Recurrent Pregnancy Loss Cases Research Articles

RNA sequencing of chorionic villi from recurrent pregnancy loss patients reveals impaired function of basic nuclear and cellular machinery.

Recurrent pregnancy loss (RPL) concerns ~3% of couples aiming at childbirth. In the current study, transcriptomes and miRNomes of 1st trimester placental chorionic villi were analysed for 2 RPL cases (≥6 miscarriages) and normal, but electively terminated pregnancies (ETP; n = 8). Sequencing was performed on Illumina HiSeq 2000 platform. Differential expression analyses detected 51 (27%) transcripts with increased and 138 (73%) with decreased expression in RPL compared to ETP (DESeq: FDR P < 0.1 and DESeq2: <0.05). RPL samples had substantially decreased transcript levels of histones, regulatory RNAs and genes involved in telomere, spliceosome, ribosomal, mitochondrial and intra-cellular signalling functions. Downregulated expression of HIST1H1B and HIST1H4A (Wilcoxon test, fc≤0.372, P≤9.37 × 10−4) was validated in an extended sample by quantitative PCR (RPL, n = 14; ETP, n = 24). Several upregulated genes are linked to placental function and pregnancy complications: ATF4, C3, PHLDA2, GPX4, ICAM1, SLC16A2. Analysis of the miRNA-Seq dataset identified no large disturbances in RPL samples. Notably, nearly 2/3 of differentially expressed genes have binding sites for E2F transcription factors, coordinating mammalian endocycle and placental development. For a conceptus destined to miscarriage, the E2F TF-family represents a potential key coordinator in reprogramming the placental genome towards gradually stopping the maintenance of basic nuclear and cellular functions.

Interferon Regulatory Factor 5 Gene Polymorphisms in Iranian Women with Unexplained Recurrent Pregnancy Loss

ABSTRACTObjective: This study aimed to examine the association of three functional IRF5 rs10954213, rs3757385, and rs41298401 polymorphisms with susceptibility to unexplained recurrent pregnancy loss (RPL) among Iranian women from south of Iran.Methods: 176 women with unexplained RPL and 173 healthy postmenopausal controls were enrolled in this case-control study. Genotyping of the polymorphisms rs10954213 and rs3757385 was carried out using touchdown tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS PCR), and polymorphism rs41298401 was typed using PCR-restriction fragment length polymorphism (PCR-RFLP).Results: Genotype frequencies were significantly different between RPL cases and controls regarding AG heterozygote genotype of rs10954213, GT genotype of rs3757385, and GG genotype of rs41298401. In addition, allele variants (G for rs10954213, T for rs3757385, and G for rs41298401) showed protective role against RPL, while GG haplotype of two first variants was shown to be a susceptibility factor for the disease.Conclusion: These data provide the first evidence, to our knowledge, of the protective role of the studied IRF5 gene polymorphisms against unexplained RPL among Iranian women from south of Iran.

Recurrent Pregnancy Loss: Generally Accepted Causes and Their Management.

Recurrent pregnancy loss (RPL), commonly defined as 3 consecutive losses <10 weeks gestation, affects up to 5% of couples. Well-accepted causes include uterine malformation, antiphospholipid syndrome, and parental chromosomal abnormalities; however, the majority of RPL cases are idiopathic (up to 75%). This chapter covers these accepted causes of RPL and provides diagnosis and management strategies for patients falling within the above categories.

Immunogenetic contributions to recurrent pregnancy loss

While sporadic pregnancy loss is common, occurring in 15% of pregnancies, recurrent pregnancy loss (RPL) impacts approximately 5% of couples. Though multiple causes are known (including structural, hormonal, infectious, autoimmune, and thrombophilic causes), after evaluation, roughly half of all cases remain unexplained. The idiopathic RPL cases pose a challenging therapeutic dilemma in addition to incurring much physical and emotional morbidity. Immunogenetic causes have been postulated to contribute to these cases of RPL. Natural Killer cell, T cell expression pattern changes in the endometrium have both been shown in patients with RPL. Human leukocyte antigen (HLA) and cytokine allelic variations have also been studied as etiologies for RPL. Some of the results have been promising, however the studies are small and have not yet put forth outcomes that would change our current diagnosis and management of RPL. Larger database studies are needed with stricter control criteria before reasonable conclusions can be drawn.

