Over the years, it has become clear that increased nuchal translucency is a marker for chromosomal abnormalities, and it is also associated with a wide spectrum of structural anomalies, genetic syndromes, a higher risk of miscarriage, and intrauterine fetal death. These risks are all proportionally related to the degree of nuchal translucency enlargement.
After the initial assessment of increased nuchal translucency, parents should be counselled by the fetal medicine specialist about the possible outcomes and the value of additional karyotyping and array comparative genomic hybridisation. A detailed late first-trimester and subsequent 20-week scan should aim at identifying structural anomalies, with special focus on the fetal heart and subtle dysmorphic features. In the absence of structural anomalies or markers, the chance of a favourable outcome is high.
Introduction
In 1992, Nicolaides et al. proposed nuchal translucency measurement as a marker for chromosomal abnormalities in the first trimester of pregnancy. Over the years, it has become clear that an increased nuchal translucency is also associated with a wide spectrum of structural anomalies, genetic syndromes, a higher risk of miscarriage, and intrauterine fetal death. These risks are all proportionally related to the degree of nuchal translucency enlargement .
At present, the most challenging part of managing pregnancies with increased nuchal translucency, after exclusion of chromosomal aberrations, is to establish an adequate diagnostic work up, and provide parents with realistic and correct information about outcome, especially long-term neurological outcome in the absence of structural anomalies .
In this chapter, we provide an overview of issues relating to nuchal translucency. We subsequently suggest a protocol for managing these pregnancies to aid parental counselling once a normal karyotype or genotype has been confirmed.
At present, nuchal translucency measurement is offered in most countries as part of first-trimester screening for Down’s syndrome. Participation rates vary considerably per country, as its uptake is influenced by local policies, socioeconomic factors, attitude towards Down’s syndrome screening, and termination of pregnancy . When women are informed about first-trimester screening, the focus of counselling is primarily on the detection of Down’s syndrome. They should, however, be informed that this type of screening may detect many other chromosomal anomalies, and an increased nuchal translucency is also a powerful marker for cardiac anomalies, other structural anomalies, and genetic syndromes . Furthermore, fetuses with an increased nuchal translucency have an increased risk of adverse pregnancy outcome, such as fetal loss and developmental delay .
Increased nuchal translucency
Nuchal translucency is a subcutaneous accumulation of fluid behind the neck of the fetus and generally visible by ultrasound up to 15 weeks of gestation. The size of the nuchal translucency is influenced by gestational age and is part of normal development . Nuchal translucency is considered abnormal only when it exceeds a certain cut-off . Many different definitions and cut-offs for increased nuchal translucency have been used in the past . Although debate continues about whether nuchal translucency should be regarded as an increase above the 95th or 99th centile, there is consensus that nuchal translucency above the 99 th centile (3.5 mm) is definitely increased.
Nuchal translucency seems to be influenced by gender. Two studies have shown that male fetuses tend to have a slightly larger nuchal translucency than females, about 0.06–0.1 mm , but this finding could not be confirmed by another study . Timmerman et al. showed, that among fetuses with an increased nuchal translucency, significantly more male fetuses had a favourable outcome compared with females (adverse outcome male 20.1% compared with 35.9% in females). The favourable outcome was especially present in male fetuses, with a marginally increased nuchal translucency (between P95 and 99), suggesting that a different cut-off may be necessary in male fetuses.
Increased nuchal translucency
Nuchal translucency is a subcutaneous accumulation of fluid behind the neck of the fetus and generally visible by ultrasound up to 15 weeks of gestation. The size of the nuchal translucency is influenced by gestational age and is part of normal development . Nuchal translucency is considered abnormal only when it exceeds a certain cut-off . Many different definitions and cut-offs for increased nuchal translucency have been used in the past . Although debate continues about whether nuchal translucency should be regarded as an increase above the 95th or 99th centile, there is consensus that nuchal translucency above the 99 th centile (3.5 mm) is definitely increased.
Nuchal translucency seems to be influenced by gender. Two studies have shown that male fetuses tend to have a slightly larger nuchal translucency than females, about 0.06–0.1 mm , but this finding could not be confirmed by another study . Timmerman et al. showed, that among fetuses with an increased nuchal translucency, significantly more male fetuses had a favourable outcome compared with females (adverse outcome male 20.1% compared with 35.9% in females). The favourable outcome was especially present in male fetuses, with a marginally increased nuchal translucency (between P95 and 99), suggesting that a different cut-off may be necessary in male fetuses.
