The 11-14-week scan

NUCHAL TRANSLUCENCY THICKNESS

During the second and third trimesters of pregnancy, abnormal accumulation of fluid behind the fetal neck can be classified as nuchal cystic hygroma or nuchal edema. In about 75% of fetuses with cystic hygromas, there is a chromosomal abnormality and, in about 95% of cases, the abnormality is Turner syndrome⁴⁵. Nuchal edema has a diverse etiology; chromosomal abnormalities are found in about one-third of the fetuses and, in about 75% of cases, the abnormality is trisomy 21 or 18. Edema is also associated with fetal cardiovascular and pulmonary defects, skeletal dysplasias, congenital infection and metabolic and hematological disorders; consequently, the prognosis for chromosomally normal fetuses with nuchal edema is poor⁴⁶.

In the first trimester, the term translucency is used, because this is the ultrasonographic feature that is observed; during the second trimester, the translucency usually resolves and, in a few cases, it evolves into either nuchal edema or cystic hygromas with or without generalized hydrops.

Measurement of nuchal translucency

Nuchal translucency can be measured successfully by transabdominal ultrasound examination in about 95% of cases; in the others, it is necessary to perform transvaginal sonography. The equipment must be of good quality (about £30000–50000), it should have a video-loop function and the callipers should be able to provide measurements to one decimal point. The average time allocated for each fetal scan should be at least 10 minutes. All sonographers performing fetal scans should be capable of reliably measuring the crown–rump length and obtaining a proper sagittal view of the fetal spine. For such sonographers, it is easy to acquire, within a few hours, the skill to measure nuchal translucency thickness. Furthermore, it is essential that the same criteria are used to achieve uniformity of results among different operators (Figure 8):

1. The minimum fetal crown–rump length should be 45mm and the maximum 84mm. The optimal gestational age for measurement of fetal nuchal translucency is 11 to 13⁺⁶ weeks. The success rate for taking a measurement at this gestation is 98–100%, falling to 90% at 14 weeks; from 14 weeks onwards, the fetal position (vertical) makes it more difficult to obtain measurements⁴⁷.

2. The results from transabdominal and transvaginal scanning are similar but reproducibility may be better with the transvaginal method⁴⁸.

3. A good sagittal section of the fetus, as for measurement of fetal crown–rump length, should be obtained.

4. The magnification should be such that the fetus occupies at least three-quarters of the image. Essentially, the magnification should be increased so that each increment in the distance between callipers should be only 0.1mm. A study, in which rat heart ventricles were measured initially by ultrasound and then by dissection, has demonstrated that ultrasound measurements can be accurate to the nearest 0.1–0.2mm⁴⁹.

5. Care must be taken to distinguish between fetal skin and amnion because, at this gestation, both structures appear as thin membranes. This is achieved by waiting for spontaneous fetal movement away from the amniotic membrane; alternatively, the fetus is bounced off the amnion by asking the mother to cough and/or by tapping the maternal abdomen.

6. The maximum thickness of the subcutaneous translucency between the skin and the soft tissue overlying the cervical spine should be measured by placing the callipers on the lines as shown in Figure 8. During the scan, more than one measurement must be taken and the maximum one should be recorded.

7. The nuchal translucency should be measured with the fetus in the neutral position. When the fetal neck is hyperextended the measurement can be increased by 0.6mm and when the neck is flexed, the measurement can be decreased by 0.4mm⁵⁰.

8. The umbilical cord may be round the fetal neck in 5–10% of cases and this finding may produce a falsely increased nuchal translucency, adding about 0.8mm to the measurement⁵¹. In such cases, the measurements of nuchal translucency above and below the cord are different and, in the calculation of risk, it is more appropriate to use the smaller measurement.

The distribution of nuchal translucency measurements as well as the quality of the images in terms of magnification, section (sagittal or oblique), calliper placement, skin line (nuchal only or nuchal and back) and visualization of the amnion separate from the nuchal membrane are taken into account in the audit of results⁵².

The ability to measure nuchal translucency and obtain reproducible results improves with training; good results are achieved after 80 and 100 scans for the transabdominal and the transvaginal routes, respectively⁵³.

