The heterogeneity of conditions associated with increased nuchal translucency suggests that there may not be a single underlying mechanism for the collection of fluid in the skin of the fetal neck. Possible mechanisms include:

  1. Cardiac failure in association with abnormalities of the heart and great arteries;

  2. Venous congestion in the head and neck, due to constriction of the fetal body in amnion rupture sequence or superior mediastinal compression found in diaphragmatic hernia or the narrow chest in skeletal dysplasia;

  3. Altered composition of the extracellular matrix;

  4. Abnormal or delayed development of the lymphatic system;

  5. Failure of lymphatic drainage due to impaired fetal movements in various neuromuscular disorders;

  6. Fetal anemia or hypoproteinemia;

  7. Congenital infection, acting through anemia or cardiac dysfunction.


Pathological studies

Pathological studies of the heart and great arteries, after surgical termination of pregnancy in 112 chromosomally abnormal fetuses identified by nuchal translucency screening at 10–14 weeks of gestation, demonstrated abnormalities of the heart and great arteries in the majority of cases (Figures 1, 2, 3, 4, 5, 6, 7, 8, 9) 1 . The commonest cardiac lesion seen in trisomy 21 fetuses was an atrioventricular or ventricular septal defect. Trisomy 18 was associated with ventricular septal defects and/or polyvalvular abnormalities. In trisomy 13, there were atrioventricular or ventricular septal defects, valvular abnormalities and either narrowing of the isthmus or truncus arteriosus. Turner syndrome was associated with severe narrowing of the whole aortic arch.

Figure 1

Figure 1 - Scanning electron micrograph (x25) showing the septal aspect of the right ventricle of a normal heart at 12 weeks of gestation. O, aorta; P, pulmonary trunk. Scale bar: 750 mm

Figure 2

Figure 2 - The ascending aorta (AoA), pulmonary trunk (PT), aortic isthmus (Aol) and ductus arteriosus (Da) from a trisomy 21-affected fetus at 14 weeks of gestation. The ascending aorta and the isthmus of the aorta show some developmental delay. The aortic isthmus is narrow compared to the distal ductus arteriosus, which is mildly dilated. Scale bar: 1 mm

Figure 3

Figure 3 - Photomicrograph showing a perimembranous ventricular septal defect (arrow), partially guarded by the septal leaflet of the tricuspid valve (T) of a 13-week trisomy 21 fetus. C, crista supraventricularis; P, pulmonary valve; RV, right ventricle. Scale bar: 1 mm

In all four groups of chromosomally abnormal fetuses, the aortic isthmus was significantly narrower than in normal fetuses, and the degree of narrowing was significantly greater in fetuses with increased nuchal translucency thickness 1. In trisomies 21 and 18, narrowing of the isthmus was associated with widening of the ascending aorta. Since blood flow is related to vessel diameter, widening of the ascending aorta and narrowing of the isthmus could result in overperfusion of the tissues of the head and neck, leading to edema. With advancing gestation, the diameter of the aortic isthmus increases more rapidly than the diameters of the aortic valve and distal ductus and, therefore, the hemodynamic consequences of narrowing of the isthmus may be overcome 2,3. Since vascular resistance depends on vessel radius by a factor of 10-4 (equation of Hagen–Poiseuille), a small increase in the diameter of the aortic isthmus would result in a major reduction in vascular resistance and possible resolution of nuchal translucency. This hypothesis could offer an explanation for the gestational age-related spontaneous resolution of nuchal translucency; for example, abnormal nuchal fluid is observed in about 70% of trisomy 21 fetuses at 11 weeks of gestation but in only 30% of cases at the 20th week 4.

