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Testing for fetal abnormality in routine antenatal care
CLINICAL REVIEW
Testing for fetal abnormality care
in routine antenatal
Josephine Green and Helen Statham
The detection of fetal abnormality is a major component of routine antenatal care. A variety of techniques are now in use, although these are constantly being modified in the pursuit of more accurate and earlier detection. In this paper we draw attention to the distinction between screening and diagnostic tests, and describe the techniques which have been most commonly used in the UK: serumscreening for neural tube defects; screening for Down’s syndrome; ultrasound scanning; amniocentesis and chorionic villus sampling.
Diagnosis -.
INTRODUCTION The detection of fetal abnormality has become a major
part of antenatal
care. A variety of tech-
niques are now in use, although stantly
being
modified
these are con-
in the pursuit
accurate
and earlier detection.
describe
the techniques
of more
In this paper we
which have been most
commonly used in the UK, and present information on what is currently known of their benefits Further information about and hazards.
vs screening ..
tests are those that can tell us, with
reasonable
certainty,
being tested is affected If we had cheap,
whether
accurate,
subgroup
124
Because a
of people for whom the risks and costs
are felt to be justified. This is why we have screening. Thus, pregnant women are screened in various ways to identify a sub-group who are more likely to be carrying an abnormal fetus than the rest of the pregnant
Requests for offprints to JG
disorder. diagnostic
tests, we could apply them to everybody.
women,
Josephine Green PhD, Senior Research Associate, Helen Statham WC, Research Associate, Centre for Family Research, University of Cambridge, Free School Lane, Cambridge CB2 3RF.
risk-free
we do not, we need to find a basis for selecting
al (1992)
(1993).
or not the person
by a particular
women’s experiences of these techniques can be found in Green (1990), Statham (1992), Green et and Green
..
Diagnostrc
once defined
population.
These
as ‘at-risk’, can be offered
diagnostic tests. A ‘risk factor’ can be anything that has been observed to have a higher than average association with fetal abnormality. Those that are identifiable at the ‘booking’ interview include maternal age, race and family history. However, as the Royal College of Physicians (1989) Report on Prenatal Diagnosis and
125
MII)WIFEKY
Genetic
Screening
congenital
observed:
malformations
‘Most infants
and chromosomal
with dis-
taken
in
most
cases
is
termination
of
the
pregnancy.
orders are born to healthy young women with no identifiable
risk factor’. Conversely,
of women who are identified
the majority
as being ‘at risk’, for
example on account of their age, give birth to healthy babies. Indeed, we should remember that we are talking
about just
2% of full-term
births that have some form of congenital mality. The vast majority the beginning
ALPHA FETO-PROTEIN SCREENING FOR NEURAL TUBE DEFECTS
abnor-
of women who reach
of the second trimester
do go on to
Alpha
feto-protein
(AFP)
duced by all human open
neural
tube
is a substance
fetuses. defect
the
higher levels are therefore
have healthy babies.
tic fluid and maternal
Where
Containers The
routine
nant women falling
and contents experience
monitors
maternal
leaks
that preg-
may be thought The
of as
first category
variables, e.g. weight, haemo-
screening measured serum
for
to identify all cases
and approximately closed
in maternal
AFP
Maternal
and
blood in such pregnancies. 85% of cases
of spina bifida. AFP is not, however,
tests and examinations
into two categories.
AFP
found in both amnio-
The extent of this is sufficient of anencephaly
pro-
there is an
lesions.
useful for
AFP
may
be
blood (known as maternal
or MSAFP),
or in amniotic
fluid.
blood is clearly the more accessible.
globin, blood pressure. These tests are to see whether the mother is a healthy container for
The optimum timing for the blood test is 1618 weeks; sensitivity is lower at other stages
her unborn child. If test results indicate deviance
of pregnancy.
from
gestation
is known because
the level of AFP in
maternal
blood rises during
the course of preg-
what is considered
to be the ideal then
action can be taken, for example advice
about
iron tablets or
rest and diet can be given.
The
nancy. about
It is important
In the second
every 4 weeks (Wald
fetal well-being.
tation
paper
is concerned
with
trimester
it increases
19% per week, approximately
second category of tests focuses on the contents rather than the container i.e. they are tests of This
that the correct
is not
& Cuckle,
accurately
1984).
known
by
doubling
then
If gesMSAFP
the aim is stated to be the delivery of a healthy
cannot be properly interpreted because the judgement that it is ‘elevated’ is made in terms of
baby,
the first
multiples
a benign
tation. The other common benign for elevated MSAFP is multiple
this second category.
For both categories
but the big difference
category
of test is intended
environment healthy,
is that
to maintain
of test
for a fetus that is (assumed
the second is intended
that are non healthy.
These
to be)
to detect fetuses
tests can only detect
fetal anomalies, they cannot correct them. Unlike the first category of tests, there is rarely
of the median
Inaccurate
dating
and
(MOM’S) for that ges-
multiple
explanation pregnancy. pregnancy
between them explain about one quarter raised MSAFP results (Robinson et al, 1989).
of
any action that can be taken on the basis of the
There are two major problems associated with MSAFP testing. One is that it does not detect all
test results which will increase
neural tube defects,
the chances
that
the baby will be born healthy. Sometimes a single investigative
procedure
can be a source of information container and contents. Ultrasound
about both scanning is
the most obvious example of this. However the point still holds: action can often be taken to correct an imperfect container, but only rarely can anything be done to change anomalies in the contents. The only ‘positive’ action that can be
especially
‘closed’ ones, and
these are also the ones least likely to be spotted by ultrasound scanning. The other is that there is a high
rate
of false
positives,
i.e.
pregnancies
where MSAFP is elevated but where there is no neural tube defect. Some of the explanation for this, as we have seen, lies with inaccurate dating and multiple
pregnancy,
but there
is also the
problem that there is a wide range of ‘normal’ levels. The choice of cut off beyond which a level
126
MIDWIFERY
is judged
to be abnormal
what is abnormal
is a pragmatic
one, but
for one group of women might
not be for others. Thus,
MSAFP
has been found
be made of this forewarning,
but the discovery
that high AFP may be linked to chromosomal abnormalities is leading to a trend towards
to vary with race (Cuckle et al, 1987; Macri et al,
amniocentesis
1987;
age, and
regardless
into
ment, which has more obvious implications
Johnson
maternal
1990a), maternal (Johnson et al, 1990b)
weight
diabetic
status,
consideration. boys having ences
et al,
which are often It is also related
higher
al, 1990).
to fetal sex, with
levels, although
are not large
explanation
not taken
enough
the differ-
to be used as an
in cases of raised MSAFP Yet a further
element
lies in the fact that MSAFP
(Calvas et
MSAFP
neural
of women found to have
will actually
tube defect.
are very variable,
The
(Campbell,
1987),
In practice,
have a fetus with a
proportions
for example:
al, 1979), 1 in 30 (Lilford
1 in 15 (Wald et
& Chard,
1985), 1 in 67
1 in 18 (Robinson
false positive
reported
et al, 1989).
rates will depend
the cut off level used to assess MSAFP incidence
of neural
tion being screening
screened.
tube defects The
condition
on
and the
in the popula-
predictive
power
of a
test (i.e. how likely it is that someone
with a positive screening
result actually has the
being sought) is strongly related to the
prevalence of the disorder being screened for. The incidence of neural tube defects in the UK has, in fact, been falling,
even in places where
there has been no screening tion (Office of Population 1983; Stone et al, 1988). because
ultrasound
powerful
tool, a number
starting
to abandon
and selective aborCensuses & Surveys, For this reason, and
was
a
more
of UK hospitals
becoming
were
mass
MSAFP
screening
during the late 1980s especially in places with a low incidence of neural tube defects. There have,
however,
been
two developments
which
have changed attitudes recently. One is the publication of data suggesting that raised AFP levels indicate a raised risk for a wide range of other fetal problems including fetal/neonatal death (Burton, 1988; Milunsky et al, 1989; Robinson et al, 1989). It appears that approximately one third of pregnancies with raised levels of MSAFP will have a problem of some kind. Unfortunately
et al, 1990).
