Cause Of Miscarriage Research Articles

The value of toll-like receptors in predicting the activation of latent herpesvirus infection during pregnancy

Introduction. Recurrent pregnancy loss is a pathological condition characterized by inevitable miscarriage before 22 weeks of pregnancy or at birth of a fetus below 500 g of weight. The causes of miscarriage are quite diverse, and viral infections, including herpesvirus infection (HVI), is one of the important etiological factors for the development of this pathology. Activation of herpesvirus infection (HVI) has an extremely adverse effect on the course of pregnancy. The issue of the mechanism of reactivation of herpes viruses (HS) and the role of toll-like receptors (TLR) in predicting the activation of latent HVI during pregnancy has been insufficiently studied until the present. The study is aimed at evaluating the possibilities of predicting the activation of latent herpesvirus infection during pregnancy.Materials and methods. A total of 110 pregnant women with different courses of HVI were examined. The examination included the study of the TLR expression level and measurement of the pro- and anti-inflammatory cytokine levels.Results and discussion. Given the high specificity of TLR8 and the interferon system (IFN) against viral antigens, it can be assumed that the activation of TLR and the development of early cytokine reactions prior to the detection of specific antibodies in patients with latent HVI are predictors of advanced herpes infection. The levels of TLR8 expression and concentration of IFN-γ and IL-10 at the local level in patients with latent BBVI can be regarded as predictors of the transition of HBV from the latent phase of the life cycle to the lytic phase.Conclusion. If HVI develops actively during pregnancy, the antiviral immune response cascade that underlie the natural immune response starts at the local level, regardless of the localization of the antigen, and only a breakdown of the compensatory and adaptive mechanisms leads to the implementation of a systemic antiviral immune response. This suggests the important role of HVI, especially of its active forms, in the suppression of immunity during pregnancy.

Optimizing the Diagnostic Strategy to Identify Genetic Abnormalities in Miscarriage.

IntroductionThe single most common cause of miscarriage is genetic abnormality.ObjectiveWe conducted a prospective cohort study to compare the performance of conventional karyotyping and chromosomal microarray analysis (CMA) using array comparative genomic hybridization (array-CGH) and single nucleotide polymorphism array (SNP-array) to identify genetic abnormalities in miscarriage specimens.MethodsA total of 63 miscarriage specimens were included. Conventional karyotyping, array-CGH, and SNP-array were performed and the results compared.ResultsGenetic abnormalities were detected in 31 cases (49.2%) by at least one testing modality. Single autosomal trisomy was the most common defect (71.0%), followed by polyploidy (16.1%), multiple aneuploidy (9.7%), and monosomy X (3.2%). Mosaicisms were identified in four cases and confirmed by fluorescence in situ hybridization (FISH) using appropriate probes. SNP-array had a higher detection rate of genetic abnormalities than array-CGH (93.5 vs. 77.4%), and conventional karyotyping had the lowest detection rate (76.0%). SNP-array enabled the detection of all types of genetic abnormalities, including polyploidy.ConclusionsAlthough conventional karyotyping and FISH are still needed, SNP-array represents the first choice for miscarriage because the technique showed excellent performance in the detection of genetic abnormalities and minimized the probability of testing failure as well as time, costs, and labor.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40291-021-00523-9.

Morphological verification of the first missed abortion

Objective. The study aimed to compare the level of INF a2 immunoexpression in tissues obtained during medical abortion with the corresponding level of IFNa2 expression in a retained fetal egg tissues after the first missed abortion. The authors compared the anamnestic data on previous inflammatory diseases of the genital tract with the results of an extended morphological study of the material obtained during the evacuation of the contents of the uterine cavity during the first non-developing pregnancy in the first trimester.Materials and methods. The study included 15 patients with first-time missed abortions caused by a viral infection (6-8 weeks of pregnancy). All patients demonstrated either recurrent herpes simplex labialis/genitalis or PCR confirmed HSV, HPV, CMV. Exclusion criteria were recurrent miscarriage, blighted ovum, endocrinopathies, male factor infertility, and other causes of miscarriage. The comparison group included 20 women of the same age that chose to undergo a medical abortion.Results. In patients from the comparison group, the main producer of IFN a2 was syncytiotrophoblast as well as maternal decidual cells in the parietal endometrium and uteroplacental area. In the main group, manifested hematogenous infection (microabscesses, vasculitis, lymphocytic and macrophage infiltration) with dystrophy and necrosis of decidual maternal cells and secondary pathological changes in the placental villi were diagnosed, which led to a significant decrease in the IFN a2 immunoexpression in all the studied cells.Conclusion. The lack of anamnestic data on previous urogenital infections does not exclude the etiological role of the inflammatory component in the genesis of non-developing pregnancy. First-time occurred pregnancy loss requires adequate postoperative interferon therapy and a thorough examination of a couple.

