Pregnancy Loss Patients Research Articles

Maternal factors predictive of first‑trimester pregnancy loss in women with pregestational diabetes

Diabetes is one of the most frequent chronic diseases in women of childbearing age, which significantly increases the risk of complications at every stage of pregnancy. The aim of the study was to investigate any maternal factors that may be associated with the risk of first‑trimester pregnancy loss in patients with pregestational diabetes. It was a retrospective study based on the data of 91 diabetic women in singleton pregnancy and with good perinatal outcome (74 women [81.3%] with type 1 and 17 [18.7%] with type 2 diabetes), and 60 diabetic women with a miscarriage (48 women [80%] with type 1 and 12 [20%] with type 2 diabetes). We analyzed selected maternal parameters at the first admission to the obstetrics department. Women in the miscarriage group were older compared with those in the good outcome group (29.5 ±5.4 years vs. 26.4 ±5.3 years; P <0.001). Hemoglobin A1c (HbA1c) was higher in the miscarriage group compared with the good outcome group (8.2% ±1.9% vs. 7.2% ±1.8%; P <0.001). In a stepwise logistic regression analysis, maternal age at booking and HbA1c were found to be significant predictors of miscarriage (odds ratio [OR], 1.10; 95% confidence interval [CI], 1.02-1.18 and OR, 1.28; 95% CI, 1.026-1.61; respectively). A statistically insignificant trend towards first-trimester pregnancy loss was observed in patients with hypertension, overweight/obesity, unplanned pregnancy, longer duration of diabetes, and diabetic vascular complications. Suboptimal metabolic control and increasing maternal age are the most significant risk factors for first‑trimester miscarriage in women with pregestational diabetes.

Presence of Autoantibody Against Two Placental Proteins, Peroxiredoxin 3 and Peroxiredoxin 4, in Sera of Recurrent Pregnancy Loss Patients

Recurrent pregnancy loss (RPL) is defined as two or more consecutive abortion before the 20th week of gestation. Autoimmune diseases increase the risk and accounts for at least 20% of RPL. Placenta is a pregnancy unique tissue, and proper formation of placenta is key phenomenal for success of a pregnancy. The aim of this study was to investigate the placental proteins that may act as antibody targets in RPL patients. Total placental proteins were extracted and separated using 2D-PAGE technique. Separated protein spots were transferred on PVDF membrane and blotted with sera from 20 RPL patients and compared with the protein spots that membrane blotted with sera from 20 normal women. Differentially blotted spots were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry mass spectrometry technique. The results of the mass analysis also were confirmed by western blot using mAb and reverse transcriptase polymerase chain reaction technique. The results indicated that RPL women may produce antibody against Peroxiredoxin 3 (Prx3) and Peroxiredoxin 4 (Prx4). Our results indicate that two placental proteins, Prx3 and Prx4, may act as new placental immune targets. Considering the role of antioxidant defense in the protection of placenta from oxidative stress, production of antibodies against peroxiredoxins 3 and 4 may introduce a new autoimmune hypothesis in RPL, which is needed to be tested in the future works.

Immune modulation treatment does not improve IVF outcomes but increase early pregnancy losses in patients with unknown cause of repeated IVF-ET failure

To investigate the pregnancy outcome of additional treatment such as prednisolone(PDS), low-molecular-weight heparin(LMWH) and intravenous Immunoglobulin(IVIG) in patients with unknown cause of repeated IVF-ET failure.

Idiopathic recurrent miscarriage is caused mostly by aneuploid embryos

To determine any beneficial effects of preimplantation genetic screening (PGS) of all chromosomes by array comparative genomic hybridization (aCGH), with either day 3 or blastocyst biopsy, for idiopathic recurrent pregnancy loss (RPL) patients compared with their expected loss rate. Case series report. Multiple fertility centers. A total of 287 cycles of couples with idiopathic RPL (defined as two or more losses). PGS was done with day 3 biopsy (n = 193) or blastocyst biopsy (n = 94), followed by analysis with aCGH. Spontaneous abortion rate, euploidy rate. A total of 2,282 embryos were analyzed, of which 35% were euploid and 60% were aneuploid. There were 181 embryo transfer cycles, of which 100 (55%) became pregnant with an implantation rate of 45% (136 sacs/299 replaced embryos) and 94 pregnancies (92%) were ongoing (past second trimester) or delivered. The miscarriage rate was found to be only 6.9% (7/102), compared with the expected rate of 33.5% in an RPL control population and 23.7% in an infertile control population. Current PGS results with aCGH indicate a significant decrease in the miscarriage rate of idiopathic RPL patients and high pregnancy rates. Furthermore, this suggests that idiopathic recurrent miscarriage is mostly caused by chromosomal abnormalities in embryos.

