Genetic Disorders and the Fetus
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Оглавление
Группа авторов. Genetic Disorders and the Fetus
Table of Contents
List of Tables
List of Illustrations
Guide
Pages
Genetic Disorders and the Fetus. Diagnosis, Prevention, and Treatment
Preface
Acknowledgments
Contributors
1 Genetic Counseling: Preconception, Prenatal, and Perinatal
The burden of genetic disorders and congenital malformations
Box 1.1 Factors that influence estimates of the incidence or prevalence in the newborn of a congenital malformation (CM) or genetic disorder
Incidence and prevalence of genetic disorders and congenital malformations
Congenital malformations and infant morbidity and mortality
Down syndrome
The goal and purpose of prenatal diagnosis
Prerequisites for genetic counseling
Knowledge of disease
Expertise in genetic counseling
Ability to communicate
Knowledge of ancillary needs
Empathy
Sensitivity to parental guilt
Guiding principles for genetic counseling
Accurate diagnosis
Nondirective counseling
Concern for the individual
Truth in counseling
Confidentiality and trust
Timing of genetic counseling
Parental counseling
Counselee education
Duty to recontact
Do no harm
Duty to warn
Preconception genetic counseling
Indications for preconception genetic counseling
Advanced maternal age
Paternal age
A previous fetus or child with a genetic disorder
A parent with a genetic disorder
A history of infertility
Parental carrier of a genetic disorder
A family history of a genetic disorder
Consanguinity
Environmental exposures that threaten fetal health
Identification of preconception options
Genetic counseling as a prelude to prenatal diagnosis
Informed consent
Presymptomatic or predictive testing
Expansion mutations and anticipation
Box 1.2 Selected genetic disorders with anticipation. Disorders with anticipation
Disorders with suspected anticipation
Imprinting and uniparental disomy
Genotype–phenotype associations
Somatic mosaicism
Genetic counseling when the fetus is affected
Decision making
Elective abortion: decision and sequel
Testing the other children
Perinatal genetic counseling
Box 1.3 Elements of a stillbirth evaluation
Box 1.4 Action checklist following stillbirth
Family matters
The surviving children
The efficacy of genetic counseling
References
2 Preimplantation Genetic Testing
Approaches to preimplantation genetic testing
Polar body‐based preimplantation genetic testing
Preimplantation genetic testing based on embryo biopsy
Prospects for noninvasive preimplantation genetic testing
Preimplantation genetic analysis
Single‐gene disorders
De novo mutations
Late‐onset disorders
HLA typing
Chromosomal disorders
Prevalence and origin of chromosomal errors
Aneuploidies
Structural rearrangements
Ethical and legal issues
Conclusion
References
3 Amniotic Fluid Constituents, Cell Culture, and Neural Tube Defects
Introduction
Amniotic fluid. Formation and circulation
Volume
Origin
Biochemical and other characteristics of amniotic fluid
Cell‐free DNA and RNA
Proteins
Proteomics
Lipids
Enzymes
Amino acids
Disaccharidases
Origin of amniotic fluid disaccharidases
Other microvillar enzyme activities
Development of amniotic fluid disaccharidases
Clinical use of amniotic fluid disaccharidases
Miscellaneous biochemical constituents and other characteristics of amniotic fluid
Trace elements
Creatinine/cystatin C
Blood group substances
Immunoglobulins
Antibacterial activity of amniotic fluid
Bacteriostatic effect
Isolation of infectious agents
Hormones
Drugs/toxicants
Amniotic fluid cell culture
Alternatives to cell culture and metaphase karyotype analysis
Amniotic fluid cell types. Cellular contents of native fluids
Colony‐forming cells: morphology and nomenclature
Biochemical characterization
Intermediate filament system
The origin of colony‐forming cell types
Cell culture and cell harvest. Colony‐forming cells
Culture methods
In situ procedure
Enhancement of amniotic fluid cell growth. Enrichment techniques
Growth on extracellular matrix surface
Reduction of oxygen supply
Testing and handling fetal bovine serum
Defined growth factor supplements
Culture failure
Syringe toxicity and delayed transportation
Microbial contamination
Mycoplasma
Plastic ware and media storage
Incubator failure
Record keeping and quality control
Safety in the laboratory
Mesenchymal stem cells in amniotic fluid
References
4 Molecular Aspects of Placental Development
Overview
Placental structure
Placental development and function
Implantation
Angiogenesis
Nutrient delivery
Immune function
Placental insufficiency
Fetal growth restriction
Genetic causes of fetal growth restriction
Developmental considerations in confined placental mosaicism
Imprinting and fetal growth restriction
Preeclampsia
Early diagnosis of preeclampsia
Genetics of preeclampsia
Genetic findings associated with molar changes in the placenta
Complete hydatidiform mole
Partial hydatidiform mole
Placental mesenchymal dysplasia
DNA methylation studies in the placenta and their clinical application
Epigenetic studies in the placenta and environment
The placenta as a predictor of child health
Further considerations
References
5 Fetal Origins of Adult Health and Disease
Introduction
Epigenetics and programming
Energy‐balance programming: under‐ and overnutrition
Environmental toxins
Maternal stress and anxiety
Glucocorticoids and prematurity
Organ‐specific programming effects. Appetite and adiposity
Hepatic programming
Pancreas programming
Cardiac programming
Bone programming
Brain programming
Renal programming
Immune system programming
Endocrine programming
Sexuality programming
Conclusion
References
6 Maternal Serum Screening for Chromosomal Abnormalities and Neural Tube Defects
Chromosomal abnormalities
Neural tube defects
Screening and prenatal diagnosis
Widely used markers
Additional markers
Marker distributions in Down syndrome, neural tube defect, and unaffected pregnancies
Risk screening for Down syndrome
Age‐specific Down syndrome risk at term
Down syndrome risk at the time of the test
Down syndrome likelihood ratios
Modeling performance of Down syndrome screening
Established multimarker Down syndrome policies
Model performance of neural tube defect screening
Prospective confirmation of the Down syndrome model
Further multimarker Down syndrome strategies
First‐trimester Contingent test
Additional first‐trimester ultrasound markers
Additional first‐trimester serum markers
First‐trimester Triple and Quad tests
Second‐trimester Combined test
Genetic sonogram
Repeat measures and highly correlated markers
