Cause Of Recurrent Pregnancy Loss Research Articles

Association of Factor V Leiden and Prothrombin G20210A Polymorphisms in Women with Recurrent Pregnancy Loss in Isfahan Province, Iran.

Background:Maternal thrombophilia has been identified as a risk factor for recurrent pregnancy loss (RPL). The aim of this study was to investigate the association between prothrombin G20210A and factor V Leiden (FVL) polymorphisms in women with RPL and a control group of parous women in Isfahan province of Iran.Methods:We studied 250 women with idiopathic RPL and 116 control cases. Prothrombin and FVL different genotypes were determined using polymerase chain reaction and reverse hybridization technique.Results:The frequencies of heterozygous mutation prothrombin G20210A were 6% and 0.9%, respectively (P = 0.025), in cases compared to the control group. The frequencies of homozygous mutation prothrombin G20210A were 0.4% and 0%, respectively, in cases compared to controls (P = 0.02). The prothrombin mutation was significantly higher in cases compared to the control group (odds ratio 8.81; 95% confidence interval: 1.16–66.62). There was no significant difference between the FVL mutation and pregnancy loss.Conclusions:The results indicated a significant higher frequency of prothrombin G20210A in women with RPL in comparison with controls. Our data suggest that the prothrombin G20210A mutation, but not the FVL mutation, may be an unrecognized cause of RPL in our population.

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Recurrent pregnancy loss (RPL) is a heterogeneous reproductive problem with multiple aetiologies and contributing factors. It becomes quite challenging to form a work-up to detect the cause of RPL in the early months as a continuation of pregnancy involves many factors. In more than half of all recurrent miscarriage the cause still remains uncertain. Thrombophilia has been identified in about 50% of women with recurrent miscarriage and thromboprophylaxis has been suggested as an option of treatment.. In obstetric APLA Syndrome (Antiphospholipid antibody) the combination of aspirin and heparin has improved outcomes. The use of low molecular weight heparin (LMWH) has become a common practise in women with inherited thrombophilia and also those with unexplained miscarriage to help safeguard the ongoing pregnancy. To evaluate if there is any effectiveness of low molecular weight heparin (enoxaparin) in women with a history of at least two miscarriages without any apparent aetiology for recurrent pregnancy loss. A prospective randomised controlled study held at Vivekananda Institute of Medical Sciences, Kolkata from August 2015- July 2018. The study assessed the effect of anticoagulant treatment on the live-birth rate (primary outcome) in 80 antenatal women with a history of at least two miscarriages without any apparent causes. Interventions included low molecular weight heparin administration in one group and the other one was not given any anti-coagulant therapy. Similar live birth rates were observed with enoxaparin and the patients who did not receive any anti-coagulant, respectively 84% and 82% (RR 0.97, 95% CI 0.81 to 1.16). There were no significant differences in live birth weight and other pregnancy outcomes between the two groups. Therefore, there is no evidence to support any incremental benefit of adding LMWH to the treatment as a routine in unexplained cases of recurrent pregnancy loss.

Analysis of the cause of recurrent pregnancy loss in Vietnam: A cross-sectional study

ABSTRACTRecurrent pregnancy loss (RPL) is a physical and mental burden for women. In Vietnam, exploring the cause of miscarriages is still a challenge to clinical physicians. We aimed to investigate the etiology of RPL in the National Hospital of Obstetrics and Gynecology in Vietnam from 2012 to 2014. The cross-sectional study included 301 pregnant women with a history of RPL. The patients were examined and offered medical testing to determine the cause(s). Based on the testing, we determined causation for (11.29%) patients who had positive scores on an antiphospholipid antibody test and who were subsequently successfully treated for their problem.

Current insights in obstetric antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is defined as the association of thrombotic events and/or obstetric morbidity in patients persistently positive for antiphospholipid antibodies (aPL). In this review, we will highlight the most important clinical presentations of APS with a focus on the obstetric morbidity, the current management strategies and the outlook for the future. The use of aspirin and heparin has improved the pregnancy outcome in obstetric APS and approximately 70% of pregnant women with APS have a successful pregnancy outcome. Unfortunately, the current standard of care does not prevent all pregnancy complications as the current treatment fails in 20-30% of APS pregnancies. This therefore highlights the need for alternative treatments to improve obstetrical outcome. Other treatment options are currently explored and retrospective studies show that pravastatin for example is beneficial in women with aPL-related early preeclampsia. Moreover, the immunmodulator hydroxychloroquine may play a beneficial role in the prevention of aPL-related pregnancy complications. APS is among the most frequent acquired risk factors for a treatable cause of recurrent pregnancy loss and increases the risk of conditions associated with ischaemic placental dysfunction, such as fetal growth restriction, preeclampsia, premature birth and intrauterine death. Current treatment is mainly based on aspirin and heparin. Studies to inform on alternative treatment options are urgently needed.

