Nicolaides The 11-13 Weeks Scan 2004

The 11–13+6 weeks scan
Kypros H. Nicolaides
FMF-English cover.indd 2-3 2004-9-28 10:41:24

Fetal Medicine Foundation, London 2004

Dedication
to
Herodotos & Despina
Contents
Introduction
1. First trimester diagnosis of chromosomal defects

Rosalinde Snijders, Kypros Nicolaides . . . . . . . . . 7
Diagnosis of chromosomal defects . . . . . . . . . . 7
Screening for chromosomal defects . . . . . . . . . . 11
Patient-specific risk for chromosomal defects . . . . . . 13
Nuchal translucency thickness . . . . . . . . . . . 21
Womens’ attitudes to 1st versus 2nd trimester screening . . . 42
2. Sonographic features of chromosomal defects

Victoria Heath, Kypros Nicolaides . . . . . . . . . . 45
First trimester ultrasonography . . . . . . . . . . . 45
Second trimester ultrasonography . . . . . . . . . . 58
3. Increased nuchal translucency with normal karyotype

Athena Souka, Constantin von Kaisenberg, Kypros Nicolaides 71
Outcome of fetuses with increased nuchal translucency . . 72
Abnormalities associated with increased nuchal translucency . 74
Pathophysiology of increased nuchal translucency . . . . . 85
Management of pregnancies with increased nuchal
translucency . . . . . . . . . . . . . . . . . . 88
4. Multiple pregnancy
Neil Sebire, Kypros Nicolaides . . . . . . . . . . . 95
Prevalence and epidemiology . . . . . . . . . . . . 95
Determination of zygosity and chorionicity . . . . . . . 97
Chorionicity and pregnancy complications . . . . . . . 98
Chromosomal defects in multiple pregnancies . . . . . . 105
Introduction
In 1866 Langdon Down noted that common characteristics of patients with

trisomy 21 are skin deficient in elasticity, giving the appearance of being too
large for the body, and flat face with a small nose. In the 1990s, it was realized
that the excess skin of individuals with Down’s syndrome can be visualized by
ultrasonography as increased nuchal translucency in the third month of
intrauterine life. Fetal nuchal translucency thickness at the 11–13+6 weeks
scan has been combined with maternal age to provide an effective method of
screening for trisomy 21; for an invasive testing rate of 5%, about 75% of
trisomic pregnancies can be identified. When maternal serum free ß-human
chorionic gonadotropin and pregnancy-associated plasma protein-A at
11–13+6 weeks are also taken into account, the detection rate of chromosomal
defects is about 85–90%. In 2001, it was found that in 60–70% of fetuses
with trisomy 21 the nasal bone is not visible at the 11–13+6 weeks scan and
examination of the nasal bone can increase the detection rate of screening by
the first trimester scan and serum biochemistry to more than 95%.
In addition to its role in the assessment of risk for trisomy 21, increased
nuchal translucency thickness can also identify a high proportion of other
chromosomal defects and is associated with major abnormalities of the heart
and great arteries, and a wide range of genetic syndromes.
Other benefits of the 11–13+6 weeks scan include confirmation that the
fetus is alive, accurate dating of the pregnancy, early diagnosis of major fetal
abnormalities, and the detection of multiple pregnancies. The early scan also
provides reliable identification of chorionicity, which is the main determinant
of outcome in multiple pregnancies.
As with the introduction of any new technology into routine clinical practice,
it is essential that those undertaking the 11–13+6 weeks scan are adequately
trained and their results are subjected to rigorous audit. The Fetal Medicine
Foundation, has introduced a process of training and certification to help to
establish high standards of scanning on an international basis. The Certificate
of Competence in the 11–13+6 weeks scan is awarded to those sonographers
that can perform the scan to a high standard and can demonstrate a good
knowledge of the diagnostic features and management of the conditions
identified by this scan.
1
FIRST TRIMESTER
DIAGNOSIS OF CHROMOSOMAL DEFECTS
In 1866, Langdon Down reported that in individuals with

trisomy 21, the condition that came to bear his name, the skin
appears to be too large for the body, the nose is small and the face
is flat. In the last decade it has become possible to observe
these features by ultrasound examination in the third month of
intrauterine life.
About 75% of trisomy 21 fetuses have increased nuchal trans-
lucency (NT) thickness and 60–70% have absent nasal bone
(Figures 1 and 2).
DIAGNOSIS OF CHROMOSOMAL DEFECTS

Non-invasive diagnosis
During the last 30 years, extensive research has aimed at devel-
oping a non-invasive method for prenatal diagnosis based on the
isolation and examination of fetal cells found in the maternal
circulation. About 1 in 103–107 nucleated cells in maternal blood
are fetal. 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
Chapter 1 • First trimester diagnosis of chromosomal defects 7

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 and absent nasal bone.
cell surface markers. The resulting sample is unsuitable for tradi-

tional 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
8 The 11–13+6 weeks scan

three-signal nuclei in some of the cells of the maternal blood
enriched for fetal cells.
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. The
sensitivity of this method is comparable to serum screening.
However, unlike serum biochemistry testing, which is relatively
easy to apply for mass population screening, analysis of fetal cells
from maternal blood is both labor intensive and requires highly
skilled operators. The extent to which the techniques for enrich-
ment 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.
Recent interest has focused on the presence of cell-free fetal
DNA in maternal plasma and the ability to quantify the concen-
tration of male fetal DNA in pregnancies with male fetuses using
real-time quantitative PCR. There is contradictory evidence
concerning the concentration of cell-free fetal DNA in trisomy
21 pregnancies with some studies reporting that the levels are
increased and in others there was no significant difference from
chromosomally normal pregnancies. The extent to which cell-free
fetal DNA will become another maternal serum marker in
screening for trisomy 21 remains to be seen.
Non-invasive diagnosis
• 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.
• There is contradictory evidence concerning the concentration
of cell-free fetal DNA in trisomy 21 pregnancies.

Invasive diagnosis
Amniocentesis
There is only one randomized trial which compared the risks of
amniocentesis to controls. In this study, 4,606 low-risk, healthy
women, 25–34 years old, at 14–20 weeks of gestation, were
randomly allocated to amniocentesis or ultrasound examination
alone (Tabor et al 1986). The total fetal loss rate in the patients
having amniocentesis was 1% higher than in the controls. The
study also reported that amniocentesis was associated with an
increased risk of respiratory distress syndrome and pneumonia.
Amniocentesis is also possible at 10–14 weeks of gestation.
However, randomized studies have demonstrated that after early
amniocentesis the rate of fetal loss is about 2% higher and
the incidence of talipes equinovarus is 1.6% higher than after
first-trimester chorionic villus sampling or second-trimester
amniocentesis.
Chorionic villus sampling

Randomized studies have demonstrated that the rate of fetal
loss following first-trimester transabdominal chorionic villus
sampling is the same as with second-trimester amniocentesis.
There is controversy as to whether the rate of fetal loss after
transcervical chorionic villus sampling is higher or not.
It is likely that in centres with experience in ultrasound guided

invasive procedures the risks of amniocentesis and chorionic
villous sampling, irrespective of route, are the same.
There is an association between chorionic villus sampling before

10 weeks and fetal transverse limb abnormalities, micrognathia
and microglossia. It is therefore imperative that chorionic villus

sampling is performed only after 11 weeks by appropriately
trained operators.
Invasive testing
• Diagnosis of fetal chromosomal defects requires invasive
testing.
• The risk of miscarriage from chorionic villus sampling in the
first trimester is the same as for amniocentesis in the second
trimester.
• Amniocentesis should not be performed before 15 weeks.
• Chorionic villous sampling should not be performed before
11 weeks.
• Invasive tests should be carried out by appropriately trained
and experienced operators.
SCREENING FOR CHROMOSOMAL DEFECTS

In prenatal screening for trisomy 21, the term screen positive rate
is used interchangeably with the invasive testing rate, because most
women with a positive screening test undergo an invasive test,
and with false positive rate (FPR) because the vast majority of
fetuses in this group are normal.
The first method of screening for trisomy 21, introduced in the
early 1970s, was based on the association with advanced maternal
age. It was apparent that amniocentesis carried a risk of mis-
carriage and this in conjunction with the financial cost impli-
cations, 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 30 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 15% 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 38 years.
In screening by maternal age with a cut-off age of 38 years, 5%
of the population is 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 concentra-
tion of various fetoplacental products in the maternal circulation.
At 16 weeks of gestation the median maternal serum concentra-
tions of a-fetoprotein (AFP), uconjugated estriol (uE3), human
chorionic gonadotropin (hCG) (total and free-b) and inhibin-A
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 screen-
ing is more effective than maternal age alone and, for the same
rate of invasive testing (about 5%), it can identify about 50–70%
of the fetuses with trisomy 21.
In the 1990s, screening by a combination of maternal age and

fetal NT thickness at 11–13+6 weeks of gestation was intro-
duced. This method has now been shown to identify about 75%
of affected fetuses for a screen-positive rate of about 5%.
Subsequently, maternal age was combined with fetal NT and

maternal serum biochemistry (free b-hCG and PAPP-A) in the

Screening
•Ultrasound
•Biochemistry
Chorionic
Villous Counselling
Sampling
Figure 3. Assessment of risk for chromosomal defects can be achieved by the combination of maternal
age, ultrasound examination for measurement of fetal nuchal translucency and assessment for the
presence/absence of the nasal bone and biochemical measurement of maternal serum free b-hCG and
PAPP-A in an one-stop clinic at 11–13+6 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.
first-trimester to identify about 85–90% of affected fetuses.

Furthermore, the development of new methods of biochemical
testing, within 30 min of taking a blood sample, made it possible
to introduce One-Stop Clinics for Assessment of Risk (Figure 3).
In 2001, it was found that in 60–70% of fetuses with trisomy 21

the nasal bone is not visible by ultrasound at 11–13+6 weeks and
preliminary results suggest that this finding can increase the
detection rate of the first trimester scan and serum biochemistry
to more than 95% (Table 1).
PATIENT-SPECIFIC 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 or a priori risk, which depends
on maternal age and gestation, and multiply this by a series of
factors or likelihood ratios, which depend on the results of a series

Table 1. Comparison of the detection rates (DR), for a false positive rate of 5%, of different methods of
screening for trisomy 21. In prenatal screening, the term screen positive rate is used interchangeably with
the invasive rate, because most women with a positive screening test undergo an invasive test, and with
false positive rate (FPR) because the vast majority of fetuses in this group are normal.
Method of screening DR (%)
Maternal age (MA) 30
MA and maternal serum biochemistry at 15–18 weeks 50–70
MA and fetal nuchal translucency (NT) at 11–13+6 wks 70–80
MA and fetal NT and maternal serum free b-hCG and 85–90

PAPP-A at 11–13+6 wks
MA and fetal NT and fetal nasal bone (NB) at 11–13+6 wks 90
MA and fetal NT and NB and maternal serum free b-hCG and 95

PAPP-A at 11–13+6 wks
hCG human chorionic gonadotropin, PAPP-A: pregnancy-associated plasma protein A
of screening tests carried out during the course of the pregnancy

to determine the patient-specific risk.
The likelihood ratio for a given sonographic or biochemical

measurement is calculated by dividing the percentage of chromo-
somally abnormal fetuses by the percentage of normal fetuses
with that measurement.
Every time a test is carried out the a priori risk is multiplied by

the likelihood ratio of the test to calculate a new risk, which then
becomes the a priori risk for the next test (Snijders and
Nicolaides 1996). This process of sequential screening neces-
sitates that the different tests are independent of each other. If the
tests are not independent of each other then more sophisticated
techniques, involving multivariate statistics, can be used to
calculate the combined likelihood ratio. With the introduction of
OSCAR, the process of sequential screening can all be achieved
in one session at about 12 weeks of pregnancy (Figure 3).

Sequential screening
• Every woman has a risk that her fetus/baby has a chromo-
somal defect.
• The background or a priori risk depends on maternal age
and gestation.
• The individual patient-specific risk is calculated by multiplying
the a priori risk with a series of likelihood ratios, 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 a priori risk is multiplied by
the likelihood ratio of the test to calculate a new risk, which
then becomes the a priori risk for the next test.
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).
Risk %
10
Trisomy 21
1
XXX/XXY/XYY
Trisomy 18
0.1 Trisomy 13
45XO
0.01
0.001
Triploidy
0.0001
20 25 30 35 40 44
Maternal age (yrs)
Figure 4. Maternal age-related risk for chromosomal abnormalities.

100
XXX/XXY/XYY
%
80
Trisomy 21
60
40
20 45XO
Trisomy 18
Trisomy 13
Triploidy
0
10 15 20 25 30 35 40
Gestation (wks)
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 surveys carried out before the introduction of
prenatal diagnosis (Hecht and Hook 1994). In the last 15 years,
with the introduction of maternal serum biochemical testing 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
(Snijders et al 1995, 1999). Such estimates were derived by
comparing, in women of the same age, the prevalence of trisomy
21 at birth to the prevalence at the time of second-trimester
amniocentesis or first-trimester chorionic villus sampling.
The rates of spontaneous fetal death in trisomy 21 between 12
weeks (when NT screening is carried out) and 40 weeks is about
30% and between 16 weeks (when second trimester maternal
serum biochemical testing is carried out) and 40 weeks is about
20%.
Similar methods were used to produce estimates of risks for other
chromosomal defects. The risk for trisomies 18 and 13 increases
with maternal age and decreases with gestation; the rate of

miscarriage or fetal death between 12 weeks and 40 weeks is
about 80% (Table 2). Turner syndrome is usually due to loss of
the paternal X chromosome and, consequently, the frequency
of conception of 45,XO 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 fetal death is not higher than in chromo-
somally 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 250 000, respectively.
Effect of maternal age and gestation on risk

• The risk for trisomies increases with maternal age.
• The risk for Turner syndrome and triploidy does not change
with maternal age.
• The earlier the gestation, the higher the risk for chromosomal
defects.
• The rates of fetal death in trisomy 21 between 12 weeks
(when NT screening is carried out) and 40 weeks is about
30% and between 16 weeks (when second trimester maternal
serum biochemical testing is carried out) and 40 weeks is
about 20%.
• In trisomies 18 and 13 and Turner syndrome, the rate of fetal
death between 12 and 40 weeks is about 80%.
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 women who had a previous pregnancy
with trisomy 21, the risk of recurrence in the subsequent

18
Table 2. Estimated risk for trisomies 21, 18 and 13 (1/number given in the table) in relation to maternal age and gestation.
Maternal Trisomy 21 Trisomy 18 Trisomy 13

age (yrs) Gestation (wks) Gestation (wks) Gestation (wks)
12 16 20 40 12 16 20 40 12 16 20 40
20 1068 1200 1295 1527 2484 3590 4897 18013 7826 11042 14656 42423
25 946 1062 1147 1352 2200 3179 4336 15951 6930 9778 12978 37567
30 626 703 759 895 1456 2103 2869 10554 4585 6470 8587 24856
31 543 610 658 776 1263 1825 2490 9160 3980 5615 7453 21573
32 461 518 559 659 1072 1549 2114 7775 3378 4766 6326 18311
33 383 430 464 547 891 1287 1755 6458 2806 3959 5254 15209
34 312 350 378 446 725 1047 1429 5256 2284 3222 4277 12380
35 249 280 302 356 580 837 1142 4202 1826 2576 3419 9876
36 196 220 238 280 456 659 899 3307 1437 2027 2691 7788
37 152 171 185 218 354 512 698 2569 1116 1575 2090 6050
38 117 131 142 167 272 393 537 1974 858 1210 1606 4650
39 89 100 108 128 208 300 409 1505 654 922 1224 3544
40 68 76 82 97 157 227 310 1139 495 698 927 2683
41 51 57 62 73 118 171 233 858 373 526 698 2020
42 38 43 46 55 89 128 175 644 280 395 524 1516

pregnancy is 0.75% higher than the maternal and gestational
age-related risk for trisomy 21 at the time of testing. 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 inter-
feres 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.
Recurrence of chromosomal defects

• If a woman has had a previous fetus or baby with a trisomy,
the risk in the current pregnancy is 0.75% higher than her a
priori risk.
• Recurrence is chromosome-specific.
Fetal nuchal translucency

Fetal NT normally increases with gestation (crown–rump
length). In a fetus with a given crown–rump length, every NT
measurement represents a likelihood ratio which is multiplied by
the a priori maternal and gestational age-related risk to calculate
a new risk. The larger the NT, the higher the likelihood ratio
becomes and therefore the higher the new risk. In contrast, the
smaller the NT measurement, the smaller the likelihood ratio
becomes and therefore the lower the new risk (Figure 6).

