Prenatal Diagnosis

The future health of a new individual can be predicted, to an extent, from clues that are apparent before birth. Prenatal diagnosis is the identification of a medical condition in a developing embryo or fetus. Prenatal testing can sample fetal cells to examine DNA sequences that correspond to specific disease-causing genes or chromosomes (the structures that carry the genes). Biochemicals obtained with the fetal cell samples can also hold clues to health. Other prenatal tests analyze a pregnant woman's blood serum for telltale biochemicals that indicate the fetus faces an elevated risk of a particular condition. Ultrasound scans provide views of many aspects of fetal anatomy. Preimplantation genetic diagnosis is a technique that is actually pre-prenatal. It provides a health check on very early embryos grown in a laboratory dish, enabling parents to select those that are most likely to develop into healthy infants.

Because prenatal tests that sample fetal cells are invasive, they carry a risk of the test causing miscarriage. Therefore, these procedures are typically offered only to those pregnant women whose risk of carrying a fetus with a detectable condition is greater than the risk of miscarriage. Reasons include already having had a child or family history with a detectable genetic or chromosomal condition, or "advanced maternal age." After age thirty-five, a woman's risk of carrying a fetus with an extra or missing chromosome exceeds the risk that the procedure will cause miscarriage.

Viewing Chromosomes

Biologists first tried to visualize the chromosomes in a human cell in the late nineteenth century, with estimates of the total number ranging from 30 to 80. As methods to untangle and stain chromosomes improved, the count narrowed to 46 or 48, and by 1956 was confirmed as 46, or 23 pairs. By 1959, the first chromosomal abnormalities were identified using size and crude staining patterns to distinguish the chromosomes. In the 1970s, vastly improved staining techniques enabled cytogeneticists to much more easily distinguish chromosomes, and they began amassing databases of specific chromosomal abnormalities and the clinical syndromes that they cause.

Also in the 1970s, general staining began to be replaced with in situ hybridization, an approach that links a radioactive molecule to a short sequence of DNA called a DNA probe, chosen to match a known gene of interest. When the DNA probe binds to its complementary sequence among a sample of chromosomes spread against a piece of photographic film, the radioactivity exposes the film exactly where the probed DNA sequence resides. In the 1990s, fluorescent molecules replaced the radioactive tags, and a procedure called fluorescence in situ hybridization (FISH) was born. A flash of light matches probe to chromosome. Today, FISH can use combinations of fluorescent labels and computer analysis to individually label each chromosome. The technique is called chromosome painting or spectral karyotyping. A karyotype is a picture of a person's chromosomes displayed in size-ordered pairs. FISH can be used to highlight chromosomes obtained by amniocentesis, CVS, or fetal cell sorting, described next.

Viewing fetal chromosomes requires obtaining cells from the fetus. The most common procedure is amniocentesis, first successfully performed in 1966. In amniocentesis, a needle is used to remove a sample of the amniotic fluid that surrounds the fetus. This is usually done after the fifteenth week of pregnancy. The fluid sample contains skin cells that the fetus has shed, and these are analyzed for their chromosomal content. Results from amniocentesis typically are available within two weeks. FISH is not routinely offered, but in the labs that do offer it, some preliminary information may be available more quickly than is possible with other testing procedures.

Aberrations of chromosomes 13, 18, 21, X, and Y are seen most commonly. This is not necessarily because they are affected more often, but because problems in other autosomes are so severe that development ceases long before prenatal testing can be done.

Biochemicals in the amniotic fluid can also be analyzed for signs of metabolic disorders, though this procedure is not commonly performed unless there is already a suspicion that one may be present. Chemical markers may also be sought for neural tube defects (NTDs), which are abnormalities in brain or fetal spinal cord development. Risk of amniocentesis causing miscarriage is about 1 in 200.

Chorionic villus sampling (CVS) can be performed earlier than FISH, from the tenth to twelfth week of pregnancy. A physician removes a small sample of the chorionic villi, reached either through the vagina or the abdominal wall. The chorionic villi are fingerlike projections of cells that form part of the placenta, which provides nutrients to the developing fetus. Because the chorionic villi originate from the fertilized ovum, their chromosomes and genes should be the same as those in fetal cells. However, in practice, sometimes a mutation affects only the chorionic villi, leading to a false positive test result, or only the fetus, leading to a false negative result. Maternal cells may also contaminate the sample. Because of these uncertainties, follow-up testing such as amniocentesis is required for clarification.

CVS has been linked to a fatal limb defect, and carries a risk of miscarriage of about 1 percent. It is typically recommended for women over the age of thirty-five, for those who have already had a child with a detectable genetic or chromosomal defect, if there is a family history of a genetic disorder, or when abnormalities are detected by ultrasound. For example, CVS is often used if there is a family history of Duchenne muscular dystrophy or Tay-Sachs disease. Unlike amniocentesis, CVS cannot detect NTDs because it does not sample biochemicals. Its advantage is that it can be performed earlier in the pregnancy.

A third technique, called fetal cell sorting, is being studied and may eventually replace amniocentesis and CVS in obtaining fetal cells. This approach isolates the rare fetal cells that enter the mother's blood stream and analyzes them for gene and chromosome abnormalities. A device called a fluorescence-activated cell sorter detects and isolates fetal cells by their different surface features compared to cells from the pregnant woman. Because fetal cell sorting requires only a blood sample from the pregnant woman, it cannot endanger the fetus.

Less Invasive Methods

An ultrasound scan bounces soundwaves off of the fetus to create an image. A scan is often performed after the sixteenth week of pregnancy, and the anatomy and size of the fetus is measured to see if it is growing and developing normally. The scan can often detect major structural problems, such as a malformed heart or spine. An unusual finding on an ultrasound scan can be a warning to investigate further. However, not all birth defects can be detected by ultrasound.