Figure 4

Figure 4 - A scanning electron micrograph of the parietal aspect of the right ventricle showing marked dysplasia of both the pulmonary (P) and tricuspid (T) valves in the heart of a trisomy 18 fetus at 12 weeks of gestation. C, crista supraventricularis

Figure 5

Figure 5 - The septal aspects of the right ventricle showing a type 1 atrioventricular septal defect (O). The right ventricular outflow tract has collapsed partially during processing of the specimen (arrow). A, right atrium; V, common atrioventricular valve; C, crista supraventricularis. Scale bar: 500 mm

Figure 6

Figure 6 - A hypoplastic pulmonary trunk (PT) and ductus arteriosus (arrow) in a trisomy 18 fetus at 13 weeks of gestation. The left pulmonary artery (L) and ascending aorta (Ao) are dilated. Scale bar: 1 mm

In trisomy 13 and Turner syndrome, narrowing of the isthmus was accompanied by narrowing of the ascending aorta and, therefore development of increased nuchal translucency cannot be explained by overperfusion of the head and neck 1 . In the case of Turner syndrome, increased nuchal translucency is thought to represent overdistension of the jugular lymphatic sacs, as a consequence of failure of communication with the internal jugular vein 1 . It has been suggested that the associated cardiovascular malformations, primarily coarctation of the aorta and other defects in the spectrum of left heart obstruction, are the consequence of altered intracardiac blood flow, due to compression of the ascending aorta by the distended intrathoracic lymphatic channels 5.

Figure 7 - Tubular hypoplasia of the aortic isthmus (arrow) in this 12-week fetus with Turner syndrome. The ductus arteriosus (D) is dilated. PT, pulmonary trunk. Scale bar: 1 mm


Figure 8 - Photomicrograph showing a bicuspid aortic valve (AV) in a fetal heart at 11 weeks of gestation. Note the two commissures (arrows) at 10 and 4 o’clock. PV, pulmonary valve; R, right ventricle. Scale bar: 1 mm

Figure 9 - Photomicrograph of the heart and great vessels in a 12-week fetus, demonstrating a double aortic arch. On the left side, the aortic isthmus (arrow) is hypoplastic, whereas, on the right, the persisting right aortic arch (arrow) is dilated. Ao, ascending aorta; T, thoracic aorta; P, pulmonary trunk; D, ductus arteriosus; o, esophagus; w, trachea. Scale bar: 1 mm

The findings in the human of an association between increased nuchal translucency thickness and abnormalities of the heart and great arteries are consistent with animal studies. The trisomy 16 mouse (Figure 10), which is considered to be a good animal model for human trisomy 21, has a combination of abnormalities of lymph vessels, cardiovascular malformations and hypoplastic thymus, which have been attributed to impaired migration of neural crest cells 6 . These cells migrate from the embryonic neural tube and play a central role in the development of the cardiovascular system 7 . There is increasing evidence that many neural crest-related cardiovascular defects may be genetically based 8 . The genetic mechanism, whereby a series of different chromosomal defects interfere with neural crest cells to result in abnormalities of the aortic arch and cardiac defects, remains to be determined.

Figure 10 - In the trisomy 16 mouse (left), which is the animal model for Down syndrome, on days 14, 15 and 16 of intrauterine life, there is a subcutaneous collection of fluid. On the right is the normal mouse. (Image kindly provided by Professor Buselmeier, University of Heidelberg)


Doppler studies of the ductus venosus

The sphincter-like ductus venosus is an important regulator of the fetal circulation; it directs well-oxygenated umbilical venous blood to the coronary and cerebral circulation, by preferential streaming through the foramen ovale into the left atrium. Blood flow in the ductus is characterized by its high velocity during ventricular systole (S-wave) and diastole (D-wave) and by the presence of forward flow during atrial contraction (A-wave). In cardiac failure, with or without cardiac defects, there is absent or reversed A-wave 9 . A study, examining ductal flow at 11–14 weeks in fetuses with increased nuchal translucency, reported absent or reverse flow during atrial contraction in 57 of 63 (90.5%) chromosomally abnormal fetuses and in only 13 of 423 (3.1%) chromosomally normal fetuses (Figure 11)10 . These findings suggest that a high proportion of chromosomally abnormal fetuses at 11–14 weeks of gestation demonstrate evidence of heart failure.