Association between polymorphisms of prokineticin receptor (PKR1 rs4627609 and PKR2 rs6053283) and recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) is a condition with complex etiologies, to which both genetic and environmental factors may contribute. During the last decade, studies indicated that the expression patterns of the prokineticin receptor (PKR1 and PKR2) are closely related to early pregnancy. However, there are few studies on the role of PKR1 and PKR2 in RPL. In this study, we purpose to investigate the association between polymorphisms of the prokineticin receptor (PKR1 rs4627609 and PKR2 rs6053283) and RPL on a group of 93 RPL cases and 169 healthy controls. Genotyping of the single nucleotide polymorphisms (SNPs) was performed using a Sequenom MassARRAY iPLEX system. The results revealed a significant association between PKR2 rs6053283 polymorphism and RPL (P=0.003), whereas no association was observed between PKR1 rs4627609 polymorphism and RPL (P=0.929) in the Chinese Han population.

Polymorphism in Regulatory T-cell (Treg)-Related Genes Is Associated with Unexplained Recurrent Pregnancy Loss

In the absence of confirmed causes for around 50% of recurrent pregnancy loss (RPL) cases this study was conducted in order to investigate the association between single nucleotide polymorphism (SNP) in regulatory T-cell related <i>STAT3</i> (rs4796793 C/G), <i>FOXP3</i> (rs3761548 A/C), <i>LIF </i> (rs3753082 T/C), <i>NKG7</i> (rs71358833 A/G) and <i>CCR5</i> (rs34418657 G/T) genes and unexplained RPL in a group of Palestinian women residing in Gaza strip. A retrospective case-control study was carried out during the period (August 2015 to March 2016). A total of 200 females, 100 RPL patients and 100 control women without previous history of RPL, aged 20–35 years were included in the study. <i>STAT3</i> (rs4796793 C/G), <i>FOXP3</i> (rs3761548 A/C), <i>LIF </i> (rs375082 T/C), <i>NKG7</i> (rs71358833 A/G) and CCR5 (rs34418657 G/T) polymorphisms were tested by PCR-RFLP. Statistically significant difference existed between RPL cases and controls in terms of the genotypic distribution of the tested polymorphisms. <i>STAT3</i> CC, <i>FOXP3</i> AA, <i>LIF </i> CC, NKG7 AA and <i>CCR5</i> GG genotypes were significantly higher in the RPL group. The tested polymorphisms shape the first elements of immune tolerance-related risk SNPs panel for RPL in the investigated population and may lead to improved therapeutic approaches.

Methylenetetrahydrofolate reductase gene polymorphisms and recurrent pregnancy loss in China: a systematic review and meta-analysis.

Recurrent pregnancy loss (RPL) is defined as two or more consecutive pregnancy losses before the 20th week of gestation with the same partner. Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms were reported to have an effect on embryonic development and pregnancy success. To clarify the effects of MTHFR polymorphisms on the risk of RPL in the Chinese population, a meta-analysis was performed. Related studies were identified from Medline, Embase, Web of Science, and Chinese Databases up to March 7th, 2015. We extracted the number of both C677T and A1298C genotypes in the cases and controls. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to estimate the associations. Data analysis was performed using Stata 13.1. Sixteen articles involving 1420 RPL cases and 1408 controls were included in this meta-analysis. MTHFR C677T polymorphism was significantly associated with RPL risk under dominant (TT+CT vs. CC; OR 2.10, 95% CI 1.76-2.50), recessive (TT vs. CC+CT; OR 2.36, 95% CI 1.92-2.90), heterozygote (CT vs. CC; OR 1.77, 95% CI 1.32-2.37), homozygote (TT vs. CC; OR 3.55, 95% CI 2.76-4.56), and additive (T vs. C; OR 1.83, 95% CI 1.64-2.05) model. Sensitivity analyses excluding studies that deviated from HWE did not change the direction of effect. For the A1298C mutation, no significant association was found. The Egger's regression asymmetry test showed no significant publication bias. Identification of MTHFR C677T mutation would have some implication for primary prevention of RPL and screening of high-risk individuals in China. Large well-designed researches are needed to fully describe the associations.

