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Background: Treg cells play an important role in development of tolerance in maternal immune system against the semi-allogenic embryo. Human forkhead box protein 3 (FOXP3) gene, is the major transcription factor responsible for the regulation of Treg function during pregnancy. Single nucleotide polymorphisms (SNPs) of FOXP3 gene have been reported as a risk factor for Recurrent Pregnancy Loss (RPL), however, results from previous studies are inconsistent., Methodology: We have collected data from different studies to investigate the overall association of FOXP3 SNPs with risk of RPL. PubMed, Google Scholar, Elsevier, and Cochrane databases were searched to identify eligible studies. Odds Ratio (OR) and 95 % Confidence Interval (CI), calculated via fixed effect or random effect models, were used to evaluate strength of association. This meta-analysis included 11 studies (1383 RPL cases and 1413 controls) of 6 SNPs: rs3761548 A/C, rs2232365 A/G, rs2294021 T/C, 2280883 T/C, rs5902434del/ATT and rs141704699C/T, with ≥2 studies per SNPs and at least 1 significant result., Results: We observed that FOXP3 polymorphism was predominantly present in Asian women with history of RPL. rs2232365 A/G, rs3761548 A/C, rs2294021 T/C, rs2280883 T/C and rs5902434del/ATT polymorphisms were significantly associated with risk of RPL in Indian population. Further, among the most commonly seen polymorphism, rs3761548 A/C was significantly associated with risk of RPL in women from Kazakhstan, China and Gaza, Palestine; rs2232365 A/G in populations of Kazakhstan, Egypt, Iran and Gaza, Palestine. Results of this study indicates that FOXP3 polymorphism is significantly associated with risk of RPL, especially in Asians., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Many studies have reported the association of VEGF -1154G/A, VEGF 936C/T, and p53 Arg72Pro polymorphisms with recurrent pregnancy loss (RPL), but the outcomes are inconsistent. We have used a meta-analysis to associate these polymorphisms with RPL, having the spiral artery remodeling as a major risk factor. The studies were identified from three different reputed databases, namely ScienceDirect, PubMed/Medline, and Scopus. The eligible studies of VEGF- 1154G/A, VEGF 936C/T, and p53 Arg72Pro polymorphisms associated with the RPL were selected for the analysis. They were segregated into three different ethnic groups as Asians, Caucasians, and mixed population. For the analysis, the overall prevalence, odds ratio, risk ratio, relative risk ratio, and p -values were calculated. A total of 3,241 RPL cases and 3,205 healthy controls from 21 different case-control studies were analyzed. RPL was highly prevalent in the mixed population with VEGF- 1154G/A and p53 Arg72Pro polymorphisms (70.04 and 66.46%, respectively) and in the Asian population with VEGF 936C/T polymorphism (53.58%). The homozygous recessive genotypes of VEGF and p53 exhibited significant association between the respective polymorphisms and RPL along with the increased risk of outcome. The current analysis conclusively reports the geographic distribution of the different genetic polymorphisms which shows high association with the progression of RPL. Understanding the spectrum of polymorphisms on different populations with the spiral artery remodeling as a risk factor encloses the importance of the vasculature during the pregnancy., Competing Interests: None declared., (Thieme. All rights reserved.)

Backgroud: To analyze the correlation between gene polymorphisms of 5,10- methylenetetrahydrofolate reductase (MTHFR) and risk of unexplained recurrent pregnancy loss (URPL) in Chinese women., Methods: Eligible studies were searched in Pubmed, Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure (CNKI) databases. Established inclusion criteria were used to screening articles, subsequently evaluate the quality of the included studies, Stata 16.0 PM and RevMan 5.3 software were conducted for meta-analysis. The pooled odds ratio (OR) with 95% confidence interval (CI) was determined to assess the relationship between MTHFR and risk of URPL in Chinese women., Results: For MTHFR C677T, fifty studies were included, involving 6677 URPL cases and 8111 controls. The overall results showed that MTHFR C677T was significantly correlated with URPL risk, especially in the homozygous model (TT vs CC; OR 3.06; 95% CI 2.56-3.66). For MTHFR A1298C, twenty-first studies were included, involving 3439 URPL cases and 3155 controls. The results showed that MTHFR A1298C was also significantly correlated with URPL risk in recessive (CC vs AC + AA; OR 1.55; 95% CI 1.25-1.93) and homozygous (CC vs AA; OR 1.53; 95% CI 1.22-1.91) models. In addition, sub-group results showed that no significant difference between north and south China populations in the MTHFR gene polymorphisms and URPL risk. Of note, the patients carrying MTHFR C677T and MTHFR A1298C joint mutants had no synergistic effect (OR 2.71; 95% CI 0.84-8.70) on the occurrence of URPL compared with the wild-type homozygous genotype (MTHFR 677CC/ MTHFR 1298AA)., Conclusion: Studies included in this meta-analysis suggested that MTHFR 677T allele and 677TT genotype and MTHFR 1298CC genotype were both associated with URPL; testing MTHFR C677T gene polymorphism was a more appropriate target compared with other mutations in the prediction of URPL., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To assess the association of conventional semen parameters and sperm DNA fragmentation with risk of recurrent spontaneous abortion (RSA)., Design: Systematic review and meta-analysis., Setting: Not applicable., Patients: Total 1,690 male partners of women with RSA, and 1,337 male partners of fertile control women., Interventions: Case-control or cohort studies were determined by searching PubMed, Google Scholar, Cochrane Libraries, China Biology Medicine disc, Chinese Scientific Journals Fulltext Database, China National Knowledge Infrastructure, and Wanfang Database. RSA was defined as two or more previous pregnancy losses. The fertile women refer to the reproductive women who have had at least a normal pregnancy history and no history of abortion., Main Outcome Measures: This study included eight outcome measures: semen volume(ml), semen pH value, sperm density(106/ml), sperm viability (%), sperm progressive motility rate (%), normal sperm morphology rate (%), sperm deformity rate(%), sperm DNA fragmentation index (DFI) (%). The summary measures were reported as standardized mean difference (SMD) with 95% confidence interval (CI)., Results: Finally, twenty-four studies were included for analysis. Overall, male partners of women with RSA had a significantly lower level of sperm density (SMD = -0.53, 95%CI: - 0.75 to -0.30), sperm viability (SMD = -1.03, 95%CI: - 1.52 to -0.54), sperm progressive motility rate (SMD = -0.76, 95%CI:-1.06 - -0.46), and normal sperm morphology rate (SMD =  -0.56, 95%CI: - 0.99 to -0.12), and had a significantly higher rate of sperm deformity rate (SMD = 1.29, 95%CI: 0.60 - 1.97), and sperm DFI (SMD = 1.60, 95%CI: 1.04 to 2.17), when compared with the reference group. However, there were no statistically significant differences for semen volume (SMD = -0.03, 95%CI: -0.14 - 0.08) and semen pH value (SMD =  -0.23, 95% CI: -0.50 to 0.05) among 2 groups., Conclusions: The results of this analysis support an association of sperm density, sperm viability, sperm progressive motility rate, normal sperm morphology rate, sperm deformity rate, as well as sperm DFI with RSA. However, given the significant heterogeneity between studies and the lack of more detailed data on the subjects, further large-scale prospective studies are needed., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

