History Of Unexplained Recurrent Miscarriage Research Articles

Septum Resection Prior to In Vitro Fertilization-Embryo Transfer: A Retrospective Controlled Study.

To investigate the effectiveness of surgery for septate uterus in infertile patients before in vitro fertilization-embryo transfer (IVF-ET). The data of 937 infertile patients with septate uterus and achieved singleton pregnancy after IVF-ET from January 2014 to December 2015 were retrospectively analyzed. Thousand five hundred seventy-eight infertile patients with a normal uterus who achieved singleton pregnancy during the same period were selected as the control group. Patients with septate uterus were divided into two groups according to whether the septum was resected. The pregnancy and perinatal outcomes of the surgical group and the nonsurgical group were compared with the control group. The secondary infertility patients who were surgically corrected septa were also chosen as self-controls and an analysis was performed on their fertility outcomes pre- and post-surgery. Compared with the control group, the surgical group had increased rates of early miscarriage, preterm delivery, and low birthweight and a significantly reduced live birth rate (P < .05). The outcomes of the nonsurgical and control groups were similar. Using secondary infertility patients who were surgically corrected septa as self-controls, after surgery, the rates of miscarriage and ectopic pregnancy were significantly lower and the live birth rate was significantly higher (P ≤ .001); however, perinatal mortality was not significantly different before and after surgery. Patients with a septum depth greater than 10 mm or 5-10 mm associated with a history of unexplained recurrent miscarriage, IVF failure, or infertility might benefit from resection of the uterine septum with hysteroscopic metroplasty.

Do fetuin-A/apha2-Heremans Schmid-glycoprotein levels have an association with recurrent pregnancy loss?

Objective Fetuin-A is a hepatokine which is previously found related to fertility and pregnancy outcomes. We aimed to investigate if recurrent pregnancy loss (RPL) is associated with increased fetuin-A levels. Materials and methods Serum fetuin-A concentrations were measured and compared in 30 non-pregnant women with a history of unexplained recurrent miscarriage, 29 women who had a history of unexplained recurrent miscarriage and were admitted to our clinic due to miscarriage during the study period and 30 fertile women who have no history of miscarriage or any other pregnancy complications with at least two previous healthy children. Results The median serum fetuin-A levels of group I, II, and III were 59.45, 62.73, and 44.52, respectively (p=.065). Serum fetuin-A levels significantly increased in group II compared to group III (p=.011). No significant differences in the levels of fetuin-A of group I compared to either group II (p=.433) or group III (p=.268). Conclusions The etiology of RPL is still a subject that is not clarified. Fetuin-A levels may have a relationship with RPL.

Distinct pattern of Th17/Treg cells in pregnant women with a history of unexplained recurrent spontaneous abortion.

The aim of the current study was to determine the pattern of immune cells and related functional molecules in peripheral blood and at the maternal-fetal interface in women with unexplained recurrent spontaneous abortion (URSA). In part I, 155 women were included and divided into four groups: non-pregnant controls with no history of URSA (NPCs), pregnant controls with no history of URSA (PCs), non-pregnant women with a history of URSA (NPUs), and pregnant women with a history of URSA (PUs). Venous blood samples were collected and analyzed. In part II, 35 subjects with URSA and 40 subjects in the early stage of normal pregnancy who chose to undergo an abortion were recruited. Samples of the decidua were collected, and the proportion of immune cells and the expression of related molecules were evaluated. Peripheral regulatory T cells (Treg cells) increased in PCs compared to NPCs, but in women with URSA the flux of Treg cells disappeared when pregnancy occurred. Levels of interleukin-10 (IL-10), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and IL-17 and the ratio of Th17/Treg cells in peripheral blood remained stable among the four groups. At the maternal-fetal interface, the percentage of Treg cells, the level of CTLA-4 of CD4+CD25+CD127lo cells and CD4+Foxp3+ cells were significantly lower in women with URSA compared to controls, respectively. Levels of transforming growth factor-β1 (TGF-β1) mRNA and protein in the decidua significantly decreased in URSA while levels of IL-6 and tumor necrosis factor-ɑ (TNF-ɑ) and the Th17/Treg ratio significantly increased. In conclusion, peripheral Treg cells did not increase in pregnant women with URSA. The decrease in Treg cells and levels of CTLA-4 and TGF-β1 and as well as the increase in levels of IL-6 and TNF-ɑ, and the Th17/Treg ratio at the maternal-fetal interface might contribute to inappropriate maternal-fetal immune tolerance in URSA.

