|
|
 |
|
|
|
|
| Home > Services and Specialties > Perinatal Center |
|
|
|
|
Ultrasound and
Screening for Chromosomal Abnormalities
INTRODUCTION
With continuing improvement in both the antenatal and postnatal evaluation
and treatment of many obstetrical and medical complications of pregnancy
congenital abnormalities now account for a significant proportion of perinatal
mortality and morbidity. It is estimated that the overall incidence of
major congenital abnormalities ranges from 1 - 3.6 % in the general population,
but account for 4 to 20% of stillbirths and 20 to 35% of neonatal deaths.
In almost 50% of stillbirths with structural anomalies there is an associated
chromosomal abnormality. Approximately 10 to 15% of newborns with structural
abnormalities will also have chromosomal anomalies. Early identification
of fetuses with chromosomal abnormalities will enable health care providers
to form the appropriate management plan for each patient. One of the most
common identifiable risk factors for genetic disorders is a family history
of an affected relative. However, a significant percentage of chromosomal
anomalies are not hereditary, and occur in families with no history of
congenital abnormalities. Screening for chromosomal abnormalities, therefore,
involves not only a careful patient and family history with appropriate
referrals for genetic counseling, but also the use of biochemical screening
tests, and appropriate ultrasonic studies. Screening for Chromosomal Abnormalities
As mentioned above, a family history of a chromosomal abnormality is an
indication for genetic studies. An additional, common risk-factor is maternal
age at time of delivery. Indeed, this is currently the most common indication
for genetic studies in the United States. The table below lists the risks
for chromosomal anomaly based on the mother's age at delivery derived
from live born and amniocentesis data.
=====================================================
COMPARISON OF LIVE-BORN AND ANTENATAL GENETIC STUDIES DATA: Incidence
of chromosomal abnormalities for Maternal age at delivery
=====================================================
|
|
FROM LIVE-BORN STUDIES |
FROM ANTENATAL STUDIES |
|
Maternal Age(years)
|
All Chromosome
Abnormalities (%) |
|
All Chromosomal
Abnormalities (%) |
|
|
Though advanced maternal age (and possible paternal
age) is a significant risk factor for chromosomal abnormalities, the majority
of infants with chromosomal abnormalities are delivered of mothers less
than thirty five years of age. Other methods of identification of patients
at risk for chromosomal anomalies, therefore, have been developed.
Maternal serum screening is currently a recommended procedure for
all obstetrical patients. Initially, maternal serum alpha-fetoprotein
(MSAFP) was used to screen for open neural tube defects (spina bifida).
Elevations of MSAFP are associated with a variety of fetal complications,
especially open neural tube defects. The use of comprehensive ultrasound
examination in patients with elevated MSAFP can be expected to identify
90% to 95% of the fetal or placental problems associated with elevated
MSAFP.
In 1984 Merkatz et al were one of the first to report the association
between low levels of MSAFP and chromosomal abnormalities. Since
then the use of MSAFP screening, frequently together with human chorionic
gonadotropin and unconjugated estriol, has been used to screen for chromosomal
anomalies. The use of these three parameter will detect approximately
60% of trisomy 21, with a false positive rate of 5% to 25 % depending
on the cutoff values used. Trisomy 18 may also be identified by very low
levels of all three components in maternal serum. The American Collage
of Obstetrics and Gynecology recommends that all pregnant patients should
be offered serum screening for trisomy 21 and 18, though not as a substitute
for traditional genetic testing in women 35 years of age or older.
Ultrasound and Chromosomal Abnormalities
Though a careful history and maternal serum screening may identify a significant
number of patients at risk for chromosomal abnormalities, a significant
portion of patients at risk will go unrecognized. A common reason for
genetic consultation, especially in low-risk patients, is the presence
of a structural or other abnormality on ultrasound examination. Our experience
with almost 4500 genetic amniocentesis indicates that the presence of
a suspicious finding on ultrasound examination gives the highest yield
of abnormal amniocentesis results.
