Risk Of Recurrent Pregnancy Loss Research Articles

Association between cytokine polymorphisms and recurrent pregnancy loss: A review of current evidence.

Cytokines are a type of protein that play an important role in the immune response and can also affect many physiological processes in the body. Cytokine polymorphisms refer to genetic variations or mutations that occur within the genes that code for cytokines, which may affect the level of cytokine production and function. Some cytokine polymorphisms have been associated with an increased risk of developing certain diseases, while others may be protective or have no significant effect on health. In recent years, the role of cytokine polymorphisms in the development of recurrent pregnancy loss (RPL) has been studied. RPL or miscarriage is defined as the occurrence of two or more consecutive pregnancy losses before the 20th week of gestation. There are diverse causes leading to RPL, including genetic, anatomical, hormonal, and immunological factors. With regard to cytokine polymorphisms, a few of them have been found to be associated with an increased risk of RPL, for instance, variations in the genes that code for interleukin-6, tumor necrosis factor-alpha, and interleukin-10. The exact mechanisms by which cytokine polymorphisms affect the risk of recurrent miscarriage are still being studied, and further research is essential to fully understand this complex condition. This brief review aims to summarize the recent literature on the association between cytokine polymorphisms and RPL.

Maternal-Fetal Compatibility in Recurrent Pregnancy Loss.

Nowadays, recurrent pregnancy loss (RPL) is an undesirable condition suffered by many patients of reproductive age. In this scenario, certain immune cell populations and molecules, involved in maternal-fetal compatibility, have emerged as factors related with the pathogenesis of RPL. Among them, uterine Natural Killer cells (uNKs) appear to be of great relevance. These cells are involved in numerous processes during pregnancy, such as the remodeling of uterine spiral arteries or the control of trophoblast invasion. These functions are regulated by the interactions that these cells establish with the extravillous trophoblast, mainly through their Killer Immunoglobulin-like Receptors (KIRs) and the Human Leukocyte Antigen-C (HLA-C) molecules expressed by the embryo. A high level of polymorphism has been reported for both molecules involved in this interaction, with some of the possible KIR-HLA-C combinations being associated with an increased risk of RPL. However, the complexity of the maternal-fetal interface goes beyond this, as other HLA molecules also appear to be related to this reproductive pathology. In this review, we will discuss the role of uNKs in pregnancy, as well as the polymorphisms and clinical implications of KIR-HLA-C binding. We will also address the involvement of other, different HLA molecules in RPL, and the current advice on the appropriate management of patients with 'immunological mismatch', thus covering the main aspects regarding the involvement of maternal-fetal compatibility in RPL.

Regulatory role of miR-125a expression with respect to its target genes LIFR, ERBB2 and STAT3 in the pathogenesis of recurrent pregnancy losses.

Studies have investigated miR-125a for its predictable role in recurrent pregnancy loss (RPL) cases to regulate many biological events required for the maintenance of pregnancy by regulating its confirmed target genes LIFR, ERBB2 and STAT3. The present study included 40 cases of women with at least two RPLs in ≤20 weeks of gestation against 40 healthy multiparous women without a previous history of abortion. Expression analysis of ERBB2, LIFR, STAT3 and miR-125a was conducted by quantitative real-time PCR (qPCR). The expression of miR-125a was significantly lower in the plasma of RPL cases (P = 0.0001) and showed a significantly increased mean expression level in product of conception (2.56-fold, P < 0.0001). Among the target gene of miR-125a, ERBB2 and STAT3 gene expression level was significantly increased (2.58-fold, P = 0.04; 1.87-fold, P = 0.025), respectively in RPL cases while the LIFR gene revealed comparable expression (P = 0.64). Furthermore, expression analysis of ERBB2 gene with respect to its regulatory miR-125a cases depicted a significant association (P = 0.0005). Kaplan-Meier survival analysis revealed cases with low miR-125a expression had significantly shorter time to miscarriages, (log-rank P = 0.02). Also, decreased expression of miR-125a significantly conferred >2-fold increased risk for RPL (HR = 2.34: P < 0.05). The overall conclusion of the study was that altered miR-125a expression may cause deregulation in target genes LIFR, ERBB2 and STAT3 resulting in adverse consequence in the outcome of pregnancy.

