First Trimester Screening For Chromosomal And Structural Malformations

Introduction

An association between an abnormally thickened nuchal translucency (NT) and chromosomal abnormalities was first noted in the early 1990s¹. However, the early studies reported widely discordant sensitivities for the detection of chromosomal malformations. These discrepancies were due to a lack of consistency between examiners with respect to:

Study group - low-risk versus high-risk
Gestational age at examination
Measurement technique
Cut-off for an abnormal nuchal translucency
Incorporation of serum markers into the evaluation
Level of sonographer training

Serum Analytes

First trimester serum analytes - free ?-hCG (HCG) and pregnancy - associated plasma protein (PAPP-A) - are currently utilized to screen for Down syndrome. HGC tends to be increased and PAPP-A decreased with Down syndrome. The detection rate for Down syndrome with the first trimester analytes alone is approximately 60% with a 5% false positive rate².

Pathophysiology of a thickened nuchal translucency

A multitude of different structural anomalies and chromosomal abnormalities are associated with an increased NT. This suggests that there is more than one pathophysiologic mechanism associated with a thick NT. The possible etiologies that have been proposed to date, include³ :

Abnormal lymphatic drainage
Altered extracellular matrix
Abnormal cardiac structure and/or function
Venous congestion
Hypoproteinemia
Genetic causes of fetal anemia (e.g., alphathalassemia)

Since the thickness of the nuchal translucency increases with gestational age, utilization of a single cut-off would tend to increase the false negative rate at earlier gestational ages and increase the false positive rate later in the first trimester. Nuchal translucency measurements, therefore, evolved from a threshold value to multiples of the median that were utilized to modify the patient's age related risk of a karyotypic abnormality. Nuchal translucency measurements without combined serum screening has a low specificity and is, no longer recommended¹.

A combination of fetal nuchal translucency with maternal serum PAPP-A and ?-hCG has a detection rate of approximately 90% for trisomies 21, 18 and 13, Turner's syndrome and triploidy with a 5% false positive rate⁴.

The resolution of a thickened NT as gestation advances is not indicative of a normal karyotype⁵.

A 12 center North American study offered first trimester screening with NT, free ?-hCG and PAPP-A to patients with a singleton pregnancy between 74 and 97 days gestation based on the crown-rump length⁶ . 8,514 women were screened. 78.7% of trisomy 21 fetuses and 90.9% of fetuses with trisomy 18 were identified with a false positive rate of 5% and 2%, respectively. In contrast to prior studies, this investigation took into consideration differences in the rates of spontaneously aborted trisomy 21 fetuses at various gestational ages. The good performance of first trimester screening was not based on the identification of pregnancies that would have spontaneously aborted. The successful screening for trisomy 21 by fetal nuchal translucency utilizing the Fetal Medicine Foundation protocol has been confirmed in other countries⁷ , as well as in the United States⁶.

Measurement Technique

The Fetal Medicine Foundation has standardized NT measurement in the first trimester. The measurement is performed at a crown-rump length between 45 mm and 84 mm⁸. Over 90% of exams are performed transabdominally; occasionally the transvaginal approach is required. The fetal head and chest should be enlarged to 75% of the screen. The fetus is imaged in a mid-sagittal plane with the head in a neutral position. The mean NT when the head is extended or flexed is 0.62 mm greater and 0.40 mm less, respectively, than an NT measured with the head in a neutral position⁹.

The amnion should be distinguished from the fetal skin. The calipers are placed on the inner border of the nuchal translucency and perpendicular to the long axis of the fetal body. The largest of three measurements is reported (Fig. 1).

Figure 1. Normal 1st trimester nuchal translucency (1.7 mm).

The importance of image size was emphasized by Edwards et al¹⁰ - an increase in image magnification from 60% to 200% resulted in a 29% decrease in the NT measurement.

