LAUSR

Pregnancy-related complications, including preeclampsia (PE), gestational diabetes mellitus (GDM), and preterm delivery (PTD), are the most significant issues modern obstetrics face, affecting at least 15% of pregnancies worldwide [1]. They have a considerable impact on maternal and fetal mortality and morbidity and are also associated with long-term adverse outcomes for the mother and the child. It is widely accepted, however, that early identification of women at risk may improve effective interventions and consequently reduce the incidence of these life-threatening conditions and the cost of neonatal care. Since their discovery in 1993, microRNAs (miRNAs), a class of noncoding RNAs known to regulate gene expression at the posttranscriptional level, have been implicated in vital cellular processes, such as tissue development, differentiation, proliferation, the maintenance of homeostasis and apoptosis [2]. Tissue miRNAs are secreted into circulation bound to specific proteins or high-density lipoproteins or packaged within exosomes, microvesicles, or apoptotic bodies in order to prevent degradation [2]. These are known as circulating miRNAs. Due to their stability and the relative ease of analysis, circulating miRNAs are considered as candidate noninvasive biomarkers with the potential to further elucidate the knowledge of various pathophysiological conditions and improve screening and diagnostic strategies. Altered miRNA expression has been consistently associated with the pathogenesis of several diseases including pregnancy-related complications. The role of miRNAs in the pathogenesis of pregnancyrelated complications, as well as their predictive, diagnostic, and therapeutic potential, has been previously discussed [2]. The current update is oriented toward novel insights in this area, focusing on circulating miRNAs as noninvasive biomarkers of pregnancy-related complications and the prospective improvement of diagnostic modalities. Although the lack of between-studies consistency still remains an issue, a long list of candidate miRNA biomarkers is available for further evaluation. Thus far, most published studies have concentrated on the identification of miRNAs differentially expressed in PE complicated pregnancies, as compared to pregnancies with no complication. Ura et al., using TaqMan Arrays, reported on 12 upregulated miRNAs and 7 downregulated miRNAs in maternal plasma of women destined to develop PE [3]. On the other hand, Luque et al., using the same methodology, failed to identify miRNAs with clinical utility for the early prediction of PE [4]. Jairajpuri et al. utilized a customized real-time miRNA PCR array to evaluate maternal plasma miRNA expression profile in a pilot group of 15 pregnant women with clinical PE, including 7 with mild and 8 with the severe type of the disease [5]. The analysis revealed higher expression of miR-215, miR-155, miR650, miR-210, and miR-21 and reduced expression of miR-18a, miR-19b1 in women with PE, as compared to the control group, thus highlighting the possible use of miRNAs as diagnostic biomarkers. They also demonstrated a significant association between miR-518b, miR-29a, miR-144, and miR-15b expression levels and the severity of the disease. Upregulation of miR-210 has been previously identified in PE-complicated placentas (reviewed in [2]) as well as the serum of women with PE [6–9]. MiR-210 is a hypoxia-responsive factor known to control hypoxia-associated pathways such as angiogenesis, cell survival, DNA repair, and mitochondrial metabolism [10]. The regulatory role of miR-210 in PE was also identified using system biology approaches [11]. Apart from miR-210, the altered expression of miR-155, miR-21, and miR-518b reported by Jairajpuri et al. [5] is in agreement with previous findings obtained using either placenta tissue biopsies or maternal peripheral blood (reviewed in [2]). Akehurst et al., using microarray coupled with real-time quantitative PCR (RT-qPCR), demonstrated a 1.4-fold increase in the expression of miR-206 in maternal plasma at 28 weeks of gestation in presymptomatic women who subsequently developed PE [12]. Further investigation of miR-206 expression in an independent cohort of placenta biopsies revealed overexpression of miR-206 in PE-complicated placentas, as well as altered expression of the clinically relevant target genes, IGF-1 and VEGF. Tsai et al., utilizing the same approach, reported higher expression levels of miR-346 and miR-582–3 in maternal plasma obtained from women with multiple pregnancy-related complications at the time of hospital admission, indicating their potential as diagnostic or therapeutic biomarkers [13]. Zhang et al. analyzed maternal plasma samples collected at 12 and 20 weeks of gestation and reported significant association of miR-942 expression levels with PE. MiR-942 showed a sensitivity