Two‐sample Combined test
Ultrasound screening for OSB. Second‐trimester lemon and banana signs
Second‐trimester anomaly scan
First‐trimester anomaly scan
First‐trimester screening
Other Down syndrome markers. A disintegrin and metalloprotease 12s (ADAM12s)
Pregnancy‐specific glycoprotein‐1
Urinary human chorionic gonadotropin species
Serum invasive trophoblast antigen
Serum thyroid‐stimulating hormone
Clinical factors
Maternal age
Previous affected pregnancy
Twins
Assisted reproduction
Maternal diabetes
Renal transplant
Previous false positive
Smoking
Ethnicity
Maternal weight
Other factors
Edwards syndrome (trisomy 18)
Other conditions associated with altered markers
Other chromosome abnormalities
X‐linked ichthyosis
Smith–Lemli–Opitz syndrome
Cornelia de Lange syndrome
Abdominal wall defects
Cardiac abnormalities
Moles and placental mesenchymal dysplasia
Fetal demise
Adverse maternal–fetal complications of pregnancy
Planning a program
Conclusion
Acknowledgments
References
7 Noninvasive Screening for Aneuploidy Using Cell‐Free Placental DNA
Introduction
Cell‐free DNA
Performance of cell‐free DNA screening
Sex chromosome aneuploidy
Cell‐free DNA screening approaches
Cell‐free DNA test failures
False‐positive cell‐free DNA results and incidental findings
Maternal malignancy
Vanishing twins
False‐negative cell‐free DNA results
Cell‐free DNA screening for microdeletion syndromes
Genome‐wide cell‐free DNA screening
Pretest counseling
Box 7.1 Pretest counseling points for cell‐free DNA screening for fetal aneuploidy22, 47, 85
Post‐test screening
Comparison of cell‐free DNA screening to traditional screening
Cost‐effectiveness
Contingent screening
Cell‐free DNA screening following a positive traditional screening test
Use of prenatal ultrasound in the setting of cell‐free DNA. First trimester
Ultrasound soft markers and cell‐free DNA screening
Discordance between fetal sex on ultrasound and cell‐free DNA screening
Multiple gestations
Cell‐based noninvasive prenatal testing
Conclusion
References
8 Noninvasive Prenatal Diagnosis and Screening for Monogenic Disorders Using Cell‐Free DNA
Introduction
Biology and characteristics of cell‐free DNA in maternal blood. Origin of fetal cell‐free DNA
Importance of the fetal fraction
General approaches for testing of single‐gene disorders by fetal cell‐free DNA analysis
Identification of de novo or paternally inherited variants
Identification of maternally inherited variants
Laboratory techniques used for cfDNA‐based single‐gene disorder analysis
Limitations of cfDNA‐based detection of single‐gene disorders
Current status of noninvasive single‐gene testing by cell‐free DNA analysis. Overview
Noninvasive fetal sex determination
Fetal RHD and other blood group genotyping
Noninvasive prenatal diagnosis of monogenic disorders
Skeletal dysplasias
Duchenne and Becker muscular dystrophy
Cystic fibrosis
Spinal muscular atrophy
Congenital adrenal hyperplasia
Hemoglobinopathies
Sickle cell anemia
Thalassemias
β‐Thalassemia
α‐Thalassemia
Noninvasive prenatal screening using panels of single‐gene disorders by cell‐free DNA analysis
Clinical implementation: ethical and social issues
Summary and future directions
References
9 Amniocentesis, Chorionic Villus Sampling, and Fetal Blood Sampling
Introduction
Amniocentesis. Prerequisites
Timing
Technique
Ultrasound guidance during amniocentesis
Amniocentesis in multiple gestations
Rh isoimmunization in amniocentesis
Significance of amniotic fluid discoloration
Safety of genetic amniocentesis
Maternal risks
Direct fetal injury
Mother‐to‐fetus transmission of human immunodeficiency virus following amniocentesis
Pregnancy losses
National collaborative studies
First‐ and Second‐Trimester Evaluation of Risk (FaSTER) Trial Research Consortium
Conclusions regarding pregnancy loss
Early amniocentesis
Initial experience with early amniocentesis
Comparative trials on early amniocentesis
Third‐trimester amniocentesis
Chorionic villus sampling
Technique of chorionic villus sampling
Complications of chorionic villus sampling
Safety of chorionic villus sampling in multiple pregnancies
Reliability of results from chorionic villus sampling
Confined placental mosaicism
Fetal abnormalities following chorionic villus sampling
Fetal blood sampling
Fetal hematologic disorders
Fetal infection
Fetal therapy
Technique of fetal blood sampling
Safety of fetal blood sampling
Fetal blood sampling in multifetal pregnancies
Fetal blood sampling in fetuses with single umbilical arteries
First‐trimester fetal blood sampling
Cardiocentesis
References
10 Prenatal Diagnosis of Neural Tube Defects
Biology of α‐fetoprotein
Amniotic fluid α‐fetoprotein
Multiple pregnancy
Causes of elevated (or low) levels of AFAFP in the absence of NTDs
Box 10.1 Fetal conditions that may be associated with elevated amniotic fluid α‐fetoprotein (AFAFP) and/or acetylcholinesterase (AChE) Likely mechanism/condition. Leakage through skin
Urinary tract leakage
Leakage of placental origin
Leakage of pulmonary origin
Reduced intestinal AFP clearance or leakage
Unknown site of “leakage”
Problems and pitfalls. Aspiration of urine
Brown or green amniotic fluid
Amniotic fluid acetylcholinesterase
Experience with AFAChE
Recommendations for prenatal diagnosis of NTDs using AFAFP and AChE assays
Other techniques to detect neural tube defects
Primary prevention of neural tube defects. Genetic counseling
Nutritional supplementation
Complications and life expectancy
References
Additional references
11 Prenatal Diagnosis of Chromosomal Abnormalities through Chorionic Villus Sampling and Amniocentesis
The incidence of chromosomal abnormalities detected by conventional cytogenetics. Data from livebirths
Data from adult biobanks
Data from amniocentesis
Data from chorionic villus sampling
Data from spontaneous abortuses
Data from induced abortuses
Data from stillbirths
Indications for prenatal cytogenetic diagnosis
Noninvasive prenatal testing and trisomy 21, trisomy 18, and trisomy 13
Noninvasive prenatal testing and sex chromosome abnormalities
Noninvasive prenatal testing and microdeletion syndromes
Genome‐wide noninvasive prenatal testing
Noninvasive prenatal testing and low fetal fraction
The first‐trimester Combined test
Second‐trimester maternal serum screening
Elevated maternal serum α‐fetoprotein
Abnormal ultrasound findings
Very high risk for fetal aneuploidy (>35 percent)
High risk for fetal aneuploidy (20–35 percent)
Moderate risk for fetal aneuploidy (10–19 percent)
Low risk for fetal aneuploidy (<10 percent)
The “genetic sonogram” or “anomaly scan”
Advanced maternal age
