33
Prenatal diagnosis
The spectrum of congenital abnormality
Screening for fetal abnormalities
Introduction
The identification of some ‘congenital abnormalities’ in pregnancy transforms what was previously an exciting and joyous event into a worrying and distressing time. Accuracy of information giving, tact, understanding and reassurance (if appropriate) are paramount. The very greatest of care should be taken in explaining any aberrant findings to parents. The advice given to parents is of such importance that it will frequently be necessary to involve senior members of the obstetric team (usually with subspecialty training), as well as members of other specialties, particularly paediatricians, and clinical geneticists and radiologists.
The aims of prenatal diagnosis are four-fold:
the identification at an early gestation of congenital abnormalities incompatible with survival, or likely to result in significant handicap, in order to prepare parents, alert other specialist clinicians and offer the option of termination of pregnancy (TOP) (if appropriate)
the identification of conditions which may influence the timing, site or mode of delivery
the identification of fetuses who would benefit from early neonatal paediatric intervention
the identification of fetuses who may benefit from in-utero treatment (relatively rare).
Discussion and non-directional counselling are mandtory. It should not be assumed that all parents are going to request TOP, even in the presence of lethal abnormality. Many couples have opted to continue pregnancies in the face of severe defects which have resulted in either intrauterine or early neonatal death, and have expressed the view that they found it easier to cope with their grief having held their child. It is essential that palliative care is coordinated by a multidisciplinary team and organized by specialist teams. Other parents, after careful and informed consideration, make the difficult decision to opt for TOP. More controversial still are the problems of chronic disease processes associated with a high risk of long-term handicap and potential suffering for both the child and the parents. The parents themselves must decide what action they wish to take – it is they who will have to live with the decisions they make. It is our role to advise, guide and respect their final wishes, irrespective of our own personal views.
Non-directive counselling
When parents are found to have an ‘abnormal baby’ they often know little or nothing about the congenital anomaly, its impact on pregnancy outcome, the long-term prognosis and the options for care. Parents know even less about termination or about recurrence risks of the condition. Parents need accurate information, and it is the role of obstetricians and genetic counsellors to inform accurately and in language that is clear to understand. Often parents ask the doctor what he or she would do, but it remains important to encourage the couple towards their own decision. It is often appropriate to involve other professional groups (i.e. paediatricians) in the discussions either jointly or at separate consultations.
Non-directive counselling has to be truly non-directive. The sentence ‘the risk of handicap is 5%’ sounds worse than ‘the baby has a 95% chance of being normal’. Expressions like ‘high risk’ or ‘severe handicap’ imply a value judgement and should be avoided if possible. ‘Common’ may be interpreted as anything from 1% to 99%, depending on the context and the listener.
It is preferable to give information in writing, to reinforce discussions. Parents need time to take in information, and it is often important that they take time to reflect on information and to consider any decisions they may make carefully. It can be extremely useful to arrange a follow-up appointment a day or two after the initial appointment.
The spectrum of congenital abnormality
Although most congenital abnormalities are individually rare, together they cause an enormous burden of suffering. Approximately 5% of fetuses have congenital malformations and 2% of newborn babies have a serious abnormality detectable at, or soon after, birth. The main ones are listed in Box 33.1.