THE STUDY OF CORRELATION BETWEEN LEIDEN V FACTOR AND METHYLEN TETRAHYDROFOLATE REDUCTASE ENZYME GENE MUTATIONS IN PRIMIGRAVIDA WITH MISSED ABORTION IN LATE FIRST TRIMESTER

Pregnancy is a hypercoagulable state secondary to an increase in coagulation factors, a reduction in naturally occurring anticoagulants, and impairment of fibrinolysis. Pregnancy losses were divided into preclinical, first trimester clinical, and second trimester. A meaningfully increased rate of preclinical pregnancy failure in Leiden mutation carriers was found than in no activated protein C deficiency patients. Another cause of miscarriages is inherited thrombophilia following damage to the maternal factor V gene G1691A (Leiden mutation) and prothrombin gene (G20210A mutation). These alterations are well studied and the test is part of the routine diagnostics of recurrent mis-carriages. In the case of factor V, both the Leiden mutation G1691A and the T1328C mutation appear to be important in the pathogenesis of RM, mainly in cases observed before the 7th week of gestation. The most common causes of inherited thrombophilia are polymorphisms in genes encoding factor V, prothrombin (factor II), factor VII, MTHFR, and plasminogen activator inhibitor, while protein C, protein S and ant thrombin deficiency is less common. The finding of a link between FVL carrier state and early RPL would have significant implications for clinical practice, as it would provide a scientific rationale for screening for FVL mutation and targeted thromboprophylaxisin affected women.

Microtubule Organizing Centers Regulate Spindle Positioning in Mouse Oocytes

During female meiosis I (MI), spindle positioning must be tightly regulated to ensure the fidelity of the first asymmetric division and faithful chromosome segregation. Although the role of F-actin in regulating these critical processes has been studied extensively, little is known whether microtubules (MTs) participate in regulating these processes. Here, we characterize a new class of MT organizing centers in the oocyte that does not contribute to spindle assembly, termed mcMTOCs. Using laser ablation, STED super-resolution microscopy and chemical manipulation, we show that mcMTOCs are required to regulate spindle positioning and faithful chromosome segregation during MI. We discuss how forces exerted by F-actin on the spindle are balanced by mcMTOC-nucleated MTs to anchor the spindle centrally and to regulate its timely migration. Our findings provide a new model for asymmetric cell division, complementing the current F-actin-based models, and implicate mcMTOCs as a new player in regulating spindle positioning, an indispensable function to avoid aneuploidy, the leading genetic cause of miscarriage and congenital abnormalities.

Novel lnc-HZ03 and miR-hz03 promote BPDE-induced human trophoblastic cell apoptosis and induce miscarriage by upregulating p53/SAT1 pathway.

Normal pregnancy is essential for human reproduction. However, environmental BaP (benzo(a)pyrene) and its metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) induce dysfunctions of human trophoblastic cells, which could further result in miscarriage. Yet, the molecular mechanisms remain poorly understood. In this work, a novel lnc-HZ03 and a novel miR-hz03 were identified. Both lnc-HZ03 and miR-hz03 were highly expressed in human recurrent miscarriage villous tissues and in BPDE-exposed trophoblastic cells. Lnc-HZ03 and miR-hz03 upregulated each other, forming a positive feedback loop. MiR-hz03 could also upregulate p53 level by enhancing its mRNA stability. Both lnc-HZ03 and p53 mRNA contained the target site for miR-hz03 and could directly interact with miR-hz03. It was this target site instead of its mutant on lnc-HZ03 that regulated p53 expression. Subsequently, the upregulated p53 facilitated SAT1 transcription and enhanced SAT1-catalyzed spermine metabolism, which further resulted in trophoblastic cell apoptosis and induced miscarriage. All together, the p53/SAT1 pathway upregulated by lnc-HZ03 and miR-hz03 could promote BPDE-induced human trophoblastic cell apoptosis and the occurrence of miscarriage, shedding novel light on the causes of miscarriage. Graphical abstract Lnc-HZ03 and miR-hz03 regulate the occurrence of recurrent miscarriage (RM). In human trophoblastic cells, lnc-HZ03 upregulates miR-hz03 level. MiR-hz03 increases the RNA stability of lnc-HZ03 and p53 mRNA. P53 promotes SAT1 transcription and reduces its cellular spermine content, resulting in cell apoptosis. Under normal conditions, lnc-HZ03/miR-hz03 and p53/SAT1 pathways are downregulated, maintaining normal pregnancy. After exposure to BPDE, lnc-HZ03/miR-hz03 and p53/SAT1 pathways are upregulated and finally induce miscarriage.

