10.1 Birth defects, prenatal diagnosis and teratogens
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 and cleft lip. 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 post-neonatal mortality in developed countries.
• are the leading cause of perinatal death (20–25% of deaths)
• are now the leading cause of post-neonatal 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
Types of structural birth defect
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 post-conception). 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, and vasoconstriction defects caused by cocaine.
• 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
Birth defects can be caused by a wide variety of mechanisms including:
• genetic abnormalities, both monogenic and polygenic
• chance events within the developing embryo (e.g. vascular accidents)
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.
Table 10.1.1 Causes of birth defects
| Mechanism | Example | Cause |
|---|---|---|
| Whole chromosome missing or duplicated | Down syndrome | Trisomy 21 |
| Turner syndrome | Monosomy X (XO) | |
| Part of chromosome deleted or duplicated | Cri du chat syndrome | Deletion 5p |
| Cat eye syndrome | Duplication 22q | |
| Sub-microscopic deletion or duplication of chromosome material | Williams syndrome | Deletion 7q |
| Velocardiofacial syndrome | Deletion 22q | |
| Charcot–Marie–Tooth disease 1A | Duplication 17p | |
| Mutation in single gene | Smith–Lemli–Opitz syndrome | 7-Dehydrocholesterol reductase |
| Holt–Oram syndrome | TBX5 | |
| Apert–Crouzon–Pfeiffer syndrome | Fibroblast growth factor receptor 2 | |
| Consequence of normal imprinting | Prader–Willi syndrome | Maternal uniparental disomy or paternal deletion for 15q12 |
| Imprinting errors | Beckwith–Wiedemann syndrome | Multiple mechanisms resulting in overexpression of IGF-2 |
| Angelman syndrome | Mutations in UBE3A gene | |
| Multifactorial/polygenic: one or more genes and environmental factors | Isolated heart malformations, neural tube defects and facial clefts | Complex interactions between genes and environment |
| Non-genetic vascular and other ‘accidents during development’ | Poland anomaly | Subclavian artery ischaemia |
| Oculoauriculovertebral dysplasia | Stapedial artery ischaemia | |
| Uterine environment | Talipes, hip dysplasia, | Oligohydramnios, twins |
| Plagiocephaly | Bicornuate uterus | |
| Maternal environment | Mental retardation | Maternal phenylketonuria |
| Caudal regression | Maternal diabetes mellitus | |
| Wider environment | Fetal rubella syndrome | Rubella infection in pregnancy |
| Fetal alcohol syndrome | Maternal alcohol ingestion | |
| Microcephaly | High-dose X-irradiation | |
| Limb deficiency | Thalidomide |
IGF-2, insulin-like growth factor 2; TBX5, T-box transcription factor 5.
Genes
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:
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.
An example of these genes is the homeotic (HOX) gene family. HOX genes are involved in the formation of structures developing from specific segments of the embryo.
Frequency
• are those with medical and social consequences
• are present with the highest prevalence among miscarriages, intermediate in stillbirths and lowest among live-born infants
The birth prevalences of the more common birth defects are shown in Table 10.1.2. 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 of the heart and urinary tract, will be recognized by 5 years of age during clinical examinations or because of symptoms.
Table 10.1.2 Prevalence of some common birth defects
| Defect | Rate per 1000 births* |
|---|---|
| Malformations of heart and great vessels | 12.0 |
| Developmental hip dysplasia | 6.9 |
| Hypospadias | 3.7 |
| Talipes equinovarus | 2.2 |
| Hypertrophic pyloric stenosis | 1.9 |
| Down syndrome | 1.8 |
| Cleft lip with or without cleft palate | 1.1 |
| Spina bifida | 0.9 |
| Anencephaly | 0.7 |
| Renal agenesis and dysgenesis | 0.6 |
| Tracheo-oesophageal fistula, oesophageal atresia and stenosis | 0.4 |
| Abdominal wall defects: exomphalos and gastroschisis | 0.6 |
* Rate per 1000 births including terminations of pregnancy, stillbirths and live-births.
Source: South Australian Birth Defects Register 1986–2003.
• are relatively frequent, but pose no significant health or social burden
• are recognized in approximately 15% of newborns
• are important to recognize, because 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.
Birth defects
• Birth defects are the leading cause of perinatal and post-neonatal 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 live-borns, and minor birth defects affect 15%.
• Preventative 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
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 (Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity) 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.
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 mid-trimester ultrasound. 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 chest X-ray.
The family was 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 array was arranged, which confirmed the diagnosis.
Some 90% of children with this condition are the first person in their family to be affected. However, 10% have inherited the condition from an undiagnosed, mildly affected parent. The recurrence risk for further pregnancies differs significantly between these two situations. 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, 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 ultrasonography, immune function tests, serum calcium levels, thyroid function tests, eye and hearing reviews, and spine X-rays and cardiology review for Craig. 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 was discussed with the couple, including sperm donation, prenatal diagnosis and pre-implantation 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 chorionic villus sampling (CVS) with testing 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:
• early warning of new environmental teratogens
• identifying precise prevalence figures for individual birth defects and syndromes
• identifying geographical and temporal trends in birth defects
• assessment of the impact of population-based prevention strategies and prenatal diagnosis
• collecting data for research into the epidemiology of birth defects.
Prevention
Despite considerable research efforts there are very few preventative 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:
• 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 that 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:
• the option of 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.
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