Review article
Nuchal translucency and other first-trimester sonographic markers of chromosomal abnormalities

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Abstract

There is extensive evidence that effective screening for major chromosomal abnormalities can be provided in the first trimester of pregnancy. Prospective studies in a total of 200,868 pregnancies, including 871 fetuses with trisomy 21, have demonstrated that increased nuchal translucency can identify 76.8% of fetuses with trisomy 21, which represents a false-positive rate of 4.2%. When fetal nuchal translucency was combined with maternal serum free–β-human chorionic gonadotropin and pregnancy-associated plasma protein-A in prospective studies in a total of 44,613 pregnancies, including 215 fetuses with trisomy 21, the detection rate was 87.0% for a false-positive rate of 5.0%. Studies from specialist centers with 15,822 pregnancies, which included 397 fetuses with trisomy 21, have demonstrated that the absence of the nasal bone can identify 69.0% of trisomy 21 fetuses, which represents a false-positive rate of 1.4%. It has been estimated that first-trimester screening by a combination of sonography and maternal serum testing can identify 97% of trisomy 21 fetuses, which represents a false-positive rate of 5%, or that the detection rate can be 91%, which represents a false-positive rate of 0.5%. In addition to increased nuchal translucency, important sonographic markers for chromosomal abnormalities, include fetal growth restriction, tachycardia, abnormal flow in the ductus venosus, megacystis, exomphalos and single umbilical artery. Most pregnant women prefer screening in the first, rather than in the second, trimester. As with all aspects of good clinical practice, those care givers who perform first-trimester screening should be trained appropriately, and their results should be subjected to external quality assurance.

Section snippets

Methods

Searches of PubMed were made to identify all articles that have been published since 1990 on first trimester sonographic markers of chromosomal abnormalities. Most publications were on fetal NT, which were grouped into series that reported on the association between increased NT and chromosomal abnormalities, into series that reported on prospective screening studies with NT alone or NT in combination with first or second trimester maternal serum biochemical testing, and into series that

Patient-specific risk for chromosomal abnormalities

Every woman has a risk that her fetus/baby has a chromosomal defect. To calculate the individual risk, it is necessary to take into account the a priori risk, which depends on maternal age and gestational age, and to multiply this by a likelihood ratio, which depends on the results of ultrasound findings and/or maternal serum biochemical tests that were performed during the course of the pregnancy to determine the patient-specific risk.9 Every time a test is carried out, the a priori risk is

Maternal age and gestation

The risk for many of the chromosomal abnormalities increases with maternal age. Additionally, because fetuses with chromosomal abnormalities are more likely to die in utero than normal fetuses, the risk decreases with advancing gestation (Table I).10., 11., 12. Estimates of the maternal age-related risk for trisomy 21 at birth are based on surveys with almost complete ascertainment of the affected patients.13 During the last decade, with the introduction of maternal serum biochemistry and

Cystic hygromas, nuchal edema, and NT

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.16., 17. In approximately 75% of fetuses with cystic hygromas, there is a chromosomal abnormality; in approximately 95% of cases, the abnormality is Turner syndrome.18 Nuchal edema has a diverse cause; chromosomal abnormalities are found in approximately one third of the fetuses, and in approximately 75% of these cases, the

Image and measurement

In the assessment of fetal NT, the ultrasound machine should be of high resolution with a video-loop function and calipers that provide measurements to 1 decimal point. Fetal NT can be measured successfully by transabdominal ultrasound examination in approximately 95% of cases; in the others, it is necessary to perform transvaginal sonography. The results from transabdominal and transvaginal scanning are similar.58

Only the fetal head and upper thorax should be included in the image for

Deviation in measurement from normal

Fetal NT increases with crown-rump length; therefore, it is essential to take gestation into account when a determination is made about whether a given NT thickness is increased.59., 81. In a study that involved 96,127 pregnancies, the median and 95th percentile at a crown-rump length of 45 mm were 1.2 and 2.1 mm; the respective values at a crown-rump length of 84 mm were 1.9 and 2.7 mm.82 The 99th percentile did not change with crown-rump length and was approximately 3.5 mm.

