Pregnancy Loss Patients Research Articles

Investigating the complications of frequent pregnancy loss in patients referred to obstetrics and gynecology clinics at King Khalid University Hospital

ABSTRACT Background: Recurrent pregnancy loss (RPL) is a common problem affecting many women. This study aimed to investigate the baseline characteristics of 400 women with RPL and to examine any differences in baseline characteristics of the recruited women with RPL throughout the years. Methods: This study used retrospective data, which included the records of patients with RPL who visited King Khalid University Hospital’s obstetric clinic between 2019 and 2022. The records of 400 patients who met the inclusion criteria were reviewed and analyzed. Results: The mean age of enrolled women was 36.5 ± 5.4 years, and the mean RPL was 3.8 ± 2.5. The study also revealed that there were significant statistical differences in obesity and vitamin D deficiency among women with RPL based on year (P = 0.013 and P = 0.036, respectively), whereas no significant statistical differences were found between women with RPL in terms of age, parity, diabetes, hypothyroidism, hyperprolactinemia, antiphospholipid antibodies (APLs), uterine malformation, or consanguinity. Conclusion: Advanced maternal age, number of previous miscarriages, parity, diabetes, hypothyroidism, APLs, uterine malformations, first-degree consanguinity, and vitamin D deficiency were found to be significant risk factors associated with RPL among women in Saudi Arabia.

Intravenous immunoglobulin improves live birth rates in patients with unexplained recurrent pregnancy loss

This real-world study aimed to assess the clinical efficacy and safety of intravenous immunoglobulin (IVIG) in treating unexplained recurrent pregnancy loss (uRPL) patients. A total of 238 patients with uRPL were enrolled in this retrospective study. According to the treatment, patients were assigned into treatment group (n=184, receiving IVIG+low molecular weight heparin [LMWH]) and control group (n=54, only LMWH). The primary outcome was the live birth rates (LBR) after 24 weeks of gestation. In addition, we performed subgroup analyses to assess the LBR in uRPL patients with age (≥30 years or <30 years), body mass index (BMI, 18–24 kg/m2 or ≥24 kg/m2), number of previous pregnancy losses (2 or ≥3), gestational week of first medication, and IVIG medication regimen during pregnancy. The LBR showed a significant increase after IVIG treatment compared to the control group (77.7 % vs. 53.7 %, P=0.001). Multivariable logistic regression indicated that IVIG was associated with increased LBR (aOR=4.383, 95 %CI 2.024–9.489). Besides, we observed a significantly lower incidence of decreased platelet count (1.6 % vs. 7.4 %, P=0.049) in the treatment group. Subgroup analyses showed that IVIG treatment was associated with improved LBR in uRPL patients with age of <30 years (aOR=4.012, 95 %CI 1.428–11.266), previous pregnancy losses ≥3 times (aOR=17.327, 95 %CI 2.525–118.921), and BMI of 18–24 kg/m2 (aOR=8.914, 95 %CI 2.985–26.618). IVIG treatment significantly improves the LBR in uRPL patients. These findings from real-world data provide evidence for the safety and efficacy of IVIG as a viable treatment for uRPL patients in clinical practice.

A nomogram and risk stratification to predict subsequent pregnancy loss in patients with recurrent pregnancy loss.

Could the risk of subsequent pregnancy loss be predicted based on the risk factors of recurrent pregnancy loss (RPL) patients? A nomogram, constructed from independent risk factors identified through multivariate logistic regression, serves as a reliable tool for predicting the likelihood of subsequent pregnancy loss in RPL patients. Approximately 1-3% of fertile couples experience RPL, with over half lacking a clear etiological factor. Assessing the subsequent pregnancy loss rate in RPL patients and identifying high-risk groups for early intervention is essential for pregnancy counseling. Previous prediction models have mainly focused on unexplained RPL, incorporating baseline characteristics such as age and the number of previous pregnancy losses, with limited inclusion of laboratory and ultrasound indicators. The retrospective study involved 3387 RPL patients who initially sought treatment at the Reproductive Immunology Clinic of Renji Hospital, Shanghai Jiao Tong University School of Medicine, between 1 January 2020 and 31 December 2022. Of these, 1153 RPL patients met the inclusion criteria and were included in the analysis. RPL was defined as two or more pregnancy losses (including biochemical pregnancy loss) with the same partner before 28 weeks of gestation. Data encompassing basic demographics, laboratory indicators (autoantibodies, peripheral immunity coagulation, and endocrine factors), uterine and endometrial ultrasound results, and subsequent pregnancy outcomes were collected from enrolled patients through initial questionnaires, post-pregnancy visits fortnightly, medical data retrieval, and telephone follow-up for lost patients. R software was utilized for data cleaning, dividing the data into a training cohort (n = 808) and a validation cohort (n = 345) in a 7:3 ratio according to pregnancy success and pregnancy loss. Independent predictors were identified through multivariate logistic regression. A nomogram was developed, evaluated by 10-fold cross-validation, and compared with the model incorporating solely age and the number of previous pregnancy losses. The constructed nomogram was evaluated using the AUC, calibration curve, decision curve analysis (DCA), and clinical impact curve analysis (CICA). Patients were then categorized into low- and high-risk subgroups. We included age, number of previous pregnancy losses, lupus anticoagulant, anticardiolipin IgM, anti-phosphatidylserine/prothrombin complex IgM, anti-double-stranded DNA antibody, arachidonic acid-induced platelet aggregation, thrombin time and the sum of bilateral uterine artery systolic/diastolic ratios in the nomogram. The AUCs of the nomogram were 0.808 (95% CI: 0.770-0.846) in the training cohort and 0.731 (95% CI: 0.660-0.802) in the validation cohort, respectively. The 10-fold cross-validated AUC ranged from 0.714 to 0.925, with a mean AUC of 0.795 (95% CI: 0.750-0.839). The AUC of the nomogram was superior compared to the model incorporating solely age and the number of previous pregnancy losses. Calibration curves, DCAs, and CICAs showed good concordance and clinical applicability. Significant differences in pregnancy loss rates were observed between the low- and high-risk groups (P < 0.001). This study was retrospective and focused on patients from a single reproductive immunology clinic, lacking external validation data. The potential impact of embryonic chromosomal abnormalities on pregnancy loss could not be excluded, and the administration of medication to all cases impacted the investigation of risk factors for pregnancy loss and the model's predictive efficacy. This study signifies a pioneering effort in developing and validating a risk prediction nomogram for subsequent pregnancy loss in RPL patients to effectively stratify their risk. We have integrated the nomogram into an online web tool for clinical applications. This study was supported by the National Natural Science Foundation of China (82071725). All authors have no competing interests to declare. N/A.

