Cause Of Miscarriage Research Articles

Non-Steroidal Anti-Inflammatory Drugs Consumption and Awareness About Risks During Pregnancy In AL-Bayda City, Libya

Non-steroidal anti-inflammatory drugs are one of the most common prescribed medications for relieving pain, fever, and inflammation. Most NSAIDs are available without a prescription, and they often consumed by pregnant women for short periods of time to treat mild pain. However, these drugs can cause substantial teratogenic effects. NSAIDs such as aspirin, diclofenac sodium and ibuprofen might cause oligohydramnios (low amniotic fluid) or prenatal renal abnormalities if taken in the late second half of pregnancy. The US Food and Drug Administration (FDA) announced that taking NSAIDs in the period from the fifth month of pregnancy to delivery is not safe. This research was conducted to explore pregnant women's knowledge about NSAIDs during gestation period as well as consumption patterns. This study was conducted during the period from 10/2/2022 to 10/3/2022 in private clinics in Al-Bayda, Al-Quba cities as well as Al -Thawra hospital targeting 250 pregnant women who asked gently to fill in a printed questionnaire. The questionnaire has a variety of questions regarding age, consumption of NSAIDs during pregnancy and awareness about the benefits and risks of these drugs. Our study indicated that 55.6% of the pregnant women were in the range of twenty-two to twenty-nine years old. Half of pregnant women (50%) did consume painkillers (NSAIDs). Aspirin was the most common drug (55%). Forty-five out of 125 were consuming these drugs without prescription (36%). The common reason for consuming NSAIDs was varicose veins (31%). 30.4% of pregnant women had a miscarriage. Poor fetal growth was the most common cause of miscarriage among 29% of participants. Sixty-five percent of the participants knew that using this kind of drugs in the last month of pregnancy affect their health negatively. Only 4% of them had miscarriage due to consumption of NSAIDs. Pain management noticed in 90% of pregnant women. Awareness about the positive and negative effects of NSAIDs was noticed in 55% of the participants. In conclusion, despite the fact which is consumption of NSAIDs throughout pregnancy has undesirable effects on pregnant women and fetus, these drugs are widely prescribed by doctors to pregnant women. NSAIDs should not be prescribed during pregnancy unless mother's outcomes exceed the possible fetal adverse effects. Our research found no significant relation between NSAIDs consumption in the period of pregnancy and miscarriage. Although our results were satisfied, concentrated education programs are needed to spread knowledge in our society and another research must be conducted on a large sample size to investigate the differences among this study with the current research.

Maternal ELL3 loss-of-function leads to oocyte aneuploidy and early miscarriage.

Up to an estimated 10% of women experience miscarriage in their lifetimes. Embryonic aneuploidy is a leading cause for miscarriage, infertility and congenital defects. Here we identify variants of ELL3, a gene encoding a transcription elongation factor, in couples who experienced consecutive early miscarriages due to embryonic aneuploidy. Maternal ELL3 knockout leads to mouse oocyte aneuploidy, subfertility and miscellaneous embryonic defects. Mechanistically, we find that ELL3 localizes to the spindle during meiosis, and that ELL3 depletion in both mouse and human oocytes increases the incidence of meiotic spindle abnormality. ELL3 coordinates with TPX2 to ensure the proper function of the microtubule motor KIF11. Live imaging analysis shows that ELL3 is paramount for promoting spindle assembly and driving chromosome movement. Together, our findings implicate maternal ELL3 deficiency in causing oocyte aneuploidy and early miscarriage.

Endometriosis does not impact aneuploidy rates of products of conception in IVF population