Centromeric AA motif in KIR as an optimal surrogate marker for precision definition of alloimmune reproductive failure

Throughout pregnancy, the decidua is predominantly populated by NK lymphocytes expressing Killer immunoglobulin-like receptors (KIR) that recognize human leukocyte antigen-C (HLA-C) ligands from trophoblast cells. This study aims to investigate the association of KIR-HLA-C phenotypes in couples facing infertility, particularly recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF), in comparison to a reference population and fertile controls. This observational, non-interventional retrospective case–control study included patients consecutively referred to our Reproductive Immunology Unit from 2015 to 2019. We analyzed the frequencies of KIR and HLA-C genes. As control groups, we analyzed a reference Spanish population for KIR analysis and 29 fertile controls and their male partners for KIR and HLA-C combinations. We studied 397 consecutively referred women with infertility and their male partners. Among women with unexplained RPL (133 women) and RIF (176 women), the centromeric (cen)AA KIR genotype was significantly more prevalent compared to the reference Spanish population (p = 0.001 and 0.02, respectively). Furthermore, cenAA was associated with a 1.51-fold risk of RPL and a 1.2-fold risk of RIF. Conversely, the presence of BB KIR showed a lower risk of reproductive failure compared to non-BB KIR (OR: 0.12, p < 0.001). Women and their partners with HLA-C1C1/C1C1 were significantly less common in the RPL-Group (p < 0.001) and RIF-Group (p = 0.002) compared to the control group. Moreover, the combination of cenAA/C1C1 in women with C1C1 partners was significantly higher in the control group than in the RPL (p = 0.009) and RIF (p = 0.04) groups, associated with a 5-fold increase in successful pregnancy outcomes. In our cohort, the cenAA KIR haplotype proved to be a more accurate biomarker than the classic AA KIR haplotype for assessing the risk of RPL and RIF, and might be particularly useful to identify women at increased risk among the heterogeneous KIR AB or Bx population. The classification of centromeric KIR haplotypes outperforms classical KIR haplotypes, making it a better indicator of potential maternal–fetal KIR-HLA-C mismatch in patients.

The paternal role in pregnancy loss.

In this comprehensive review, the intricate relationship between paternal factors and pregnancy loss is examined. While pregnancy loss has historically been predominantly attributed to maternal factors, recent research underscores the significant contribution of the male partner. The review delves into various aspects of paternal influence, including paternal age, health, chromosome abnormalities, Y chromosome deletions, and sperm DNA fragmentation. Notably, advanced paternal age is found to be associated with an increased risk of recurrent pregnancy loss, shedding light on the importance of understanding the impact of aging on male fertility. Additionally, paternal health, particularly metabolic syndrome, emerges as a noteworthy factor contributing to pregnancy loss. Chromosome abnormalities in male partners, such as balanced translocations, and Y chromosome microdeletions are explored in the context of pregnancy loss risk. Moreover, the review highlights the growing body of evidence linking sperm DNA fragmentation and sperm protein abnormalities to spontaneous pregnancy loss, emphasizing the significance of sperm health in reproductive outcomes. Overall, this review provides a comprehensive overview of the multifaceted role of the male partner in pregnancy loss, calling for a more inclusive approach to pregnancy loss investigations that encompasses both maternal and paternal factors.

Maternal HLA class II alleles and haplotypes associated with altered risk of recurrent pregnancy loss: A case‐control study