To evaluate the associations between Tumor necrosis factor-α (TNF-α)(-238G>A) and Interleukin-6 (IL-6)(-174G>C) polymorphism and risk of unexplained recurrent spontaneous abortion (URSA).Correlated case-control studies were collected by computer retrieval. A meta-analysis was conducted by Stata 12.0 software to analysis the strength of association between polymorphism of TNF-α -238G>A and IL-6 -174G>C and URSA.Twenty-one articles with twenty-two studies were included, of which 12 and 10 studies were respectively related to mutation of TNF-α -238G>A, IL-6 -174G>C and URSA. The integrated results showed that the TNF-α-238G>A gene mutation was significantly correlated with the risk of URSA under homozygote model (AA vs GG;OR 1.533,95% CI 1.022-2.301) and recessive model (AA vs GG+AG;OR 1.571,95%CI 1.050-2.350)(P < .05). There was no association between URSA and TNF-α -238G>A under heterozygote model (AG vs GG;OR 0.963,95% CI 0.816-1.137), dominant model (AA+AG vs GG; OR 1.031,95%CI 0.880-1.209) and additive model (A vs G;OR 1.046,95%CI 0.909-1.203)(P > .05). The results of subgroup analysis based on ethnicity showed that -238G>A was significantly correlated with the risk of URSA in Asians under all gene models except for heterozygote model (AG vs GG; OR 1.129,95% CI 0.857-1.487) (P < .05). In Caucasians, it was dominant model (AA+AG vs GG; OR 1.430,95%CI 1.040-1.965) (P < .05) rather than others that showed relationship with URSA. From the integrated results, association was manifested between -174G>C and URSA under all gene models (P < .05) except for recessive model (CC vs GG+CG, OR 1.166, 95%CI 0.938-1.449) (P > .05), which is identical to subgroup analysis based on ethnicity.It is of great guiding significance for screening out and preventing URSA among high-risk women to test on TNF-α -238G>A and IL-6 -174G>C under gene models mentioned above which are highly associated with the risk of URSA, which can act as biological markers for URSA.

Background: The present study was performed to investigate whether genetic variants of VEGF are associated with recurrent pregnancy loss (RPL) in Korean women and to provide insight into the role of VEGF in the pathogenesis of RPL development., Methods: A cohort of 384 women with idiopathic RPL with a history of two or more uxexplained consecutive early pregnancy losses and 236 control women were recruited from an infertility center of university-teaching hospital in Korea between March 1999 and February 2010. We examined three VEGF polymorphisms (rs833061, rs3025020 and rs25648). Genotyping was assessed by polymerase chain reaction (PCR)-restriction fragment length polymorphism analyses (rs3025020) or real-time PCR (rs833061, rs25648)., Results: There was no statistically significant difference in frequency of each three VEGF polymorphic loci between the control and RPL groups. Allele combinations of VEGF rs3025020/rs833061 TT/TC and TT/TC + CC genotypes were associated with an increased frequency of RPL development [odds ratio (OR) = 3.525, 95% confidence interval (CI) = 1.154-10.767, p = 0.027 and OR = 3.815, 95% CI = 1.256-11.588, p = 0.018, respectively]. Haplotype analysis revealed that two allele combinations (rs833061/rs3025020 C-T and rs25648/rs3025020 T-T) were associated with an increased prevalence of RPL (OR = 2.548, 95% CI = 1.502-4.320, p = 0.0004 and OR = 16.50, 95% CI = 0.976-278.8, p = 0.003, respectively). Allele combinations and haplotypes of rs3025020/rs833061 were associated with maternal blood hematocrit (HCT) levels in the RPL group (p = 0.048 and 0.006, respectively)., Conclusions: The VEGF rs833061/rs3025020 genotype allele was related to the development of RPL and was also associated with maternal blood HCT levels in RPL patients. However, further studies are needed to clarify the exact mechanism of how VEGF and HCT are involved in RPL development., (© 2018 John Wiley & Sons, Ltd.)

Mutations of hemostasis/coagulation-related genes have been speculated to cause recurrent spontaneous abortion (RSA). This study investigated the genetic association between the polymorphisms of factor V (F5), factor II (F2), antithrombin (SERPINC1), protein C (PROC), protein S (PROS1), protein Z (PROZ), factor XIII (F13A1), and carboxypeptidase B2 (CPB2) genes and RSA. The 426 patients with RSA and 444 controls were recruited in this study, and single-nucleotide polymorphisms (SNPs) were analyzed by using SNPscan technology. Genotype and allele frequencies of rs3136520 in F2, rs3024731 in PROZ, and rs1050782 in F13A1 showed statistically significant differences between the 2 groups. TT genotype of rs3136520 ( P = .031, odds ratio [OR] = 0.986, 95% confidence interval [CI] = 0.976-0.997) and AA genotype of rs2069906 in PROC ( P = .021, OR = 0.114, 95% CI = 0.014-0.902) in their recessive models and AG + GG variants of rs1050782 ( P = .007, OR = 0.681, 95% CI = 0.516-0.899) in the dominant model might be associated with the reduced risk of RSA. AT + TT variants of rs3024731 ( P = .010, OR = 1.479, 95% CI = 1.098-1.994) may increase disease susceptibility in dominant model. Haplotype analysis of rs3024731 and rs3024735 in PROZ displayed that the AA and TG haplotype were inclined to decrease and increase the risk of RSA, respectively. These results suggested that rs3136520, rs2069906, rs3024731, and rs1050782 may have a significant association with the genetic susceptibility of RSA in Chinese Han women.

