Recurrent Pregnancy Loss Women Research Articles

Thrombosis-related characteristics of pregnant women with antithrombin deficiency, protein C deficiency and protein S deficiency in Japan

Background We previously conducted a primary survey of pregnant women with hereditary thrombophilia based on national surveillance in Japan, but did not examine their thrombosis-related characteristics. Antithrombin (AT) deficiency, protein C (PC) deficiency and protein S (PS) deficiency are the major types of hereditary thrombophilia in Japan.MethodsWe examined their detailed information related to thrombosis, and evaluated peripartum outcomes in comparison with control data obtained from the Japan Society of Obstetrics and Gynecology.ResultsDefinite or probable AT deficiency, PC deficiency and PS deficiency were observed in 80, 50, and 317 pregnancies, respectively, from 2014 to 2018 in Japan, with prevalence rates among total deliveries of 0.011%, 0.007%, 0.044%. The number of pregnancies with AT, PC and PS deficiency might have been as many as 27, 17 and 108 every year if complete answers had been provided. In the peripartum period of current pregnancies, 27.5% of women with AT deficiency, 28.0% with PC deficiency and 13.2% with PS deficiency developed thrombosis (p < 0.001 vs. control). Pregnant women with AT and PC deficiency were more susceptible to thrombosis than those with PS deficiency (P < 0.01). Of the thromboses, 92.3% occurred during pregnancy, 62.8% at less than 15 gestational weeks. The earliest onset of thrombosis was 5 gestational weeks. Prophylactic anticoagulation significantly prevented the onset of both antepartum and postpartum thrombosis (p < 0.0001). The rate of recurrent pregnancy loss in women with low PC or PS activities was significantly higher than in controls (p < 0.0001); however, it is unknown whether recurrent pregnancy loss is related to hereditary PS deficiency. There seem to have been few serious maternal or fetal/neonatal complications due to placental insufficiency related to a hypercoagulable state other than growth restriction.ConclusionsThis survey revealed the thrombosis-related characteristics of pregnant women with hereditary thrombophilia in Japan. We suggest prophylactic anticoagulation to prevent maternal or fetal/neonatal complications.

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.

Oral administration of Bifidobacterium longum ES1 reduces endometrial inflammation in women with recurrent pregnancy loss.

Over-activation of endometrial inflammasome NALP-3 (Nod-like receptor family pyrin domain containing 3) can be found in recurrent pregnancy loss (RPL) women probably due to leaky gut and passage into circulation of lipopolysaccharides (LPS). Leaky gut can be caused by exposure to gluten in RPL women genetically predisposed to celiac disease, positive for Human Leukocyte Antigen (HLA)-DQ2/DQ8 haplotype. Oral administration of Bifidobacterium longum ES1 (GliadinES®) can inactivate gluten peptides toxicity to epithelial gut cells and improve gut barrier. We investigated by enzyme-linked immunoassay: (a) serum levels of LPS and zonuline (a marker of leaky gut); (b) LPS, NALP-3, caspase-1, interleukine (IL)-1β and IL-18 concentration in endometrial fluids, in untreated women with uncomplicated pregnancies (negative HLA-DQ2/DQ8 haplotype) (n=22) and in women with unexplained RPL, HLA-DQ2/DQ8 positive (n=22), before and after daily oral administration for 3 months of GliadinES®. RLP women showed higher serum levels of LPS (p<0.0001) and higher concentration of LPS (p<0.0001), NALP-3 (p<0.01); Caspase-1 (p<0.0001), IL-1β (p<0.0001), and IL-18 (p<0.0001) in endometrial fluids compared to controls. GliadinES® treatment significantly reduced serum levels of both LPS (p<0.0001) and zonuline (p<0.01), as well as LPS (p<0.5), NALP-3 (p<0.01), Caspase-1 (p<0.001), IL-1β (p<0.001), and IL-18 (p<0.01) concentrations in endometrial fluids of RPL women. RPL women positive for HLA-DQ2/DQ8 haplotype show increased circulating and endometrial levels of LPS and endometrial inflammasome NALP-3 over-activation. Oral administration of GliadinES® can reduce gut permeability, decrease serum levels of LPS and, contextually, improve endometrial inflammation in this specific subset of RPL women.

