Multiple Miscarriages Research Articles

A single-center investigational study of CD36 antigen deficiency and platelet alloantibody distribution in different populations in Northern China as well as platelet alloantibodies effect on pregnancy

BackgroundPlatelet antibodies can lead to clinical diseases such as platelet transfusion refractoriness (PTR), fetal/neonatal alloimmune thrombocytopenia (FNAIT), etc. This study is aimed at understanding CD36 expression, platelet alloantibody distribution in different populations in Northern China, and effects of platelet alloantibodies on pregnancy. Study design and methodsWhole blood samples of 612 subjects including hematological patients, pregnant women, and blood donors were collected at a single center, then CD36 expressions were determined, followed by platelet antibody screening and characterization of platelet antibody specificity. A retrospective analysis was performed in 1552 pregnant women admitted to Department of Obstetrics, in order to investigate FNAIT occurrence. ResultsRate of CD36 deficiency expression was 2.12% (13/612), all cases exhibited type II deficiency without type I deficiency being detected, and such rate is lower than that in Southern China (3.43%), Japanese (4.87%) and in the black people (4.18%), and higher than that in the White people (0.09%). Positive rates of platelet antibody screening in hematological patient group (6.86%, 14/204) and in pregnant women group (6.31%, 13/206) are higher than that in blood donor group (0.49%, 1/202), P < .01. Out of 1552 pregnant women, there were not children with FNAIT. ConclusionThe frequency of CD36 deficiency in northern China was low, all of them were type II deficiency, and no CD36 antibody was detected. It is speculated that the risk of immune-related thrombocytopenia caused by CD36 deficiency in this population is very low. Platelet antibodies should be monitored early in patients with hematological and multiple miscarriages pregnant.

38. CASE STUDY: PREGNANCY WITH MOSAIC OF TRISOMY / MONOSOMY 18 AFTER TRANSFER OF AN APPARENTLY EUPLOID BLASTOCYST TESTED BY ACGH

Introduction It is already known that accuracy of preimplantation genetic testing for aneuploidy (PGT-A) might be compromised by relatively high frequency of mosaics in human preimplantation embryos, even in the blastocyst stage. Giving into account low number of cells which may be removed from embryo for analysis, the fact that all the cells are biopsied in a cluster from one locus of trophectoderm (TE) and that TE represents not foetal but future placental tissue, PGT-A should not be considered as a diagnostic examination but only as a screening test that may contribute to a better assessment of embryonal viability. Material & methods We present a case of a couple with multiple recurrent miscarriages in the first trimester after spontaneous conceptions. In 2016 the couple decided to undergo IVF/ICSI treatment with PGT-A by array comparative genome hybridization (aCGH) on TE samples (24sure, Bluegnome /Illumina). All (8) analyzed blastocysts were shown to be euploid. The first (double) embryotransfer resulted in pregnancy and the patient gave birth to a healthy girl (2017). After two subsequent (single) embryo transfers in 2018 patient got pregnant but the pregnancy resulted in a missed abortion in 10th week of pregnancy. Results Analysis of aborted tissue by quantitative fluorescent polymerase chain reaction (QF-PCR; Devyser Complete v2/ Devyser 18 v2, Devyser AB) showed aneuploidy of chromosome 18 in a form not conflicting with trisomy of mitotic origin (all short tandem repeats (STR) markers were in 2:1 ratio). aCGH (SurePrint G3, ISCA v2, 8x60K, Agilent Technologies) confirmed trisomy 18 corresponding with 75% representation of the trisomic cell line. Re-analysis of stored amplified TE sample by next generation sequencing (NGS) method (VeriSeq, Illumina) revealed, by aCGH unrecognized, monosomy 18 at the level corresponding with 20% of monosomic cells. Both trophectoderm and aborted tissue samples showed origin from the same individual (Devyser 18 v2, Devyser AB). Conclusions The presented case clearly documents limitation of PGT-A, and caution which should be taken when the test is offered to patients and particularly when doing interpretation of the results. It also supports the opinion that embryos with proven mosaic monosomy of chromosomes 13, 18, 21 should be always avoided from the transfer.