Color Doppler Energy "Arteriography" of the vessels
Normal Sonogram
(S= systole; D= diastole; A= atrial contraction)
Increased Nuchal translucency with abnormal Doppler of the ductus venosus
Abnormal Sonogram
(S= systole; D= diastole; A= atrial contraction)


Evidence that the heart failure is temporary is provided from those cases where chromosomal abnormalities were diagnosed in the first trimester but the parents chose to continue with the pregnancy. Thus, in a case of trisomy 21 with increased nuchal translucency at 13 weeks but no cardiac defect, there was abnormal ductal flow; at 15 weeks, both the translucency and the abnormal A-wave resolved 10 . Similarly, in a case of trisomy 18 with a membranous septal defect presenting at 13 weeks with increased nuchal translucency and reversed A-wave in the ductus, there was resolution of both the translucency and the abnormal ductal flow with advancing gestation 11.

Molecular biology studies

Atrial natriuretic peptide and brain natriuretic peptide (which are encoded on chromosome 1) are involved in fluid–electrolyte homeostasis, with potent diuretic–natriuretic and vasorelaxing effects. A number of extracardiac tissues have been shown to express atrial natriuretic peptide but synthesis and secretion are almost exclusively confined to the cardiac atria. The major source of circulating brain natriuretic peptide is the cardiac ventricles. A study of trisomic fetuses with increased nuchal translucency thickness reported increased levels of atrial and brain natriuretic peptide mRNA in fetal hearts 12 . On the basis of these results, it could be postulated that trisomic fetuses demonstrate heart strain. Certainly, in postnatal life, upregulation of natriuretic peptides is considered to occur as a compensatory mechanism to the characteristic changes of sodium retention and increased vascular resistance associated with congestive cardiac failure 13 .

Diaphragmatic hernia

Increased nuchal translucency thickness is present in about 40% of fetuses with diaphragmatic hernia, including more than 80% of those that result in neonatal death due to pulmonary hypoplasia and in about 20% of the survivors 14. It is possible that, in those cases with increased nuchal translucency at 11–14 weeks, there is indeed intrathoracic herniation of the abdominal viscera during this stage of gestation, and the increased nuchal translucency may be the consequence of venous congestion in the head and neck due to mediastinal compression and impedance to venous return. In such cases, prolonged intrathoracic compression of the lungs causes pulmonary hypoplasia. In the cases where diaphragmatic hernia is associated with a good prognosis, the intrathoracic herniation of viscera may be delayed until the second or third trimesters of pregnancy 15. An alternative hypothesis is that, in all cases of diaphragmatic hernia, there is intrathoracic herniation by 11 weeks, but increased nuchal translucency is only observed in those with sufficiently severe compression of the lungs to cause pulmonary hypoplasia. Screening for diaphragmatic hernia at the 11–14-week scan will help to determine which of the hypotheses is likely to be true.

Skeletal dysplasias

Intrathoracic compression may also be the underlying mechanism for the increased nuchal translucency observed in a wide range of skeletal dysplasias, which are associated with a narrow thoracic cage (see Chapter 2). However, in at least some of the cases, such as osteogenesis imperfecta, an additional or alternative mechanism for the increased translucency may be the altered composition of the extracellular matrix.


The extracellular matrix consists of ground substance (mucoproteins and mucopolysaccharides) and collagen fibers. Collagens, which are produced by fibroblasts, are triple-helical proteins. Cells are fixed to the matrix and to each other by a group of molecules known as integrins (laminin and fibronectin).

