First Trimester Screening for Chromosomal Aneuploidies

INTRODUCTION

The incidence of fetal numerical chromosomal aneuploidies such as trisomy 21 (T21; Down syndrome), trisomy 18 (T18; Edwards syndrome), and trisomy 13 (T13; Patau syndrome) increases with advancing maternal age. The presence of fetal chromosomal aneuploidies has been associated with significant pregnancy complications such as multiple malformations, growth restriction, and perinatal deaths. Prenatal screening for chromosomal aneuploidies has received significant attention over the past 30 years and is now considered an integral part of prenatal care. Several major developments impacted prenatal screening for chromosomal abnormalities, such as the identification of ultrasound markers for aneuploidy, the introduction of the second trimester biochemical screen, the introduction of the first trimester screen with nuchal translucency (NT), and recently fetal cell-free DNA in maternal plasma. Advancement in aneuploidy screening has currently led to the prenatal identification of most fetuses with chromosomal abnormalities. The largest study to date on the first trimester role of thickened NT and major malformations in the detection of chromosomal aneuploidies was recently published¹ and included a total of 108,982 fetuses with 654 cases of trisomies 21, 18, or 13. The presence of at least one of the following findings: thickened NT (>3.5 mm), holoprosencephaly, omphalocele, or megacystis had the potential to detect 57% of all aneuploidies. Interestingly, one or more of these four findings was found in 53% of all T21, in 72% of all T18, and 86% of all T13 fetuses.¹ In this chapter, we present detailed first trimester sonographic features of aneuploidies in addition to aspects of other genetic diseases and syndromes.

FIRST TRIMESTER ULTRASOUND AND MATERNAL BIOCHEMICAL MARKERS IN ANEUPLOIDY

Trisomy 21

The association in the first trimester fetus of increased nuchal fluid and aneuploidy was first described more than two decades ago,², ³, ⁴ and this finding has led to the establishment of first trimester aneuploidy screening with NT and biochemical markers. A thickened NT has been correlated with the presence of trisomy 21 (T21) and T21 fetuses have a mean NT thickness of 3.4 mm.⁵ In a study involving 654 fetuses with T21, more than half were shown to have an NT ≥3.5 mm.¹ The NT in the normal fetus increases with increasing crown-rump length (CRL) measurement and NT screening has been successfully used to adjust the pregnancy’s aneuploidy a priori risk established by maternal age. This has been one of the most important elements of aneuploidy screening as it resulted in a significant reduction in unnecessary invasive testing on pregnant women with advanced maternal age.

In pregnancies with T21 fetuses, the maternal serum concentration of free β-human chorionic gonadotropin (β-hCG) is about twice as high and pregnancy-associated plasma protein A (PAPP-A) is reduced to half compared to euploid pregnancies (Table 6.1). Although NT measurement alone identifies about 75% to 80% of T21 fetuses, the combination of NT with maternal biomarkers in the first trimester increases the T21 detection rate to 85% to 95%, while keeping the false-positive rate at 5%.⁵,⁶ Indeed, in a recent prospective validation study of screening for trisomies 21, 18 and 13 by a combination of maternal age, fetal NT, fetal heart rate and serum free β-hCG
and PAPP-A at 11+0 to 13+6 weeks of gestation in 108,982 singleton pregnancies, T21, 18, and 13 were detected in 90%, 97%, and 92% respectively with a false-positive rate of 4%.⁶ Monosomy X was also detected in more than 90% of cases along with more than 85% of triploidies and more than 30% of other chromosomal abnormalities.⁶ In addition to NT, other sensitive first trimester ultrasound markers of T21 include absence or hypoplasia of the nasal bone (Fig. 6.1), cardiac malformations (atrioventricular septal defect) with or without generalized edema (Figs. 6.2 and 6.3), tricuspid regurgitation (Fig. 6.4A), aberrant right subclavian artery (Fig. 6.4B), echogenic intracardiac focus (Fig. 6.4C), and increased impedance
to flow in the ductus venosus (Fig. 6.5). First trimester features of fetuses with T21 are listed in Table 6.2. Additional first trimester findings in T21 fetuses are shown in images in various chapters of this book.