AbstractProblemThis study analyzed the contribution of DRB1, DQB1, and DPB1 HLA class II alleles and resulting 3‐locus haplotypes to the overall risk of idiopathic recurrent pregnancy loss (RPL).Method of studyThe study participants included 188 Tunisian participants comprising 84 women with established diagnoses of RPL, and 104 matched multiparous females as controls. Genotyping of HLA alleles was done by PCR‐SSP.ResultsThe allelic frequencies of DPB1, DRB1, and DQB1 were consistent with Hardy‐Weinberg equilibrium among control subjects. Among class II alleles, DRB1*04:01:01 (p = .03), DRB1*08:01:01 (p = .04), and DPB1*01:01:01 (p = .04) were positively associated, whereas DPB1*04:01:01 (p = .012) and DPB1*14:01:01 (p = .006) were negatively associated with risk of RPL. The association of DRB1 and DPB1 alleles with RPL was lost after correction for multiple comparisons. The prevalence of the seven determined DQB1 alleles was not significantly different among case and control groups. Higher prevalence of DRB1*07:01:01∼ DQB1*02:01:01∼DPB1*04:01:01 (0.0417 vs. 0.000; p = .049) coupled with lower prevalence of DRB1*13:01:01∼DQB1*06:01:01∼DPB1*02:01:01 (0.0167 vs. 0.1000; p = .014) haplotypes was noted in women with RPL, thus could be considered as an RPL at‐risk and RPL‐protective haplotype, respectively.ConclusionThe study establishes weak/no contribution of class II alleles and corresponding 3‐locus haplotypes to the altered risk of RPL among Tunisian women and does not confirm previous findings on other Arab‐speaking populations of an HLA association with RPL.

Influence of forkhead box protein 3 gene polymorphisms in recurrent pregnancy loss: A meta-analysis

BackgroundTreg 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. MethodologyWe 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. ResultsWe 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.

PGT-A: What Is Its Value in Treating Recurrent Pregnancy Loss?

PGT has been widely applied in the world, but its effectiveness for the treatments of recurrent pregnancy loss is still inconclusive. There is currently no consensus over the precise definition of RPL, according to the ESHRE guideline in 2022, a diagnosis of Recurrent Pregnancy Loss (RPL) could be considered after the loss of two or more pregnancies. The etiology of RPL is complex and highly heterogeneous, the higher proportion of embryo aneuploidy is an important reason, which can be affected significantly by maternal age. RPL has been listed as one of the common indications for PGT-A worldwide. However, the new RPL guideline by EHSRE in 2022, indicated that limited evidence for PGT in couples with RPL shows no clear benefit of treatment with very low quality. We reviewed the published studies, three retrospective studies showed that PGT-A may improve live birth rate for RPL patients, while two studies showed negative results. Most importantly, there were no randomized studies published on the application of PGT-A among RPL couples. Our data also showed similar cumulative live birth rates between PGT-A group and the control, regardless of maternal age, but PGT-A may favour in reducing miscarriage recurrence risk for RPL couples over 37 years old who obtained transferrable embryos. The presence of mosaic embryos and false positive/negative results, which can cause a high rate of cycle cancellation, may be the main reasons that compromise the efficacy of PGT-A. The cost-effectiveness of PGT-A is another important concern. In conclusion, there is still no sufficient evidence to support whether PGT-A can effectively improve the pregnancy outcomes for RPL couples, and proper-designed RCT is required in the future.

Role of the CD40–CD40L expression level pathway in the diagnosis of unexplained recurrent pregnancy loss

Background Unexplained recurrent spontaneous pregnancy loss (URPL) lacks effective treatment and reliable early diagnosis and prediction. Immunologic dysfunction can be an underlying cause of recurrent pregnancy loss (RPL). Considering the regulatory role of CD40–CD40L in immune responses, we explored its clinical significance in URPL. Methods The 108 women with URPL who were treated in Hebei Yanda Hospital from January 2020 to December 2022 were selected as study subjects, and another 108 healthy women who were not pregnant and matched with the age and body mass index of the study group were selected as the control group. CD40 and CD4 + CD25 + Treg cells in peripheral blood mononuclear cells (PBMCs) and CD40L in peripheral blood platelets were measured by flow cytometry. The predictive value of CD40–CD40L in URPL for the risk of RPL was determined by receiver operating characteristic (ROC) curves. The correlations of CD40–CD40L with CD4 + CD25 + Treg cells and serum pro-inflammatory factors were assessed by Pearson’s analysis. Results CD40 on the surface of PBMCs and CD40L on the surface of platelets were up-regulated in URPL patients. CD40 in combination with CD40L had high predictive value for the risk of RPL in URPL patients. Peripheral blood CD40–CD40L was positively linked to IL-17 and IL-23, and negatively to CD4 + CD25 + Treg cells and IL-10 in URPL patients. Conclusions The CD40–CD40L pathway expression in peripheral blood can help predict the risk of RPL in URPL patients.

