Unexplained Recurrent Spontaneous Abortion Research Articles

Clinical Efficacy of Low Molecular Heparin on Unexplained Recurrent Spontaneous Abortion.

To study the clinical effect of low molecular heparin on unexplained recurrent spontaneous abortion (URSA). A total of 120 URSA patients were collected in our hospital from October 2015 to September 2017. They were divided into two groups: control group (n = 60) and observation group (n = 60). The patients in the control group were administered with progesterone and human chorionic gonadotropin, and the observation group with low molecular heparin. Pregnancy outcomes, incidence of complications in pregnancy and adverse drug reactions were compared in the two groups. The pregnancy success rate of patients in the observation group (90.00%) is higher than that in the control group (68.33%) (p < 0.05). The incidence of complications in pregnancy in the observation group (90.00%) is lower than those in the control group (68.33%) (p < 0.05). The incidence of adverse drug reactions between the patients in the observation group (20.00%) and those in the control group (23.33%) showed no significant difference (p > 0.05). Low molecular heparin treatment can improve pregnancy success rate and reduce the incidence of complications in the URSA patients. Low molecular heparin is characterized by safety and reliability and has potential for application in clinic.

Clinical efficacy of low molecular heparin on unexplained recurrent spontaneous abortion

Objective: To study the clinical effect of low molecular heparin administered to patients with Unexplained Recurrent Spontaneous Abortion (URSA). Methodology: A total of 120 URSA patients admitted to our hospital from October 2015 to September 2017 were taken as observation subjects. They were divided into two groups based on a random number table, that is, control group (n=60) and observation group (n=60). The patients in the control group were administered with progesterone and human chorionic gonadotropin, while the patients in the observation group were administered with low molecular heparin. The two groups were compared statistically in terms of pregnancy outcomes, incidence of complications in pregnancy, and incidence of adverse drug reactions. Results: For the pregnancy outcomes, the pregnancy success rate of patients in the observation group is higher than that of the patients in the control group at 90.00% and 68.33%, respectively, indicating a significant difference (P 0.05). Conclusion: Low molecular heparin administered to the URSA patients manifests a strong clinical effect. This treatment not only improves the pregnancy success rate but also reduces the incidence of complications. Furthermore, low molecular heparin is characterized by safety and reliability, and has potential for application in clinical studies.

Thyroid-stimulating hormone in pregnancy: are we in need of a lower cutoff value?

Background No consensus has been reached regarding the normal range of thyroid-stimulating hormone (TSH) in the first trimester of pregnancy. Aim To determine the effect of TSH levels and thyroid peroxidase antibody (TPOAb) positivity on miscarriage outcome among Egyptian euthyroid women. Materials and methods The study was a prospective case–control study conducted at Al-Azhar University Hospital in New Damietta. It included 80 newly-diagnosed pregnant euthyroid women: 40 women with unexplained recurrent miscarriage, assigned as group 1 (subdivided into two subgroups according to the presence of TPOAb), and a control; group of 40 randomly selected fertile pregnant women who had no history of miscarriage, assigned as group 2. Free T4, TSH, and TPOAb assays were performed at 8-week gestational age. We followed all cases periodically every 4 weeks and when necessary. Results The study revealed significant higher frequency of positive TPOAb in group 1 than group 2 (P=0.045). During the study observation, miscarriage occurred more than two-fold higher in group 1 than group 2 (17.5 vs. 7.5%, respectively, P=0.176) but was significantly higher among TPOAb positive than TPOAb negative women within group 1 (54.5 vs. 3.4% respectively, P Conclusion TPOAb is a useful marker for identifying the risk for miscarriage among Egyptian euthyroid women. The risk was augmented when TSH exceeded 2.5 mU/l in the first trimester of pregnancy, and in the presence of family history of autoimmune thyroid disease.

The Reproductive Outcome in Patients Having Primary Infertility or Recurrent Miscarriages after Performing Hysteroscopic Septal Resection

Objective: To assess the reproductive outcome after hysteroscopic septal resection in women with unexplained infertility or recurrent miscarriage. Design: Prospective clinical trial. Setting: Zagazig university hospitals, Egypt.

