Ultrasound Obstet Gynecol 2002; 19: 235– 239
First-trimester umbilical cord diameter: a novel marker
of fetal aneuploidy
Blackwell Science Ltd
F. GHEZZI*, L. RAIO†, E. DI NARO‡, M. FRANCHI*, M. BUTTARELLI* and H. SCHNEIDER†
*Department of Obstetrics and Gynecology, University of Insubria, Varese, Italy, †Department of Obstetrics and Gynecology, University of Bern,
Switzerland and ‡Department of Obstetrics and Gynecology, University of Bari, Italy
KE YWORDS: Chromosomal abnormalities, Nuchal translucency, Umbilical cord, Wharton’s jelly
ABSTRACT
Objective To compare the umbilical cord diameter at 10–
14 weeks of gestation of chromosomally normal and
abnormal fetuses.
Methods In a consecutive series of women, who were undergoing routine sonographic evaluation at 10–14 weeks of
gestation, umbilical cord diameter and nuchal translucency
were measured. Reference ranges for umbilical cord diameter
according to gestational age and crown–rump length were
constructed. Fetal karyotype was obtained at chorionic villus
sampling, amniocentesis or at delivery in newborns with
features suspicious for chromosomal abnormalities.
Results During the study period, 784 patients met the
inclusion criteria. Of these, a fetal or placental chromosomal
abnormality was present in 17 cases. The mean umbilical cord
diameter increased with gestational age (r = 0.41, P < 0.001).
The proportion of fetuses with an umbilical cord diameter
above the 95th centile was higher in the presence of fetal or
placental chromosomal abnormalities than in normal
fetuses (5/17 vs. 39/767, P < 0.01). Among fetuses with an
abnormal fetal or placental karyotype, nuchal translucency
was above the 95th centile for gestational age in 10 cases.
When only fetal chromosomal abnormalities were considered (n = 14), the combined detection rate was 85.7%
(12/14).
Conclusions Sonographic assessment of the umbilical cord
in early gestation appears to identify a subset of fetuses at
increased risk of chromosomal abnormalities.
INTRODUCTION
Early identification of women at increased risk of fetal chromosomal abnormalities remains one of the most important
challenges in prenatal medicine. The most extensively studied
early sonographic feature of chromosomal defects is fetal
nuchal translucency (NT), which is also a marker for cardiac
defects and for some genetic syndromes1–5.
A structure which is always easily visible at ultrasound
in the late first trimester is the umbilical cord. We have
previously reported that the umbilical cord diameter in the
first trimester is correlated with the growth of the embryo
and its measurement might be useful for identifying a subset
of fetuses at risk of spontaneous abortion and pre-eclampsia6.
Morphologic alterations of the umbilical cord structure and
composition have been found at delivery in a variety of pathologic conditions, such as hypertensive disorders7, gestational
diabetes8,9, fetal distress10 and growth restriction11. Umbilical
cords with single artery12, uncoiled cords13 and short umbilical
cords14 have been described in cases with chromosomal defects
and other genetic syndromes. Moreover, it has been reported
that fetuses with Down syndrome have significantly shorter
umbilical cords compared to normal infants15.
The purpose of this study was to investigate whether there
is a difference in umbilical cord diameter in early gestation
between normal fetuses and fetuses with chromosomal
abnormalities.
PATIENTS AND METHODS
Consecutive pregnant women referred to our departments
for a detailed ultrasound examination at 10–14 weeks of gestation were included in the study. In addition to measurement
of the fetal crown–rump length (CRL) and nuchal translucency, as recommended by The Fetal Medicine Foundation16,
we also measured umbilical cord diameter as outer-to-outer
border at the maximal magnification. Two measurements
were made in a free loop of the umbilical cord from the long-axis
view (Figure 1) and the average of the two was calculated. All
ultrasound examinations were performed with commercially
available ultrasound machines (Sequoia 512 and XP 128,
Acuson, Mountain View, CA, USA; 1700 Dyna View II, Aloka,
Tokyo, Japan) equipped with a 3.5–5-MHz transducer. Intraand interobserver variability were 4.1% and 4.8%, respectively6.
Correspondence: Dr Fabio Ghezzi, Department of Obstetrics and Gynecology, University of Insubria, Viale Borri 57, 21100 Varese, Italy
(e-mail: fabio.ghezzi@uninsubria.it)
Presented at The Fetal Medicine Foundation’s Meeting on Research and Developments in Fetal Medicine, London, 30 August 2001.