Deregulated immunity is one of the most important factors implicated in recurrent pregnancy loss (RPL). The possible role of interleukin-33 (IL-33) and forkhead/winged helix transcription factor (Foxp3) in RPL have not been fully investigated. We aimed to evaluate IL-33 rs1929992 and Foxp3 rs2232365 single nucleotide polymorphisms (SNPs) and their serum levels in Egyptian RPL females. Blood samples were collected from 142 RPL patients and 123 women as healthy controls. IL-33 rs1929992 SNP was determined by polymerase chain reaction restriction fragment length polymorphism and Foxp3 rs2232365 SNP was determined using allele specific polymerase chain reaction. The serum IL-33 and Foxp3 levels were measured by enzyme linked immunosorbent assay. Foxp3 rs2232365 SNP showed statistically significant association with RPL. The risk of RPL was significantly higher in women carrying Foxp3 G allele than those carrying A allele. Lower serum levels of Foxp3 and IL-33 were observed in RPL patients than controls (P < 0.001). Foxp3 serum levels were much lower in carriers of G allele than those carrying A allele in all studied groups. Foxp3 rs2232365 SNP could be considered as a risk factor for RPL. The lowered serum levels of IL-33 and Foxp3 in RPL patients suggested that they might have an important role in the pathogenesis of the disease. Therefore, we hypothesized that Foxp3 polymorphisms may be important in RPL pathogenesis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: This study aimed to examine the association between recurrent pregnancy loss and the risk of cardiovascular disease mortality., Methods: We identified 54,652 women who were pregnant during the Japan Collaborative Cohort Study. These women were 40-79 years at the date of cohort entry between 1988 and 1990. Participants received municipal health screening examinations and completed self-administered questionnaires. The cause of death was confirmed by annual or biannual follow-up surveys for a median of 18 years. The exposure was the number of pregnancy loss. The outcome was mortality from total cardiovascular disease and its subtypes according to the International Classification of Diseases, 10th Revision. Adjustment variables included age, number of deliveries, education, body mass index, physical activity, smoking status, and drinking status. Kaplan-Meier survival curves were used to estimate the cumulative mortality., Results: The number of pregnancy loss tended to be inversely associated with the risk of mortality from total stroke, intracerebral hemorrhage, and total cardiovascular disease. The multivariable hazard ratio of total cardiovascular disease for ≥2 pregnancy losses versus no pregnancy loss was .84 (95% confidence interval, .74-0.95). A 2-fold excess risk of mortality from ischemic stroke associated with ≥2 pregnancy losses was observed in women aged 40-59 years, with a multivariable hazard ratio of 2.19 (95% confidence interval, 1.06-4.49), but not in older women., Conclusions: Recurrentpregnancy loss tends to be associated with a lower risk of mortality from cardiovascular disease at 40-79 years. Younger women have an excess risk of ischemic stroke mortality associated with recurrent pregnancy loss., (Copyright © 2017. Published by Elsevier Inc.)

Oestrogen receptors are implicated in the pathogenesis of recurrent spontaneous abortion (RSA). Non-genomic oestrogen responses can be mediated by GPER. The prevalence of polymorphisms in GPER1 gene in RSA was assessed in 747 Chinese women from Yunnan province (171 Bai, 258 Chinese Han, 234 Dai, 33 Achang and 51 Jingpo patients). Snapshot technology was used for genotyping the polymorphisms of the GPER1 gene. The rs4265085G was significantly increased in the Dai and Bai groups versus controls (Dai: P < 0.0001, P adj < 0.0001, OR 95% CI 2.34 [1.79 to 3.05]; Bai: P = 0.0004, P adj = 0.0012, OR 95% CI 1.71 [1.27 to 2.31]); recessive model of rs4265085 in the Dai (P = 0.003, P adj = 0.009, OR 95% CI 2.71 [1.38 to 5.30]); Bai (P < 0.0001, P adj < 0.0001, OR 95% CI 3.37 [1.93 to 5.91]). Haplotype frequencies containing rs10269151G-rs4265085G-rs11544331C were separately significantly different in Dai and Bai ethnic groups (Dai: P = 0.0002, P adj = 0.001, OR 95% CI = 2.12 [1.43 to 3.17]; Bai: P = 0.005, P adj = 0.025, OR 95% CI = 1.82 [1.18 to 2.78]) compared with controls. The intron variant rs4265085 may confer risk for RSA in Dai and Bai ethnic groups., (Copyright © 2017 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

The one-carbon metabolism pathway disorder was important role in successful pregnancy. The MTHFR and TS protein were crucial factor in one-carbon metabolism. To investigate the association between recurrent implantation failure (RIF) and enzymes in the one-carbon metabolism pathway. A total of 120 women diagnosed with RIF and 125 control subjects were genotyped for MTHFR 677C>T, 1298A>C, TSER 2R/3R and TS 1494del/ins by a polymerase chain reaction-restriction fragment length polymorphism assay. According to the gene-gene combination analysis, the MTHFR 677/MTHFR 1298 (TT/AA) and MTHFR 677/TS 1494 (TT/6bp6bp) genetic combinations were associated with relatively higher risks [adjusted odds ratio (AOR), 2.764; 95% CI, 1.065-7.174; P = 0.037 and AOR, 3.186; 95% CI, 1.241-8.178; P = 0.016] in RIF patients compared to the CC/AA (MTHFR 677/MTHFR 1298) and TT/6bp6bp (MTHFR 677/TS 1494) combinations, respectively. The results suggested that the combined MTHFR 677/MTHFR 1298 genotype might be associated with increased risk of RIF. To the best of our knowledge, this study is the first to elucidate the potential association of MTHFR, TS and TSER polymorphisms with RIF risk in Korean patients., Competing Interests: The authors have declared that no competing interests exist.

Objective: To explore the association between the C46T polymorphism of coagulation factor Ⅻ (FⅫ) gene and the involvement of FⅫ activity (FⅫ:C) in patients with unexplained recurrent spontaneous abortion (URSA), and to elucidate its role in the pathogenesis of URSA., Methods: This study included 203 patients with URSA (URSA group) and 171 healthy women with at least one child and no history of infertility or miscarriage (control group) in the southern area of Zhejiang Province. The C46T polymorphism of the FⅫ gene was analyzed with matrix-assisted laser desorption/ionization time of flight-mass spectrometry (MALDI-TOF-MS) in all subjects. The values of prothrombin time, activated partial thromboplastin time (APTT), fibrinogen, FⅫ:C and other coagulant parameters were determined. The frequency distribution of the wild-type (CC), heterozygote (CT), homozygote (TT) genotypes and C and T alleles were compared between the patients and controls. A comprehensive analysis of association was conducted between C46T genotypes and the FⅫ:C levels in URSA patients., Results: The CC, CT, TT genotypes of the FⅫ gene were observed in 7 (3.4%, 7/203), 83 (40.9%, 83/203) and 113 (55.7%, 113/203) patients with URSA versus 7 (4.1%, 7/171), 46 (26.9%, 46/171) and 118 (69.0%, 118/171) controls. The frequency of CT in the patients with URSA was significantly higher than that in controls, but the frequency of TT in the patients was lower than that in controls (χ(2)=7.939, OR=1.884, 95%CI: 1.210-2.935, P<0.05). The frequencies of allele C and allele T were observed in 97 (23.9%, 97/406) and 309 (76.1%, 309/406) patients with URSA versus 60 (17.5%, 60/342) and 282 (82.5%, 282/342) controls. The distribution frequency of allele T in URSA group was lower than that in control group (χ(2)=4.510, OR=1.475, 95%CI: 1.029-2.115, P<0.05). The FⅫ: C levels in the patients were (102±13)% in CC genotype, (78±11)% in CT genotype and (59±9)% in TT genotype, respectively. The differences of the FⅫ: C levels between the CC and CT, CT and TT, CC and TT genotypes in the patients were significant (all P<0.05)., Conclusions: The low level of FⅫ:C maybe result from the T allele of the FⅫ gene in URSA patients. The CT genotype might be relative to the pathogenesis of URSA in a Chinese Han female population from the southern area of Zhejiang province.