Subtelomeric Rearrangements in Patients with Recurrent Miscarriage.

BackgroundThe subtelomeric rearrangements are increasingly being investigated in cases of idiopathic intellectual disabilities (ID) and congenital abnormalities (CA) but are also thought to be responsible for unexplained recurrent miscarriage (RM). Such rearrangements can go unnoticed through conventional cytogenetic techniques and are undetectable even with high-resolution molecular cytogenetic techniques such as array comparative genomic hybridization (aCGH), especially when DNA of the stillbirth or families are not available. The aim of the study is to evaluate the rate of subtelomeric rearrangements in patients with RM.Materials and MethodsIn this cross-sectional study, fluorescent in situ hybridization (FISH), based on ToTelVysion telomeric probes, was undertaken for 21 clinically normal couples exhibiting a “normal” karyotype with at least two abortions. Approximately 62% had RM with a history of stillbirth or CA/ID while the other 38% had only RM.ResultsFISH detected one cryptic rearrangement between chromosomes 3q and 4p in the female partner of a couple (III:4) [46,XX,ish t(3;4)(q28-,p16+;p16-,q28+)(D3S4559+,D3S4560-,D4S3359+; D3S4560+, D4S3359- ,D4S2930+)] who presented a history of RM and family history of ID and CA. Analysis of the other family members of the woman showed that her sisters (III:6 and III:11) and brother (III:8) were also carriers of the same subtelomeric translocation t(3;4)(q28;p16).ConclusionWe conclude that subtelomeric FISH should be undertaken in couples with RM especially those who not only have abortions but also have had at least one child with ID and/or CA, or other clinically recognizable syndromes. For balanced and cryptic anomalies, subtelomeric FISH still remains the most suitable and effective tool in characterising such chromosomal rearrangements in RM couples.

Transcriptomic profiles in peripheral blood between women with unexplained recurrent implantation failure and recurrent miscarriage and the correlation with endometrium: A pilot study.

AimTo study the transcriptome profiles in the blood of recurrent implantation failure (RIF), recurrent miscarriage (RM) and fertile women during the window of implantation, and further analysis the correlation of transcriptome profiles between blood and endometrium.MethodsThis is an observational prospective study. In total 9 subjects were recruited, 3 RIF, 3 RM, and 3 controls. Paired samples (endometrium and peripheral blood) from the same subjects were precisely timed on the 7th days after luteal hormone surge (LH+7). RNA sequencing was applied to investigate the transcriptome profiles.ResultsThe results of transcriptome in peripheral blood cannot be used to characterize women with RIF and unexplained RM. There was a medium level correlation between transcriptome in peripheral blood and endometrium during the window of implantation.ConclusionThe differential transcriptome patterns in blood are not representative of those in endometrium, and the blood transcriptome cannot differentiate among the women with RIF, RM or fertile.

Paternal HLA-C is a risk factor in unexplained recurrent miscarriage.

HLA-C is the only classical HLA-I antigen expressed on trophoblast. We hypothesized that the alloimmune response to paternal HLA-C plays a role in unexplained recurrent miscarriage. In a case-control design, we included 100 women with at least three unexplained consecutive miscarriages along with their partners and children. For the first control group, we included 90 women with an uneventful singleton pregnancy without pregnancy complications in their history along with their children. The second control group consisted of 425 families. HLA-C*07 and HLA-C*17 frequencies, which are the most immunogenic HLA-C antigens, along with HLA-C mismatches, and the presence of specific HLA antibodies in the mother were determined. HLA-C and HLA-C*07 mismatches were significantly increased in couples with recurrent miscarriage compared to control subjects (P=.016, P=.008, respectively). The incidence of child-specific HLA-C*07/HLA-C*17 antibodies was increased in women with recurrent miscarriage (P=.007). The results show that HLA-C incompatibility between couples is significantly associated with unexplained recurrent miscarriage.

