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The Heart

Key Points Current evidence suggests that prenatal diagnosis of congenital heart disease (CHD) reduces morbidity and mortality, gives expectant parents time to prepare and allows planning for delivery in a tertiary care centre. About 85% of babies born with CHD are born to mothers that are ‘low risk’, suggesting that screening of the entire pregnant population is essential to optimise detection. A comprehensive fetal heart examination…

Sonography of the Fetal Central Nervous System

Key Points Prenatal ultrasound of the fetal brain in the second and third trimester is described, from basics to advanced neurosonography. Classification of central nervous system anomalies is discussed. The neurodevelopment stage determines some of the pathological conditions; others are related to external factors interfering with normal brain development. The diagnosis of neural tube defects deserves attention in the light of potential fetal surgery. Analysis of…

Prenatal Screening for Thalassemias

Key Points Homozygous α 0 -thalassemia and β-thalassemia major are global autosomal disorders. Different α- and β-thalassemia genotypes may be associated with variable phenotypes. Universal screening is preferred for high-prevalence areas and countries with migrants from high-prevalence areas. Screening by mean corpuscular volume or mean corpuscular haemoglobin with or without haemoglobin (Hb) pattern is feasible. Workup for screen-positive couples includes Hb and molecular studies. Molecular diagnosis…

Expanded Carrier Screening

Key Points This chapter describes the novel concept of expanded carrier screening (ECS), whereby individuals are simultaneously screened for up to 200 genetic conditions. Different laboratory techniques are used in ECS and include targeted genotyping and next-generation sequencing approaches. The choice of conditions to be included in ECS varies among laboratories, and no consensus presently exists. Various screening strategies exist, including premarital carrier screening, cascade screening,…

Advances in Molecular Genetics Including Fetal Sequencing

Key Points Fetal malformations can be caused by chromosomal defects detectable by fetal karyotype and chromosomal microarray analysis, by sequence variants (mutations) in single genes or can be multifactorial in origin. Single-gene disorders can be inherited from parents (autosomal recessive, autosomal dominant or X-linked) with substantial recurrence risk or can be caused by de novo mutations in the fetus with an extremely low recurrence risk. When…

Prenatal Diagnosis of Chromosome Abnormalities

Key Points Chorionic villi, amniotic fluid and fetal blood are the specimen types currently used for prenatal diagnostic testing for chromosome abnormalities. The spectrum of chromosomal alterations seen during prenatal testing include autosomal or sex chromosome aneuploidy, balanced or unbalanced structural rearrangements, triploidy, supernumerary marker chromosomes, submicroscopic deletions and duplications, mosaicism and uniparental disomy. Methods for detecting chromosomal abnormalities in prenatal specimens include karyotype of G-banded…

Invasive Diagnostic Procedures

Key Points Amniocentesis is used from 15 weeks of gestation onwards for prenatal diagnosis of chromosomal abnormalities, single-gene disorders, fetal lung maturity, fetal infections and inflammation. Chorionic villus sampling (CVS) is used from 10 weeks of gestation onwards for prenatal diagnosis of single-gene defects and chromosomal abnormalities. Early amniocentesis (<15 weeks) and early CVS (<10 weeks) have been proscribed because of increased risk for fetal loss…

Noninvasive Prenatal Diagnosis for Single-Gene Disorders

Key Points Noninvasive prenatal diagnosis (NIPD) based on analysis of cell-free DNA in maternal plasma for fetal sex determination is now an established clinical service in many countries. NIPD for a small number of single-gene disorders, including achondroplasia, thanatophoric dysplasia, Apert and Crouzon syndromes, congenital adrenal hyperplasia and cystic fibrosis, is now offered in accredited clinical practice in the United Kingdom. NIPD for monogenic disorders offers…

Noninvasive Screening for Cytogenetic Disorders (Fetal Aneuploidy Including Microdeletions)

Key Points The origins of intact fetal circulating trophoblast cells and nucleated red blood cells in maternal plasma are reviewed, and their pitfalls and promises for noninvasive prenatal testing are discussed. The discovery of cell-free fetal DNA (cffDNA) in maternal circulation and how it has allowed the development of an excellent noninvasive screening test for common aneuploidies and sex chromosomal abnormalities in both the high-risk and…