Increased nuchal translucency and aetiology
The pathophysiology behind increased nuchal translucency is not yet fully understood, and many hypotheses about the cause of nuchal translucency and the pathophysiology behind an increased nuchal translucency have been forwarded . One of the possible causes for increased nuchal translucency is a congenital heart defect, but it is difficult to explain the exact mechanism behind this possible relationship, as different types of congenital heart defects with their own corresponding haemodynamics are encountered. An alternative explanation could be heart failure , although at present the relationship between impaired cardiac function as the main cause of increased nuchal translucency has not yet been established by all research groups . Bekker et al. suggested that impaired endothelial development could be the link between increased nuchal translucency and congenital heart defects.
Another possibility is developmental delay of the lymphatic system. Lymphatic jugular sacs are part of the lymphatic system, and a delay in development of these sacs, could cause increased nuchal translucency owing to fluid accumulation . A study by de Mooij et al. showed that a disturbance in lymphatic endothelial differentiation is present in euploid fetuses, with increased nuchal translucency, and that this disturbance has a similar phenotype as aneuploid fetuses with enlarged jugular lymphatic sacs. More research, however, is needed to ascertain that this is a plausible explanation for all cases of increased nuchal translucency.
Changes in the extra-cellular matrix, owing to a higher concentration of hyaluronan, and as a result excessive hydration of the extracellular matrix and a perturbed function or migration of the neural crest cells, have also been suggested as plausible causes of increased nuchal translucency . The latter disturbance plays a key role in determining the craniofacial defects and cardiac abnormalities that are present in Noonan syndrome and other syndromes associated with increased nuchal translucency .
Increased nuchal translucency and chromosomal abnormalities
About 20% of fetuses with increased nuchal translucency will have a chromosomal abnormality . The incidence increases with nuchal translucency thickness from about 7% for nuchal translucency between the 95th and 99 th centile (3.5 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 .
Submicroscopic chromosomal abnormalities generally missed by conventional karyotyping may be responsible for, the sometimes subtle, structural anomalies or developmental delay later in the life of a fetus with increased nuchal translucency and apparently ‘normal’ karyotype. These submicroscopic chromosomal abnormalities may be identified using comparative genomic hybridisation (CGH) microarray. The main advantage of CGH-array is the ability to detect simultaneously aneuploidies, deletions, duplications, amplifications, or both, of any locus represented on an array. In addition, CGH-array has proven to be a powerful tool for the detection of submicroscopic chromosomal abnormalities in individuals with idiopathic mental retardation and various birth defects.
A systematic review and meta-analysis by Hillman et al. showed that, when conventional karyotyping was normal, array-CGH detected 3.6% additional genomic imbalances (regardless of referral indication). This increased to 5.2% when the referral indication was structural malformation on ultrasound. Leung et al. showed that one out of 10 fetuses with increased nuchal translucency and an apparently normal karyotype had a submicroscopic chromosomal abnormality likely to be pathological.
A challenge of the application of CGH-array prenatally is determining whether a copy number variant (CNV) is de novo and likely to be causative, or inherited and likely to be benign. In case of doubt, the CGH-array of the fetus should be compared with the CNV’s in parental blood.
A disadvantage of CGH-array is that balanced rearrangements, such as translocations and inversions, cannot be identified. Furthermore, information is gained on treatable and non-treatable diseases that may develop later in life, and parents need to decide whether they wish to receive this information.
Fetuses with increased nuchal translucency should undergo conventional karyotyping and also receive counselling about array-CGH.
Increased nuchal translucency and structural abnormalities
Convincing evidence shows that increased nuchal translucency in an euploid fetus is associated with an increased risk for structural anomalies, most commonly congenital heart defects . A review by Souka et al. showed large differences between studies in the prevalence of major anomalies, ranging from 3% to 50%, mainly because of differences in population, differences in definition of increased nuchal translucency and varying distribution of the nuchal translucency . A study by Westin et al. showed that nuchal translucency 3 mm or more increased the likelihood of lethal or serious malformation about 15-fold, nuchal translucency 3.5 mm or more about 40-fold, and nuchal translucency 4.5 mm or more about 80-fold.
