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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 -
Medicina (Kaunas, Lithuania) 2017Ultrasound imaging in obstetrics and gynecology dates back to 1958 when The Lancet published the first article about the use of ultrasonography for fetal and... (Review)
Review
Ultrasound imaging in obstetrics and gynecology dates back to 1958 when The Lancet published the first article about the use of ultrasonography for fetal and gynecological assessments. It is now almost inconceivable, 60 years later, to think of effective performance in obstetrics and gynecology without the variety of ultrasound, for example, real time imaging, power and color Doppler, 3D/4D ultrasonography, etc. Such examinations facilitate the assessment of intrauterine fetal growth and development during pregnancy, provide alerts about the risk of pre-eclampsia and preterm birth, help identify anatomic reasons for infertility, diagnose ectopic pregnancies, uterine, ovary and tubal pathology. Ultrasonography is also used for diagnostic and treatment procedures during pregnancy or for the treatment of infertility. This article is an overview of the development of fetal ultrasound, the methodology and interpretation of ultrasound in the assessment of intrauterine fetal growth and fetal biometry standards both worldwide and in Lithuania.
Topics: Biometry; Female; Fetus; Humans; Lithuania; Obstetrics; Pre-Eclampsia; Pregnancy; Ultrasonography; Ultrasonography, Prenatal
PubMed: 29482879
DOI: 10.1016/j.medici.2018.01.004 -
Prenatal Diagnosis Jun 2022Prenatal exome sequencing (ES) for monogenic disorders in fetuses with structural anomalies increases diagnostic yield. In England there is a national trio ES service...
BACKGROUND
Prenatal exome sequencing (ES) for monogenic disorders in fetuses with structural anomalies increases diagnostic yield. In England there is a national trio ES service delivered from two laboratories. To minimise incidental findings and reduce the number of variants investigated, analysis uses a panel of 1205 genes where pathogenic variants may cause abnormalities presenting prenatally. Here we review our laboratory's early experience developing and delivering ES to identify challenges in interpretation and reporting and inform service development.
METHODS
A retrospective laboratory records review from 01.04.2020 to 31.05.2021.
RESULTS
Twenty-four of 116 completed cases were identified as challenging including 13 resulting in difficulties in analysis and reporting, nine where trio inheritance filtering would have missed the diagnosis, and two with no prenatal diagnosis; one due to inadequate pipeline sensitivity, the other because the gene was not on the panel. Two cases with copy number variants identified were not detectable by microarray.
CONCLUSIONS
Variant interpretation requires close communication between referring clinicians, with occasional additional examination of the fetus or parents and communication of evolving phenotypes. Inheritance filtering misses ∼5% of diagnoses. Panel analysis reduces but does not exclude incidental findings. Regular review of published literature is required to identify new reports that may aid classification.
Topics: Exome; Female; Fetus; Humans; Pregnancy; Prenatal Diagnosis; Retrospective Studies; Ultrasonography, Prenatal; Exome Sequencing
PubMed: 35506549
DOI: 10.1002/pd.6165 -
BMC Biology Oct 2023The maternal microbiota modulates fetal development, but the mechanisms of these earliest host-microbe interactions are unclear. To investigate the developmental impacts...
BACKGROUND
The maternal microbiota modulates fetal development, but the mechanisms of these earliest host-microbe interactions are unclear. To investigate the developmental impacts of maternal microbial metabolites, we compared full-term fetuses from germ-free and specific pathogen-free mouse dams by gene expression profiling and non-targeted metabolomics.
RESULTS
In the fetal intestine, critical genes mediating host-microbe interactions, innate immunity, and epithelial barrier were differentially expressed. Interferon and inflammatory signaling genes were downregulated in the intestines and brains of the fetuses from germ-free dams. The expression of genes related to neural system development and function, translation and RNA metabolism, and regulation of energy metabolism were significantly affected. The gene coding for the insulin-degrading enzyme (Ide) was most significantly downregulated in all tissues. In the placenta, genes coding for prolactin and other essential regulators of pregnancy were downregulated in germ-free dams. These impacts on gene expression were strongly associated with microbially modulated metabolite concentrations in the fetal tissues. Aryl sulfates and other aryl hydrocarbon receptor ligands, the trimethylated compounds TMAO and 5-AVAB, Glu-Trp and other dipeptides, fatty acid derivatives, and the tRNA nucleobase queuine were among the compounds strongly associated with gene expression differences. A sex difference was observed in the fetal responses to maternal microbial status: more genes were differentially regulated in male fetuses than in females.