Study of the association of forkhead box P3 (FOXP3) gene polymorphisms with unexplained recurrent spontaneous abortions in Indian population

Recurrent spontaneous abortions (RSA) is defined as three or more consecutive pregnancy losses before 20 weeks of gestation. Various causes of RSA have been identified, still 50% cases remain unexplained after evaluation. One of the causes of unexplained recurrent spontaneous abortions (URSA) is supposed to be the disruption of immunological tolerance at foeta-maternal interface. Regulatory T cells (Tregs) are responsible for the development of immune-tolerant environment at foetal-maternal interface and supports pregnancy. Forkhead/winged helix transcription factor (FOXP3) gene plays an important role in the development and function of Tregs. In URSA, Tregs (CD4+CD25+) are reduced in peripheral blood and decidua of pregnant women. This reduction of Tregs (CD4+CD25+) is associated with decreased expression of FOXP3 gene. This study evaluated the association between singlenucleotide polymorphisms (SNPs) in FOXP3 gene and URSA in Indian population. In this study, 100 patients with a history of URSA and 100 healthy ethnically matched women with at least one normal pregnancy and no abortion were included as case and control groups, respectively. Four SNPs of FOXP3 gene, two in the promoter region: -924A/G and -3279C/A, and two intronic, -20G/A and +459T/C, were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). -924A/G and +459T/C polymorphisms were found to be associated with URSA. -3279C/A and -20G/A polymorphism were not found to be associated with URSA. The odds ratio (OR) of mutant allele G for -924A/G polymorphism was 2.5 (95% CI 1.7-3.8; P< 0.001) and mutant allele C for +459T/C polymorphism was 1.7 (95% CI 1.1-2.6; P= 0.01). For -20G/A polymorphism, only GG genotype was found in both URSA and controls. These results suggest that -924A/G and +459T/C polymorphisms of the FOXP3 gene might be associated with URSA and -20G/A polymorphism is likely to be rare in Indian population and might not be associated with URSA.

Efficacy of sildenafil citrate in women with unexplained recurrent miscarriage preconceptional and during 1st trimester of pregnancy

Objective: To evaluate the effect of low dose of sildenafil citrate on females with history of unexplained recurrent miscarriage (RM) before and during 1st trimester of pregnancy.Patients and Methods: 120 women divided into Group I: Includes 60 patients who received aspirin 75 mg/ day + folic acid 5 mg/ day orally; Group II: Includes 60 patients who received aspirin 75 mg/ day+ folic acid 5 mg/ day + sildenafil citrate 20 mg/day, orally. The treatment starts from day 1 and continues till the end of the cycle. If menstruation occurred, the treatment is repeated for another 5 cycles or pregnancy occurs. If pregnancy occurred, the treatment continues till 14 weeks of gestation.Results: Pulsatile index (PI), resistance index (RI) was significantly lower in sildenafil treated women in comparison with sildenafil non treated women. Serum NO level, conception rate and number of cases passed 1st trimester were increased significantly in sildinafil treated group when compared to sildenafil non treated group.Conclusion: Administration of low dose of sildenafil citrate (20mg/day) orally with mild tolerable side effects resulted high possibility of conception and better chance for patients with unexplained RM to maintain their pregnancies in the 1st trimester.

Genotyping analysis of the factor V Nara mutation, Hong Kong mutation, and 16 single-nucleotide polymorphisms, including the R2 haplotype, and the involvement of factor V activity in patients with recurrent miscarriage.