Association of recurrent implantation failure and recurrent pregnancy loss with peripheral blood natural killer cells and interferon-gamma level.

Fetal uterine survival depends on maintaining an immune balance between the mother and fetus. This study aimed to investigate the correlation of blood peripheral natural killer (NK) cells and interferon-gamma (IFN-γ) with recurrent recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL). In this case-control study, peripheral blood samples were obtained from three groups of RPL, RIF, and parous women without a history of abortion or infertility problems and analyzed by lymphocyte-based flow cytometry. Afterward, the levels of NK cells and IFN-γ were determined. All data were analyzed using one-way analysis of variance and nonparametric Kruskal-Wallis tests. The level of IFN-γ in the RPL group was significantly higher than that in parous women and the RIF group (P<0.05), whereas its level in the RIF group was not significantly different from the control group (P>0.05). A significant correlation was found between the levels of IFN-γ and NK cells in the RPL group (r=0.481; P=0.02). However, no significant correlation was found between the levels of IFN-γ and the active NK cells in the RPL group (P=0.08). Moreover, no significant correlation was found between the levels of NK cells (whether activated or not) and IFN-γ in the RIF patients (P>0.05). Immune dysfunction may not be involved in implantation failure during IVF but may be involved in recurrent miscarriage, probably by increasing IFN-γ levels.

The role of Natural Killer cells in pregnancy and their potential impact on cancer prevention

Immune cells such as Natural Killer (NK) cells play a central role in immunosurveillance, preserving the physiological integrity of tissues by fighting infection and combating tumor cells, as it has the potential to release specific cytotoxic substances. Some studies suggest that a high number and/or inadequate presence/frequency of activated NK cells is involved in the Recurrent Pregnancy Loss (RPL) condition once it might trigger an immunological imbalance in women’s bodies. Our hypothesis states that a higher number of activated NK cells could be associated to lower cancer rates in women with RPL. To test this idea, we propose to evaluate abortion material, peripheral blood and uterine samples from both RPL and non-RPL women, comparing histological, cellular, and molecular features in order to identify and differentiate the immunological profile of both groups. Once established the immunological profile of both RPL and non-RPL women, an investigation of the epidemiological history of women with/without RPL can approach the possible correlation between different NK patterns and cancer reports. Scientific literature concerning this potential correlation is scarce, and we believe that a better understanding of the NK cell behavior associated to different gestational outcomes could increase our comprehension on the mechanisms underlying both cancer development and immunological aspects of pregnancy.

Reproductive outcomes in couples with recurrent pregnancy loss after embryonic chromosomal microarray analysis.

Chromosomal microarray analysis (CMA) has been widely applied to explore the genetic etiology in recurrent pregnancy loss (RPL). However, the reproductive prognosis in RPL couples with different types of chromosomally abnormal miscarriage remains unclear. The main purpose of this study was to evaluate the reproductive prognosis among RPL couples after genetic testing in products of conception (POCs) by CMA. In this retrospective study, 1101 RPL couples referred for genetic testing in POCs by CMA. A total of 830 couples who met the inclusion criteria were followed up for at least 24months after the index miscarriage. The rates of live birth and adverse pregnancy events in subsequent pregnancy and cumulative pregnancies were examined. For couples with three or more miscarriage, compared with those with chromosomally normal miscarriage, a significantly higher subsequent live birth rate was found in couples with chromosomally abnormal miscarriage (66.9% vs 71.6%, P = .040). However, differences in cumulative live birth rate among couples with chromosomally abnormal miscarriage and normal miscarriage were nonsignificant (82.7% vs 80.2%, P = .131). Women with advanced maternal age showed a significant decrease in the live birth rate (P < 0.01) and an increase in the miscarriage rate (P < 0.01) than those aged < 35years old, regardless of whether the miscarriage was chromosomally normal or abnormal. RPL couples with chromosomally normal miscarriage showed a significant decrease in live birth rates in subsequent pregnancy and cumulative pregnancies, when they had experienced a large number of previous miscarriages; however, no significant difference was observed in those with chromosomally abnormal miscarriage. For women with three or more previous miscarriages, RPL couples with chromosomally normal miscarriage manifested a poorer reproductive prognosis than those with chromosomally abnormal miscarriage in subsequent pregnancy, while the cumulative live birth rate was similar. Advanced maternal age was a predictor of adverse pregnancy events, regardless of embryonic chromosomal results. Furthermore, among RPL women with large numbers of previous miscarriages, the supportive care and counselling regarding individual risk is necessary for those with chromosomally normal miscarriage.