Box 33.1
Selected congenital abnormalities
Down syndrome (trisomy 21)
Edwards syndrome (trisomy 18)
Patau syndrome (trisomy 13)
Triploidy
Sex chromosome abnormalities
XO (Turner syndrome)
XXY (Klinefelter syndrome)
XYY
XXX
Apparently balanced rearrangements (translocations or inversions)
Unbalanced chromosomal structural abnormalities
Gene disorders (e.g. fragile X syndrome, Huntington’s chorea, Tay–Sachs disease)
Congenital heart disease
Neural tube defects (e.g. anencephaly, encephalocele, spina bifida)
Abdominal wall defects (e.g. exomphalos, gastroschisis)
Genitourinary abnormalities (e.g. renal dysplasia, polycystic kidney disease, pyelectasis, posterior urethral valves, Potter syndrome)
Lung disorders (e.g. pulmonary hypoplasia, diaphragmatic herniae, cystic fibrosis)
Toxoplasmosis
Rubella
Cytomegalovirus
Herpes simplex virus
Chickenpox
Erythrovirus
Hepatitis
Listeria monocytogenes
Syphilis
Beta-haemolytic streptococci – group B
Assessing the risk
In general, the risk for congenital abnormalities is very small, for most couples. The risk of autosomal trisomies, particularly trisomy 21 (Down syndrome) increases with increasing maternal age. In some instances, however, there may be a family history of an inherited condition, for example, Duchenne muscular dystrophy, cystic fibrosis, sickle cell disease or myotonic dystrophy. Consanguinity increases the risk of single gene anomalies, particularly in relation to autosomal recessive conditions. Structural abnormalities are also usually slightly more likely to occur in those with a family history and the risk is also higher for certain anomalies if the parents have had a previous child with an anomaly; for example, a woman who has had a child with spina bifida has an approximately 2% risk of a recurrence compared with the background risk of about 0.2%.
It is important to consider medical conditions when assessing prenatal risk of congenital anomalies. Women with pre-existing diabetes have an increased risk of cardiac and neural tube defects, and those with seizures are also at increased risk of fetal structural anomalies, particularly if taking potentially teratogenic anticonvulsants (e.g. congenital heart disease). The majority of structural and chromosomal problems, however, occur de novo, in those who have no predisposing history or recognized risk factors, and screening tests are offered to those at apparently low risk.
Screening for fetal abnormalities
The decision to screen for fetal abnormality rests with each individual couple. It is appropriate to offer testing to all couples: some wish no screening tests at all; others may be keen to consider all of the options (Table 33.1).
Table 33.1
Overview of potential screening programmes for chromosomal and structural abnormalities
| Programme | Advantages | Disadvantages |
| NT and serum at 11–14 weeks | Good detection of Down syndrome at early gestation (11–14 weeks) | Use of CVS may increase miscarriage rate Minimal detection of structural abnormalities |
| NT and serum at 11–14 weeks and FDS at 18 weeks | Good detection of Down syndrome at early gestation (11–14 weeks) Good detection of structural abnormalities |
Use of CVS may increase miscarriage rate |
| FDS at 18 weeks | Good detection of structural abnormalities | Minimal detection of Down syndrome |
| Serum screening alone at 16 weeks | Good detection of Down syndrome Amniocentesis may be safer than CVS Reasonable detection of open lesions, particularly neural tube defects |
Minimal detection of other structural abnormalities |
| Serum screening at 16 weeks with FDS at 18 weeks | Good detection of Down syndrome Amniocentesis may be safer than CVS Good detection of structural abnormalities |
Down syndrome not identified until relatively late (17–18 weeks) |
CVS, chorionic villus sampling; FDS, fetal detailed scan; NT, nuchal translucency.
Ultrasound scanning
Structural anomalies may be visualized on ultrasound scan and it is recommended that all women should be offered a detailed ultrasound at around 18–21 weeks’ gestation. This has the advantage that those with major or lethal anomalies (e.g. anencephaly, lethal skeletal dysplasias or renal agenesis) can be offered termination, and it also allows planned deliveries of those conditions which may require early neonatal intervention (e.g. gastroschisis or transposition of the great arteries).
Ultrasound scanning has the limitation, however, that some anomalies may not be identified. It is likely, for example, that less than 50% of cardiac defects are recognized and the false reassurance provided by a scan may become a source of parental resentment. Furthermore, a ‘soft marker’ may be uncovered, the significance of which is often unclear. These soft markers are ultrasound appearances, which in themselves are not an abnormality, but which may point to other problems, particularly chromosomal abnormalities. They are found in approximately 5% of all pregnancies at a second-trimester scan and cause a lot of parental anxiety. Such markers include choroid plexus cysts (Fig. 33.1), mild renal pelvic dilatation, echogenic cardiac foci (Fig. 33.2) and mild cerebral ventricular dilatation. If the soft marker is isolated, the risk of chromosomal problems is low, but if more than one is found, or if there are any other structural defects, the risk of a chromosomal problem is very much higher. Ultrasound markers of chromosome anomaly are not sensitive or specific enough to be used for screening of aneuploidy.
