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Principal Investigator: RAINA N. FICHOROVA
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2024
Award: $733,193
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
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.
Terms: <Aberrant Chromosome><Address><Adverse effects><Affect><Anatomic Sites><Anatomic structures><Anatomy><Antenatal Diagnosis><Biologic Factor><Biological><Biological Factors><Blood><Blood Coagulation Disorders><Blood Reticuloendothelial System><Body Tissues><Case-Base Studies><Case-Comparison Studies><Case-Compeer Studies><Case-Referent Studies><Case-Referrent Studies><Case/Control Studies><Cells Placenta-Tissue><Chemical Exposure><Chemicals><Chromosomal Aberrations><Chromosomal Abnormalities><Chromosomal Alterations><Chromosomal Loss><Chromosome Aberrations><Chromosome Alterations><Chromosome Anomalies><Chromosome abnormality><Chronologic Fetal Maturity><Circulation><Clinical><Coagulation Disorder><Coagulopathy><Communities><Conceptions><Conceptus><Cytogenetic Aberrations><Cytogenetic Abnormalities><Data><Data Bases><Data Set><Databases><Distal><Dysfunction><Elements><Endometrial><Environmental Exposure><Environmental Factor><Environmental Risk Factor><Environmental Toxin><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Event><Fetal Age><Functional RNA><Functional disorder><Gene Expression><Gestation><Gestational Age><Glues><Health><Hemostatic Agents><Hemostatics><Hormone imbalance><Inflammation><Injury><Intrauterine Diagnosis><Laboratories><Lead><Live Birth><Massachusetts><Maternal Health><Measures><Mediating><Michigan><Micro RNA><MicroRNAs><Miscarriage><Molecular><Molecular Fingerprinting><Molecular Profiling><NICHD><National Institute of Child Health and Human Development><National Institute of Children's Health and Human Development><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Normal Placentoma><North America><Oxidative Stress><Participant><Pathway interactions><Pattern><Pb element><Phenotype><Physiologic><Physiological><Physiopathology><Placenta><Placenta Embryonic Tissue><Placentome><Predisposition><Pregnancy><Pregnancy Complications><Pregnancy loss><Pregnant Women><Prenatal Diagnosis><Process Measure><Public Health><Public Health Practice><RNA><RNA Gene Products><Reporting><Research><Research Resources><Resources><Ribonucleic Acid><Risk Factors><Risk Marker><Sampling><Single Base Polymorphism><Single Nucleotide Polymorphism><Spontaneous abortion><Strategic Planning><Stress><Susceptibility><Symptoms><Technology><Testing><Time><Tissues><Toxic Environmental Agents><Toxic Environmental Substances><Translational Inhibition><Translational Repression><Untranslated RNA><Urine><Villous><Woman><adverse pregnancy outcome><antepartum diagnosis><biologic><biological specimen archives><biomarker driven><biosample archive><biospecimen archive><bleeding disorder><case-controlled studies><chromosomal defect><chromosome defect><circulating miRNA><circulating miRNAs><circulating microRNA><circulating microRNAs><clinical practice><clotting disorder><cohort><compare to control><comparison control><complications during pregnancy><computer based prediction><data base><diagnostic biomarker><diagnostic marker><differential expression><differentially expressed><early pregnancy><early pregnancy loss><environmental chemical><environmental risk><environmental toxicant><epigenetically><expectant mother><expecting mother><health data><heavy metal Pb><heavy metal lead><high dimensional data><hormonal imbalance><injuries><innovate><innovation><innovative><insight><intra-uterine diagnosis><mRNA Degradation><mRNA Transcript Degradation><malleable risk><miRNA><miRNAs><modifiable risk><molecular profile><molecular signature><multidimensional data><multidimensional datasets><noncoding><novel><participant enrollment><pathophysiology><pathway><patient enrollment><predictive modeling><pregnancy-related complications><pregnant mothers><prenatal screening><prenatal testing><prevent><preventing><prospective><public health priorities><risk predictor><risk predictors><single nucleotide variant><social><social factors><socio-demographics><socio-economic><socio-economically><sociodemographics><socioeconomically><socioeconomics><specimen archive><stressor><toxicant><transcriptional differences><transcriptomics><trophoblast>