Advanced paternal age
Multiple gestation pregnancy
Carrier of a balanced structural rearrangement
Non‐Robertsonian reciprocal translocation
Robertsonian translocation
Chromosome inversion
Intrachromosomal and interchromosomal insertions
Previous child with trisomy
Previous child with a de novo unbalanced rearrangement: isochromosome 21q and others
Genetic variation in folate metabolism and previous child with a neural tube defect
History of repeated fetal losses: parents' karyotype unknown
History of fetal loss: fetal karyotype considerations
Fetal demise, current pregnancy
Male or female subfertility, cytogenetic causes
Reduced ovarian complement
Abnormal parental karyotype (other than a balanced structural rearrangement)
Prenatal sex determination for X‐linked disorders
Prenatal diagnosis for a nonchromosomal disorder
Miscellaneous
Interpretation issues: chromosome mosaicism and pseudomosaicism. General considerations
Diagnosing mosaicism in chorionic villus sampling
Summary conclusions and recommendations for diagnosing mosaicism in CVS
Diagnosing mosaicism in amniotic fluid cell cultures
Summary conclusions and recommendations for diagnosing mosaicism in AFC culture
Mosaicism involving gain of an autosome: data for individual chromosomes
Chromosome 1
Chromosome 2
Chromosome 3
Chromosome 4
Chromosome 5
Chromosome 6
Chromosome 7
Chromosome 8
Chromosome 9
Chromosome 10
Chromosome 11
Chromosome 12
Chromosome 13
Chromosome 14
Chromosome 15
Chromosome 16
Chromosome 17
Chromosome 18
Chromosome 19
Chromosome 20
Chromosome 21
Chromosome 22
Autosomal monosomy mosaicism
Complex and variegated aneuploidy
Summary conclusions and recommendations for mosaicism involving gain or loss of autosomes
Mosaicism involving an autosomal structural abnormality (excluding supernumerary marker chromosomes) in CVS
Mosaicism involving an autosomal structural abnormality (excluding supernumerary and marker chromosomes) in AFC
del(10)(q11.2), del(10)(q23), del(10)(q25), and deletions at other fragile sites
i(20q)
Sex chromosome mosaicism in chorionic villus sampling
Sex chromosome mosaicism in amniotic fluid cells
45,X/46,XY mosaicism
45,X/46,XX mosaicism
46,XY/47,XXY mosaicism
Other sex chromosome mosaicism involving a 45,X cell line (excluding 45,X/46,XX or 45,X/46,XY)
Mosaicism involving an additional sex chromosome other than XXY
Mosaicism involving a structurally abnormal X
Mosaicism involving a structurally abnormal Y chromosome
Occult Y chromosome mosaicism or rearrangement
Summary conclusions and recommendations for mosaicism involving a sex chromosome
Other types of mosaicism. Diploid/triploid mosaicism
Diploid/tetraploid mosaicism
Guidelines for the diagnosis of mosaicism
Genetic counseling and chromosome mosaicism
Interpretation issues: chromosome rearrangements
Familial structural rearrangements
De novo structural rearrangements
Apparently balanced de novo rearrangements
Unbalanced de novo rearrangements (excluding supernumerary marker chromosomes)
De novo supernumerary chromosomes (including mosaic cases)
Uniparental disomy in familial and de novo rearrangements
Balanced Robertsonian translocations
Balanced non‐Robertsonian translocations and supernumerary chromosomes
Summary conclusions and recommendations for chromosome rearrangements
Interpretation issues: chromosome polymorphisms, common inversions, and other structural variations
Polymorphisms of chromosomes 1, 9, 16, and Y
Polymorphisms of acrocentric chromosomes
Polymorphism of other chromosomes, “common” inversions, and translocations
Summary conclusions and recommendations for polymorphisms and other variations
Interpretation issues: maternal cell contamination. Maternal cell contamination in chorionic villus sampling
Summary conclusions and recommendations for MCC in CVS
Maternal cell contamination in amniotic fluid cell culture
Summary conclusions and recommendations for MCC in AFC
Factors affecting diagnostic success rate and accuracy. Twin pregnancy
Mycoplasma contamination of cell cultures
Toxic syringes or tubes
Other causes of culture failure
Technical standards for prenatal cytogenetics laboratories
Error rates in prenatal cytogenetic diagnosis
Discordance between karyotyping and molecular genetic testing
Conclusion
Acknowledgments
References
12 Prenatal Diagnosis of Sex Chromosome Abnormalities
Incidence
Ascertainment bias
Patterns of inheritance
Prenatal diagnosis
Turner syndrome
Diagnosis and management
Cognitive/psychologic development
Karyotype variations
45,X
46,X,i(Xq)
46,X,del(Xq) or 46,X,Xq2
46,X,r(X)
45,X/46,XY
Other variants
Prenatal counseling for Turner syndrome
45,X mosaicism
45,X/46,XX
45,X/47,XXX
45,X/46,XX/47,XXX
45,X/46,XY and variants
Klinefelter syndrome
Clinical features and management
Cognitive/psychologic development
Prenatal counseling for 47,XXY
47,X,i(Xq),Y
47,XXY mosaicism
Other types of 47,XXY mosaicism
48,XXYY
48,XXXY
49,XXXXY
49,XXXYY
Triple X and poly‐X syndromes
Clinical features and medical management
Cognitive/psychologic development
Prenatal counseling for 47,XXX
47,XXX mosaicism. 46,XX/47,XXX
Other 47,XXX mosaicism
48,XXXX
49,XXXXX
47,XYY males
Historical perspective
Clinical features and medical management
Cognitive/psychologic development
Prenatal counseling for 47,XYY
46,XY/47,XYY mosaicism
Polysomy Y karyotypes
48,XYYY
49,XYYYY
49,XXYYY
Structural abnormalities of the X chromosome
Xp deletions: del(Xp) or Xp2
Xq deletions: del(Xq) or Xq2
Xp duplications: dup(Xp)
Xq duplications: dup(Xq)
Isochromosome Xp: i(Xp)
Isochromosome Xq: i(Xq)
Marker X
Inversion X: inv(X)
X;autosome translocations
Balanced X;autosome translocations
Unbalanced X;autosome translocations
X;X translocations
Structural abnormalities of the Y chromosome. Yp deletions: del(Yp)
Yq deletions: del(Yq)
Isochromosome Yp: i(Yp)
Isochromosome Yq: i(Yq)
Isodicentric Yp: idic(Yp)
Isodicentric Yq: idic(Yq)
Ring Y: r(Y)
Marker Y: mar(Y)
Inversion Y: inv(Y)
Satellited Yq: Yqs
Y;autosome translocations
X;Y translocations
Y;Y translocations
Disorders of sex development
46,XX males
45,X males
47,XXX males
46,XY females
Androgen insensitivity syndrome or testicular feminizing syndrome
Swyer syndrome or complete gonadal dysgenesis
Mixed gonadal dysgenesis or 46,XY partial gonadal dysgenesis
5α‐Reductase deficiency
46,XY and “true hermaphroditism”
Other sex reversal syndromes
Ovotesticular disorders of sex development
Conclusion
References
13 Prenatal Diagnosis of Chromosomal Abnormalities: From Karyotype to Microarray
The study and impact of chromosome abnormalities in humans
Traditional cytogenetic testing: analysis of the G‐banded metaphase