The other
developfor
action, is the finding that LOW levels of MSAFP are associated
with Down’s syndrome
al 1984;
Merkatz
discussed
below.
et al,
1984),
(Cuckle et
which
will be
levels may vary from
within 30% of the true mean (Carter et al, 1988). Thus only a minority
Warner
of uncertainty
day to day and a single sample is likely only to fall
raised
1989;
following raised MSAFP, of other indications (Cowan et al,
it is not clear what use can
SCREENING SYNDROME
FOR DOWN’S
Down’s syndrome somal
is the most common
chromo-
abnormality,
accounting for approximately 50% of those that can be detected. There is an exceedingly
wide range of other chromoso-
ma1 defects that make up the other 50%, most of them very rare. Many are incompatible for others, particularly
sex chromosome
lies, the consequences
are uncertain.
little
mentioned
chromosomal
hazard
disorders:
found whose prognosis
of
with life; anomaThis
anomalies
for
may
be
is not known. Parents are
rarely told in advance about this possibility. probability
is a
screening
The
of having a child with a chromosomal
disorder rises with maternal age. As shown in Table 1, this relationship is stronger for Down’s syndrome
than for other
chromosomal
abnor-
malities. Until screening
recently,
maternal
age
was the
test for Down’s syndrome
sole
and other
chromosomal abnormalities. In the UK the precise age at which a diagnostic test would be offered Table 1 Estimated
varies between
different
incidence of chromosomal
Health Service
abnormalities
Maternal age
Liveborn babies Down’s syndrome All chromosomal
21 27 35 37 40 45
l/l 500 1/1000 l/400 11220 l/l00 l/30
l/500 II450 II200 l/l25 l/60 l/20
From: Berini R Y & Kahn E (1987) p 59. Reprinted by permission of Blackwell Scientific Publications, Inc.
MIDWIFERY
Kegions. It is usually between 35 and 38 years. It is around this age that the probability of having an affected pregnancy is greater than that of spontaneous abortion as a result of the procedure (this is of course, a curious piece of algebra assuming as it does that having a child with Down’s syndrome and experiencing a miscarriage are equivalent events). A number of Health Districts are now using various biochemical markers in maternal blood as an additional screening method. These tests are focused on Down’s syndrome, rather than chromosome abnormalities in general. Originally low levels of AFP were measured in the same samples that were used to test for neural tube defects, and this is still the case in some areas. Subsequently unconjugated oestriol and human chorionic gonadotrophin (hCG) have also been shown to be linked to Down’s syndrome (Wald et al, 1988). It is the use of these three together, plus age, that is known as the ‘Bart’s test’, or ‘triple test’. There continues to be considerable debate about the relative usefulness of these different parameters (e.g. Macri et al, 1990a; 1990b; Suchy & Yeager, 1990; Dawson & Keynolds, 1992; Spencer, 1992) and it seems that the search for additional maternal serum markers to increase the screen’s sensitivity and specificity will continue. In Britain the use of serum screening in conjunction with maternal age is increasing rapidly, although in a very piecemeal way (Wald et al, 1992a). Wald et al (1992a) estimated that by the end of 1992,69% of Health Districts would be providing some form of serum screening to pregnant women of all ages. The princ$rle of serum screening is the same as using maternal age: every woman is assigned a risk figure which says how likely it is that she is carrying a baby with Down’s syndrome. Where age is the screening method, this risk figure is based on the observed frequency with which women of a given age have Down’s syndrome babies. Thus the risk assigned to a particular 35-year old woman will be the same as that rziven to any other 35-year old woman. With &urn screening, age is still taken into account, but in addition there is information about this particular pregnancy. This means that everyone will be assigned their own particular risk figure which is
127
likely to be different from other women’s. However, in the same way as with age, a cut off is still chosen and risks higher than this are called ‘high’ or ‘screen positive’ and those below ‘low’or ‘screen negative’. The usual cut-off in the UK is 1 in 250, but it varies. The higher the cut-off the fewer women will go on to have amniocentesis, but the more likely it is that babies with Down’s syndrome will be missed. This is an inherent dilemma for any screening programme: maximising the number of affected pregnancies detected while minimising the number of false positives. The chances of a woman having a screen positive result, and the probability that a true positive will actually be detected, both increase with maternal age, as shown in Table 2. The positive predictive value of the test also increases with age, i.e. the probability that a woman with a screen positive result is, in fact, carrying a Down’s syndrome child (Reynolds et al, 1993). Thus, a 16-year-old who screens positive on the triple test has only a l/l 11 chance of having a Down’s baby, while for a 44-year-old the probability is l/26. Knowledge of the relationship between serum screening results and age should be of benefit to midwives counselling pregnant women. The aim of serum screening is to provide a better screening test than age alone. Age as a screening method has not had a substantial impact on the number of Down’s babies born, and there was, in fact, a slight increase in the birth incidence of Down’s syndrome from 1988 Table 2 Probability of a screen positive result and proportion of Down’s pregnancies detected for women of different ages using a 1 in 250 cut-off
Maternal age group (years) under 25 25-29 3Q-34
35-39 40-44 45 and over
All
Probability of screen positive
Proportion of DS detected
I/45 l/32 If15 l/5 l/2 > l/2
35% 40% 54% 76% 93%
> 99%
l/20
58%
Table courtesy of Wald 81 Kennard, personal communication (derived from parameters in Wald et al (1992c).
128 to
MIDWIFERY
1989
(Robinson,
1991),
women are having children
perhaps
of Down’s babies were detected
antenatally
this rose to 38% in 1991 (Mutton This
represented
women 1991.
59%
because
later. In 1989,30%
of
and
et al, 1993).
those
carried
by
aged 35 and over in 1989 and 62% in In
the
under
35-year
age
group
the
proportions detected were 8% and 17%. The proportion of diagnoses that followed a positive serum
screen
rose
from
5%
to 21%
should
be possible
pregnancies women
that using the triple to detect
while needing
to amniocentesis.
age alone
detects,
involves 7-S%
at best,
60%
test it
of Down’s
screening
subsequent
based
of cases
on and
(i.e. all women published
(or about
even if they were found
ULTRASOUND method virtually
every
fetus;
is the most widely used for fetal abnormality,
pregnant
woman
obtained
from
gestations.
beginning
1992; Herrou
to et al,
Wald et al, 1992c).
sorts
of
scans
This
performed
paper
to consider alone.
measuring
is primarily
ultrasound
scanning
While these indicate that the test is not perform-
fore
three
ultrasound
detecting
about
syndrome
with a false positive rate of approxim-
50%
of fetuses
tely 5%, a more recent 9 1% detection
publication
with Down’s has shown a
rate for a 4.1% amniocentesis
(Cheng et al, 1993). Serum screening for Down’s syndrome mean
fewer
diagnostic detected.
women testing
However,
subjected and
more
anxiety
to the stress of affected
fetuses
to some
is causing consider-
women
(Marteau
et al,
1988; Abuelo et al, 1991; Keenan et al, 1991; Green, 1993; Statham & Green, 1993). It is also apparent
that
a higher
proportion
of screen
positive women elect to have amniocentesis than women offered it on grounds of age. This means that in some places the number of amniocenteses being carried out has increased, even though the number of women identified as eligible has decreased. As Donnai and Andrews (1988) predicted, the idea that being over 35 years puts a woman at risk for Down’s syndrome is now so well established that these older women are
and localisof the
We will therehow useful
apart from detecting
is
fetal abnormali-
ties; how useful is it for detecting
fetal abnorma-
lities; and what are the long term risks? The
data concerning
uses of routine
sound on low risk populations other
should
it is evident that, at least in its
early days, serum screening able
rate
questions:
in this
counting,
even if the main function
ing quite as well in practice
consider
be
concerned
Any scan will involve
for abnormalities.
but is
can
it is not possible,
scan is looking
as in theory,
and the
at different
and dating the baby(ies)
ing the placenta,
UK
is a source
information
with tests for fetal abnormality;
with
in the
about both the mother
different
context
et al, 1992;
SCANNING
scanning
for testing
however,
of the use of serum now
in a
still want amniocentesis,
rates has been based on retrospective
appear (Dawson 8c Reynolds,
would want
syndrome
to be ‘low risk’.
However
Phillips
Down’s
but 76% of them would
analyses.
are
for
of information
35%
diagnostic
pregnancy,
detection
practice
to
Screening
Most of what has been
in
‘right’
having at least one scan. Ultrasound
aged 35 years or over) having amniocentesis
screening
their
et al (1993) found that 55% of
to subject only 5% of
of the population
reports
lose
155 older women in the Netherlands serum
Ultrasound
It was estimated
1992;
to
in that
period.
