KH
Nicolaides, NJ Sebire, RJM Snijders |
|
‘The
hair is not black, as in the real Mongol, but of a brownish
colour, straight and scanty. The face is flat and broad, and
destitute of prominence. The cheeks are roundish, and extended
laterally. The eyes are obliquely placed, and the internal canthi
more than normally distant from one another. The palpebral fissure
is very narrow. The forehead is wrinkled transversely from the
constant assistance which the levatores palpebrarum derive from
the occipito-frontalis muscle in opening of the eyes. The lips
are large and thick with transverse fissures. The tongue is
long, thick, and is much roughened. The nose is small. The
skin has a slight dirty yellowish tinge, and is deficient
in elasticity, giving the appearance of being too large for
the body.’
The
above is an extract from the paper ‘Observations on an ethnic
classification of idiots’ by Langdon Down, published in 18661.
Down, who was a physician at the London Hospital, coined the phrase
Mongolian idiots because he felt that a subgroup of his patients
had a resemblance to the Mongolian peoples and this fitted in
with his theory of ‘retrogression’ of ethnic type. Down’s
theory of ethnic regression was in keeping with Darwin’s contemporary
scientific reasoning for evolution. In 1924, Crookshank suggested
that the regression was not merely to a primitive Oriental human
type but also to the orangutan2. Even though the
theory of ethnic regression was proven to be inaccurate,
Down’s description of the appearance of the skin was the basis
for the observation, made more than one century later, that affected
individuals during the 3rd month of intrauterine life, have a
subcutaneous collection of fluid behind the neck (Figure 1), which can be visualized by ultrasound
as nuchal translucency (Figure 2).
|
|
 |
 |
Figure
1 - Fetus with subcutaneous collection of fluid at the
back of the neck.
Image kindly provided by Dr Eva Pajkrt, University
of Amsterdam. |
Figure
2 - Ultrasound picture of a 12-week fetus with trisomy
21, demonstrating increased nuchal translucency thickness |
Langdon
Down in 1866 and Fraser and Mitchell in 1876 recognized that the
condition was congenital, dating from intrauterine life, and in
1914 Goddard found that there was no increased incidence within
families1,3,4. A number of conditions were advocated
as potential causes of Down’s syndrome, including syphilis, tuberculosis,
parental alcoholism, epilepsy, insanity, nervous instability and
mental retardation in a close relative, thyroid deficiency, hypoplasia
of the fetal adrenal glands, dysfunction of the fetal pituitary
and abnormality of the fetal thymus1,6–13.
The
association between Down’s syndrome and increased maternal age
was noted in 1909 by Shuttleworth6, who examined 350
cases and reported that:
‘It
would seem fair inference... that more than half of the Mongolian
imbeciles in institutions are last-born children, mostly of
long families, and that in a considerable proportion – from
one-half to one-third – the mothers were at the time of gestation
approaching the climacteric period, and that in consequence
the reproductive powers were at a low ebb. Which of the two
factors – the advanced age of the mother or her exhaustion
by a long series of previous pregnancies – is the more potent
factor is open to doubt.’6
As
a result of the above observation, hypotheses were based upon
theoretical degeneration of the ovum14–16. However,
advanced maternal age could not be the only factor, because, in
some cases, there appeared to be a hereditary factor as well.
For instance, dizygotic twins were unequally affected whereas
monozygotic twins were equally affected17. It was also
noticed that the condition could be transmitted from mother to
baby, and, when more than one member of a family was affected,
the dependence on the mother’s age was weakened18–21.
The concept of non-dysjunction in Down’s syndrome was suggested
by Waardenburg in 193222. In 1934, Bleyer proposed
that an unequal migration of chromosomes during cell division
may result in trisomy16.
In
1956, Tjio and Levan, working with improved techniques on cultures
of lung fibroblasts, established that the normal diploid chromosome
number is 4623. In the same year, Ford and Hamerton
found that the haploid number was 23 in human spermatocytes24.
These discoveries led a number of laboratories to study the karyotype in
various pathological conditions and in 1959 Lejeune et al.
and Jacobs et al. demonstrated that an extra acrocentric
chromosome was present in persons with Down’s syndrome, resulting
in an aneuploid chromosome number of 4725,26.
There
were familial cases of Down’s syndrome which were not the result
of trisomy. In 1960 Polani et al. examined the chromosomes
of a child with Down’s syndrome from a 21-year-old mother, there
were 46 chromosomes with a centric fusion of two chromosomes
(15:21)27. Familial transmission of this type of translocation
was demonstrated by Penrose et al. in 1960 in a family
with two Down’s syndrome sibs28. In 1961, Clarke et al.
reported on a 2-year-old girl with normal intelligence but some
physical features suggestive of Down’s syndrome; she was discovered
to be a mosaic for normal and trisomic cells29.
Today
we know that Down’s syndrome occurs when either the whole or a
segment of the long arm of chromosome 21 is present in three copies
instead of two. This can occur as a result of three separate mechanisms:
non-dysjunction, found in about 95% of cases, translocation
and mosaicism. In 1991, Antonarakis et al. examined
DNA polymorphisms in Down’s syndrome infants and demonstrated
that 95% of non-dysjunction trisomy 21 is maternal in origin30.
The region that codes for most of the Down’s syndrome phenotype
is the distal portion of band q21.1 and bands q22.2 and q22.3.
This region determines the facial features, heart defects, mental
retardation and probably the dermatoglyphic changes in affected
individuals31.
In
1966, 100 years after the original essay of Langdon Down, it became
possible to diagnose trisomy 21 prenatally by karyotyping of cultured
amniotic fluid cells32,33.
The
first method of screening for trisomy 21, introduced in the early
1970s, was based on the observation of Shuttleworth on the association
with advanced maternal age6. It was apparent that amniocentesis
carried a risk of miscarriage and this in conjunction with the
cost implications, meant that prenatal diagnosis could not be
offered to the entire pregnant population. Consequently, amniocentesis
was initially offered only to women with a minimum age of 40 years.
Gradually, as the application of amniocentesis became more
widespread and it appeared to be ‘safe’, the ‘high-risk’ group
was redefined to include women with a minimum age of 35 years;
this ‘high-risk’ group constituted 5% of the pregnant population.
In
the last 20 years, two dogmatic policies have emerged in terms
of screening. The first, mainly observed in countries with private
healthcare systems, adhered to the dogma of the 35 years of age
or equivalent risk; since the maternal age of pregnant women has
increased in most developed countries, the screen-positive group
now constitute about 10% of pregnancies. The second policy, instituted
in countries with national health systems, has adhered to the
dogma of offering invasive testing to the 5% group of women with
the highest risk; in the last 20 years, the cut-off age for invasive
testing has therefore increased from 35 to 37 years. In screening
by maternal age with a cut-off age of 37 years, 5% of the population
are classified as ‘high risk’ and this group contains about 30%
of trisomy 21 babies.
In
the late 1980s, a new method of screening was introduced that
takes into account not only maternal age but also the concentration
of various fetoplacental products in the maternal circulation.
At 16 weeks of gestation the median maternal serum concentrations
of a-fetoprotein,
estriol and human chorionic gonadotropin (hCG) (total and free-b)
in trisomy 21 pregnancies are sufficiently different from normal
to allow the use of combinations of some or all of these substances
to select a ‘high-risk’ group. This method of screening is more
effective than maternal age alone and, for the same rate of invasive
testing (about 5%), it can identify about 60% of the fetuses with
trisomy 21.
In
the 1990s, screening by a combination of maternal age and fetal
nuchal translucency thickness at 11–14 weeks of gestation was
introduced. This method has now been shown to identify about 75%
of affected fetuses for a screen-positive rate of about 5%.
Recent
evidence suggests that maternal age can be combined with fetal
nuchal translucency and maternal serum biochemistry (free b-hCG
and pregnancy-associated plasma protein (PAPP-A)) at 11–14 weeks
to identify about 90% of affected fetuses. Furthermore, the development
of new methods of biochemical testing, within 30min of taking
a blood sample, has now made it possible to introduce One-Stop
Clinics for Assessment of Risk (Figure 3).
 |
Figure
3 - Assessment of risk for chromosomal defects can be
achieved by the combination of maternal age and history
of previously affected pregnancies, ultrasound measurement
of fetal nuchal translucency and biochemical measurement
of maternal serum free b-hCG and PAPP-A in an OSCAR at 11-14
weeks of gestation. After counselling, the patient can decide
if she wants fetal karyotyping, which can be carried out
by chorionic villus sampling in the same visit.
|
|
| CALCULATION
OF RISK FOR CHROMOSOMAL DEFECTS |
|
|
Every
woman has a risk that her fetus/baby has a chromosomal defect.
In order to calculate the individual risk, it is necessary to
take into account the background risk (which depends on
maternal age, gestation and previous history of chromosomal defects)
and multiply this by a series of factors, which depend
on the results of a series of screening tests carried out during
the course of the pregnancy. Every time a test is carried out
the background risk is multiplied by the test factor to
calculate a new risk, which then becomes the background risk for
the next test34. This process is called sequential
screening. With the introduction of OSCAR, this can all be
achieved in one session at about 12 weeks of pregnancy (Figure 3).
| Maternal
age and gestation |
The
risk for many of the chromosomal defects increases with maternal
age (Figure 4). Additionally, because fetuses with chromosomal
defects are more likely to die in utero than normal fetuses,
the risk decreases with gestational age (Figure 5).
| |
|
| Figure
4 - Maternal age-related risk for chromosomal abnormalities |
Figure
5 -Gestational age-related risk for chromosomal abnormalities.
The lines represent the relative risk according to the risk
at 10 weeks of gestation. |
| |
Estimates
of the maternal age-related risk for trisomy 21 at birth are based
on two surveys with almost complete ascertainment of the affected
patients; in a survey in South Belgium, every neonate was examined
for features of trisomy 21 and, in a survey in Sweden, information
was verified using several sources such as hospital notes, cytogenetic
laboratories, genetic clinics and schools for the mentally handicapped35,36.
The data from these surveys were used to calculate maternal age-specific
incidences of trisomy 21 at birth37.
During
the last decade, with the introduction of maternal serum biochemistry
and ultrasound screening for chromosomal defects at different
stages of pregnancy, it has become necessary to establish maternal
age and gestational age-specific risks for chromosomal defects.
Such estimates were derived by comparing the birth prevalence
of trisomy 2137 to the prevalence in women undergoing
second-trimester amniocentesis or first-trimester chorionic villus
sampling. Rates of spontaneous fetal death between different gestations
and delivery at 40 weeks were estimated on the basis of both the observed
prevalence in pregnancies that had antenatal fetal karyotyping
and the reported prevalence in live births.
Snijders
et al. examined the prevalence of trisomy 21 in 57614 women
who had fetal karyotyping at 9–16 weeks of gestation for the sole
indication of maternal age of 35 years or more; this group
included 538 pregnancies with trisomy 2138–40. They
found that the prevalence of trisomy 21 was higher in early pregnancy
than in live births and the estimated rates of fetal loss were
36% from 10 weeks, 30% from 12 weeks, and 21% from 16 weeks38.