Incidence and spectrum of chromosome abnormalities observed in prenatal diagnosis
Rapid identification of the common aneuploidies
Fluorescence in situ hybridization
Quantitative fluorescence polymerase chain reaction
Multiplex ligation‐dependent probe amplification
Chromosome microarray analysis adds diagnostic yield over karyotyping and rapid aneuploidy techniques
Types of microarrays
Array comparative hybridization
Single‐nucleotide polymorphisms arrays
Microarray design for clinical testing
Interpreting and reporting of CMA results
Cytogenomic tools and tips for interpreting CNVs
Factors affecting CMA diagnostic yield
Number of probes on the array and CNV size cutoff
Impact on variants of uncertain significance
The benefit of SNPs
CMA in routine pregnancies
CMA in pregnancies with ultrasound anomalies
CMA versus karyotyping: additional points to consider
CMA and genetic counseling
Conclusion
References
14 Molecular Genetics and Prenatal Diagnosis
Diagnostic methods: use, limitations, and pitfalls. Source of DNA for analysis
Methods of analysis
Box 14.1 Selected databases and in silico tools commonly used in molecular genetics. Clinical databases
In silico tools
Carrier detection
Presymptomatic/predictive DNA tests
Mutation detection
Clinical caveats, cautions, limitations, and pitfalls. Dynamic mutations and anticipation
Mosaicism
Imprinting and uniparental disomy
Genotype–phenotype correlations
Additional cautions and considerations
Prenatal diagnosis of mitochondrial disorders
Reporting incidental (secondary) results
Ethical considerations in prenatal testing
References
15 Prenatal Diagnosis of Cystic Fibrosis
Genetics and epidemiology
Clinical features
Diagnosis
Treatment
Discovery of the cystic fibrosis gene
The CFTR gene and its protein product
CFTR mutations and variants
Genotype–phenotype correlation
Congenital bilateral absence of the vas deferens
Modifier genes
Ethnic variation in mutation frequencies
Development and implementation of public policy for CF population carrier screening and the core mutation panel
Laboratory methods
Expanded panels
Outcomes of the CF carrier screening program
Special prenatal diagnosis situations
Positive–negative couples
Positive family history
Echogenic bowel
Assisted reproduction and preimplantation diagnosis
Newborn screening
Future directions
References
16 Prenatal Diagnosis and the Spectrum of Involvement from Fragile X Mutations
Introduction
Epidemiology
Clinical involvement in those with the full mutation
Clinical phenotype in the premutation
Pathogenesis of the premutation‐associated disorder FXTAS
Neuropathology
Molecular pathogenesis
Molecular prenatal diagnosis methodology
Preimplantation genetic testing and polar body analysis
Neurobiologic advances and targeted treatment in the full mutation
Genetic counseling
Acknowledgments
References
17 Prenatal Diagnosis of Fetal Malformations by Ultrasound
Introduction
Craniospinal defects
Neural tube defects
Acrania–exencephaly–anencephaly sequence
Open spina bifida
Encephalocele
Ventriculomegaly – hydrocephaly
Hydranencephaly
Holoprosencephaly
Microcephaly
Corpus callosum agenesis
Posterior fossa malformations
Mega cisterna magna
Blake's pouch cyst
Vermian hypoplasia
Dandy–Walker malformation
Fetal face
Cleft lip and/or palate
Micrognathia and retrognathia
Pulmonary and thoracic abnormalities. Congenital pulmonary airway malformation
Congenital diaphragmatic hernia
Pleural effusions
Congenital high airway obstruction syndrome
Fetal hydrops (immune and nonimmune)
Cardiovascular defects
Cardiac anomalies
Ventricular septal defect
Atrioventricular septal defect
Transposition of the great arteries
Tetralogy of Fallot
Abdominal wall defects
Omphalocele (exomphalos)
First trimester
Gastroschisis
First trimester
Second and third trimester
Body stalk anomaly
Bladder exstrophy and cloacal exstrophy
Gastrointestinal anomalies
Esophageal atresia
Duodenal atresia
Second and third trimester
Small bowel obstruction
Meconium peritonitis
Abdominal cysts
Kidneys and urinary tract anomalies
Renal development and CAKUT
Dilatation of the renal pelvis. Antenatal hydronephrosis
Uteropelvic junction obstruction
Obstructive uropathy
Structural kidney malformations. Dysplastic kidneys. Multicystic dysplastic kidneys
Polycystic kidney disease
Nephronophthisis (former Potter 3 renal dysplasia)
Renal agenesis. Unilateral renal agenesis
Bilateral renal agenesis
Abnormalities of pelvic migration
Pelvic kidney
Horseshoe kidney
Skeletal anomalies
Nuchal translucency
Phenotypic expression in chromosome anomalies
Trisomy 21 – Down syndrome
Trisomy 18 – Edwards syndrome
Trisomy 13 – Patau syndrome
Triploidy
Turner syndrome
References
18 Prenatal Diagnosis and Management of Abnormal Fetal Development in the Third Trimester of Pregnancy
Cardiac anomalies
Value of the four‐chamber view in screening for congenital heart disease
Abnormalities in four‐chamber view screening
Abnormal heart rate
Abnormal cardiac size
Anomaly of the position of the heart
Anomaly of the axis of the heart
Septal defects of the heart
Abnormalities of the atrioventricular valves
Anomalies of ventricular morphology
Vessels behind the heart
Hypoplastic left heart
Functional assessment of the fetal heart
Cardiac function and hypoplastic left heart
Echogenic lung lesions. Bronchopulmonary sequestration
Congenital cystic adenomatoid malformation
Congenital high airway obstruction sequence
Hydrothorax
Congenital diaphragmatic hernia
Anomalies of gastrointestinal tract and abdominal wall
Gastrointestinal obstruction
Esophageal atresia
Ultrasound diagnosis
Obstetric management, postnatal therapies, and outcome
Duodenal atresia
Ultrasound diagnosis
Obstetric management, postnatal therapies, and outcome
Abdominal wall defects
Omphalocele
Ultrasound diagnosis
Obstetric management, postnatal therapies, and outcome
Gastroschisis
Ultrasound diagnosis
Obstetric management, postnatal therapies, and outcome
Urinary tract anomalies. Incidence and etiology
Diagnosis
Fetal treatment
Prognosis
Central nervous system malformations
Fetal ventriculomegaly
Spina bifida
Absence of cavum septum pellucidum and abnormalities in the midline
Holoprosencephaly
Agenesis of the corpus callosum
Schizencephaly
Absent cavum septum pellucidum
Abnormalities of the posterior cranial fossa and cerebellar anomalies
Parental counseling after diagnosis of fetal brain abnormalities
References
19 Prenatal Diagnosis by Fetal Magnetic Resonance Imaging
Introduction
MRI of the fetal central nervous system
Technical issues
Fetal brain MRI: when and why?