Objective: The aim of this study was to investigate whether interleukin-10 (IL-10) polymorphisms are associated with susceptibility to recurrent pregnancy loss (RPL)., Methods: We conducted a literature search using the PubMed and EMBASE databases and performed meta-analyses on the associations between IL-10 -1082 G/A, -819 C/T, and -592 C/A polymorphisms and RPL, using fixed- or random-effects models., Results: A total of 15 papers involving 1858 RPL patients and 1949 controls were considered in this study. Meta-analysis of IL-10 -1082 G/A polymorphism revealed no association between RPL and the IL-10 -1082 G allele (OR=0.999, 95% CI=0.815-1.223, p=0.989). However, meta-analysis of IL-10 -819 C/T polymorphism in all study subjects revealed an association between RPL and the IL-10 -819 C allele (OR=0.680, 95% CI=0.498-0.927, p=0.015). Stratification by ethnicity indicated an association between the IL-10 -819 C allele and RPL in the Asian group (OR=0.421, 95% CI=0.226-0.783, p=0.006), but not in the Caucasian and Arab groups (OR=1.053, 95% CI=0.218-5.077, p=0.949, and OR=0.800, 95% CI=0.606-1.081, p=0.152, respectively). Furthermore, a relationship between the IL-10 -592 C allele and RPL was identified in the Asian group (OR=0.763, 95% CI=0.633-0.919, p=0.004), but not in the Caucasian and Arab groups., Conclusions: The meta-analyses demonstrate that IL-10 -819 C/T and -592 C/A polymorphisms are associated with RPL susceptibility in Asian women, but not in the Caucasian and Arab populations., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: 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., Materials and Methods: 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., Results: 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., Conclusions: 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.

Aims: Hereditary as well as acquired thrombophilia is associated with a higher incidence of severe obstetric complications such as preeclampsia, spontaneous pregnancy loss, placental abruption, and fetal growth retardation. The aim of our study was to examine the association of selected thrombophilic polymorphisms (factor V Leiden, MTHFR C677T, and MTHFR A1298C) with pregnancy complications in the Slovak majority population and the Roma (Gypsy) ethnic population. The study included 354 women; 120 patients and 105 controls from the Slovak majority population, 50 patients and 79 controls from the Slovak Roma population. Genotyping was performed by the real-time polymerase chain reaction method using TaqMan(®) MGB probes., Results: A statistically significant higher frequency of factor V Leiden (p=0.001, odds ratio [OR]=5.9) and MTHFR C677T polymorphism (p=0.011, OR=1.7) was observed in the Slovak majority patient group compared to the control group. The incidence of MTHFR A1298C polymorphism between patients and controls did not differ significantly. None of the three polymorphisms studied was in association with pregnancy complications in the group of Roma women., Conclusions: Our study has confirmed the variable distribution of selected thrombophilic polymorphisms in different ethnic groups as well as their various effects on the clinical phenotype.

Objective: To determine whether the frequency of euploid miscarriage is increased in obese women with recurrent early pregnancy loss (REPL)., Design: Observational cohort study using prospectively collected data., Setting: Academic RPL program., Patient(s): A total of 372 women with REPL, defined as ≥2 pregnancy losses<10 weeks, and at least one ultrasound-documented miscarriage with chromosome results., Intervention(s): Body mass index (BMI) was measured at the initial consultation and at each subsequent pregnancy. Conventional cytogenetic analysis and, when indicated, microsatellite analysis and/or comparative genomic hybridization was performed., Main Outcome Measure(s): Frequency of euploid miscarriage in obese (BMI≥30 kg/m2) and nonobese (BMI<30 kg/m2) subjects, before and subsequent to REPL evaluation., Result(s): There were 578 miscarriages with chromosome results. Of the subjects, 18% were obese at the time of miscarriage. The mean maternal age at miscarriage was similar between the obese and nonobese groups. Due to the high rate of maternal cell contamination in the prior miscarriages, only subsequent miscarriages with chromosome results were included in the primary analysis. Of the 117 subsequent miscarriages, the frequency of an euploid miscarriage among obese women was 58% compared with 37% of nonobese women (relative risk=1.63; 95% confidence interval 1.08-2.47)., Conclusion(s): Obese women with REPL have an increased frequency of euploid miscarriage, which is a known risk factor for subsequent miscarriage., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Recurrent spontaneous abortion (RSA) is a health problem that affects nearly 1% of fertile couples. However, the underlying etiology and mechanism(s) remain elusive. The aim of this study was to investigate estrogen receptor (ESR) 1 gene polymorphisms for risk association of unexplained recurrent spontaneous abortion (URSA) in the Chinese Han population. The entire coding region of the ESR1 gene was sequenced from 129 URSA patients and 183 healthy controls. There was a significant difference between the G allele and GG genotype distributions, of the ESR1 gene (XbaI) polymorphism, between the URSA and the control groups (χ(2) = 14.93, df = 1, p < 0.001, OR = 2.01 95% CI: 1.41-2.88 by allele; χ(2) = 12.24, df = 2, p = 0.002 by genotype). The PvuII polymorphism, C allele frequency was higher in RSA than in controls (41.9% vs. 34.7%, respectively). Women carrying C-G haplotype were associated with an increased risk of URSA in this population (permutation test p value = 0.016, OR = 1.76 95% CI: 1.19-2.59). Estrogen receptor 1 gene PvuII and XbaI polymorphisms were associated with URSA in a Chinese Han population. However, independent replication of these associations are necessary to assure veracity.

Objective: To confirm the effect of single nucleotide polymorphisms (SNPs) in chorionic gonadotropin beta (CGB) genes in modulating the susceptibility to recurrent miscarriage (RM) in Danes and in a meta-analysis across Danes and the discovery samples from Estonia and Finland., Design: Case-control association study, restriction fragment length polymorphism genotyping, resequencing., Setting: Fertility clinics at the Rigshospitalet, Copenhagen, and Aalborg Hospital, Aalborg, Denmark., Patient(s): Four hundred fifty Danish women and men from couples with RM and 119 women with children and no miscarriages in new study. A total of 634 women and men from RM couples and 314 female controls in a combined study of Estonians, Finns, and Danes., Intervention(s): None., Main Outcome Measure(s): Distribution of CGB5 and CGB8 allele and haplotype frequencies in patients and controls., Result(s): For the majority of studied SNPs, the allelic and haplotypic distribution differed statistically between the Danish and the previous Estonian-Finnish sample. In Danes, two CGB5 promoter SNPs (c5-155; c5-142) exhibited a nonsignificant trend for higher allele frequency in fertile women compared with RM patients. The meta-analysis of results from three populations confirmed a modest but significant effect on carriage of c5-155C (odds ratio = 0.64; 95% confidence interval [CI] 0.44-0.94) and c5-142A (odds ratio = 0.66; 95% CI, 0.45-0.94) variants in reducing the risk of RM. None of the investigated genetic variants in the CGB8 gene was associated with RM., Conclusion(s): Carriage of particular variants in the promoter of the CGB5 gene seems to protect against RM. No common genetic variants in CGB5 and CGB8 were associated with increased RM susceptibility in the studied North European populations., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Immune response to infections has been associated with recurrent pregnancy loss (RPL). Low plasma mannose binding lectin (MBL) levels, an innate immunity factor in infections, has been related to RPL. In this study, we tested the hypothesis that MBL genotypes that are known to cause reduced plasma MBL levels are significantly more frequent among women experiencing unexplained RPL., Methods: This study included 219 Caucasian women diagnosed with unexplained RPL and 236 control women. All participants were genotyped for two promoter (-550 C > G and -221 G > C) and three missense (R52C, G54D and G57E) mutations in exon 1. These mutations are known to be associated with variations in plasma MBL levels. Genotype frequencies were estimated by gene counting and were compared to the expectation of Hardy-Weinberg equilibrium by chi-squared (X(2)) analysis and Fisher's exact test. Allele and genotype frequencies were compared in cases and controls using X(2) contingency table analysis., Results: There was no difference in demographics between cases and controls. The number of miscarriages in the participants with RPL ranged from 2 to 10 spontaneous abortions (SAB's) per participant. Populations genotyped were in Hardy-Weinberg equilibrium. There was no association between a history of RPL and multi-SNP genotypes at the MBL locus. In unexplained RPL, the number of SAB's and live birth rates were unaffected by MBL genotype. There was no association between MBL genotype and the risk of unexplained RPL. The occurrence of live birth was not associated with MBL genotype., Conclusion: Genotypes known to cause low MBL plasma levels are not associated with an increased risk of unexplained RPL.