268 Utility of the INCODE algorithm to identify cause of stillbirth in clinical settings

The Initial Causes of Fetal Death Evaluation (INCODE) algorithm was developed by the Stillbirth Collaborative Research Network (SCRN) as a research tool to assign causes of death of stillbirth in which standardized postmortem examination (PME) is performed. Our goal was to assess the utility of INCODE in a retrospective cohort of stillbirths (SB) at a single tertiary hospital where PME was not routinely performed. Chart reviews were performed for all cases of SB from Dec 2013 to Oct 2019. Narrative summaries and PME results were recorded. Cause of death was assigned based on INCODE as described by SCRN investigators. Of the 99 identified SB, probable cause of death was identified in 70 (70.7%; 95% CI, 61.7-79.7%) and possible or probable cause in 92 (92.9%; 95% CI, 87.9-98.0%). The most common causes of SB were placental (n=40 [40.4%; 95% CI, 30.7-50.1%]), obstetric (n=36 [36.4%; 95% CI, 26.9-45.8%]), and fetal genetic/structural abnormalities (n=28 [28.3%; 95% CI, 19.4-37.2%]). Most frequently performed testing included maternal antibody screen (98; 99.0%), syphilis screening (91; 91.9%), and placental histology (94; 94.9%) while less than half of cases underwent PME (45; 45.5%). While antibody screen and syphilis testing infrequently yielded positive results (n=4, 4.1%; and 0), placental histologic examinations (n=72, 76.6%) and PME (n=36, 80%) contributed significantly to the assignment of possible or probable cause of death. Of women with SB and no PME (n=54), probable cause of SB was found in 61% (n=33 [95% CI, 48.1-74.1%]) and probable or possible cause identified in 89% (n=48 [95% CI, 80.5-97.3%]). Over one-third of SB occurred between 20 to 24 weeks gestation (n=38; 38.4%). Of SB at gestations less than 24 weeks, a greater proportion of SB occurred intrapartum than those at 24 weeks or later (34.1%vs12.7%; 95% CI, 4.8-37.9%, P=0.011). The INCODE algorithm identified a possible or probable cause of death in the majority of SB, comparing favorably to the results reported by SCRN, confirming its utility in a clinical setting where PME is not routinely performed.

Selective progesterone receptor modulator as an alternative for long-term therapy of uterine fibroids in women of reproductive age

Uterine fibroids are the most common benign uterine tumors in women of reproductive age. They are the most frequent cause of profuse uterine hemorrhage, which significantly decreases the quality of life of women of reproductive age [1, 2]. In 20 to 30 % of cases, fibroids are an etiological factor of infertility and in 15 to 30 % of cases – the cause of miscarriage. The highest incidence of uterine fibroids – over 50 % – is observed in the premenopausal period [3, 4].At present, women’s reproductive health is a topical issue of obstetrics and gynecology, therefore, great importance is attributed to timely diagnosis and prevention of diseases that influence fertility [5, 6, 7].In recent years, various medicines have been suggested for the treatment of uterine fibroids, including nonsteroidal anti-inflammatory drugs, tranexamic acid, progestogens (intrauterine devices that release levonorgestrel), gonadotropin-releasing hormone antagonists, progesterone receptor modulators, including mifepristone. The use of modern conservative methods of treatment of uterine fibroids enables a decreased incidence of complications, the preservation of uterus and of women’s reproductive function, an improved efficiency of treatment and quality of patients’ life [8, 9, 10].

Aneuploidy in human eggs: contributions of the meiotic spindle.