Novel nucleotide variations in the thrombomodulin (THBD) gene involved in coagulation pathways can increase the risk of recurrent pregnancy loss (RPL)

Recurrent pregnancy loss (RPL) is a common but complex complication in fertility conditions, affecting about 15–20% of couples. Although several causes have been proposed for RPL, it occurs in about 35–60% of cases without a known explanation. A strong assumption is that genetic factors play a role in the etiology and pathophysiology of PRL. Therefore, several genes are proposed as candidates in the pathogenesis of RPL. The current study aimed to investigate the effects of nucleotide changes in the THBD (thrombomodulin) gene as an RPL-related candidate gene. This gene encodes a cell receptor for thrombin and is involved in reproductive loss in RPL cases. Its involvement in the natural anticoagulant system has been extensively studied. By genetic screening of the entire coding and noncoding regions of the THBD gene, we found twenty-seven heterozygous and homozygous nucleotide changes. Ten of them led to amino acid substitutions, seven variants were identified in the promoter region, and eight of them occurred in 3′UTR. Potentially, the pathogenicity effects of these variations on THBD protein were evaluated by several prediction tools. The numerous genomic variations prompted noticeable modifications of the protein’s structural and functional properties. Furthermore, in-silico scores were consistent with deleterious effects for these mutations. The results of this study provide genetic information that will be useful in the future for clinicians, scientists, and students to understand the unknown causes of RPL better. It may also pave the way for developing diagnostic/prognostic approaches to help treat PRL patients.

Oxidative/nitrosative stress increased the risk of recurrent pregnancy loss–Taiwan Recurrent Pregnancy Loss and Environmental Study (TREPLES)

ObjectiveOxidative stress biomarkers (OSBs) may be strongly associated with disease progression and recurrent pregnancy loss (RPL). However, the research on associations of most OSBs (e.g., 8-nitroguanine [8-NO2Gua] and 4-hydroxy-2-nonenal-mercapturic acid [HNE-MA]) with RPL is limited. Therefore, we aimed to investigate the effect of OSBs exposure on RPL risk by performing a case-control study. Material and methodsWe use our established dataset, Taiwan Recurrent Pregnancy Loss and Environmental Study (TREPLES), which included 514 Taiwanese reproductive age women (aged 20–50 years; 397 cases and 117 controls) from National Cheng Kung University Hospital. RPL is clinically defined by a history of two or more consecutive miscarriages, where a miscarriage is defined as the termination of pregnancy before 20 weeks of gestation. The urinary levels of several OSBs (e.g., 8-hydroxy-2′-deoxyguanosine [8-OHdG], 8-NO2Gua, 8-isoprostaglandin F2α [8-isoPGF2α], and HNE-MA) and malondialdehyde (MDA) were measured using isotope dilution liquid chromatography-tandem mass spectrometry and thiobarbituric acid reactive substances, respectively. ResultsThe median levels of 8-NO2Gua (6.15 vs. 3.76 ng/mL) and HNE-MA (30.12 and 21.54 ng/mL) were significantly higher in the RPL group than in the control group. By categorizing the OSBs data into tertiles, after we adjusted for age and urine creatinine levels discovered that the RPL risk associated with 8-NO2Gua and HNE-MA levels in the third tertile were approximately 2 times higher than those in the first tertile (8-NO2Gua, adjusted OR = 3.27, 95 % CI = 1.66–6.43; HNE-MA, adjusted OR = 1.96, 95 % CI = 1.05–3.64; p < 0.05). These findings suggest that the oxidative stress biomarkers of 8-NO2Gua and HNE-MA are risk factors for RPL. ConclusionOur findings indicate that specific OSBs are associated with an increased RPL risk, suggesting that reducing OSB levels can improve RPL risk. Nevertheless, more studies on preventive medicine are required to understand the exposure sources and adverse outcome pathways of OSBs associated with RPL.

Association of IL-17 and IL-27 polymorphisms with susceptibility to recurrent pregnancy loss and pre-eclampsia: A systematic review and meta-analysis.

