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Journal of Medicine and Life 2019The last decade has seen incredible advances in the genetic era, in next-generation sequencing of cell-free DNA in the maternal plasma, detecting abnormal fetal... (Review)
Review
The last decade has seen incredible advances in the genetic era, in next-generation sequencing of cell-free DNA in the maternal plasma, detecting abnormal fetal chromosomes. Non-invasive prenatal testing (NIPT) has showed increased sensitivity and specificity for Down syndrome superior to any other screening test. Technical advances have made possible the detection of other conditions which does not necessarily mean clinical benefit for the patient. Private laboratories have added multiple conditions in the panel of NIPT, but some of these abnormalities are so rare, that their prevalence is not even clear. Data regarding clinical performance of extended NIPT is lacking. Implementation of such a test has to be carefully weighed, and not only the benefits but also the harm should be taken into account.
Topics: Counseling; Down Syndrome; Female; Fetus; Humans; Pregnancy; Prenatal Diagnosis; Trisomy; World Health Organization
PubMed: 31666820
DOI: 10.25122/jml-2019-0053 -
Prenatal Diagnosis Jun 2022About 3% of newborns show malformations, with about 20% of the affected having genetic causes. Clarification of genetic diseases in postnatal diagnostics was...
OBJECTIVE
About 3% of newborns show malformations, with about 20% of the affected having genetic causes. Clarification of genetic diseases in postnatal diagnostics was significantly improved with high-throughput sequencing, in particular through whole exome sequencing covering all protein-coding regions. Here, we aim to extend the use of this technology to prenatal diagnostics.
METHOD
Between 07/2018 and 10/2020, 500 pregnancies with fetal ultrasound abnormalities were analyzed after genetic counseling as part of prenatal diagnostics using WES of the fetus and parents.
RESULTS
Molecular genetic findings could explain ultrasound abnormalities in 38% of affected fetuses. In 47% of these, disease-causing de novo variants were found. Pathogenic variants in genes with autosomal recessive or X-linked inheritance were detected in more than one-third (70/189 = 37%). The latter are associated with increased probability of recurrence, making their detection important for further pregnancies. Average time from sample receipt to report was 12 days in the recent cases.
CONCLUSION
Trio exome sequencing is a useful addition to prenatal diagnostics due to its high diagnostic yield and short processing time (comparable to chromosome analysis). It covers a wide spectrum of genetic changes. Comprehensive interdisciplinary counseling before and after diagnostics is indispensable.
Topics: Exome; Female; Fetus; Humans; Infant, Newborn; Pregnancy; Prenatal Diagnosis; Ultrasonography, Prenatal; Exome Sequencing
PubMed: 34958143
DOI: 10.1002/pd.6081 -
Lipids in Health and Disease Jun 2022Preeclampsia (PE) is a multisystemic syndrome specific to pregnancy. Although PE is the leading cause of death from complications associated with pregnancy, its... (Review)
Review
Preeclampsia (PE) is a multisystemic syndrome specific to pregnancy. Although PE is the leading cause of death from complications associated with pregnancy, its aetiology is still unknown. In PE, lipid metabolism is altered. When lipids are damaged, both the mother and the foetus may be at risk. Lipoproteins contain apolipoproteins, triacylglycerols, free and esterified cholesterol, and phospholipids, all of which are susceptible to oxidative stress when high levels of oxygen and nitrogen free radicals are present. Lipoperoxidation can occur in three stages: mild, moderate, and severe. In severe lipid damage, highly toxic products such as malondialdehyde (MDA) can be generated; under these conditions, low-density lipoprotein (LDL) proteins can be oxidized (oxLDL). oxLDL is a biomolecule that can affect the production of nitric oxide (NO), the main vasodilator derived from the endothelium. oxLDL can interfere with the transduction of the signals responsible for triggering the activation of endothelial nitric oxide synthase (eNOS), causing reduced vasodilation and endothelial dysfunction, which are the main characteristics of preeclampsia. The objective of the review was to analyse the information the current information about exists about the impact generated by the oxidation of LDL and HDL lipoproteins in neonates of women with preeclampsia and how these alterations can predispose the neonate to develop diseases in adulthood.PE can cause foetal loss, intrauterine growth restriction, or developmental complications. Neonates of mothers with PE have a high risk of cardiovascular diseases, stroke, mental retardation, sensory deficiencies and an increased risk of developing metabolic diseases. PE not only affects the foetus, generating complications during pregnancy but also predisposes them to chronic diseases in adulthood.