Human eggs frequently contain an incorrect number of chromosomes, a condition termed aneuploidy. Aneuploidy affects ∼10–25% of eggs in women in their early 30s, and more than 50% of eggs from women over 40. Most aneuploid eggs cannot develop to term upon fertilization, making aneuploidy in eggs a leading cause of miscarriages and infertility. The cellular origins of aneuploidy in human eggs are incompletely understood. Aneuploidy arises from chromosome segregation errors during the two meiotic divisions of the oocyte, the progenitor cell of the egg. Chromosome segregation is driven by a microtubule spindle, which captures and separates the paired chromosomes during meiosis I, and sister chromatids during meiosis II. Recent studies reveal that defects in the organization of the acentrosomal meiotic spindle contribute to human egg aneuploidy. The microtubules of the human oocyte spindle are very frequently incorrectly attached to meiotic kinetochores, the multi-protein complexes on chromosomes to which microtubules bind. Multiple features of human oocyte spindles favour incorrect attachments. These include spindle instability and many age-related changes in chromosome and kinetochore architecture. Here, we review how the unusual spindle assembly mechanism in human oocytes contributes to the remarkably high levels of aneuploidy in young human eggs, and how age-related changes in chromosome and kinetochore architecture cause aneuploidy levels to rise even higher as women approach their forties.

GENETIC ASPECTS OF CERVICAL INSUFFICIENCY PROBLEM

Cervical insufficiency is the main cause of miscarriage in the second trimester of pregnancy (up to 40 %), and in the third trimester occurs in a one third of women with preterm birth. Diagnosis of this pathology is based on the identification of structural changes in the cervix, which determines the impossibility of predicting this pathology before pregnancy. Current morphological studies have shown that connective tissue predominates in the cervix, represented mainly by collagen, which provides up to 85 % of the weight of the cervical tissue, elastin and proteoglycans. A key factor in the development of CI is currently considered a defect in collagen synthesis and the development of cervical incompetence is considered as a manifestation of undifferentiated connective tissue dysplasia. The results of recent studies show that cervical insufficiency is a genetically determined condition and polymorphisms in genes related to the metabolism of connective tissue can play a role in the development of CI.

Development and validation of a model for individualized prediction of cervical insufficiency risks in patients undergoing IVF/ICSI treatment

BackgroundWomen who conceived with in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) are more likely to experience adverse pregnancy outcomes than women who conceived naturally. Cervical insufficiency (CI) is one of the important causes of miscarriage and premature birth, however there is no published data available focusing on the potential risk factors predicting CI occurrence in women who received IVF/ICSI treatment. This study aimed to identify the risk factors that could be integrated into a predictive model for CI, which could provide further personalized and clinically specific information related to the incidence of CI after IVF/ICSI treatment.Patients and methodsThis retrospective study included 4710 patients who conceived after IVF/ICSI treatment from Jan 2011 to Dec 2018 at a public university hospital. The patients were randomly divided into development (n = 3108) and validation (n = 1602) samples for the building and testing of the nomogram, respectively. Multivariate logistic regression was developed on the basis of pre-pregnancy clinical covariates assessed for their association with CI occurrence.ResultsA total of 109 patients (2.31%) experienced CI among all the enrolled patients. Body mass index (BMI), basal serum testosterone (T), gravidity and uterine length were associated with CI occurrence. The statistical nomogram was built based on BMI, serum T, gravidity and uterine length, with an area under the curve (AUC) of 0.84 (95% confidence interval: 0.76–0.90) for the developing cohort. The AUC for the validation cohort was 0.71 (95% confidence interval: 0.69–0.83), showing a satisfactory goodness-of-fit and discrimination ability in this nomogram.ConclusionThe user-friendly nomogram which graphically represents the risk factors and a pre-pregnancy predicted tool for the incidence of CI in patients undergoing IVF/ICSI treatment, provides a useful guide for medical staff on individualized decisions making, where preventive measures could be carried out during the IVF/ICSI procedure and subsequent pregnancy.