It has been debated whether endometriosis (EMS) adversely affects oocyte quality, potentially leading to a higher incidence of genetically unbalanced embryos or other egg factors that affect the developmental potential. In this study, we explored the effects of endometriosis on risk of chromosomally aberrant in miscarried products of conception (POC) after assisted reproductive treatment (ART), including fresh and frozen cycles. Miscarried POCs were collected from EMS patients (N = 102) and non-EMS patients (N = 441). Single nucleotide polymorphism (SNP) array analysis was conducted on all collected samples. Propensity score matching (PSM, ratio of 1:4) based on maternal age was applied in data analysis. Logistic regression analysis was performed to identify risk factors for chromosomal aberration-induced miscarriage between the two cohorts. A total of 228 (41.99% of 543) conceptuses were identified as having chromosomal aberrations. The results showed that women with EMS had a significantly lower antral follicle count (AFC) (10 ± 5 vs. 14 ± 7, P < 0.01) compared to the control group. Additionally, the EMS group had a relatively lower anti-Mullerian hormone (AMH), higher basal follicle stimulating hormone (FSH) and fewer oocytes, (P > 0.05). There was no significant difference in the chromosomal aberration rate of POCs between EMS and non-EMS groups (35.29% vs. 43.54%; odds ratio (OR) = 1.03, 95% confidence intervals (CIs) 0.79–1.35). This is the first study to show that EMS maybe associated with decreased ovarian reserve, but not related to chromosomal abnormalities in POCs. These results suggest that chromosomal abnormalities may not be the only cause of miscarriage in EMS patients.

Chromosome architecture and low cohesion bias acrocentric chromosomes towards aneuploidy during mammalian meiosis

AbstractAneuploidy in eggs is a leading cause of miscarriages or viable developmental syndromes. Aneuploidy rates differ between individual chromosomes. For instance, chromosome 21 frequently missegregates, resulting in Down Syndrome. What causes chromosome-specific aneuploidy in meiosis is unclear. Chromosome 21 belongs to the class of acrocentric chromosomes, whose centromeres are located close to the chromosome end, resulting in one long and one short chromosome arm. We demonstrate that acrocentric chromosomes are generally more often aneuploid than metacentric chromosomes in porcine eggs. Kinetochores of acrocentric chromosomes are often partially covered by the short chromosome arm during meiosis I in human and porcine oocytes and orient less efficiently toward the spindle poles. These partially covered kinetochores are more likely to be incorrectly attached to the spindle. Additionally, sister chromatids of acrocentric chromosomes are held together by lower levels of cohesin, making them more vulnerable to age-dependent cohesin loss. Chromosome architecture and low cohesion therefore bias acrocentric chromosomes toward aneuploidy during mammalian meiosis.

Computer-Aided Diagnosis in Spontaneous Abortion: A Histopathology Dataset and Benchmark for Products of Conception.

Spontaneous abortion, commonly known as miscarriage, is a significant concern during early pregnancy. Histopathological examination of tissue samples is a widely used method to diagnose and classify tissue phenotypes found in products of conception (POC) after spontaneous abortion. Background: Histopathological examination is subjective and dependent on the skill and experience of the examiner. In recent years, artificial intelligence (AI)-based techniques have emerged as a promising tool in medical imaging, offering the potential to revolutionize tissue phenotyping and improve the accuracy and reliability of the histopathological examination process. The goal of this study was to investigate the use of AI techniques for the detection of various tissue phenotypes in POC after spontaneous abortion and evaluate the accuracy and reliability of these techniques compared to traditional manual methods. Methods: We present a novel publicly available dataset named HistoPoC, which is believed to be the first of its kind, focusing on spontaneous abortion (miscarriage) in early pregnancy. A diverse dataset of 5666 annotated images was prepared from previously diagnosed cases of POC from Atia General Hospital, Karachi, Pakistan, for this purpose. The digital images were prepared at 10× through a camera-connected microscope by a consultant histopathologist. Results: The dataset's effectiveness was validated using several deep learning-based models, demonstrating its applicability and supporting its use in intelligent diagnostic systems. Conclusions: The insights gained from this study could illuminate the causes of spontaneous abortion and guide the development of novel treatments. Additionally, this study could contribute to advancements in the field of tissue phenotyping and the wider application of deep learning techniques in medical diagnostics and treatment.