The frequency of chromosomal anomalies associated
with abnormal ultrasound findings ranges from about 5% to 75%, depending
on the types of ultrasound anomalies seen. The number of abnormalities
seen at the time of ultrasound examination is directly related to an increasing
risk for chromosomal defects. If any abnormality is seen at the time of
an ultrasound examination, therefore, a careful, detailed examination
of the fetus for any other problem is indicated since the risk of chromosomal
abnormalities significantly increases if additional problems are seen.
Ultrasound Findings and Chromosomal Abnormalities
A number of abnormalities seen at the time of ultrasound examination of
the fetus are associated with a significant increased incidence of specific
chromosomal defects.
Cystic Hygroma / Nuchal Thickening
Cystic hygroma (a large swelling in the back of the neck), caused by a
malformation of the fetal lymphatic system, is found commonly in fetuses
with Monosomy X (Turner syndrome) and some other chromosomal anomalies.
Cystic hygroma can also be seen in fetuses with Noonan syndrome (incidence
1 in 1-2000 livebirths), an apparent autosomal dominant anomaly characterized
by fascial dysmorphism, webbed neck, renal and lymphatic abnormalities,
and congenital heart disease (septal defects and pulmonic stenosis).
In the second trimester an increased thickness of the posterior aspect
of the fetal neck, the fetal nuchal fold, is frequently found in
fetuses with trisomy 21. Values greater than 6 millimeters are usually
considered to be abnormal, though some authors have proposed lower values
to improve sensitivity The nuchal fold is most likely the result of nuchal
edema or a resolving cystic hygroma.
In the first trimester, the presence of nuchal edema has been shown to
be associated with trisomy 21 and other chromosomal abnormalities, and
has been recommended as a screening tool to identify fetuses at risk.
Values equal to or greater than 3mm are considered to be abnormal
by most authors, though lower cutoff values have been proposed. A number
of investigators have used the measurement of nuchal thickness in the
first trimester together with maternal serum screening or maternal age
to improve the accuracy of risk assessment for chromosomal abnormalities.
Choroid Plexus Cysts
The choroid plexus is a mass of epithelial, mesenchymal, and vascular
cells that occupy a large portion of the body of the lateral ventricles
in early and mid gestation. Chorioid plexus cysts are round or
ovoid structures seen within the choroid plexus usually prior to 24 weeks
of gestation. There have been scattered reports of chromosomal anomalies,
primarily Trisomy 18, associated with chorioid plexus cysts, but the vast
majority of these cysts are benign and will disappear by 24 to 25 weeks.
The incidence of choroid plexus cysts ranges from 0.2% to 3.6% in the
literature. The presence of a chord plexus cyst(s) should be an indication
for a careful and detailed ultrasonic examination of the fetus. Choroid
plexus cysts have been reported to be associated with trisomy 18 in 1%
to 6% of cases, usually associated with other structural anomalies. Whether
or not to offer genetic studies to patients with isolated choroid plexus
cysts remains highly controversial.
Fetal Hand
Abnormalities of the fetal hand (which may include polydactyly [extra
fingers], over-riding fingers, or abnormal hand positioning), especially
if associated with polyhydramnios, have been reported to be associated
with fetal chromosomal abnormalities.
Club Foot
The intrauterine diagnosis of club foot has been reported by a number
of investigators. The diagnosis can be made by imaging the distal lower
extremity (tibia and fibula) in a longitudinal plane. The foot and ankle
should be seen within this plane at right angles to the tibia and fibula.
Repeated failure to obtain this relationship suggests club foot, though
false positive diagnosis can occur. Club foot has been reported to be
associated with a variety of chromosomal abnormalities, especially trisomy
13 and 18, in 10% to 20% of cases. Other structural abnormalities are
usually present in fetuses with club foot when it is associated with chromosomal
abnormalities. Whether or not infants with isolated club foot are at significant
increased risk of chromosomal anomalies is still unresolved.
