Management Of Recurrent Pregnancy Loss Research Articles

Recurrent pregnancy loss: current perspectives.

Recurrent pregnancy loss is an important reproductive health issue, affecting 2%–5% of couples. Common established causes include uterine anomalies, antiphospholipid syndrome, hormonal and metabolic disorders, and cytogenetic abnormalities. Other etiologies have been proposed but are still considered controversial, such as chronic endometritis, inherited thrombophilias, luteal phase deficiency, and high sperm DNA fragmentation levels. Over the years, evidence-based treatments such as surgical correction of uterine anomalies or aspirin and heparin for antiphospholipid syndrome have improved the outcomes for couples with recurrent pregnancy loss. However, almost half of the cases remain unexplained and are empirically treated using progesterone supplementation, anticoagulation, and/or immunomodulatory treatments. Regardless of the cause, the long-term prognosis of couples with recurrent pregnancy loss is good, and most eventually achieve a healthy live birth. However, multiple pregnancy losses can have a significant psychological toll on affected couples, and many efforts are being made to improve treatments and decrease the time needed to achieve a successful pregnancy. This article reviews the established and controversial etiologies, and the recommended therapeutic strategies, with a special focus on unexplained recurrent pregnancy losses and the empiric treatments used nowadays. It also discusses the current role of preimplantation genetic testing in the management of recurrent pregnancy loss.

Practical Work-up and Management of Recurrent Pregnancy Loss for the Front-Line Clinician.

Only a few so-called etiologies of recurrent pregnancy loss recurrent pregnancy loss in otherwise healthy women are adequately supported by well-designed investigations of association. The majority of proposed "treatments" have not been subjected to rigorous trials. The American Board of Internal Medicine Choosing Wisely initiative urges providers and patients to have constructive dialog aimed at choosing health care that is supported by evidence, not duplicative of other tests or procedures already received, free from harm, and truly necessary. We support the refreshing, objective frankness promoted by this campaign. A version of the Choosing Wisely "Do" and "Don't" format for recurrent pregnancy loss is presented.

Cytogenetic analysis of spontaneously discharged products of conception by array-based comparative genomic hybridization.

BackgroundCytogenetic analysis of products of conception (POC) is essential for the management of recurrent pregnancy loss (RPL), but the currently-performed G-banding method is not necessarily applicable to spontaneously discharged POC because of poor quality for culture. We analyzed the karyotypes of 15 spontaneously discharged POC by array-based comparative genomic hybridization (array-CGH).ResultsAll specimens were successfully analyzed and 10 cases had abnormal results: gain in copy number (n = 7) and loss in copy number (n = 3). Most of them were estimated to be whole chromosome aneuploidy, whereas one case was compatible with microdeletion. Two cases were suspected to be male diploid contaminated by maternal DNA or triploid because of the unsatisfactory signal patterns on X/Y chromosomes. Two of three cases with normal female DNA pattern were identified to be contaminated with maternal DNA by the additional analysis of short tandem repeats.ConclusionsGiven the potential to analyze non-viable POC specimens, array-CGH is a feasible cytogenetic tool for women, in particular, with a history of RPL who desire non-surgical or expectant management of miscarriages and/or a thorough investigation on the cause for recurrent miscarriage, although it needs to take into account high incidence of maternal contamination in spontaneously discharged POC.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-2594-6) contains supplementary material, which is available to authorized users.

Immunogenetic contributions to recurrent pregnancy loss

While sporadic pregnancy loss is common, occurring in 15% of pregnancies, recurrent pregnancy loss (RPL) impacts approximately 5% of couples. Though multiple causes are known (including structural, hormonal, infectious, autoimmune, and thrombophilic causes), after evaluation, roughly half of all cases remain unexplained. The idiopathic RPL cases pose a challenging therapeutic dilemma in addition to incurring much physical and emotional morbidity. Immunogenetic causes have been postulated to contribute to these cases of RPL. Natural Killer cell, T cell expression pattern changes in the endometrium have both been shown in patients with RPL. Human leukocyte antigen (HLA) and cytokine allelic variations have also been studied as etiologies for RPL. Some of the results have been promising, however the studies are small and have not yet put forth outcomes that would change our current diagnosis and management of RPL. Larger database studies are needed with stricter control criteria before reasonable conclusions can be drawn.

