Recurrent Early Pregnancy Loss Research Articles

An Update on Recurrent Early Pregnancy Loss: Causes, Controversies and Cure

Recurrent Pregnancy Loss (RPL) is an important reproductive issue, affecting 1-5% of couples. It is characterised by repeated miscarriage, impairing the ability to have a live birth. The proven causes are diverse, such as cytogenetic abnormality, uterine anomalies, antiphospholipid antibody, metabolic and endocrine abnormalities, and about 50% cases of RPL remain still unexplained. To facilitate the diagnosis, different screening tests have been recommended, such as antiphospholipid antibody tests, thyroid stimulating hormone, glucose tolerance test, chromosomal assessment, ultrasound testing etc. RPL is associated with psychological trauma and financial burden. An evidence-based treatment is available for the majority of causes and it is seen that most of the women eventually become pregnant with an appropriate treatment plan, regardless of the cause. It has also been shown that patients presenting no abnormality on various tests may achieve a good rate of live births without special treatment. This study also includes certain controversial aetiologies and unconventional tests. This review touches on the management of various abnormalities in brief. Recurrent pregnancy loss has a significant negative life impact due to its repetitive nature; however, emotional care along with appropriate management improves chances of future pregnancy.

Stimulating Hormone Level in Cases of Recurrent Early Pregnancy Loss

Stimulating Hormone Level in Cases of Recurrent Early Pregnancy Loss

Genetic Screening and Early Recurrent Pregnancy Loss

Purpose of Review The purpose of this review is to identify current data and provide a clear treatment path specifically the role of preimplantation genetic screening (PGS) for the evaluation and treatment of recurrent early pregnancy loss (RPL).

LMWH in IVF – Biomarkers and benefits

There is biological plausibility that coagulation activation underlies a proportion of in vitro fertilisation IVF failures and recurrent early clinical pregnancy loss (RPL). However, low-molecular-weight heparin (LMWH) use, based upon previous clinical outcome alone, is not effective in preventing RPL. RPL is heterogeneous in mechanism. Identifying those with an underlying thrombotic mechanism would allow stratification for LMWH treatment. Annexin A5 is an anticoagulant protein expressed on the trophoblast surface. The annexin A5 M2 haplotype (ANXA5 M2) is associated with several placenta mediated pregnancy complications (PMPC) and poor IVF outcome. It is transmitted equally by males and females. A pragmatic observational study of IVF couples screened for M2 carriage and treated with LMWH achieved a 37.9% live birth rate, similar to an unscreened and untreated group with fewer adverse risk factors for conception and a better prognosis from assisted conception. This suggests that LMWH may counteract the adverse effects of M2 carriage. Using this biomarker to stratify IVF and PMPC patients for LMWH treatment merits further evaluation.

HMG as a treatment for unexplained recurrent early pregnancy loss

HMG as a treatment for unexplained recurrent early pregnancy loss

Genotyping analysis of protein S-Tokushima (K196E) and the involvement of protein S antigen and activity in patients with recurrent pregnancy loss

ObjectivePreston et al. indicated that Protein S (PS) deficiency was associated with stillbirths but not miscarriages. The PS-Tokushima missense variant was reported to serve as a genetic risk factor for deep vein thrombosis in the Japanese population. A previous cross-sectional study showed no increase in the prevalence of PS-Tokushima in patients with recurrent early pregnancy loss or in patients with intra uterine fetal death and/or fetal growth restriction. There has been limited number of prospective studies examining the pregnancy outcome in patients with both a PS deficiency and recurrent pregnancy loss (RPL). We examined the association between PS deficiency, PS-Tokushima and RPL. Study designThe study group consisted of 355 Japanese women with two or more consecutive pregnancy losses and 101 parous women. The frequency of PS-Tokushima and the subsequent live birth rate in relation to a PS deficiency defined as low PS-specific activity (total PS activity/total PS antigen) and the carriage of PS-Tokushima were examined. Results and conclusionsThere was no significant difference in the frequency of PS-Tokushima between patients and controls. The 8 patients carriers of PS-Tokushima variant were capable of a subsequent live birth without the use of heparin. There was no significant difference in subsequent live birth rates between patients with low or normal PS-specific activity/PS activity without heparin prophylaxis after excluding miscarriages caused by an abnormal embryonic karyotype using multivariate logistic regression analysis. There was no association between PS-Tokushima and RPL and a PS deficiency or low PS activity was shown not to serve as a reliable clinical predictor of subsequent miscarriage.

