Early pregnancy loss, or loss of an intrauterine pregnancy within the first trimester, is encountered commonly in clinical practice. Obstetricians and gynecologists should understand the use of various diagnostic tools to differentiate between viable and nonviable pregnancies and offer the full range of therapeutic options to patients, including expectant, medical, and surgical management. The purpose of this Practice Bulletin is to review diagnostic approaches and describe options for the management of early pregnancy loss.

To validate externally five approaches to predict ectopic pregnancy (EP) in pregnancies of unknown location (PUL): the M6P and M6NP risk models, the two‐step triage strategy (2ST, which incorporates M6P), the M4 risk model, and beta human chorionic gonadotropin ratio cut‐offs (BhCG‐RC).

Pregnancy loss is often caused by chromosomal abnormalities of the conceptus. The prevalence of these abnormalities and the allocation of (ab)normal cells in embryonic and placental lineages during intrauterine development remain elusive. In this study, we analyzed 1,745 spontaneous pregnancy losses and found that roughly half (50.4%) of the products of conception (POCs) were karyotypically abnormal, with maternal and paternal age independently contributing to the increased genomic aberration rate. We applied genome haplarithmisis to a subset of 94 pregnancy losses with normal parental and POC karyotypes. Genotyping of parental DNA as well as POC extra-embryonic mesoderm and chorionic villi DNA, representing embryonic and trophoblastic tissues, enabled characterization of the genomic landscape of both lineages. Of these pregnancy losses, 35.1% had chromosomal aberrations not previously detected by karyotyping, increasing the rate of aberrations of pregnancy losses to 67.8% by extrapolation. In contrast to viable pregnancies where mosaic chromosomal abnormalities are often restricted to chorionic villi, such as confined placental mosaicism, we found a higher degree of mosaic chromosomal imbalances in extra-embryonic mesoderm rather than chorionic villi. Our results stress the importance of scrutinizing the full allelic architecture of genomic abnormalities in pregnancy loss to improve clinical management and basic research of this devastating condition.

Chromosome abnormalities account for half of the recorded miscarriages. Data from cytogenetic analysis of the products of conception (POC) in miscarriages are reviewed in the paper. Genetic analysis of POC allows patients to be given prognostic information. Molecular genetic techniques can overcome the pitfalls of conventional karyotyping, such as culture failure and trace submicroscopic abnormalities. We compare the pros and cons when these technologies are applied to the analysis of POC after miscarriage. Guidance is also provided for future clinical applications. The objective of the review is to help clinicians understand the limitations and to optimise the usefulness of genetic analysis of POC.

Approximately 50% of pregnancy losses are caused by chromosomal abnormalities, such as aneuploidy. The remainder has an apparent euploid karyotype, but it is plausible that there are cases of pregnancy loss with other genetic aberrations that are not currently routinely detected. Studies investigating the use of exome sequencing and chromosomal microarrays in structurally abnormal pregnancies and developmental disorders have demonstrated their clinical application and/or potential utility in these groups of patients. Similarly, there have been several studies that have sought to identify genes that are potentially causative of, or associated with, spontaneous pregnancy loss, but the evidence has not yet been synthesized.The objective was to identify studies that have recorded monogenic genetic contributions to pregnancy loss in euploid pregnancies, establish evidence for genetic causes of pregnancy loss, identify the limitations of current evidence, and make recommendations for future studies. This evidence is important in considering additional research into Mendelian causes of pregnancy loss and appropriate genetic investigations for couples experiencing recurrent pregnancy loss.A systematic review was conducted in MEDLINE (1946 to May 2018) and Embase (1974 to May 2018). The search terms 'spontaneous abortion', 'miscarriage', 'pregnancy loss', or 'lethal' were used to identify pregnancy loss terms. These were combined with search terms to identify the genetic contribution including 'exome', 'human genome', 'sequencing analysis', 'sequencing', 'copy number variation', 'single-nucleotide polymorphism', 'microarray analysis', and 'comparative genomic hybridization'. Studies were limited to pregnancy loss up to 20 weeks in humans and excluded if the genetic content included genes that are not lethal in utero, PGD studies, infertility studies, expression studies, aneuploidy with no recurrence risk, methodologies where there is no clinical relevance, and complex genetic studies. The quality of the studies was assessed using a modified version of the Newcastle-Ottawa scale.A total of 50 studies were identified and categorized into three themes: whole-exome sequencing studies; copy number variation studies; and other studies related to pregnancy loss including recurrent molar pregnancies, epigenetics, and mitochondrial DNA aberrations. Putatively causative variants were found in a range of genes, including CHRNA1 (cholinergic receptor, nicotinic, alpha polypeptide 1), DYNC2H1 (dynein, cytoplasmic 2, heavy chain 1), and RYR1 (ryanodine receptor 1), which were identified in multiple studies. Copy number variants were also identified to have a causal or associated link with recurrent miscarriage.Identification of genes that are causative of or predisposing to pregnancy loss will be of significant individual patient impact with respect to counselling and treatment. In addition, knowledge of specific genes that contribute to pregnancy loss could also be of importance in designing a diagnostic sequencing panel for patients with recurrent pregnancy loss and also in understanding the biological pathways that can cause pregnancy loss.© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Congenital uterine anomalies (CUA) can be associated with impairments of early and late pregnancy events.To assess the impact of CUA on reproductive outcomes in pregnancies conceived spontaneously or after assisted reproduction.Systematic review and meta-analysis of cohort studies comparing patients with CUA versus women with normal uterus. A structured literature search was performed in leading scientific databases to identify prospective and retrospective studies. The Newcastle-Ottawa scale, adapted to AHRQ standards, was used to assess the risk of bias. Pooled odds ratios (OR) were calculated. Publication bias and statistical heterogeneity were assessed, and meta-regression was used to analyse the heterogeneity.Miscarriage, ectopic pregnancy, placental abruption, term, and premature rupture of membranes (PROM), malpresentation at delivery, preterm delivery prior to 37, 34 and 32 weeks, caesarean delivery, intrauterine growth restriction/small for gestational age, foetal mortality and perinatal mortality.32 studies were included. CUAs increased significantly the risk of first/second trimester miscarriage (OR:1.54;95%CI:1.14-2.07), placental abruption (OR:5.04;3.60-7.04), PROM (OR:1.71;1.34-2.18), foetal malpresentation at delivery (OR:21.04;10.95-40.44), preterm birth (adjusted OR:4.34;3.59-5.21), a caesarean delivery (adjusted OR:7.69;4.17-14.29), intrauterine growth restriction/small for gestational age (adjusted OR:50;6.11-424), foetal mortality (OR:2.07;1.56-2.73) and perinatal mortality (OR:3.28;2.01-5.36).CUA increases the risk of complications during pregnancy, delivery, and postpartum. Complications most frequent in CUA patients were preterm delivery, foetal malpresentation, and caesarean delivery.Bicornuate uterus was associated with the highest number of adverse outcomes, followed by didelphys, subseptate and septate uterus.