Many of the component proteins of the extracellular matrix are encoded on chromosomes 21, 18 or 13 (Table 1). Immunohistochemical studies, using antibodies against collagen types I, III, IV, V and VI and against laminin and fibronectin to examine the skin of chromosomally abnormal fetuses, have demonstrated specific alterations of the extracellular matrix which may be attributed to gene dosage effects 16,17. Thus, the dermis of trisomy 21 fetuses is rich in collagen type VI (Figure 12), whereas dermal fibroblasts of trisomy 13 fetuses demonstrate an abundance of collagen type IV and those of trisomy 18 fetuses an abundance of laminin 16.

Table 1 - Structural proteins of the extracellular matrix and gene loci. Genes that are likely to be overexpressed as a result of trisomies are indicated in bold type17
Component Gene Chromosome
Collagen Type I COL1A1 17q
Collagen type III COL3A1 2q
Collagen type III COL3A1 2q
Collagen type IV COL4A1 13q
Collagen type III COL3A1 2q
Collagen type III COL3A1 2q
Collagen type IV COL4A1 13q
COL4A2 13q
COL4A3 2q
  COL4A4 2q
  COL4A5 Xq
  COL4A6 X
Collagen type V COL5A1 9q
COL5A2 22
Collagen type VI COL6A1 21q
COL6A2 21q
COL6A3 2q
Collagen type VI COL6A1 21q
COL6A2 21q
COL6A3 2q
Laminin LAMA1 18q
LAMA2 6q
LAMA3 18q
LAMA4 6q
LAMB1 7q
LAMB2 1q
LAMB2 3q
Fibronectin VNR (alpha) 2
  FNR (alpha) 12q

Overexpression of several other genes found in chromosome 21 is thought to be the underlying mechanism for the phenotypic characteristics of trisomy 21. For example, overexpression of the amyloid precursor protein gene results in deposition of amyloid in the brain and early onset of Alzheimer’s disease 18. Additionally, transgenic mice that carry the Ets2 gene, a proto-oncogene and transcription factor that is overexpressed in human trisomy 21, develop cranial and cervical skeletal abnormalities that are similar to those in Down’s syndrome 19.

The molecule of collagen type VI, which forms microfibrils in tissues, is composed of three polypeptide chains a1, a2 and a3. In nuchal skin of trisomy 21 fetuses, the ratio of the expression of COL6A1 (which is located on chromosome 21) to COL6A3 (which is located on chromosome 2) is twice as high as in normal fetuses 16. It is therefore possible that the composition and consequently the properties of collagen type VI are altered in trisomy 21 fetuses, leading to the accumulation of subcutaneous edema. Thus, collagen type VI binds to hyaluronic acid (a very large molecular weight polysaccharide)20, which can entrap large amounts of solvent in the extracellular matrix. In postnatal life, conditions with increased levels of hyaluronic acid, such as inflammatory rheumatic diseases or cirrhotic liver disease, are associated with interstitial edema 21,22.

Figura 12a
Figura 12b

Figure 12 - Immunofluorescence detection of collagen type VI in a section through nuchal skin of a fetus with trisomy 21 (a) and in a normal control fetus (b). In trisomy 21, there is intense staining of the extracellular matrix, extending to the dermis–subcutis junction, whereas, in the normal fetus, intense staining is restricted to the upper dermis immediately underlying the basement membrane

Immunohistochemical studies of fetal nuchal skin have demonstrated that, in fetuses with trisomy 21, there is a substantial increase in hyaluronic acid, whereas, in trisomies 18 and 13 and Turner syndrome, the amount is similar to that in chromosomally normal controls. The increased hyaluronic acid in trisomy 21 fetuses may be the consequence of increased synthesis or decreased degradation, but the gene loci for the enzymes involved in these processes have not yet been mapped. However, superoxide dismutase, which protects against free radical-mediated degradation of hyaluronic acid, is encoded by chromosome 21 23. Since superoxide dismutase is overexpressed in trisomy 21 fetuses 24, there may be a decrease in the degradation of hyaluronic acid.