The estimated maternal age and gestational age-related risks for
trisomy 21 are given in Table 1.
| Risk of trisomy 21
(Snijders
et al. Ultrasound Obstet Gynecol 1999;13:167–70) |
| Maternal age (years) |
Gestational age |
|
10 weeks |
12 weeks |
14 weeks |
16 weeks |
20 weeks |
40 weeks |
| 20
25
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45 |
1/983
1/870
1/576
1/500
1/424
1/352
1/287
1/229
1/180
1/140
1/108
1/82
1/62
1/47
1/35
1/26
1/20
1/15 |
1/1068
1/946
1/626
1/543
1/461
1/383
1/312
1/249
1/196
1/152
1/117
1/89
1/68
1/51
1/38
1/29
1/21
1/16 |
1/1140
1/1009
1/668
1/580
1/492
1/409
1/333
1/266
1/209
1/163
1/125
1/95
1/72
1/54
1/41
1/30
1/23
1/17 |
1/1200
1/1062
1/703
1/610
1/518
1/430
1/350
1/280
1/220
1/171
1/131
1/100
1/76
1/57
1/43
1/32
1/24
1/18 |
1/1295
1/1147
1/759
1/658
1/559
1/464
1/378
1/302
1/238
1/185
1/142
1/108
1/82
1/62
1/46
1/35
1/26
1/19 |
1/1527
1/1352
1/895
1/776
1/659
1/547
1/446
1/356
1/280
1/218
1/167
1/128
1/97
1/73
1/55
1/41
1/30
1/23 |
In
a similar study, Halliday et al. compared the prevalence
of trisomy 21 in 10545 women having chorionic villus sampling
or amniocentesis to the prevalence in live births from 12921 women
of similar age who did not have fetal karyotyping41.
Their estimated fetal loss rate between 10 weeks and term was
31% and between 16 weeks and term was 18%. Morris et al.
examined outcome data from 4148 trisomy 21 pregnancies reported
to the National Down Syndrome Cytogenetic Register in the UK with
correction for elective terminations. Their study population included
441 cases diagnosed at 11–13 weeks of gestation and 2035 cases
diagnosed at 16–18 weeks; they estimated that the loss rates between
12 and 16 weeks and term were 31% and 24%, respectively42.
These estimates for spontaneous loss between the first trimester
and term are lower than the 48% reported by Mackintosh et al.
who compared the prevalence of trisomy 21 at chorionic villus
sampling and birth; the most likely explanation for this high
rate (48%), compared to rates derived in the other reports (31%),
is that the study included a substantial proportion of cases in
which chorionic villus sampling was performed before 10 weeks
of gestation43.
Similar
methods were used to produce estimates of risks for other chromosomal
abnormalities40. The risk for trisomy
18 and trissomy 13 increases with
maternal age and decreases with gestation; the rate of intrauterine
lethality between 12 weeks and 40 weeks is about 80% (Table
2 and Table 3). Turner syndrome is
usually due to loss of the paternal X chromosome and, consequently,
the frequency of conception of 45,X embryos, unlike that of trisomies,
is unrelated to maternal age. The prevalence is about 1 per 1500
at 12 weeks, 1 per 3000 at 20 weeks and 1 per 4000 at 40 weeks.
For the other sex chromosome abnormalities (47,XXX, 47,XXY and
47,XYY), there is no significant change with maternal age and
since the rate of intrauterine lethality is not higher than in
chromosomally normal fetuses the overall prevalence (about 1 per
500) does not decrease with gestation. Polyploidy affects about
2% of recognized conceptions but it is highly lethal and thus
very rarely observed in live births; the prevalences at 12 and
20 weeks are about 1 per 2000 and 1 per 250000, respectively40.
| Risk of trisomy 18
(Snijders
et al. Fetal Diag Ther 1995;10:356–67) |
| Maternal
age (years) |
Gestational age |
|
10 weeks |
12 weeks |
14 weeks |
16 weeks |
20 weeks |
40 weeks |
| 20
25
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44 |
1/1993
1/1765
1/1168
1/1014
1/860
1/715
1/582
1/465
1/366
1/284
1/218
1/167
1/126
1/95
1/71
1/53
1/40 |
1/2484
1/2200
1/1456
1/1263
1/1072
1/891
1/725
1/580
1/456
1/354
1/272
1/208
1/157
1/118
1/89
1/66
1/50 |
1/3015
1/2670
1/1766
1/1533
1/1301
1/1081
1/880
1/703
1/553
1/430
1/330
1/252
1/191
1/144
1/108
1/81
1/60 |
1/3590
1/3179
1/2103
1/1825
1/1549
1/1287
1/1047
1/837
1/659
1/512
1/393
1/300
1/227
1/171
1/128
1/96
1/72 |
1/4897
1/4336
1/2869
1/2490
1/2490
1/1755
1/1429
1/1142
1/899
1/698
1/537
1/409
1/310
1/233
1/175
1/131
1/98 |
1/18013
1/15951
1/10554
1/9160
1/7775
1/6458
1/5256
1/4202
1/3307
1/2569
1/1974
1/1505
1/1139
1/858
1/644
1/481
1/359 |
| Risk of trisomy 13
(Snijders
et al. Fetal Diag Ther 1995;10:356–67) |
| Maternal
age (years) |
Gestational age |
|
10 weeks |
12 weeks |
14 weeks |
16 weeks |
20 weeks |
40 weeks |
| 20
25
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44 |
1/6347
1/5621
1/3719
1/3228
1/2740
1/2275
1/1852
1/1481
1/1165
1/905
1/696
1/530
1/401
1/302
1/227
1/170
1/127 |
1/7826
1/6930
1/4585
1/3980
1/3378
1/2806
1/2284
1/1826
1/1437
1/1116
1/858
1/654
1/495
1/373
1/280
1/209
1/156 |
1/9389
1/8314
1/5501
1/4774
1/4052
1/3366
1/2740
1/2190
1/1724
1/1339
1/1029
1/784
1/594
1/447
1/335
1/251
1/187 |
1/11042
1/9778
1/6470
1/5615
1/4766
1/3959
1/3222
1/2576
1/2027
1/1575
1/1210
1/922
1/698
1/526
1/395
1/295
1/220 |
1/14656
1/12978
1/8587
1/7453
1/6326
1/5254
1/4277
1/3419
1/2691
1/2090
1/1606
1/1224
1/927
1/698
1/524
1/392
1/292 |
1/42423
1/37567
1/24856
1/21573
1/18311
1/15209
1/12380
1/9876
1/7788
1/6050
1/4650
1/3544
1/2683
1/2020
1/1516
1/1134
1/846 |
Creating
the model for calculation of the maternal and gestational age-specific
risks made it possible to counsel patients presenting at different
stages of pregnancy about the risk for their fetus having a chromosomal
defect and the chance that the pregnancy will result in a live
birth with a specific condition. Furthermore, these data can be
applied in the evaluation of new ultrasonographic or biochemical
methods of screening by calculating the expected prevalence of
chromosomal defects in any study group.
| Previous
affected pregnancy |
The
risk for trisomies in women who have had a previous fetus or child
with a trisomy is higher than the one expected on the basis of
their age alone. In a study of 2054 women who had a previous pregnancy
with trisomy 21, the risk of recurrence in the subsequent pregnancy
was 0.75% higher than the maternal and gestational age-related
risk for trisomy 21 at the time of testing. In 750 women who had
a previous pregnancy with trisomy 18, the risk of recurrence in
the subsequent pregnancy was also about 0.75% higher than the
maternal and gestational age-related risk for trisomy 18; the
risk for trisomy 21 was not increased44. Thus,
for a woman aged 35 years who has had a previous baby with trisomy
21, the risk at 12 weeks of gestation increases from 1 in 249
(0.40%) to 1 in 87 (1.15%), and, for a woman aged 25 years, it
increases from 1 in 946 (0.106%) to 1 in 117 (0.856%).
The
possible mechanism for this increased risk is that a small proportion
(less than 5%) of couples with a previously affected pregnancy
have parental mosaicism or a genetic defect that interferes with
the normal process of dysjunction, so in this group the risk of
recurrence is increased substantially. In the majority of couples
(more than 95%), the risk of recurrence is not actually increased.
Currently available evidence suggests that recurrence is chromosome-specific
and, therefore, in the majority of cases, the likely mechanism
is parental mosaicism.
| Fetal
nuchal translucency at the 11–14-week scan |
The
nuchal translucency normally increases with gestation (crown–rump
length). In a fetus with a given crown–rump length, every nuchal
translucency measurement represents a factor which is multiplied
by the background risk to calculate a new risk. The larger the
nuchal translucency, the higher the multiplying factor becomes
and therefore the higher the new risk. In contrast, the smaller
the nuchal translucency measurement, the smaller the multiplying
factor becomes and therefore the lower the new risk (Figure 6).
 |
 |
| Crown–Rump
Length - CRL
6 to 14 weeks +6days |
Nuchal
translucency normally increases with gestation (crown–rump
length) |
To
calculate the multiplying factor (likelihood ratio), it is first
necessary to determine the distributions of nuchal translucency
thickness in the chromosomally normal and trisomy 21 groups. For
a given nuchal translucency, a likelihood ratio is calculated
by dividing the percentage of trisomy 21 fetuses by the percentage
of normal fetuses with that translucency. The combined risk is
then calculated by multiplying the background maternal and gestational
age-related risk by the likelihood ratio.
 |
| Figure
6 - Maternal age-related risk for trisomy 21 at 12 weeks
of gestation and the effect of fetal nuchal translucency thickness
(NT) |
| Maternal
serum biochemistry at 11–14 weeks |
The
level of free b-hCG in maternal blood normally decreases with
gestation. The higher the b-hCG, the higher the risk for trisomy
21. Again, for a given gestation, each hCG level represents a
factor that is multiplied by the background risk to calculate
the new risk (Figure 7). The level of PAPP-A in maternal blood normally
increases with gestation. The lower the PAPP-A, the higher the
risk for trisomy 21. Again, for a given gestation, each PAPP-A
level represents a factor that is multiplied by the background
risk to calculate the new risk (Figure 7).
 |
| Figure
7 - Maternal age-related risk for trisomy 21 at 12 weeks
of gestation
and the effect of maternal serum free b-hCG (left) and PAPP-A
(right) |
|
|
During
the second and third trimesters of pregnancy, abnormal accumulation
of fluid behind the fetal neck can be classified as nuchal cystic
hygroma or nuchal edema. In about 75% of fetuses with cystic hygromas,
there is a chromosomal abnormality and, in about 95% of cases,
the abnormality is Turner syndrome45. Nuchal edema
has a diverse etiology; chromosomal abnormalities are found in
about one-third of the fetuses and, in about 75% of cases,
the abnormality is trisomy 21 or 18. Edema is also associated
with fetal cardiovascular and pulmonary defects, skeletal dysplasias,
congenital infection and metabolic and hematological disorders;
consequently, the prognosis for chromosomally normal fetuses with
nuchal edema is poor46.
In
the first trimester, the term translucency is used, because this
is the ultrasonographic feature that is observed; during the second
trimester, the translucency usually resolves and, in a few cases,
it evolves into either nuchal edema or cystic hygromas with or
without generalized hydrops.
| Measurement
of nuchal translucency |
Nuchal
translucency can be measured successfully by transabdominal ultrasound
examination in about 95% of cases; in the others, it is necessary
to perform transvaginal sonography. The equipment must be of good
quality (about £30000–50000), it should have a video-loop function
and the callipers should be able to provide measurements to one
decimal point. The average time allocated for each fetal scan should
be at least 10 minutes. All sonographers performing fetal scans
should be capable of reliably measuring the crown–rump length
and obtaining a proper sagittal view of the fetal spine. For such
sonographers, it is easy to acquire, within a few hours, the skill
to measure nuchal translucency thickness. Furthermore, it is essential
that the same criteria are used to achieve uniformity of
results among different operators (Figure 8):
-
The
minimum fetal crown–rump length should be 45mm and the maximum
84mm. The optimal gestational age for measurement of fetal
nuchal translucency is 11 to 13+6 weeks. The success
rate for taking a measurement at this gestation is 98–100%,
falling to 90% at 14 weeks; from 14 weeks onwards, the fetal
position (vertical) makes it more difficult to obtain measurements47.
-
The
results from transabdominal and transvaginal scanning are
similar but reproducibility may be better with the transvaginal
method48.
-
A
good sagittal section of the fetus, as for measurement of
fetal crown–rump length, should be obtained.
