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Recurrent Miscarriage (RM), as the loss of 2
or more pregnancies before the 20th week of gestation, is described by The
American Society of Reproductive Medicine (ASRM) (1).
Its prevalence in all pregnancies is about 1 to 5% (2)
and can occur for different causes, including genetic, anatomical, infectious,
hormonal and immune deficiencies, although in many cases the cause of recurrent miscarriage
remains unknown (3).
It is estimated that the etiology of over 50% of abortion cases remains unknown
that are called as unexplained Recurrent Miscarriage (uRM) (4).
Thus, the lack of a non-invasive biomarker has always been one of the main
challenges for patients with uRM.

MicroRNAs
(miRNAs), which were introduced for the first time in the
early 2000s (5),
are non-coding RNAs, usually made up of 18-25 nucleotides, and they regulate
gene expression through degradation
of target mRNA or blocking the translation of protein (6).

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Recently, it has been discovered
that many miRNAs exist in the bloodstream, in plasma, erythrocytes, platelets,
and nucleated blood cells, and miRNAs of plasma is more stable than the pH and
temperature conditions (7).
Thus, these can be used as diagnostic biomarkers for the treatment of many
diseases. It has been suggested that miRNAs play an important role in
regulating many diseases of the reproductive system, including endometriosis,
preeclampsia, infertility and RM (8-11). In 2012, one
study demonstrated that microRNA polymorphisms (miR-146aC>G, miR-149T>C,
miR-196a2T>C, and miR-499A>G) in Korean patients are associated with
spontaneous abortion in Korean patients (11).
Also, the results an investigation that was performed in order to evaluate the
potential role of circulating microRNAs as a diagnostic biomarker for
unexplained spontaneous abortion (URSA) patients, showed that the expression of
four micro-ribonucleic acid, miR-320b, miR-146b-5p, miR-221-3p and miR-559 were
increased and the expression of miR-101-3p was reduced in URSA patients (12).

Additionally, one of the causes
for miscarriage can be a defect in the embryo implantation stages, especially
in the process of angiogenesis (13, 14). Angiogenesis,
a common characteristic of embryo implantation and proliferation of cancer
cells, is the process of formation of new vessels from the pre-built vascular
system (15).
This process is a common feature of embryo implantation and tumor metastasis (16).
The reducing the level of this process during pregnancy, due to abnormal
expression of the genes involved in it, can lead to abnormal growth of the
fetus and miscarriage (17).
Even, new studies have shown that increased expression levels of genes involved
in angiogenesis may lead to RM (18).

The microRNAs 16 and 21 are the most
important miRNAs involved in angiogenesis and miscarriage. In previous studies
has been proven that one of the targets of miR-16 is VEGF-A, and is involved in
the angiogenesis of the placenta. In embryonic villus sampling, high expression
level of this miRNA is associated with recurrent abortions (19).
Also, PTEN is the main gene target of miR-21 which is indirectly involved in
angiogenesis phenomenon. Therefore, the study of the expression of these miRNAs
and their relationship with the target genes can help the pathology of patients
with uRM and their early diagnosis (20).

The aim of this study was to
compare the expression levels of these circulating miRNAs and their gene
targets in peripheral blood mononuclear cells (PBMCs) and plasma of patients
with uRM and women with a history of natural pregnancy.