An ultrasound is sometimes done at weeks five or six to confirm that a pregnancy is present. This early, the embryo looks like a lima bean with a pulsating blip in the middle, which is the beating heart. Ultrasound performed late in pregnancy can provide clues to the approaching birth date. New three-dimensional ultrasound scans offer spectacular views of the fetus.

Another noninvasive method to detect fetuses at risk for some birth defects is maternal serum marker screening. A sample of blood from a pregnant woman taken at approximately weeks 15 to 18 is analyzed for the amount of several substances, including alpha fetoprotein (AFP); a form of estrogen called unconjugated estriol; and human chorionic gonadotropin (hCG), a hormone produced only during pregnancy.

Maternal serum screening began in the 1970s with the AFP test, invented by a man whose son was born with a neural tube defect. High levels of AFP in a woman's blood indicate an increased risk for a neural tube defect in the fetus. The neural tube forms by approximately day 28 of gestation, when a portion of the flat embryo (the neural plate) folds to form a tube that will develop into the brain and spinal cord. The tube normally closes up like a zipper starting at several points along its length. If a hole remains, the brain and spinal cord underneath are exposed, causing damage.

Several years after the AFP test was developed for neural tube defects, researchers noted that low AFP correlates to an increased risk that a fetus will have an extra chromosome, particularly at positions 18 or 21. This condition is called a trisomy. Trisomy 21, an extra chromosome 21, is the most common cause of Down syndrome. Over the years, analysis of other substances have been added to refine this test, which is now offered routinely to pregnant women. Abnormal results on maternal serum screening tests indicate that amniocentesis should be done to diagnose a neural tube or chromosome defect, and that genetic counseling should be offered.

Preimplantation Genetic Diagnosis

Amniocentesis, CVS, and maternal serum screening are performed after a pregnancy is confirmed or in progress. In contrast, preimplantation genetic diagnosis (PGD) occurs before the embryo implants in the womb. This technique is performed on an embryo that has been derived from in vitro fertilization (IVF) and is growing in a laboratory dish. At about the 8-cell (day 3) stage, a cell is removed and the DNA and chromosomes are checked using FISH or a probe for a specific gene. If the cell is free of the defects being probed, the remaining 7-celled embryo is implanted into the woman, where it continues development.

The first PGD was done in 1989, when it was used to enable families with X-linked disorders to select a girl, who would not be affected by the condition. Then it was used to conceive Chloe O'Brien, a youngster free of the cystic fibrosis that affected her brother. PGD attracted widespread public attention in 2001, when a Minnesota couple, Lisa and Jack Nash, conceived their son Adam so that his umbilical cord stem cells could be used to cure his sister Molly's Fanconi anemia. Adam not only had not inherited Fanconi anemia, but he was also a tissue match for Molly, saving her life.

PGD has been used to eliminate embryos with a variety of single-gene disorders, including metabolic disorders, dwarfism, cystic fibrosis, hemophilia, muscular dystrophies, and several other genetically inheritable diseases. The technique is being increasingly used in couples for whom IVF has repeatedly failed because they manufacture eggs or sperm that have abnormal numbers of one or more chromosomes. PGD enables physicians to sort through embryos to identify and transfer those few that have normal chromosomes. PGD has about a 66 percent success rate for identification of genetic disorders.

Genetic Counseling and the Ethics of Prenatal Diagnosis

A genetic counselor helps educate individuals, couples, and families about prenatal tests, and helps them to understand and cope with the results. The couselor also informs the prospective parents of the limitations of the tests, explaining that they can rule out certain conditions but cannot guarantee a healthy baby.

Ethical issues can arise in the decision to undergo prenatal testing. For example, the Nash family received criticism for their decision to intentionally conceive one child to save another. Some people also question the use of prenatal tests or PGD to reject embryos because of a gene that causes an adult-onset disease, such as Alzheimer's disease. In a more general sense, picking and choosing offspring based on genes can be considered eugenic, with the caveat that the intent is not to improve the gene pool, but to prevent suffering. This may mean terminating a pregnancy in which the fetus has a very bleak prognosis, which people opposed to abortion might find unethical. Opponents to this view point out that "letting nature take its course" can be painful for the fetus and may endanger the life of the woman.

The ethics of prenatal diagnosis becomes more complicated when the goal is not to prevent suffering, but to choose a child of a particular sex. Doctors have long reported patients using CVS or amniocentesis to learn the sex of the fetus, then terminating the pregnancy if the outcome is not what is desired. PGD is sometimes used for this purpose, too. Some people have compared this practice to a high-tech version of the ancient practice of leaving girl babies outside city walls to perish. The American Society for Reproductive Medicine endorses the use of PGD for sex selection to avoid passing on an X-linked disease, but discourages use for family planning as "inappropriate use and allocation of medical resources."

The ethical concerns that arose with the ability to foretell the sex of a child are certain to mushroom as data from the Human Genome Project continue to lengthen the list of disorders that can be detected before birth. Physicians and parents-to-be in the future will have to decide just how much they want to know about their offspring and how they will use that information.

Ricki Lewis

Bibliography

Ethics Committee of the American Society for Reproductive Medicine. "Preconception Gender Selection for Nonmedical Reasons." Fertility and Sterility 75, no. 5 (May 2001): 861-864.

Gottlieb, Scott. "Scientists Screen Embryo for Genetic Predisposition to Cancer."British Medical Journal 322 (June 23, 2001): 1505.

Josefson, D. "Couple Selects Healthy Embryo to Provide Stem Cells for Sister."British Medical Journal 321 (October 14, 2000): 917.

Lewis, Ricki. "Preimplantation Genetic Diagnosis: The Next Big Thing?" Scientist14, no. 22 (November 13, 2000): 16.