Perceptions of parents and religious leaders regarding minimal invasive tissue sampling to identify the cause of death in stillbirths and neonates: results from a qualitative study

BackgroundRecently, the minimal invasive tissue sampling (MITS) procedure has been developed to support determination of the cause of death as an alternate to conventional autopsy, especially in countries where complete diagnostic autopsy is not routine. To assess the feasibility of implementation of the MITS procedure for a study to determine cause of death in premature births and stillbirths in south Asia, we explored the views and perceptions of parents and religious leaders on the acceptability of MITS.MethodsA qualitative study was conducted at the National Institute of Child Health (NICH) hospital of Karachi, Pakistan. Focus group discussions (FGDs) were conducted with parents of newborns who visited well-baby clinics of the NICH hospital for post-natal check-ups. Key-informant interviews (KIIs) were conducted with religious leaders. Data were analyzed using NVivo 10 software.ResultsA total of 13 interviews (FGDs = 8; KIIs = 5) were conducted. Three overarching themes were identified: (I) acceptability of MITS; (II) concerns affecting the implementation of MITS; and (III) religious and cultural perspectives. Participants’ acceptance of MITS was based on personal, religious, cultural and social beliefs. Parents widely recognized the need for this procedure in cases where the couple had experienced multiple stillbirths, neonatal deaths and miscarriages. Counseling of parents was considered vital to address emotional concerns of the parents and the family. Religious leaders indicated acceptability of the MITS procedure from a religious perspective and advised that respect for the deceased and consent of the guardians is mandatory when performing MITS.ConclusionsThis qualitative study provided a unique opportunity to understand the views of parents and religious leaders towards the use of MITS. Generally, MITS appears to be an acceptable method for identifying the cause of death in neonates and stillbirths, provided that the deceased is respected and buried as soon as possible without any delays and parents are counseled appropriately. Findings from this research are essential in approaching families for consent for MITS.

Prospect of Preimplantation Genetic Testing (PGT) without In vitro fertilization (IVF)

The objective of this talk is whether it is possible to consistently and reliably capture in-vivo conceived embryos from the uterus to conduct PGT-A, PGT-M and what utility can this method bring to fertility medicine and research. The approach is based on uterine lavage, a procedure developed originally by Buster et. al. in 1983, as a method to conduct embryo donation. Recent trials conducted in Punta Mita, Mexico, utilizing a newly designed medical device and system to perform uterine lavage, indicate that the procedure and method can consistently, safely and reliably be used to capture embryos, conduct PGT-A after trophectoderm biopsy and cryopreserve the embryo for future use. Recent trial results show that uterine lavage may provide an alternative option to IVF for fertile couples who desire a PGT-A, PGT-M prior to the establishment of pregnancy. Implications of uterine lavage: although a nascent technology, studies indicate that uterine lavage may have the potential to provide a new tool to acquire genetic information on embryos. Commercially, the procedure has the potential to provide a low cost, minimally invasive, reproducible and effective way to acquire in-vivo conceived and genetically tested embryos. As a procedure uterine lavage may be useful in commercial applications such as fertility preservation, aneuploidy detection, or detection of genetic diseases such as cystic fibrosis. Uterine lavage may also have utility in addressing some infertility indications such as advanced maternal age or multiple miscarriage. From a research perspective, the study of in-vivo conceived embryos may provide new scientific insights to the field of embryology. Furthermore, comparison studies between in-vivo conceived and IVF-derived embryos may provide researchers enhanced understanding with respect to aneuploidy, mosaicism and other genetic profiles currently only understood from the cohort of IVF-published data. The objective of this talk is whether it is possible to consistently and reliably capture in-vivo conceived embryos from the uterus to conduct PGT-A, PGT-M and what utility can this method bring to fertility medicine and research. The approach is based on uterine lavage, a procedure developed originally by Buster et. al. in 1983, as a method to conduct embryo donation. Recent trials conducted in Punta Mita, Mexico, utilizing a newly designed medical device and system to perform uterine lavage, indicate that the procedure and method can consistently, safely and reliably be used to capture embryos, conduct PGT-A after trophectoderm biopsy and cryopreserve the embryo for future use. Recent trial results show that uterine lavage may provide an alternative option to IVF for fertile couples who desire a PGT-A, PGT-M prior to the establishment of pregnancy. Implications of uterine lavage: although a nascent technology, studies indicate that uterine lavage may have the potential to provide a new tool to acquire genetic information on embryos. Commercially, the procedure has the potential to provide a low cost, minimally invasive, reproducible and effective way to acquire in-vivo conceived and genetically tested embryos. As a procedure uterine lavage may be useful in commercial applications such as fertility preservation, aneuploidy detection, or detection of genetic diseases such as cystic fibrosis. Uterine lavage may also have utility in addressing some infertility indications such as advanced maternal age or multiple miscarriage. From a research perspective, the study of in-vivo conceived embryos may provide new scientific insights to the field of embryology. Furthermore, comparison studies between in-vivo conceived and IVF-derived embryos may provide researchers enhanced understanding with respect to aneuploidy, mosaicism and other genetic profiles currently only understood from the cohort of IVF-published data.