Low-dose lymphocyte immunotherapy rebalances the peripheral blood Th1/Th2/Treg paradigm in patients with unexplained recurrent miscarriage

BackgroundThe published results regarding lymphocytes immunotherapy for unexplained recurrent miscarriage (uRM) patients are conflicting due to different screening criteria and therapeutic protocols. The objective of the present study is to evaluate the effectiveness of immunotherapy using low-dose lymphocytes in patients with uRM and Th1/Th2/Treg paradigm disorders.MethodsSixty-four uRM patients who received low-dose lymphocytes immunotherapy served as the immunotherapy group, while the other 35 women who did not receive the treatment served as the control group. The proportions of peripheral blood Th1 cells, Th2 cells and Treg cells; and the concentration of TGF-β1 in serum were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively, before and after the immunotherapy.ResultsThe proportion of Th1 cells was significantly decreased while the proportions of Th2 cells and Treg cells were significantly increased in immunotherapy group patients after treatment. In addition, the concentration of TGF-β1 in serum was significantly higher after immunotherapy than before. Forty-three uRM patients achieved pregnancy after receiving immunotherapy and 5 patients underwent miscarriages in the immunotherapy group (11.6%, 5/43), while 8 of the 23 pregnant patients experienced a miscarriage in the control group (34.8%, 8/23; p < 0.05).ConclusionsLow-dose lymphocyte immunotherapy is beneficial for restoring balance in the Th1/Th2/Treg paradigm and improving pregnancy outcome in uRM patients.Trial registrationNCT03081325. ClinicalTrials.gov. Retrospectively registered July 2015.

Ovarian reserve testing and uterine blood flow assessment using two-dimensional and three-dimensional Doppler in patients with unexplained recurrent miscarriage.

Ovarian reserve testing and uterine blood flow assessment using two-dimensional and three-dimensional Doppler in patients with unexplained recurrent miscarriage.

Expanded alleles of the FMR1 gene are related to unexplained recurrent miscarriages.

Up to 50% of recurrent miscarriage cases in women occur without an underlying etiology. In the current prospective case–control study, we determined the impact of CGG trinucleotide expansions of the fragile-X mental retardation 1 (FMR1) gene in 49 women with unexplained recurrent miscarriages. Case group consisted of women with two or more unexplained consecutive miscarriages. Blood samples were obtained and checked for the presence of expanded alleles of the FMR1 gene using PCR. Patients harboring the expanded allele, with a threshold set to 40 repeats, were further evaluated by sequencing. The number of abortions each woman had, was not associated with her respective CGG repeat number (P=0.255). The repeat sizes of CGG expansion in the FMR1 gene were significantly different in the two population groups (P=0.027). All the positive cases involved intermediate zone carriers. Hence, the CGG expanded allele of the FMR1 gene might be associated with unexplained multiple miscarriages; whether such an association is coincidental or causal can be confirmed by future studies using a larger patient cohort.

Aspirine : indications et utilisation durant la grossesse

Aspirin (acetylsalicylic acid) has been used ever since the Antiquity for its painkilling and anti-inflammatory effects. Its antiplatelet properties have then extended its indications to the field of coronaropathy and vascular cerebral disease, and finally to vascular placental disease. Aspirin has been widely prescribed since the 1980's to prevent pre-eclampsia, intra-uterine growth retardation and fetal death of vascular origin. It has also been proposed to prevent unexplained recurrent miscarriages. Its use during pregnancy is considered as safe, provided the daily doses do not exceed 100mg. Aspirin has been proven efficient to prevent pre-eclampsia and fetal growth restriction in high-risk patients. The benefits of prescribing aspirin have been demonstrated neither for vascular placental disease prevention in low risk patients, nor in cases of unexplained recurrent miscarriages.

Maternal natural killer cell immunoglobulin receptor genes and human leukocyte antigen-C ligands influence recurrent spontaneous abortion in the Han Chinese population.

