Manual on Fetal Surveillance Ameet Patki, Shailesh Kore, Abhay Patanaik
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Ultrasound Markers of Chromosomal AnomaliesChapter 1

Shailesh Kore
Rashmi Patil
The chromosomal abnormalities occur in 0.1% to 0.2% of all live births1. Chromosomal anomalies are major cause of perinatal mortality and morbidity. They are often associated with abortions, stillbirths and congenital anomalies. The actual incidence of these anomalies is much higher as many of these fetuses are lost in first half of pregnancy.
Ultrasound evaluation is an important tool in present obstetrics. Mahieu-Caputo et al. said that “One of the major progresses in fetal medicine in recent years is the increased sensitivity of sonographic screening for fetal malformations, due to technical improvement but also due to a better training of professionals.”2
At present, USG screening for fetal abnormalities is rapidly becoming part of routine antenatal care.3
Invasive procedures like chorion villus sampling and amniocentesis are only definitive diagnostic tools to detect fetal chromosomal abnormalities. But, obviously because of inherent 0.5% to 1.0% fetal loss rate associated with such invasive procedures, we require screening tool to select woman who are at higher risk of having fetus with chromosomal anomalies.4, 5 Ultrasound and biochemical markers are commonly used modalities to screen such cases in clinical practice.
Sonographic markers are useful to minimize invasive procedure and the risk of abortion. Literature suggests that if no sonography markers are visible then risk is reduced by 80%. Another study by Nyberg suggests that if no markers are present then risk reduces by 50%. Thus if one remains optimistic and accepts the Nyberg's study, then invasive procedures can be minimized by 50%. That is why soft markers are useful.6
 
MAJOR DEFECTS
The most commonly encountered anomalies are Trisomy-21, trisomy-18, trisomy-13, and Turners syndrome. Down syndrome is most common karyotype abnormality in live born infant (1 in 800 live births).7 The chromosomal defects are often associated with congenital defects, which can be picked up on antenatal sonography1. Often, these anomalies present in a particular pattern of abnormalities that are well established in pattern of particular chromosomal 2syndrome. In such cases, in fact, we are not only looking for various anomalies, but also series of specific abnormalities, a constellation of findings which fit together like pieces in a ‘jigsaw’ puzzle to form final picture. The final diagnosis of such syndrome can be often useful in counseling and further management on ongoing pregnancy but also future ones.8,9
For example, trisomy 21 is associated with a tendency for brachycephaly, mild ventriculomegaly, flattening of the face, nuchal edema, atrioventricular septal defects, duodenal atresia and echogenic bowel, mid-phalanx hypoplasia of the fifth finger. Trisomy 18 is associated with strawberry-shaped head, choroid plexus cysts, absent corpus callosum, enlarged cisterna magna, facial cleft, micrognathia, nuchal edema, heart defects, diaphragmatic hernia, esophageal atresia, exomphalos, renal defects, myelomeningocele, growth restriction and shortening of the limbs, radial aplasia, overlapping fingers and talipes or rocker bottom feet.
It must be remembered that, some defects, even if isolated carry more risk than some other defects. The anomalies with relative low risk of chromosomal anomalies include gastroschisis, hemivertebra, CAM and ovarian cyst. Also risk of chromosomal defect may be inversely proportional to severity of defect. Thus, small omphalocele and mild pylectesis have higher risk of having chromosomal defect than large omphalocele with liver and larger hydronephrosis.9,10
The overall risk for chromosomal abnormalities increases with the total number of defects that are identified (Table 1).11
Table 1   Incidence of chromosomal defects in relation to number of sonographically detected abnormalities
No. of Abnormalities
N
Incidence of Chromosomal defects
1
1128
2%
2
490
11%
3
220
32%
4
115
52%
5
53
66%
6
40
63%
7
16
69%
⩾8
24
92%
(Nicolaides et al., Lancet 1992; 340: 704–7)
It is therefore recommended that, whenever defect/marker is detected at routine ultrasound examination, a thorough check is made for the other features of the chromosomal abnormality known to be associated with that marker; should additional defects be identified, the risk is dramatically increased. In the case of apparently isolated defects, the decision of whether to carry out an invasive test depends on the type of defect.
If the mid-trimester scan demonstrates major defects, some authors advise fetal karyo-typing, even if these defects are apparently isolated. The prevalence 3of these defects is low and therefore the cost implications are small. If the defects are either lethal or they are associated with severe handicap, fetal karyotyping constitutes one of the series of investigations to determine the possible cause and thus the risk of recurrence. Examples of these defects include hydrocephalus, holoprosencephaly, multicystic renal dyplasia and severe hydrops. In the case of isolated neural tube defects, there is controversy as to whether the risk for chromosomal defects is increased. Similarly, for skeletal dysplasias where the likely diagnosis is obvious by ultrasonography, it would probably be unnecessary to perform karyotyping. If the defect is potentially correctable by intrauterine or postnatal surgery, it may be logical to exclude an underlying chromosomal abnormality. Examples include facial cleft, diaphragmatic hernia, esophageal atresia, exomphalos and many of the cardiac defects. In the case of isolated gastroschisis or small bowel obstruction, there is no evidence of increased risk of trisomies.11
 
