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Screening for congenital
anomalies
1 Introduction
2 Genetic counseling
3 Methods of screening and diagnosis
3.1 Ultrasound
3.2 Cytogenetic techniques
3.2.1 Amniocentesis
3.2.2 Chorion villus sampling
3.3 Serum alpha-fetoprotein
4 Conclusions
1 Introduction
Prenatal screening for congenital abnormalities and genetic disorders
has become increasingly important and increasingly complex, since the
introduction of amniocentesis in 1969. A number of factors must be
considered in the planning of a genetic-screening program, including
the prevalence of the condition in the population to be tested, the
severity of the disorder, how successfully available tests separate those
with the condition from those without it (sensitivity and specificity),
and the costs.
Costs are not wholly financial. It is equally important to weigh the
human costs. Although screening programs may bring reassurance to
some women who are tested, for others they may generate anxiety
by merely raising the question of abnormality. The consequences of
erroneous diagnoses, both positive and negative, warrant particularly
careful consideration.
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SOURCE: Murray Enkin, Marc J.N.C. Keirse, James Neilson, Caroline Crowther, Lelia Duley, Ellen Hodnett, and
Justus Hofmeyr. A Guide to Effective Care in Pregnancy and Childbirth, 3rd ed. Oxford, UK: Oxford University
Press, 2000.
DOWNLOAD SOURCE: Maternity Wise website at www.maternitywise.org/prof/
Oxford University Press 2000
2 Genetic counseling
The prevention and treatment of genetic disease is still a new branch
of medicine, but genetic counseling is becoming an increasingly
important component of health care. The list of disorders that are
amenable to prenatal diagnosis continues to grow, especially with
advances in molecular genetics.
Counseling prior to prenatal testing is important. The central issue
is, of course, one of risk. What is the risk of producing an abnormal
child? What is the risk of the investigating procedure? How can that
risk be most clearly explained to the woman who must make the final
decision? One individual may interpret risk figures very differently
from another. Parental decisions may depend, not only on the actual
level of risk, but on whether or not they could imagine handling the
consequences of having an abnormal child.
The decision to screen, and the action taken as a result of a screening
test, should be determined by the individuals concerned, after they
have been made thoroughly aware of the potential risks, adverse effects,
and possible benefits. Therefore, every screening program must
provide adequate time for thorough counseling when it is required.
The practice, common in some centers, is for women undergoing
amniocentesis to be scheduled for counseling on the same day that the
procedure is carried out. It would be preferable, as a rule, for coun-
seling to be given earlier, to allow time for couples to think carefully
without feeling pressured into reaching a decision.
Personal or religious beliefs will influence whether screening is
undertaken at all. There is seldom any point in carrying out prenatal
diagnosis for chromosome studies when the couple would refuse a
termination under any circumstances. Nevertheless, no one should be
made to feel that once they have undergone screening they are bound
to follow a rigid course of action. The couple should feel free to exer-
cise whatever options they choose.
Genetic-screening tests often yield information that is relevant to
other family members. Usually there is no barrier to a free exchange of
information within the family but, occasionally, individuals will wish
to keep the results of tests to themselves. This puts the counselor in a
difficult position. He or she must preserve confidentiality, but at the
same time may be concerned about relatives at risk of genetic disease
who should be traced and tested. The womans preference must be
respected.
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3 Methods of screening and diagnosis
3.1 Ultrasound
Ultrasound may be employed in three ways to assist the identification
of fetal malformations: to directly visualize the malformation; to facil-
itate other diagnostic techniques, such as amniocentesis and chorion
villus sampling; and to allow fetal measurement (thereby maximizing
the performance of other tests that require accurate knowledge of
gestational age).
A large and growing number of abnormalities can be detected by
modern ultrasound imaging. Some defects, such as anencephaly, are
easily identified, while others, such as certain cardiac anomalies, may
be very difficult to identify. The presence of one defect may suggest the
presence of others and/or a chromosomal abnormality. Sometimes
features that are not malformations in themselves but identify an
increased risk of genetic conditions, can be identified. Detection rates
may vary with the quality of the equipment, the expertise of the ultra-
sonographer, and the time available for the examination. More time
and expertise are likely to be available when the ultrasound examina-
tion is performed because of high-risk features (such as a previously
malformed baby or raised alpha-fetoprotein levels), than when it is
performed as a routine screening examination. Ultrasound can be
particularly helpful in demonstrating to parents who have previously
had a malformed baby that their fetus in the current pregnancy does
not have the same defect.