: Recurrent miscarriage can arise from a large diversity of causes and the factors responsible have not been fully clarified. The coagulation factor V R506Q (Leiden) mutation is a well known risk factor for recurrent miscarriage, although it has not been found in Japanese populations. We examined whether the factor V Nara and Hong Kong mutations, the factor V gene (F5) 16 single-nucleotide polymorphisms (SNPs), including the factor V R2 haplotype, and plasma factor V activity (FV:C) were risk factors for recurrent miscarriage. A cross-sectional study was conducted among 88 patients with a history of unexplained recurrent miscarriage and 95 fertile controls. None of the patients or controls was homozygous or heterozygous for the factor V Nara or Hong Kong mutation. In the 16 SNPs of F5, frequencies of the G/T and T/T genotypes at Ser156Ser were significantly lower in patients than in controls (OR 0.45, 95% CI 0.22-0.91, OR 0.32, 95% CI 0.14-0.72) and the allele frequency of C at Leu1288Leu was significantly higher in patients than that in controls (OR 1.66, 95% CI 1.02-2.71). The mean FV:C values were not significantly different between patients and controls. However, the prevalence of patients with a high or low FV:C (>95th or <fifth percentile) was significantly greater than the controls (OR 3.59, 95% CI 1.11-11.60: OR 3.94, 95% CI 1.23-12.60). These results suggest that some SNPs of F5 and a high or low FV:C level might be associated with recurrent miscarriage.

OLR1 and Loxin Expression in PBMCs of Women with a History of Unexplained Recurrent Miscarriage: A Pilot Study.

The aim of this study was to evaluate the expression of OLR1 and its alternative splicing isoform Loxin in unexplained recurrent miscarriage (uRM). Sixty-three women of reproductive age were recruited and were divided into four groups: 18 pregnant and 23 non-pregnant women with uRM, and 12 pregnant and 10 non-pregnant women with physiological pregnancies. Complementary DNA derived from peripheral blood mononuclear cells (PBMCs) was analyzed by quantitative real-time PCR to evaluate the expression of OLR1 and Loxin. Oxidized low-density lipoproteins (ox-LDLs) were assayed from serum by a commercially available kit. Pregnant uRM women presented with a higher, though not significant, OLR1/Loxin ratio and a higher ox-LDLs serum level (p ≤ 0.05) compared with pregnant control women. OLR1 and Loxin levels were significantly decreased in non-pregnant uRM women compared with the control (OLR1: 0.00018 vs. 0.00043, p ≤ 0.005; Loxin: 0.00018 vs. 0.00060, p ≤ 0.005, respectively). Loxin expression decreased by about two-thirds (p ≤ 0.005) in pregnant women compared with non-pregnant control women. A higher expression of OLR1 in pregnant women compared with non-pregnant women with uRM (p ≤ 0.05) was observed, but no variation in Loxin expression was observed. The results of this study show an association of peripheral OLR1 and Loxin expression levels in uRM women, and they suggest the possible existence of an uncontrolled oxidative stress in these women in the first trimester of pregnancy.

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

Background and aim The aim of this study was to evaluate ovarian reserve, uterine artery blood flow, and endometrial and subendometrial blood flow in women with unexplained recurrent miscarriage compared with normal fertile women. Patients and methods The study design was a case–control one. The study was conducted in the Department of Obstetrics and Gynaecology, Benha University, Benha, Egypt. Women were divided into two groups: those with a history of unexplained recurrent miscarriage (the study group, n=50), and those who had no history of miscarriage and had at least one child born at term (the control group, n=50). At days 3–4 of the cycle, ovarian reserve testing was performed for all women by measuring follicle-stimulating hormone, luteinizing hormone and oestradiol levels. Thereafter, two-dimensional (2D) and 3D transvaginal ultrasonography and power Doppler were performed to detect antral follicle count, ovarian volume, and ovarian stromal Vascularization Index (VI), Flow Index (FI) and Vascularization Flow Index (VFI). Between days 18 and 23 of the cycle, transvaginal ultrasonography was performed for all women using 2D, pulsed Doppler and 3D-power Doppler mode to detect endometrial thickness, Uterine Artery Pulsatility Index, endometrial volume and endometrial and subendometrial blood flow presented by the indices VI, FI and VFI. The indices between the two groups were compared. Results Uterine Artery Pulsatility Index was significantly higher in the study group (P=0.001), whereas endometrial VI (P≤0.001), FI (P=0.01) and VFI (P≤0.001) and subendometrial VI, FI and VFI (P≤0.001) were significantly lower in the study group. The ovarian reserve tests, endometrial thickness and endometrial volume, however, were not significantly different between the two groups. Conclusion The presence of good uterine and endometrial blood flow is an important prerequisite for successful implantation and continuation of pregnancy as shown by higher uterine artery blood flow resistance and lower endometrial and subendometrial blood flow in recurrent unexplained miscarriage cases. We could not find any cutoff values that could predict the occurrence of miscarriage, and hence larger prospective studies are needed to confirm such results and reaching values that can accurately predict the occurrence of miscarriage.