MINOR DEFECTS OR MARKERS
Soft markers are not actual malformations but they are sonography findings which are more frequently associated with the chromosomal abnormality. Though, these markers are the indicators for high probability of abnormal chromosomes, they on their own are not the indications for terminations.
Soft markers can be either minimally increased measurement of fetal organs (i.e. Increased nuchal translucency, Borderline ventriculomegaly or mild Pelviectasis) or can be normal variant without much pathological significance (e.g. Choroid plexus cyst, Echogenic foci in heart, Echogenic bowel)
These defects are common and they are not usually associated with any handicap, unless there is an associated chromosomal abnormality. Routine karyotyping of all pregnancies with these markers would have major implications, both in terms of miscarriage and in economic costs. It is best to base counseling on an individual estimated risk for a chromosomal abnormality, rather than the arbitrary advice that invasive testing is recommended because the risk is ‘high’. The estimated risk can be derived by multiplying the background risk (based on maternal age, gestational age, history of previously affected pregnancies and, where appropriate, the results of previous screening by nuchal translucency and / or biochemistry in the current pregnancy) by the likelihood ratio of the specific defect. For the following conditions, there are sufficient data in the literature to estimate the likelihood ratios for trisomy.12, 13, 14 The likelihood ratio (LR) is defined as sensitivity/False positive rate. An LR of >1 suggests a positive association with a particular finding.
 
FIRST TRIMESTER MARKERS
 
1. Nuchal Translucency
Increased nuchal translucency at 11-13 wks is associated with increased risk of chromosomal and congenital anomalies (Figure 1). As NT increases, likelyhood ratio increases exponentially.
The topic of NT is discussed in detail in chapter-3.4
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Figure 1: Nuchal translucency
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Figure 2: FrontoMaxillary facial angle
 
2. Fetal Nasal Bone
Nasal bone is absent or hypoplastic in 69% of fetuses with trisomy 21 in the 11-13.6 weeks scan period and thus useful in screening for trisomy- 21 during this period.15 The nasal bone is absent in 50% of trisomy 18 and 30 % of trisomy 13 fetuses.
 
3. Fetal Facial Angle
The facial angle also known as the fronto maxillary facial angle (FMF), is the quantification of the flat facial profile seen in fetuses with trisomy.16 The angle is measured between a line along the superior surface of the palate and a line drawn from the antero-superior corner of the maxilla to the anterior surface of the frontal bones (Figure 2).
 
4. Ductus venosus
Abnormal ductus venosus flow is associated with chromosomal anomalies, cardiac abnormalities and adverse fetal outcome 17. Eighty percent of trisomy 21 fetuses and about 5% of normal fetuses show decreased or reversed flow. Having a weak correlation with abnormal NT measurements, it serves as an independent marker for improving screening.5
 
5. Tricuspid regurgitation
Evaluation of tricuspid flow has been shown in recent studies to enhance performance of first trimester screening.18
 
SECOND TRIMESTER MARKERS
 
1. Nuchal Edema or Fold of More Than 6 mm
This is the second-trimester form of nuchal translucency. It is found in about 0.5% of fetuses and it may be of no pathological significance. However, it is sometimes associated with chromosomal defects, cardiac anomalies, infection or genetic syndromes. For isolated nuchal edema, the risk for trisomy 21 may be 15 times the background. 6, 19
 
2. Mild Ventriculomegaly
Measurement of fetal ventricles is done at atrium of lateral ventricle at glomus of choroid plexus. It measures between 3-10 mm between 15-35 weeks of pregnancy and when ventricle is 11-15 mm, it is ventriculomegaly. Association of ventriculomegaly and poor outcome of fetus is well documented. Although it may resolve on its own, chances of normal development is low20.
In a study by Pilu et al, isolated borderline cerebral lateral ventriculomegaly in most cases has no consequence. However, this finding carries an increased risk of cerebral maldevelopment, delayed neurological development and, possibly, chromosomal aberrations.21,22
 
3. Short Femur
If the femur is below the 5th centile and all other measurements are normal, the baby is likely to be normal rather short but rarely it can be sign of dwarfism. Occasionally, it may be a marker of chromosomal defects. On the basis of existing studies, short femur is found four times as commonly in trisomy 21 fetuses compared to normal fetuses.11 However, there is some evidence that isolated short femur may not be more common in trisomic than in normal fetuses.6
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Figure 3: Nuchal oedema
6
 
4. Hyperechogenic Bowel
When small bowel is as echoic as the bone, they are termed echogenic bowel. This is found about 0.5% of fetuses and is usually of no pathological significance. The commonest cause is intra-amniotic bleeding, but occasionally it may be a marker of cystic fibrosis, chromosomal defects, cytomegalovirus infection or early onset growth retardation. For isolated hyperechogenic bowel the risk for trisomy may be three times the background.6, 23
 
5. Echogenic Foci in the Heart
These are found in about 4% of pregnancies and they are usually of not pathological significance. They are nothing but microcalcification in papillary muscle. However, they are sometimes associated with cardiac defects and chromosomal abnormalities. For isolated hyperechogenic foci, the risk for trisomy 21 is increased.6, 24 When associated with other malformation or soft marker, it becomes indication for chromosomal analysis.
 