This guidance focuses on methodological aspects of lupus anticoagulant (LA) testing, as well as interpretation of results for clinicians. The main changes in how to test for LA compared with the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee 2009 guidelines, in the preanalytical phase are more detailed recommendations on how to handle testing in anticoagulated patients, and the timing of testing. Also, routine coagulation tests are advised to obtain more information on the coagulation background of the patient, and when necessary, anti-Xa activity measurement for heparins or specific assays for direct oral anticoagulants should be performed. The three-step procedure with two test systems (diluted Russell's viper venom time and activated partial thromboplastin time [aPTT]) is essentially not changed. Silica remains the preferable activator in the aPTT assays, but ellagic acid is not excluded. We advise simultaneous performance of the mixing and confirmatory step, in each sample with a prolonged screening test. The confirmatory step can also be performed on a mixture of patient plasma and normal pooled plasma. Cutoff values should be established in-house on at least 120 normals, with transference of the manufacturer's cutoffs as an alternative. Reporting of results has not been changed, although more attention is focused on what clinicians should know. Patient selection for LA testing has been expanded.© 2020 International Society on Thrombosis and Haemostasis.

The laboratory detection of lupus anticoagulants (LA) in anticoagulated patients represents a challenge and there is no consensus on the types of assays/procedures to be adopted.This communication of the International Society on Thrombosis and Haemostasis (ISTH), Scientific and Standardization Committee (SSC) aims to give guidance on the procedures to be adopted.Members of the ISTH-SSC on Lupus Anticoagulant/Antiphospholipid Antibodies reviewed the literature to search for evidence on the most appropriate assays/procedures to be adopted.Anticoagulants are able to interfere with the tests used for LA detection, giving rise to occasional false-positive or false-negative LA. Some commercial tests include in their composition heparin-neutralizers able to quench unfractionated or low molecular weight heparin up to 1.0 U/mL. LA tests are less affected by low molecular weight heparin, but caution is needed in the interpretation of results. Vitamin K antagonists (VKAs) may affect LA detection. Dilution of test plasma into pooled normal plasma is not a reliable solution as false-negative or false-positive LA may occur. Direct oral anticoagulants (DOACs) affect LA detection. Hence, it is not recommended to attempt LA detection in those patients. The use of DOAC adsorbents is a promising solution and should be further investigated on LA-positive and LA-negative patient populations. Taipan/Ecarin tests may be a solution for VKAs and anti-FXa DOACs, but independent evidence on their value and standardized kits is needed.LA detection during anticoagulation remains a challenge, especially for VKAs. DOAC removal by in vitro addition to plasma of appropriate absorbents is promising.© 2020 International Society on Thrombosis and Haemostasis.

Is there an association between hereditary thrombophilia in pregnant women and risk of recurrent pregnancy loss (RPL)?

