Book Review

Screening for Down's Syndrome

N Engl J Med 1995; 333:532August 24, 1995

Article

Screening for Down's Syndrome
Edited by J.G. Grudzinskas, T. Chard, M. Chapman, and H. Cuckle. 346 pp. New York, Cambridge University Press, 1995. $89.95. ISBN: 0-521-45271-6

Screening for fetal Down's syndrome first became possible in the late 1960s, when the positive association between maternal age and the prevalence of Down's syndrome at birth was identified and a diagnostic test (amniocentesis and fetal karyotyping) became available. Until the 1980s, the screening test essentially was the question, “How old are you?” If the pregnant woman was, for example, 35 or older, she was offered counseling and diagnostic testing. In 1984, it was reported that fetal Down's syndrome was associated with reduced maternal levels of serum alpha-fetoprotein in the second trimester and that this reduction was independent of maternal age. Biochemical screening with alpha-fetoprotein measurements was rapidly introduced and used in combination with maternal age. Researchers also realized that other fetal and possibly placental products might be markers for Down's syndrome. In fact, one of the editors of this book (Dr. Chard) suggested in 1984 that human chorionic gonadotropin should be investigated as a possible marker for Down's syndrome. In 1987, elevated levels of human chorionic gonadotropin were shown to be associated with Down's syndrome, and this marker is now considered to be one of the most discriminating.

Screening for Down's Syndrome is a compilation of presentations made at a spring 1993 symposium in London on recent advances in the field. The contributors are well known in the field of prenatal screening and represent such diverse disciplines as clinical chemistry, epidemiology, obstetrics, and genetics. The first few chapters introduce the natural history of Down's syndrome and concepts concerning the perception and calculation of risk. The middle portion of the book covers statistical, laboratory, and programmatic issues related to current biochemical screening programs that use maternal age with various combinations of the levels of alpha-fetoprotein, human chorionic gonadotropin, the free β subunit of human chorionic gonadotropin, and unconjugated estriol. The remainder of the book covers new screening techniques.

The chapter on risk estimation contains valuable guidance for evaluating candidate markers in a screening protocol for Down's syndrome. For example, in several tables, the author demonstrates the effect of adding a new marker to current triple-marker screening protocols by varying the degree of discrimination of the new marker, the correlation of the new marker with other markers, and the age-associated risk in the screened population. It is unfortunate that the author did not have the space to describe these concepts in more detail.

Although the book contains many excellent summaries of the literature, along with interpretations of widely discussed issues, it also contains a few misleading and sometimes incorrect analyses. Several authors note that as the number of markers used to estimate the risk of Down's syndrome increases, the imprecision of the risk estimate increases. In the chapter on test combinations, only the imprecision attributable to assay errors is addressed; other, more important sources of imprecision, such as gestational dating or within-person variability, are not considered. The conclusion that the imprecision of assays alone imposes a limit of two biochemical markers does not take into account accompanying increases in accuracy. The chapter on the United Kingdom National External Quality Assessment Scheme reports large coefficients of variation for the risk of Down's syndrome when calculated on a linear scale. However, the next page contains a figure demonstrating that the distribution of risks is logarithmic.

Readers who are knowledgeable in the area of prenatal diagnosis will find the discussions of issues stimulating and will refer to the book often. The index is especially useful in identifying topics addressed by several authors, often with opposing conclusions. The book is also intended for general providers of obstetrical care, but they are likely to find many of these sections confusing. The book might have been more appropriate for obstetricians had it included, for example, a chapter on the risks and benefits of ultrasonography for the further evaluation of patients with positive screening results. However, obstetricians will be interested in the chapters presenting screening tests for possible use in the first trimester, including tests for increased areas of fetal nuchal translucency and for reduced levels of pregnancy-associated plasma protein A in maternal serum, as well as fluorescence in situ hybridization of fetal cells isolated from the maternal circulation. All these tests appear promising, but none are yet ready for routine use.

Glenn E. Palomaki, B.S.
Foundation for Blood Research, Scarborough, ME 04074