Intracardiac Echogenic Focus
Increased echogenicity (a bright echo) of the fetal cardiac papillary
muscles or chordae tendineae (usually left-sided) is seen in 3 to 5% of
fetuses scanned and is considered by most investigators to be a benign
ultrasound finding. Reports of Bromley et al and others, however, have
suggested that there is an association between this finding and trisomy
21. This group found that 6% of fetuses with an echogenic intracardiac
focus had trisomy 21. They estimated that in a low risk population with
an age adjusted risk of Down syndrome of 1/250, the presence of an intracardiac
echogenic focus would have a 1.5% predictive value for trisomy 21. However,
other investigators (including data from SJMMC) have not been able to
find a statistically significant association between isolated echogenic
foci in the fetal heart and chromosomal abnormalities. Further research
in this area still needs to be done to clarify the significance of Intracardiac
echogenic foci.
Single Umbilical Artery
Normally there are three vessels in the umbilical cord: two arteries and
one vein. A single umbilical artery is found in 0.5 to 2% of newborns
and is associated with structural or other anomalies in 20% to 50% of
cases: usually relatively minor anomalies of the renal or genital tracts.
Whether or not the presence of an isolated single umbilical artery
is an indication for genetic studies is still uncertain. Catanzarite et
al recommended genetic studies in patients with an isolated single umbilical
artery if growth restriction was present. Other investigators feel that
an isolated single umbilical artery is not an indication for genetic studies.
Cerebellar Hypoplasia (small cerebellum)
The cerebellum is the posterior part of the brain involved in motor coordination.
Mild cerebellar hypoplasia is frequently found in children and adults
with trisomy 21. Measurement of the fetal cerebellar hemispheres has been
reported to be one method of screening for trisomy 21, but many investigators
feel that there is too wide a biological range and too low a predictive
value from cerebellar measurements to recommend this technique as a screening
tool for trisomy 21.
Scoring Systems
Many investigators have suggested that the presence of more than one abnormal
ultrasonic finding markedly increases the risks of chromosomal abnormalities
(see table) and have recommended the use of an ultrasonic scoring system
to screen for chromosomal abnormalities, primarily trisomy 21. Benacerraf
et al then developed a scoring system, based on the presence or absence
of seven ultrasonic parameters, and found that this method was more effective
in identifying affected fetuses than advanced maternal age alone. Studies
at our own institution have confirmed the value of this scoring system.
=======================================================
An Ultrasonic Scoring System for Screening for Chromosomal Abnormalities
=======================================================
|
|
Parameter |
Score |
|
Nuchal fold
Major defect
Short femur
Short humerus
Renal pyelectasis
Echogenic bowl
Choroid plexus cyst
|
2
2
1
1
1
1
1 |
Score of 2 or greater is considered positive
=======================================================
O'Brien et al suggested that combining maternal serum screening with the BPD/FL
ratio may improve screening accuracy, while Vintzileos et al recommended that
genetic studies be offered when any of the following ultrasonic abnormalities
were seen: structural malformations(any), short femur or humerus, increased
nuchal fold, echogenic bowel, choroid plexus cyst, hypoplastic middle phalanx of
the fifth digit, wide space between the first and second toes, two vessel
umbilical cord, or short ear length.
Vintzileos et al also calculated the age adjusted risk of trisomy 21 when there
was a normal ultrasound examination and felt that in the presence of a normal
ultrasonography, when no anomalies and none of the markers were present, genetic
amniocentesis was not warranted except in women over the age of 45. This data
has been confirmed at a number of institutions. A good quality, normal
ultrasound examination will decrease the risks of chromosomal abnormalities 2 to
3 fold; but in many high-risk situations this may still leave the patient with
at risk.