-
The
magnification should be such that the fetus occupies at least
three-quarters of the image. Essentially, the magnification
should be increased so that each increment in the distance
between callipers should be only 0.1mm. A study, in which
rat heart ventricles were measured initially by ultrasound
and then by dissection, has demonstrated that ultrasound measurements
can be accurate to the nearest 0.1–0.2mm49.
-
Care
must be taken to distinguish between fetal skin and amnion
because, at this gestation, both structures appear as thin
membranes. This is achieved by waiting for spontaneous fetal
movement away from the amniotic membrane; alternatively, the
fetus is bounced off the amnion by asking the mother to cough
and/or by tapping the maternal abdomen.
-
The
maximum thickness of the subcutaneous translucency between
the skin and the soft tissue overlying the cervical spine
should be measured by placing the callipers on the lines as
shown in Figure 8. During the scan, more than one measurement
must be taken and the maximum one should be recorded.
-
The
nuchal translucency should be measured with the fetus in the
neutral position. When the fetal neck is hyperextended the
measurement can be increased by 0.6mm and when the neck
is flexed, the measurement can be decreased by 0.4mm50.
-
The
umbilical cord may be round the fetal neck in 5–10% of cases
and this finding may produce a falsely increased nuchal translucency,
adding about 0.8mm to the measurement51. In such
cases, the measurements of nuchal translucency above and below
the cord are different and, in the calculation of risk, it
is more appropriate to use the smaller measurement.
The
distribution of nuchal translucency measurements as well as the
quality of the images in terms of magnification, section (sagittal
or oblique), calliper placement, skin line (nuchal only or nuchal
and back) and visualization of the amnion separate from the nuchal
membrane are taken into account in the audit of results52.
The
ability to measure nuchal translucency and obtain reproducible
results improves with training; good results are achieved after
80 and 100 scans for the transabdominal and the transvaginal routes,
respectively53.
The
ability to achieve a reliable measurement of nuchal translucency
is dependent on the motivation of the sonographer. A study comparing
the results obtained from hospitals where nuchal translucency
was used in clinical practice (interventional) compared to those
from hospitals where they merely recorded the measurements but
did not act on the results (observational), reported that, in
the interventional group, successful measurement of nuchal translucency
was achieved in 100% of cases and the measurement was >
2.5mm in 2.3% of cases; the respective percentages in the observational
group were 85% and 12%54,55.
Appropriate
training, high motivation and adherence to a standard technique
for the measurement of nuchal translucency are essential
prerequisites for good clinical practice. Monni et al.
reported that, after modifying their technique of measuring nuchal
translucency thickness, by following the guidelines established
by The Fetal Medicine Foundation, their detection rate of trisomy
21 improved from 30% to 84%56.
| Repeatability
in the measurement of nuchal translucency |
A
potential criticism of screening by ultrasound is that scanning
not only requires highly skilled operators but it is also prone
to operator variability. This issue was addressed by a prospective
study at 10–14 weeks of gestation in which the nuchal translucency
was measured by two of four operators in 200 pregnant women57.
This study demonstrated that, after an initial measurement, the
second one made by the same (intra-) observer or another
(inter-) observer varies from the first by less than 0.54mm and
0.62mm, respectively in 95% of the cases. Additionally, the study
demonstrated that the calliper placement repeatability was similar
to the intra-observer and inter-observer repeatabilities, suggesting
that a large part of the variation in measurements can be accounted
for by the placement of the callipers rather than the generation
of the image57. Subsequent studies have reported that
the intra-observer and inter-observer differences in measurements
were less than 0.5mm in 95% of cases58,59.
Digital
image processing and automation of calliper placement may reduce
the variation of measurements60. In the meantime, it
is best to rely on the mean of two good measurements for the calculation
of risk, rather than on a single one.
| Increase
in nuchal translucency with gestational age |
Fetal
nuchal translucency thickness increases with crown–rump length49,61,
and therefore it is essential to take gestation into account when
determining whether a given translucency thickness is increased.
In a study involving more than 100000 pregnancies, the median
increased from 1.2mm at 11 weeks to 1.9mm at 13+6 weeks62.
Figure 9 illustrates the increases in the 5th,
25th, 50th, 75th and 95th centiles of nuchal translucency with
crown–rump length; the 99th centile is about 3.5mm throughout
this gestational range.
 |
| Figure
9 - Reference range of fetal nuchal translucency with
crown–rump length showing the 5th, 25th, 50th, 75th and 95th
centiles |
| |
| Snijders,
Nicolaides |
| Observational
studies: increased nuchal translucency and chromosomal defects |
In
the early 1990s, several reports of small series in high-risk
pregnancies demonstrated a possible association between increased
nuchal translucency and chromosomal defects in the first
trimester of pregnancy (Table 4)63–80. Although the mean prevalence
of chromosomal defects in 20 series involving a total of 1698
patients was 29%, there were large differences between the studies
with the prevalence ranging from 11% to 88%. This variation in
results presumably reflects differences in the maternal age distributions
of the populations examined as well as in the definition of the
minimum abnormal translucency thickness, which ranged from 2mm
to 10mm.
Subsequently,
a series of screening studies in high-risk pregnancies were carried
out; these involved measurement of nuchal translucency thickness
immediately before fetal karyotyping, mainly for advanced maternal
age. Pandya et al. examined a total of 1273 pregnancies
and reported that the nuchal translucency thickness was above
the 95th centile of the normal range in about 80% of trisomy 21
fetuses81. Similar findings were obtained in an additional
four studies of pregnancies undergoing first-trimester fetal karyotyping
73,74,76,78. However, in another study involving 1819
pregnancies, nuchal translucency thickness of equal to or greater
than 3mm identified only 30% of the chromosomally abnormal fetuses
(no data were provided specifically for trisomy 21) and the false-positive
rate was 3.2%72.
| Table
4 - Summary of reported series on first-trimester fetal
nuchal translucency (NT) providing data on gestational age
(GA) in weeks, criteria for diagnosis of increased NT thickness
and the presence of associated chromosomal defects
|
 |
An
important finding of the screening studies in high-risk pregnancies
was that the prevalence of chromosomal defects is dependent
on both fetal nuchal translucency thickness and maternal
age. For example, in a study of 1015 pregnancies with increased
fetal nuchal translucency thickness at 10–14 weeks of gestation,
the observed numbers of trisomies 21, 18 and 13 in fetuses with
translucencies of 3mm, 4mm, 5mm and > 6mm were approximately
3 times, 18 times, 28 times and 36 times higher than the
respective number expected on the basis of maternal age67. The
incidences of Turner syndrome and triploidy were 9 times and 8
times higher, whilst the incidence of other sex chromosome aneuploidies
was similar to that expected67.
| Implementation
of nuchal translucency screening in routine practice |
There
are nine studies that have examined the implementation of nuchal
translucency screening in routine practice and the results are
summarized in Table 554,74,82–88. The number of trisomy
21 pregnancies in all but one86 of these studies is
too small to allow assessment of the sensitivity of the test.
However, these studies demonstrate a series of important points:
-
It
is possible to measure nuchal translucency successfully during
a routine first-trimester scan in 96–100% of cases, provided
that, first, the gestation is 11–14 weeks and, second, the
sonographers are motivated to take such a measurement. Thus,
in the two studies that examined the feasibility of measuring
nuchal translucency but in which (a) they included patients
from as early as 8 weeks, and (b) no action was taken on the
results of the translucency measurement, such a measurement
was obtained in only 58% and 66% of cases, respectively83,84.
-
The
false-positive rate varied from as low as 0.886
to as high as 6.3%54,84, demonstrating the need
for unifying the criteria in (a) obtaining the appropriate
image, (b) calliper placement, and (c) using the same
normal range and same cut-off.
| Table
5 Studies examining the implementation of fetal nuchal
translucency (NT) screening |
 |
The
Frimley Park Hospital, Camberley and St. Peter’s Hospital, Chertsey,
UK82
Frimley
Park and St. Peter’s are general hospitals within the NHS offering
routine antenatal care, and their combined annual number of deliveries
is approximately 6000. Prior to the introduction of nuchal translucency
scanning, the policy of these hospitals was to offer amniocentesis
to women aged 35 years or older. During 1993 there were 11 fetuses
with Down’s syndrome and only two of these were detected prenatally.
Subsequently, nuchal translucency screening at 10–14 weeks of
gestation was introduced and the implementation of this policy
was achieved without the need for increasing the number of staff
or the equipment. Women with fetal translucency of 2.5mm or more
were offered fetal karyotyping. In addition women aged 35 years
or older were offered amniocentesis at 16 weeks’ gestation.
The data of the first 5 months after the introduction of the new
policy were analyzed following completion of the pregnancies.
During this period, 74% of women delivering in the two hospitals
attended for first-trimester scanning and the nuchal translucency
was successfully measured in all pregnancies. The nuchal translucency
was raised in 3.6% of cases and the total percentage of invasive
procedures was 5.1%. All four cases of Down’s syndrome that occurred
in this period were diagnosed prenatally82.
University
College Hospital, London, UK83
In
a screening study of 1704 women with singleton pregnancies attending
University College Hospital, London, for routine antenatal care
at 8–14 weeks of gestation, transabdominal ultrasound examination
was performed. In 20% of cases, the sonographers forgot to measure
the nuchal translucency thickness. In a further 18% of those women
in whom a measurement was attempted, this was unsuccessful. In
28% of the 1127 cases in whom measurements were made, the scans
were carried out before 10 weeks of gestation. The nuchal translucency
was equal to or greater than 3mm in 6% of the cases. The population
contained three fetuses with trisomy 21, all in women aged equal
to or greater than 39 years, and increased nuchal translucency
was found in one83.
Queen
Charlotte’s and Guy’s Hospitals, London, UK54
This
report combined the data from two centers; in one the study was
observational and in the other it was interventional. The nuchal
translucency was equal to or greater than 3mm in four (50%) of
the eight trisomy 21 pregnancies. In the interventional center,
969 pregnancies were examined, the nuchal translucency was successfully
measured in all cases and the translucency was equal to or greater
than 3mm in 20 (2.0%) of the 966 chromosomally normal pregnancies.
In contrast, in the observational center, 512 pregnancies were
examined, the nuchal translucency was successfully measured in
470 (92%) of cases and the translucency was equal to or greater
than 3mm in 73 (14.5%) of the 505 chromosomally normal pregnancies.
These results suggest that the accuracy of measurements depends
on the motivation of the sonographers54.
University
Hospital, Groningen, The Netherlands84
This
was a screening study of an apparently low-risk population, but
in 54% of the cases the mothers were equal to or greater than
36 years old or had a history of a previous chromosomally abnormal
fetus/child. In total, 923 fetuses were scanned transabdominally
at equal to or less than 13 weeks of gestation by four ultrasonographers
who were instructed not to take more than 3 minutes in making
a nuchal translucency measurement. In 54% of cases, the fetal
crown–rump length was <33mm. Furthermore, in 42% of cases,
the nuchal translucency could not be measured. In this population,
there were seven cases of trisomy 21 and the authors suggested
that the sensitivity of nuchal translucency screening is low because
only two of the fetuses had increased translucency. However, in
reality, only three of the fetuses with trisomy 21 had a crown–rump
length of > 38mm and a nuchal translucency measurement, and
in two of these the translucency was increased84.
Helsinki
University Hospital and Jorvi Hospital, Finland86
In
this study, transvaginal sonography was performed in 10010 singleton
pregnancies at 10–16 weeks of gestation. Scans were performed
by one of six sonographers who were successful in obtaining an
ultrasound measurement in 98.6% of cases. Increased nuchal translucency
(equal to or greater than 3mm) was observed in 76 (0.8%) of the
fetuses and this group included seven (54%) of the 13 fetuses
with trisomy 21; the sensitivity for pregnancies at 10–14 weeks
was 66% (four of six), for a screen-positive rate of only 0.9%86.
