Increased Levels of hsa-miR-199a-3p and hsa-miR-382-5p in Maternal and Neonatal Blood Plasma in the Case of Placenta Accreta Spectrum

Abstract

Despite the increasing number of placenta accreta spectrum (PAS) cases in recent years, its impact on neonatal outcomes and respiratory morbidity, as well as the underlying pathogenetic mechanism, has not yet been extensively studied. Moreover, no study has yet demonstrated the effectiveness of antenatal corticosteroid therapy (CT) for the prevention of respiratory distress syndrome (RDS) in newborns of mothers with PAS at the molecular level. In this regard, microRNA (miRNA) profiling by small RNA deep sequencing and quantitative real-time PCR was performed on 160 blood plasma samples from preterm infants (gestational age: 33-36 weeks) and their mothers who had been diagnosed with or without PAS depending on the timing of the antenatal RDS prophylaxis. A significant increase in hsa-miR-199a-3p and hsa-miR-382-5p levels was observed in the blood plasma of the newborns from mothers with PAS compared to the control group. A clear trend toward the normalization of hsa-miR-199a-3p and hsa-miR-382-5p levels in the neonatal blood plasma of the PAS groups was observed when CT was administered within 14 days before delivery, but not beyond 14 days. Direct correlations were found among the hsa-miR-382-5p level in neonatal blood plasma and the hsa-miR-199a-3p level in the same sample (r = 0.49; p < 0.001), the oxygen requirements in the NICU (r = 0.41; p = 0.001), the duration of the NICU stay (r = 0.31; p = 0.019), and the severity of the newborn's condition based on the NEOMOD scale (r = 0.36; p = 0.005). Logistic regression models based on the maternal plasma levels of hsa-miR-199a-3p and hsa-miR-382-5p predicted the need for cardiotonic therapy, invasive mechanical ventilation, or high-frequency oscillatory ventilation in newborns during the early neonatal period, with a sensitivity of 95-100%. According to the literary data, these miRNAs regulate fetal organogenesis via IGF-1, the formation of proper lung tissue architecture, surfactant synthesis in alveolar cells, and vascular tone.

Keywords: PCR; RDS; antenatal corticosteroid therapy; blood plasma; deep sequencing; miRNA; neonatal complication; placenta accreta spectrum.

Figure 1

PLS-A analysis of deep sequencing data of miRNA in the peripheral blood plasma of day-old newborns from mothers with PAS and without PAS (control).

Figure 2

The dependence of hsa-miR-382-5p and hsa-miR-199a-3p content in the blood plasma of newborns and their mothers on the severity of placenta accreta spectrum (PAS) and the timing of antenatal corticosteroid therapy (CT). Levels of miR-382-5p (−∆Ct, PCR data) in the blood plasma of newborns from mothers with placenta accreta or placenta increta or placenta percreta without CT or with CT 2–14 days before delivery in comparison with control group—without PAS and without CT (A). Levels of miR-382-5p (−∆Ct, PCR data) in the blood plasma of pregnant women with placenta accreta or placenta increta or placenta percreta without CT or with CT 2–14 days before delivery in comparison with control group—without PAS and without CT (B). Levels of miR-199a-3p (−∆Ct, PCR data) in the blood plasma of newborns from mothers with placenta accreta or placenta increta or placenta percreta without CT or with CT 2–14 days before delivery in comparison with control group—without PAS and without CT (C). Levels of miR-199a-3p (−∆Ct, PCR data) in the blood plasma of pregnant women with placenta accreta or placenta increta or placenta percreta without CT or with CT 2–14 days before delivery in comparison with control group—without PAS and without CT (D). “Wo” means “without”.

Figure 3

Dynamics of changes in hsa-miR-199a-3p levels in the blood plasma of newborns relative to their mothers’ blood plasma, with and without PAS, depending on the antenatal corticosteroid therapy (CT). “Wo” means “without”.

Figure 4

Levels of hsa-miR-199a-3p and hsa-miR-382-5p in the blood plasma of newborns with PAS, categorized by their severity score according to the Neomod scale.

Figure 5

Levels of miR-181a-5p, miR-199a-3p and miR-382-5p in blood plasma of pregnant women with/without PAS and with/without antenatal corticosteroid therapy. “Wo” means “without”.

Figure 6

Logistic regression models for predicting neonatal complications by plasma miR-199a-3p and/or miR-382-5p levels in pregnant women with PAS using miR-181a-5p as a reference endogenous RNA. (A) Respiratory complications probability models. (B) Cardiovascular complications probability models. Se—sensitivity, Sp—specificity.

Figure 7

Enrichment analysis of gene targets of hsa-miR-382-5p and hsa-miR-199a-3p using FunRich software tool.