Recurrent Pregnancy Loss Research Articles

Intraoperative ultrasound for uterine septum resection: a systematic review and meta-analysis.

Septate uterus is one of the most common uterine malformations. Recent studies suggest that uterine septa may negatively affect fertility. In cases of recurrent pregnancy loss (RPL) or infertility, hysteroscopic metroplasty has been considered the primary treatment for septate uterus. This systematic review and meta-analysis aims to evaluate whether intraoperative ultrasound monitoring may improve the efficacy of hysteroscopic metroplasty compared to other types of intraoperative monitoring or to unguided resections. An electronic database search was performed to identify articles published until June 15, 2023. Five studies (two randomized clinical trials, two prospective studies and one retrospective cohort study) fulfilled the inclusion criteria. The primary outcome was the rate of residual septum > 10mm after hysteroscopic metroplasty in the ultrasound (US) monitoring group compared to the rate of residual septum using other types of intraoperative monitoring/no monitoring (control group). The secondary outcomes were any residual septa, surgical time, complications, uterine perforations and reproductive outcomes. Intraoperative ultrasound for uterine septum resection significantly reduced the rate of residual septum > 10mm and the rate of any residual septa compared to the control group. There was no statistically significant difference in the procedure time between women undergoing intraoperative US monitoring versus the control group. A trend toward reduction of surgical complications was observed in the intraoperative US group compared to the control group. In conclusion, intraoperative ultrasound during metroplasty may reduce the rate of the residual septum with no surgical time differences. Further studies are warranted to understand how this may improve reproductive outcomes.

Recurrent Early Pregnancy Loss and Congenital Thrombophilia: A Prospective Study

Background/Objectives: This study aims to investigate the role of congenital single nucleotide thrombophilia in young females with early recurrent pregnancy loss (RPL). Methods: We studied 120 pregnant females with RPL and 80 matched females as a control with no RPL. Females were aged ≤ 35 years, had at least two consecutive first-trimester RPLs, and the acquired cause of RPL was excluded. A matched control group of 80 pregnant women with no RPL was studied. Coagulation tests included prothrombin time (PT), partial thromboplastin time (PTT), thrombin time (TT), a Factor XIII functional assay, and detecting IgM and IgG anti-beta2-Glycoprotein I (β2GPI) antibodies by an ELISA. The DNA samples were tested for Factor V Leiden, Factor II G20210A, Methylenetetrahydrofolate reductase (MTHFR C677T, A1298C), FXIII V34L, plasminogen activator inhibitor-1 (PAI-1) 4G/5G, endothelial protein C receptor (EPCR) A4600G, and endothelial protein C receptor (EPCR) G4678C. Results: Of the single nucleotide gene mutations investigated, the most relevant mutations were MTHFR C677T, MTHFR A1298C, heterozygous FXIII Val34Leu, and heterozygous FXIII 1694 C>T. Each of them conferred a statistically significant effect. There was a statistically significant protective role for the endothelial protein C receptor (EPCR) A2/A2, wild FXIII Val34Leu, and heterozygousFXIII1694 C>T. Conclusions: Our findings suggest the important role of congenital single nucleotide thrombophilia mutations in young Middle Eastern women with early RPL, particularly MTHFR mutations and FXIII Val34Leu. We found a protective effect of EPCR A2/A2, wild FXIIIVal34Leu, and heterozygous FXIII1694 C>T. We recommend additional studies to explore detrimental factors and protective factors.

Complex chromosomal rearrangements in female carriers experiencing recurrent pregnancy loss or poor obstetric history and literature review.