Psychological changes among women with recurrent pregnancy loss during the COVID-19 period in northeastern China: a cross-sectional study

BackgroundIt aimed to investigate the prevalence of anxiety and depression in recurrent pregnancy loss (RPL) women and the related factors in Northeastern China during the Coronavirus disease 2019 (COVID-19) pandemic.MethodsFrom March to June 2021, we conducted an electronic questionnaire survey of 267 RPL women who attended the recurrent pregnancy loss clinic at Shengjing Hospital of China Medical University. The State–Trait Anxiety Inventory (STAI), Beck Depression Inventory-II (BDI-II), Perceived Stress Scale (PSS), and Medical Outcomes Study Social Support Survey (MOS-SSS-C) were used to screen for anxiety, depression, stress, and social support. Logistic regression was used to explore the related factors of anxiety and depression.ResultsRPL women had severe psychological problems during the pandemic: 56.6% showed state anxiety or trait anxiety, 26.6% showed high levels of stress, and 13.1% showed depression. Economic pressure caused by COVID-19, and high stress were common related factors for anxiety and depression. The interval since last miscarriage &amp;lt;6 months, worse mood changes due to COVID-19, and concerns about COVID-19 were associated with anxiety. A history of pregnancy loss &amp;gt;14 weeks was associated with depression. While adequate social support and actively seeking health help were protective factors for trait anxiety. And identifying the etiology was a protective factor for depression.ConclusionThe study revealed the prevalence of anxiety, depression, and the associated factors in RPL women during COVID-19. More attention should be paid to the psychology of RPL women and adequate social support should be provided.

Myeloid-derived suppressor cells as a potential biomarker for recurrent pregnancy loss and recurrent implantation failure: Increased levels of MDSCs in recurrent reproductive failure.

Recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) represent distinct clinical conditions with established definitions, both of which have been linked to an underlying pro-inflammatory state. This study aimed to explore the levels of monocytic-myeloid-derived suppressor cells (M-MDSCs) and regulatory T cells (TReg ) in a cohort of RPL and RIF women and their potential contribution to RPL and RIF. One hundred and eight non-pregnant women were evaluated: 40 RPL, 41 RIF, and 27 fertile healthy controls (HC). A multiparametric flow cytometry approach was utilized to measure and quantify the frequency of M-MDSCs and TReg cells. Cytokine levels in plasma samples were evaluated through a multiplex assay. M-MDSCs levels were significantly higher in RPL and RIF patients compared to HC. M-MDSCs levels were significantly higher in RPL (9.4% [7-11.6]) and RIF (8.1% [5.9-11.6]) patients compared to HC (6% [4.2-7.6]). An optimal cut-off of 6.1% for M-MDSCs disclosed a sensitivity of 75.6% and 89.7% and a specificity of 57.7% and 57.7% in RIF and RPL groups, respectively. A significant negative correlation was observed between M-MDSCs and TReg (p=.002, r=-.51). Our preliminary data allowed us to build a predictive model that may aid as a potential diagnostic tool in the clinic. These findings could provide a better understanding of these pathologies and a better definition of patients that could benefit from personalized treatments to promote pregnancy. Additional exploration and confirmation in distinct study groups are needed to fully assess the diagnostic capabilities of this biomarker.

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.

ANRIL rs4977574 Gene Polymorphism in Women with Recurrent Pregnancy Loss.