Presence of autoantibody against two placental proteins, Peroxiredoxin 3 (Prx3) &amp; Peroxiredoxin 4 (Prx4) in sera of recurrent pregnancy loss (RPL) patients

Presence of autoantibody against two placental proteins, Peroxiredoxin 3 (Prx3) &amp; Peroxiredoxin 4 (Prx4) in sera of recurrent pregnancy loss (RPL) patients

Blocking factors in serum from recurrent pregnancy loss patients and from imminent aborters were detected by modified complement-dependent cytotoxicity test

Blocking factors in serum from recurrent pregnancy loss patients and from imminent aborters were detected by modified complement-dependent cytotoxicity test

Incidence of Endometritis in Recurrent Pregnancy Loss Patients

Incidence of Endometritis in Recurrent Pregnancy Loss Patients

Apolipoprotein E polymorphisms and spontaneous pregnancy loss in patients with endometriosis

Endometriosis affects >10% of women during their reproductive years, many of whom report high rates of spontaneous pregnancy loss (SPL). We examined whether gene polymorphisms in apolipoprotein E (APOE), which is involved in lipoprotein metabolism, are associated with endometriosis and/or endometriosis-associated infertility. We conducted a cross-sectional genetic association study of women surgically confirmed to have endometriosis (n = 345) and no surgical evidence of the disease (n = 266). Genotyping of APOE polymorphism (ε2, ε3, ε4) was conducted by polymerase chain reaction-restriction fragment length polymorphism followed by visualization of specific patterns by gel electrophoresis. Statistical significance of differences in genotype and allelic frequencies was assessed using Pearson's χ(2) test and Risk analysis. Overall, we found no association between APOE genotype and diagnosis of endometriosis. However, patients with endometriosis who reported at least one SPL were three times more likely to be ε2 carriers and 2-fold less likely to be ε4 carriers. Compared with ε3 carriers, patients with endometriosis who were ε2 carriers and had at least one live birth reported four times the rate of SPL, while ε4 carriers were <0.4-fold less likely to report an SPL. Our data suggest that there may be an association between APOE allelic frequency and SPL in patients with endometriosis, which appears to be independent of mechanisms associated with infertility, an intriguing observation that deserves further investigation.

Recurrent pregnancy loss in patients with thyroid dysfunction

Purpose of the Review:Thyroid disturbances are common in women during their reproductive years. Thyroid dysfunction interferes with human reproductive physiology, reduces the likelihood of pregnancy and adversely affects pregnancy outcome, thus becoming relevant in the algorithm of reproductive dysfunction. This review highlights the gap in knowledge regarding the contribution of thyroid dysfunction in reproduction.Literature Reviewed:Following implantation, the maintenance of the pregnancy is dependent on a multitude of endocrinological events that will eventually aid in the successful growth and development of the fetus. It is estimated that approximately 8-12% of all pregnancy losses are the result of endocrine factors. Autoimmune thyroid disease is present in around 4% of young females and up to 15% are at risk because they are thyroid antibody-positive. There is a strong relationship between thyroid immunity on one hand and infertility, miscarriage, and thyroid disturbances in pregnancy and postpartum, on the other hand. Even minimal hypothyroidism can increase rates of miscarriage and fetal death and may also have adverse effects on later cognitive development of the offspring. Hyperthyroidism during pregnancy may also have adverse consequences.Summary:Pregnant women with subclinical hypothyroidism or thyroid antibodies have an increased risk of complications, especially pre-eclampsia, perinatal mortality, and miscarriage. Universal screening for thyroid hormone abnormalities is not routinely recommended at present, but thyroid function must be examined in female with fetal loss or menstrual disturbances. Practitioners providing health care for women should be alert to thyroid disorders as an underlying etiology for recurrent pregnancy loss.

TLR1 polymorphisms in Europeans and spontaneous pregnancy loss

Toll-like receptors (TLRs) are critical components of the pathogen recognition by the host innate immune system. Recently it has been shown that TLR1 is under evolutionary pressure in Europeans. This involves the positive selection of the nonsynonymous TLR1 1805G variant in Europeans, although this is associated with poor TLR1 response and unfavorable prognosis in various infections. In terms of natural selection, differential fertility is another mechanism, independent of infection susceptibility, that may explain the polymorphism pattern observed for TLR1. To test this hypothesis, we assessed the correlation of two TLR1 SNPs (T1805G and G239C) with spontaneous pregnancy loss in a case–control study that included 132 spontaneous pregnancy loss patients and 142 control volunteers. Similar allele frequencies of T1805G were observed between cases and controls, but GG genotype tended to be associated with pregnancy loss (OR 1.91; 95%CI 1.03, 3.53). No differences were observed for the TLR1 G239C SNP. Our findings showed slight differences in the distribution of T1805G variants in women with pregnancy loss, but these were not indicative of a protective effect of the TLR1 1805G allele for this fertility disorder. Although our hypothesis was not proven, potential effects of TLR1 polymorphisms on pregnancy outcome have been suggested, and future studies in larger cohorts are warranted.