Complex chromosomal rearrangements (CCRs) often remain unidentified as they are rarely observed in the general population. Females with CCRs are generally recognized on the identification of an affected child with multiple congenital anomalies (MCA) or having a history of repeated pregnancy loss/bad obstetric history (RPL/BOH). In contrast, males with CCRs are diagnosed primarily due to infertility. This study aimed to carry out a systematic epidemiological analysis of CCRs in one of the largest series from the Indian population. In addition, a review of the literature on female CCR carriers experiencing RPL/BOH has been compiled in an attempt to identify the genomic landscape of breakpoints, commonly involved chromosomes, and the breakpoint regions. A total of 8560 healthy individuals with normal physical and mental well-being and had no history of any obvious genetic disorder at the time of presentation were referred for chromosome analysis in view of RPL/BOH between 1994 and 2024. Of them, 8158 had a normal chromosome complement whereas, 402 (4.7%) showed chromosomal aberrations. CCRs were detected in seven individuals, i.e., one partner in each of seven couples with structural rearrangements, all of whom were females. Comprehensive characterization of CCR was carried out using various molecular cytogenetic techniques. Seven CCR carriers had a total of 25 pregnancies: 20 leading to miscarriages (80%), one leading to the birth of an abnormal child (4%), two medically terminated pregnancies (8%) due to abnormal antenatal findings, and the remaining two were healthy (8%). A total of 13 different chromosomes with 24 non-recurring breakpoints were identified in these cases. Chromosome (#) 2 showed four breaks (16.7%), followed by #1, #4, #6, and #13 with three breaks each (12.5% each), while one break each (4.2% each) was seen on the remaining eight chromosomes (#3, #5, #8, #11, #14, #15, #17, and #21). Type I and type IV CCRs were observed in five (71.4%) and one case (14.3%), respectively, along with a "not a true" CCR (14.3%) in the present study group. Overall, the prevalence of CCRs in couples with RPL/BOH was 0.16%. To the best of our knowledge, this is the first study on the epidemiology of CCRs in couples with RPL/BOH of Indian origin. The incidence of CCRs in couples experiencing RPL/BOH in the present cohort was found to be 0.16% with type I CCR being the most predominant of all types, which is congruent with observations from non-Hispanic white and South East Asian populations. The uniqueness and rarity of each CCR pose a challenge in genetic and reproductive counseling.

Effect of vitamin D adjuvant therapy on the proportion of regulatory T cells in peripheral blood and pregnancy outcome of patients with recurrent miscarriage.

Recurrent miscarriage (RM) is influenced by immune factors, particularly regulatory T cells, which can impact immune function and miscarriage risk. Vitamin D (VD) is known to regulate the immune system, potentially improving pregnancy outcomes in RM patients. This study aims to assess the effect of VD adjuvant therapy on regulatory T cells and pregnancy outcomes in RM patients. Clinical data from 104 individuals with RM admitted to our hospital between March 2022 and February 2023 were allocated at random to either the VD group (VDG) or the control group (CG), with 52 patients in each group. Both groups received standard treatment; the CG was treated with aspirin, while the VDG received additional VD therapy. Outcomes measured included regulatory T cell proportion, metabolic factors, immune inflammatory markers, and pregnancy outcomes. After treatment, the proportion of regulatory T cells in VDG was considerably higher (p < 0.05). Additionally, triglyceride levels, leptin, fasting blood glucose, and fasting insulin were lower in the VDG, whereas adiponectin levels were higher (p < 0.05). Levels of progesterone, luteinizing hormone, and 25-hydroxy VD were also higher in the VDG (p < 0.05). Furthermore, interleukin-17, gamma interferon, tumor necrosis factor-α, and C-reactive protein were lower in the VDG (p < 0.05). The pregnancy success rate in the VDG was higher, and the preterm birth rate was lower (p < 0.05). Adjuvant treatment with VD can increase the proportion of regulatory T cells in peripheral blood of individuals with recurrent abortion, regulate metabolic disorder, alleviate immune inflammation, and improve pregnancy outcome.

Potential shared gene signatures and molecular mechanisms between recurrent pregnancy loss and ovarian cancer

Potential shared gene signatures and molecular mechanisms between recurrent pregnancy loss and ovarian cancer

Compromised C3b-VSIG4 axis between decidual NK cells and macrophages contributes to recurrent spontaneous abortion.

NK cells and macrophages constitute the predominant immune cell subsets in the decidua during the first trimester of pregnancy, with macrophages typically adopting an anti-inflammatory phenotype. Conversely, in the third trimester, macrophages undergo a shift towards a pro-inflammatory phenotype concurrent with a reduction in NK cell numbers. The direct regulatory impact of NK cells on macrophage phenotype remains poorly explored. In our investigation, we observed that ICAM1+ macrophages stimulate the expression of intracellular C3 in LFA1+ decidual NK cells. Notably, Cathepsin W within NK cells exhibit the potential to generate active C3b fragments, effectively inhibit the proinflammatory phenotype of macrophages by binding to VSIG4. Our study unveils a direct regulatory mechanism orchestrated by decidual NK cells over macrophages, providing a potential pathogenic explanation for recurrent spontaneous abortion.