The underlying mechanism of recurrent spontaneous abortion (RSA) has remained elusive for many years. Several previous studies have suggested that the killer cell immunoglobulin receptor (KIR) gene family is associated with RSA, however, it is not clear exactly how. The present study detected KIR and human leukocyte antigen-C (HLA-C) genes in 110 Han Chinese women with unexplained RSA and 105 Han Chinese healthy females. The aim of the present study was to determine if certain genotypes were more susceptible to the occurrence of miscarriage. The frequency of KIR genes and different KIR haplotypes in the 2 groups demonstrated no statistical differences. However, in women who had miscarried ≥3 times, the frequency of KIR3DL1 was significantly reduced and the BB haplotype frequency was significantly higher compared with the control group. HLA-C2C2 was significantly increased in the KIR AB and KIR BB groups in the RSA groups compared with the control group. The women in the RSA group who had a homozygous HLA-C2C2 had a significantly higher frequency of the 2DS1 gene compared with the control group. The reduction of inhibitory gene and increased activation combinations may induce the activation of uterine natural killer cells, which may reduce the probability of fetal survival. To the best of our knowledge, the present study is the first report demonstrating the association between maternal KIR and HLA-C genes and RSA in women of a Han Chinese ethnicity. The present study revealed that females who miscarry ≥3 times may be used as selection criteria for RSA and so may exhibit higher research value.

The M2 haplotype of ANXA5 gene in the context of unexplained recurrent miscarriages

The M2 haplotype of ANXA5 gene in the context of unexplained recurrent miscarriages

Genome copy number variations of patients with unexplained recurrent spontaneous abortion

Genome copy number variations of patients with unexplained recurrent spontaneous abortion

Decreased expression of WNT2 in villi of unexplained recurrent spontaneous abortion patients may cause trophoblast cell dysfunction via downregulated Wnt/β-catenin signaling pathway.

WNT2 has been reported to be important for placental development, especially for the proper vascularization of the placenta. However, its precise role in first-trimester trophoblast cells is still unknown. WNT2 expression in the villous tissues of unexplained recurrent spontaneous abortion (URSA) patients was compared with that of healthy women by Western blot. The function of WNT2 in HTR-8/SVneo trophoblast cells was evaluated by altering the cellular WNT2 level through overexpression and shRNA knockdown. The molecular mechanism of the effect of WNT2 on trophoblast cells was investigated. The association of WNT2 with the Wnt/β-catenin signaling pathway was studied through Western blot and immunofluorescence. Results showed that WNT2 protein expression was significantly decreased in villi of the URSA group compared with the control group. In vitro studies showed that WNT2 could promote human trophoblast cell proliferation and migration through activating the Wnt/β-catenin signaling pathway. Moreover, upon the knockdown of WNT2, trophoblast cell proliferation and migration were significantly suppressed. In conclusion, our study indicated that WNT2 plays an important role in trophoblast function. WNT2 insufficiency might cause impaired trophoblast cell proliferation and migration via downregulation of Wnt/β-catenin signaling pathway.

Predictive value of serum progesterone level on β-hCG check day in women with previous repeated miscarriages after in vitro fertilization.

ObjectiveTo evaluate the predictive value of the progesterone level at the beta-human chorionic gonadotropin (β-hCG) check day for ongoing pregnancy maintenance in in vitro fertilization (IVF) cycles in women with previous unexplained repeated miscarriages.Materials and methodsOne hundred and forty-eight women, with visible gestational sac after IVF, were recruited in this observational study. All subjects had unexplained recurrent miscarriages in more than two previous IVF cycles. The progesterone level at the β-hCG check day (i.e. 14 days after oocyte retrieval) was assessed. The area under the curve (AUC) of the progesterone level was evaluated to predict the ongoing pregnancy or miscarriage outcomes.ResultsThe overall ongoing pregnancy rate was 60.8% (90/148). The cut-off value with β-hCG levels higher than 126.5 mIU/mL and with progesterone levels higher than 25.2 ng/mL could be the predictive factors for ongoing pregnancy maintenance (AUC = 0.788 and 0.826; sensitivity = 0.788 and 0.723; specificity = 0.689 and 0.833; P < 0.0001 and P < 0.0001, respectively). The miscarriage rates were 19.5% (15/77) in the women with β-hCG > 126.5 mIU/mL and 13.0% (10/77) in those with > 25.2 ng/mL. In the comparison of the ROC curves between both values, a similar significance was found. The subjects with β-hCG > 126.5 mIU/mL and progesterone > 25.2 ng/mL showed higher ongoing pregnancy rates [98.0% (49/50) vs. 41.8% (41/98)] than those with β-hCG ≤ 126.5 mIU/mL or progesterone ≤ 25.2 ng/mL.ConclusionsThe progesterone level at 14 days after oocyte retrieval can be a good predictive marker for ongoing pregnancy maintenance in women with repeated IVF failure with miscarriage, together with the β-hCG level. The combined cut-off value of progesterone > 25.2 ng/mL and β-hCG > 126.5 mIU/mL may suggest a good prognosis.

