BIOCHEMISTRY

A number of proteins in the maternal circulation have been found during the time of pregnancy.  Many of these are made or modified by the placenta.  Differences in levels of some of the proteins have been observed in patients carrying a fetus with Down syndrome and certain other chromosome abnormalities.  The discovery of these slight differences in protein levels has been largely based on observation- we really don't know why they work in most cases.  Nevertheless, we can take advantage of these differences in screening protocols.  These are referred to as biochemical markers.  Certain patterns of biochemical markers have been associated with fetal Down syndrome as well as other conditions.  Click here to see some of these associations.  It is important to know that these proteins change during pregnancy, so interpretation requires an knowledge of the gestational age.  Also, the effectiveness of these proteins varies with gestational ages.  For example, differences in protein levels may be observed during the second trimester but not the first, while other proteins show differences during the first trimester but not the second.  Individual proteins are described below.  Click here for a brief summary of screening options and terminology.  Click here for a more detailed slide show of screening options with fetal Down Syndrome that includes biochemistry and ultrasound.

SECOND TRIMESTER (15-20 WEEKS)

ALPHA-FETOPROTEIN (AFP)

The first protein routinely measured in the maternal blood was AFP (alpha-fetoprotein).  High AFP levels were originally used to identify fetuses at risk for neural tube defects.  In 1984 it was reported by Merkatz et al that low AFP levels may help identify fetuses with Down syndrome as well as fetuses with trisomy 18.  AFP remains one of the proteins used for screening during the second trimester, but it is actually one of the least useful markers.  Also screening for elevated AFP levels is a  now poor method of screening for neural tube defects where high quality obstetric ultrasound is available.  It remains useful where high quality obstetric ultrasound is not available or not applied.

HUMAN CHORIONIC GONADOTROPIN (HCG)

The second useful blood test was high levels of  HCG, reported by Bogart et al in 1987.  This is the same protein used for pregnancy testing, although it turns out there are many different forms of this protein.  HCG or a another form (free beta HCG) is one of the most useful of the blood markers and it is the only one that works in both the second and the first trimester.

ESTRIOL

Low levels of estriol  were reported to be associated with an increased risk for Down syndrome by Cannick in 1998.  Addition of estriol to the other 2 markers produced a panel of markers which was commonly referred to as the "triple screen". This model was proposed by Wald in the late 1980s and it became the primary method for screening in the United States through out the 1990s.  The addition of estriol showed only a small incremental benefit, however, to the other 2 markers and use of estriol was a controversial topic.  In Great Britain, estriol was not added so the standard was using a "dual" marker panel of AFP and HCG.  The triple screen had a detection rate of about 65% for a 5% false positive rate.

INHIBIN A

Differences in inhibin A levels were observed in the early 1990s.  However, the assay was unstable and could not be used in a practical way until the late 1990s.  Addition of inhibin-A to the triple screen resulted into the so called "quad screen”.    The quad screen can detect 70-75% of cases of fetal Down syndrome.
 

FIRST TRIMESTER (9-14 WEEKS)

It is important to know that these proteins change during pregnancy, so interpretation requires an knowledge of the gestational age.  Also, the effectiveness of these proteins varies with gestational ages.  For example, differences in protein levels may be observed during the second trimester but not the first, while other proteins show differences during the first trimester but not the second.

FREE BETA HCG

There are many metabolites of  HCG.  One of these is free beta HCG.  Elevated levels of free beta HCG can be used during the first trimester to help screen for fetal Down syndrome.

PAPP-A (PREGNANCY ASSOCIATED PLASMA PROTEIN-A)

Low levels of PAPP-A were found to be associated with fetal chromosome abnormalities during the early 1990s. This is one of the most useful blood marker during the first trimester.