The ability to achieve a reliable measurement of nuchal translucency is dependent on the motivation of the sonographer. A study comparing the results obtained from hospitals where nuchal translucency was used in clinical practice (interventional) compared to those from hospitals where they merely recorded the measurements but did not act on the results (observational), reported that, in the interventional group, successful measurement of nuchal translucency was achieved in 100% of cases and the measurement was > 2.5mm in 2.3% of cases; the respective percentages in the observational group were 85% and 12%^54,55.

Appropriate training, high motivation and adherence to a standard technique for the measurement of nuchal translucency are essential prerequisites for good clinical practice. Monni et al. reported that, after modifying their technique of measuring nuchal translucency thickness, by following the guidelines established by The Fetal Medicine Foundation, their detection rate of trisomy 21 improved from 30% to 84%⁵⁶.

Repeatability in the measurement of nuchal translucency

A potential criticism of screening by ultrasound is that scanning not only requires highly skilled operators but it is also prone to operator variability. This issue was addressed by a prospective study at 10–14 weeks of gestation in which the nuchal translucency was measured by two of four operators in 200 pregnant women⁵⁷. This study demonstrated that, after an initial measurement, the second one made by the same (intra-) observer or another (inter-) observer varies from the first by less than 0.54mm and 0.62mm, respectively in 95% of the cases. Additionally, the study demonstrated that the calliper placement repeatability was similar to the intra-observer and inter-observer repeatabilities, suggesting that a large part of the variation in measurements can be accounted for by the placement of the callipers rather than the generation of the image⁵⁷. Subsequent studies have reported that the intra-observer and inter-observer differences in measurements were less than 0.5mm in 95% of cases^58,59.

Digital image processing and automation of calliper placement may reduce the variation of measurements⁶⁰. In the meantime, it is best to rely on the mean of two good measurements for the calculation of risk, rather than on a single one.

Increase in nuchal translucency with gestational age

Fetal nuchal translucency thickness increases with crown–rump length^49,61, and therefore it is essential to take gestation into account when determining whether a given translucency thickness is increased. In a study involving more than 100000 pregnancies, the median increased from 1.2mm at 11 weeks to 1.9mm at 13⁺⁶ weeks⁶². Figure 9 illustrates the increases in the 5th, 25th, 50th, 75th and 95th centiles of nuchal translucency with crown–rump length; the 99th centile is about 3.5mm throughout this gestational range.

Observational studies: increased nuchal translucency and chromosomal defects

In the early 1990s, several reports of small series in high-risk pregnancies demonstrated a possible association between increased nuchal translucency and chromosomal defects in the first trimester of pregnancy (Table 4)^63–80. Although the mean prevalence of chromosomal defects in 20 series involving a total of 1698 patients was 29%, there were large differences between the studies with the prevalence ranging from 11% to 88%. This variation in results presumably reflects differences in the maternal age distributions of the populations examined as well as in the definition of the minimum abnormal translucency thickness, which ranged from 2mm to 10mm.

Subsequently, a series of screening studies in high-risk pregnancies were carried out; these involved measurement of nuchal translucency thickness immediately before fetal karyotyping, mainly for advanced maternal age. Pandya et al. examined a total of 1273 pregnancies and reported that the nuchal translucency thickness was above the 95th centile of the normal range in about 80% of trisomy 21 fetuses⁸¹. Similar findings were obtained in an additional four studies of pregnancies undergoing first-trimester fetal karyotyping ^73,74,76,78. However, in another study involving 1819 pregnancies, nuchal translucency thickness of equal to or greater than 3mm identified only 30% of the chromosomally abnormal fetuses (no data were provided specifically for trisomy 21) and the false-positive rate was 3.2%⁷².

An important finding of the screening studies in high-risk pregnancies was that the prevalence of chromosomal defects is dependent on both fetal nuchal translucency thickness and maternal age. For example, in a study of 1015 pregnancies with increased fetal nuchal translucency thickness at 10–14 weeks of gestation, the observed numbers of trisomies 21, 18 and 13 in fetuses with translucencies of 3mm, 4mm, 5mm and > 6mm were approximately 3 times, 18 times, 28 times and 36 times higher than the respective number expected on the basis of maternal age⁶⁷. The incidences of Turner syndrome and triploidy were 9 times and 8 times higher, whilst the incidence of other sex chromosome aneuploidies was similar to that expected⁶⁷.