THE ROLE OF COMPLEX TREATMENT OF UTERINE FIBROIDS IN WOMEN WITH INFERTILITY AND RECOVERY OF THE REPRODUCTIVE FUNCTION

A nation’s reproductive health is an important medical and public indicator. A significant decrease in the birth rate has put Ukraine on the list of Top 8 European countries with the lowest birth rate.
 Uterine fibroids are one of the most widely spread gynecological diseases, which ranks the 2nd place after the inflammatory processes of the small pelvis organs and affects from 20 to 30% of women above 30 years. In 13.3 to 27% of cases, uterine fibroids are observed in the reproductive age. In recent years, there has been a steady increase in the number of young women affected by the tumor. Uterine fibroids remain a serious issue and are one of the main causes of miscarriage and infertility, especially in women above 30 years [1, 2, 3].
 The treatment of uterine fibroids remains a disputable issue. The slow development of the disease, without obvious clinical manifestations, has long been the reason for passive observation of patients, until the onset of symptoms requiring surgical treatment. The clinical manifestations of the disease, which are observed in every second patient affected by uterine fibroids, require a more active strategy of management of such patients. One of the factors impeding effective organ preservation treatment of fibroids is the lack of information about the mechanisms of the tumor development. As it is known, the progression of any tumor is directly dependent on it blood supply [4, 5].
 So far, radical treatment (hysterectomy) remains the main method of treatment of uterine fibroids and is applied in 75 - 83% of cases. However, such radicalism is not justified in the majority of patients as new treatment methods come into being, which inhibit tumor growth and lead to the regression of the disease symptoms. According to various authors, the percentage of fibroidectomy in the total number of surgeries is lower than 1%, which is unreasonably low. The main advantage of fibroidectomy is the preservation of fertility, the main disadvantage – is the high risk of disease recurrence – from 15 to 20% [6].
 There has been more and more debate recently about the issue of interrelation of uterine fibroids, the results of assisted reproductive technologies and embryo transfer. The improvement of results of ART after fibroidectomy encourages the broadening of indications for such surgeries in patients with symptomless fibroids. Drug therapy also makes it possible to preserve the reproductive function but, in contrast to surgical treatment, it does not mean the risk of intra- and postoperative complications. The combination of drug therapy and organ preservation surgeries reduces the risk of complications related to surgical treatment and contributes to the preservation of fertility. The use of complex rehabilitation measures with hormone therapy improves the results of surgical treatment, reduces the risk of recurrence of uterine fibroids and contributes to a more favorable postoperative course.
 At present, there are no clear criteria for managing patients after organ preservation surgeries on the uterus; at the outpatient stage, there are few effective approaches aimed at the recovery of fertility and the rehabilitation of such patients. Thus, the recovery and preservation of the reproductive function is one of the priorities in the development of medicine in Ukraine.

Premature senescence of placental decidua cells as a possible cause of miscarriage produced by mycophenolic acid

BackgroundSuccessful pregnancy is supported by a healthy maternal–fetal interface (i.e., the decidual tissues) which holds the conceptus and safeguards it against stressors from the beginning of pregnancy. Any disturbance of this interface can presumably lead to the loss of pregnancy. The use of the immunosuppressive drug mycophenolic acid (MPA) should be discontinued in pregnancy given its abortive and embryotoxic effects. Direct teratogenic effects have been observed in mammalian embryos cultured in MPA, but the underlying mechanisms of abortion by MPA are less understood.MethodsDecidual stromal cells isolated from human placentas are cultured in the presence of clinically relevant doses of MPA. Data regarding the effects of MPA on the proliferation and viability of decidua cultures are first analysed and then, molecular pathways contributing to these effects are unravelled.ResultsMPA treatment of decidual stromal cells results in loss of proliferation capacity and a decrease in the viability of decidua cultures. The molecular pathways involved in the effects of MPA on decidual stromal cells are a reduction in pre-rRNA synthesis and subsequent disruption of the nucleolus. The nucleolar stress stabilizes p53, which in turn, leads to a p21–mediated cell cycle arrest in late S and G2 phases, preventing the progression of the decidua cells into the mitosis. Furthermore, MPA does not induce apoptosis but activate mechanisms of autophagy and senescence in decidual stromal cells.ConclusionThe irreversible growth arrest of decidua cells, whose role in the maintenance of the pregnancy microenvironment is known, may be one cause of miscarriage in MPA treated pregnant women.