Cell-Free DNA Analysis of Fetal Aneuploidies in Early Pregnancy Loss.

Background: Products of conception samples are often collected and analyzed to try to determine the cause of an early pregnancy loss. However, sample collection may not always be possible, and maternal cell contamination and culture failure can affect the analysis. Cell-free DNA-based analysis of a blood sample could be used as an alternative method in early pregnancy loss cases to detect if aneuploidies were present in the fetus. Methods: In this prospective study, blood samples from early pregnancy loss patients were analyzed for the presence of fetal aneuploidies using a modified version of a noninvasive prenatal testing assay for cell-free DNA analysis. Results from cell-free DNA analysis were compared against the gold standard, microarray analysis of products of conception samples. This study was registered with ClinicalTrials.gov, identifier: NCT04935138. Results: Of the 76 patient samples included in the final study cohort, 11 were excluded from performance calculations. The 65 patient samples included in the final analysis included 49 with an abnormal microarray result and 16 with a normal microarray result. Based on results from these 65 samples, the study found that genome-wide cell-free DNA analysis had a sensitivity of 73.5% with a specificity of 100% for the detection of fetal aneuploidies in early pregnancy loss cases. Conclusions: This prospective study provides further support for the utility of cell-free DNA analysis in detecting fetal aneuploidies in early pregnancy loss cases. This approach could allow for a noninvasive method of investigating the etiology of miscarriages to be made available clinically.

P-389 Miscarriage in recurrent pregnancy loss (RPL) patients is associated with decreased peripheral T follicular helper cells and double-positive T cells

Abstract Study question Is there a relation between certain T cell subpopulations in the peripheral blood and the reproductive outcome in patients with recurrent pregnancy loss (RPL)? Summary answer We found that miscarriage in RPL patients is associated with low quantities of peripheral T follicular helper cells (TFH) and double-positive T cells (DPT). What is known already Previous studies showed that, the quantity of certain types of immune cells, such as natural killer cells and B cells has been associated with recurrent miscarriages. It is also well known that the first trimester is characterized by inflammation profile, required for successful implantation and specific Th1/Th2-type immune microenvironment. Follicular T helper cells and rare T-cells populations such as double-positive and double-negative T cells also have an important effect on the post-implantation processes. However, the effect of these specific immune cell types and their relative quantities in relation to the reproduction outcome is not fully understood. Study design, size, duration This observational study was performed from November 2022 to September 2023. Blood samples were collected from 65 pregnant RPL women (≥2 gestational losses) aged 28-49 years during the first trimester, at 8-10 weeks of pregnancy. Patients were followed up and divided into two groups according to their reproductive outcome: live birth or miscarriage. The exclusion criteria were history of recent inflammatory, autoimmune or oncological diseases, recent antibiotic treatment, and endometrial pathologies. Participants/materials, setting, methods The percentage of eight peripheral T cell subpopulations were measured by flow cytometry: T helpers (CD3+CD4+CD8-), T killers (CD3+CD4-CD8+), double-positive T cells (DPT) (CD3+CD4+CD8+), double-negative T cells (CD3+CD4-CD8-), T follicular helper cells (TFH) (CD3+CD4+CD8-CD185+), T helper type 1 (TH1) (CD4+CD183+CD196-CD194-), type 2 (TH2) (CD4+CD183-CD194+CD196-), and type 17 (TH17) (CD4+CD183-CD194+CD196+) cells. Study groups were compared by Student’s t-test using SPSS v.21 (IBM Corp., Armonk, NY, USA). Main results and the role of chance Among the studied RPL patients, 41 women gave live birth and 24 patients had a miscarriage after the blood sample. The mean percentage and standard deviation in the of the studied T cell subpopulations was: T helpers (49.86%±14.07%), T killers (39.49%±11.50%), DPT (2.96%±1.12%), DNT (5.61%±4.76%), TFH (8.09%±3.03%), TH1 (20.86%±8.81%), TH2 (6.22%±3.68%), and TH17 (3.93%±2.37%).The performed Student’s t-test revealed significant difference only in the percentage of TFH and DPT cells between the two studied patient groups. The percentages of TFH cells and DPT cells were significantly lower in patient group with miscarriage compared to the patient group with live birth (8.07% vs. 13.35%, p = 0.04, and 1.07% vs. 2.44%, p = 0.02, respectively). Limitations, reasons for caution The study was limited in sample size. It would be beneficial future studies to include more subsets of T cells, such as TH9, TH22, and T reg. Wider implications of the findings Low percentage of peripheral TFH and DPT cells in RPL patients could be considered as an indication for potential risk of miscarriage. Routine measurement of these immune biomarkers from the peripheral blood might be beneficial for an adequate assessment and treatment of patients with previous pregnancy losses. Trial registration number not applicable

