Methods for Obtaining Samples for Prenatal Diagnosis

Amniocentesis is frequently used synonymously with the term prenatal testing. Amniocentesis is in fact merely a technique for removal, via a needle puncture of the uterus, of amniotic fluid from the sac which surrounds the fetus during pregnancy. This fluid contains fetal cells on which analyses can be performed. The usefulness of amniocentesis is tightly linked to expanding knowledge about genetics, the development of techniques of fetal analysis, and changing legal and social norms.

In 1955, it was first demonstrated that fluid could be removed from the amniotic sac, that fetal cells could then be cultured, and that the total number of chromosomes— including the sex chromosomes—could be ascertained—a process called karyotyping. The first use of karyotyping was to identify male fetuses of women who carried serious genetic conditions on their X chromosome. However, this was initially of limited usefulness as no information other than fetal sex was obtainable, the safety of the procedure needed further investigation, and pregnancy termination for fetal anomaly was not legal.

The later finding that a karyotype showing three rather than two copies of a chromosome (trisomy 21) was indicative of Down syndrome presented the possibility of much broader use for amniocentesis. Not only was Down syndrome an important cause of mental retardation, it was also predicted by a pregnant woman's increasing age rather than by her genetic history. When, in the mid-1970s, a large study demonstrated the safety of amniocentesis (NICHD National Registry for Amniocentesis Study Group) at approximately the same time that the Supreme Court decision in Roe v. Wade made abortion legal in the United States, the way was opened to the population-based use of this technique for women of advanced maternal age.

Serious maternal complications from amniocentesis are rare; the primary medical risk of amniocentesis is fetal loss from the procedure. For this reason, the age, at which amniocentesis is routinely offered, is driven by an equation that looks for equipoise between the risk of procedure-related miscarriage and the age-related risk of Down syndrome. It is worth noting that one can infer from this equation an equivalence between the negative outcome of a fetal death and birth of a child with a disability, an equivalence which, as discussed below, would be contested from various positions critical of prenatal testing. Nevertheless, as rates of procedure-related miscarriage have decreased—due primarily to the use of real-time ultrasound to guide the needle—the age at which women are routinely offered amniocentesis has also decreased. At the beginning of the twenty-first century, it is standard of care to offer amniocen-tesis to women over age thirty-five.

Although amniocentesis is most closely associated with trisomy 21, any chromosomal abnormality can be detected through karyotyping, and the sample of fluid obtained can be used to diagnose any fetal anomaly for which a cytogenetic, biochemical, or DNA test has been developed (e.g., Tay-Sachs, sickle cell anemia, Huntington's disease).

EARLY AMNIOCENTESIS AND CHORIONIC VILLUS SAMPLING. Amniocentesis is performed in the middle of the second trimester of pregnancy. By this time, pregnant women have often experienced quickening (perceived fetal movement) and the fetus is nearing the age of viability. These factors have led to a search for earlier modes of fetal sample collection, including first trimester ("early") amniocentesis and chorionic villus sampling (CVS).

Although there was initial enthusiasm for early amnio-centesis performed in the eleventh through thirteenth weeks of pregnancy, recent data suggest that this procedure may pose significantly greater fetal risks than traditional amnio-centesis, including high rates of pregnancy loss and risk of fetal malformations (e.g., club foot) (Bianchi, 2000). In addition, early amniocentesis is more technically difficult and thus more often will fail to obtain a fluid sample adequate for cell culture. Enthusiasm for the procedure has waned, although it is possible that future solutions to these problems will revitalize interest.

Rather, it is CVS that appears likely to become the procedure of choice for earlier fetal sample collection. The chorionic villi are precursors of the placenta and have proved a good source of fetal tissue. CVS can be performed safely as early as the tenth week of pregnancy, either transabdominally or transvaginally; the risks have been found to compare well with second trimester amniocentesis (Bianchi, 2000). In addition, the waiting period for results following CVS is shorter than in amniocentesis—three to eight rather than ten to fourteen days. Since there is considerable documented anxiety for parents waiting for prenatal test results, this represents a significant advantage.

MATERNAL SERUM FETAL CELL RECOVERY. Both CVS and amniocentesis are invasive techniques. They share disadvantages of potential fetal harm and are relatively costly to perform. Thus, there continues to be interest in finding a non-invasive, less expensive technique that could be used to gather a fetal sample early in pregnancy. There is only one such technique on the horizon in 2003—maternal serum fetal cell recovery.

It is known that a small number of fetal cells are sloughed off and cross into maternal blood circulation. After isolation from a maternal blood draw, these cells can then be used for any desired fetal analysis. However, fetal cells are numerically rare in maternal blood and their identification and isolation is difficult. In addition, the type of cell most amenable to detection and isolation is not ideal for chromosomal analysis (Holzgreve and Hahn). Nevertheless, work on this technique progresses and a prospective multicenter trial of this technique as a screen for chromosomal anomalies began in the mid-1990s (Bianchi, 2002). Early results were promising for chromosome analysis, but the future goal of fetal cell recovery remains broader than this: To be able to perform not only analysis of chromosomal abnormalities, but to capture the larger number of fetal cells needed for DNA techniques. This goal holds the promise of genetic analysis for any disorder of interest.

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