Implementation of nuchal translucency screening in routine practice

There are nine studies that have examined the implementation of nuchal translucency screening in routine practice and the results are summarized in Table 5^{54,74,82–88}. The number of trisomy 21 pregnancies in all but one⁸⁶ of these studies is too small to allow assessment of the sensitivity of the test. However, these studies demonstrate a series of important points:

1. It is possible to measure nuchal translucency successfully during a routine first-trimester scan in 96–100% of cases, provided that, first, the gestation is 11–14 weeks and, second, the sonographers are motivated to take such a measurement. Thus, in the two studies that examined the feasibility of measuring nuchal translucency but in which (a) they included patients from as early as 8 weeks, and (b) no action was taken on the results of the translucency measurement, such a measurement was obtained in only 58% and 66% of cases, respectively^83,84.

2. The false-positive rate varied from as low as 0.8⁸⁶ to as high as 6.3%^54,84, demonstrating the need for unifying the criteria in (a) obtaining the appropriate image, (b) calliper placement, and (c) using the same normal range and same cut-off.

The Frimley Park Hospital, Camberley and St. Peter’s Hospital, Chertsey, UK⁸²

Frimley Park and St. Peter’s are general hospitals within the NHS offering routine antenatal care, and their combined annual number of deliveries is approximately 6000. Prior to the introduction of nuchal translucency scanning, the policy of these hospitals was to offer amniocentesis to women aged 35 years or older. During 1993 there were 11 fetuses with Down’s syndrome and only two of these were detected prenatally. Subsequently, nuchal translucency screening at 10–14 weeks of gestation was introduced and the implementation of this policy was achieved without the need for increasing the number of staff or the equipment. Women with fetal translucency of 2.5mm or more were offered fetal karyotyping. In addition women aged 35 years or older were offered amniocentesis at 16 weeks’ gestation. The data of the first 5 months after the introduction of the new policy were analyzed following completion of the pregnancies. During this period, 74% of women delivering in the two hospitals attended for first-trimester scanning and the nuchal translucency was successfully measured in all pregnancies. The nuchal translucency was raised in 3.6% of cases and the total percentage of invasive procedures was 5.1%. All four cases of Down’s syndrome that occurred in this period were diagnosed prenatally⁸².

University College Hospital, London, UK⁸³

In a screening study of 1704 women with singleton pregnancies attending University College Hospital, London, for routine antenatal care at 8–14 weeks of gestation, transabdominal ultrasound examination was performed. In 20% of cases, the sonographers forgot to measure the nuchal translucency thickness. In a further 18% of those women in whom a measurement was attempted, this was unsuccessful. In 28% of the 1127 cases in whom measurements were made, the scans were carried out before 10 weeks of gestation. The nuchal translucency was equal to or greater than 3mm in 6% of the cases. The population contained three fetuses with trisomy 21, all in women aged equal to or greater than 39 years, and increased nuchal translucency was found in one⁸³.

Queen Charlotte’s and Guy’s Hospitals, London, UK⁵⁴

This report combined the data from two centers; in one the study was observational and in the other it was interventional. The nuchal translucency was equal to or greater than 3mm in four (50%) of the eight trisomy 21 pregnancies. In the interventional center, 969 pregnancies were examined, the nuchal translucency was successfully measured in all cases and the translucency was equal to or greater than 3mm in 20 (2.0%) of the 966 chromosomally normal pregnancies. In contrast, in the observational center, 512 pregnancies were examined, the nuchal translucency was successfully measured in 470 (92%) of cases and the translucency was equal to or greater than 3mm in 73 (14.5%) of the 505 chromosomally normal pregnancies. These results suggest that the accuracy of measurements depends on the motivation of the sonographers⁵⁴.