Developing brain
Developmental abnormalities
CNS malformations
Ventriculomegaly and genetic disorders
Inborn errors of metabolism
Subependymal cysts
Brain injury
MRI of non‐CNS fetal systems
Technical issues
Fetal neck
Fetal chest
Congenital diaphragmatic hernia
Bronchopulmonary airway malformations
Lung hypoplasia
Fetal heart and mediastinum
Fetal abdomen and pelvis
Liver and biliary pathologies
Abdominal or pelvic masses
Bowel obstructions, anorectal malformations
Urinary tract pathologies, kidney diseases, and genital malformations
Skeletal malformations
Conclusion
References
20 Prenatal Diagnosis of Skeletal Dysplasias and Connective Tissue Disorders
Prenatal sonographic diagnosis of skeletal dysplasias
Abnormal fetal morphology as an unexpected finding
Molecular testing during pregnancy
Estimating the probability of recurrence
Achondroplasia, thanatophoric dysplasia, and hypochondroplasia (FGFR3 disorders)
Prenatal diagnosis
Osteogenesis imperfecta
Prenatal diagnosis
Disorders due to defects in type II collagen (achondrogenesis type 2, hypochondrogenesis, and spondyloepiphyseal dysplasia congenita)
Prenatal diagnosis
Disorders due to defects in the diastrophic dysplasia sulfate transporter gene (achondrogenesis 1B, atelosteogenesis type 2, and diastrophic dysplasia)
Prenatal diagnosis
Joint dislocations: Larsen syndrome and connective tissue disorders
Prenatal diagnosis
Marfan syndrome and Marfan overlap disorders
Pregnancy‐related aspects and prenatal diagnosis
Acknowledgments
References
21 Prenatal Diagnosis of Disorders of Carbohydrate Metabolism
Introduction
Glycogen storage diseases
Type I GSD (glucose‐6‐phosphatase and glucose‐6‐phosphate translocase deficiency, von Gierke disease)
Type II GSD (acid α‐glucosidase deficiency, Pompe disease)
Type III GSD (debrancher deficiency, limit dextrinosis, Cori or Forbes disease)
Type IV GSD (branching enzyme deficiency, amylopectinosis, or Andersen disease)
Type V GSD (muscle phosphorylase deficiency, McArdle disease, myophosphorylase deficiency)
Type VI GSD (liver phosphorylase, Hers disease)
Type VII GSD (phosphofructokinase deficiency, Tarui disease)
Type IX GSD (phosphorylase b kinase deficiency)
Glycogen synthase deficiency
Hepatic glycogenosis with renal Fanconi–Bickel syndrome
Disorders of galactose metabolism
Galactosemia with transferase deficiency
Galactokinase deficiency
Uridine diphosphate galactose‐4‐epimerase (UDPgal‐4‐epimerase) deficiency
Disorders of fructose metabolism. Essential fructosuria
Hereditary fructose intolerance (fructose‐1‐phosphate aldolase B deficiency)
Disorders of gluconeogenesis. Fructose‐1,6‐bisphosphatase deficiency
Phosphoenolpyruvate carboxykinase deficiency
Pentosuria
Acknowledgments
References
22 Disorders of Metabolism of Amino Acids and Related Compounds
Introduction
Inborn errors of metabolism
Amino acid disorders
Methods of prenatal screening of amino acid disorders
Enzyme assay in fetal cells
Amniotic fluid analysis
DNA analysis
The placenta as a filter
Maternal nutrition and amino acid disorders: potential impact on the fetus
Intoxication disorders
Urea cycle disorders
Carbamoyl phosphate synthetase I deficiency
Risk to pregnant mother with CPS1 deficiency
Risk to fetus with CPS1 deficiency
Prenatal diagnosis
N‐Acetylglutamate synthase deficiency
Risk to pregnant mother with NAGS deficiency
Risk to fetus with NAGS deficiency
Prenatal diagnosis
Ornithine transcarbamylase deficiency
Risk to pregnant mother with OTC deficiency
Risk to fetus with OTC deficiency
Prenatal diagnosis
Argininosuccinate synthetase deficiency (or citrullinemia type 1)
Risk to pregnant mother with argininosuccinate synthetase deficiency
Risk to fetus with argininosuccinate synthetase deficiency
Prenatal diagnosis
Argininosuccinate lyase deficiency (or argininosuccinic aciduria)
Risk to pregnant mother with argininosuccinate lyase deficiency
Risk to fetus with argininosuccinate lyase deficiency
Prenatal diagnosis
Arginase deficiency (hyperargininemia)
Risk to pregnant mother with arginase deficiency
Risk to fetus with arginase deficiency
Prenatal diagnosis
Other disorders presenting with hyperammonemia or involving urea cycle intermediates. Citrin deficiency (citrullinemia type 2)
Risk to pregnant mother with citrin deficiency
Risk to fetus with citrin deficiency
Prenatal diagnosis
Disorders of ornithine metabolism. Hyperornithinemia, hyperammonemia, and homocitrullinuria
Risk to pregnant mother with HHH syndrome
Risk to fetus with HHH syndrome
Prenatal diagnosis
Ornithine aminotransferase deficiency with gyrate atrophy of the choroid and retina
Risk to pregnant mother with OAT deficiency
Risk to fetus with OAT deficiency
Prenatal diagnosis
Lysinuric protein intolerance
Risk to pregnant mother with LPI
Risk to fetus with LPI
Prenatal diagnosis
Sulfite oxidase deficiency
Risk to pregnant mother with sulfite oxidase deficiency
Risk to fetus with sulfite oxidase deficiency
Prenatal diagnosis
Nonketotic hyperglycinemia
Risk to pregnant mother with NKH
Risk to fetus with NKH
Prenatal diagnosis
Mevalonic aciduria
Risk to pregnant mother with mevalonic aciduria
Risk to fetus with mevalonic aciduria
Prenatal diagnosis
4‐Hydroxybutyric aciduria (succinic semialdehyde dehydrogenase deficiency)
Risk to pregnant mother with SSADH deficiency
Risk to fetus with maternal SSADH deficiency
Prenatal diagnosis
Disorders of organic acids
Propionic acidemia (propionyl‐CoA carboxylase deficiency)
Risk to pregnant mother with propionic acidemia
Risk to fetus with maternal propionic acidemia
Prenatal diagnosis
Methylmalonic acidemia (methylmalonyl‐CoA mutase deficiency)
Risk to pregnant mother with MMA
Risk to fetus with maternal MMA
Prenatal diagnosis
Isovaleric acidemia
Risk to pregnant mother with IVA
Risk to fetus with maternal IVA
Prenatal diagnosis
Other disorders of catabolism of branched‐chain amino acids
Maple syrup urine disease (branched‐chain ketoaciduria, leucinosis)
Risk to pregnant mother with MSUD
Risk to fetus with maternal MSUD
Prenatal diagnosis
β‐Ketothiolase deficiencies (ketolytic disorders) (disorders of ketone production)
Risk to pregnant mother with β‐ketothiolase deficiency
Risk to fetus with maternal β‐ketothiolase deficiency
Prenatal diagnosis
3‐Hydroxyisobutyric aciduria (a disorder of valine metabolism)
Risk to pregnant mother with 3‐hydroxyisobutyric aciduria
Risk to fetus with maternal 3‐hydroxyisobutyric aciduria
Prenatal diagnosis
Isolated 2‐methylbutyryl‐CoA dehydrogenase deficiency (a disorder of isoleucine metabolism)
Risk to pregnant mother with 2‐methylbutyryl‐CoA dehydrogenase deficiency