CVS).
unwilling
testing. Roelofsen
than the detection
ultra-
for investigations
of fetal abnormalities
(assessment of gestational age, identification of multiple pregnancies, detection of intrauterine growth
retardation
(IUGR)
and placenta
via) provide little evidence of improved
prae-
perinatal
outcomes. From an initial sample of 2 17 1 pregnant women Ewigman et al (1990) randomised 915 women who were less than 18 weeks pregnant into groups receiving ‘routine ultrasound’ or ‘usual prenatal care’; 24% of those in the usual-care group received an ultrasound scan. No differences were found between the groups in induction of labour or adverse perinatal outcomes. One of seven sets of twins in the usual-care group was not diagnosed until delivery at 36 weeks, but this did not affect the outcome. Similar findings were reported from a much larger trial in Finland (Saari-Kemppainen et al, 1990). Although perinatal mortality was
MIDWIFERY
lower in screened women, this was because they were more likely to have terminated a pregnancy following detection of a fetal abnormality. A number of other studies which have considered the reliability of ultrasound in assessing gestat&al age and IUGK have recently been reviewed by Kinga et al (1989) and by Breart and Ringa (1990). These authors concluded that as a routine examination for the general population any benefits were marginal, although the value for women for whom it was clinically indicated was clear. Ultrasound is of use as an aid to dating the pregnancy and for detecting multiple pregnancies, both of which are necessary for the accurate interpretation of maternal serum test results. In some hospitals the two forms of screening are deliberately co-ordinated with a dating scan preceding the blood test and an anomaly scan performed after the results are known. Wald et al (1992b) have calculated that the routine use of a dating scan before serum screening will increase the detection rate from 58-67% while maintaining the same false positive rate, or could be used to reduce the false positive rate while maintaining the same detection rate. The use of dating scans only after a positive screening test is not recommended, especially since there is evidence of growth retardation in some Down’s syndrome fetuses (Nyberg et al, 1990). Ultrasound scanning is also used as an adjunct to amniocentesis and CVS; localisation of the fetus and placenta minimise the risks of these procedures. The effectiveness of routine ultrasound in the detection of fetal abnormality has been the subject of a number of recent reports, three from the UK. Rosendahl 8cKivinen (1989) have reported data on nine thousand pregnancies routinely scanned in Finland between 1980 and 1988. Ninety-three babies (1.03%) showed major abnormalities and 54 of these (58%) were detected antenatally. In 85 of the 93 cases there was no indicative family history, and in only 26% of the cases was there any suspicion of fetal abnormality prior to the scan although in a study by Sollie et al (1988) selective scanning of a sample of their population defined as high risk (because of IUGR, polyhydramnios, family his-
129
tory) resulted in the identification of 60% of the malformations present. Chitty et al (199 I) and Luck (1992) have both described findings obtained in single district general hospitals while the Northern Regional Survey Steering Group (1992) have described regional results, including mismatches between antenatal and postnatal diagnoses. A number of key points arise from these studies. Firstly, ultrasound scanning which is primarily directed at the detection of fetal abnormalities is best carried out at around 18-20 weeks gestation. The evidence from the Northern Region Fetal Abnormality Survey (Scott & Renwick, 1993) shows clearly that detection of urological abnormalities increases from 26% in women scanned at 16 weeks or less to 93% in women scanned between 17 and 20 weeks. Secondly, false positive diagnoses do occur (Atkins & Hey, 1991); in the two single hospital studies no pregnancy was terminated erroneously because all suspected anomalies were scanned twice. In ten out of 30 cases of suspected major malformation in a Finnish study (Saari-Kemmpainen et al, 1990) the abnormality disappeared spontaneously. Urological problems are particularly susceptible to false positive diagnoses (Rosendahl & Kivinen, 1989; Scott & Renwick, 1993); hydronephrosis is the most common urological abnormality and in the Northern Region 55% were found to be normal postnatally although all those diagnosed in Luck’s (1992) study were reported to be under the care of a paediatrician. Thirdly, not all detectable abnormalities are detected; overall detection rate was 74% in the study of Chitty et al (1991) and 85% in that of Luck (1992). In this latter study, the detection of renal and central nervous system anomalies was 100% while sensitivity of detecting heart anomalies was 36%. Fourthly, not all women in whom serious anomalies are detected go on to terminate the pregnancy, as also shown in an American study by Pryde et al (1992). The fifth point is that there is considerable variation between different maternity units which ‘does not seem to be linked to unit size, to the type of equipment in use, or to the amount of antenatal ultrasound work done’, ‘Had the antenatal diagnostic ability of every unit in the region matched that of the best, a
130
MIDWIFEKY
hundred more significant diagnoses would have been made in the region each year in the last five
sis takes 3 to 4 weeks because
years’
(Northern
cultured.
Croup,
1992). In Luck’s (1992)
accuracy
Regional
increased
radiographer. Journal
Survey
Steering
study diagnostic
with the experience
of the
A recent special issue of the AIMS
(1993) on ultrasound
comments
that we
do not know how many of those carrying obstetric
scans
are
qualified
in
out
medical
ultrasound. campaign
ultrasound ordinary
against
the
in pregnancy.
routine
should
so little is known
about
effects.
A recent
(Reece
logical
review
that there
effects,
but
wholesale
exposure
ultrasound
scanning
were the
be so widely of its
the long term et al,
1990)
no confirmed
problem
of a whole
of
extra-
given the shortness
history,
concluded
use
It is indeed
that a‘technique
used when, necessarily,
the Associ-
bio-
is that
the
generation
to
has made it virtually impos-
Given
is unlikely
the cervix or through abdominal
problems extremely
scanning
such as reading difficult
major
advantage
In addition
(e.g.
et al, 1990).
The
of CVS over amniocentesis
that it can be performed of pregnancy,
usually between results
9 and 11 weeks.
are available results
can be obtained
without
the need for cells to be cultured.
that this was
ways of teaching
children
to
whose risk status is established and it is therefore
to screening
erally agreed amniocentesis, reasons that
which CVS
take
is gen-
than that following
but there is a lack of consensus is. There
for this (Goldberg
base
to
early in
not of use as an
programmes
to be higher
to what this rate
read.
The
is that it is only of relevance
place during the second trimester. The miscarriage rate following
and not the result
quickly
chromosome
difficulties,
to demonstrate
more
because
pregnancy,
is
at a much earlier stage
adjunct
it would be
through the trans-
to be preferred
Brambati
caused relatively subtle
indeed an effect of ultrasound of, say, different
it were the case
means of obtain-
the abdomen;
route is tending
Elias et al, 1989;
women
Thus, if, for example,
(CVS) is an alterna-
ing fetal cells. The villi can be sampled
other
influences.
of serious fetal abnor-
villus sampling
results
that ultrasound
the 20th week.
tive, and less widely available,
scanning
of
are
to English law mean that there is
on grounds
disadvantage
the
amniocenteses
mality.
from
are
most
now no longer a legal time limit for performing terminations
may result
what
that
amniocente-
cells have to be
to take place before
Recent changes
sible to know what problems and
analysis following
carried out at 16 weeks or later, any termination
Chorionic
The AIMS special issue continues ation’s
Chromosome
loss rates
are
are a number et al, 1990).
difficult
the risk of spontaneous
as of
One is
to establish
DIAGNOSING CHROMOSOMAL ABNORMALITIES: AMNIOCENTESIS AND CVS
because
confirmed
at 8 weeks will abort
To detect chromosomal abnormalities it is necessary to have a sample of fetal cells. This is most commonly obtained from amniotic fluid from
(Simpson,
1990), this figure may be less than 2%
with maternal
age. Thus,
that overall approximately
abortion
although
rises
it is agreed
3% of all pregnancies spontaneously
for women under 36 years of age, but more than 10% for women over 40 (Cohen-Overbeek et al,
which fetal cells may be cultured. This procedure - amniocentesis - is usually carried out between 16 and 20 weeks of pregnancy. The
1990). Jahoda women under
et al (1989) found 3% losses in 36 years and 6% over, following
CVS. Another
confounding
removal of amniotic
ators get better with time (Breed
fluid carries with it possible
risks to the fetus (Turnbull, 1984), including the suggestion that children may be more prone to bilateral middle ear impedance abnormalities (Finegan et al, 1990). The main risk, however, is a probability of spontaneous abortion of about 1 in 200.
