The 11-14 weeks scan - KH Nicolaides, NJ Sebire, RJM Snijders, AP Souka

Chapter 2

FIRST TRIMESTER ULTRASONOGRAPHY

At 11-13+6 weeks, all major chromosomal defects are associated with increased nuchal translucency (NT) thickness (Snijders et al 1998). In trisomies 21, 18 and 13 the pattern of increase in NT is similar and the average NT in these defects is about x mm above the normal median for crown-rump length. In Turner syndrome, the median NT is about x mm above normal (Figure 1).

In addition to increased NT, in trisomy 21, 60-70% of fetuses have absent nasal bone, 25% have a short maxilla, and 80% have abnormal flow velocity waveforms in the ductus venosus. In trisomy 18, there is early onset fetal growth restriction, a tendency for bradycardia, and exomphalos in 30% of cases, absent nasal bone in 55% and single umbilical artery in 75%. In trisomy 13, there is tachycardia in more than 65% of the cases, early onset fetal growth restriction, and megacystis, holoprosencephaly or exomphalos in about 40% of the cases. In Turner syndrome, there is tachycardia in about 50% of cases and early onset fetal growth restriction. In triploidy, there is early onset asymmetrical fetal growth restriction, bradycardia in 30% of cases, holoprosencephaly, exomphalos or posterior fossa cyst in about 40% and molar changes in the placenta in about 30%.

Absence of fetal nasal bone

In 1866 Langdon Down noted that a common characteristic of patients with trisomy 21 is a small nose. Anthropometric studies in patients with Down’s syndrome have reported that the nasal root depth is abnormally short in 50% of cases (Farkas et al 2001). Similarly, post mortem radiological studies in aborted fetuses with trisomy 21 have reported absence of ossification or hypoplasia of the nasal bone in about 50% of cases. Sonographic studies at 15-24 weeks of gestation reported that about 65% of trisomy 21 fetuses have absent or short nasal bone.

The fetal nasal bone can be visualized by sonography at 11-13+6 weeks of gestation (Cicero et al 2001) (Figures 1 and 2). Several studies have demonstrated a high association between absent nasal bone at 11-13+6 weeks and trisomy 21, as well as other chromosomal abnormalities (Nicolaides 2004). In the combined data from these studies on a total of 15,822 fetuses the fetal profile was successfully examined in 97.4% cases and the nasal bone was absent in 1.4% of the chromosomally normal fetuses and in 69% of fetuses with trisomy 21. An important finding of these studies was that the incidence of absent nasal bone decreased with fetal crown-rump length, increased with NT thickness and was substantially higher in Afro-Caribbeans than in Caucasians. Consequently, in the calculation of likelihood ratios in screening for trisomy 21 adjustments must be made for these confounding factors (Cicero et al 2004).

Examination of the nasal bone

• The gestation should be 11-13+6 weeks and the fetal crown–rump length should be 45-84 mm.
• The image should be magnified so that the head and the upper thorax only are included in the screen.
• A mid-sagittal view of the fetal profile should be obtained with the ultrasound transducer held in parallel to the direction of the nose.
• In the image of the nose there should be three distinct lines. The top line represents the skin and the bottom one, which is thicker and more echogenic than the overlying skin, represents the nasal bone. A third line, almost in continuity with the skin, but at a higher level, represents the tip of the nose.
• At 11-13+6 weeks the fetal profile can be successfully examined in more than 95% of cases
• In chromosomally normal fetuses the incidence of absent nasal bone is less than 1% in Caucasian populations and about 10% in Afro-Caribbeans.
• The nasal bone is absent in 65-70% of trisomy 21 fetuses and in more than 50% of trisomy 18 and 30% of trisomy 13 fetuses.
• For a false positive rate of 5%, screening by a combination of sonography for fetal NT and nasal bone and maternal serum free β-hCG and PAPP-A can potentially identify more than 95% of trisomy 21 pregnancies.
• It is imperative that sonographers undertaking risk assessment by examination of the fetal profile receive appropriate training and certification of their competence in performing such a scan.
  

Integrated first-trimester sonographic and biochemical screening

A case-control study comprising of 100 trisomy 21 and 400 chromosomally normal singleton pregnancies at 11-13+6 weeks of gestation examined the potential performance of screening for trisomy 21 by a combination of sonography for measurement of fetal NT and assessment of the presence or absence of the fetal nasal bone and measurement of maternal serum free β-hCG and PAPP-A (Cicero et al 2003). It was estimated that for a false positive rate of 5%, the detection rate of trisomy 21 would be 97%.

Crown–rump length

Trisomy 18 and triploidy are associated with moderately severe growth restriction, trisomy 13 and Turner syndrome with mild growth restriction, whereas in trisomy 21 growth is essentially normal (Figure 3; Nicolaides et al 1996).

