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Genetics of recurrent miscarriage: challenges, current knowledge, future directions.
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PMID:  22457663     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Recurrent miscarriage (RM) occurs in 1-3% of couples aiming at childbirth. Due to multifactorial etiology the clinical diagnosis of RM varies. The design of genetic/"omics" studies to identify genes and biological mechanisms involved in pathogenesis of RM has challenges as there are several options in defining the study subjects (female patient and/or couple with miscarriages, fetus/placenta) and controls. An ideal study would attempt a trio-design focusing on both partners as well as pregnancies of the couple. Application of genetic association studies focusing on pre-selected candidate genes with potential pathological effect in RM show limitations. Polymorphisms in ∼100 genes have been investigated and association with RM is often inconclusive or negative. Also, implication of prognostic molecular diagnostic tests in clinical practice exhibits uncertainties. Future directions in investigating biomolecular risk factors for RM rely on integrating alternative approaches (SNPs, copy number variations, gene/protein expression, epigenetic regulation) in studies of single genes as well as whole-genome analysis. This would be enhanced by collaborative network between research centers and RM clinics.
Kristiina Rull; Liina Nagirnaja; Maris Laan
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Type:  Journal Article     Date:  2012-03-19
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Title:  Frontiers in genetics     Volume:  3     ISSN:  1664-8021     ISO Abbreviation:  Front Genet     Publication Date:  2012  
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Created Date:  2012-03-29     Completed Date:  2012-10-02     Revised Date:  2013-08-13    
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Nlm Unique ID:  101560621     Medline TA:  Front Genet     Country:  Switzerland    
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Languages:  eng     Pagination:  34     Citation Subset:  -    
Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu Tartu, Estonia.
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Journal ID (nlm-ta): Front Genet
Journal ID (publisher-id): Front. Gene.
ISSN: 1664-8021
Publisher: Frontiers Research Foundation
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Copyright © 2012 Rull, Nagirnaja and Laan.
Received Day: 29 Month: 1 Year: 2012
Accepted Day: 24 Month: 2 Year: 2012
epreprint publication date: Day: 16 Month: 2 Year: 2012
Electronic publication date: Day: 19 Month: 3 Year: 2012
collection publication date: Year: 2012
Volume: 3E-location ID: 34
ID: 3306920
PubMed Id: 22457663
DOI: 10.3389/fgene.2012.00034

Genetics of Recurrent Miscarriage: Challenges, Current Knowledge, Future Directions
Kristiina Rull12
Liina Nagirnaja1
Maris Laan1*
1Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of TartuTartu, Estonia
2Department of Obstetrics and Gynecology, Women’s Clinic of Tartu University HospitalTartu, Estonia
[edited-by] Edited by: Ryan Yuen, The Hospital for Sick Children, Canada
[edited-by] Reviewed by: Carolyn E. Banister, Brown University, USA; Fouad Janat, Siemens Diagnostics, USA
Correspondence: *Correspondence: Maris Laan, Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Riia 23, 51010 Tartu, Estonia. e-mail:
[other] This article was submitted to Frontiers in Epigenomics, a specialty of Frontiers in Genetics.


The occurrence of recurrent miscarriage (RM) has been estimated 1–3% of couples attempting to bear children (Berry et al., 1995; Rai and Regan, 2006; Branch et al., 2010). While fetal chromosomal abnormalities are responsible for 70% of sporadic miscarriages (Ogasawara et al., 2000; Philipp et al., 2003; Menasha et al., 2005), they account for considerably smaller fraction of pregnancy losses in RM couples. Today, clinical practice includes testing of several factors potentially increasing the risk of (recurrent) miscarriage, e.g., parental chromosomal anomalies, maternal thrombophilic, anatomic, endocrine, and immunological disorders (Bricker and Farquharson, 2002; Christiansen et al., 2008; Branch et al., 2010; Tang and Quenby, 2010). At least 50% of the RM cases have no deviations in any applied diagnostic test and are considered idiopathic, unexplained origin. In addition to clinical, environmental, and life-style risk factors, there is a growing evidence that RM has also genetic susceptibility. A review of initial observations indicated two to sevenfold increased prevalence of RM among first-degree blood relatives compared to the background population (Christiansen, 1996). Population-based register studies showed that overall frequency of miscarriage among the siblings of idiopathic RM is approximately doubled compared to general population (Nybo Andersen et al., 2000; Kolte et al., 2011). A recent genome-wide linkage scan using sibling pairs with idiopathic RM confirmed heterogeneity of contributing genetic factors (Kolte et al., 2011).

Unexplained RM is a stressful condition for a couple and supportive care is currently the only assistance that can be offered. Still, early recognition of a potential risk to miscarriage and systematic monitoring has beneficial effect in increasing live birth rates in RM couples (Jauniaux et al., 2006; Branch et al., 2010; Tang and Quenby, 2010; Musters et al., 2011). Genetic and genomic studies of RM have three main purposes: (1) identify DNA/RNA-based markers exhibiting direct predictive value to a couple’s risk to experience recurrent pregnancy losses; (2) capture the gene/protein expression profiles, pathways, and networks involved in (un)successful establishment of pregnancy; (3) apply hypothesis-based and hypothesis-free studies to pinpoint loci coding for novel non-invasive biomarkers applicable in clinical conditions for early pregnancy complications.

Challenges in Study Design to Investigate Genetics and “Omics” of RM

The design of genetic/“omics” studies to identify genes and biological mechanisms involved pathogenesis of RM is complex having several contradictory aspects regarding to the definition of phenotype, study objects, and functional effects to address (Figure 1).

Discrepancies in definition of the RM phenotype

Recurrent miscarriage is classically defined as the loss of three or more consecutive pregnancies before 20th gestational weeks (Berry et al., 1995; Jauniaux et al., 2006; Branch et al., 2010). Some experts consider two consecutive pregnancy losses sufficient for the diagnosis of RM because the recurrence rate and risk factors are similar to that after three losses (Branch et al., 2010). The faulty recall of the reproductive history, including or excluding the biochemical pregnancies (pregnancies documented only by a positive urine or serum hCG test) and center-specific ascertainment biases cause discrepancies in setting the diagnosis of RM (Christiansen et al., 2005).

The couples with RM can be divided into subgroups according to their reproductive history: primary (no successful pregnancies), secondary (series of miscarriages after a live birth) and tertiary (three non-consecutive miscarriages) RM and they should be considered as separate entities representing probably different pathophysiological mechanisms leading to pregnancy loss. Immunological factors have been suggested to play a greater role secondary RM, especially after the first-born son (Christiansen et al., 2004; Nielsen, 2011). Non-immunological risk factors, e.g., factor V Leiden mutation, tend to be associated mainly with primary RM (Wramsby et al., 2000).

The analysis power of genetics/“omics” research depends on the quality of the clinical history and applied diagnostic tests. Currently, the cases of idiopathic RM have been considered as preferred phenotype for the genetics research. However, the definition of idiopathic RM based on exclusions of known risk RM factors is facilities- and study-dependent. The association and/or causality of an etiologic factor with RM varies from “doubtful” to “definite” complicating the definition of idiopathic RM (Christiansen et al., 2005).

In summary, as RM is characterized by multifactorial etiology and variable penetrance and clinical outcome of recognized risk factors, a consensus in the clinical and research community has to be reached what factors should be tested before defining a particular case as idiopathic addressed via genetic/genomic studies.

Options for defining the study objects

One of the most challenging questions in investigating the genetics of RM is defining the study object(s): female patient and/or couple with miscarriages, fetus, or placenta (Figure 1). In genetic/genomic context these options target three different genomes (mother, father, fetus/placenta) and four (epi)genomes (different for placenta and fetus). In addition, as the definition of RM is based on longitudinal data (several independent events), one should remember that each pregnancy and each conceptus is a unique genetic combination with unique epigenetic settings, unique environmental conditions regarding the efficiency of established maternal–fetal interphase, maternal nutrition, and health.

Several genes that regulate implantation, fetal and placental development, and maternal adaptation to pregnancy are synthesized by the fetus or the placenta, e.g., placental hormones as hCG, placental growth hormone and lactogen (Mannik et al., 2010; Nagirnaja et al., 2010; Newbern and Freemark, 2011). In this context, a placental (fetal) genome would represent an ideal RM case for (epi)genetic and genomic studies. However, there are severe limitations–the recruitment of couples/women at the RM event and difficulties in obtaining pure tissue material from the aborted fetus with no contamination with maternal cells. There are some genetic studied focused on RM compared to control placentas (e.g., HLA-C, HLA-G, p53, mtDNA mutations; Table 1) but the sample sizes in these studies never reach required statistical power.

As a solution, an ideal study would attempt a trio-design focusing on both partners of clinically well-described RM couples as well as aborted cases and live born children (as inner control) of the same couple. This would allow to directly address parental- and allele-specific gene expression or epigenetic modifications in placenta. The paternally inherited genetic factors contribute and combine with maternally inherited factors in the placental/fetal (epi)genome (Rull et al., 2008; Faridi and Agrawal, 2011; Uuskula et al., 2011). So far, most studies of couples have been limited to parental karyotyping, and in case of a structural chromosomal abnormalities their effect on couple’s offsprings (Stephenson and Sierra, 2006; Franssen et al., 2011).

The identification of a suitable control group for women/couples with RM has its own great challenges. The ideal controls should be exposed to similar number of pregnancies at the same age of partners as the cases, and never experienced miscarriage. In a typical study the controls have been defined as women/couples with proven fertility when having at least one child, with limited information about their full reproductive history during the present or past partnerships. Delaying the childbirth until older reproductive age, the usage of contraceptive methods after birth of the one or two planned children, the change of co-habitant partners are frequent limitations for recruitment of the ideal control group.

Challenges in linking the genetic variants with the pathological functional effect

A successful pregnancy can be achieved only via balanced dialog between mother and the fetus mediated through placenta. The pathologies may locate and influence physiology in different compartments (Figure 1). In maternal side, RM has been associated with genes responsible for impaired endometrial decidualization, apoptosis as well as inflammatory processes (Salker et al., 2010). Multiple (epi)genetic/genomic factors decrease sperm quality causing DNA damage and thus leading to poor fertilization, impaired embryo development and possibly to RM (McLachlan and O’Bryan, 2010; Brahem et al., 2011). The development of placenta and release of placentally expressed proteins strongly influence both the fetal and maternal metabolism during the pregnancy (Fowden et al., 2009; Lewis et al., 2012).

Genetic Association Studies of RM: Biases, Contradictions, Limitations

All conducted genetic association studies targeting RM have been designed as hypothesis-based candidate gene studies. The most frequently addressed genes in the context of RM are associated with the developing immunotolerance and inflammation and also with changes of maternal metabolism and blood coagulation (Table 1). Female partner of RM couple has been the most commonly addressed study subject.

The polymorphisms in almost 90 different genes have been investigated (Table 1). In most studies the association between a polymorphism and RM is negative, has not been replicated in follow-up studies or shows opposite results between studies. Inconsistencies may arise due to (i) differences in study design, definitions of RM and control group; (ii) focus on RM women instead of couples or placenta; (iii) low statistical power due to small sample size; (iv) ethnic difference in risk variants, population-specific low-impact gene variants increasing RM risk in consort; (v) contribution of life-style and environmental factors on the pregnancy course; (vi) secondary pathways affecting protein translation/metabolism leading to discrepancies between genotype and respective protein levels, e.g., Factor XII, Protein Z (Iinuma et al., 2002; Topalidou et al., 2009).

Most popular clinically tested polymorphisms in RM patients are thrombophilia-associated factor V (Leiden factor) mutation, factor II (prothrombin) G20210A mutation and MTHFR C667T variant encoding the methylenetetrahydrofolate reductase enzyme with reduced activity. However, meta-analyses or large studies focusing on these factors in relation to RM risk have controversial results (Table 1). There is also uncertainty about prognostic implications of positive tests as full thrombophilia screen can produce abnormal results in 20% of women with uncomplicated obstetric histories (Branch et al., 2010; Tang and Quenby, 2010).