C-reactive protein gene variants associated with recurrent pregnancy loss independent of CRP serum levels: A case-control study

The aim of this study is to investigate the association of recurrent pregnancy loss (RPL) with altered C-reactive protein (CRP) serum levels, and genetic variation in CRP gene. This was a retrospective case–control study, involving 275 women with three or more consecutive pregnancy losses, and 290 age-matched control women, who were recruited from outpatient obstetrics/gynecology clinics. CRP serum levels (hs-CRP) were determined by latex-enhanced nephelometry, and CRP genotyping was done by allelic discrimination. Mean serum CRP levels were higher in RPL cases than in control women, and carriage of the (minor) T allele of rs2794520 was associated with significant increase in CRP levels (P=0.017). Minor allele frequency (MAF) of rs7553007 was significantly different between RPL cases and control women, and was associated with reduced risk of RPL after adjusting for BMI and menarche. There was a significant enrichment of minor allele-carrying genotypes of rs1130864 and rs1417938 SNPs, and reduced frequency of minor allele-carrying genotypes of rs876537, rs2794520, and rs7553007 in RPL cases, thus assigning RPL-susceptible and -protective nature to these genotypes, respectively. Carriage of (minor) T allele of only rs2794520 was associated with significant increase in CRP levels. CRP variants that influenced circulating CRP levels in chronic inflammatory conditions are also associated with RPL, pointing to CRP as RPL candidate gene.

High mobility group box 1 protein polymorphism affects susceptibility to recurrent pregnancy loss by up-regulating gene expression in chorionic villi.

Inflammation in chorionic villi is involved in the development of recurrent pregnancy loss (RPL). High mobility group box 1 protein (HMGB1) plays critical roles in inflammation and expression of the protein can be found in chorionic villi. The purpose of the study was to investigate the association between HMGB1 genetic polymorphisms and susceptibility to RPL and to examine the mechanism underlying this correlation. Two HMGB1 polymorphisms, rs2249825C/G and rs1412125T/C, were examined in 112 RPL patients and 118 healthy controls by the polymerase chain reaction-restriction fragment length polymorphism assay. Percentage of rs2249825GG was significantly increased in patients than in controls (Odd ratio [OR] =2.33, 95 % confidence interval [CI]: 1.18-4.58, P = 0.013). Also, prevalence of rs2249825G allele was significantly higher in RPL cases (OR = 1.77, 95 % CI: 1.20-2.62, P = 0.004). Function analysis of rs2249825C/G revealed that the polymorphism did not affect serum level of HMGB1. Interestingly, we found significantly increased level of HMGB1 in chorionic villi from RPL patients. Moreover, patients with rs2249825GG genotype presented significantly elevated level of HMGB1 in chorionic villi compared to those with CG or CC genotypes. These results suggest that HMGB1 rs2249825C/G polymorphism is associated with increased risk of RPL and can elevate gene expression in chorionic villi.