Risk to fetus with maternal 2‐methylbutyryl‐CoA dehydrogenase deficiency
Prenatal diagnosis
Biotin‐resistant 3‐methylcrotonylglycinuria (a disorder of leucine metabolism)
Risk to pregnant mother with biotin‐resistant 3‐methylcrotonylglycinuria
Risk to fetus with maternal biotin‐resistant 3‐methylcrotonylglycinuria
Prenatal diagnosis
3‐Methylglutaconic aciduria (a disorder of leucine metabolism)
Risk to pregnant mother with 3‐MGA
Risk to fetus with maternal 3‐MGA
Prenatal diagnosis
3‐Hydroxy‐3‐methylglutaryl‐CoA lyase deficiency (a disorder of leucine metabolism)
Risk to pregnant mother with HMG‐CoA lyase deficiency
Risk to fetus with maternal HMG‐CoA lyase deficiency
Prenatal diagnosis
Glutaric acidemia type I (a disorder of lysine metabolism)
Risk to pregnant mother with glutaric acidemia type I
Risk to fetus with maternal glutaric acidemia type I
Prenatal diagnosis
Phenylketonuria
Maternal phenylketonuria
Risk to pregnant mother with PKU
Risk to fetus with maternal PKU
Prenatal diagnosis
Hyperphenylalaninemia due to tetrahydrobiopterin deficiency
Risk to pregnant mother with tetrahydrobiopterin deficiency
Risk to fetus with maternal tetrahydrobiopterin deficiency
Prenatal diagnosis
Hereditary tyrosinemia type I (hepatorenal type)
Risk to pregnant mother with tyrosinemia type I
Risk to fetus with maternal tyrosinemia type I
Prenatal diagnosis
Other types of tyrosinemia
Risk to pregnant mother with tyrosinemia type II
Risk to fetus with maternal tyrosinemia type II
Prenatal diagnosis
Disorders of sulfur amino acid metabolism
Homocystinuria due to cystathionine β‐synthase deficiency
Risk to pregnant mother with CBS deficiency
Risk to fetus with maternal CBS deficiency
Prenatal diagnosis
Disorders of energy production. L‐2‐Hydroxyglutaric aciduria
Risk to pregnant mother with L‐2‐HGA
Risk to fetus with maternal L‐2‐HGA
Prenatal diagnosis
D‐2‐Hydroxyglutaric aciduria
Risk to pregnant mother with D‐2‐HGA
Risk to fetus with maternal D‐2‐HGA
Prenatal diagnosis
Glutaric aciduria type II (multiple acyl‐CoA dehydrogenase disorder)
Risk to pregnant mother with MADD
Risk to fetus with maternal MADD
Prenatal diagnosis
Very rare amino acid disorders. Hypervalinemia (a disorder of valine metabolism)
Hypermethioninemia due to methionine adenosyltransferase deficiency
Combined D-2‐ and L‐2‐hydroxyglutaric aciduria
Methylenetetrahydrofolate reductase deficiency
Risk to pregnant mother with MTHFR deficiency
Risk to fetus with maternal MTHFR deficiency
Prenatal diagnosis
Prolidase deficiency
Risk to pregnant mother with prolidase deficiency
Risk to fetus with maternal prolidase deficiency
Prenatal diagnosis
Disorders of proline metabolism
Risk to pregnant mother with hyperprolinemia I/II
Risk to fetus with maternal hyperprolinemia I/II
Prenatal diagnosis
Disorders of renal amino acid transport
Risk to pregnant mother with renal transport disorders
Risk to fetus with maternal renal transport disorders
Prenatal diagnosis
In conclusion
References
23 The Mucopolysaccharidoses: Prenatal Diagnosis, Neonatal Screening and Emerging Therapies
Introduction
Disease and biochemical characteristics. Clinical and biochemical fundamentals
Structure and function of glycosaminoglycans
Prenatal diagnosis
Clinical characteristics and disease pathogenesis. Clinical heterogeneity
Genetic heterogeneity
Genotype–phenotype correlations
Mucopolysaccharidose disease pathogenesis
Pathophysiology of disease
Pathogenesis of MPS skeletal disease
Pathogenesis of MPS nervous system disease
Postnatal MPS therapeutics
Newborn screening
Fetal considerations
Future directions
References
24 Prenatal Diagnosis of the Peroxisomal and Mitochondrial Fatty Acid Oxidation Deficiencies
Introduction
Mitochondrial versus peroxisomal fatty acid beta‐oxidation
Mitochondrial fatty acid beta‐oxidation disorders
Primary carnitine deficiency (OCTN2 deficiency) (OMIM 212140)
Carnitine palmitoyl transferase‐1 A deficiency (OMIM 600528)
Carnitine–acylcarnitine translocase deficiency (OMIM 212138)
Carnitine palmitoyl transferase 2 deficiency (OMIM 600649, 600650, 255110, 608836)
Very long‐chain acyl‐CoA dehydrogenase deficiency (OMIM 201475)
Medium‐chain acyl‐CoA dehydrogenase deficiency (OMIM 201450)
Mitochondrial trifunctional protein deficiency (OMIM 600890)
Secondary disorders of mitochondrial fatty acid oxidation
Peroxisomal fatty acid beta‐oxidation disorders
Primary peroxisomal fatty acid oxidation disorders. X‐linked adrenoleukodystrophy (OMIM 300100)
Acyl‐CoA oxidase 1 deficiency (OMIM 264470)
Acyl‐CoA oxidase 2 deficiency (OMIM 601641)
D‐bifunctional protein deficiency (OMIM 261515)
Sterol carrier protein X deficiency (OMIM 613724)
2‐Methylacyl‐CoA racemase deficiency (OMIM 604489)
PMP70 deficiency (OMIM 170995) and ACBD5 deficiency (OMIM 616618)
Secondary disorders of peroxisomal fatty acid oxidation
References
25 Prenatal Diagnosis of Disorders of Lipid Metabolism
Introduction
Lipoprotein‐associated disorders
Defects in the metabolism of glycosphingolipids. Structure of glycosphingolipids
Function and distribution of glycosphingolipids
Biosynthesis of glycosphingolipids
Defects in the biosynthesis of glycosphingolipids
Laboratory diagnosis
Therapy
The lysosomal catabolism of glycosphingolipids
GM1‐gangliosidosis/mucopolysaccharidosis IVB (Morquio B)
Clinical
Genetics and genotype/phenotype
Laboratory diagnosis
Therapy
GM2‐gangliosidoses
Tay–Sachs disease: mutations in HEXA gene (α‐subunit) (OMIM: 272800)
B1 variant
Pseudodeficiency
Population screening for carriers
Prenatal diagnosis
Hexosaminidase S
Sandhoff disease: mutations in HEXB (β‐subunit) (GM2‐gangliosidosis 0 variant) (OMIM: 268800)
Variant AB
Therapy
Fabry disease
Clinical
Genetics and genotype/phenotype
Laboratory diagnosis
Therapy
Gaucher disease
Clinical
Genetics
Laboratory diagnosis
Therapy
Metachromatic leukodystrophy
Clinical
Genetics
Laboratory diagnosis
Therapy
Multiple sulfatase deficiency
Clinical
Genetics
Laboratory diagnosis
Therapy
Krabbe disease (globoid cell leukodystrophy)
Clinical
Genetics
Laboratory diagnosis
Therapy and newborn screening
Niemann–Pick disease
Niemann–Pick disease types A and B (acid sphingomyelinase deficiency)
Genetics
Laboratory diagnosis
Therapy
Niemann–Pick type C
Clinical
Genetics
Laboratory diagnosis
Therapy
Farber disease
Clinical
Molecular genetics and genotype/phenotype
Laboratory diagnosis
Therapy
Lysosomal acid lipase deficiency: Wolman disease and cholesteryl ester storage disease
Clinical
Genetics and genotype/phenotype
Laboratory diagnosis
Therapy
The neuronal ceroid lipofuscinoses
Acknowledgments
References
26 Prenatal Diagnosis of Primary Immunodeficiency Diseases
Family history