Other Ultrasound Findings
A number of additional ultrasonic findings are frequently associated with
chromosomal abnormalities.
1) Omphalocele (exomphalos: failure of the umbilical ring to close with
abdominal contents extruded into the amniotic cavity) has a 10% to 40%
association with chromosomal abnormalities. Snijders et al reviewed their
experience and the literature and found a 36% incidence of chromosomal
abnormalities associated with omphalocele: 66% were trisomy 18, 16% were trisomy
13, and the remainder were triploid or other anomalies. Conversely, 23% of
fetuses with trisomy 18 had an omphalocele present. The figures for trisomy 13
and triploid were 9% and 13%, respectively. The frequency, however, varied
directly with maternal age and inversely with gestational age at examination.
The presence of a fetal omphalocele, therefore, is an indication for genetic
amniocentesis.
2) Polyhydramnios (excess amniotic fluid) is associated with structural
or chromosomal abnormalities in approximately 10% to 20% of the cases. The
severity of the polyhydramnios appears to be directly related to an increased
incidence of abnormal findings. A wide variety of structural anomalies have been
found with polyhydramnios, and, therefore, a large number of chromosomal
anomalies may be seen. Barnhard et al found a 4.1% incidence of chromosomal
anomalies in fetuses with polyhydramnios, and most investigators recommend
genetic studies be offered when any structural anomaly is seen in association
with polyhydramnios. Even subtle abnormalities, such as decreased fetal movement
or abnormal positioning of fetal hands or feet, when associated with
polyhydramnios may significantly increase the risk for chromosomal
abnormalities. Isolated polyhydramnios is more problematical. Two studies showed
a 1.4% incidence of chromosomal anomalies associated with isolated
polyhydramnios, and many authors recommend offering genetic studies to patients
with isolated polyhydramnios.
Intrauterine Growth Restriction: A significant percentage of fetuses with
chromosomal abnormalities are growth restricted. In a series of 1196 high-risk
patients evaluated at the author's institution, there were 18 fetuses with
chromosomal abnormalities (1.5%). Sixty-one percent of the infants with
chromosomal anomalies were small, and 5.4% of all small infants had chromosomal
anomalies. Since 25% to 35% of fetuses with chromosomal abnormalities
(especially trisomy 21) will have no obvious structural anomalies on ultrasound
examination, some investigators have suggested that the presence of IUGR alone
is an indication for genetic studies.
4) Many additional structural anomalies such as isolated pericardial effusion,
separation of the great toe, shortened ear length, or fetal cholocystomegaly
(enlarged gallbladder) have been found to be associated with chromosomal
anomalies. When these findings are seen in isolation, it is still controversial
whether or not amniocentesis should be offered.
SPECIFIC CHROMOSOMAL ANOMALIES AND THEIR ASSOCIATED
ULTRASOUND FINDINGS
Trisomy 21 (Down's syndrome - extra #21 chromosome)
Trisomy 21 is one of the more "common" chromosomal abnormalities, with an
incidence of 1 in 700 births. It was the first anomaly shown to have a strong
correlation with maternal age. Unless there are significant associated
structural abnormalities most infants will have only a slightly shortened life
span. Intellectual function varies widely and can be significantly influenced by
how the child is educated.
A number of ultrasonic findings have been found in fetuses with trisomy 21.
Abnormal fetal measurements (especially of the long bones) is one of the more
common techniques recommended as a screening tool for Down syndrome. Other
ultrasonic findings include:
1) Increased nuchal fold thickness;
2) Renal pyelectasis: mild dilatation of the fetal renal pelvis has been
found in 25% of fetuses with trisomy 21; and 3 to 4% of fetuses with mild
pyelectasis will have Down syndrome. Some controversy exists as to what is the
upper limit of normal for the measurements of the renal pelvis.
3) Hyperechoic bowl: Bromley et al and Nyberg et al both observed that
approximately 15% of fetuses with hyperechoic bowl (as echogenic, or bright, as
the surrounding bone) will have trisomy 21. Other investigators have not found
as strong an association.