Table 6.1 • Biochemical and Sonographic Features of Trisomies 21, 18, and 13

NT Mixture Model	Euploid	Trisomy 21	Trisomy 18	Trisomy 13
CRL-independent distribution, %	5	95	70	85
Median CRL-independent NT, mm	2.0	3.4	5.5	4.4
Median serum free β-hCG, MoM	1.0	2.0	0.2	0.5
Median serum PAPP-A, MoM	1.0	0.5	0.2	0.3
Absent nasal bone, %	2.5	60	53	45
Tricuspid regurgitation, % %	1.0	55	33	30
Ductus venosus reversed A-wave, %	3.0	66	58	55
NT, nuchal translucency; CRL, crown-rump length; β-hCG, β-human chorionic gonadotropin; MoM, multiple of the median; PAPP-A, pregnancy-associated plasma protein A.
From Nicolaides KH. Screening for fetal aneuploidies at 11 to 13 weeks. Prenat Diagn. 2011;31:7-15; copyright John Wiley & Sons, with permission.

Figure 6.1: Midsagittal view of the face in six fetuses with trisomy 21 between 11 and 13 weeks of gestation. Note the various thicknesses of the nuchal translucency (asterisk) and the absence (A, C, F) or poor ossification (B, D, E) of the nasal bone (arrows).

Figure 6.2: Sagittal view of the fetal head and chest (A) and transverse view of the chest (B) in a fetus with trisomy 21 at 13 weeks of gestation. Note the presence of early hydrops with body skin edema (white arrows in A and B) and a thickened nuchal translucency (asterisk in A). Note also the presence of an atrioventricular septal defect (yellow arrow) in B.

Figure 6.3: Transverse views of the fetal chest at the level of the four-chamber view in gray scale (A) and color Doppler (B) in a fetus with trisomy 21 at 12 weeks of gestation. Note the presence of an atrioventricular septal defect (asterisk) in A and B, which represents the typical cardiac anomaly of this syndrome. Also note the associated body edema (arrows), which resolved at 16 weeks upon follow-up. See Figure 6.4 for additional sonographic markers of trisomy 21 in the first trimester. LV, left ventricle; RV, right ventricle.

Trisomy 18 and Trisomy 13

Thickened NT is not specific to T21 as it can be also found in other aneuploidies. In T18 and T13, NT median values were shown to be 5.5 and 4.0 mm, respectively.⁵,⁶ The PAPP-A value is also reduced in both trisomies with a median value of 0.2 MoM for T18 and 0.3 MoM for T13. Unlike in T21, free β-hCG values are decreased in T18 and T13 with median values of 0.2 MoM and 0.5 MoM, respectively (Table 6.1). For physicians and sonographers with expertise in the first trimester ultrasound examination, T18 or T13 is often first suspected by the presence of typical ultrasound features, rather than by biochemical screening. In a study involving 5,613

normal fetuses and 37 fetuses with T18, the first trimester ultrasound examination was found to be a good screening test for T18.⁷ The mean NT thickness was 5.4 mm in T18 fetuses as compared to 1.7 mm in euploid fetuses.⁷ Congenital heart defects were observed in 70.3% of T18 fetuses and in 0.5% of euploid fetuses and extracardiac malformations were identified in 35.1% of T18 fetuses and in 0.8% of euploid fetuses.⁷ Only one case of T18 demonstrated no sonographic markers of aneuploidy.⁷

Figure 6.4: Additional sonographic findings in fetuses with trisomy 21 in the first trimester. Tricuspid regurgitation shown in A on color and pulsed (arrow) Doppler, an aberrant course of the right subclavian artery (ARSA) shown in B and an echogenic intracardiac focus shown in the left ventricle (LV) in C (arrow). RA, right atrium; RV, right ventricle.