Supplementation with progestogens in the first trimester of pregnancy to prevent miscarriage in women with unexplained recurrent miscarriage: a systematic review and meta-analysis of randomized, controlled trials

To investigate whether treatment with progestogens in the first trimester of pregnancy would decrease the incidence of miscarriage in women with a history of unexplained recurrent miscarriage. Systematic review and meta-analysis. Not applicable. Women with a history of unexplained recurrent miscarriage. Randomized, controlled trials were identified by searching electronic databases. We included randomized, controlled trials comparing supplementation with progestogens (i.e., intervention group) in the first trimester of pregnancy with control (either placebo or no treatment) in women with a history of recurrent miscarriage. All types of progestogens, including natural P and synthetic progestins, were analyzed. The primary outcome was the incidence of miscarriage. The summary measures were reported as relative risk (RR) with 95% confidence interval (CI). Ten trials including 1,586 women with recurrent miscarriage were analyzed. Eight studies used placebo as control and were double-blind. Regarding the intervention, two RCTs used natural P, whereas the other eight studies used progestins: medroxyprogesterone, cyclopentylenol ether of progesterone, dydrogesterone, or 17-hydroxyprogesterone caproate. Pooled data from the 10 trials showed that women with a history of unexplained recurrent miscarriage who were randomized to the progestogens group in the first trimester and before 16weeks had a lower risk of recurrent miscarriage (RR 0.72, 95% CI 0.53-0.97) and higher live birth rate (RR 1.07, 95% CI 1.02-1.15) compared with those who did not. No statistically significant differences were found in the other secondary outcomes, including preterm birth (RR 1.09, 95% CI 0.71-1.66), neonatal mortality (RR 1.80, 95% CI 0.44-7.34), and fetal genital abnormalities (RR 1.68, 95% CI 0.22-12.62). Our findings provide evidence that supplementation with progestogens may reduce the incidence of recurrent miscarriages and seem to be safe for the fetuses. Synthetic progestogens, including weekly IM 17-hydroxyprogesterone caproate, but not natural P, were associated with a lower risk of recurrent miscarriage. Given the limitations of the studies included in our meta-analysis, it is difficult to recommend route and dose of progestogen therapy. Further head-to-head trials of P types, dosing, and route of administration are required.

PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation.

Progesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained recurrent miscarriage (RM). The PROMISE trial was conducted to answer this question. A concurrent cost-effectiveness analysis was conducted. A randomised, double-blind, placebo-controlled, international multicentre study, with economic evaluation, conducted in hospital settings across the UK (36 sites) and in the Netherlands (nine sites). Women with unexplained RM (three or more first-trimester losses), aged between 18 and 39 years at randomisation, conceiving naturally and giving informed consent, received either micronised progesterone (Utrogestan(®), Besins Healthcare) at a dose of 400 mg (two vaginal capsules of 200 mg) or placebo vaginal capsules twice daily, administered vaginally from soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) until 12 completed weeks of gestation (or earlier if the pregnancy ended before 12 weeks). Live birth beyond 24 completed weeks of gestation (primary outcome), clinical pregnancy at 6-8 weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use. Participants were randomised after confirmation of pregnancy. Randomisation was performed online via a secure internet facility. Data were collected on four occasions of outcome assessment after randomisation, up to 28 days after birth. A total of 1568 participants were screened for eligibility. Of the 836 women randomised between 2010 and 2013, 404 received progesterone and 432 received placebo. The baseline data (age, body mass index, maternal ethnicity, smoking status and parity) of the participants were comparable in the two arms of the trial. The follow-up rate to primary outcome was 826 out of 836 (98.8%). The live birth rate in the progesterone group was 65.8% (262/398) and in the placebo group it was 63.3% (271/428), giving a relative risk of 1.04 (95% confidence interval 0.94 to 1.15; p = 0.45). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Economic analysis suggested a favourable incremental cost-effectiveness ratio for decision-making but wide confidence intervals indicated a high level of uncertainty in the health benefits. Additional sensitivity analysis suggested the probability that progesterone would fall within the National Institute for Health and Care Excellence's threshold of £20,000-30,000 per quality-adjusted life-year as between 0.7145 and 0.7341. There is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM. This study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle. Future research could explore the efficacy of progesterone supplementation administered during the luteal phase of the menstrual cycle in women attempting natural conception despite a history of RM. Current Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 41. See the NIHR Journals Library website for further project information.

