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Depressed mixed lymphocyte culture reactivity in mothers with recurrent spontaneous abortion.

One-way mixed wife-husband lymphocyte culture (MLC) reaction as well as human lymphocyte antigen (HLA) typing were performed on 29 couples, most of whom were infertile because of recurrent spontaneous abortion, and compared with 35 fertile couples with no abortion history. The 29 couples had been selected from 280 couples with a karyotyped spontaneous abortion. A significantly depressed MLD response (P=0.04) was observed in mothers of karyotypically normal abortuses when stimulated by the fathers but not when they were stimulated by males from the fertile couples. No significant difference in the frequency of HLA-A-and HLA-B-incompatible matings, respectively, was found between the abortion and the fertile couples. It is concluded that depressed maternal cellular response to paternal stimulation can be explained as a consequence of recurrent spontaneous abortion and that it is uncertain whether this depressed response plays a role in the etiology of recurrent abortion.

Abortion, Habitual

Polycystic ovarian syndrome (PCOS) and recurrent spontaneous abortion (RSA) are associated with the PI3K-AKT pathway activation.

AIMS: We aimed to elucidate the mechanism leading to polycystic ovarian syndrome (PCOS) and recurrent spontaneous abortion (RSA). BACKGROUND: PCOS is an endocrine disorder. Patients with RSA also have a high incidence rate of PCOS, implying that PCOS and RSA may share the same pathological mechanism. OBJECTIVE: The single-cell RNA-seq datasets of PCOS (GSE168404 and GSE193123) and RSA GSE113790 and GSE178535) were downloaded from the Gene Expression Omnibus (GEO) database. METHODS: Datasets of PSCO and RSA patients were retrieved from the Gene Expression Omnibus (GEO) database. The "WGCNA" package was used to determine the module eigengenes associated with the PCOS and RSA phenotypes and the gene functions were analyzed using the "DAVID" database. The GSEA analysis was performed in "clusterProfiler" package, and key genes in the activated pathways were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Real-time quantitative PCR (RT-qPCR) was conducted to determine the mRNA level. Cell viability and apoptosis were measured by cell counting kit-8 (CCK-8) and flow cytometry, respectively. RESULTS: The modules related to PCOS and RSA were sectioned by weighted gene co-expression network analysis (WGCNA) and positive correlation modules of PCOS and RSA were all enriched in angiogenesis and Wnt pathways. The GSEA further revealed that these biological processes of angiogenesis, Wnt and regulation of cell cycle were significantly positively correlated with the PCOS and RSA phenotypes. The intersection of the positive correlation modules of PCOS and RSA contained 80 key genes, which were mainly enriched in kinase-related signal pathways and were significant high-expressed in the disease samples. Subsequently, visualization of these genes including PDGFC, GHR, PRLR and ITGA3 showed that these genes were associated with the PI3K-AKT signal pathway. Moreover, the experimental results showed that PRLR had a higher expression in KGN cells, and that knocking PRLR down suppressed cell viability and promoted apoptosis of KGN cells. CONCLUSION: This study revealed the common pathological mechanisms between PCOS and RSA and explored the role of the PI3K-AKT signaling pathway in the two diseases, providing a new direction for the clinical treatment of PCOS and RSA.

Humans

Mechanism of Shoutai Wan against recurrent spontaneous abortion: regulation of decidual vascular remodeling via ERβ-ANGPT2 signaling axis.

Shoutai Wan (STW), a classic traditional Chinese medicine formula used to tonify the kidney and prevent miscarriage, has been widely applied in the clinical management of recurrent spontaneous abortion (RSA). Increasing clinical evidence supports its efficacy in reducing miscarriage rates and improving pregnancy outcomes. However, the molecular basis by which STW alleviates defective decidual vascular remodeling in unexplained RSA remains insufficiently understood. Clinically, decidual ERβ and ANGPT2 expression, as well as serum estradiol, ANGPT2 and VEGFA levels were significantly decreased in RSA patients, accompanied by reduced decidual microvascular density. Furthermore, ERβ expression was positively correlated with ANGPT2 and microvascular density. In vivo, STW dose-dependently reduced embryo loss in RSA mice, repaired the damaged decidual-placental interface structure, and improved vascular maturation, structural stability and endothelial-pericyte ultrastructural connections. Mechanistically, STW upregulated ERβ expression. We demonstrated that ERβ binds to the ANGPT2 promoter, suggesting transcriptional upregulation of ANGPT2, thereby activating Tie2 and the downstream PI3K/AKT pathway and increasing NO and VEGFA secretion. In vitro, hypoxia inhibited ERβ nuclear translocation and ANGPT2 secretion in mDSCs, while STW-containing serum reversed these abnormalities. ERβ knockdown impaired the pro-angiogenic capacity of mDSCs, which was partially rescued by exogenous ANGPT2 supplementation. Network pharmacology predicted that STW targets were mainly enriched in PI3K-Akt, estrogen, VEGF and angiogenesis-related pathways. Transcriptomic GSEA further revealed that the gene signatures of angiogenesis and PI3K-Akt signaling were markedly suppressed in the RSA model, and STW treatment significantly normalized these transcriptional signatures.