A nuchal cord is present in approximately 8% of 10-14 week fetuses. A nuchal cord will add 0.8 mm to the NT measurement. If a nuchal cord is suspected, color Doppler should be used to exclude this possibility before an NT measurement is obtained¹¹ (Figs. 2, 3).

Figure 2. 1st trimester fetus with the umbilical cord around the neck (arrow) affecting the nuchal translucency measurement.

Figure 3. Transverse image of the fetus in figure 2. Power Doppler is used to show the cord around the neck.

Nuchal Translucency Screening in Multiple Gestations

In one study the nuchal translucency thickness was above the 95th centile in 7.3% of twin fetuses, including 88% with trisomy 21¹² . In chromosomally normal twins, the prevalence of an increased NT is higher in monochorionic (8.4%) versus dichorionic (5.4%) twins. It has been postulated that the increased false positive rate with monochorionic twins is due to a thickened NT being an early manifestation of a shared placental circulation, i.e. twin-to-twin transfusion syndrome.

Outcome in fetuses with normal chromosomes and a thick nuchal translucency

As the NT increases in chromosomally normal fetuses, the risk of the following poor outcome variables also increases:

Miscarriage
Intrauterine death
Major structural defects
Postnatal demise

The chance of an adverse outcome with normal chromosomes and an NT of 3.5 - 4.4 mm, 4.5 - 5.4 mm (Fig. 4a), 5.5 - 6.4 mm and >= 6.5 mm (Fig. 4b) is 32%, 49%, 67% and 89%, respectively¹³ . The persistence of nuchal edema at a 20 week scan increases the likelihood of an adverse outcome by 9-fold overall¹³.

Figure 4a. 4.9 mm thick 1st trimester nuchal translucency.

Figure 4b. 9.0 mm thick 1st trimester nuchal translucency.

The prevalence of major abnormalities in chromosomally normal fetuses increases from 2.5% with an NT between the 95th and 99th centile to 45% when the NT is >= 6.5 mm¹³,¹⁴. Numerous structural abnormalities have been associated with an increased NT. However, an association does not indicate that a true relationship exists between a thickened NT and a particular structural defect. The prevalence of congenital heart defects, diaphragmatic hernia, and fetal akinesia deformation sequence appears to be substantially higher in fetuses with a thickened NT than in the general population³.

The list of structural abnormalities that have been associated with a thick first trimester NT continues to increase (Table I)³ . Since some of these abnormalities have subtle features, a completely normal second trimester ultrasound examination will reduce the risk of an underlying abnormality to approximately 2%, i.e. the normal background risk of a structural malformation³,¹⁵.

Table I. Structural defects and genetic syndromes associated with a thick nuchal translucency³.

Cardiac defects
Diaphragmatic hernia
Omphalocele
Duodenal atresia
Esophageal atresia
Skeletal dysplasias
Lethal congenital arthryogryposis
Smith-Lemli-Optiz syndrome
Megacystis
Fryn syndrome
Joubert syndrome
Meckel-Gruber syndrome
VATER association

Major Cardiac Defects

In karyotypically normal fetuses with a thickened nuchal translucency, the prevalence of major cardiac defects increases exponentially with the thickness of the fetal NT. Atzei et al¹⁶ reported a prevalence of major cardiac defects of 35.2/1,000, 64.4/1,000 and 126.7/1,000 with an NT of 3.5 - 4.4 mm, 4.5 - 5.4 mm and >= 5.5 mm, respectively.

In a meta-analysis of first trimester NT screening for major cardiac defects, Makrydimas et al¹⁷ found that the 99th percentile for NT detected approximately 30% of congenital heart defects. The type of congenital heart defects reported include ventricular septal defects, tetrology of Fallot, atrioventricular canal defects, and complex cardiac abnormalties¹⁸. Hence, in karyotypically normal fetuses with a thickened NT, a careful second trimester evaluation of cardiac anatomy should be performed.