Effect of online problem-solving counseling on the sexual anxiety and intimacy of women with recurrent pregnancy loss: A clinical trial

Effect of online problem-solving counseling on the sexual anxiety and intimacy of women with recurrent pregnancy loss: A clinical trial

CD163 Expression in Chronic Intervillositis of Unknown Etiology and SARS-CoV-2 Placentitis.

Chronic intervillositis of unknown etiology (CIUE) is an aberrant maternal inflammatory infiltrate comprised primarily of macrophages that collect in the intervillus space and is associated with poor outcomes including recurrent pregnancy loss. An abnormal maternal Th1-type response to pregnancy may be the basis for pathogenesis of CIUE but macrophage in the maternal infiltrate of CIUE have been reported to have an anti-inflammatory M2 phenotype characterized by increased expression of CD163. This study assesses expression of CD163 in CIUE and SARS-CoV-2 placentitis, which has a similar histopathological presentation, using an automated approach to minimize observer-related variability. The data show that the maternal inflammatory infiltrate of CIUE contains a blended population of high and low CD163 expressing macrophage with a prominent bias towards an anti-inflammatory M2 phenotype when compared to normal control tissue. A similar pattern is seen in SARS-CoV-2 placentitis, suggesting pathophysiologic similarity with CIUE, although SARS-CoV-2 also appears to promote decreased CD163 expression in Hofbauer cells, which is not seen in CIUE.

Association of the miR-143 Gene rs353292 Polymorphism with Recurrent Pregnancy Loss in Caucasian Women: A Novel Finding in a Multifactorial Devastating Problem

Association of the miR-143 Gene rs353292 Polymorphism with Recurrent Pregnancy Loss in Caucasian Women: A Novel Finding in a Multifactorial Devastating Problem

MAGNETIC RESONANCE IMAGING IN DIAGNOSIS AND CLASSIFICATION OF MULLERIAN DUCT ANOMALIES: CASE SERIES

Objectives: Mullerian duct anomalies (MDAs) arise from the aberrant development of the uterus, cervix, and vagina, impacting the potential for successful conception and full-term pregnancy. This category encompasses a diverse range of developmental defects, leading to a spectrum of clinical presentations such as amenorrhea, infertility, recurrent miscarriages, intrauterine growth retardation, malposition of the fetus, preterm labor, and retained placenta. Case(s): In this study, we present 17 cases of MDA with a wide array of clinical manifestations. The varied symptoms included amenorrhea, infertility, repeated miscarriages, intrauterine growth retardation, malposition of the fetus, preterm labor, and retained placenta. Accurate categorization of these cases is crucial for determining the appropriate surgical intervention. While ultrasonography aids in the initial diagnosis of MDA, our focus on accurate classification necessitates the use of magnetic resonance imaging (MRI). Conclusion: Our findings underscore the significance of MRI in precisely categorizing MDA, and facilitating effective management strategies. The 17 cases presented demonstrate the diverse spectrum of MDA manifestations, emphasizing the need for tailored surgical interventions for successful conception and optimal pregnancy outcomes. The use of MRI proves instrumental in guiding clinical decisions, offering a comprehensive understanding of MDA, and informing targeted interventions to enhance reproductive success.

Seroprevalence and Molecular Detection of Cytomegalovirus UL146 and US28 Gene Expression in Women With Recurrent Pregnancy Loss

Seroprevalence and Molecular Detection of Cytomegalovirus UL146 and US28 Gene Expression in Women With Recurrent Pregnancy Loss

Impaired inducibility of immune regulatory capacity of peripheral B cells of patients with recurrent pregnancy loss.

