Part 10
INHERITED AND METABOLIC PROBLEMS
10.1
Birth defects, prenatal diagnosis and teratogens
J. Liebelt, N. J. Hotham
Birth defects
A birth defect is any abnormality, structural or functional, identified at any age, that began before birth, or the cause of which was present before birth. Examples of structural birth defects include spina bifida, congenital heart malformations and cleft lip. Phenylketonuria, Duchenne muscular dystrophy and Huntington disease are examples of functional birth defects.
With continued advances in obstetric and paediatric medicine, birth defects have become the most important cause of perinatal and postneonatal mortality in developed countries.
Birth defects:
•are the leading cause of perinatal death (20–25% of deaths)
•are now the leading cause of postneonatal deaths (25–30%), as deaths due to sudden infant death syndrome continue to decline
•are responsible for a major proportion of the morbidity and disability experienced by children and young adults
•are the cause for 20–30% of the admissions to a tertiary paediatric hospital
•have an immense impact on the emotional and physical wellbeing of the children and their families
•have a significant financial cost for the community.
Types of structural birth defect
Structural birth defects may be classified on the basis of the mechanism by which they arise:
•Malformations arise during the initial formation of the embryo and fetus as a result of genetic and/or environmental factors during organogenesis (2–8 weeks postconception). Malformations may include failure of formation, incomplete formation or abnormal configuration. Examples include spina bifida, cleft palate and hypospadias
•Disruptions result from a destructive process that alters structures after formation. Examples include early amnion rupture causing amputation defects of digits, or an abdominal wall defect
•Deformations result from moulding of a part by mechanical forces, usually acting over a prolonged period. Examples include talipes, congenital hip dislocations and plagiocephaly associated with oligohydramnios.
Causes of birth defects
Birth defects can be caused by a wide variety of mechanisms. These range from genetic abnormalities, both monogenic and polygenic, through presumably accidental events within the developing embryo, e.g. vascular accidents, to environmental factors, including teratogens generated by the mother, e.g. maternal phenylketonuria and maternal diabetes, and those originating outside the fetomaternal unit, e.g. medications, infectious agents and high-dose X irradiation. Table 10.1.1 provides a framework for thinking about causes of birth defects. Most have a multifactorial basis, reflecting interaction between genes, environment and chance events within the developing embryo and fetus.
Genes and birth defects
Early human development from fertilized ovum to fetus involves numerous processes controlled by genes, expressed sequentially in a defined cascade. The processes and developmental phases include such things as definition of polarity, cell division, formation of the germ layers, segmentation of the embryo, cell migration, organ formation, cell differentiation, interactions between cells, tissues and organs and programmed cell death.
There has been a recent rapid increase in knowledge of the genes that determine or predispose to birth defects. This has resulted from technological advances in molecular genetics, in phenotype delineation, gene mapping and gene discovery in humans and other species, and an understanding of the cascade of sequential gene expression during embryonic development in other species.
Examples of these genes include the homeotic (HOX) and paired box (PAX) gene families. HOX genes are involved in the formation of structures developing from specific segments of the embryo and PAX genes have an important role in eye development. Birth defects caused by mutations in selected developmental genes are shown in Table 10.1.2.
Frequency of birth defects
Major birth defects
Major birth defects:
•are those with medical and social consequences
•are present with the highest prevalence among miscarriages, intermediate in stillbirths and lowest among liveborn infants
•are recognized at birth in 2–3% of liveborn infants.
The birth prevalences of the more common birth defects are shown in Table 10.1.3. They represent the frequency with which the defect occurred during development (its incidence), less the spontaneous loss of affected fetuses during pregnancy. An almost equal number of additional major abnormalities, particularly heart defects and urinary tract abnormalities, will be recognized by 5 years of age during clinical examinations or because of symptoms.
Minor birth defects
Minor birth defects:
•are relatively frequent but pose no significant health or social burden
•are recognized in approximately 15% of newborns
•are important to recognize, as their presence prompts a search for coexistent, more important abnormalities.
Infants free of minor defects have a low incidence of major malformations, approximately 1%. Those with one, two or three minor defects have risks of major malformations of 3%, 10% and 20%, respectively.
Practical points
Birth defects
•Birth defects are the leading cause of perinatal and postneonatal deaths, and result in substantial morbidity and disability in developed countries
•There is a wide variety of mechanisms including genetic, environmental and multifactorial
•Major birth defects affect 2–3% of liveborns, and minor birth defects affect 15%
•Preventive strategies remain limited, but include maternal folic acid supplementation, reduction in teratogen exposure, alternative reproductive options, prenatal detection and neonatal screening
Multiple birth defects
Various terms have been used to classify multiple birth defects in the hope that the terminology will convey information about aetiology, pathogenesis and the relationship between the birth defects. However, no system of naming meets all these criteria or is able to meet all the situations encountered in clinical practice. Some commonly used terms are syndrome, association, sequence and developmental field defect: these are defined in Chapter 10.3. Phenotype is a useful general term that makes no assumptions about aetiology or pathogenesis but registers the fact that multiple birth defects are present and are related in some way. Complex and spectrum are alternative terms that have been used in this context.