Microdeletion of Y chromosome as a cause of recurrent pregnancy loss

CONTEXT:In majority of couples experiencing recurrent pregnancy loss (RPL), etiology is still unknown. Two genetic factors have been suggested to underlie miscarriage in a subset of patients, namely skewed X chromosome inactivation in females and Y chromosome microdeletions in their partners. In males, microdeletions of the Y chromosome are known to cause spermatogenetic failure and male infertility.AIMS:The aim of the study was to find out the role of Y chromosome microdeletion in male partners of couples experiencing RPL.SETTINGS AND DESIGN:University hospital and genetic laboratory. Prospective case–control study.SUBJECTS AND METHODS:59 couples with a history of RPL and 20 fertile controls (FC) with no miscarriage were included in the study. The study subjects were divided into male partners of RPL couples with abnormal semen parameters (AS) (n = 8), and couples with normal semen parameters (NS) (n = 51). Fertile controls with normal semen parameters were (FC) (n = 20). Y chromosome microdeletion was performed on 40 male partners of RPL and 20 FC.STATISTICAL ANALYSIS USED:Chi-square test. P <0.05 were considered statistically significant.RESULTS:13 of the 40 RPL cases showed deletion in three azoospermia factor loci on the long arm of Y chromosome. The P value was significant with Y chromosome microdeletion in RPL cases as compared to 20 FC where no Y chromosome microdeletion was present.CONCLUSIONS:Y chromosome microdeletion may be an important hidden cause of recurrent pregnancy miscarriage and can be offered to couples with the undiagnosed cause of miscarriage.

Frequency of hereditary thrombophilia in women with recurrent pregnancy loss in Northern Pakistan.

Hereditary thrombophilia (HT) screening is performed as routine work-up of recurrent pregnancy loss (RPL) in Pakistan. In Northern Pakistan the prevalence of HT is not known. HT is not detected in the majority of RPL cases, especially in patients with ≤ 3 pregnancy losses (PL). The aim of this study was to determine the frequency of HT in women with RPL, and to find the prevalence of HT in patients with ≤ 3 PL and > 3 PL. Lupus-anticoagulant-negative patients with unexplained RPL were screened for protein C, protein S, antithrombin, and factor V Leiden. A total of 315 patients with RPL were screened and 13 (4%) had evidence of HT. Protein C and protein S deficiency were detected in 6/140 (4.3%) women with > 3 PL and in 2/175 (1.1%) women with ≤ 3 PL. Antithrombin deficiency was detected in 2/140 (0.75%) women with > 3 PL and in no patients with ≤ 3 PL. Factor V Leiden was detected in 3/26 (12%) women with > 3 PL and in no patients with ≤ 3 PL. The prevalence of HT in patients with >3 PL was significantly higher than in patients with ≤ 3 PL (P = 0.002). We detected a strong association between HT and >3 PL (odds ratio 7.3; 95% confidence interval: 1.60-33.85) as compared to ≤ 3 PL. HT was detected in 4% of patients with RPL. The prevalence of HT in patients with > 3 PL is significantly higher than in patients with ≤ 3 PL.

What is the impact of SOCS3, IL-35 and IL17 in immune pathogenesis of recurrent pregnancy loss?

Objective: To investigate the plasma levels of interleukin-4 (IL-4), IL-6, IL-10, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), transforming growth factor-beta (TGF-beta), IL-17, IL-35 and suppressor of cytokine signaling 3 (SOCS3) in the women with history of idiopathic recurrent pregnancy loss (RPL) and in the fertile controls.Methods: This study was conducted with 60 idiopathic RPL cases and 40 age-matched fertile controls. Mid-follicular plasma levels of IL-17, IFN-gamma, TNF-alpha, TGF-beta, IL-6, IL-4, IL-10, SOCS3 and IL-35 were assayed by an enzyme linked immunosorbent assay.Results: The mean age of RPL and control cases were 31.6 ± 0.6 and 32.1 ± 0.7 years, respectively. While plasma IL-35 and SOCS3 levels of RPL group were significantly lower than that of the control group; IFN-gamma, TNF-alpha, IL-4, IL-6, IL-10, IL-17 and TGF-beta levels of RPL group were significantly higher than that of the control group. The comparison of cytokine ratios between RPL and control groups indicated significantly high TNF-alpha/IL-10, TNF-alpha/IL-4, IFN-gamma/IL-10, IFN-gamma/IL-6 and IFN-gamma/IL-4 ratios in the RPL group. IL-35/IL-17 ratio was significantly low in the RPL group compared to that in the control group. Overstimulation of TNF-alpha presented moderate influence on recurrent miscarriage risk.Conclusion: Decreased SOCS3 and IL-35 plasma levels and increased Th1/Th2 cytokine ratios in RPL cases pointed out the supression of anti-inflammatory process and this supression might play an important role in the pathogenesis of idiopathic RPL.