Analysis of Chromosome Test Results of 24,175 Miscarried Fetuses in Japan from 2000 to 2021

Background: Fetal chromosome abnormalities, the most common cause of spontaneous abortion, were investigated pre-1980s. In recent years, chromosome testing has been outsourced to testing companies in Japan, and there have been few epidemiological studies of chromosome testing of miscarried fetuses on a nationwide scale. Methods: We analyzed the chromosome test data of SRL Inc., one of the largest clinical laboratories that has collected tissue specimens of products of conception derived from miscarried fetuses from hospitals throughout Japan from 2000 to 2021. Results: We collected and analyzed 24,175 cases, among which 8,726 (36.1%) with normal chromosomes, 1,298 (5.4%) with sex chromosome aberrations, 9,735 (40.3%) with autosomal trisomy, 73 (0.3%) with autosomal monosomy, 840 (3.5%) with polyploidy, 512 (2.1%) with chromosomal structural abnormality, and 2,991 (12.4%) with mosaic, respectively. The frequency of autosomal trisomy increased at the older maternal ages. By chromosome number, trisomies 22, 16, 21, and 15 were associated with advanced maternal age, but trisomies 13, 14, and 18 were not associated with advanced maternal age. The presence or absence of this maternal age effect was correlated with the chromosome segregation being due to maternal meiosis I or meiosis II. For the sex ratios of the fetuses, we focused on trisomies 22, 21, 18, 16, 15, 14, and 13 and found that only trisomy 16 was significantly more frequently seen in female fetuses. Conclusion: The findings of this study provide insights into the basic understanding of miscarriage and will be useful in counseling and medical education.

An Appraisal of Recurrent Miscarriage in Sub-Saharan Africa: Occurrence and Possible Solution

A recurrent miscarriage may be defined in the African context as the foetal demise of two or more successive pregnancies before the attainment of the age of viability. A literature review was done to assess the trend of recurrent miscarriage in sub-Saharan Africa. Identifying the main causes, considering the population at risk, and the availability of accurate diagnostic utilities to effectively ensure good management of recurrent miscarriage is an important gynaecologic issue. Over the years, studies have identified several etiologies and yet there’s been no tangible implementation of therapeutic strategies. Routine modifications should also be employed to develop new approaches to reproductive prognosis. There is notably scanty information on the cases of spontaneous abortion due to chromosomal abnormalities. Genetic and immunological factors should be considered in the work-up plan for women with RM. About 70% of the cases of RM are considered unexplained, and this may be due to limited resources. We concluded that there is relatively poor management of miscarriage and cases of missed and inaccurate diagnosis of the causes of spontaneous abortion in sub-Saharan Africa. More studies are needed in order to assess the extent of genetic induced miscarriage, where resources are limited, folic acid supplements should be provided for pregnant women.

The Role of Plain Radiography in Assessing Aborted Foetal Musculoskeletal Anomalies in Everyday Practice.

Conventional radiography is widely used for postmortem foetal imaging, but its role in diagnosing congenital anomalies is debated. This study aimed to assess the effectiveness of X-rays in detecting skeletal abnormalities and guiding genetic analysis and counselling. This is a retrospective analysis of all post-abortion diagnostic imaging studies conducted at a centre serving a population of over 300,000 inhabitants from 2008 to 2023. The data were analysed using descriptive statistics. X-rays of 81 aborted foetuses (total of 308 projections; mean: 3.8 projections/examination; SD: 1.79) were included. We detected 137 skeletal anomalies. In seven cases (12.7%), skeletal anomalies identified through radiology were missed by prenatal sonography. The autopsy confirmed radiological data in all cases except for two radiological false positives. Additionally, radiology failed to identify a case of syndactyly, which was revealed by anatomopathology. X-ray is crucial for accurately classifying skeletal abnormalities, determining the causes of spontaneous abortion, and guiding the request for genetic counselling. Formal training for both technicians and radiologists, as well as multidisciplinary teamwork, is necessary to perform X-ray examinations on aborted foetuses and interpret the results effectively.

ARHGAP26 deficiency drives the oocyte aneuploidy and early embryonic development failure.

