The Principles of Clinical Cytogenetics - Extra Materials - Springer

Prenatal Cytogenetics 303
Table 14 (continued)
Risk(s) of aneuploidy
Risk(s) of aneuploidy if other ultrasound
Finding if isolated finding abnormalities are present Comment
Short humerus, femur Positive predictive value Increased to variable If all long bones are of
for trisomy 21 in women degrees normal length and other
with risks of 1 in 500 ultrasound findings
and 1 in 1000 = 2.3% and normal, some feel
1.2%, respectively, for amniocentesis is not
short humerus (201). For indicated in women
short femur, some studies under 40 (201). Racial
found very little increased factors should be
risk (202,203) considered in any long
bone measurement (204).
Absent nasal bone Absent or hypoplastic Appears to be independent Also seen more frequently
in 67–80% trisomy 21 finding from nuchal in other chromosome
fetuses compared to translucency, so can be abnormalities (171)
1–2% chromosomally used as independent
normal fetuses markers in multiple
(168–173) marker algorithm (173)
Other maternal serum markers have been studied, but none is used as commonly as TMS (231).
This will probably change in the next 10 years in favor of first-trimester screening alone or integrated
screening strategies including data from first and second trimesters. The goal is to maximize detection
while minimizing screen positive rates. See the discussion of integrated screening below.
QUADRUPLE SCREENING
Dimeric inhibin A, referred to as simply inhibin A or inhibin in some studies, was added to the triple
marker screen panel in recent years in some centers and has been shown in several studies to increase
the detection of trisomy 21 in the second trimester. In one study of 72 second-trimester fetuses with
trisomy 21 and 7063 unaffected fetuses, the detection of trisomy 21 at a risk cutoff of 1 in 270 was
81.5% with a screen-positive rate of 6.9% and a positive predictive value of 1 in 42 (232). In other
words, 1 in 42 amniocentesis procedures yielded a result of trisomy 21. In a second, larger study of
23,704 women with unaffected pregnancies and 45 women with trisomy 21-affected pregnancies, the
sensitivity of the quadruple screen was 85.8%, with an initial screen-positive rate of 9.0%, corrected to
8.2% after gestational age error corrections. The positive predictive rate was 1 in 51. Women who were
true positives had very high risks—median risk 1 in 22—compared to risks in women with false-positive
results—median risk 1 in 111 (233). Hackshaw and Wald evaluated the increase in detection of trisomy
21 by performing the triple marker screen followed by the quadruple screen in a series of patients. They
found an increase in detection of 1–5% at a 5% screen-positive rate. Their interpretation was that the
“modest increase . . . is probably not worthwhile in the light of the extra cost and delay” (234). It should
be pointed out, however, that similar arguments were made when unconjugated estriol was added to
what at the time was a double screen. Based on a study by Spencer et al. in 45 cases of trisomy 18 and
493 control pregnancies at 10–14 weeks’ gestation, inhibin A was found not to add to the detection of
trisomy 18 over TMS alone (235). Nevertheless, second-trimester quadruple screening has gained in
popularity in recent years and this can be expected to continue.
First-Trimester Screening
In 1995 and 1996, first-trimester detection of trisomy 21 using free β-hCG and pregnancy-associated
plasma protein A (PAPP-A) (236,237), were reported. Several more articles have been published since