100 - 5.0 mm
3.5 mm
3.0 mm
2.5 mm
10 - a priori
Risk (%)
1 -
0.1 -
0.01 -
-
-
20 25 30 35 40 45
Maternal age (yrs)
Figure 6. Maternal age-related risk for trisomy 21 at 12 weeks of gestation (a priori) and the effect of
fetal nuchal translucency thickness (NT).
Nasal bone and other first-trimester sonographic markers

At 11–13+6 weeks the nasal bone is not visible by ultra-
sonography in about 60–70% of fetuses with trisomy 21 and in
about 2% of chromosomally normal fetuses. Abnormalities in the
flow velocity waveform from the ductus venosus are observed
in about 80% of fetuses with trisomy 21 and in 5% of
chromosomally normal fetuses.
Similarly, the prevalence of other sonographic markers, such as
exomphalos, megacystis and single umbilical artery, are higher
in certain chromosomal abnormalities than in chromosomally
normal fetuses. Each of these sonographic markers is associated
with a likelihood ratio, which can be multiplied by the a priori
risk to calculate a new risk.
Maternal serum biochemistry in the first-trimester

The level of free b-hCG in maternal blood normally decreases
with gestation. In trisomy 21 pregnancies free b-hCG is

increased. The level of PAPP-A in maternal blood normally
increases with gestation and in trisomy 21 pregnancies the level is
decreased. For a given gestation, each b-hCG and PAPP-A level
represents a likelihood ratio that is multiplied by the a priori risk
to calculate the new risk. The higher the level of b-hCG and the
lower the level of PAPP-A the higher the risk for trisomy 21
(Figure 7).
NUCHAL TRANSLUCENCY THICKNESS

Cystic hygromas, nuchal edema and nuchal translucency
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 syndrome. Nuchal
edema has a diverse etiology; chromosomal abnormalities are
found in about one-third of the fetuses and, in about 75% of
Risk (%) ß-hCG PAPP-A

Risk (%)
100 100
4.0 MoM 0.25 MoM
3.0 MoM 0.33 MoM
2.0 MoM 0.50 MoM
10 10
a priori a priori
1 1
0.1 0.1
0.01 0.01
20 25 30 35 40 45 20 25 30 35 40 45
Maternal Age (yrs) Maternal Age (yrs)
Figure 7. Maternal age-related risk for trisomy 21 at 12 weeks of gestation (a priori) and the effect of
maternal serum free b-hCG (left) and PAPP-A (right).

cases, the abnormality is trisomy 21 or 18. Edema is also associ-
ated with fetal cardiovascular and pulmonary defects, skeletal
dysplasias, congenital infections and metabolic and hematological
disorders; consequently, the prognosis for chromosomally normal
fetuses with nuchal edema is poor.
In the first trimester, the term translucency is used, irrespective
of whether it is septated or not and whether it is confined to the
neck or envelopes the whole fetus. 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. Neither the incidence of chromosomal
defects nor the prognosis can be predicted by the ultrasono-
graphic appearance of the lesion.
Increased NT is associated with trisomy 21, Turner syndrome and
other chromosomal defects as well as many fetal malformations
and genetic syndromes. The incidence of these abnormalities
is related to the thickness, rather than the appearance, of NT.
Furthermore, it is possible to standardize and audit the results of
a measurement but not those of a subjective appearance.
Nuchal translucency – definition

• Nuchal translucency is the sonographic appearance of sub-
cutaneous accumulation of fluid behind the fetal neck in the
first trimester of pregnancy.
• The term translucency is used, irrespective of whether it is
septated or not and whether it is confined to the neck or
envelopes the whole fetus.
• The incidence of chromosomal and other abnormalities is
related to the size, rather than the appearance of NT.
• 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
The ability to achieve a reliable measurement of NT is dependent
on appropriate training and adherence to a standard technique in
order to achieve uniformity of results among different operators.
Gestation and crown-rump length

The optimal gestational age for measurement of fetal NT is 11
weeks to 13 weeks and 6 days. The minimum fetal crown–rump
length should be 45 mm and the maximum 84 mm.
There are two reasons for selecting 11 weeks as the earliest

gestation for measurements of NT. Firstly, screening necessitates
the availability of a diagnostic test and chorionic villous sampling
before this gestation is associated with transverse limb reduction
defects. Secondly, many major fetal defects can be diagnosed at
the NT scan, provided the minimum gestation is 11 weeks. For
example, diagnosis or exclusion of acrania and therefore anence-
phaly, cannot be made before 11 weeks because sonographic
assessment of ossification of the fetal skull is not reliable before
this gestation. Examination of the four-chamber view of the heart
and main arteries is possible only after 10 weeks. At 8–10 weeks
all fetuses demonstrate herniation of the midgut that is visualized
as a hyperechogenic mass in the base of the umbilical cord, and
it is therefore unsafe to diagnose or exclude exomphalos at this
gestation. The fetal bladder can be visualized in only 50% of
fetuses at 10 weeks, in 80% at 11 weeks and in all cases by
12 weeks.
The reasons for selecting 13 weeks and 6 days as the upper limit
are firstly, to provide women with affected fetuses the option

of first rather than second trimester termination, secondly, the
incidence of abnormal accumulation of nuchal fluid in chromo-
somally abnormal fetuses is lower at 14–18 weeks than before
14 weeks, and thirdly, the success rate for taking a measurement
at 10–13 weeks is 98–100%, falling to 90% at 14 weeks because
the fetus becomes vertical making it more difficult to obtain the
appropriate image.
Image and measurement

In the assessment of fetal NT the ultrasound machine should be
of high resolution with a video-loop function and callipers that
provide measurements to one decimal point. Fetal NT can be
measured successfully by transabdominal ultrasound examination
in about 95% of cases; in the others, it is necessary to perform
transvaginal sonography. The results from transabdominal and
transvaginal scanning are similar.
Only the fetal head and upper thorax should be included in the
image for measurement of NT (Figure 8a). The magnification
should be as large as possible and always such that each slight
movement of the callipers produces only a 0.1 mm change in the
measurement. In magnifying the image, either pre or post freeze
zoom, it is important to turn the gain down. This avoids the
mistake of placing the calliper on the fuzzy edge of the line which
causes an underestimate of the nuchal measurement.
A good sagittal section of the fetus, as for measurement of fetal

crown–rump length, should be obtained and the NT should be
measured with the fetus in the neutral position. When the fetal
neck is hyperextended the measurement can be increased by
0.6 mm and when the neck is flexed, the measurement can be
decreased by 0.4 mm.

(a) (b)
(c) (d)
(e) (f)
Figure 8. Ultrasound pictures of 12-weeks fetus. In all six images there is a good sagittal section of the
fetus. Image (a) is appropriate for measurement of the nuchal translucency (NT) because only the fetal
head and upper thorax are included and the nuchal membrane, which is thin, can be seen separate from
the amniotic membrane. In (b) the magnification is too small for accurate measurement of NT. In (c) the
fetal neck is hyperextended and in (d) the neck is too flexed. In (e) the maximum measurement of NT
should be taken. In (f) the umbilical cord is round the neck. In this case the NT should be measured both
above and below the cord and the average of the two measurements should be used in the calculation
of risk.
Care must be taken to distinguish between fetal skin and amnion

because, at this gestation, both structures appear as thin mem-
branes (Figure 8a). 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 (Figure 8e). The callipers should be placed
on the lines that define the NT thickness – the crossbar of the
calliper should be such that it is hardly visible as it merges with
the white line of the border and not in the nuchal fluid. During
the scan, more than one measurement must be taken and the
maximum one should be recorded.
The umbilical cord may be round the fetal neck in 5–10% of

cases and this finding may produce a falsely increased NT. In
such cases, the measurements of NT above and below the cord
are different and, in the calculation of risk, it is more appropriate
to use the average of the two measurements (Figure 8f ).
There are no clinically relevant effects on NT measurements

by ethnic origin, parity or gravidity, cigarette smoking, diabetic
control, conception by assisted reproduction techniques, bleeding
in early pregnancy or fetal gender.
The intra-observer and inter-observer differences in measure-

ments of fetal NT are less than 0.5 mm in 95% of cases.
Deviation in measurement from normal

Fetal NT increases with crown–rump length and therefore it
is essential to take gestation into account when determining
whether a given NT thickness is increased. In a study involving
96,127 pregnancies, the median and 95th centile at a

crown-rump-length of 45 mm were 1.2 and 2.1 mm and the
respective values at crown rump length of 84 mm were 1.9 and
2.7 mm (Snijders et al 1998).
In screening for chromosomal defects patient-specific risks are

derived by multiplying the a priori maternal age and gestation-
related risk by a likelihood ratio, which depends on the difference
(Delta value in mm) in fetal NT measurement from the normal
median for the same crown-rump length (Figures 9–11).
In screening using maternal serum biochemical markers a differ-

ent approach has been used to take into account the gestational
age related change in marker levels. This method involves
converting the measured concentration into a multiple of the
median (MoM) of unaffected pregnancies of the same gestation.
Essentially, the Gaussian distributions of log10 (NT MoM) in
trisomy 21 and unaffected pregnancies are derived and the
heights of the distributions at a particular MoM, which is the
likelihood ratio for trisomy 21, is used to modify the a priori
maternal age-related risk to derive the patient-specific risk.
8.0
7.0
Nuchal translucency (mm)
6.0
5.0
4.0
3.0
2.0
1.0
0.0
35 45 55 65 75 85
Crown-rump length (mm)
Figure 9. Nuchal translucency measurement in 326 trisomy 21 fetuses plotted on the normal range for
crown–rump length (95th and 5th centiles).

25
20
Frequency (%)
15
10
-1 0 1 2 3 4 5 6
Nuchal translucency deviation (mm)
Figure 10. Distribution of fetal nuchal translucency thickness expressed as deviation from the normal
median for crown–rump length in chromosomally normal fetuses (black bars) and 326 with trisomy 21
(blue bars).
60
50
Likelihood ratio
40
30
20
10
0
-0.5 0 0.5 1 1.5 2 2.5
Nuchal translucency deviation (mm)
Figure 11. Likelihood ratios for trisomy 21 in relation to the deviation in fetal nuchal translucency
thickness from the normal median for crown–rump length.
In screening by NT the Delta approach provides accurate

patient-specific risks (Spencer et al 2003). In contrast, the MoM
approach was found to be inappropriate for this purpose, because
none of the three basic assumptions that underpin this method
are valid. Firstly, in the unaffected population the distributions
of NT MoM and log10(NT MoM) are not Gaussian, secondly,

the SD’s do not remain constant with gestation and thirdly, the
median MoM in the trisomy 21 pregnancies is not a constant
proportion of the median for unaffected pregnancies. The MoM
approach results in women being given an overestimate of risk
for trisomy at 11 weeks and a considerable underestimate of risk
at 13 weeks.
Nuchal translucency – measurement

• The gestation should be 11–13+6 weeks and the fetal crown–
rump length should be 45–84 mm.
• A mid-sagittal section of the fetus should be obtained and the
NT should be measured with the fetus in the neutral position.
• Only the fetal head and upper thorax should be included in
the image. The magnification should be as large as possible
and always such that each slight movement of the callipers
produces only a 0.1 mm change in the measurement.
• The maximum thickness of the subcutaneous translucency
between the skin and the soft tissue overlying the cervical
spine should be measured. Care must be taken to distinguish
between fetal skin and amnion.
• The callipers should be placed on the lines that define the NT
thickness – the crossbar of the calliper should be such that it
is hardly visible as it merges with the white line of the border
and not in the nuchal fluid.
• During the scan, more than one measurement must be taken
and the maximum one should be recorded.
Training and quality assessment in the measurement of NT

Appropriate training of sonographers and adherence to a
standard technique for the measurement of NT are essential
prerequisites for good clinical practice. Furthermore, the success
of a screening program necessitates the presence of a system for

regular audit of results and continuous assessment of the quality
of images.
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
NT thickness. However, the ability to measure NT and obtain
reproducible results improves with training. Good results are
achieved after 80 scans for the transabdominal route and 100
scans transvaginally.
Several studies have demonstrated that ongoing regular audit of
images and the distribution of measurements of NT is essential
for assessing the quality of a centre and is also useful in identify-
ing individual sonographers whose results deviate from the mean
performance. The inter-examination variation in measurements
is reduced considerably after an initial learning phase and after
feedback to the sonographers on the distribution of their
measurements and the quality of their images.
The Fetal Medicine Foundation (FMF), which is a UK
registered charity, has established a process of training and
quality assurance for the appropriate introduction of NT screen-
ing into clinical practice. Training is based on a theoretical
course, practical instruction on how to obtain the appropriate
image and make the correct measurement of NT, and presenta-
tion of a logbook of images. These are examined to determine
if the magnification is adequate, the section of the fetus is truly
sagittal and the head is in the neutral position, the amnion is seen
separately from the nuchal membrane and the callipers are placed
appropriately. Ongoing quality assurance is based on assessment
of the distribution of fetal NT measurements (Figure 12) and
examination of a sample of images obtained by each sonographer
involved in screening.

6.0
(a)

5.0
4.0
3.0
2.0
1.0
0.0
45 50 55 60 65 70 75 80 85
Crown- rump length (mm)
4.0 (b)
3.0
2.0
1.0
0.0
45 50 55 60 65 70 75 80 85
4.0
(c)
3.0
2.0
1.0
0.0
45 50 55 60 65 70 75 80 85
Figure 12. Distribution of fetal nuchal translucency thickness. In (a) the distribution is good, in (b) the
measurements are underestimated and in (c) the measurements are overestimated.

Nuchal translucency – training and quality assurance
• Appropriate training of sonographers and adherence to a
standard technique for the measurement of NT are essential
prerequisites for good clinical practice.
• The success of a screening program necessitates the presence
of a system for regular audit of results and continuous assess-
ment of the quality of images.
• Training is based on a theoretical course, practical instruction
on how to obtain the appropriate image and make the
correct measurement of NT, and presentation of a logbook of
images.
• Ongoing quality assurance is based on assessment of the
distribution of fetal NT measurements and examination of a
sample of images obtained by each sonographer involved in
screening.
Nuchal translucency thickness and risk for chromosomal defects

In 1992 a study, in which fetal NT was measured before CVS for
fetal karyotyping, reported that in a high proportion of chromo-
somally abnormal fetuses the NT thickness was increased
(Nicolaides et al 1992).
This association was subsequently confirmed in several other
studies in the early 1990s. Thus, in the combined data from 17
series involving a total of 1,690 patients with increased fetal NT
the incidence of chromosomal defects was 29% (Nicolaides
2004). However, there were large differences between the studies
in the incidence of chromosomal defects, ranging from 11% to
88%, because of differences in the maternal age distributions of
the populations examined and the definition of the minimum
abnormal NT thickness, which ranged from 2 mm to 10 mm.
Studies in the mid 1990’s demonstrated that firstly, in normal
pregnancies, fetal NT thickness increases with gestation,

secondly, in trisomy 21 and other major chromosomal defects
fetal NT is increased, and thirdly, the risk for trisomies can be
derived by multiplying the a priori maternal age and gestation-
related risk by a likelihood ratio, which depends on the degree of
deviation in fetal NT measurement from the normal median for
that crown–rump length (Nicolaides et al 1994, Pandya et al
1995).
It was estimated that, in a pregnant population with a mean
maternal age of 28 years, using the risk cut-off of 1 in 300 to
define the screen positive group would detect about 80% of
trisomy 21 fetuses for a false positive rate of 5%.
Nuchal translucency – calculation of patient-specific risk

• The risk for trisomies is derived by multiplying the a priori
maternal age and gestation-related risk by the NT likelihood
ratio.
• The NT likelihood ratio depends on the degree of deviation
in fetal NT measurement from the normal median for that
crown–rump length.
Implementation of nuchal translucency screening in routine practice

Several prospective interventional studies have examined the
implementation of NT screening in routine practice (Nicolaides
2004).
In some of the studies the screen positive group was defined by a
cut-off in fetal NT or a combined risk derived from the maternal
age and deviation in fetal NT from the normal median for fetal
crown-rump length.
The important findings of these studies are, firstly, fetal NT was
successfully measured in more than 99% of cases, secondly, there
were inevitable variations in false positive and detection rates
between the studies because of differences in the maternal age

distribution of their populations and in fetal NT or risk cut-offs
used, and thirdly, in the combined data on more than 200,000
pregnancies, including more than 900 fetuses with trisomy 21,
fetal NT screening identified more than 75% of fetuses with
trisomy 21 and other major chromosomal defects for a false posi-
tive rate of 5%, or the detection rate was about 60% for a false
positive rate of 1% (Nicolaides 2004).
In the largest study, coordinated by the FMF, 100,311 singleton
pregnancies were examined by 306 appropriately trained
sonographers in 22 UK centers (Snijders et al 1998). In all cases
the fetal NT and crown–rump length were measured and indi-
vidual patient-specific risks, based on maternal age, gestational
age and fetal NT were calculated. Follow-up was obtained from
96,127 cases, including 326 with trisomy 21 and 325 with other
chromosomal defects (Table 3). The median gestation at the time
Table 3. Multicentre study coordinated by the Fetal Medicine Foundation. Number of pregnancies with
nuchal translucency (NT) thickness above the 95th centile and an estimated risk for trisomy 21, based on
maternal age and fetal nuchal translucency and crown-rump length, of 1 in 300 or more (Snijders et al
1998).
Fetal karyotype N NT >95th centile Risk ≥1 in 300
Normal 95,476 4,209 (4.4%) 7,907 (8.3%)
Trisomy 21 326 234 (71.2%) 268 (82.2%)
Trisomy 18 119 89 (74.8%) 97 (81.5%)
Trisomy 13 46 33 (71.7%) 37 (80.4%)
Turner syndrome 54 47 (87.0%) 48 (88.9%)
Triploidy 32 19 (59.4%) 20 (62.5%)
Other* 64 41 (64.1%) 51 (79.7%)
Total 96,127 4,767 (5.0%) 8,428 (8.8%)
*Deletions, partial trisomies, unbalanced translocations, sex chromosome aneuploidies

of screening was 12 weeks and the median maternal age was
31 years.
The estimated risk for trisomy 21 was 1 in 300 or more in 8% of
the normal pregnancies, in 82% of those with trisomy 21 and
in 78% with other chromosomal defects. For a screen-positive
rate of 5%, the detection rate was 77% (95% confidence interval
72–82%).
The issue of spontaneous fetal death

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 chromo-
somally abnormal pregnancies that are destined to miscarry.
Approximately 30% of affected fetuses die between 12 weeks of
gestation and term. This issue of preferential spontaneous death
in fetuses with chromosomal defects is, of course, a potential
criticism of all methods of antenatal screening, including second-
trimester maternal serum biochemistry, because the rate of fetal
death between 16 weeks and term is about 20%.
In prenatal screening studies it is impossible to know how many
of the trisomy 21 pregnancies that were terminated would have
resulted in live births. However, it is possible to estimate the
impact of prenatal screening on the prevalence of trisomy 21 in
live births. This can be done by comparing the number of
affected live births with the number estimated on the basis of the
maternal age-related prevalence of trisomy 21 in live births and
the maternal age distribution of the population screened. In the
FMF screening study, by a combination of maternal age and
fetal NT, a risk cut-off of 1 in 300 was associated with a false
positive rate of 8% and a detection rate of 82% (Snijders et al