Recurrent pregnancy loss (RPL) and pre-eclampsia (PE) are immune-related pregnancy complications that have been linked to CD4+ T cells and their cytokines, which can be influenced by genetic polymorphisms. This meta-analysis aimed to investigate the relationship between interleukin (IL)-17 and -27 polymorphisms and the susceptibility to RPL and PE. All eligible case-control studies published up to February 2023 were identified by searching PubMed, EMBASE, Cochrane, Web of Science, and Google Scholar. The risk of recurrent pregnancy loss and PE associated with the IL-17 rs2275913, IL-17 rs763780, IL-27 rs153109, and IL-27 rs17855750 polymorphisms were estimated for each study. The meta-analysis incorporated a total of 13 studies. The overall analysis indicated that IL-17 rs2275913, IL-17 rs763780, IL-27 rs153109, and IL-27 rs17855750 polymorphisms were not significantly associated with immune-related pregnancy complications, including RPL and PE. However, when the analysis was stratified by disease type, the IL-17 rs2275913 polymorphism was found to be associated with an increased risk of RPL (recessive model AA/GA + GG: OR = 1.68, 95% confidence interval [CI]: 1.13-2.49, p = .01). The IL-17 rs763780, IL-27 rs153109, and IL-27 rs17855750 polymorphisms were not significantly associated with RPL and PE, whereas the IL-17 rs2275913 polymorphism was associated with the susceptibility to recurrent miscarriage.

Thyroid autoimmunity and future pregnancy outcome in women of recurrent pregnancy loss: a meta-analysis.

Thyroid autoimmunity (TAI) has been associated with the risk of recurrent pregnancy loss (RPL). This systematic review and meta-analysis was conducted to evaluate the influence of TAI on subsequent pregnancy outcome of women with RPL. A systematic search of Medline, Web of Science, and Embase was conducted to identify studies evaluating the influence of TAI on subsequent risk of pregnancy loss (PL) in women with RPL. Study quality was evaluated via the Newcastle-Ottawa Scale. A random-effects model was utilized to pool the results, accounting for heterogeneity. Ten observational studies were included. Compared to women without thyroid autoantibodies, RPL women with TAI had a higher risk of PL in their subsequent pregnancy (risk ratio [RR]: 1.46. 95% confidence interval [CI]: 1.20 to 1.78, p < 0.001; I2 = 35%). Sensitivity analyses showed consistent results in studies with thyroid peroxidase antibody positivity (RR: 1.50, 95% CI: 1.23 to 1.82) and in studies with TAI assessed before pregnancy (RR: 1.28, 95% CI: 1.07 to 1.53). Subgroup analyses showed that the results were not significantly different in prospective and retrospective studies, in RPL defined as at least two or three PL, in euthyroid women and women with euthyroidism or subclinical hypothyroidism, in women with and without levothyroxine treatment, in studies reporting first-trimester or overall PL, and in studies with different quality scores (p for subgroup difference all > 0.05). In women with RPL, positive for TAI may be related to a higher risk of PL in subsequent pregnancy.

The role of the HLA-complex genes in genesis of human idiopathic recurrent pregnancy loss

Aim.To study the immunogenetic prerequisites of idiopathic recurrent spontaneous pregnancy losses in humans of allo- and autoimmune genesis. Methods. PCR-SSP (polymerase chain reaction with sequence-specific primers). Results. A comprehensive analysis of the distribution and frequency of allelic variants of the HLA-DRB1, HLA-DQA1, HLA-DQB1 genes testifies to an increased risk of recurrent pregnancy losses with a total homology of 50 % or more in couples and presence of the DQ2.5 genotype in a woman. The OR indicates that the risk of idiopathic recurrent spontaneous pregnancy loss increases 2.68 times when the homology of the couples is 50 % or more for two loci (HLA-DRB1, HLA-DQA1) and 12.8 times when the homology is 50 % or more for by three loci (HLA-DRB1, HLA-DQA1, HLA-DQB1), and if the DQ2.5 genotype is present in women, this risk increases 4 times. Conclusions. HLA genotyping of married couples with a history of spontaneous pregnancy loss is important for preconceptional prevention of recurrent pregnancy losses.

