Plasma miRNA Profiles in Pregnant Women
Predict Infant Outcomes following Prenatal
Alcohol Exposure

Sridevi Balaraman1, Jordan J. Schafer2, Alexander M. Tseng1, Wladimir Wertelecki2,3,7, Lyubov Yevtushok3,4,7, Natalya Zymak-Zakutnya3,5,7, Christina D. Chambers2,6,7³, Rajesh
C. Miranda1,7³*

1 Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, College of Medicine, Bryan, Texas, United States of America, 2 Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America, 3 Omni-Net Ukraine Birth Defects Prevention Program, Rivne, Ukraine, 4 Rivne Provincial Medical Diagnostic Center and OMNI-Net Center, Rivne, Ukraine, 5 Khmelnytsky City Perinatal Center and OMNI-Net Center, Khmelnytsky, Ukraine, 6 Department of Family Medicine and Public Health, University of California San Diego, La Jolla, California, United States of America, 7 The Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD), San Diego, California, United States of America

³ CDC and RCM are joint senior authors on this work.

Fetal alcohol spectrum disorders (FASD) are difficult to diagnose since many heavily exposed infants, at risk for intellectual disability, do not exhibit craniofacial dysmorphology or growth deficits. Consequently, there is a need for biomarkers that predict disability. In both animal models and human studies, alcohol exposure during pregnancy resulted in significant alterations in circulating microRNAs (miRNAs) in maternal blood. In the current study, we asked if changes in plasma miRNAs in alcohol-exposed pregnant mothers, either alone or in conjunction with other clinical variables, could predict infant outcomes. Sixtyeight pregnant women at two perinatal care clinics in western Ukraine were recruited into the study. Detailed health and alcohol consumption histories, and 2nd and 3rd trimester blood samples were obtained. Birth cohort infants were assessed by a geneticist and classified as unexposed (UE), heavily prenatally exposed and affected (HEa) or heavily exposed but apparently unaffected (HEua). MiRNAs were assessed in plasma samples using qRT-PCR arrays. ANOVA models identified 11 miRNAs that were all significantly elevated in maternal plasma from the HEa group relative to HEua and UE groups. In a random forest analysis classification model, a combination of high variance miRNAs, smoking history and socioeconomic status classified membership in HEa and UE groups, with a misclassification rate of 13%. The RFA model also classified 17% of the HEua group as UElike, whereas 83% were HEa-like, at least at one stage of pregnancy. Collectively our data indicate that maternal plasma miRNAs predict infant outcomes, and may be useful to classify difficult-to-diagnose FASD subpopulations.

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