Aneuploidy, the presence of a chromosomal anomaly, is a major cause of spontaneous abortions and recurrent pregnancy loss in humans. However, the underlying molecular mechanisms still remain poorly understood. Here, we report that ARHGAP26, a putative tumor suppressor gene, is a newly identified regulator of oocyte quality to maintain mitochondrial integrity and chromosome euploidy, thus ensuring normal embryonic development and fertility. Taking advantage of knockout mouse model, we revealed that genetic ablation of Arhgap26 caused the oocyte death at GV stage due to the mitochondrial dysfunction-induced ROS accumulation. Lack of Arhgap26 also impaired both in vitro and in vivo maturation of survived oocytes which results in maturation arrest and aneuploidy, and consequently leading to early embryonic development defects and subfertility. These observations were further verified by transcriptome analysis. Mechanistically, we discovered that Arhgap26 interacted with Cofilin1 to maintain the mitochondrial integrity by regulating Drp1 dynamics, and restoration of Arhgap26 protein level recovered the quality of Arhgap26-null oocytes. Importantly, we found an ARHGAP26 mutation in a patient with history of recurrent miscarriage by chromosomal microarray analysis. Altogether, our findings uncover a novel function of ARHGAP26 in the oocyte quality control and prevention of aneuploidy and provide a potential treatment strategy for infertile women caused by ARHGAP26 mutation.

Miscarriage of Justice as a Phenomenon of Social Reality

The article is devoted to the study of social aspects of a miscarriage of justice, the public view of which is formed through such concepts as «fair court decision», «fair justice», and «legality». These categories are directly related to the issue of a miscarriage of justice, which is a consequence of a violation of these principles and the result of improper law enforcement activities of a judge. The existence of a miscarriage of justice is not always proof of an inhumane approach of the court to the resolution of a case. Courts often face the problem of balancing legality and justice. At the same time, both the lack of legality and justice are assessed by society as a misunderstanding or application of the law, i.e. a miscarriage of justice that undermines confidence in justice. The article also emphasizes the existence of formal (legal), real (social) and procedural justice. According to the author, the achievement of formal (legal) justice depends not only on the actions of the judge, but also on the justice of the law itself. He believes that the cause of miscarriages of justice may be the abstract nature of the law, which leads to injustice in its application. In this case, there is a need to make a decision in which the moral aspect of the circumstances of the case prevails over the law. With regard to procedural justice, it is noted that this is the only type of justice that has been enshrined in law in Ukraine. Regarding real (social) justice, the author argues that it depends to a greater extent on the moral account of the judges themselves and the system of values they profess. The article also mentions the ways of solving the existing problem, namely, combating miscarriages of justice arising either due to excessive formalism in case resolution (literal understanding of the law without regard to natural justice) or, on the contrary, when a judge goes beyond the powers granted to him/her by law (broad judicial discretion in the matter of the moral component of the law), by legislatively enshrining the principle of justice. The author emphasizes that the mere mentioning in the law of the principle of justice without defining its content will not solve the existing problem and may result in new miscarriages of justice against the background of a judge’s distorted view of justice. Key words: miscarriage of justice, fair justice, legality, natural justice.

Miscarriages after Natural Conception &amp; IVF: Comparative Study of Genetic Analysis of Products of Conception

Assisted reproductive technologies (ART), including in vitro fertilization (IVF), are modern medical technologies widely used in developed countries. A frequent complication of pregnancy resulting from ART is miscarriage. The leading cause of miscarriage, both sporadic and recurrent, is chromosomal abnormalities (CA) of the embryo. To compare the frequency and structure of chromosomal abnormalities (CA) of the embryo during miscarriages after IVF and natural conception. Retrospective cohort comparative study. The study, conducted in 2018-2022, included 1,000 products of conception (POCs) samples from patients with miscarriage. The study participants were divided into 2 groups depending on the origin of pregnancy: group 1 – women whose pregnancy occurred naturally (n = 862), group 2 – women whose pregnancy occurred as a result of in vitro fertilization (IVF) (n = 138). Miscarriage was confirmed by ultrasound performed at 6-10 weeks of pregnancy. A genetic study of POCs was carried out using chromosomal microarray analysis (CMA). In total, CA was detected in 580 samples (58%), and a normal molecular karyotype was determined in 420 (42%). CAs in abortive material during pregnancy loss are detected with a frequency of 59.05% in cases of natural conception and with a frequency of 51.05% in pregnancies resulting from IVF (p = 0.093). There were no statistically significant differences in the frequency and structure of CA in the study groups. Autosomal trisomies were most often detected. In our study, among all autosomal trisomies, the most common were trisomy 16, trisomy 22 and trisomy 15. Among the sex chromosome abnormalities, monosomy X was most often detected - in total, it was determined in 66 (6.6%) samples, which significantly exceeds the frequency of monosomy X among live births. Only in 0.2-0.3% of cases, when the embryo has monosomy X, pregnancy progresses and ends in a live birth. Copy number variations (CNVs) were often detected - a total of 52 (5.2%) samples with different CNVs, respectively 46 (5.3%) and 6 (4.3%) in groups 1 and 2. Detection of such abnormality is critically important, as it can be the result of carriage of a balanced CAs in one of the parents, which significantly increases the risk of miscarriage in the future. In pregnancies resulting from IVF, mosaicism in abortive material was more common, but the differences were not statistically significant. In group 1, mosaicism was detected in 66 (7.6%) cases and in group 2 - 13 (9.4%) cases. The IVF procedure does not increase the risk of CA in the embryo but also does not significantly reduce it. Considering the high frequency of CA in miscarriage, persons referred for IVF and with a history of idiopathic recurrent pregnancy loss should be informed about the possibility of PGT.