Diagnosis of birth defects
Hundreds of patterns of multiple birth defects have been defined and the diagnosis for a child with multiple birth defects is often not obvious.
The primary reasons for pursuing a diagnosis are that a specific diagnosis allows:
•discussion with the parents about the prognosis for their child
•parents to develop an understanding of how the birth defect arose
•counselling of the parents regarding recurrence risk and possibilities for reduction of this risk.
Thorough investigation, including autopsy if the child dies, may lead to a diagnosis, and referral to a clinical geneticist should be considered. Diagnosis is aided by computerized syndrome identification systems such as POSSUM and the London Dysmorphology Database. In spite of the large number of known syndromes, clinicians continue to encounter many children with birth defects the cause of which cannot be diagnosed or ascertained.
Birth defect/congenital malformation registers
Birth defects registers were established in many countries following the ‘thalidomide tragedy’ in which hundreds of children were born with a range of anomalies following maternal use of thalidomide in pregnancy as an antiemetic.
Clinical example
Susan and Craig’s first child Anna was diagnosed soon after birth with a significant congenital heart defect (tetralogy of Fallot) that required surgery. No concerns had been raised at the midtrimester ultrasound, which had been performed in the regional centre for the region in which they lived. Anna was also noted to have a number of minor birth defects, including unusually shaped ears, and a hemivertebra in the thoracic spine, seen on a chest X-ray.
The family were referred to a clinical geneticist for an opinion regarding the possibility of an underlying genetic condition to account for Anna’s health issues. The geneticist also noted that Anna had relatively long, slender fingers and that her mother reported frequent nasal regurgitation of milk during feeds, suggesting palatal dysfunction. This combination of issues raised the possibility of a condition called velocardiofacial syndrome, caused by a microdeletion on chromosome 22q. A chromosome analysis was arranged, including a specific fluorescent in situ hybridization (FISH) test for this microdeletion, which confirmed the diagnosis.
90% of children with this condition are the first person in their family to be affected. However, 10% have inherited the condition from a parent, who may be unaware they are affected, as the medical issues it has caused them have been mild. As the recurrence risk for further pregnancies differs significantly between these two situations, blood tests were arranged for Susan and Craig. Craig was found also to have the microdeletion on chromosome 22q and, when his medical history was taken, he reported having required serial plastering for talipes as an infant and that he had had recurrent ear infections as a child, had struggled academically at school and was now being treated for depression, all of which can be features of this condition.
Given the wide variability of potential medical issues associated with velocardiofacial syndrome, a number of screening tests were arranged for Anna and Craig to detect any previously unrecognized birth defects. This included renal ultrasounds, immune function tests, serum calcium levels, thyroid function tests, eye and hearing reviews, and spine X-rays and cardiology review for Craig. Anna was found to have only one normally functioning kidney. The potential long-term consequences of the condition were discussed with the family and they were put in touch with the local support group. Anna was referred to a general paediatrician for ongoing medical and developmental follow-up. It was discussed with the family that there would be a 50% chance that any further children they conceived would also inherit the condition, but that they might experience more or less severe medical issues.
A range of reproductive options were discussed with the couple, including sperm donation, prenatal diagnosis and preimplantation genetic diagnosis. Anna required multiple hospitalizations in the first few years of life related to her condition, which placed a great deal of stress on the family. Subsequently in the couple’s second pregnancy they chose to have a CVS with FISH for the microdeletion to assess whether the fetus had inherited velocardiofacial syndrome. The results showed that the fetus had not inherited the condition and a healthy boy was subsequently born.
Registers serve a number of purposes, including:
•provision of early warning of new environmental teratogens
•provision of precise prevalence figures for individual birth defects and syndromes
•monitoring of geographical and temporal trends in birth defects
•comparison of birth defect prevalence in different populations
•assessment of the impact of population-based prevention strategies and prenatal diagnosis
•research into the epidemiology of birth defects.
Prevention of birth defects
Despite considerable research efforts there are very few preventive strategies that effectively reduce the incidence of birth defects. Some effective population-based examples include:
•oral folic acid supplementation at least 1 month prior to and in the early months of pregnancy can reduce the incidence of neural tube defects by up to 70%
•education and legislation to reduce potential exposure to teratogens:
•
public health policy on rubella immunization
•
restrictions on prescribing of known teratogens such as thalidomide and retinoids
•
education about avoidance of foods in pregnancy that may predispose to maternal infection with known teratogenic agents, e.g. toxoplasmosis and uncooked meat
•genetic counselling and the development of alternative reproductive options, including donor gametes and embryos, to allow avoidance of the risk of conception of a child with a birth defect related to a specific genetic condition
•neonatal screening to detect children with those types of birth defect which do not cause permanent damage before birth, with a view to early treatment and improved prognosis. Neonatal screening for phenylketonuria, hypothyroidism and cystic fibrosis, and clinical examination for hip dislocation are examples of highly successful screening programmes.
