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Reproductive failure (RF) is the inability to conceive or to carry a pregnancy to term, and its prevalence is not negligible. Pregnancy is a prothrombotic condition, which can be abnormally exaggerated in women with thrombophilia. Antiphospholipid syndrome is a cause of RF and effectively managed with heparin and aspirin. However, there are yet insufficient data in patients with RF and inherited thrombophilia. This review focuses on the significance of inherited thrombophilia and RF and the role of anticoagulants in pregnancy outcomes. A few randomized case‐control studies have investigated the effect of anticoagulation in RF with thrombophilia, and the results are yet debatable. Some inherited thrombophilia including mutations of factor V Leiden, prothrombin, and methylenetetrahydrofolate reductase and protein S deficiency are associated with RF and/or late pregnancy complications. There are several implications which influence the diagnosis and treatment. First, there is a lack of studies revealing appropriate thrombophilia markers and its cutoff values for RF specifically. Second, some thrombophilia markers change with sex and age. Lastly, the study designs of previous studies are heterogeneous in selecting the thrombophilia markers and drugs. Further studies to find adequate thrombophilia markers of RF are warranted and eventually elucidate the subgroups beneficial to anticoagulation treatment. [ABSTRACT FROM AUTHOR]

Aberrant apoptosis at the trophoblast–maternal interface and abnormal expression of Fas and Fas ligand (FasL) have been reported in complicated pregnancies with recurrent pregnancy losses (RPL) and preeclampsia. We assessed the prevalence of Fas and FasL genetic polymorphisms in Korean women with RPL and in fertile controls. In total, 306 women with RPL and 298 fertile controls were enrolled. Genotype distributions of Fas and FasL in RPL patients versus fertile controls were examined under the Hardy–Weinberg equilibrium. Fas −670 A/G genotype (AA versus AG versus GG, p = 0.340) and allele frequencies (A versus G, p = 0.412) were not different between the RPL and control groups. There was no difference in each Fas −1377 G/A and FasL −844 C/T genotype, and their allele frequencies. In addition, the unions of two zygosities of each genotype and their combined genotypes did not differ between two groups. No difference in the prevalence of Fas and FasL single-nucleotide polymorphisms (SNPs) was observed between women with RPL and fertile controls among Korean women. To determine the possibility of genetic polymorphisms in Fas and its ligand as risk factors for RPL, further studies in various races and a large study population are needed. [ABSTRACT FROM AUTHOR]

Since the first study was published reporting the candidate association between the prolactin receptor gene intron C/T polymorphism (rs37389) and recurrent miscarriage, no replication study has been performed. In this study, we investigated the role of the prolactin receptor gene C/T polymorphism in 311 Korean women with recurrent pregnancy loss and 314 controls. Genotyping for prolactin receptor gene intron C/T polymorphism was performed using a TaqMan assay. The significance of difference in the genotype distribution was assessed using a chi-square test, and continuous variables were compared using a Student’st-test. The genotype distribution of the prolactin receptor gene C/T polymorphism in the recurrent pregnancy loss group did not differ from that in the control group (CC/CT/TT rates were 49.8%/41.5%/8.7% and 52.5%/37.6%/9.9% for the recurrent pregnancy loss patient and control groups, respectively,p = .587). When the analysis was restricted to patients with three or more consecutive spontaneous miscarriages or patients without prior live birth, there were also no differences in the genotype distribution between these subgroups and controls. In conclusion, the findings of the current study suggest that the prolactin receptor gene intron C/T polymorphism is not a major determinant of the development of recurrent pregnancy loss.Impact statementWhat is already known: Many studies have investigated whether there is a genetic component for the risk of recurrent pregnancy loss. Recently, one study investigated whether genetic polymorphisms involved in the regulation of the hypothalamic-pituitary-ovarian axis would be associated with recurrent miscarriage. Among 35 polymorphisms in 20 candidate genes, genotype distribution with regard to the prolactin receptor gene intron C/T polymorphism (rs37389) differed between the recurrent miscarriage and the control groups. Since this study reporting the candidate association between the prolactin receptor gene and recurrent miscarriage, no replication study has been performed.What the results of this study add: The genotype distribution of the prolactin receptor gene C/T polymorphism in the recurrent miscarriage group did not differ from that in the control group.What the implications are of these findings: Our study may be useful in that it is the first replication study since the initial report of the association of prolactin receptor gene polymorphism with recurrent miscarriage. Although no association was found, the potential role of prolactin in pregnancy loss needs to be further investigated because prolactin and its receptor have been postulated to play an important role in the maintenance of normal pregnancy. [ABSTRACT FROM PUBLISHER]

