The nuchal translucency and the fetal heart: a literature review

In this overview the current knowledge of the relationship between an increased nuchal translucency (NT) measurement and fetal heart structure and function in chromosomally normal fetuses is reviewed. Relevant pathophysiological theories behind the increased NT are discussed. Fetuses with an increased NT have an increased risk for congenital heart disease (CHD) with no particular bias for one form of CHD over another. This risk increases with increasing NT measurement. Although the NT measurement is only a modestly effective screening tool for all CHD when used alone, it may indeed be effective in identifying specific CHD “likely to benefit” from prenatal diagnosis. The combination of an increased NT, tricuspid regurgitation and an abnormal ductus venosus (DV) Doppler flow profile, is a strong marker for CHD. A fetal echocardiogram should be performed at 20 weeks' gestation in fetuses with an NT ≥ 95th percentile but < 99th percentile. When the NT measurement is ≥ 99th percentile, or when tricuspid regurgitation and/or an abnormal DV flow pattern is found along with the increased NT, an earlier echocardiogram is indicated, followed by a repeat scan at around 20 weeks' gestation. The resultant increased demand for early fetal echocardiography and sonographers with this special expertise needs to be planned and provided for. Copyright © 2009 John Wiley & Sons, Ltd.     

Increased nuchal translucency as a prenatal manifestation of congenital adrenal hyperplasia

We present two cases of pregnant women with a previous history of congenital adrenal hyperplasia. In both cases the only abnormal feature in the initial pregnancy had been increased nuchal translucency at 10–14 weeks of gestation. The fetal karyotype was normal and a diagnosis of congenital adrenal hyperplasia was made after delivery. In their current pregnancies, both fetuses also had increased nuchal translucency and normal fetal karyotype. Diagnosis of 21-hydroxylase deficiency was made prenatally by DNA analysis. These findings in four affected fetuses suggest that congenital adrenal hyperplasia should be added to the list of genetic anomalies associated with an increase in nuchal translucency. Copyright © 2001 John Wiley & Sons, Ltd.     

Early amniocentesis and fetal nuchal translucency in women requesting karyotyping for advanced maternal age

Fetal nuchal translucency was measured at 11–14 weeks' gestation in 97 pregnancies referred for early amniocentesis for advanced maternal age. The nuchal translucency was abnormal in 11 fetuses and the fetal karyotype was abnormal in five of these 11 cases. The karyotype was normal in 86 cases with normal nuchal translucency. The culture failure and miscarriage rates associated with early amniocentesis were 3·3 per cent and 2·2 per cent respectively. Amniotic fluid leakage occurred in 6 per cent of cases. In women requesting fetal karyotyping for advanced maternal age without additional biochemical screening, fetal nuchal translucency should be measured at 11–14 weeks. If the nuchal thickness is ≥ 3 mm, a first-trimester diagnostic procedure is indicated; however, if it is <3 mm, amniocentesis should be delayed until 16 weeks' gestation.     

First-trimester fetal heart block and increased nuchal translucency: an indication for early fetal echocardiography

Prevalence of congenital heart disease increases with nuchal translucency (NT) thickness. First-trimester fetal bradycardia may result from heart block associated with complex congenital heart disease. We report two cases detected in the first trimester of pregnancy, in which both fetuses showed an increased nuchal translucency and bradycardia. Fetal karyotype was normal in both fetuses. First-trimester fetal echocardiography was performed and, in both cases, complex congenital heart disease was diagnosed. We discuss the added role of fetal heart rate in first-trimester ultrasound screening, in fetuses with increased nuchal translucency and normal karyotype. We stress, as well, the importance of echocardiography performed in the first trimester as a potential tool for early diagnosis in selected cases. Copyright © 2005 John Wiley & Sons, Ltd.     

Promises and pitfalls of first trimester sonographic markers in the detection of fetal aneuploidy

First trimester sonographic markers are the only markers achieving detection rates above 50% in the prenatal detection of fetal aneuploidy. Although potentially they are the best markers, some concerns have arisen about its clinical application. Pitfalls may be due to inability to examine the markers, incorrect assessment, or incorrect interpretation of the findings. Markers may be unable to be examined due to maternal (maternal body habitus, previous surgery) or fetal reasons (incompatible fetal position or fetal movements). Causes of incorrect interpretation may be insufficient image magnification, incorrect caliper placement (nuchal translucency), incorrect insonation angle (nasal bone), venous contamination (ductus venosus), or arterial contamination (tricuspid regurgitation), among others. Venous contamination in ductus venosus waveforms may mimic an abnormal blood flow when it is normal, and the opposite can also occur. Finally, incorrect interpretation of a substantially increased nuchal translucency may lead to a false impression of an ominous fetal prognosis or may be confounded with a cystic hygroma. Copyright © 2008 John Wiley & Sons, Ltd.     