Association of MTHFR gene polymorphism in preeclampsia and recurrent pregnancy loss: A case-control study from South India

BackgroundPreeclampsia (PE) and recurrent pregnancy loss (RPL), both of which affect maternal and reproductive health, are obstetrical-gynecological issues. Pregnancies that meet one or more of these criteria are considered high risk. This study aims to examine and understand how specific methylation within the MTHFR gene (rs 1,801,131 and rs 1,801,133) polymorphisms may contribute to preeclampsia and recurrent miscarriages in the South Indian population. MethodsA combination of recurrent pregnancy loss and preeclampsia were taken as a case (146), and healthy controls (152) were enrolled in the study. 5 ml of human blood was taken after getting consent from the participants. The DNA was isolated from the peripheral blood lymphocytes and genotyped using ARMS-PCR. ResultThe findings of this study suggest that the MTHFR gene (rs1801131) is not associated with PE and RPL risk. A significant association has been observed between rs1801133 and the derived allele T (OR = 0.6, 95% CI -0.4-0.8, p = 0.001). Furthermore, a p-value of 0.01 was calculated for the homozygous recessive genotype TT (OR = 0.5, 95% CI - 0.29-0.1). ConclusionsThe results of this study suggest that preeclampsia and recurrent pregnancies are more common among South Indian women who carry a variant of the MTHFR gene 1,801,133. According to the conclusion, higher sample sizes and a wider study are necessary to verify these findings. More diverse and valuable information can be obtained through large sample sizes and combined studies, allowing the results to be applied to a wide population.

P-507 Oxidative/Nitrative Stress Biomarkers Increased the Risk of Recurrent Pregnancy Loss

Abstract Study question Whether oxidative/nitrative stress biomarkers increased the risk of recurrent pregnancy loss (RPL)? Summary answer Patients with higher oxidative/nitrative stress biomarkers of 8-NO2Gua and HNE-MA had an increased risk of recurrent pregnancy loss compared with controls. What is known already In reproductive medicine, recurrent pregnancy loss (RPL) is a major problem including the most unknown and lack of evidence-based diagnostics and therapies. Certain oxidative stress markers play an important role in the progress of some diseases. In one study, subsequent increases in 8-OHdG levels in the RPL group indicated extensive DNA damage and the lipid peroxidation products dramatically increased before an abortion occurred. Large unknowns of other indicators of oxidative stress, such as markers of lipid peroxidation (8-isoPF 2α, HNE-MA, and MDA), and DNA damage (8-NO2Gua), are studied for their impacts on RPL. Study design, size, duration We used an established case-control study, the Taiwan Recurrent Pregnancy Loss and Environmental Study (TRIPLES), which included 514 reproductive age (20-50) women (including 397 cases and 117 controls) from obstetric clinics at National Cheng Kung University Hospital in southern Taiwan from 2013 to 2022. Participants/materials, setting, methods The physicians diagnosed two or more consecutive miscarriages before 20 weeks of pregnancy as RPL cases. They excluded uterine anomalies, maternal diseases, chromosomal abnormalities, polycystic ovarian syndrome (PCOS), premature ovarian failure, and endometriosis. As a control group, we included married women, who delivered at least one child without artificial reproduction, underwent laparotomy for other clinical reasons, and did not suffer from the above-mentioned gynecological diseases. Main results and the role of chance Recurrent pregnancy loss (RPL) groups were older (mean=35.13) and had more time to prepare for pregnancy (mean=10.66 months). Their marital status mainly was married, their household income exceeded around 33,000 USD, and they consumed coffee habits. The median oxidative/nitrative stress biomarkers of 8-NO2Gua and HNE-MA in the case group were significantly higher than those in the control group (6.15 and 30.12 vs. 3.77 and 21.54 ug/L, p&amp;lt;0.001), indicating that the oxidative stress biomarkers of 8-NO2Gua and HNE-MA could be an essential effect factor in RPL. By categorizing the data by tertile of oxidative/nitrative stress biomarkers, we found that the RPL risk was 3.19 times higher in the third tertile of log 8-NO2Gua than in the first tertile (OR: 3.19, 95% CI: 1.66–6.10) and that the RPL risk in log HNE-MA was higher in the third tertile (OR: 2.05, 95% CI: 1.12–3.74). After adjustment for age, time to pregnancy (months), and coffee drinking habits, the RPL risk in the third tertile of log 8-NO2Gua was 2.01 times significantly higher than that in the first tertile (AOR: 2.01, 95% CI: 1.00–4.04). Limitations, reasons for caution Limitation of a case-control study. The oxidative stress biomarkers 8-NO2Gua and HNE-MA were significantly higher in the RPL groups, however, the causes of oxidative stress (like multiple environmental exposures, etc.) remain more studies to elucidate. Wider implications of the findings We provided evidence for oxidative/nitrative stress biomarkers in RPL patients, which implies the reduction of oxidative/nitrative stress may improve the progress of RPL. As important information for preventive medicine, more studies are needed to understand the adverse outcome pathway of oxidative/nitrative stress in RPL. Trial registration number MOST 109-2314-B-400 −022 -MY3 and EM-112-PP-11