The Time has come: Gestational Carrier and the Use of Pre-implantation Genetic Testing (PGT)

Purpose of review: Gestational carrier reproduction is restricted in much of the industrialized world due to complex ethical issues between the intended parents (IP) and the gestational carrier (GC), as well as safety concerns for the GC. Over 3% of all embryo transfers done in the United States involve GCs. Recent review has revealed high perinatal risks associated with assisted reproductive technologies (ART) for GCs. Compared to spontaneous conception, which the GC is familiar with, GCs using IVF have increased risk for twins and triplets of 20 and 46 fold, respectively. The resultant perinatal mortality rates are increased 4-6 fold. Costs in the first year of life for multiples are 5 to 20 times greater than for singletons. As GC cycles continue to increase, we must develop strategies to reduce perinatal risks for GCs and their offspring.Recent findings: Recent advances in IVF with pre-implantation genetic testing allow detection of euploidy for all 24 chromosomes. Elective single embryo transfer has reduced the risk of multiple pregnancy, preterm delivery and perinatal morbidity for women across the age spectrum.Summary: Elective euploid single embryo transfer, through the use of PGT, allows for very high pregnancy rates while reducing perinatal morbidity to natural levels. Both multiple gestation and miscarriage are dramatically reduced. Implementation of this technology in GCs will greatly enhance the safety of pregnancies, protecting this vulnerable population of altruistic women.

Endometrial scratching for infertile women undergoing a first embryo transfer: a systematic review and meta-analysis of published and unpublished data from randomized controlled trials

To investigate endometrial scratch injury (ESI) as an intervention to improve IVF outcome in women undergoing a first ET. Systematic review and meta-analysis. Not applicable. Infertile women undergoing a first fresh/frozen embryo transfer. We included published and unpublished data from randomized controlled trials in which the intervention group received ESI and controls received placebo or no intervention. Pooled results were expressed as relative risk (RR) with 95% confidence interval (CI). The review protocol was registered in PROSPERO to start the data extraction (CRD42018087786). Ongoing pregnancy/live birth rate (OPR/LBR), clinical pregnancy rate (CPR), multiple pregnancy rate (MPR), miscarriage rate (MR), and ectopic pregnancy rate (EPR). Seven studies were included (1,354 participants). We found a nonsignificant difference between groups in terms of OPR/LBR, CPR, MR, MPR, and EPR. Subgroup analysis found that ESI on the day of oocyte retrieval (achieved by a Novak curette) reduced OPR/LBR (RR 0.31, 95% CI 0.14-0.69) and CPR (RR 0.36, 95% CI 0.18-0.71), whereas ESI during the cycle preceding ET (performed through soft devices) had no effect on OPR/LBR and CPR. No difference in the impact of ESI was observed between fresh and frozen embryo transfer. Current evidence does not support performing ESI with the purpose of improving the success of a first ET attempt.

Mortality and cancer incidence in carriers of constitutional t(11;22)(q23;q11) translocations: A prospective study.

The constitutional t(11;22)(q23;q11) translocation is the only recurrent non‐Robertsonian translocation known in humans. Carriers are phenotypically normal and are usually referred for cytogenetic testing because of multiple miscarriages, infertility, or having aneuploidy in offspring. A breast cancer predisposition has been suggested, but previous studies have been small and had methodological shortcomings. We therefore conducted a long‐term prospective study of cancer and mortality risk in carriers. We followed 65 male and 101 female carriers of t(11;22)(q23;q11) diagnosed in cytogenetic laboratories in Britain during 1976–2005 for cancer and deaths for an average of 21.4 years per subject. Standardised mortality (SMR) and incidence (SIR) ratios were calculated comparing the numbers of observed events with those expected from national age‐, sex‐, country‐ and calendar‐period‐specific population rates. Cancer incidence was borderline significantly raised for cancer overall (SIR = 1.56, 95% CI: 0.98–2.36, n = 22), and significantly raised for invasive breast cancer (SIR = 2.74, 95% CI: 1.18–5.40, n = 8) and in situ breast cancer (SIR = 13.0, 95% CI: 3.55–33.4, n = 4). Breast cancer risks were particularly increased at ages <50 (SIR = 4.37, 95% CI: 1.42–10.2 for invasive, SIR = 22.8, 95% CI: 2.76–82.5 for in situ). Mortality was borderline significantly raised for breast cancer (SMR = 4.82, 95% CI: 0.99–14.1) but not significantly raised for other cancers or causes. Individuals diagnosed with t(11;22)(q23;q11) appear to be at several‐fold increased breast cancer risk, with the greatest risks at premenopausal ages. Further research is required to understand the genetic mechanism involving 11q23 and 22q11 and there may be a need for enhanced breast cancer surveillance among female carriers.