Crown-rump length and chromosomal defects

• Trisomy 18 and triploidy are associated with moderately severe growth restriction
• Trisomy 13 and Turner syndrome are associated with mild growth restriction
• In trisomy 21 growth is essentially normal

Maxillary length

Langdon Down observed that in individuals with trisomy 21 ‘the face is flat’. This may be the consequence of underdevelopment of the maxilla. Anthropometric and radiological studies in patients with Down’s syndrome have demonstrated underdevelopment of the maxilla in more than 50% of cases (Farkas et al 2001).

The fetal maxilla can be easily visualized and measured by sonography at 11-13+6 weeks of gestation (Cicero et al 2004). A mid-sagittal view of the fetal profile is first obtained and the transducer is then gently angled laterally so that both the maxillary bone and mandible, including the ramus and condylar process, can be seen (Figure 4). In chromosomally normal fetuses maxillary length increases linearly with gestation by about 0.1 mm for each 1 mm increase in crown-rump length. In the trisomy 21 fetuses the median maxillary length is significantly below the normal mean for crown-rump length by 0.7 mm and it is below the 5th centile of the normal range in about 25% the cases (Figure 5). However, there is a significant association between maxillary bone length and NT thickness and in fetuses with absent nasal bone the maxilla is shorter than in those with present nasal bone. Consequently, the independent contribution of maxillary length in screening for trisomy 21 remains to be determined. In fetuses with other chromosomal defects there were no significant differences from normal in the maxillary length.

Maxillary length and chromosomal defects

• At 11-13+6 weeks the fetal maxilla can be successfully visualized and measured
• In chromosomally normal fetuses maxillary length increases linearly with gestation by about 0.1 mm for each 1 mm increase in crown-rump length.
• In the trisomy 21 fetuses, maxillary length is reduced
• The role of maxillary length in screening for trisomy 21 remains to be determined
• In fetuses with other chromosomal defects maxillary length is normal
  

Ear length

In postnatal life, short ears constitute the most consistent clinical characteristic of patients with Down’s syndrome. The fetal ears can be easily visualized and measured by sonography at 11-13+6 weeks of gestation (Sacchini et al 2003). Although in trisomy 21 fetuses the median ear length is significantly below the normal mean for crown-rump length, the degree of deviation from normal is too small for this measurement to be useful in screening for trisomy 21.

Femur and humerus length

Trisomy 21 is characterised by short stature and during the second trimester the condition is associated with relative shortening of the femur and more so the humerus. At 11-13+6 weeks in trisomy 21 fetuses the median femur and humerus lengths are significantly below the appropriate normal mean for crown-rump length but the degree of deviation from normal is too small for these measurements to be useful in screening (Longo et al 2004).

Single umbilical artery

A single umbilical artery, found in about 1% of deliveries, is associated with malformations of all major organ systems and chromosomal defects. In the first-trimester the umbilical arteries can be visualized by color flow mapping on either side of the bladder and in continuity with the umbilical cord insertion to the fetus in an oblique transverse section of the lower fetal abdomen. At 11-13+6 weeks single umbilical artery is found in about 3% of chromosomally normal fetuses and in 80% of fetuses with trisomy 18 (Rembouskos et al 2003). In the fetuses with single umbilical artery the observed number of cases of trisomy 21 is not significantly different from the number estimated on the basis of maternal age and fetal NT. In contrast, a single umbilical artery is associated with a seven fold increase in risk of trisomy 18. However, a high proportion of trisomy 18 fetuses have other major defects that are easily detectable at the 11-13+6 weeks scan and many other abnormalities that are detectable at 16-20 weeks. It is therefore unlikely that the finding of a single umbilical artery per se should be an indication for fetal karyotyping.

Megacystis

The fetal bladder can be visualized by sonography in about 80% of fetuses at 11 weeks of gestation and in all cases by 13 weeks. At this gestation the fetal bladder length is normally less than 6 mm. Fetal megacystis in the first-trimester, defined by a longitudinal bladder diameter of 7 mm or more, is found in about 1 in 1,500 pregnancies (Figure 6). When the longitudinal bladder diameter is 7-15 mm the incidence of chromosomal defects, mainly trisomies 13 and 18, is about 20%, but in the chromosomally normal group there is spontaneous resolution of the megacystis in about 90% of cases (Liao et al 2003). In contrast, in megacystis with bladder diameter greater than 15 mm the incidence of chromosomal defects is about 10% and in the chromosomally normal group the condition is invariably associated with progressive obstructive uropathy. Megacystis is associated with increased NT, which is observed in about 75% of those with chromosomal abnormalities and in about 30% of those with normal karyotype. After taking into account maternal age and fetal NT the presence of megacystis increases the likelihood for trisomy 13 or 18 by a factor of 6.7

Exomphalos

At 11-13+6 weeks the incidence of exomphalos (Figure 7) is about 1 in 1000, which is four times higher than in live births. The incidence of chromosomal defects, mainly trisomy 18, is about 60%, compared to about 30% at mid-gestation and 15% in neonates. The risk for trisomy 18 increases with maternal age and, since this trisomy is associated with a high rate of intrauterine lethality, its prevalence decreases with gestational age. In contrast, the rate of fetal death in chromosomally normal fetuses with exomphalos is not higher than in fetuses without this abnormality. Consequently, the prevalence of exomphalos and the associated risk for chromosomal defects increase with maternal age and decrease with gestational age (Snijders et al 1995).