O-314 Investigating the embryonic contribution to recurrent pregnancy loss: a retrospective analysis of embryo quality, chromosomal status and morphokinetics in 11,169 embryos

Abstract Study question What is the embryonic contribution, in terms of embryo quality, chromosomal status and morphokinetics, to the reproductive success of recurrent pregnancy loss (RPL) patients? Summary answer RPL patients undergoing PGT-A had significantly fewer embryos available for biopsy, higher aneuploidy rates and showed morphokinetic alterations around the time of blastulation. What is known already RPL is diagnosed following the loss of two or more pregnancies before the 24th week of gestation. RPL has a multifactorial etiology encompassing both maternal and embryonic factors, such as uterine malformations, the presence of anti-phospholipid antibodies, maternal obesity or embryo aneuploidy, among others. While some studies have shown increased rates of chromosomal abnormalities in blastocysts from idiopathic RPL patients, a comprehensive characterization of the embryonic contribution to the disorder remains limited, and the role of embryo morphokinetics is still underexplored. Study design, size, duration This retrospective cohort study analyzed 11,169 embryos from 3,005 PGT-A cycles performed across 9 European fertility clinics between January 2017 and July 2023. Differences in the number of biopsied embryos, aneuploidy rates and embryo quality were compared between RPL and non-RPL patients. Morphokinetic timings were evaluated in a subset of 704 RPL embryos from 2 fertility centers, which was then compared to a separate cohort of embryos (n = 952) derived from double gamete donation cycles (n = 134). Participants/materials, setting, methods Genetic and clinical outcomes were assessed by multivariate analyses adjusting for maternal age, paternal age, the presence of male factor and embryo grade, as appropriate. Kaplan-Meier survival curves were constructed for each morphokinetic parameter (tPNf, t2, t3, t4, t5, t8, tSB and tB) and analyzed by Cox regression using maternal age and male factor as adjusting variables. P-values &amp;lt;0.05 were considered statistically significant. Main results and the role of chance RPL patients undergoing PGT-A represented 15.47% (n = 465/3,005) of the cohort and were significantly younger than the rest of the patients (34,97±6.6 vs 36.38±6.6, p &amp;lt; 0.0001). RPL patients obtained significantly fewer blastocysts available for biopsy (coefficient -0.39, 95%CI: -0.703- -0.076, p = 0.01) and had significantly higher aneuploidy rates (OR = 1.19, 95%CI: 1.06-1.35, p = 0.004). However, embryo quality (excellent vs. rest, p &amp;gt; 0.05) was comparable between the two groups (n = 11,169 embryos). As anticipated, biochemical and clinical pregnancy rates were comparable between RPL patients and non-RPL patients (OR = 0.94, 95%CI:0.72-1.24, p = 0.68; OR = 0.95, 95%CI: 0.72-1.24, p = 0.71, respectively), however patients with RPL presented with significantly higher miscarriage rates (OR = 1.66, 95% CI:1.03-2.74, p = 0.04). Compared to double donation embryos, RPL embryos exhibited significant delays in all analyzed times (tPNf: 23.7±3.1 vs. 22.7±3.1; t2: 26.5±4.1 vs. 25.6±3.4; t3: 37.1±5.4 vs. 36.0±4.7; t4: 39.2±6.3 vs. 37.9±5.3; t5: 50.2±7.9 vs. 49.3±7.4; tsB: 99.4±10.3 vs. 97.9±9.7; tB: 110.3±11.5 vs. 106.4±11.8; p &amp;lt; 0.05). Notably, delays in blastocyst formation were also observed when adjusting for maternal age and male factor (Hazard Ratio=0.38, 95% CI: 0.18-0.79, p = 0.009). Significantly, morphokinetic alterations persisted even when exclusively comparing euploid RPL embryos to the double donation group (n = 41, t8: Hazard Ratio=1.78, 95% CI: 1.22-2.57, p = 0.002; tsB: Hazard Ratio=1.70, 95% CI: 1.17-2.48, p = 0.006). Limitations, reasons for caution The main limitation of the study is its retrospective design, where known RPL risk factors leading to the selection of a PGT-A cycle were not considered, potentially introducing biases. Wider implications of the findings These findings highlight the intricate interplay between embryo quality, aneuploidy, and morphokinetics in RPL, guiding personalized patient management. Higher embryo aneuploidy and morphokinetic alterations observed even in euploid RPL embryos suggest an embryonic role, underscoring the condition’s multifactorial nature and urging exploration of molecular mechanisms linking embryonic factors to RPL. Trial registration number not applicable