Viable pregnancies beyond 28 weeks gestation in women with a history of unexplained recurrent miscarriage have reduced platelet function

ObjectiveThe aim of this study was to characterize platelet function in pregnant patients with a history of unexplained recurrent miscarriage (RM) in the third trimester of a subsequent viable pregnancy, a time at which platelet dysfunction may be associated with an increased obstetric risk. Study designA prospective study was performed comparing 30 viable pregnancies that had reached at least 28 weeks’ gestation amongst patients who had a background history of unexplained RM, with 30 healthy pregnant controls at a similar gestational age. Platelet function was determined by means of platelet aggregation in response to 5 different agonists at multiple concentrations. ResultsAmongst the 30 RM patients with ongoing viable pregnancies, we demonstrated significantly reduced platelet aggregation compared to the pregnant controls in the third trimester. For three out of five agonists, we demonstrated statistically significantly decreased platelet aggregation and for all five agonists we demonstrated significantly decreased platelet aggregation in the postnatal period. There were no obvious differences in obstetric outcomes. ConclusionThis study shows that women with a history of unexplained RM have reduced platelet function after 28 weeks’ gestation in their subsequent pregnancies compared to healthy pregnant controls, but without this difference leading to any obvious increase in adverse obstetric risk.

Modulation of Cytokine Production by the Dydrogesterone Metabolite Dihydrodydrogesterone.

Previous studies have shown that dydrogesterone, the orally administered progestogen, upregulates the production of Th2 cytokines and downregulates Th1 cytokine production. This study was designed to ascertain whether dihydrodydrogesterone (DHD), the major metabolite of dydrogesterone, is similarly capable of modulating cytokine production by peripheral blood mononuclear cells (PBMC) from women with a history of unexplained recurrent miscarriage. Mitogen-stimulated PBMC from women with unexplained recurrent miscarriage were exposed to progesterone or dydrogesterone or DHD, and the levels of pro-inflammatory (IFN-γ, TNF-α) and anti-inflammatory (IL-4, IL-10, IL-13) cytokines were estimated by ELISA. To ascertain whether DHD mediates its effects via the progesterone receptor, RU486, a progesterone agonist, was added to cultures along with mitogen and DHD. The metabolite DHD, like its parent molecule dydrogesterone, suppresses the production of the pro-inflammatory cytokines IFN- γ and TNF-α and upregulates the production of the anti-inflammatory cytokine IL-4. The progesterone antagonist RU486 reverses the effect of DHD, suggesting that this molecule mediates its cytokine-modulating effect via the progesterone receptor. Dihydrodydrogesterone retains the immunomodulatory effects of the progestogen dydrogesterone by bringing about a shift in cytokine production profiles that might be conducive to the success of pregnancy.

Enoxaparin for prevention of unexplained recurrent miscarriage: a multicenter randomized double-blind placebo-controlled trial

AbstractIt is common practice in many centers to offer antithrombotic medications to women with unexplained recurrent miscarriage, in the presence or absence of inherited thrombophilia. Although no benefit of aspirin vs placebo has been clearly demonstrated, a double-blind placebo-controlled trial on the effect of low-molecular-weight heparin is lacking. We enrolled 258 pregnant women with a history of unexplained recurrent miscarriage (≥2 consecutive miscarriages before 15 weeks' gestation) and a negative thrombophilia workup. They were randomly assigned to receive one daily subcutaneous injection of enoxaparin 40 mg or placebo until 35 weeks' gestation. We included 256 women (mean age 32 years, ≥3 miscarriages: 72%; mean gestational age 39 days of amenorrhea) in the intention-to-treat analysis; 66.6% of 138 who received enoxaparin had a live birth vs 72.9% of 118 who received placebo. The absolute difference was −6% (95% CI, −17.1 to 5.1), excluding a 10% increase in the rate of live-birth on enoxaparin (P = .34). In this first randomized, double-blind, placebo-controlled trial, enoxaparin (40 mg once daily) did not improve the chance of a live birth in nonthrombophilic women with unexplained recurrent miscarriage. This trial is registered at www.ClinicalTrials.gov as #NCT00740545 and the French National Health and Drug Safety Agency (EudraCT #2006-003350-18).

