Prenatal diagnosis is important in detecting and preventing
genetic disease. Significant advances since the mid-1980s have
been the development of chorionic villus sampling procedures
in the first trimester and the application of recombinant DNA
techniques to the diagnosis of many mendelian disorders.
Techniques for undertaking diagnosis on single cells has more
recently made preimplantation diagnosis of some genetic
disorders possible. Various prenatal procedures are available,
generally being performed between 10 and 20 weeks’ gestation.
Having prenatal tests and waiting for results is stressful for
couples. They must be supported during this time and given
full explanation of results as soon as possible. Most tertiary
centres have developed fetal management teams consisting of
obstetricians, midwives, radiologists, neonatologists, paediatric
surgeons, clinical geneticists and counsellors, to provide
integrated services for couples in whom prenatal tests detect an
abnormality.
Saturday, April 11, 2009
Indications for prenatal diagnosis
Prenatal diagnosis occasionally allows prenatal treatment to be
instituted but is generally performed to permit termination of
pregnancy when a fetal abnormality is detected, or to reassure
parents when a fetus is unaffected. Since an abnormal result on
prenatal testing may lead to termination this course of action
must be acceptable to the couple. Careful assessment of their
attitudes is important, and all couples who elect for
termination following an abnormal test result need counselling
and psychological support afterwards. Couples who would not
contemplate termination may still request a prenatal diagnosis
to help them to prepare for the outcome of the pregnancy, and
these requests should not be dismissed. The risk of the disorder
occurring and its severity influence a couple’s decision to
embark on testing, as does the accuracy, timing and safety of
the procedure itself.
instituted but is generally performed to permit termination of
pregnancy when a fetal abnormality is detected, or to reassure
parents when a fetus is unaffected. Since an abnormal result on
prenatal testing may lead to termination this course of action
must be acceptable to the couple. Careful assessment of their
attitudes is important, and all couples who elect for
termination following an abnormal test result need counselling
and psychological support afterwards. Couples who would not
contemplate termination may still request a prenatal diagnosis
to help them to prepare for the outcome of the pregnancy, and
these requests should not be dismissed. The risk of the disorder
occurring and its severity influence a couple’s decision to
embark on testing, as does the accuracy, timing and safety of
the procedure itself.
Identifying risk
Pregnancies at risk of fetal abnormality may be identified in
various ways. A pregnancy may be at increased risk of Down
syndrome or other chromosomal abnormality because the
couple already have an affected child, because of abnormal
results of biochemical screening, or because of advanced
maternal age. The actual risk is usually low, but prenatal testing
is often appropriate, since this allows most pregnancies to
continue with less anxiety. There is a higher risk of a
chromosomal abnormality in the fetus when one of the parents
is known to carry a familial chromosome translocation or when
congenital abnormalities have been identified by prenatal
ultrasound scanning. In other families, a high risk of a single
gene disorder may have been identified through the birth of an
affected relative. Couples from certain ethnic groups, whose
pregnancies are at high risk of particular autosomal recessive
disorders, such as the haemoglobinopathies or Tay–Sachs
disease, can be identified before the birth of an affected child
by population screening programmes. Screening for carriers of
cystic fibrosis is also possible, but not generally undertaken on a
population basis. In many mendelian disorders, particularly
autosomal dominant disorders of late onset and X linked
recessive disorders, family studies are needed to assess the risk
to the pregnancy and to determine the feasibility of prenatal
various ways. A pregnancy may be at increased risk of Down
syndrome or other chromosomal abnormality because the
couple already have an affected child, because of abnormal
results of biochemical screening, or because of advanced
maternal age. The actual risk is usually low, but prenatal testing
is often appropriate, since this allows most pregnancies to
continue with less anxiety. There is a higher risk of a
chromosomal abnormality in the fetus when one of the parents
is known to carry a familial chromosome translocation or when
congenital abnormalities have been identified by prenatal
ultrasound scanning. In other families, a high risk of a single
gene disorder may have been identified through the birth of an
affected relative. Couples from certain ethnic groups, whose
pregnancies are at high risk of particular autosomal recessive
disorders, such as the haemoglobinopathies or Tay–Sachs
disease, can be identified before the birth of an affected child
by population screening programmes. Screening for carriers of
cystic fibrosis is also possible, but not generally undertaken on a
population basis. In many mendelian disorders, particularly
autosomal dominant disorders of late onset and X linked
recessive disorders, family studies are needed to assess the risk
to the pregnancy and to determine the feasibility of prenatal
Severity of the disorder
Several important factors must be carefully considered before
prenatal testing, one of which is the severity of the disorder. For
many genetic diseases this is beyond doubt; some disorders lead
inevitably to stillbirth or death in infancy or childhood.