P-538 Liquid biopsy (niPOC) as a new approach to genetic studies in early pregnancy loss. First clinical experience in Spain

Abstract Study question How accurate is the use of liquid biopsy as a new tool for aneuploidy testing in cases of pregnancy losses? Summary answer This study demonstrates that genome-wide cfDNA testing in the maternal bloodstream (niPOC) constitutes a simple, tissue-independent, straightforward and reliable complement/alternative to traditional POC analysis. What is known already Around 50-70% of clinical miscarriages are caused by aneuploidies, mostly trisomies. To date, conventional cytogenetic and advanced molecular techniques are used for the analysis of POC to identify the genetic cause of miscarriage, providing valuable information for genetic counseling. However, both approaches are based in the direct analysis of the abortive tissue, which entails several limitations due to a risk of culture failure and/or maternal cell contamination. To solve these drawbacks, maternal cell-free DNA (cfDNA) testing emerges as a promising alternative due to the accumulated evidence. Study design, size, duration Retrospective study and first clinical experience, both conducted in our facilities from January 2021 to December 2023. Before carrying out the fetal tissues collection for the POC analysis, a blood sample was drawn to evaluate possible aneuploidies by cfDNA testing. Using NGS+STR POC results as the gold standard, results derived from both studies were compared to assess the percentage of concordance and the cases of non-informativeness (fetal fraction (FF) &amp;lt;2%), false positives, and false negatives. Participants/materials, setting, methods Herein we present a clinical validation (n = 152) and the first clinical experience (n = 103). Maternal peripheral blood samples were extracted for aneuploidy evaluation using Illumina’s sequencing platform. Genetic testing on POCs was performed using NGS (Thermo Fisher Scientific) to detect aneuploidies, and short tandem repeats to detect cases with MCC and/or polyploidy. In both groups (niPOC and POC), the percentage of concordance and cases of non-informativeness (by fetal fraction &amp;lt;2%, or CCM) were evaluated. Main results and the role of chance In the validation set, no significant differences in non-informativity were observed between POC and niPOC [9.2% (14/152) vs 13.8% (21/152)]. Excluding triploids, the sensitivity of niPOC compared with the pregnancy tissue sequencing result was 90.1%, specificity of 97.1% and an accuracy of 88%. In the first clinical experience, non-informativity was similar to that found in the validation (17/103, 16.5%). The percentage of abnormal cases was 43%, very close to the 50% expected according to the scientific literature. Regarding turnaround time, reports in niPOC were released in an average of 3.8 working days. Limitations, reasons for caution Current cfDNA testing technology fails in polyploidy, uniparental disomy identification, which is a potential cause of pregnancy loss. Aneuploidy detection is only feasible if the blood collection was performed before the fetal remains evacuation. Wider implications of the findings CfDNA testing before curettage or pharmacological treatment could be an alternative to POC analysis. If optimized, cfDNA testing could be used contingently with the molecular POC analysis in cases where maternal cell contamination is present. As a result, the overall success rate in the POC program could be substantially improved. Trial registration number Not applicable