4) Hands and feet: Abnormalities in the appearance of the fetal hands or
feet are also associated with trisomy 21. Abnormal palmar creases (simian
crease) are frequently seen in neonates with trisomy 21. Jeanty reported the
presence of a transverse palmar line detected by ultrasound in seven fetuses
over a two year period (incidence: approximately 1 per 1000). Three of these
seven fetuses had trisomy 21. This finding has not been confirmed by other
investigators. Benacerraf et al search for a more objective finding that is
frequently seen in the hands of neonates with trisomy 21: shortening of the
middle phalanx of the fifth digit (resulting in clinodactyly [curving and
overlapping] in the 5th finger). The use of this measurement may aid in the
identification of fetuses at risk for trisomy 21, but probably should not be
used as a screening tool in the general population. Increased separation of the
first and second toe has also been reported as a possible ultrasonic finding in
fetuses with trisomy 21.
5) Duodenal atresia: is significantly more common in fetuses with trisomy
21. Twenty to 30% of fetuses with duodenal atresia with also have Down syndrome.
6) Cardiac anomalies: Various cardiac defects (especially endocardial
cushion defects) have been reported in as high as 50% to 85% of fetuses with
trisomy 21. A discussion of echogenic intracardiac focus is presented earlier.
7) Other structural anomalies: Approximately 30% of fetuses with trisomy
21 will have associated major structural defects. A wide variety have been
reported, including cystic hygroma, omphalocele, hydrothorax, ventriculomegaly
imperforate anus, and short umbilical cord length.
Trisomy 13 (Patau syndrome - extra #13 chromosome)
Trisomy 13 is a severe, usually lethal abnormalities with an estimated
incidence of 1 in 4000-10000 pregnancies. Most neonates die within the first six
months of life. All of the survivors have severe mental retardation. Common
ultrasound findings (seen in more than 25% of cases) include: IUGR;
holoprosencephaly; microcephaly; cleft lip/palate; echogenic and/or enlarged
kidneys; cardiac defects; polydactyly; clinodactyly; echogenic chordae tendineae;
single umbilical artery. One or more of these anomalies are seen in over 90% of
fetuses with trisomy 13. Cardiac defects, IUGR, cleft lip/palate, and
holoprosencephaly are seen alone, or in combination, in over 50% of the fetuses.
The most common cardiac defects associated with trisomy 13 are atrial or
ventricular septal defects, and dextroposition of the heart. Many other
structural abnormalities have also been described.
Trisomy 18 (Edwards syndrome - extra #18 chromosome)
Trisomy 18 has a frequency similar to that of trisomy 13: 1 in 8000 births.
Its prognosis is similar to trisomy 13, though infants may live slightly longer.
Common ultrasound findings (seen in more than 25% of cases) include: Choroid
plexus cysts; cystic hygroma or nuchal thickening; omphalocele; large cisterna
magna; cardiac anomalies; IUGR. Cardiac anomalies and/or IUGR are seen in over
50% of the cases. The significant IUGR seen with trisomy 18 appears to occur
very early in gestation. Droste et al found symmetrical growth restriction,
including smaller than expected crown-rump lengths early in gestation, in 17
cases of trisomy 18.
Increase width of the cisterna magna (space in the back of the skull) has been
reported by a number of investigators to be associated with trisomy 18. An
abnormal measurement of the cisterna magna may be helpful in identifying fetuses
with trisomy 18, especially if other sonographic markers are present. Mild
cerebellar hypoplasia may also be associated with trisomy 18. Many investigators
have reported a high correlation between the presence of choroid plexus cysts
and trisomy 18.
Sex Chromosome Abnormalities
Abnormalities of the fetal sex chromosomes appear to be a very common
chromosomal abnormality in conceptuses, with an estimated incidence of 1.4%.
