In the first trimester, a common feature of many chromosomal defects is increased NT. In later pregnancy each chromosomal defect has its own syndromal pattern of abnormalities.
Phenotypic expression of chromosomal defects
Trisomy 21 is associated with a tendency for brachycephaly, mild ventriculomegaly, nasal hypoplasia, nuchal edema (or increased nuchal fold thickness), cardiac defects (mainly atrioventricular septal defects), duodenal atresia and echogenic bowel, mild 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, diaphragmatic hernia, esophageal atresia, exomphalos, usually with bowel only in the sac, single umbilical artery, renal defects, echogenic bowel, myelomeningocele, growth restriction and shortening of the limbs, radial aplasia, overlapping fingers and talipes or rocker-bottom feet. In trisomy 13, common defects include holoprosencephaly and associated facial abnormalities, microcephaly, cardiac and renal abnormalities with often enlarged and echogenic kidneys, exomphalos and postaxial 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, myelomeningocele, syndactyly, and ‘hitch-hiker’ toe deformity. The lethal type of Turner syndrome presents with large nuchal cystic hygromata, generalized edema, mild pleural effusions and ascites, cardiac abnormalities and horseshoe kidney, which are suspected by the ultrasonographic appearance of bilateral mild hydronephrosis.
Individual patient-specific risks based on ultrasound findings
The overall risk for chromosomal abnormalities increases with the total number of defects that are identified50. It is therefore recommended that when a 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, because the presence of additional defects increases the risk substantially.
In contrast, absence of any major or minor defects is associated with a reduction in the background risk. In the combined data from two leading centers of obstetric ultrasound in the USA there were no identifiable major defects or any of the following markers—increased nuchal fold thickness, echogenic bowel, echogenic intracardiac focus, mild hydronephrosis, short humerus or short femur—in 25.7% of the 350 fetuses with trisomy 21 and in 86.5% of the 9384 chromosomally normal fetuses51, 52. Consequently, the likelihood ratio for trisomy 21 if there is no detectable defect or marker is 0.30 (95% CI 2.25–0.35).
A patient attending for amniocentesis at 16 weeks of gestation because she is 35 years old and considers her risk for trisomy 21 (1 in 246, see Table 2) to be sufficiently high to justify the 1 in 100 risk of miscarriage from an invasive test will inevitably have an ultrasound examination by the competent practitioner who is about to carry out the amniocentesis. If this scan demonstrates no major or minor defects the patient should be informed that her risk for trisomy 21 is actually reduced to 1 in 820 (which is equivalent to that of a 27-year-old) and she may well change her mind and avoid having an amniocentesis. The same is obviously true for a 31-year-old (background risk of 1 in 536) who after second-trimester biochemical testing is informed that she is now screen-positive and is offered an amniocentesis because her risk has increased to 1 in 200. However, the patient should also be informed that if an ultrasound examination shows no major defects or markers her risk can be reduced to 1 in 667 (which is equivalent to that of a 29-year-old) and she may well choose this option.
If the mid-trimester scan demonstrates major defects it is advisable to offer fetal karyotyping, even if these defects are apparently isolated. The prevalence of these defects is low and therefore the cost implications are small. If the defects 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 defect is potentially correctable by intrauterine or postnatal surgery, such as diaphragmatic hernia, it may be logical to exclude an underlying chromosomal abnormality—especially because, for many of these conditions, the associated chromosomal abnormality is trisomy 18 or 13.
Minor defects or markers 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 NT and/or biochemistry in the current pregnancy) by the likelihood ratio of the specific defect.