CONCLUSIONS
The maternal microbiota has a major impact on the developing fetus, with male fetuses potentially more susceptible to microbial modulation. The expression of genes important for the immune system, neurophysiology, translation, and energy metabolism are strongly affected by the maternal microbial status already before birth. These impacts are associated with microbially modulated metabolites. We identified several microbial metabolites which have not been previously observed in this context. Many of the potentially important metabolites remain to be identified.
Topics: Pregnancy; Male; Female; Animals; Mice; Intestines; Placenta; Microbiota; Brain; Fetus
PubMed: 37794486
DOI: 10.1186/s12915-023-01709-9 -
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 -
International Journal of Molecular... Dec 2019Androgens and anti-Müllerian hormone (AMH), secreted by the foetal testis, are responsible for the development of male reproductive organs and the regression of female... (Review)
Review
Androgens and anti-Müllerian hormone (AMH), secreted by the foetal testis, are responsible for the development of male reproductive organs and the regression of female anlagen. Virilization of the reproductive tract in association with the absence of Müllerian derivatives in the XX foetus implies the existence of testicular tissue, which can occur in the presence or absence of SRY. Recent advancement in the knowledge of the opposing gene cascades driving to the differentiation of the gonadal ridge into testes or ovaries during early foetal development has provided insight into the molecular explanation of XX maleness.
Topics: Animals; Disorders of Sex Development; Fetus; Humans; Male; Mammals; Models, Biological; Sex Differentiation
PubMed: 31816857
DOI: 10.3390/ijms20236089 -
Hong Kong Medical Journal = Xianggang... Jun 2016This review covers the recent literature on fetal brain magnetic resonance imaging, with emphasis on techniques, advances, common indications, and safety. (Review)
Review
INTRODUCTION
This review covers the recent literature on fetal brain magnetic resonance imaging, with emphasis on techniques, advances, common indications, and safety.
METHODS
We conducted a search of MEDLINE for articles published after 2010. The search terms used were "(fetal OR foetal OR fetus OR foetus) AND (MR OR MRI OR [magnetic resonance]) AND (brain OR cerebral)". Consensus statements from major authorities were also included. As a result, 44 relevant articles were included and formed the basis of this review.
RESULTS
One major challenge is fetal motion that is largely overcome by ultra-fast sequences. Currently, single-shot fast spin-echo T2-weighted imaging remains the mainstay for motion resistance and anatomical delineation. Recently, a snap-shot inversion recovery sequence has enabled robust T1-weighted images to be obtained, which is previously a challenge for standard gradient-echo acquisitions. Fetal diffusion-weighted imaging, diffusion tensor imaging, and magnetic resonance spectroscopy are also being developed. With multiplanar capabilities, superior contrast resolution and field of view, magnetic resonance imaging does not have the limitations of sonography, and can provide additional important information. Common indications include ventriculomegaly, callosum and posterior fossa abnormalities, and twin complications. There are safety concerns about magnetic resonance-induced heating and acoustic damage but current literature showed no conclusive evidence of deleterious fetal effects. The American College of Radiology guideline states that pregnant patients can be accepted to undergo magnetic resonance imaging at any stage of pregnancy if risk-benefit ratio to patients warrants that the study be performed.
CONCLUSIONS
Magnetic resonance imaging of the fetal brain is a safe and powerful adjunct to sonography in prenatal diagnosis. It can provide additional information that aids clinical management, prognostication, and counselling.
Topics: Adult; Brain; Diffusion Tensor Imaging; Female; Fetal Diseases; Fetus; Gestational Age; Humans; Magnetic Resonance Imaging; Pregnancy; Prenatal Diagnosis
PubMed: 27101791
DOI: 10.12809/hkmj154678 -
Scientific Reports Oct 2020Foetus sterility until parturition is under debate due to reports of microorganisms in the foetal environment and meconium. Sufficient controls to overcome sample...