Genetic analysis of the M2/ANXA5 haplotype as recurrent pregnancy loss predisposition in the Malay population.

The aim of this study was to evaluate a new predisposition factor, M2/ANXA5 (RPRGL3), in recurrent pregnancy loss (RPL) patients of Malay origin, since it was previously known that the prevalence of this condition is relatively high among the Malay population of Malaysia, where conventional hereditary thrombophilia factors have been generally ruled out. A total of 232 women who had experienced ≥2 unexplained RPL and 141 available male partners were recruited, with 360 healthy Malay and 166 parous female controls. Prevalence of M2 carriage and RPL odds ratios were calculated in (a) control and patient groups; (b) clinically defined subgroups in categories of pregnancy loss, primary, secondary, and tertiary; and (c) timing of pregnancy loss in early, ≤15th gestation week and "late" fetal losses, and >15th gestation week subgroups. Both male and female subjects had similar M2/ANXA5 allele frequencies. The carrier rate of M2/ANXA5 for the general Malay population was 42.2 and 34.9% for parous controls. These carrier rates compared to Malay RPL subjects (52% M2 carriers) resulted in elevated odds ratios (95% confidence interval) of 1.53 (1.1 to 2.1) and 1.97 (1.3 to 3.1) accordingly for early fetal losses. Moreover, exceeding copy numbers of M2/ANXA5 alleles seemed to afflict a greater chance of RPL in couples, especially when both partners were M2 carriers. This study confirmed the proposed role of M2/ANXA5 as embryonic, genetically associated thrombophilia predisposition factor for early RPL among ethnic Malay of Malaysia.

Maternal serum amyloid A level as a novel marker of primary unexplained recurrent early pregnancy loss.

To assess maternal serum amyloid A (SAA) levels among women with primary unexplained recurrent early pregnancy loss (REPL). A prospective study was conducted among women with missed spontaneous abortion in the first trimester at Ain Shams University Maternity Hospital, Cairo, Egypt, between January 21 and December 25, 2014. Women with at least two consecutive primary unexplained REPLs and no previous live births were enrolled. A control group was formed of women with no history of REPL who had at least one previous uneventful pregnancy with no adverse outcomes. Serum samples were collected to measure SAA levels. The main outcome was the association between SAA and primary unexplained REPL. Each group contained 96 participants. Median SAA level was significantly higher among women with REPL (50.0μg/mL, interquartile range 26.0-69.0) than among women in the control group (11.6μg/mL, interquartile range 6.2-15.5; P<0.001). The SAA level was an independent indicator of primary unexplained REPL, after adjusting for maternal age and gestational age (odds ratio 1.12, 95% confidence interval 1.06-1.19; P<0.001). Elevated SAA levels found among women with primary unexplained REPL could represent a novel biomarker for this complication of pregnancy.

Ectopic Pregnancy in Cases of Recurrent Implantation Failure and Cases of Recurrent Early Pregnancy Loss

Objectives: To calculate the incidence of ectopic pregnancy in cases with recurrent early pregnancy loss and cases of recurrent implantation failure. Methods and materials: This is a retrospective cohort study. 200 women were recruited from the infertility clinic at shat by maternity university hospital seeking fertility. 100 of them were with history of recurrent implantation failure (RIF) and 100 with history of recurrent pregnancy loss (RPL). Revisiting their hospital files for the history of ectopic pregnancy was done. Results: 8% of cases of RPL had history of ectopic pregnancy while only 6% of cases of RIF had the history. There was no significant difference between the two groups (p = 0.579). There was significantly higher incidence of ectopic pregnancy in both groups if compared with the general population (p = 0.0001 and 0.043) in RPL and RIF consecutively. Conclusions: RPL and RIF may be considered as a risk factor for ectopic pregnancy.