The association between inherited thrombophilia and recurrent pregnancy loss in Turkish women

Objective: To investigate the relation between recurrent pregnancy loss (RPL) and factor V Leiden, prothrombin G20210A, and C677T methylenetetrahydrofolate reductase (MTHFR) mutations. Materials and Methods: A case-control study was conducted on 95 consecutive cases with RPL, and 40 age-matched controls who had no history of pregnancy loss and had at least one successful pregnancy. After application of exclusion criteria, 60 patients in the study group and 40 control cases were compared for thrombophilic factors. Results: Thirteen out of 60 RPL cases and one out of 40 in the control group were carriers of factor V Leiden mutation. While six patients were carriers of prothrombin G20210A gene mutation, none in the control group carried this mutation. Twenty-nine out of 60 RPL cases and 17 out of 40 control cases had MTHFR mutation. Conclusion: The authors found a positive correlation between RPL and FVL and FII gene mutations, but no significant association between RPL and MTHFR gene mutation.

Association of the IL-10 Receptor A536G (S138G) Loss-of-Function Variant with Recurrent Miscarriage

We investigated the association of interleukin-10 receptor (IL10R1) loss-of-function variant A536G/S138G with recurrent pregnancy loss (RPL). Study subjects comprised 300 women with ≥3 miscarriages, and 350 control women. Significantly higher 536G-allele frequency was seen in RPL cases, thus assigning pathogenic role for this allele. Significant difference in A536G/S138G genotypes distribution was seen between RPL cases and controls, evidenced by enrichment of 536A/G and 536G/G genotypes in RPL cases. Setting A/A genotype as reference (OR = 1.00), increased RPL risk was seen with 536A/G, and more in 536G/G carriers, thereby establishing dose-dependency. IL10R1 loss-of-function A536/S138G polymorphism may contribute to RPL pathogenesis.

IL-10 gene promoter and intron polymorphisms and changes in IL-10 secretion in women with idiopathic recurrent miscarriage

Is recurrent pregnancy loss (RPL) associated with polymorphisms in the promoter and intron regions of the interleukin-10 (IL-10) gene? IL-10 rs1518111 was found to be associated with RPL but the commonly studied promoter variants rs1800872, rs1800871 and 1800896 were not. Reduced expression of IL-10 is implicated in RPL, due to defective maternal immune tolerance (causing early miscarriages) or placental vascular insufficiency (causing late losses). IL-10 production is in part inherited, and IL-10 gene variants associated with reduced IL-10 expression have been analyzed for their association with RPL, often with inconclusive results. A retrospective case-control study was performed between January 2011 and April 2012. The subjects comprised 296 RPL cases and 305 control women. Genotyping of the IL-10 intron (rs1878672, rs3024492, rs1554286, rs1518111, rs3024491, rs3024490) and promoter (rs1800872, rs1800871, rs1800896) variants was done by real-time PCR, with defined clusters. A higher minor allele frequency (MAF) of rs1518111 (P = 0.03) was in seen RPL cases; but the MAFs of the remaining SNPs were comparable between cases and controls. Setting the homozygous major allele genotype (1/1) as the reference, significantly higher frequencies of heterozygous rs1554286 and rs1800872, and homozygous rs1800896 genotype carriers, and a reduced frequency of homozygous rs1518111 genotype carriers, were seen in RPL cases, while the distribution of the remaining genotypes were comparable between cases and controls. Serum IL-10 levels were significantly reduced in RPL cases compared with control women (P = 0.002), and this correlated with rs1518111 and rs1800871 genotypes in both groups, and with the rs1800872 genotype among control women. A nine-locus (rs1878672, rs3024492, rs1554286, rs1518111, rs3024491, rs3024490, rs1800872, rs1800871 and rs1800896) haploview analysis demonstrated an increased frequency of haplotype 112112121 in RPL cases, thus conferring a disease susceptibility nature to this haplotype. The main limitation of this study was that it was limited to Bahraini Arabs, thereby necessitating parallel studies of other ethnic groups. Another limitation is the study design, which prompts speculation on whether it is a cause-effect relationship. While the lack of association of the various IL-10 promoter variants with RPL was in agreement with reports from varied ethnic groups, this is the first study to confirm the association between IL-10 rs151811 intronic variant and RPL. The study was funded by grants from the Arabian Gulf University Research Fund. None of the authors report any competing interests.

