False Negatives

A mother on one of the pregnancy boards had both an AFP and an amniocentesis done at the same visit. Her AFP came back normal but the amnio results were positive for a form of Down syndrome that generally results in a stillborn infant. How common is it to have a false "normal" with an AFP?

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Peg Plumbo CNM

Peg Plumbo has been a certified nurse-midwife (CNM) since 1976. She has assisted at over 1,000 births and currently teaches in the... Read more

AFP is produced sequentially by the fetal yolk sac, the gastrointestinal tract and the liver. It reaches a peak concentration in fetal serum of approximately 300 mg/dl by the end of the first trimester. The fetal liver produces a constant amount of AFP through the 30th week of gestation, although levels in the fetal blood decrease as the pregnancy advances. This is best explained by a dilutional effect in the enlarging fetal intravascular compartment. After 30 weeks gestation, fetal AFP production declines precipitously.

AFP is also found in high concentrations in amniotic fluid. The decrease in amniotic fluid AFP throughout the second and third trimester closely parallels the decrease in AFP in the fetal blood. A small proportion of AFP enters the amniotic fluid after filtration of the fetal blood trough the kidney. As the fetus swallows amniotic fluid, AFP is destroyed by gastrointestinal proteolytic enzymes. AFP concentration in amniotic fluid is approximately 150 times less than in fetal serum.

In the maternal circulation, AFP levels rise until the 30th gestational week. Thereafter, levels decline until term and drop precipitously after delivery. During the second trimester, maternal serum AFP levels increase while fetal serum levels decline. This paradox is not completely understood, but may be due to the enlarging placenta allowing a greater capacity for diffusion of AFP, or changes in the permeability of the placenta to AFP. The mechanism for transfer of AFP to the maternal circulation is both transplacental (two thirds) and transamniotic (one third). A comparison of AFP levels in the maternal and fetal compartments is shown diagrammatically in Figure 1.6

Understanding Multiples of the Median

An alpha-fetoprotein test measurement is typically reported as a multiple of the median (MoM). This statistical convention was introduced by the First U.K. Collaborative Study on AFP7 as a method for participating laboratories to compare individual test results. Measurements of AFP can be affected by laboratory technique, resulting in difficulty comparing absolute results between centers. Standard deviations are influenced by data spread. Since MoM is a reflection of an individual patient's value compared to the median, it is not influenced by outlying values. Each laboratory should develop reference data, with a median MSAFP value from unaffected pregnancies calculated for each week of gestation. The AFP calculation for an individual patient is adjusted by other variables that affect the interpretation of the result. These variable include maternal weight, race, multiple gestation and insulin dependent diabetes mellitus.

The adjusted AFP result is expressed as a MoM by dividing the AFP concentration by the median value for the appropriate week of gestation. The log Gaussian distribution of maternal serum AFP levels in unaffected pregnancies, as well as those with open spina bifida and Down Syndrome, is shown in Figure 2. The median MSAFP value for each week of gestation is designated as 1.0 MoM. Most commonly, MSAFP in open spina bifida has a median MoM of 3.3 to 3.8, anencephaly, 7.7 MoM; gastroschisis, 7.8 MoM; and omphalocele, 4.5 MoM.

MSAFP is not used as a diagnostic test but rather as a screening test. Screening differs from diagnostic testing in that a positive MSAFP result does not mean that the patient has an affected fetus, but rather that the patient is in a category of sufficient risk to warrant further studies such as ultrasound or amniocentesis.

A low maternal serum AFP is associated with an increased incidence of Down Syndrome (Trisomy 21). There are other types of trisomy defects, some of which are incompatible with life. AFP (in conjunction with other tests) is useful only in determining risk of two of the trisomy defects, 18 and 21.

Several studies support the use of more than AFP in detection of Down Syndrome (i.e., additional markers). HCG is the major contributor to the increased sensitivity of screening programs, but substantial improvement in detection of second-trimester Down syndrome can be accomplished by adding hCG to AFP and age.

One study I read used three markers and a one in 250 cut-off risk; the estimated false-positive rate was about 5.3 percent and the detection rate was about 58 percent. In another study, using four serum markers -- AFP, uE3, free beta-hCG and free alpha-hCG -- in addition to maternal age, 65 per cent of Down syndrome pregnancies were detected for a five per cent false-positive rate, compared with 59 per cent with the conventional triple test (AFP, estriol and total hCG with maternal age).

So, even when only considering Down syndrome, there are substantial numbers who are missed. That is why women at true risk and those over 35 should be offered amniocentisis in preference to AFP screening. But even amnio is subject to problems such as contamination and retrieving too few cells or maternalcells. The results are only as good as the analysis done in the lab, which depends on how or if the cells grow and the skill of the technician.

Ultrasound in combination with AFP and/or amnio can detect 90 percent of all trisomy defects in the second trimester. Still, some are missed. But AFP can only reliably detect risk of Down syndrome, and not other trimsomy problems.

I hope this has helped. Thanks for writing.

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