At present, the primary approach to the prevention of the birth of children affected by birth defects is prenatal diagnosis.
Prenatal diagnosis
Prenatal diagnosis refers to testing performed in pregnancy aimed at the detection of birth defects in the fetus. Depending on the type of birth defect identified, the gestation of the pregnancy and the perceptions of the parents, prenatal detection of a birth defect may allow:
•termination of an affected fetus
•potential treatment in utero or postnatally to improve prognosis related to the defect
•preparation for the birth of a child with a specific medical condition.
The number of prenatal tests available and the range of birth defects that may be detected are expanding rapidly. Many chromosome abnormalities, structural anomalies, enzymatic and single gene defects are already potentially detectable prenatally. Advances in knowledge regarding the aetiology of birth defects and technical aspects of testing will expand this range further. Despite these advances, the majority of birth defects remain undetected until after birth.
In our society, it is an individual decision whether or not to utilize prenatal testing in a pregnancy. The provision of antenatal care must therefore ensure that parents are able to make informed decisions about testing and are supported throughout the testing process.
Types of prenatal test
Prenatal tests fall into two main categories:
•screening tests
•diagnostic tests.
These are discussed further below.
Screening tests
Prenatal screening tests:
•are aimed at all pregnant women
•assess whether an individual pregnancy is at increased or low risk of a particular birth defect
•generally pose no risk to maternal or fetal wellbeing
•are followed by an offer of a diagnostic test if an increased risk is identified
•are aimed primarily at the detection of structural anomalies and chromosomal abnormalities, in particular Down syndrome.
Screening tests in pregnancy are evolving rapidly, with the aim being earlier, more accurate and more accessible tests.
Screening tests available
Currently, screening tests are either performed on a serum sample from the mother, or utilizing ultrasound.
Maternal serum screening
•maternal serum screening (MSS) is primarily aimed at the detection of Down syndrome and, in some programmes, trisomy 18
•MSS involves measuring the levels of a number of different analytes produced by the fetus in a blood sample from the mother
•the analytes have been selected on the basis that large population studies have shown that the levels of the analytes in maternal serum differ significantly between pregnancies in which the fetus does or does not have Down syndrome
•MSS is most commonly offered in the second trimester (around 15–18 weeks) using various combinations of three or four analytes. These may include, estriol, alphafetoprotein (AFP), inhibin and the alpha and beta subunits of human chorionic gonadotrophin (hCG)
•a computer based algorithm, which takes into account the mother’s age-related risk, the gestation of the pregnancy and the analyte levels, is used to calculate a risk figure for Down syndrome in that pregnancy
•if the risk figure is greater than a predetermined ‘cutoff’ risk, the risk is considered to be increased and a diagnostic test is offered to clarify the situation
•most programmes are designed so that 5% of women having the test will receive an increased risk result. The majority of these women will go on to have healthy babies
•if all these women chose to have a diagnostic test, the screening programme would be expected to detect about 60–70% of cases of Down syndrome
•if AFP is one of the analytes used in second trimester MSS, then the test can also be used to screen for open neural tube defects, as AFP will be elevated if neural tissue is exposed to the amniotic fluid. If it is elevated, then the diagnostic test is a tertiary level ultrasound to examine the fetal spine
•first-trimester maternal serum screening programmes are being developed using inhibin and pregnancy-associated protein A (PAPP-A) as analytes
Ultrasound
Ultrasound uses sonar waves to allow real-time, two-dimensional visualization of the fetus in utero. The fetus can be examined in different views and fetal movements can be studied. Improved technology and training allow excellent views to be obtained to allow detection of many specific structural anomalies. Most antenatal care programmes now offer an ultrasound between 18 and 20 weeks gestation to screen for fetal anomalies.
Ultrasound is usually considered a screening rather than a diagnostic test as:
•some structural anomalies may not be readily detected, e.g. cleft palate
•interpretation of a possible anomaly and its impact on fetal development may be limited
•the detection rate of anomalies is dependent on the skill of the operator, equipment and fetal views obtained.
Potential advances that may enhance the value of fetal imaging as a screening test in pregnancy include three-dimensional ultrasound and alternative imaging techniques such as fetal magnetic resonance imaging (MRI).
Nuchal translucency screening
During the last decade, a new form of ultrasound-based screening for Down syndrome in the first trimester has been developed, based on the MSS model. This depends on the assessment of the nuchal (posterior neck) region of the fetus:
•All fetuses have a collection of fluid in the nuchal region that can be visualized as a translucent area and can be measured by ultrasound at the end of the first trimester (11–13 weeks gestation)
•Large population studies have shown that on average this nuchal translucency measurement is increased in pregnancies in which the fetus has Down syndrome
•As with MSS, a computer algorithm that takes into account the mother’s age-related risk, the gestation and the thickness of the nuchal translucency measurement is used to calculate a risk for that individual pregnancy
•If the risk is above a predetermined ‘cutoff risk’ a diagnostic test is offered