Objective: The aim of this study is to analyze NLRP7 mutation frequency in 20 Mexican patients with recurrent hydatidiform moles (RHMs)., Patients: Twenty patients with RHMs, 50 couples with recurrent pregnancy loss (RPL), and 100 controls were included in the study. Molecular analysis of the NLRP7 coding region was performed in patients with RHMs. Restriction enzyme digestion analysis and direct sequencing of the identified mutations were performed in controls and patients with RPL., Results: Patients displayed between two and six moles, and 10 of them presented other forms of pregnancy loss. Twelve (60%) patients were homozygous for the missense mutation c.2248C > G (p.L750V), five (25%) patients were heterozygous for the p.L750V mutation and the c.1018 G > A (p.E340K) variant, and three (15%) patients were heterozygous for the c.1018 G > A (p.E340K) variant. Five (5%) control women and four women and one man (5%) with RPL were heterozygous for the p.L750V mutation and two (2%) patients with RPL were heterozygous for the p.E340K variant., Conclusions: A total of 60% of our RHM patients presented homozygous p.L750V mutations, 25% were compound heterozygotes for p.L750V mutation and the p.E340K variant, and 15% were heterozygous for p.E340K variant. Heterozygous p.L750V mutations were frequently observed in our population. Homozygous mutations were also present in patients with RHMs. Additional studies are needed to understand the role of the p.E340K variant in RHMs and RPL., (© 2013 John Wiley & Sons, Ltd.)

Objective: To investigate whether kinase insert domain-containing receptor (KDR) gene polymorphisms are risk factors for recurrent spontaneous abortion (RSA) in Korean women., Design: Case-control study., Setting: University hospital., Patient(s): Three hundred twenty-seven idiopathic RSA patients and 230 controls with Korean ethnicity., Intervention(s): None., Main Outcome Measure(s): The KDR -604T→C (rs2071559), 1192G→A (rs2305948), and 1719A→T (rs1870377) polymorphisms were assessed., Result(s): KDR -604TC and TC+CC genotypes were more prevalent in RSA patients than in controls (adjusted odds ratio [AOR] = 2.091 and 2.076, respectively). KDR -604TC+CC/1192GG, -604TC+CC/1719AA, and -604TC+CC/1719TA+TT combined genotypes exhibited higher frequencies in RSA patients (AOR = 2.422, 2.611, and 2.216, respectively). KDR -604C/1192G/1719A, -604C/1192G/1719T, -604C/1192G, -604C/1719A, and -604C/1719T haplotype frequencies were higher in RSA patients (OR = 1.778, 2.659, 2.089, 1.678, and 1.806, respectively), whereas -604T/1192G/1719A, -604T/1192G, and -604T/1719A haplotype frequencies were lower in RSA patients (OR = 2.422, 2.611, and 2.216, respectively). No association was found between RSA and KDR 1192G→A or 1719A→T., Conclusion(s): An association between the KDR -604T→C polymorphism and RSA was found in Korean women. Carriers of the -604C variant allele were more frequent among RSA patients than among controls, suggesting that KDR -604C may confer RSA risk. The association of 1719A→T with RSA that was found in Taiwanese Han women was not observed in Korean women., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Recurrent pregnancy loss is an important clinical problem. Recently, high-level homocysteine in blood has been considered as a possible cause. Genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) have been proved to be the common hereditary factors of high-level homocysteine. The association between MTHFR polymorphisms and unexplained recurrent pregnancy loss (URPL) has been reported but with controversial results. The purpose of present study is to collect and analyze published available data, and evaluate the association between MTHFR polymorphisms and URPL., Methods: A meta-analysis was performed to examine the association between MTHFR polymorphisms (C677T and A1298C) and URPL. Odds ratio (OR) and its 95% confidence interval (CI) were used in each study of genotype and allele contrast., Result(s): MTHFR C677T: The analysis included 3559 URPL cases and 5097 healthy controls. Overall random-effects odds ratios (ORs) were 1.68 (95% CI, 1.32-2.13; P<0.0001) for TT versus total genotypes, 1.35 (95% CI, 1.04-1.76; P=0.0224) for TT and CT genotype combined versus total genotypes and 1.34 (95%CI, 1.13-1.58; P<0.0001) for T versus total alleles. Although significant heterogeneity was found in C677T, it became weaker in the East Asian subgroup and the mixed subgroup when separated by ethnic subgroups. The results showed significant association between MTHFR C677T and URPL in the East Asian subgroup (ORs 2.11 for TT versus total genotype (P=0.0004) and 1.53 for T versus total alleles (P<0.0001)) and in the mixed subgroup (ORs 3.47 for TT versus total genotypes (P<0.0001) and 1.80 for T versus total alleles (P<0.027)), but not in Caucasian subgroup. MTHFR A1298C: The study involved 1163 URPL cases and 1061 healthy controls. Overall random-effects odds ratios (ORs) were 1.37 (95% CI, 0.71-2.67; P=0.3456) for CC versus total genotypes, 1.16 (95%CI, 0.98-1.38; P=0.0833) for CC+AC versus total genotypes and 1.04 (95%CI, 0.84-1.29; P=0.7112) for C versus total alleles. No significant association between MTHFR A1298C polymorphism and URPL was found., Conclusions: These results indicate a significant association between MTHFR C677T mutation and URPL in the East Asian subgroup and mixed subgroup, but no significance in MTHFR A1298C mutation., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A fine balance between coagulation and fibrinolysis is critical in early pregnancy. Plasminogen activator inhibitor-1 (PAI-1) and angiotensin converting enzyme (ACE) are involved in the fibrinolytic process, and several studies have reported the association between their gene polymorphisms and recurrent pregnancy loss (RPL). This study was conducted to investigate the association between PAI-1 and ACE polymorphisms and idiopathic RPL, using meta-analyses. A systematic review of the published literature from the MEDLINE and EMBASE databases before April 2012 was conducted. Of 209 potentially relevant studies, 22 case-control studies comprising a total of 2,820 RPL patients and 3,009 controls were included. Among these studies were 11 reports of PAI-1 4G/5G and 11 of ACE I/D polymorphisms in patients with RPL. A significant association was found withthe ACE I/D polymorphism [summary odds ratio 1.29 (95% confidence interval 1.02-1.62)] in studies including more than two recurrent abortions. Subgroup analysis did not show significant associations with RPL in Caucasian and non-Caucasian patients. Meta-analyses of PAI-1 4G/5G polymorphism were not found associations with RPL in studies including more than two or three recurrent abortions, and in studies of Caucasian and non-Caucasian patients. In conclusion, meta-analyses showed a significant association between the ACE I/D polymorphism and idiopathic RPL. High clinical heterogeneity existed among studies of PAI-1 4G/5G, and the aggregated data failed to confer higher susceptibility to idiopathic RPL. More well-designed studies with different ethnic populations are required for future integration.

