Gene Reports 20 (2020) 100685

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Gene Reports
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Recurrent IVF failure: Review of genetic factors T

a a a a b,⁎
Kimia Vakili , Mobina Fathi , Shirin Yaghoobpoor , Niloofar Deravi , Soudeh Ghafouri-Fard
a
Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
b
Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

ARTICLE INFO ABSTRACT

Keywords: Recurrent implantation failure (RIF) is a term for description of conditions in which women have experienced
Recurrent IVF failure three failed in vitro fertilization (IVF) cycles in spite of the presence of good quality embryos. Several uterine,
Genetics male, or embryo factors, or parameters related with IVF protocol are associated with the occurrence of RIF.
However, a number of recent studies have associated this condition with genetic mutations and the presence of
some variants in the genome. Variants have been found in p53, VEGF, COX2, LIF and some other genes.
Moreover, dysregulation of expression of angiogenesis-associated genes as well as pathways that modulate
circadian rhythm, proteasome, complement and coagulation cascades, cell adhesion molecules, inflammatory
responses, cell cycle, and renin–angiotensin system has been detected in RIF. In the current review, we sum-
marize the available literature on this issue.

1. Introduction
Implantation failure is a term being applied to define patients who
have never had measurable signs of implantation including over-pro-
duction of hCG, in addition to patients who have shown hCG produc-
tion but without a gestational sac (Coughlan et al., 2014). Yet, recurrent
implantation failure (RIF) is a term for description of conditions in
which women have experienced three failed in vitro fertilization (IVF)
cycles in spite of the presence of good quality embryos. In this de-
scription, advanced maternal age and embryo stage are also taken into
account. This condition is associated with several uterine, male, or
embryo factors, or parameters related with IVF protocol (Bashiri et al.,
2018). Generally, implantation failure can be caused by maternal fac-
tors or embryonic factors. The former comprise uterine anatomic
anomalies, thrombophilia, abnormalities in the receptiveness of the
endometrium and immune-related causes. The latter is related with
genetic factors or other inherent embryonic abnormalities that interfere
with the ability of embryo to grow in the uterine space, and the sub-
sequent hatching and implantation (Simon and Laufer, 2012). Im-
plantation involves several steps including adherence of embryo to the
luminal surface of the endometrium, its migration over the luminal
epithelium and subsequent invasion into the deep portions of the en-
dometrium (Coughlan et al., 2014). Based on the acknowledged roles of
genetic factors in almost all steps of embryo development (Mohebi and
Ghafouri-Fard, 2019), it is not surprising that these factors contribute in
the pathogenesis of RIF. Although the role of environmental and life
style factors, immunological abnormalities, psychological disturbances
and infection has been comprehensively reviewed in the context of RIF
(Bashiri et al., 2018), there is lack of such approach about the role of
genetic factors such as mutations and single nucleotide polymorphisms
(SNPs) in this process. In the current review, we aimed at assessment of
contribution of these factors in RIF. Thus, we summarize the results of
studies which assessed expression of certain factors in the context of RIF
and those which appraised association between SNPs/mutations and
risk of this condition. Although Rif and recurrent pregnancy loss might
share some molecular mechanisms, we only focused on the former
entity to detect molecular mechanisms of very early stages of preg-
nancy.
2. Expression assays
Several studies have reported dysregulation of genes in tissue
samples or peripheral blood of patients with RIF. The reported genes
were mostly associated with implantation. In a prospective case-control
investigation, Guo et al. have assessed expression of a number of cell
adhesion-associated genes that may contribute in the process of embryo
implantation in the endometrium samples of patients who experienced
RIF compared with those got pregnant in their first IVF cycle. Notably,
they reported decreased expression of the endothelial cell adhesion
molecule 1 (PECAM1) and transforming growth factor β1 (TGF-β1) in

Abbreviations: RIF, recurrent IVF failure; IVF, in vitro fertilization; SNP, single nucleotide polymorphism
⁎
Corresponding author.
E-mail address: s.ghafourifard@sbmu.ac.ir (S. Ghafouri-Fard).