1998). It was estimated that prenatal screening followed by
invasive diagnostic testing and selective termination of affected
fetuses would have reduced the potential live birth prevalence of
trisomy 21 by 78–82%.
Nuchal translucency – effectiveness of screening for trisomy 21

• Prospective studies in more than 200,000 pregnancies,
including more than 900 fetuses with trisomy 21, have
demonstrated that NT screening can identify more than 75%
of fetuses with trisomy 21 for a false positive rate of 5%.
• Increased NT does not necessarily identify those trisomic
fetuses that are destined to die in utero.
• The observed detection rate of trisomy 21 with first trimester
NT screening is only 2–3% higher than the detection rate of
affected pregnancies that would potentially result in livebirths.
Observational studies
The ability to achieve a reliable measurement of NT is dependent
on appropriate training, adherence to a standard technique and
motivation of the sonographer. All three components are well
illustrated by the differences in results between interventional
and observational studies, in which the sonographers were asked
to record the fetal NT measurements but not act on the results
(Nicolaides 2004). Thus, successful measurement of NT was
achieved in more than 99% of cases in the interventional studies,
but in only 75% of cases in the observational studies. Further-
more in the interventional studies there was increased NT in
76.8% of the trisomy 21 and 4.2% of the chromosomally normal
fetuses, compared to the respective rates of 38.4% and 5.0% in
the observational studies.
In the observational studies, the scans were often carried out at
inappropriate gestations and the sonographers were either not
trained adequately or they were not sufficiently motivated to

measure NT. For example, in one of the studies, in which
sonographers were instructed to take no extra scanning time
other than that necessary for measurement of the crown-rump
length, fetal NT was successfully measured in only 66% of cases
(Roberts et al 1995). In another study, the fetal crown-rump
length was less than 33 mm in 54% of cases and the
sonographers, who were instructed to measure fetal NT within
three minutes, were unable to do so in 42% of cases (Kornman
et al 1996). These methodological problems are further high-
lighted by a study of 47,053 singleton pregnancies examined at
6–16 weeks (Wald et al 2003a). In 23% of the patients no valid
NT measurement was taken because the scans were carried out
at inappropriate gestations or the sonographers were unable to
obtain a measurement or none of the images were deemed to be
of an acceptable quality.
Further evidence on the difference between observational and
interventional studies is provided by Crossley et al (2002). In this
observational study, 17,229 pregnancies were recruited and fetal
NT was successfully measured in 73% of cases. In a subsequent
study of more than 2,000 pregnancies in which the results of
the scan were given to the women, fetal NT was successfully
measured in 99.8% of cases.
Nuchal translucency and maternal serum biochemistry

Trisomic pregnancies are associated with altered maternal serum
concentrations of various feto-placental products, including AFP,
free b-hCG, uE3, inhibin A and PAPP-A. Screening in the
second trimester by maternal age and various combinations of
free b-hCG, AFP, uE3 and Inhibin A can identify 50–75% of
trisomy 21 pregnancies for a false positive rate of 5%. Screening
in the first trimester by a combination of maternal age and serum
free b-hCG and PAPP-A identifies about 60% of affected
pregnancies for a false positive rate of 5%. However, an essential

component of biochemical screening is accurate dating of the
pregnancy by ultrasound, otherwise the detection rate is reduced
by about 10%.
Fetal NT and maternal serum testing in the first-trimester

In trisomy 21 pregnancies at 12 weeks, the maternal serum
concentration of free b-hCG (about 2 MoM) is higher than in
chromosomally normal fetuses whereas PAPP-A is lower (about
0.5 MoM). The difference in maternal serum free b-hCG
between normal and trisomy 21 pregnancies increases with
advancing gestation and the difference in PAPP-A decreases
with gestation. These temporal variations in marker levels, their
interrelation and their association with maternal weight should be
taken into account when developing risk algorithms in order to
produce accurate patient-specific risks.
There is no significant association between fetal NT and
maternal serum free b-hCG or PAPP-A in either trisomy 21 or
chromosomally normal pregnancies and therefore the ultra-
sononographic and biochemical markers can be combined to
provide more effective screening than either method individually
(Spencer et al 1999). Six prospective screening studies have
confirmed the feasibility and effectiveness of combining fetal NT
and maternal serum free b-hCG and PAPP-A. In the combined
data on a total of 38,804 pregnancies, including 182 with trisomy
21, the detection rate for trisomy 21 at a 5% false positive rate
was 86% (Nicolaides 2004).
In trisomies 18 and 13 maternal serum free b-hCG and
PAPP-A are decreased. In cases of sex chromosomal anomalies
maternal serum free b-hCG is normal and PAPP-A is low. In
paternally derived triploidy maternal serum free b-hCG is greatly
increased, whereas PAPP-A is mildly decreased. Maternally
derived triploidy is associated with markedly decreased maternal

serum free b-hCG and PAPP-A. Screening by a combination of
fetal NT and maternal serum PAPP-A and free b-hCG can
identify about 90% of all these chromosomal abnormalities for a
screen positive rate of 1%, in addition to the 5% necessary in
screening for trisomy 21.
An important development in biochemical analysis is the intro-
duction of a new technique (random access immunoassay ana-
lyzer using time-resolved-amplified-cryptate-emission), which
provides automated, precise and reproducible measurements
within 30 minutes of obtaining a blood sample. 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) (Bindra et al 2002, Spencer et al 2003b).
Fetal NT and maternal serum testing in the second-trimester

In women having second-trimester biochemical testing following
first-trimester NT screening the a priori risk needs to be adjusted
to take into account the first-trimester screening results.
Prospective studies of screening by a combination of fetal NT in
the first trimester and maternal serum biochemistry in the second
trimester reported that for a false positive rate of 5% the detection
rate of trisomy 21 (85–90%) is similar to combined screening in
the first trimester (Nicolaides 2004).
Integration of first and second trimester testing

A statistical model combining first-trimester fetal NT and
maternal serum PAPP-A with second-trimester free b-hCG, uE3
and inhibin A, estimated that for a false positive rate of 5% the
detection rate of trisomy 21 could be 94% (Wald et al 1999).
This test assumes complete compliance by the pregnant women
in firstly, participating in a two stage process separated by one
month, secondly, in having an ultrasound scan without receiving

information as to whether the fetus looks normal or not, and
thirdly, accepting second rather than first trimester diagnosis and
termination. It is therefore likely that even if the estimates of this
hypothetical test are found to be true in prospective studies, it
will not gain widespread clinical acceptability.
Some of the logistical problems in the implementation of an
integrated test are highlighted by the results of a multicentre
observational study (SURUSS) investigating first and second
trimester screening for trisomy 21 (Wald et al 2003a). The aim
was to obtain a measurement of fetal NT in the first trimester and
collect maternal serum and urine samples in the first and second
trimesters. Intervention was based on the second trimester serum
results and all other data were analyzed retrospectively. However,
of the 47,053 women that were recruited, only 60% completed all
components of the protocol. In this study there were 101 fetuses
with trisomy 21 and satisfactory NT images were obtained only
from 75 of the cases. The data were used to derive a statistical
model suggesting that for a 5% false positive rate, 93% of trisomy
21 fetuses could be detected by the integrated test. However, it is
likely that this model is inaccurate. For example, the predicted
detection rates, for a 5% false positive rate, were 71% for the
double test, 77% for the triple test and 83% for the quadruple
test, which are substantially higher than the respective rates
of 61%, 66% and 75% reported by the same authors in their
prospective screening studies (Wald et al 2003b).
A similar study in the USA (FASTER trial), reported its
findings in the subgroup of 33,557 pregnancies with complete
first and second trimester data, including 84 cases of trisomy 21
(Malone et al 2004). It was estimated that, for a 5.4% false
positive rate, 90% of trisomy 21 fetuses could be detected.
Prospective studies have demonstrated that such results are
achievable by screening with fetal NT and maternal serum

free b-hCG and PAPP-A in the first-trimester (Bindra et al
2002, Spencer et al 2003b). It is therefore essential that, in
screening, attention is paid to the provision of high quality sono-
graphic and biochemical services for early diagnosis of chromo-
somal defects, rather than the development of theoretical models
which would delay diagnosis until the second trimester and are,
in any case, unlikely to be implemented in clinical practice.
Screening by nuchal translucency and serum biochemistry

• In trisomy 21 pregnancies at 11–13+6 weeks, the maternal
serum concentration of free b-hCG is higher (about 2 MoM)
and PAPP-A is lower (about 0.5 MoM) than in chromosomally
normal fetuses.
• There is no significant association between fetal NT and
maternal serum free b-hCG or PAPP-A in either trisomy 21 or
chromosomally normal pregnancies. The ultrasononographic
and biochemical markers can be combined to provide more
effective screening than either method individually.
• Prospective studies, in more than 50,000 pregnancies, includ-
ing more than 250 fetuses with trisomy 21, have demon-
strated that screening by a combination of fetal NT and either
first or second trimester maternal serum biochemistry can
identify 85–90% of fetuses with trisomy 21 for a false positive
rate of 5%.
• In trisomies 18 and 13 maternal serum free b-hCG and
PAPP-A are decreased. In sex chromosomal anomalies mater-
nal serum free b-hCG is normal and PAPP-A is low. In pater-
nally derived triploidy maternal serum free b-hCG is greatly
increased, whereas PAPP-A is mildly decreased. Maternally
derived triploidy is associated with markedly decreased
maternal serum free b-hCG and PAPP-A. Screening by a
combination of fetal NT and maternal serum PAPP-A and
free b-hCG can identify about 90% of all these chromosomal
abnormalities for a screen positive rate of 1%, in addition to
the 5% in screening for trisomy 21.

WOMENS’ ATTITUDES TO 1ST VERSUS 2ND TRIMESTER SCREENING
Studies investigating the preference of pregnant women in terms
of the methods of screening, have reported that the vast majority
prefer this to be carried out in the first rather than in the second
trimester. A criticism of NT screening has been that some
women with increased fetal NT will face unnecessary decisions
regarding invasive testing and ultimately pregnancy termination
in an affected pregnancy that would otherwise have ended in
spontaneous miscarriage. In a survey of women’s preferences,
about 70% stated that they would still choose NT screening even
if all the Down’s syndrome pregnancies identified by this method
miscarried before the second trimester (Mulvey and Wallace
2000). The women wanted to know if their fetus had had Down’s
syndrome regardless of the pregnancy outcome and they also
valued the knowledge of an underlying reason for a miscarriage
if it occurred.
Clinical importance of respect for autonomy

Respect for autonomy is a central principle in medical ethics and
law. This ethical principle obliges the physician to elicit and
implement the patient’s preferences. The relevance of respect for
autonomy to first trimester screening is two-fold. Firstly, early
diagnosis of fetal abnormality and the option of early termination
of pregnancy are important to many women. Secondly, most first
trimester screening tests provide reassurance for many women
who would prefer not to have an invasive procedure if the
risk is low. Consequently, the provision of a high-quality first
trimester screening service significantly enhances the autonomy
of pregnant women (Chasen et al 2001).
The vast majority of pregnant women prefer screening and
diagnosis to be performed in the first, rather than in the second
trimester.

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the quadruple test. Lancet 2003b;361:835–6.

2
SONOGRAPHIC FEATURES OF CHROMOSOMAL DEFECTS
Each chromosomal defect has its own syndromal pattern of

detectable abnormalities. This chapter describes the sonographic
features of trisomy 21 and other major chromosomal defects in
the first and second trimesters of pregnancy.
FIRST TRIMESTER ULTRASONOGRAPHY

At 11–13+6 weeks, all major chromosomal defects are associated
with increased NT thickness (Snijders et al 1998). In trisomies
21, 18 and 13 the pattern of increase in NT is similar and the
average NT in these defects is about 2.5 mm above the normal
median for crown-rump length. In Turner syndrome, the median
NT is about 8 mm above the normal median.
In addition to increased NT, in trisomy 21, 60–70% of fetuses
have absent nasal bone, 25% have a short maxilla, and 80%
have abnormal Doppler waveforms in the ductus venosus. In
trisomy 18, there is early onset fetal growth restriction, a ten-
dency for bradycardia and exomphalos in 30% of cases, absent
nasal bone in 55% and single umbilical artery in 75%. In trisomy
13, there is tachycardia in about 70% of the cases and early
onset fetal growth restriction, megacystis, holoprosencephaly or
exomphalos in about 40% of the cases. In Turner syndrome,
there is tachycardia in about 50% of cases and early onset fetal
growth restriction. In triploidy, there is early onset asymmetrical
Chapter 2 • Sonographic features of chromosomal defects 45

fetal growth restriction, bradycardia in 30% of cases, holopro-
sencephaly, exomphalos or posterior fossa cyst in about 40% and
molar changes in the placenta in about 30%.
Absence of fetal nasal bone

In 1866 Langdon Down noted that a common characteristic of
patients with trisomy 21 is a small nose. Anthropometric studies
in patients with Down’s syndrome have reported that the
nasal root depth is abnormally short in 50% of cases (Farkas et al
2001). Similarly, post mortem radiological studies in aborted
fetuses with trisomy 21 have reported absence of ossification or
hypoplasia of the nasal bone in about 50% of cases. Sonographic
studies at 15–24 weeks of gestation reported that about 65% of
trisomy 21 fetuses have absent or short nasal bone.
The fetal nasal bone can be visualized by sonography at 11–13+6
weeks of gestation (Cicero et al 2001). Several studies have demon-
strated a high association between absent nasal bone at 11–13+6
weeks and trisomy 21, as well as other chromosomal abnormalities
(Nicolaides 2004). In the combined data from these studies on a
total of 15,822 fetuses the fetal profile was successfully examined
in 97.4% cases and the nasal bone was absent in 1.4% of the chro-
mosomally normal fetuses and in 69% of fetuses with trisomy 21.
An important finding of these studies was that the incidence
of absent nasal bone decreased with fetal crown-rump length,
increased with NT thickness and was substantially higher in
Afro-Caribbeans than in Caucasians. Consequently, in the calcu-
lation of likelihood ratios in screening for trisomy 21 adjustments
must be made for these confounding factors (Cicero et al 2004).
Integrated first-trimester sonographic and biochemical screening

A case-control study comprising of 100 trisomy 21 and 400
chromosomally normal singleton pregnancies at 11–13+6 weeks

of gestation examined the potential performance of screening for
trisomy 21 by a combination of sonography for measurement of
fetal NT and assessment of the presence or absence of the fetal
nasal bone and measurement of maternal serum free b-hCG and
PAPP-A (Cicero et al 2003). It was estimated that for a false
positive rate of 5%, the detection rate of trisomy 21 would be 97%.
Examination of the nasal bone

• The gestation should be 11–13+6 weeks and the fetal
crown–rump length should be 45–84 mm.
• The image should be magnified so that the head and the
upper thorax only are included in the screen.
• A mid-sagittal view of the fetal profile should be obtained
with the ultrasound transducer held in parallel to the direction
of the nose.
• In the image of the nose there should be three distinct lines.
The top line represents the skin and the bottom one, which is
thicker and more echogenic than the overlying skin, repre-
sents the nasal bone. A third line, almost in continuity with the
skin, but at a higher level, represents the tip of the nose.
• At 11–13+6 weeks the fetal profile can be successfully
examined in more than 95% of cases.
• In chromosomally normal fetuses the incidence of absent
nasal bone is less than 1% in Caucasian populations and
about 10% in Afro-Caribbeans.
• The nasal bone is absent in 60–70% of trisomy 21 fetuses,
in about 50% of trisomy 18 fetuses and 30% of trisomy 13
fetuses.
• For a false positive rate of 5%, screening by a combination of
sonography for fetal NT and nasal bone and maternal serum
free b-hCG and PAPP-A can potentially identify more than
95% of trisomy 21 pregnancies.
• It is imperative that sonographers undertaking risk assessment
by examination of the fetal profile receive appropriate
training and certification of their competence in performing
such a scan.

Crown–rump length
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 (Figure 1; Nicolaides et al 1996).
Crown-rump length and chromosomal defects

• Trisomy 18 and triploidy are associated with moderately
severe growth restriction
• Trisomy 13 and Turner syndrome are associated with mild
growth restriction
• In trisomy 21 growth is essentially normal
100
90
80
Crown-rump-length (mm)
70
60
50
40
30
20
70 75 80 85 90 95 100
Gestation (days)
Figure 1. Fetal crown-rump length in fetuses with triploidy plotted on the reference range (mean, 95th
and 5th centiles) with gestation of chromosomally normal fetuses.

Maxillary length
Langdon Down observed that in individuals with trisomy 21
‘the face is flat’. This may be the consequence of under-
development of the maxilla. Anthropometric and radiological
studies in patients with Down’s syndrome have demonstrated
underdevelopment of the maxilla in more than 50% of cases
(Farkas et al 2001).
The fetal maxilla can be easily visualized and measured by
sonography at 11–13+6 weeks of gestation (Cicero et al 2004).
A mid-sagittal view of the fetal profile is first obtained and
the transducer is then gently angled laterally so that both the
maxillary bone and mandible, including the ramus and condylar
process, can be seen (Figure 2). In chromosomally normal
fetuses maxillary length increases linearly with gestation by about
0.1 mm for each 1 mm increase in crown-rump length. In the
trisomy 21 fetuses the median maxillary length is significantly
below the normal median for crown-rump length by 0.7 mm.
Figure 2. Ultrasound picture of a 12-weeks fetus demonstrating measurement of maxillary length.