Lack of association between thrombophilic gene variants and recurrent pregnancy loss

Recurrent pregnancy loss (RPL) is defined as the occurrence of two or more consecutive pregnancy losses. It is an important reproductive condition with a complex etiology. In approximately 50% of RPL cases an explanation for the cause is not found and they are therefore classified as idiopathic RPL. One of the causes implicated in RPL is thrombophilia, which consists of hemostatic disorders that lead to an increase in thromboembolic processes. The aim of this study was to evaluate polymorphic variants in genes related to thrombophilia as a risk factor in women with RPL. We investigated 145 women with at least two consecutive pregnancy losses and 135 women with at least two children and no history of pregnancy loss. Genotypes for the polymorphisms MTHFR C677T, FVL, FII (prothrombin), eNOS T-786C, and eNOS Glu298Asp were determined using a real-time PCR. Information about the exposure to environmental risk factors was also collected. There was no significant association between the environmental risk factors assessed and the polymorphisms studied. We did not find statistically significant differences in genotypic or allelic frequencies for the polymorphisms studied, in either the women with RPL or in the control group. Such polymorphisms should therefore not be considered as risk factors for this condition in this population.

Cytogenetic Investigation in Prenatal Specimecimens for Effective Prognosis of Pregnancy Related Complications

Background: Alterations in chromosomal content of mother and infant are central characteristics of various complications related to pregnancy and early childhood. About 60% of the pregnancy losses, 2-3% of all the neonates and 50% of childhood deafness, blindness, mental retardation and 1 to 10 % of all the malignancies are directly due to genetic factors. Hence cytogenetic testing of pre and post natal samples can prove to be useful for discovery of non-invasive markers for prevention of such conditions beforehand. Aim of the study: The present study was carried out to detect numerical and structural abnormalities in 56 subjects with repeated miscarriages, bad obstetric history and sub fertility by analysing peripheral blood, products of conception (POC) material, and recovered cell lines from prenatal samples. Methods: Conventional cytogenetics: Peripheral blood culture (PBC) supplemented with mitogen Phytohemagglutinin (PHA), metaphase chromosomes was harvested after 72 hours for chromosome analysis. Tissue cytogenetics: Culture of solid tissue was used as a source for mitotic cells from products of conception (POC) from first trimester spontaneous abortions for aneuploidy detection; and Prenatal chromosome analysis was performed by either chorionic villus sampling (CVS), amniotic fluid and cord blood after culture. Image acquisition and analysis was performed by using automated karyotyping (IKAROS) software based on G, C and R banding. Results: Chromosomal abnormalities were located in all types of specimens but were predominantly observed in recurrent pregnancy loss (RPL) and product of conception (POC) samples. Aberrations observed were mainly translocations, satellites, additions in RPL cases like 46,XX with instances of (D/D,D/G,G/Gassociations);45,XX,rob(13;14);46,XXt(4;21);46,XX,(9qh+);46,XX,(14ps+);46,XX, t(5;6) and ploidy involving 67,XX+;64,XXX+;69,XXX;63,XXX;58,XX+ in the POC cases. Conclusion: Cytogenetic screening could provide to be a useful method for monitoring patients with abnormal pregnancies. The cytogenetic result is an independent prognostic indicator, with certain karyotypes associated with a good prognosis for the better treatment.