https://doi.org/10.1016/j.genrep.2020.100685
Received 11 March 2020; Received in revised form 7 April 2020; Accepted 15 April 2020
Available online 18 April 2020
2452-0144/ © 2020 Elsevier Inc. All rights reserved.
K. Vakili, et al.
RIF group at both transcript and protein levels. Their functional studies
showed that PECAM1 silencing can reduce expression of TGF-β1 in
Ishikawa cells, as well as in primary human endometrial epithelial cells
and stromal cells. Based on these results, authors concluded that
PECAM1 and TGF-β1 can participate in regulation of endometrial re-
ceptivity (Guo et al., 2018).
In a cross-sectional study, Kalem et al. have compared expression of
Chemokine (CeC motif) ligand 2 (CCL2) as well as total antioxidant
status (TAS), total oxidant status (TOS), and the oxidative stress index
(OSI) between patients who experienced RIF, nulliparous patients with
recurrent pregnancy loss (RPL) and healthy controls. Both patients
groups had higher levels of CCL2 compared with the control subjects.
However, there was no significant difference in The TOS, TAS, and OSI
levels between three groups. So, they concluded that although CCL2
might a predictive marker for unfavorable pregnancy outcome, oxida-
tive stress markers in the pregestational phase are not useful markers in
this regard.
In their gene expression profiling, Bastu et al. have showed differ-
ential expression of 641 genes between RIF patients and healthy con-
trols. These genes were enriched in 44 pathways including circadian
rhythm, cancer-related pathways, proteasome, complement and coa-
gulation cascades, citrate cycle, adherens junction, inflammatory re-
sponses, cell cycle, and renin–angiotensin system (Bastu et al., 2019).
Bansal et al. have reported higher serum levels of VEGF-A in RIF
cases compared with healthy subjects. However, there was no sig-
nificant difference in VEGF-R1 quantities between groups. Most no-
tably, they detected no correlation between VEGF-A or VEGF-R1 and
the total amounts of circulating NK cells, CD69 activated NK cells or NK
cytotoxicity which indicates independence of VEGF production and NK
cell activity in this condition (Bansal et al., 2017).
Martínez-Zamora et al. have assessed expression of thrombin-acti-
vatable fibrinolysis inhibitor (TAFI) in patients with RIF, females ex-
periencing a first successful IVF and healthy fertile women. Notably,
level of this antigen was higher in the RIF group that the other study
groups. Yet, they detected no differences in distribution of TAFI poly-
morphisms between groups (Martínez-Zamora et al., 2011).
In a 10-year-long study, RoyChoudhury et al. have compared levels
of eight metabolites between RIF patients and recurrent IVF success
(RIS) group. They reported lower levels of valine, adipic acid, L-lysine,
creatine, ornithine, glycerol, D-glucose and urea in RIS group compared
with RIF patients. Moreover, serum eNOS levels were decreased in
women with RIF compared with the other group which implies prob-
able deficiency in nitric oxide production (RoyChoudhury et al., 2016).
As a perfect example of high throughput studies in RIF, Koot et al.
have collected gene signatures from mid-luteal phase endometrial
biopsies of females with RIF and healthy subjects. Through a bioin-
formatics approach, they recognized a signature of 303 genes which
could predict occurrence of RIF. Notably, expression profiles of these
genes could be used for classification of RIF patients into distinctive
groups with unlike successive implantation success rates (Koot et al.,
2016).
Engin-Ustun et al. have assessed serum levels of Sirtuin 1 as a cri-
tical regulator of apoptosis and cellular stress in a cohort of women
including RIF patients, healthy women who got pregnant by IVF and
females with a 1-cycle failure of IVF as controls. Although the levels of
this factor were higher in RIF group compared with the other groups,
the difference did not reach the level of significance because of the low
sample size of the study (Engin-Ustun et al., 2017).
Coughlan et al. have appraised expression of integrins α1, α4, and
αVβ3 in the glandular and luminal epithelium, stroma, and vascular
cells of the endometrium from women with RIF and control females.