Evaluation of Thyroid Antibodies and Thyroid Stimulating Hormone Level in Cases of Recurrent Early Pregnancy Loss

Evaluation of Thyroid Antibodies and Thyroid Stimulating Hormone Level in Cases of Recurrent Early Pregnancy Loss

The Association Between Sperm DNA Fragmentation and Idiopathic Early Recurrent Pregnancy Loss

&lt;p&gt;&lt;strong&gt;Introduction&lt;/strong&gt;&lt;/p&gt;&lt;p&gt;Various etiologies of recurrent pregnancy loss (RPL) have been extensively studied, but more than half of them still remain unknown. Male factor may play a role in incidence of idiopathic early recurrent pregnancy loss. Sperm DNA fragmentation as one of sperm test for male factor can be measured and expressed by a DNA Fragmentation Index (DFI). The aim of the study is to evaluate the association between sperm DNA fragmentation and the incidence of idiopathic early recurrent pregnancy loss.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Material &amp;amp; Methods&lt;/strong&gt;&lt;/p&gt;&lt;p&gt;A prospective study was done by recruiting 40 cases of male couple from patients with a history of idiopathic early recurrent pregnancy loss and 40 cases of control from normal fertile population from May 2010 to September 2011 in Halim Fertility Center. Sperm DNA fragmentation was detected by halosperm kit.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results&lt;/strong&gt;&lt;br /&gt;Both of groups were comparable in terms of the age of male patients, body mass index, duration of infertility, history of miscarriage and sperm parameters. Sperm DFI in the case group was 34.12%. and in the control group was 16.02%. There was significantly higher sperm DFI in the case group than in the control group. Sperm DFI &amp;lt;30 was increased in control group (95%) compared with case group (40%). Sperm DFI ≥30 was increased in case group (60%) compared with control group (5%). There was a significant association between sperm DFI ≥30 and idiopathic early recurrent pregnancy loss (p&amp;lt;0,05).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion&lt;/strong&gt;&lt;/p&gt;&lt;p&gt;There is an association between higher sperm DNA fragmentation and incidence of idiopathic early recurrent pregnancy loss.&lt;/p&gt;

Whole exome sequencing in recurrent early pregnancy loss.

Exome sequencing can identify genetic causes of idiopathic recurrent pregnancy loss (RPL). We identified compound heterozygous deleterious mutations affecting DYNC2H1 and ALOX15 in two out of four families with RPL. Both genes have a role in early development. Bioinformatics analysis of all genes with rare and putatively pathogenic mutations in miscarriages and couples showed enrichment in pathways relevant to pregnancy loss, including the complement and coagulation cascades pathways. Next generation sequencing (NGS) is increasingly being used to identify known and novel gene mutations in children with developmental delay and in fetuses with ultrasound-detected anomalies. In contrast, NGS is rarely used to study pregnancy loss. Chromosome microarray analysis detects putatively causative DNA copy number variants (CNVs) in ∼2% of miscarriages and CNVs of unknown significance (predominantly parental in origin) in up to 40% of miscarriages. Therefore, a large number of miscarriages still have an unknown cause. Whole exome sequencing (WES) was performed using Illumina HiSeq 2000 platform on seven euploid miscarriages from four families with RPL. Golden Helix SVS v8.1.5 was used for data assessment and inheritance analysis for deleterious DNA variants predicted to severely disrupt protein-coding genes by introducing a frameshift, loss of the stop codon, gain of the stop codon, changes in splicing or the initial codon. Webgestalt (http://bioinfo.vanderbilt.edu/webgestalt/) was used for pathway and disease association enrichment analysis of a gene pool containing putatively pathogenic variants in miscarriages and couples in comparison to control gene pools. Compound heterozygous mutations in DYNC2H1 and ALOX15 were identified in miscarriages from two families with RPL. DYNC2H1 is involved in cilia biogenesis and has been associated with fetal lethality in humans. ALOX15 is expressed in placenta and its dysregulation has been associated with inflammation, placental, dysfunction, abnormal oxidative stress response and angiogenesis. The pool of putatively pathogenic single nucleotide variants (SNVs) and small insertions and deletions (indels) detected in the miscarriages showed enrichment in 'complement and coagulation cascades pathway', and 'ciliary motility disorders'. We conclude that CNVs, individual SNVs and pool of deleterious gene mutations identified by exome sequencing could contribute to RPL. The size of our sample cohort is small. The functional effect of candidate mutations should be evaluated to determine whether the mutations are causative. This is the first study to assess whether SNVs may contribute to the pathogenesis of miscarriage. Furthermore, our findings suggest that collective effect of mutations in relevant biological pathways could be implicated in RPL. The study was funded by Canadian Institutes of Health Research (grant MOP 106467) and Michael Smith Foundation of Health Research Career Scholar salary award to ERS.

Inherited thrombophilia and reproductive disorders.