Evaluation of platelet parameters, coagulation markers, antiphospholipid syndrome, and thyroid function in palestinian women with recurrent pregnancy loss

BackgroundMultiple etiologies contribute to recurrent pregnancy loss (RPL) including immunological, endocrine, anatomical, genetic and infection but more than 50% of cases remain unexplained. Evidences of thrombotic and inflammatory processes were observed at maternal-fetal interface and considered pathological findings in most RPL cases including unexplained cases. This study aimed to evaluate the association between RPL and several risk factors: platelet parameters, coagulation factors, antiphospholipid syndrome, and thyroid function.MethodsThis is an unmatched case-control study that included 100 RPL and 100 control women. Anthropometric and health data were collected and a gynecologist examined participants to assure fitting the inclusion criteria. Platelet parameters [including Mean Platelet Mass (MPM), Concentration (MPC) and Volume (MPV)] and ratios (MPV/Platelet, MPC/Platelet, MPM/Platelet, Platelet/Mononuclear cells), coagulation markers [Protein C (PC), Protein S (PS), Antithrombin III, D-dimer], antiphospholipid antibodies [Anti-phospholipid (APA), Anti-cardiolipin (ACA) and anti-B2-glycoprotein 1], Lupus anticoagulant, Antinuclear antibodies, and thyroid function (Thyroid stimulating hormone and anti-thyroid peroxidase) were measured.ResultsMean ages of cases and controls at marriage were 22.5 years for both, and their current ages were 29.4 and 33.0, respectively. 92% of cases and 99% of controls aged blow 30 years at marriage. 75% of cases have 3–4 miscarriages and 9% have ≥ 7 miscarriages. Our results indicated significantly lower male/female age ratio (p = .019), PC (p = .036) and PS (p = .025) in cases compared to controls. Plasma D-dimer (p = .020) and antiphospholipid antibodies [ACA (IgM and IgG), APA (IgM)] were significantly higher in cases compared to controls. No significant differences were observed between cases and controls concerning APA (IgG), anti-B2-glycoprotein 1 (IgM and IgG), Lupus anticoagulant, Antinuclear antibodies, platelet parameters, thyroid markers, family history of miscarriage, consanguineous marriage, and other health data.ConclusionsThis is the first study that investigated the association between platelet, coagulation, antiphospholipid, autoimmune and thyroid parameters, and RPL in Palestinian women. Significant associations between male/female age ratio, PC, PS, D-dimer, ACA (IgM, IgG), APA (IgM) and RPL were observed. These markers could be used in evaluating RPL. These findings confirm the heterogeneous nature of RPL and emphasize the need for further studies to find out risk factors for RPL.

Thrombophilic gene polymorphisms and recurrent pregnancy loss: a systematic review and meta-analysis.