Termination of pregnancy will be acceptable to many couples when
the fetus has a lethal abnormality, such as anencephaly, or a defect likely
to result in major handicap, such as spina bifida with hydrocephalus.
Difficulties can arise when defects have less predictable sequelae, and
also because diagnostic errors may occur. Prior consultation with
surgical colleagues should help to reduce unnecessary elective early
delivery (and the morbidity resulting from iatrogenic immaturity) of
babies with conditions that will not benefit from early surgery.
The increasing sophistication of ultrasound technology can lead
to the diagnosis of many minor defects, of uncertain significance. It
is vital that ultrasound does not lead to a diagnosis of abnormality
in a baby that is normally formed. Such false-positive diagnoses are
particularly tragic if they lead to the termination of a wanted normal
pregnancy.
The finding of a malformation does not mandate termination of
the pregnancy. Diagnosis of a malformation may help some parents
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prepare for the birth of an impaired child. On the other hand, some
parents may suffer a prolonged and devastating upset through such
information. Skilled counseling is needed to help them plan ahead for
the care of their child. Imparting information about important defects
requires personal sensitivity and the availability of people who can be
supportive.
The use of ultrasound during amniocentesis can probably minim-
ize the risk of placental and fetal contact during the insertion of the
needle into the amniotic cavity. In addition, the presence of a multiple
pregnancy may be identified, fetal life confirmed, and gestational age
estimated. Both the pregnant woman and the operator may be reas-
sured by seeing that the fetus appears unaffected by the procedure.
3.2 Cytogenetic techniques
Studies on newborn infants show a worldwide frequency of chromo-
some disorders of about 6 per 1000 births. The total population load
of chromosome abnormalities is far greater still, as the majority of
affected embryos are spontaneously miscarried early in pregnancy.
Over half of all clinically recognizable spontaneous miscarriages are
chromosomally abnormal.
There has been a steady rise in demand for prenatal diagnosis for
chromosome disorders. The majority of referrals for prenatal chromo-
some diagnosis have been of older women (aged 35 and over), who
have an increased risk of carrying a fetus with Down syndrome
(trisomy 21) and most other chromosomal abnormalities. Up to the
age of about 29 there is little effect of maternal age on the frequency of
Down syndrome (the incidence ranging from approximately 0.5 to
1.0 per 1000 live births). Between the ages of 30 and 34 the frequency
begins to rise; by age 35 it is 23 per 1000 live births, and at the age
of 40 it is 8 or 9 per 1000. Until recently, most centres used an age of
35 as the cut-off point for offering prenatal diagnosis, a decision
governed partly by available resources. Policies are changing with the
introduction of new tests that offer improved detection rates. Risk
assessment based on measurements of one or more of serum alpha-
fetoprotein, human chorionic gonadotrophin (HCG), and oestriol,
together with maternal age, can further improve the selection of
women for cytogenetic study.
Invasive techniques in current use for the prenatal diagnosis of chro-
mosome disorders are amniocentesis, chorion villus sampling, and, less
frequently, fetal blood sampling (cordocentesis).
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3.2.1 Amniocentesis
The overall safety of early second trimester amniocentesis has been well
established from several large studies, but the procedure is not without
hazard. A controlled trial of genetic amniocentesis in over 4000 women
at low risk of an abnormality showed that the procedure was associ-
ated with a high incidence of feto-maternal bleeding, an almost three-
fold increase in the miscarriage rate, and perhaps most noteworthy, a
significant increase in the incidence of very-low-birthweight babies and
of respiratory distress syndrome. In absolute terms, the additional risk
of miscarriage associated with the procedure is approximately 0.51%,
and of a very-low-birthweight baby, about 0.5%,
Amniotic fluid cell chromosome studies have two major drawbacks.
First, it usually takes 23 weeks from the time the sample is taken until
the result is available. Many women find this long wait in itself
distressing. Second, amniocentesis is not usually carried out before the
14th16th week of pregnancy. Thus, if termination is requested, it has
to be carried out at a relatively late stage in pregnancy. Culture failure
occurs in about 2% of samples. In these cases a repeat sample becomes
necessary, and the pregnancy may be distressingly far advanced by the
time the result is available.
To try to obtain earlier diagnoses, amniocentesis at around 1012
weeks has been tested in trials to assess safety and diagnostic perfor-
mance. The results are not reassuring, since there are higher miscar-
riage rates when compared with both chorion villus sampling and
mid-trimester amniocentesis.