The pathogenesis of recurrent pregnancy loss (RPL) is unclear. RPL may have an association with disruption of immune tolerance. The aim of this study is to characterize the inducibility of immune regulatory ability in peripheral naïve B cells of patients with RPL. In this study, blood samples were taken from patients with RPL. B220+ B cells were isolated by flow cytometry cell sorting. The gene profile of B cells was analyzed using RNA sequencing (RNAseq). The results showed that peripheral B220+ B cells of RPL patients had lower expression of IL10 and exacerbated ER stress. The induction of IL10 expression in peripheral B220+ B cells of RPL patients were impaired. High ubiquitination of c-Maf inducing protein (CMIP) was detected in RPL B cells. Exposure to thapsigargin (an ER stress agonist) decreased the amount of CMIP in B cells. The effects of ER stress on reducing CMIP quantity in B cells were mediated by the histone H2B E3 ubiquitin ligase ring finger protein 20 (RNF20). Inhibition of RNF20 or ER stress restored the inducibility of immune regulatory functions of B220+ B cells of RPL patients. In summary, peripheral B cells in patients with RPL show impaired immune regulation capacity, in which exacerbated ER stress plays a crucial role. Regulation of ER stress or inhibition of RNF20 can restore the immune regulatory capacity in the B cells.

The effect of hereditary thrombophilia on recurrent pregnancy loss: a retrospective cohort study

ObjectiveThrombophilia screening has been performed in patients with conditions such as previous fetal death, (fetal growth restriction) FGR, preeclampsia, (hemolysis. elevated liver enzyme, low platelet count) HELLP Syndrome, previous abruptio placentae, previous thrombosis in pregnancy, and abnormal placental histology. The actual role of hereditary thrombophilia in recurrent pregnancy loss (RPL) is still debated. This study was intended to determine the incidence of specific gene defects for hereditary thrombophilia and to ascertain their impact on RPL in central Anatolia in Turkey.MethodsThis retrospective cohort study was performed between January 2012 and December 2022. All pregnant women with a complete hereditary screening profile were included. The investigated gene polymorphisms were methylenetetrahydrofolate reductase (MTHFR) C677T, MTHFR A1298C, Factor V Leiden G1691A, and Factor II prothrombin G20210A. Cases of pregnant women at least two or more consecutive pregnancy losses before 22 weeks of gestation were defined as RPL. The rates of genetic screening and their association with RPL were analyzed.ResultsRPL was identified in 224 (27.58%) of the 812 pregnant women with complete genetic screening. Although there was no difference in terms of age, body mass index, numbers of ectopic pregnancies, molar pregnancies, or dilatation & curettage (p > 0.05), gravity (2.0 [2.0–3.0] vs. 4.0 [3.0–5.0]), parity (1.0 [1.0–2.0] vs. 1.0 [0–1.0]), live birth (1.0 [1.0–2.0] vs. 1.0 [0–1.0]), anembryonic pregnancy (0 [0–0] vs. 0 [0–0]), miscarriage (0 [0–1.0] vs. 3.0 [2.0–3.0]), and stillbirth (0 [0–0] vs. 0 [0–0]) numbers differed significantly between the groups (p < 0.05). While no significant differences were determined in MTHFR A1298C, Factor V Leiden, factor II prothrombin G20210A, or homocysteine levels (p > 0.05), the homozygous MTHFR C677T positivity rates differed significantly (6.3% in the non-RPL group vs. 11.6% in the RPL group, p = 0.027) .ConclusionThe homozygous MTHFR C677T polymorphisms was found to be more frequent in women with RPL. Further studies with larger cohorts are needed to confirm our results.

Analysis of Pregnancy Outcomes in Patients Exhibiting Recurrent Miscarriage With Concurrent Low-Titer Antiphospholipid Antibodies.