ORIGINAL PAPER
235
First-trimester umbilical cord diameter
The fetal karyotype was established by chorionic villus sampling or amniocentesis or at delivery in newborns with features
suggestive of chromosomal abnormalities. Each patient was
included only once. Since we did not know whether placental
chromosomal abnormalities might influence the morphology of
the umbilical cord, a separate analysis was conducted, including and excluding cases with confined placental mosaicisms.
Informed consent was obtained from all patients and
the Human Research Review Committee of the participating
institutions approved the study. The data of the first 304
fetuses were utilized in a previously published study6.
Statistical analysis
Statistical analysis was performed using SPSS for Windows
(SPSS Inc., Chicago, IL, USA) and with GraphPad Prism
version 3.00 for Windows (GraphPad Software, San Diego,
CA, USA). The data were analyzed as previously described by
Royston and Wright17. Polynomial regression analysis was
performed to identify the regression curves that best fitted the
mean and standard deviation (SD) as a function of gestational
age and CRL. The SD scores (Z-scores) were calculated using
the formula:
(Observed umbilical cord diameter – mean umbilical cord
diameter)/SD
To assess the model fit, the Gaussian distributions of the Zscores were checked using the Kolmogorov–Smirnov test.
The 5th and 95th centiles for umbilical cord diameter with
gestation and in relation with CRL were obtained as previously
described18 using the formula: mean ± 1.645 SD. Spearman
rank correlation was used to assess the correlation between
umbilical cord measurements and both gestational age and
CRL. Fisher’s exact test was used to compare proportions.
P < 0.05 was considered statistically significant.
RESULTS
The entry criteria were met by 784 patients. Of these,
chromosomal abnormalities were present in 17 cases. To
Ghezzi et al.
construct nomograms for the umbilical cord diameter
according to gestational age, the analysis was restricted to
patients whose fetus had a normal karyotype (n = 767). The
clinical characteristics of these patients are summarized in
Table 1. A significant correlation was found between umbilical cord diameter and gestational age (r = 0.41, P < 0.001).
The regression equation for the mean umbilical cord diameter
(y) according to gestational age (x) was y = – 0.4245 + 0.3568x
and for the SD (y′) was y′ = 0.001802 + 0.04226x. The normal
distribution of Z-scores was confirmed by the Kolmogorov–
Smirnov test. Figure 2 shows the umbilical cord diameters
observed measurements and the fitted 5th, 50th and 95th
centiles. The clinical characteristics of cases with placental
or fetal abnormal karyotype are shown in Table 2. In five
fetuses (29.4%) with chromosomal abnormalities, the
umbilical cord was greater than the 95th centile for gestational
age (Figure 3). The proportion of fetuses with an umbilical
cord diameter above the 95th centile was higher among those
with fetal or placental chromosomal abnormalities compared
to normal fetuses (5/17 vs. 39/767, P < 0.01). Three cases of
an abnormal karyotype at chorionic villus sampling were
confirmed at amniocentesis to have confined placental
mosaicisms. When these cases were removed from the analysis, the proportion of chromosomally abnormal fetuses
with an umbilical cord diameter above the 95th centile
increased from 29.4% to 35.7% (5/14).
To explore the significance of an increased umbilical cord
diameter, the analysis was further restricted to fetuses with a
CRL of 45–85 mm, as recommended for the evaluation of
Table 1 Characteristics of patients used for the generation of the
umbilical cord diameter nomogram
Characteristics
n = 767
Maternal age (years) (mean ± SD)
Gestational age at examination (weeks) (mean ± SD)
Gestational age at delivery (weeks) (mean ± SD)
Nulliparous (n), %
Birth weight (g) (mean ± SD)
Placental weight (g) (mean ± SD)
30.8 ± 6.2
11.7 ± 0.78
39.6 ± 1.7
338 (44.1)
3432 ± 504
593 ± 126
Umbilical cord diameter (mm)
10
9
8
7
6
5
4
3
2
1
0
10
11
12
13
14
Gestational age (weeks)
Figure 1 Sonographic measurement of the umbilical cord diameter in
the first trimester of pregnancy.
236
Figure 2 Umbilical cord diameter measurements plotted on the
estimated centiles for gestational age. Lines represent the 5th, 50th and
95th centile.
Ultrasound in Obstetrics and Gynecology
First-trimester umbilical cord diameter
Ghezzi et al.