Recurrent pregnancy loss (RPL) is affecting 1-4% of women who conceive approximately, and no cause could be found in more than 50% of women suffering from RPL. Inherited thrombophilias have got increasing attention in women with unexplained RPL, so we aim to explore the relationship among these most common thrombophilic polymorphisms and RPL through a literature review and meta-analysis. Observational studies from PubMed, Embase, Cochrane, and Web of Science from 1997 to 7 April 2022 were searched. For each genetic variant, a fixed or random-effect model was used according to the heterogeneity test to calculate pooled ORs and 95% CIs for both dominant and recessive genetic models. Egger's line regression test was used to assess publication bias. The quality of the included articles was assessed by the Newcastle Ottawa scale. A total of 124 articles comprising 17,278 RPL patients and 16,021 controls were included. Results showed that hyperhomocysteinemia (MTHFR) C677T (dominant model: OR, 1.43; 95% CI, 1.25-1.64; recessive model: OR, 1.60; 95% CI, 1.36-1.87), MTHFR A1298C (dominant model: OR, 1.66; 95% CI, 1.26-2.18; recessive model: OR, 1.79; 95% CI, 1.42-2.26), PAI-1 4G/5G (dominant model: OR, 1.67; 95% CI, 1.36-2.06; recessive model: OR, 1.80; 95% CI, 1.39-2.32), angiotensin-converting enzyme I/D (OR, 1.23; 95% CI, 1.00-1.53), Factor XIII V34L (OR, 1.38; 95% CI, 1.02-1.87), and β-fibrinogen-455G/A (OR, 1.60; 95% CI, 1.02-2.51) were significantly associated with RPL. This study provides potentially useful clinical markers to evaluate the risk of RPL or to help unexplained RPL patients identify possible causes, which may allow for targeted treatment.

Assessment Of Endometrial Integrin Beta 5 In Women With Unexplained Recurrent Pregnancy Loss.

To examine the relationship between endometrial integrin beta 5 level and risk of recurrent pregnancy loss. The descriptive, prospective, observational, case-controlstudy was conducted at the Kafrelsheikh University Hospital, Egypt, from January to May 2022, and comprised women aged up to 35 years with at least 1 live birth delivery beyond 20-week gestation with normal thyroid and prolactin levels. Age-matched normal fertile women were enrolled as controls. All the participants were subjected to detailed history and complete clinical examination. Endometrial integrin beta 5 was assessed using an antibody sandwich enzyme-linked immunosorbent assay. Data was analysed using SPSS 20. Of the 50 subjects, 25(50%) were cases with a mean age of 26.72±2.64 years, and 25(50%) were controls with a mean age of 25.36±2.16 years. The integrin beta 5 level was significantly lower among the cases than the controls (p<0.05). The best cut-off level of serum integrin beta 5 was ≤2.5765 with area under curve 0.886, sensitivity 88%, specificity 76%, positive predictive value 78.6%, negative predictive value 86.4%, and accuracy 82%. Therewas an inverse correlationbetween endometrial integrinbeta 5 andthe risk ofrecurrentpregnancy loss.

Association of cytotoxic T-lymphocyte-associated protein 4 polymorphisms with recurrent pregnancy loss: A case-control study.

A large proportion of cases of recurrent pregnancy loss (RPL) are associated with immunological factors. This study investigated the association between single nucleotide polymorphisms of cytotoxic T-lymphocyte-associated protein (CTLA)-4 gene in women with a history of RPL compared to healthy women. A case-control study was performed on 2 groups consisting of 120 healthy women with no history of abortion and at least one delivery (control) and 120 women with a history of 2 or more primary RPLs (case). In addition, 5 mL of peripheral blood sample was taken from all subjects. The frequencies of CTLA-4 rs3087243 and rs231775 polymorphisms were assayed by restriction fragment length polymorphism polymerase chain reaction and rs5742909 using the high-resolution melting real-time polymerase chain reaction method. The mean age of the women in the control and RPL groups were 30.03 4.23 (range 21-37), and 28.64 3.61 yr (range 20-35), respectively. Pregnancy loss numbers ranged between 2-6 in women with a history of RPL, and between 1 and 4 in the successful pregnancy group. Statistical analysis showed a significant difference between the genotypes of GG and AG in the 2 groups in rs3087243 polymorphism (OR 1.00 for GG genotype and OR 2.87 for AG genotype, p = 0.0043). No significant difference was observed in the genotype frequencies of rs231775 and rs5742909 polymorphisms, of the 2 groups (p = 0.37, and p = 0.095), respectively. Our findings indicated that CTLA-4 polymorphism, rs3087243, might be associated with a risk of RPL in Iranian women.