In a screening for

Training and quality assessment in the measurement of NT

Appropriate training of sonographers and adherence to a standard technique for the measurement of NT are essential prerequisites for good clinical practice. Furthermore, the success of a screening program necessitates the presence of a system for regular audit of results and continuous assessment of the quality of images. In 1997, a study group of the Royal College of Obstetricians and Gynaecologists in the United Kingdom recommended that NT screening should only be conducted by highly

NT thickness and risk for chromosomal abnormalities

In the early 1990s, several reports demonstrated that increased fetal NT thickness is associated with a high incidence of trisomy 21 and other chromosomal abnormalities (Table II).20., 21., 92., 93., 94., 95., 96., 97., 98., 99., 100., 101., 102., 103., 104., 105., 106. In the combined data from 17 series that involved a total of 1690 patients, the incidence of chromosomal abnormalities was 28.7%. However, there were large differences between the studies in the incidence of chromosomal

Implementation of NT screening in routine practice

Several prospective interventional studies have examined the implementation of NT screening in routine practice; the results are summarized in Table III, Table IV.43., 82., 109., 110., 111., 112., 113., 114., 115., 116., 117., 118., 119., 120., 121., 122., 123., 124., 125., 126., 127., 128., 129., 130. In some of the studies, the screen-positive group was defined by a cut-off in fetal NT (Table III) or a combined risk that was derived from the maternal age and the deviation in fetal NT from the

The issue of fetal lethality

Screening for chromosomal abnormalities 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.10., 11., 12., 14., 15. This issue

Observational studies

The ability to achieve a reliable measurement of NT is dependent on appropriate training, adherence to a standard technique, and motivation of the sonographer. All 3 components are well illustrated by the differences in results between interventional (Table III, Table IV) and observational studies, in which the sonographers were asked to record the fetal NT measurements but not act on the results (Table VI).132., 133., 134., 135., 136., 137. Thus, successful measurement of NT was achieved in

Fetal NT and maternal serum biochemistry

Trisomic pregnancies are associated with altered maternal serum concentrations of various fetoplacental products, which included α-fetoprotein (AFP), free β–human chorionic gonadotropin (β-hCG), inhibin A, and unconjugated estriol.138., 139., 140., 141., 142. Screening by maternal age and various combinations of these fetoplacental products can identify 60% to 75% of trisomy 21 pregnancies, which represents a false-positive rate of 5%.143 However, an essential component of biochemical screening

NT followed by second-trimester ultrasonography

In the first trimester, a common feature of many chromosomal abnormalities is increased NT thickness. In the second trimester scan, each chromosomal defect has its own syndromal pattern of detectable abnormalities. For example, trisomy 21 is associated with nasal hypoplasia, increased nuchal fold thickness, cardiac defects, intracardiac echogenic foci, duodenal atresia and echogenic bowel, mild hydronephrosis, shortening of the femur and more so of the humerus, sandal gap, and clinodactyly or

Absence of fetal nasal bone

In 1866 Down noted that a common characteristic of patients with trisomy 21 is a small nose.1 An anthropometric study in 105 patients with Down syndrome at 7 months to 36 years of age reported that the nasal root depth was abnormally short in 49.5% of cases.166 In the combined data from 4 postmortem radiologic studies in a total of 105 aborted fetuses with trisomy 21 at 12 to 25 weeks of gestation, there was absence of ossification of the nasal bone in 32.4% of cases and nasal hypoplasia in

Sonographic assessment

The fetal nasal bone can be visualized by sonography at 11+0 to 13+6 weeks of gestation.176 This examination requires that the image is magnified so that the head and the upper thorax only are included in the screen (Figure 1, Figure 2). A mid-sagittal view of the fetal profile is obtained with the ultrasound transducer being held parallel to the longitudinal axis of the nasal bone. The angle of insonation is crucial because the nasal bone will not be visible almost invariably when the

Association with chromosomal abnormalities

Several studies have demonstrated a high association between absent nasal bone at 11+0 to 13+6 weeks of gestation and trisomy 21 and other chromosomal abnormalities (Table XII, Table XIII).176., 179., 180., 181., 182., 183., 184., 185., 186. In the combined data from these studies on a total of 15,822 fetuses, the fetal profile was examined successfully in 15,413 cases (97.4%), and the nasal bone was absent in 176 of 12,652 chromosomally normal fetuses (1.4%) and in 274 of 397 fetuses (69.0%)

Integrated sonographic and biochemical screening in the first trimester

A case-control study comprised of 100 trisomy 21 and 400 chromosomally normal singleton pregnancies at 11+0 to 13+6 weeks of gestation examined the potential performance of screening for trisomy 21 by a combination of sonography for the measurement of fetal NT and the assessment of the presence or absence of the fetal nasal bone and measurement of maternal serum free β-hCG and PAPP-A at 11+0 to 13+6 weeks of gestation. It was estimated that, for a false-positive rate of 5%, the detection rate