6. Choroid Plexus Cysts
These are found in about 1-2% of pregnancies and they are usually of no pathological significance. When other defects are present, there is a high risk of chromosomal defects, usually trisomy 18 but occasionally trisomy 21. For isolated choroid plexus cyst, the risk for trisomy 18 and trisomy 21 is about 1.5 times the background.14
When choroid plexus cyst is detected, further evaluation depends on maternal age, biochemical marker result and associated malformations. Isolated choroid plexus cyst does not require chromosomal analysis.
 
7. Mild Hydronephrosis
Dilated and distended renal tract is definitely an abnormality if it is moderate to severe. This is found in about 1-2% of pregnancies and is usually of no pathological significance. When other abnormalities are present, there is a high risk of chromosomal defects, usually trisomy 21.
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Figure 4: Short femur
7
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Figure 5: Hyperechogenic bowel
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Figure 6: Hyperecogenic foci in heart
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Figure 7: Choroid plexus cyst
For isolated mild hydronephrosis, the risk for trisomy 21 is about 1.5 times the background 14, 25. (Figure-8)
There are no data on the interrelation between these second-trimester ultrasound markers and nuchal translucency at 11-14 weeks or first-and second – trimester biochemistry. However, there is no obvious physiological reason for such an interrelation and it is therefore reasonable to assume that they are independent. Consequently, in estimating the risk in a pregnancy with a marker, it is logical to take into account the result of previous screening tests.8
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Figure 8: Mild pylectesis
For example, in a 20-year-old woman at 20 week of gestation (background risk of 1 in 1295), who had a 11-14 week nuchal translucency measurement that resulted in a 5-fold reduction in risk (to about 1 in 6475), after the diagnosis of mild hydronephrosis at the 21-week scan, the estimated risk will increase by a factor of 1.5 to 1 in 4317. In contrast, for the same ultrasound finding of fetal mild hydronephrosis in a 40-year-old woman (background risk of 1 in 82), who did not have nuchal translucency or biochemistry screening; the new estimated risk is 1 in 55.
There are some exceptions to this process of sequential screening, which assumes independence between the findings of different screening results. The findings of nuchal edema or a cardiac defect at the mid-trimester scan cannot be considered independently of nuchal translucency screening at 11 – 14 weeks. Similarly, hyperechogenic bowel (which may be due to intra – amniotic bleeding) and relative shortening of the femur (which may be due to placental insufficiency) may well be related to serum bio-chemistry (high free b-hCG and inhibin–A and low estriol may be markers of placental damage) and can therefore not considered independently in estimating the risk for trisomy 21. For example, in a 20-year-old woman (background risk for trisomy 21 of 1 in 1295), with high free b-hCG and inhibin – A and low estriol at the 16-week serum testing resulting in a 10-fold increase in risk (to 1 in 129), the finding of hyperechogenic bowel at the 20-week scan should not lead to the erroneous conclusion of a further three – fold increase in risk (to 1 in 43). The coincidence of biochemical and sonographic features of placental insufficiency makes it very unlikely that the problem is trisomy 21 and should lead to increased monitoring for pre-eclampsia and growth restriction, rather than amniocentesis for fetal karyotyping.11, 12, 13, 14
All invasive procedures like Chorionic villus sampling, Amniocentesis, Cord blood samplings are associated with the inherent risk of abortion. So on just doubt of abnormal chromosome, invasive procedures cannot be performed. If the risk of invasive procedure is less than risk of having fetus with chromosomal abnormality then option of invasive procedure can be justified.
Benaceraf et al developed method of calculation of risk based on ‘Scoring Index’.269
The major defect and marker like NT, nuchal edema etc carry score of two (2), while other markers like mild pylectesis, Echogenic cardiac focus etc would carry score of one (1). In any woman with score of two or more (≥2) would be a candidate for definitive diagnosis by fetal tissue sampling. By using this scoring index, Benaceraf found 81% sensitivity with 4.4% of false positive rate.
Philip Jaunty has simplified this by his scoring system. When more than 1% risk, then one shall advocate chromosomal analysis.
  • 1 major anomaly (>1% risk)-Karyotype: Omphalocele, endocardial cushion defects, holoprosencephaly, duodenal atresia
  • 1 small anomaly (<1% risk)-Do nothing, further monitoring is advised: Echogenic focus, choroid plexus cyst, ventriculomegaly
  • 2 small anomalies (>1% risk)-Karyotype: single umbilical artery + choroid plexus cyst, pyelectasis + echogenic focus
Though such scoring methods are useful in overall calculation of risk, it is necessary to individualize each case based on her age, past and family history, other risk factors, type of major anomaly and soft marker before taking decision of invasive procedure.
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