Correlation between unexplained recurrent spontaneous abortion with CD4+CD25+ regulatory T-cell and killer cell immunoglobulin-like receptor levels.

The present study investigated the correlation between unexplained recurrent spontaneous abortion (URSA) with CD4+CD25+ regulatory T-cell (Treg) and killer cell immunoglobulin-like receptor (KIR)-2DL1 levels. A total of 76 URSA patients were enrolled (35 without pregnancy, Group A, and 41 with early abortion, Group B). Additionally, 30 patients who received a regular abortion as planned (Group C) and 30 healthy volunteers (Group D) were selected. Peripheral venous blood and fresh decidual tissue samples were obtained from all the patients, and flow cytometry was performed to detect CD4+CD25+Treg and Foxp3 transcription factor levels. mRNA and protein KIR-2DL1 expression levels were assayed using quantitative PCR and western blot analysis, respectively. No statistically significant differences in peripheral venous blood CD4+CD25+Treg/CD4+ and Foxp3+/CD4+CD25+Treg cell proportions were found among the groups (P>0.05). However, the decidual tissues of Group C presented significantly higher levels of both cell types versus other groups (P<0.05). No statistically significant differences were found in comparisons among Groups A, B, and D (P>0.05). In peripheral venous blood, mRNA and protein KIR-2DL1 expression levels in Group C were significantly higher than those in the other three groups (P<0.05), but again, there were no statistically significant differences among Groups A, B, and D (P>0.05). In decidual tissues, KIR-2DL1 levels were significantly higher in Group C relative to Groups A, B, and D (P<0.05). Decreased CD4+CD25+Treg counts and KIR-2DL1 expression levels were closely associated with the onset of URSA. CD4+CD25+Tregs mainly exert their effects on decidual tissues, while KIR-2DL1 can act on peripheral venous blood and decidual tissues. These may present new targets for early intervention in URSA.

Unexplained recurrent miscarriages are associated with an aberrant sperm protamine mRNA content

Are unexplained recurrent miscarriages associated with abnormal protamine-1 and protamine-2 mRNA levels in spermatozoa? Both protamine-1 and protamine-2 mRNA levels as well as the protamine-1 to protamine-2 mRNA ratio in spermatozoa from men whose female partners experienced two or more consecutive miscarriages were significantly different compared to those from both healthy control men and subfertile couples undergoing IVF/ICSI. Aberrant sperm protamine ratios are known to be associated with male-factor infertility. Data from this study suggest that the protamine mRNA ratio may additionally affect early embryo development. The study population was recruited from men whose female partners presented with two or more consecutive unexplained miscarriages in a consultation for recurrent pregnancy loss between 2014 and 2016. At the research laboratory of the Urological Clinic of the University Giessen, spermatozoa from cases and controls were subjected to reverse transcription quantitative PCR (RTqPCR) using specific primer pairs for protamine-1 and protamine-2. Protamine-1 and protamine-2 mRNA levels were analysed in semen samples from 25 men whose female partners experienced at least two consecutive idiopathic miscarriages before the 20th week of gestation. The couples were recruited during consultation at the Fertility Center of the LMU Munich, Germany, and at the Clinical Division of Gynecologic Endocrinology and Reproductive Medicine of the Medical University of Vienna, Austria. Results were compared with those from 32 healthy donors (WHO, 2010) recruited at the Department of Urology, Pediatric Urology and Andrology, Giessen, Germany, and 107 men whose partners participated in an IVF/ICSI program at the Fertility Center of the LMU Munich, Germany. Protamine-1 and protamine-2 mRNA levels as well as the protamine mRNA ratio and all routine semen parameters revealed significant differences between recurrent miscarriage couples and healthy volunteers (P < 0.01). When comparing recurrent miscarriage couples with couples undergoing IVF/ICSI, Ct-values of protamine-1 and protamine-2 mRNAs were significantly higher and the protamine mRNA ratio was significantly lower in RM couples (P < 0.01). When comparing protamine mRNA levels and the protamine mRNA ratio with routine semen parameters, a significant negative correlation was evident between progressive motility and the protamine-2 mRNA level (P = 0.015), as well as between non-progressive motility and the protamine mRNA ratio (P = 0.023). Although our data demonstrate significant abnormalities in RM, larger sample sizes will be needed to confirm our results. Larger sample sizes should also balance the fact that we had to focus mainly on median protamine mRNA levels. Finally, men in the healthy control group were younger in age than those in the case group, which might have introduced some bias, at least concerning the classic semen parameters. Moreover, only protamine mRNA instead of protein levels could be measured. Although the exact mechanism remains to be elucidated, our data suggest that protamine mRNA levels in spermatozoa are not only important for successful fertilization, but also for proper development of the early embryo. Grant from the University Clinic Giessen and Marburg (UKGM 29/2015GI). There are no competing interests. N/A.