Other sonographic markers in the first trimester

In addition to increased NT, chromosomal abnormalities are associated with a pattern of characteristic sonographic findings in the first trimester. Trisomy 21 is associated with abnormal flow velocity patterns in the ductus venosus and maxillary hypoplasia. In trisomy 18, there is early onset fetal growth restriction, bradycardia in approximately 20% of cases, exomphalos in 30% of cases, absent nasal bone in 55% of cases, and single umbilical artery in 75% of cases. Trisomy 13 is characterized

Chromosomal abnormalities in multiple pregnancies

In multiple pregnancies that are compared with singleton pregnancies, prenatal diagnosis of chromosomal abnormalities is complicated because the techniques of invasive testing may provide uncertain results or may be associated with higher risks of miscarriage and because the fetuses may be discordant for an abnormality, in which case 1 of the options for the subsequent management of the pregnancy is selective feticide.

Selective feticide can result in spontaneous abortion or severe preterm

Screening by maternal age

In dizygotic pregnancies, the maternal age-related risk for chromosomal abnormalities for each twin may be the same as in singleton pregnancies; therefore, the chance that at least 1 fetus is affected by a chromosomal defect is twice as high as in singleton pregnancies. Furthermore, because the rate of dizygotic twinning increases with maternal age, the proportion of twin pregnancies with chromosomal abnormalities is higher than in singleton pregnancies. In monozygotic twins, the risk for

Screening by second-trimester maternal serum biochemistry

In singleton pregnancies, screening for trisomy 21 by a combination of maternal age and second-trimester maternal serum biochemistry can detect 50% to 70% of trisomy 21 cases, which represents a 5% false-positive rate.159 In twin pregnancies, the median value for maternal serum markers (such as AFP, hCG, free β-hCG, and inhibin-A) are approximately twice those for singleton pregnancies.200 When this is taken into account in the mathematic modeling for calculation of risks, the estimate was that

Screening by fetal NT thickness

Pandya et al201 reported that, in 9 twin pregnancies that were discordant for trisomies 21 or 18, fetal NT at 10+3 to 13+6 weeks of gestation was >2.5 mm in 8 of the 9 trisomic fetuses and in 1 of the 9 chromosomally normal fetuses. Maymon et al202 examined 174 twin pregnancies; the fetal NT was >95th percentile in 16 of the fetuses (4.6%), which included all 5 chromosomally abnormal fetuses. A study of 60 twin pregnancies, in which fetal NT was measured in the first trimester and maternal

Screening by fetal NT thickness and maternal serum biochemistry

In a prospective screening study by fetal NT, maternal serum free β-hCG was measured in 4181 singleton and 148 twin pregnancies. In the twin pregnancies, there were 12 pregnancies with trisomy 21. In the normal twin pregnancies, compared with singleton pregnancies, the median maternal serum free β-hCG adjusted for maternal weight was 1.94 MoM. In the 12 trisomy 21 twin pregnancies, the median level of free β-hCG was significantly higher than in normal twin pregnancies.208 In a study of 159 twin

Screening in higher-order multiple pregnancies

Fetal NT is the only reliable method of screening for chromosomal abnormality in multifetal pregnancies. In a study of 79 fetuses from 24 pregnancies with ≥3 fetuses that were conceived by assisted reproduction, fetal NT was measured successfully in all cases, and the distribution of measurements was similar to that in singleton pregnancies.211

Women's attitudes to first- versus second-trimester screening

Two studies have investigated the preference of pregnant women in terms of the methods of screening. In the first study, 43 of 224 women (19.2%) did not want to have any screening. In those who wanted screening, 177 of 181 of the women (97.8%) preferred the screening to be carried out in the first rather than in the second trimester.212

In the second study, 100 women who indicated an interest in having prenatal screening for Down syndrome were interviewed at their first hospital antenatal visit

Clinical importance of respect for autonomy

Respect for autonomy is a central principle in medical ethics and law.215 This ethical principle obliges the physician to elicit and implement the patient's preferences. The relevance of respect for autonomy to first-trimester screening is 2-fold. First, early diagnosis of fetal abnormality and the option of early termination of pregnancy are important to many women. Second, most first-trimester screening tests provide reassurance for many women who would prefer not to have an invasive

Comment

Diagnosis of fetal chromosomal abnormalities requires invasive testing. Randomized studies have demonstrated that the risk of miscarriage from chorionic villus sampling in the first trimester is the same as for amniocentesis in the second trimester, provided these procedures are carried out by appropriately trained and experienced operators.

Most pregnant women prefer screening to be performed in the first rather than in the second trimester. The provision of a high-quality first-trimester

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