ANRIL rs4977574 gene polymorphism has been associated with arterial thrombosis and cardiovascular disease development. ANRIL rs4977574 gene polymorphism could also be associated with recurrent pregnancy loss (RPL) since there is increasing evidence in favor of a potential shared pathophysiological mechanism with cardiovascular disease, potentially through arterial thrombosis. This study's goal is to investigate the differences in ANRIL rs4977574 gene polymorphism between women with and without RPL, if any, as well as a potential association with the number of pregnancy losses. DNA was isolated from peripheral blood samples, and the sequence containing the polymorphism of interest was amplified with PCR. Results were visualized under UV light following electrophoresis in 3% agarose gel with ethidium bromide. ANRIL rs4977574 (A>G) prevalence was compared between 56 women with and 69 without RPL. Results were adjusted for women's age and BMI, while a stratified analysis was performed according to number of pregnancy losses. Allele A was significantly more prevalent in the control group compared to RPL women [31 (44.9%) vs. 14 (25%), p = 0.021]. Although not reaching statistical significance, a gradually decreasing prevalence of allele A with an increasing number of pregnancy losses was observed [31 (44.9%) in control, eight (30.7%) with two, six (23.1%) with three, and 0 (0.0%) with four pregnancy losses, p = 0.078]. Results were also similar following adjustment. This is the first study that demonstrates an association between RPL presence and ANRIL rs4977574 gene polymorphism (lower prevalence of allele A), while a difference according to the number of pregnancy losses cannot be excluded.

Rapid Ovarian Reserve Decline in a Woman with Pericentric Inv(9) Variant

Inv(9) is one of the most common chromosomal variants and is generally considered to be a variant of no clinical significance. We describe a case of a 35-year-old woman with a normal baseline fertility workup who presented to a university-affiliated fertility clinic after eight months of attempting conception. She underwent a rapid decline in anti-Mullerian hormone (AMH) from 10.0 ng/mL to 0.5 mg/mL and cycle day 3 (CD3) antral follicle count (AFC) from 58 to 4 total follicles during 18 months of follow-up. Her karyotype demonstrated a reportedly benign 46XX, Inv(9)(p11q13) variant. During follow-up and fertility treatment, she achieved pregnancy three times, but they all ended in chemical pregnancies. A systematic review of the literature identified 24 publications evaluating the association between infertility or recurrent pregnancy loss (RPL) and Inv(9). We report the prevalence of Inv(9) in women with infertility and the prevalence of infertility or RPL in women with Inv(9) mutation. Although Inv(9) has previously been considered to be a normal variant, several publications support the possible correlation between Inv(9) with reproductive failure. There has been limited literature regarding this association, and future studies should consider higher-resolution genomic detection methods to identify Inv(9)-related chromosomal rearrangements in couples presenting with infertility.

Treatment of recurrent pregnancy loss in women with euthyroid-based thyroid peroxidase antibody syndrome.

Recurrent pregnancy loss (RPL) due to thyroid peroxidase antibody (TPOAb) syndrome remains a significant challenge in pregnancy. The current study offers better insights into miscarriages that occur due to the presence of TPOAb with euthyroid in pregnant women with a history of RPL. Out of the 347 women confirmed with unexplained RPL, only 70 (20.2%) tested positive for TPOAb (215±53). After eight women were excluded from the study due to failure to follow up, 62 participants (age range: 33±4.8 years; body mass index (BMI):25-30kg/m2 (58%) and >30kg/m2 (42%)) were included. The TPOAb-dependent RPL patients were divided according to their RPL types into 23 (30.7%) nulliparous (1˚) and 39 (69.3%) multiparous (2˚) patients, respectively. Out of the sample, 69.2% and 30.8% had a history of miscarriages during the 1st and 2nd trimesters, respectively. For treatment purposes, while screening for the TPOAb, the women received 50µg/day of L-thyroxine (LTx) for three months prior to pregnancy and during the first three months of pregnancy and were followed up until giving birth or miscarriage. Thyroxine treatment was correlated to successful normal births in 56.6% and 21.2% of pregnant women after 36 and during 28-36 weeks of gestation, respectively. However, miscarriages occurred in 18.1% and 4.1% of patients during 14-28 weeks and before 14 weeks of gestation, respectively. The current findings show the promising use of thyroxine in the control of RPL caused by euthyroid-based thyroid peroxidase antibody syndrome. This treatment has led to a significant number of women experiencing successful full-term pregnancies and giving birth to healthy babies.

