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Speciality Spotlight
Chromosomal
Abnormalities
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Abdalla Mohamed G.K, Beattie R Bryan
Ultrasound Markers of Chromosomal abnormalities.
Progress in Obstetrics and Gynaecology.p.24-45 Edited by Studd J
Most fetuses with chromosomal abnormalities have either external or internal defects which can be recognised by detailed ultrasonographic examination. Studies from tertiary referral centres have found that nearly all fetuses with trisomy 13, 77-100% of fetuses with trisomy 18 and 33-50% of fetuses with Down’s syndrome have significant sonographic signs which may be detected by a second trimester scan. Trisomy 21, or Down’s syndrome, is by far the most common chromosomal abnormality and an important cause of perinatal death and infant handicap. It occurs in 1/660 births and its incidence is related to increasing maternal age.
Screening for Chromosomal Abnormalities.
Until a decade ago, pre-natal karyotyping was usually restricted to women of 35 years or older, but screening based on this criterion identified only 20% of all trisomy 21 fetuses. Screening protocols combining maternal age, a-fetoprotein and free b-chorionic gonadotrophin (b-hCG) have improved detection rates up to 69% with a 5.2% false positive rate in the second trimester.
Before the introduction of serum screening, 140 amniocenteses would have been required to identify one case of Down’s syndrome based on a maternal age of more than 35 years. This figure has been reduced to one in 60 amniocenteses after the introduction of serum screening. The use of serum screening has enabled prenatal karyotyping to be focused on pregnancies at highest risk for chromosomal abnormalities.
An alternative, and possibly complementary, method of screening for fetal chromosomal abnormalities is ultrasonography, which is non-invasive and has no inherent procedure related loss.
Ultrasound Markers
There are 2 types of markers. The first category comprises major fetal structural abnormalities that are associated with Down’s syndrome, namely congenital heart defects, ventriculomegaly and doudendal atresia. The other category comprises many minor sonographic appearances, soft markers which may be present in normal fetuses, but have been found in association with abnormal karyotypes.
Soft Markers
Nuchal Fold Thickness
A literature review showed an overall risk for aneuploidy with abnormal nuchal findings of 32% in 1649 cases in 21 series. A risk which is clearly high enough to warrant karyotypic evaluation, even when such abnormality present in isolation, and regardless of gestational age at diagnosis.
Traditionally, turner’s syndrome (45,X) was the anomaly associated with nuchal folds or membranes. Although its incidence is high (8%), Down’s syndrome (trisomy 21) is the most common aneuploidy reported (13%). However, Turner’s syndrome is the most common aneuploidy rated in the group with septated membranes, with the highest rate found in the later mid-trimester (35%).
An important part of evaluation of nuchal membrane is the evaluation of the subtle signs of hydrops fetalis. Even in the presence of a normal karyotype, perinatal outcome is extremely poor in the presence of fetal hydrops.
In cases without underlying aneuploidy, nuchal membranes may be indicative of, or result from, cardiac anomalies. The fluid collection may represent very early signs of cardiac failure, and fetal echocardiogram is recommended in such cases, as detection of cardiac defects by the standard four chamber view is poor even in experienced hands (detection rate about 50%). The ultrasound identification of these defects could however, be improved by the use of colour flow mapping and Doppler.
Choroid Plexus Cysts:
It was found that 71% of fetuses with trisomy 18 have choroid plexus cysts. Trisomy 18 is however, usually associated with additional sonographic abnormalities, and the detection of choroid plexus cysts should alert the sonographer to search for additional anomalies, including subtle ones such as overlapping fingers, micrognathia, club foot, and sandal gap.
These risks increase substantially in the presence of other sonographic abnormalities and with advanced maternal age. Hence karyotyping should be offered irrespective of maternal age in the presence of choroid plexus and also other sonographic abnormalities.
Also, the level of ultrasound expertise within individual units should be taken into consideration as a factor when deciding whether to offer amniocentesis or not in fetuses with isolated choroid plexus cysts.