factor is that operet al, 1990). The
final problem identified by Goldberg et al (1990) is reporting bias. In a table entitled ‘As you like it’ they demonstrate that by reorganising the same data, CVS loss rates can range from 4.3 to 8.2%! There are still some doubts about the accuracy and safety of CVS and false negative results have
MlDWII;EKY
been reported (Lilford et al, 1991). The MKC European multi-centre randomised control trial involving 3248 women published its findings in June 199 1. These showed that women allocated to CVS were significantly less likely to achieve the desired result of a liveborn healthy child than women allocated to amniocentesis: 14% in the CVS group had unsuccessful pregnancies compared with 9% in the amniocentesis group. The difference arose from a greater number of spontaneous fetal deaths before 28 weeks, more terminations for chromosomal abnormality, and more neonatal deaths. The greater number of terminations (43 vs 28) arises partly because earlier diagnosis (by any method) means that cases will be detected that would otherwise have aborted spontaneously before the 16th week. The other possible explanation for the greater number of terminations is that some of the results were false positives, i.e. the diagnosis of a chromosomal abnormality was wrong. The MKC working party was, unfortunately, not able to say how many of these occurred, because post-termination karyotyping was not always carried out. Neither, of course, were they able to say how many true positives would have aborted spontaneously before the 16th week. Either way, the higher termination rate is a risk of the procedure that women should be aware of. Another way in which CVS compared badly with amniocentesis was in the need for retesting (6% vs 2%). In the CVS group 100 women needed a second test (which often meant waiting until 16 weeks to have amniocentesis), compared with 35 women in the amniocentesis group. The most common reason for retesting was failure to obtain an adequate sample. The Canadian multicentre trial, which reported its results in 1989, also found that 10% of women having CVS went on to have amniocentesis as well. Another problem that is more common with CVS is ‘mosaicism’, when an abnormality is evident in only some, but not all cultures, from the same specimen. These ambiguous findings are the other main reason for retesting. Since publication of the MKC trial results, there has been somewhat less enthusiasm for CVS. This was reinforced by reports of limb and facial abnormalities, which had started to appear
13 1
shortly before (Boyd et al, 1990; Firth et al, 1991). These reports led many other groups to report their own experiences, some claiming that the numbers could have occurred by chance, others supporting the interpretation that the events were causally linked. The number of cases now reported makes it quite likely that there is in fact a real effect (Lilford, 1991). It is now recommended that CVS should not be carried out before 9.5 weeks’ gestation, that CVS should be carried out with a minimum of placental damage, that women who have had CVS should be offered a detailed scan at 18-20 weeks, and that all babies whose mother had an early CVS should be followed up and examined in detail (Rodeck, 1993). There is one other important point to be made about CVS vs amniocentesis, which is raised by Robinson et al (199 1) concerning miscarriage after CVS. Compared with amniocentesis, a relatively large number of women will miscarry after CVS, partly because it does actually cause more fetal losses than amniocentesis and partly because there is a higher rate of spontaneous loss at the earlier stage of pregnancy. However, no-one can know whether their particular miscarriage was a consequence of the procedure or was one that would have happened anyway. Robinson et al (1991) found that women who miscarried after CVS experienced a great deal of guilt and blamed their loss on their selfish desire for an earlier test result. They in fact had even less reason for feeling this way than might be supposed because they were part of the randomised trial and had not actually chosen to have CVS. This is an important point which should be taken into account when counselling women for prenatal diagnosis.
THE FUTURE This paper has described the techniques for detecting fetal abnormalities that are most commonly used in the UK at present. This is, however, a constantly changing held. Most efforts at the moment are being directed towards earlier diagnosis and alternative screening methods. It used to be thought that amniocente-
132
MIDWIFERY
sis could
not be carried
gestation
because
amniotic
fluid.
are
now
However,
reporting
between
out before
9 and
16 weeks
there would not be sufficient a number
successful
14 weeks (Elejalde
Nevin et al, 1990; Kebello
of centres
amniocentesis et al, 1990;
et al, 1991;
Parker
et
prenatal
diagnosis
England
and Wales
shows
that
of
Down’s
(Mutton
the increase
syndrome
in
et al, 1993)
also
in detection
rates
in
women aged under 35 years is the result of improved detection through ultrasound as well as via serum
screening.
In fact, for each of the
al, 1991). This is not yet widely available and no
years 1989,
randomised
nancies in women under 35 years were detected
control
trials of early amniocentesis
via ultrasound
have yet been published. A recent development is the transvaginal examination technique
1988). It is suggested the prenatal
abnormalities
(Lancet
editorial,
although,
in
1989;
early
Cullen
of
1990),
as the Lancet points out, it will be some
before
detected
the
implications
of
anomalies
at this stage can be understood.
who have experienced
the procedure
women is that, unlike traditional ultrasound, fortably that
the fetus
ultrasound,
fold
syndrome thickness positive therefore
with and
Down’s
without
such as the thickness
and
the
BPD/femur
et al, 1987;
rate in a prospective is likely
ratio
et al, 1989).
75% of Down’s a nuchal skin for a 1% false study.
that ultrasound
syndrome
of the
length
Brumfield
pregnancies with of 6 mm or greater appear
Even
abnorma-
to be other measurable
babies
Crane and Gray (1991) identified
Women
It would
screening
to become
for
a major
area of investigation.
transabdominal
The disadvantages
is exposed
ever earlier
to higher
in pregnancy;
may be levels of there
no available data on any possible miscarriage The
screening.
they do not need to have an uncom-
full bladder.
associated
nuchal
as part of
IVF treatment are reported to find it acceptable (Lavy et al, 1987). A particular advantage for
between
Down’s syndrome (Benecerrdf
pregnancy
et al,
lities, there are thought differences
that this
diagnosis
than via serum
when there are not obvious structural
ultrasound
probe which enables detailed
will enable
structural
while
in obstetric
of the fetus in the first trimester
(Green & Hobbins,
1990 and 199 1 more Down’s preg-
is
risk
with this more invasive procedure.
other
ultrasound
new development in
abnormalities. abnormalities
screening A
number
are associated
is the use of
for
chromosomal
of
chromosomal
with structural
ano-
malies (Nyberg et al, 1990) although not all investigators have found this to be the case for Down’s syndrome
(Lynch et al, 1989; Marquette
et al, 1990). However two large studies in France (Eydoux et al, 1989) and the UK (Nicolaides et al, 1992) have published impressive findings on the use of ultrasound detected anomalies as indicators for amniocentesis. The French study found a considerably higher proportion of chromosoma1 abnormalities detected in women who had amniocentesis because of anomalies picked up on scan than amongst those having amniocentesis because oftheir age. The British report found that 14% (i.e. 1 in 7) of those selected on the basis of ultrasound anomalies had chromosomal abnormalities. A recent report on trends in
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and transabdominal ultrasound for monitoring follicular development in an in vitro fertilization and embryo transfer program: patient response. Journal of In Vitro Embryo Transfer 4: 293-295 Lilford R J 199 I The rise and fall of chorionic villus sampling. British Medical Journal 303: 936937 Lilford R J, Chard T 3985 The routine use of ultrasound. British Journal of Obstetrics & Gynaecology 92: 434-436 Lilford R 1, Caine A, Linton G et al 1991 Short-term culture&d false-negative results for Down’s syndrome on chorionic villus sampling. Lancet 337: 861 Luck C A 1992 Value of routine ultrasound scanning at 19 weeks: a four year study of 8849 deliveries. British MedicalJournal 364: 1474-1478 Lynch L, Berkowitz (; S, Chitkaran V et al 1989 Ultrasound detection of Down syndrome: is it really possible? Obstetrics & Gynecology 73: 267-270 Macri 1 N, Kasturi B E, Mannysha (; H et al 1987 Maternal serum alpha-fetoprotein screening. III. Pitfalls in evaluating black gravid women. American Journal of Obstetrics & Gynecology 157: 826-822 Macri.J N, Kasturi R V, Krantz D A et al 199Oa Maternal serum Down syndrome screening: unconiuEdted estriol is not useful. American journal ., of Obstetrics & Gynecology 162 (3): 672-673Macri 1 N. Kasturi R V. Krantz D A et al 1990b Matkrnal serum Down syndrome screening: Free Bprotein is a more effective marker than human chorionic gonadotropin. American .Journal of Obstetrics & Gynecology 162: 1248 Marquette G P, Boucher M, Desrochers M et al 1990 Screening for trisomy 2 I with ultrasonogrdphic determination of bipdrietal diameter/femur length ratio. American Journal of Obstetrics & Gynecology 163 (5): 1604-1605 Marteau T M, Kidd J, Cook R et al 1988 Screening for Down’s Syndrome. British Medical Journal 297: 1469 Merkatz I R, Nitowsky H M, Macri J N et al 1984 An association between low maternal serum alpha fetoprotein and fetal chromosomal abnormalities. American Journal of Obstetrics &