Based on similar levels of expression of these genes between cases and
controls, authors concluded lack of prognostic value of these genes in
IVF treatment (Coughlan et al., 2013).
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Gene Reports 20 (2020) 100685
3. Association between SNPs and RIF
SNPs within genes that regulate different steps in the implantation
process can be associated with RIF. Preliminary results indicate that
variations in the maternal killer immunoglobulin-like receptor (KIR) gene
and fetal HLA-C genes might affect implantation success (Moffett et al.,
2016). The vascular endothelial growth factor (VEGF) is another con-
tributor in the process of RIF, since it is an important regulator of an-
giogenesis. Boudjenah et al. have assessed the association between the
VEGF +405C/G genotype and RIF in a cohort of patients experiencing
intracytoplasmic sperm injection (ICSI). They reported higher fre-
quency of the VEGF +405C/C genotype in RIF patients compared with
controls. Thus, they concluded that the mentioned polymorphism might
affect embryo implantation (Boudjenah et al., 2012). Jung et al. have
genotyped rs833061 (-460T > C), rs25648 (-7C > T) and rs3025020
(-583C > T) VEGF SNPs in Korean RIF patients and healthy subjects.
They reported association between the rs833061 C allele and rs25648 T
allele and higher susceptibility to RIF. Moreover, the rs833061/rs25648
TC/CT, TC/CT+TT, and rs833061/rs3025020 TC+CC/TT genotypes
were over-represented in the RIF patients compared with the healthy
subjects (Jung et al., 2016). Cramer et al. have genotyped two SNPs in
human progesterone receptor coding gene (H770H (C/T genotype) and
+331G/A polymorphism) in patients who had at least two IVF failures
and females who conceived after 1 IVF attempt. Their results showed
association between the H770H T allele and lower risk for implantation
failure in women aged < 35 years. Besides, the +331A allele was as-
sociated with higher risk of implantation failure in subjects who
weighed < 135 pounds. Notably, the +331G/A SNP tended to augment
the risk for implantation failure in females who had the H770H C/C
genotype. Most notably, the chance that a subject carries the +331G/A
SNP escalates with the number of failed IVF attempts (Cramer et al.,
2003). Cho et al. have assessed association between miR-146aC > G,
miR-149T > C, miR-196a2T > C, and miR-499A > G polymorphisms
and risk of RIF in Korean population. They showed higher frequency of
the combined miR-146aCG+GG/miR-196a2CC genotype in RIF cases
compared with controls. On the contrary, the frequencies of G-T-T-A
(miR-146a/-149/-196a2/-499) and G-T-T inferred genotypes (miR-
146a/-149/-196a2) were lower in RIF cases. Based on these observa-
tions and assessment of expression of the mentioned miRNAs, authors
concluded that SNPs in miR-146a and miR-196a2 could change ex-
pression of their target mRNAs (Cho et al., 2016). Goodman et al. have
genotyped p53 codon 72 Arg/Pro, the 4G/4G polymorphism of the
plasminogen activator inhibitor 1 (PAI-1), and VEGF -1154A/A in pa-
tients with RIF and fertile control females. They observed higher re-
presentation of homozygous p53 Pro72, PAI 4G/4G, and VEGF
-1154AA among RIF cases compared with controls (Goodman et al.,
2009). Table 1 summarizes the studies which assessed association be-
tween SNPs and RIF.
4. Genetic mutations
There are a few reports which detected deleterious mutations in
implantation-related genes in female subjects who experienced RIF.
Among them is the study conducted by Zhao et al. Authors have de-
tected homozygous or compound-heterozygous mutations or variants in
WEE2 gene in five out of 19 assessed cases. The identified variants were
as follow: c.293_294insCTGAGACACCAGCCCAACC (p.Pro98Pro fsX2),
c.1576T > G (p.Tyr526Asp), c.991C > A (p.His331Asn),
c.1304_1307delCCAA (p.Thr435Met fsX31), c.341_342 del AA
(p.Lys114Asn fsX20), c.864G > C (p.Gln288His), c.1A > G (p.0?) and
c.1261G > A (p.Gly421Arg). Two of these variants namely
c.1576T > G and c.864G > C have been formerly reported as rare
SNPs. Pedigree analyses indicated autosomal recessive inheritance in at
least 2 cases. These variants might result in repeated pronucleus for-
mation failure and infertility in female cases (Zhao et al., 2019).
 K. Vakili, et al.