Danube
Hospital, Vienna, Austria87
In
a screening study of 4371 women with singleton pregnancies attending
a government hospital in Vienna for routine antenatal care at
10–14 weeks of gestation, transabdominal ultrasound examination
was performed and the fetal nuchal translucency thickness was
successfully measured in all cases. The nuchal translucency thickness
was equal to or greater than 2.5mm in 1.7% of the cases and this
group included three (43%) of seven with trisomy 2187.
Academic
Medical Center, Amsterdam, The Netherlands88
This
study examined 1547 pregnancies, including 24% aged > 36 years
old, at 10–14 weeks. Scans were performed by one of six sonographers
who were successful in obtaining an ultrasound measurement in
96% of cases. Nuchal translucency was equal to or greater than
3mm in 33 (2.2%) cases and this group included six (67%) of the
nine fetuses with trisomy 2188.
Albert
Szent-Gyorgyi Medical University Hospital, Szeged, Hungary74
In
this study involv- ing 3380 women at 9–12 weeks of gestation,
nuchal translucency was successfully measured transvaginally in
all cases. Increased translucency (equal to or greater than 3mm)
was observed in 81 (2.4%) of fetuses and this group included 28
(90%) of 31 fetuses with trisomy 2174.
University
Hospital, Zurich, Switzerland85
In
this study, nuchal translucency was measured in 1131 pregnancies
at 10–13 weeks of gestation. Increased translucency (equal to
or greater than 3mm) was observed in 24 (2.1%) of fetuses and
this group included two (67%) of three fetuses with trisomy 2185.
| Screening
by a combination of maternal age and fetal nuchal translucency |
The
Multicenter Screening Study
In
a multicenter study in the UK, involving the Harris Birthright
Centre and four District General Hospitals (St. Peters, Chertsey;
Frimley Park, Camberly; Queen Mary’s, Sidcup; Heatherwood, Ascot),
nuchal translucency screening at 10–14 weeks of gestation was
carried out in 20804 pregnancies, including 164 cases of chromosomal
abnormalities61. This study demonstrated that:
-
In
normal pregnancies, nuchal translucency thickness increases
with gestation;
-
In
chromosomally abnormal pregnancies, nuchal translucency is
increased;
-
The
risk for trisomies can be derived by multiplying the background
maternal age and gestation-related risk by a likelihood
ratio, which depends on the degree of deviation in nuchal
translucency measurement from the expected normal median for
that crown–rump length;
-
In
about 5% of pregnancies, the estimated risk for trisomy 21
was at least 1 in 100 and this group included 80% of fetuses
with trisomy 21 and 77% of those with other chromosomal abnormalities.
Because the maternal age of the screened population was higher
than in Britain as a whole, it was estimated that the cut-off
risk to include 5% of the British population (median maternal
age of 28 years) is 1 in 300; using this cut-off, the sensitivity
of the test for trisomy 21 was estimated to be about 80%.
The
Fetal Medicine Foundation Ongoing Multicenter Project
There
are now 43 countries with centers approved by The Fetal Medicine
Foundation for carrying out nuchal translucency screening. In
the audit of results from the first 100000 pregnancies examined
in the UK, the nuchal translucency was above the 95th centile
in more than 70% of fetuses with trisomy 2162. The
scans were carried out by 306 appropriately trained sonographers
in 22 centers. In each pregnancy, the fetal crown–rump length
and nuchal translucency were measured and the risk of trisomy
21 was calculated from the maternal age and gestational age-related
prevalence, multiplied by a likelihood ratio depending on the
deviation in nuchal translucency from normal (Figures 10–12). The distribution of risks was determined
and the sensitivity of a cut-off risk of 1 in 300 was calculated62.
 |
| Figure
10 -Nuchal translucency measurement in 326 trisomy 21
fetuses plotted on the normal range for crown–rump length
(95th and 5th centiles)62 |
 |
| Figure
11 - Distribution of fetal nuchal translucency thickness
expressed as deviation from expected normal median for crown-rump
length in chromosomally normal fetuses (open bars) and 326
with trisomy 21 (solid bars)62 |
 |
Figure
12 - Likelihood ratios for trisomy 21 in relation to
the deviation in fetal nuchal translucency thickness from
the expected normal median for crown-rump length62 |
In
total, 100311 singleton pregnancies were examined and follow-up
was obtained from 96127 cases, including 326 with trisomy 21 and
325 with other chromosomal abnormalities. The median gestation
at the time of screening was 12 weeks (range 10–14 weeks) and
the median maternal age was 31 years (range 14–49 years); in 13315
(13.3%) cases, the maternal age was at least 37 years. The fetal
nuchal translucency was above the 95th centile for crown–rump
length in 4210 (4.4%) of the normal pregnancies and in 234 (71.8%)
of those with trisomy 21 (Figure 10). The estimated risk for trisomy 21 based
on maternal age and fetal nuchal translucency was above 1 in 300
in 7907 (8.3%) of the normal pregnancies and in 268 (82.2%) of
those with trisomy 21. For a screen-positive rate of 5%, the sensitivity
was 77% (95% confidence interval (CI) 72–82%)62.
Table 6 illustrates the observed prevalence of trisomy
21 according to the predicted risk based on maternal age and fetal
nuchal translucency thickness. These results demonstrate the high
degree of accuracy of the model.
| Table
6 - Accuracy of estimated risk (median and range) for
trisomy 21 by a combination of maternal age and fetal nuchal
translucency thickness62 |
|
| Estimated
risk |
n |
Trissomy
21 |
Observed
prevalence |
|
| 1
in 7 (1 in 2 - 1 in 19) |
1.305 |
187 |
1
in 47 |
| 1
in 59 (1 in 20 - 1 in 99) |
2.001 |
49 |
1
in 41 |
| 1
in 198 (1 in 100 - 1 in 999) |
18.279 |
31 |
1
in 159 |
| 1
in 632 (1 in 300 - 1 in 999) |
19.445 |
14 |
1
in 1389 |
| 1
in 3072 (1 in 2000 - 1 in 6000) |
49.991 |
13 |
1
in 3846 |
|
Other
screening studies using nuchal translucency expressed as
centiles
|
The Royal Free Hospital, London, UK89
In
this study, nuchal translucency was measured at 11–14 weeks
in 2281 pregnancies with a mean maternal age of 30 years. The
nuchal translucency was equal to or greater than 99th centile
for crown–rump length in six of the eight (75%) fetuses with trisomy
21. In the two trisomic pregnancies with low nuchal translucency,
maternal serum biochemistry at 16 weeks also showed a low risk.
Homerton–St.
Bartholomew’s–Royal London Hospitals, London, UK90
In
this study, women were offered screening by a combination of maternal
age and fetal nuchal translucency at 12–13 weeks. A risk cut-off
of 1 in 100 was used to identify the high-risk group; the screen-positive
rate was 2.6% and this group contained five (71%) of seven cases
of trisomy 21.
The
Greek multicenter study91
This
was a multicenter study involving routine measurement of nuchal
translucency thickness in 3550 pregnancies at 10–14 weeks of gestation.
The median maternal age was 29 years and 7.8% were aged 37 years
or more. All five ultrasonographers had received a Certificate
of Competence in first-trimester scanning by The Fetal Medicine
Foundation. Successful measurements of nuchal translucency were
obtained in all cases. The risk of trisomy 21, based on a combination
of maternal age and fetal nuchal translucency thickness, was equal
to or greater than 1 in 300 in 4.9% of the population and this
high-risk group contained 10 of the 11 (91%) fetuses with trisomy
21, and all five cases of trisomies 18 or 13.
Ospedale
Regionale per le Microcitemie, Cagliari, Italy56
Monni
et al. (1997) introduced screening on the basis of
fetal nuchal translucency in January 1995; by May 1995 a total
of 1176 patients with a crown–rump length of 17–85mm had been
examined. They identified only 30% of fetuses with a chromosome
abnormality using a cut-off of equal to or greater than 3mm. In
1996, sonographers modified the technique to follow guidelines
established by The Fetal Medicine Foundation. In the subsequent
year, the detection rate based on maternal age and fetal nuchal
translucency thickness improved to 84%56.
University
of Florence Hospital, Florence, Italy92
Biagiotti
et al. evaluated screening on the basis of fetal nuchal
translucency in 3241 pregnancies examined at 9–13 weeks of gestation.
The authors compared two different methods, delta nuchal translucency
and multiples of the expected median. They concluded that expressing
values as multiples of the median, as used in screening with maternal
serum biochemistry, provides optimal results. Screening based
on maternal age and fetal nuchal translucency identified 59% of
the cases for a 5% false-positive rate92.
Cervello
Hospital, Palermo, Italy93
Orlandi
et al. evaluated screening for aneuploidy with fetal
nuchal translucency and maternal serum biochemistry at 9–14 weeks
of gestation. Nuchal translucency was measured in 744 pregnancies
and was above the 95th centile in four (57%) of seven fetuses
with trisomy 21 and in 42 (5.8%) of the 730 normal fetuses. The
findings further indicated that screening by a combination of
maternal age, fetal nuchal translucency and maternal serum biochemistry
at 9–14 weeks of gestation identifies 87% of affected pregnancies
for a 5% false-positive rate93.
| Lethality
of trisomy 21 fetuses with increased nuchal translucency |
Screening
for chromosomal defects in the first rather than the second trimester
has the advantage of earlier prenatal diagnosis and consequently
less traumatic termination of pregnancy for those couples who
choose this option. A potential disadvantage is that earlier screening
preferentially identifies those chromosomally abnormal pregnancies
that are destined to miscarry. Approximately 30% of affected fetuses
die between 12 weeks of gestation and term38,41,42.
This issue of preferential intrauterine lethality of chromosomal
defects is, of course, a potential criticism of all methods of
antenatal screening, including second-trimester maternal serum
biochemistry; the estimated rate of intrauterine lethality between
16 weeks and term is about 20%38,41,42. This section
examines the interrelation between increased nuchal translucency
in trisomy 21 and fetal lethality.
Decision
to continue with the pregnancy after the diagnosis of trisomy
21
In
a study of 108 fetuses with trisomy 21 diagnosed in the first
trimester because of increased nuchal translucency, the parents
chose to continue with the pregnancy in five cases, whereas in
103 cases they opted for termination94. Trisomy 21
was also diagnosed in one of the fetuses in a twin pregnancy where
the parents elected to avoid invasive prenatal diagnosis or selective
fetocide94. In five of the six fetuses, the translucency
resolved, and at the second-trimester scan the nuchal-fold thickness
was normal (less than 7mm). All six trisomy 21 babies were born
alive. One had a major atrioventricular septal defect and died
at the age of 6 months. Another two of the babies had small ventricular
septal defects and these were managed conservatively, awaiting
spontaneous closure. These data suggest that increased nuchal
translucency does not necessarily identify those trisomic fetuses
that are destined to die in utero.
Decision
to terminate the pregnancy after the diagnosis of trisomy 21
In
a study of 70 pregnancies with trisomy 21 diagnosed at 12 (range
11–14) weeks of gestation, the parents opted for elective termination
which was carried out at 14 (12–20) weeks. Ultrasound examination
to determine if the fetus was alive was carried out at the time
of chorionic villus sampling as well as just before termination95.
Eight fetuses died in the interval between chorionic villus sampling
and termination and the rate of lethality increased with
nuchal translucency thickness from 5.3% for those with nuchal
translucency of 0–3mm to 23.5% for nuchal translucency of equal
to or greater than 7mm. Assuming that the relative rate of intrauterine
lethality of trisomy 21 fetuses according to the nuchal translucency
thickness remains the same throughout pregnancy, it was estimated
that a policy of screening by maternal age and fetal nuchal translucency
followed by selective termination of affected fetuses would be
associated with at least a 70% reduction in the live birth incidence
of trisomy 21.