Unlike structural abnormalities, chromosomal abnormalities can be much more difficult to identify on ultrasound scan. Around two-thirds of fetuses with Down syndrome (trisomy 21) will have a normal appearance at 18 weeks, and the remaining third may demonstrate only minor defects which are not pathognomonic of the condition. Most fetuses with the less common trisomies, e.g. Edwards syndrome (trisomy 18) or Patau syndrome (trisomy 13), do show some abnormality, although the abnormality is again often neither specific nor diagnostic. Since trisomy 18 and 13 are usually lethal in the perinatal period, there are fewer lifelong implications than for trisomy 21. Much of the screening work has therefore been directed at trisomy 21, in particular measuring specific markers in the maternal blood (serological screening), or measuring the thickness of nuchal fluid behind the fetal neck (nuchal translucency assessment).
Nuchal translucency: in the first trimester combined screening test
Screening for fetal chromosomal anomalies (principally trisomy 21) is also possible by measuring the fetal nuchal translucency (NT) on first-trimester ultrasound scanning (Fig. 33.3). The risk of Down syndrome increases with larger NT measurements. NT measurement is combined with first trimester biochemistry (measuring free β-HCG and PAPP-A) in order to provide an estimate of risk of Down syndrome. In the first trimester, it has been recommended that a ‘cut-off’ of high risk is taken as 1 in 150 at term. Using such a threshold, the first trimester combined screening test can detect up to a 90% of babies with trisomy 21, with a 2.5% risk of being offered an invasive, prenatal procedure. The sensitivity of the test may further be improved by the visualization of a fetal ‘nasal bone’ and exclusion of right sided cardiac ‘tricuspid regurgitation’. These latter tests are not routine in their use.
Parents then may be offered a prenatal diagnostic test. Chorionic villous sampling (CVS) may be used to establish a diagnosis at an earlier gestational age than with amniocentesis (see below), thereby allowing the option of an early surgical termination of pregnancy rather than a late medical termination. There is, however, evidence to suggest that parental psychological morbidity is independent of whether a diagnosis is made in the first or second trimester, and indeed medical termination may carry less psychological morbidity than surgical (even if medical complications are higher).
Increased nuchal translucency is also a marker for structural defects, particularly cardiac anomalies (when used in combination with tricuspid blood flow measurements to exclude regurgitation), renal, abdominal wall disease, as well as diaphragmatic herniae.
This may also be used in multiple pregnancies. In dichorionic twins, each twin has its ‘individualized risk’ and in monochorionic twins, the risk is the ‘average’ of that calculated for the two fetuses.
Serological screening
This is used almost exclusively to detect two abnormalities: spina bifida and chromosomal anomalies. Alpha-fetoprotein (αFP) is an alpha-globulin of similar molecular weight to albumin which is synthesized by the fetal liver. If there is a break in the fetal skin (for example with spina bifida), αFP escapes into the maternal circulation and the maternal serum level becomes elevated.
Normal serum αFP levels rise with advancing gestation and most laboratories report results as multiples of the median (MoM) for unaffected pregnancies at the gestation of sampling. A level of 1.0 is normal, and for screening purposes levels raised to more than 2.0–2.5 MoM indicate the need for detailed scanning to look for neural tube defects, multiple pregnancy, gastroschisis or intrauterine death. As there is a large overlap between normal and affected pregnancies, a raised level of maternal serum αFP is therefore only a screening test and not a diagnostic test. An ultrasound scan provides the final diagnosis.