O-146 Oocyte donation does not increase live birth rates in young women suffering from recurrent pregnancy loss

Abstract Study question Does oocyte donation improve reproductive outcomes in recurrent pregnancy loss (RPL) patients? Summary answer Oocyte donation increases live birth and reduces miscarriage rates in RPL women older than 35, but it does not improve reproductive outcomes in younger patients. What is known already Recurrent pregnancy loss (RPL) is defined as 2 or more pregnancy losses prior to 20-24 weeks of gestation and has an incidence of approximately 1 to 2% in couples trying to conceive. Known risk factors for RPL are embryo aneuploidy, advanced maternal age (AMA), previous miscarriages, uterine abnormalities, parental chromosomal abnormalities, antiphospholipid syndrome, endocrine factors, such as thyroid function or obesity, and thrombophilia. However, 50-70% of patients suffering from RPL do not present any known risk factor, making the management of idiopathic RPL patients particularly challenging for ART clinicians. Study design, size, duration This is a cohort retrospective study involving 2 centers. Charts from 18,273 women undergoing IVF treatment between 2011 and 2020 were reviewed. A total of 912 patients (5%) met the definition of RPL and were classified into study groups based on their age and oocyte origin: ≤35 years old receiving oocyte donation (n = 39) or using their own oocytes (n = 35), and AMA women using donor eggs (n = 716) or their own (n = 122). Participants/materials, setting, methods Demographic variables analysed included known risk factors, number of transferred embryos, day of embryo transfer (3 vs 5) and sperm origin (partner/donor). Differences in biochemical, clinical, ongoing pregnancy, miscarriage and live birth rates were assessed by Pearson’s Chi-squared or Fisher’s exact test. P-values &amp;lt;0.05 were considered significant. Main results and the role of chance RPL patients had 2.77±1.27 pregnancy losses overall (2.76±1.37 in women ≤35 and 2.77±1.26 in patients &amp;gt;35). Most RPL patients (91.9%) were of AMA. Other RPL-associated risk factors, including uterine malformations, previous pregnancy losses, chromosomal abnormalities and thrombophilia were identified in 207/912 patients (22.7%). Interestingly, these were more frequent in patients &amp;lt;35 (37.8% vs 21%, p = 0.001). Young RPL women presented higher rates of karyotype abnormalities than older patients (17.6% vs 3.8%, p &amp;lt; 1x10-04), while showing a similar incidence of uterine abnormalities (14.9% vs 12.9%, p &amp;gt; 0.63) and thrombophilia (4.1% vs 4.7%, p &amp;gt; 0.81). RPL patients &amp;gt;35 preferentially underwent oocyte donation (85.4% vs 52.7%, p &amp;lt; 1x10-04), which led to significantly higher biochemical (52.5% vs 17.1%, p &amp;lt; 1x10-04), clinical (42.4% vs. 8.5% p &amp;lt; 1x10-04), ongoing pregnancy (37.9% vs 5.1%, p &amp;lt; 1x10-04), live birth (32% vs 4%, p &amp;lt; 1x10-04) and lower miscarriage rates (10.5% vs 40%, p = 0.0186) than in autologous cycles. In contrast, RPL patients &amp;lt;35 had similar reproductive outcomes: biochemical (41% vs. 52.9), clinical (28.2% vs. 37.1%), ongoing pregnancy (25.6% vs 29.4%), live birth (25.6% vs 26.4%) and miscarriage rates (9% vs 23%), regardless of oocyte origin (donated vs own, p &amp;gt; 0.05 for all cases). Importantly, this was also true for a small subgroup of idiopathic young RPL patients (n = 13). Limitations, reasons for caution The main limitation of this study is its retrospective nature, which does not allow for full elucidation of all potential confounders. The number of young RPL patients undergoing oocyte donation may be too low to draw significant conclusions. Wider implications of the findings RPL can be resolved in AMA patients by using donor oocytes, which points to key roles of oocyte quality and aneuploidy underlying RPL aetiology. However, RPL is not ameliorated by oocyte donation in young women, suggesting an endometrial/systemic origin and highlighting the need to further study mechanisms driving this disorder. Trial registration number Not applicable

P-487 Preimplantation genetic testing for aneuploidy for recurrent pregnancy loss: a systematic review and meta-analysis