Hyperechogenic Fetal Bowel
This finding has been described as normal variant, but may also be associated with cystic fibrosis, meconium peritonitis, trisomy 21 or cytomegalovirus (CMV) infection.
Because of the relatively low prevalence of hyperechogenic bowel, studies to date have involved small populations, although it was found that hyperechogenic bowel is a physiological and normal variant in many instances (approx. 67% of cases). Its association with increased risk of cystic fibrosis, meconial ileus, trisomy 21, CMV infection and adverse fetal outcome like intra-uterine growth retardation (IUGR) and intra-uterine fetal death (IUD) warrants further investigations.
Screening for infectious diseases should be implemented routinely when hyperechogenic bowel is identified. The higher fetal loss rate from cordocentesis for fetal CMV IgG and IgM analysis is not justified. Karyotyping for aneuploidy, particularly trisomy 21 is part of the diagnostic work-up.
Cardiac Echogenic Foci
They are defined as hyperechogenicity located in chordae tendinae not attached to the ventricular walls and moving simultaneously with the aterioventricular valves.
The clinical significance of golf balls is unclear and, although most of these echogenic foci resolve spontaneously and the neonates are born normal, several reports recently indicated an association with chromosomal trisomies, particularly that of trisomy 21. The calculated risk of trisomy 21 was found to be 1 in 500 (0.002%).
Therefore, it was concluded that the finding of isolated fetal heart echogenic foci in the general, low risk population under 35 years of age is not associated with increased risk of Down’s syndrome.
Pelvi-Calyceal Dilatation (PCD)
The major benefit of prenatal diagnosis of fetal PCD is to identify fetuses who are at increased risk of developing renal disease in the future, and to detect clinically silent lesions that may manifest themselves later in life.
Although some investigators believe that an antero-posterior diameter of the renal pelvis less than 10mm is physiological and does not require any post-natal investigations, others have recommended post-natal follow-up if the diameter is ³ 4mm before 33 weeks or ³ 7mm after 33 weeks.
Ultrasonic evaluation is however, warranted in the first day of life in a male baby, with bilateral PCD and big bladder because of the possibility of posterior urethral valve (PUV).
One study showed that bilateral PCD is more likely to regress in utero with advancing gestation. Moreover, fetuses that do have persistent bilateral PCD have a significantly lower risk of urinary tract pathology at birth compared to those with unilateral involvement.
Long Bone Biometry
Limb length is usually compared with biparietal diameter (BPD) rather than menstrual age due to the uncertainty of the menstrual history.
In one study, either short humerus or short femur was found in 31.1% of fetuses with Down’s syndrome, compared with 7.5% of normal fetuses (relative risk = 4.1). Furthermore, fetuses with both short humeri and short femurs carry an 11-fold greater risk of Down’s syndrome (relative risk = 11.1). Currently, tables are available to adjust the risk of trisomy 21 according to presence or absence of long bone shortening.
This ultrasound risk adjustment may lead to better selection of candidates for amniocentesis.
DEBATE
Second trimester ultrasonogram as a screening tool and Automatic inclusion of markers in 18-20 weeks anomaly scan.
Fetal karyotyping is usually offered whenever cardiac defects are identified sonographically, regardless of the presence of other markers, as the prevalence of chromosomal abnormalities in such cases is 5-10%.
Both detection rates – 38% for second trimester nuchal translucency and 45% for structural heart defects – are substantially less than the detection rate achievable with serum screening (69%). Therefore, the use of second trimester ultrasound as a primary screening method for trisomy 21 is not yet justified.
Marker scans after high Down’s risk on serum screening
One or more sonographic anomalies were detected in 50% of fetuses with trisomy 21, compared with only 7.2% of normal fetuses. Detection of one or more ultrasonographic markers in pregnancies that are serum screen positive could increase the risk of trisomy 21 by 5- to 8- fold (likelihood ratio of 41) and their absence could decrease this risk by 5-fold (likelihood ratio 0.2).