Another set of thoroughly investigated polymorphisms providing contradictory results in association with RM are in genes involved in inflammation (e.g., IL1B, IL6, IL10, IFNγ, TNFα; Table 1). The balance of locally produced pro-inflammatory and anti-inflammatory cytokines was suggested to be critical for successful pregnancy (Choi and Kwak-Kim, 2008). It was proposed that a spectrum of thrombophilic and inflammation related genetic variants rather than single polymorphisms shape the cumulative risk of RM (Rey et al., 2003; Jivraj et al., 2006; Christiansen et al., 2008).

The immunological mechanisms responsible for the development of the tolerance to semi-allogeneic fetal “graft” by the maternal immune system has been the third attractive target for genetic studies. Positively, a majority of association studies with immune response related genes have been conducted for RM couples (Table 1). Unfortunately, most reports on the studied gene variants in relation to RM are controversial. There are numerous studies on polymorphisms affecting the expression of HLA-G (e.g., 14 bp indel in exon 8 of the 3′ UTR), the most dominant HLA antigen in blastocysts and trophoblastic tissue. Recent analyses have suggested that specific combinations of fetal (paternal) HLA-C and maternal killer immunoglobulin-like receptor (KIR) gene variants correlate with the risk to RM and other pregnancy complications (Hiby et al., 2010; Chazara et al., 2011; Colucci et al., 2011). KIRs regulate activity of uterine NK cells that are implicated in trophoblast invasion.

During the last years the focus has gradually switched from maternal factors to the genes involved in the function of placenta, carrying maternally and paternally originated gene copies (Table 1). The investigators have targeted placenta-specific genes such as hCG beta coding CGB5 and CGB8, as well as loci with wider expressional profile but exhibiting a specific role in placental function such as PAPPA, IGF-2, and p53 (Suzuki et al., 2006; Ostojic et al., 2008; Tang et al., 2011). Although initial genetic studies have exhibited positive association between identified novel gene variants and an increased risk to RM, replication studies have to confirm these findings.

Advances and Future Directions in “Omics” and (epi)Genetics

Genetic association studies based on pre-selected candidate genes have shown their limitations as RM represents a complex phenotype with no identified major genetic factor(s). In order to achieve the main goal – to identify predictive genetic risk factors and biomarkers for RM, advances are needed in clinic as well as in the research strategies.

Recruitment strategy

Suggested advances in clinic include networking of research groups aiming to collect large sample-sets targeting RM phenotype under joint criteria and guidelines. Recruitment of both couples suffering from RM as well as controls should be encouraged, along with detailed clinical and reproductive history. Andrologists are to be involved to analyze reproductive parameters of male partners. Recruitment of duos (mother–placenta/fetus) or trios (mother–father–placenta/fetus) would provide further bonus. Studies should be enhanced by collecting the material for DNA, RNA, and protein studies from the same recruited family, e.g., parental blood samples, paternal sperm analysis, maternal endometrial tissue, multisite placental tissue sampling. A network of targeted clinics would facilitate carrying out validation of novel identified biomarkers by setting up the large multicentre studies.

Introducing “omics” into RM research

With rapidly evolving technological advances in genetics/“omics” there are multiple appealing perspectives in RM biomolecular research (Figure 1).

Up to now, no hypothesis-free genome-wide association studies (GWAS) for identification of common risk variants for RM have been performed. The main reason is that large number of uniformly defined RM affected individuals/couples is required to reach sufficient power in such heterogenous phenotype (Eichler et al., 2010). Copy number variations (CNVs) involving one or several loci are expected to exhibit a stronger effect on the phenotype compared to SNPs. Comparative genome hybridization-based microarray analysis of 26 euploidic miscarriages picked up 11 unique inherited CNVs, two of them involve genes TIMP2 (86 kb duplication) and CTNNA3 (72 kb deletion) that are imprinted and maternally expressed in the placenta (Rajcan-Separovic et al., 2010). The first results of ongoing study using genome-wide genotyping data to map common CNVs demonstrated significantly more frequent prevalence of a 52.4-kb locus duplication on chromosome 5 among RM couples in Estonian and Danish population (Nagirnaja et al., 2011). These pilot studies alert for further investigations of rare and common CNVs as risk factors for RM.

Transcriptomics and proteomics based gene expression profiling in tissues responding to ongoing miscarriage event offers an attractive approach to identify differentially expressed biomarkers (Baek et al., 2007). A decreased expression level in chorionic villi from RM patients was shown for angiogenesis related loci, whereas the expression of several apoptosis-related genes was increased (Choi et al., 2003; Baek, 2004). The first whole-genome gene expression profiling of placental tissue from RM compared to uncomplicated pregnancies identified and replicated significant differential expression of TNF-related apoptosis-inducing ligand (TNFSF10; TRAIL) and S100A8 encoding for inflammatory marker calprotectin (heterodimer S100A8/A9; Rull et al., 2012). In comparative proteomics study applying 2-DE and MALDI-TOF/MS analyses of the follicular fluids of RM patients, abnormal expression of complement component C3c chain E, fibrinogen γ, antithrombin, angiotensinogen, and hemopexin precursor was reported (Kim et al., 2006b), and in the blood serum from RM patients the expression of ITI-H4 was altered (Kim et al., 2011).

Integrating of genetics and epigenetics

An important factor of placental development and function is epigenetic regulation governing the control of gene expression (Nelissen et al., 2011). Epigenomic marks include CpG methylation in DNA, histone modifications in chromatin, and non-coding regulatory RNAs. The specific features in placental epigenome are (i) active temporal dynamics – changes in epigenetic marks over course of pregnancy (Novakovic et al., 2011); (ii) complex organization of the DNA methylome and presence of tissue-specific differentially methylated regions (Choufani et al., 2011; Chu et al., 2011); (iii) abundance of parental-specific imprinted genes (Constancia et al., 2004; Moore and Oakey, 2011); (iv) evidence of polymorphic methylation or imprinting (Yuen et al., 2009); (v) placenta-specific microRNAs (miRNAs; Luo et al., 2009; Maccani and Marsit, 2009; Noguer-Dance et al., 2010); (vi) effect of environmental factors, e.g., maternal smoking (Maccani et al., 2010). Although altered placental epigenetics has been demonstrated in cases of fetal growth disturbances, preeclampsia, and gestational diabetes (Nelissen et al., 2011), there is limited information on the role of aberrant epigenetic profiling in RM. Epigenetic comparison of different cell types in early pregnancy is technically challenging. The only systematically addressed topic is skewed X-chromosome inactivation (XCI; the preferential inactivation of one of two X-chromosomes in female cells). Initial findings that XCI is increased in women with RM were promising (Sangha et al., 1999; Lanasa and Hogge, 2000; Van den Veyver, 2001), but the follow-up studies have revealed that the skewed XCI is associated rather with maternal age and fetal karyotype than solely with RM (Hogge et al., 2007; Pasquier et al., 2007; Warburton et al., 2009). Only single studies are available for gene-specific methylation in RM-related tissues (placenta, endometrium, maternal blood). For the biallelically expressed hCG beta-subunit coding CGB5, three placentas (including two RM) were reported with monoallelic expression of maternal alleles and hemimethylated gene promoters suggesting the association of methylation allelic polymorphism with pregnancy loss (Uuskula et al., 2011). Methyl transferase (G9aMT) and methylated histone (H3-K9) expressions were significantly lower in decidual/endometrial tissue of unexplained RM cases compared to controls (Fatima et al., 2011). As a support to the contribution of epigenetic regulation of implantation, significantly more abnormal methylation values for APC and imprinted PEG3 were reported in chorionic villus samples of abortions/stillbirth than in other studied genes (Zechner et al., 2009).

No targeted microRNA expression profiling has been performed for RM-related tissues. Still, there are placenta-specific miRNAs capable of crossing the placental barrier and detectable in maternal plasma (Chim et al., 2008; Miura et al., 2010) and an altered profile of several miRNAs has been shown in pregnancy complications. Among the RM-associated genes, the expression of HLA-G was shown to be modulated by a 3′ UTR polymorphism exhibiting allele-specific affinity to microRNAs miR-148a, miR-148b, and miR-152, and consequently differential mRNA degradation and translation suppression processes (Tan et al., 2007). A recent study showed association between two SNPs in pre-miR-125a and increased risk to RM (Hu et al., 2011). As miRNA expression data has been suggested to harbor potential in discriminating disease samples with high accuracy (Scholer et al., 2011), there might be also strong perspectives in RM research and potential clinical implications.

In conclusion, future directions in investigating biomolecular risk factors for RM rely on integrating alternative approaches (DNA variants, gene and protein expression, epigenetic regulation) in studies of individual genes as well as whole-genome analysis. This would be greatly enhanced by extensive collaborative network between research centers and RM clinics.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The studies on the genetics of recurrent miscarriages in the laboratory of Maris Laan have been supported by Wellcome Trust International Senior Research Fellowship (070191/Z/03/A) in Biomedical Science in Central Europe, HHMI International Scholarship Grant #55005617, Estonian Science Foundation (grants #7471, #9030), and Estonian Ministry of Education and Science core grants SF0182721s06, SF0180022s12.

