Molecular autopsy for fetal structural anomaly: diagnostic and clinical utility of multidisciplinary team approach.

Objective: In the West Midlands regional genetics service, cases of perinatal death with a possible genetic diagnosis are evaluated by the perinatal pathology genetic multidisciplinary team (MDT). The MDT assesses autopsy findings and suggests appropriate genomic assessment. The objective of this retrospective service evaluation was to determine the clinical utility of the MDT in assessing perinatal deaths associated with structural anomaly.

Risk factors for adverse outcomes in twin pregnancies: a narrative review.

Purpose: Globally, the incidence of twin pregnancies is rising owing to the use of assisted reproductive technologies (ART), emigration and deferment of pregnancy until advanced maternal age (AMA). While twin pregnancies have higher absolute risks of adverse outcomes, including miscarriage, stillbirth, neonatal death and preterm delivery, the impact of specific exposures and risk factors related to these outcomes may differ between twin pregnancies and singleton pregnancies. Regarding modifiable factors, data are sometimes based on evidence extrapolated from singleton or whole obstetric populations.

Evaluating antenatal risk in twin pregnancies-A feasibility study to identify modifiable factors associated with adverse pregnancy outcomes.

Introduction: Twin pregnancies have significantly higher rates of perinatal morbidity and mortality compared to singleton pregnancies; current attempts to reduce perinatal mortality have been less successful in twin pregnancies. The paucity of information about modifiable risk factors for adverse neonatal outcomes in twin pregnancies, as well as independent effects of chorionicity may have contributed to this outcome. This study aimed to explore the feasibility of an observational study to identify modifiable factors associated with adverse neonatal outcomes in twin pregnancies.

Next Generation Sequencing after Invasive Prenatal Testing in Fetuses with Congenital Malformations: Prenatal or Neonatal Investigation.

Congenital malformations diagnosed by ultrasound screening complicate 3-5% of pregnancies and many of these have an underlying genetic cause. Approximately 40% of prenatally diagnosed fetal malformations are associated with aneuploidy or copy number variants, detected by conventional karyotyping, QF-PCR and microarray techniques, however monogenic disorders are not diagnosed by these tests. Next generation sequencing as a secondary prenatal genetic test offers additional diagnostic yield for congenital abnormalities deemed to be potentially associated with an underlying genetic aetiology, as demonstrated by two large cohorts: the 'Prenatal assessment of genomes and exomes' (PAGE) study and 'Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study' performed at Columbia University in the US.

Monocytes are increased in pregnancy after gestational hypertensive disease.

Monocytes derive from bone marrow and circulate in the blood. They phagocytose, produce cytokines and present antigens. Individual monocyte subsets play distinct roles in the pathogenesis of cardiovascular disease, but their implications in gestational hypertensive disease are unclear.

Altered cardiac and vascular stiffness in pregnancy after a hypertensive pregnancy.

Hypertensive disorders of pregnancy are an important cause of morbidity and mortality, impacting on both maternal and fetal wellbeing. Affected women are at higher risk of future cardiovascular morbidity and mortality. Our study objective was to assess differences in cardiovascular function in pregnant women previously affected by gestational hypertension or preeclampsia.

The prenatal exome - a door to prenatal diagnostics?

: Prenatal exome sequencing (ES) allows parents the opportunity to obtain arapid molecular diagnosis of monogenic etiology when their fetus is found to have structural anomalies detected on prenatal ultrasound. Such information can improve antenatal and neonatal counseling, decision-making and management, and expand reproductive options in subsequent pregnancies.: This review appraises the evidence, from acomprehensive search of bibliographic databases, for the introduction of ES into the fetal medicine care pathway when investigating congenital malformations.

Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes.

Purpose: Several clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly or capillary malformations with arteriovenous malformations 2 (CM-AVM2) have been associated with EPHB4 (Ephrin type B receptor 4) variants, demanding new approaches for deciphering pathogenesis of novel variants of uncertain significance (VUS) identified in EPHB4, and for the identification of differentiated disease mechanisms at the molecular level.

Methods: Ten index cases with various phenotypes, either fetal hydrops, CM-AVM2, or peripheral lower limb lymphedema, whose distinct clinical phenotypes are described in detail in this study, presented with a variant in EPHB4. In vitro functional studies were performed to confirm pathogenicity.

Accuracy of the combination of commercially available biomarkers and cervical length measurement to predict preterm birth in symptomatic women: A systematic review.

An accurate prognostic method for preterm birth (PTB) could avoid unnecessary treatment(s) with potentially negative effects. The objective was to explore the prognostic accuracy of commercially available bedside cervicovaginal biomarker tests in combination with cervical length (CL) compared to CL measurement alone and/or a biomarker test alone, for PTB within 7 days after testing symptomatic women at 22-34 weeks. The MEDLINE, Cochrane, Embase and Web of Science databases were searched from inception to August 28th, 2019.

Comparison of perinatal outcomes for all modes of second stage delivery in obstetric theatres: a retrospective observational study.

Objective: To compare rates of vaginal delivery and adverse outcomes of instrumental delivery trials in obstetric theatre compared to primary emergency full dilation caesarean section.

Design: Retrospective cohort study.