Umbilical cord diameter (mm)
10
9
8
7
6
5
4
3
2
1
0
10
9
9
7
6
5
4
3
2
55
60
65
70
75
80
85
8
7
6
5
4
3
2
1
1
0
50
Figure 4 Umbilical cord diameter measurements plotted on the
estimated centiles for embryonic crown–rump length. Lines represent
the 5th, 50th and 95th centile.
10
8
45
Crown–rump length (mm)
Umbilical cord diameter (mm)
Umbilical cord diameter (mm)
nuchal translucency2. In this group of patients, 645 women
had a normal fetus while 14 had a fetus with an abnormal
karyotype. A significant correlation was found between
umbilical cord diameter and CRL (r = 0.35, P < 0.001). The
regression equation for the mean umbilical cord diameter
(y) according to CRL (x) was y = 2.206 + 0.03002x and for
the SD (y′) was y′ = –0.3021 + 0.204x. Figure 4 shows the
relationship between the umbilical cord diameter observed
measurements and the CRL, as well as the umbilical cord
diameter fitted 5th, 50th and 95th centiles. In four out of 14
fetuses with chromosomal abnormalities and with a CRL of
45–85 mm, the umbilical cord diameter was above the 95th
centile (28.6%) (Figure 5). The proportion of fetuses with an
umbilical cord diameter greater than the 95th centile was
higher among those with fetal or placental abnormal karyotype compared to normal fetuses (4/14 vs. 35/631, P < 0.01).
When cases with confined placental mosaicism were excluded
from the analysis, the proportion of fetuses with abnormal
10
11
12
13
0
14
45
50
55
65
70
75
80
85
Crown–rump length (mm)
Gestational age (weeks)
Figure 3 Umbilical cord diameter of fetuses with an abnormal
karyotype plotted on reference ranges for gestational age.
60
Figure 5 Umbilical cord diameter of fetuses with an abnormal
karyotype plotted on reference ranges for crown–rump length.
Table 2 Characteristics of fetuses with abnormal karyotype
Gestational age
at examination
(weeks)
Umbilical cord
diameter
(mm)
Nuchal
translucency
(mm)
Crown–rump
length
(mm)
Biparietal
diameter
(mm)
Karyotype
10.1
10.4
10.9
11.1
11.4
11.4
11.6
11.6
11.6
11.7
11.9
12.1
12.3
12.4
12.9
14.0
13.0
5.3
3.5
3.0
3.8
3.9
5.0
3.5
3.8
4.1
3.7
9.0
5.1
4.3
3.4
3.6
7.6
3.2
1.8
1.0
2.9
1.1
2.5
9.6
0.5
3.0
3.8
1.6
11.0
2.1
1.0
4.0
4.8
8.0
3.3
36.7
38.0
33.9
55.5
53.0
65.0
53.1
52.3
53.6
55.5
53.0
57.5
56.8
61.3
47.3
80.0
65.4
13.5
15.5
13.6
19.5
18.0
18.2
19.2
19.3
19.0
20.7
19.0
22.1
21.9
19.3
18.5
29.7
28.8
47XX + 21
45XO
47XY + 21
47XXY
47XX + 21
47XY + 21
Confined placental mosaicism
47XY + 21
47XX + 21
Confined placental mosaicism
45XO
47XY + 13
Confined placental mosaicism
47XX + 21
47XX + 18
45XO
47XY + 18
Ultrasound in Obstetrics and Gynecology
237
First-trimester umbilical cord diameter
karyotype and an umbilical cord diameter higher than the
95th centile was 36.4% (4/11).
Of the 17 fetuses with an abnormal fetal or placental karyotype, the nuchal translucency was above the 95th centile for
gestational age in 10 cases. Among the five fetuses with an
umbilical cord diameter above the 95th centile, the nuchal
translucency was increased in three cases. In our population,
combining the measurement of nuchal translucency and
umbilical cord diameter, the detection rate of fetal or placental aneuploidies was 70.6% (12/17) with a net increase of
11.8% compared to nuchal translucency alone (10/17; 58.8%).
When only fetal chromosomal abnormalities are considered
the combined detection rate was 85.7% (12/14).
DISCUSSION
This study shows that a relationship exists between fetal
chromosomal abnormalities and the morphology of the
umbilical cord. Although the underlying pathophysiologic
mechanism leading to an increased umbilical cord diameter
in fetuses with chromosomal abnormalities remains to be
explored, certain etiologic mechanisms might explain the increase
in both nuchal translucency and umbilical cord diameter.