Female

Embryonic development in consecutive specimens from recurrent spontaneous abortions.

Although habitual abortion occurs in a relatively small number of patients, its successful management is often difficult. Etiologic factors may be either maternal or embryonic or both; there is much information available on maternal factors but little is known of factors related to the embryo. Information obtained from examining and karyotyping the aborted embryo or fetus may be of considerable importance in determining the possible cause of the abortion and subsequent investigation and counseling of the patient. At least two specimens from over 50 women who have had two or more consecutive spontaneous abortions have been examined and the results show that: (1) Patients aborted conceptuses of the same developmental stage, i.e., embryo or fetus, in consecutive pregnancies. This suggests that investigation should be directed to factors which may be important in the stage of pregnancy indicated. (2) Late abortions were associated with normal fetal development and factors related to the uterine environment. (3) The conceptus in an early abortion was significantly more likely to have a cytogenetic abnormality, suggesting a problem at, or prior to, conception/fertilization. A case study is also included.

Abortion, Habitual

[Frequency of chromosome variants in human populations].

Chromosome variants were analyzed in the course of the population chromosome investigation of 6000 newborns and clinical cytogenetic studies of 403 married couples with recurrent spontaneous abortions, stillbirths or offsprings having congenital malformations or Down's syndrome. The following variants were determined: 1) Igh+, 9gh+, 16gh+ - the enlargement of the secondary constrictions of the size, more than 1/4 of the long arm of the chromosome; 2) Dp+ or Gp+ - the enlargement of the short arms of acrocentrics, their size being more than the short arm of the chromosome 18; 3) Ds+ or Gs - large satellites of the acrocentrics which are equal or more than the thickness of the chromatids of the long arms; 4) Es+ - satellites on the short arms of the chromosomes 17 or 18; 5) Dss of Gss - double satellites; 6) Yq+ - the enlargement of the long arm of Y chromosome, the size of which being more than G chromosome; 7) Yq- - deletion of the long arm of Y chromosome, the size of the long arm being less than chromosomes 21--22. The total frequency of variants in newborns was 12.8/1000 births. The incidence of different types of variants per 1000 births was as follows: Igh+ - 0.33; 9gh+ - 0.17; 16gh+ - 0.50; Ds+ - 2.33; Dp+ - 1.50; Dp- - 0.17; Gs+ - 0.83; Gp+ - 2.17; Yq+ - 6.91/1000 males; Yg- - 0.99/1000 males; double variants - 0.33; other variants - 0.33. 4.0% of married couples with recurrent spontaneous abortions had major chromosome aberrations, 14.6% - extreme variants of chromosomes. Among 113 couples with the history of congenital malformations in their offsprings major chromosome abnormalities were found in 4.4%, chromosome variants - 13.3%. The frequency of chromosome variants among 139 patients with Down's syndrome was 7.2%. In one case Robertsonian translocation t(DqGa) was determined. The most frequent types of variant chromosomes were Ds+, Dp+, Es+, Yq+.

Abortion, Habitual

Chromosome studies in couples with repeated spontaneous abortions.

Karyotypes were prepared from peripheral blood leukocytes in 77 couples in whom there was no apparent cause for recurrent spontaneous abortion. In addition to conventional staining, chromosomes were stained by the new technics for Q-, G-, or C-banding. Translocations were found in 5 of 154 persons (3.25% or 1:31 individuals). The frequency of translocations in the general adult population is 0.4% (1:255). Two translocations were apparent only with the new technics for banding. The incidence of chromosomal microanomalies was 7.79% (2.6% in the general population). Karyotyping of couples with recurrent abortion is recommended, with use of the new staining technics.