Nyberg D A, Resta R G, Luthy D A et al I990 Prenatal ‘so&graphic findings of Down syndrome: review of 94 cases. Obstetrics & Gvnecologv 76 (3): 370-377 Office of Population Censuses andSurveys 1983. 19711980 Congenital malformation statistics, Series MB3, 1, 69-75 England and Wales: Government Statistical Service, London Parker M, James D, Davies T et al 1991 Diagnostic amniocentesis before 16 weeks. Journal of Obstetrics & Gynaecology I 1: 109-l I 1 Phillips 0 P, Elias S, Shulman L P et al 1992 Maternal serum screening for fetal Down syndrome in women less than 35 years of age using alpha-fetoprotein, hC<;, and unconjugated estriol: a prospective 2-year study. Obstetrics & Gynecology 80: 353-358 Pryde P G, Isada N B, Hallak M et al 1992 Determinants of parental decision to abort or continue after non-aneuploid ultrasound-detected fetal abnormalities. Journal of Obstetrics & Gynaecology 80: 53-56 Rebello M T, Gray C T H, Rooney D E et al 1991 Cytogenetic studies of amniotic fluid taken before the 15th week of pregnancy for earlier prenatal diagnosis: a report of 114 consecutive cases. Prenatal Diagnosis. I I : 35-40 Reece E A, Assimakopoulos E, Zheng X et al 1990 The safety of obstetric ultrasonography: concern for the fetus. Obstetrics & Gynecology 76 (1): l39- 146 Reynolds T M, Nix A B, Dunstan F D et al 1993 Age-specific detection and false positive rates: an aid to counselling in Down Syndrome risk screening. Obstetrics &
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Scott J E S, Renwick M 1993 Urological anomalies in the Northern Region Fetal Abnormality Survey. Archives of Disease in Childhood 68: 22-26 Simpson J L 1990 Incidence and timing of pregnancy losses: relevance to evaluating safety of early prenatal diagnosis. American Journal of Medical Genetics 35: 165-173 Sollie J E, Van Geijn H, Arts N 1988 Validity of a selective policy for ultrasound examination of fetal congenital anomalies. European Journal of Obstetrics, Gynecology and Reproductive Bmlogy 27: 125- I32 Spencer K 1992 Antenatal screening for Down’s syndrome. British Medical Journal 305: 769 Statham H 1992 Professional understanding and parents experience of termination. In Brock D J, Rodeck C H & Ferguson Smith M A (eds) Prenatal Screening and Diagnosis. Churchill Livingstone, London Statham H, Green J 3993 Issues raised by serum screening for Down’s syndrome: some women’s experiences. British Medical Journal 3.7: 174 176 Stone D H, Smalls M J, Rosenberg K et al 1988 Screening for congenital neural tube defects in a high-risk area: an epidemiological perspective. Journal of Epidemiology & Community Health 42: 27 l-273 Suchy S F, Yeager M T 1990 Down syndrome screening in women under 35 with maternal serum hCG. Obstetrics & Gynecology 76 (I): 20-24 Turnbull A C I984 Amniocentesis. In Wdld NJ (ed)
135
Antenatal and neonatal screening. Oxford University Press, Oxford Wald NJ. Cuckle H S 1984 Open neural-tube defects. In Wald NJ (ed) Antenatal and neonatal Screening. Oxford University Press, Oxford Wald N J, Cuckle H S, Harwood C A 1979 Screening for open neural-tube defects in England and Wales. British Medical Journal 2: 33 1 Wald NJ, Cuckle H S, Densem J W et al 1988 Maternal serum unconjugated oestriol as an antenatal screening tes; for Down’s Syndrome. British ,Journal of Obstetrics & Gynaecology 95: 334-341 Wald N, Wdld K, Smith D 1992a The extent of Down’s syndrome screening in Britain in 199 1. Lancet, 34: 494 Wald NJ, Cuckle H S, Densem J W et al 1992b Maternal serum screening for Down’s syndrome: the effect of routine ultrasound scan determination of gestational age and ad.justment for maternal weight. British .Journal of Obstetrics & Gynaecology 99: 144149 Wald NJ, Kennard A, Densem J W et al 1992~ Antenatal maternal serum screening for Down’s syndrome: results of a demonstrati& project. British Medical lournal305: 39 l-394 Warner Ak, Pettenati M J, Burton B K 1990 Risk of fetal chromosomal anomalies in patients with elevated maternal serum alpha-fetoprotein. Obstetrics Bc Gynecology 75: 64-66
Testing for fetal abnormality care
in routine antenatal
Josephine Green and Helen Statham
The detection of fetal abnormality is a major component of routine antenatal care. A variety of techniques are now in use, although these are constantly being modified in the pursuit of more accurate and earlier detection. In this paper we draw attention to the distinction between screening and diagnostic tests, and describe the techniques which have been most commonly used in the UK: serumscreening for neural tube defects; screening for Down’s syndrome; ultrasound scanning; amniocentesis and chorionic villus sampling.
Diagnosis -.
INTRODUCTION The detection of fetal abnormality has become a major
part of antenatal
care. A variety of tech-
niques are now in use, although stantly
being
modified
these are con-
in the pursuit
accurate
and earlier detection.
describe
the techniques
of more
In this paper we
which have been most
commonly used in the UK, and present information on what is currently known of their benefits Further information about and hazards.
vs screening ..
tests are those that can tell us, with
reasonable
certainty,
being tested is affected If we had cheap,
whether
accurate,
subgroup
124
Because a
of people for whom the risks and costs
are felt to be justified. This is why we have screening. Thus, pregnant women are screened in various ways to identify a sub-group who are more likely to be carrying an abnormal fetus than the rest of the pregnant
Requests for offprints to JG
disorder. diagnostic
tests, we could apply them to everybody.
women,
Josephine Green PhD, Senior Research Associate, Helen Statham WC, Research Associate, Centre for Family Research, University of Cambridge, Free School Lane, Cambridge CB2 3RF.
risk-free
we do not, we need to find a basis for selecting
al (1992)
(1993).
or not the person
by a particular
women’s experiences of these techniques can be found in Green (1990), Statham (1992), Green et and Green
..
Diagnostrc
once defined
population.
These
as ‘at-risk’, can be offered
diagnostic tests. A ‘risk factor’ can be anything that has been observed to have a higher than average association with fetal abnormality. Those that are identifiable at the ‘booking’ interview include maternal age, race and family history. However, as the Royal College of Physicians (1989) Report on Prenatal Diagnosis and
125
MII)WIFEKY
Genetic
Screening
congenital
observed:
malformations
‘Most infants
and chromosomal
with dis-
taken
in
most
cases
is
termination
of
the
pregnancy.
orders are born to healthy young women with no identifiable
risk factor’. Conversely,
of women who are identified
the majority
as being ‘at risk’, for
example on account of their age, give birth to healthy babies. Indeed, we should remember that we are talking
about just
2% of full-term
births that have some form of congenital mality. The vast majority the beginning
ALPHA FETO-PROTEIN SCREENING FOR NEURAL TUBE DEFECTS
abnor-
of women who reach
of the second trimester
do go on to
Alpha
feto-protein
(AFP)
duced by all human open
neural
tube
is a substance
fetuses. defect
the
higher levels are therefore
have healthy babies.
tic fluid and maternal
Where
Containers The
routine
nant women falling
and contents experience
monitors
maternal
leaks
that preg-
may be thought The
of as
first category
variables, e.g. weight, haemo-
screening measured serum
for
to identify all cases
and approximately closed
in maternal
AFP
Maternal
and
blood in such pregnancies. 85% of cases
of spina bifida. AFP is not, however,
tests and examinations
into two categories.
AFP
found in both amnio-
The extent of this is sufficient of anencephaly
pro-
there is an
lesions.
useful for
AFP
may
be
blood (known as maternal
or MSAFP),
or in amniotic
fluid.
blood is clearly the more accessible.
globin, blood pressure. These tests are to see whether the mother is a healthy container for
The optimum timing for the blood test is 1618 weeks; sensitivity is lower at other stages
her unborn child. If test results indicate deviance
of pregnancy.
from
gestation
is known because
the level of AFP in
maternal
blood rises during
the course of preg-
what is considered
to be the ideal then
action can be taken, for example advice
about
iron tablets or
rest and diet can be given.
The
nancy. about
It is important
In the second
every 4 weeks (Wald
fetal well-being.
tation
paper
is concerned
with
trimester
it increases
19% per week, approximately
second category of tests focuses on the contents rather than the container i.e. they are tests of This
that the correct
is not
& Cuckle,
accurately
1984).
known
by
doubling
then
If gesMSAFP
the aim is stated to be the delivery of a healthy
cannot be properly interpreted because the judgement that it is ‘elevated’ is made in terms of
baby,
the first
multiples
a benign
tation. The other common benign for elevated MSAFP is multiple
this second category.
For both categories
but the big difference
category
of test is intended
environment healthy,
is that
to maintain
of test
for a fetus that is (assumed
the second is intended
that are non healthy.