Foetus sterility until parturition is under debate due to reports of microorganisms in the foetal environment and meconium. Sufficient controls to overcome sample contamination and provide direct evidence of microorganism viability in the pre-rectal gastrointestinal tract (GIT) have been lacking. We conducted molecular and culture-based analyses to investigate the presence of a microbiome in the foetal GIT of calves at 5, 6 and 7 months gestation, while controlling for contamination. The 5 components of the GIT (ruminal fluid, ruminal tissue, caecal fluid, caecal tissue and meconium) and amniotic fluid were found to contain a pioneer microbiome of distinct bacterial and archaeal communities. Bacterial and archaeal richness varied between GIT components. The dominant bacterial phyla in amniotic fluid differed to those in ruminal and caecal fluids and meconium. The lowest bacterial and archaeal abundances were associated with ruminal tissues. Viable bacteria unique to the ruminal fluids, which were not found in the controls from 5, 6 and 7 months gestation, were cultured, subcultured, sequenced and identified. We report that the foetal GIT is not sterile but is spatially colonised before birth by a pioneer microbiome.
Topics: Animals; Archaea; Bacteria; Cattle; Fetus; Gastrointestinal Tract; Microbiota
PubMed: 33077862
DOI: 10.1038/s41598-020-74677-7 -
Ultrasound in Obstetrics & Gynecology :... Jun 2023To report on a large cohort of fetuses with mild forms of tubulinopathy and to define prenatal ultrasound and magnetic resonance imaging (MRI) features that can...
OBJECTIVE
To report on a large cohort of fetuses with mild forms of tubulinopathy and to define prenatal ultrasound and magnetic resonance imaging (MRI) features that can facilitate prenatal diagnosis.
METHODS
This was a retrospective multicenter study of fetuses diagnosed between January 2007 and February 2022 with a mild tubulinopathy (without lissencephaly or microlissencephaly). We collected and reviewed brain imaging and genetic data, and defined major criteria as findings observed in ≥ 70% of the patients and minor criteria as those observed in ≥ 50% but < 70% of the patients.
RESULTS
Our cohort included 34 fetuses. The mean gestational age at ultrasound screening, when suspicion of a central nervous system anomaly was first raised, was 24.2 (range, 17-33) weeks. Callosal anomalies (n = 19 (56%)) and abnormal ventricles (n = 18 (53%)) were the main reasons for referral. The mean gestational age at neurosonography was 28.3 (range, 23-34) weeks and that at MRI was 30.2 (range, 24-35) weeks. Major ultrasound criteria were midline distortion, ventricular asymmetry, dysmorphic and/or dilated frontal horn(s) and abnormal sulcation. Minor ultrasound criteria were distortion of the cavum septi pellucidi, abnormal corpus callosum, absent or asymmetric olfactory sulci, ventriculomegaly and basal ganglia dysmorphism. Major MRI criteria were midline distortion, distortion of the cavum septi pellucidi, ventricular asymmetry, dilatation (generally unilateral) and/or distortion, dysmorphic and/or dilated frontal horn(s) and abnormal sulcation (mainly dysgyria). Minor MRI criteria were absent or asymmetric olfactory sulci, abnormal bulge of the pons, anteroposterior diameter of the pons ≤ 5 centile and brainstem asymmetry. A mutation was found in TUBB3 (44.1% of cases), TUBB (23.5%), TUBB2B (14.7%) or TUBA1A (17.6%). The mutation was inherited from a parent in 18/34 cases. The pregnancy was terminated in 23/34 cases.
CONCLUSIONS
Prenatal diagnosis of mild forms of tubulinopathy is possible but challenging. We have defined, in this large series of fetuses, major and minor criteria that can help identify this entity in utero. Most findings can be visualized on ultrasound. This evaluation is also important for prenatal counseling. Once a prenatal diagnosis of mild tubulinopathy is suspected, the family members should be referred for exome sequencing and MRI. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Pregnancy; Female; Humans; Infant; Ultrasonography, Prenatal; Nervous System Malformations; Brain; Prenatal Diagnosis; Fetus; Gestational Age; Retrospective Studies; Magnetic Resonance Imaging
PubMed: 36484554
DOI: 10.1002/uog.26140