Detection of Large Structural Variants Causing Inherited Retinal Diseases.

Current application of next-generation sequencing (NGS) leads to detection of the underlying disease-causing gene and mutation or mutations in from 60% to 85% of patients with inherited retinal diseases (IRDs), depending on the methods used, disease type, and population tested. In a cohort of 320 families with autosomal dominant retinitis pigmentosa (adRP), we have detected the mutation in 82% of cases using a variety of methods, leaving more than 50 families with "elusive" disease genotypes. All of the remaining families have been screened for mutations in known IRD genes using retinal-targeted-capture NGS, and most have been tested by whole-exome NGS. Linkage mapping has been conducted in several large families. In one of these families, with DNA samples from ten affected family members and six unaffected, linking members, we observed substantial maximum two-point LOD scores for linkage to both chromosomes 2 and 4. Subsequent 10X Genomics Chromium™ sequencing, which facilitates linked-read, phase-known chromosomal analysis, revealed a balanced translocation of the q terminus arms of chromosomes 2 and 4 involving 35 Mb and 73 Mb of 2 and 4, respectively. The balanced translocation is present in all affected family members and absent from all unaffected individuals. Family histories suggest multiple miscarriages are associated with the translocation. The breakpoint on chromosome 4 is within or 5' to the LRAT gene, whereas the chromosome 2 break is in a gene-poor region. We conclude that the balanced translocation is the cause of adRP in this family, which may lead to dysregulation of the LRAT gene. Since multiple miscarriages are a hallmark of balanced translocations, this possibility should be considered in evaluating family histories. Further, large structural variants, which are not easily detected by conventional sequencing methods, may account for a significant fraction of the remaining unsolved families.

A Familial Case Report of a 13;22 Chromosomal Translocation with Recurrent Intracytoplasmic Sperm Injection Failure.

The importance of cytogenetic analysis in a family with reproductive failure in two siblings is highlighted, where two siblings and their mother presented with a balanced translocation between chromosomes 13;22. The clinical evaluation had shown the female to be normal and the male to be oligoasthenoteratozoospermic despite repeated semen analysis. The couple was referred to our laboratory after three consecutive intracytoplasmic sperm injection (ICSI) failures at a local assisted reproductive technique (ART) center. Peripheral blood lymphocytes, obtained for karyotyping, were studied by a standard G-banding technique. Chromosomal analysis of the members of the pedigree, including the probands, showed the presence of the same translocation, t(13;22)(q21.2;q13.3), carried by three generations of the family. The sister and the mother of the proband had multiple spontaneous abortions in the first trimester. The spouses, when examined cytogenetically, were found to be normal. We propose the involvement of a balanced t(13;22)(q21.2;q13.3) chromosomal translocation in the pathogenesis of recurrent ART or spontaneous reproductive failures. Hence, it is suggested that all cases with structural chromosomal abnormalities be counseled prior to opting for ART and undergoing pre-implantation genetic diagnosis (PGD). This would prevent recurrent financial, physical and emotional stress in couples seeking ART.

Successful Pregnancy on a Gluten-Free Diet in a Woman with Seven Miscarriages and Nonceliac Gluten Sensitivity

ABSTRACT Objective: To describe a case in which a gluten-free diet led to a successful full-term delivery in a woman with recurrent miscarriages and nonceliac gluten sensitivity (NCGS). Methods: Reduced incidences of spontaneous abortions have been reported in patients with celiac disease who adhere to a gluten-free diet, but little is known about improvement in reproductive issues in women with NCGS. We present a case of a woman with multiple miscarriages who improved on a gluten-free diet. Results: A 33-year-old woman presented with history of hypothyroidism and recurrent first-trimester fetal loss. On exam, body mass index was 24.9 kg/m2, and she did not appear cushingoid. She was on levothyroxine, and thyroid function tests were within normal limits. Thyroid peroxidase antibody and anti-phospholipid antibody were negative. Although she denied gastrointestinal symptoms, undiagnosed celiac disease was considered, as she had family members with celiac disease. Anti-gliadin immunoglobulin (Ig)G antibody w...