Al-Khateeb G. M.,Sater M. S.,Finan R. R.,Mustafa F. E.,Al-Busaidi A. S.,Al-Sulaiti M. A.,Almawi W. Y.. (Year: 2011). Analysis of interleukin-18 promoter polymorphisms and changes in interleukin-18 serum levels underscores the involvement of interleukin-18 in recurrent spontaneous miscarriage. Fertil. Steril.96, 921–92610.1016/j.fertnstert.2011.06.07921840518
Alsheikh F. S.,Finan R. R.,Almawi A. W.,Mustafa F. E.,Almawi W. Y.. (Year: 2012). Association of the R67X and W303X nonsense polymorphisms in the protein Z-dependent protease inhibitor gene with idiopathic recurrent miscarriage. Mol. Hum. Reprod.18, 156–16010.1093/molehr/gar06922039093
Amani D.,Ravangard F.,Niikawa N.,Yoshiura K.,Karimzadeh M.,Dehaghani A. S.,Ghaderi A.. (Year: 2011). Coding region polymorphisms in the indoleamine 2,3-dioxygenase (INDO) gene and recurrent spontaneous abortion. J. Reprod. Immunol.88, 42–4710.1016/j.jri.2010.07.00721030093
Aruna M.,Nagaraja T.,Andal Bhaskar S.,Tarakeswari S.,Reddy A. G.,Thangaraj K.,Singh L.,Reddy B. M.. (Year: 2011). Novel alleles of HLA-DQ and -DR loci show association with recurrent miscarriages among South Indian women. Hum. Reprod.26, 765–77410.1093/humrep/der02421325036
Aruna M.,Sudheer P. S.,Andal S.,Tarakeswari S.,Reddy A. G.,Thangaraj K.,Singh L.,Reddy B. M.. (Year: 2010). HLA-G polymorphism patterns show lack of detectable association with recurrent spontaneous abortion. Tissue Antigens76, 216–22210.1111/j.1399-0039.2010.01505.x20492598
Baek K. H.. (Year: 2004). Aberrant gene expression associated with recurrent pregnancy loss. Mol. Hum. Reprod.10, 291–29710.1093/molehr/gah04915026541
Baek K. H.,Lee E. J.,Kim Y. S.. (Year: 2007). Recurrent pregnancy loss: the key potential mechanisms. Trends Mol. Med.13, 310–31710.1016/j.molmed.2007.05.00517574920
Baxter N.,Sumiya M.,Cheng S.,Erlich H.,Regan L.,Simons A.,Summerfield J. A.. (Year: 2001). Recurrent miscarriage and variant alleles of mannose binding lectin, tumour necrosis factor and lymphotoxin alpha genes. Clin. Exp. Immunol.126, 529–53410.1046/j.1365-2249.2001.01663.x11737072
Berry C. W.,Brambati B.,Eskes T. K.,Exalto N.,Fox H.,Geraedts J. P.,Gerhard I.,Gonzales Gomes F.,Grudzinskas J. G.,Hustin J.. (Year: 1995). The Euro-Team Early Pregnancy (ETEP) protocol for recurrent miscarriage. Hum. Reprod.10, 1516–15207593527
Beydoun H.,Saftlas A. F.. (Year: 2005). Association of human leucocyte antigen sharing with recurrent spontaneous abortions. Tissue Antigens65, 123–13510.1111/j.1399-0039.2005.00367.x15713211
Bianca S.,Barrano B.,Cutuli N.,Indaco L.,Cataliotti A.,Milana G.,Barone C.,Ettore G.. (Year: 2010). No association between apolipoprotein E polymorphisms and recurrent pregnancy loss. Fertil. Steril.93, 27610.1016/j.fertnstert.2009.12.01519732892
Bogdanova N.,Horst J.,Chlystun M.,Croucher P. J.,Nebel A.,Bohring A.,Todorova A.,Schreiber S.,Gerke V.,Krawczak M.,Markoff A.. (Year: 2007). A common haplotype of the annexin A5 (ANXA5) gene promoter is associated with recurrent pregnancy loss. Hum. Mol. Genet.16, 573–57810.1093/hmg/ddm01717339269
Bolor H.,Mori T.,Nishiyama S.,Ito Y.,Hosoba E.,Inagaki H.,Kogo H.,Ohye T.,Tsutsumi M.,Kato T.,Tong M.,Nishizawa H.,Pryor-Koishi K.,Kitaoka E.,Sawada T.,Nishiyama Y.,Udagawa Y.,Kurahashi H.. (Year: 2009). Mutations of the SYCP3 gene in women with recurrent pregnancy loss. Am. J. Hum. Genet.84, 14–2010.1016/j.ajhg.2008.12.00219110213
Bombell S.,McGuire W.. (Year: 2008). Cytokine polymorphisms in women with recurrent pregnancy loss: meta-analysis. Aust. N. Z. J. Obstet. Gynaecol.48, 147–15410.1111/j.1479-828X.2008.00843.x18366487
Bottini E.,Coromaldi L.,Carapella E.,Pascone R.,Nicotra M.,Coghi I.,Lucarini N.,Gloria-Bottini F.. (Year: 1983). Intrauterine death: an approach to the analysis of genetic heterogeneity. J. Med. Genet.20, 196–19810.1136/jmg.20.3.1966683759
Brahem S.,Mehdi M.,Landolsi H.,Mougou S.,Elghezal H.,Saad A.. (Year: 2011). Semen parameters and sperm DNA fragmentation as causes of recurrent pregnancy loss. Urology78, 792–79610.1016/j.urology.2011.08.06421813165
Branch D. W.,Gibson M.,Silver R. M.. (Year: 2010). Clinical practice. Recurrent miscarriage. N. Engl. J. Med.363, 1740–174710.1056/NEJMcp100533020979474
Bricker L.,Farquharson R. G.. (Year: 2002). Types of pregnancy loss in recurrent miscarriage: implications for research and clinical practice. Hum. Reprod.17, 1345–135010.1093/humrep/17.5.134511980763
Buchholz T.,Lohse P.,Kosian E.,Thaler C. J.. (Year: 2004). Vasoconstrictively acting AT1R A1166C and NOS3 4/5 polymorphisms in recurrent spontaneous abortions (RSA). Am. J. Reprod. Immunol.51, 323–32810.1111/j.1600-0897.2004.00163.x15212666
Buchholz T.,Lohse P.,Rogenhofer N.,Kosian E.,Pihusch R.,Thaler C. J.. (Year: 2003). Polymorphisms in the ACE and PAI-1 genes are associated with recurrent spontaneous miscarriages. Hum. Reprod.18, 2473–247710.1093/humrep/deg47414585904
Cecati M.,Giannubilo S. R.,Emanuelli M.,Tranquilli A. L.,Saccucci F.. (Year: 2011). HLA-G and pregnancy adverse outcomes. Med. Hypotheses76, 782–78410.1016/j.mehy.2011.02.01721376476
Chazara O.,Xiong S.,Moffett A.. (Year: 2011). Maternal KIR and fetal HLA-C: a fine balance. J. Leukoc. Biol.90, 703–71610.1189/jlb.051122721873457
Chim S. S.,Shing T. K.,Hung E. C.,Leung T. Y.,Lau T. K.,Chiu R. W.,Lo Y. M.. (Year: 2008). Detection and characterization of placental microRNAs in maternal plasma. Clin. Chem.54, 482–49010.1373/clinchem.2007.09797218218722
Choi H. K.,Choi B. C.,Lee S. H.,Kim J. W.,Cha K. Y.,Baek K. H.. (Year: 2003). Expression of angiogenesis- and apoptosis-related genes in chorionic villi derived from recurrent pregnancy loss patients. Mol. Reprod. Dev.66, 24–3110.1002/mrd.1033112874795
Choi Y. K.,Kwak-Kim J.. (Year: 2008). Cytokine gene polymorphisms in recurrent spontaneous abortions: a comprehensive review. Am. J. Reprod. Immunol.60, 91–11010.1111/j.1600-0897.2008.00602.x18573127
Choufani S.,Shapiro J. S.,Susiarjo M.,Butcher D. T.,Grafodatskaya D.,Lou Y.,Ferreira J. C.,Pinto D.,Scherer S. W.,Shaffer L. G.,Coullin P.,Caniggia I.,Beyene J.,Slim R.,Bartolomei M. S.,Weksberg R.. (Year: 2011). A novel approach identifies new differentially methylated regions (DMRs) associated with imprinted genes. Genome Res.21, 465–47610.1101/gr.111922.11021324877
Christiansen O. B.. (Year: 1996). A fresh look at the causes and treatments of recurrent miscarriage, especially its immunological aspects. Hum. Reprod. Update2, 271–29310.1093/humupd/2.4.2719080226
Christiansen O. B.,Nybo Andersen A. M.,Bosch E.,Daya S.,Delves P. J.,Hviid T. V.,Kutteh W. H.,Laird S. M.,Li T. C.,van der Ven K.. (Year: 2005). Evidence-based investigations and treatments of recurrent pregnancy loss. Fertil. Steril.83, 821–83910.1016/j.fertnstert.2004.12.01815820784
Christiansen O. B.,Pedersen B.,Nielsen H. S.,Nybo Andersen A. M.. (Year: 2004). Impact of the sex of first child on the prognosis in secondary recurrent miscarriage. Hum. Reprod.19, 2946–295110.1093/humrep/deh51615513982
Christiansen O. B.,Riisom K.,Lauritsen J. G.,Grunnet N.,Jersild C.. (Year: 1989). Association of maternal HLA haplotypes with recurrent spontaneous abortions. Tissue Antigens34, 190–19910.1111/j.1399-0039.1989.tb01736.x2595724
Christiansen O. B.,Ring M.,Rosgaard A.,Grunnet N.,Gluud C.. (Year: 1999). Association between HLA-DR1 and -DR3 antigens and unexplained repeated miscarriage. Hum. Reprod. Update5, 249–25510.1093/humupd/5.3.24910438109
Christiansen O. B.,Steffensen R.,Nielsen H. S.,Varming K.. (Year: 2008). Multifactorial etiology of recurrent miscarriage and its scientific and clinical implications. Gynecol. Obstet. Invest.66, 257–26710.1159/00014957518679035
Chu T.,Handley D.,Bunce K.,Surti U.,Hogge W. A.,Peters D. G.. (Year: 2011). Structural and regulatory characterization of the placental epigenome at its maternal interface. PLoS ONE6, e1472310.1371/journal.pone.001472321373191
Colucci F.,Boulenouar S.,Kieckbusch J.,Moffett A.. (Year: 2011). How does variability of immune system genes affect placentation?Placenta32, 539–54510.1016/j.placenta.2011.05.00121665273
Constancia M.,Kelsey G.,Reik W.. (Year: 2004). Resourceful imprinting. Nature432, 53–5710.1038/432053a15525980
Coulam C. B.,Jeyendran R. S.,Fishel L. A.,Roussev R.. (Year: 2006a). Multiple thrombophilic gene mutations rather than specific gene mutations are risk factors for recurrent miscarriage. Am. J. Reprod. Immunol.55, 360–36810.1111/j.1600-0897.2006.00376.x16635210
Coulam C. B.,Kay C.,Jeyendran R. S.. (Year: 2006b). Role of p53 codon 72 polymorphism in recurrent pregnancy loss. Reprod. Biomed. Online12, 378–38210.1016/S1472-6483(10)61004-816569330
Crisan T. O.,Trifa A.,Farcas M.,Militaru M.,Netea M.,Pop I.,Popp R.. (Year: 2011). The MTHFD1 c.1958 G > A polymorphism and recurrent spontaneous abortions. J. Matern. Fetal Neonatal Med.24, 189–19210.3109/1476705100370279420334533
Cupisti S.,Fasching P. A.,Ekici A. B.,Strissel P. L.,Loehberg C. R.,Strick R.,Engel J.,Dittrich R.,Beckmann M. W.,Goecke T. W.. (Year: 2009). Polymorphisms in estrogen metabolism and estrogen pathway genes and the risk of miscarriage. Arch. Gynecol. Obstet.280, 395–40010.1007/s00404-009-0927-119152063
Dahabreh I. J.,Jones A. V.,Voulgarelis M.,Giannouli S.,Zoi C.,Alafakis-Tzannatos C.,Varla-Leftherioti M.,Moutsopoulos H. M.,Loukopoulos D.,Fotiou S.,Cross N. C.,Zoi K.. (Year: 2009). No evidence for increased prevalence of JAK2 V617F in women with a history of recurrent miscarriage. Br. J. Haematol.144, 802–80310.1111/j.1365-2141.2008.07510.x19036091