KAT8-mediated H4K16ac is essential for sustaining trophoblast self-renewal and proliferation via regulating CDX2

Abnormal trophoblast self-renewal and differentiation during early gestation is the major cause of miscarriage, yet the underlying regulatory mechanisms remain elusive. Here, we show that trophoblast specific deletion of Kat8, a MYST family histone acetyltransferase, leads to extraembryonic ectoderm abnormalities and embryonic lethality. Employing RNA-seq and CUT&Tag analyses on trophoblast stem cells (TSCs), we further discover that KAT8 regulates the transcriptional activation of the trophoblast stemness marker, CDX2, via acetylating H4K16. Remarkably, CDX2 overexpression partially rescues the defects arising from Kat8 knockout. Moreover, increasing H4K16ac via using deacetylase SIRT1 inhibitor, EX527, restores CDX2 levels and promoted placental development. Clinical analysis shows reduced KAT8, CDX2 and H4K16ac expression are associated with recurrent pregnancy loss (RPL). Trophoblast organoids derived from these patients exhibit impaired TSC self-renewal and growth, which are significantly ameliorated with EX527 treatment. These findings suggest the therapeutic potential of targeting the KAT8-H4K16ac-CDX2 axis for mitigating RPL, shedding light on early gestational abnormalities.

O-262 Karyotyping of single sperm from non-obstructive azoospermia patients and obstructive azoospermia patients using a combination of micromanipulation and next-generation sequencing

Abstract Study question Is there a difference in the frequency of aberrant karyotype in sperm when the cause of infertility is non-obstructive azoospermia (NOA) versus obstructive azoospermia (OA)? Summary answer Aberrant karyotype was found in 7 of 46 sperm with NOA, none of 26 sperm with OA and none of 28 sperm with control. What is known already It is known that aberrant karyotype occurs more frequently in sperm from infertile men than sperm from general population, and that the severity of infertility is proportional to the frequency of sperm chromosomal abnormality. In fact, miscarriage rates are high in cases where TESE-ICSI is performed for azoospermia, and embryonic chromosomal aneuploidy derived from sperm is thought to be one of the causes of miscarriage. Azoospermia is classified into OA and NOA. However, it is unclear whether there is a difference in the frequency of sperm chromosomal abnormality between NOA and OA. Study design, size, duration Sperm were picked up individually by micromanipulation for the OA and NOA groups who underwent TESE in clinical practice. For comparison, ejaculated sperm from males who underwent IVF or ICSI for female infertility were picked up. As a quality control, ejaculated sperm from balanced reciprocal translocation (RcT) carriers were also picked up. Each sperm was karyotyped by next-generation sequencing (NGS) to compare the number of normal haploid sperm and aberrant sperm. Participants/materials, setting, methods Under the ethical review of Yokohama City University and informed consent with patients, we collected human sperm which were discarded after clinical use. Sperm samples were picked up individually by micromanipulation. Following whole-genome amplification (WGA), karyotyping was performed by NGS. For each sperm, if even one of all chromosomes had abnormality, that sperm was counted as aberrant sperm, and if all chromosomes were haploid, it was counted as haploid sperm. Main results and the role of chance We analyzed 10 sperm per patient. Karyotyping analysis was performed on sperm from 2 patients in the RcT group,4 patients in the control group, 4 patients in the OA group, and 5 patients in the NOA group. WGA was successful in 90% (18/20) of RcT carriers group, 95% (38/40) of the control group, 72.5% (29/40) of the OA group, and 92% (46/50) of the NOA group. Acquisition rate of karyotyping was 90% (18/20) of RcT carriers group, 70% (28/40) of the Control group, 65% (26/40) of the OA group, and 95% (46/50) of the NOA group. The results of karyotype analysis showed 28 haploid sperm and no aberrant sperm in the control group, 26 haploid sperm and no aberrant sperm in the OA group, and 39 haploid sperm and 7 aberrant sperm in the NOA group. Karyotyping of sperm from RcT carriers group showed sperm with unbalanced chromosomes derived from translocations of the carriers. The frequency of aberrant karyotype was significantly higher in NOA than control (P = 0.0297). It was also higher in NOA than OA(P = 0.0363). Limitations, reasons for caution In our research, micromanipulation was performed manually to isolate sperm, and the number of sperm that could be analyzed was small. Sperm with good morphology are selected using micromanipulation and analyzed by NGS, so the results do not reflect the results of all sperm actually collected by TESE. Wider implications of the findings In this study, sperm with good morphology were selected by micromanipulation and analyzed, so it is thought that the karyotype of sperm actually reflects the karyotype used in clinical practice. These results suggest that PGT-A is particularly effective in preventing miscarriages among patients whose azoospermia was caused by NOA. Trial registration number not applicable