Alteration of Th17 and Foxp3+ regulatory T cells in patients with unexplained recurrent spontaneous abortion before and after the therapy of hCG combined with immunoglobulin.

We conducted this study to investigate the effects of the combination therapy of human chorionic gonadotropin (hCG) plus immunoglobulin (IG) on the levels of T helper 17 (Th17) cells and Foxp3+ regulatory T cells (Treg) in patients with unexplained recurrent spontaneous abortion (URSA). Twenty pregnant women with URSA underwent combination therapy of hCG plus IG. Flow cytometry was performed to measure the proportions of Th17 and Treg cells before and after treatment. RT-PCR and ELISA were applied to detect the concentrations of interleukin (IL)-17, IL-6, IL-10, and transforming growth factor (TGF)-β1 in the peripheral blood. The therapy of hCG combined with IG may induce a decrease in the Th17/Treg ratio and the Treg bias, which may be beneficial for the maintenance of pregnancy. The levels of Th17 cells and related cytokines IL-17 and IL-6 decreased after the treatment (P<0.05). At the same time, levels of Treg cells and the related cytokines IL-10 and TGF-β1 increased (P<0.05). The Th17/Treg ratio decreased significantly after treatment. In conclusion, the occurrence of URSA may be associated with the Th17/Treg balance disorder, and correcting the disorder may be one of the mechanisms behind the efficacy of combination therapy for URSA.

Treg/Th17 Cell Imbalance and IL-6 Profile in Patients With Unexplained Recurrent Spontaneous Abortion.

Regulatory T cells (Treg) and T helper 17 cells (Th17) are 2 distinct subsets of CD4+ T cells, which are mutually antagonistic in the immune response. Recently, dysregulation of these 2 cell subsets have been described in the pathogenesis of unexplained recurrent spontaneous abortion (URSA). The purpose of this study was to investigate whether the Treg/Th17 balance was perturbed in URSA patients and to explore contributing factors. We found that the proportion of Treg cells and expression of forkhead box P3 (Foxp3) messenger RNA (mRNA) were significantly lower in URSA patients than in healthy controls. However, the proportion of Th17 cells and expression of retinoid-related orphan nuclear receptor-γt (ROR-γt) mRNA were higher in URSA patients than in controls, revealing inverse correlation with Treg. The ratio of Treg/Th17 and Foxp3/ROR-γt decreased in patients with URSA compared to healthy controls. The serum levels of interleukin (IL)-6 and IL-17A were significantly higher, whereas IL-10 was lower in URSA patients compared with controls, and the level of IL-6 showed a positive correlation with Th17, ROR-γt and inverse correlation with Treg, Foxp3. The present study indicated that an imbalance between Treg and Th17 cells might be implicated in the pathogenesis of URSA and this seems to relate to elevation in serum IL-6 level.