Does a high-normal TSH level >2.5 mIU/L pose an increased risk of pregnancy loss in patients undergoing art?

To evaluate if a TSH level > 2.5 mIU/L poses an increased risk of pregnancy loss (MC) in patients who achieved a pregnancy from ART Retrospective. Women undergoing a first, fresh-embryo IVF or ICSI cycle between January 2002-2010 were analyzed.Continuous data were compared using t-test or Mann-Whitney U while categorical data were analyzed using chi-square.While adjusting for age, prior spontaneous loss (SAB) and maximum FSH levels, multivariate logistical regression was performed to determine whether TSH was predictor of MC or live birth (LB) Of the 1517 cycles reviewed, 642(42%) resulted in a positive pregnancy test.Complete data was available for 426 cycles.Of these, 358 cycles had TSH levels within normal range (0.4-4.5 mIU/L) and these cycles were grouped according to low-normal (0.4-2.5mIU/L) or high-normal (2.51-4.5mIU/L) TSH levels.Patient characteristics, including age, BMI, prior SAB, maximum FSH and etiology of infertility were statistically similar amongst groups. 241 LB (67.3%), 60 biochemical pregnancies (BC)(16.8%) and 32 MC (8.9%) were reported,with no statistical difference amongst the rates of BC, MC or LB between the two groups,however women in the low-normal group had a 7.3% higher LB rate compared to women in the high-normal group(68.4% vs. 61.1%, respectively, P=0.29).Logistical regression revealed that age and having a prior SAB were positive predictors of MC,while age,a prior SAB and high maximum FSH,were negative predictors of LB.After controlling for these predictors,logistical regression revealed that a TSH level of 0.4-2.5 mIU/L or 2.51-4.5 mIU/L prior to an IVF or ICSI cycle was not a predictor of MC(OR: 1.34, 95% CI: 0.52-3.42 P=0.55) or LB(OR: 0.73, 95% CI: 0.40-1.32 P=0.30). Having a high-normal TSH level was not a risk factor for MC, however, although there seems to be no advantage to having a TSH level ≤2.5 mIU/L in achieving a LB,this study is currently underpowered to detect a difference of 7.3% that may be clinically important.

Danaparoid versus heparin therapy in recurrent pregnancy loss patients with antiphospholipid antibody

Danaparoid versus heparin therapy in recurrent pregnancy loss patients with antiphospholipid antibody

An immunohistochemical study of metroplastic surgical specimens from patients with a septate uterus.

To elucidate the etiology of recurrent pregnancy loss in patients with congenital uterine anomalies, an immunohistochemical technique was used to quantitatively evaluate the vascular arrangement of septate uteri with respect to vascular density and morphology. Nine specimens obtained from patients who had undergone metroplastic surgery for the treatment of a septate uterus and 10 control specimens from patients who had undergone a hysterectomy because of cervical carcinoma were used in this study. Formalin-fixed paraffin-embedded uterine specimens were then immunostained for CD34, which is specifically expressed in vascular endothelial cells. The mean blood vessel count (mean ± SD) for the myometrium was 149.7 ± 22.7/field in the septate uteri and 162.2 ± 36.4/field in the control uteri; these values were not significantly different. However, the total vessel cross-sectional areas, as evaluated quantitatively using the KS400 image analysis system, were 10350.4 ± 1024.3 μm2/field for the septate uteri and 12002.9 ± 2232.3 μm2/field for the control uteri; these values were significantly different (p < 0.05). The vessel morphology expressed by vessel irregularity and deformity showed a characteristic change in the septate uterus. A significant difference in the distribution of the blood vessels existed between the septate and control uteri, presumably impairing blood flow in the myometrium and the adverse pregnancy outcome.