Requests for prenatal diagnosis in these situations are high.
The decision to terminate an affected pregnancy may be easier
to make if there is no chance of the baby having prolonged
survival. Equally important, however, are conditions that result
in children surviving with severe, multiple, and often
progressive, physical and mental handicaps, such as Down
syndrome, neural tube defects, muscular dystrophy and many
of the multiple congenital malformation syndromes. Again,
most couples are reluctant to embark upon another pregnancy
in these cases without prenatal diagnosis. Termination of
pregnancy is not always the consequence of an abnormal
prenatal test result. Some couples wish to know whether their
baby is affected so that they can prepare themselves for the
birth and care of an affected child.
prenatal testing, one of which is the severity of the disorder. For
many genetic diseases this is beyond doubt; some disorders lead
inevitably to stillbirth or death in infancy or childhood.
Requests for prenatal diagnosis in these situations are high.
The decision to terminate an affected pregnancy may be easier
to make if there is no chance of the baby having prolonged
survival. Equally important, however, are conditions that result
in children surviving with severe, multiple, and often
progressive, physical and mental handicaps, such as Down
syndrome, neural tube defects, muscular dystrophy and many
of the multiple congenital malformation syndromes. Again,
most couples are reluctant to embark upon another pregnancy
in these cases without prenatal diagnosis. Termination of
pregnancy is not always the consequence of an abnormal
prenatal test result. Some couples wish to know whether their
baby is affected so that they can prepare themselves for the
birth and care of an affected child.
Treatment for the disorder
It is also important to consider the availability of treatment for
conditions amenable to prenatal diagnosis. When treatment is
effective, termination may not be appropriate and invasive
prenatal tests are generally not indicated, unless early diagnosis
permits more rapid institution of treatment resulting in a better
prognosis. Phenylketonuria, for example, can be treated
effectively after diagnosis in the neonatal period, and prenatal
diagnosis, although possible for parents who already have an
affected child, may be inappropriate. Postnatal treatment for
congenital adrenal hyperplasia due to 21-hydroxylase deficiency
is also available and some couples will choose not to terminate
affected pregnancies. However, in this condition, affected
female fetuses become masculinised during pregnancy and
have ambiguous genitalia at birth requiring reconstructive
surgery. This virilisation can be prevented by starting treatment
with steroids in the first trimester of pregnancy. Because of this,
it may be appropriate to undertake prenatal tests to identify
those pregnancies where treatment needs to continue and
those where it can be safely discontinued. Prenatal diagnosis by
non-invasive ultrasound scanning of major congenital
malformations amenable to surgical correction is also
important, as it allows the baby to be delivered in a unit with
facilities for neonatal surgery and intensive care.
conditions amenable to prenatal diagnosis. When treatment is
effective, termination may not be appropriate and invasive
prenatal tests are generally not indicated, unless early diagnosis
permits more rapid institution of treatment resulting in a better
prognosis. Phenylketonuria, for example, can be treated
effectively after diagnosis in the neonatal period, and prenatal
diagnosis, although possible for parents who already have an
affected child, may be inappropriate. Postnatal treatment for
congenital adrenal hyperplasia due to 21-hydroxylase deficiency
is also available and some couples will choose not to terminate
affected pregnancies. However, in this condition, affected
female fetuses become masculinised during pregnancy and
have ambiguous genitalia at birth requiring reconstructive
surgery. This virilisation can be prevented by starting treatment
with steroids in the first trimester of pregnancy. Because of this,
it may be appropriate to undertake prenatal tests to identify
those pregnancies where treatment needs to continue and
those where it can be safely discontinued. Prenatal diagnosis by
non-invasive ultrasound scanning of major congenital
malformations amenable to surgical correction is also
important, as it allows the baby to be delivered in a unit with
facilities for neonatal surgery and intensive care.