Health professionals' roles and practices in supporting women experiencing miscarriage: A qualitative study.

Miscarriage can result in significant psychological morbidity. Research suggests health professionals play a role in shaping women's experience of miscarriage. This study explored the views and practices of Australian health professionals in caring for women experiencing miscarriage. Twelve health professionals from disciplines including medicine, midwifery and sonography were purposively sampled. Semi-structured interviews were recorded, transcribed and subjected to thematic analysis. Participants acknowledged miscarriage is often a distressing event associated with feelings of grief and failure. They believed women who conceived through in vitro fertilisation, had experienced multiple miscarriages, or had a pre-existing mental illness were likely to experience more distress than others. Despite limited training, participants generally felt competent in their abilities to provide emotional support. They viewed their role largely as guilt-mitigation, which they achieved by stressing the frequency of miscarriage and emphasising that women were not at fault. Follow-up practices varied, and where they did occur, focused on physical recovery. Generally, participants relied on women to express the need for further support. Participants reported that time and resource issues, compassion fatigue and a need for self-protection restricted their abilities to provide better support care. There are discrepancies between the emotional support health professionals think women want and are able to provide, and the support women would like. This exploratory study suggests the need for further investigation into provision of improved health professional support for women.

New insights into the mechanisms underlying recurrent pregnancy loss.

Recurrent pregnancy loss (RPL), defined as multiple consecutive miscarriages, is a devastating disorder for which there are no good treatment options. Two opposing paradigms have emerged to explain RPL. The prevailing clinical viewpoint is that RPL is caused by a spectrum of subclinical disorders, ranging from thrombophilia to anatomical, endocrine and immunological disorders, that somehow converge on a 'fragile' early pregnancy state, leading to miscarriage. A new paradigm, based on emerging concepts around early implantation events, challenges the conventional thinking around RPL. It purports that the high incidence of embryonic aneuploidies and mosaicism coupled with a cycling endometrium necessitates the introduction of multiple 'quality control' checkpoints in the first trimester of pregnancy to limit maternal investment in a failing pregnancy. Here we review the evidence underpinning both paradigms and examine how new thinking around RPL may lead to more effective preventative strategies.

Vasodilators for women undergoing fertility treatment.

The rate of successful pregnancies brought to term has barely increased since the first assisted reproductive technology (ART) technique became available. Vasodilators have been proposed to increase endometrial receptivity, thicken the endometrium, and favour uterine relaxation, all of which could improve uterine receptivity and enhance the chances for successful assisted pregnancy. To evaluate the effectiveness and safety of vasodilators in women undergoing fertility treatment. We searched the following electronic databases, trial registers, and websites: the Cochrane Gynaecology and Fertility Group (CGF) Specialised Register of controlled trials, the Cochrane Central Register of of Controlled Trials, via the Cochrane Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Knowledge, the Open System for Information on Grey Literature in Europe (OpenSIGLE), the Latin American and Caribbean Health Science Information Database (LILACS), clinical trial registries, and the reference lists of relevant articles. We conducted the search in October 2017 and applied no language restrictions. Randomised controlled trials (RCTs) comparing vasodilators alone or in combination with other treatments versus placebo or no treatment or versus other agents in women undergoing fertility treatment. Four review authors independently selected studies, assessed risk of bias, extracted data, and calculated risk ratios (RRs). We combined study data using a fixed-effect model and assessed evidence quality using Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE) methods. Our primary outcomes were live birth or ongoing pregnancy and vasodilator side effects. Secondary outcomes included clinical pregnancy, endometrial thickness, multiple pregnancy, miscarriage, and ectopic pregnancy. We included 15 studies with a total of 1326 women. All included studies compared a vasodilator versus placebo or no treatment. We judged most of these studies as having unclear risk of bias. Overall, the quality of evidence was low to moderate for most outcomes. The main limitations were imprecision due to low numbers of events and participants and risk of bias due to unclear methods of randomisation.Vasodilators probably make little or no difference in rates of live birth compared with placebo or no treatment (RR 1.18, 95% confidence interval (CI) 0.83 to 1.69; three RCTs; N = 350; I² = 0%; moderate-quality evidence) but probably increase overall rates of side effects including headache and tachycardia (RR 2.35, 95% CI 1.51 to 3.66; four RCTs; N = 418; I² = 0%; moderate-quality evidence). Evidence suggests that if 236 per 1000 women achieve live birth with placebo or no treatment, then between 196 and 398 per 1000 will do so with the use of vasodilators.Compared with placebo or no treatment, vasodilators may slightly improve clinical pregnancy rates (RR 1.45, 95% CI 1.19 to 1.77; 11 RCTs; N = 1054; I² = 6%; low-quality evidence). Vasodilators probably make little or no difference in rates of multiple gestation (RR 1.15, 95% CI 0.55 to 2.42; three RCTs; N = 370; I² = 0%; low-quality evidence), miscarriage (RR 0.83, 95% CI 0.37 to 1.86; three RCTs; N = 350; I² = 0%; low-quality evidence), or ectopic pregnancy (RR 1.48, 95% CI 0.25 to 8.69; two RCTs; N = 250; I² = 5%; low-quality evidence). All studies found benefit for endometrial thickening, but reported effects varied (I² = 92%) and ranged from a mean difference of 0.80 higher (95% CI 0.18 to 1.42) to 3.57 higher (95% CI 3.01 to 4.13) with very low-quality evidence, so we are uncertain how to interpret these results. Evidence was insufficient to show whether vasodilators increase the live birth rate in women undergoing fertility treatment. However, low-quality evidence suggests that vasodilators may slightly increase clinical pregnancy rates. Moderate-quality evidence shows that vasodilators increase overall side effects in comparison with placebo or no treatment. Adequately powered studies are needed so that each treatment can be evaluated more accurately.