Evidence-Based Management of Recurrent Pregnancy Loss

Evidence-Based Management of Recurrent Pregnancy Loss

Evidence-Based Management of Recurrent Pregnancy Loss

Evidence-Based Management of Recurrent Pregnancy Loss

Harnessing Molecular Biology to Evaluate Recurrent Pregnancy Loss

Diagnosis and management of recurrent pregnancy loss (RPL; ≥2 consecutive losses before 13 weeks' gestation) is difficult, with no recognized cause

Novel strategies for the management of recurrent pregnancy loss.

This article discusses the current trends in the diagnosis and treatment of recurrent pregnancy loss. Genetic testing of the miscarriage tissue by 23-chromosome microarray and the ability to identify maternal cell contamination have increased our awareness of the role of aneuploidy as a cause of recurrent pregnancy loss. This increasing influence and the role of genetic testing in developing a strategy for the evaluation of recurrent pregnancy loss are described and discussed. The most common questions that practicing physicians ask about recurrent pregnancy loss include how many losses are needed to make the diagnosis, what counts as a pregnancy loss, what constitutes a full workup, should we get karyotypes on the parents and the miscarriage, and what is the prognosis for a live birth? This review attempts to answer those questions based on current research and clinical experience to expand our current understanding of recurrent pregnancy loss.

Poor obstetrics outcome in an undiagnosed sub-septate uterus

This is a case of a 22-year-old woman who has had a second-trimester abortion and two preterm deliveries incidentally diagnosed of sub-septate uterus on hysterosalpingography (HSG). The case is presented to emphasize on the value of HSG in the management of recurrent pregnancy loss due to suspected Mullerian duct anomaly (MDA). The degree of intercornual angle distinguishes between the types of MDAs and angles of <75° that have a high diagnostic accuracy for the septate uterus variety.

Evidence-based management of recurrent miscarriages.

Recurrent miscarriages are postimplantation failures in natural conception; they are also termed as habitual abortions or recurrent pregnancy losses. Recurrent pregnancy loss is disheartening to the couple and to the treating clinician. There has been a wide range of research from aetiology to management of recurrent pregnancy loss. It is one of the most debated topic among clinicians and academics. The ideal management is unanswered. This review is aimed to produce an evidence-based guidance on clinical management of recurrent miscarriage. The review is structured to be clinically relevant. We have searched electronic databases (PubMed and Embase) using different key words. We have combined the searches and arranged them with the hierarchy of evidences. We have critically appraised the evidence to produce a concise answer for clinical practice. We have graded the evidence from level I to V on which these recommendations are based.

Recurrent miscarriage

Recurrent miscarriage is defined as three or more consecutive pregnancy losses prior to the 24th week of gestation. The condition affects 1% of couples attempting to conceive and in the majority of cases no cause is identified. It can be an anxious and worrying time for those involved, and our role as GPs is made up of reassurance, support and tertiary referral where necessary. Fortunately, many couples proceed to having a successful pregnancy without the need for medical intervention. This article aims to discuss the aetiology, investigation and subsequent evidence-based management of recurrent pregnancy loss.

Aspirin and Low-Molecular Weight Heparin Combination Therapy Effectively Prevents Recurrent Miscarriage in Hyperhomocysteinemic Women