Abstract Study question Can preimplantation genetic testing for aneuploidy (PGT-A) improve the live rate of recurrent pregnancy loss(RPL)? Summary answer PGT-A can improve the live birth rate and reduce the rate of miscarriages in women with RPL following in vitro fertilization-embryo transfer (IVF-ET). What is known already PGT-A has been widely used in women with RPL over the past decade. However, there is no consensus supporting this approach to the management of RPL. Study design, size, duration Systematic review and meta-analysis according to PRISMA guidelines. The research population was focused on RPL women. The intervention was PGT-A. The comparator was IVF/ICSI without PGT-A or expectant management. The primary outcome was the live birth rate per woman, and the secondary outcomes were the miscarriage rate and clinical pregnancy rate. Participants/materials, setting, methods PubMed, EMBASE, The Cochrane Library, and trial registers were searched for studies on PGT-A and RPL up to October 2022. There were no limitations regarding the year of publication or duration of follow-up but to the English language. The primary outcome was the live birth rate per woman, and the secondary outcomes were the miscarriage rate and clinical pregnancy rate. Main results and the role of chance Out of 1466 search results, 9 studies (including one RCT, one prospective pilot study, and seven retrospective cohort studies) were included in the review. Seven of these studies compared the live birth rate of RPL with PGT-A versus without PGT-A following in vitro fertilization-embryo transfer (IVF-ET). PGT-A significantly increased live birth rate (odds ratio(OR): 2.07; 95% confidence interval: 1.88 to 2.27) and lowered miscarriage rate (OR: 0.21; 95% confidence interval: 0.13 to 0.34). However, PGT-A did not improve the clinical pregnancy rate. In two studies comparing the live birth rate/ongoing pregnancy of RPL with PGT-A versus expectant management, the result shows that PGT-A did not improve the live birth rate (OR: 1.11; 95% confidence interval: 0.74 to 1.67). Limitations, reasons for caution Limitations include the retrospective design and heterogeneity of studies included, limiting comparison and pooling of data. Some studies have limited sample sizes. The data collected in the database could not exclude anatomic or chromosomal abnormalities in women with RPL. Wider implications of the findings PGT-A can improve the live birth rate and reduce the rate of miscarriages in women with RPL following IVF-ET. However, there is no evidence of a beneficial effect of PGT-A if compared with expectant management. It is important to evaluate carefully the application of PGT-A in clinical practice. Trial registration number not applicable

The association of APOH and NCF1 polymorphisms on susceptibility to recurrent pregnancy loss in women with antiphospholipid syndrome.

Recurrent pregnancy loss (RPL) is the main manifestation of pathological pregnancy in antiphospholipid syndrome (APS) women. The immune state plays a significant role in the occurrence/development of APS and RPL susceptibility, but there is little research on genetic factors. Previous studies have described the important role of APOH and NCF1 in APS and pregnancy. To explore the association of APOH and NCF1 gene variants with RPL susceptibility in APS patients, we collected and analyzed 871 controls, 182 APS and RPL, and 231 RPL patients. Four single nucleotide polymorphisms (SNPs) (rs1801690, rs52797880, and rs8178847 of APOH and rs201802880 of NCF1) were selected and genotyped. We found rs1801690 (p = 0.001, p = 0.003), rs52797880 (p = 8.73e-04, p = 0.001), and rs8178847 (p = 0.001, p = 0.001) of APOH and rs201802880 (p = 3.77e-26, p = 1.31e-26) of NCF1 showed significant differences between APS and RPL patients and controls in allelic and genotype frequencies respectively. Moreover, rs1801690, rs52797880, and rs8178847 showed strong linkage disequilibrium. Especially, our results revealed a complete linkage disequilibrium (D' = 1) between rs52797880 and rs8178847. Furthermore, higher serum TP (total protein) level was described in APOH rs1801690 CG/GG (p = 0.007), rs52797880 AG/GG (p = 0.033), and rs8178847 CT/TT (p = 0.033), while the higher frequency of positive serum ACA-IgM was found in NCF1 rs201802880 GA (p = 0.017) in APS and RPL patients. Rs1801690, rs52797880, and rs8178847 of APOH and rs201802880 of NCF1 were associated with RPL susceptibility in APS patients.

The risk factors of progestational anxiety, depression, and sleep disturbance in women with recurrent pregnancy loss: A cross-sectional study in China.