University Hospital, Groningen, The Netherlands⁸⁴

This was a screening study of an apparently low-risk population, but in 54% of the cases the mothers were equal to or greater than 36 years old or had a history of a previous chromosomally abnormal fetus/child. In total, 923 fetuses were scanned transabdominally at equal to or less than 13 weeks of gestation by four ultrasonographers who were instructed not to take more than 3 minutes in making a nuchal translucency measurement. In 54% of cases, the fetal crown–rump length was <33mm. Furthermore, in 42% of cases, the nuchal translucency could not be measured. In this population, there were seven cases of trisomy 21 and the authors suggested that the sensitivity of nuchal translucency screening is low because only two of the fetuses had increased translucency. However, in reality, only three of the fetuses with trisomy 21 had a crown–rump length of > 38mm and a nuchal translucency measurement, and in two of these the translucency was increased⁸⁴.

Helsinki University Hospital and Jorvi Hospital, Finland⁸⁶

In this study, transvaginal sonography was performed in 10010 singleton pregnancies at 10–16 weeks of gestation. Scans were performed by one of six sonographers who were successful in obtaining an ultrasound measurement in 98.6% of cases. Increased nuchal translucency (equal to or greater than 3mm) was observed in 76 (0.8%) of the fetuses and this group included seven (54%) of the 13 fetuses with trisomy 21; the sensitivity for pregnancies at 10–14 weeks was 66% (four of six), for a screen-positive rate of only 0.9%⁸⁶.

Danube Hospital, Vienna, Austria⁸⁷

In a screening study of 4371 women with singleton pregnancies attending a government hospital in Vienna for routine antenatal care at 10–14 weeks of gestation, transabdominal ultrasound examination was performed and the fetal nuchal translucency thickness was successfully measured in all cases. The nuchal translucency thickness was equal to or greater than 2.5mm in 1.7% of the cases and this group included three (43%) of seven with trisomy 21⁸⁷.

Academic Medical Center, Amsterdam, The Netherlands⁸⁸

This study examined 1547 pregnancies, including 24% aged > 36 years old, at 10–14 weeks. Scans were performed by one of six sonographers who were successful in obtaining an ultrasound measurement in 96% of cases. Nuchal translucency was equal to or greater than 3mm in 33 (2.2%) cases and this group included six (67%) of the nine fetuses with trisomy 21⁸⁸.

Albert Szent-Gyorgyi Medical University Hospital, Szeged, Hungary⁷⁴

In this study involv- ing 3380 women at 9–12 weeks of gestation, nuchal translucency was successfully measured transvaginally in all cases. Increased translucency (equal to or greater than 3mm) was observed in 81 (2.4%) of fetuses and this group included 28 (90%) of 31 fetuses with trisomy 21⁷⁴.

University Hospital, Zurich, Switzerland⁸⁵

In this study, nuchal translucency was measured in 1131 pregnancies at 10–13 weeks of gestation. Increased translucency (equal to or greater than 3mm) was observed in 24 (2.1%) of fetuses and this group included two (67%) of three fetuses with trisomy 21⁸⁵.

Screening by a combination of maternal age and fetal nuchal translucency

The Multicenter Screening Study

In a multicenter study in the UK, involving the Harris Birthright Centre and four District General Hospitals (St. Peters, Chertsey; Frimley Park, Camberly; Queen Mary’s, Sidcup; Heatherwood, Ascot), nuchal translucency screening at 10–14 weeks of gestation was carried out in 20804 pregnancies, including 164 cases of chromosomal abnormalities⁶¹. This study demonstrated that:

1. In normal pregnancies, nuchal translucency thickness increases with gestation;

2. In chromosomally abnormal pregnancies, nuchal translucency is increased;

3. The risk for trisomies can be derived by multiplying the background maternal age and gestation-related risk by a likelihood ratio, which depends on the degree of deviation in nuchal translucency measurement from the expected normal median for that crown–rump length;

4. In about 5% of pregnancies, the estimated risk for trisomy 21 was at least 1 in 100 and this group included 80% of fetuses with trisomy 21 and 77% of those with other chromosomal abnormalities. Because the maternal age of the screened population was higher than in Britain as a whole, it was estimated that the cut-off risk to include 5% of the British population (median maternal age of 28 years) is 1 in 300; using this cut-off, the sensitivity of the test for trisomy 21 was estimated to be about 80%.