Aims: Th1 and Th2 balance is crucial for maintenance of pregnancy, and intracellular JAK and STAT proteins significantly contribute to it. In view of evidence linking JAK2 and STAT3 variants with recurrent spontaneous miscarriage (RSM), here we investigated the association of JAK2 (rs2230724) and STAT3 (rs1053023 and rs1053004) to RSM susceptibility in Tunisians., Subjects and Methods: A retrospective case-control study. Subjects comprised 235 RSM cases and 235 control subjects. JAK2 and STAT3 were genotyped by the allelic discrimination method., Results: STAT3 rs1053023 and, to a lower extent, rs1053004 were significantly associated with RSM under the additive and dominant, but not recessive models. This remained significant after adjustment for the covariates age, smoking, and gravida. In contrast to STAT3 variants, JAK2 rs2230724 was not associated with RSM under any of the genetic models tested. Two-locus STAT3 (rs1053023/rs1053004) haplotype analysis revealed increased frequency of the C/G haplotype in patients with RSM. Multivariate regression analysis confirmed the association of C/G haplotype with RSM (p=0.001; odds ratio=2.01; 95% confidence interval=1.32-3.07), thus conferring RSM susceptibility nature. These differences remained significant after applying the Bonferroni correction for multiple testing (Pc=0.004)., Conclusions: STAT3 rs1053023, more so than the STAT3 rs1053004 or JAK2 rs2230724 polymorphisms, is associated with RSM risk.

We investigated the contribution of JAK2 rs2203724 and STAT3 rs1053023 and rs1053004 to the susceptibility of idiopathic recurrent miscarriage (IRM) in Bahraini (246 cases and 279 controls) and Tunisian (235 cases and 235 controls) Arabs. The distribution of JAK2 rs2203724 and STAT3 rs1053023 genotypes were in Hardy-Weinberg equilibrium (HWE) in both communities, while mild deviation from HWE was noted for rs1053004 in Tunisians but not Bahraini. JAK2 rs2203724 was not associated with IRM in either community, while STAT3 rs1053023 was positively associated with IRM in both Bahraini and Tunisian women. STAT3 rs1053004 displayed mixed association: it was positively associated with IRM in Bahraini (P < 0.001), but not Tunisian women (P = 0.10). Genotype association confirmed the association of both STAT3 variants with IRM under additive, dominant, and recessive models, while the association of STAT3 rs1053023 was seen under additive and dominant, but not recessive models in Tunisians. The contribution of JAK2 and STAT3 variants to IRM susceptibility must be evaluated regarding specific variants, and the ethnic/racial background.

Background: Recurrent pregnancy loss (RPL) had said to be related to the angiotensin converting enzyme insertion/deletion polymorphisms (ACE I/D) gene polymorphisms. But the conclusions were controversial. This meta-analysis was conducted to investigate the real association in ACE I/D polymorphisms and RPL firstly., Methods: Combine Pubmed Embase and HuGENet database in data analysis for this meta-analysis from October 2000 to November 2011. The metagen system was used to select the models and effects. Odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of this association., Results: 9 studies from six countries with 1264 RPL and 845 controls were included according to our criterion. Following the metagen system, we used the dominant model with random effects. The summary OR =1.61 (95% CI: 1.10-2.36, I (2) = 59.0%), which suggested the ACE D allele might increase the RPL risk in Asia (OR=1.97, 95% CI: 1.31-2.98, I (2) = 44.4%), among Asians (OR=1.69, 95% CI: 1.06-2.36, I (2) =32.7%). In additional, after conducting sensitivity analysis, the results had no differences except for Caucasian subgroup reached to the significance (OR=2.059, 95% CI: 1.455-2.914), so we couldn't ignore the relationship between the polymorphisms of ACE D/I gene and Caucasians yet. There seemed no publication bias in our eligible studies with Begg's test (P = 0.867)., Conclusions: Results in this meta-analysis presented the positive function of the ACE I/D polymorphism in increasing the RPL risk. Furfure prospective studies were needed to confirm the precise relationship between the ACE I/D and RPL.

Objectives: To investigate the association of 1082G > A(RsaI) (rs1256049) and 1730A > G(AluI) (rs4986938) single nucleotide polymorphisms(SNPs), respectively - located on estrogen receptor β (ESR2) gene with recurrent spontaneous abortion (RSA) in Chinese population., Methods: The study group consisted of 196 patients with RSA and 182 fertile women as control. Two functional polymorphisms 1082G > A (a silent mutation in exon 5) and 1730A > G (3' nontranslated region of the exon 8) of ESR2 were studied by association analysis., Results: There were no significant differences between ESR2 gene polymorphisms and RSA (χ(2) =1.793, P=0.408; χ(2) =.432, P=0.489, respectively)., Conclusion: The present data indicate that the studied SNPs on ESR2 gene may not be associated with RSA in Chinese population.

Constitutional chromosomal aberrations contribute to infertility and repeated miscarriage leading to reproductive failure in couples. These aberrations may show no obvious clinical manifestations and remain undetected across multiple generations. However, infertility or recurrent spontaneous pregnancy loss, and/or genotypic/phenotypic aberrations may be manifested in the progeny during gametogenesis. The current study was a retrospective analysis to examine the chromosomal aberrations and prevalence in 2000 couples of Indian ethnicity with reproductive failure. Cytogenetic analysis via conventional G-band karyotyping analysis was carried out on phytohaemagglutinin stimulated peripheral blood lymphocytes, cultured in RPMI1640 medium. The chromosomes were enumerated as per International System for Human Cytogenetic Nomenclature at 500-550 band resolution, and recorded in the screening sheets. Chromosomal aberrations were detected in a total of 110 (2.78%) couples, with structural chromosomal aberrations in 88 cases including reciprocal translocations in 56 cases, Robertsonian translocations in 16 cases, inversions in eight cases, deletions in three cases, derivative chromosomes in five cases and numerical chromosome aberrations in 23 cases. The study emphasizes the importance of cytogenetic work up in both the partners associated with a history of reproductive failure. Genetic counselling with an option of prenatal diagnosis should be offered to couples with chromosomal aberrations., (Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Recurrent miscarriage is often unexplained. In our study, we test the hypothesis that unexplained recurrent miscarriage is associated with premature ovarian ageing by comparing the basal follicle-stimulating hormone (FSH) level between women with recurrent miscarriage and a control group of subjects in two different ethnic centres: one in Guangzhou, China and the other in Sheffield, UK. The subjects were stratified into three different age groups, and all of them were under the age of 40 years. We found no significant difference in basal FSH level between the subjects and the control groups, and the proportion of women with high FSH (>10 IU/l) was higher in the Guangzhou cohort but not in the Sheffield cohort. Our observation suggests that premature ovarian ageing is not a significant contributory factor of recurrent miscarriage, but a study on the ethnic variation in the aetiology of recurrent miscarriage is needed.