Pregnancy before recurrent pregnancy loss more often complicated by post-term birth and perinatal death.

The cause of recurrent pregnancy loss often remains unknown. Possibly, pathophysiological pathways are shared with other pregnancy complications. All women with secondary recurrent pregnancy loss (SRPL) visiting Leiden University Medical Center (January 2000-2015) were included in this retrospective cohort to assess whether women with SRPL have a more complicated first pregnancy compared with control women. SRPL was defined as three or more consecutive pregnancy losses before 22 weeks of gestation, with a previous birth. The control group consisted of all Dutch nullipara delivering a singleton (January 2000-2015). Information was obtained from the Dutch Perinatal Registry. Outcomes were preeclampsia, preterm birth, post-term birth, intrauterine growth restriction, breach position, induction of labor, cesarean section, congenital abnormalities, perinatal death and severe hemorrhage in the first ongoing pregnancy. Subgroup analyses were performed for women with idiopathic SRPL and for women ≤35 years. In all, 172 women with SRPL and 1 196 178 control women were included. Women with SRPL were older and had a higher body mass index; 29.7 years vs. 28.8 years and 25.1 kg/m2 vs. 24.1 kg/m2 , respectively. Women with SRPL more often had a post-term birth (OR 1.86, 95% CI 1.10-3.17) and more perinatal deaths occurred in women with SRPL compared with the control group (OR 5.03, 95% CI 2.48-10.2). Similar results were found in both subgroup analyses. The first ongoing pregnancy of women with (idiopathic) SRPL is more often complicated by post-term birth and perinatal death. Revealing possible links between SRPL and these pregnancy complications might lead to a better understanding of underlying pathophysiology.

Inherited thrombophilia and thromboprophylaxis: a retrospective analysis of pregnancy outcomes in 106 patients

Objective: Low-molecular-weight heparin (LMWH) and low-dose aspirin (LDA) given in combination were evaluated in females with five commonly inherited thrombophilia polymorphisms to address unexplained recurrent pregnancy loss (RPL). Materials and Methods: After excluding other causes of RPL, 106 of 183 females suffering RPL and diagnosed with inherited thrombophilia were studied along with 62 healthy, age-matched control subjects carrying one or more pregnancies successfully (no gestational complications or abortion). Test patients were given a combination of LMWH and LDA. All participants were screened for five thrombophilic mutations: factor V Leiden G1691A, prothrombin (FII) A20210G, PAI-1 4G/5G insertion/deletion, and two methylenetetrahydrofolate reductase (MTHFR) polymorphisms (C677T and A1298C). Results: With thromboprophylaxis, 73 of 84 (86.9%) pregnancies succeeded, representing a significant increase in the rate of live births (vs. 232 prior losses). Of the five test panel mutations, three or more (homozygous and/or heterozygous) were observed in 48 test patients (45.3%), whereas only three control subjects (4.8%) were similarly affected (p vs. controls), with PAI-1 4G/5G and MTHFR (C677T and A1298C) identified via binary logistic regression as independent correlates of habitual abortion. Conclusion: The risk of RPL increases with three or more homozygous or heterozygous genotypes in inherited thrombophilia, especially with PAI-1 4G/5G and MTHFR (C677T and A1298C). As in acquired thrombophilia, LMWH/LDA combination treatment may increase live birth rates in patients with inherited thrombophilia.

The Association Between Serological Markers of Celiac Disease and Idiopathic Recurrent Pregnancy Loss

ABSTRACTIntroduction: Antiphospholipid syndrome, uterine anomalies, and chromosomal aberrations are identifiable causes of recurrent pregnancy loss (RPL). Herein, our aim is to investigate the relationship between celiac disease (CD) specific antitransglutaminase antibodies (ATA) and unexplained RPL. Materials and Methods: This was a cross sectional case-control study conducted on 86 women (45 RPL and 41 controls) in a tertiary level maternity hospital. Elisa kit was used to determine ATA IgA and IgG levels. Results: One (2.2%) patient with ATA IgG positivity was present in the RPL group. There were three (7.3%) cases with positive for ATA IgA in the control group, and one (2.2%) case in the study group. No statistically significant differences were observed between the groups in terms of ATA IgG and IgA. Conclusion: There is no association between CD markers and unexplained RPL. For the present, we do not recommend screening for ATA IgA and ATA IgG in patients with a history of RPL.