Daher S.,Shulzhenko N.,Morgun A.,Mattar R.,Rampim G. F.,Camano L.,DeLima M. G.. (Year: 2003). Associations between cytokine gene polymorphisms and recurrent pregnancy loss. J. Reprod. Immunol.58, 69–7710.1016/S0165-0378(02)00059-112609526
Dendana M.,Hizem S.,Magddoud K.,Messaoudi S.,Zammiti W.,Nouira M.,Almawi W. Y.,Mahjoub T.. (Year: 2011). Common polymorphisms in the P-selectin gene in women with recurrent spontaneous abortions. Gene. Available at:
Dendana M.,Messaoudi S.,Hizem S.,Jazia K. B.,Almawi W. Y.,Gris J. C.,Mahjoub T.. (Year: 2012). Endothelial protein C receptor 1651C/G polymorphism and soluble endothelial protein C receptor levels in women with idiopathic recurrent miscarriage. Blood Coagul. Fibrinolysis23, 30–3410.1097/MBC.0b013e328349cae522036807
Denschlag D.,Marculescu R.,Unfried G.,Hefler L. A.,Exner M.,Hashemi A.,Riener E. K.,Keck C.,Tempfer C. B.,Wagner O.. (Year: 2004). The size of a microsatellite polymorphism of the haem oxygenase 1 gene is associated with idiopathic recurrent miscarriage. Mol. Hum. Reprod.10, 211–21410.1093/molehr/gah02414981149
Dossenbach-Glaninger A.,van Trotsenburg M.,Helmer H.,Oberkanins C.,Hopmeier P.. (Year: 2008). Association of the protein Z intron F G79A gene polymorphism with recurrent pregnancy loss. Fertil. Steril.90, 1155–116010.1016/j.fertnstert.2007.07.137618177644
Dudding T. E.,Attia J.. (Year: 2004). The association between adverse pregnancy outcomes and maternal factor V Leiden genotype: a meta-analysis. Thromb. Haemost.91, 700–71115045131
Eichler E. E.,Flint J.,Gibson G.,Kong A.,Leal S. M.,Moore J. H.,Nadeau J. H.. (Year: 2010). Missing heritability and strategies for finding the underlying causes of complex disease. Nat. Rev. Genet.11, 446–45010.1038/nrg280920479774
Faridi R. M.,Agrawal S.. (Year: 2011). Killer immunoglobulin-like receptors (KIRs) and HLA-C allorecognition patterns implicative of dominant activation of natural killer cells contribute to recurrent miscarriages. Hum. Reprod.26, 491–49710.1093/humrep/deq34121159685
Faridi R. M.,Das V.,Tripthi G.,Talwar S.,Parveen F.,Agrawal S.. (Year: 2009). Influence of activating and inhibitory killer immunoglobulin-like receptors on predisposition to recurrent miscarriages. Hum. Reprod.24, 1758–176410.1093/humrep/dep21719279038
Fatima N.,Ahmed S. H.,Salhan S.,Rehman S. M.,Kaur J.,Owais M.,Chauhan S. S.. (Year: 2011). Study of methyl transferase (G9aMT) and methylated histone (H3-K9) expressions in unexplained recurrent spontaneous abortion (URSA) and normal early pregnancy. Mol. Hum. Reprod.17, 693–70110.1093/molehr/gar03821606120
Fatini C.,Gensini F.,Battaglini B.,Prisco D.,Cellai A. P.,Fedi S.,Marcucci R.,Brunelli T.,Mello G.,Parretti E.,Pepe G.,Abbate R.. (Year: 2000). Angiotensin-converting enzyme DD genotype, angiotensin type 1 receptor CC genotype, and hyperhomocysteinemia increase first-trimester fetal-loss susceptibility. Blood Coagul. Fibrinolysis11, 657–66210.1097/00001721-200010000-0001011085286
Finan R. R.,Mustafa F. E.,Al-Zaman I.,Madan S.,Issa A. A.,Almawi W. Y.. (Year: 2010). STAT3 polymorphisms linked with idiopathic recurrent miscarriages. Am. J. Reprod. Immunol.63, 22–2710.1111/j.1600-0897.2009.00765.x20059466
Fowden A. L.,Sferruzzi-Perri A. N.,Coan P. M.,Constancia M.,Burton G. J.. (Year: 2009). Placental efficiency and adaptation: endocrine regulation. J. Physiol.587, 3459–347210.1113/jphysiol.2009.17596819451204
Franssen M. T.,Musters A. M.,van der Veen F.,Repping S.,Leschot N. J.,Bossuyt P. M.,Goddijn M.,Korevaar J. C.. (Year: 2011). Reproductive outcome after PGD in couples with recurrent miscarriage carrying a structural chromosome abnormality: a systematic review. Hum. Reprod. Update17, 467–47510.1093/humupd/dmr01121504961
Galazios G.,Papazoglou D.,Zografou C.,Maltezos E.,Liberis V.. (Year: 2011). Alpha2B-adrenergic receptor insertion/deletion polymorphism in women with spontaneous recurrent abortions. J. Obstet. Gynaecol. Res.37, 108–11110.1111/j.1447-0756.2010.01325.x21159032
Gerhardt A.,Scharf R. E.,Mikat-Drozdzynski B.,Krussel J. S.,Bender H. G.,Zotz R. B.. (Year: 2005). The polymorphism of platelet membrane integrin alpha2beta1 (alpha2807TT) is associated with premature onset of fetal loss. Thromb. Haemost.93, 124–12915630502
Gloria-Bottini F.,Nicotra M.,Lucarini N.,Borgiani P.,La Torre M.,Amante A.,Gimelfarb A.,Bottini E.. (Year: 1996). Phosphotyrosine-protein-phosphatases and human reproduction: an association between low molecular weight acid phosphatase (ACP1) and spontaneous abortion. Dis. Markers12, 261–2698718786
Goodman C.,Goodman C. S.,Hur J.,Jeyendran R. S.,Coulam C.. (Year: 2009a). The association of Apoprotein E polymorphisms with recurrent pregnancy loss. Am. J. Reprod. Immunol.61, 34–3810.1111/j.1600-0897.2008.00659.x19086990
Goodman C.,Hur J.,Goodman C. S.,Jeyendran R. S.,Coulam C.. (Year: 2009b). Are polymorphisms in the ACE and PAI-1 genes associated with recurrent spontaneous miscarriages?Am. J. Reprod. Immunol.62, 365–37010.1111/j.1600-0897.2009.00744.x19821806
Goodman C. S.,Coulam C. B.,Jeyendran R. S.,Acosta V. A.,Roussev R.. (Year: 2006). Which thrombophilic gene mutations are risk factors for recurrent pregnancy loss?Am. J. Reprod. Immunol.56, 230–23610.1111/j.1600-0897.2006.00419.x16938111
Hanna C. W.,Blair J. D.,Stephenson M. D.,Robinson W. P.. (Year: 2011). Absence of SYCP3 mutations in women with recurrent miscarriage with at least one trisomic miscarriage. Reprod. Biomed. Online. Available at:
Hefler L. A.,Tempfer C. B.,Bashford M. T.,Unfried G.,Zeillinger R.,Schneeberger C.,Koelbl H.,Nagele F.,Huber J. C.. (Year: 2002). Polymorphisms of the angiotensinogen gene, the endothelial nitric oxide synthase gene, and the interleukin-1beta gene promoter in women with idiopathic recurrent miscarriage. Mol. Hum. Reprod.8, 95–10010.1093/molehr/8.1.9511756575
Heuser C. C.,Eller A. G.,Warren J.,Branch D. W.,Salmon J.,Silver R. M.. (Year: 2011). A case-control study of membrane cofactor protein mutations in two populations of patients with early pregnancy loss. J. Reprod. Immunol.91, 71–7510.1016/j.jri.2011.05.00721840606
Hiby S. E.,Apps R.,Sharkey A. M.,Farrell L. E.,Gardner L.,Mulder A.,Claas F. H.,Walker J. J.,Redman C. W.,Morgan L.,Tower C.,Regan L.,Moore G. E.,Carrington M.,Moffett A.. (Year: 2010). Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2. J. Clin. Invest.120, 4102–411010.1172/JCI4399820972337
Hiby S. E.,Regan L.,Lo W.,Farrell L.,Carrington M.,Moffett A.. (Year: 2008). Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage. Hum. Reprod.23, 972–97610.1093/humrep/den01118263639
Hirvonen A.,Taylor J. A.,Wilcox A.,Berkowitz G.,Schachter B.,Chaparro C.,Bell D. A.. (Year: 1996). Xenobiotic metabolism genes and the risk of recurrent spontaneous abortion. Epidemiology7, 206–20810.1097/00001648-199603000-000188834564
Hogge W. A.,Prosen T. L.,Lanasa M. C.,Huber H. A.,Reeves M. F.. (Year: 2007). Recurrent spontaneous abortion and skewed X-inactivation: is there an association?Am. J. Obstet. Gynecol.196, e381–386; discussion e386–e388.10.1016/j.ajog.2006.12.012
Hohlagschwandtner M.,Unfried G.,Heinze G.,Huber J. C.,Nagele F.,Tempfer C.. (Year: 2003). Combined thrombophilic polymorphisms in women with idiopathic recurrent miscarriage. Fertil. Steril.79, 1141–114810.1016/S0015-0282(02)04958-012738509
Hu Y.,Liu C. M.,Qi L.,He T. Z.,Shi-Guo L.,Hao C. J.,Cui Y.,Zhang N.,Xia H. F.,Ma X.. (Year: 2011). Two common SNPs in pri-miR-125a alter the mature miRNA expression and associate with recurrent pregnancy loss in a Han-Chinese population. RNA Biol.8, 861–87210.4161/rna.8.5.16034
Hviid T. V.,Hylenius S.,Lindhard A.,Christiansen O. B.. (Year: 2004). Association between human leukocyte antigen-G genotype and success of in vitro fertilization and pregnancy outcome. Tissue Antigens64, 66–6910.1111/j.1399-0039.2004.00239.x15191524
Iinuma Y.,Sugiura-Ogasawara M.,Makino A.,Ozaki Y.,Suzumori N.,Suzumori K.. (Year: 2002). Coagulation factor XII activity, but not an associated common genetic polymorphism (46C/T), is linked to recurrent miscarriage. Fertil. Steril.77, 353–35610.1016/S0015-0282(01)02989-211821096
Ivanov P. D.,Komsa-Penkova R. S.,Konova E. I.,Tsvyatkovska T. M.,Kovacheva K. S.,Simeonova M. N.,Tanchev S. Y.. (Year: 2010). Polymorphism A1/A2 in the cell surface integrin subunit beta3 and disturbance of implantation and placentation in women with recurrent pregnancy loss. Fertil. Steril.94, 2843–284510.1016/j.fertnstert.2010.05.01521109038
Jauniaux E.,Farquharson R. G.,Christiansen O. B.,Exalto N.. (Year: 2006). Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Hum. Reprod.21, 2216–222210.1093/humrep/del15016707507
Jivraj S.,Rai R.,Underwood J.,Regan L.. (Year: 2006). Genetic thrombophilic mutations among couples with recurrent miscarriage. Hum. Reprod.21, 1161–116510.1093/humrep/dei46616431900
Kaare M.,Butzow R.,Ulander V. M.,Kaaja R.,Aittomaki K.,Painter J. N.. (Year: 2009a). Study of p53 gene mutations and placental expression in recurrent miscarriage cases. Reprod. Biomed. Online18, 430–43510.1016/S1472-6483(10)60105-819298746
Kaare M.,Gotz A.,Ulander V. M.,Ariansen S.,Kaaja R.,Suomalainen A.,Aittomaki K.. (Year: 2009b). Do mitochondrial mutations cause recurrent miscarriage?Mol. Hum. Reprod.15, 295–30010.1093/molehr/gap02119297417