Endometrial scratch injury for women with one or more previous failed embryo transfers: a systematic review and meta-analysis of randomized controlled trials

To investigate endometrial scratch injury (ESI) as an intervention to improve IVF outcome in women with a history of ET failure. Systematic review and meta-analysis. Not applicable. Infertile women undergoing IVF after one or more failed ET. We included all randomized controlled trials of women undergoing IVF after one or more failed ET, where the intervention group received ESI and controls received placebo or no intervention. Pooled results were expressed as relative risk (RR) with a 95% confidence interval (95% CI). The review protocol was registered in PROSPERO before starting the data extraction (CRD42017082777). Live birth rate (LBR), clinical pregnancy rate (PR), multiple PR, miscarriage rate, ectopic pregnancy (EP) PR. Ten studies were included (1,468 participants). The intervention group showed higher LBR (RR 1.38, 95% CI 1.05-1.80) and clinical PR (RR 1.34, 95% CI 1.07-1.67) in comparison to controls, without difference in terms of multiple PR, miscarriage rate, and EP PR. Double luteal ESI with pipelle was associated with the greatest effect on LBR (RR 1.54, 95% CI 1.10-2.16) and clinical PR (RR 1.30, 95% CI 1.03-1.65). The ESI was beneficial for patients with two or more previous ET failure, but not for women with a single previous failed ET. No effect was found in women undergoing frozen-thawed ET cycles. The ESI may improve IVF success in patients with two or more previous ET failures undergoing fresh ET. The ESI timing and technique seem to play a crucial role in determining its effect on embryo implantation.

A balanced translocation disrupting SCN5A in a family with Brugada syndrome and sudden cardiac death

Brugada syndrome (BrS) is a primary arrhythmia syndrome affecting 1 in 2000 of the general population. Genetic testing identifies pathogenic variants in the sodium voltage-gated channel α-subunit 5 gene (SCN5A) in up to 25% of familial BrS. Balanced translocations, which involve the exchange of the ends of 2 different chromosomes, are found in approximately 1 in 500 people. They usually are benign and only rarely are reported to cause arrhythmogenic disorders. The purpose of this study was to identify the genetic mechanism underlying a family with BrS, sick sinus syndrome, cardiac hypertrophy, sudden cardiac death, and multiple miscarriages. We clinically evaluated family members with an electrocardiogram, 2-dimensional echocardiogram, and provocation testing with ajmaline challenge. Cytogenetic testing included karyotype and fluorescent in situ hybridization (FISH) analysis. We performed gene panel, exome, and genome sequencing analysis. Sequencing of 128 cardiac genes and exome sequencing of a family with BrS, sick sinus syndrome, cardiac hypertrophy, sudden cardiac death, and multiple miscarriages did not reveal a pathogenic variant. Karyotype and FISH analysis identified a balanced translocation breaking the SCN5A gene on chromosome 3 and the multiple chromosome maintenance 10 gene (MCM10) on chromosome 10 t(3;10)(p22.2;p13). We characterized both translocation breakpoint junctions using genome sequencing and found no regions of sequence homology. A balanced translocation breaking SCN5A is a novel mechanism underlying disease in a family with BrS, sick sinus syndrome, cardiac hypertrophy, and sudden cardiac death. Genome sequencing can identify rare chromosomal aberrations causing inherited diseases that may otherwise be missed using gene panel and exome sequencing-based approaches.