The risk factors of progestational anxiety, depression, and sleep disturbance in women with a history of recurrent pregnancy loss (RPL) remain controversial, additional study is needed to investigate the incidence and risk factors of progestational anxiety, depression, and sleep quality in RPL women. A cross-sectional study was conducted among 663 non-pregnant RPL women in Northeast China from October 2019 to July 2022. We assessed the state of anxiety, depression, and sleep quality before pregnancy using structured questionnaires, including sociodemographic characteristics, state-trait anxiety scale (STAI), center for epidemiological survey, depression scale (CES-D), Pittsburgh sleep quality index (PSQI), and symptom self-rating scale (SCL-90). Logistic regression was used to evaluate the association between sleep quality and anxiety, depression. Pearson's correlation was used to evaluate the correlation between anxiety and depression. Multivariate logistic regression analysis was used to find the risk factors of depression symptoms. The receiver operating characteristic curve (ROC) was used to evaluate the predictive value of the model. The incidence of state anxiety, trait anxiety, depression, and sleep disturbance in RPL women were 60.3, 51.7, 33.9, and 31.2%, respectively. The level of anxiety and depression in RPL women varied at different stages of treatment. In a longitudinal study (25 pairs), we found the level of state anxiety and trait anxiety were significantly lower after the cause was identified. Sleep disturbance is positively correlated with anxiety and depression. Logistic regression showed that the number of miscarriages ≥4 (Odds ratio (OR) = 2.268, 95%CI 1.300-3.956), Low household family income (OR = 1.613, 95%CI 1.036-2.513/OR = 2.361, 95%CI 1.095-5.092), interval since last miscarriage <6 months (OR = 2.154, 95%CI 1.246-3.726) and sleep disturbance (OR = 5.523, 95%CI 3.542-8.614) were associated with the occurrence of depressive symptoms. At the same time, anxiety can be used as a predictor of depression. Recurrent pregnancy loss women have a certain degree of anxiety, depression, and sleep disturbance. Education level, interval since the last miscarriage <6 months, and sleep disturbance are risk factors for anxiety and depression. A history of pregnancy loss after 14 weeks and no living birth are also closely related to anxiety. Therefore, it is necessary to pay close attention to the psychological state of RPL women and provide appropriate psychosocial support to reduce the occurrence of negative emotions.

Analysis of FCGR3A-p.176Val variants in women with recurrent pregnancy loss and the association with CD16a expression and anti-HLA antibody status

Natural Killer (NK) cells have been implicated in recurrent pregnancy loss (RPL). The p.Val176Phe (or Val158Phe) Single Nucleotide Polymorphism (SNP) in the FCGR3A gene encoding the FcγRIIIA or CD16a receptor has been associated with an enhanced affinity for IgG and stronger NK-mediated antibody-dependent cellular cytotoxicity. We hypothesized that the presence of at least one p.176Val variant associates with RPL and increased CD16a expression and alloantibodies e.g., against paternal human leukocyte antigen (HLA). In 50 women with RPL, we studied frequencies of the p.Val176Phe FCGR3A polymorphisms. Additionally, CD16a expression and anti-HLA antibody status were analyzed by flowcytometry and Luminex Single Antigens. In woman with RPL, frequencies were: 20% (VV), 42% (VF) and 38% (FF). This was comparable to frequencies from the European population in the NCBI SNP database and in an independent Dutch cohort of healthy women. NK cells from RPL women with a VV (22,575 [18731-24607]) and VF (24,294 [20157-26637]) polymorphism showed a higher expression of the CD16a receptor than NK cells from RPL women with FF (17,367 [13257-19730]). No difference in frequencies of the FCGR3A-p.176 SNP were detected when comparing women with or without class I and class II anti-HLA antibodies. Our study does not provide strong evidence for an association between the p.Val176Phe FCGR3A SNP and RPL.

Interferon-λ contributes to endometrial receptivity.

IFN-λs participate in the fetal-maternal immune interaction, involving in immune regulation, uterine receptivity, cell migration and adhesion, and endometrium apoptosis. Our study helps to elucidate the underlying causes of the IFN-λs deficiency to spontaneous pregnancy loss in women. Immunotherapy has been commonly used to prevent recurrent pregnancy loss in women with inadequate uterus receptivity or immunological imbalance. Many immune regulators are now identified as having crucial roles at the embryo-maternal interface. However, the clinical efficacy of immunity-related markers during the peri-implantation period remains to be explored in depth. Here, we demonstrated that endometrial expression of interferon-λ (IFN-λ), regarded as a newer class of interferons, is aberrantly lower in women who suffered from recurrent implantation failure than that in fertile control. We further uncovered genetic and biochemical evidence that IFN-λ is induced directly by estrogen in the endometrial cells, and IFN-λ pathway may play multiple roles involving the inflammatory response, uterine receptivity, cell migration, and blastocyst adhesion. Furthermore, we indicated IFN-λ lessens the sensitivity of endometrium to FASL-mediated apoptosis. In addition to uncovering this IFN-λ as a novel nonredundant regulator that participates in the fetal-maternal immune interaction, our study helps to elucidate the underlying causes of spontaneous pregnancy loss in women.