Abortion, Spontaneous

Autophagy in the Regulation of Placental Development: From Trophoblast Differentiation to Metabolic Stress Adaptation.

Successful pregnancy depends on precise placental development, where trophoblast differentiation, syncytialization, invasion, and adaptation to metabolic stress are critical. Autophagy, a lysosome-mediated degradation pathway, has emerged as an important regulator of cellular homeostasis, yet its integrated role in trophoblast fate and functions has not been comprehensively summarised. This review synthesises current evidence on autophagy's functions throughout placentation, from trophoblast differentiation to syncytialization and extravillous trophoblast invasion. We examine how autophagy enables cellular remodelling during differentiation, supports metabolic adaptation under hypoxia and nutrient stress, and maintains mitochondrial quality control through selective mitophagy. Autophagy is essential for syncytiotrophoblast formation via endoplasmic reticulum stress-coordinated activation and p53 downregulation. However, its effects on trophoblast invasion are context-dependent, influenced by oxygen tension, autophagic flux completeness, and differentiation state, which can potentially be shaped by parent-offspring genetic conflicts through genomic imprinting. Both excessive and insufficient autophagy contribute to pregnancy complications, including pre-eclampsia, foetal growth restriction, gestational diabetes mellitus, preterm birth, recurrent spontaneous abortion and obstetric antiphospholipid syndrome through distinct molecular mechanisms. Autophagy functions as a dynamically tuned homeostatic mechanism in placental development. Understanding condition-specific autophagy dysregulation is thereby crucial for improving pregnancy outcomes.

Autophagy

Corpus luteum dysfunction: serum progesterone levels in diagnosis and assessment of therapy for recurrent and threatened abortion.

These studies were designed to show that properly timed measurements of serum progesterone (P) can be conveniently used in the diagnosis and treatment of patients with recurrent and threatened abortion. Luteal phase serum P levels between 2 and 10 ng/ml and serum P levels below 15 ng/ml in the first 10 weeks of gestation were considered diagnostic of corpus luteum (CL) dysfunction. Patients were treated with clomiphene, gonadotropins, and/or progesterone suppositories in order to correct serum P levels, thus elevating the serum P into the normal range. When treatment of patients with subnormal P levels resulted in normalization of serum P, successful pregnancies occurred. CL dysfunctions, either before or after conception, were found in eight of the nine patients with histories of recurrent spontaneous abortions. Correction of serum P was associated with successful pregnancy in these eight patients. Twelve patients with threatened abortion were also found to have subnormal serum P levels. Progesterone suppositories corrected the serum P levels in nine of the eleven patients treated, and none of these patients aborted. Serum P measurements provide a means for evaluation of CL function during early gestation. Management of patients with CL dysfunction can also be monitored with serial serum P measurements, provided that progesterone is the therapeutic agent rather than synthetic progestins.

Abortion, Habitual

Structural differences in reciprocal translocations. Potential for a model of risk in Rcp.

Interchange segment sizes and the sizes of chromosome imbalance arising from the different modes of meiotic segregation were measured in a selected sample of 20 reciprocal translocations (Rep). The Rep were selected by two modes of ascertainment: (I) neonates with an unbalanced form of the translocation, and (II) couples with recurrent spontaneous abortions without evidence of full-term translocation aneuploid offspring. The measurements (% of haploid autosomal length: %HAL) were plotted as the observed or potential chromosomal imbalance with monosomy (abscissa) and trisomy (ordinate). It was found that (a) the interchange segments were larger in the spontaneous abortion Rcp, (b) that all of the imbalances observed in full-term neonates plotted close to the origin and to the left of the line joining 4% trisomy to 2% monosomy, and (c) the imbalances observed in the neonates in each individual Rcp were of the smallest size possible arising by any segregation mode. It was concluded that a major factor in the survival to term of aneuploid conceptuses is the size (proportion of genome) of the chromosome abnormality, irrespective of the origin of the chromosome regions. These results are discussed in relation to their use as a model to evaluate the risk of abnormal offspring in the progeny of translocation heterozygotes (the Chromosome Imbalance Size-Viability Model).

