Causal associations between 1400 circulating metabolites and spontaneous abortion: A bidirectional 2-sample Mendelian
Xuan Zhou1,2, Yu-Xuan Fang3, Da-Wei Zhang1,2
1Henan University of Chinese Medicine, Zhengzhou, China.
Medicine
|November 27, 2025
Summary
Metabolic disturbances may causally influence spontaneous abortion (SA). This study identified specific circulating metabolites linked to SA risk, offering potential biomarkers for early pregnancy loss.
Area of Science:
- Metabolomics
- Reproductive Health
- Genetic Epidemiology
Background:
- Spontaneous abortion (SA) affects 10-15% of pregnancies, with metabolic links poorly understood.
- Investigating the causal role of metabolites in SA is crucial for understanding early pregnancy loss.
Purpose of the Study:
- To evaluate causal associations between 1400 plasma metabolites and spontaneous abortion (SA) using Mendelian randomization.
- To identify specific metabolites that may play a causal role in the pathophysiology of SA.
Main Methods:
- Bidirectional 2-sample Mendelian randomization (MR) analysis.
- Utilized genome-wide association study data for 1400 metabolites and large-scale SA summary statistics (FinnGen R12).
- Employed inverse variance weighted, MR-Egger, and weighted median methods, with sensitivity analyses for robustness.
Main Results:
- Thirty-six circulating metabolites showed significant causal associations with SA.
- Phenylacetylglutamine demonstrated a protective effect (OR, 0.89).
- Glycerol-to-carnitine ratio (OR, 1.07), 1-methyl-5-imidazoleacetate (OR, 1.09), and caffeine-to-theophylline ratio (OR, 1.08) showed risk-enhancing effects.
Conclusions:
- Provides genetic evidence for a causal role of specific circulating metabolites in SA.
- Identified potential biomarkers for reproductive risk stratification and targeted interventions for early pregnancy loss.
- Findings offer novel mechanistic insights into spontaneous abortion pathophysiology.
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