Major congenital heart defects are found in about 4–5% of chromosomally normal fetuses with increased nuchal translucency . The prevalence increases from 0.6 to 2.5% with nuchal translucency between 95 th and 99 th centile to 64% in nuchal translucency greater than 8.5 mm . No specific type of congenital heart defect predominantes .
A meta-analysis by Makrydimas et al. showed that the 99 th centile threshold captures about 30% of congenital heart defects, instead of 56%, initially suggested by Hyett et al. . Michailidis et al. found that 27% and 36% of all major cardiac defects occurred within the group of chromosomally normal fetuses with nuchal translucency above the 95 th and 99 th centile, respectively. In contrast, Mavrides et al. found that only 11% and 15% of major congenital heart defects occurred in those similar groups. Muller et al. found similar results, with a prevalence of major congenital heart defects in fetuses with nuchal translucency above the 99th centile of 9.5%.
A meta-analysis by Sotiriadis et al. showed that when analysis was restricted to studies with operators certified by the Fetal Medicine Foundation, the sensitivity was 40.7% using the 95 th centile cut-off and 14.5% using the 99 th centile cut-off.
Wald et al. found that an enlarged nuchal translucency is especially of value in identifying (duct dependent) congenital heart defects that benefit from prenatal detection. Thus far, the heterogeneity of studies prevents the assessment of the true predictive value of nuchal translucency measurement in the screening for congenital heart defects. At present, however, nuchal translucency measurement is the most effective early screening method for cardiac defects. Future research should focus on the role of the Doppler of the hepatic artery, ductus venosus and tricuspid valve as sonomarkers for congenital heart defects in fetuses with and without increased nuchal translucency.
Besides congenital heart defects, a clear association can also be found between orofacial clefts and increased nuchal translucency. Timmerman et al. showed a 19-fold higher chance of having a facial cleft in fetuses with an increased nuchal translucency compared with fetuses with a normal nuchal translucency.
A study by Bilardo et al. and Souka et al. showed that when no (subtle) structural anomalies or markers are present at the 20-week anomaly scan, the chance of a normal outcome is similar to that of the general population, around 4%, irrespective of the enlargement of the nuchal translucency. A limitation of these studies is the small number of fetuses with a large nuchal translucency.
Scott et al. examined 120 cases of fetuses with a nuchal translucency over 6.5 mm; 74% had a chromosomal abnormality and 26% had a normal karyotype. In the group with a normal karyotype, only eight babies were liveborn, of whom seven showed no abnormalities at the detailed ultrasound scan. Four of the seven babies had a structural abnormality or genetic syndrome at birth. It is difficult to draw a definite conclusion on outcome of fetuses with a large nuchal translucency, as few are alife due to a high chance of fetal demise or termination of pregnancy. Furthermore, follow up over a longer period of time is necessary as some conditions present later in childhood.
Increased nuchal translucency and genetic syndromes
In 3% of fetuses with an increased nuchal translucency, an increased nuchal fold (≥6 mm) will be present at the 20-week anomaly scan . The cause of this phenomenon is not yet clear, although many hypotheses exist . When an increased nuchal fold is present, a 10% risk on a genetic syndrome or fetal hydrops and possible perinatal death is present .
A long, and still growing, list of genetic syndromes present with increased nuchal translucency . For syndromes, such as Noonan syndrome and syndromes with mutations in the same pathway, Smith–Lemli–Opitz syndrome, spinal muscular atrophy and other muscle-skeletal disorders, the association with increased nuchal translucency is undisputed. In sporadic syndromes, the association with an enlarged nuchal translucency is more difficult to prove. Some syndromes are rare, and the available information is based on case reports, implying that the association could be coincidental. In case a genetic syndrome is suspected, a clinical geneticist should be consulted to discuss additional genetic testing.
Prenatally, Noonan syndrome is the most frequently reported genetic syndrome in association with increased nuchal translucency, with an incidence ranging from 25% . It is an autosomal dominant disorder, and is caused in about 50% of the cases by a missense mutation in the PTPN11 gene on chromosome 12 . Mutations in the SOS1 -, RAF1- , KRAS- , BRAF- , MAP2K1/2- , NRAS- and SHOC2 -genes account for a small percentage of Noonan syndrome cases . In chromosomally normal fetuses with enlarged nuchal translucency, the prevalence of Noonan syndrome tested by PTPN 11 seems to vary from 6 to 18% .