In fetuses with trisomy 21, increased amounts of hyaluronic acid may not be restricted to the nuchal skin but are probably found in other tissues and organs contributing to the pathogenesis of other abnormalities. A single chain of hyaluronic acid, through link proteins, is bound to a great number of aggrecan (a protein) monomers to form large aggregates which inhibit cell movement. For example, matrices containing hyaluronan-aggregating proteoglycans inhibit the migration of neural crest cells 25. This may be the underlying mechanism for Hirschsprung disease, which is associated with trisomy 21 and which is thought to be the consequence of failure of migration of neuroblasts from the neural crest to the bowel segments, a process which normally occurs at 6–12 weeks of gestation.

Another possible mechanism for a link between alterations in the composition of collagen type VI (which is a powerful substrate for cell adhesion) and increased nuchal translucency is impairment in cardiac function or structure. The atrioventricular–septal defects, commonly observed in trisomy 21, may be the consequence of failure of endocardial cushion fusion, due to increased adhesiveness of fibroblasts 26,27.

Altered composition of the extracellular matrix may also be the underlying mechanism for increased fetal nuchal translucency in an expanding number of genetic syndromes (Table 2), which are associated with alterations in collagen metabolism (such as achondrogenesis type II, Nance–Sweeney syndrome, osteogenesis imperfecta type II), abnormalities of fibroblast growth factor receptors (such as achondroplasia and thanatophoric dysplasia) or disturbed metabolism of peroxisome biogenesis factor (such as Zellweger syndrome).


In normal embryos, the main lymphatics develop from the venous walls, but they subsequently lose their connections with the veins to form a separate lymphatic system, except for the juguloaxillary sacs, which drain the lymph to the venous system 28. A possible mechanism for increased translucency is dilatation of the jugular lymphatic sacs, because of developmental delay in the connection with the venous system, or a primary abnormal dilatation or proliferation of the lymphatic channels interfering with a normal flow between the lymphatic and venous systems 29.

A microscopical study, examining the lymphatic vessels in the skin of spontaneously aborted fetuses with cervical cystic hygromas, reported that in non-Turner fetuses there were numerous dilated lymphatic vessels, whereas in fetuses with Turner syndrome there were very few such vessels. In the skin of normal fetuses with no cystic hygromas, lymphatic vessels were evenly distributed 30.

Further support for lymphatic hypoplasia in Turner syndrome has been provided by studies investigating women with ovarian dysgenesis as a result of a 45,XO karyotype; in these cases, lymphangiography revealed hypoplastic lymphatic vessels in the lower limbs, pelvis and retroperitoneal space 31.

Immunohistochemical studies have investigated the distribution of lymphatic vessels in nuchal skin tissue from fetuses with Turner syndrome, compared to fetuses with trisomies 21, 18 and 13, that also had increased nuchal translucency, and chromosomally normal controls 32. The distribution of vessels was examined using PTN63 (an antibody against 5'nucleotidase, which primarily stains lymphatic vessels, but is also present in large endothelial venules of lymphoid tissues), laminin (which is a major component of basement membranes and therefore highlights large lymphatics and both large and small blood vessels) and FLT-4 (an antibody against the vascular endothelial growth factor receptor-3, whose expression is essentially restricted to lymphatic endothelia during development). Vascular endothelial growth factors (VEGF) play important roles in angiogenesis and vascular development during embryogenesis; these growth factors act through three receptors VEGFR1, VEGFR2 and VEGFR3 33. In the nuchal skin of normal fetuses and those with trisomies 21, 18 and 13, PTN63-positive, laminin-positive and FLT-4-positive vessels were evenly distributed throughout the dermis and subcutis. In Turner syndrome, there was a chain of large vessels at the border between the dermis and subcutis, which was stained by all three stains. However, in the upper dermis, although there was intense staining with laminin of small and medium-size vessels, there were no PTN63-positive or FLT-4-positive vessels. These findings indicate that, in Turner syndrome, the lymphatic vessels in the upper dermis are hypoplastic (Figure 13). In contrast, the increased nuchal translucency of trisomic fetuses cannot be attributed to lymphatic hypoplasia.

