adverse pregnancy outcomes can also affect blood mtDNA copy number, suggesting that blood mtDNA copy number may serve as a molecular biomarker for early clinical risk prediction of adverse pregnancy outcomes.