Nuchal translucency thickness and outcome in chromosome translocation diagnosed in the first trimester

In order to determine the significance of nuchal translucency thickness on the subsequent natural history of first-trimester fetuses with a chromosome translocation, seven consecutive cases diagnosed between 11 and 13 weeks of gestation were reviewed. Nuchal translucency measurements were successfully obtained before chorionic villus sampling (CVS) in all cases. Three fetuses had an unbalanced translocation and all were associated with increased nuchal translucency and multiple anomalies at the detailed second-trimester scan. There were no survivors in this group. The remaining four fetuses had a balanced translocation; all had normal nuchal translucency thickness and no structural anomalies were detected in the second trimester. Three of these fetuses were born at ≥35 weeks of gestation and were phenotypically normal. However, an unexpected single fetal demise occurred in a dichorionic twin pregnancy at 28 weeks of gestation. It is concluded that nuchal translucency measurements provide important prognostic information on pregnancy outcome in first-trimester fetuses with a chromosome translocation. In parents with a known balanced translocation, the detection of increased nuchal translucency at 11–14 weeks of gestation is associated with unbalanced translocations, structural anomalies and poor pregnancy outcome. Copyright © 2001 John Wiley & Sons, Ltd.     

Trisomy 10: ultrasound features and natural history after first trimester diagnosis

We report on the ultrasound features and natural history of trisomy 10. At 12 weeks' gestation in a routine scan examination, the fetus presented with increased nuchal translucency thickness, mild skin oedema, bilateral pleural effusion, marked micrognathia, cardiomegaly, unilateral talipes and reversed A-wave in the ductus venosus blood flow. Karyotyping on chorionic villus sampling (CVS) led to the diagnosis of trisomy 10, which was confirmed by fetal blood sampling at 22 weeks' gestation. As the parents opted to continue with the pregnancy, the natural history and following ultrasound features are described. This is the third case of trisomy 10 in the literature reporting on the physical features. The most frequent ultrasound findings presented in trisomy 10 are increased nuchal translucency, micrognathia, renal agenesis, facial cleft, limbabnormalities, cardiac defects and early severe growth retardation. Copyright © 2001 John Wiley & Sons, Ltd.     

Early detection of fetal cardiac abnormalities: how effective is it and how should we manage these patients?

Congenital heart defects (CHDs), the most commonly occurring congenital malformations, cause significant mortality and morbidity. With the recognition of early markers for CHD and the development of better ultrasound resolution, interest has turned toward performing a screening anomaly scan, including the heart, together with the nuchal scan. It is also possible, with adequate skill and training, to competently perform an echocardiogram <16 weeks' gestation. This article reviews the detection of major CHD in the first trimester and early second trimester including specific markers that help to identify high-risk groups for early fetal echocardiography (EFEC). CHD detection during first-trimester screening is low (2.3–56%) depending on the center's experience and the population studied. An increased nuchal translucency, abnormal ductus venosus flow, and tricuspid regurgitation in the first trimester are associated with an increased CHD risk and can be used together to identify high-risk fetuses for EFEC. EFEC requires skilled scanning and the expertise of a fetal echocardiographer. In high-risk populations, it is 78.5% sensitive with a 74.5% concordance between the EFEC and the mid-gestational echocardiogram. The availability of qualified personnel and diagnostic accuracy are prerequisites before EFEC can be introduced into management protocols. The limitations of EFEC should be recognized, and a later confirmatory echocardiogram is recommended. © 2014 John Wiley & Sons, Ltd.     

The effect of fetal gender on nuchal translucency at 10–14 weeks of gestation

Recent data have suggested that fetal nuchal translucency (NT) is affected by fetal gender. We investigated the size of this effect in 12 189 unselected pregnancies with known normal outcomes that had undergone NT measurements between 10 and 14 weeks of gestation. NT increased with gestation and was converted to multiples of the median (MoM) for the gestational day. The median NT MoM (95% CI) for female fetuses was 0.98 (0.97–0.99). This was significantly lower than that of the male fetuses (1.03; range1.02–1.04) (p<0.0005; Wilcoxon rank-sum test). The gender difference was not observed at 10 weeks but was observed from 11 weeks onwards. There is no obvious explanation for the above findings. Copyright © 2001 John Wiley & Sons, Ltd.     

