Down syndrome is the most commonly encountered, clinically significant autosomal chromosome aberration affecting individuals beyond infancy. This genetic defect, which can be detected by cytogenetic analysis, is trisomy 21. More than 90% of Down cases occur as a result of meiotic nondisjunction. Down syndrome is characterized by intellectual disability, cardiac malformations, malformations of the digestive tract, eyes, and ears, and the development of an Alzheimer-like disease process in later life.
Down syndrome is the most commonly encountered, clinically significant autosomal chromosome aberration affecting individuals beyond infancy. This genetic defect, which can be detected by cytogenetic analysis, is trisomy 21. The neonatal diagnosis of Down syndrome is clinical, with metaphase chromosome analysis on peripheral blood serving merely to confirm the diagnosis.
The overall birth prevalence of Down syndrome is approximately 1 in 1000 births. However, a woman's individual risk to deliver an infant with Down syndrome depends substantially on her age. The risk increases significantly past age 35 years, with an incidence in the range of 1:270 to 1:100 by age 40 years.
The neonatal diagnosis of Down syndrome is clinical, with metaphase chromosome analysis on peripheral blood serving merely to confirm the diagnosis.
Noninvasive fetal screening for Down syndrome involves many more tests (Table 7–2) that are used in combination to develop a risk assessment of Down syndrome during pregnancy. Definitive diagnosis of fetal Down syndrome during pregnancy is established by an invasive test, namely, metaphase analysis of cells from either chorionic villus sampling (typically limited to first trimester) or amniotic fluid collection. The decision to engage in fetal screening for Down syndrome or to move from screening tests to invasive diagnostic testing once a risk assessment is completed depends on patient preference. The invasive tests to assess for Down syndrome during pregnancy do carry a risk of miscarriage.
Table 7–2Laboratory Evaluation for Down Syndrome ||Download (.pdf) Table 7–2 Laboratory Evaluation for Down Syndrome
|Laboratory Test ||Result/Comment |
|First-trimester screen || |
|Pregnancy-associated plasma protein A (PAPP-A) ||Low in pregnancy with Down syndrome fetus |
|Free beta hCG ||Elevated in pregnancy with Down syndrome fetus |
|Nuchal translucency ||Ultrasound exam; permits evaluation of each fetus in multiple gestation pregnancy |
|Quadruple screen ||Second-trimester screen |
|Alpha-fetoprotein (AFP) ||Low in pregnancy with Down syndrome fetus; elevated with fetal neural tube defect |
|hCG ||Elevated in pregnancy with Down syndrome fetus |
|Unconjugated estriol (UE3) ||Low in pregnancy with Down syndrome fetus |
|Inhibin A ||Elevated in pregnancy with Down syndrome fetus |
|DNA sequence of circulating cell-free fetal DNA ||Can detect trisomy 21 as well as other defects including trisomy 18 and trisomy 13 |
|Metaphase chromosome analysis ||Diagnostic test; can be performed on chorionic villus sample, cells from amniotic fluid, and newborn blood |
First-trimester screening typically consists of measurement of 2 analytes in maternal serum: pregnancy-associated plasma protein A (PAPP-A) and the free beta subunit of human chorionic gonadotropin (fβhCG); the former is low and the latter high in mothers carrying a Down syndrome fetus. A third part of first-trimester screening is ultrasound assessment for nuchal translucency, which is increased as a result of fluid accumulation in the neck of a Down syndrome fetus. This first-trimester screening is associated with a sensitivity of approximately 85%, with a 5% false-positive rate. Nuchal translucency alone is not recommended in singleton pregnancy because its sensitivity is only about 70%. However, in multiple gestation pregnancies, the interpretation of maternal serum markers can be problematic, while the nuchal translucency test permits evaluation of each fetus. Determination of nuchal translucency is highly operator-dependent and requires specific training.
Second-trimester screening typically consists of the so-called quadruple screen of maternal serum, consisting of measurement of the following analytes: alpha-fetoprotein, unconjugated estriol (both decreased in mothers carrying a Down syndrome fetus), and total hCG and inhibin A (both increased in such mothers). The quadruple screen has a detection rate of approximately 81% with a 5% false-positive rate. An older test, the “triple screen” includes all of these second-trimester markers except inhibin A. It is characterized by higher false-positive rates and lower detection rates. Maternal serum results are typically described in the form of “multiples of the median” (or MoM); the normal range is highly dependent on several factors including gestational age, number of gestations, maternal weight, and race.
Combining first- and second-trimester screens can provide an even higher level of detection. One approach is to sequentially conduct the tests; that is, inform the patient of the results of the first-trimester screen as soon as they are available (this permits her to choose a more definitive diagnostic method if indicated), and later perform the quadruple screen in the second trimester if appropriate. A noninvasive test that rivals the sensitivity and specificity of invasive testing is DNA sequencing of circulating cell-free fetal DNA (ccffDNA) in maternal serum. This test could also identify other chromosome aneuploidy syndromes such as trisomy 18 and trisomy 13. Current recommendations for follow-up of positive ccffDNA sequencing results are to confirm the abnormality by invasive testing (metaphase analysis on chorionic villus or amniotic fluid samples), but a negative ccffDNA sequencing test in a patient whose first- or second-trimester screen is positive for Down syndrome may provide an option to forgo invasive testing.
A final point about maternal serum screening is that the alpha-fetoprotein assay in the quadruple screen, if elevated, provides a measure of increased risk for neural tube defects such as spina bifida. These cases can be further studied by amniotic fluid collection, with assessment of acetylcholinesterase as well as alpha-fetoprotein (both elevated with neural tube defects) and high-resolution ultrasound examination.