However, there is a significant association between maxillary
bone length and NT thickness and in fetuses with absent
nasal bone the maxilla is shorter than in those with present nasal
bone. Consequently, the independent contribution of maxillary
length in screening for trisomy 21 remains to be determined. In
fetuses with other chromosomal defects there are no significant
differences from normal in the maxillary length.
Ear length
In postnatal life, short ears constitute the most consistent clinical
characteristic of patients with Down’s syndrome. The fetal ears
can be easily visualized and measured by sonography at 11–13+6
weeks of gestation (Sacchini et al 2003). Although in trisomy
21 fetuses the median ear length is significantly below the
normal median for crown-rump length, the degree of deviation
from normal is too small for this measurement to be useful in
screening for trisomy 21.
Femur and humerus length

Trisomy 21 is characterised by short stature and during the
second trimester the condition is associated with relative short-
ening of the femur and more so the humerus. At 11–13+6
weeks in trisomy 21 fetuses the median femur and humerus
lengths are significantly below the appropriate normal median
for crown-rump length but the degree of deviation from normal
is too small for these measurements to be useful in screening
(Longo et al 2004).
Single umbilical artery

A single umbilical artery, found in about 1% of deliveries, is
associated with malformations of all major organ systems and

chromosomal defects. In the first-trimester the umbilical arteries
can be visualized by color flow mapping on either side of the
bladder and in continuity with the umbilical cord insertion to the
fetus in an oblique transverse section of the lower fetal abdomen.
At 11–13+6 weeks single umbilical artery is found in about 3%
of chromosomally normal fetuses and in 80% of fetuses with
trisomy 18 (Rembouskos et al 2003). In the fetuses with single
umbilical artery the observed number of cases of trisomy 21
is not significantly different from the number estimated on the
basis of maternal age and fetal NT. In contrast, a single umbilical
artery is associated with a seven fold increase in risk of trisomy
18. However, a high proportion of trisomy 18 fetuses have other
major defects that are easily detectable at the 11–13+6 weeks scan
and many other abnormalities that are detectable at 16–20 weeks.
It is therefore unlikely that the finding of a single umbilical artery
per se should be an indication for fetal karyotyping.
Megacystis
The fetal bladder can be visualized by sonography in about 80%
of fetuses at 11 weeks of gestation and in all cases by 13 weeks.
At this gestation the fetal bladder length is normally less than
6 mm. Fetal megacystis in the first-trimester, defined by a longi-
tudinal bladder diameter of 7 mm or more, is found in about 1 in
1,500 pregnancies (Figure 3). When the longitudinal bladder
diameter is 7–15 mm the incidence of chromosomal defects,
mainly trisomies 13 and 18, is about 20%, but in the chromo-
somally normal group there is spontaneous resolution of the
megacystis in about 90% of cases (Liao et al 2003). In contrast,
in megacystis with bladder diameter greater than 15 mm the
incidence of chromosomal defects is about 10% and in the chro-
mosomally normal group the condition is invariably associated

Figure 3. Ultrasound picture of a 12-weeks fetus with megacystis.
with progressive obstructive uropathy. Megacystis is associated

with increased NT, which is observed in about 75% of those with
chromosomal defects and in about 30% of those with normal
karyotype. After taking into account maternal age and fetal
NT the presence of megacystis increases the likelihood for
trisomy 13 or 18 by a factor of 6.7.
Exomphalos
At 11–13+6 weeks the prevalence of exomphalos (Figure 4) is
about 1 in 1000, which is four times higher than in live births.
The incidence of chromosomal defects, mainly trisomy 18, is
about 60%, compared to about 30% at mid-gestation and 15% in
neonates. The risk for trisomy 18 increases with maternal age
and, since this trisomy is associated with a high rate of intraute-
rine death, its prevalence decreases with gestational age. In con-
trast, the rate of fetal death in chromosomally normal fetuses with
exomphalos is not higher than in fetuses without this abnormality.
Consequently, the prevalence of exomphalos and the associated

Figure 4. Ultrasound picture of a 12-weeks trisomy 18 fetus with exomphalos and increased nuchal
translucency thickness.
risk for chromosomal defects increase with maternal age and

decrease with gestational age (Snijders et al 1995).
Choroid plexus cysts, pyelectasis and cardiac echogenic foci

At 11–14 weeks the prevalences of choroid plexus cysts,
pyelectasis and cardiac echogenic foci were 2.2, 0.9 and 0.6%
(Whitlow et al 1998). Preliminary results suggest that, as in the
second trimester, the prevalence of these markers may be higher
in chromosomally abnormal than normal fetuses. However,
calculation of likelihood ratios requires the study of many
more chromosomally abnormal fetuses to determine the true
prevalence of these markers.
Placental volume
The placental volume, determined at 11–13+6 by 3D ultrasound,
increases with fetal crown-rump length. In trisomy 21 fetuses,

placental volume is not significantly different from normal but
in trisomy 18 placental volume is substantially decreased.
Fetal heart rate

In normal pregnancy, the fetal heart rate (FHR) increases
from about 100 bpm at 5 weeks of gestation to 170 bpm at 10
weeks and then decreases to 155 bpm by 14 weeks. At 10–13+6
weeks, trisomy 13 and Turner syndrome are associated with
tachycardia, whereas in trisomy 18 and triploidy there is fetal
bradycardia (Figure 5; Liao et al 2001). In trisomy 21, there is
a mild increase in FHR. Measurement of FHR is unlikely
200
190
180
170
Fetal heart rate (bpm)
160
150
140
130
120
110
40 50 60 70 80
Crown-rump length (mm)
Figure 5. Fetal heart rate in fetuses with trisomy 13 plotted on the reference range (mean, 95th and
5th centiles) with crown-rump length of the chromosomally normal fetuses.

to improve first trimester screening for trisomy 21 but it is a
useful measurement in identifying fetuses with trisomy 13.
Doppler in the ductus venosus

The ductus venosus is a unique shunt directing well-oxygenated
blood from the umbilical vein to the coronary and cerebral
circulations by preferential streaming through the foramen ovale
into the left atrium. Blood flow in the ductus has a characteristic
waveform with high velocity during ventricular systole (S-wave)
and diastole (D-wave), and forward flow during atrial contrac-
tion (a-wave). In the second and third trimesters of pregnancy
abnormal flow with absent or reverse a-wave is observed in
impending or overt cardiac failure.
At 10–13+6 weeks abnormal ductal flow (Figure 6) is associated

with chromosomal defects, cardiac abnormalities and adverse
pregnancy outcome (Matias et al 1998, Borrell et al 2003).
Studies from specialist centres, in more than 5,000 pregnancies,
including about 280 fetuses with trisomy 21, have demonstrated
that at 10–13+6 weeks there is abnormal flow in the ductus
venosus in about 80% of trisomy 21 fetuses and in about 5%
of chromosomally normal fetuses (Nicolaides 2004). There is
no or only a weak association between increased fetal NT and
the incidence of abnormal ductal flow. These findings indicate
that assessment of the ductus venosus can be combined with
measurement of fetal NT to improve the effectiveness of early
sonographic screening for trisomy 21.
Examination of ductal flow is time-consuming and requires

highly skilled operators and at present it is uncertain if this
assessment will be incorporated into the routine first-trimester
scan. However, it could be used in specialist centres to

Figure 6. Flow velocity waveforms from the fetal ductus venosus at 12 weeks’ gestation demonstrating
normal pattern (top) and abnormal a-wave (bottom).
re-evaluate the risk in patients with borderline results after

screening by fetal NT and maternal serum biochemistry.
Abnormal flow in the ductus venosus and chromosomal defects

• At 11–13+6 weeks abnormal ductal flow is observed in 5%
of chromosomally normal fetuses and in about 80% of fetuses
with trisomy 21.
• Assessment of the ductus venosus can be combined with
measurement of fetal NT to improve the effectiveness of early
sonographic screening for trisomy 21.
• Examination of ductal flow is time-consuming and requires
highly skilled operators. It is therefore unlikely to be used in
routine screening, but it could be used in specialist centres to
re-evaluate the risk in patients with borderline results after
screening by fetal NT and maternal serum biochemistry.

Doppler in other vessels
Uterine arteries
Uterine artery Doppler studies at 11–13+6 weeks found no signi-
ficant differences in pulsatility index between chromosomally
normal and abnormal fetuses. Consequently, the high rates of
fetal death and fetal growth restriction of the major chromosomal
defects are unlikely to be the consequence of impaired placentation
in the first trimester of pregnancy. Uterine artery Doppler is not a
useful screening test for chromosomal defects.
Umbilical artery
Umbilical artery Doppler is not useful in screening for trisomy 21.
However, in trisomy 18, impedance to flow is increased and in
about 20% of cases there is persistent reversal of end-diastolic flow
(REDF).
Umbilical vein
In second and third-trimester fetuses, pulsatile umbilical venous
flow is a late and ominous sign of fetal compromise. At 11–13+6
weeks there is pulsatile flow in the umbilical vein in about
25% of chromosomally normal fetuses and in 90% of fetuses
with trisomy 18 or 13. However, in fetuses with trisomy 21, the
prevalence of pulsatile venous flow is not significantly different
from that in chromosomally normal fetuses.
Jugular vein and carotid artery

There are no significant associations between the pulsatility index
in the fetal jugular vein and carotid artery and fetal NT and
no significant differences between the chromosomally normal
and abnormal fetuses.

SECOND TRIMESTER ULTRASONOGRAPHY
In the second trimester scan, as in the first trimester, each chromo-
somal defect has its own syndromal pattern of detectable abnor-
malities (Table 1; Snijders and Nicolaides 1996, Nicolaides et al
1992). It is therefore recommended that, when an abnormality/
marker is detected at routine ultrasound examination, a thorough
check is made for the other features of the chromosomal defect
known to be associated with that marker; should additional
abnormalities be identified, the risk is dramatically increased. In
the case of apparently isolated abnormalities, the decision of
Table 1. Common chromosomal defects in fetuses with sonographic abnormalities.

Trisomy 21 Trisomy 18 Trisomy 13 Triploidy Turner
Ventriculomegaly + + + +
Holoprosencephaly +
Choroid plexus cysts +
Dandy Walker complex + +
Facial cleft + +
Micrognathia + +
Nasal hypoplasia +
Nuchal edema + + +
Cystic hygromas +
Diaphragmatic hernia + +
Cardiac defect + + + + +
Exomphalos + +
Duodenal atresia +
Esophageal atresia + +
Renal defects + + + + +
Short limbs + + + +
Clinodactyly +
Overlapping fingers +
Polydactyly +
Syndactyly +
Talipes + + +
Fetal growth restriction + + +

whether to carry out an invasive test depends on the type of
abnormality.
Second trimester scan: phenotypic expression of chromosomal

defects
• Trisomy 21 is associated with nasal hypoplasia, increased
nuchal fold thickness, cardiac defects, intracardiac echogenic
foci, duodenal atresia and echogenic bowel, hydronephrosis,
shortening of the femur and more so of the humerus, 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, dia-
phragmatic hernia, esophageal atresia, exomphalos, usually
with bowel only in the sac, single umbilical artery, renal
abnormalities, echogenic bowel, myelomeningocoele, growth
restriction and shortening of the limbs, radial aplasia,
overlapping fingers and talipes or rocker bottom feet.
• Trisomy 13 is associated with holoprosencephaly, micro-
cephaly, facial abnormalities, cardiac abnormalities, enlarged
and echogenic kidneys, exomphalos and post axial polydactyly.
• Triploidy where the extra set of chromosomes is paternally
derived is associated with a molar placenta and the pregnancy
rarely persists beyond 20 weeks. When there is a double
maternal chromosome contribution, the pregnancy may persist
into the third trimester. The placenta is of normal consistency
but thin and the fetus demonstrates severe asymmetrical
growth restriction. Commonly there is mild ventriculomegaly,
micrognathia, cardiac abnormalities, myelomeningocoele,
syndactyly, and ‘hitch-hiker’ toe deformity.
• Turner syndrome is associated with large nuchal cystic hygro-
mas, generalised edema, mild pleural effusions and ascites,
cardiac abnormalities and horseshoe kidneys, which are
suspected by the ultrasonographic appearance of bilateral
mild hydronephrosis.

Ventriculomegaly
The birth prevalence of ventriculomegaly is about 1 per
1,000. Causes include chromosomal and genetic defects, brain
hemorrhage or infection but in many cases no clear-cut etiology
is identified. The overall prevalence of chromosomal defects
in fetal ventriculomegaly is about 10% and the commonest
chromosomal defects are trisomies 21, 18, 13 and triploidy. The
prevalence of chromosomal defects is higher in those with mild
to moderate, rather than severe ventriculomegaly.
Holoprosencephaly
The birth prevalence of holoprosencephaly is about 1 per 10,000.
Although in many cases the cause is a chromosomal defect or a
genetic disorder in the majority of cases the etiology is unknown.
The overall prevalence of chromosomal defects in fetal holopro-
sencephaly is about 30% and the commonest chromosomal
defects are trisomies 13 and 18. Holoprosencephaly is commonly
associated with a wide variety of mid-facial abnormalities but
the incidence of chromosomal defects in only increased in fetuses
with holoprosencephaly and extrafacial abnormalities but not
in those where the holoprosencephaly is either isolated or it is
associated with facial abnormalities only.
Choroid plexus cysts

These are found in approximately 2% of fetuses at 16–24 weeks
of gestation but in more than 95% of cases they resolve by 28
weeks and are of no pathological significance. There is an asso-
ciation between choroid plexus cysts and chromosomal defects,
particularly trisomy 18. However, the vast majority of fetuses
with trisomy 18 have multiple other abnormalities and therefore,
the detection of fetal choroid plexus cysts should stimulate
the sonographer to search for the other features of trisomy 18. If

the cysts are apparently isolated the risk for trisomy 18 is only
marginally increased.
Dandy-Walker complex
This refers to a spectrum of abnormalities of the cerebellar
vermis, cystic dilatation of the fourth ventricle and enlargement
of the cisterna magna. The condition is classified into Dandy-
Walker malformation (complete or partial agenesis of the cerebel-
lar vermis and enlarged posterior fossa), Dandy-Walker variant
(partial agenesis of the cerebellar vermis without enlargement
of the posterior fossa) and mega-cisterna magna (normal vermis
and fourth ventricle). The birth prevalence of Dandy-Walker
malformation is about 1 per 30,000. Causes include chromo-
somal defects, more than 50 genetic syndromes, congenital infec-
tions or teratogens such as warfarin, but it can also be an isolated
finding. The overall prevalence of chromosomal defects is about
40%, usually trisomies 18 or 13 and triploidy.
Facial cleft
Cleft lip and/or palate is found in approximately 1 per 800 live
births, and both genetic and environmental factors are implicated
in their causation. Postnatally, chromosomal defects are found
in less than 1% of babies with facial cleft. However, in prenatal
series the prevalence is about 20%, most commonly trisomies
13 and 18. This apparent discrepancy is because in the prenatal
studies the populations examined are pre-selected and include
many fetuses with multiple other abnormalities.
Micrognathia
The birth prevalence of micrognathia is about 1 per 1,000. This
is a non-specific finding in a wide range of genetic syndromes
and chromosomal defects, mainly trisomy 18 and triploidy.

In two studies reporting on fetal micrognathia the prevalence
of chromosomal defects was about 60% but all fetuses had
additional malformations and/or growth restriction.
Nasal hypoplasia
Sonographic studies at 15–24 weeks of gestation reported that
about 65% of trisomy 21 fetuses have nasal bone hypoplasia,
defined by a nasal bone that is not visible or with a length of less
than 2.5 mm (Sonek and Nicolaides 2002, Cicero et al 2003). In
chromosomally normal fetuses, the prevalence of nasal hypoplasia
is related to the ethnic origin of the mothers, being less than
1% in Caucasians and up to 10% in African-Caribbeans. It is
premature to speculate on the precise detection rates that could
be achieved in the second trimester by a combination of maternal
age, serum biochemistry and ultrasound examination for the fetal
nasal bone and other sonographic markers. Nevertheless, on the
basis of currently available data, nasal hypoplasia is likely to be
the single most sensitive and specific second trimester marker of
trisomy 21.
Diaphragmatic hernia
The birth prevalence of diaphragmatic hernia is about 1 per
4,000 and the condition is usually sporadic. The prevalence of
chromosomal defects, mainly trisomy 18, is about 20%.
Cardiac abnormalities
Abnormalities of the heart and great arteries are found in 4–7
per 1,000 live births and in about 30 per 1,000 stillbirths. The
etiology of heart abnormalities is heterogeneous and probably
depends on the interplay of multiple genetic and environmental
factors. Heart abnormalities are found in more than 90% of

fetuses with trisomy 18 or 13 and 40% of those with trisomy
21 or Turner syndrome. Prenatal studies of ultrasonographically
detectable fetal cardiac abnormalities, have reported chromosomal
defects in about 25% of cases.
Exomphalos
The birth prevalence of exomphalos is about 1 per 4,000. The
condition is usually sporadic but in some cases there may be
an associated genetic syndrome. Chromosomal defects, mainly
trisomies 18 and 13, are found in about 30% of cases at mid-
gestation and in 15% of neonates. The prevalence of chromo-
somal defects is four-times higher when the exomphalos sac
contains only bowel than in cases where the liver is included.
Esophageal atresia
The birth prevalence of esophageal atresia is about 1 per 3,000.
In 90% of cases there is an associated tracheoesophageal fistula.
The condition is sporadic. Chromosomal defects are found in
3–4% of affected neonates. Prenatally, chromosomal defects,
mainly trisomy 18, are found in about 20% of cases.
Duodenal atresia
The birth prevalence of duodenal atresia or stenosis is about 1
per 5,000. In most cases the condition is sporadic, although in
some cases there is an autosomal recessive pattern of inheritance.
Trisomy 21 is found in about 40% of cases.
Urinary tract abnormalities