The Fetal Medicine Foundation Ongoing Multicenter Project

There are now 43 countries with centers approved by The Fetal Medicine Foundation for carrying out nuchal translucency screening. In the audit of results from the first 100000 pregnancies examined in the UK, the nuchal translucency was above the 95th centile in more than 70% of fetuses with trisomy 21⁶². The scans were carried out by 306 appropriately trained sonographers in 22 centers. In each pregnancy, the fetal crown–rump length and nuchal translucency were measured and the risk of trisomy 21 was calculated from the maternal age and gestational age-related prevalence, multiplied by a likelihood ratio depending on the deviation in nuchal translucency from normal (Figures 10–12). The distribution of risks was determined and the sensitivity of a cut-off risk of 1 in 300 was calculated⁶².

In total, 100311 singleton pregnancies were examined and follow-up was obtained from 96127 cases, including 326 with trisomy 21 and 325 with other chromosomal abnormalities. The median gestation at the time of screening was 12 weeks (range 10–14 weeks) and the median maternal age was 31 years (range 14–49 years); in 13315 (13.3%) cases, the maternal age was at least 37 years. The fetal nuchal translucency was above the 95th centile for crown–rump length in 4210 (4.4%) of the normal pregnancies and in 234 (71.8%) of those with trisomy 21 (Figure 10). The estimated risk for trisomy 21 based on maternal age and fetal nuchal translucency was above 1 in 300 in 7907 (8.3%) of the normal pregnancies and in 268 (82.2%) of those with trisomy 21. For a screen-positive rate of 5%, the sensitivity was 77% (95% confidence interval (CI) 72–82%)⁶².

Table 6 illustrates the observed prevalence of trisomy 21 according to the predicted risk based on maternal age and fetal nuchal translucency thickness. These results demonstrate the high degree of accuracy of the model.

Other screening studies using nuchal translucency expressed as centiles

The Royal Free Hospital, London, UK⁸⁹

In this study, nuchal translucency was measured at 11–14 weeks in 2281 pregnancies with a mean maternal age of 30 years. The nuchal translucency was equal to or greater than 99th centile for crown–rump length in six of the eight (75%) fetuses with trisomy 21. In the two trisomic pregnancies with low nuchal translucency, maternal serum biochemistry at 16 weeks also showed a low risk.

Homerton–St. Bartholomew’s–Royal London Hospitals, London, UK⁹⁰

In this study, women were offered screening by a combination of maternal age and fetal nuchal translucency at 12–13 weeks. A risk cut-off of 1 in 100 was used to identify the high-risk group; the screen-positive rate was 2.6% and this group contained five (71%) of seven cases of trisomy 21.

The Greek multicenter study⁹¹

This was a multicenter study involving routine measurement of nuchal translucency thickness in 3550 pregnancies at 10–14 weeks of gestation. The median maternal age was 29 years and 7.8% were aged 37 years or more. All five ultrasonographers had received a Certificate of Competence in first-trimester scanning by The Fetal Medicine Foundation. Successful measurements of nuchal translucency were obtained in all cases. The risk of trisomy 21, based on a combination of maternal age and fetal nuchal translucency thickness, was equal to or greater than 1 in 300 in 4.9% of the population and this high-risk group contained 10 of the 11 (91%) fetuses with trisomy 21, and all five cases of trisomies 18 or 13.

Ospedale Regionale per le Microcitemie, Cagliari, Italy⁵⁶

Monni et al. (1997) introduced screening on the basis of fetal nuchal translucency in January 1995; by May 1995 a total of 1176 patients with a crown–rump length of 17–85mm had been examined. They identified only 30% of fetuses with a chromosome abnormality using a cut-off of equal to or greater than 3mm. In 1996, sonographers modified the technique to follow guidelines established by The Fetal Medicine Foundation. In the subsequent year, the detection rate based on maternal age and fetal nuchal translucency thickness improved to 84%⁵⁶.