Topics: Female; Fetus; Humans; Infant, Newborn; Lipoproteins; Lipoproteins, HDL; Lipoproteins, LDL; Malondialdehyde; Pre-Eclampsia; Pregnancy
PubMed: 35658865
DOI: 10.1186/s12944-022-01663-5 -
Ultrasound in Obstetrics & Gynecology :... Oct 2019To examine the performance of the routine 11-13-week scan in detecting fetal non-chromosomal abnormalities.
OBJECTIVE
To examine the performance of the routine 11-13-week scan in detecting fetal non-chromosomal abnormalities.
METHODS
This was a retrospective study of prospectively collected data from 100 997 singleton pregnancies attending for a routine ultrasound examination of fetal anatomy, performed according to a standardized protocol, at 11-13 weeks' gestation. All continuing pregnancies had an additional scan at 18-24 weeks and 71 754 had a scan at either 30-34 or 35-37 weeks. The final diagnosis of fetal abnormality was based on the results of postnatal examination in cases of live birth and on the findings of the last ultrasound examination in cases of pregnancy termination, miscarriage or stillbirth. The performance of the 11-13-week scan in the detection of fetal abnormalities was determined.
RESULTS
The study population contained 1720 (1.7%) pregnancies with a fetal abnormality, including 474 (27.6%) detected on the first-trimester scan, 926 (53.8%) detected on the second-trimester scan and 320 (18.6%) detected in the third trimester or postnatally. At 11-13 weeks' gestation, we diagnosed all cases of acrania, alobar holoprosencephaly, encephalocele, tricuspid or pulmonary atresia, pentalogy of Cantrell, ectopia cordis, exomphalos, gastroschisis and body-stalk anomaly and > 50% of cases of open spina bifida, hypoplastic left heart syndrome, atrioventricular septal defect, complex heart defect, left atrial isomerism (interrupted inferior vena cava with normal intracardiac anatomy), lower urinary tract obstruction, absence of extremities, fetal akinesia deformation sequence and lethal skeletal dysplasia. Common abnormalities that were detected in < 10% of cases at 11-13 weeks included ventriculomegaly, agenesis of the corpus callosum, isolated cleft lip, congenital pulmonary airway malformation, ventricular septal defect, abdominal cysts, unilateral renal agenesis or multicystic kidney, hydronephrosis, duplex kidney, hypospadias and talipes.
CONCLUSIONS
A routine 11-13-week scan, carried out according to a standardized protocol, can identify many severe non-chromosomal fetal abnormalities. A summary statistic of the performance of the first-trimester scan is futile because some abnormalities are always detectable, whereas others are either non-detectable or sometimes detectable. To maximize prenatal detection of abnormalities, additional scans in both the second and third trimesters are necessary. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.
Topics: Adult; Congenital Abnormalities; Female; Fetus; Gestational Age; Humans; Nuchal Translucency Measurement; Pregnancy; Pregnancy Trimester, First; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Prenatal Care; Retrospective Studies; Ultrasonography, Prenatal
PubMed: 31408229
DOI: 10.1002/uog.20844 -
Anaesthesia Apr 2021Over the last three decades, advances in early diagnosis of fetal anomalies, imaging and surgical techniques have led to a huge expansion in fetal surgery. A small... (Review)
Review
Over the last three decades, advances in early diagnosis of fetal anomalies, imaging and surgical techniques have led to a huge expansion in fetal surgery. A small number of specialist centres perform fetal surgery, which involves high-risk anaesthesia for the mother and fetus. The anaesthetist plays an integral role within the large multispecialty and multidisciplinary team, involved in planning and delivering care for complex surgical procedures. This article reviews three fetal surgical procedures, congenital diaphragmatic hernia, myelomeningocele repair and ex-utero intrapartum treatment for airway obstruction. The underlying fetal pathology, surgical management, anaesthetic considerations and risks for both the mother and fetus are described for each. Fundamental to this is the understanding that clear communication and collaboration between all team members is vital to ensure successful outcomes of patients, the mother and the fetus.
Topics: Airway Obstruction; Anesthetics; Female; Fetus; Hernias, Diaphragmatic, Congenital; Humans; Laryngoscopy; Meningomyelocele; Prenatal Diagnosis
PubMed: 33682103
DOI: 10.1111/anae.15423 -
Genome Medicine Oct 2022Exome sequencing (ES) is becoming more widely available in prenatal diagnosis. However, data on its clinical utility and integration into clinical management remain...