Mitochondrial DNA variations are associated with recurrent pregnancy loss

Cases with three or more consecutive spontaneous abortions before the 20th week of gestation are termed as recurrent pregnancy loss (RPL). Problems in implantation of the foetus and any retarded growth of the foetus in the uterus can be correlated to RPL. Possible causes of RPL would include the genetic variations in the regulatory enzymes of the crucial metabolic pathways, clotting factors, hormones and hormone receptors. This defect of the mitochondrial respiratory chain is recognized as a major cause of human disease. We investigated 73 women with RPL and 100 healthy normal controls. By using the direct sequencing method, the amplified products including the mtDNA complex I genes were analyzed. Overall, seven variations in mitochondrial complex I genes were found (T4216C, A5153G, C10142T, C12062T, A12662G, G14179A and T14263C) using direct sequencing technique. The RPL group had significantly higher proportions of the different variants than those observed of the control group. In conclusion, more research is essentially needed to understand the effect and role of the mitochondrial variations in the progress of RPL, which may vary among individuals and different ethnic groups.

Increased Anti-HSP60 and Anti-HSP70 Antibodies in Women with Unexplained Recurrent Pregnancy Loss.

Vascular dysfunction has been reported in women with recurrent pregnancy loss (RPL). We investigated the severity of vascular dysfunction in non-pregnant women with RPL and its correlation with anti-heat shock protein (HSP) antibodies that are known to induce arteriosclerosis. We measured the serum anti-HSP60 antibodies, anti-HSP70 antibodies, and anti-phospholipid antibodies (APA) in 68 women with RPL and 29 healthy controls. Among the women with RPL, 14 had a diagnosis of antiphospholipid syndrome (APS), and in the remaining 54, the causes for RPL were unexplained. Compared to the controls, the brachial-ankle pulse wave velocity (baPWV), carotid augmentation index (cAI), and uterine artery pulsatility index (PI) were all significantly higher in the women with both APS and unexplained RPL. Compared to the controls, the anti-HSP60 antibody levels were significantly higher in the APA-positive group of women with unexplained RPL, and the anti-HSP70 antibody levels were significantly higher in APS and APA-positive group of women with unexplained RPL. However, the anti-HSP60 and anti-HSP70 antibody levels did not correlate with the values of baPWV or cAI. Our results demonstrated anti-HSP60 and anti-HSP70 antibodies are increased in women with unexplained RPL. Further studies are needed to elucidate the roles of anti-HSP antibodies and their pathophysiology in unexplained RPL.

Role of Th-1 cell cytokines, leukemia inhibitory factor and hoxA genes in women with recurrent pregnancy loss

Abstract Objective Immunological problems have been identified as a potential cause of recurrent pregnancy loss (RPL). The aim of this study was to investigate the effect of Th-1 cell cytokines, leukemia inhibitory factor and hoxA genes in women with RPL. Materials & methods A prospective, case-control study conducted in Assiut Women Health Hospital, Egypt included 37 women presented with a history of RPL. Samples of uterine flush and endometrial biopsy were taken during the implantation window from those confirmed as not pregnant. Cytokine (LIF and Th1 induced) levels were measured by ELISA, while hox A10 and hox A11 gene expression was evaluated by Taq-man Real Time PCR. Results Higher cytokine mean levels were seen in the RPL group when compared to the control group (TNF-α and LIF cytokines, p ≤ 0.001; INF-γ and IL2 cytokines, p ≤ 0.01). The opposite was true with regards to gene expression, with lower means in both sets found in the RPL group ( hox A11, p ≤ 0.000). A statistically significant positive correlation between INF-γ and TNF-α, hox A10 and hox A11, as well as between LIF and hox A11 was demonstrated. Conclusion This study suggests that women with a history of RPL can have abnormal cytokine and gene expression even when not pregnant. Our findings can be a basis for providing of future successful immunological therapy for women with RPL.

