Longitudinal Changes In Maternal Circulating Micrornas As Potential Biomarkers of Specific Events During Healthy Pregnancy

Abstract Background: Novel high-resolution tools for pregnancy monitoring, including early detection of prenatal disorders, are needed. Changes in circulating microRNAs (c-miRNAs) during pregnancy could potentially inform about the functional status of the mother, the placenta and/or the fetus. However, whether c-miRNA profiles actually reflect distinct pregnancy-specific events at all stages remains unclear. Methods: Longitudinal large-scale RNAseq c-miRNA profiles at early, middle and late pregnancy, and after birth derived from eight women with healthy term pregnancies (n=32 plasma samples) were compared against corresponding circulating profiles derived from age-matched non-pregnant women (n=10). Data of fetal sex and growth indicators obtained during pregnancy evolution of the same women, were used to identify specific c-miRNA correlates in circulation. Results: 1449 c-miRNAs were detected in circulation in both pregnant and non-pregnant women with only 48 c-miRNAs differentially expressed relative to non-pregnant controls in at least one of the four studied stages (FDR<0.05). Surprisingly, c-miRNA subpopulations with reported prominent expression in various pregnancy-associated compartments (placenta, amniotic fluid, umbilical cord plasma and breast milk) were found collectively under-expressed in maternal circulation throughout pregnancy (p<0.05). Furthermore, we found a bias in global miRNAs expression in direct association with fetal sex right from the first trimester, in addition to a specific c-miRNA signature of fetal growth (R = 0.7, p < 0.01). Conclusion: Our results demonstrate the existence of temporal changes in c-miRNAs populations associated to distinct aspects of pregnancy, including correlates of placental function and lactation, as well as fetal gender and growth, revealing a wider potential of c-miRNAs as biomarkers of specific aspects of maternal health and fetal growth.