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombotic events and adverse pregnancy outcomes, often associated with elevated antiphospholipid antibodies (aPLs). The 2023 ACR/EULAR criteria for APS necessitate persistent medium to high titers of aPLs for laboratory confirmation. However, the impact of persistently low-titer aPLs in recurrent miscarriage (RM) patients remains controversial. This study aims to analyze the effect of treatment on pregnancy outcomes and maternal-fetal complications in patients with low-titer aPLs. The study encompassed 252 pregnancies in 237 RM patients tested for aPLs at the Third Hospital of Guangzhou Medical University from January 2018 to July 2022. Patients were divided into two groups based on aPLs titers: 86 with low-titer aPLs (92 pregnancies) and 151 aPLs-negative (160 pregnancies). Of the low-titer group, 71 received treatment, while 21 and all aPLs-negative patients did not. Seventy-one treated patients with low-titer aPLs were divided into two groups. Group A (n = 15) received a standard treatment regimen that included low-dose aspirin (LDA) and low-molecular-weight heparin (LMWH). In contrast, Group B (n = 56) received a multidrug regimen, which included hydroxychloroquine (HCQ) and/or glucocorticoids (GC) and/or intravenous immunoglobulin (IVIG) in addition to the standard treatment of LDA and LMWH. Pregnancy outcomes and maternal-fetal complications were subsequently compared. The highest positivity rates were for aCL-IgM (76.2% in the untreated low-titer aPLs group and 81.7% in the treated low-titer aPLs group), followed by aβ2GPI-IgM (23.8% in the untreated low-titer aPL group and 11.4% in the treated low-titer aPLs group), and LA (5.6% in the untreated low-titer aPLs group and 3.3% in the treated low-titer aPLs group). Single antibody positivity was 90.5% in the untreated low-titer aPL group and 87.3% in the treated low-titer aPLs group, with double positivity at 9.5% in the untreated low-titer aPLs group and 12.7% in the treated low-titer aPLs group. No triple positivity was detected. The treated low-titer aPLs group had more previous miscarriages (p < 0.05) and a higher ANA positivity rate (p < 0.05) than the aPLs-negative group. Additionally, the treated low-titer aPLs group had lower complement levels than the aPLs-negative group. Immunoglobulin IgM levels were higher in both the untreated and treated low-titer aPL groups compared to the aPLs-negative group (p < 0.05). Post treatment, the live birth rate in the low-titer group significantly exceeded that of the untreated group (67.6%vs. 33.3%; p = 0.005). The miscarriage rate was notably lower in untreated low-titer patients compared to aPLs-negative patients (32.4%vs. 66.7%; p = 0.005). No significant differences were observed in maternal or fetal complications between the groups. In the standard treatment group (Group A), there were 8 (53.3%) live births, whereas the multidrug treatment group (Group B) had 40 (71.4%) live births, a significantly higher rate than in the standard treatment group, although the difference lacked statistical significance. The study indicates that untreated RM patients with low-titer positive aPLs have a higher recurrence of miscarriage compared to the aPLs-negative RM group. However, recurrence significantly decreases following appropriate intervention, suggesting the benefits of treatment for RM patients with low-titer aPLs.

Serum Anti-Müllerian Hormone does not predict adverse perinatal outcomes in a cohort of women diagnosed with recurrent pregnancy loss

Serum Anti-Müllerian Hormone does not predict adverse perinatal outcomes in a cohort of women diagnosed with recurrent pregnancy loss

Methylation aberrations in partner spermatozoa and impaired expression of imprinted genes in the placentae of early-onset preeclampsia

IntroductionDisturbed paternal epigenetic status of imprinted genes has been observed in infertility and recurrent spontaneous abortions. Shallow placentation has been associated with early-onset preeclampsia. Hence, the present study aimed to investigate the methylation patterns of imprinted genes involved in placental development, in the spermatozoa of partners of women experiencing preeclampsia. MethodsThe study involved recruitment of couples into preeclampsia (n = 14) and control (n = 25) groups. Methylation analysis of imprinted gene differentially methylated regions (DMRs) and LINE1 repetitive element was carried out by pyrosequencing in the spermatozoa and placental villi. Global 5mC levels in the spermatozoa were measured through ELISA. Expression of imprinted genes was quantified in the placental villi by real time qPCR. Association of birth weight with DNA methylation and gene expression was assessed. ResultsKvDMR, PEG3 DMR, PEG10 DMR and DLK1-GTL2 IG-DMR were differentially methylated in the spermatozoa and placental villi of preeclampsia group. Global 5mC content and LINE1 methylation levels did not differ between the spermatozoa of the two groups. Increased transcript levels of PEG3, IGF2, DLK1, PHLDA2 and CDKN1C were observed in the preeclamptic placental villi. Birth weight showed significant association with KvDMR, PEG10 DMR, DLK1-GTL2 IG-DMR and LINE1 methylation levels in the spermatozoa. DLK1 expression levels showed a negative association with birth weight. DiscussionThe study highlighted the paternal contribution to early-onset preeclampsia, in the form of disrupted sperm DNA methylation patterns at imprinted gene loci. These loci, after further evaluation in future studies, could serve as sperm-based preeclampsia predictive markers, for couples planning pregnancy.