Effect of Reproductive System Dysbiosis on the Course of Pregnancy

Abstract Genetic, endocrine and immunological disorders, anatomical defects in the reproductive tract, certain chronic diseases, toxic substances, or advanced age of the mother are most cited among the main causes of pregnancy loss at various stages. However, the cause of miscarriage or preterm labor in some cases remains unclear. Determination of the etiology about these clinical conditions may reduce the rate of reproductive failure. Similarly, the etiology of other obstetric disorders, such as preeclampsia or postpartum hemorrhage, has not been fully explained. One of the postulated and still under-researched causes of these disorders may be dysbiosis within the reproductive tract. A disturbed microbial balance is not always associated with the presence of an acute infection with clear clinical symptoms. Dysbiosis in conjunction with other pathophysiological factors may increase the risk of the mentioned clinical conditions. The aim of this paper is to show the information indicating the existence of a correlation between dysbiosis and an increase in the risk of obstetric disorders. Further analysis is also required to clarify the mechanism of the effect of dysbiosis on the disruption of metabolic and biochemical processes within the reproductive system during pregnancy.

Analysis of copy number variants detected by sequencing in spontaneous abortion.

The incidence of spontaneous abortion (SA), which affects approximately 15-20% of pregnancies, is the most common complication of early pregnancy. Pathogenic copy number variations (CNVs) are recognized as potential genetic causes of SA. However, CNVs of variants of uncertain significance (VOUS) have been identified in products of conceptions (POCs), and their correlation with SA remains uncertain. Of 189 spontaneous abortion cases, trisomy 16 was the most common numerical chromosome abnormality, followed by monosomy X. CNVs most often occurred on chromosomes 4 and 8. Gene Ontology and signaling pathway analysis revealed significant enrichment of genes related to nervous system development, transmembrane transport, cell adhesion, and structural components of chromatin. Furthermore, genes within the VOUS CNVs were screened by integrating human placental expression profiles, PhyloP scores, and Residual Variance Intolerance Score (RVIS) percentiles to identify potential candidate genes associated with spontaneous abortion. Fourteen potential candidate genes (LZTR1, TSHZ1, AMIGO2, H1-4, H2BC4, H2AC7, H3C8, H4C3, H3C6, PHKG2, PRR14, RNF40, SRCAP, ZNF629) were identified. Variations in LZTR1, TSHZ1, and H4C3 may contribute to embryonic lethality. CNV sequencing (CNV-seq) analysis is an effective technique for detecting chromosomal abnormalities in POCs and identifying potential candidate genes for SA.

Deficiency of UCHL1 results in insufficient decidualization accompanied by impaired dNK modulation and eventually miscarriage