Test reliability
A prenatal test must be sufficiently reliable to permit decisions
to be made once results are available. Some conditions can be
diagnosed with certainty, others cannot, and it is important that
couples understand the accuracy and limitations of any tests
being undertaken. Chromosomal analysis usually provides
results that are easily interpreted. Occasionally there may be
difficulties, because of mosaicism or the detection of an
unusual abnormality. In some cases, an abnormality other than
the one being tested for will be identified, for example a sex
chromosomal abnormality may be detected in a pregnancy
being tested for Down syndrome. For many mendelian
disorders biochemical tests or direct mutation analysis is
possible. The biochemical abnormality or the presence of a
mutation in an affected person or obligate carrier in the family
needs to be confirmed prior to prenatal testing. Once this has
been done, prenatal diagnosis or exclusion of these conditions
is highly accurate. In other inherited disorders, neither
biochemical analysis nor direct mutation testing is possible.
DNA analysis using linked markers may enable a quantified risk
to be given rather than an absolute result.
to be made once results are available. Some conditions can be
diagnosed with certainty, others cannot, and it is important that
couples understand the accuracy and limitations of any tests
being undertaken. Chromosomal analysis usually provides
results that are easily interpreted. Occasionally there may be
difficulties, because of mosaicism or the detection of an
unusual abnormality. In some cases, an abnormality other than
the one being tested for will be identified, for example a sex
chromosomal abnormality may be detected in a pregnancy
being tested for Down syndrome. For many mendelian
disorders biochemical tests or direct mutation analysis is
possible. The biochemical abnormality or the presence of a
mutation in an affected person or obligate carrier in the family
needs to be confirmed prior to prenatal testing. Once this has
been done, prenatal diagnosis or exclusion of these conditions
is highly accurate. In other inherited disorders, neither
biochemical analysis nor direct mutation testing is possible.
DNA analysis using linked markers may enable a quantified risk
to be given rather than an absolute result.
Screening tests
Screening tests aim to detect common abnormalities in
pregnancies that are individually at low risk and provide
reassurance in most cases. There is widespread application of
routine screening tests for Down syndrome and neural tube
defects by biochemical testing and for fetal abnormality by
ultrasound scanning. Most couples will have little knowledge of
the disorders being tested for and will not be anticipating an
abnormal outcome at the time of testing, unlike couples
undergoing specific tests for a previously recognised risk of a
particular disorder. It is very important to provide information
before screening so that couples know what is being tested for
and appreciate the implications of an abnormal result, so that
they can make an informed decision about having the tests.
When abnormalities are detected, arrangements need to be
made to give the results in an appropriate setting, providing
sufficient information for the couple to make fully informed
decisions, with continuing support from clinical staff who have
experience in dealing with these situations.
pregnancies that are individually at low risk and provide
reassurance in most cases. There is widespread application of
routine screening tests for Down syndrome and neural tube
defects by biochemical testing and for fetal abnormality by
ultrasound scanning. Most couples will have little knowledge of
the disorders being tested for and will not be anticipating an
abnormal outcome at the time of testing, unlike couples
undergoing specific tests for a previously recognised risk of a
particular disorder. It is very important to provide information
before screening so that couples know what is being tested for
and appreciate the implications of an abnormal result, so that
they can make an informed decision about having the tests.
When abnormalities are detected, arrangements need to be
made to give the results in an appropriate setting, providing
sufficient information for the couple to make fully informed
decisions, with continuing support from clinical staff who have
experience in dealing with these situations.
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