The combined data from Nyberg et al. and Bromley et al. are summarized in Table 551, 52. The incidence of each marker in trisomy 21 pregnancies can be divided by their incidence in chromosomally normal pregnancies to derive the appropriate likelihood ratio. For example, an intracardiac echogenic focus is found in 28.2% of trisomy 21 fetuses and in 4.4% of 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 5. Thus, in a 25-year-old woman undergoing an ultrasound scan at 20 weeks of gestation the background risk is about 1 in 1000. If the scan demonstrates an intracardiac echogenic focus, but the nuchal fold is not increased, the humerus and femur are not 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 1000. The same is true if the only abnormal finding is mild hydronephrosis, which has a combined likelihood ratio of 1.0 (6.77 × 0.67 × 0.68 × 0.62 × 0.75 × 0.87 × 0.79). In contrast, if the fetus is found to have both an intracardiac echogenic focus and mild hydronephrosis but no other defects 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 1000 to 1 in 119.
Table 5. Incidence of major and minor defects or markers in the second-trimester scan in trisomy 21 and chromosomally normal fetuses in the combined data of two major series.51, 52 From these data the positive and negative likelihood ratios (with 95% CIs) for each marker can be calculated
|Nuchal fold||107/319 (33.5)||59/9331 (0.6)||53.05 (39.37–71.26)||0.67 (0.61–0.72)||9.8|
|Short humerus||102/305 (33.4)||136/9254 (1.5)||22.76 (18.04–28.56)||0.68 (0.62–0.73)||4.1|
|Short femur||132/319 (41.4)||486/9331 (5.2)||7.94 (6.77–9.25)||0.62 (0.56–0.67)||1.6|
|Hydronephrosis||56/319 (17.6)||242/9331 (2.6)||6.77 (5.16–8.80)||0.85 (5.16–8.80)||1.0|
|Echogenic focus||75/266 (28.2)||401/9119 (4.4)||6.41 (5.15–7.90)||0.75 (0.69–0.80)||1.1|
|Echogenic bowel||39/293 (13.3)||58/9227 (0.6)||21.17 (14.34–31.06)||0.87 (0.83–0.91)||3.0|
|Major defect||75/350 (21.4)||61/9384 (0.65)||32.96 (23.90–43.28)||0.79 (0.74–0.83)||5.2|
A recently described second-trimester ultrasound marker that is likely to have a major impact on screening for trisomy 21 is nasal bone hypoplasia, defined by a nasal bone that is not visible or with a length of less than 2.5 mm53. In 1046 singleton pregnancies undergoing amniocentesis for fetal karyotyping at 15–22 weeks, the nasal bone was hypoplastic in 21/34 (61.8%) fetuses with trisomy 21, in 12/982 (1.2%) chromosomally normal fetuses and in 1/30 (3.3%) fetuses with other chromosomal defects. In the chromosomally normal group, hypoplastic nasal bone was found in 0.5% of Caucasians and in 8.8% of Afro-Caribbeans. The likelihood ratio for trisomy 21 for hypoplastic nasal bone was 132.1 (95% CI 49.1–351.9) for Caucasians and 8.5 (95% CI 2.7–20.1) for Afro-Caribbeans and the respective values for present nasal bone were 0.39 (95% CI 0.24–0.58) and 0.27 (95% CI 0.05–0.77). 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, the findings of the study, that nasal hypoplasia is likely to be the single most sensitive and specific second-trimester marker of trisomy 21, indicate that examination of the nasal bone will inevitably be incorporated into a sonographic or combined screening program for trisomy 21.
There are no data on the interrelation between the second-trimester ultrasound markers and NT 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 results of previous screening tests. For example, in a 39-year-old woman at 20 weeks of gestation (background risk for trisomy 21 of about 1 in 100), who had a 11–14-week assessment by fetal NT and serum free β-hCG and PAPP-A that resulted in a ten-fold reduction in risk (to about 1 in 1000), after the diagnosis of a short femur but no other abnormal findings at the 20-week scan (likelihood ratio of 1.6, see Table 5), the estimated new risk is 1 in 625.
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 NT 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 biochemistry (high free β-hCG and inhibin-A and low estriol may be markers of placental damage) and can therefore not be 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 1175), with high free β-hCG and inhibin-A and low estriol at the 16-week serum testing resulting in a ten-fold increase in risk (to 1 in 118), 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 39). 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.