Obstetrics & Gynecology:
Relation Between Increased Fetal Nuchal Translucency Thickness and Chromosomal Defects
Kagan, Karl Oliver MD1; Avgidou, Kyriaki MD1; Molina, Francisca S. MD1; Gajewska, Katarzyna MD1; Nicolaides, Kypros H. MD1
From the 1Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital Medical School, London, United Kingdom.
See related editorial on page 2.
Supported by a grant from the Fetal Medicine Foundation (Charity No. 1037116).
Corresponding author: Professor K. H. Nicolaides, Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital Medical School, Denmark Hill, London SE5 8RX, United Kingdom; e-mail: firstname.lastname@example.org.
OBJECTIVE: To examine the prevalence and distribution of all chromosomal defects in fetuses with increased nuchal translucency thickness.
METHODS: Assessment of risk for trisomy 21 was carried out by a combination of maternal age and fetal nuchal translucency thickness at 11–13 + 6 weeks. A search of the database was made to identify, first, all singleton pregnancies in which fetal karyotyping was carried out and, second, the cases where the fetal nuchal translucency was equal to or above the 95th centile for fetal crown-rump length. The prevalence and distribution of chromosomal defects were determined for each nuchal translucency category: between the 95th centile for crown-rump length and 3.4 mm, 3.5–4.4 mm, 4.5–5.4 mm, 5.5–6.4 mm, 6.5–7.4 mm, 7.5–8.4 mm, 8.5–9.4 mm, 9.5–10.4 mm, 10.5–11.4 mm, and 11.5 mm or more.
RESULTS: The search identified 11,315 pregnancies. The median maternal age was 34.5 (range 15–50) years, and the median fetal crown-rump length was 64 (range 45–84) mm. The fetal karyotype was abnormal in 2,168 (19.2%) pregnancies, and the incidence of chromosomal defects increased with nuchal translucency thickness from approximately 7% for those with nuchal translucency between the 95th centile for crown-rump length and 3.4 mm to 75% for nuchal translucency of 8.5 mm or more. In the majority of fetuses with trisomy 21, the nuchal translucency thickness was less then 4.5 mm, whereas in the majority of fetuses with trisomies 13 or 18 it was 4.5–8.4 mm, and in those with Turner syndrome it was 8.5 mm or more.
CONCLUSION: In fetuses with increased nuchal translucency, approximately one half of the chromosomally abnormal group is affected by defects other than trisomy 21. The distribution of nuchal translucency is different for each type of chromosomal defect.
LEVEL OF EVIDENCE: II-3
Fetal nuchal translucency refers to the sonographic finding of a subcutaneous collection of fluid behind the fetal neck in the first trimester of pregnancy, and the term is used irrespective of whether the fluid is septated and whether it is confined to the neck or envelopes the whole fetus.1 Nuchal translucency is considered to be increased if the vertical thickness, measured in the midsagittal section of the fetus, is equal to or above the 95th centile of a reference range established in a screening study involving 96,127 pregnancies.2 The 95th centile of nuchal translucency increased linearly with fetal crown-rump length (CRL) from 2.1 mm at a CRL of 45 mm to 2.7 mm for CRL of 84 mm, whereas the 99th centile did not change with CRL, and it was approximately 3.5 mm.2
Increased nuchal translucency is associated with trisomy 21 and other chromosomal abnormalities as well as many fetal malformations and genetic syndromes.3–5 Several studies have established that, first, increased nuchal translucency, both on its own and in combination with other sonographic or maternal serum biochemical markers, is effective in first trimester screening for trisomy 21, and second, the incidence of trisomy 21 increases with fetal nuchal translucency thickness.3 The aim of this study was to examine the prevalence and distribution of all chromosomal defects in fetuses with increased nuchal translucency thickness.
PATIENTS AND METHODS
This was a retrospective study examining the relation between nuchal translucency thickness and chromosomal abnormalities in singleton pregnancies with increased nuchal translucency at 11–13 + 6 weeks of gestation. In our center assessment of risk for trisomy 21 by a combination of maternal age and fetal nuchal translucency has been carried out since 1992.1–3 In all patients attending for the 11–13 + 6 weeks scan, maternal demographic characteristics and ultrasound findings, including nuchal translucency thickness and CRL, were recorded in a computer database. The patient-specific risk for trisomy 21 was calculated by multiplying the maternal age and gestational age–related risk by the likelihood ratio for fetal nuchal translucency, which is dependent on the degree of deviation in the measured nuchal translucency from the normal median for the same CRL.2 The parents were counseled regarding the estimated risk for trisomy 21, and if they considered this risk to be high, they were offered the option of an invasive diagnostic test—chorionic villus sampling or amniocentesis. Karyotype results and details on pregnancy outcomes were added into the computer database as soon as these became available.
A search of the database was made to identify, first, all pregnancies in which fetal karyotyping was carried out between January 1992 and April 2005, and second, the cases where the fetal nuchal translucency was equal to or above the 95th centile for fetal CRL.2 Approval for the study was obtained from King’s College Hospital Research Ethics Committee.