These
to be)
to detect fetuses
tests can only detect
fetal anomalies, they cannot correct them. Unlike the first category of tests, there is rarely
of the median
Inaccurate
dating
and
(MOM’S) for that ges-
multiple
explanation pregnancy. pregnancy
between them explain about one quarter raised MSAFP results (Robinson et al, 1989).
of
any action that can be taken on the basis of the
There are two major problems associated with MSAFP testing. One is that it does not detect all
test results which will increase
neural tube defects,
the chances
that
the baby will be born healthy. Sometimes a single investigative
procedure
can be a source of information container and contents. Ultrasound
about both scanning is
the most obvious example of this. However the point still holds: action can often be taken to correct an imperfect container, but only rarely can anything be done to change anomalies in the contents. The only ‘positive’ action that can be
especially
‘closed’ ones, and
these are also the ones least likely to be spotted by ultrasound scanning. The other is that there is a high
rate
of false
positives,
i.e.
pregnancies
where MSAFP is elevated but where there is no neural tube defect. Some of the explanation for this, as we have seen, lies with inaccurate dating and multiple
pregnancy,
but there
is also the
problem that there is a wide range of ‘normal’ levels. The choice of cut off beyond which a level
126
MIDWIFERY
is judged
to be abnormal
what is abnormal
is a pragmatic
one, but
for one group of women might
not be for others. Thus,
MSAFP
has been found
be made of this forewarning,
but the discovery
that high AFP may be linked to chromosomal abnormalities is leading to a trend towards
to vary with race (Cuckle et al, 1987; Macri et al,
amniocentesis
1987;
age, and
regardless
into
ment, which has more obvious implications
Johnson
maternal
1990a), maternal (Johnson et al, 1990b)
weight
diabetic
status,
consideration. boys having ences
et al,
which are often It is also related
higher
al, 1990).
to fetal sex, with
levels, although
are not large
explanation
not taken
enough
the differ-
to be used as an
in cases of raised MSAFP Yet a further
element
lies in the fact that MSAFP
(Calvas et
MSAFP
neural
of women found to have
will actually
tube defect.
are very variable,
The
(Campbell,
1987),
In practice,
have a fetus with a
proportions
for example:
al, 1979), 1 in 30 (Lilford
1 in 15 (Wald et
& Chard,
1985), 1 in 67
1 in 18 (Robinson
false positive
reported
et al, 1989).
rates will depend
the cut off level used to assess MSAFP incidence
of neural
tion being screening
screened.
tube defects The
condition
on
and the
in the popula-
predictive
power
of a
test (i.e. how likely it is that someone
with a positive screening
result actually has the
being sought) is strongly related to the
prevalence of the disorder being screened for. The incidence of neural tube defects in the UK has, in fact, been falling,
even in places where
there has been no screening tion (Office of Population 1983; Stone et al, 1988). because
ultrasound
powerful
tool, a number
starting
to abandon
and selective aborCensuses & Surveys, For this reason, and
was
a
more
of UK hospitals
becoming
were
mass
MSAFP
screening
during the late 1980s especially in places with a low incidence of neural tube defects. There have,
however,
been
two developments
which
have changed attitudes recently. One is the publication of data suggesting that raised AFP levels indicate a raised risk for a wide range of other fetal problems including fetal/neonatal death (Burton, 1988; Milunsky et al, 1989; Robinson et al, 1989). It appears that approximately one third of pregnancies with raised levels of MSAFP will have a problem of some kind. Unfortunately
et al, 1990).
The other
developfor
action, is the finding that LOW levels of MSAFP are associated
with Down’s syndrome
al 1984;
Merkatz
discussed
below.
et al,
1984),
(Cuckle et
which
will be
levels may vary from
within 30% of the true mean (Carter et al, 1988). Thus only a minority
Warner
of uncertainty
day to day and a single sample is likely only to fall
raised
1989;
following raised MSAFP, of other indications (Cowan et al,
it is not clear what use can
SCREENING SYNDROME
FOR DOWN’S
Down’s syndrome somal
is the most common
chromo-
abnormality,
accounting for approximately 50% of those that can be detected. There is an exceedingly
wide range of other chromoso-
ma1 defects that make up the other 50%, most of them very rare. Many are incompatible for others, particularly
sex chromosome
lies, the consequences
are uncertain.
little
mentioned
chromosomal
hazard
disorders:
found whose prognosis
of
with life; anomaThis
anomalies
for
may
be
is not known. Parents are
rarely told in advance about this possibility. probability
is a
screening
The
of having a child with a chromosomal
disorder rises with maternal age. As shown in Table 1, this relationship is stronger for Down’s syndrome
than for other
chromosomal
abnor-
malities. Until screening
recently,
maternal
age
was the
test for Down’s syndrome
sole
and other
chromosomal abnormalities. In the UK the precise age at which a diagnostic test would be offered Table 1 Estimated
varies between
different
incidence of chromosomal
Health Service
abnormalities
Maternal age
Liveborn babies Down’s syndrome All chromosomal
21 27 35 37 40 45
l/l 500 1/1000 l/400 11220 l/l00 l/30
l/500 II450 II200 l/l25 l/60 l/20
From: Berini R Y & Kahn E (1987) p 59. Reprinted by permission of Blackwell Scientific Publications, Inc.
MIDWIFERY
Kegions. It is usually between 35 and 38 years. It is around this age that the probability of having an affected pregnancy is greater than that of spontaneous abortion as a result of the procedure (this is of course, a curious piece of algebra assuming as it does that having a child with Down’s syndrome and experiencing a miscarriage are equivalent events). A number of Health Districts are now using various biochemical markers in maternal blood as an additional screening method. These tests are focused on Down’s syndrome, rather than chromosome abnormalities in general. Originally low levels of AFP were measured in the same samples that were used to test for neural tube defects, and this is still the case in some areas. Subsequently unconjugated oestriol and human chorionic gonadotrophin (hCG) have also been shown to be linked to Down’s syndrome (Wald et al, 1988). It is the use of these three together, plus age, that is known as the ‘Bart’s test’, or ‘triple test’. There continues to be considerable debate about the relative usefulness of these different parameters (e.g. Macri et al, 1990a; 1990b; Suchy & Yeager, 1990; Dawson & Keynolds, 1992; Spencer, 1992) and it seems that the search for additional maternal serum markers to increase the screen’s sensitivity and specificity will continue. In Britain the use of serum screening in conjunction with maternal age is increasing rapidly, although in a very piecemeal way (Wald et al, 1992a). Wald et al (1992a) estimated that by the end of 1992,69% of Health Districts would be providing some form of serum screening to pregnant women of all ages. The princ$rle of serum screening is the same as using maternal age: every woman is assigned a risk figure which says how likely it is that she is carrying a baby with Down’s syndrome. Where age is the screening method, this risk figure is based on the observed frequency with which women of a given age have Down’s syndrome babies. Thus the risk assigned to a particular 35-year old woman will be the same as that rziven to any other 35-year old woman. With &urn screening, age is still taken into account, but in addition there is information about this particular pregnancy. This means that everyone will be assigned their own particular risk figure which is
127
likely to be different from other women’s. However, in the same way as with age, a cut off is still chosen and risks higher than this are called ‘high’ or ‘screen positive’ and those below ‘low’or ‘screen negative’. The usual cut-off in the UK is 1 in 250, but it varies. The higher the cut-off the fewer women will go on to have amniocentesis, but the more likely it is that babies with Down’s syndrome will be missed. This is an inherent dilemma for any screening programme: maximising the number of affected pregnancies detected while minimising the number of false positives. The chances of a woman having a screen positive result, and the probability that a true positive will actually be detected, both increase with maternal age, as shown in Table 2. The positive predictive value of the test also increases with age, i.e. the probability that a woman with a screen positive result is, in fact, carrying a Down’s syndrome child (Reynolds et al, 1993). Thus, a 16-year-old who screens positive on the triple test has only a l/l 11 chance of having a Down’s baby, while for a 44-year-old the probability is l/26. Knowledge of the relationship between serum screening results and age should be of benefit to midwives counselling pregnant women. The aim of serum screening is to provide a better screening test than age alone. Age as a screening method has not had a substantial impact on the number of Down’s babies born, and there was, in fact, a slight increase in the birth incidence of Down’s syndrome from 1988 Table 2 Probability of a screen positive result and proportion of Down’s pregnancies detected for women of different ages using a 1 in 250 cut-off
Maternal age group (years) under 25 25-29 3Q-34
35-39 40-44 45 and over
All
Probability of screen positive
Proportion of DS detected
I/45 l/32 If15 l/5 l/2 > l/2
35% 40% 54% 76% 93%
> 99%
l/20
58%
Table courtesy of Wald 81 Kennard, personal communication (derived from parameters in Wald et al (1992c).
128 to
MIDWIFERY
1989
(Robinson,
1991),
women are having children
perhaps
of Down’s babies were detected
antenatally
this rose to 38% in 1991 (Mutton This
represented
women 1991.