Kaare M.,Ulander V. M.,Painter J. N.,Ahvenainen T.,Kaaja R.,Aittomaki K.. (Year: 2007). Variations in the thrombomodulin and endothelial protein C receptor genes in couples with recurrent miscarriage. Hum. Reprod.22, 864–86810.1093/humrep/del43617099210
Kamali-Sarvestani E.,Zolghadri J.,Gharesi-Fard B.,Sarvari J.. (Year: 2005). Cytokine gene polymorphisms and susceptibility to recurrent pregnancy loss in Iranian women. J. Reprod. Immunol.65, 171–17810.1016/j.jri.2005.01.00815811521
Kanai T.,Fujii T.,Keicho N.,Tokunaga K.,Yamashita T.,Hyodo H.,Miki A.,Unno N.,Kozuma S.,Taketani Y.. (Year: 2001). Polymorphism of human leukocyte antigen-E gene in the Japanese population with or without recurrent abortion. Am. J. Reprod. Immunol.45, 168–17310.1111/j.8755-8920.2001.450308.x11270642
Karhukorpi J.,Laitinen T.,Karttunen R.. (Year: 2003). Searching for links between endotoxin exposure and pregnancy loss: CD14 polymorphism in idiopathic recurrent miscarriage. Am. J. Reprod. Immunol.5, 346–35010.1034/j.1600-0897.2003.00092.x14672339
Karvela M.,Papadopoulou S.,Tsaliki E.,Konstantakou E.,Hatzaki A.,Florentin-Arar L.,Lamnissou K.. (Year: 2008a). Endothelial nitric oxide synthase gene polymorphisms in recurrent spontaneous abortions. Arch. Gynecol. Obstet.278, 349–35210.1007/s00404-008-0577-818299866
Karvela M.,Stefanakis N.,Papadopoulou S.,Tsitilou S. G.,Tsilivakos V.,Lamnissou K.. (Year: 2008b). Evidence for association of the G1733A polymorphism of the androgen receptor gene with recurrent spontaneous abortions. Fertil. Steril.90, e9–e1210.1016/j.fertnstert.2008.07.34118692840
Kim M. S.,Gu B. H.,Song S.,Choi B. C.,Cha D. H.,Baek K. H.. (Year: 2011). ITI-H4, as a biomarker in the serum of recurrent pregnancy loss (RPL) patients. Mol. Biosyst.7, 1430–144010.1039/c0mb00319k21331437
Kim N. K.,Choi Y. K.,Kang M. S.,Choi D. H.,Cha S. H.,An M. O.,Lee S.,Jeung M.,Ko J. J.,Oh D.. (Year: 2006a). Influence of combined methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase enhancer region (TSER) polymorphisms to plasma homocysteine levels in Korean patients with recurrent spontaneous abortion. Thromb. Res.117, 653–65810.1016/j.thromres.2005.03.02715985285
Kim Y. S.,Kim M. S.,Lee S. H.,Choi B. C.,Lim J. M.,Cha K. Y.,Baek K. H.. (Year: 2006b). Proteomic analysis of recurrent spontaneous abortion: identification of an inadequately expressed set of proteins in human follicular fluid. Proteomics6, 3445–345410.1002/pmic.20050093316637005
Kolte A. M.,Nielsen H. S.,Moltke I.,Degn B.,Pedersen B.,Sunde L.,Nielsen F. C.,Christiansen O. B.. (Year: 2011). A genome-wide scan in affected sibling pairs with idiopathic recurrent miscarriage suggests genetic linkage. Mol. Hum. Reprod.17, 379–38510.1093/molehr/gar00321257601
Kolte A. M.,Steffensen R.,Nielsen H. S.,Hviid T. V.,Christiansen O. B.. (Year: 2010). Study of the structure and impact of human leukocyte antigen (HLA)-G-A, HLA-G-B, and HLA-G-DRB1 haplotypes in families with recurrent miscarriage. Hum. Immunol.71, 482–48810.1016/j.humimm.2010.02.00120149831
Kovalevsky G.,Gracia C. R.,Berlin J. A.,Sammel M. D.,Barnhart K. T.. (Year: 2004). Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: a meta-analysis. Arch. Intern. Med.164, 558–56310.1001/archinte.164.5.55815006834
Kruse C.,Steffensen R.,Varming K.,Christiansen O. B.. (Year: 2004). A study of HLA-DR and -DQ alleles in 588 patients and 562 controls confirms that HLA-DRB1*03 is associated with recurrent miscarriage. Hum. Reprod.19, 1215–122110.1093/humrep/deh20015070884
Lanasa M. C.,Hogge W. A.. (Year: 2000). X chromosome defects as an etiology of recurrent spontaneous abortion. Semin. Reprod. Med.18, 97–10310.1055/s-2000-1348011299525
Lewis R. M.,Cleal J. K.,Hanson M. A.. (Year: 2012). Review: placenta, evolution and lifelong health. Placenta33, S28–S3210.1016/j.placenta.2011.12.00322205051
Litridis I.,Kapnoulas N.,Natisvili T.,Agiannitopoulos K.,Peraki O.,Ntostis P.,Pantos K.,Lamnissou K.. (Year: 2011). Genetic variation in the CYP17 gene and recurrent spontaneous abortions. Arch. Gynecol. Obstet.283, 289–29310.1007/s00404-009-1348-x20069306
Luo S. S.,Ishibashi O.,Ishikawa G.,Ishikawa T.,Katayama A.,Mishima T.,Takizawa T.,Shigihara T.,Goto T.,Izumi A.,Ohkuchi A.,Matsubara S.,Takeshita T.. (Year: 2009). Human villous trophoblasts express and secrete placenta-specific microRNAs into maternal circulation via exosomes. Biol. Reprod.81, 717–72910.1095/biolreprod.108.07548119494253
Maccani M. A.,Avissar-Whiting M.,Banister C. E.,McGonnigal B.,Padbury J. F.,Marsit C. J.. (Year: 2010). Maternal cigarette smoking during pregnancy is associated with downregulation of miR-16, miR-21, and miR-146a in the placenta. Epigenetics5, 583–58910.4161/epi.5.7.1276220647767
Maccani M. A.,Marsit C. J.. (Year: 2009). Epigenetics in the placenta. Am. J. Reprod. Immunol.62, 78–8910.1111/j.1600-0897.2009.00716.x19614624
Mannik J.,Vaas P.,Rull K.,Teesalu P.,Rebane T.,Laan M.. (Year: 2010). Differential expression profile of growth hormone/chorionic somatomammotropin genes in placenta of small- and large-for-gestational-age newborns. J. Clin. Endocrinol. Metab.95, 2433–244210.1210/jc.2010-002320233782
Masini S.,Ticconi C.,Gravina P.,Tomassini M.,Pietropolli A.,Forte V.,Federici G.,Piccione E.,Bernardini S.. (Year: 2009). Thrombin-activatable fibrinolysis inhibitor polymorphisms and recurrent pregnancy loss. Fertil. Steril.92, 694–70210.1016/j.fertnstert.2008.07.01518774564
McLachlan R. I.,O’Bryan M. K.. (Year: 2010). Clinical review: state of the art for genetic testing of infertile men. J. Clin. Endocrinol. Metab.95, 1013–102410.1210/jc.2009-192520089613
Menasha J.,Levy B.,Hirschhorn K.,Kardon N. B.. (Year: 2005). Incidence and spectrum of chromosome abnormalities in spontaneous abortions: new insights from a 12-year study. Genet. Med.7, 251–26310.1097/01.GIM.0000160075.96707.0415834243
Messaoudi S.,Al-Khateeb G. M.,Dendana M.,Sater M. S.,Jazia K. B.,Nouira M.,Almawi W. Y.,Mahjoub T.. (Year: 2011). Genetic variations in the interleukin-21 gene and the risk of recurrent idiopathic spontaneous miscarriage. Eur. Cytokine Netw.22, 123–12621768062
Miura K.,Miura S.,Yamasaki K.,Higashijima A.,Kinoshita A.,Yoshiura K.,Masuzaki H.. (Year: 2010). Identification of pregnancy-associated microRNAs in maternal plasma. Clin. Chem.56, 1767–177110.1373/clinchem.2010.14766020729298
Miyamura H.,Nishizawa H.,Ota S.,Suzuki M.,Inagaki A.,Egusa H.,Nishiyama S.,Kato T.,Pryor-Koishi K.,Nakanishi I.,Fujita T.,Imayoshi Y.,Markoff A.,Yanagihara I.,Udagawa Y.,Kurahashi H.. (Year: 2011). Polymorphisms in the annexin A5 gene promoter in Japanese women with recurrent pregnancy loss. Mol. Hum. Reprod.17, 447–45210.1093/molehr/gar00821289001
Mizutani E.,Suzumori N.,Ozaki Y.,Oseto K.,Yamada-Namikawa C.,Nakanishi M.,Sugiura-Ogasawara M.. (Year: 2011). SYCP3 mutation may not be associated with recurrent miscarriage caused by aneuploidy. Hum. Reprod.26, 1259–126610.1093/humrep/der03521357605
Moghraby J. S.,Tamim H.,Anacan V.,Al Khalaf H.,Moghraby S. A.. (Year: 2010). HLA sharing among couples appears unrelated to idiopathic recurrent fetal loss in Saudi Arabia. Hum. Reprod.25, 1900–190510.1093/humrep/deq15420566486
Moore G. E.,Oakey R.. (Year: 2011). The role of imprinted genes in humans. Genome Biol.12, 10610.1186/gb-2011-12-3-10621418582
Mosaad Y. M.,Abdel-Dayem Y.,El-Deek B. S.,El-Sherbini S. M.. (Year: 2011). Association between HLA-E *0101 homozygosity and recurrent miscarriage in Egyptian women. Scand. J. Immunol.74, 205–20910.1111/j.1365-3083.2011.02559.x21410502
Musters A. M.,Taminiau-Bloem E. F.,van den Boogaard E.,van der Veen F.,Goddijn M.. (Year: 2011). Supportive care for women with unexplained recurrent miscarriage: patients’ perspectives. Hum. Reprod.26, 873–87710.1093/humrep/der02121317153
Naeimi S.,Ghiam A. F.,Mojtahedi Z.,Dehaghani A. S.,Amani D.,Ghaderi A.. (Year: 2006). Interleukin-18 gene promoter polymorphisms and recurrent spontaneous abortion. Eur. J. Obstet. Gynecol. Reprod. Biol.128, 5–910.1016/j.ejogrb.2006.02.01216584830
Nagirnaja L.,Kasak L.,Palta P.,Rull K.,Christiansen O. B.,Esko T.,Remm M.,Metspalu A.,Laan M.. (Year: 2011). Role of DNA copy number variations in genetic predisposition to recurrent pregnancy loss. J. Reprod. Immunol.90, 14510.1016/j.jri.2011.06.029
Nagirnaja L.,Rull K.,Uuskula L.,Hallast P.,Grigorova M.,Laan M.. (Year: 2010). Genomics and genetics of gonadotropin beta-subunit genes: unique FSHB and duplicated LHB/CGB loci. Mol. Cell. Endocrinol.329, 4–1610.1016/j.mce.2010.04.02420488225
Nelen W. L.,Blom H. J.,Steegers E. A.,den Heijer M.,Eskes T. K.. (Year: 2000). Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis. Fertil. Steril.74, 1196–119910.1016/S0015-0282(00)01595-811119750
Nelissen E. C.,van Montfoort A. P.,Dumoulin J. C.,Evers J. L.. (Year: 2011). Epigenetics and the placenta. Hum. Reprod. Update17, 397–41710.1093/humupd/dmq05220959349
Newbern D.,Freemark M.. (Year: 2011). Placental hormones and the control of maternal metabolism and fetal growth. Curr. Opin. Endocrinol. Diabetes Obes.18, 409–41621986512
Nicotra M.,Bottini N.,Grasso M.,Gimelfarb A.,Lucarini N.,Cosmi E.,Bottini E.. (Year: 1998). Adenosine deaminase and human reproduction: a comparative study of fertile women and women with recurrent spontaneous abortion. Am. J. Reprod. Immunol.39, 266–27010.1111/j.1600-0897.1998.tb00363.x9553651