Unravelling the oxygen factor - An investigation of transcriptional activation of hypoxia associated placental angiogenesis in recurrent pregnancy loss (RPL) patients from Assam, India

IntroductionRecurrent pregnancy loss (RPL) is defined as the spontaneous loss of two or more consecutive pregnancies before 20 weeks of gestation, and affects 7.46 % of the Indian population. About 40–50 % of RPL cases are idiopathic making it a therapeutic challenge for clinicians. This study focuses on elucidating the role of hypoxia-associated placental angiogenesis in these idiopathic RPL cases. MethodsWhole blood and product of conception (POCs) were collected from RPL patients (N = 87) and cases of voluntary abortions (medically terminated pregnancy, MTP; n = 110) as controls with informed consent. Serum separated from whole blood was used to study the ROS-antioxidant status in the cases and controls through colorimetric assays and ELISA. The mRNA extracted from placental tissue samples were used to determine the hypoxic and angiogenic status in cases and controls through real time PCR. Statistical analysis was also carried out to correlate the differential hypoxic status between RPL and MTP cohorts with the expression of angiogenic factors (VEGFA, VEGFR1 and VEGFR2). ResultsHIF1α mRNA expression was found to be upregulated in the RPL cases. While the serum levels of H2O2 (p = 0.012), guanine oxides and lipid hydroperoxides (LPO) were increased in the RPL cases, reduced glutathione (GSH) was found to be significantly decreased (p = 0.012). Additionally, AUROC analysis also shows an excellent discriminatory ability of 0.850 for serum H2O2 levels. VEGF-A and VEGF-R1 mRNA expression was also found to be downregulated in the RPL cases compared to MTP. DiscussionThis study indicates that increased oxidative stress may lead to aberrations in the VEGF pathway resulting in improper placentation in RPL cases, and subsequently, pregnancy loss.

Analysis of Risk Factors for Recurrent Pregnancy Loss in Patients Undergoing in vitro Fertilization-Embryo Transfer

Recurrent pregnancy loss (RPL) presents a formidable challenge for individuals undergoing in vitro fertilization-embryo transfer (IVF-ET), forming both a clinical dilemma and a focal point for scientific inquiry. This study endeavors to investigate the intricate interplay between clinical features, such as age, body mass index (BMI), and waist-to-hip ratio (WHR), and routine laboratory parameters, including sex hormones, blood composition, liver and thyroid functions, thyroid antibodies, and coagulation indicators, in RPL patients undergoing IVF-ET. By meticulously analyzing these variables, we aim to uncover the latent risk factors predisposing individuals to RPL. Identifying potential factors such as advanced maternal age, obesity, and insulin resistance will provide clinicians with vital insights and empirical evidence to strengthen preventive strategies aimed at reducing miscarriage recurrence. This retrospective case-controlled study included RPL patients who underwent IVF-ET treatment at Sun Yat-sen Memorial Hospital, Sun Yat-sen University, between January 2012 and March 2021 as the case cohort, compared with women receiving assisted reproductive treatment due to male infertility as the control cohort. The fasting peripheral blood was collected 5 days before the first menstrual cycle at least 12 weeks after the last abortion. The clinical characteristics and relevant laboratory indexes of the two groups were compared. Employing both univariate and multivariate logistic regression analyses, we sought to unearth potential high-risk factors underlying RPL. Additionally, a linear trend analysis was conducted to assess the linear relationship between total testosterone (TT) levels and the number of miscarriages. In contrast to the control cohort, the RPL cohort exhibited significant increases in age, BMI, and WHR (P<0.05). Notably, TT levels were markedly lower in the RPL cohort (P=0.022), while no significant differences were observed between the two groups concerning basal follicle-stimulating hormone, luteinizing hormone, estradiol, progesterone, prolactin levels, and anti-Müllerian hormone levels (P>0.05). Moreover, fasting insulin (FINS) levels and HOMA-IR index were notably elevated in the RPL cohort relative to the control cohort (P<0.001), although no significant differences were observed in fasting blood glucose levels (P>0.05). Furthermore, the neutrophil (NEU) count and NEU-to-lymphocyte ratio were notably higher in the RPL cohort (P<0.01). Univariate logistic regression analysis identified several factors, including age≥35 years old, BMI≥25 kg/m2, WHR>0.8, FINS>10 mU/L, HOMA-IR>2.14, NEU count>6.3×109 L－1, and an elevated NEU/lymphocyte ratio (NLR), as significantly increasing the risk of RPL (P<0.05). Although TT levels were within the normal range for both cohorts, higher TT levels were associated with a diminished RPL risk (odds ratio [OR]=0.67, 95% confidence interval [CI]: 0.510-0.890, P=0.005). After adjustments for confounding factors, age≥35 years old (OR=1.91, 95% CI: 1.06-3.43), WHR>0.8 (OR=2.30, 95% CI: 1.26-4.19), and FINS>10 mU/L (OR=4.50, 95% CI: 1.30-15.56) emerged as potent risk factors for RPL (P<0.05). Conversely, higher TT levels were associated with a reduced RPL risk (OR=0.59, 95% CI: 0.38-0.93, P=0.023). Furthermore, the linear trend analysis unveiled a discernible linear association between TT levels and the number of miscarriages (P trend=0.003), indicating a declining trend in TT levels with escalating miscarriage occurrences. In patients undergoing IVF-ET, advanced maternal age, lower TT levels, increased WHR, and elevated FINS levels emerged as potent risk factors for RPL. These findings provide clinicians with valuable insights and facilitate the identification of patients who are at high risks and the formulation of preventive strategies to reduce the recurrence of miscarriages.