Perceived Subfecundity and Contraceptive Use Among Young Adult U.S. Women.

Women who view themselves as having difficulty becoming pregnant (i.e., being subfecund) may feel that they do not need to use contraceptives to prevent unintended pregnancy. However, subfecundity perceptions are not always medically accurate and may therefore confer a false sense of protection. The extent to which perceived fecundity is related to contraceptive use is not well understood. Multinomial logistic regression was used to investigate the relationship between perceived fecundity at age 25-30 and contraceptive use among 2,091 women from the National Longitudinal Survey of Youth 1997 cohort. Compared with women who considered themselves very likely to become pregnant, those who thought that they were only somewhat likely and those who viewed themselves as not very likely to do so had significantly higher risks of not using contraceptives within the next year (risk ratios, 1.9 and 2.4, respectively). Results were similar in analyses controlling for either a medical diagnosis of infertility, a history of multiple miscarriages or stillbirths, or absence of pregnancy following at least six months of unprotected sex, suggesting that perceived subfecundity operates independently of experienced subfecundity. Because few studies have investigated fecundity perceptions in their own right, more research is needed to understand how women evaluate their fecundity and to integrate these perceptions into broader frameworks describing women's perception of pregnancy risk. Such work may help identify potential levers to improve contraceptive use.

History of spontaneous miscarriage and the risk of diabetes mellitus among middle-aged and older Chinese women.

Epidemiological studies of the long-term maternal health outcomes of spontaneous miscarriages have been sparse and inconsistent. The objective of our study is to examine the association between spontaneous miscarriages and diabetes among middle-aged and older Chinese women. A total of 19,539 women from the Dongfeng-Tongji cohort study who completed a questionnaire and had medical examinations performed on were included in the analysis. History of spontaneous miscarriage was obtained by self-reporting in the first follow-up questionnaire interview. The presence of diabetes was determined by a fasting plasma glucose level, self-reported physician diagnosis and use of antidiabetic medication. A series of multivariate logistic regression models were used to calculate the odds ratios and 95% CI across spontaneous miscarriage categories (0, 1, 2, ≥ 3) after adjustment for potential confounding factors. The prevalence rate of diabetes was 18.8% among the participants. In the fully adjusted logistic regression model, women who had 1, 2 or ≥ 3 spontaneous miscarriages had 0.86 times (95% CI 0.68, 1.08), 1.30 times (95% CI 0.82, 2.04) and 2.11 times (95% CI 1.08, 4.11) higher risk of diabetes, respectively, compared with women who had no history of spontaneous miscarriage. There is an increased risk of diabetes among women with a history of a higher number of spontaneous miscarriages. History of multiple spontaneous miscarriages should be taken into consideration when assessing the risk of diabetes.

ESHRE/ESGE female genital tract anomalies classification system—the potential impact of discarding arcuate uterus on clinical practice