Specific immune defects
Lymphocyte deficiencies. T‐cell and combined deficiencies
Antibody deficiencies
Phagocyte deficiencies
Defects with autoimmunity or immune dysregulation
Complement deficiencies
Additional syndromic immune defects
References
27 Prenatal Diagnosis of the Hemoglobinopathies
Introduction
Clinical types
α‐Thalassemia
Hb Bart's hydrops fetalis syndrome
Hb H disease
β‐Thalassemia
β‐Thalassemia major
β‐Thalassemia intermedia
Hb E disorders
Hb E/β‐thalassemia
Hb AE Bart's disease
Hb EF Bart's disease
Hb E/E plus αCSα/αCSα
Sickle cell disorders
Sickle cell anemia
Hb S/β‐thalassemia
Hb S/δβ‐thalassemia
Hb S/Hb C
Hb S/Hb E
Hb S/Hb D‐Punjab
Hb S/Hb O‐Arab
Hb S/Hb C‐Harlem
Hb S/Hb S‐Southend
Hb S‐Antilles
Hb S‐Oman
Other sickling variants
Hb S/other rare β‐chain variants
Carrier screening
Reduced red cell indices with a raised Hb A2 value
Reduced red cell indices with a normal Hb A2 value
Strategy for fetal diagnosis
Approaches to prenatal diagnosis
Amniotic fluid DNA
Chorionic villus DNA
Noninvasive prenatal diagnosis
NIPD: fetal cells in maternal blood
NIPD: fetal DNA in maternal plasma
Preimplantation diagnosis
DNA diagnosis of the hemoglobinopathies
α‐Thalassemia
Gap‐polymerase chain reaction diagnosis
Multiplex ligation‐dependent probe amplification analysis
Other techniques
Polymerase chain reaction techniques for nondeletion mutations
β‐Thalassemia
Allele‐specific oligonucleotides
Primer‐specific amplification
Other methods for point mutations
Gap‐polymerase chain reaction and multiplex ligation‐dependent probe amplification for deletions
The δβ‐thalassemias, Hb Lepore, and hereditary persistence of fetal hemoglobin disorders
δβ‐Thalassemia
Hb Lepore
Hereditary persistence of fetal hemoglobin
Molecular diagnosis
Abnormal hemoglobins
Hb S
Hb C
Hb D‐Punjab and Hb O‐Arab
Hb E
Diagnostic pitfalls and best practice for fetal diagnosis
Maternal DNA contamination
Technical errors
Diagnostic error rate
Guidelines for best practice
Summary
References
28 Prenatal Diagnosis of Inherited Disorders of Folate and Cobalamin Metabolism
Inborn errors of folate metabolism
Hereditary malabsorption of folate
Cerebral folate deficiency
Glutamate formiminotransferase deficiency
Methylenetetrahydrofolate reductase deficiency
Dihydrofolate reductase deficiency
MTHFD1 deficiency
Methenyltetrahydrofolate synthetase deficiency
Inborn errors of cobalamin metabolism
Disorders of cobalamin uptake
Transcobalamin deficiency
Transcobalamin receptor deficiency
Disorders of cobalamin utilization
Isolated methylmalonic aciduria
Isolated methylcobalamin deficiency
Combined methylmalonic aciduria and homocystinuria
Prenatal diagnosis and fetal therapy
References
29 Fetal Surgery
Introduction
Brief history of fetal surgery
Ethical considerations
Imaging principles for fetal intervention and surgical procedures
Control of fetal pain
Closed fetal therapies
Conditions treated using fetoscopic procedures. Placental laser photocoagulation for twin‐to‐twin transfusion syndrome
Placental laser photocoagulation for twin anemia polycythemia sequence
Placental laser photocoagulation in monochorionic diamniotic twin pregnancies with selective fetal growth restriction
Congenital diaphragmatic hernia
Tracheal occlusion in human fetuses
Urinary tract obstruction
Fetal pleural effusion
Congenital cystic adenomatoid malformation
Other conditions treated with fetoscopic procedures. Amniotic band syndrome
Vasa previa
Chorioangioma
Selective termination in monochorionic gestation
Open fetal surgery technique and complications
Conditions treated with open fetal surgery. Myelomeningocele
Sacrococcygeal teratoma
Other potentially beneficial fetal interventions. Congenital heart defect interventions
Ex utero intrapartum treatment
Recent advances in fetal surgery. Complex fetoscopic surgery
References
30 In Utero Stem Cell Transplantation, Enzyme Replacement, and Gene Therapy
Introduction to in utero therapy
In utero hematopoietic stem cell transplantation. Background and preclinical studies
Preclinical studies in large‐animal models
Clinical studies
Hemoglobinopathies
Osteogenesis imperfecta
Future of in utero hematopoietic stem cell transplantation
In utero enzyme replacement therapy. Background
Preclinical studies
Clinical studies
Future of in utero enzyme replacement therapy
In utero gene therapy. Background
Treating prior to disease onset or progression
Immunologic advantages of fetal gene therapy
Treating neurologic disorders by in utero gene therapy
Greater vector‐to‐target ratio
Risks of in utero gene therapy
Off‐target effects of gene therapy
Germline transmission
Maternal effects of in utero gene therapy
Preclinical studies of in utero gene therapy. Hemophilia
Thalassemias
Neuronopathic Gaucher disease
Spinal muscular atrophy
Clinical studies of in utero gene therapy
Conclusions
References
31 Maternal Genetic Disorders That Affect Fetal Health
Introduction to inherited metabolic disorders
A genetic disorder with a teratogenic effect on the fetus: phenylketonuria
Genetic disorders precipitated by catabolic states including the late third trimester, intrapartum, and the puerperium: disabled protein breakdown. Urea cycle disorders. Ornithine transcarbamylase deficiency
Carbamoyl‐phosphate synthetase I deficiency
Hyperornithinemia–hyperammonemia–homocitrullinuria syndrome
Other disorders of amino acid metabolism. Maple syrup urine disease
Homocystinuria (cystathionine β‐synthetase deficiency)
Organic acid disorders of protein metabolism. Propionic acidemia
Methylmalonic acidemia
Disorders of energy metabolism aggravated by maternal–fetal anabolic states. Disorders of fatty acid and lipid metabolism. Mitochondrial β‐oxidation disorders/VLCAD, LCHAD, MCAD, and SCAD deficiencies
Carnitine deficiency
Biotin deficiency/multiple carboxylase deficiency
Sphingolipidoses
Fabry disease
Gaucher disease
Disorders of carbohydrate metabolism. Glycogen storage disorders
GSD type I or von Gierke disease
GSD type II or Pompe disease
GSD type III
Galactosemia
Disorders of metal metabolism. Wilson disease
Connective tissue disorders. Ehlers–Danlos syndrome
Marfan syndrome
Loeys–Dietz syndrome
Maternal skeletal dyplasias (chondrodystrophies)
Turner syndrome (monosomy X)
Cystic fibrosis
Neuromuscular disorders. Myotonic dystrophy
Duchenne/Becker muscular dystrophy
Hematologic disorders. Sickle cell disorders
β‐Thalassemia major
Fanconi anemia
Hereditary coagulopathies and inherited platelet disorders
References
32 Pregnancy Termination for Genetic Disorders: Indications and Complications
Introduction
First‐trimester pregnancy termination techniques
Suction aspiration