Developmental Delay

In chromosomally normal fetuses with NT >= 3.5 mm, some concern has been raised about a possible 2 - 4% risk of developmental problems in early childhood¹⁹ . When a cut-off of 4 mm is used, the risk of a significant neurologic handicap was 11.1%²⁰ . The studies to date are flawed by: 1) variable NT measurements used to enter the study group; 2) limited sample size; 3) the use of a retrospective questionnaire rather than a neonatal examination; and 4) duration of follow up after delivery. Prospective long-term follow up of children with a thickened NT and normal chromosomes is, therefore, required.

Ductus Venosus

An association has been established between absent or reversed flow in the ductus venosus and aneuploidy (Fig. 5). It has been hypothesized that the abnormal ductus venosus blood flow indicates either a defective atrial contraction or poor ventricular compliance. The finding of an abnormal ductus venosus pattern is, therefore, indirect evidence for cardiac failure as one possible etiologic mechanism of a thickened NT²¹ . In a highly selected at-risk population, Mavrides et al²² noted that an abnormal ductal pattern increased the risk of aneuploidy by 10-fold. By combining nuchal translucency serum analytes and abnormal ductal blood flow, a sensitivity of 90.5%²³ to 94%²² has been achieved for the detection of trisomy 21. However, the prevalence of absent or reversed flow in normal pregnancies has not yet been ascertained. In addition, the overlapping of signals from adjoining vessels sometimes makes interpretation of the ductal waveform patterns difficult.

Figure 5a. Diastolic flow is present within the ductus venosus (transverse).

Figure 5b. Diastolic flow is present within the ductus venosus (sagittal).

Because of the specialized nature of this test, it has not yet gained wide acceptance. Its application may lie, not in screening, but as a second-tier test to reduce the false positive rate in patients considered at risk for a karyotypic abnormality based upon the nuchal translucency measurement and serum analytes. Matias and Montenegro²⁴ have calculated that this schema would detect about 85% of trisomy 21 pregnancies after invasive testing in < 0.5% of the population. Nicolaides et al²⁵ reported a 90% detection rate for trisomy 21 with a 2% - 3% false positive rate using the same two-stage first trimester screen.

Nasal Bone Length

The assessment of the nasal bone reduces the false positive rate of a first trimester genetic screen²⁶. Since the length of the nasal bone increases with advancing gestation, the false positive rate is higher at 11, in contrast to 13, weeks. Ethnicity may also play a role in the rate of an absent nasal bone²⁷. With a fixed 1/250 risk cut-off, Orlandi et al26 increased the detection rate of first trimester screening by including an assessment of the nasal bone from 87% to 90% with a reduction in the false positive rate from 4.3% to 2.5%.

In order to visualize the nasal bone between 11 and 13 weeks 6 days, a mid-sagittal view of the profile is required. With appropriate magnification only the head and upper chest should be on the image. When the correct view is obtained the skin line and underlying nasal bone are in parallel; the echogenic tip of the nose is also on the image²⁷ (Fig. 6). Experienced sonographers generally require between 40 and 120 scans to become competent in looking for the first trimester nasal bone²⁸.

Figure 6. 1st trimester nasal bone (arrow).

The success rate of obtaining a fetal profile between 11 and 14 weeks' gestation is between 75.9%²⁹ and 98.9%²⁷ . Maternal body mass index was found to significantly affect nasal bone imaging²⁹ . The FASTER trial evaluated 6,324 first trimester patients for the presence or absence of the nasal bone and concluded that an evaluation of the nasal bone did not improve the detection rate of aneuploidy in the general population. Additional studies of a general population in which the nasal bone is assessed by appropriately trained sonographers is, therefore, required. The advantage of evaluating the nasal bone is in its reduction of the false positive rate. As a result, this examination may find a place as a second tier study in fetuses with a thick NT.

First Trimester Screening For Chromosomal And Structural Malformations

Chapter 1