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It is possible to diagnose in utero, before the middle of the second trimester, mendelian disorders for which a gene is associated, all chromosome aberrations, and a number of congenital malformations that are not mendelian. The first step toward prenatal diagnosis is taken when the expecting couple, the primary care provider, or the obstetrician thinks of the need for it. However, even for the most common indication for such service—advanced maternal age—less than 50% of all women 35 years and older in the United States are offered prenatal testing.


Prenatal diagnosis depends on the ability to assay the fetus directly (fetal blood sampling, fetoscopy), indirectly (analysis of amniotic fluid, amniocytes or trophoblastic cells, ultrasound), or remotely (analysis of maternal serum). Some of these techniques satisfy the requirements for screening (eTable 40–4) and should be offered to all pregnant women; others carry considerable risk and should be reserved for specific circumstances. Several centers have preimplantation diagnosis of the embryo, a single cell is plucked from the six- to eight-cell blastocyst, which has been cultured after in vitro fertilization, generally without harming future development. The genome of the cell can be studied by FISH, by cytogenomic array, or by DNA analysis. Another approach is isolation of fetal DNA that is circulating in minute amounts in the maternal circulation.

Ultrasound scanning of the fetus is a safe, noninvasive procedure that can diagnose gross skeletal malformations as well as nonbony malformations known to be associated with specific diseases, eg, measurement of nuchal translucency in Down syndrome (see below). Some obstetricians routinely perform fetal ultrasound at least once between 12–20 weeks’ gestation.

Other prenatal diagnostic procedures—fetoscopy, fetography, and amniography—are more invasive and a definite risk to the mother and fetus. They are indicated only if the risk of the suspected abnormality is high and the information cannot be obtained by other means.

Maternal serum can be assayed for multiple markers that predict the risk that the fetus has a neural tube defect (elevated alpha-fetoprotein) or one of the common autosomal trisomies. Such screening is offered in the first trimester so that the results can be used, along with ultrasound and maternal age, to counsel the couple about the utility of further testing, such as chorionic villus sampling or amniocentesis.

All the cytogenomic, biochemical, and DNA analytic techniques discussed above can be applied to specimens from the fetus. Aside from screening for alpha-fetoprotein in maternal serum to detect neural tube defects, analysis of fetal chromosomes is the most frequently performed test. Chromosomal analysis can be performed on amniotic cells and on trophoblastic cells grown in culture and directly on any trophoblastic cells that happen to be undergoing mitosis. Amniotic fluid cells are derived primarily from the fetal urinary system. Amniocentesis can be performed during gestational weeks 16–18 to permit unhurried sample analysis, transmission of results, and ...

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