The Principles of Clinical Cytogenetics - Extra Materials - Springer

290 Linda Marie Randolph
Fig. 3. Ultrasound image of increased nuchal fold (NF) measuring 6.1 mm (indicated by +) in a secondtrimester
fetus. (Courtesy of Greggory DeVore, M.D.
Nuchal membranes have been recorded as early as 9 weeks’ gestation. Measurement of the nuchal
thickness, with or without first-trimester serum screening, has become the most sensitive firsttrimester
ultrasound finding used for Down syndrome detection (139–141). Nicolaides, a pioneer of
first-trimester nuchal thickness ultrasound scans, cites a detection rate of 90% for chromosome abnormalities
when performed in conjunction with pregnancy-associated plasma protein-A (PAPP-A) and
free β-hCG at 11–14 weeks of pregnancy, with an invasive pregnancy testing rate of 5% (139).
Nuchal folds and cystic hygromas have been known to be associated with chromosome abnormalities
since 1966, with an incidence of chromosome abnormalities ranging from 22% to more than
70% in various series (142). Based on 22 other studies plus their own data, Landwehr et al. (142)
found that 32% of 1649 karyotyped fetuses with nuchal folds or membranes and/or cystic hygromas
had a chromosome abnormality. These included 207 cases of trisomy 21, 108 cases of trisomy 18, 30
cases of trisomy 13, 131 cases of 45,X, and 48 other chromosome abnormalities. This study included
first- and second-trimester ultrasound scans, which employ different criteria for nuchal thickness.
In a 12-center study designed to determine the sensitivity and specificity of second-trimester softtissue
nuchal fold measurement for the detection of trisomy 21, 3308 fetuses of 14–24 weeks’ gestation
were evaluated (143). Using 6 mm as a cutoff, a nuchal skin fold was seen in 8.5% of
chromosomally normal fetuses and in 38% of those with trisomy 21. A false-positive rate below 5%
was obtained by 81% of the investigators. The authors concluded that this sign is useful in skilled
hands in the second trimester, but it does not appear suitable for population screening because of the
high variability in the results among the investigators.
A nuchal thickness cutoff of 4 mm was chosen by Nadel et al. (144) in a study of 71 fetuses of
10–15 weeks’ gestation, of which 63 were karyotyped. Abnormal karyotypes were found in 31 of 37
hydropic fetuses and in 12 of 26 nonhydropic fetuses. The nonhydropic fetuses also had no septations
in the hygromas. Twenty-two of the fetuses with septated hygromas had chromosome analysis and 19
had abnormal chromosomes. Of fetuses with hydrops and no septations, 11 of the 14 had abnormal
chromosomes.
There have been several first-trimester ultrasound studies of nuchal thickening. Van Vugt et
al. (145) karyotyped 102 first-trimester fetuses with a nuchal translucency of 3 mm or more and
found that 46% had an abnormal karyotype: 19 had trisomy 21, 9 had trisomy 18, 13 had 45,X, 1
had 47,XXX, and 5 had other chromosome abnormalities. Multiple logistic regression analysis was
used to take into account data modifiers such as gestational age and maternal age. The authors exam-