Turner syndrome-omphalocele association: Incidence,karyotype, phenotype and fetal outcome

Objective

Omphalocele is known to be associated with genetic anomalies like trisomy 13, 18 and Beckwith–Wiedemann syndrome, but not with Turner syndrome (TS). Our aim was to assess the incidence of omphalocele in fetuses with TS, the phenotype of this association with other anomalies, their karyotype, and the fetal outcomes.

Method

Retrospective multicenter study of fetuses with confirmed diagnosis of TS. Data were extracted from a detailed questionnaire sent to specialists in prenatal ultrasound.

Results

680 fetuses with TS were included in this analysis. Incidence of small omphalocele in fetuses diagnosed ≥12 weeks was 3.1%. Including fetuses diagnosed before 12 weeks, it was 5.1%. 97.1% (34/35) of the affected fetuses had one or more associated anomalies including increased nuchal translucency (≥3 mm) and/or cystic hygroma (94.3%), hydrops/skin edema (71.1%), and cardiac anomalies (40%). The karyotype was 45,X in all fetuses. Fetal outcomes were poor with only 1 fetus born alive.

Conclusion

TS with 45,X karyotype but not with X chromosome variants is associated with small omphalocele. Most of these fetuses have associated anomalies and a poor prognosis. Our data suggest an association of TS with omphalocele, which is evident from the first trimester.     

Detection of fetal structural abnormalities at the 11–14 week ultrasound scan

The aim of this study was to evaluate the detection of fetal structural abnormalities by the 11–14 week scan. 2853 pregnant women were submitted to a routine ultrasound scan between the 11th and 14th week and the fetal skull, brain, spine, abdominal wall, limbs, stomach and bladder were examined. Following the scans the patientes were examined in the second or third trimester of pregnancy. An isolated increased nuchal translucency was not considered an abnormality. However, these patients had an early echocardiography assessment. Fetal structural abnormalities were classified as major or minor and of early or late onset. A total of 130 (4.6%) defects were identified and 29 (22.3%) of these were diagnosed at the 11–14 week scan, including nine cardiac defects associated with increased nuchal translucency. The antenatal ultrasound detection rate was 71.5%, and 31.2% were detected in the first-trimester assessment. 78.8% of the major defects were diagnosed by the prenatal scan and 37.8% by the 11–14 week scan. Fetal structural abnormalities at the 11–14 week scan were detected in approximately 22.3% of the cases, therefore, a second-trimester anomaly scan is important in routine antenatal care to increase the prenatal detection of fetal defects. Copyright © 2002 John Wiley & Sons, Ltd.     

Cardiac flow after fetal blood sampling in normally grown and growth-retarded fetuses

The objective of this study was to evaluate the effect of fetal blood sampling on cardiac flow velocity waveforms. Flow velocity waveforms were measured from the ascending aorta and pulmonary artery immediately before and after fetal blood sampling in 29 normally grown and 12 growth-retarded fetuses. The latter group was characterized by abnormal Doppler indices in the umbilical artery and middle cerebral artery suggestive of uteroplacental insufficiency as the causative factor of the impaired growth. The flow velocity parameters studied were the peak velocity, the time to peak velocity, and the left and right cardiac output and their ratio. In normally grown fetuses, the peak velocity and right and left cardiac output values increased significantly after fetal blood sampling, while no significant changes were observed in the other indices considered. The gestational age at the time of the procedure was positively related to the amplitude of these changes. In growth-retarded fetuses, fetal blood sampling did not induce any significant increase in cardiac output or peak velocities, while in more than 50 per cent of the fetuses these Doppler indices decreased. The amplitude of the decrease was significantly related to the severity of acidosis in the umbilical vein. In conclusion, the cardiac haemodynamic response to fetal blood sampling differs between normally grown and growth-retarded fetuses. This difference may explain the higher rate of complications occurring in the latter group of fetuses after blood sampling.     

Does nuchal translucency have a role in fetal cardiac screening?