59%
because
later. In 1989,30%
of
and
et al, 1993).
those
carried
by
aged 35 and over in 1989 and 62% in In
the
under
35-year
age
group
the
proportions detected were 8% and 17%. The proportion of diagnoses that followed a positive serum
screen
rose
from
5%
to 21%
should
be possible
pregnancies women
that using the triple to detect
while needing
to amniocentesis.
age alone
detects,
involves 7-S%
at best,
60%
test it
of Down’s
screening
subsequent
based
of cases
on and
(i.e. all women published
(or about
even if they were found
ULTRASOUND method virtually
every
fetus;
is the most widely used for fetal abnormality,
pregnant
woman
obtained
from
gestations.
beginning
1992; Herrou
to et al,
Wald et al, 1992c).
sorts
of
scans
This
performed
paper
to consider alone.
measuring
is primarily
ultrasound
scanning
While these indicate that the test is not perform-
fore
three
ultrasound
detecting
about
syndrome
with a false positive rate of approxim-
50%
of fetuses
tely 5%, a more recent 9 1% detection
publication
with Down’s has shown a
rate for a 4.1% amniocentesis
(Cheng et al, 1993). Serum screening for Down’s syndrome mean
fewer
diagnostic detected.
women testing
However,
subjected and
more
anxiety
to the stress of affected
fetuses
to some
is causing consider-
women
(Marteau
et al,
1988; Abuelo et al, 1991; Keenan et al, 1991; Green, 1993; Statham & Green, 1993). It is also apparent
that
a higher
proportion
of screen
positive women elect to have amniocentesis than women offered it on grounds of age. This means that in some places the number of amniocenteses being carried out has increased, even though the number of women identified as eligible has decreased. As Donnai and Andrews (1988) predicted, the idea that being over 35 years puts a woman at risk for Down’s syndrome is now so well established that these older women are
and localisof the
We will therehow useful
apart from detecting
is
fetal abnormali-
ties; how useful is it for detecting
fetal abnorma-
lities; and what are the long term risks? The
data concerning
uses of routine
sound on low risk populations other
should
it is evident that, at least in its
early days, serum screening able
rate
questions:
in this
counting,
even if the main function
ing quite as well in practice
consider
be
concerned
Any scan will involve
for abnormalities.
but is
can
it is not possible,
scan is looking
as in theory,
and the
at different
and dating the baby(ies)
ing the placenta,
UK
is a source
information
with tests for fetal abnormality;
with
in the
about both the mother
different
context
et al, 1992;
SCANNING
scanning
for testing
however,
of the use of serum now
in a
still want amniocentesis,
rates has been based on retrospective
appear (Dawson 8c Reynolds,
would want
syndrome
to be ‘low risk’.
However
Phillips
Down’s
but 76% of them would
analyses.
are
for
of information
35%
diagnostic
pregnancy,
detection
practice
to
Screening
Most of what has been
in
‘right’
having at least one scan. Ultrasound
aged 35 years or over) having amniocentesis
screening
their
et al (1993) found that 55% of
to subject only 5% of
of the population
reports
lose
155 older women in the Netherlands serum
Ultrasound
It was estimated
1992;
to
in that
period.
CVS).
unwilling
testing. Roelofsen
than the detection
ultra-
for investigations
of fetal abnormalities
(assessment of gestational age, identification of multiple pregnancies, detection of intrauterine growth
retardation
(IUGR)
and placenta
via) provide little evidence of improved
prae-
perinatal
outcomes. From an initial sample of 2 17 1 pregnant women Ewigman et al (1990) randomised 915 women who were less than 18 weeks pregnant into groups receiving ‘routine ultrasound’ or ‘usual prenatal care’; 24% of those in the usual-care group received an ultrasound scan. No differences were found between the groups in induction of labour or adverse perinatal outcomes. One of seven sets of twins in the usual-care group was not diagnosed until delivery at 36 weeks, but this did not affect the outcome. Similar findings were reported from a much larger trial in Finland (Saari-Kemppainen et al, 1990). Although perinatal mortality was
MIDWIFERY
lower in screened women, this was because they were more likely to have terminated a pregnancy following detection of a fetal abnormality. A number of other studies which have considered the reliability of ultrasound in assessing gestat&al age and IUGK have recently been reviewed by Kinga et al (1989) and by Breart and Ringa (1990). These authors concluded that as a routine examination for the general population any benefits were marginal, although the value for women for whom it was clinically indicated was clear. Ultrasound is of use as an aid to dating the pregnancy and for detecting multiple pregnancies, both of which are necessary for the accurate interpretation of maternal serum test results. In some hospitals the two forms of screening are deliberately co-ordinated with a dating scan preceding the blood test and an anomaly scan performed after the results are known. Wald et al (1992b) have calculated that the routine use of a dating scan before serum screening will increase the detection rate from 58-67% while maintaining the same false positive rate, or could be used to reduce the false positive rate while maintaining the same detection rate. The use of dating scans only after a positive screening test is not recommended, especially since there is evidence of growth retardation in some Down’s syndrome fetuses (Nyberg et al, 1990). Ultrasound scanning is also used as an adjunct to amniocentesis and CVS; localisation of the fetus and placenta minimise the risks of these procedures. The effectiveness of routine ultrasound in the detection of fetal abnormality has been the subject of a number of recent reports, three from the UK. Rosendahl 8cKivinen (1989) have reported data on nine thousand pregnancies routinely scanned in Finland between 1980 and 1988. Ninety-three babies (1.03%) showed major abnormalities and 54 of these (58%) were detected antenatally. In 85 of the 93 cases there was no indicative family history, and in only 26% of the cases was there any suspicion of fetal abnormality prior to the scan although in a study by Sollie et al (1988) selective scanning of a sample of their population defined as high risk (because of IUGR, polyhydramnios, family his-
129
tory) resulted in the identification of 60% of the malformations present. Chitty et al (199 I) and Luck (1992) have both described findings obtained in single district general hospitals while the Northern Regional Survey Steering Group (1992) have described regional results, including mismatches between antenatal and postnatal diagnoses. A number of key points arise from these studies. Firstly, ultrasound scanning which is primarily directed at the detection of fetal abnormalities is best carried out at around 18-20 weeks gestation. The evidence from the Northern Region Fetal Abnormality Survey (Scott & Renwick, 1993) shows clearly that detection of urological abnormalities increases from 26% in women scanned at 16 weeks or less to 93% in women scanned between 17 and 20 weeks. Secondly, false positive diagnoses do occur (Atkins & Hey, 1991); in the two single hospital studies no pregnancy was terminated erroneously because all suspected anomalies were scanned twice. In ten out of 30 cases of suspected major malformation in a Finnish study (Saari-Kemmpainen et al, 1990) the abnormality disappeared spontaneously. Urological problems are particularly susceptible to false positive diagnoses (Rosendahl & Kivinen, 1989; Scott & Renwick, 1993); hydronephrosis is the most common urological abnormality and in the Northern Region 55% were found to be normal postnatally although all those diagnosed in Luck’s (1992) study were reported to be under the care of a paediatrician. Thirdly, not all detectable abnormalities are detected; overall detection rate was 74% in the study of Chitty et al (1991) and 85% in that of Luck (1992). In this latter study, the detection of renal and central nervous system anomalies was 100% while sensitivity of detecting heart anomalies was 36%. Fourthly, not all women in whom serious anomalies are detected go on to terminate the pregnancy, as also shown in an American study by Pryde et al (1992). The fifth point is that there is considerable variation between different maternity units which ‘does not seem to be linked to unit size, to the type of equipment in use, or to the amount of antenatal ultrasound work done’, ‘Had the antenatal diagnostic ability of every unit in the region matched that of the best, a
130
MIDWIFEKY
hundred more significant diagnoses would have been made in the region each year in the last five
sis takes 3 to 4 weeks because
years’
(Northern
cultured.
Croup,
1992). In Luck’s (1992)
accuracy
Regional
increased
radiographer. Journal
Survey
Steering
study diagnostic
with the experience
of the
A recent special issue of the AIMS
(1993) on ultrasound
comments
that we
do not know how many of those carrying obstetric
scans
are
qualified
in
out
medical
ultrasound. campaign
ultrasound ordinary
against
the
in pregnancy.
routine
should
so little is known
about
effects.
A recent
(Reece
logical
review
that there
effects,
but
wholesale
exposure
ultrasound
scanning
were the
be so widely of its
the long term et al,
1990)
no confirmed
problem
of a whole
of
extra-
given the shortness
history,
concluded
use
It is indeed
that a‘technique
used when, necessarily,
the Associ-
bio-
is that
the
generation
to
has made it virtually impos-
Given
is unlikely
the cervix or through abdominal
problems extremely
scanning
such as reading difficult
major
advantage
In addition
(e.g.
et al, 1990).
The
of CVS over amniocentesis
that it can be performed of pregnancy,
usually between results
9 and 11 weeks.
are available results
can be obtained
without
the need for cells to be cultured.
that this was
ways of teaching
children
to
whose risk status is established and it is therefore
to screening
erally agreed amniocentesis, reasons that
which CVS
take
is gen-
than that following
but there is a lack of consensus is. There
for this (Goldberg
base
to
early in
not of use as an
programmes
to be higher
to what this rate
read.