Wybrane genetyczne przyczyny poronień

Streszczenie Około 15–25% ciąż kończy się poronieniem samoistnym, czyli wydaleniem z organizmu matki zarodka bądź płodu o masie poniżej 500 g lub przed 20. tygodniem trwania ciąży. Ustalenie etiologii poronień jest trudne ze względu na jej heterogenny charakter. Przyczyną 38,6–80% poronień są zmiany stwierdzane w chromosomach. Największą grupą (93%) aberracji chromosomowych w kariotypie poronionych płodów są zmiany liczbowe – aneuploidie i poliploidie. 7% stanowią niezrównoważone zmiany strukturalne chromosomów, powstałe de novo lub odziedziczone od rodzica nosiciela. U par z poronieniami najczęściej stwierdza się translokacje chromosomowe wzajemne (TCW), rzadziej translokacje robertsonowskie oraz inwersje. Bardziej złożone nieprawidłowości chromosomowe, np. podwójne aneuploidie, stwierdza się u 3,8% płodów. Inną grupą przyczyn poronień, są choroby monogenowe zarodka lub płodu, powstające w wyniku mutacji autosomalnych dominujących lub recesywnych albo mutacji sprzężonych z chromosomem X. Wśród mutacji mogących się przyczynić do utraty ciąży znajdują się m.in. mutacja typu Leiden (c.1601G>A, dawniej 1691G>A) w genie czynnika V krzepnięcia osoczowego i mutacja w genie protrombiny (c.97G>A, dawniej 20210G>A). Nadal prowadzone są badania nad mutacjami genów kandydujących, m.in.: ALOX15, CR1, CYP1A1, CYP17, CYP2D6, FOXP3, HLA-G, IL-6, KHDC3L, NLRP7, NOS3, PLK4, SYCP3, TLR3, TNF, TP35 i VEGFA.

Роль хромосомных аберраций эмбриона в генезе привычного и спорадического невынашивания беременности

Objective. To compare the frequency and nature of embryo/fetus chromosomal abnormalities (CA) in sporadic and recurrent pregnancy loss. Patients and methods. A retrospective cohort study that included 1000 patients with pregnancy loss at 6–12 weeks of gestation. The first group consisted of 681 patients who had their first sporadic miscarriage. The second group consisted of 319 patients who previously had a miscarriage. Chromosomal microarray analysis (CMA) of abortive material was performed. Results. In the first group, various chromosomal abnormalities in the embryo/fetus were detected in 378 (55.5%) samples, in the second group – in 203 (63.5%). The incidence of CA in patients with a history of miscarriage was higher than in sporadic miscarriage, the differences were statistically reliable (p = 0.015). No significant differences were found in the structure of CA. Autosomal trisomies and numerical abnormalities of sex chromosomes were most frequently detected. Conclusion. Chromosomal abnormalities in the embryo are a significant cause of miscarriage, both sporadic and recurrent. Genetic analysis of abortive material is an important component of the examination for choosing further management tactics for patients. CMA is an effective research method when conducting genetic analysis of conception products. Key words: pregnancy loss, preconception planning, recurrent miscarriage, chromosomal abnormalities, chromosomal microarray analysis

Maternal Pregnancy Associated Plasma Protein-A Levels in Late First Trimester as a Predictor of Miscarriage- A Cross-sectional Study

Indroduction: Miscarriage is the most common complication of pregnancy. Defective implantation is one of the common causes of miscarriage. Pregnancy Associated Plasma Protein-A (PAPP-A) is secreted from syncytiotrophoblast and it enables trophoblast invasion. Few studies have shown association of PAPP-A with miscarriage. However, there is limited data available to establish the role of PAPP-A as a predictive marker of miscarriage, especially in Indian population. Aim: To determine the potential of maternal PAPP-A level estimation in asymptomatic women in late first trimester (10-13 weeks) with viable foetus in predicting subsequent miscarriage. Materials and Methods: This was an observational, cross-sectional study conducted from November 2016 to April 2018 at University College of Medical Science and Guru Teg Bahadur Hospital, Delhi, India. Asymptomatic pregnant women (N=500) at 10-13 weeks of gestation were recruited from an antenatal clinic after confirmation of foetal viability. A 2 mL of blood sample was collected and serum PAPP-A level was measured. Independent t-test and Chi-square test was used to compare continuous data and Mann-Whitney U test was used to compare PAPP-A Multiple of Median (MOM). Logistic regression was used to estimate risk of miscarriage. Results: Out of 500 participants, 9 were lost to follow-up. From remaining N=491, 32 (6.5%) women had a miscarriage. PAPP-A levels were significantly decreased in miscarriage group compared to ongoing pregnancy group with median MOM 0.116 (0.080-0.17) and 1.25 (0.665-3.249) respectively (p-value <0.001). PAPP-A MOM value of ≤10th percentile sensitivity and specificity of detection of miscarriage was 81.25% and 94.98% and at ≤5th percentile sensitivity and specificity was 40.62% and 97.82%, respectively. Lower the percentile cut-off of serum PAPP-A value, higher was the specificity and positive predictive value for prediction of miscarriage. By applying logistic regression we found that if PAPP-A MOM decreases by 1 unit the chances of miscarriage increased by 1.2 times. By this model 63.2% of cases could be explained (Nagelkerke R Square=0.632). For prediction of pregnancies likely to miscarry, the area under Receiver Operator Characteristic (ROC) curve (95% CI) was 0.969 (0.955-0.983). Conclusion: Low serum PAPP-A levels from asymptomatic women in late 1st trimester is a good predictive marker of miscarriage.