Technique
Choice of manual or electric aspiration
Morbidity
Complications
Mortality
Medical abortion
Second‐trimester techniques
Dilation and evacuation
Technique
Box 32.1 Ovum forceps used for second‐ trimester dilation and evacuation
Morbidity
Mortality
Systemic abortifacients
Morbidity and mortality
Intra‐amniotic abortifacients and hysterotomy/hysterectomy
Selective abortion/fetal reduction in multiple gestations
First‐trimester selective fetal reduction
Technique
Morbidity and mortality
Second‐trimester selective fetal reduction
Technique
Morbidity and mortality
Counseling patients about multifetal pregnancy selective reduction procedures
Conclusions
Acknowledgments
References
33 Providing Supportive Psychosocial Care to Parents after Perinatal Loss
Introduction
Perinatal Loss
Complex grief after perinatal loss
Highly intense grief and associated health issues
Termination of pregnancy for severe or lethal fetal anomaly
Needs of healthcare providers
Hutti Theoretical Framework of Perinatal Grief Intensity
Reality
Congruence
Confront others
Use of the Hutti Theoretical Framework in clinical practice
Perinatal Grief Intensity Scale
Communicating bad news to parents
Box 33.1 Communicating bad news to parents after perinatal loss: suggestions for healthcare providers
Interventions for high‐quality perinatal bereavement care
Box 33.2 Interventions for caring for parents after perinatal loss. Preparing parents for the experience of perinatal loss
Labor and birth
After hospital discharge
Subsequent pregnancy
Regoaling
Conclusion
References
34 Prenatal Diagnosis of Fetal Infection
Prenatal diagnosis of fetal toxoplasmosis
Parasitology
Epidemiology
Risk factors
Prenatal diagnosis. Indications
Prenatal diagnosis using polymerase chain reaction
In utero therapeutic options. Therapeutic tools
Indications for treatment when prenatal diagnosis is positive
Indications for treatment when prenatal diagnosis is negative
Efficiency of prenatal treatment
Management at birth
Prevention of fetal toxoplasmosis: education
Summary
Prenatal diagnosis of fetal cytomegalovirus infection
Virology
Epidemiology
Pathogenesis of congenital infection
Pathology
Congenital infection. Symptomatic infection
Asymptomatic infection
Clinical maternal manifestations
Serology
Management
Diagnosis of congenital CMV infection in the fetus
Ultrasonographic signs. CNS abnormalities
Non‐CNS abnormalities
Value of ultrasound
Usefulness of fetal brain MRI
Forming a prognosis for fetal CMV infection
Treatment of congenital CMV infection. The aims
The tools. Antiviral agents
Hyperimmune globulin
Vaccination
Prevention of CMV infection
Screening for congenital CMV infection
Prenatal diagnosis of congenital rubella
Risk of fetal infection
Definition of maternal infection
Prenatal diagnosis of fetal infection
Summary
Prenatal diagnosis of fetal varicella infection
Virologic bases
Epidemiology
Clinical aspects of maternal infection
Consequences for the pregnancy and the fetus
Pathogenesis of fetal VZV infection
Diagnosis of fetal VZV infection
Frequency of VZV transmission
Treatment and prevention of VZV
Summary
Prenatal diagnosis of human parvovirus B19 infection
Epidemiology, maternal infection, and vertical transmission of parvovirus B19
Prenatal diagnosis of parvovirus B19
Treatment of parvovirus B19
Prenatal diagnosis of Zika virus
Maternal infection with Zika virus
Infection of the fetus with the Zika virus
Prenatal counseling in the midst of the SARS‐CoV‐2 pandemic
Acknowledgments
References
35 Medicolegal Aspects of Prenatal Diagnosis
General concepts of medical malpractice
The constitutional right of privacy in reproductive decisions
The role of informed consent in medical treatment
Suits for wrongful birth and wrongful life
Wrongful pregnancy – the parents' claim, usually after having a healthy, but unwanted child
Wrongful birth – the parents' claim after having a child with a genetic disorder or congenital anomaly
Wrongful life – the child's claim
Wrongful life claims against the parents
The impact of concerns about abortion on wrongful birth and wrongful life claims
Future trends
Summary of alleged negligent acts and outcomes in wrongful birth and wrongful life suits
Statutes addressing claims for wrongful birth and wrongful life as well as abortion in the case of fetal anomaly
References
36 Prenatal and Preimplantation Diagnosis: International Policy Perspectives
Introduction
Prenatal diagnosis
Legal approaches
Professional guidelines
Preimplantation genetic diagnosis
Legal approach. Countries permitting PGT
Countries that once prohibited PGT
Professional guidelines
“Hybrid” regulatory approach
Sex selection in prenatal diagnosis and preimplantation genetic diagnosis
Emerging technologies, new issues?
References
37 Ethical Issues in the Diagnosis and Management of Genetic Disorders in the Fetus
Professional ethics in obstetrics
The ethical principle of beneficence
The ethical principle of respect for autonomy
The ethical concept of the fetus as a patient
The viable fetus as a patient
The previable fetus as a patient
Clinical applications of professional ethics in obstetrics. Prenatal genetic counseling
Counseling regarding the viable fetus
Counseling regarding the previable fetus
Diagnosis of genetic disorders in the fetus. Competence and referral in prenatal diagnosis
Disclosure of results of prenatal diagnosis
Confidentiality of findings
Routine offering of risk assessment and invasive genetic diagnosis
Step one: the woman's response to a nondirective offer of risk assessment and invasive diagnosis
Step two: the woman's response to the results of risk assessment
Preimplantation diagnosis and the “savior sibling”
Management of pregnancies complicated by genetic disorders. Termination of pregnancy before viability
Selective termination
First indication: achieving a pregnancy that results in livebirth of infant(s) with minimal neonatal morbidity and mortality
Second indication: achieving a pregnancy that results in livebirth of infant(s) without prenatally detected anomalies
Third indication: achieving a pregnancy that results in a singleton livebirth
Termination of pregnancy after viability
Termination of pregnancy
Nonaggressive management
Cephalocentesis
Ethical issues in clinical innovation and research. Genomic alteration research
Maternal–fetal medical and surgical intervention for fetal benefit innovation and research
Human embryonic stem cell research
Conclusion
References
Index
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Dedicated to
Laura and Francia
.....
Laurence B. McCullough, phd
Department of Obstetrics and Gynecology
.....