Data
from The Fetal Medicine Foundation Multicenter Project
Among
the 100000 pregnancies that were screened within the multicenter
project, trisomy 21 was diagnosed, prenatally or at birth, in
326 cases62. On the basis of the maternal age distribution
in this population and the maternal age-related prevalence of trisomy
21 in live births, it was estimated that 266 babies with trisomy
21 would have been born alive had there not been any antenatal
testing and selective termination of affected pregnancies.
In
the screen-negative group (estimated risk of less than 1 in 300),
there were 35 live births with trisomy 21 and 23 other cases where
the pregnancies were terminated following prenatal diagnosis.
On the extreme assumption that all 23 of these pregnancies would
have resulted in live births, then the number of trisomy 21 live
births in the screen-negative group would have been 58, or 22%
of the total 266 potential live births with trisomy 21. Consequently,
assessment of risk by a combination of maternal age and fetal
nuchal translucency, followed by invasive diagnostic testing for
those with a risk of equal to or greater than 1 in 300, and selective
termination of affected fetuses would have reduced the potential
live birth prevalence of trisomy 21 by at least 78% (208 of 266)62.
|
| INCREASED
NUCHAL TRANSLUCENCY AND OTHER CHROMOSOMAL DEFECTS |
|
| Pranav
Pandya |
|
In
The Fetal Medicine Foundation Multicenter Project of screening
for trisomy 21 by a combination of maternal age and fetal
nuchal translucency thickness at 10–14 weeks, 325 with
chromosomal abnormalities other than trisomy 21 were identified62.
In 229 (70.5%) of these, the fetal nuchal translucency
was above the 95th centile of the normal range for crown–rump
length (Table 7). Furthermore, in 253 (77.9%) of the pregnancies,
the estimated risk for trisomy 21, based on maternal age
and fetal nuchal translucency, was more than 1 in 300.
| Table
7 - Nuchal translucency thickness above the
95th centile and an estimated risk for trisomy 21
of more than 1 in 300 in pregnancies with chromosomal
abnormalities other than trisomy 21 |
 |
In
trisomy 21, the median nuchal translucency thickness is
about 2.0mm above the normal median for crown–rump
length. The corresponding values for trisomies 18 and
13, triploidy and Turner syndrome are 4.0mm, 2.5mm, 1.5mm
and 7.0mm, respectively.
In
addition to increased nuchal translucency, there are other
characteristic sonographic findings in these fetuses (Table 8). In trisomy 18, there is early onset intrauterine
growth restriction, relative bradycardia and, in about
30% of the cases, there is an associated exomphalos (Figure 13)96.
| |
| Figure
13 - Increased nuchal translucency and exomphalos
in a trisomy 18 fetus at 12 weeks of gestation |
Trisomy
13 is characterized by fetal tachycardia, observed in
about two-thirds of the cases, early onset intrauterine
growth restriction, and holoprosencephaly or exomphalos
in about 30% of the cases97. In triploidy,
there is early onset asymmetrical intrauterine growth
restriction (Figure 14), relative bradycardia, holoprosencephaly,
exomphalos or posterior fossa cyst in about 40% of cases
and molar changes in the placenta in about one-third of
cases99.
| |
| Figure
14 - Severe asymmetrical growth restriction in
a 13-week fetus with triploidy. The placenta looks
normal |
| Table
8 - Ultrasound findings in chromosomally abnormal
fetuses at 10–14 weeks of gestation |
|
| Fetal
karyotype |
Ultrasound
findings |
|
| Trissomy
18 |
growth
restriction, bradycardia, exomphalos |
| Trissomy
13 |
growth
restriction, tachycardia, holoprosencephaly, exomphalos |
| Turner
|
growth
restriction, tachycardia, large nucal translucency
(cystic higromas) |
| Triploidy |
gowth
restriction, bradycardia, holoprosencephaly, posterior
fossa cyst, exomphalos, molar placenta |
|
Turner
syndrome is characterized by fetal tachycardia, observed
in about 50% of the cases, and early onset intrauterine
growth restriction98.
 |
 |
| large
nuchal translucency |
growth
restriction, cystic hygromas |
 |
 |
| skin
edema, ascite |
increased
echogenicity of the lungs, pleural efusion, echogenic
bowel |
| Increased
Nucal translucency, simetric growth restriction in
Tuner syndrome note the large NT, septation and edema. |
|
|
| CROWN–RUMP
LENGTH IN CHROMOSOMALLY ABNORMAL FETUSES |
|
|
|
Low
birth weight is a common feature of many chromosomal abnormalities100,101.
Furthermore, prenatal studies during the second and third
trimesters of pregnancy have reported a high prevalence
of aneuploidies in severe intrauterine growth restriction102.
Studies
examining first-trimester growth in chromosomally abnormal
fetuses have demonstrated that trisomy 18 and triploidy
are associated with moderately severe growth restriction,
trisomy 13 and Turner syndrome with mild growth restriction,
whereas in trisomy 21 growth is essentially normal (Table
9 and Table 10, Figure 15).
In
10–45% of pregnancies, women are uncertain of their last
menstrual period, they have irregular menstrual cycles
or they became pregnant soon after stopping the oral contraceptive
pill109,110. Additionally, because of considerable
variations in the day of ovulation, in approximately
10% of women with certain dates and regular 28-day cycles,
there is a discrepancy of more than 7 days in gestation
calculated from the menstrual history and by ultrasound111.
For these reasons, accurate dating of pregnancy necessitates
ultrasonographic examination. A policy of routine pregnancy
dating by measurement of crown–rump length will not
affect the interpretation of results in screening
by nuchal translucency thickness for trisomy 21. In the
case of the other chromosomal defects, dating by crown–rump
length will actually improve their detection since nuchal
translucency normally increases with gestation.
|
|
| FETAL
HEART RATE IN CHROMOSOMALLY ABNORMAL FETUSES |
|
|
Studies
examining first-trimester fetal heart rate in chromosomally
abnormal fetuses have demonstrated that trisomy 13
and Turner syndrome are associated with tachycardia, whereas
in trisomy 18 and triploidy there is a tendency for bradycardia.
In trisomy 21, there is a mild increase in fetal heart
rate (Table 11, Figure 16).
| Table
11 - Harris Birthright Research Centre for Fetal
Medicine 10–14-week Ultrasound Study. The fetal
heart rate in 842 chromosomally abnormal pregnancies
is presented as a percentage of cases above the
95th and 50th and below the 5th centiles of the
normal range for crown–rump length, derived from
10,083 normal pregnancies |
 |
In
a study of 10083 normal pregnancies at the Harris Birthright
Research Centre for Fetal Medicine, the mean fetal heart
rate decreased with gestation from 169bpm at a fetal crown–rump
length of 38mm to 154bpm at a crown–rump length of 84mm.
The data were normally distributed and the 95th and 5th
centiles were 10bpm above and below the appropriate normal
mean for crown–rump length, respectively. In trisomy 13,
Turner syndrome and trisomy 21, the respective mean fetal
heart rates were 14bpm, 11.4bpm and 1.4bpm above the normal
mean for crown–rump length, whereas, in trisomy 18 and
triploidy, the fetal heart rates were 3.4bpm and 4.8bpm
below the normal mean, respectively.
|
|
 |
 |
 |
 |
| Figure
16 - Fetal heart rate (FHR) in trisomy 21 (top
left), trisomy 13 (top right), Turner syndrome (bottom
left) and triploidy (q) and trisomy 18 (r) (bottom
right) plotted on the normal range for gestation (median,
95th and 5th centiles) |
Previous
studies on trisomy 21 fetuses have reported conflicting
results. In a longitudinal study of one trisomy 21 fetus
at 6–9 weeks of gestation, the heart rate was consistently
below the 3rd centile of the normal range112.
In another cross-sectional study of five affected fetuses
at 7–13 weeks, the heart rate was always within the normal
range113. A study of 17 trisomy 21 fetuses
at 10–13 weeks reported that, in 23.5% of cases, the heart
rate was either above the 97th centile or below the 2.5th
centile114. In another study of 85 trisomy
21 fetuses at 10–14 weeks, the heart rate was above the
95th centile in 21% of cases and the increase in heart
rate was not related to fetal nuchal translucency thickness.
This finding raises the possibility of including fetal
heart rate in the model of risk assessment for trisomy
21 along with maternal age and fetal nuchal translucency115.
In our extended series of 451 fetuses with trisomy 21
at 10–14 weeks, 13.7% had a heart rate above the 95th
centile (Table 11).
In
normal pregnancy, the fetal heart rate increases from
about 110bpm at 5 weeks of gestation, to 170bpm at
9 weeks and then gradually decreases to 150bpm by 14 weeks115–118.
The early increase in heart rate coincides with the morphological
development of the heart, and the subsequent decrease
may be the result of functional maturation of the parasympathetic
system116,118,119.
The
tachycardia in Turner syndrome and trisomy 13 fetuses
may be due to a delay in the functional maturation of
the parasympathetic system, resulting in a delay in the
physiological decrease in heart rate with gestation after
9 weeks. Alternatively, the higher heart rate of such
fetuses represents a compensatory response to the heart
strain that may also be responsible for the increased
nuchal translucency120. In fetal life, the
heart normally performs near the peak of the Frank–Starling
curve of ventricular function121 and therefore
compensatory increase in cardiac output can only be achieved
by relative tachycardia122. Maximum tachycardia
may be reached, with early heart failure offering an explanation
for the lack of a significant association between the
extent of increase in nuchal translucency thickness and
fetal heart rate. The same hypothesis may also be advanced
for the observed mild increase in heart rate of trisomy
21 fetuses.
The
relative bradycardia of trisomy 18 fetuses may be related
to the fact that, in this chromosomal abnormality, there
is early onset growth restriction and the developmental
delay is more severe than in trisomies 21 and 13; in such
fetuses, the maturation in heart rate would be equivalent
to about 8 weeks of gestation. Triploidy is associated
with a high rate of early intrauterine lethality and the
observed bradycardia in some of these fetuses may represent
a preterminal event.
The
tables 11a and 11b shows th effects of the chromossomal
defects on fetal heart rate at 10-14 weeks. (Liao et col,
Ultrasound Obstet Gynecol 2000; 16: 610-611)
| Table
11 a - Difference in mean fetal heart rate from
the normal mean for crown-rump-lenght in each of the
chromossomal defects (A.W. Liao et col, 2000) |
|
| Karyotype |
n |
Mean
difference (SD) |
95%
confidence interval |
t |
P |
|
| Trissomy
21 |
554 |
0,17
(1,19) |
0,07
to 0,27 |
3,43 |
0,0006 |
| Trissomy
18 |
219 |
-0,48
(1,79) |
-0,72
to -0,25 |
-4,00 |
<
0,0001 |
| Trissomy
13 |
95 |
2,21
(1,55) |
1,90
to 2,53 |
13,92 |
<
0,0001 |
| Triplody |
50 |
-0,82
(1,72) |
-1,31
to -0,33 |
-
3,38 |
0,0014 |
| Turner |
115 |
1,71
(1,45) |
1,44
to 1,98 |
12,62 |
<
0,0001 |
| Other
sex chromossomes |
28 |
-0,30
(1,00) |
-0,69
to 0,09 |
-1,58 |
0,126 |
|
| Table
11b - Number of cases with fetal heart rate below
the 5th centile, above the median or above the 95th
centile of the normal range for crown-rump-lenght
in each of the chromossomal defects. (A.W. Liao
et col, 2000) |
|
| Karyotype |
n |
<
5th centile |
>
median |
>
95th centile |
|
| Trissomy
21 |
554 |
5,2
% (29) |
54,0%
(29%) |
9,7%
(54) |
| Trissomy
18 |
219 |
18,7%
(41) |
39,7
(87) |
4,6%
(10) |
| Trissomy
13 |
95 |
2,1%
(2) |
94,7%
(90) |
67,4%
(64) |
| Triplody |
50 |
30,0%
(15) |
26,0%
(13) |
4,0%
(2) |
| Turner |
115 |
1,7%
(2) |
89,6%
(103) |
52,2%
(60) |
| Other
sex chromossomes |
28 |
7,1%
(2) |
35,7%
(10) |
0%
(0) |
|
|
| DOPPLER
ULTRASOUND FINDINGS IN CHROMOSOMALLY ABNORMAL FETUSES |
|
Adolfo
Liao
|
|
Doppler
ultrasound studies have demonstrated that impedance
to flow (measured as pulsatility index) decreases
with gestation123,124. This decrease
is believed to be a consequence of the increase
in the number of vessels (and their relative volume)
within the chorionic villi and the expansion of
the intervillous circulation125.
| |
| Doppler
sites of interesse in the first trimester |
 |
 |
|
Uterine
Artery |
Spiral
Artery |
 |
 |
|
Umbilical
Artery (6-12 weeks)
Note the absence of the end diastolic velocity
in the umbilcal artery and the umbilical
vein pulsatility - normal findings in the
1o trimester. |
Umbilical
Artery (10-14 weeks)
Note the positive of the end diastolic velocity
in the umbilcal artery and the absence of
umbilical vein pulsatility - normal findings
in the 1o trimester. |
 |
 |
| Middle
Cerebral Artery |
Descending
Aorta |
 |
 |
| Circle
of Willis (13-14 weeks) |
Ductus
Venosus |
There
is contradictory evidence on the possible association
of trisomy 21 at 11–14 weeks of gestation and
increased umbilical artery pulsatility index.