Initial Spindle Positioning at the Oocyte Center Protects Against Incorrect Kinetochore-Microtubule Attachment and Aneuploidy in Mice

Spindle formation and positioning are two critical events that must be regulated tightly to avoid erroneous chromosome segregation. Following nuclear envelope breakdown (NEBD), the spindle is predominantly assembled centrally before migrating towards the cortex to allow the first asymmetric division. The biological significance of primary central positioning of the spindle has not yet been studied. Because the spindle forms where NEBD occurs, nucleus position greatly influences the site of spindle assembly. We find that nucleus positioning is a dynamic process that depends on maternal age. Moreover, we show that preferential initial spindle positioning at the oocyte center is an insurance mechanism to avoid premature exposure to cortical Cdc42 signaling that hinders proper kinetochore-microtubule attachments, thereby protecting against the development of aneuploid gametes. These findings will help in understanding why female gametes are notoriously associated with high rates of aneuploidy, the leading genetic cause of miscarriage and infertility in women.

Non-Invasive Prenatal Testing: Current Perspectives and Future Challenges.

Fetal aneuploidies are among the most common causes of miscarriages, perinatal mortality and neurodevelopmental impairment. During the last 70 years, many efforts have been made in order to improve prenatal diagnosis and prenatal screening of these conditions. Recently, the use of cell-free fetal DNA (cff-DNA) testing has been increasingly used in different countries, representing an opportunity for non-invasive prenatal screening of pregnant women. The aim of this narrative review is to describe the state of the art and the main strengths and limitations of this test for prenatal screening of fetal aneuploidies.

Mechanobiology of the Mitotic Spindle.

The mitotic spindle is a microtubule-based assembly that separates the chromosomes during cell division. As the spindle is basically a mechanical micro machine, the understanding of its functioning is constantly motivating the development of experimental approaches based on mechanical perturbations, which are complementary to and work together with the classical genetics and biochemistry methods. Recent data emerging from these approaches in combination with theoretical modeling led to novel ideas and significant revisions of the basic concepts in the field. In this Perspective, we discuss the advances inthe understanding of spindle mechanics, focusing on microtubule forces that control chromosome movements.

Genetic findings in miscarriages and their relation to the number of previous miscarriages

PurposeEarly pregnancy loss leads to a devastating situation for many couples. Genetic disorders found in the pregnancy tissue are a frequent cause of miscarriages. It is unclear whether maternal age or previous miscarriages are associated with a higher chromosomal anomaly rate. This study aimed to determine the cytogenetical distribution of chromosomal disorders in couples after one or more previous miscarriages as well as the influence of maternal age.Methods406 fetal tissue samples obtained after spontaneous abortion between 2010 and 2014 were successfully karyotyped. This included 132 couples with at least two losses and 274 couples with sporadic miscarriage. Normal and abnormal karyotype rate was determined for age, parity, gravidity, gestational week and number of previous miscarriages by logistic regression analysis.Results145 (35.71%) fetal tissue samples had a normal karyotype, and 261 (64.8%) did not.After adjusting for age, older patients have a statistically significantly higher probability of genetic disorders in the pregnancy tissue (p < 0.001, OR 1.064, 95% CI 1.03–1.11). With each additional year, the probability of finding chromosomal abnormalities in a miscarriage increased by 6.4%. Patients younger than 35 years have a lower probability of having chromosomal disorders in the aborted material after two or more miscarriages than after sporadic miscarriages (50.7 vs. 58.9%) (p = 0.014, OR 0.67, 95% CI 0.48–0.914). Nevertheless, the risk of embryonic chromosomal disorders in patients aged 35 and above increased from 75.5% in sporadic miscarriages to 82.4% after more than one pregnancy losses (p = 0.59, OR 1.14, 95% CI − 0.72 to 1.92).ConclusionChromosomal disorders found after one or more previous miscarriages are related to patients’ age. Couples suffering two or more miscarriages should be further researched, especially in younger patients.