Nicotra M.,Lucarini N.,Battista C.,Discepoli L.,Coghi I. M.,Bottini E.. (Year: 1982). Genetic polymorphisms and human reproduction: a study of phosphoglucomutase in spontaneous abortion. Int. J. Fertil.27, 229–2336131042
Nielsen H. S.. (Year: 2011). Secondary recurrent miscarriage and H-Y immunity. Hum. Reprod. Update17, 558–57410.1093/humupd/dmr00521482560
Noguer-Dance M.,Abu-Amero S.,Al-Khtib M.,Lefevre A.,Coullin P.,Moore G. E.,Cavaille J.. (Year: 2010). The primate-specific microRNA gene cluster (C19MC) is imprinted in the placenta. Hum. Mol. Genet.19, 3566–358210.1093/hmg/ddq27220610438
Novakovic B.,Yuen R. K.,Gordon L.,Penaherrera M. S.,Sharkey A.,Moffett A.,Craig J. M.,Robinson W. P.,Saffery R.. (Year: 2011). Evidence for widespread changes in promoter methylation profile in human placenta in response to increasing gestational age and environmental/stochastic factors. BMC Genomics12, 52910.1186/1471-2164-12-52922032438
Nybo Andersen A. M.,Wohlfahrt J.,Christens P.,Olsen J.,Melbye M.. (Year: 2000). Maternal age and fetal loss: population based register linkage study. BMJ320, 1708–171210.1136/bmj.320.7251.170810864550
Ober C.,Aldrich C. L.,Chervoneva I.,Billstrand C.,Rahimov F.,Gray H. L.,Hyslop T.. (Year: 2003). Variation in the HLA-G promoter region influences miscarriage rates. Am. J. Hum. Genet.72, 1425–143510.1086/37550112721954
Ogasawara M.,Aoki K.,Okada S.,Suzumori K.. (Year: 2000). Embryonic karyotype of abortuses in relation to the number of previous miscarriages. Fertil. Steril.73, 300–30410.1016/S0015-0282(99)00495-110685533
Ostojic S.,Pereza N.,Volk M.,Kapovic M.,Peterlin B.. (Year: 2008). Genetic predisposition to idiopathic recurrent spontaneous abortion: contribution of genetic variations in IGF-2 and H19 imprinted genes. Am. J. Reprod. Immunol.60, 111–11710.1111/j.1600-0897.2008.00601.x18573128
Ostojic S.,Volk M.,Medica I.,Kapovic M.,Meden-Vrtovec H.,Peterlin B.. (Year: 2007). Polymorphisms in the interleukin-12/18 genes and recurrent spontaneous abortion. Am. J. Reprod. Immunol.58, 403–40810.1111/j.1600-0897.2007.00501.x17922692
Papazoglou D.,Galazios G.,Papatheodorou K.,Liberis V.,Papanas N.,Maltezos E.,Maroulis G. B.. (Year: 2005). Vascular endothelial growth factor gene polymorphisms and idiopathic recurrent pregnancy loss. Fertil. Steril.83, 959–96310.1016/j.fertnstert.2004.12.01715820807
Parveen F.,Faridi R. M.,Alam S.,Agrawal S.. (Year: 2011a). Genetic analysis of eNOS gene polymorphisms in association with recurrent miscarriage among North Indian women. Reprod. Biomed. Online23, 124–13110.1016/j.rbmo.2011.03.02221565555
Parveen F.,Faridi R. M.,Singh B.,Agrawal S.. (Year: 2011b). Analysis of CCR5 and CX3CR1 gene polymorphisms in association with unexplained recurrent miscarriages among north Indian women. Cytokine56, 239–24410.1016/j.cyto.2011.07.00921820915
Parveen F.,Faridi R. M.,Das V.,Tripathi G.,Agrawal S.. (Year: 2010). Genetic association of phase I and phase II detoxification genes with recurrent miscarriages among North Indian women. Mol. Hum. Reprod.16, 207–21410.1093/molehr/gap09619892789
Parveen F.,Tripathi G.,Singh B.,Agrawal S.. (Year: 2009a). Association of chemokines receptor (CCR5 Delta32) in idiopathic recurrent miscarriages among north Indians. Arch. Gynecol. Obstet.280, 229–23410.1007/s00404-008-0901-319116725
Parveen F.,Tripathi G.,Singh B.,Faridi R. M.,Agrawal S.. (Year: 2009b). Acetylcholinesterase gene polymorphism and recurrent pregnancy loss. Int. J. Gynaecol. Obstet.106, 68–6910.1016/j.ijgo.2009.02.00519327769
Pasquier E.,Bohec C.,De Saint Martin L.,Le Marechal C.,Le Martelot M. T.,Roche S.,Laurent Y.,Ferec C.,Collet M.,Mottier D.. (Year: 2007). Strong evidence that skewed X-chromosome inactivation is not associated with recurrent pregnancy loss: an incident paired case control study. Hum. Reprod.22, 2829–283310.1093/humrep/dem26417823131
Philipp T.,Philipp K.,Reiner A.,Beer F.,Kalousek D. K.. (Year: 2003). Embryoscopic and cytogenetic analysis of 233 missed abortions: factors involved in the pathogenesis of developmental defects of early failed pregnancies. Hum. Reprod.18, 1724–173210.1093/humrep/deg30912871891
Pietrowski D.,Bettendorf H.,Riener E. K.,Keck C.,Hefler L. A.,Huber J. C.,Tempfer C.. (Year: 2005). Recurrent pregnancy failure is associated with a polymorphism in the p53 tumour suppressor gene. Hum. Reprod.20, 848–85110.1093/humrep/deh69615608028
Pietrowski D.,Tempfer C.,Bettendorf H.,Burkle B.,Nagele F.,Unfried G.,Keck C.. (Year: 2003). Angiopoietin-2 polymorphism in women with idiopathic recurrent miscarriage. Fertil. Steril.80, 1026–102910.1016/S0015-0282(03)01011-214556828
Pihusch R.,Buchholz T.,Lohse P.,Rubsamen H.,Rogenhofer N.,Hasbargen U.,Hiller E.,Thaler C. J.. (Year: 2001). Thrombophilic gene mutations and recurrent spontaneous abortion: prothrombin mutation increases the risk in the first trimester. Am. J. Reprod. Immunol.46, 124–13110.1111/j.8755-8920.2001.460202.x11506076
Prigoshin N.,Tambutti M.,Larriba J.,Gogorza S.,Testa R.. (Year: 2004). Cytokine gene polymorphisms in recurrent pregnancy loss of unknown cause. Am. J. Reprod. Immunol.52, 36–4110.1111/j.1600-0897.2004.00179.x15214940
Rai R.,Regan L.. (Year: 2006). Recurrent miscarriage. Lancet368, 601–61110.1016/S0140-6736(06)69204-016905025
Rajcan-Separovic E.,Diego-Alvarez D.,Robinson W. P.,Tyson C.,Qiao Y.,Harvard C.,Fawcett C.,Kalousek D.,Philipp T.,Somerville M. J.,Stephenson M. D.. (Year: 2010). Identification of copy number variants in miscarriages from couples with idiopathic recurrent pregnancy loss. Hum. Reprod.25, 2913–292210.1093/humrep/deq20220847186
Ren A.,Wang J.. (Year: 2006). Methylenetetrahydrofolate reductase C677T polymorphism and the risk of unexplained recurrent pregnancy loss: a meta-analysis. Fertil. Steril.86, 1716–172210.1016/j.fertnstert.2006.05.05217074326
Rey E.,Kahn S. R.,David M.,Shrier I.. (Year: 2003). Thrombophilic disorders and fetal loss: a meta-analysis. Lancet361, 901–90810.1016/S0140-6736(03)12771-712648968
Risch N.,Merikangas K.. (Year: 1996). The future of genetic studies of complex human diseases. Science273, 1516–151710.1126/science.273.5281.15168801636
Rodger M. A.,Betancourt M. T.,Clark P.,Lindqvist P. G.,Dizon-Townson D.,Said J.,Seligsohn U.,Carrier M.,Salomon O.,Greer I. A.. (Year: 2010). The association of factor V Leiden and prothrombin gene mutation and placenta-mediated pregnancy complications: a systematic review and meta-analysis of prospective cohort studies. PLoS Med.7, e100029210.1371/journal.pmed.100029220563311
Rull K.,Nagirnaja L.,Ulander V. M.,Kelgo P.,Margus T.,Kaare M.,Aittomaki K.,Laan M.. (Year: 2008). Chorionic gonadotropin beta-gene variants are associated with recurrent miscarriage in two European populations. J. Clin. Endocrinol. Metab.93, 4697–470610.1210/jc.2008-110118782867
Rull K.,Tomberg K.,Kõks S.,Männik J.,Möls M.,Sirotkina M.,Värv S.,Laan M.. (Year: 2012). TNF-related apoptosis-inducing ligand TRAIL as a potential biomarker for early pregnancy complications. J. Clin. Endocrinol. Metab.9710.1210/jc.2011-3192
Saijo Y.,Sata F.,Yamada H.,Konodo T.,Kato E. H.,Kataoka S.,Shimada S.,Morikawa M.,Minakami H.,Kishi R.. (Year: 2004a). Interleukin-4 gene polymorphism is not involved in the risk of recurrent pregnancy loss. Am. J. Reprod. Immunol.52, 143–14610.1111/j.1600-0897.2004.00193.x15274656
Saijo Y.,Sata F.,Yamada H.,Suzuki K.,Sasaki S.,Kondo T.,Gong Y. Y.,Kato E. H.,Shimada S.,Morikawa M.,Minakami H.,Kishi R.. (Year: 2004b). Ah receptor, CYP1A1, CYP1A2 and CYP1B1 gene polymorphisms are not involved in the risk of recurrent pregnancy loss. Mol. Hum. Reprod.10, 729–73310.1093/molehr/gah09615299091
Salker M.,Teklenburg G.,Molokhia M.,Lavery S.,Trew G.,Aojanepong T.,Mardon H. J.,Lokugamage A. U.,Rai R.,Landles C.,Roelen B. A.,Quenby S.,Kuijk E. W.,Kavelaars A.,Heijnen C. J.,Regan L.,Macklon N. S.,Brosens J. J.. (Year: 2010). Natural selection of human embryos: impaired decidualization of endometrium disables embryo-maternal interactions and causes recurrent pregnancy loss. PLoS ONE5, e1028710.1371/journal.pone.001028720422017
Sangha K. K.,Stephenson M. D.,Brown C. J.,Robinson W. P.. (Year: 1999). Extremely skewed X-chromosome inactivation is increased in women with recurrent spontaneous abortion. Am. J. Hum. Genet.65, 913–91710.1086/30255210441596
Sata F.,Yamada H.,Kondo T.,Gong Y.,Tozaki S.,Kobashi G.,Kato E. H.,Fujimoto S.,Kishi R.. (Year: 2003a). Glutathione S-transferase M1 and T1 polymorphisms and the risk of recurrent pregnancy loss. Mol. Hum. Reprod.9, 165–16910.1093/molehr/gag02112606593
Sata F.,Yamada H.,Yamada A.,Kato E. H.,Kataoka S.,Saijo Y.,Kondo T.,Tamaki J.,Minakami H.,Kishi R.. (Year: 2003b). A polymorphism in the CYP17 gene relates to the risk of recurrent pregnancy loss. Mol. Hum. Reprod.9, 725–72810.1093/molehr/gag02114561815
Sata F.,Yamada H.,Suzuki K.,Saijo Y.,Kato E. H.,Morikawa M.,Minakami H.,Kishi R.. (Year: 2005). Caffeine intake, CYP1A2 polymorphism and the risk of recurrent pregnancy loss. Mol. Hum. Reprod.11, 357–36010.1093/molehr/gah17515849225
Scholer N.,Langer C.,Kuchenbauer F.. (Year: 2011). Circulating microRNAs as biomarkers – true blood?Genome Med3, 7210.1186/gm28822112937
Seyedhassani S. M.,Houshmand M.,Kalantar S. M.,Modabber G.,Aflatoonian A.. (Year: 2010). No mitochondrial DNA deletions but more D-loop point mutations in repeated pregnancy loss. J. Assist. Reprod. Genet.27, 641–64810.1007/s10815-010-9435-220499271