University of Florence Hospital, Florence, Italy⁹²

Biagiotti et al. evaluated screening on the basis of fetal nuchal translucency in 3241 pregnancies examined at 9–13 weeks of gestation. The authors compared two different methods, delta nuchal translucency and multiples of the expected median. They concluded that expressing values as multiples of the median, as used in screening with maternal serum biochemistry, provides optimal results. Screening based on maternal age and fetal nuchal translucency identified 59% of the cases for a 5% false-positive rate⁹².

Cervello Hospital, Palermo, Italy⁹³

Orlandi et al. evaluated screening for aneuploidy with fetal nuchal translucency and maternal serum biochemistry at 9–14 weeks of gestation. Nuchal translucency was measured in 744 pregnancies and was above the 95th centile in four (57%) of seven fetuses with trisomy 21 and in 42 (5.8%) of the 730 normal fetuses. The findings further indicated that screening by a combination of maternal age, fetal nuchal translucency and maternal serum biochemistry at 9–14 weeks of gestation identifies 87% of affected pregnancies for a 5% false-positive rate⁹³.

Lethality of trisomy 21 fetuses with increased nuchal translucency

Screening for chromosomal defects in the first rather than the second trimester has the advantage of earlier prenatal diagnosis and consequently less traumatic termination of pregnancy for those couples who choose this option. A potential disadvantage is that earlier screening preferentially identifies those chromosomally abnormal pregnancies that are destined to miscarry. Approximately 30% of affected fetuses die between 12 weeks of gestation and term^38,41,42. This issue of preferential intrauterine lethality of chromosomal defects is, of course, a potential criticism of all methods of antenatal screening, including second-trimester maternal serum biochemistry; the estimated rate of intrauterine lethality between 16 weeks and term is about 20%^38,41,42. This section examines the interrelation between increased nuchal translucency in trisomy 21 and fetal lethality.

Decision to continue with the pregnancy after the diagnosis of trisomy 21

In a study of 108 fetuses with trisomy 21 diagnosed in the first trimester because of increased nuchal translucency, the parents chose to continue with the pregnancy in five cases, whereas in 103 cases they opted for termination⁹⁴. Trisomy 21 was also diagnosed in one of the fetuses in a twin pregnancy where the parents elected to avoid invasive prenatal diagnosis or selective fetocide⁹⁴. In five of the six fetuses, the translucency resolved, and at the second-trimester scan the nuchal-fold thickness was normal (less than 7mm). All six trisomy 21 babies were born alive. One had a major atrioventricular septal defect and died at the age of 6 months. Another two of the babies had small ventricular septal defects and these were managed conservatively, awaiting spontaneous closure. These data suggest that increased nuchal translucency does not necessarily identify those trisomic fetuses that are destined to die in utero.

Decision to terminate the pregnancy after the diagnosis of trisomy 21

In a study of 70 pregnancies with trisomy 21 diagnosed at 12 (range 11–14) weeks of gestation, the parents opted for elective termination which was carried out at 14 (12–20) weeks. Ultrasound examination to determine if the fetus was alive was carried out at the time of chorionic villus sampling as well as just before termination⁹⁵. Eight fetuses died in the interval between chorionic villus sampling and termination and the rate of lethality increased with nuchal translucency thickness from 5.3% for those with nuchal translucency of 0–3mm to 23.5% for nuchal translucency of equal to or greater than 7mm. Assuming that the relative rate of intrauterine lethality of trisomy 21 fetuses according to the nuchal translucency thickness remains the same throughout pregnancy, it was estimated that a policy of screening by maternal age and fetal nuchal translucency followed by selective termination of affected fetuses would be associated with at least a 70% reduction in the live birth incidence of trisomy 21.

Data from The Fetal Medicine Foundation Multicenter Project

Among the 100000 pregnancies that were screened within the multicenter project, trisomy 21 was diagnosed, prenatally or at birth, in 326 cases⁶². On the basis of the maternal age distribution in this population and the maternal age-related prevalence of trisomy 21 in live births, it was estimated that 266 babies with trisomy 21 would have been born alive had there not been any antenatal testing and selective termination of affected pregnancies.