Preimplantation factor negates embryo toxicity and promotes embryo development in culture

Preimplantation factor (PIF) is secreted by viable mammalian embryos and promotes implantation and trophoblast invasion. Whether PIF also has a direct protective or promoting effect on the developing embryo in culture is unknown. This study examined the protective effects of synthetic PIF (sPIF) on embryos cultured with embryo toxic serum (ETS) from recurrent pregnancy loss patients ( n = 14), by morphological criteria at 72 h of culture, and determined sPIF-promoting effect on singly cultured bovine IVF embryo development. sPIF negated the ETS-induced effect by increasing mouse blastocyst rate versus other embryonic stages (odds ratio (OR) 2.01, 95% confidence intervals (CI) 1.14–3.55, chi-squared = 12.74, P = 0.002), increased blastocyst rate (39.0% versus 23.7% ETS alone) and lowered embryo demise rate (11.0% versus 28.8%, OR 0.24, 95% CI 0.11–0.54), which was not replicated by scrambled PIF or the control. sPIF added to bovine embryos for 3 days promoted development at day 7 of culture (11% versus 0%, chi-squared = 4.0, P = 0.045). In conclusion, sPIF prevented embryo demise caused by exposure to ETS and promoted development of singly cultured bovine IVF embryos following short-term exposure. sPIF-based therapy for reducing recurrent pregnancy loss and improving lagging cultured IVF embryo development should be explored. Preimplantation factor (PIF) is a novel peptide, secreted by the embryo at the 2-cell stage. It is present throughout viable pregnancy but absent in non-viable pregnancy. PIF has essential immune-modulatory, acceptance and maintenance effects on the maternal system for embryo implantation, creating the necessary environment in the uterus and helping better embedding of the placenta. Herein we investigate in two complementary models whether PIF can help embryos survive under adverse conditions, protect against recurrent pregnancy loss and promote lagging embryo development. PIF’s synthetic analogue (sPIF) is available at suitable purity for human use and its use is proposed in physiological range doses. sPIF administration strongly suggested a targeted and safe treatment regimen, successfully negating the toxicity present in the blood (serum) of patients suffering from recurrent miscarriages in the relevant pooled mouse embryo model used. sPIF showed an equally important beneficial effect to prevent suboptimally developed embryo demise and improve their development. In a (single bovine) IVF model, highly relevant for low-responder human embryos that produce low-quality but viable embryos, sPIF increased embryo survival under adverse conditions. To document sPIF’s specific effect, an inactive, same-composition (scrambled) protein was tested, which showed no effect. To evidence sPIF’s safety and unique needs-based action, high concentrations added to optimally cultured embryos equally showed no effect. We conclude that sPIF administration may specifically reduce cases of repeat miscarriage and improve viable but suboptimal embryo survival. These added observations help complete PIF’s overall crucial function in accommodating and facilitating successful pregnancy.

Reduced expression of gap junction gene connexin 43 in recurrent early pregnancy loss patients

Connexin 43 (Cx43) gap junctions play an important role in development and differentiation of endometrium and placenta. Therefore, aberrant expression of Cx43 could result in altered physiological and pathological processes leading to recurrent early pregnancy loss (REPL). To investigate if expression of Cx43 is effected in REPL patients as compared to controls, Cx43 expression was compared in the chorionic villi and uterine decidua samples of 15 REPL patients and 15 induced abortion subjects as controls. Cx43 levels were evaluated using semi-quantitative RT-PCR, quantitative Real-time PCR and by western blot. Cx43 expression at mRNA and protein level was significantly decreased in both chorionic villi and decidua (p < 0.05) of REPL patients. Reduced expression of Cx43 transcript and protein in fetal chorionic villi and maternal decidua indicate the key role of Cx43 in REPL risk.

Incidence of Moderate to Severe Depression in Recurrent Pregnancy Loss Patients

OBJECTIVE(S): Recurrent pregnancy loss (RPL) affects 1-5% of reproductive age women. For many couples, the experience can lead to prolonged grief and the feeling of loss of control. Although rarely reported in the literature, the incidence of depression in women with RPL is likely to be greater than unaffected women. The objective of our current study is to determine the incidence and severity of depression in a multispecialty RPL program using the validated Beck's Depression Inventory Questionnaire.