However, at birth, the overall incidence is 1 in 400, indicating than the
majority of fetuses with sex chromosome abnormalities abort spontaneously. A
number of different sex chromosome abnormalities exist, but, with the exception
of monosomy X, none of them have specific ultrasonic findings that might suggest
that they are present in the fetus.
Monosomy X, or Turner syndrome (absence of an X chromosome), occurs in
approximately 1 in 2500 newborns. Over 95% of 45,X fetuses abort or are
stillborn. Cystic hygroma is a common finding in fetuses with monosomy X. Other
common ultrasonic findings include cardiac anomalies, renal anomalies, and
edema.
The outcome for neonates with monosomy X is relatively good. Most children have
normal IQs and, with the exception of infertility, can have normal life
expectancy if managed appropriately.
Triploidy
Triploid pregnancy (an extra haploid set of chromosomes) is estimated to
occur in 1% of conceptions, though the majority of these pregnancies
spontaneously abort prior to the second trimester. Jauniaux et al reviewed 70
cases of triploid pregnancy seen between 13 and 29 weeks' gestation. Hand
abnormalities associated with ventriculomegaly or cardiac anomalies were the
most common findings present. In addition, hydroptic or molar changes in the
placenta were seen in over 25% of the cases. Oligohydramnios was common (44%).
Most fetuses had asymmetrical growth and all of the fetuses had at least one
ultrasonic parameter below the normal range for gestational age.
Other Anomalies
A variety of rare chromosomal anomalies and their associated structural
abnormalities that may be seen on ultrasonic examination. With the development
of newer genetic diagnostic techniques, a number of genetic syndromes have
recently been identified as having, at least in a small percentage of cases, a
structural chromosomal abnormality. Some examples would be the Beckwith-Weidemann
syndrome (trisomy 11pter); Prader-Willi syndrome, frequently associated with
polyhydramnios and fetal hypotonia (deletion of 15q12); Miller-Dieker syndrome
(deletion of 17p13.3); and the DiGeorge syndrome (deletion of 22q11).
Routine Ultrasound Screening for Fetuses at Risk for
Chromosomal Abnormalities
Experience with the use of routine ultrasound screening for congenital
abnormalities associated with chromosomal anomalies, primarily in Europe, have
yielded good results. However, reports from the multi-center RADIUS (routine
antenatal imaging with ultrasound study) study in the United States lead to
recommendations that routine ultrasound examination of all pregnant women not be
done.
A number of investigators have looked at the reports of the RADIUS study in
detail and found significant problems with the study. Lack of adequate
statistical power, lack of any management plan, and, most importantly, lack of
sufficient accuracy in the diagnostic capabilities of many of the centers preforming the ultrasound examination was felt to be the real reason that the
RADIUS study failed to support the routine use of ultrasound in pregnancy.
Indeed, Devore felt that the RADIUS study proved that all patients should be
referred into a tertiary ultrasound facility during the second trimester for a
detailed ultrasound examination which would provide optimal prenatal diagnostic
options; decrease medicolegal liability for the referring physician; allow the
primary care provider to offer ultrasound to the patient for first or third
trimester indications; reduce the cost per malformation detected to a rate less
than that of maternal serum alpha-fetoprotein screening; and provide a more
detailed evaluation of each pregnancy. Both Nyberg and DeVore reported cost
analysis studies of the use of routine ultrasound to screen for fetal
malformations and showed it to be more accurate and equal or less expensive than
routine maternal serum screening programs.
Though the controversy still continues, many physicians feel that it is
appropriate to offer all patients the opportunity to undergo detailed second
trimester ultrasound examination for fetal anomalies in order to offer genetic
studies to those patients with abnormal findings. The topic is a complicated
one, and involves not only medical facts, but also social, financial and ethical
considerations.
Additional information can be obtained at the March of Dimes website:
www.modimes.org |
|
|
|