The Value of Parental Karyotyping in Recurrent Pregnancy Loss Lies in Individual Risk Assessments

Background and Objectives: Recurrent pregnancy loss (RPL) is a multifactorial condition, encompassing genetic, anatomical, immunological, endocrine, as well as infectious and environmental factors; however, the etiology remains elusive in a substantial number of cases. Genetic factors linked to RPL include parental karyotype abnormalities (e.g., translocations, inversions, copy number variants), an increase in sperm aneuploidy, fetal microchimerism, severe skewing of X chromosome inactivation, and various gene polymorphisms. Our study aims to explore the value of routine conventional parental karyotyping in couples with RPL. Materials and Methods: A total of 213 couples (426 individuals) with a history of RPL were enrolled in this retrospective study. The peripheral blood samples included in this study were referred to the Human Genomics Laboratory of the University of Medicine and Pharmacy in Craiova, Romania, for conventional cytogenetic analysis between January 2013 and December 2023, by the Outpatient Medical Genetics Clinic of the Emergency Clinical County Hospital of Craiova. Chromosome analysis was performed using standard protocols and karyotypes were reported according to ISCN. Results: Out of 426 patients provided with conventional G-banded chromosome analysis, 410 had a normal karyotype (96.2%) and 16 had chromosome abnormalities (3.8%). The most common chromosomal abnormalities were reciprocal and Robertsonian translocations, with chromosomes 8, 11, 14, and 21 being most frequently involved. A single numerical anomaly was detected (47,XYY). One or multiple chromosomal polymorphisms were identified in 104 subjects (24.4%). In addition, we conducted a stratified analysis of the unselected group and detected chromosome abnormalities in only four cases (0.94%). Conclusions: Our results are consistent with recommendations for paternal karyotyping after an individual risk assessment in instances such as a previous live birth with congenital anomalies and/or the detection of unbalanced chromosomes or a translocation in product of conception or chorionic villi/amniotic fluid samples. In the absence of a positive history, blindly karyotyping couples may prove too expensive and labor intensive, while providing no information on fertility status or live birth rates.

Effect of low-dose aspirin on mid-luteal phase uterine Artery blood flow in women with unexplained recurrent pregnancy loss

Objectives: As a possible therapy for recurrent pregnancy loss, this study sought to ascertain if low-dose aspirin was effective in increasing uterine artery blood flow. Study Design: This investigation was structured as a single-arm clinical trial Patients and Methods: All participants were aged 39 years or younger and had no prior or current indications of abnormal glucose tolerance, thyroid dysfunction, hyperprolactinemia, or Antiphospholipid antibody syndrome. Bilateral assessments of the Systolic/Diastolic (S/D) ratio, Resistive Index (RI), and Pulsatility Index (PI) were conducted in the chosen patients in the mid-luteal phase, before to and following a minimum of two weeks of low-dose aspirin administration. Results: The results of this investigation showed significant variation in the S/D and PI prior to and following aspirin administration. There was no discernible shift in RI. The analysis revealed a statistically significant reduction in uterine artery PI after aspirin administration (1.92±0.29) compared to the pre-treatment value (2.22±0.27), with a p-value of 0.0001. Remarkably, the pulsatility indices of the left and right uterine arteries did not significantly differ from one another. Conclusion: For women who have a history of miscarriages, low-dose aspirin can be recommended as an adjuvant therapy as it effectively improves uterine artery blood flow in these patients. However, more well-designed research is required to ascertain whether improved pregnancy outcomes are correlated with improved uterine perfusion. The current study supported the aspirin guideline for women with a history of recurrent miscarriages by showing that aspirin treatment resulted in a reduction in uterine artery PI.