Investigating into microbiota in the uterine cavity of the unexplained recurrent pregnancy loss patients in early pregnancy

IntroductionThe majority of unexplained recurrent pregnancy loss (URPL) cases have been attributed to immune abnormalities. Inappropriate changes in microbiota could lead to immune disorders. However, the specific role of uterine cavity microbiota in URPL remains unclear, and only a limited number of related studies are available for reference. MethodsWe utilized double-lumen embryo transfer tubes to collect uterine cavity fluid samples from pregnant women in their first trimester. Subsequently, we conducted 16S rRNA sequencing to analyze the composition and abundance of the microbiota in these samples. ResultsFor this study, we enlisted 10 cases of URPL and 28 cases of induced miscarriages during early pregnancy. Microbial communities were detected in all samples of the URPL group (100 %, n = 10), whereas none were found in the control group (0 %, n = 28). Among the identified microbes, Lactobacillus and Curvibacter were the two most dominant species. The abundance of Curvibacter is correlated with the number of NK cells in peripheral blood (r = −0.759, P = 0.018). DiscussionThis study revealed that during early pregnancy, Lactobacillus and Curvibacter were the predominant colonizers in the uterine cavity of URPL patients and were associated with URPL. Consequently, alterations in the dominant microbiota may lead to adverse pregnancy outcomes.

Increased levels of villus-derived exosomal miR-29a-3p in normal pregnancy than uRPL patients suppresses decidual NK cell production of interferon-γ and exerts a therapeutic effect in abortion-prone mice

ObjectiveRecurrent pregnancy loss (RPL) patients have higher absolute numbers of decidual natural killer (dNK) cells with elevated intracellular IFN-γ levels leading to a pro-inflammatory cytokine milieu, which contributes to RPL pathogenesis. The main objective of this study was twofold: first to explore the regulatory effects and mechanisms of villus-derived exosomes (vEXOs) from induced abortion patients or RPL patients at the level of intracellular IFN-γ in dNK cells; second to determine the validity of application of vEXOs in the treatment of unexplained RPL (uRPL) through in vitro experiments and mouse models.MethodsExosomes were isolated from villus explants by ultracentrifugation, co-cultured with dNK cells, and purified by enzymatic digestion and magnetically activated cell sorting. Flow cytometry, enzyme-linked immunosorbent assays, and RT-qPCR were used to determine IFN-γ levels. Comparative miRNA analysis of vEXOs from induced abortion (IA) and uRPL patients was used to screen potential candidates involved in dNK regulation, which was further confirmed by luciferase reporter assays. IA-vEXOs were electroporated with therapeutic miRNAs and encapsulated in a China Food and Drug Administration (CFDA)-approved hyaluronate gel (HA-Gel), which has been used as a clinical biomaterial in cell therapy for > 30 years. In vivo tracking was performed using 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyaine iodide (DiR) labelling. Tail-vein and uterine horn injections were used to evaluate therapeutic effects of the engineered exosomes in an abortion-prone mouse model (CBA/J × DBA/2 J). Placental growth was evaluated based on placental weight. IFN-γ mRNA levels in mouse placentas were measured by RT-qPCR.ResultsIFN-γ levels were significantly higher in dNK cells of uRPL patients than in IA patients. Both uRPL-vEXOs and IA-vEXOs could be efficiently internalized by dNK cells, whereas uRPL-vEXOs could not reduce the expression of IFN-γ by dNK cells as much as IA-vEXOs. Mechanistically, miR-29a-3p was delivered by vEXOs to inhibit IFN-γ production by binding to the 3′ UTR of IFN-γ mRNA in dNK cells. For in vivo treatment, application of the HA-Gel effectively prolonged the residence time of vEXOs in the uterine cavity via sustained release. Engineered vEXOs loaded with miR-29a-3p reduced the embryo resorption rate in RPL mice with no signs of systemic toxicity.ConclusionOur study provides the first evidence that villi can regulate dNK cell production of IFN-γ via exosome-mediated transfer of miR-29a-3p, which deepens our understanding of maternal–fetal immune tolerance for pregnancy maintenance. Based on this, we developed a new strategy to mix engineered vEXOs with HA-Gel, which exhibited good therapeutic effects in mice with uRPL and could be used for potential clinical applications in uRPL treatment.Graphical

Effect of anti-Müllerian hormone on early pregnancy loss in hormone replacement therapy-frozen-thawed embryo transfer cycles: An analysis including 6597 pregnant patients undergoing their first invitro fertilization/intracytoplasmic sperm injection cycle.