The first genome-wide association study identifying new susceptibility loci for obstetric antiphospholipid syndrome

Antiphospholipid syndrome (APS) is the most important treatable cause of recurrent pregnancy loss. The live birth rate is limited to only 70-80% in patients with APS undergoing established anticoagulant therapy. Lupus anticoagulant (LA), but not anticardiolipin antibody (aCL), was found to predict adverse pregnancy outcome. Recent genome-wide association studies (GWAS) of APS focusing on aCL have shown that several molecules may be involved. This is the first GWAS for obstetric APS focusing on LA. A GWAS was performed to compare 115 Japanese patients with obstetric APS, diagnosed according to criteria of the International Congress on APS, and 419 healthy individuals. Allele or genotype frequencies were compared in a total of 426 344 single-nucleotide polymorphisms (SNPs). Imputation analyses were also performed for the candidate regions detected by the GWAS. One SNP (rs2288493) located on the 3'-UTR of TSHR showed an experiment-wide significant APS association (P=7.85E-08, OR=6.18) under a recessive model after Bonferroni correction considering the number of analyzed SNPs. Another SNP (rs79154414) located around the C1D showed a genome-wide significant APS association (P=4.84E-08, OR=6.20) under an allelic model after applying the SNP imputation. Our findings demonstrate that a specific genotype of TSHR and C1D genes can be a risk factor for obstetric APS.

Chronic Endometritis and Recurrent Pregnancy Loss

Chronic endometritis is generally an asymptomatic condition typically diagnosed by the histopathological presence of plasma cell infiltration in the endometrial stromal compartment. Emerging data suggests that chronic endometritis may be a cause of recurrent pregnancy loss (RPL). Chronic endometritis is prevalent in cases of otherwise unexplained recurrent pregnancy loss. Treatment appears to lead to improved pregnancy outcomes in subsequent pregnancies. The use of CD138 immunohistochemistry as a supplement to traditional hematoxylin and eosin staining of plasma cells increases the detection rate of chronic endometritis. Chronic endometritis is emerging as a treatable cause of RPL.

Antiphospholipid Syndrome as a Cause of Recurrent Pregnancy Loss: 3 Case Reports and Successful Outcome

Recurrent pregnancy loss is common problem now a days and is commonly found in our daily practice.There are so many causes that are established as causative factors for recurrent pregnancy loss. Among them systemic causes includes uncontrolled diebetes mellitus, uncontrolled chronic hypertension, hypothyroidism and local causes includes uterine polyp, uterine fibroid, cervical incompetency etc. Anti-phospholipid syndrome has recently been found to be one of the causes for recurrent pregnancy loss and we have not yet enough study in our country regarding this problem that causes recurrent pregnancy loss. Pregnancy with Anti-phospholipid Syndrome (APS) is rare and it is one of the important factor that causes recurrent pregnancy loss at any trimester of pregnancy. Early diagnosis and pre-conceptional precaution for prevention of recurrent pregnancy loss is essential to deliver a healthy fetus in a diagnosed case of APS. Three cases of anti-phospholipid syndrome (APS) are reported here who have successfully deliverd healthy baby. All the cases were presented with the complaints of recurrent pregnancy loss.Bangladesh J Obstet Gynaecol, 2014; Vol. 29(2) : 106-110

Pregnancy and Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is classified as the association of thrombotic events and/or obstetric morbidity in patients persistently positive for antiphospholipid antibodies (aPL). APS is also the most frequently acquired risk factor for a treatable cause of recurrent pregnancy loss and increases the risk of conditions associated with ischemic placental dysfunction, such as stillbirth, intrauterine death, preeclampsia, premature birth, and fetal growth restriction. The use of low-dose aspirin and heparin has improved the pregnancy outcome in obstetric APS and approximately 70% of pregnant women with APS will deliver a viable live infant. However, current management does not prevent all maternal, fetal, and neonatal complications of APS and the current treatment fails in 20 to 30% of APS pregnancies, raising the need to explore other treatments to improve obstetrical outcome. Two clinical studies of retrospective design have suggested that the immunomodulator hydroxychloroquine (HCQ) may play a role in the prevention of pregnancy complications in women with aPL and APS. The randomized controlled multicenter trial of hydroxychloroquine versus placebo during pregnancy in women with antiphospholipid antibodies (HYPATIA) of HCQ versus placebo will provide scientific evidence on the use of HCQ in pregnant women with aPL.

Genetic Causes of Recurrent Pregnancy Loss.

Pregnancy loss is one of the most common obstetric complications, affecting over 30% of conceptions. A considerable proportion of losses are due to genetic abnormalities. Indeed, over 50% of early pregnancy losses have been associated with chromosomal abnormalities. Most are due to de novo nondisjunctional events but balanced parental translocations are responsible for a small but important percentage of genetic abnormalities in couples with recurrent pregnancy loss. In the past, assessment of genetic abnormalities was limited to karyotype performed on placental or fetal tissue. However, advances in molecular genetic technology now provide rich genetic information about additional genetic causes of and risk factors for pregnancy loss. In addition, the use of preimplantation genetic testing in couples undergoing in vitro fertilization has the potential to decrease the risk of pregnancy loss from genetic abnormalities. To date, efficacy is uncertain but considerable potential remains. This chapter will review what is known about genetic causes of recurrent pregnancy loss with a focus on novel causes and potential treatments. Remaining knowledge gaps will be highlighted.