Increased nuchal translucency is the strongest single marker for chromosomal abnormality. Consequently, it is currently becoming established as the foundation of most early screening programmes for Down syndrome. In the absence of chromosomal abnormality, increased nuchal translucency has been shown to be associated with other congenital anomalies including cardiac defects. Several datasets have now reported this association and here these are reviewed to assess the effectiveness of nuchal translucency measurement as a screening tool for the prenatal detection of congenital heart disease. Copyright © 2004 John Wiley & Sons, Ltd.     

Gender impact on first trimester markers in Down syndrome screening

The influence of fetal gender on the level in the first trimester of the serological markers alpha-fetoprotein (AFP), pregnancy-associated plasma protein-A (PAPP-A) and free beta human chorionic gonadotropin (βhCG) and on nuchal translucency is described for 2637 singleton pregnancies with normal outcome. Mean log MoM values for pregnancies with female and male fetuses were calculated using regression of log marker values on gestational age expressed as crown rump length and on maternal weight. A pronounced gender impact was found for free βhCG, being 16% higher for female than for male fetuses. Copyright © 2002 John Wiley & Sons, Ltd.     

Quantitative evaluation of collagen type VI and SOD gene expression in the nuchal skin of human fetuses with trisomy 21

Objective To investigate the involvement of the genes encoding for COL6A1, COLA2 and super-oxide dismutase (SOD) in the mechanism for the retention of subcutaneous fluid in fetuses with trisomy 21. Methods During a 7-month period (November 2004–May 2005), human fetal skin from the nuchal region was obtained from euploid fetuses and from fetuses with trisomy 21 following abortions and terminations of pregnancy. Cell cultures were performed from nuchal skin. Quantification of COL6A1, COL6A2, COL6A3 and SOD mRNAs were performed using real-time quantitative RT-PCR. Results Twelve fetuses were studied between 13–15 and 19–20 weeks of gestation including 7 cases of trisomy 21. A significant overexpression of genes of interest was demonstrated in trisomy 21 fetuses when compared with euploid fetuses, in the first and in the second trimester of pregnancy (p < 0.0001). Conclusion This study demonstrates a homogeneous overexpression of the genes encoding for α1 and α2 chains of Collagen type VI, and SOD in nuchal skin of human trisomy 21 fetuses. Persistence of this overexpression in the second trimester of pregnancy, despite the absence of an enlarged nuchal translucency (NT), may characterize some compensatory mechanisms. Copyright © 2007 John Wiley & Sons, Ltd.     

Screening for fetal aneuploidies at 11 to 13 weeks

Effective screening for major aneuploidies can be provided in the first trimester of pregnancy. Screening by a combination of fetal nuchal translucency and maternal serum free-β-human chorionic gonadotrophin and pregnancy-associated plasma protein-A can identify about 90% of fetuses with trisomy 21 and other major aneuploidies for a false-positive rate of 5%. Improvement in the performance of first-trimester screening can be achieved by firstly, inclusion in the ultrasound examination assessment of the nasal bone and flow in the ductus venosus, hepatic artery and across the tricuspid valve, and secondly, carrying out the biochemical test at 9 to 10 weeks and the ultrasound scan at 12 weeks. Copyright © 2011 John Wiley & Sons, Ltd.     

The clinical impact of the first-trimester nuchal translucency between the 95th–99th percentiles

Objectives

To evaluate the clinical significance of nuchal translucency (NT) between the 95th–99th percentile in terms of typical and atypical chromosomal abnormalities (ACAs), associated fetal congenital defects and postnatal outcome.

Methods

A retrospective cohort study of fetuses with NT between the 95th–99th percentile. Data regarding the rate of associated fetal defects, genetic abnormalities and postnatal outcome were collected.

Results

A total of 306 cases of fetuses with an NT between the 95th–99th percentiles were included. The overall rate of genetic abnormalities was 12.1% (37/306). Chromosomal abnormalities were found in 10.1% (31/306) of cases and 2% were ACA (6/306). Within this group, two were pathogenic Copy Number Variants (CNVs) and four were single gene disorders. The overall rate of fetal congenital defects was 13.7% (42/306). All ACAs were found in fetuses with congenital defects. Postnatally, a new diagnosis of a single gene disorder was made in 0.85% of cases (2/236).

Conclusions

The presence of an NT between the 95th–99th percentiles carries a 10-fold increased risk of fetal defects, representing an indication for referral for a detailed fetal anatomy evaluation. The risk of ACA is mainly related to the presence of fetal defects, irrespective of the combined test risk.     