The
is that it is only of relevance
place during the second trimester. The miscarriage rate following
and not the result
quickly
chromosome
difficulties,
to demonstrate
more
because
pregnancy,
is
at a much earlier stage
adjunct
it would be
through the trans-
to be preferred
Brambati
caused relatively subtle
indeed an effect of ultrasound of, say, different
it were the case
means of obtain-
the abdomen;
route is tending
Elias et al, 1989;
women
Thus, if, for example,
(CVS) is an alterna-
ing fetal cells. The villi can be sampled
other
influences.
of serious fetal abnor-
villus sampling
results
that ultrasound
the 20th week.
tive, and less widely available,
scanning
of
are
to English law mean that there is
on grounds
disadvantage
the
amniocenteses
mality.
from
are
most
now no longer a legal time limit for performing terminations
may result
what
that
amniocente-
cells have to be
to take place before
Recent changes
sible to know what problems and
analysis following
carried out at 16 weeks or later, any termination
Chorionic
The AIMS special issue continues ation’s
Chromosome
loss rates
are
are a number et al, 1990).
difficult
the risk of spontaneous
as of
One is
to establish
DIAGNOSING CHROMOSOMAL ABNORMALITIES: AMNIOCENTESIS AND CVS
because
confirmed
at 8 weeks will abort
To detect chromosomal abnormalities it is necessary to have a sample of fetal cells. This is most commonly obtained from amniotic fluid from
(Simpson,
1990), this figure may be less than 2%
with maternal
age. Thus,
that overall approximately
abortion
although
rises
it is agreed
3% of all pregnancies spontaneously
for women under 36 years of age, but more than 10% for women over 40 (Cohen-Overbeek et al,
which fetal cells may be cultured. This procedure - amniocentesis - is usually carried out between 16 and 20 weeks of pregnancy. The
1990). Jahoda women under
et al (1989) found 3% losses in 36 years and 6% over, following
CVS. Another
confounding
removal of amniotic
ators get better with time (Breed
fluid carries with it possible
risks to the fetus (Turnbull, 1984), including the suggestion that children may be more prone to bilateral middle ear impedance abnormalities (Finegan et al, 1990). The main risk, however, is a probability of spontaneous abortion of about 1 in 200.
factor is that operet al, 1990). The
final problem identified by Goldberg et al (1990) is reporting bias. In a table entitled ‘As you like it’ they demonstrate that by reorganising the same data, CVS loss rates can range from 4.3 to 8.2%! There are still some doubts about the accuracy and safety of CVS and false negative results have
MlDWII;EKY
been reported (Lilford et al, 1991). The MKC European multi-centre randomised control trial involving 3248 women published its findings in June 199 1. These showed that women allocated to CVS were significantly less likely to achieve the desired result of a liveborn healthy child than women allocated to amniocentesis: 14% in the CVS group had unsuccessful pregnancies compared with 9% in the amniocentesis group. The difference arose from a greater number of spontaneous fetal deaths before 28 weeks, more terminations for chromosomal abnormality, and more neonatal deaths. The greater number of terminations (43 vs 28) arises partly because earlier diagnosis (by any method) means that cases will be detected that would otherwise have aborted spontaneously before the 16th week. The other possible explanation for the greater number of terminations is that some of the results were false positives, i.e. the diagnosis of a chromosomal abnormality was wrong. The MKC working party was, unfortunately, not able to say how many of these occurred, because post-termination karyotyping was not always carried out. Neither, of course, were they able to say how many true positives would have aborted spontaneously before the 16th week. Either way, the higher termination rate is a risk of the procedure that women should be aware of. Another way in which CVS compared badly with amniocentesis was in the need for retesting (6% vs 2%). In the CVS group 100 women needed a second test (which often meant waiting until 16 weeks to have amniocentesis), compared with 35 women in the amniocentesis group. The most common reason for retesting was failure to obtain an adequate sample. The Canadian multicentre trial, which reported its results in 1989, also found that 10% of women having CVS went on to have amniocentesis as well. Another problem that is more common with CVS is ‘mosaicism’, when an abnormality is evident in only some, but not all cultures, from the same specimen. These ambiguous findings are the other main reason for retesting. Since publication of the MKC trial results, there has been somewhat less enthusiasm for CVS. This was reinforced by reports of limb and facial abnormalities, which had started to appear
13 1
shortly before (Boyd et al, 1990; Firth et al, 1991). These reports led many other groups to report their own experiences, some claiming that the numbers could have occurred by chance, others supporting the interpretation that the events were causally linked. The number of cases now reported makes it quite likely that there is in fact a real effect (Lilford, 1991). It is now recommended that CVS should not be carried out before 9.5 weeks’ gestation, that CVS should be carried out with a minimum of placental damage, that women who have had CVS should be offered a detailed scan at 18-20 weeks, and that all babies whose mother had an early CVS should be followed up and examined in detail (Rodeck, 1993). There is one other important point to be made about CVS vs amniocentesis, which is raised by Robinson et al (199 1) concerning miscarriage after CVS. Compared with amniocentesis, a relatively large number of women will miscarry after CVS, partly because it does actually cause more fetal losses than amniocentesis and partly because there is a higher rate of spontaneous loss at the earlier stage of pregnancy. However, no-one can know whether their particular miscarriage was a consequence of the procedure or was one that would have happened anyway. Robinson et al (1991) found that women who miscarried after CVS experienced a great deal of guilt and blamed their loss on their selfish desire for an earlier test result. They in fact had even less reason for feeling this way than might be supposed because they were part of the randomised trial and had not actually chosen to have CVS. This is an important point which should be taken into account when counselling women for prenatal diagnosis.
THE FUTURE This paper has described the techniques for detecting fetal abnormalities that are most commonly used in the UK at present. This is, however, a constantly changing held. Most efforts at the moment are being directed towards earlier diagnosis and alternative screening methods. It used to be thought that amniocente-
132
MIDWIFERY
sis could
not be carried
gestation
because
amniotic
fluid.
are
now
However,
reporting
between
out before
9 and
16 weeks
there would not be sufficient a number
successful
14 weeks (Elejalde
Nevin et al, 1990; Kebello
of centres
amniocentesis et al, 1990;
et al, 1991;
Parker
et
prenatal
diagnosis
England
and Wales
shows
that
of
Down’s
(Mutton
the increase
syndrome
in
et al, 1993)
also
in detection
rates
in
women aged under 35 years is the result of improved detection through ultrasound as well as via serum
screening.
In fact, for each of the
al, 1991). This is not yet widely available and no
years 1989,
randomised
nancies in women under 35 years were detected
control
trials of early amniocentesis
via ultrasound
have yet been published. A recent development is the transvaginal examination technique
1988). It is suggested the prenatal
abnormalities
(Lancet
editorial,
although,
in
1989;
early
Cullen
of
1990),
as the Lancet points out, it will be some
before
detected
the
implications
of
anomalies
at this stage can be understood.
who have experienced
the procedure
women is that, unlike traditional ultrasound, fortably that
the fetus
ultrasound,
fold
syndrome thickness positive therefore
with and
Down’s
without
such as the thickness
and
the
BPD/femur
et al, 1987;
rate in a prospective is likely
ratio
et al, 1989).
75% of Down’s a nuchal skin for a 1% false study.
that ultrasound
syndrome
of the
length
Brumfield
pregnancies with of 6 mm or greater appear
Even
abnorma-
to be other measurable
babies
Crane and Gray (1991) identified
Women
It would
screening
to become
for
a major
area of investigation.
transabdominal
The disadvantages
is exposed
ever earlier
to higher
in pregnancy;
may be levels of there
no available data on any possible miscarriage The
screening.
they do not need to have an uncom-
full bladder.
associated
nuchal
as part of
IVF treatment are reported to find it acceptable (Lavy et al, 1987). A particular advantage for
between
Down’s syndrome (Benecerrdf
pregnancy
et al,
lities, there are thought differences
that this
diagnosis
than via serum
when there are not obvious structural
ultrasound
probe which enables detailed
will enable
structural
while
in obstetric
of the fetus in the first trimester
(Green & Hobbins,
1990 and 199 1 more Down’s preg-
is
risk
with this more invasive procedure.
other
ultrasound
new development in
abnormalities. abnormalities
screening A
number
are associated
is the use of
for
chromosomal
of
chromosomal
with structural
ano-
malies (Nyberg et al, 1990) although not all investigators have found this to be the case for Down’s syndrome
(Lynch et al, 1989; Marquette
et al, 1990). However two large studies in France (Eydoux et al, 1989) and the UK (Nicolaides et al, 1992) have published impressive findings on the use of ultrasound detected anomalies as indicators for amniocentesis. The French study found a considerably higher proportion of chromosoma1 abnormalities detected in women who had amniocentesis because of anomalies picked up on scan than amongst those having amniocentesis because oftheir age. The British report found that 14% (i.e. 1 in 7) of those selected on the basis of ultrasound anomalies had chromosomal abnormalities. A recent report on trends in
References Abuelo
D N, Hopmann
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(; et al
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