Cardiac dysfunction
Central to the hypothesis that heart failure contributes to increased
NT is the observation that in both chromosomally abnormal and normal fetuses
there is a high association between increased NT and abnormalities of
the heart and great arteries. Furthermore, Doppler studies have reported
abnormal flow in the ductus venosus in fetuses with chromosomal and/or
major cardiac defects and increased NT (Matias et al 1999).
Venous congestion in the head and neck
Venous congestion in the head and neck could result from constriction
of the fetal body as encountered in amnion rupture sequence, superior
mediastinal compression found in diaphragmatic hernia or the narrow chest
in skeletal dysplasias. However, in at least some of the skeletal dysplasias
cases, such as osteogenesis imperfecta, an additional or alternative mechanism
for the increased NT may be the altered composition of the extracellular
matrix.
Altered composition of the extracellular matrix
Many of the component proteins of the extracellular matrix are encoded
on chromosomes 21, 18 or 13. Immunohistochemical studies, examining the
skin of chromosomally abnormal fetuses, have demonstrated specific alterations
of the extracellular matrix which may be attributed to gene dosage effects
(von Kaisenberg et al 1998). Altered composition of the extracellular
matrix may also be the underlying mechanism for increased fetal NT in
an expanding number of genetic syndromes, 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).
Failure of lymphatic drainage
A possible mechanism for increased NT 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. Immunohistochemical studies in nuchal skin tissue from fetuses
with Turner syndrome have shown that the lymphatic vessels in the upper
dermis are hypoplastic (von Kaisenberg et al 1999). In chromosomally normal
fetuses with increased NT, deficient lymphatic drainage, due to hypoplastic
or aplastic lymphatic vessels, is found in association with Noonan syndrome
and congenital lymphedema. In congenital neuromuscular disorders, such
as fetal akinesia deformation sequence, myotonic dystrophy and spinal
muscular atrophy, increased NT may be the consequence of impaired lymphatic
drainage due to reduced fetal movements.
Fetal anaemia
Fetal anemia is associated with a hyperdynamic circulation and fetal
hydrops develops when the hemoglobin deficit is more than 7 g/dL (Nicolaides
et al 1988). This is true for both immune and non-immune hydrops fetalis.
However, in red blood cell isoimmunization severe fetal anemia does not
occur before 16 weeks of gestation, presumably because the fetal reticuloendothelial
system is too immature to result in destruction of antibody coated erythrocytes.
Consequently, red blood cell isoimmunization does not present with increased
fetal NT. In contrast, genetic causes of fetal anemia (a-thalassemia,
Blackfan-Diamond anemia, congenital erythropoietic porphyria, dyserythropoietic
anemia, Fanconi anemia) and possibly congenital infection-related anemia
can present with increased fetal NT.
Fetal hypoproteinemia
Hypoproteinemia is implicated in the pathophysiology of both immune and
non-immune hydrops fetalis (Nicolaides et al 1995). In the first trimester,
hypoproteinemia due to proteinuria may be the underlying mechanism for
the increased NT in fetuses with congenital nephrotic syndrome of the
Finnish type and diffuse mesangial sclerosis.
Fetal infection
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 pregnancies with increased
fetal NT and normal karyotype, only 1.5% of the mothers have evidence
of recent infection and the fetuses are rarely infected (Sebire et al
1997). These findings suggest that, in pregnancies with increased fetal
NT, 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 NT does not signify
the presence of fetal infection with these organisms. Therefore, increased
NT 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. The only infection that has been
reported in association with increased fetal NT is Parvovirus B19. In
this condition the increased NT has been attributed to myocardial dysfunction
or fetal anemia due to suppression of hemopoiesis. |