Abortion, Spontaneous

Genetic causes and workup of male and female infertility. 2. Abnormalities presenting between birth and adult life.

At birth some 6/1,000 persons have chromosome abnormalities; in about 60% of cases these abnormalities cause death or infertility, and in one third fertility is reduced. Some 1.7% of persons (3.4% of couples) with recurrent spontaneous abortion, infertility, or both have a chromosome abnormality. Chromosome abnormalities are far more common in men than in women with infertility; 15% to 20% of men with azoospermia have the Klinefelter syndrome. Meiotic defects explain 20% of male infertility in patients with apparently normal somatic chromosomes. Congenital malformations of the genitalia are more common in males than in females; about 0.82% of liveborn males have hypospadias. Almost one sixth of women with primary amenorrhea have some form of müllerian atresia, usually with associated renal anomalies.

Chromosome Aberrations

HLA-A,B compatibility in parents of offspring with neural-tube defects or couples experiencing involuntary fetal wastage.

To test the contribution of a putative human analogue of the murine T locus to neural-tube defects (N.T.D.) and involuntary fetal wastage, HLA-A, B compatibility between husband and wife was studied in a group of 77 couples with known obstetric histories. The frequency of sharing of HLA-A,B antigens was significantly higher in 13 couples with recurrent fetal loss at one gestational age and in 11 couples whose offspring had had a lethal N.T.D. than in 17 couples with three or more normal pregnancies. The extent of HLA compatibility--that is, the number of antigens shared by husbands and wives--was significantly higher in 16 couples with one spontaneous abortion, 23 couples with recurrent spontaneous abortions, and 21 couples with N.T.D. offspring than in controls. These data are consistent with a contribution of a locus in or near the HLA complex to N.T.D. and involuntary fetal wastage.

Abortion, Spontaneous

HLA antigen studies in women with recurrent gestational disorders.

The frequencies of HLA antigens were determined in an experimental group of women with recurrent gestational disorders mainly expressed as spontaneous abortions of unknown etiology. The estimated antigen frequencies in this group were compared with the antigen frequencies in 158 unrelated persons (79 couples with no record of secondary infertility). A significantly higher frequency of antigen HLA-A9 was found in the experimental group as compared with the controls (corrected P = 0.0015). A greater degree of HLA compatibility was found between each woman from this group and her husband, considering 45 couples, as compared with 79 control couples. These results indicate that gene(s) close to the HLA region may have an influence on the reproductive performance in humans.

Abortion, Spontaneous

Sequential analysis of spontaneous abortion. II. Collaborative study data show that gravidity determines a very substantial rise in risk.

Evidence from more than 14,000 reproductive histories in the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke indicates that the risk of spontaneous abortion increases considerably with gravidity. Maternal age, memory errors, and sampling bias related to recurrence risk do not account for the trend. Clustering, or tendency for abortions to follow one another, occurs in histories which include live births.

Abortion, Spontaneous

[Repeated abortions, sterility and systemic dysimmunopathy (author's transl)].

A patient with lupus disease had a previous medical history of five recurrent temporary bouts of thrombopenia which were followed by spontaneous abortions. This raises the two-fold problem of the relationship between circulating immune complexes disease and thrombopenia, and dysimmunopathy and pregnancy disorders. The hypothesis is raised of a trophoblastic necrotizing angeitis due to abnormal immunity processes involved in some cases of sterility, spontaneous abortions, and even nephropathies during pregnancy.

Abortion, Habitual

Familial occurrence of gastroschisis. Four new cases and review of the literature.

In two unrelated families, there was familial occurrence of gastroschisis. In one family, a boy and girl were affected and there was a family history of stillbirth, abortion, prematurity, and esophageal obstruction. In the second family, two boys were affected and there was a family history of spontaneous abortion, inguinal hernia, and umbilical hernia. The recurrence of gastroschisis, generally considered a sporadic congenital effect, suggests that the condition may be genetic in nature. Furthermore, the pedigree of one of the families suggests that gastroschisis may be a severe expression of umbilical hernia or other abdominal wall defects. Autosomal dominant inheritance with variable expressivity or multifactorial inheritance may explain the occurrence of gastroschisis in the two families. Thus, a family history of abdominal wall defects may increase the risk for gastroschisis.

Abdominal Muscles