Does a ‘notched’ nuchal translucency indicate Down syndrome fetuses or other adverse pregnancy outcome?

The aim of the present study was to assess the sonographic contour of the increased nuchal translucency (NT) and to correlate this with pregnancy outcome. Fifty sonographic images of fetuses with increased NT [>95th centile thickness of the normal range for crown–rump length (CRL) between 38 and 84 mm] were retrospectively assessed. In all the cases a complete pregnancy and even infancy follow-up (<36 months) was available. The NT appearances were subdivided into two forms: a ‘notched’ or ‘uniform’ appearance. The images were correlated with karyotype results [trisomy 21 (DS) vs euploid cases] and pregnancy outcome. Complicated outcomes were classified as being either DS fetuses, miscarriage or termination of pregnancy because of structural anomaly. Thus 30/35 (86%) of the euploid fetuses had a ‘uniformly’ increased NT, whereas 8/13 DS cases (62%) had a ‘notched’ appearance (Fisher's exact test, p=0.004). Additionally, 27/29 fetuses (93%) which had an uneventful pregnancy outcome had a ‘uniform’ increased NT, whereas 12/26 (57%) of the fetuses which had adverse pregnancy outcome had a ‘notched’ appearance of their NT (Fisher's exact test, p<0.001). Although it was not possible to correlate the sonographic data with post-evacuation microdissection findings, it is possible that a uniformly shaped, increased NT may be more representative of a developmental delay in a normal fetus. Conversely, a ‘notched’ nuchal surface may represent abnormal lymphatic or cardiovascular development more commonly seen in DS fetuses. Copyright © 2001 John Wiley & Sons, Ltd.     

Is there still a role for nuchal translucency measurement in the changing paradigm of first trimester screening?

Objectives

To give an overview of the genetic and structural abnormalities occurring in fetuses with nuchal translucency (NT) measurement exceeding the 95th percentile at first-trimester screening and to investigate which of these abnormalities would be missed if cell-free fetal DNA (cfDNA) were used as a first-tier screening test for chromosomal abnormalities.

Methods

This is a national study including 1901 pregnancies with NT≥95th percentile referred to seven university hospitals in the Netherlands between 1 January 2010 and 1 January 2016. All cases with unknown pregnancy outcome were excluded. Results of detailed ultrasound examinations, karyotyping, genotyping, pregnancy and neonatal outcomes, investigation by a clinical geneticist and post-mortem investigations were collected.

Results

In total, 821 (43%) pregnancies had at least one abnormality. The rate of abnormalities was 21% for fetuses with NT between 95^th and 99^th percentile and 62% for fetuses with NT≥99^th percentile. Prevalence of single-gene disorders, submicroscopic, chromosomal and structural abnormalities was 2%, 2%, 30% and 9%, respectively.

Conclusion

Although cfDNA is superior to the combined test, especially for the detection of trisomy 21, 34% of the congenital abnormalities occurring in fetuses with increased NT may remain undetected in the first trimester of pregnancy, unless cfDNA is used in combination with fetal sonographic assessment, including NT measurement.     

Three- versus two-dimensional ultrasound for nuchal translucency thickness measurements: comparison of feasibility and levels of agreement

We have determined feasibility and levels of agreement for visualizing the nuchal translucency within a time limit with three-dimensional (3D) and two-dimensional (2D) transvaginal ultrasound. A total of 213 women of median gestational age 13 weeks (range 11–14 weeks) undergoing first-trimester nuchal translucency (NT) thickness measurements with 2D transabdominal ultrasound were included in the study. Additionally all women underwent 2D and 3D transvaginal NT examination within a time limit of 90 s. These two methods were compared with each other and with our standard method (2D transabdominal ultrasound) with respect to visualization of fetal nuchal fold and to the levels of agreement. The nuchal fold was visualized by 3D and 2D transvaginal ultrasound in 85.9% (95% CI: 80.5%, 90.3%) and 25.8% (95% CI: 20.1%, 32.2%), respectively (p<0.001). There was a statistically significant underestimation of the NT by 2D transabdominal as compared with 3D transvaginal ultrasound of 0.1 mm (p<0.001), and by 3D transvaginal as compared with 2D transvaginal ultrasound of even 0.1 mm (p<0.001). 3D transvaginal ultrasound of the nuchal fold has increased feasibility to 2D transvaginal ultrasound within a short examination time and with minimal, but significant, measurement differences. Copyright © 2001 John Wiley & Sons, Ltd.