Prenatal studies have established that urinary tract abnormalities
are commonly found in many chromosomal defects. The risk for

chromosomal defects is similar for fetuses with unilateral or
bilateral involvement, different types of renal abnormalities,
urethral or ureteric obstruction, and oligohydramnios or normal
amniotic fluid volume. However, the prevalence of chromosomal
abnormalities in females is double that in males. The pattern
of chromosomal defects, and consequently that of associated
malformations, is related to the different types of renal
abnormalities. Thus, in mild hydronephrosis, the commonest
chromosomal defect is trisomy 21, whereas in moderate/severe
hydronephrosis, multicystic kidneys, or renal agenesis the
commonest defects are trisomies 18 and 13.
Limb abnormalities
Trisomies 21, 18, triploidy and Turner syndrome are associated
with relative shortening of the long bones. Syndactyly is asso-
ciated with triploidy, clinodactyly and sandal gap with trisomy 21,
polydactyly with trisomy 13, overlapping fingers, rocker bottom
feet and talipes with trisomy 18.
Fetal growth restriction

Low birth weight is a common feature of many chromosomal
defects, but the prevalence of chromosomal defects in small for
gestational age neonates is only about 1%. However, data derived
from postnatal studies underestimate the association between
chromosomal defects and growth restriction, since many preg-
nancies with chromosomally abnormal fetuses result in spontane-
ous abortion or intrauterine death. The commonest chromosomal
defects associated with growth restriction are triploidy and
trisomy 18.
The highest prevalence of chromosomal defects is found in those
cases where in addition to the growth restriction there are fetal
structural abnormalities, the amniotic fluid volume is normal or

increased and in the group with normal Doppler flow velocity
waveforms from both uterine and umbilical arteries. Therefore,
growth restriction due to chromosomal defects presents differently
from growth restriction due to placental insufficiency, which is
characterized by reduced amniotic fluid volume and increased
impedance to flow in the uterine and/or umbilical arteries with
redistribution in the fetal circulation.
Major abnormalities
If the second trimester scan demonstrates major abnormalities, it
is advisable to offer fetal karyotyping, even if these abnormalities
are apparently isolated. The prevalence of such abnormalities is
low and therefore the cost implications are small.
If the abnormalities are either lethal or they are associated with
severe handicap, such as holoprosencephaly, fetal karyotyping
constitutes one of a series of investigations to determine the
possible cause and thus the risk of recurrence.
If the abnormality is potentially correctable by intrauterine
or postnatal surgery, such as diaphragmatic hernia, it may be
logical to exclude an underlying chromosomal defect – especially
because, for many of these conditions, the usual defect is trisomy
18 or 13.
Minor abnormalities or soft markers

Minor fetal abnormalities or soft markers are common and they
are not usually associated with any handicap, unless there is an
underlying chromosomal defect. Routine karyotyping of all preg-
nancies with these markers would have major implications, both
in terms of miscarriage and in economic costs. It is best to base
counseling on an individual estimated risk for a chromosomal

defect, rather than the arbitrary advice that invasive testing is
recommended because the risk is ‘high’.
The estimated risk can be derived by multiplying the a priori
risk (based on maternal age, gestational age, history of previously
affected pregnancies and, where appropriate, the results of
previous screening by NT and/or biochemistry in the current
pregnancy) by the likelihood ratio of the specific abnormality or
marker.
The best estimates of both the positive and negative likelihood
ratios for each of the common markers of trisomy 21 are given
in Table 2 (Nyberg et al 2001, Bromley et al 2002, Nicolaides
2003).
Major or minor abnormalities are found in about 75% of fetuses
with trisomy 21 and in 10–15% of chromosomally normal
fetuses. On the basis of these data the likelihood ratio for trisomy
21 if there is no detectable abnormality or marker is 0.30.
In each case the likelihood ratio is derived by dividing the
prevalence of a given marker in trisomy 21 pregnancies by its
prevalence in chromosomally normal pregnancies. For example,
an intracardiac echogenic focus is found in 28.2% of trisomy
21 fetuses and in 4.4% chromosomally normal fetuses, resulting
in a positive likelihood ratio of 6.41 (28.2 / 4.4) and a negative
likelihood ratio of 0.75 (71.8 / 95.6). Consequently, the finding
of an echogenic focus increases the background risk by a factor
of 6.41, but at the same time absence of this marker should
reduce the risk by 25%.
The same logic applies to each one of the six markers in Table 2.
Thus, in a 25 year old woman undergoing an ultrasound scan
at 20 weeks of gestation the a priori risk is about 1 in 1,000. If
the scan demonstrates an intracardiac echogenic focus, but the
nuchal fold is not increased, the humerus and femur are not

Table 2. Prevalence of major and minor abnormalities or markers in the second trimester scan in trisomy
21 and chromosomally normal fetuses in the combined data of two major series (Nyberg et al 2001,
Bromley et al 2002). From these data the positive and negative likelihood ratios (with 95% confidence
interval) for each marker can be calculated. In the last column is the likelihood ratio for each marker
found in isolation.
Sonographic Trisomy Normal Positive Negative LR for

marker 21 LR LR isolated
marker
Nuchal fold 107/319 59/9331 53.05 0.67 9.8

(33.5%) (0.6%) (39.37–71.26) (0.61–0.72)
Short humerus 102/305 136/9254 22.76 0.68 4.1

(33.4%) (1.5%) (18.04–28.56) (0.62–0.73)
Short femur 132/319 486/9331 7.94 0.62 1.6

(41.4%) (5.2%) (6.77–9.25) (0.56–0.67)
Hydronephrosis 56/319 242/9331 6.77 0.85 1.0

(17.6%) (2.6%) (5.16–8.80) (5.16–8.80)
Echogenic focus 75/266 401/9119 6.41 0.75 1.1

(28.2%) (4.4%) (5.15–7.90) (0.69–0.80)
Echogenic bowel 39/293 58/9227 21.17 0.87 3.0

(13.3%) (0.6%) (14.34–31.06) (0.83–0.91)
Major defect 75/350 61/9384 32.96 0.79 5.2

(21.4%) (0.65%) (23.90–43.28) (0.74–0.83)
LR = Likelihood ratio
short and there is no hydronephrosis, hyperechogenic bowel or

major defect, the combined likelihood ratio should be 1.1
(6.41×0.67×0.68×0.62×0.85×0.87×0.79) and consequently
her risk remains at about 1 in 1,000. The same is true if the
only abnormal finding is mild hydronephrosis (likelihood ratio
of 1). In contrast, if the fetus is found to have both an intra-
cardiac echogenic focus and mild hydronephrosis but no other
abnormalities the combined likelihood ratio should be 8.42
(6.41×6.77×0.67×0.68×0.62×0.87×0.79) and consequently
the risk is increased from 1 in 1,000 to 1 in 119.

There are no data on the interrelation between these second-
trimester ultrasound markers and fetal NT or maternal serum
free b-hCG or PAPP-A at 11–13+6 weeks. 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 32-year-old woman at 20 weeks
of gestation (background risk of 1 in 559), who had an 11–13+6
week assessment by NT measurement that resulted in a 7-fold
reduction in risk (to 1 in 3913), after the diagnosis of isolated
echogenic bowel at the 20-week scan, the estimated risk would
increase by a factor of three to 1 in 1304. However, for the same
ultrasound finding in the absence of prior NT screening the risk
would increase from 1 in 559 to 1 in 186.
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 independ-
ently of NT screening at 11–13+6 weeks.

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of gestation: Chromosomal defects and outcome according to bladder length.
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Nicolaides KH, Sebire NJ, Snijders JM. Crown rump length in chromosomally
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abnormalities. New York: Parthenon Publishing, 1996, pp31–3.
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3
INCREASED NUCHAL TRANSLUCENCY WITH

NORMAL KARYOTYPE
Increased fetal NT thickness is a common phenotypic expression

of trisomy 21 and other chromosomal abnormalities, but it is
also associated with fetal death and a wide range of fetal malfor-
mations, deformations, dysgeneses, and genetic syndromes. This
chapter reviews the outcome of chromosomally normal fetuses
with increased NT. On the basis of these data it is possible to
estimate, for each NT group, the chances of intrauterine survival
and delivery of a healthy baby with no major abnormalities.
These data are useful in counselling parents of pregnancies with
increased fetal NT and in planning the appropriate follow-up
investigations.
In normal fetuses NT thickness increases with fetal crown-rump

length (CRL). The median and 95th centile of NT at a CRL of
45 mm are 1.2, and 2.1 mm and the respective values at CRL of
84 mm are 1.9 and 2.7 mm (Snijders et al 1998). The 99th centile
does not change significantly with CRL and it is about 3.5 mm.
Increased NT, refers to a measurement above the 95th centile and
the term is used irrespective of whether the collection of fluid
is septated or not and whether it is confined to the neck or
envelopes the whole fetus. After 14 weeks, increased NT usually
resolves but in some cases it evolves into nuchal edema or cystic
hygromas.
Chapter 3 • Increased nuchal translucency with normal karyotype 71

Table 1. Relation between nuchal translucency thickness and prevalence of chromosomal defects,
miscarriage or fetal death and major fetal abnormalities. In the last column is the estimated prevalence
of delivery of a healthy baby with no major abnormalities.
Nuchal Chromosomal Normal karyotype Alive and

translucency Defects well
Fetal death Major fetal
abnormalities
<95th centile 0.2% 1.3% 1.6% 97%
95 –99 centiles
th th
3.7% 1.3% 2.5% 93%
3.5–4.4 mm 21.1% 2.7% 10.0% 70%
4.5–5.4 mm 33.3% 3.4% 18.5% 50%
5.5–6.4 mm 50.5% 10.1% 24.2% 30%
≥6.5 mm 64.5% 19.0% 46.2% 15%
OUTCOME OF FETUSES WITH INCREASED NUCHAL TRANSLUCENCY

The relation between NT thickness and the prevalence of
chromosomal defects, miscarriage or fetal death and major fetal
abnormalities is summarized in Table 1 (Souka et al 2004).
Chromosomal defects
The prevalence of chromosomal defects increases exponentially
with NT thickness (Table 1; Snijders et al 1998). In the chro-
mosomally abnormal group, about 50% have trisomy 21, 25%
have trisomy 18 or 13, 10% have Turner syndrome, 5% have
triploidy and 10% have other chromosomal defects.
Fetal death
In chromosomally normal fetuses, the prevalence of fetal death
increases exponentially with NT thickness from 1.3% in those

with NT between the 95th and 99th centiles to about 20% for NT
of 6.5 mm or more (Table 1; Souka et al 2001, Michailidis
and Economides 2001). The majority of fetuses that die do so by
20 weeks and they usually show progression from increased NT
to severe hydrops.
Fetal abnormalities
Major fetal abnormalities are defined as those requiring medical
and/or surgical treatment or conditions associated with mental
handicap. Several studies have reported that increased fetal NT
is associated with a high prevalence of major fetal abnormalities.
In the combined data of 28 studies on a total of 6153 chromo-
somally normal fetuses with increased NT the prevalence of
major abnormalities was 7.3% (Souka et al 2004) However, there
were large differences between the studies in the prevalence
of major abnormalities, ranging from 3% to 50%, because of
differences in their definition of the minimum abnormal NT
thickness, which ranged from 2 mm to 5 mm.
The prevalence of major fetal abnormalities in chromosomally

normal fetuses increases with NT thickness, from 1.6%, in those
with NT below the 95th centile, to 2.5% for NT between the 95th
and 99th centiles and exponentially thereafter to about 45% for
NT of 6.5 mm or more (Table 1; Souka et al 2001, Michailidis
and Economides 2001).
Developmental delay
Studies on the long term follow up of chromosomally and
anatomically normal fetuses with increased NT reported that the
prevalence of developmental delay is 2–4% (Souka et al 2004).

However, it is difficult to assess the true significance of these
findings because only one of the studies had a control group for
comparison. Brady et al (1998), performed a clinical follow up
study of 89 children that in fetal life had NT of 3.5 mm or more
and 302 children whose fetal NT was less than 3.5 mm. Delay in
achievement of developmental milestones was observed in one of
the children in each group.
ABNORMALITIES ASSOCIATED WITH INCREASED NT

A wide range of fetal abnormalities have been reported in fetuses
with increased NT and these are summarized in Table 2.
The observed prevalence for some of the abnormalities, such

as anencephaly, holoprosencephaly, gastroschisis, renal abnor-
malities and spina bifida, may not be different from that in the
general population. However, the prevalence of major cardiac
abnormalities, diaphragmatic hernia, exomphalos, body stalk
anomaly, skeletal abnormalities, and certain genetic syndromes,
such as congenital adrenal hyperplasia, fetal akinesia deformation
sequence, Noonan syndrome, Smith-Lemli-Opitz syndrome and
spinal muscular atrophy, appears to be substantially higher than
in the general population and it is therefore likely that there is a
true association between these abnormalities and increased NT.
Cardiac defects
There is a high association between increased NT and cardiac
defects in both chromosomally abnormal and normal fetuses
(Hyett et al 1997, 1999). Eight studies have reported on the
screening performance of NT thickness for the detection of
cardiac defects (Souka et al 2004). In total, 67,256 pregnancies

Table 2. Fetal abnormalities in fetuses with increased nuchal translucency thickness.
Central nervous system Gastrointestinal defect Fetal anemia
defect
Acrania / anencephaly Crohn’s disease Blackfan Diamond anaemia
Agenesis of the corpus callosum Duodenal atresia Congenital erythropoietic porphyria
Craniosynostosis Esophageal atresia Dyserythropoietic anaemia
Dandy Walker malformation Small bowel obstruction Fanconi anemia
Diastematomyelia Parvovirus B19 infection
Encephalocele Genitourinary defect Thalassaemia-a
Fowler syndrome Ambiguous genitalia
Holoprosencephaly Congenital adrenal hyperplasia Neuromuscular defect
Hydrolethalus syndrome Congenital nephrotic syndrome Fetal akinesia deformation sequence
Iniencephaly Hydronephrosis Myotonic dystrophy
Joubert syndrome Hypospadias Spinal muscular atrophy
Macrocephaly Infantile polycystic kidneys
Microcephaly Meckel-Gruber syndrome Metabolic defect
Spina bifida Megacystis Beckwith-Wiedemann syndrome
Trigonocephaly C Multicystic dysplastic kidneys GM1 gangliosidosis
Ventriculomegaly Renal agenesis Long-chain 3-hydroxyacyl-coenzyme
A dehydrogenase deficiency
Mucopolysaccharidosis type VII
Facial defect Skeletal defect Smith-Lemli-Opitz syndrome
Agnathia/micrognathia Achondrogenesis Vitamin D resistant rickets
Facial cleft Achondroplasia Zellweger syndrome
Microphthalmia Asphyxiating thoracic dystrophy
Treacher-Collins syndrome Blomstrand Other defect
osteochondrodysplasia
Campomelic dwarfism Body stalk anomaly
Nuchal defect Cleidocranial dysplasia Brachmann-de Lange syndrome
Cystic hygroma Hypochondroplasia CHARGE association
Neck lipoma Hypophosphatasia Deficiency of the immune system
Jarcho-Levin syndrome Congenital lymphedema
Cardiac defect Kyphoscoliosis EEC syndrome
Di George syndrome Limb reduction defect Neonatal myoclonic encephalopathy
Nance-Sweeney syndrome Noonan syndrome
Pulmonary defect Osteogenesis imperfecta Perlman syndrome
Cystic adenomatoid Roberts syndrome Stickler syndrome
malformation
Diaphragmatic hernia Robinow syndrome Unspecified syndrome
Fryn syndrome Short-rib polydactyly syndrome Severe developmental delay
Sirenomelia
Abdominal wall defect Talipes equinovarus
Cloacal exstrophy Thanatophoric dwarfism
Exomphalos VACTER association
Gastroschisis

were examined and the prevalence of major cardiac defects was
2.4 per 1,000. For a false positive rate of 4.9%, the detection rate
of cardiac defects was 37.5%.
A meta-analysis of screening studies reported that the detection

rates were about 37% and 31% for the respective NT cut-offs
of the 95th and 99th centiles (Makrydimas et al 2003). In
chromosomally normal fetuses, the prevalence of major cardiac
defects increases exponentially with NT thickness from 1.6 per
1,000 in those with NT below the 95th centile, to about 1% for
NT of 2.5–3.4 mm, 3% for NT of 3.5–4.4 mm, 7% for NT of
4.5–5.4 mm, 20% for NT of 5.5–6.4 mm and 30% for NT of
6.5 mm or more (Souka et al 2004).
The clinical implication of these findings is that increased NT

constitutes an indication for specialist fetal echocardiography.
Certainly, the overall prevalence of major cardiac defects in such
a group of fetuses (1–2%) is similar to that found in pregnancies
affected by maternal diabetes mellitus or with a history of a
previously affected offspring, which are well accepted indications
for fetal echocardiography.
At present, there may not be sufficient facilities for specialist

fetal echocardiography to accommodate the potential increase in
demand if the 95th centile of nuchal translucency thickness is
used as the cut-off for referral. In contrast, a cut-off of the 99th
centile would result in only a small increase in workload and, in
this population the prevalence of major cardiac defects would be
very high.
Patients identified by NT scanning as being at high risk for

cardiac defects need not wait until 20 weeks for specialist echo-
cardiography. Improvements in the resolution of ultrasound
machines have now made it possible to undertake detailed

cardiac scanning in the first trimester of pregnancy. A specialist
scan from 13 weeks can effectively reassure the majority of
parents that there is no major cardiac defect. In the cases with
a major defect, the early scan can either lead to the correct
diagnosis or at least raise suspicions so that follow-up scans are
carried out.
The best strategy of screening for major cardiac abnormalities

is to carry out specialist fetal echocardiography in patients with
increased NT at 11–13+6 weeks and in those with an abnormal
four-chamber view in the routine mid-trimester scan. These
two indications are complimentry. Thus, major defects, such
as tetralogy of Fallot, transposition of the great arteries and
coarctation of the aorta are rarely detected by routine examination
of the four-chamber view. However, a high proportion of these
abnormalities present with increased NT.
Body stalk anomaly

This lethal, sporadic abnormality is found in about 1 in 10,000
fetuses at 10–13+6 weeks. The ultrasonographic features are
major abdominal wall defect, severe kyphoscoliosis and short
umbilical cord with a single artery (Daskalakis et al 1997). The
upper half of the fetal body is seen in the amniotic cavity, whereas
the lower part is in the celomic cavity, suggesting that early
amnion rupture before obliteration of the celomic cavity is a pos-
sible cause of the syndrome. Although the fetal NT is increased
in about 85% of the cases, the karyotype is usually normal.
Diaphragmatic hernia
Increased NT thickness is present in about 40% of fetuses with
diaphragmatic hernia, including more than 80% of those that

result in neonatal death due to pulmonary hypoplasia and in
about 20% of the survivors (Sebire et al 1997). It is possible
that in fetuses with diaphragmatic hernia and increased NT the
intrathoracic herniation of the abdominal viscera occurs in the
first trimester and prolonged compression of the lungs causes
pulmonary hypoplasia. In the cases where diaphragmatic hernia
is associated with a good prognosis, the intrathoracic herniation
of viscera may be delayed until the second or third trimesters of
pregnancy.
Exomphalos
At 11–13+6 weeks the incidence of exomphalos is about 1 in
1,000 and the incidence of chromosomal defects, mainly trisomy
18, is about 60% (Snijders et al 1995). Increased NT is
observed in about 85% of chromosomally abnormal and 40%
of chromosomally normal fetuses with exomphalos.
Megacystis
Fetal megacystis at 11–13+6 weeks of gestation, defined by a
longitudinal bladder diameter of 7 mm or more, is found
in about 1 in 1,500 pregnancies. Megacystis is associated with
increased NT, which is observed in about 75% of those with
chromosomal abnormalities, mainly trisomy 13, and in about
30% of those with normal karyotype (Liao et al 2003).
Genetic syndromes
The genetic syndromes associated with increased NT are
summarised in Table 3.