Table 1
Results of studies which assessed association between SNPs and RIF (IVF: in vitro fertilization, ET: embryo transfer, ICSI: intracytoplasmic sperm injection, RIF: recurrent IVF failure, SNP: single nucleotide polymorphism,
VEGF: vascular endothelial growth factor, miR: microRNA).
SNP Gene Number of samples Results Reference

+405 C/G VEGF 40 women with RIF defined by absence of pregnancy after higher frequency of the VEGF +405C/C genotype in RIF patients Boudjenah et al.
transfer of > 10 embryos and 131 women control, with at compared with controls (2012)
least one live birth after the transfer of fewer than 10 embryos
rs833061 (-460T > C), rs25648 (-7C > T) and VEGF 119 women diagnosed with RIF and 236 control subjects VEGF SNPs might be useful for prediction of RIF development. Jung et al. (2016)
rs3025020 (-583C > T)
H770H (C/T genotype) and +331G/A progesterone receptor 317 women with at least 2 embryo transfers without a clinical Although human progesterone receptor SNPs do not clearly Cramer et al. (2003)
pregnancy and 288 women who became pregnant after 1 IVF influence the risk of RIF in most women, the chance that a woman
carries the +331G/A SNP increases with the number of failed IVF
attempts.
miR-146aC > G, miR-149T > C, miR-196a2T > C, – 120 patients with RIF and 234 healthy controls with at least Expression levels of miR-146aC > G, miR-196a2T > C and Cho et al. (2016)
and miR-499A > G one live birth and no history of pregnancy loss possible gene-gene interaction between these miRNAs contribute
in RIF development.
Codon 72 Arg/Pro, the 4G/4G polymorphism and P53, PAI-1, VEGF 70 women with history of RIF after IVF-ET and 73 fertile A panel of tests for mentioned SNPs may be useful to identify Goodman et al.
-1154A/A control women women at risk for RIF after IVF-ET. (2009)
ins/del polymorphism HLA-G 40 women with history of RIF and 40 women with pregnancy Heterozygote genotype of ins/del enhances risk of RIF. Enghelabifar et al.
following IVF (2014)