MTHFR polymorphism testing is frequently ordered by physicians as part of the clinical evaluation for thrombophilia. It was previously hypothesized that reduced enzyme activity of MTHFR led to mild hyperhomocysteinemia which led to an increased risk for venous thromboembolism, coronary heart disease, and recurrent pregnancy loss. Recent meta-analyses have disproven an association between hyperhomocysteinemia and risk for coronary heart disease and between MTHFR polymorphism status and risk for venous t-hromboembolism. There is growing evidence that MTHFR polymorphism testing has minimal clinical utility and, therefore should not be ordered as a part of a routine evaluation for thrombophilia.

To develop diagnostic criteria for chronic endometritis and compare the prevalence of chronic endometritis between women with recurrent pregnancy loss (RPL) and controls.Cohort study.Single academic fertility center.Women with unexplained RPL (two or more pregnancy losses) and prospectively recruited controls without a history of RPL or infertility.Endometrial samples were stained with hematoxylin and eosin and CD138. A pathologist blinded to patient history recorded the number of plasma cells per 10 high-power fields (HPFs). In addition, the presence or absence of endometrial stromal changes was documented.Prevalence of chronic endometritis.Endometrial samples from 50 women with unexplained RPL and 26 controls were evaluated. When chronic endometritis was defined as the presence of one or more plasma cells per 10 HPFs, 31% of controls and 56% of women with RPL met the criterion. When both endometrial stromal changes and plasma cells were required for a diagnosis of chronic endometritis, no controls and 30% of women with RPL met the criteria.Although rare plasma cells were found in biopsy samples from controls, the presence of both plasma cells and endometrial stromal changes was limited to the RPL cohort. We propose that chronic endometritis be defined as the presence of one or more plasma cells per 10 HPFs in the setting of endometrial stromal changes. With the use of these strict diagnostic criteria, women with RPL have a significantly higher rate of chronic endometritis, supporting an association between chronic endometritis and RPL.Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Infertility affects more than 14% of couples, 30% being caused by male factor infertility. This meta-analysis includes 28 studies, selected according to PRISMA guidelines. Data were extracted from these studies to collate cycles separating paternal age at 30, 35, 40, 45 and 50 years (±1 year). Primary outcomes of interest were clinical pregnancy, live birth and miscarriage rates. Secondary outcomes were the number of fertilized eggs, cleavage-stage embryos and blastocysts, and embryo quality per cycle. Fixed-effects and random-effects models giving pooled odds ratios (OR) were used to assess the effect of paternal age. This meta-analysis included a total 32,484 cycles from 16 autologous oocyte studies and 12 donor oocyte studies. In autologous cycles, a statistically significant effect of paternal age <40 years was noted in clinical pregnancy (OR 1.65, 95% confidence interval [CI] 1.27-2.15), live birth (OR 2.10, 95% CI 1.25-3.51) and miscarriage (OR 0.74, 95% CI 0.57-0.94) rates. Paternal age <50 years significantly reduced miscarriage rate (OR 0.68, 95% CI 0.54-0.86), and increased blastocyst rate (OR 1.61, 95% CI 1.08-2.38) and number of cleavage-stage embryos (OR 1.67, 95% CI 1.02-2.75) in donor oocyte cycles, where maternal age is controlled. This is an important public and societal health message highlighting the need to also consider paternal age alongside maternal age when planning a family.Copyright © 2022. Published by Elsevier Ltd.

Several studies have explored the relationship among traditional semen parameters, sperm DNA fragmentation (SDF), and unexplained recurrent miscarriage (RM); however, the findings remain controversial. Hence, we conducted a meta-analysis to explore the relationship among traditional semen parameters, SDF, and unexplained RM. Multiple databases, including PubMed, Google Scholar, MEDLINE, Embase, Cochrane Library, Web of Science, and China National Knowledge Infrastructure (CNKI), were searched to identify relevant publications. From the eligible publications, data were extracted independently by two researchers. A total of 280 publications were identified using the search strategy. According to the inclusion/exclusion criteria, 19 publications were eligible. A total of 1182 couples with unexplained RM and 1231 couples without RM were included in this meta-analysis to assess the relationship among traditional semen parameters, SDF, and unexplained RM. Our results showed that couples with unexplained RM had significantly increased levels of SDF and significantly decreased levels of total motility and progressive motility compared with couples without RM, although significant differences were not observed in the semen volume, sperm concentration, and total sperm count between couples with and without RM. The SDF assay may be considered for inclusion in evaluations of couples with unexplained RM.

Recurrent pregnancy loss (RPL), defined as two or more failed clinical pregnancies, affects 1%–3% of couples trying to conceive. Nowadays up to 50% of cases remain idiopathic. In this context, paternal factors evaluation is still very limited. The aim is to address the topic of the male factor in RPL with a broad approach, analyzing collectively data on sperm DNA fragmentation (SDF) and semen parameters. We systematically searched in Pubmed/MEDLINE and Google Scholar from inception to February 2023. A protocol has been registered on PROSPERO (ID number CRD42022278616). PRISMA guidelines were followed.