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 developed 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 and 20 weeks of 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 of 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 reproductive decisions. The time from obtaining the sample to a final reading of the genome for imbalances has now been shortened to a few days. Chorionic villus sampling (CVS) for trophoblastic cells (derived embryologically from the same fertilized egg as the fetus) is usually done during gestational weeks 10–13. If the tissue can be analyzed directly, cytogenomic results can be obtained within a few days. The advantage of CVS is that the results are available early in pregnancy, so that termination, if elected, can occur earlier in the pregnancy and the obstetric complications of termination are fewer.
The risk of CVS is somewhat higher than that of amniocentesis, though both are relatively safe. Between 0.5% and 1% of pregnancies are lost as a complication of CVS, whereas less than 1 in 300 amniocenteses result in fetal loss. Some centers offer "early amniocentesis," performed during gestational weeks 12–14; the magnitude of the risks is similar to that of CVS. These figures are lower than—but are in addition to—the baseline 2–3% spontaneous abortion rate after the first trimester ends.
When fetal DNA is analyzed by array methods, the finding of a deletion or duplication that is not clearly associated with a clinical phenotype (eg, trisomy 21) will require analysis of the parental DNA, and this adds to the time required to produce an interpretation and the complexities of the genetic counseling.
Fragments of fetal DNA circulate in maternal blood during much of pregnancy. This enables 'noninvasive' fetal DNA testing. Using free fetal DNA to test for trisomies 21 and 18 has lower false-positive rates and improved positive predictive values compared to the use of maternal serum analytes. The entire fetal genome has been sequenced from these circulating fragments, which is opening the possibility to detecting disorders for which the fetus is known to be at risk, for conditions that may not be evident until adulthood, and for carrier status of any metabolic disorder.