The management of recurrent pregnancy loss (RPL) still remains a great challenge, and women with polycystic ovarian syndrome (PCOS) are at a greater risk for spontaneous abortion. Treatment with low-molecular-weight heparin (LMWH) has become an accepted treatment option for women with RPL; however, the subgroup of women, who are likely to respond to LMWH, has not been precisely identified. The present study evaluated the efficacy of LMWH with reference to PCOS and associated metabolic phenotypes including hyperhomocysteinemia (HHcy), insulin resistance (IR) and obesity. This prospective observational study was conducted at Institute of Reproductive Medicine, Kolkata, India. A total of 967 women with history of 2 or more consecutive first trimester abortions were screened and 336 were selected for the study. The selected patients were initially divided on the basis of presence or absence of PCOS, while subsequent stratification was based on HHcy, IR and/or obesity. The subjects had treatment with aspirin during one conception cycle and aspirin-LMWH combined anticoagulant therapy for the immediate next conception cycle, if the first treated cycle was unsuccessful. Pregnancy salvage was the sole outcome measure. The overall rate of pregnancy salvage following aspirin therapy was 43.15%, which was mostly represented by normohomocysteinemic women, while the salvage rate was lower in the HHcy populations irrespective of the presence or absence of PCOS, IR, or obesity. By contrast, aspirin-LMWH combined therapy could rescue 66.84% pregnancies in the aspirin-failed cases. Logistic regression analyses showed that HHcy remained a significant factor in predicting salvage rates in the PCOS, IR, and obese subpopulations controlled for other confounding factors. With regard to pregnancy salvage, combined anticoagulant therapy with aspirin and LMWH conferred added benefit to those with HHcy phenotype.

Psychological adjustment and psychosocial stress among Japanese couples with a history of recurrent pregnancy loss

Little is known about the effects of recurrent pregnancy loss (RPL) on the psychological adjustment of couples. The aim of this study was to elucidate psychological adjustment and RPL-associated psychosocial stress affecting Japanese couples with a history of RPL, focusing on gender differences and quality of the marital relationship. The study included 76 RPL couples who visited the outpatient clinic of a tertiary hospital. They completed self-administered questionnaires that assessed RPL-associated stress, quality of their marital relationship (Quality Marriage Index, QMI), depression (Beck Depression Index) and anxiety (State-Trait Anxiety Inventory). Women showed significantly higher levels of depression, anxiety and RPL-associated personal and social stress compared with men. Although there were no differences in QMI scores and RPL-associated marital stress between men and women, women with a low perception of marital relationship quality (low QMI) had significantly higher levels of depression and anxiety compared with women with a moderate or high QMI. In contrast, depression and anxiety scores did not differ according to the quality of the marital relationship among men. Of 76 couples, 26 men (34%) and 45 women (59%) who had considered professional mental health consultations regarding their RPL status but had not yet initiated the process were more depressed and anxious than 48 men and 24 women, respectively, who had never considered such consultation. Women were significantly more distressed than men. Poor quality of the marital relationship was significantly associated with impaired psychological adjustment among women, but not among men. These gender discrepancies may foster a mutual worsening of psychological adjustment and marital relationships in RPL couples. The need to seek help not only in women but also in a substantial portion of men suggests the importance of couple-based psychological care in the management of RPL.

Management of Recurrent Pregnancy Loss Associated with a Parental Carrier of a Reciprocal Translocation: A Systematic Review

This study reviews systematically the effectiveness of management strategies for carriers of a reciprocal translocation involving two chromosomes, ascertained on the basis of recurrent pregnancy loss. Subsequent pregnancy outcomes were tabulated based on whether management was medical or involved in vitro fertilization/preimplantation genetic diagnosis (IVF/PGD). A total of 129 cases from 13 articles met the criteria, of which 89% were managed medically. Before management, the overall live birthrate was 4% (19 of 484 pregnancies). Management was medical in 109 cases and IVF/PGD in 20 cases. Cumulative live birthrate was 74% (81 of 109 cases) in the medical management group and 35% (7 of 20) in the IVF/PGD group. Based on this systematic review, successful pregnancy outcomes are high following either medical management or IVF/PGD for carriers of a reciprocal translocation, ascertained on the basis of recurrent pregnancy loss. But it is difficult to compare outcomes directly for these two strategies because of the different end points reported. Understanding the differences is essential for effective counseling. Until a well-designed study comparing the two strategies is performed, or at least prospective cohort studies with strict entry criteria and definitions, the cumulative experience and success of both medical management and IVF/PGD must be used to counsel patients who are carriers of a reciprocal translocation, ascertained on the basis of recurrent pregnancy loss.