Apart from its established role in the pathogenesis of venous thromboembolism (VTE), inherited thrombophilia has been proposed as a possible cause of pregnancy loss and vascular gestational complications. There is a lot of controversy in the literature on the relationship between inherited prothrombotic defects and these obstetric complications. This is a review of the literature on inherited thrombophilia and reproductive disorders. Factor V Leiden, prothrombin G20210A mutation, and protein S deficiency seem to be associated with late and recurrent early pregnancy loss, while their impact on other pregnancy complications is conflicting. No definite association has been established between protein C and antithrombin deficiency and adverse pregnancy outcome, primarily due to their low prevalence. Screening is suggested only for women with early recurrent loss or late pregnancy loss. Anticoagulant treatment during pregnancy should be considered for women with complications who were tested positive for thrombophilia.

Maternal thrombophilia causes at recurrent early pregnancy loss

Maternal thrombophilia causes at recurrent early pregnancy loss

Elevated Factor VIII Levels and Shortened APTT in Recurrent Abortions.

Thrombotic disorders have been found to be associated with recurrent abortions. Several risk factors have been identified. APTT reflects the common pathway and intrinsic pathway of coagulation cascade and hence is a good marker for thrombotic work. Elevated factor VIII: C has also been identified as risk factor for recurrent miscarriage. This study aims at identifying association of elevated factor VIII levels, shortened APTT and recurrent abortions in Indian population as little has been studied about this and the literature available is also based on studies done in European population. This study also aims to find whether shortened APTT can be an independent risk as well. Women referred to the obstetrics department with a history of early recurrent early pregnancy loss (at least three pregnancy losses before 13 weeks of gestation) were included in this study. Exclusion criteria were elevated CRP levels, positive antiphospholipid antibodies, endocrine, immunological or anatomical cause of embryo demise. A total of 68 cases of recurrent abortion were included in this study, 68 normal pregnant females (<15 weeks of gestation) were also included as controls with no history of abortion. The age group of the cases as well as control was 20-45 years. Activated partial thromboplastin time and factor VIII assay (one stage APTT based) were done on the blood samples. Increased factor VIII levels were seen in 25 cases (36.4%); 19 cases showed shortened APTT (27.3%); 12 cases showed both increased factor VIII levels as well as shortened APTT (18%). All risk factors were negative in 36 cases (52.9%). None of the controls showed elevated factor VIII levels or shortened APTT. The mean APTT values of the control subjects was 31.01 and cases were 27.01 (p=0.001). The mean factor VIII levels of case were 152.85% and control 144.953% (p=0.012). There was significant association between recurrent abortions and elevated factor VIII :c levels and shortened APTT. Shortened APTT was also identified as an independent risk factor.

Approach to Recurrent Early Pregnancy Loss

Abortus is the most common complication of pregnancy. Recurrent pregnancy lost is the termination of the sequential termination of at least two or more pregnancies before the week 20. Early fetal lost consists of abortus before 12th week of gestation. The ones between 12–20 weeks is called late abortus. It is a threatening state that effects 5% of the woman who wants to give birth and 1% of infertile ones. In half of the cases even after a detailed examination, the etiology can not be found. It is a disappointing situation for both the patient and clinician. Treatment and diagnosis of recurrent pregnancy lost is one of the challenging topics of the obstetric. Today, it can be prevented to a certain extent by the usage of diagnostic and interventional studies, some biochemical markers and medical, surgical and/or observational approaches. The etiology of recurrent pregnancy lost is parental and fetal chromosomal anomalies, antiphosholipid syndrome, structural uterine anomalies, some thrombophilia, autoimmune diseases and endocrinopathies. In this study, it is aimed to revise the etiology, current treatment and evaluation of a couple with recurrent pregnancy lost in the light of literature.

Thrombophilia and Pregnancy Complications.

There is a paucity of strong evidence associated with adverse pregnancy outcomes and thrombophilia in pregnancy. These problems include both early (recurrent miscarriage) and late placental vascular-mediated problems (fetal loss, pre-eclampsia, placental abruption and intra-uterine growth restriction). Due to poor quality case-control and cohort study designs, there is often an increase in the relative risk of these complications associated with thrombophilia, particularly recurrent early pregnancy loss, late fetal loss and pre-eclampsia, but the absolute risk remains very small. It appears that low-molecular weight heparin has other benefits on the placental vascular system besides its anticoagulant properties. Its use is in the context of antiphospholipid syndrome and recurrent pregnancy loss and also in women with implantation failure to improve live birth rates. There is currently no role for low-molecular weight heparin to prevent late placental-mediated complications in patients with inherited thrombophilia and this may be due to small patient numbers in the studies involved in summarising the evidence. There is potential for low-molecular weight heparin to improve pregnancy outcomes in women with prior severe vascular complications of pregnancy such as early-onset intra-uterine growth restriction and pre-eclampsia but further high quality randomised controlled trials are required to answer this question.

