Testing for Congenital Diseases

Routine testing during pregnancy currently includes evaluation of the risk of neural tube defects and Down sydrome, using the biochemical assays discussed below. In the near future, improved understanding of the human genome and the structure of specific abnormal genes will allow a wide variety of genetic diseases to be tested for prior to birth. Although we will concentrate on the science involved, you should be aware that the ability to do this type of testing raises a number of ethical and logistical questions and you should be sensitive to the issues your patients will face in dealing with whether to use these tests and what to do about the results.

Testing for neural tube defects and Down's syndrome currently begins with assay of alpha-fetoprotein in maternal serum.

Alpha-fetoprotein (AFP)

  1. AFP is the major globulin in fetal serum (it serves functions similar to albumin in postnatal life).

  2. It enters the amniotic fluid via the urine and leaks across the placenta to reach the maternal circulation

  3. AFP levels in amniotic fluid peak around 14-15 weeks of gestation, then decline

  4. In contrast, maternal serum AFP continues to increase throughout pregnancy. This is partly because the increasing volume of amniotic fluid comprises an increasing load of total AFP available for leakage, even though the concentration of the protein in the amniotic fluid is declining.

  5. AFP levels in the amniotic fluid, and thus the maternal serum, are elevated by direct leakage from open neural tube defects (anencephaly, spina bifida), abdominal wall defects (gastroschisis), fetal or placental hemorrhage, and multiple pregnancy.

  6. AFP levels in maternal serum and amniotic fluid are expressed as multiples of the median (MoM) value of AFP levels for that week of gestation.

  7. In general, abnormal AFP results should be followed up by repeat testing in one week.

Open neural tube defects

Open neural tube defects include anencephaly and spina bifida. These defects allow leakage between the CSF (with high levels of AFP) and the amniotic fluid and therefore raise the amniotic fluid and maternal serum concentration of AFP. Affected pregnancies generally have substantially elevated AFP values, with MoM greater than 2.0 to 2.5 (the actual cutoff varies among laboratories). There is a small amount of overlap between the upper end of the normal distribution of MoM values and the lower end of the distribution of the affected population, so a risk calculation (e.g., 1 in 10 chance of open neural tube defect) is normally given along with the MoM.

Normal follow-up of an elevated maternal serum AFP value includes:

  1. A repeat maternal serum AFP one week later

  2. Ultrasound to confirm gestational age by skull measurements (bi-parietal diameter), to identify a multiple pregnancy if present (multiple pregnancies normally have elevated AFP values), and to directly identify a neural tube defect if possible.

  3. Amniocentesis if necessary.

Samples of amniotic fluid from amniocentesis can be assayed for AFP (which will confirm the elevated serum AFP if a defect is present) and acetylcholinesterase, which leaks into the amniotic fluid if an open neural tube defect is present.

Down syndrome

Down syndrome (trisomy 21) is the most common chromosomal disorder. Its incidence is strongly correlated with maternal age. For a number of years, the risk of Down syndrome at age 35 (1 in 385 pregnancies) has been considered to warrant the risk of amniocentesis for definitive diagnosis by chromosomal analysis.

Subsequently, it was found that maternal serum and amniotic fluid AFP is decreased in Down Syndrome, though the distribution of MoM values in the affected population has a substantial overlap with the normal distribution of MoM values. Though the overlap does not allow good separation of normal and affected populations (as is possible in open neural tube defects), a risk calculation can be carried out based on both maternal age and the AFP value. If the resulting risk of Down syndrome is greater than 1:385 (the risk for a 35-year-old mother that is considered to warrant amniocentesis), amniocentesis is usually offered.

Additional markers show abnormal distributions in Down syndrome, with an overlap of the normal distribution similar to the situation with AFP. Maternal serum hCG is increased, and serum unconjugated estriol is decreased, in Down syndrome. Most laboratories today report two (AFP and hCG) or three (AFP, hCG and estriol) marker risk calculations (inclusion of hCG is generally accepted as improving the risk calculation, but estriol's benefit is still controversial). These multiple-marker analyses may be capable of identifying greater than 80% of cases of Down syndrome. As previously, women with risk greater than 1:385 are offered definitive diagnosis by amniocentesis and chromosomal analysis.

In the near future genetic testing will become more sensitive and specific, using techniques like direct molecular hybridization and restriction fragment length polymorphism analysis to detect genetic abnormalities. In the not-too-distant future, these techniques will be automated so that they are generally available at low cost, and with rapid turnaround.

Ectopic Pregnancy and Spontaneous Abortion

Hemolytic Disease of the Newborn

Back to Pathology Overview

Back to Prenatal Testing Outline

Last modified: 1/23/97; Author: J. Harrison