Problem We investigated the therapeutic effect of intravenous immunoglobulin (IVIG) in women with recurrent pregnancy loss (RPL). Method of study This was a retrospective observational study. Total 189 RPL women who experienced ≥2 miscarriages were enrolled and investigated conventional etiologies, thrombophilia, and cellular immunity. Patients were divided into four groups; known etiology with (Gr1) and without cellular immune abnormality (Gr2), unknown etiology with (Gr3) and without cellular immune abnormality (Gr4). IVIG was administrated from early pregnancy to 30 weeks of gestation to women with cellular immune abnormality (Gr1 + Gr3). Results Cellular immune abnormalities (increased level or cytotoxicity of NK cells and Th1/Th2 ratio) were present in 111 of 189 RPL women (58.7%). Live birth rates of women with and without cellular immune abnormality were not different (Gr1 + Gr3, 84.8% versus Gr2 + Gr4, 89.7%). Furthermore, IVIG success rates were the same between Gr1 and Gr3, those who had cellular immune abnormality. Nevertheless lack of an appropriate control in this study, our IVIG outcome demonstrated better live birth rate compared with those of other investigators. Conclusion Treatment modalities stratified by underlying etiologies of RPL may improve pregnancy outcome. Administration of IVIG is likely to have clinical efficacy in RPL women with cellular immune abnormality. [ABSTRACT FROM AUTHOR]

Estrogen might play a key role in the maintenance of pregnancy. We investigated the role of the ER-β gene +1730 G/A, +1082 G/A, and CA repeat polymorphisms in Korean patients with recurrent pregnancy loss (RPL). Genotyping was performed using the TaqMan assay in 305 patients with at least two unexplained consecutive spontaneous miscarriages before 20 weeks of gestation and 299 controls. The genotype distributions of the ER-β gene +1082 G/A and +1730 G/A polymorphisms in the RPL group did not differ from those in the control group. When the analysis was restricted to patients with three or more consecutive spontaneous miscarriages, there were also no differences in the genotype distribution between this subgroup and controls. The number of CA repeats was distributed from 13 to 28 with two large peaks at 18 and 23 in patients with RPL and controls. Using the two major peaks as cut-offs, the allele distributions were compared between patients and controls. However, the distribution of ER-β gene CA repeats did not differ between women with recurrent miscarriage and controls. Findings of the current study suggest that the ER-β gene polymorphisms are not major determinants of the development of RPL in Korean women. 雌激素可能在妊娠维持中起关键作用。我们研究了在雌激素受体-β基因中的+1730 G/A, +1082 G/A及CA重复多态性在韩国复发性流产患者中的作用。基因分析使用TaqMan实验方法，选取305例至少有连续2次孕20周以前的不明原因的流产史的女性为病例组以及299例正常对照组。复发性流产组的雌激素受体-β基因中的+1082 G/A，+1730 G/A多态性基因分布与正常对照组没有区别。当分析仅限于有3次及以上连续自然流产史的患者时，在这个子组和对照组之间的基因型分布仍没有区别。复发性流产组和对照组中CA重复的数量分布从13到28，并且在18和23有两个主峰。以这两个主要的峰值作为临界，比较了两组之间等位基因的分布。然而雌激素受体-β基因中的CA重复的数量在复发性流产组和对照组中没有明显区别。目前的研究表明，雌激素受体-β基因的多态性不是韩国妇女复发性流产发展的主要决定性因素。 [ABSTRACT FROM PUBLISHER]

Problem Thrombophilia has been postulated to be a contributor to the pathophysiology of recurrent pregnancy loss (RPL). We investigated the role of the plasminogen activator inhibitor type 1 (PAI-1) 4G/5G and angiotensin converting enzyme (ACE) I/D polymorphisms in Korean patients with RPL. Method of study Genotyping was performed using the TaqMan assay in 227 RPL patients and 304 controls. Results The genotype distributions of both polymorphisms in the RPL group did not differ from those of controls. Because the frequency of being homozygous for ACE D/D and the PAI-I 4G/4G combination has been reported to be significantly higher in RPL patients, this was also analyzed. However, no significant difference was noted; 3.1% of RPL patients had both ACE D/D and PAI-I 4G/4G, as did 4.9% of controls ( P = 0.791). Conclusion The current study suggests that both polymorphisms, either alone or in combination, are not major determinants of the development of RPL in Korean women. [ABSTRACT FROM AUTHOR]

Inflammatory immune response plays a key role in reproductive failures such as multiple implantation failures ( MIF), early pregnancy loss, and recurrent pregnancy losses ( RPL). Cellular immune responses particularly mediated by natural killer ( NK), and T cells are often dysregulated in these conditions. Excessive or inappropriate recruitment of peripheral blood NK cells to the uterus may lead to cytotoxic environment in utero, in which proliferation and differentiation of trophoblast is hampered. In addition, inadequate angiogenesis by uterine NK cells often leads to abnormal vascular development and blood flow patterns, which, in turn, leads to increased oxidative stress or ischemic changes in the invading trophoblast. T-cell abnormalities with increased Th1 and Th17 immunity, and decreased Th2 and T regulatory immune responses may play important roles in RPL and MIF. A possible role of stress in inflammatory immune response is also reviewed. [ABSTRACT FROM AUTHOR]