Martinez et al. reported that the
umbilical artery pulsatility index was above the
95th centile in 55% of their nine cases of
trisomy 21 and this was not always associated
with an increased nuchal translucency; they
estimated that the measurements of both factors
might allow detection of up to 89% of cases of
trisomy 21126. In contrast, Jauniaux
et al. examined 11 cases of trisomy
21 and reported that there was no significant
difference in umbilical artery pulsatility
index compared to normal fetuses and that in none
of their cases was the pulsatility index
above the 95th centile127. Similarly,
Brown et al. examined 19 trisomy 21
fetuses with increased nuchal translucency at
11–14 weeks and reported that the umbilical
artery pulsatility index was not significantly
different from normal; the pulsatility index
was above the 95th centile in only two of the
cases124.
 |
|
| Umbilical
artery and Vein |
Umbilical
artery and Vein |
| Umbilical
artery: high impedance to flow and absent
end diastolic flow (normal). |
Umbilical
artery: high impedance to flow and presence
of diastolic flow (normal). |
| Umbilical
Vein: pulsatile flow pattern, |
Umbilical
Vein: presence of continuous flow pattern,
sometimes the pulsatil pattern could persit
a liittle longer, bu must be absent before
complete 20 weeks |
In
normal second- and third-trimester fetuses, pulsatile
umbilical venous flow is observed only during
fetal breathing. Pulsatile venous flow is also
observed in fetuses with growth restriction and
in non-immune hydrops and is considered to be
a late and ominous sign of fetal compromise128,129.
Evidence from growth-restricted human fetuses
and animal models suggests that pulsatile venous
flow may result from an increased reversal of
flow in the inferior vena cava during atrial contraction,
associated with heart failure and abnormal cardiac
filling129,130.
A
Doppler study at 11–14 weeks of gestation reported
the presence of pulsatile flow in the umbilical
vein in about 25% of 302 chromosomally normal
fetuses and in 90% of 18 fetuses with trisomy
18 or 13; in 18 fetuses with trisomy 21, the prevalence
of pulsatile venous flow was not significantly
different from that in chromosomally normal fetuses,
but in trisomies 13 and 18 the prevalence was
increased131.
The
ductus venosus is a unique shunt that carries
well-oxygenated blood from the umbilical vein
through the inferior atrial inlet on its way across
the foramen ovale. It appears to be the most useful
vessel in assessing disturbed cardiac function132.
Blood flow in the ductus is characterized by high
velocity during ventricular systole (S-wave) and
diastole (D-wave) and by the presence of forward
flow during atrial contraction (A-wave). In cardiac
failure, with or without cardiac defects, there
is absent or reversed A-wave (see Chapter 3, page
102)133.
| |
Color
Doppler Energy "Arteriography"
showing the anatomy of the vessels at mid-sagittal
plane of the fetal thrunk. |
It
is possible to assess ductus venosus blood flow
at 11–14 weeks of gestation by Doppler ultrasound,
both transabdominally and transvaginally. A right
ventral mid-sagittal plane of the fetal trunk
is first obtained during fetal quiescence and
the pulsed Doppler gate is placed in the distal
portion of the umbilical sinus. The inferior vena
cava, left and medial hepatic veins and the ductus
venosus drain into a common sub-diaphragmatic
vestibulum and therefore, when attempting to obtain
flow velocity waveforms from the ductus, care
should be taken to avoid contamination from the
other veins.
 |
 |
| Normal
Ductus venosus sonogram.
Positive A wave. |
Abnormal
Ductus venosus sonogram.
Reverse A wave |
| S=
systole; D= diastole; A= atrial contraction |
A
study, examining ductal flow at 11–14 weeks in
fetuses with increased nuchal translucency, reported
absent or reversed flow during atrial contraction
in 57 of 63 (90.5%) chromosomally abnormal fetuses
and in only 13 of 423 (3.1%) chromosomally normal
fetuses134. In seven of the 13 chromosomally
normal fetuses with absent or reversed flow, an
ultrasound scan at 14–16 weeks demonstrated a
major cardiac defect134.
Examination
of ductal flow is time-consuming and requires
skilled operators. It is therefore unlikely that
this assessment will be incorporated into the
routine first-trimester scan. However, the data
suggest that the assessment of ductal flow can
potentially play a major role as a secondary method
of screening in order to achieve a major reduction
in the false-positive rate of primary screening
for chromosomal abnormalities by a combination
of maternal age, fetal nuchal translucency and
maternal serum free b-hCG and PAPP-A at 11–14
weeks. A policy of reserving invasive testing
only for those with abnormal ductal flow could
reduce the overall need for chorionic villus sampling
from 5% to less than 0.5%, with a small reduction
(5–10%) in the estimated sensitivity of 90%134. |
|
| NUCHAL
TRANSLUCENCY AND MATERNAL SERUM BIOCHEMISTRY |
|
|
| In
trisomy 21 during the first trimester of pregnancy,
the maternal serum concentration of free
b-hCG is higher than in chromosomally normal fetuses
(Table 12), whereas PAPP-A is lower (Table 13). Pregnancy-specific b-1 glycoprotein (SP1),
a-fetoprotein and inhibin-A do not provide a useful
distinction between affected and normal pregnancies135–137.
| Table
12 - Median MoM in published studies of
free b-hCG in trisomy 21 pregnancies |
 |
| |
| Table
13 - Median MoM in published studies of
PAPP-A in trisomy 21 pregnancies |
 |
| Maternal
serum free b-hCG |
Maternal
serum free b-hCG normally decreases with gestation
after 10 weeks. In trisomy 21 pregnancies, the
levels are increased and the difference between
these and those of normal pregnancies increases
with advancing gestation. This may account for the
variation in the reported median MoM between the
various studies (Table 12)138–158, because there was a considerable
variation in the gestational age range of the
populations that were examined. Consequently,
population parameters derived from studies using
a wide gestational age range are not appropriate
if screening is to be focused on the optimal time
for nuchal translucency measurement (11–14 weeks).
The increase with gestation in the difference
between trisomy 21 and normal pregnancies has
also been shown in studies of paired samples from
trisomy 21 pregnancies collected in the first
and second trimesters153. In a study
involving 210 trisomy 21 pregnancies that were
examined at 10–14 weeks, the median free b-hCG
was 2.15MoM (95% CI, 1.94–2.33); at a 5% screen-positive
rate, the detection rate using free b-hCG alone
is about 35% and, in combination with maternal
age, the detection increases to about 45%158.
Maternal
serum PAPP-A normally increases with gestation.
In trisomy 21 pregnancies, the levels are lower
but the difference between trisomy 21 and normal
pregnancies decreases with advancing gestation.
This may account for the variation in the reported
median MoM between the various studies (Table 13)140,143,145,146,150,152,153,155–166.
In a study involving 210 trisomy 21 pregnancies
that were examined at 10–14 weeks, the median
PAPP-A was 0.51MoM (95% CI, 0.44–0.56); at a 5%
screen-positive rate, the detection rate using
PAPP-A alone is about 40% and, in combination
with maternal age, the detection increases to
about 50%158.
| Maternal
serum free b-hCG and PAPP-A |
When
considering to combine biochemical markers, it
is necessary to take into account the degree of
correlation between the markers. In our study,
involving 210 trisomy 21 and 946 chromosomally
normal controls, the correlations were 0.216 and
0.160, respectively158. Additionally,
each marker showed a small but significant negative
correlation with maternal weight (PAPP-A, r
= -0.278; free b-hCG, r = -0.146).
After combining free b-hCG and PAPP-A with maternal
age in mathematical models, it has been estimated
that the detection rate of trisomy 21 is about
60% at a 5% screen-positive rate (Table 14) 150,152,153,155–158,167,168.
| Table
14 - Estimated detection rate for trisomy
21 by a combination of maternal age and first-trimester
maternal serum PAPP-A and free b-hCG at a
5% fixed screen-positive rate |
 |
| Fetal
nuchal translucency and maternal serum free
b-hCG and PAPP-A |
There
is no significant association between fetal nuchal
translucency and maternal serum free b-hCG or
PAPP-A in either trisomy 21 or chromosomally normal
pregnancies 147,158,164. The estimated
detection rate for trisomy 21 by a combination
of maternal age, fetal nuchal translucency and
maternal serum PAPP-A and free b-hCG is about
90% for a screen-positive rate of 5% (Table 15)148,157,158,164,167,169. Alternatively,
at a fixed detection rate of 70%, the screen-positive
rate would be only 1%158. The performance
of the combined test now requires assessment in
prospective studies.
| Table
15 - Estimated detection rate for trisomy
21 by a combination of maternal age, fetal
nuchal translucency and first-trimester maternal
serum PAPP-A and free b-hCG at a 5% fixed
false-positive rate |
 |
| One-stop
clinics for early assessment of fetal risk |
An
important development in biochemical analysis
is the introduction of a new technique (random
access immunoassay analyzer using time-resolved-amplified-cryptate-emission),
which provides automated, precise and reproducible
measurements within 30 minutes of obtaining a
blood sample158. This has made it possible
to combine biochemical and ultrasonographic testing
as well as to counsel in one-stop clinics
for early assessment of fetal risk (OSCAR). |
|
| NUCHAL
TRANSLUCENCY FOLLOWED BY SECOND-TRIMESTER BIOCHEMISTRY |
|
Maria
Brizot and Penelope Noble
|
| At
16 weeks of gestation, the median maternal serum
concentrations of a-fetoprotein, estriol, hCG
(total and free b) and inhibin A in trisomy 21
pregnancies are different from normal. The risk
for trisomy 21 can be derived by multiplying the
background maternal age and gestational
age-related risk by the likelihood ratios for
these substances, after corrections for the interrelations
between them. The risk of trisomy 21 is increased
if the levels of hCG and/or inhibin A are high,
and the levels of a-fetoprotein and/or estriol
are low. The estimated detection rates are 50–70%
for a screen-positive rate of about 5%.
In
women having second-trimester biochemical testing
following first-trimester nuchal translucency
screening (with or without maternal serum biochemistry),
the background risk needs to be adjusted
to take into account the first-trimester screening
results. Since first-trimester screening identifies
almost 90% of trisomy 21 pregnancies, second-trimester
biochemistry will identify – at best – 6% (60%
of the residual 10%) of the affected pregnancies,
with doubling of the overall invasive testing
rate (from 5% to 10%). It is theoretically possible
to use various statistical techniques to combine
nuchal translucency with different components
of first-trimester and second-trimester biochemical
testing. One such hypothetical model has combined
first-trimester nuchal and PAPP-A with second-trimester
free b-hCG, estriol and inhibin A, claiming a
potential sensitivity of 94% for a 5% false-positive
rate170.