Use of serum leptin and insulin hormones levels as predictors of pregnancy outcome in pregnant women with history of recurrent early pregnancy loss

Abstract Aim To evaluate levels of leptin and insulin in cases of unexplained early RPL in comparison with cases of previous normal pregnancies and suggest these levels as prognostic factors for the continuation of pregnancy beyond the 20th week. Methods A prospective comparative controlled study was conducted at Obstetrics unit of Tanta University Hospital from Jan to Aug 2014 on 50 pregnant women who were divided into two groups: the study group included 25 cases with history of early RPL, and the control group included 25 cases with previous normal pregnancies. Serum levels of leptin and insulin were measured twice in both groups; at 5–8th and 10–12th week. Results Leptin levels in ng/ml in the first sample were 9.414 ± 3.183 and 30.559 ± 10.672 in the control and study groups respectively with significant difference. As for the second sample, it was 11.672 ± 2.611 and 29.733 ± 9.133 in the control and study groups respectively with significant difference. Insulin levels in μlU/ml in the first sample were 18.075 ± 5.845 and 32.502 ± 13.057 in the control and study groups respectively with significant difference. In the second sample, on the other hand, it was 20.237 ± 4.944 and 34.128 ± 12.677 in the control and study groups respectively with significant difference. Leptin showed higher accuracy than insulin in prediction of early pregnancy loss. Conclusion Higher levels of leptin and insulin were found in cases with early RPL especially in the aborted cases. The two hormones could be used as predictors of pregnancy continuation in these cases.

Plasma Homocysteine Levels in Polycystic Ovarian Syndrome with Early Recurrent Pregnancy Loss: A Case-Control Study

Background: Recurrent Pregnancy Loss (RPL) is defined as the occurrence of three (or) more clinically recognised pregnancy losses before 20 weeks of gestation. Spontaneous abortions occur in 15% of clinically recognised pregnancies in reproductive age group women. Hyper homocysteinemia has been associated with clinical vascular thrombosis and this could be the cause for early decidual and chorionic vessel damage that might result in disturbed implantation of the conceptus. Aim: To determine the plasma homocysteine levels in patients with polycystic ovarian syndrome (PCOS) having recurrent pregnancy loss (RPL) compared with women with PCOS who had uneventful pregnancies and assess the role of hyper homocysteinemia for RPL in PCOS. Materials and Methods: This is a case-control study on 20 PCOS women with RPL and 20 control PCOS women with uneventful pregnancies matched by age, marriage duration and body mass index(BMI). Plasma homocysteine levels were assessed from Feb, 2013 to Feb, 2014. Results: The mean plasma homocysteine in the cases and controls were 19.10±1.01 and 16.41±1.24 (p=0.0001). The difference in the homocysteine levels was found to be statistically significant. Conclusion: Risk of RPL in patients with PCOS is increased with hyperhomocysteinemia (p< 0.0001). Key-words: Plasma homocysteine levels, PCOS, early recurrent pregnancy loss

Incidence, pathophysiology, and clinical manifestations of antiphospholipid syndrome.

Antiphospholipid syndrome (APLS) is a complex systemic disease with a wide variety of clinical manifestations. In the obstetric population, recurrent early pregnancy loss, fetal loss, and thrombosis are hallmarks of the disease. Patients with APLS have developed one or more pathogenic auto-antibodies directed against plasma and cell surface proteins. These antibodies are characterized by their affinity for anionic phospholipids. Interactions between APLS antibodies and their protein targets influence a wide variety of biological systems and signaling pathways, including monocytes, platelets, the complement system, and endothelial cells. While much research is currently directed at understanding the mechanisms involved in this autoimmune disease, the key clinical presentation is the hypercoagulable state resulting in thrombosis occurring in essentially any arterial or venous location, as well as numerous obstetrical complications. Treatment of APLS is generally directed at preventing thrombosis and poor pregnancy outcomes by ameliorating the hypercoagulable state.