Recurrent Pregnancy Loss: Generally Accepted Causes and Their Management.

Recurrent pregnancy loss (RPL), commonly defined as 3 consecutive losses <10 weeks gestation, affects up to 5% of couples. Well-accepted causes include uterine malformation, antiphospholipid syndrome, and parental chromosomal abnormalities; however, the majority of RPL cases are idiopathic (up to 75%). This chapter covers these accepted causes of RPL and provides diagnosis and management strategies for patients falling within the above categories.

Immunologic Abnormalities, Treatments, and Recurrent Pregnancy Loss: What Is Real and What Is Not?

Recurrent pregnancy loss, depending on the definition, affects 1% to 3% of women aiming to have a child. Little is known about the direct causes of recurrent pregnancy loss, and the condition is considered to have a multifactorial and complex pathogenesis. The aim of this review was to summarize the evaluation and the management of the condition with specific emphasis on immunologic biomarkers identified as risk factors as well as current immunologic treatment options. The review also highlights and discusses areas in need of further research.

Significant correlation of angiotensin converting enzyme and glycoprotein IIIa genes polymorphisms with unexplained recurrent pregnancy loss in north of Iran

Spontaneous abortion is considered as the most complex problem during pregnancy. Thrombophilia is resumed as a cause of recurrent pregnancy loss (RPL). Glycoprotein IIIa (GPIIIa) gene is involved in thrombosis and abortion. Angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II and is involved in thrombosis. The most common polymorphism in this gene is the insertion/deletion (I/D). In this study, we analyzed the association between ACE I/D and GPIIIa c.98C >T polymorphisms in women with unexplained RPL from the north of Iran. Sample population consisted of 100 women with unexplained RPL and 100 controls. The ACE I/D and GPIIIa c.98C>T polymorphisms were genotyped by TETRA-ARMS PCR. The association between genotypes frequency and RPL were analyzed using χ(2) and exact fisher tests. Associated risk with double genotype combinations was also investigated by binary logistic regression. There was significant association between ACE DD genotype and RPL (OR=2.04; 95% CI=0.94-4.44; p=0.036). ACE D Allele was also significantly associated with the RPL (OR=1.59; 95% CI=1.05-2.41; p=0.013). No significant association was observed between GPIIIa c.98C>T polymorphism and RPL. ACE I/D polymorphism may probably be a prognostic factor in female family members of women with the history of recurrent abortion.

What about superfertility, decidualization, and natural selection?

Recurrent pregnancy loss, defined as two or more failed pregnancies by the American Society for Reproductive Medicine [1], is a clinical problem because known effective treatment is limited. Effective treatment depends on the cause of the reproductive failure. Thus, attention has been focused on determining causes of recurrent pregnancy loss. Even so, to date, only chromosomal abnormalities of the conceptus and immunologic risk factors have been generally accepted as etiologies of recurrent pregnancy loss. Recently, a novel pathologic pathway that involves impaired decidualization of endometrial stromal cells has been proposed as a cause of recurrent pregnancy loss [2]. Further, it has been hypothesized that the impaired decidualization is manifested by the prolongation of the window of implantation allowing for increased fecundity and Bsuperfertility^ [2–7]. The following paragraphs will describe the evidence for these notions.

Transabdominal Cervical Cerclage: Laparoscopy or Laparotomy

Cervical incompetence is one of the common causes of recurrent pregnancy loss. Transabdominal cervical cerclage is the option where previous vaginal cerclages have failed or in patients with congenital short or absent cervix, a lacerated cervix, severe scarring of the cervix, and multiple deep cervical defects. So this review is aimed to study the effectiveness of laparoscopic cerclage in comparison with cervical cerclage by laparotomy. A literature search was performed using Springer link, BMJ, Journals of Minimal Access Surgery, and major general search engines like Google, MSN, HighWire Press, and Yahoo. The stu dies between 2000 and 2015 were selected and were reviewed for the prolongation of pregnancy, intraoperative and postoperative complications, operating time, blood loss, postoperative recovery in both the laparoscopic and open procedure. The review concludes that if transabdominal cervical cerclage is preferred then laparoscopic approach is superior to laparotomy as it is as effective as open method with fast postoperative recovery.