Even if the assumptions made in this statistical
technique are valid, it is unlikely that it will
gain widespread clinical acceptability171.
Two
studies have reported on the impact of first-trimester
screening by nuchal translucency on second-trimester
serum biochemical testing. In one study, the proportion
of affected pregnancies in the screen-positive
group (positive predictive value) of screening
by the double test in the second trimester was
1 in 40; after the introduction of screening by
nuchal translucency, 83% of trisomy 21 pregnancies
were identified in the first trimester and the
positive predictive value of biochemical screening
decreased to 1 in 200172. In the second
study, first-trimester screening by nuchal translucency
identified 71% of trisomy 21 pregnancies for a
screen-positive rate of 2%, and the positive predictive
value of second-trimester screening by the quadruple
test was only 1 in 150173.
In
women who had first-trimester screening by a combination
of fetal nuchal translucency and maternal serum
PAPP-A and free b-hCG, it is clearly advisable
that second-trimester biochemical testing is avoided
because, first, the sensitivities of first- and
second-trimester biochemical screening are similar;
second, the main component of the second-trimester
biochemical screening is free b-hCG, and, third,
there is a good correlation between first-
and second-trimester maternal serum hCG levels.
If both first- and second-trimester biochemical
testing have been carried out, then the likelihood
ratio from the measurement of nuchal translucency
can be multiplied with the results of either
first- or second-trimester serum testing. This
is certainly valid for second-trimester programs
that are mainly based on free b-hCG because the interrelation
between nuchal translucency and this metabolite
has been established148. |
|
NUCHAL
TRANSLUCENCY FOLLOWED BY SECOND- TRIMESTER
ULTRASONOGRAPHY |
|
|
|
Major
chromosomal abnormalities are often associated
with multiple fetal defects that can be detected
by ultrasound examination. For example,
trisomy 21 is associated with a tendency for brachycephaly,
mild ventriculomegaly, flattening of the face,
nuchal edema, atrioventricular septal defects,
duodenal atresia and echogenic bowel, mild hydronephrosis,
shortening of the limbs, sandal gap and clinodactyly
or mid-phalanx hypoplasia of the fifth finger.
Trisomy 18 is associated with strawberry-shaped
head, choroid plexus cysts, absent corpus callosum,
enlarged cisterna magna, facial cleft, micrognathia,
nuchal edema, heart defects, diaphragmatic hernia,
esophageal atresia, exomphalos, renal defects,
myelomeningocele, growth restriction and shortening
of the limbs, radial aplasia, overlapping fingers
and talipes or rocker bottom feet.
The
overall risk for chromosomal abnormalities increases
with the total number of defects that are identified
(Figure 17)174. It is therefore recommended
that, when a defect/marker is detected at routine
ultrasound examination, a thorough check is made
for the other features of the chromosomal abnormality
known to be associated with that marker; should
additional defects be identified, the risk is
dramatically increased. In the case of apparently
isolated defects, the decision of whether to carry
out an invasive test depends on the type of defect.
| |
Figure
17 - Incidence of chromosomal abnormalities
in relation to number of sonographically
detected defects174 |
If
the mid-trimester scan demonstrates major defects,
it is advisable to offer fetal karyotyping, even
if these defects are apparently isolated. The
prevalence of these defects is low and therefore
the cost implications are small. If the defects
are either lethal or they are associated with
severe handicap, fetal karyotyping constitutes
one of a series of investigations to determine
the possible cause and thus the risk of recurrence.
Examples of these defects include hydrocephalus,
holoprosencephaly, multicystic renal dysplasia
and severe hydrops. In the case of isolated neural
tube defects, there is controversy as to whether
the risk for chromosomal defects is increased.
Similarly, for skeletal dysplasias where the likely
diagnosis is obvious by ultrasonography, it would
probably be unnecessary to perform karyotyping.
If the defect is potentially correctable by intrauterine
or postnatal surgery, it may be logical to exclude
an underlying chromosomal abnormality – especially
because, for many of these conditions, the usual
abnormality is trisomy 18 or 13. Examples
include facial cleft, diaphragmatic hernia, esophageal
atresia, exomphalos and many of the cardiac defects.
In the case of isolated gastroschisis or small
bowel obstruction, there is no evidence of increased
risk of trisomies.
These
defects are common and they are not usually associated
with any handicap, unless there is an associated
chromosomal abnormality. Routine karyotyping of
all pregnancies with these markers would have
major implications, both in terms of miscarriage
and in economic costs. It is best to base counselling
on an individual estimated risk for a chromosomal
abnormality, rather than the arbitrary advice
that invasive testing is recommended because the
risk is ‘high’. The estimated risk can be derived
by multiplying the background risk (based
on maternal age, gestational age, history of previously
affected pregnancies and, where appropriate, the
results of previous screening by nuchal translucency
and/or biochemistry in the current pregnancy)
by the likelihood ratio of the specific defect175–177.
For the following conditions, there are sufficient
data in the literature to estimate the likelihood
ratio for trisomy 21.
| Nuchal
edema or fold of more than 6mm |
 |
This
is the second-trimester form of nuchal translucency.
It is found in about 0.5% of fetuses
and it may be of no pathological significance.
However, it is sometimes associated with
chromosomal defects, cardiac anomalies,
infection or genetic syndromes46.
For isolated nuchal edema, the risk for
trisomy 21 may be 15 times the background178,179.
|
 |
If
the femur is below the 5th centile and all
other measurements are normal, the baby
is likely to be normal but rather short.
Rarely is this a sign of dwarfism. Occasionally,
it may be a marker of chromosomal defects.
On the basis of existing studies, short
femur is found four times as commonly in
trisomy 21 fetuses compared to normal fetuses180–185.
However, there is some evidence that isolated
short femur may not be more common in trisomic
than in normal fetuses178.
|
 |
This
is found in about 0.5% of fetuses and is
usually of no pathological significance.
The commonest cause is intra-amniotic
bleeding, but occasionally it may be a marker
of cystic fibrosis or chromosomal defects.
For isolated hyperechogenic bowel, the risk
for trisomy 21 may be three times the background178,186,187.
|
| Echogenic
foci in the heart |
 |
These
are found in about 4% of pregnancies and
they are usually of no pathological significance.
However, they are sometimes associated with
cardiac defects and chromosomal abnormalities.
For isolated hyperechogenic foci the risk,
for trisomy 21 may be four-times the background178,189–191.
|
 |
These
are found in about 1–2% of pregnancies and
they are usually of no pathological significance.
When other defects are present, there is
a high risk of chromosomal defects, usually
trisomy 18 but occasionally trisomy 21.
For isolated choroid plexus cysts, the risk
for trisomy 18 and trisomy 21 is about 1.5
times the background177.
|
 |
This
is found in about 1–2% of pregnancies and
is usually of no pathological significance.
When other abnormalities are present, there
is a high risk of chromosomal defects, usually
trisomy 21. For isolated mild hydronephrosis,
the risk for trisomy 21 is about 1.5 times
the background176,192,193.
|
There
are no data on the interrelation between these
second-trimester ultrasound markers and nuchal
translucency at 11–14 weeks or first- and second-trimester
biochemistry. However, there is no obvious physiological
reason for such an interrelation and it is therefore
reasonable to assume that they are independent.
Consequently, in estimating the risk in a pregnancy
with a marker, it is logical to take into account
the results of previous screening tests. For example,
in a 20-year-old woman at 20 weeks of gestation
(background risk of 1 in 1295), who had a 11–14
week assessment by nuchal translucency measurement
that resulted in a 5-fold reduction in risk (to
about 1 in 6475), after the diagnosis of mild
hydronephrosis at the 20-week scan, the estimated
risk has increased by a factor of 1.5 to 1 in
4317. In contrast, for the same ultrasound finding
of fetal mild hydronephrosis in a 40-year-old
woman (background risk of 1 in 82), who did
not have nuchal translucency or biochemistry screening,
the new estimated risk is 1 in 55.
There
are some exceptions to this process of sequential
screening, which assumes independence between
the findings of different screening results. The
findings of nuchal edema or a cardiac defect at
the mid-trimester scan cannot be considered independently
of nuchal translucency screening at 11–14 weeks.
Similarly, hyperechogenic bowel (which may be
due to intra-amniotic bleeding) and relative shortening
of the femur (which may be due to placental insufficiency)
may well be related to serum biochemistry (high
free b-hCG and inhibin-A and low estriol may be
markers of placental damage) and can therefore
not be considered independently in estimating
the risk for trisomy 21. For example, in a 20-year-old
woman (background risk for trisomy 21 of 1 in
1295), with high free b-hCG and inhibin-A and
low estriol at the 16-week serum testing resulting
in a 10-fold increase in risk (to 1 in 129), the
finding of hyperechogenic bowel at the 20-week
scan should not lead to the erroneous conclusion
of a further three-fold increase in risk (to 1
in 43). The coincidence of biochemical and sonographic
features of placental insufficiency makes it very
unlikely that the problem is trisomy 21 and should
lead to increased monitoring for pre-eclampsia
and growth restriction, rather than amniocentesis
for fetal karyotyping. |
|
NON-INVASIVE
DIAGNOSIS USING FETAL CELLS FROM MATERNAL BLOOD
|
|
|
During
the last 30 years, extensive research has aimed
at developing a non-invasive method for prenatal
diagnosis based on the isolation and examination
of fetal cells found in the maternal circulation.
Erythroblasts have attracted most attention because
they are abundant in early fetal blood; they are
extremely rare in normal adult blood and their
half-life in adult blood is only about 30 days.
Trophoblastic cells entering the maternal circulation
are cleared by the maternal lungs and are therefore
not useful candidates for prenatal diagnosis.
Fetal white blood cells are present in maternal
blood but their number is very low and they have
a very long half-life (about 5 years), which may
therefore lead to contamination from previous
pregnancies.
About
1 in 103–107 nucleated cells
in maternal blood are fetal194–196.
The proportion of fetal cells can be enriched
to about 1 in 10–100 by techniques such as magnetic
cell sorting (MACS) or fluorescence activated
cell sorting (FACS) after attachment of magnetically
labelled or fluorescent antibodies on to specific
fetal cell surface markers194,197–199.
The most commonly used antibody is anti-CD71,
which is directed against the transferrin receptor
present on the surface of all cells actively incorporating
iron198,200. Other cell types in maternal
blood, such as activated lymphocytes, have this
receptor but anti-CD71 provides a reasonable level
of enrichment once maternal lymphocytes have been
removed. Magnetic cell sorting is cheaper, quicker
and requires less expertise to perform than FACS.
The technique utilizes metallic beads labelled
with an antibody specific for the target cell.
The antibody is incubated with the sample and
the cell–antibody–bead complex is isolated by
placing on a magnet. Successful use of MACS involves
prior separation of cells by triple density centrifugation.
Essentially, the maternal blood sample is placed
in a tube containing three sugar-based reagents
of different density and, after centrifugation,
the middle layer containing erythroblasts and
neutrophil granulocytes is separated. These cells
are incubated with magnetically labelled CD71
antibody and MACS is then carried out (Figure 18).
| |
Figure
18 - Triple density centrifugation and
magnetic cell sorting techniques, using
magnetically labelled anti-CD71 (antibody
against transferrin receptor antigen) |
The
resulting sample is unsuitable for traditional
cytogenetic analysis because it is still highly
contaminated with maternal cells. However, with
the use of chromosome-specific DNA probes and
fluorescent in situ hybridization (FISH),
it is possible to suspect fetal trisomy by the
presence of three-signal nuclei in some of the
cells of the maternal blood enriched for fetal
cells. It is now possible to identify simultaneously
all major chromosomal abnormalities by the use
of multicolor probes directed against chromosomes
21, 18, 13, Y and X in interphase nuclei (Figure 19). One of the major problems with FISH is
that 1–2% of normal diploid cells give three-signal
nuclei and about 10–20% of trisomic cells give
two-signal nuclei201.
| |
| Figure
19 - Fluorescence in situ hybridization
analyzed cells, in maternal blood enriched
for fetal cells, from trisomy 21 (A), trisomy
18 (B) and trisomy 13 (C). Pregnancies demonstrating
three-signal nuclei with the appropriate
chromosome-specific probe |
Bianchi
et al. detected three-signal nuclei
from a trisomy 21 pregnancy after enrichment for
fetal cells in maternal blood by FACS202.