It is suggested that a combination of maternal age, serum biochemical screening, and subsequent second trimester ultrasound could provide a better mechanism for selection of pregnancies to undergo invasive testing.
The problem with soft markers is that, even when karyotypic abnormalities are excluded, the parents as well as the obstetrician may remain in doubt as to their significance. The psychological sequelae of false positive results of routine prenatal screening tests are considerable.
In the case of ultrasound screening, these psychological costs may be exacerbated by the visual imagery, which is an integral part of the procedure.
Information about ultrasonographic markers is relatively new. The second trimester anomaly scan is optional and patients should be given an informed choice whether to have it done or not.
Comparison between first trimester ultrasound screening and second trimester serum screening for chormosomal abnormalities.
Nuchal translucency (NT) measurement in the first trimester seems highly discriminatory and its performance has improved by adjusting its measurement for gestational age. Nicolaides et al reported a detection rate for trisomy 21, in routine screening, of 84% for a false positive rate of 5.8% using a risk cut-off point of 1:300. This risk has been calculated on the basis of maternal age and NT adjusted for gestational age based on crown-rump length.
Two serum markers stand out as being useful in screening at 10-14 weeks’ gestation-namely, free b-subunit human chorionic gonadotrophin (b-hCG), and pregnancy associated plasma protein-A (PAPP-A). In trisomy 21, free b-hCG is higher and PAPP-A is lower when compared with chromosomally normal fetuses. At a risk cut-off point of 1 in 300, the screening performance of free b-hCG and PAPP-A is 63% for a false positive rate of 5.5%. This screening performance is comparable with second trimester serum screening by the triple test (b-hCG, a-fetoprotein, and oestradiol).
The relationship between first trimester serum screening utilising b-hcg or PAPP-A and first trimester NT measurement in chromosomally normal and abnormal fetuses has been examined. It was found that they are independent variables (i.e. no significant association). Therefore, a combination of both is estimated to have a positive predictive value of 90% for Down’s syndrome and 5% false positive rate.
It is clear that NT measurement in the first trimester, whether used alone or in combination with serum b-hCG or PAPP-A, is highly discriminatory and has a higher positive predictive value for chromosomal abnormalities (84% and 90%, respectively), when compared with serum screening in the second trimester (69%), without concomitant increase in the false-positive rate of nearly 5% for both.
There are, however, several potential problems with NT measurement in the first trimester as a screening tool for chormosomal abnormalities. A proper sagittal view of the fetal spine.is necessary. For sonographers, it is easy to acquire within few hours the skill to accurately measure the NT without additional costs or significantly increasing the scanning time. The repeatability was unrelated to the size of the NT and when the mean of two measurements was used, 95% of the time inter-and intra-observer variability was 0.62mm and 0.54mm respectively. Also by combining the trans-abdominal (TA) and transvaginal (TV) approach, repeatability coefficients were 0.4mm and 0.2mm respectively.
Failure to measure NT is another potential problem. A number of studies have demonstrated an increase in miscarriage rates in fetuses with increased NT measurement in the first trimester irrespective of their chromosomal pattern. The estimated spontaneous loss rate is about 25% in fetuses with Down’s syndrome between 10-15 weeks’ gestation.
A further criticism of NT measurement in the first trimester is that early identification of women at increased risk of aneuploidy entails the invasive diagnostic procedure of CVS. CVS is less widely available, and associated with a higher miscarriage rate (2 in 100), when compared with amniocentesis (0.5-1%). In addition, it is more expensive and has a false positive rate of about 2%, as a result of placental mosaicism.
In summary using second trimester marker scan as an alternative to serum screening cannot be justified at present. Also the adjusted risk tables are based on data derived from a small number of affected pregnancies came from tertiary referral centres, which make these data mostly biased, in addition to the fact that the likelihood ratios may differ between separate units.
High level of specialist counseling before and after screening for chormosomal abnormalities using ultrasound markers is required as the anxiety and psychological costs may be tremendous and out-weigh the potential gain.