Figure 6.5: Ductus venosus (DV) Doppler flow assessment in two fetuses (A and B) with trisomy 21 at 13 weeks of gestation. Note the presence of reverse flow during the atrial contraction phase (A) of the cardiac cycle (arrow). Fetus A had no associated cardiac defect, whereas fetus B had a cardiac defect, which may explain the more severe reverse flow of the A-wave (arrow in B). Normal Doppler waveforms of the ductus venosus show antegrade flow throughout the cardiac cycle with low impedance. S, systolic flow; D, diastolic flow.

Table 6.2 • First Trimester Features of Trisomy 21

Thickened nuchal translucency (NT)

High human chorionic gonadotropin (HCG, β-hCG)

Low pregnancy-associated plasma protein A (PAPP-A)

Absent or hypoplastic nasal bone

Reversal of flow in diastole or high impedance flow in ductus venosus

Tricuspid regurgitation

Increased fronto-maxillary-facial (FMF) angle, short maxilla reflecting midface hypoplasia

Aberrant right subclavian artery

Echogenic focus

Echogenic bowel

Renal tract dilation

Increased peak velocity in the hepatic artery

Ductus venosus directly draining into the inferior vena cava

Structural anomalies such as atrioventricular septal defect, tetralogy of Fallot, and others

Figure 6.6: Midsagittal view of the body of a fetus with trisomy 18 at 12 weeks of gestation showing several typical abnormalities. Note the short crown-lump length (1), the thickened nuchal translucency (2), the absence of an ossified nasal bone (3), the dilated fourth ventricle (4), the small omphalocele with bowel content (5), and the maxillary gap as a sign of cleft lip and palate (6). See Figures 6.7, 6.8, 6.9, 6.10 and 6.11 for associated fetal abnormalities with trisomy 18.

Figures 6.6, 6.7, 6.8, 6.9, 6.10, 6.11, 6.12, 6.13, 6.14, 6.15, 6.16 and 6.17 show common sonographic features of T18 in the first trimester, including thickened NT (Figs. 6.6, 6.8, and 6.9), absent/hypoplastic nasal bone (Figs. 6.6 and 6.8), dilated fourth ventricle/abnormal posterior fossa (Figs. 6.6, 6.7 and 6.8), megacystis (Fig. 6.7), spina bifida (Figs. 6.7 and 6.8), cardiac malformations (Figs. 6.10, 6.11 and 6.12), small omphalocele (Figs. 6.6, 6.7, and 6.13), abnormal extremities (Figs. 6.14 and 6.15), cleft lip and palate (Figs. 6.6 and 6.15), short CRL (Figs. 6.6, 6.7, and 6.15), and single umbilical artery/cord abnormalities (Fig. 6.16 and 6.17).¹,⁸

Figure 6.7: Midsagittal view of the body of a fetus with trisomy 18 at 13 weeks of gestation showing typical associated abnormalities. Note the presence of a short crown-rump length (1), an omphalocele (2), a megacystis (3), an abnormal posterior fossa (4), and thickened brainstem and no fluid in the fourth ventricle due to an open spina bifida (5). Note that the nuchal translucency (6) is not markedly thickened.

Figure 6.8: Midsagittal view of the fetal face in three fetuses (A-C) with trisomy 18 at 13, 12, and 14 weeks of gestation, respectively. Note the presence of a normal nuchal translucency (NT) in A, a mildly increased NT in C, and a markedly increased NT in B. All three fetuses have an absent or poorly ossified nasal bone (NB). The posterior fossa is an interesting marker in trisomy 18 and can be normal as in fetus A, but is often dilated as seen in fetus B (open arrow) and occasionally compressed as in fetus C (double headed arrow) in the presence of an open spina bifida. Fetus A was diagnosed with trisomy 18 due to the presence of radius aplasia (see Fig. 6.14) and cardiac abnormalities. Fetus B has a cleft in the maxilla (arrow) suggesting the presence of a facial cleft.

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