BackgroundMiscarriage is a frustrating complication of pregnancy that is common among women of reproductive age. Insufficient decidualization which not only impairs embryo implantation but disturbs fetomaternal immune-tolerance, has been widely regarded as a major cause of miscarriage; however, the underlying mechanisms resulting in decidual impairment are largely unknown.MethodsWith informed consent, decidual tissue from patients with spontaneous abortion or normal pregnant women was collected to detect the expression profile of UCHL1. Human endometrial stromal cells (HESCs) were used to explore the roles of UCHL1 in decidualization and dNK modulation, as well as the mechanisms involved. C57/BL6 female mice (7–10 weeks old) were used to construct pregnancy model or artificially induced decidualization model to evaluate the effect of UCHL1 on mice decidualization and pregnancy outcome.ResultsThe Ubiquitin C-terminal hydrolase L1 (UCHL1), as a deubiquitinating enzyme, was significantly downregulated in decidua from patients with miscarriage, along with impaired decidualization and decreased dNKs. Blockage of UCHL1 led to insufficient decidualization and resultant decreased expression of cytokines CXCL12, IL-15, TGF-β which were critical for generation of decidual NK cells (dNKs), whereas UCHL1 overexpression enhanced decidualization accompanied by increase in dNKs. Mechanistically, the promotion of UCHL1 on decidualization was dependent on its deubiquitinating activity, and intervention of UCHL1 inhibited the activation of JAK2/STAT3 signaling pathway, resulting in aberrant decidualization and decreased production of cytokines associated with dNKs modulation. Furthermore, we found that inhibition of UCHL1 also disrupted the decidualization in mice and eventually caused adverse pregnancy outcome.ConclusionsUCHL1 plays significant roles in decidualization and dNKs modulation during pregnancy in both humans and mice. Its deficiency indicates a poor pregnancy outcome due to defective decidualization, making UCHL1 a potential target for the diagnosis and treatment of miscarriage.Graphical

Copy number variation sequencing for the products of conception: What is the optimal testing strategy

BackgroundCopy number variation sequencing (CNV-seq) is crucial in prenatal diagnosis, but its limitations in detecting polyploidy, maternal cell contamination (MCC), and uniparental disomy (UPD) restrict its application in the analysis of products of conception (POCs). This study aimed to investigate an optimal genetic testing strategy for POCs in the era of CNV-seq. MethodsCNV-seq and quantitative fluorescent polymerase chain reaction (QF-PCR) were performed in all 4,211 spontaneous miscarriage cases. Different testing strategies were compared and the optimal testing strategies were proposed. ResultsOf the 4,211 cases, 2561 (60.82%) exhibited clinically significant chromosomal abnormalities. CNV-seq alone, without QF-PCR, might misdiagnose 311 (7.39%) cases, including 278 polyploidy, 13 UPD, and 20 MCC. In 20 MCC cases identified by QF-PCR, CNV-seq successfully pinpointed the cause of miscarriage in 13 cases. Furthermore, in cases where QF-PCR suggested polyploidy, CNV-seq improved the diagnostic accuracy in 54 (1.28%) hypo/hypertriploidy cases. After comparing four different strategies, the sequential approach (initiating with CNV-seq followed by QF-PCR if necessary) emerged as advantageous, reducing approximately 70% of the cost associated with QF-PCR while maintaining result accuracy. ConclusionsWe propose an initial CNV-seq followed by QF-PCR if needed—an efficient and cost-effective strategy for the genetic analysis of POCs.

“White spots” in the diagnostic search for the causes of recurrent miscarriage

Recurrent pregnancy loss is not only a medical, but also a social problem of a multifactorial nature. This problem remains unsolvable despite the constant search and application of new diagnostic and therapeutic strategies. The presented review examines the literature data on evidence-based methods for diagnosing the causes of miscarriage, as well as methods whose use remains controversial. Special attention is paid to the immunological foundations of a normal pregnancy formation, the violation of which creates the prerequisites for a recurrent miscarriage. The paper also analyzes current data on the role of endometrial receptivity and the contribution of the male factor to the problem of miscarriage, and presents prospects for further research on the problem of recurrent pregnancy loss.

Mechanism of chromosomal mosaicism in preimplantation embryos and its effect on embryo development.

Aneuploidy is one of the main causes of miscarriage and in vitro fertilization failure. Mitotic abnormalities in preimplantation embryos are the main cause of mosaicism, which may be influenced by several endogenous factors such as relaxation of cell cycle control mechanisms, defects in chromosome cohesion, centrosome aberrations and abnormal spindle assembly, and DNA replication stress. In addition, incomplete trisomy rescue is a rare cause of mosaicism. However, there may be a self-correcting mechanism in mosaic embryos, which allows some mosaicisms to potentially develop into normal embryos. At present, it is difficult to accurately diagnose mosaicism using preimplantation genetic testing for aneuploidy. Therefore, in clinical practice, embryos diagnosed as mosaic should be considered comprehensively based on the specific situation of the patient.