Evaluation and Management of Recurrent Pregnancy Loss

Evaluation and Management of Recurrent Pregnancy Loss

The role of assisted reproductive technology in the management of recurrent pregnancy loss

Description of genetic screening of preimplantation embryos as a means of reducing miscarriages in patients with recurrent pregnancy loss. That the promise of preimplantation genetic screening (PGS) for ameliorating recurrent pregnancy loss has been fulfilled is controversial. An array of comparative studies has suggested a positive effect of PGS on implantation rate, but these have been balanced by studies showing no effect or a negative effect, highlighting the need for more rigorously designed studies and randomized controlled trials. Emerging technologies may provide more information from the embryo biopsies even as the mosaicism of the embryo and its implications for interpreting PGS data are recognized. Through the screening of embryos for abnormality in chromosome number or structure and selecting only normal embryos for transfer, PGS was envisioned and applied as a therapeutic tool for improving implantation and live birth rates from in-vitro fertilization and providing a means of attenuating pregnancy loss in recurrent pregnancy loss patients. An array of reports on the effects of PGS on embryo implantation and live birth rates has been made since its introduction, showing, variously, increases, decreases or no changes in these parameters. Various factors may influence the efficacy of PGS, including the patient population to which it is applied, technical aspects such as embryo biopsy, the genetic analysis and embryo culture environment, the current limitation of the genetic analysis (a subset of, rather than all, the 24 chromosomes) and the mosaicism of the embryo and blastocyst. Collectively, these contribute to the challenge of optimizing PGS and understanding how the screening result reflects the ultimate genetic constitution of the conceptus. Emerging cytogenetic and molecular technologies such as comparative genomic hybridization and microarray analysis may provide a broader appraisal of the embryo for a more comprehensive evaluation of developmental potential and prognosis for live birth.

Low Molecular Weight Heparin to Achieve Live Birth Following Unexplained Pregnancy Loss: A Meta-Analysis.

Abstract 489 The management of recurrent pregnancy loss is uncertain. Some cohort studies have identified an association between inherited thrombophilias and recurrent or late-nonrecurrent pregnancy loss which has prompted investigators to evaluate the benefit of low molecular weight heparin to achieve live birth. A similar benefit for low molecular weight heparin has also been proposed independent of thrombophilia status. A recent Cochrane Review on this topic included the results of a single randomized trial in their analysis. As there are several recent randomized trials using low molecular weight heparin in women with recurrent pregnancy loss published in the obstetrical literature, we performed a meta-analysis to evaluate the benefit of low molecular weight heparin in women who experienced unexplained recurrent or late-nonrecurrent pregnancy loss. Methods: We conducted a meta-analysis of randomized controlled trials investigating the benefit of low molecular weight heparin versus a non-anticoagulant control arm in women with a history of ≥2 early pregnancy losses or ≥1 late pregnancy loss; we excluded women with antiphospholipid antibodies and those with an underlying cause of recurrent fetal loss, except for the hereditary thrombophilias. We planned to use random-effects analysis as the primary summary model due to the anticipated variations in enrollment criteria and interventions between the studies. Results: A total of 757 women were enrolled in five studies that satisfied the eligibility criteria. Using the random effects model, the risk ratio of fetal loss for low molecular weight heparin versus control was 0.49 (0.25-0.97 95% CI, P=0.04). There was significant heterogeneity observed between studies (Q-value was 15.59, P=0.004, and I2=74.33%). A priori, we identified the presence or absence of a hereditary thrombophilia as a potential source of heterogeneity. However, subgroup analysis of the studies according to the inclusion or exclusion of women with hereditary thrombophilia did not resolve the observed heterogeneity between studies. Exclusion of the only trial that enrolled women following a non-recurrent pregnancy loss improved the observed heterogeneity but diminished the apparent benefit of low molecular weight heparin (0.63, 95% CI 0.34-1.16, P=0.14). In this trial, the observed birth rate in the control arm was significantly lower than in the other two trials included in this meta-analysis with aspirin-only controls (29% versus 84% or 87% in aspirin-only arms, P&lt;0.001). Conclusion: There is a trend for increased live births when using low molecular weight heparin for the prevention of recurrent pregnancy loss. However, considering the observed heterogeneity across studies, there is insufficient evidence to support the routine use of low molecular weight heparin to improve pregnancy outcomes in women with a history of pregnancy loss. Disclosures: Off Label Use: low molecular weight heparin to prevent pregnancy loss. Bauer:Bayer Healthcare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Speakers Bureau; GTC Biotherapeutics: Membership on an entity's Board of Directors or advisory committees. Zwicker:Sanofi-Aventis: Research Funding.