Table 3. Genetic syndromes reported in fetuses with increased nuchal translucency thickness.
Genetic syndrome Inheritance Birth prevalence Prognosis and common sonographically detectable abnormalities
Achondrogenesis AR 1 in 40,000 Lethal skeletal dysplasia. Severe limb shortening, narrow thorax, hypomineralization of
the vertebral bodies. Mineralization of the skull normal in type II and poor in type I.
Achondroplasia* AD 1 in 26,000 Intelligence and life expectancy are normal. Macrocephaly, depressed nasal bridge,
lumbar lordosis and short limbs, usually after 22 weeks.
Adrenal hyperplasia* AR 1 in 5,000 Deficiency in one of the enzymes of cortisol biosynthesis, resulting in overproduction of
cortisol precursors and androgens. Increased NT, ambiguous genitalia in females.
Asphyxiating thoracic AR 1 in 70,000 Variable prognosis from neonatal death to normal survival. Narrow chest and rhizomelic
dystrophy limb shortening, which may not become apparent until after 22 weeks.
Beckwith–Wiedemann Sporadic 1 in 14,000 In some cases, there is mental handicap, which is thought to be secondary to
syndrome inadequately treated hypoglycemia. About 5% develop tumors during childhood, most
commonly nephroblastoma and hepatoblastoma. Prenatal sonographic features include
macrosomia and exomphalos.
Chapter 3 • Increased nuchal translucency with normal karyotype

Blackfan-Diamond AD, AR 1 in 200,000 Congenital hypoplastic anemia requiring treatment with steroids and repeated blood
anemia transfusions. The risk of hematologic malignancies, mainly acute leukemia, is increased.
Thumb defects, hypertelorism, cardiac and urogenital anomalies.
Blomstrand AR Rare Lethal skeletal dysplasia. Severe limb shortening, narrow thorax, increased bone density.
osteochondrodysplasia
Brachmann-Cornelia de AD 1 in 160,000 Mental handicap. Fetal growth restriction, short limbs, heart defects, diaphragmatic
Lange syndrome hernia.
Campomelic dysplasia AR 1 in 200,000 Lethal skeletal dysplasia. Short and bowed lower limbs with narrow thorax.
CHARGE association Sporadic Rare Acronym for Coloboma of the eye, Heart anomaly, choanal Atresia, growth and mental
Retardation, Gonadal hypoplasia and Ear abnormalities and/or deafness. There may
not be any antenatal sonographic findings.
Cleidocranial dysplasia AD Rare Normal life expectancy. Hypoplastic clavicles and nasal bone.
79
80
Table 3. Continued
Di George syndrome Sporadic 1 in 4,000 Results from de novo 22q11 deletion in 90% of cases. Characterized by neonatal
hypocalcemia, due to hypoplasia of the parathyroid glands, and susceptibility to
infection due to hypoplasia or aplasia of the thymus gland. A variety of cardiac
malformations are seen, including tetralogy of Fallot, interrupted aortic arch, truncus
arteriosus, right aortic arch and aberrant right subclavian artery. Short stature and mild
to moderate learning difficulties are common.
Dyserythropoietic AD, AR Rare Congenital, usually mild anemia. In some cases there is severe anemia presenting with
anemia fetal hydrops.
Ectrodactyly-ectodermal AD Rare Wide variability in phenotypic expression. Split hand and foot, cleft lip and/or palate.
dysplasia-cleft palate
syndrome
Erythropoietic AR Rare Usually presents during childhood with severe cutaneous photosensitivity with
porphyria progressive bullous lesions, leading to infection, bone resorption, cutaneous deformity
(Gunther’s disease) and chronic hemolytic anemia. Severe cases present with fetal hydrops.
Fanconi anemia AR 1 in 22,000 Congenital aplastic anemia characterised by pancytopenia and spontaneous
chromosome instability. The phenotype and age of onset are variable. There may be no
prenatal sonographically detectable abnormalities.
Fetal akinesia AR, Rare Heterogeneous group of conditions resulting in multiple joint contractures, frequently
deformation sporadic associated with fetal myopathy, neuropathy or an underlying connective tissue
sequence abnormality. Severe cases present with arthrogryposis and increased NT in the first
trimester.
Fowler syndrome AR Rare Proliferative vasculopathy of the central nervous system that leads to disruption,
disorganisation and hemorrhagic necrosis of the developing brain. Prenatal features
include hydranencephaly and arthrogryposis.
Fryn syndrome AR 1 in 15,000 Usually lethal. Diaphragmatic hernia, digital defects, short webbed neck.

Table 3. Continued
GM1-Gangliosidosis* AR Rare Progressive neurological deterioration, resulting in early and severe retardation of both
motor and mental development. Death occurs within the first 10 years of life from chest
infections. Prenatal sonographic findings include visceromegaly and generalized edema.
Hydrolethalus AR 1 in 20,000 Lethal condition characterized by hydrocephalus, absent corpus callosum, facial cleft,
syndrome micrognathia, polydactyly, talipes and cardiac septal defects.
Hypochondroplasia AD 1 in 26,000 Resembles achondroplasia and is characterised by short-limb dwarfism manifesting
during childhood. Prenatally there may be short limbs and macrocephaly.
Hypophosphatasia AR 1 in 100,000 Subdivided into perinatal, infantile, childhood and adult forms, according to the age of
onset of symptoms. In the perinatal type there is hypomineralization of the skull and
spine, short limbs and narrow thorax.
Infantile polycystic AR 1 in 10,000 Subdivided into perinatal, neonatal, infantile, and juvenile, depending on the severity of
kidney disease the disease and age of presentation. Prenatal sonographic features include large,
echogenic kidneys and oligohydramnios.
Jarcho–Levin AR 1 in 500,000 Heterogeneous disorder characterized by scoliosis and disorganization of the spine.

syndrome There are two types. In spondylothoracic dysplasia there is a narrow thorax and lethal
respiratory insufficiency in infancy. Spondylocostal dysplasia is associated with survival
to adult life but with some degree of physical disability.
Joubert syndrome AR Rare Profound mental retardation and developmental delay. Death usually occurs in the first
5 years of life. Partial or complete absence of the cerebellar vermis.
Long-chain AR Rare Lethal disorder. Muscular hypotonia, cardiomyopathy, hydrops.
3-hydroxyacyl-
coenzyme A
dehydrogenase
deficiency*
Lymphedema AD Rare Hypoplastic/aplastic lymphatic vessels, usually affecting the lower limbs. Three clinical
subtypes, congenital (Milroy disease, present at birth), praecox (pubertal onset) and
tarda (midlife onset), with congenital lymphedema being the rarest and most severe of
the three. There may be no prenatal sonographic findings.
81
82
Table 3. Continued
Meckel–Gruber AR 1 in 10,000 Lethal. Typical features are encephalocele, bilateral polycystic kidneys, polydactyly.
syndrome
Mucopolysaccharidosis AR Rare Mental retardation, short stature, macrocephaly, hearing loss, corneal opacities and
type VII* recurrent lower respiratory tract infection.
Myotonic dystrophy* AD 1 in 25,000 The genetic defect is an amplified trinucleotide repeat in a protein kinase gene on
chromosome 19. Age of onset and severity of disease vary with the number of
repeats. The mutation can worsen progressively in successive generations and the
severe congenital form occurs almost exclusively in the offspring of affected women.
Prenatal sonographic signs may be decreased fetal movements and polyhydramnios
in the third trimester.
Nance–Sweeney AR Rare Intelligence and life expectancy are normal. Short limbs, vertebral abnormalities.
syndrome
Nephritic syndrome* AR 1 in 8,000 Renal failure requiring transplantation within the first 4 years of life. Prenatally may
in Finland present with transient hydrops.
Noonan syndrome AD 1 in 2,000 Life expectancy is probably normal in those without severe heart disease. Mild
mental retardation is present in about one-third of cases. The majority of cases are
diagnosed postnatally. Prenatal sonographic findings include skin edema,
hydrothorax, polyhydramnios and cardiac defects, such as pulmonic stenosis and
hypertrophic cardiomyopathy but these may become apparent only in the third
trimester.
Osteogenesis AR 1 in 60,000 Lethal skeletal dysplasia. Short limbs and ribs with multiple fractures,
imperfecta type II* hypomineralization of the skull.
Perlman syndrome AR Rare Similar to Beckwith–Wiedemann syndrome. Fetal and neonatal mortality is more than
60% and, in survivors, there is a high incidence of neurodevelopmental delay.
Sonographic features include progressive macrosomia and enlarged kidneys.

Table 3. Continued
Roberts syndrome AR Rare Associated with the cytogenetic finding of premature centromere separation and
puffing. Characterized by symmetrical limb defects of variable severity
(tetraphocomelia), facial cleft, microcephaly and growth restriction.
Robinow syndrome AR Rare Skeletal defect with short forearms, frontal bossing, hypertelorism and vertebral
anomalies.
Short-rib polydactyly AR Rare Lethal skeletal dysplasia. There are four types. Type I (Saldino–Noonan) has narrow
syndrome metaphyses; type II (Majewski) has facial cleft and disproportionally shortened tibiae;
type III (Naumoff) has wide metaphyses with spurs; type IV (Beemer–Langer) is
characterized by median cleft lip, extremely short ribs and proruberant abdomen
with umbilical hernia. Prenatal sonographic findings include short limbs, narrow
thorax and polydactyly.
Smith–Lemli–Opitz AR 1 in 20,000 High perinatal and infant mortality and severe mental retardation. Prenatal
syndrome* sonographic features include polydactyly, cardiac defects, ambiguous or female
external genitalia in the male.

Spinal muscular AR 1 in 7,000 Progressive muscle weakness leading to death before two years of age because of
atrophy type 1* respiratory failure. Decreased fetal movements are commonly reported and
symptoms usually start at birth or up to six months of age.
Stickler syndrome AD 1 in 10,000 Progressive myopia beginning in the first decade of life, resulting in retinal
detachment and blindness, sensorineural hearing loss, marfanoid habitus with
normal height, premature degenerative changes in various joints. There may be no
prenatal sonographic findings but in some cases there is a facial cleft, or
micrognathia.
Thalassaemia-a* AR Common in The alpha locus determines a polypeptide chain, the á-chain, which is present in
Mediterranean adult hemoglobin (a2/b2), fetal hemoglobin (a2/c2) and embryonic hemoglobin
and Asian (a2/d2). Normally there are four alpha gene copies. Absence of all four a-genes
populations results in homozygous a-thalassemia, which presents with hydrops fetalis,
usually in the second trimester.
83
84
Table 3. Continued
Thanatophoric Sporadic 1 in 10,000 Lethal skeletal dysplasia. Severe limb shortening, narrow thorax, enlarged head with
dysplasia* prominent forehead.
Treacher Collins AD 1 in 50,000 Normal life expectancy. Micrognathia, deformities of the ears.
syndrome
Trigonocephaly ‘C’ AR 1 in 15,000 About half of the affected individuals die in infancy while survivors are severely
syndrome mentally handicapped with progressive microcephaly.Trigonocephaly, short nose,
prominent maxilla.
VACTER association Sporadic, AR 1 in 6,000 Acronym for Vertebral abnormalities, Anal atresia, Cardiac defects, Tracheo-
Esophageal fistula with esophageal atresia, Radial and Renal defects. Prognosis
depends on the particular combination and severity of the abnormalities present.
Mental function is usually normal.
Vitamin D resistent AR Rare None.
rickets
Zellweger syndrome* AR 1 in 25,000 Death occurs in the first two years of life, most commonly due to chest infections and
liver failure. Prenatal features include hypertelorism, brain and cardiac defects,
hepatomegaly, growth restriction.
*Genetic syndromes which are amenable to prenatal diagnosis by DNA analysis

PATHOPHYSIOLOGY OF INCREASED FETAL NT
The heterogeneity of conditions associated with increased NT
suggests that there may not be a single underlying mechanism for
the collection of fluid under the skin of the fetal neck. Possible
mechanisms include cardiac dysfunction, venous congestion in
the head and neck, altered composition of the extracellular
matrix, failure of lymphatic drainage, fetal anemia or hypopro-
teinemia and congenital infection.
Pathophysiology of increased nuchal translucency

• Cardiac dysfunction
• Venous congestion in the head and neck
• Altered composition of the extracellular matrix
• Failure of lymphatic drainage
• Fetal anemia
• Fetal hypoproteinemia
• Fetal infection.
Cardiac dysfunction
Central to the hypothesis that heart failure contributes to
increased NT is the observation that in both chromosomally
abnormal and normal fetuses there is a high association between
increased NT and abnormalities of the heart and great arteries.
Furthermore, Doppler studies have reported abnormal flow in
the ductus venosus in fetuses with chromosomal and/or major
cardiac defects and increased NT (Matias et al 1999).
Venous congestion in the head and neck

Venous congestion in the head and neck could result from
constriction of the fetal body as encountered in amnion rupture

sequence, superior mediastinal compression found in diaphrag-
matic hernia or the narrow chest in skeletal dysplasias. However,
in at least some of the cases of skeletal dysplasias, such as
osteogenesis imperfecta, an additional or alternative mechanism
for the increased NT may be the altered composition of the
extracellular matrix.
Altered composition of the extracellular matrix

Many of the component proteins of the extracellular matrix are
encoded on chromosomes 21, 18 or 13. Immunohistochemical
studies, examining the skin of chromosomally abnormal fetuses,
have demonstrated specific alterations of the extracellular matrix
which may be attributed to gene dosage effects (von Kaisenberg
et al 1998). Altered composition of the extracellular matrix may
also be the underlying mechanism for increased fetal NT in an
expanding number of genetic syndromes, which are associated
with alterations in collagen metabolism (such as achondrogenesis
type II, Nance–Sweeney syndrome, osteogenesis imperfecta
type II), abnormalities of fibroblast growth factor receptors (such
as achondroplasia and thanatophoric dysplasia) or disturbed
metabolism of peroxisome biogenesis factor (such as Zellweger
syndrome).
Failure of lymphatic drainage

A possible mechanism for increased NT is dilatation of the
jugular lymphatic sacs, because of developmental delay in the
connection with the venous system, or a primary abnormal dilata-
tion or proliferation of the lymphatic channels interfering with
a normal flow between the lymphatic and venous systems.
Immunohistochemical studies in nuchal skin tissue from fetuses

with Turner syndrome have shown that the lymphatic vessels in
the upper dermis are hypoplastic (von Kaisenberg et al 1999).
In chromosomally normal fetuses with increased NT, deficient
lymphatic drainage, due to hypoplastic or aplastic lymphatic
vessels, is found in association with Noonan syndrome and
congenital lymphedema. In congenital neuromuscular disorders,
such as fetal akinesia deformation sequence, myotonic dystrophy
and spinal muscular atrophy, increased NT may be the con-
sequence of impaired lymphatic drainage due to reduced fetal
movements.
Fetal anemia
Fetal anemia is associated with a hyperdynamic circulation and
fetal hydrops develops when the hemoglobin deficit is more than
7 g/dL (Nicolaides et al 1988). This is true for both immune and
non-immune hydrops fetalis. However, in red blood cell isoim-
munization severe fetal anemia does not occur before 16 weeks of
gestation, presumably because the fetal reticuloendothelial system
is too immature to result in destruction of antibody coated
erythrocytes. Consequently, red blood cell isoimmunization does
not present with increased fetal NT. In contrast, genetic causes
of fetal anemia (a-thalassemia, Blackfan-Diamond anemia,
congenital erythropoietic porphyria, dyserythropoietic anemia,
Fanconi anemia) and possibly congenital infection-related anemia
can present with increased fetal NT.
Fetal hypoproteinemia
Hypoproteinemia is implicated in the pathophysiology of both
immune and non-immune hydrops fetalis (Nicolaides et al
1995). In the first trimester, hypoproteinemia due to proteinuria

may be the underlying mechanism for the increased NT in
fetuses with congenital nephrotic syndrome.
Fetal infection
In about 10% of cases of ‘unexplained’ second- or third-trimester
fetal hydrops, there is evidence of recent maternal infection
and, in these cases, the fetus is also infected. In contrast, in
pregnancies with increased fetal NT and normal karyotype, only
1.5% of the mothers have evidence of recent infection and the
fetuses are rarely infected (Sebire et al 1997).
These findings suggest that, in pregnancies with increased fetal

NT, the prevalence of maternal infection with the TORCH
group of organisms is not higher than in the general population.
Furthermore, in cases of maternal infection, the presence of
increased fetal NT does not signify the presence of fetal infection
with these organisms. Therefore, increased NT in chromo-
somally normal fetuses need not stimulate the search for maternal
infection unless the translucency evolves into second- or third-
trimester nuchal edema or generalized hydrops.
The only infection that has been reported in association with

increased NT is Parvovirus B19. In this condition the increased
NT has been attributed to myocardial dysfunction or fetal
anemia due to suppression of hemopoiesis.
MANAGEMENT OF PREGNANCIES WITH INCREASED NT

The relation between NT thickness and chromosomal defects,
miscarriage or fetal death and prevalence of major fetal defects is
summarized in Table 1. On the basis of these data it is possible
to estimate, for each NT group, the chances of intrauterine

survival and delivery of a healthy baby with no major defects.
These data are useful in counselling parents of pregnancies with
increased fetal NT and in planning the appropriate follow-up
investigations (Figure 1).
Chromosomal defects
11-14 weeks Major abnormalities
Fetal karyotyping
Anomaly scan
Normal karyotype
No abnormalities
Major abnormalities
14-16 weeks
No abnormalities TORCH & Parvovirus screen
Anomaly scan
Persistent nuchal Genetic testing
Echocardiography
No abnormalities
Resolving nuchal
Major abnormalities
20 weeks
Anomaly scan No abnormalities TORCH & Parvovirus screen
Echocardiography Persistent nuchal Genetic testing
No abnormalities
Figure 1. Management of pregnancies with increased nuchal translucency thickness.
Fetal NT below the 99th centile

In pregnancies with fetal NT below the 99th centile (3.5 mm)
the decision by the parents in favour or against fetal karyotyping
will depend on the patient-specific risk for chromosomal defects,
which is derived from the combination of maternal age,
sonographic findings and serum free b-hCG and PAPP-A at
11–13+6 weeks.
The parents can be reassured that the chances of delivering a
baby with no major abnormalities is about 97% for NT below the
95th centile and 93% for NT between the 95th and 99th centiles.
Furthermore, many of the major fetal abnormalities can be diag-
nosed or suspected at the time of the high-resolution scan at
11–13+6 weeks.