The Wharton’s jelly mainly comprises a ground substance of hyaluronic acid and proteoglycans in an aqueous
solution of salts, metabolites and plasma proteins distributed in a fine network of collagen microfibrils19. The most
predominant cellular population consists of fibroblasts
involved in synthesizing collagen and glycosaminoglycans20.
Approximately 70% of the soluble part of the Wharton’s
jelly is composed of collagen type IV and hyaluronic
acid20 which, in turn, is capable of entrapping large amounts
of fluid21. Moreover, several types of collagen (types I, III,
IV, V and VI) are found to be homogeneously distributed
in the media of the umbilical vessels or in the Wharton’s
jelly22,23. The precipitation of collagen, laminin and
heparan sulfate has been observed as early as the first trimester around the canalicular-like structure of the Wharton’s
jelly22.
A number of studies have demonstrated that alterations
of the extracellular matrix are present in fetuses affected by
trisomy 21, 13 and 1823,24. In fetuses with trisomy 21, the
extracellular matrix of the nuchal skin is much richer in
glucosaminoglycan, especially hyaluronan, compared to
chromosomally normal fetuses23,25. This appears to be the
consequence of a decreased degradation of hyaluronan in
fetuses with trisomy 21. In the nuchal skin of trisomy 18
fetuses, the distribution and organization of collagen types I
and III is different compared to normal fetuses, resembling
modification occurring with aging25. Finally, in trisomy 18,
most dermal fibroblasts have been found to be laminin positive and in trisomy 13 most dermal fibroblasts are collagen
type IV positive23. In gestational age-matched control normal
fetuses, this was never found to be the case23.
Therefore, an over-expression, as well as an under-expression,
of different structural proteins, polysaccharides and proteoglycans of the extracellular matrix, which might result in
abnormal accumulation of fluid, could explain both the increased
nuchal translucency and increased umbilical cord diameter.
238
Ghezzi et al.
Another interesting question is why fetuses with Turner
syndrome might have a wider than normal umbilical cord.
The most plausible mechanism to explain the hygroma colli
generally present in fetuses with Turner syndrome is lymphatic vessel hypoplasia in the upper dermis26. This does
not explain the increased umbilical cord diameter in fetuses
affected by Turner syndrome because lymphatic vessels are
completely absent in the umbilical cord and in the placenta27.
However, alterations of proteoglycan expression have been
found in the skin of fetuses with Turner syndrome. It has been
reported that, in fetuses with Turner syndrome, biglycan,
which is encoded on chromosome X, is under-expressed and
chondroitin-6-sulfate is over-expressed28. Thus, it reasonable
to assume that similar extracellular matrix modifications
might also affect the Wharton’s jelly which for a large part is
composed of proteoglycans.
Another mechanism that might explain the increased
umbilical cord size is venous congestion26. Considering that
the amount of Wharton’s jelly in the first and early second
trimesters is lower than that in the third trimester27, the
increase in umbilical cord size in early gestation could
either be the consequence of a progressive enlargement of
the umbilical cord vessels or an overrepresentation of
Wharton’s jelly, or both. Cardiac defects and abnormalities
of the great arteries are common findings in fetuses with
increased nuchal translucency16. Moreover, an absent or
reverse flow during atrial contraction at the level of the
ductus venosus has been reported in a very high proportion
of chromosomally abnormal fetuses between 11 and
14 weeks of gestation29. As a consequence, umbilical vein
congestion may cause umbilical vein dilatation, transudation of fluid into the Wharton’s jelly and enlargement of the
umbilical cord size. Noteworthy, it has been demonstrated
that Wharton’s jelly is a metabolically active tissue involved
in the exchanges between amniotic fluid and the blood in
umbilical vessels30. Hence, it is possible that venous congestion, frequently seen in trisomic fetuses, might cause an
alteration in the transfer of fluid normally present in the
first trimester of gestation31 between Wharton’s jelly and
the umbilical vessels. The sonographic counterpart of the
abnormal accumulation of fluid in the Wharton’s jelly is an
increased umbilical cord size.
In conclusion, the results of the present study suggest that
umbilical cord size early in gestation is different between normal and chromosomally abnormal fetuses. We hypothesize
that the underlying pathophysiologic mechanisms leading to
an increase in umbilical cord diameter might be those that also
explain the increased nuchal translucency in fetuses with
abnormal karyotype, such as alterations of the extracellular
matrix components or fetal venous congestion. Larger
studies should aim to explore the possible clinical application of routine sonographic evaluation of the umbilical cord
in early gestation.
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