Positive association of sperm dysfunction in the pathogenesis of recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) is one of the most frustrating and difficult areas in reproductive medicine, because the aetiology is often unknown and there are few evidence-based diagnostic and treatment strategies. RPL diagnosis is mainly focused on the female partner. The male factor contributing in evaluation of RPL has been less investigated, it is restricted to karyotype and basic semen analysis, assessment of functionality of sperm is largely ignored. To investigate the role of sperm factors in RPL through regular semen analysis preceded with sperm function tests. We performed a case control study of 95 males whose partner has experienced two or more pregnancy loss as case and 37 volunteers who had fathered child/children without the history of RPL as control group. Basic semen analysis and sperm function test (Nuclear chromatin decondensation {NCD}, Hypo osmotic swelling {HOS} and Acrosome intactness test {AIT} was performed. The results were analysed by performing Independent-sample t-test using SPSS (version 14.0). One individual had anatomical abnormality which was confirmed through trans-rectal ultrasound scanning and RPL group showed statistically significant (p<0.05) value for NCD, HOS and AIT and 36.8% of RPL individuals had reduced score for sperm count and motility. Less than 4% normal morphology was recorded in 16.8% individuals of RPL group. Our study revealed that the positive association of sperm dysfunction in RPL cases, hence male may be considered for a routine part of the evaluation along with his partner in the near future in order to achieve desirable outcome.

Association between apolipoprotein E gene polymorphism and the risk of recurrent pregnancy loss: A meta-analysis

The association between apolipoprotein E (ApoE) gene polymorphism and the risk of recurrent pregnancy loss (RPL) remains controversial. The present meta-analysis was performed to derive a precise estimate of the relationship. We searched the PubMed, Embase, and Web of Science data- bases for studies related to the association between the ApoE genotype and the risk of RPL. We estimated the summary odds ratio (OR) with 95% confidence interval (CI) to assess the association. Seven studies, including 2,090 RPL cases and 742 control samples, were identified. The results showed a significant association between ApoE E4 mutation and RPL risk (for E4 allele: OR =1.98, 95 %CI =1.14-3.43, P=0.499; for E2E3 vs. E3E3: OR =1.33, 95%CI =1.12-1.42, P=0.008; for E2E4 vs. E3E3: OR =1.26, 95 % CI =1.07-1.49, P=0.005). The meta-analysis suggests an association between ApoE E4 mutation and increased risk of RPL.

The association of idiopathic recurrent pregnancy loss with polymorphisms in hemostasis-related genes

Recurrent pregnancy loss (RPL) is a complex, multifactorial condition. Inherited thrombophilia is the leading cause of thromboembolism and is associated with an increased risk of RPL. The aims of the current study were to investigate the effects of polymorphisms in hemostasis-related genes antithrombin (SERPINC1), thrombomodulin (THBD), tissue factor pathway inhibitor (TFPI), factor V, factor II and annexin A5 (ANXA5), involved in reproductive failure in 94 RPL cases with two or more consecutive pregnancy losses prior to 20weeks of pregnancy and 169 healthy controls who had at least one term delivery and no history of pregnancy loss. The genotypes of SERPINC1 G786A, THBD C1418T, TFPI T-33C, factor V G1628A, factor II A19911G and ANXA5 G76A were assayed by the Sequenom MassARRAY system. Genotype and allele frequencies for SERPINC1 (rs2227589), TFPI (rs8176592), factor V (rs6020), factor II (rs3136516) and ANXA5 (rs113588187) in cases and controls were similar. The distribution of THBD C1418T allele showed significant differences between RPL cases and healthy controls (odds ratio (OR): 1.58, 95%, confidence interval (CI): 1.05–2.39, P=0.027). In univariate logistic regression analyses, carriers of THBD 1418T allele (CT+TT) had an increased risk of RPL (OR: 1.83, 95%, CI: 1.10–3.06, P=0.020). This indicated that THBD 1418T allele was associated with increasing the risk of RPL.