In terms of the subsequent management of the pregnancy it
would be best to carry out a detailed fetal scan at 20 weeks
to determine fetal growth and diagnose or exclude major
abnormalities that could not be identified at the 11–13+6 weeks
scan.
In the 4% of fetuses with NT between the 95th and 99th centiles,

special care should be taken to firstly, confirm that the nuchal
fold thickness is not increased, secondly, to examine the fetal
anatomy with the knowledge that the prevalence of major abnor-
malities is about 2.5%, rather than 1.6% in those with NT below
the 95th centile, and thirdly, to examine the fetal heart. It would
be preferable if specialist fetal echocardiography is carried out
but the feasibility of this will primarily depend on the availability
of such service.
Fetal NT above the 99th centile

A fetal NT above 3.5 mm is found in about 1% of pregnancies.
The risk of major chromosomal defects is very high and
increases from about 20% for NT of 4.0 mm to 33% for NT of
5.0 mm, 50% for NT of 6.0 mm and 65% for NT of 6.5 mm
or more. Consequently, the first line of management of such
pregnancies should be the offer of fetal karyotyping by CVS.
In patients with a family history of the genetic syndromes which

are associated with increased NT and are amenable to prenatal
diagnosis by DNA analysis (Table 3), the CVS sample can also
be used for the diagnosis or exclusion of these syndromes. In
addition, a detailed scan should be carried out at 11–13+6 weeks
in search of the many major abnormalities that have been
reported in association with increased NT (Table 3).

Resolution of increased NT
In the chromosomally normal group, a detailed scan, including
fetal echocardiography, should be carried out at 14–16 weeks to
determine the evolution of the NT and to diagnose or exclude
many fetal defects. If this scan demonstrates resolution of the
NT and absence of any major abnormalities the parents can be
reassured that the prognosis is likely to be good and the chances
of delivering a baby with no major abnormalities is more than
95%.
The only necessary additional investigation is a detailed scan at

20–22 weeks for the exclusion or diagnosis of both major abnor-
malities and the more subtle defects that are associated with the
genetic syndromes listed in Table 3. If none of these is found, the
parents can be counseled that the risk of delivering a baby with a
serious abnormality or neurodevelopmental delay may not be
higher than in the general population.
Evolution to nuchal edema

Persistence of unexplained increased NT at the 14–16 weeks
scan or evolution to nuchal edema or hydrops fetalis at 20–22
weeks, raise the possibility of congenital infection or a genetic
syndrome. Maternal blood should be tested for toxoplasmosis,
cytomegalovirus, and parvovirus B19. Follow-up scans to define
the evolution of the edema should be carried out every four
weeks. Additionally, consideration should be given to DNA
testing for certain genetic conditions, such as spinal muscular
atrophy, even if there is no family history for these conditions.
In pregnancies with unexplained nuchal edema at the 20–22

weeks scan the parents should be counseled that there is a 10%
risk of evolution to hydrops and perinatal death or a livebirth

with a genetic syndrome, such as Noonan syndrome. The risk of
neurodevelopmental delay is 3–5%.
• Increased fetal NT thickness at 11–13+6 weeks is a common

phenotypic expression of chromosomal defects and a wide
range of fetal malformations and genetic syndromes.
• The prevalence of fetal abnormalities and adverse pregnancy
outcome increases exponentially with NT thickness. However,
the parents can be reassured that the chances of delivering
a baby with no major abnormalities is more than 90% if the
fetal NT is between the 95th and 99th centiles, about 70% for
NT of 3.5–4.4 mm, 50% for NT 4.5–5.4 mm, 30% for NT of
5.5–6.4 mm and 15% for NT of 6.5 mm or more.
• The vast majority of fetal abnormalities associated with
increased NT can be diagnosed by a series of investigations
that can be compled by 14 weeks of gestation.

REFERENCES
Brady AF, Pandya PP, Yuksel B, Greenough A, Patton MA, Nicolaides KH. Outcome
of chromosomally normal livebirths with increased fetal nuchal translucency at 10–14
weeks’ gestation. J Med Genet 1998;35:222–4.
Hyett JA, Moscoso G, Nicolaides KH. Abnormalities of the heart and great arteries in
first trimester chromosomally abnormal fetuses. Am J Med Genet 1997;69:207–16.
Hyett J, Perdu M, Sharland G, Snijders R, Nicolaides KH. Using fetal nuchal translu-
cency to screen for major congenital cardiac defects at 10–14 weeks of gestation:
population based cohort study. BMJ 1999;318:81–5.
Liao AW, Sebire NJ, Geerts L, Cicero S, Nicolaides KH. Megacystis at 10–14 weeks
of gestation: Chromosomal defects and outcome according to bladder length.
Makrydimas G, Sotiriadis A, Ioannidis JP. Screening performance of first-trimester

nuchal translucency for major cardiac defects: a meta-analysis. Am J Obstet Gynecol
2003;189:1330–5.
Matias A, Huggon I, Areias JC, Montenegro N, Nicolaides KH. Cardiac defects in

chromosomally normal fetuses with abnormal ductus venosus blood flow at 10–14
weeks. Ultrasound Obstet Gynecol 1999;14:307–10.
Michailidis GD, Economides DL. Nuchal translucency measurement and pregnancy

outcome in karyotypically normal fetuses. Ultrasound Obstet Gynecol 2001;17:102–5.
Nicolaides KH, Warenski JC, Rodeck CH. The relationship of fetal plasma protein
concentration and hemoglobin level to the development of hydrops in rhesus
isoimmunization. Am J Obstet Gynecol 1985;1:152:341–4.
Nicolaides KH, Soothill PW, Clewell WH, Rodeck CH, Mibashan R, Campbell S. Fetal
haemoglobin measurement in the assessment of red cell isoimmunisation. Lancet
1988;1:1073–5.
Sebire NJ, Snijders RJM, Davenport M, Greenough A, Nicolaides KH. Fetal nuchal
translucency thickness at 10–14 weeks of gestation and congenital diaphragmatic
hernia. Obstet Gynecol 1997;90:943–7.
Sebire NJ, Bianco D, Snijders RJM, Zuckerman M, Nicolaides KH. Increased fetal
nuchal translucency thickness at 10–14 weeks: is screening for maternal-fetal infection
necessary? BJOG 1997;104:212–5.
Snijders RJM, Brizot ML, Faria M, Nicolaides KH. Fetal exomphalos at 11–14 weeks
of gestation. J Ultrasound Med 1995;14:569–74.


Souka AP, von Kaisenberg CS, Hyett JA, Sonek JD, Nicolaides KH. Increased nuchal
translucency with normal karyotype. Am J Obstet Gynecol 2004; in press
Souka AP, Krampl E, Bakalis S, Heath V, Nicolaides KH. Outcome of pregnancy in

chromosomally normal fetuses with increased nuchal translucency in the first trimester.
von Kaisenberg CS, Krenn V, Ludwig M, Nicolaides KH, Brand-Saberi B. Morpho-

logical classification of nuchal skin in fetuses with trisomy 21, 18 and 13 at 12–18
weeks and in a trisomy 16 mouse. Anat Embryol 1998;197:105–24.
von Kaisenberg CS, Nicolaides KH, Brand-Saberi B. Lymphatic vessel hypoplasia in

fetuses with Turner syndrome. Hum Reprod 1999;14:823–6.

4
MULTIPLE PREGNANCY
Multiple pregnancy results from the ovulation and subsequent

fertilisation of more than one oocyte. In such case the fetuses
are genetically different (polyzygotic or non-identical). Multiple
pregnancy can also result from splitting of one embryonic mass
to form two or more genetically identical fetuses (monozygotic).
In all cases of polyzygotic multiple pregnancy each zygote
develops its own amnion, chorion and placenta (polychorionic).
In monozygotic pregnancies, there may be sharing of the same
placenta (monochorionic), amniotic sac (monoamniotic) or even
fetal organs (conjoined or Siamese).
When the single embryonic mass splits into two within three days
of fertilisation, which occurs in one-third of monozygotic twins,
each fetus has its own amniotic sac and placenta (diamniotic and
dichorionic) (Figure 1). When embryonic splitting occurs after
the third day following fertilisation, there are vascular communi-
cations within the two placental circulations (monochorionic).
Embryonic splitting after the 9th day following fertilisation results
in monoamniotic monochorionic twins and splitting after the 12th
day results in conjoined twins.
PREVALENCE AND EPIDEMIOLOGY

Twins account for about 1% of all pregnancies with two-thirds
being dizygotic and one-third monozygotic.
Chapter 4 • Multiple pregnancy 95

33% 65% 2%
DICHORIONIC
Placentas MONOCHORIONIC
Sacs MONOAMNIOTIC
Fetuses SIAMESE
Days 0 3 9 12 15
Figure 1. In monozygotic twins embryonic splitting within the first three days of fertilisation results in a
diamniotic and dichorionic pregnancy, splitting between days 3 and 9 results in a diamniotic monochori-
onic pregnancy, splitting between days 9 and 12 results in a monoamniotic monochorionic pregnancy,
and splitting after the 12th day results in conjoined twins.
The prevalence of dizygotic twins varies with ethnic group (up to

5-times higher in certain parts of Africa and half as high in parts
of Asia), maternal age (2% at 35 years), parity (2% after four
pregnancies) and method of conception (20% with ovulation
induction).
The prevalence of monozygotic twins is similar in all ethnic
groups and does not vary with maternal age or parity, but may
be 2–3 times higher following in-vitro fertilisation procedures,
possibly because with these methods the architecture of the zona
pellucida is altered although the mechanism remains uncertain.
In the last 20 years the rate of twinning has increased. This
increase is most marked for dizygotic twins. It is estimated that
about one third of the increase in multiple births is a consequence
of childbearing later in life, but the majority of the effect is due to
the use of assisted reproduction techniques.

DETERMINATION OF ZYGOSITY AND CHORIONICITY
Zygosity can only be determined by DNA fingerprinting, which
requires amniocentesis, chorion villus sampling or cordocentesis.
Determination of chorionicity can be performed by ultrasono-
graphy and relies on the assessment of fetal gender, number of
placentas, and characteristics of the membrane between the two
amniotic sacs (Monteagudo et al 1994).
Different-sex twins are dizygotic and therefore dichorionic, but

in about two-thirds of twin pregnancies the fetuses are of the
same sex and these may be either monozygotic or dizygotic.
Similarly, if there are two separate placentas the pregnancy is
dichorionic, but in the majority of cases the two placentas are
adjacent to each other and there are often difficulties in disting-
uishing between dichorionic-fused and monochorionic placentas.
In dichorionic twins the inter-twin membrane is composed of a

central layer of chorionic tissue sandwiched between two layers of
amnion, whereas in monochorionic twins there is no chorionic
layer present. The best way to determine chorionicity is by an
ultrasound examination at 6–9 weeks of gestation. Dichorionic
twins can be easily distinguished by the presence of a thick
septum between the chorionic sacs. This septum becomes pro-
gressively thinner to form the chorionic component of the inter-
twin membrane, but remains thicker and easier to identify at the
base of the membrane as a triangular tissue projection, or lambda
sign (Bessis et al 1981, Sepulveda et al 1996, 1997, Monteagudo
et al 2000).
Sonographic examination of the base of the inter-twin membrane

at 10–13+6 weeks of gestation for the presence or absence of the
lambda sign (Figure 2) provides reliable distinction between
dichorionic and monochorionic pregnancies. With advancing

Figure 2. Ultrasound appearance of monochorionic (left) and dichorionic (right) twin pregnancies at
12 weeks of gestation. Note that in both types there appears to be a single placental mass but in the
dichorionic type there is an extention of placental tissue into the base of the intertwin membrane forming
the lambda sign.
gestation there is regression of the chorion laeve and the ‘lambda’

sign becomes progressively more difficult to identify. Thus by 20
weeks only 85% of dichorionic pregnancies demonstrate the
lambda sign.
Therefore, absence of the lambda sign at 20 weeks, and presum-

ably thereafter, does not constitute evidence of monochorionicity
and does not exclude the possibility of dichorionicity or dizygosity.
Conversely, because none of the pregnancies classified as mono-
chorionic at the 10–13+6 week scan subsequently develop the
lambda sign, the identification of this feature at any stage of
pregnancy should be considered as evidence of dichorionicity.
CHORIONICITY AND PREGNANCY COMPLICATIONS

Miscarriage
In singleton pregnancies with a live fetus demonstrated at the
11–13+6 weeks scan the rate of subsequent miscarriage or fetal

death before 24 weeks is about 1%. The rate of fetal loss in
dichorionic twins is about 2% and in monochorionic twins it
is about 10% (Sebire et al 1997a). This high mortality confined
to monochorionic pregnancies is the consequence of severe
early-onset TTTS.
Reduction of the excess fetal loss in twins, compared to singletons,

can only be achieved through early identification of monochori-
onic pregnancies by ultrasound examination at 11–13+6 weeks,
close surveillance and appropriate treatment, with endoscopic
laser coagulation of the communicating placental vessels, in those
that develop severe TTTS (Ville et al 1995, Senat et al 2004).
Perinatal mortality
The perinatal mortality rate in twins is about 5-times higher than
in singletons. This increased mortality, which is mainly due to
prematurity-related complications, is higher in monochorionic
(5%) than dichorionic (2%) twin pregnancies (Sebire et al 1997a).
In monochorionic twins, an additional complication to prematurity
is TTTS.
Early preterm delivery

The most important complication of any pregnancy is delivery
before term and especially before 32 weeks. Almost all babies
born before 24 weeks die and almost all born after 32 weeks
survive. Delivery between 24 and 32 weeks is associated with
a high chance of neonatal death and handicap in the survivors.
The chance of spontaneous delivery between 24 and 32 weeks
is about 1% in singletons, 5% in dichorionic and 10% in
monochorionic twin pregnancies (Sebire et al 1997a).

Growth restriction
In singleton pregnancies the prevalence of babies with birth
weight below the 5th centile is 5%, in dichorionic twins it is
about 20% and in monochorionic twins it is 30% (Sebire et al
1997a, 1998a). Furthermore, the chance of growth restriction of
both twins is about 2% in dichorionic and 8% in monochorionic
pregnancies.
In singleton pregnancies the two main factors determining fetal

growth are genetic potential and placental function. In mono-
chorionic twin pregnancies both factors should be the same for
the two fetuses. Consequently, inter-twin disparities in growth
are likely to reflect the degree of unequal splitting of the initial
single cell mass or the magnitude of imbalance in the flow of
fetal blood through placental vascular communications between
the two circulations. In contrast, since about 90% of dichorionic
pregnancies are dizygotic, inter-twin disparities in size would be
due to differences in genetic constitution of the fetuses and their
placentas.
Pre-eclampsia
The prevalence of pre-eclampsia is about 4-times greater in
twin than in singleton pregnancies but it is not significantly dif-
ferent between monochorionic and dichorionic twins (Savvidou
et al 2001).
Death of one fetus

Intrauterine death of a fetus in a twin pregnancy may be associ-
ated with adverse outcome for the co-twin but the type and
degree of risk is dependent on the chorionicity of the pregnancy.