Evidence for Routine Ultrasound Screening for Fetal Abnormalities in the Second and Third Trimesters

Key Points The main objective of routine midtrimester ultrasonography (US) is to provide accurate diagnostic information for the delivery of optimised antenatal care, including delivery planning. Routine early US is beneficial because of better estimates of gestational age. Routine US examination leads to earlier detection of clinically unsuspected fetal malformations and earlier detection of multiple pregnancies. Individuals who routinely perform obstetrics scans should have specialised training…

Ultrasound Screening for Fetal Abnormalities in the First Trimester

Key Points Early diagnosis of structural anomalies is increasingly possible. About half of the congenital anomalies can be diagnosed in the late first trimester. Severe and often lethal anomalies can be diagnosed, allowing parents the options of continuing with the pregnancy or, if acceptable, termination of pregnancy. Women appreciate the opportunity of early reassurance or early diagnosis, making this scan an essential first step in screening…

Ultrasound and Biochemical Screening for Fetal Aneuploidy

Key Points First trimester screening for Down syndrome (DS) with a combination of ultrasound, nuchal translucency and two maternal serum markers (combined test) has a much better performance than second trimester screening with four serum markers (quad test). Combined test performance can be improved by the addition of serum markers such as placental growth factor (PlGF) and ultrasound markers such as nasal bone determination. Quad test…

Conveying Information About Screening and Diagnosis

Key Points Good practice in information giving is essential as choosing to have a prenatal screening test can have far-reaching consequences. To be of good quality, information must be up to date and evidence-based. It should as a minimum include the purpose of the test; information about the tested-for condition(s), what the test procedure involves, any risks associated with the test, implications of the possible test…

Principles of Screening

Key Points Screening is the identification of unrecognised disease or defect found by testing an asymptomatic population. Prenatal screening detects conditions that are deleterious to the mother, fetus or both. Prenatal screening allows for diagnostic testing and subsequent pregnancy options, including termination of the pregnancy, preparation for the birth of a child with chronic or fatal illness or the use of advanced reproductive technology to avoid…

Epidemiologic and Research Methods in Fetal Medicine

Key Points The randomised controlled trial (RCT) is the least biased method of assessing the effectiveness of clinical interventions. It has been little used in fetal medicine, but reports are increasing. The details of good clinical trial methodology are now well established. It is critically important to avoid selection bias by ensuring allocation concealment at randomisation. Research synthesis allows the reader to review the totality of…

The Perinatal Postmortem Examination

Key Points Perinatal autopsy (examination after death) fulfils several roles, including determination or clarification of the underlying diagnosis, answering specific questions raised by parents and clinicians, quality assurance, governance and public health aspects, and improved understanding of disease mechanisms through research. Examination after death may involve a spectrum of investigations, including placental pathology, genetic testing, postmortem imaging and internal organ examination or sampling. Parents should be…

Development of the Kidneys and Urinary Tract in Relation to Renal Anomalies

Key Points Development of the kidneys (nephrogenesis) occurs between the 5th and 32nd weeks of human gestation when the ureteric bud interacts with metanephric mesenchyme, which undergoes mesenchymal–epithelial conversion to form glomeruli and tubules and renal stroma, with coordinated vascular development and signalling being critical. Nephron number is the major factor determining long-term kidney function. The development of the nephrons is finalised by the 32nd week;…

Lung Growth and Maturation

Key Points Survival at birth depends upon the lung attaining an adequate size and degree of structural maturity during fetal life. This chapter deals with mechanisms underlying normal and impaired lung growth and lung maturation before birth. The airways of the fetal lung contain a liquid that is actively secreted by the epithelium; this ‘lung liquid’ causes the lung to develop in an expanded state, which…

Development of the Heart and Cardiovascular System in Relation to Cardiac Abnormalities

Key Points The heart is largely derived from mesoderm. A single heart tube forms with venous and arterial connections. It elongates by addition of cells at either end from the surrounding mesenchyme. The tube folds to the right and lies in the pericardial cavity. The atria and ventricles form by ballooning from the tube; septation of the atria and ventricles is largely achieved by this method.…