Ganshirt-Ahlert et al. found three-signal
nuclei in 9–17% of cells from ten trisomy 21 and
six trisomy 18 pregnancies after sorting by MACS;
in ten chromosomally normal pregnancies, 0–7%
of cells had three-signal nuclei203.
Simpson and Elias reported the presence of three-signal
nuclei, after sorting by FACS, in 2.8–74% of cells
from five trisomy 21 and two trisomy 18 pregnancies,
but in none of 61 chromosomally normal pregnancies204.
Al-Mufti
et al. took maternal peripheral blood
immediately before chorionic villus sampling from
230 women with singleton pregnancies at 11–14
weeks of gestation199. These pregnancies
had been identified as being at high risk for
trisomies after screening by a combination of
maternal age and fetal nuchal translucency thickness.
Triple density gradient centrifugation, followed
by incubation of the erythroblast-rich fraction
with magnetically labelled CD71 antibody,
MACS and FISH were carried out. In 3% of cases,
no fetal hemoglobin-positive cells were observed.
In the chromosomally abnormal group, the percentage
of cells demonstrating three-signal nuclei was
higher than in the normal group but there was
an overlap in values between the two groups (Figure 20).
| |
Figure
20 - Percentage of cells with three-signal
nuclei using the 21 chromosome-specific
probe in maternal blood enriched for fetal
cells from chromosomally normal pregnancies
and those with trisomy 21 |
Using
a 21-chromosome-specific probe, three-signal nuclei
were present in at least 5% of the enriched
cells from 61% of the trisomy 21 pregnancies and
in none of the normal pregnancies. For a cut-off
of 3% of three-signal nuclei, the sensitivity
for trisomy 21 was 97% for a false-positive rate
of 13%. Similar values were obtained in trisomies
18 and 13 using the appropriate chromosome-specific
probe (Table 16).
| Table
16 - Sensitivity and false-positive
rate for the various cut-off percentages
of cells with three-signal nuclei in the
chromosomally abnormal and normal groups
using fluorescent probes for chromosomes
21, 18 and 13 |
 |
The
findings that, with the 21-chromosome-specific
probe, three-signal nuclei were present in
at least 5% of the enriched cells from about 60%
of trisomy 21 pregnancies and in none of the normal
pregnancies, suggest that this method could be associated
with the same rate of detection of trisomy 21
as second-trimester serum biochemistry but with
the advantage that the invasive testing rate may
be as low as 0% rather than 5%. However,
unlike serum biochemistry testing, which is relatively
easy to apply for mass population screening, enrichment
of fetal cells by triple density gradient centrifugation
and MACS, followed by FISH, is both labor intensive
and requires highly skilled operators. In the
case of FISH, there are promising developments for
automated computerized analysis of cells which
are likely to simplify processing of the slides.
The extent to which the techniques for enrichment
of fetal cells could be improved, to achieve
a higher yield of the necessary cells, as well
as become automated, to allow simultaneous analysis
of a large number of samples, remains to be seen.
On
the basis of currently available technology, examination
of fetal cells from maternal peripheral blood
is more likely to find an application as a method
for assessment of risk, rather than the non-invasive
prenatal diagnosis of chromosomal defects. First-line
screening by a combination of maternal age, fetal
nuchal translucency and maternal serum free b-hCG
with PAPP-A could detect 90% of trisomy 21 pregnancies
for an invasive testing rate of about 5%158.
One option in the management of the high-risk
group is to carry out FISH on maternal blood enriched
for fetal cells and reserve chorionic villus
sampling only for those pregnancies where no fetal
hemoglobin-positive cells are recovered and those
where at least 3% of the cells demonstrate three
signals with the 21-chromosome specific probe.
Such a policy could potentially reduce the need
for invasive testing to less than 1% of the whole
population with a minor loss (about 3%) in the
sensitivity for detection of trisomy 21. |
|
INVASIVE
DIAGNOSIS OF CHROMOSOMAL DEFECTS
|
|
Raghad
Al-Mufti
|
|
The feasibility of culturing and karyotyping amniotic
fluid cells was first demonstrated in the late
1960s32,33. Early attempts at genetic
amniocentesis were made transvaginally, but subsequently
the transabdominal approach was adopted. In the
early 1970s, amniocentesis was performed ‘blindly’.
In the late 1970s and early 1980s, ultrasound,
initially static and subsequently real-time, was
used to identify a placenta-free area for entry
into a pocket of amniotic fluid. The position
of this was marked on the maternal abdomen and,
after a variable length of time, in some studies
up to 2 days, the operator would ‘blindly’ insert
the needle. It is therefore not surprising that
early reports on the use of ultrasound produced
conflicting conclusions, with some suggesting
that it was actually detrimental. Amniocentesis
is now performed with continuous ultrasound guidance.
Ager
and Oliver reported a critical appraisal of all
the studies on amniocentesis that were published
during 1975–85205. There were 28 major
national studies, each involving at least 1000
cases; the total post-amniocentesis fetal loss
rate, including spontaneous abortion, intrauterine
death and neonatal death was 2.4–5.2%. In four
of the 28 studies, there were matched controls
that did not undergo amniocentesis; the total
fetal loss rate was 1.8–3.7%. On the basis of
these data it was estimated that the procedure-related
risk of fetal loss from amniocentesis was 0.2–2.1%205.
The
only randomized trial was performed in Denmark206.
In this study, 4606 low-risk, healthy women, 25–34
years old, at 14–20 weeks of gestation, were randomly
allocated to amniocentesis or ultrasound examination
alone. The total fetal loss rate in the patients
having amniocentesis was 1% higher than in the
controls. There were significant associations
between spontaneous fetal loss and (1) puncture
of the placenta, (2) high maternal serum a-fetoprotein
and (3) discolored amniotic fluid. The Danish
study also reported that amniocentesis was associated
with an increased risk of respiratory distress
syndrome and pneumonia in neonates. Some studies
have reported an increased incidence of talipes
and dislocation of the hip after amniocentesis,
but this was not confirmed by the Danish study206.
In
the late 1980s, early amniocentesis was introduced
and studies with complete pregnancy follow-up
have reported that the procedure-related fetal
loss rate was around 3–6%.
A
prospective study involving 1301 singleton pregnancies
compared early amniocentesis with chorionic villus
sampling at 10–13 weeks of gestation207.
The procedures were performed (1) for the same
indication, (2) at the same gestational range,
(3) by the same group of operators, (4) using
essentially the same technique of transabdominal
ultrasound-guided insertion of a 20-G needle,
and (5) the samples were sent to the same laboratories.
Successful samplings resulting in a non-mosaic
cytogenetic result were the same for both early
amniocentesis and chorionic villus sampling (97.5%).
Furthermore, the intervals between sampling and
obtaining results were similar for the two techniques.
The main indication for repeat testing in the
chorionic villus sampling group was mosaicism,
whereas, in the early amniocentesis group, it
was failed culture; this failure was related to
gestation at sampling: 5.3% at 10 weeks and 1.6%
at 11–13 weeks. Spontaneous loss (intrauterine
and neonatal death) after early amniocentesis
was approximately 3% higher than after chorionic
villus sampling. The gestation at delivery and
birth weight of the infants were similar after
both procedures, and the frequencies of preterm
delivery or low birth weight were not higher than
those that would be expected in a normal
population. In the early amniocentesis group,
the incidence of talipes equinovarus (1.63%) was
higher than in the chorionic villus sampling group
(0.56%)207.
A
randomized study in Denmark involving 1160 pregnancies
compared transabdominal chorionic villus sampling
at 10–12 weeks with early amniocentesis at 11–13
weeks using a filtration technique; randomization
was at 10 weeks208. Fetal loss after
chorionic villus sampling was 4.8% and after early
amniocentesis it was 5.4%, but this difference
was not significant. The study was stopped early
because interim analysis of results demonstrated
a significantly higher rate of talipes equinovarus
(1.7%) after early amniocentesis than after chorionic
villus sampling (0%)208.
A
randomized study in Canada involving 4374 pregnancies
compared early amniocentesis at 11–13 weeks with
amniocentesis at 15–17 weeks using a 22-G needle;
randomization was at 9–12 weeks209.
Total fetal loss in the early amniocentesis group (7.6%)
was significantly higher than in the late amniocentesis
group (5.9%). Furthermore, early amniocentesis
was associated with a significantly higher incidence
of talipes (1.3% compared to 0.1%) and postprocedural
amniotic fluid leakage (3.5% compared to 1.7%)209.
On
the basis of existing data, it is therefore clear
that amniocentesis should not be carried
out before 13 weeks of gestation. The extent to
which early amniocentesis performed after 13 weeks
will prove to be safer than chorionic villus sampling
is currently under investigation by an NIH-sponsored
study in the USA.
| Chorionic
villus sampling |
Chorionic
villus sampling was first attempted in the late
1960s by hysteroscopy, but the technique was
associated with low success in both sampling and
karyotyping and was abandoned in favor of amniocentesis.
In the 1970s, the desire for early diagnosis led
to the revival of chorionic villus sampling, which
was initially carried out by aspiration via a cannula
that was introduced ‘blindly’ into the uterus through
the cervix. Subsequently, ultrasound guidance was
used for the transcervical or transabdominal insertion
of a variety of cannulas or biopsy forceps.
Four
randomized studies have examined the rate of fetal
loss following first-trimester chorionic villus
sampling compared to that of amniocentesis at
16 weeks of gestation (Table 17)210–213. In total, about 10000
pregnancies were examined and the results demonstrated
that, in centers experienced in both procedures,
fetal loss is no greater after first-trimester
chorionic villus sampling compared to second-trimester
amniocentesis. The most likely explanation for
the increased loss after chorionic villus sampling
in the European study is the participation of
many centers with little experience in this technique.
| Table
17 - Total fetal loss rate in four randomized
studies comparing first-trimester chorionic
villus sampling with second-trimester amniocentesis
|
 |
In
1991, severe transverse limb abnormalities, micrognathia
and microglossia were reported in five of 289
pregnancies that had undergone chorionic villus
sampling at less than 10 weeks of gestation214.
Subsequently, a series of other reports confirmed
the possible association between early chorionic
villus sampling and fetal defects; analysis of
75 such cases demonstrated a strong association
between the severity of the defect and the gestation
at sampling215. Thus, the median gestation
at chorionic villus sampling was 8 weeks for those
with amputation of the whole limb and 10 weeks
for those with defects affecting the terminal
phalanxes. The background incidence of terminal
transverse limb defects is about 1.8 per 10000
live births216, and the incidence following
early chorionic villus sampling is estimated at
1 in 200–1000 cases. The types of defects are
compatible with the pattern of limb development,
which is essentially completed by the 10th week
of gestation. Possible mechanisms by which early
sampling may lead to limb defects include hypoperfusion,
embolization or release of vasoactive substances,
and all these mechanisms are related to trauma.
It is therefore imperative that chorionic villus
sampling is performed only after 11 weeks by appropriately
trained operators. The data from the International
Registry on chorionic villus sampling are disputing
the association between this procedure and limb
reduction defects217. |
|
Chapter
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The
11-14-week scan
Copyright © 2001 by KH Nicolaides, NJ Sebire,
RJM Snijders, RLS Ximenes & G. Pilu
produced at Centrus
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