Maternal circulating exosomal miR-185-5p levels as a predictive biomarker in patients with recurrent pregnancy loss.

The aim of this study was to explore the predictive role of microRNAs (miRNAs) from maternal serum exosomes in early recurrent pregnancy loss (RPL) and the related mechanism in early pregnancy. Maternal serum was collected from pregnant women with RPL history or women with ongoing pregnancy (OP); serum exosomes were extracted and identified. Differentially expressed (DE) miRNAs in exosomes were screened by RNA sequencing and further validated by qRT-PCR. Next, the predictive value of exosomal miRNA and the clinical indicators for subsequent miscarriage in RPL patients were evaluated. Additionally, we verified the regulatory relationship between miR-185-5p and vascular endothelial growth factor (VEGF) in decidual natural killer (dNK) cells by overloading or inhibiting the exosomal miR-185-5p level in trophoblast cells. The miRNA sequencing revealed 43 DE miRNAs between OP and RPL patients. The five most significant DE miRNAs (miR-22-3p, miR-185-5p, miR-335-3p, miR-362-5p, and miR-378a-3p) were selected for identification, and miR-185-5p was increased in RPL patients. The area under curve (AUC) of the receiver operating characteristic was 0.925 when using miR-185-5p as a biomarker for subsequent miscarriage in RPL patients. In addition, miR-185-5p in exosomes secreted from HTR-8 cells reduces VEGF expression of dNK cells. The current study, for the first time, successfully constructed the correlation between maternal circulating exosomal miR-185-5p expression pattern and RPL, which may be involved in the pathogenesis of RPL by downregulating the VEGFA of dNK cells and perturbing angiogenesis at the maternal-fetal interface.

The evaluation of CD39, CD73, and HIF-1 α expression besides their related miRNAs in PBMCs of women with recurrent pregnancy loss

The molecular mechanisms involved in the pathogenesis of recurrent pregnancy loss (RPL) are not completely recognized. The present study aimed to assess the molecules associated with ATP catabolism and hypoxia besides their related miRNAs in patients with RPL. The frequency of Th17 and Treg cells in PBMCs of RPL women and healthy pregnant women were evaluated with Flow cytometry. The expression levels of CD39, CD73, and Hypoxia-inducible factor-alpha (HIF-1α), miR-18a, miR-30a, and miR-206 in PBMCs of two groups were measured with real-time PCR and western blotting. Then, serum levels of IGF-1, TGF-β, and HIF-1α were measured by ELISA. Our results indicated a higher (p = 0.0002) and lower (p < 0.0001) frequency of Th17 and Treg lymphocytes in RPL women, respectively. The expression level of CD39 decreased in PBMCs of RPL women whereas the level of CD73 and HIF-α increased (p = 0.0010, 0.0023, 0.0006 respectively). The results of CD39 and CD37 were also confirmed by protein analysis (p = 0.0047, 0.0364 respectively). Almost, the same results for CD39 and CD73 expression at mRNA and protein levels were observed in isolated Treg cells. Moreover, we found the higher expression of miR-206 and miRNA-30a (p = 0.0038, 0.0123), but the lower expression of miRNA-18a (p = 0.0101) in RPL. The concentration level of IGF-1, and TGF-β reduced (p = 0.0017, 0.0065 respectively) while the level of HIF-α elevated (p = 0.0235) in serum samples of RPL. In conclusion, we observed the dysregulation of molecules that are involved in ATP catabolism and hypoxia, including CD39, CD73, and HIF-1a which is related to miR-18a, miR-30a, and miR-206 change in RPL women. It may be potentially used for RPL prognosis by more comprehensive future studies.