To investigate the relationship between anti-Müllerian hormone (AMH) level and early pregnancy loss in patients who underwent their first embryo transfer by hormone replacement therapy-frozen-thawed embryo transfer (HRT-FET) and analyze the threshold effect. A retrospective cohort analysis was performed on pregnant women undergoing HRT-FET at the Reproductive Medical Center of Henan Provincial People's Hospital from January 2016 to December 2021. The patients were divided into four groups based on AMH concentration according to the Poseidon criteria: group A (≤1 μg/L), group B (1-≤2 μg/L), group C (2-≤6 μg/L), and group D (>6 μg/L). Univariate analysis, multivariate logistic regression analysis, smooth curve fitting, and threshold effect analysis were applied to investigate the influence of AMH on the outcome of early pregnancy loss in invitro fertilization/intracytoplasmic sperm injection and HRT-FET cycles. Of the 6597 pregnant women, early pregnancy loss occurred in 893, giving an early pregnancy loss rate of 13.54%. Univariate regression analysis demonstrated that age, female body mass index, AMH, antral follicle count, endometrial thickness at endometrial transformation day, total retrieved oocyte number, number of pregnancies, duration of infertility, type of infertility, and the number of embryos transferred were all factors influencing the early pregnancy loss rate (P < 0.050). Multivariate logistic regression analysis, after adjusting for confounders, further stratified the analysis of patients of different ages. With group A as the control group, the results showed that when age was younger than 35 years, the pregnancy loss rates in groups B, C, and D were lower than that in group A, with statistical significance (P < 0.050); when age was 35 years or older, there was no statistically significant difference in outcome indicators between the groups (P > 0.050). A threshold effect analysis revealed that the AMH threshold was 2.83 μg/L. When the AMH concentration was less than 2.83 μg/L, the early pregnancy loss rate decreased significantly with increasing AMH concentration; the early pregnancy loss rate decreased by 21% for each unit increase in AMH (odds ratio 0.79; 95% confidence interval 0.71-0.88; P < 0.001); when the AMH concentration was 2.83 μg/L or more, there was no statistical difference in the change in early pregnancy loss rate (odds ratio 1.01; 95% confidence interval 0.99-1.03; P = 0.383). For pregnant women after their first embryo transfer, there is a curvilinear relationship between the influences of AMH levels on early pregnancy loss rates in patients younger than 35 years. When the AMH level was less than 2.83 μg/L, the early pregnancy loss rate declined significantly with increasing AMH levels.

Immunological Risk Factors in Recurrent Pregnancy Loss in Patients With Hereditary Thrombophilia.

Recurrent pregnancy loss (RPL) is a complicated reproductive disorder with underlying genetic and immunological causes. RPL may be influenced by hereditary thrombophilia, a class of blood clotting-related genetic abnormalities, via the vascular and immune systems. This study examines the immunological characteristics that hereditary thrombophilia patients have in common with RPL. A prospective cohort study included 300 patients split into two groups: a control group without hereditary thrombophilia and a group with the condition. Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ)levels were measured, along with demographic specifics, antiphospholipid antibodies, natural killer (NK) cell counts, and other cytokines. Group differences were found using statistical analysis. Antiphospholipid antibodies were significantly more common in the thrombophilia group (42% testing positive, p=0.001) compared to the control group (12% testing positive), despite demographic factors being similar between groups (p=0.372 and p=0.093).When body mass index (BMI) was taken into account, the studyfound a statistically significant difference (p=0.046), with the thrombophilia group having a higher mean BMI (26.3 kg/m2, standard deviation (SD): 2.8) than the control group (24.7 kg/m2, SD: 3.1). IL-6(14.8 pg/mL, SD: 3.2, p=0.029) were higher than the control group (12.4 pg/mL,SD: 2.1), and TNF-α levels were higher in the thrombophilia group (10.5 pg/mL, SD: 2.0, p=0.012) compared to the control group (8.9 pg/mL,SD: 1.5), but NK cell counts did not differ significantly (p=0.213). This study emphasizes the role of elevated pro-inflammatory cytokines (IL-6 and TNF-α) and antiphospholipid antibodies in RPL among people with hereditary thrombophilia. In this population, early detection and immunomodulatory interventions may improve pregnancy outcomes. To fully comprehend these mechanisms and create customized treatments, collaborative research is required.

Predicting risk of subsequent pregnancy loss among women with recurrent pregnancy loss: An immunological factor-based multivariable model.