Platelet function in patients with a history of unexplained recurrent miscarriage who subsequently miscarry again

ObjectiveThis study was designed to evaluate platelet aggregation in pregnant women with a history of unexplained recurrent miscarriage (RM) and to compare platelet function in such patients who go on to have either another subsequent miscarriage or a successful pregnancy. Study designA prospective longitudinal study was performed to evaluate platelet function in a cohort of patients with a history of unexplained RM. Platelet reactivity testing was performed at 4–7 weeks gestation, to compare platelet aggregation between those with a subsequent miscarriage and those who had successful live birth outcomes. Platelet aggregation was calculated using a modified assay of light transmission aggregometry with multiple agonists at different concentrations. ResultsIn a cohort of 39 patients with a history of RM, 30 had a successful pregnancy outcome while nine had a subsequent miscarriage again. Women with subsequent miscarriage had reduced platelet aggregation in response to adenosine diphosphate (P value 0.0012) and thrombin receptor activating peptide (P value 0.0334) when compared to those with successful pregnancies. Women with subsequent miscarriages also had a trend towards reduced platelet aggregation in response to epinephrine (P value 0.0568). ConclusionPatients with a background history of unexplained RM demonstrate reduced platelet function if they have a subsequent miscarriage compared to those who go on to have a successful pregnancy.

Do uterine natural killer cell numbers in peri-implantation endometrium predict hypertensive disorder in pregnancy in women with a history of reproductive failure?

The aim of this study was to investigate whether or not increased uterine natural killer (uNK) cell numbers in the peri-implantation endometrium are associated with an increased risk of hypertensive disorders in a subsequent pregnancy. This is a retrospective study including 80 women with a history of unexplained recurrent miscarriage or recurrent implantation failure. Precisely timed endometrial biopsies were obtained from women 7–9 days after the luteinising hormone surge. uNK cells were immunostained for CD56+ and expressed as a percentage of total stromal cells. Patients were defined as having a high uNK cell count if the percentage of total stromal cells was more than 13.9%. Five out of 29 (17.2%) women in the high uNK cell count group and 5 out of 51 (9.8%) women in the normal uNK cell count group developed gestational hypertension. Pre-eclampsia was diagnosed in 2 (6.9%) patients in the high uNK cell count group and 1 (2.0%) patient from the normal uNK cell count group. There was no significant difference in the incidence of either gestational hypertension (P=0.483) and pre-eclampsia (P=0.296) between groups. The overall incidence of hypertensive disease in women with high uNK cell count (24.1%) was two times higher than women with normal uNK cell count (11.8%), but it was not statistically significant (P=0.208). An increased uNK cells count in the peri-implantation period in a cycle prior to conception did not appear to significantly increase the likelihood of hypertensive disease of pregnancy.

Perinatal outcomes of women with a prior history of unexplained recurrent miscarriage

Objective: We sought to determine subsequent pregnancy outcomes in a cohort of women with a history of unexplained recurrent miscarriage (RM) who were not receiving medical treatment.Study design: This was a prospective cohort study, of women with a history of three unexplained consecutive first trimester losses, who were recruited and followed in their subsequent pregnancy. Control patients were healthy pregnant patients with no previous adverse perinatal outcome.Results: A total of 42 patients with a history of unexplained RM were recruited to the study. About nine (21.4%) experienced a further first trimester miscarriage, one case of ectopic and one case of partial molar pregnancy. About 74% (23/31) of the RM cohort had a vaginal delivery. There was one case of severe pre-eclampsia. The RM group delivered at a mean gestational age of 38 + 2 weeks and with a mean birthweight of 3.23 kg. None of the neonates were under the 10th centile for gestational age. Overall, there was no significant difference in pregnancy outcomes between the two cohorts.Conclusion: Our study confirms the reassuring prognosis for achieving a live birth in the unexplained RM population with a very low incidence of adverse events with the majority delivering appropriately grown fetuses at term.