Houweling et al. advocate that, given the high incidence of Noonan syndrome in fetuses with increased nuchal translucency and normal karyotype, genetic counselling and Noonan syndrome mutation detection should be offered in all cases, irrespective of additional abnormalities. It is debatable, however, if nuchal translucency measurement should be used as a screening tool for Noonan syndrome, mainly as this syndrome has a highly variable expression and most cases only have mild dysmorphic features and normal neurodevelopment .
Moreover, testing for Noonan is expensive, and the important clinical question is in which cases testing should be offered. Our group proposes a more cost-effective selection of cases. We showed that the diagnosis of Noonan syndrome can be suspected prenatally, especially in chromosomally normal fetuses with a large nuchal translucency and one or more of the following characteristics: persistent nuchal fold or cystic hygroma, hydrops fetalis, pleural effusion, cardiac anomalies, polyhydramnios, or specific facial features . Croonen et al. recommend that, in the presence of the above mentioned ultrasound features, testing should be extended to KRAS , RAF1 , BRAF , and MAP2k1 genes for mutations, in case PTPN11 is negative.
Increased nuchal translucency and development (delay)
Fourteen original studies have reported on the long-term follow up of fetuses with increased nuchal translucency, normal ultrasound findings, and normal karyotype. The proportion of developmental delay in early childhood reported in these studies ranges from 0 to 8.7% ( Table 1 ) . Interpretation of the studies so far is hampered by lack of standardisation: the cut-off values used to define increased nuchal translucency range between 3 mm, 3.5 mm, 4 mm, 95 th centile and the 99 th centile; the age of the children at follow up ranges from 6 months to 75 months; there are different ascertainment methods for developmental delay; and only three studies use a control group .
| Author | Study | Nuchal translucency | Control group | Follow up (months) | Follow up type | Developmental delay | |
|---|---|---|---|---|---|---|---|
| Case | Control | ||||||
| Van Vugt et al., 1998 | P | ≥3 mm | No | 7–75 | Questionnaire | (1/34) 2.9% | |
| Brady et al., 1998 | C-C | ≥3.5 mm | Yes | 6–42 | Clinical examination | (1/89) 1.1% | (1/302) 0.33% |
| Adekunle et al., 1999 | P | ≥4 mm | No | 12–38 | Questionnaire | (2/23) 8.7% | |
| Maymon et al., 2000 | P | ≥95th centile | No | 12–36 | Questionnaire or by telephone | (0/36) 0 | |
| Souka et al., 2001 | R | ≥3.5 mm | No | NA | Information from maternity units, the patient or GP | (4/980) 0.4% | |
| Hiippala et al., 2001 | P | ≥3 mm | No | 24–84 | Clinical examination | (1/50) 2% | |
| Senat et al., 2002 | R | ≥4 mm | No | 12–72 | Clinical examination | (3/54) 5.6% | |
| Cheng et al., 2004 | R | ≥3.0 mm | No | 8–30 | Clinical examination | (1/14) 7.1% | |
| Senat et al., 2007 | P/R | ≥99 th centile | Yes | 0–24 | Clinical examination and ASQ | (2/162) 1.2% | (?/370) ? |
| Bilardo et al., 2007 | R | ≥95 th centile | No | 6–60 | Questionnaires or by telephone | (7/425) 1.6% | |
| Saldanha et al., 2009 | P | ≥95 th centile | No | 29 days to 72 months | Questionnaires and clinical examination | (0/128) 0 | |
| Mula et al., 2012 | P | ≥99th centile | No | 24 | Four paediatric consultations or ASQ | (4/108) 3.7% | |
| Miltoft et al., 2012 | C-C | ≥99 th centile | Yes | 24 | ASQ | (1/80) 1.3% | (6/137) 4.4% |
| Sotiriadis et al., 2012 | SR | Total | (28/2458) 1.14% | ||||
| ≥95 th centile | (7/669) 1.05% | ||||||
| ≥99 th centile | (15/1567) 0.96% | ||||||
| >3.0 mm | (6/222) 2.70% | ||||||
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