Studies on subsequent pregnancy loss prediction models specific for recurrent pregnancy loss (RPL) patients are very limited. This study aims to develop a risk predictive model based on the immunological parameters for the subsequent pregnancy loss risk in northwest Chinese RPL patients. Totally of 357 RPL patients recruited from Lanzhou University Second Hospital were included in this retrospective study. Univariate analysis was performed on RPL patients with outcomes of live birth or pregnancy loss. Subsequently, the least absolute shrinkage and selection operator (LASSO) regression and multivariate logistic regression were utilized to select variables among baseline and clinical characteristics and to develop a pregnancy loss risk prediction model with all 357 RPL patients. The area under the curve (AUC), calibration curve and decision curve analyses were used to evaluate the performance of the prediction model; moreover, 10-fold cross-validation was used for internal validation. Ten factors of maternal age, age of menarche, previous pregnancy loss, IL-10, complement 4, IgA, antiprothrombin antibody IgG/IgM, rheumatoid factor IgA, and lupus anticoagulant (LA) 1/LA2 ratio were finally selected as variables for the prediction model of pregnancy loss risk. The AUC value and Hosmer-Lemeshow test p-value of the model were.707 and.599, respectively, indicating a satisfactory discrimination and calibration performance. Moreover, the clinical decision curve suggested this prediction model have a good positive net benefit. This is the first prediction model for the risk of subsequent pregnancy loss in northwest Chinese women with RPL, providing a user-friendly tool to clinicians for the early prediction and timely management of RPL patients.

The Yolk Sac Abnormalities, Maternal Serum Level of Cancer Antigen 125 (CA-125) and Beta Human Chorionic Gonadotropin (B-HCG) as an Early Predictors of First Trimester Pregnancy Loss in Patients with Threatened Miscarriage: Review Article

The Yolk Sac Abnormalities, Maternal Serum Level of Cancer Antigen 125 (CA-125) and Beta Human Chorionic Gonadotropin (B-HCG) as an Early Predictors of First Trimester Pregnancy Loss in Patients with Threatened Miscarriage: Review Article

The Yolk Sac Abnormalities, Maternal Serum Level of Cancer Antigen 125 (CA-125) and Beta Human Chorionic Gonadotropin (B-HCG) as an Early Predictors of First Trimester Pregnancy Loss in Patients with Threatened Miscarriage

Background: Pregnancy loss before 20 weeks is considered a miscarriage, as is the loss of a fetus weighing less than 500 grams before viability. A medical emergency, threatened miscarriage affects 15–25% of pregnancies. &#x0D; Aim and objectives: The goal of this study was to assess the predictive value of maternal blood levels of Cancer Antigen 125 (CA-125) and beta-human chorionic gonadotropin (B- HCG) in individuals at risk of miscarriage during the first trimester. &#x0D; Subjects and methods: This study was a prospective cohort study. This study included 120 pregnant women with threatened abortion between (6-11 weeks) and followed up till end of 14th week. Results: 36(30%) of pregnant women aborted, while 84(70%) of women continued till 14th weeks of pregnancy. At a cut-off value of 45 U/ml, the CA125 test was shown to have a sensitivity of 88.9% and a specificity of 77.5%, respectively, while also having a positive predictive value of 79.8% and a negative predictive value of 87.5%. At a cut-off value of 18.501 mlIU/ml, the B-HCG test's sensitivity and specificity were determined to be 96.3 and 88.9, respectively, with a positive predictive value of 89.7% and a negative predictive value of 96%. &#x0D; Conclusion: Even before fetal morphology can be investigated sonographically, abnormalities in the size of the yolk sac can be utilized as a good prognostic sign of early pregnancy loss. Pregnancy viability can be estimated from first trimester serum CA 125 and Beta HCG measurements.

Intrauterine perfusion of dexamethasone improves pregnancy outcomes in recurrent reproductive failure patients with elevated uterine natural killer cells. A retrospective cohort study

AbstractObjectiveTo determine the effect of intrauterine perfusion of dexamethasone (DXM) on pregnancy outcomes in recurrent reproductive failure (RRF) patients with elevated uNK cells.MethodsThis retrospective cohort study included 132 RRF patients with elevated uNK cells: 56 patients received DXM treatment and 76 patients refused it in the frozen‐thawed embryo transfer cycles. To determine the efficacy of intrauterine perfusion of DXM, multivariate logistic regression models and diagnosis‐based subgroup analysis were performed. We also compared the pregnancy outcomes of patients with different responsiveness to DXM treatment.ResultsIntrauterine perfusion of DXM significantly improved clinical pregnancy rate (aOR: 3.188, 95% CI: 1.395–7.282, P = .006) and live birth rate (aOR: 3.176, 95% CI: 1.318–7.656, P = .010) in RRF patients with elevated uNK cells, but there was no significant association with miscarriage rate. Subgroup analysis revealed that intrauterine perfusion of DXM in patients with recurrent implantation failure (RIF) showed significant improvement in clinical pregnancy rate (aOR: 6.110, 95% CI: 1.511–24.713, P = .011) and live birth rate (aOR: 9.904, 95% CI: 1.963–49.968, P = .005), but there was insufficient evidence of benefit in recurrent pregnancy loss (RPL) patients. Additionally, uNK cell levels dropped to normal range was achieved in only 35.90% of RRF patients after DXM treatment, no significant difference was found in pregnancy outcomes among patients with different responsiveness to DXM treatment (all P &gt; .05).ConclusionIntrauterine perfusion of DXM was a promising and effective treatment to enhance clinical pregnancy rate and live birth rate in RRF women with abnormally elevated uNK cells, and RIF patients are more likely to benefit than RPL patients.