3.2.2 Chorion villus sampling
Chorion villus sampling constitutes a theoretically attractive alterna-
tive to conventional amniocentesis, since it can be performed in the
first trimester. It involves the use of a cannula (catheter) or biopsy
forceps under ultrasound guidance, to take a small biopsy of villi from
the developing placenta. In general, the transabdominal route results
in a lower failure rate, less bleeding, and fewer miscarriages than the
transcervical route. Some small trials have attempted to evaluate differ-
ences between different types of cannulas, or between cannulas and
biopsy forceps, for chorion villus sampling; no clear differences have
emerged. No benefit has been demonstrated from betamimetic admin-
istration prior to chorion villus sampling.
The advantages of first-trimester diagnosis are obvious, but for some
women these are likely to be offset by obstetrical and cytogenetic prob-
lems. Direct comparisons of first-trimester chorion villus sampling
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with second-trimester amniocentesis, show that complications are
uncommon with both procedures, but that chorion villus sampling is
associated with significantly more need for a repeat test, more bleeding
following the test, and more false-positive diagnoses. Total pregnancy
loss (including miscarriage, stillbirths, and neonatal deaths) were more
common among the women allocated to chorion villus sampling, and
fewer of these women were able to achieve a term delivery or have a
normal birthweight baby. Thus, the increased risk of the procedure has
to be balanced against the advantage of earlier diagnosis. A couple with,
for example, a 1 in 4 risk of having a baby with cystic fibrosis, may feel
this risk justified; others, with lower risks of anomaly, may not.
The possibility has been raised that chorion villus sampling, espe-
cially when performed very early in pregnancy, may cause face or limb
abnormalities on rare occasions. This risk has not been proven; there
is, however, sufficient concern for some experts to recommend that
chorion villus sampling should not be used before 10 weeks, thereby
reducing some of its advantages. Information about the risks of early
diagnostic procedures (chorion villus sampling and first-trimester
amniocentesis) represent important data to inform decisions about
whether first-trimester screening programs for Down syndrome by
biochemical testing, or ultrasound measurement of nuchal translu-
cency (see Chapter 8), or both, should be developed.
Apart from technical difficulties, there are other important aspects
of prenatal diagnosis by chorion villus sampling that require consider-
ation. A number of chromosomally unbalanced embryos are miscar-
ried spontaneously in early pregnancy. Thus, a significant proportion
of the chromosomally abnormal fetuses that are detected through
chorion villus sampling may have been destined for spontaneous
miscarriage before amniocentesis would have been carried out.
3.3 Serum alpha-fetoprotein
Serum alpha-fetoprotein determination for the detection of neural
tube defects has made screening of the general population feasible.
Such screening is cost-effective where the incidence of this disorder is
high. When the result from a serum test shows an elevated level
of alpha-fetoprotein the woman should undergo either a detailed
ultrasound examination or amniocentesis to allow the more sensitive
amniotic fluid alpha-fetoprotein assay to be carried out. When appro-
priate ultrasound expertise is available, amniocentesis is unnecessary.
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4 Conclusions
Genetic screening and diagnosis now has a well-established place in
modern obstetric care. It should be offered as an option to those
women or couples who are deemed to be at significant risk. The poten-
tial benefits and potential adverse effects should be made known to
them, so that they can make a properly informed choice.
The indications for genetic screening require further clarification,
including, in particular, surveys of womens views of the desirability of
the screening and of the psychological effects of both positive and nega-
tive results.
The benefits of earlier exclusion or diagnosis of some fetal disorders
afforded by first-trimester chorion villus sampling, as compared with
late amniocentesis, must be set against the greater risks of the former.
Women considering prenatal diagnosis must be fully informed about
the risks and benefits of the alternative procedures.
Sources
Effective care in pregnancy and childbirth
Daker, M. and Bobrow, M., Screening for genetic disease and fetal
anomaly during pregnancy.
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for prenatal diagnosis.
Early amniocentesis versus transabdominal chorion villus sampling
for prenatal diagnosis.
Alfirevic, Z., Gosden, C. and Neilson, J.P., Chorion villus sampling
versus amniocentesis for prenatal diagnosis.
Bastian, H., Keirse, M.J.N.C., Middleton, P. and Searle. J., Interven-
tions to influence peoples experiences of screening [protocol].
Thornton, J.G., Ways of providing information for helping parents
make decisions about prenatal testing [protocol].
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Tabor, A., Philip, J., Madsen, M., Bang, J., Obel, E.B. and Norgaard-
Pedersen, B. (1986). Randomised controlled trial of genetic amnio-
centesis in 4606 low-risk women. Lancet, 1, 128793.
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