Molecular Antecedents of Miscarriage

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Miscarriage - defined as pregnancy loss prior to 20 weeks of gestation - is the most common pregnancy complication, affecting 10-20% of clinically recognized pregnancies. While advances have been made in noninvasive prenatal diagnosis of chromosomal abnormalities leading to pregnancy loss, the pathophysiology and environmental causes of chromosomally normal losses – the bulk of miscarriages occurring after the 6th gestation week – remain largely unexplained. We hypothesize that microRNAs serve as a physiologic “glue” for common pathways predicting loss of chromosomally normal pregnancies. MicroRNAs are non-coding RNAs that negatively regulate gene expression by inducing translational inhibition or mRNA degradation. Because of their remarkable stability in the circulation and their ability to report on or regulate cellular and tissue phenotypes in distal anatomic sites, they present an attractive novel target for mechanistic and diagnostic biomarker research. miRNA expression is controlled by a variety of exposures not yet deciphered in pregnant women. In our global transcriptomics pilot, we discovered circulating miRNAs that are differentially expressed in typical pregnancy compared to pre-conception and to pregnancy in women who later miscarry. This application responds to a strategic priority identified by NICHD. We leverage the rich dataset of demographic, socio-economic and maternal health data and the biospecimen archive of three large early pregnancy cohorts (>8000 enrolled participants) and align them with technological resources offered under GLP practice by four participating laboratories. Drawing on the largest sample of miscarriages ever examined in relation to prospectively obtained biological data (250 chromosomally normal miscarriages) and building on the technological resources offered under GLP practice by four participating laboratories, we will: Aim 1: Identify prodromal molecular signatures of miscarriage, in pre-miscarriage maternal blood, free of common chromosomal defects: 1.1 identify miRNAs and miRNA-targeted pathways dysregulated in such miscarriages and 1.2 test associations with gestational age at miscarriage;1.3 determine whether hypothesis-driven biomarkers of deficient endometrial function, inflammation, oxidative stress, hormonal imbalance, and coagulopathy/hemostatic injury are associated with such miscarriages; and 1.4. whether they mediate an association between miRNA and miscarriage. Aim 2: Apply omics in maternal urine to identify environmental exposures associated with miscarriages free of common chromosomal defects; and Aim 3: Explore whether miRNA antecedents mediate an association between miscarriage and elements of the maternal exposome, including chemicals, and socioeconomic and health- related stressors. The proposed research will generate high-dimensional data for the research community and open the door to novel predictive models of the adverse effects of chemical exposures in pregnant women. The study is innovative in its focus on understanding mechanisms and environmental exposures associated with miscarriage and may identify molecular predictors and modifiable risk factors of early pregnancy complications.