Background: C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) has been associated with recurrent pregnancy loss (RPL). However, results were conflicting. The aim of this study was to quantitatively summarize the evidence for MTHFR C677T polymorphism and RPL risk., Methods: Electronic search of PubMed and the Chinese Biomedicine database was conducted to select studies. Case-control studies containing available genotype frequencies of C677T were chosen, and odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of this association., Results: The case-control studies including 2427 cases and 3118 controls were identified. The meta-analysis stratified by ethnicity showed that individuals with the homozygous TT genotype had increased risk of RPL (OR=1.574, 95% CI: 1.163-2.13, p=0.003), in Asians (OR=1.663, 95% CI: 1.012-2.731, p=0.045). Results among Caucasians did not suggest an association (OR=1.269, 95% CI: 0.914-1.761, p=0.155). A symmetric funnel plot, the Egger's test (p=0.285), and the Begg's test (p=0.529) were all suggestive of the lack of publication bias. The studies conducted in each of the defined number of pregnancy losses-two or more pregnancy losses, and three or more pregnancy losses-showed no effect of the C677T polymorphism on RPL except for the TT versus CT+CT genotype comparison for the three or more pregnancy loss subgroup (OR=1.792, 95% CI: 1.187-2.704, p=0.005)., Conclusion: This meta-analysis supports the idea that MTHFR C677T genotype is associated with increased risk of RPL, except for Caucasians. To draw comprehensive and true conclusions, further prospective studies with larger numbers of participants worldwide are needed to examine associations between MTHFR C677T polymorphism and RPL.

Objective: HSD3B1 gene encodes the 3β-hydroxysteroid deydrogenases/isomerase (3β-HSD) enzyme, which plays a crucial role in the biosynthesis of all hormonal steroids. The aim of this study was to examine the potential impact of a T → C substitution at codon Leu(338) of HSD3B1 gene on pregnancy outcome., Methods: In this prospective case-control study, 162 patients and 139 healthy controls were investigated for the possible association between the HSD3B1 T/C polymorphism and the risk of recurrent spontaneous abortions (RSA). The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used in order to genotype the subjects., Results: The frequencies of TT, TC, and CC genotypes were 0.20, 0.51, and 0.29, respectively, in the patient group and 0.20, 0.45, and 0.35, respectively, in the control group. The allele frequencies were 0.456 and 0.428 for T allele for the patient group and control group, respectively and 0.543 and 0.572 for C allele for the patient and control group, respectively. The data between the two groups were analyzed by chi-square test or Fisher's exact test. Our results showed that there are no significant differences in genotype (P = 0.56) or in allele frequencies (P = 0.51) between the patient and the control group., Conclusion: The HSD3B1 T/C polymorphism cannot be used as genetic marker for the risk for RSA in our Caucasian population.

Although there are plenty of evidence that single-nucleotide polymorphisms (SNPs) that fall within coding sequences of genes are involved in recurrent pregnancy loss (RPL), it is still unknown whether the polymorphisms in microRNAs (miRNAs) are related with RPL. In this study, we established this kind of association by confirming significant differences in genotype distribution of rs41275794 (P= 0.0005) and rs12976445 (P= 0.001) within the pri-miR-125a in 217 Han Chinese patients of RPL compared with 431 controls. Based on this observation, two-locus haplotypes were constructed and the A-T haplotype was found to be associated with an increased risk of RPL (OR=2.84, 95%C.I. 1.98-4.07, P=0.0000000057). Further analysis showed that the levels of pre- and mature- miR-125a were down-regulated in the cells transfected with the A-T haplotype, which was consistent with in vivo detection that the level of mature miR-125a was lower in 30 pregnant women with A-T haplotype than that with G-C haplotype. During in vitro RNA processing assays, we found a similar decrease in the amount of pre-miR-125a and decline in binding capacity of nuclear factors to pri-miR-125a with A-T haplotype. More importantly, the reduction in miR-125a, as a consequence of A-T haplotype, further led to less efficient inhibition of target genes, LIFR and ERBB2, which play important roles in the embryo implantation and decidualization. Thus, our data collectively suggest that two common polymorphisms in pre-miR-125a might contribute to the genetic predisposition to RPL by disrupting the production of miR-125a, which consequently interfered in the expression and function of target genes of miR-125a.

BACKGROUND Vascular endothelial growth factor (VEGF) and its kinase insert domain receptor (KDR) play an important role in angiogenesis, and their gene expression patterns also suggest a close relationship with early pregnancy. However, limited information is available regarding the role of the VEGF system, especially its KDR receptor, in recurrent pregnancy loss (RPL). This study was conducted to investigate a genetic association between VEGF and its receptor gene (KDR) with idiopathic RPL. METHODS In this case-control study, 115 women who had experienced at least two consecutive spontaneous miscarriages (n= 62 women with two miscarriages, n= 53 with three or more) and 170 controls were included. A total of 14 tag single-nucleotide polymorphisms (SNPs) of VEGF and KDR were selected from the HapMap Web site and three functional SNPs [rs1570360 (-1154G/A) of VEGF; rs2305948 (V297I) and rs1870377 (Q472H) of the KDR gene] were genotyped using primer extension analysis. We further used multifactor dimensionality reduction analysis to evaluate gene-gene interactions. RESULTS One tag SNP (rs6838752) and the functional SNP (Q472H) of the KDR gene were in complete linkage and showed significant differences between patients and controls (P< 0.05). The frequencies of haplotypes of VEGF (A-T-G haplotype) and KDR (A-C-A-T-G haplotype) showed significant differences in patients versus controls (P< 0.05). All comparisons with controls remained significant when the subgroup of women with three or more miscarriages was analyzed. CONCLUSIONS VEGF and its receptor gene (KDR) are associated with idiopathic RPL. The VEGF/KDR system jointly contributes to recurrent miscarriage in Taiwanese Han women.

Objectives: TNF-alpha is a critical cytokine produced by Th1 cells while altered T helper 1 (Th1)-Th2 balance is found crucial for a successful pregnancy., Study Design: A cohort of 132 Southern Chinese Han RSA patients and 152 controls constituted the subjects of this study. Two functional polymorphisms -308 and -238 of TNF-alpha were studied by association analysis., Results: lack of association was found in TNF-alpha -308 SNP yet a significant difference was discovered in -238 polymorphism., Conclusion: This study suggested that TNF-alpha may be a risk factor in Chinese RSA patients. However the ethnic differences may also contribute to the results.