BACKGROUND
Exome sequencing (ES) is becoming more widely available in prenatal diagnosis. However, data on its clinical utility and integration into clinical management remain limited in practice. Herein, we report our experience implementing prenatal ES (pES) in a large cohort of fetuses with anomalies detected by ultrasonography using a hospital-based in-house multidisciplinary team (MDT) facilitated by a three-step genotype-driven followed by phenotype-driven analysis framework.
METHODS
We performed pES in 1618 fetal cases with positive ultrasound findings but negative for karyotyping and chromosome microarray analysis between January 2014 and October 2021, including both retrospective (n=565) and prospective (n=1053) cohorts. The diagnostic efficiency and its correlation to organ systems involved, phenotypic spectrum, and the clinical impacts of pES results on pregnancy outcomes were analyzed.
RESULTS
A genotype-driven followed by phenotype-driven three-step approach was carried out in all trio pES. Step 1, a genotype-driven analysis resulted in a diagnostic rate of 11.6% (187/1618). Step 2, a phenotype-driven comprehensive analysis yielded additional diagnostic findings for another 28 cases (1.7%; 28/1618). In the final step 3, data reanalyses based on new phenotypes and/or clinical requests found molecular diagnosis in 14 additional cases (0.9%; 14/1618). Altogether, 229 fetal cases (14.2%) received a molecular diagnosis, with a higher positive rate in the retrospective than the prospective cohort (17.3% vs. 12.4%, p<0.01). The diagnostic rates were highest in fetuses with skeletal anomalies (30.4%) and multiple organ involvements (25.9%), and lowest in fetuses with chest anomalies (0%). In addition, incidental and secondary findings with childhood-onset disorders were detected in 11 (0.7%) cases. Furthermore, we described the prenatal phenotypes for the first time for 27 gene-associated conditions (20.0%, 27/135) upon a systematic analysis of the diagnosed cases and expanded the phenotype spectrum for 26 (19.3%) genes where limited fetal phenotypic information was available. In the prospective cohort, the combined prenatal ultrasound and pES results had significantly impacted the clinical decisions (61.5%, 648/1053).
CONCLUSIONS
The genotype-driven approach could identify about 81.7% positive cases (11.6% of the total cohort) with the initial limited fetal phenotype information considered. The following two steps of phenotype-driven analysis and data reanalyses helped us find the causative variants in an additional 2.6% of the entire cohort (18.3% of all positive findings). Our extensive phenotype analysis on a large number of molecularly confirmed prenatal cases had greatly enriched our current knowledge on fetal phenotype-genotype correlation, which may guide more focused prenatal ultrasound in the future. This is by far the largest pES cohort study that combines a robust trio sequence data analysis, systematic phenotype-genotype correlation, and well-established MDT in a single prenatal clinical setting. This work underlines the value of pES as an essential component in prenatal diagnosis in guiding medical management and parental decision making.
Topics: Pregnancy; Female; Humans; Exome; Retrospective Studies; Cohort Studies; Prospective Studies; Ultrasonography, Prenatal; Prenatal Diagnosis; Fetus
PubMed: 36307859
DOI: 10.1186/s13073-022-01130-x -
Journal of Clinical Pharmacology Sep 2022Medicines and vaccines prescribed to pregnant women often have not had pregnant women or lactating women included in clinical trials and products are often not approved... (Review)
Review
Medicines and vaccines prescribed to pregnant women often have not had pregnant women or lactating women included in clinical trials and products are often not approved by regulatory agencies for use in pregnant women. As a result, practitioners may need to prescribe medicines and give vaccines to this special population with limited drug efficacy and safety information available. Multiple regulatory guidance documents regarding the development of medications for pregnant and lactating women have been developed to encourage drug development and the investigation of medicines and vaccines used in this population. However, clinical, regulatory, ethical, and drug development challenges are encountered when designing clinical trials that include pregnant women and their fetuses, in which innovative methods and trial designs are essential. This article provides an overview of an industry perspective on maternal-fetal drug development that includes a review of the regulatory landscape for developing medicines for pregnant women and their fetuses, trial designs that include pregnant women, identification of gaps and challenges, and strategies for potential maternal-fetal drug development considerations for the future development of medicines and vaccines for pregnant women. Early involvement and discussion of drug and vaccine products with multiple stakeholders, including therapeutic experts, patients, physicians, and regulators, is encouraged to optimize the development of safe and effective medicines and vaccines for pregnant women and their fetuses.
