Screening for neural tube defects

NeuronsA neural tube defect (NTD) is a birth defect of the spinal cord and/or brain.  The term is used to describe a group of disorders that occur very early in pregnancy and can be mild to severe or even fatal.

During the first 3 weeks of pregnancy, specific cells fuse to form a hollow tube (the neural tube) that forms the basis of what will become the spinal cord and brain.  A NTD occurs when that neural tube fails to close completely somewhere along its length.

The two most common NTDs are spina bifida and anencephaly.  Spina bifida is the most common.  There are different types of spina bifida and each has varying degrees of severity but it nearly always results in some nerve damage that can cause at least some paralysis of the legs.  Anencephaly is the most severe NTD and results in the lack of development of the brain and skull and is not compatible with life.  NTDs that are covered by skin are called “closed” defects while those that are not covered by skin are considered to be “open.”  Only open NTDs are detected by screening tests.

Alpha-fetoprotein (AFP) testing is used to screen for a NTD during the second trimester of pregnancy.  Ideally it takes place between 16 and 18 weeks of gestation but between 15 and 22 weeks is acceptable.  The concentration of AFP in fetal blood is 100,000 times greater than it is in maternal blood.  Some of the fetal AFP normally enters the maternal blood and so the AFP concentration in maternal blood will begin to increase.  A fetus with an open NTD will transfer more AFP into maternal blood than an unaffected fetus and so an unusually high AFP concentration in maternal blood can indicate that the fetus has an open NTD.

Because AFP concentrations normally increase during pregnancy (by about 15 percent each week), a statistic called the “multiple of the median” (MoM) is used to normalize the test result.  The MoM is a measure of how far an individual test result deviates from the median (middle) value of a large set of AFP results obtained from unaffected pregnancies.  For example, if the median AFP result at 16 weeks of gestation is 30 ng/mL and a pregnant woman’s AFP result at that same gestational age is 60 ng/mL, then her AFP MoM is equal to 60 divided by 30 (60/30) or 2.0.  In other words, her AFP result is 2 times higher than “normal.”

So how is the AFP MoM interpreted?  What is considered an abnormal result?  Although the AFP MoM cutoff varies by lab, the two most commonly used are 2.0 and 2.5.  Results above the cutoff are considered to be abnormal.  A cutoff of 2.0 will detect about 85 percent of open NTD and a cutoff of 2.5 will detect about 75 percent.  Most cases of anencephaly are detected with maternal serum AFP screening.  The figure below illustrates the distribution of AFP MoM results in women with unaffected fetuses, those with spina bifida, and fetuses with anencephaly.

Results to the right of the blue line (a cutoff of 2.5 MoM) would be interpreted as "abnormal" while an AFP MoM to the left of the line would be considered "normal."  Note that there is no single MoM cutoff that can completely separate unaffected from affected fetuses.  There will always be affected fetuses that screen normal and unaffected fetuses that screen abnormal.

Because this is a screening test, women with an abnormal result require additional testing to confirm if the fetus has a NTD.  More about these tests in future post.

AFP and NTD
Lastly, it’s important to keep in mind that most abnormal NTD screening tests are false-positives.  There are several reasons why AFP might be elevated in the absence of an open NTD such as: an abnormality in the fetal kidneys, a ventral wall defect (opening in the abdomen), the death of the fetus, a twin gestation, or, most commonly, underestimated gestational age.

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