The aim of this study was to examine the relationship between peripheral natural killer (NK) cells and recurrent miscarriage by improved methods. Peripheral NK cell measurement was carried out using flow cytometry of morning blood samples obtained in the early follicular phase, analysed within 8 h of collection. Eighty-five Chinese women with recurrent miscarriage who previously tested negative for autoantibodies, and 27 control subjects who were not using any hormonal methods for contraception, were recruited. No significant difference was found in the number of peripheral NK cells and their subsets between women with recurrent miscarriages and control subjects. Only 5% of women with recurrent miscarriage had high peripheral NK cells. The number of previous miscarriages did not appear to have an impact on the number of NK cells. In conclusion, there appears to be limited value in the routine measurement of peripheral NK cells in women with recurrent miscarriage.

It was the objective of this study to analyse the influence of confounders, such as ethnicity, severity of illness and method of testing, in articles concerning the still moot relationship of thrombophilias to adverse pregnancy outcome (APO). Relevant case-control studies were identified using Medline and EMBASE databases between 1966 and 2006. Search terms were recurrent fetal loss, intrauterine fetal death, preeclampsia, HELLP-syndrome, eclampsia, fetal growth restriction, abruptio placentae, combined with maternal thrombophilias. Data was extracted from the articles per subgroup of APO regardless of confounder. These subgroups were tested if they fulfilled the heterogeneity testing criterion (I(2) > 35%) to weigh the influence of the confounder. Confounders were selected and examined with Mantel-Haenszel method. Increased thrombophilia prevalence was confirmed in most adverse pregnancy outcomes. Ethnicity, genetic testing only and severity of illness were confounders in the various forms of APO. Stronger relationships between factor V Leiden and severity of disease were found in 2(nd) and 3(rd) trimester than 1(st) trimester recurrent fetal loss, in preeclampsia with: blood pressure > or =160/110 mmHg than > or =140/90 mmHg; proteinuria > or =5 grams per day than <5 grams; onset before than after 28 weeks, in fetal growth restriction <3(rd) percentile than <5(th), than <10(th), and in earlier occurrence of abruptio placentae than 3(rd) trimester. In conclusion, reports on the prevalence of maternal thrombophilias and APO are influenced by various confounders, which are not always appropriately analysed. The differences we have identified reflect the differential impact of these confounders. These data emphasise the importance of more uniform research.

Objective: To investigate whether A/G polymorphism at position 49 in exon 1 of cytotoxic T lymphocyte antigen-4 (CTLA-4) gene confers the susceptibility to unexplained recurrent spontaneous abortion in Chinese population., Methods: One hundred and sixty-eight restrictive Chinese women with unexplained recurrent spontaneous abortion (URSA) and 117 women with normal pregnancy as control were included in this study. Polymerase chain reaction restrictive fragment length polymorphism (PCR-RFLP) was used to detect the polymorphism at position 49 in exon 1 of CTLA-4 gene. The frequency of alleles G/A, genotypes AA/AG/GG and phenotypes A+ (AA + AG)/G+ (GG + AG) of CTLA-4 were compared between URSA patients and controls., Results: The different distributions of alleles G/A, genotype AA/AG/GG and phenotypes A+/G+ of CTLA-4 were observed between URSA patients and controls. The frequencies of both G allele [68.4% (230/336) vs 59.4% (139/234), P < 0.05] and GG genotype [48.8% (82/168) vs 33.3% (39/117), P < 0.05] were significantly higher in URSA group than that in control group, while the frequencies of AG genotype [39.3% (66/168) vs 52.1% (61/117), P < 0.05] and A+ (AA + AG) phenotype [51.2% (86/168) vs 66.7% (78/117), P < 0.05] were significantly lower in URSA group than that in control group., Conclusions: The results suggest that A/G polymorphism in exon-1 of CTLA-4 might confer the susceptibility to RSA in Chinese women.

Objective: Different prevalences of antiphospholipid antibodies (aPL) have been reported in different populations of patients with systemic lupus erythematosus (SLE). Chinese are generally believed to have lower risk of vascular thrombosis. We examined the prevalence of aPL including lupus anticoagulant (LAC), anticardiolipin (aCL) and anti-beta2-glycoprotein I (anti-beta2-GPI) antibodies, the level of thrombotic risk, and the association of aPL with thrombotic and pregnancy outcomes in a Chinese cohort with SLE at the university lupus clinic during the period 1986-2003., Methods: aPL were measured in 272 SLE patients, and medical records were reviewed for vascular thrombosis and pregnancy outcomes., Results: The prevalence of LAC, IgG aCL, and IgG anti-beta2-GPI antibodies was 22.4%, 29.0%, and 7.7%, respectively. There were 38 episodes of thrombosis after a mean duration of followup of 11.0 +/- 6.8 SD years, giving a thrombotic rate of 1.26/100 patient-years. All aPL were shown to be associated with vascular thrombosis. IgG anti-beta2-GPI antibodies were found to be associated with recurrent thrombosis [8.0/100 patient-years or 25.0% (7/28)]. Patients taking hydroxychloroquine were found to have fewer thrombotic complications than those who were not (OR 0.17, 95% CI 0.07-0.44; p < 0.0001). LAC was the strongest factor associated with recurrent miscarriages [relative risk 12.3, 95% CI 1.22-123.31; p = 0.03). The diagnosis of secondary antiphospholipid syndrome was satisfied in 8.9% of patients., Conclusion: The lifetime and recurrent thrombotic rates in our patients with aPL were not particularly different from those in the literature. However, the lower prevalence of aPL in our cohort may suggest a role of other prothrombotic factors in predisposition to thrombosis.

Recurrent spontaneous abortion (RSA) is regarded as a common pregnancy complication in southern Iran. The exact causes of RSA are not yet known. Transforming growth factor-beta1 (TGF-beta1) is produced by T regulatory lymphocytes (Treg), which play an important role in the physiology of pregnancy. Several polymorphisms of the TGF-beta1 gene have been reported, some with important correlation with disease severity. In this investigation, the polymorphism of the TGF-beta1 gene at promoter region positions -800 (G/A) and -509 (C/T) was studied in 111 RSA and 110 normal female subjects from southern Iran by PCR-RFLP. Results indicated that at position -800 (G/A) polymorphism, 75.7% of RSA cases and 77.3% of normals were homozygote GG. In addition, 23.4% of cases and 22.7% of normal individuals were heterozygote AG. Only one of the patients appeared to be homozygote AA. None of the normal individuals were found to be homozygote AA at this position. In the case of the -509 (C/T) polymorphism, 38.7% of patients and 28.2% of controls were homozygote CC. While 40.6% of cases and 50.9% of normal individuals were heterozygote CT, 20.7% of RSA cases and 20.9% of controls were homozygote TT. The results indicate that there are no statistically significant differences of genotype distribution and allele frequency between RSA cases and controls at both polymorphic sites. In conclusion, the promoter region polymorphisms of TGF-beta1 at positions -800 (G/A) and -509 (C/T) may not be associated with RSA.