Low molecular weight heparin to achieve live birth following unexplained pregnancy loss: a systematic review.

The management of recurrent pregnancy loss is uncertain. Some cohort studies have identified an association between inherited thrombophilias and recurrent or late non-recurrent pregnancy loss, which has prompted investigators to evaluate the benefit of low molecular weight heparin (LWMH) to achieve live birth. A similar benefit for LMWH has also been proposed independent of thrombophilia status. We conducted a systematic review of randomized controlled trials to assess the benefit of LMWH in achieving live birth for women with a history of recurrent or late non-recurrent pregnancy loss in the absence of antiphospholipid antibodies. For the five studies that satisfied the eligibility criteria, the risk ratio of live birth for women with a history of pregnancy loss treated with LWMH compared with control ranged from 0.95 to 3.00. There was considerable heterogeneity among studies in terms of treatment effect (Q-value was 41.7, P=0.000, and I2=90.4%) independent of thrombophilia status. There was also a wide variation among all studies in terms of definition of early or late pregnancy loss, thrombophilic risk factors, and number of prior pregnancy losses. There is a trend for increased live births when using LWMH for the prevention of recurrent pregnancy loss. Currently, there is insufficient evidence to support the routine use of LWMH to improve pregnancy outcomes in women with a history of pregnancy loss. Not only are additional studies necessary but standardized criteria for trials evaluating the benefit of an intervention in recurrent pregnancy loss should be established.

Autoantibodies and coagulation in reproductive medicine.

Management of recurrent pregnancy loss (RPL) is considered to be difficult, in part because of cunfusion between autoantibodies and coagulation disorders. Autoantibodies and coagulation are related; two groups of multicenter studies concerning autoantibodies and coagulation reported that factor XII deficiency, hypofibrinolysis, anti-phosphatidylethanolamine (aPE), anti-beta2-glycoprotein I, anti-annexin A5, and lupus anticoagulant (LA) were found to be frequent risk factors in RPL women. Therefore, discrimination of autoantibodies and coagulation is important in understanding RPL well. We propose three types of pathways regarding reproduction, which are different and independent: (1) Negatively charged-phospholipid related antibodies (anti-phosphatidylserine; aPS, anti-cardiolipin; aCL, lupus anticoagulant; LA, anti-annexin A5; aANX), (2) factor XII-aPE-fibrinolysis: suppression of fibrinolysis, (3) protein C-protein S-factor V: loss of inactivation against activated factor V. Women with RPL and infertility showed similar findings in terms of the above clinical tests. Available data, however, is not enough to conclude whether these are pathogenic to infertile women.

P-504: Management of recurrent pregnancy loss associated with a parental carrier of a reciprocal translocation: Review of the literature

Published reproductive outcomes are limited in carriers of structural chromosome rearrangements because of their low prevalence. In addition, reproductive outcomes should be stratified for the type of rearrangements and the indication for ascertainment. This study was designed to review the published cases of parental carriers of a reciprocal translocation, ascertained on the basis of recurrent pregnancy loss (RPL), defined as at least two miscarriages of less than 20 weeks of gestation. Subsequent pregnancy outcomes were tabulated, based on whether management was medical or in vitro fertilization/preimplantation genetic diagnosis (IVF/PGD).