The prevalence and distribution of chromosomal defects were estimated for each nuchal translucency category: between the 95th centile for CRL and 3.4 mm, 3.5–4.4 mm, 4.5–5.4 mm, 5.5–6.4 mm, 6.5–7.4 mm, 7.5–8.4 mm, 8.5–9.4 mm, 9.5–10.4 mm, 10.5–11.4 mm, and 11.5 mm or more. The prevalence of trisomies 21, 18, and 13 increases with maternal age and decreases with gestational age.6,7 The prevalence of Turner syndrome, other sex chromosome aneuploidies, and triploidy does not change with maternal age but decreases with gestation, and at 12 weeks the respective prevalences are approximately 1 in 1,500, 1 in 500, and 1 in 2,000.7 For each nuchal translucency category, the maternal and gestational age distribution and the previously published risk for each aneuploidy were used6,7 to estimate the expected number of fetuses with trisomies 21, 18, and 13, Turner syndrome, other sex chromosome aneuploidies, and triploidy. The observed-to-expected ratio was then calculated, and regression analysis was used to determine the significance of the association between the ratio and nuchal translucency thickness.
Fetal karyotyping was performed in 11,315 singleton pregnancies with high nuchal translucency thickness. The median maternal age was 34.5 (range 15–50) years, and the median fetal CRL was 64 (range 45–84) mm. The fetal karyotype was abnormal in 2,168 (19.2%) pregnancies, including 1,170 cases of trisomy 21 (Table 1). The overall incidence of chromosomal defects increased with nuchal translucency thickness from approximately 7% for those with nuchal translucency between the 95th centile for CRL and 3.4 mm to 20% for nuchal translucency of 3.5–4.4 mm, 50% for nuchal translucency of 5.5–6.4 mm, and 75% for nuchal translucency of 8.5 mm or more. In the majority of fetuses with trisomy 21, the nuchal translucency thickness was less than 4.5 mm, whereas in the majority of fetuses with trisomies 13 or 18, it was 4.5–8.4 mm, and in those with Turner syndrome, it was 8.5 mm or more.
The observed prevalence of trisomies 21, 18, and 13, Turner syndrome, other sex chromosome aneuploidies, and triploidy was higher than the respective prevalences estimated on the basis of the maternal age and gestational age distribution of the population (Table 2). The observed-to-expected ratio increased significantly with nuchal translucency thickness for trisomy 21 (r = 0.919, P = .008), trisomy 18 (r = 0.970, P < .001), trisomy 13 (r = 0.870, P = .007), Turner syndrome (r = 0.987, P < .001) and other sex chromosome abnormalities (r = 0.759, P = .011) but not for triploidy (r = 0.684, P = .255) (Fig. 1).
The findings of this study confirm the high association between increased nuchal translucency and trisomy 21 as well as other chromosomal defects.1–3 Thus, the incidence of chromosomal defects increases with nuchal translucency thickness from approximately 7% for those with nuchal translucency between the 95th centile for CRL and 3.4 mm to 75% for nuchal translucency of 8.5 mm or more.
The data demonstrate that in fetuses with increased nuchal translucency approximately one half of the chromosomally abnormal group is affected by defects other than trisomy 21. Furthermore, the distribution of nuchal translucency is different for each type of chromosomal defect. Thus, the nuchal translucency thickness was less than 4.5 mm in approximately 50% of fetuses with trisomy 21 and those with triploidy. In contrast, the nuchal translucency thickness was 4.5 mm or more in approximately 60% of fetuses with trisomy 13, 75% of those with trisomy 18, and 90% of fetuses with Turner syndrome. Additionally, the observed-to-expected ratio of trisomies 21, 18, and 13 increases with nuchal translucency thickness to a peak at approximately 8–9 mm and thereafter decreases, whereas in the case of Turner syndrome, the ratio increases exponentially with fetal nuchal translucency. For other sex chromosome defects the ratio decreases with nuchal translucency, and for triploidy it does not change significantly with nuchal translucency.
The difference in phenotypic pattern of nuchal translucency thickness characterizing each chromosomal defect presumably reflects the heterogeneity in causes for the abnormal accumulation of subcutaneous fluid in the nuchal region. Suggested mechanisms for increased nuchal translucency include cardiac dysfunction in association with abnormalities of the heart and great arteries;8,9 superior mediastinal compression due to diaphragmatic hernia, which is commonly found in fetuses with trisomy 18;10,11 failure of lymphatic drainage due to impaired development of the lymphatic system, which has been demonstrated by immunohistochemical studies in nuchal skin tissue from fetuses with Turner syndrome;12 and altered composition of the subcutaneous connective tissue, leading to the accumulation of subcutaneous edema.13,14 Although cardiac defects are commonly found in association with all major chromosomal abnormalities, there are differences in the pattern of cardiac defects and consequently different severities of cardiac dysfunction.8,9 Many of the component proteins of the extracellular matrix are encoded on chromosomes 21, 18, or 13, and immunohistochemical studies of the skin of chromosomally abnormal fetuses have demonstrated specific alterations of the extracellular matrix that may be attributed to gene dosage effects. Thus, the dermis of trisomy 21 fetuses is rich in collagen type VI, whereas dermal fibroblasts of trisomy 13 fetuses demonstrate an abundance of collagen type IV and those of trisomy 18 fetuses an abundance of laminin.13,14
The clinical implications of our findings are, first, increased nuchal translucency is an effective marker not only of trisomy 21 but also of all major chromosomal defects and, second, in nuchal translucency screening for trisomy 21, the finding of increased nuchal translucency should prompt ultrasonographers to consider the possibility of other chromosomal defects and undertake a systematic examination of the fetus for detectable features of such defects. These include nasal bone hypoplasia and atrioventricular septal defect in trisomy 21, fetal growth restriction, diaphragmatic hernia, exomphalos, overlapping fingers and single umbilical artery in trisomy 18, holoprosencephaly, facial cleft, megacystis, polydactyly and tachycardia in trisomy 13, fetal growth restriction and tachycardia in Turner syndrome, and severe asymmetrical growth restriction with either molar or hypoplastic placenta in diandric and digynic triploidy respectively.15–23
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