Immunological methods to investigate alloimmune habitual abortion

Journal of Reproductive Immunology 101–102 (2014) 18–39 33 Results: Compared with the value of the mid-luteal phase before pregnancy, the ratio of TNF/IL-10, NK cytotoxicity, and the absolute count of CD3+ T cells andNK cells were significantly decreased at both week 12 and week 24 of thepregnancy. The TNFcytokine and absolute count of CD4+ T cells were significantly decreased at week 12 of the pregnancy; the IFNcytokine, the ratio of IFN/IL-10, the percentageofNKcells and theabsolute countofBcellswere significantly decreasedwhereas the percentages of CD3+T cells, CD4+ T cells, CD69+ T cells, and CD69+ NK cells were significantly increased at week 24 of the pregnancy. Conclusions: The decrease in TNF/IL-10 ratio, NK cytotoxicity, NK cell and T cell counts probably contribute to the immune tolerance to the fetus and successful pregnancy in patients with a history of unexplained recurrent miscarriage. Furthermore, these parameters could be the potential markers for immunotherapy for unexplained recurrent miscarriage. http://dx.doi.org/10.1016/j.jri.2013.12.105

Alterations in peripheral blood lymphocytes before and after successful pregnancy of patients with a history of unexplained recurrent miscarriage

Alterations in peripheral blood lymphocytes before and after successful pregnancy of patients with a history of unexplained recurrent miscarriage

Elevated natural killer cell levels and autoimmunity synergistically decrease uterine blood flow during early pregnancy.

ObjectiveTo investigate whether natural killer (NK) cell and autoimmune antibody acts synergistically, by the action of autoantibodies to increase NK cell number and cytotoxicity, to decrease uterine blood flow during early pregnancy in pregnant women with a history of recurrent spontaneous abortion (RSA).MethodsSeventy-five pregnant women (between 5 and 7 weeks gestation) with a history of unexplained RSA were included in the study group. Forty-one pregnant women without a history of RSA were included as controls. All women with a history of RSA were tested for autoantibodies and number of peripheral blood natural killer (pbNK) cell by flow cytometry. Study populations were stratified into four groups by existence of autoantibody and degree of increase of pbNK cells. The uterine radial artery resistance index (RI) was measured by color-pulsed Doppler transvaginal ultrasound.ResultsThe mean RI of the autoimmune antibody-positive (AA+) group (0.63±0.09) was significantly higher than that of the normal control group (0.53±0.10, P=0.001). The mean RI of the AA+/only-NK elevated (eNK) group (0.63±0.09) was significantly higher than those of the only-AA+ group (0.55±0.07, P=0.019) and the only-eNK group (0.57±0.07, P=0.021).ConclusionConcurrent elevation in NK cells and autoimmunity results in decreased uterine blood flow during early pregnancy. However, the majority of cases of RSA remain unexplained and larger scale studies are needed to confirm our conclusion and to develop diagnostic and therapeutic plans for women with a history of RSA.

Mixed lymphocyte reaction blocking factors (MLR-Bf) as potential biomarker for indication and efficacy of paternal lymphocyte immunization in recurrent spontaneous abortion

The majority of cases of unexplained recurrent spontaneous abortion (RSA) remains unclear and is found to be associated with alloimmune antibodies termed as mixed lymphocyte reaction blocking factor (MLR-Bf). The decreased production of MLR-Bf may play major role in the immunologic failure of pregnancy and can lead to abortion. The present study was aimed at evaluating MLR-Bf as potential biomarker of indication and the efficacy of immunotherapy with paternal lymphocytes (LIT) in women with RSA. A total of 97 women with history of unexplained RSA were recruited for this prospective study. These women showed negative for MLR-Bf and registered for lymphocyte immunotherapy with husband cells. Women with autoimmune pathology or anti-phospholipid syndrome were excluded. All individuals gave their consent to participate in the study. We have analyzed MLR proliferative response and MLR-Bf in nonpregnant women with history of RSA before and after LIT. Following LIT, the initially low MLR proliferative response was restored at 76.6% of women, and MLR-Bf activity in blood serum could be detected in 74% of women. The rate of successful pregnancy was shown to be significantly higher in women positive for MLR-Bf (50/72) as compared with the MLR-Bf negative women (7/25; χ (2)=0.0003). The data obtained demonstrate that LIT with the paternal lymphocytes in MLR-Bf negative women is accompanied by increased proliferative cell response to the paternal alloantigens and by enhanced production of soluble suppressor activity factors (MLR-Bf) that is associated with improved pregnancy outcome in women with history of RSA.