Problem Th17 cells and Foxp3+ regulatory T ( Treg) cells have been proposed as new risk factors for recurrent pregnancy loss ( RPL). Intravenous immunoglobulin G ( IVIG) was reported to modulate various immune cells. In this study, we investigated the effect of IVIG on the levels of Th17 and Treg cells and pregnancy outcome in women with RPL. Method of study Thirty-seven pregnant women with RPL were enrolled in this study. All had cellular immune abnormality in preconceptional evaluation. Blood was drawn on the day of IVIG treatment and 1 week later from the study subjects during early pregnancy. The proportions of IL-17+ and Foxp3+ T cells were analyzed using flow cytometry. Results Study population was divided into four groups ( Q1- Q4) based on ascending order of the levels of Th17 and Foxp3+ T cells. IVIG down-regulated Th17 cells in the highest quartile, Q4 ( P = 0.001), and up-regulated CD4+ Foxp3+ T cells in Q1 and Q2 ( P = 0.025 and 0.029, respectively). In addition, Th17/ CD4+ Foxp3+ T cell ratio decreased in Q4 ( P = 0.040). We also found a positive trend between successful pregnancy outcome and CD8+ IL-17+ T cells before IVIG treatment ( P = 0.05). Conclusion Intravenous immunoglobulin G treatment modulated imbalance of Th17 and Foxp3+ Treg cells in pregnant RPL women with cellular immune abnormality. [ABSTRACT FROM AUTHOR]

Problem Dysregulated natural killer ( NK) immunity and T-cell immunity are associated with recurrent pregnancy loss ( RPL). We aim to define clinically relevant NK and T-cell parameters for RPL and determine their cutoff values. Methods of study Ninety-five women with RPL ( >3) including 42 idiopathic and 53 known-etiology RPL, and 29 age-matched fertile controls were enrolled. Peripheral blood immunophenotype, NK cell cytotoxicity ( NKC), and T-helper (Th) 1 and Th2 cytokine producing cell ratios (Th1/Th2) were measured using flowcytometry. The cutoff values were determined using Youden's J with likelihood ratio ( LR) >2. Results Natural killer cell percentage and NKC, TNF-α+ Th1 cells, and TNF-α/ IL-10 producing Th1/Th2 cell ratio were significantly higher in idiopathic RPL than controls. By the area under the curve ( AUC) analysis, NK cell percentage ( AUC = 0.691), NKC ( AUC = 0.649), TNF-α+ Th1 cells ( AUC = 0.681) and Th1/Th2 cell ratio ( AUC = 0.660) were highly specific for RPL. The cutoff values for NK cell percentage, NKC (E:T cell ratio 25:1), and TNF-α/ IL-10 producing Th1/Th2 cell ratio are 16.1, 23.8, and 36.2%, respectively. Seventy-six percent of idiopathic RPL showed at least one of more immune abnormalities by these criteria. Conclusion Differences in NK cell percentages, NKC and Th1/Th2 cell ratio differentiated RPL from fertile controls. [ABSTRACT FROM AUTHOR]

Objective The balance of apoptosis and proliferation is an important part in the embryonic development during pregnancy. It has been reported that the p53 gene plays a significant role in angiogenesis and placental development, namely in reproduction and is suggested as a potential mediator of pregnancy. This study was performed to investigate whether the genetic polymorphism of the p53 gene is associated with idiopathic recurrent pregnancy loss (RPL). Study design We conducted a case–control study in the Korean population. Study subjects consisted of 294 patients with idiopathic RPL and 300 postmenopausal controls. The genotyping for the p53 codon 72 polymorphism was performed using a Taqman assay. Continuous variables were compared using Student's t test and the χ 2 test was used to evaluate differences in the genotype distributions between the RPL and the controls. Results There were no significant differences in the genotype distributions or allele frequencies of the p53 codon 72 polymorphism between the RPL and control group. There was also no significant association between the p53 codon 72 polymorphism and RPL risk in both recessive (Pro/Pro vs. Arg-carriers, p = 0.314) and dominant model (Pro-carriers vs. Arg/Arg, p = 0.383: data not shown). Conclusion The codon 72 polymorphism in the p53 gene did not show any correlation with idiopathic RPL in Korean women, implying that it may not be susceptible allelic variants or be insufficient to cause RPL. [ABSTRACT FROM AUTHOR]