Choroid plexus cysts, pyelectasis and cardiac echogenic foci

At 11-14 weeks the prevalences of choroid plexus cysts, pyelectasis and cardiac echogenic foci were 2.2, 0.9 and 0.6% (Whitlow et al 1998). Preliminary results suggest that, as in the second trimester, the prevalence of these markers may be higher in chromosomally abnormal than normal fetuses. However, calculation of likelihood ratios requires the study of many more chromosomally abnormal fetuses to determine the true prevalence of these markers.

Placental volume

The placental volume, determined at 11-13+6 weeks by 3D ultrasound, increases with fetal crown-rump length. In trisomy 21 fetuses, placental volume is not significantly different from normal but in trisomy 18 placental volume is substantially decreased.

Fetal heart rate

In normal pregnancy, the fetal heart rate (FHR) increases from about 100 bpm at 5 weeks of gestation to 170 bpm at 10 weeks and then decreases to 155 bpm by 14 weeks. At 10-13+6 weeks, trisomy 13 (Figure 8) and Turner syndrome are associated with tachycardia, whereas in trisomy 18 and triploidy there is fetal bradycardia (Liao et al 2001). In trisomy 21, there is a mild increase in FHR. Measurement of FHR is unlikely to improve first trimester screening for trisomy 21 but it is a useful measurement in identifying fetuses with trisomy 13.

Doppler in the ductus venosus

The ductus venosus is a unique shunt directing well-oxygenated blood from the umbilical vein to the coronary and cerebral circulation by preferential streaming through the foramen ovale into the left atrium. Blood flow in the ductus has a characteristic waveform with high velocity during ventricular systole (S-wave) and diastole (D-wave), and forward flow during atrial contraction (a-wave). In the second and third trimesters of pregnancy abnormal flow with absent or reverse a-wave is observed in impending or overt cardiac failure.

At 10-13+6 weeks abnormal ductal flow (Figure 9) is associated with chromosomal abnormalities, cardiac defects and adverse pregnancy outcome (Matias et al 1998, Borrell et al 2003). Studies from specialist centres, in more than 5,000 pregnancies, including about 280 fetuses with trisomy 21, have demonstrated that at 10-13+6 weeks there is abnormal flow in the ductus venosus in about 80% of trisomy 21 fetuses and in about 5% of chromosomally normal fetuses (Nicolaides 2004). There is no or only a weak association between increased fetal NT and the incidence of abnormal ductal flow. These findings indicate that assessment of the ductus venosus can be combined with measurement of fetal NT to improve the effectiveness of early sonographic screening for trisomy 21. However, examination of ductal flow is time-consuming and requires highly skilled operators and at present it is uncertain if this assessment will be incorporated into the routine first-trimester scan.

Abnormal flow in the ductus venosus and chromosomal defects

• At 11-13+6 weeks abnormal ductal flow is observed in 5% chromosomally normal fetuses, in about 80% with trisomy 21 and 75% with all chromosomal abnormalities
• Assessment of the ductus venosus can be combined with measurement of fetal NT to improve the effectiveness of early sonographic screening for trisomy 21
• Examination of ductal flow is time-consuming and requires highly skilled operators and at present it is uncertain if this assessment will be incorporated into the routine first-trimester scan.
  

Doppler in other vessels

Uterine arteries

Uterine artery Doppler studies at 10-13+6 weeks found no significant differences in pulsatility index between chromosomally normal and abnormal fetuses. Consequently, the high intrauterine lethality and fetal growth restriction of the major chromosomal abnormalities are unlikely to be the consequence of impaired placentation in the first trimester of pregnancy. Uterine artery Doppler is not a useful screening test for chromosomal defects.

Umbilical artery

Umbilical artery Doppler is not useful in screening for trisomy 21. However, in trisomy 18, impedance to flow is increased and in about 20% of cases there is persistent reversal of end-diastolic flow (REDF).

Umbilical vein

In second and third-trimester fetuses, pulsatile umbilical venous flow is a late and ominous sign of fetal compromise. At 11-13+6 weeks there is pulsatile flow in the umbilical vein in about 25% of chromosomally normal fetuses and in 90% of fetuses with trisomy 18 or 13. However, in fetuses with trisomy 21, the prevalence of pulsatile venous flow is not significantly different from that in chromosomally normal fetuses.

Jugular vein and carotid artery

There are no significant associations between the pulsatility index in the fetal jugular vein and carotid artery and fetal NT and no significant differences between the chromosomally normal and abnormal groups.