3
R72P p53 70 women with implantation failure, 205 women experiencing The frequency of Pro72 was higher among women experiencing Kay et al. (2006)
recurrent pregnancy loss and 20 control women RIF compared with women experiencing recurrent miscarriage
and with control women.
R72P P53 83 oocyte donors as controls, 44 cases with RIF and 54 cases Patients carrying a PP genotype on p53 codon 72 will have less Lledo et al. (2014)
with recurrent pregnancy loss chance to achieve an ongoing pregnancy.
rs929271 (T/G) LIF 411 women who underwent ICSI The G/G genotype was associated with a higher implantation rate, Oliveira et al. (2016)
ongoing pregnancy rate/patient and ongoing pregnancy rate/
transfer. This SNP might be a susceptibility biomarker for
prediction of implantation efficiency and pregnancy outcomes.
-765G > C COX-2 106 patients with no history of successful pregnancy and a This SNP is associated with RIF and may be a novel molecular Salazar et al. (2010)
diagnosis of infertility undergoing assisted reproductive biomarker for this condition.
protocols and 80 healthy controls
p53-R72P; IL-11-1082-AG; VEGF-1154-AG; IL-10; P53, IL-11, VEGF, IL-10, 89 patients with recurrent pregnancy loss, 77 RIF patients and Significant association was detected between the E4 isoform Turienzo et al.
APOE-R112C; APOE-R158C APOE 89 controls (R122-R158) of the APOE gene and RIF. The R72P SNP of the p53 (2018)
gene and the 1154-AG of the VEGF gene demonstrated different
distribution.
Intron region of TP63, VEGFA, MMP2, ESR1, and TP63, VEGFA, MMP2, 42 patient with RIF, 63 women who became pregnant after the The ESR1/AA (rs12199722) and LIF/GT (rs929271) were Vagnini et al. (2019)
ESR2 genes and in the 3′ untranslated region of ESR1, ESR2, LIF first IVF/ICSI and 65 fertile women who had at least two associated with RIF.
the LIF gene children without any treatment and no history of miscarriage
Ile89Leu ALPP, encoding the 100 controls and 100 patients affected with recurrent Ile89Leu was associated with a decreased risk of IVF failure. ALPP Vatin et al. (2014)
placental alkaline spontaneous abortion; confirmation in 92 additional controls genotyping is suggested as a strong predictor of implantation
phosphatase and 612 additional patients success.
7 unit repeat polymorphism NALP3 (CIAS1) 243 women who were undergoing IVF CIAS1 7 unit repeat polymorphism increases the chance of Witkin et al. (2010)
mycoplasma infection-related female infertility.
Gene Reports 20 (2020) 100685
K. Vakili, et al.
5. Discussion
RIF is a complex condition with high psychological and health
burden. This condition is associated with abnormal expression or ac-
tivity of several growth factors, metabolites, and inflammatory cyto-
kines (Guo et al., 2018). Results of high throughput techniques also
verified the involvement of several signaling pathways in the patho-
genic process of RIF (Bastu et al., 2019). Notably, RIF has been mostly
associated with decreased cellular proliferation (Koot et al., 2016).
Assessment of genomic variants that influence the embryo im-
plantation might help in prediction of IVF prognosis. However, a
number of studies have reported different expression level of certain
proteins between RIF patients and healthy controls in spite of similar
distribution of SNP variants between groups (Martínez-Zamora et al.,
2011). Thus, the role of epigenetic factors should not be ignored in the
process of RIF.
Differences between RIF patients and healthy subjects have not been
limited at genomic, transcriptomic and proteomic levels. At a metabo-
lomic level, studies have reported dysregulation of energy metabolism,
lipid metabolism and the arginine metabolic pathway in RIF patients
(RoyChoudhury et al., 2016).
Based on the multifaceted nature of RIF, treatment strategies should
be designed in a personalized manner. This approach necessitates in-
dividualized assessment of patients and retrieval of genomic and tran-
scriptomic data of each case to suggest an optimized treatment method.
With the advent of next generation sequencing technology, this ap-
proach is expected to be applied in the clinical setting in the near fu-
ture. Assessment of expression data of relevant genes in the biological
samples is not only useful for providing practical counseling for RIF
patients but also it guides design of new treatment strategies. Successful
down-regulation of TNF-α, the Th1 transcription factor T-bet, and up-
regulation of IL-10 and the Th2 transcription factor GATA-3 by hy-
droxychloroquine in RIF patients (Ghasemnejad-Berenji et al., 2018), is
an example of application of basic science in the clinical setting.
Future studies are needed to replicate the results of genetic asso-
ciation studies such as those referred to role of VEGF SNPs in larger
cohorts of RIF patients from different populations. Meta-analysis of the
obtained data would help in identification of predictive markers for
RIF. A proper example in this regard is a previous meta-analysis of
genotyping data the p53 codon 72 SNP in a population of 1056 patients
who underwent their first IVF cycle. A total of 289 patients from this
cohort did not get pregnant, so attempted a second cycle. In 72 of them,
no implantation occurred, so they entered a third cycle. Assessment of
data of these large cohort revealed no significant difference in embryo
implantation rate in association with the mentioned SNP (Patounakis
et al., 2009). Therefore, large scale studies are needed to assess other
possible associations. Totally, identification of genetic factors of RIF has
practical significance in the genetic counseling of couples suffering
from this condition especially when discussing the possible option of
gamete/embryo donation.
Declaration of competing interest
Authors declare no conflicts of interests.
Acknowledgement
The current study was supported by a grant from Urogenital Stem
Cell Research Center, Shahid Beheshti University of Medical Sciences,
Tehran, Iran.
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