What would be a potential impact of implementing the new ESHRE/European Society of Gynaecological Endoscopy (ESGE) female genital anomalies classification system on the management of women with previous diagnosis of arcuate uteri based on the modified American Society for Reproductive Medicine (ASRM) criteria? A significant number of women with previous diagnosis of arcuate uteri are reclassified as having partial septate uteri according to the new ESHRE/ESGE classification system which may increase the number of remedial surgical procedures. The ESHRE/ESGE classification system has defined measurement techniques, reference points and specific cut-offs to facilitate the differentiation between normal and septate uteri. These criteria have been arbitrarily defined and they rely on the measurement of uterine wall thickness and depth of distortion of uterine fundus. This was a retrospective cohort study. We searched our ultrasound clinic database from January 2011 to December 2014 to identify all women diagnosed with arcuate uterus on three-dimensional ultrasound according to the modified ASRM criteria. For each woman, the ultrasound images were stored in our clinical database and they were re-examined according to ESHRE/ESGE specifications. The presence and location of all acquired uterine anomalies, such as fibroids or adenomyosis was noted. We applied the two diagnostic approaches as specified by the ESHRE/ESGE classification: the main option (MO) and the alternative option (AO). We used the Kappa statistic to quantify the agreement between the two approaches. We also compared the number of previous miscarriages in women with normal and partial septate uteri according to the ESHRE/ESGE classification. Non-parametric Mann-Whitney and Kruskal-Wallis tests were used for the analyses and receiver-operating characteristic curves were constructed to assess the predictive values of the calculated uterine distortion indices for the detection of women at risk of suffering multiple pregnancy losses. We included 270 women diagnosed with arcuate uterus in the study. In all, 77 women (28.5%, 95% confidence interval (CI) 23.1-33.9) had evidence of fibroids or adenomyosis. These abnormalities precluded the application of either proposed ESHRE/ESGE techniques to assess uterine morphology in 25 women (9.3%, 95% CI 5.8-12.7). When using the MO, 138/237 (58.2%, 95% CI 51.9-64.3) women were diagnosed with partial septate uterus compared to 61/230 (26.5%, 95% CI 21.2-32.6) women when using the AO. In 222 women in whom we were able to apply both MO and AO, there was agreement in the diagnosis of septate uterus between the two techniques in 146/222 cases (65.8%, 95% CI 59.3-71.7; Kappa 0.42, 95%CI 0.35-0.5). There was no statistical difference in the proportion of women with history of previous multiple miscarriages between those diagnosed with normal or partial septate uteri using either MO (6.2%, 95% CI 2.9-12.9 vs. 9.5%, 95% CI 5.6-15.6; P = 0.47) or AO (7.2%, 95% CI 4.2-12.1 vs. 11.7%, 95% CI 5.8-22.2; P = 0.29). This study was retrospective in nature and the definition of arcuate uterus used in the study is not universally accepted. The reproductive history data were collected retrospectively and therefore may be prone to bias. There are methodological weaknesses in the new ESHRE/ESGE classification system which would need to be addressed in future revisions. There was no significant difference in the past reproductive outcomes between women diagnosed with normal and anomalous uteri and the clinicians should exercise caution when offering surgical correction to women diagnosed with partial septate uteri using the new ESHRE/ESGE classification. No study funding was received and no competing interests are present. N/A.

Perifollicular Vascularity in Poor Ovarian Responders in In vitro Fertilization Cycles.

Context:Poor response is reported in 9%–24% of stimulated cycles. Color Doppler indices of follicular blood flow are correlated with oocyte recovery, fertilization rate, developmental potential of oocyte, and pregnancy rate in in vitro fertilization (IVF) treatment.Aim:The aim of this study is to find out the correlation between perifollicular vascularity with clinical outcomes in poor ovarian responders during IVF cycles.Settings and Design:A total of 49 poor ovarian responder women undergoing conventional IVF-embryo transfer procedure at a tertiary care hospital between September 2014 and 2015 were included in the study. It was a prospective observational study.Subjects and Methods:Patients were recruited on the day of trigger following a transvaginal ultrasound if they developed ≤4 dominant follicles of ≥16 mm diameter. After ovarian stimulation patients who had all follicles with low-grade vascularity were classified as Group A, those with follicles with high-grade vascularity were Group C, and Group B included patients with follicles of both good and poor vascularity.Statistical Analysis Used:Analysis of variance and Chi-square/Fisher's exact test and software, namely SAS 9.2 and SPSS 15, has been used.Results:A total 49 patients were recruited for the study.10 patients were allocated in Group A, 26 patients in Group B and 13 in Group C. Both groups were comparable in terms of age, period of infertility, follicle-stimulating hormone, luteinizing hormone, and gonadotrophin requirement. The number of metaphase II oocytes and good quality oocytes was significantly higher in Group C. Implantation rate, clinical pregnancy rate, multiple pregnancy rate, miscarriage rate, and live birth rate were comparable among all groups.Conclusions:Perifollicular vascularity has an important role to play in clinical outcomes in poor ovarian responders in IVF cycles.

Antiphospholipid antibody syndrome: The difficulties of diagnosis.

Antiphospholipid antibody syndrome (APS) is an autoantibody-mediated thrombophilic disorder that causes a hypercoagulable state and can lead to venous thromboembolism, stroke, multiple miscarriages, and other pregnancy complications with the presence of antiphospholipid antibodies. This article reviews screening, diagnosis, and management of APS with a focus on the prevention of long-term complications.