Deciphering the link: A cutting-edge exploration of the intriguing connection between recurrent pregnancy loss and rare earth elements-Lutetium, praseodymium, samarium, dysprosium, and cerium.

To evaluate the levels of serum rare earth elements (REEs): lutetium [Lu], praseodymium [Pr], samarium [Sm], dysprosium [Dy], and cerium [Ce] in pregnant women with recurrent pregnancy loss (RPL) and evaluate their relationship with total antioxidant capacity (TAC) and 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of DNA damage. A case-controlled study was conducted on a cohort of 60 female participants, with first-trimester healthy pregnant women as the control group and pregnant women with a history of consecutive abortions as the recurrent pregnancy loss (RPL) group. Following blood collection, serum concentrations of Lu, Pr, Sm, Dy, and Ce were measured using an inductively coupled plasma mass spectrophotometer (ICP-MS). Oxidative stress and DNA damage were evaluated through TAC and DNA damage marker (8-OHdG). Serum levels of Lu, Pr, Sm, Dy, and Ce were higher in women with RPL compared with control (P < 0.001). Intriguingly, a strong significant negative correlation was observed between TAC and REEs (P < 0.05). Lu, Dy, and Ce demonstrated a significant positive correlation with increased DNA damage in the RPL group (P < 0.05). Contrary, there was no evidence of a correlation between 8-OHdG and Pr and Sm. The study highlights a potential association between Lu, Sm, Dy, and Ce and an increased risk of RPL, highlighting REE-induced toxicity as a major risk factor for RPL. The outcome of the study is to advance our understanding of the interplay between rare earth elements and RPL, with potential implications for reproductive medicine, environmental health, and the development of preventive strategies for individuals at risk of RPL.

Impact of Vitamin D deficiency on immunological and metabolic responses in women with recurrent pregnancy loss: focus on VDBP/HLA-G1/CTLA-4/ENTPD1/adenosine-fetal-maternal conflict crosstalk

Background and aimRecurrent pregnancy loss (RPL), also known as recurrent implantation failure (RIF), is a distressing condition affecting women characterized by two or more consecutive miscarriages or the inability to carry a pregnancy beyond 20 weeks. Immunological factors and genetic variations, particularly in Vit D Binding Protein (VDBP), have gained attention as potential contributors to RPL. This study aimed to provide insight into the immunological, genetic, and metabolic networks underlying RPL, placing a particular emphasis on the interactions between VDBP, HLA-G1, CTLA-4, ENTPD1, and adenosine-fetal-maternal conflict crosstalk.MethodsA retrospective study included 198 women with three or more consecutive spontaneous abortions. Exclusion criteria comprised uterine abnormalities, endocrine disorders, parental chromosomal abnormalities, infectious factors, autoimmune diseases, or connective tissue diseases. Immunological interplay was investigated in 162 female participants, divided into two groups based on their Vit D levels: normal Vit D-RPL and low Vit D-RPL. Various laboratory techniques were employed, including LC/MS/MS for Vit D measurement, ELISA for protein detection, flow cytometry for immune function analysis, and molecular docking for protein–ligand interaction assessment.ResultsGeneral characteristics between groups were significant regarding Vit D and glucose levels. Low Vit D levels were associated with decreased NK cell activity and downregulation of HLA-G1 and HLA-G5 proteins, while CTLA-4 revealed upregulation. VDBP was significantly downregulated in the low Vit D group. Our findings highlight the intricate relationship between Vit D status and adenosine metabolism by the downregulation of SGLT1, and NT5E, key components of adenosine metabolism, suggests that Vit D deficiency may disrupt the regulation of adenosine levels, leading to an impaired reproductive outcome. HNF1β, a negative regulator of VDBP, was upregulated, while HNF1α, a positive regulator, was downregulated in low Vit D women after RPL. Molecular docking analysis revealed crucial residues involved in the interaction between Vit D and HNF1β.ConclusionCollectively, these findings underscore the importance of Vit D in modulating immune function and molecular pathways relevant to pregnancy maintenance, highlighting the need for further research to elucidate the mechanisms and potential therapeutic interventions for improving pregnancy outcomes in individuals with Vit D deficiency and RPL.