In singleton pregnancies death and retention of the fetus may
be associated with maternal disseminated intravascular coagu-
lation; however, in twin pregnancies with one dead fetus this
complication has only rarely been reported.
Death of one fetus in dichorionic pregnancies carries a risk to

the remaining fetus, mainly due to preterm delivery, which may
be the consequence of release of cytokines and prostaglandins
by the resorbing dead placenta. In dichorionic twins the risk of
death or handicap in such cases is about 5–10% whereas in
monochorionic twins, there is at least a 30% risk of death or
neurological handicap to the co-twin due to hypotensive episodes
in addition to the risk of preterm delivery. The acute hypotensive
episode is the result of hemorrhage from the live fetus into the
dead fetoplacental unit (Fusi et al 1991). Intrauterine blood
transfusion within 24 hours of death of the co-twin may prevent
fetal death.
Structural defects
Structural fetal defects in twin pregnancies can be grouped into
those which also occur in singletons and those specific to the
twinning process; the latter being unique to monozygotic twins.
For any given defect the pregnancy may be concordant or dis-
cordant in terms of both the presence or type of abnormality and
its’ severity. The prevalence of structural defects per fetus in
dizygotic twins is the same as in singletons, whereas the rate in
monozygotic twins is 2–3 times higher (Burn et al 1991, Baldwin
et al 1994). Concordance of defects (both fetuses being affected)
is uncommon, being found in about 10% of dichorionic and 20%
of monochorionic pregnancies.
Multiple pregnancies discordant for a fetal abnormality can
essentially be managed expectantly or by selective fetocide of the

abnormal twin (Sebire et al 1997b). In cases where the abnor-
mality is non-lethal but may well result in serious handicap the
parents need to decide whether the potential burden of a handi-
capped child is enough to risk the loss of the normal twin from
fetocide-related complications. In cases where the abnormality is
lethal it may be best to avoid such risk to the normal fetus, unless
the condition itself threatens the survival of the normal twin.
In the case of dichorionic pregnancies fetocide can be carried
out by intracardiac injection of potassium chloride, whereas in
monochorionic pregnancies fetocide necessitates occlusion of the
umbilical cord vessels.
Twin-to-twin transfusion syndrome

In monochorionic twin pregnancies there are placental vascular
anastomoses which allow communication of the two fetoplacental
circulations; these anastomoses may be arterio-arterial, veno-
venous, or arterio-venous in nature. Anatomical studies demon-
strated that arterio-venous anastomoses are deep in the placenta
but the feeding vessels are invariably superficial (Benirschke et al
1973). In about 30% of monochorionic twin pregnancies, imbal-
ance in the net flow of blood across the placental vascular arterio-
venous communications from one fetus, the donor, to the other,
the recipient, results in twin-to-twin transfusion syndrome; in
about half of these the condition is severe.
Severe disease, with the development of polyhydramnios, be-
comes apparent at 16–24 weeks of pregnancy. The pathogno-
monic features of severe TTTS by ultrasonographic examination
are the presence of a large bladder in the polyuric recipient fetus
in the polyhydramniotic sac and ‘absent’ bladder in the anuric
donor that is found ‘stuck’ and immobile at an edge of the
placenta or the uterine wall where it is held fixed by the collapsed
membranes of the anhydramniotic sac (Figure 3).

Figure 3. Severe twin-to-twin transfusion syndrome at 20 weeks of gestation. In the polyuric
recipient there is polyhydramnios and the anuric donor is held fixed to the placenta by the collapsed
membranes of the anhydramniotic sac.
Early prediction of twin-to twin transfusion syndrome

Ultrasonographic features of the underlying hemodynamic
changes in severe TTTS may be present from as early as 11–
13+6 weeks of gestation and manifest as increased NT thickness
in one or both of the fetuses. In monochorionic twin pregnancies
at 11–13+6, the prevalence of increased NT thickness in at least
one of the fetuses in those that subsequently develop TTTS is
about 30%, compared to 10% in those that do not develop
TTTS (Sebire et al 2000).
Another early ultrasound marker of severe TTTS may be abnor-

mal Doppler flow velocity waveform in the ductus of the recipient
twin (Matias et al 2000). Intertwin discrepancies in crown-rump
length are not predictive of subsequent development of TTTS.
An early manifestation of disparity in amniotic fluid volume due

to TTTS is inter-twin membrane folding (Figure 4). In about

Figure 4. Monochorionic twin pregnancy at 16 weeks of gestation affected by early twin-to-twin trans-
fusion syndrome showing folding of the inter-twin membrane, pointing towards the recipient amniotic sac
and the increased echogenicity of the amniotic fluid in the donor sac.
30% of monochorionic twin pregnancies at 15–17 weeks of

gestation there is a membrane folding, and in about half of such
cases (15% of total) there is progression to the polyhydramnios/
anhydramnios sequence of severe TTTS; in the other 15% there
is moderate TTTS with large discrepancies in amniotic fluid
volume and fetal size persisting throughout pregnancy (Sebire
et al 1998b).
In two-thirds of monochorionic twin pregnancies, there is no

membrane folding and these pregnancies are not at increased risk
for miscarriage or perinatal death due to TTTS.
Twin reversed arterial perfusion sequence

The most extreme manifestation of twin-to-twin transfusion
syndrome, found in approximately 1% of monozygotic twin preg-
nancies, is acardiac twinning. This twin disorder has been named
twin reversed arterial perfusion (TRAP) sequence because the
underlying mechanism is thought to be disruption of normal
vascular perfusion and development of the recipient twin due to

an umbilical arterial-to-arterial anastomosis with the donor or
pump-twin (Van Allen et al 1983). At least 50% of donor twins
die due to congestive heart failure or severe preterm delivery, due
to polyhydramnios. All perfused twins die due to the associated
multiple malformations. Prenatal treatment is by occlusion of the
blood flow to the acardiac twin by ultrasound-guided diathermy
of the umbilical cord or laser coagulation of the umbilical cord
vessels within the abdomen of the acardiac twin, which is carried
out at about 16 weeks of gestation.
Importance of prenatal determination of chorionicity

• Chorionicity, rather than zygosity, is the main factor deter-
mining pregnancy outcome.
• In monochorionic twins the rates of miscarriage, perinatal
death, preterm delivery, fetal growth restriction and fetal
abnormalities are much higher than in dichorionic twins.
• Death of a monochorionic fetus is associated with a high
chance of sudden death or severe neurological damage in the
co-twin.
CHROMOSOMAL DEFECTS IN MULTIPLE PREGNANCIES

In multiple pregnancies compared to singletons, prenatal diag-
nosis of chromosomal abnormalities is complicated because,
firstly, the techniques of invasive testing may provide uncertain
results or may be associated with higher risks of miscarriage and,
secondly, the fetuses may be discordant for an abnormality, in
which case one of the options for the subsequent management of
the pregnancy is selective fetocide.
Selective fetocide can result in spontaneous abortion or severe

preterm delivery, which may occur several months after the

procedure. The risk for these complications is related to the
gestation at fetocide. Selective fetocide after 16 weeks is asso-
ciated with a three-fold increase in risk compared to reduction
before 16 weeks, and there is an inverse correlation between the
gestational age at fetocide with the gestation at delivery (Evans
et al 1994).
Amniocentesis in twins is effective in providing a reliable

karyotype for both fetuses and the procedure-related fetal loss
rate is about 2%. In the case of chorionic villus sampling, the
procedure-related fetal loss rate is about 1%, but in about 1% of
cases there may be a diagnostic error, either due to sampling the
same placenta twice or cross-contamination. The main advantage
of chorionic villus sampling is that it provides results sufficiently
early to allow for safer selective fetocide.
Screening by maternal age

In dizygotic pregnancies, the maternal age-related risk for chro-
mosomal abnormalities for each twin is the same as in singleton
pregnancies and therefore the chance that at least one fetus is
affected by a chromosomal defect is twice as high as in singleton
pregnancies. Furthermore, since the rate of dizygotic twinning
increases with maternal age the proportion of twin pregnancies
with chromosomal abnormalities is higher than in singleton
pregnancies.
In monozygotic twins, the risk for chromosomal abnormalities

is the same as in singleton pregnancies and in the vast majority
of cases both fetuses are affected.
The relative proportion of spontaneous dizygotic to monozygotic

twins in Caucasian populations is about two-to-one and therefore
the prevalence of chromosomal abnormalities affecting at least

one fetus in twin pregnancies would be expected to be about
1.6 times higher than in singletons.
In counselling parents it is possible to give more specific estimates
of one and/or both fetuses being affected depending on chori-
onicity. Thus in monochorionic twins the parents can be coun-
seled that both fetuses would be affected and this risk is similar to
that in singleton pregnancies. If the pregnancy is dichorionic,
then the parents can be counseled that the risk of discordancy
for a chromosomal abnormality is about twice that in singleton
pregnancies whereas the risk that both fetuses would be affected
can be derived by squaring the singleton risk ratio. For example,
in a 40 year old woman with a risk for trisomy 21 of about 1 in
100 based on maternal age, in a dizygotic twin pregnancy the risk
that one fetus would be affected would be 1 in 50 (1 in 100 plus
1 in 100), whereas the risk that both fetuses would be affected
is 1 in 10,000 (1 in 100 × 1 in 100). This is in reality an over-
simplification, since, unlike monochorionic pregnancies that are
always monozygotic, only about 90% of dichorionic pregnancies
are dizygotic.
Screening by second trimester maternal serum biochemistry

In singleton pregnancies, screening for trisomy 21 by a combi-
nation of maternal age and second trimester maternal serum
biochemistry can detect 50–70% of trisomy 21 cases for a 5% false
positive rate (Cuckle 1998).
In twin pregnancies, the median value for maternal serum
markers, such as AFP, hCG, free b-hCG and inhibin-A are about
twice those for singleton pregnancies. When this is taken into
account in the mathematical modeling for calculation of risks it
was estimated that serum screening in twins may identify about
45% of affected fetuses for a 5% false positive rate (Cuckle 1998).

Even if prospective studies demonstrate that serum testing in
twins is effective, the following problems would still need to
be addressed; (a) the detection rate for an acceptable low false
positive rate, especially since invasive testing in multiple pregnan-
cies is technically more demanding, (b) in the presence of a
‘screen positive’ result, there is no feature to suggest which
fetus may be affected, and (c) if the pregnancy is discordant for
chromosomal defect, further management by way of selective
termination carries increased risk in the second compared to
the first trimester.
Screening by fetal nuchal translucency thickness

In dichorionic twin pregnancies, the detection rate (75–80%) and
false positive rate (5% per fetus or 10% per pregnancy) of fetal
NT in screening for trisomy 21 are similar to those in singleton
pregnancies (Sebire et al 1996a, 1996b). Patient specific-risks for
trisomy 21 are calculated for each fetus based on maternal age
and fetal NT. Effective screening and diagnosis of major chro-
mosomal abnormalities can be achieved in the first trimester,
allowing the possibility of earlier and therefore safer selective
fetocide for those parents that choose this option.
An important advantage of screening by fetal NT in dichorionic
twins is that when there is discordancy for a chromosomal abnor-
mality, the presence of a sonographically detectable marker helps
to ensure the correct identification of the abnormal twin should
the parents choose selective termination.
In monochorionic pregnancies, the false-positive rate of NT
screening (8% per fetus or 14% per pregnancy) is higher than in
dichorionic twins, because increased NT is an early manifestation
of TTTS. The risk for trisomy 21 is calculated for each fetus,
based on maternal age and fetal NT and then the average risk
between the two fetuses is considered to be the risk for the
pregnancy as a whole.

Screening by fetal NT thickness and maternal serum biochemistry
In normal twin pregnancies, compared to singletons, the median
maternal serum free b-hCG and PAPP-A, adjusted for maternal
weight, are about 2.0 MoM. In trisomy 21 twin pregnancies
the median level of free b-hCG is significantly higher and
PAPP-A lower than than in normal twins. At a false positive rate of
10% (compared to 5% in singletons) screening by a combination
of fetal NT and maternal serum biochemistry could identify
85–90% of trisomy 21 pregnancies (Spencer and Nicolaides
2003). Chorionicity is not associated with significant differences in
maternal serum free b-hCG or PAPP-A values in first trimester.
Management of twin pregnancies with chromosomal abnormalities

When both fetuses are chromosomally abnormal the parents usu-
ally chose termination of pregnancy. In pregnancies discordant for
chromosomal defects the main options are either selective fetocide
or expectant management. In such cases the decision is essentially
based on the relative risk of selective fetocide causing miscarriage
and hence death of the normal baby, compared to the potential
burden of caring for a handicapped child (Sebire et al 1997c).
Selective fetocide after 16 weeks of gestation is associated with
three-fold increase in risk of spontaneous abortion compared to
reduction before 16 weeks and there is and inverse correlation
between the gestation at fetocide with the gestation at delivery
(Evans et al 1994). It is possible that the resorbing dead
fetoplacental tissue triggers an intrauterine inflammatory process
that is proportional to the amount of dead tissue and therefore
the gestation at fetocide. Such an inflammatory process could
result in the release of cytokines and prostaglandins which would
in turn induce uterine activity with consequent miscarriage/
preterm labour.

In pregnancies discordant for trisomy 21 the usual choice is
selective fetocide, because with expectant management the major-
ity of affected babies would survive. In the case of more lethal
defects, such as trisomy 18, about 85% of affected fetuses die
in-utero and those that are live born usually die within the first
year of life. In this respect, expectant management may be the
preferred option; this would certainly avoid the procedure-related
complications from selective fetocide. The alternative view is that
the amount of dead fetoplacental tissue (and therefore the risk for
consequent miscarriage or preterm labour) would be less after
fetocide at 12 weeks rather than spontaneous death of the trisomy
18 fetus at a latter stage of pregnancy.
Screening for trisomy 21 in monochorionic twins
• In monozygotic twins, the risk for chromosomal abnormalities
is the same as in singleton pregnancies.
• In monochorionic pregnancies, the false-positive rate of NT
screening (8% per fetus or 14% per pregnancy) is higher
than in dichorionic twins, because increased NT is an early
manifestation of TTTS.
• The risk for trisomy 21 is calculated for each fetus, based on
maternal age, fetal NT and maternal serum biochemistry and
then the average risk between the two fetuses is considered to
be the risk for the pregnancy as a whole.
Screening for trisomy 21 in dichorionic twins

• Screening by a combination of fetal NT and maternal
serum biochemistry identifies about 85–90% of trisomy 21
fetuses for a false positive rate of 10% (compared to 5% in
singletons).
• In pregnancies discordant for chromosomal defects the
main options are either selective fetocide or expectant
management.
• Selective fetocide after 16 weeks of gestation is associated
with three-fold increase in risk of spontaneous abortion
compared to reduction before 16 weeks.

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Burn J. Disturbance of morphological laterality in humans. Ciba Found Symp

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monochorionic twin pregnancy. Is there a role for nuchal translucency and ductus
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Nicolaides The 11-13 Weeks Scan 2004

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The 11–13+6 weeks scan

The 11–13+6 weeks scan

FMF-English cover.indd 2-3 2004-9-28 10:41:24

Fetal Medicine Foundation, London 2004

1. First trimester diagnosis of chromosomal defects

2. Sonographic features of chromosomal defects

3. Increased nuchal translucency with normal karyotype

In 1866 Langdon Down noted that common characteristics of patients with

In 1866, Langdon Down reported that in individuals with

DIAGNOSIS OF CHROMOSOMAL DEFECTS

Chapter 1 • First trimester diagnosis of chromosomal defects 7

cell surface markers. The resulting sample is unsuitable for tradi-

8 The 11–13+6 weeks scan

Chapter 1 • First trimester diagnosis of chromosomal defects 9

Chorionic villus sampling

It is likely that in centres with experience in ultrasound guided

There is an association between chorionic villus sampling before

10 The 11–13+6 weeks scan

SCREENING FOR CHROMOSOMAL DEFECTS

Chapter 1 • First trimester diagnosis of chromosomal defects 11

In the late 1980s, a new method of screening was introduced that

In the 1990s, screening by a combination of maternal age and

Subsequently, maternal age was combined with fetal NT and

12 The 11–13+6 weeks scan

first-trimester to identify about 85–90% of affected fetuses.

In 2001, it was found that in 60–70% of fetuses with trisomy 21

PATIENT-SPECIFIC RISK FOR CHROMOSOMAL DEFECTS

Chapter 1 • First trimester diagnosis of chromosomal defects 13

Method of screening DR (%)

Maternal age (MA) 30

MA and maternal serum biochemistry at 15–18 weeks 50–70

MA and fetal nuchal translucency (NT) at 11–13+6 wks 70–80

MA and fetal NT and maternal serum free b-hCG and 85–90

MA and fetal NT and fetal nasal bone (NB) at 11–13+6 wks 90

MA and fetal NT and NB and maternal serum free b-hCG and 95

hCG human chorionic gonadotropin, PAPP-A: pregnancy-associated plasma protein A

of screening tests carried out during the course of the pregnancy

The likelihood ratio for a given sonographic or biochemical

Every time a test is carried out the a priori risk is multiplied by

14 The 11–13+6 weeks scan

Maternal age and gestation

Maternal age (yrs)

Figure 4. Maternal age-related risk for chromosomal abnormalities.

Chapter 1 • First trimester diagnosis of chromosomal defects 15

Estimates of the maternal age-related risk for trisomy 21 at birth

16 The 11–13+6 weeks scan

Effect of maternal age and gestation on risk

Previous affected pregnancy

Chapter 1 • First trimester diagnosis of chromosomal defects 17

Maternal Trisomy 21 Trisomy 18 Trisomy 13

The 11–13+6 weeks scan

Recurrence of chromosomal defects

Fetal nuchal translucency

Chapter 1 • First trimester diagnosis of chromosomal defects 19

Nasal bone and other first-trimester sonographic markers

Maternal serum biochemistry in the first-trimester

20 The 11–13+6 weeks scan

NUCHAL TRANSLUCENCY THICKNESS

Risk (%) ß-hCG PAPP-A