Topics: Clinical Trials as Topic; Female; Fetus; Humans; Lactation; Pregnancy; Pregnant Women; Vaccines
PubMed: 36106788
DOI: 10.1002/jcph.2124 -
Frontiers in Endocrinology 2022Insulin-like peptide 3 (INSL3) is a small peptide hormone of the insulin-relaxin family which is produced and secreted by the fetal Leydig cells in the testes only. It... (Review)
Review
Insulin-like peptide 3 (INSL3) is a small peptide hormone of the insulin-relaxin family which is produced and secreted by the fetal Leydig cells in the testes only. It appears to be undetectable in female fetuses. In the human fetus INSL3 synthesis begins immediately following gonadal sex determination at weeks 7 to 8 post coitum and the peptide can be detected in amniotic fluid 1 to 2 weeks later. INSL3 acts through a unique G-protein-coupled receptor, called RelaXin-like Family Peptide receptor 2 (RXFP2), which is expressed by the mesenchymal cells of the gubernacular ligament linking the testes to the inguinal wall. The role of INSL3 in the male fetus is to cause a thickening of the gubernaculum which then retains the testes in the inguinal region, while the remainder of the abdominal organs grow away in an antero-dorsal direction. This represents the first phase of testis descent and is followed later in pregnancy by the second inguino-scrotal phase whereby the testes pass into the scrotum through the inguinal canal. INSL3 acts as a significant biomarker for Leydig cell differentiation in the fetus and may be reduced by maternal exposure to endocrine disrupting chemicals, such as xenoestrogens or phthalates, leading to cryptorchidism. INSL3 may have other roles within the fetus, but as a Leydig cell biomarker its reduction acts also as a surrogate for anti-androgen action.
Topics: Biomarkers; Female; Fetus; Humans; Insulin; Male; Proteins; Receptors, G-Protein-Coupled; Relaxin; Testis
PubMed: 35464060
DOI: 10.3389/fendo.2022.868313 -
Biomaterials Science Aug 2019Fetal surgery and fetal therapy involve surgical interventions on the fetus in utero to correct or ameliorate congenital abnormalities and give a developing fetus the... (Review)
Review
Fetal surgery and fetal therapy involve surgical interventions on the fetus in utero to correct or ameliorate congenital abnormalities and give a developing fetus the best chance at a healthy life. Historical use of biomaterials in fetal surgery has been limited, and most biomaterials used in fetal surgeries today were originally developed for adult or pediatric patients. However, as the field of fetal surgery moves from open surgeries to minimally invasive procedures, many opportunities exist for innovative biomaterials engineers to create materials designed specifically for the unique challenges and opportunities of maternal-fetal surgery. Here, we review biomaterials currently used in clinical fetal surgery as well as promising biomaterials in development for eventual clinical translation. We also highlight unmet challenges in fetal surgery that could particularly benefit from novel biomaterials, including fetal membrane sealing and minimally invasive myelomeningocele defect repair. Finally, we conclude with a discussion of the underdeveloped fetal immune system and opportunities for exploitation with novel immunomodulating biomaterials.
Topics: Biocompatible Materials; Fetal Therapies; Fetus; Humans; Immunity; Risk
PubMed: 31099350
DOI: 10.1039/c9bm00177h -
Best Practice & Research. Clinical... Mar 2023Providing pain relief during labour is a fundamental human right and can benefit both mother and foetus. Epidural analgesia remains the 'gold standard', providing... (Review)
Review
Providing pain relief during labour is a fundamental human right and can benefit both mother and foetus. Epidural analgesia remains the 'gold standard', providing excellent pain relief, as well as the facility to convert to anaesthesia should operative intervention be required. While maternal well-being remains the primary focus, epidural analgesia may also have implications for the foetus. Data from meta-analyses finds that epidural compared with systemic opioids in labour is associated with reduced neonatal respiratory depression. Clinically relevant neonatal outcomes such as Apgar score <7 at 5 min, neonatal resuscitation and need for admission to a neonatal unit are reassuring, with the benefits of epidural analgesia for both mother and neonate outweighing any potential risks. Recent concerns regarding an association of epidural with the development of autism spectrum disorder in childhood appear to be unfounded, with several large observational studies refuting this association. This review discusses the evidence relating to maternal neuraxial analgesia in labour, implications for the foetus in utero, and childhood outcomes both in the immediate peripartum period and longer term.
Topics: Pregnancy; Female; Infant, Newborn; Humans; Autism Spectrum Disorder; Analgesia, Obstetrical; Labor Pain; Resuscitation; Analgesia, Epidural; Fetus
PubMed: 37295856
DOI: 10.1016/j.bpa.2023.02.005