![]() ![]() ![]() There was essentially universal agreement that among the single markers in the second trimester that hCG, free β-hCG, and inhibin have the greatest discriminatory power. Whilst the switch over from AFP alone to two ( double test), three ( triple test) or four ( quadruple test) marker combinations has gradually taken place in most countries, there have been continual disputes over the best combinations. 7 Both intact (or total) hCG and free β-hCG are established markers of both Down syndrome and trisomy 18, being increased on average in the former and decreased in the latter type of aneuploidy. Intact hCG assays are often termed ‘total β’ or simply ‘βhCG’ assays and some researchers have also described free β-hCG as βhCG. 3 Unfortunately, inconsistency in the terminology used to describe hCG assays has created confusion when comparing first trimester screening studies. However, since the intact dimer is present in the maternal serum in a 200-fold molar excess relative to the free-β subunit, these assays primarily reflect the intact hCG concentration. Most modern hCG assays are actually non-specific and measure both the intact dimer and the free-β subunit. This molecule is a heterodimer consisting of α and β subunits which is present in maternal serum predominantly as the biologically active intact dimer, but also exists to a much lesser degree as both the free-α subunit and free-β subunits. The situation was changed in the late 1980s, when the first highly discriminatory biochemical marker was discovered, namely human chorionic gonadotropin (hCG). While the use of maternal serum AFP was a notable improvement over “how old are you?”, it left much to be desied. However, many clinicians did not consider a low risk AFP result in an older woman as sufficient grounds for not offering invasive testing. The optimal use of a biochemical or ultrasound marker is to screen all women regardless of age and to define high risk purely on the basis of the screening result. Maternal serum AFP screening for aneuploidy was widely adopted and had the potential to increase the detection rate, but it was inefficient. ![]() The detailed practical mechanics of biochemical screening, such as adjustments for gestational age, race, diabetic status, multiple gestation status, and maternal weight have been published previously and are not repeated here. In practice, to calculate the risk accurately requires further statistical manipulation, much more than for other tests done in clinical chemistry. The likelihood ratio was derived from a Gaussian model of the AFP distributions in aneuploidy and unaffected pregnancies. This was done by the calculation of a likelihood ratio (proportion of aneuploidy pregnancies divided by proportion of unaffected pregnancies with the given AFP level) and using this to increase or decrease the maternal age-specific risk. ![]() Since AFP was already widely being used to screen for neural tube defects, at 16–18 weeks' gestation, it was relatively simple to extend the test interpretation to include aneuploidy. For example, trisomy 18 has much lower values on average than Down syndrome. 5 In subsequent years there was a gradual acceptance of the association, as well as an eventual understanding that the extent of AFP reduction differed according to the type of aneuploidy. confirmed that this holds for Down syndrome. published the association of low maternal serum α-fetoprotein (AFP) with an increased risk of aneuploidy in general, 4 and Cuckle et al. Much has been written over the years describing the state of the art at given times and extensive detail regarding previous eras is not repeated here. 1, 2, 3, 4 Incorporation of these approaches has been haphazard with huge variability around the world and even within countries. Over the past 25 years, there have been several generations of “best available” approaches which have increasingly improved the statistics of screening. 3, 4 Using a cut-off maternal age of 35, a 30–40% sensitivity and 90–95% specificity (or 5–10% false-positive rate) were the best available statistics throughout the 1970s and early 1980s. These have improved the sensitivity (proportion of aneuploidy pregnancies at high risk or detection rate) and specificity (proportion of unaffected pregnancies not at high risk). Over the past three decades, attempts have been made to refine the assessment of an individual woman’s risk using biochemical and ultrasound markers within pregnancy. 1, 2, 3 In all countries, women above a fixed cut-off age were regarded as at high enough risk of aneuploidy to warrant the costs and hazards of performing an invasive diagnostic procedure. The association of aneuploidy with advanced maternal age was the be all and end all of prenatal assessment for half a century. ![]()
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