ITI-H4, as a biomarker in the serum of recurrent pregnancy loss (RPL) patients

Recurrent pregnancy loss (RPL) is defined as at least three pregnancy losses in series prior to the 20-28 weeks of pregnancy. There are several etiological factors associated with immunology, anatomy, endocrinology, genetic, infection, chromosomal abnormalities, and environmental factors contributing to the condition. The aim of this study was to identify RPL associated factors in human blood using proteomics. Since it is difficult to obtain tissues or follicular fluids, we used blood samples from normal and RPL patients to conduct a comparative proteomic study. Three RPL blood samples and one cocktailed blood sample from 3 normal women were used. We performed 2-DE and selected spots were analyzed with MALDI-TOF/MS. In the three RPL blood samples, 2-DE analysis revealed 549, 563 and 533 spots to be differentially expressed, respectively. Through a comparative analysis between the control and RPL, 21 spots were shown to be differentially expressed. Of these, 5 proteins were confirmed by Western blot analysis. One of these proteins, ITI-H4 (inter-α trypsin inhibitor-heavy chain 4), was weakly expressed at a molecular weight of 120 kDa, but was highly expressed at a modified molecular weight of 36 kDa in RPL patients. These findings suggest that ITI-H4 expression may be used as a biomarker, which could facilitate the development of novel diagnostic and therapeutic tools.

Serum Leptin and Insulin Hormone Level in Recurrent Pregnancy Loss

To measure serum leptin and insulin levels in women with recurrent pregnancy loss using modified methods of High Performance Liquid Chromatography (HPLC), and to examine their influence on recurrent loss at different pregnancy trimesters. A case control study was conducted from, 1 September 2008 to 30 December 2009 in the Obstetric and Gynecological Department-Al-Khadimiya Teaching Hospital. HPLC technique with new modified method was used to estimate serum leptin and insulin hormones in samples of women with recurrent pregnancy loss (patients group, n=64) and healthy pregnant women at the end of the third gestational trimester as a control group (n=51). Both serum leptin and insulin levels were high in women with pregnancy loss in their three trimesters. A significant correlation was found between age (r=0.535, p<0.018) and serum total leptin in women with RPL during the first trimester. Also, a highly significant correlation was found between serum total leptin and insulin in women with RPL during the first, second and third trimesters (r=0.894, r=0.931, and r =0.995) respectively. The number of women who lost their pregnancy during the first trimester was higher than those losing during other trimesters. It can be concluded that recurrent pregnancy loss in women at different trimester is associated with endocrine abnormalities where serum leptin and insulin levels increase in a different way compared with normal healthy pregnant women.

Antiphosphatidylethanolamine antibodies might not be an independent risk factor for further miscarriage in patients suffering recurrent pregnancy loss

The prevalence of antiphosphatidylethanolamine antibodies (aPEs) is higher in recurrent pregnancy loss patients than that in women with normal pregnancy. We conducted a cohort study to examine the predictive value of aPE for recurrent pregnancy loss and to determine its clinical significance. We examined plasma protein dependent (P+) and independent (P-) aPE IgG and IgM antibodies in 367 women with two or more unexplained consecutive pregnancy losses. We also examined conventional antiphospholipid antibodies (aPL) such as beta2-glycoprotein I-dependent anticardiolipin antibodies (beta2GPI-dependent aCL), lupus anticoagulant with reference to the dilute activated partial thromboplastin time (aPTT) and the diluted Russell's viper venom time (RVVT). Subsequent pregnancy outcome without medication was examined, and patients with and without aPE were compared. Totals of 37 (10.1%), 14 (3.8%), 23 (6.3%), 6 (1.6%), 9 (2.5%), 10 (2.7%) and 50 (13.6%) of the 367 patients were, respectively, positive for P+aPE IgG, P-aPE IgG, P+aPE IgM, P-aPE IgM, beta2GPI-dependent aCL, lupus anticoagulant by RVVT and LA by aPTT. The patients with aPE differed from patients with beta2GPI-dependent aCL or lupus anticoagulant by RVVT. No difference in live birth rate was apparent between positive and negative aPE patients with no medication. The areas under the curves for each ROC curve for the four aPEs were 0.535, 0.612, 0.546 and 0.533, respectively, so there was no significant variation in diagnostic capacity. We did not obtain any evidence that aPE elevation is an independent risk factor to predict further miscarriage in recurrent pregnancy loss patients.

The Role of NK Cells in the Autoimmune Thyroid Disease-associated Pregnancy Loss

Pregnancy loss is a frequent event. Autoimmune thyroid disorders and altered natural killer (NK) cell functions are two distinct risk factors, which independently could induce adverse pregnancy outcome. Thyroid autoimmunity has been an object of increased attention by investigators in the context of pregnancy loss. Peripheral NK cells and uNK cells comprise distinct cell populations in terms of phenotype and function but they play an important role in the course of a normal human pregnancy via several potential functions. In autoimmune thyroid diseases, several abnormalities of killer cell activity have been described. The functional defects involving NK maturation and/or functional activation observed in Graves' disease patients could independently influence the reproductive outcome. This suggestion needs extensive investigation and could be important for the therapeutical approach in preventing pregnancy loss in patients with thyroid autoimmunity.