OC 25.3 A Multicentre Cohort Study Evaluating Pregnancy Loss in Patients with Von Willebrand Disease and Unspecified Bleeding Disorders

OC 25.3 A Multicentre Cohort Study Evaluating Pregnancy Loss in Patients with Von Willebrand Disease and Unspecified Bleeding Disorders

GPR65 inhibits human trophoblast cell adhesion through upregulation of MYLK and downregulation of fibronectin via cAMP-ERK signaling in a low pH environment

BackgroundExtravillous trophoblasts (EVTs) are essential cells during the formation of the placenta, with the major function of invading the maternal decidua, anchoring the developing placenta to the uterus, remodeling uterine arteries, and regulating immune responses to prevent rejection. During early pregnancy, the decidua undergoes a hypoxic and acidic microenvironment, which has been shown to participate in tumor cell migration, invasion, growth, and angiogenesis. Nevertheless, the mechanisms by which EVTs sense and respond to the acidic microenvironment, thereby executing their functions, remain poorly understood.MethodsThe effects of G protein-coupled receptor 65 (GPR65) on cell adhesion and other cellular functions were tested using JAR spheroids, mouse blastocysts, and HTR-8/SVneo cells. Specifically, we employed HTR-8/SVneo cells for gene overexpression and silencing to investigate the underlying mechanism of GPR65's impact on trophoblast cell function under acidic conditions. Additionally, villus tissue samples obtained from early pregnancy loss patients were utilized to explore the potential association between GPR65 and its related signaling pathway molecules with the disease.ResultsThis study identified GPR65 expression widely in trophoblasts, with the highest level in EVTs. Importantly, optimal GPR65 levels are required for maintaining normal adhesion, migration, and invasion, whereas overexpression of GPR65 inhibits these functions by activating the cAMP-ERK signaling pathway, upregulating myosin light chain kinase (MYLK) and MYLK3 expression, and subsequently downregulating fibronectin. Consistently, elevated expression of GPR65, MYLK, and MYLK3 is observed in patients suffering from early pregnancy loss.ConclusionsThis work offers insights into the suppressive effects of GPR65 on EVT function under acidic conditions and highlights a putative target for therapeutic intervention in early pregnancy complications.E9R9tt1jd9fu3QritsNs7QVideo

Obesity and recurrent miscarriage: The interconnections between adipose tissue and the immune system.

Currently, obesity is considered a global public health problem. It is the main risk factor for noncommunicable diseases and reproductive complications, such as recurrent miscarriage (RM). RM affects approximately 1% of couples of reproductive age, and recent studies suggest that its prevalence is increasing. Immunological abnormalities may be responsible for a significant number of cases of unexplained RM. Obesity is recognized as a chronic low-grade inflammatory condition. The accumulation of fat in obese adipose tissue promotes changes in the local and systemic immune response. Adipokines, exosomes, micro-RNAs, lipids, and other factors released or secreted by adipose tissue are responsible for the interconnection between obesity and the immune system. Obesity-induced dysregulation of the innate and acquired immune response is also involved in the immunopathology of pregnancy loss in patients with unexplained RM. Therefore, understanding the communication pathways between maternal adipose tissue and the immune response in women living with obesity and RM is an important objective. Thus, diagnostic tools and new immunomodulatory therapies may be proposed for the management of patients with concurrent obesity and RM.

The number of prior pregnancy losses does not impact euploidy rates in young patients with idiopathic recurrent pregnancy loss.

Our study aimed to determine the possible factors that might impact the probability of obtaining a euploid blastocyst following intracytoplasmic sperm injection (ICSI) and preimplantation genetic testing for aneuploidy (PGT-A) procedures in idiopathic recurrent pregnancy loss (RPL) patients. This single-center retrospective cohort analysis included 180 oocyte retrieval cycles of 166 women under 35years old and those diagnosed with idiopathic RPL according to American Society of Reproductive Medicine (ASRM) guidelines. Trophectoderm biopsy and next-generation sequencing (NGS) were the techniques used. Patients were stratified by the number of previous losses (Group A: 2, Group B: 3, and Group C: > 3). Baseline and embryological characteristics showed no statistically significant differences. The euploidy rate per analyzed blastocyst was comparable within the groups (63.3%, 58.2%, and 58.5%; p = 0.477). Logistic regression analyses confirmed that only the trophectoderm scores of A and B increased the probability of obtaining a euploid embryo [OR: 1.82, 95% CI (1.120-2.956), p: 0.016]. It is concluded that there was no correlation between the number of previous losses and the chance of finding at least one euploid embryo in ICSI cycles of women younger than 35years.