Figure 13a
Figure 13b

Figure 13 - Nuchal skin of fetuses with Turner syndrome. On the left (a) is a picture from single staining with monoclonal PTN63 antibody (red) showing the absence of lymphatic vessels in the upper dermis and a chain of dilated vessels in the junction between the dermis and subcutis. On the right (b) is double staining with both PTN63 and laminin antibodies demonstrating yellow–orange fluorescence in the chain of dilated vessels. Vessels in the upper dermis are only laminin-positive (green)

A possible mechanism for hypoplasia of lymphatic vessels in Turner syndrome is deficiency in the tyrosine kinase BMX, whose gene is located on chromosome X. This tyrosine kinase is expressed in the endothelial cells of several human tissues 34 and it is possible that this kinase plays an important role in mediating the effects of the vascular endothelial growth factors for the development of early blood and lymphatic vessels.

Immunohistochemistry and in situ hybridization studies examined the distribution of a wide range of proteoglycans in the nuchal skin of chromosomally abnormal fetuses with increased nuchal translucency. Proteoglycans are involved in fluid retention as well as growth and migration of lymphatic vessels. Altered composition of the extracellular matrix may result in abnormal accumulation of fluid, but it can also entrap and inhibit the physiological effects of growth factors on developing blood and lymphatic vessels. The studies demonstrated that, in the skin of fetuses with Turner syndrome, proteoglycan expression was substantially different from normal. In particular, biglycan, which is encoded on chromosome X, was underexpressed and chondroitin-6-sulfate was overexpressed. In fetuses with trisomies 21, 18 or 13, compared to chromosomally normal controls, there was no obvious difference in proteoglycan expression.


Anemia and hypoproteinemia are implicated in the pathophysiology of both immune and non-immune hydrops fetalis 35–37. Since trisomy 21 is associated with reduced maternal serum concentration of a-fetoprotein, it is possible that these fetuses are hypoproteinemic (the source of maternal serum a-fetoprotein is the fetus). However, investigation of the a-fetoprotein mRNA gene expression in the liver of fetuses with trisomy 21 showed no significant difference from normal 38.

In a study of 32 fetuses with homozygous a-thalassemia, there was an overall increase in nuchal translucency thickness by about 0.4 mm, compared to normal controls, but this increase was clinically insignificant 39. This finding indirectly suggests that the increased nuchal translucency in trisomic fetuses cannot be explained by fetal anemia.


In about 10% of cases of ‘unexplained’ second- or third-trimester fetal hydrops, there is evidence of recent maternal infection and, in these cases, the fetus is also infected. In a study of 426 pregnancies with increased fetal nuchal translucency and normal karyotype, only 1.5% of the mothers had evidence of recent infection and none of the fetuses was infected 40. These findings suggest that, in pregnancies with increased fetal nuchal translucency, the prevalence of maternal infection with the TORCH group of organisms is not higher than in the general population. Furthermore, in cases of maternal infection, the presence of increased fetal nuchal translucency does not signify the presence of fetal infection with these organisms. Therefore, increased nuchal translucency in chromosomally normal fetuses need not stimulate the search for maternal infection unless the translucency evolves into second- or third-trimester nuchal edema or generalized hydrops.

In a report of three cases of recent maternal infection with parvovirus B19, fetal hydrops developed at 12 weeks of gestation; in all three cases, the hydrops resolved by 22 weeks and healthy babies were born 41. The possible mechanism for the transient hydrops is heart failure due to myocardial infection. The alternative of bone marrow suppression, leading to fetal anemia and high-output heart failure, is unlikely because at 12 weeks the main hemopoietic organ in the fetus is the liver rather than the marrow.

Chapter 3 - References
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The 11-14-week scan
Copyright © 2001 by KH Nicolaides, NJ Sebire, RJM Snijders & RLS Ximenes
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