Setting: University teaching hospital.

Medical therapy to attenuate fetal anaemia in severe maternal red cell alloimmunisation.

Haemolytic disease of the fetus and newborn (HDFN) remains an important cause of fetal mortality with potential neonatal and longer-term morbidity. HDFN is caused by maternal red cell alloimmunisation, with IgG antibodies crossing the placenta to destroy fetal erythroid cells expressing the involved antigen. Intrauterine fetal blood transfusion is the therapy of choice for severe fetal anaemia.

COngenital heart disease and the Diagnostic yield with Exome sequencing (CODE) study: prospective cohort study and systematic review.

Objective: To determine the incremental yield of antenatal exome sequencing (ES) over chromosomal microarray analysis (CMA) or conventional karyotyping in prenatally diagnosed congenital heart disease (CHD).

Methods: A prospective cohort study of 197 trios undergoing ES following CMA or karyotyping owing to CHD identified prenatally and a systematic review of the literature were performed. MEDLINE, EMBASE, CINAHL and ClinicalTrials.

Red cell alloimmunization: A 2020 update.

Management of maternal red cell alloimmunization has been revolutionized over the last 60 years. Advances in the prevention, screening, diagnosis, and treatment of alloimmune-induced fetal anemia make this condition an exemplar for contemporary practice in fetal therapy. Since survival is now an expectation, attention has turned to optimization of long-term outcomes following an alloimmunized pregnancy.

Updated guidance for the management of twin and triplet pregnancies from the National Institute for Health and Care Excellence guidance, UK: What's new that may improve perinatal outcomes?

In September 2019, NICE published updated guidance on the management of multiple pregnancy (NG 137). Many of the previous recommendations for care are upheld but there have been important changes: increased frequency of combined ultrasound/specialist antenatal care appointments for pregnancies containing a monochorionic placenta (twins and triplets), increased frequency of ultrasound monitoring in all triplet pregnancies, changes in the definition of selective growth restriction and its subsequent referral pathways, the introduction of some monitoring for twin (or triplet) anemia polycythemia sequence in monochorionic pregnancies (albeit in complex pregnancies or at an advanced stage), and a recommended timing of birth for any pregnancy with monoamniotic fetuses. New recommendations have been made for mode of delivery, fetal monitoring in labor, maternal analgesia, and the prevention of postpartum hemorrhage.

Exome sequencing in the assessment of congenital malformations in the fetus and neonate.

Major congenital anomalies are often associated with perinatal mortality, long-term morbidity and prolonged hospitalisation. Prenatal ultrasound remains the principle diagnostic test for many anomalies, but despite this up to one-third are only identified in the neonatal period. The primary step in determining underlying aetiology is to define accurately the phenotype by recognition of dysmorphology (both prenatally and postnatally).

Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study.

Background: Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES).

Prognosis of the co-twin following spontaneous single intrauterine fetal death in twin pregnancies: a systematic review and meta-analysis.

Background: Single intrauterine fetal death affects approximately 6% of twin pregnancies and can have serious sequelae for the surviving co-twin.

Objectives: Determine the prognosis of the surviving co-twin following spontaneous single intrauterine fetal death to aid counselling patients and highlight future research areas.

Search Strategy: Medline, Embase, Web of Science, and Cochrane Library, from 1980 to June 2017.

Clinical utility of exome sequencing in the prenatal diagnosis of congenital anomalies: A Review.

Advances in prenatal genomics have enabled the assessment of not only the sub-microscopic structure of chromosomes using chromosomal microarray analysis, but also the detection of "pathogenic variants" to the resolution of a single base pair with the use of next generation sequencing. Research is emerging on the additional prenatal diagnostic yield that exome sequencing offers when structural fetal anomalies are detected on ultrasound examination, in particular the identification of monogenic abnormalities defining prognosis and recurrence of anomalies. Primarily assessed using fetal DNA obtained by invasive techniques (amniocytes or chorionic villi), this technology is progressing into a non-invasive approach using maternal plasma.

Molecular autopsy by trio exome sequencing (ES) and postmortem examination in fetuses and neonates with prenatally identified structural anomalies.

Purpose: To determine the diagnostic yield of combined exome sequencing (ES) and autopsy in fetuses/neonates with prenatally identified structural anomalies resulting in termination of pregnancy, intrauterine, neonatal, or early infant death.

Methods: ES was undertaken in 27 proband/parent trios following full autopsy. Candidate pathogenic variants were classified by a multidisciplinary clinical review panel using American College of Medical Genetics and Genomics (ACMG) guidelines.

Early prognostic factors of outcomes in monochorionic twin pregnancy: systematic review and meta-analysis.

Background: Monochorionic twin pregnancies are high-risk, however at present, no screening test is available to predict which monochorionic twin pregnancy will develop complications.

Objective: We sought to assess ability of first-trimester pregnancy-related factors (ultrasound measurements, maternal characteristics, biomarkers) to predict complications in monochorionic twin pregnancies.

Data Sources: Data sources were MEDLINE, Embase, ISI Web of Science, CINAHL, the Cochrane Central Registration of Controlled Trials and Research Registers, and Google Scholar, from inception to May 12, 2017.