Silver R. M.,Zhao Y.,Spong C. Y.,Sibai B.,Wendel G. Jr.,Wenstrom K.,Samuels P.,Caritis S. N.,Sorokin Y.,Miodovnik M.,O’Sullivan M. J.,Conway D.,Wapner R. J.. (Year: 2010). Prothrombin gene G20210A mutation and obstetric complications. Obstet. Gynecol.115, 14–2010.1097/AOG.0b013e3181c8891820027028
Singh K.,Nair R. R.,Khanna A.. (Year: 2012). Functional SNP -1562C/T in the promoter region of MMP9 and recurrent early pregnancy loss. Reprod. Biomed. Online24, 61–6510.1016/j.rbmo.2011.10.01222118839
Sotiriadis A.,Makrigiannakis A.,Stefos T.,Paraskevaidis E.,Kalantaridou S. N.. (Year: 2007). Fibrinolytic defects and recurrent miscarriage: a systematic review and meta-analysis. Obstet. Gynecol.109, 1146–115510.1097/01.AOG.0000260873.94196.d617470597
Steck T.,van der Ven K.,Kwak J.,Beer A.,Ober C.. (Year: 1995). HLA-DQA1 and HLA-DQB1 haplotypes in aborted fetuses and couples with recurrent spontaneous abortion. J. Reprod. Immunol.29, 95–10410.1016/0165-0378(95)00937-G7500323
Steffensen R.,Christiansen O. B.,Bennett E. P.,Jersild C.. (Year: 1998). HLA-E polymorphism in patients with recurrent spontaneous abortion. Tissue Antigens52, 569–57210.1111/j.1399-0039.1998.tb03088.x9894856
Stephenson M. D.,Sierra S.. (Year: 2006). Reproductive outcomes in recurrent pregnancy loss associated with a parental carrier of a structural chromosome rearrangement. Hum. Reprod.21, 1076–108210.1093/humrep/dei41716396938
Su M. T.,Lin S. H.,Chen Y. C.. (Year: 2011a). Association of sex hormone receptor gene polymorphisms with recurrent pregnancy loss: a systematic review and meta-analysis. Fertil. Steril.96, 1435–144410.1016/j.fertnstert.2011.07.23022014881
Su M. T.,Lin S. H.,Lee I. W.,Chen Y. C.,Kuo P. L.. (Year: 2011b). Association of polymorphisms/haplotypes of the genes encoding vascular endothelial growth factor and its KDR receptor with recurrent pregnancy loss. Hum. Reprod.26, 758–76410.1093/humrep/deq40121257617
Su M. T.,Lin S. H.,Lee I. W.,Chen Y. C.,Hsu C. C.,Pan H. A.,Kuo P. L.. (Year: 2010). Polymorphisms of endocrine gland-derived vascular endothelial growth factor gene and its receptor genes are associated with recurrent pregnancy loss. Hum. Reprod.25, 2923–293010.1093/humrep/deq25620847187
Sullivan A. E.,Nelson L.,Frias A. E.,Porter T. F.,Branch D. W.,Silver R. M.. (Year: 2006). The aryl hydrocarbon receptor nuclear translocator gene polymorphism in patients with recurrent miscarriage. Am. J. Reprod. Immunol.55, 51–5310.1111/j.1600-0897.2005.00323.x16364012
Suryanarayana V.,Deenadayal M.,Singh L.. (Year: 2004). Association of CYP1A1 gene polymorphism with recurrent pregnancy loss in the South Indian population. Hum. Reprod.19, 2648–265210.1093/humrep/deh46315333597
Suryanaryana V. V.,Rao L.,Kanakavalli M. K.,Padmalatha V. V.,Deenadayal M.,Singh L.. (Year: 2007). Role of CYP17 and CYP19 polymorphisms in idiopathic recurrent miscarriages among South Indian women. Reprod. Biomed. Online14, 341–34710.1016/S1472-6483(10)60877-217359589
Suzuki K.,Sata F.,Yamada H.,Saijo Y.,Tsuruga N.,Minakami H.,Kishi R.. (Year: 2006). Pregnancy-associated plasma protein-A polymorphism and the risk of recurrent pregnancy loss. J. Reprod. Immunol.70, 99–10810.1016/j.jri.2005.11.00416540175
Takakuwa K.,Hataya I.,Arakawa M.,Kikuchi A.,Higashino M.,Yasuda M.,Kurabayashi T.,Tanaka K.. (Year: 1999). Possible susceptibility of the HLA-DPB1*0402 and HLA-DPB1*04 alleles to unexplained recurrent abortion: analysis by means of polymerase chain reaction-restricted fragment length polymorphism method. Am. J. Reprod. Immunol.42, 233–23910.1111/j.1600-0897.1999.tb00096.x10580605
Tan Z.,Randall G.,Fan J.,Camoretti-Mercado B.,Brockman-Schneider R.,Pan L.,Solway J.,Gern J. E.,Lemanske R. F.,Nicolae D.,Ober C.. (Year: 2007). Allele-specific targeting of microRNAs to HLA-G and risk of asthma. Am. J. Hum. Genet.81, 829–83410.1086/52120017847008
Tang A. W.,Quenby S.. (Year: 2010). Recent thoughts on management and prevention of recurrent early pregnancy loss. Curr. Opin. Obstet. Gynecol.22, 446–45110.1097/GCO.0b013e32833e124e20724930
Tang W.,Zhou X.,Chan Y.,Wu X.,Luo Y.. (Year: 2011). p53 codon 72 polymorphism and recurrent pregnancy loss: a meta-analysis. J. Assist. Reprod. Genet.28, 965–96910.1007/s10815-011-9618-521842249
Topalidou M.,Effraimidou S.,Farmakiotis D.,Papadakis E.,Papaioannou G.,Korantzis I.,Garipidou V.. (Year: 2009). Low protein Z levels, but not the intron F G79A polymorphism, are associated with unexplained pregnancy loss. Thromb. Res.124, 24–2710.1016/j.thromres.2008.09.01719026439
Toth B.,Vocke F.,Rogenhofer N.,Friese K.,Thaler C. J.,Lohse P.. (Year: 2008). Paternal thrombophilic gene mutations are not associated with recurrent miscarriage. Am. J. Reprod. Immunol.60, 325–33210.1111/j.1600-0897.2008.00630.x18754836
Traina E.,Daher S.,Moron A. F.,Sun S. Y.,Franchim C. S.,Mattar R.. (Year: 2011). Polymorphisms in VEGF, progesterone receptor and IL-1 receptor genes in women with recurrent spontaneous abortion. J. Reprod. Immunol.88, 53–5710.1016/j.jri.2010.07.00620956022
Tsai A. F.,Kaufman K. A.,Walker M. A.,Karrison T. G.,Odem R. R.,Barnes R. B.,Scott J. R.,Schreiber J. R.,Stephenson M. D.,Ober C.. (Year: 1998). Transmission disequilibrium of maternally-inherited CTLA-4 microsatellite alleles in idiopathic recurrent miscarriage. J. Reprod. Immunol.40, 147–15710.1016/S0165-0378(98)00073-49881742
Unfried G.,Schneeberger C.,Szabo L.,Nagele F.,Huber J. C.,Tempfer C. B.. (Year: 2001). Tryptophan hydroxylase gene polymorphism (A218C) and idiopathic recurrent miscarriage. Obstet. Gynecol.98, 664–66710.1016/S0029-7844(01)01538-111576585
Uuskula L.,Rull K.,Nagirnaja L.,Laan M.. (Year: 2011). Methylation allelic polymorphism (MAP) in chorionic gonadotropin beta5 (CGB5) and its association with pregnancy success. J. Clin. Endocrinol. Metab.96, E199–E20710.1210/jc.2010-164720962020
Van den Veyver I. B.. (Year: 2001). Skewed X inactivation in X-linked disorders. Semin. Reprod. Med.19, 183–9110.1055/s-2001-1539811480916
Vanniarajan A.,Govindaraj P.,Carlus S. J.,Aruna M.,Aruna P.,Kumar A.,Jayakar R. I.,Lionel A. C.,Gupta S.,Rao L.,Gupta N. J.,Chakravarthy B.,Deenadayal M.,Selvaraj K.,Andal S.,Reddy B. M.,Singh L.,Thangaraj K.. (Year: 2011). Mitochondrial DNA variations associated with recurrent pregnancy loss among Indian women. Mitochondrion11, 450–45610.1016/j.mito.2011.01.00221292039
von Linsingen R.,Bompeixe E. P.,Bicalho Mda G.. (Year: 2005). A case-control study in IL6 and TGFB1 gene polymorphisms and recurrent spontaneous abortion in southern Brazilian patients. Am. J. Reprod. Immunol.53, 94–9910.1111/j.1600-0897.2005.00250.x15790343
Walch K.,Riener E. K.,Tempfer C. B.,Endler G.,Huber J. C.,Unfried G.. (Year: 2005). The C46T polymorphism of the coagulation factor XII gene and idiopathic recurrent miscarriage. BJOG112, 1434–143610.1111/j.1471-0528.2005.00686.x16167952
Wang X.,Lin Q.,Ma Z.,Hong Y.,Zhao A.,Di W.,Lu P.. (Year: 2005). Association of the A/G polymorphism at position 49 in exon 1 of CTLA-4 with the susceptibility to unexplained recurrent spontaneous abortion in the Chinese population. Am. J. Reprod. Immunol.53, 100–10510.1111/j.1600-0897.2004.00251.x15790344
Warburton D.,Kline J.,Kinney A.,Yu C. Y.,Levin B.,Brown S.. (Year: 2009). Skewed X chromosome inactivation and trisomic spontaneous abortion: no association. Am. J. Hum. Genet.85, 179–19310.1016/j.ajhg.2009.07.00219646676
Witt C. S.,Goodridge J.,Gerbase-Delima M. G.,Daher S.,Christiansen F. T.. (Year: 2004). Maternal KIR repertoire is not associated with recurrent spontaneous abortion. Hum. Reprod.19, 2653–265710.1093/humrep/deh48315333596
Wramsby M. L.,Sten-Linder M.,Bremme K.. (Year: 2000). Primary habitual abortions are associated with high frequency of factor V Leiden mutation. Fertil. Steril.74, 987–99110.1016/S0015-0282(00)01545-411056246
Yenicesu G. I.,Cetin M.,Ozdemir O.,Cetin A.,Ozen F.,Yenicesu C.,Yildiz C.,Kocak N.. (Year: 2009). A prospective case-control study analyzes 12 thrombophilic gene mutations in Turkish couples with recurrent pregnancy loss. Am. J. Reprod. Immunol.63, 126–13610.1111/j.1600-0897.2009.00770.x19906129
Yu X. W.,Li X.,Ren Y. H.,Li X. C.. (Year: 2007). Tumour necrosis factor-alpha receptor 1 polymorphisms and serum soluble TNFR1 in early spontaneous miscarriage. Cell Biol. Int.31, 1396–139910.1016/j.cellbi.2007.06.00517686637
Yuen R. K.,Avila L.,Penaherrera M. S.,von Dadelszen P.,Lefebvre L.,Kobor M. S.,Robinson W. P.. (Year: 2009). Human placental-specific epipolymorphism and its association with adverse pregnancy outcomes. PLoS ONE4, e738910.1371/journal.pone.000738919838307
Zechner U.,Pliushch G.,Schneider E.,El Hajj N.,Tresch A.,Shufaro Y.,Seidmann L.,Coerdt W.,Muller A. M.,Haaf T.. (Year: 2009). Quantitative methylation analysis of developmentally important genes in human pregnancy losses after ART and spontaneous conception. Mol. Hum. Reprod.16, 704–71310.1093/molehr/gap10720007506
Zhang S.,Wang J.,Wang B.,Ping Y.,Ma X.. (Year: 2011). Strong association between angiotensin I-converting enzyme I/D polymorphism and unexplained recurrent miscarriage of Chinese women – a case-control study. Reprod. Sci.18, 743–74610.1177/193371911141586521795738
Zusterzeel P. L.,Nelen W. L.,Roelofs H. M.,Peters W. H.,Blom H. J.,Steegers E. A.. (Year: 2000). Polymorphisms in biotransformation enzymes and the risk for recurrent early pregnancy loss. Mol. Hum. Reprod.6, 474–47810.1093/molehr/6.5.47410775653


[Figure ID: F1]
Figure 1 

Two broad options to investigate the inheritable component of recurrent miscarriage (RM) are family based linkage studies and comparison of unrelated cases and controls. For multifactorial diseases in adulthood the genetic association studies are superior compared to linkage analysis in pedigrees in terms of study design and power (Risch and Merikangas, 1996). In case of RM studies the addressed subjects/biological materials represent genetic material from two generations: mother–father and offspring(s), both providing own advantages and limitations. The affected processes are located in different compartments (mother–placenta–fetus) and involve aberrations in gene/protein expression influencing both maternal and fetal organisms.

[TableWrap ID: T1] Table 1 

Genes targeted to genetic association studies in relation to RM risk.

Gene name Genetic associationa
Main effect of the polymorphismc
Key reference
Single study Meta-analysis Study casesb Mother Fetus/placenta
IFNG Y/N Y/N F Bombell and McGuire (2008), Daher et al. (2003)
IL1B Y/N Y/N F Bombell and McGuire (2008)
IL1RN Y/N F Choi and Kwak-Kim (2008)
IL1R1 N F Traina et al. (2011)
IL4 N F Kamali-Sarvestani et al. (2005), Saijo et al. (2004a)
IL6 Y/N Y/N F Bombell and McGuire (2008), Daher et al. (2003)
IL10 Y/N Y/N F Bombell and McGuire (2008), Daher et al. (2003)
IL12B N F Ostojic et al. (2007)
IL18 Y/N F Al-Khateeb et al. (2011), Naeimi et al. (2006)
IL21 Y F Messaoudi et al. (2011)
TNFα Y/N N F Bombell and McGuire (2008), Daher et al. (2003)
TNFβ N F Kamali-Sarvestani et al. (2005), Prigoshin et al. (2004)
TNFR1 N F Yu et al. (2007)
ACE Y/N F Goodman et al. (2009b), Zhang et al. (2011)
ACHE Y F Parveen et al. (2009b)
AGT N F Goodman et al. (2009b), Hefler et al. (2002)
ANXA5 Y F Bogdanova et al. (2007), Miyamura et al. (2011)
APOB N F, C Hohlagschwandtner et al. (2003), Yenicesu et al. (2009)
APOE Y/N F Bianca et al. (2010), Goodman et al. (2009a)
AT1R Y/N F Buchholz et al. (2004), Fatini et al. (2000)
EPCR Y/N F, C Dendana et al. (2012), Kaare et al. (2007)
F2 Y/N Y/N F, C Kovalevsky et al. (2004), Silver et al. (2010), Toth et al. (2008)
F5 Y/N Y/N F, C Dudding and Attia (2004), Kovalevsky et al. (2004), Rey et al. (2003), Rodger et al. (2010), Toth et al. (2008)
FGB N F, C Goodman et al. (2006), Yenicesu et al. (2009)
F12 N N F Sotiriadis et al. (2007), Walch et al. (2005)
F13A Y/N N F, C Coulam et al. (2006a), Sotiriadis et al. (2007), Yenicesu et al. (2009)
GPIa Y F Gerhardt et al. (2005)
GPIIIa Y/N F, C Ivanov et al. (2010), Pihusch et al. (2001), Yenicesu et al. (2009)
HMOX1 Y F Denschlag et al. (2004)
JAK2 N F Dahabreh et al. (2009)
MTHFD1 N F Crisan et al. (2011)
MTHFR Y/N Y/N F, C Nelen et al. (2000), Ren and Wang (2006), Toth et al. (2008)
PAI-1 Y/N N F Buchholz et al. (2003), Goodman et al. (2009b), Sotiriadis et al. (2007)
PZ Y/N F Dossenbach-Glaninger et al. (2008), Topalidou et al. (2009)
SELP Y F Dendana et al. (2011)
TAFI Y F Masini et al. (2009)
TGFB1 N F Prigoshin et al. (2004), von Linsingen et al. (2005)
TM N C Kaare et al. (2007)
TSER N F Kim et al. (2006a)
VEGF Y/N F Papazoglou et al. (2005), Traina et al. (2011)
ZPI Y F Alsheikh et al. (2012)
AHR N F Saijo et al. (2004b)
ARNT N F Sullivan et al. (2006)
CYP1A1 Y/N F Parveen et al. (2010), Saijo et al. (2004b)
CYP1A2 Y/N F Saijo et al. (2004b), Sata et al. (2005)
CYP1B1 N F Saijo et al. (2004b)
CYP2D6 Y/N F Parveen et al. (2010), Suryanarayana et al. (2004)
GSTM1 Y/N F Parveen et al. (2010), Sata et al. (2003a)
GSTP1 Y/N F Parveen et al. (2010), Zusterzeel et al. (2000)
GSTT1 Y/N F Parveen et al. (2010), Sata et al. (2003a)
NAT2 N F Hirvonen et al. (1996)
SYCP3 Y/N F Bolor et al. (2009), Hanna et al. (2011), Mizutani et al. (2011)
CCR5 Y/N F Parveen et al. (2009a, 2011b)
CTLA4 Y F, trio Tsai et al. (1998), Wang et al. (2005)
CX3CR1 Y F Parveen et al. (2011b)
HLA-A, B Y/N N C, trio Beydoun and Saftlas (2005), Christiansen et al. (1989), Kolte et al. (2010)
HLA-C Y/N N F, C, P Beydoun and Saftlas (2005), Faridi and Agrawal (2011), Hiby et al. (2010), Moghraby et al. (2010)
HLA-E Y/N F, C Kanai et al. (2001), Mosaad et al. (2011), Steffensen et al. (1998)
HLA-G Y/N F, C, trio Aruna et al. (2010), Cecati et al. (2011), Hviid et al. (2004), Kolte et al. (2010), Ober et al. (2003)
HLA-DPB1 Y C Takakuwa et al. (1999)
HLA-DQA1, HLA-DQB1 Y/N F, C, trio Aruna et al. (2011), Kruse et al. (2004), Steck et al. (1995)
HLA-DR Y/N Y F, C, trio Beydoun and Saftlas (2005), Christiansen et al. (1999), Kolte et al. (2010), Kruse et al. (2004)
INDO N F Amani et al. (2011)
KIR Y/N F, C Faridi et al. (2009), Hiby et al. (2008), Witt et al. (2004)
MBL N C Baxter et al. (2001)
AR (and XCI)d Y/N Y F Karvela et al. (2008b), Su et al. (2011a)
hCG beta (CGB5/8) Y C Rull et al. (2008)
CYP17A1 Y/N F Litridis et al. (2011), Sata et al. (2003b)
CYP19A1 Y F Cupisti et al. (2009), Suryanaryana et al. (2007)
PROGINS, ESR1/2 Y/N N F Su et al. (2011a), Traina et al. (2011)
ACP1 Y F ? ? Gloria-Bottini et al. (1996)
ADA Y F ? ? Nicotra et al. (1998)
ADRA2B N F Galazios et al. (2011)
ANGPT2 N F Pietrowski et al. (2003)
CD14 N F Karhukorpi et al. (2003)
EG-VEGF, PKR1, PKR2 Y F Su et al. (2010)
H19 N C Ostojic et al. (2008)
IGF-2 Y C Ostojic et al. (2008)
KDR Y F Su et al. (2011b)
MCP N F Heuser et al. (2011)
MMP9 N F Singh et al. (2012)
NOS3 Y/N F Karvela et al. (2008a), Parveen et al. (2011a)
P53 Y/N Y F, C, trio Coulam et al. (2006b), Kaare et al. (2009a), Pietrowski et al. (2005), Tang et al. (2011)
PAPPA Y F Suzuki et al. (2006)
PGM1 Y C Bottini et al. (1983), Nicotra et al. (1982)
STAT3 Y F Finan et al. (2010)
TPH1 N F Unfried et al. (2001)
Mutational burden Y/N F, C, trio Kaare et al. (2009b), Seyedhassani et al. (2010), Vanniarajan et al. (2011)

tfn1aY, positive association studies; N, negative studies.

tfn2bF, female RM patients; C, RM couple; P, placenta; trio, parents + fetus/placenta.

tfn3cFunctional effect coded by maternal genome (e.g., expression in endometrium) or by fetal/placental genome is shown with ; ? specific localization of the effect not clearly determined.

tfn4dSkewed X-chromosome inactivation (XCI) test is can be used to indirectly determine the association between androgen receptor (AR) CAG repeat expansion and RM (Su et al., 2011a).

ACE, angiotensin I converting enzyme 1; ACHE, acetylcholinesterase; ACP1, acid phosphatase 1; ADA, adenosine deaminase; ADRA2B, adrenergic, alpha-2B-, receptor; AGT, angiotensinogen; AHR, aryl hydrocarbon receptor; ANGPT2, angiopoietin 2; ANXA5, annexin A5; APOB, apolipoprotein B; APOE, apolipoprotein E; AR, androgen receptor; ARNT, aryl hydrocarbon receptor nuclear translocator; AT1R, angiotensin II type-1 receptor; CCR5, chemokine receptor 5; CD14, CD14 molecule; CGB5, chorionic gonadotropin, beta polypeptide 5; CGB8, chorionic gonadotropin, beta polypeptide 8; CTLA4, cytotoxic T-lymphocyte-associated protein 4; CX3CR1, chemokine (C-X3-C motif) receptor 1; CYP1A1, cytochrome P450, family 1, subfamily A, polypeptide 1; CYP1A2, cytochrome P450, family 1, subfamily A, polypeptide 2; CYP1B1, cytochrome P450, family 1, subfamily B, polypeptide 1; CYP2D6, cytochrome P450, family 2, subfamily D, polypeptide 6; CYP17A1, cytochrome P450, family 17, subfamily A, polypeptide 1; CYP19A1, cytochrome P450, family 19, subfamily A, polypeptide 1; EG-VEGF, endocrine-gland-derived vascular endothelial growth factor; EPCR, endothelial protein C receptor; ESR1, estrogen receptor 1; ESR2, estrogen receptor 2; F2, coagulation factor II/prothrombin; F5, coagulation factor V/factor V Leiden; F12, coagulation factor XII; F13A, coagulation factor XIII, A1 polypeptide; FGB, fibrinogen beta chain; GPIa, platelet glycoprotein Ia; GPIIIa, platelet glycoprotein IIIa; GSTM1, glutathione S-transferase mu 1; GSTP1, glutathione S-transferase pi 1; GSTT1, glutathione S-transferase theta 1; H19, imprinted maternally expressed transcript (non-protein coding); HLA-A, major histocompatibility complex, class I, A; HLA-B, major histocompatibility complex, class I, B; HLA-C, major histocompatibility complex, class I, C; HLA-E, major histocompatibility complex, class I, E; HLA-G, major histocompatibility complex, class I, G; HLA-DPB1, major histocompatibility complex, class II, DP beta 1; HLA-DQA1, major histocompatibility complex, class II, DQ alpha 1; HLA-DQB1, major histocompatibility complex, class II, DQ beta 1; HLA-DR′, major histocompatibility complex, class II, DR loci; HO-1, heme oxygenase 1; IFNG, interferon, gamma; IGF-2, insulin-like growth factor 2; IL1B, interleukin 1, beta; IL1RN, interleukin 1 receptor antagonist; IL1R1, interleukin 1 receptor, type I; IL4, interleukin 4; IL6, interleukin 6; IL10, interleukin 10; IL12B, interleukin 12B; IL18, interleukin 18; IL21, interleukin 21; INDO, indole 2,3-dioxygenase; JAK2, Janus kinase 2; KDR, kinase insert domain receptor; KIR, killer cell immunoglobulin-like receptor; MBL, mannose binding lectin; MCP, membrane cofactor protein; MMP9, matrix metallopeptidase 9; MTHFD1, methylenetetrahydrofolate dehydrogenase 1; MTHFR, methylenetetrahydrofolate reductase; NAT2, N-acetyltransferase 2; NOS3, nitric oxide synthase 3; P53, p53 tumor suppressor; PAI-1, plasminogen activator inhibitor 1; PAPPA, pregnancy-associated plasma protein A; PGM1, phosphoglucomutase 1; PROGINS, progesterone receptor; PKR1, prokineticin receptor 1; PKR2, prokineticin receptor 1; PZ, protein Z; SELP, selectin P; STAT3, signal transducer and activator of transcription 3; SYCP3, synaptonemal complex protein 3; TAFI, thrombin-activatable fibrinolysis inhibitor; TGFB1, transforming growth factor, beta 1; TM, thrombomodulin; TNFα, tumor necrosis factor-alpha; TNFβ, tumor necrosis factor beta; TNFR1, tumor necrosis factor-alpha receptor 1; TSER, thymidylate synthetase enhancer region; TPH1, tryptophan hydroxylase 1; VEGF, vascular endothelial growth factor A; ZPI, protein Z-dependent protease inhibitor.

Article Categories:
  • Genetics
    • Mini Review

Keywords: recurrent miscarriage, genetics, epigenetics, study design, research and clinical collaboration, association studies, omic’s studies, placenta.

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