Screening Markers and Tests

αlpha can be used with up to 12 different markers for first trimester (10 weeks to 13 weeks 6 days) and second trimester (14 weeks to 22 weeks 6 days) screening.  It is supplied ready to use for Down's syndrome screening with the following markers for first trimester, second trimester, Integrated and sequential screening (Reference 1)

First trimester markers

  • Plasma Protein A (PAPP-A)
  • Total human Chorionic Gonadothrophin (T-hCG)
  • Free β-hCG
  • Placental Growth Factor (PlGF)
  • Nuchal Translucency (NT)
  • Ductus Venosus Pulsatility Index (DVPI)
  • a nasal bone examination

Second trimester markers

  • Alphafetoprotein (AFP)
  • Unconjucated Estriol (uE3)
  • T-hCG
  • Free β-hCG
  • Inhibin-A

Screening tests for Down's syndrome

αlpha can be used to screen for Down's syndrome using the screening markers in any combination including those in the table below (Reference 1):

Test Markers
Integrated Maternal age with nuchal translucency and PAPP-A in the first trimester, and AFP, uE3, total or free ß hCG  and inhibin-A in the second trimester. Measurement of first trimester PlGF, DVPI and a nasal bone examination can optionally be included. Click for more information.
Serum integrated Maternal age with PAPP-A in the first trimester, and AFP, uE3, total or free ß hCG and inhibin-A in the second trimester. Measurement of first trimester PlGF can optionally be included. Click for more information.
Combined Maternal age with first trimester nuchal translucency, total or free ß hCG and PAPP-A. Measurement of first trimester PlGF, DVPI and a nasal bone examination can optionally be included. Click for more information.
Quadruple AFP, uE3, total or free ß hCG  and inhibin-A

Ductus venosus blood flow can also be included as a categorical variable in the screening interpretation (Reference 5).

Screening performance

At a False Positive Rate of 5%, the estimated  Detection Rate for the Integrated test, serum integrated test, combined test and quadruple test are 95%, 88%, 87% and 84% respectively.

The figure below show a plot of the false-positive rate against detection rate for the four tests (first trimester markers measured at 11 weeks) (Reference 1)

Measurement of first trimester PlGF, DVPI and a nasal bone examination improves the screening performance of first trimester and Integrated tests. Click for more information

Open neural tube defect screening

AFP can be used for screening for open neural tube defects between 15 weeks and 22 weeks 6 days.  The estimated detection rate for open spina bifida at gestational ages between 15 and 20 weeks is given in the table below (from reference 8)

  Detection Rate (%)
Gestational age (weeks)
 
Method used to
estimate gestational
age
AFP
(MoM
15 16 17 18 19 20 FPR (%)
15-20 weeks
Dates ≥2.0 68 77 81 82 78 70 3.4
≥2.5 57 68 73 73 69 59 0.8
≥3.0 47 59 64 65 60 50 0.2
BPD ≥2.0 83 89 92 92 90 84 2.0
≥2.5 74 83 86 87 84 76 0.3
≥3.0 66 76 80 81 77 68 0.1

Screening tests for trisomy 18

αlpha can be used to screen for trisomy 18 using maternal age with second trimester measurements of AFP, uE3, total hCG and Free β-hCG,  maternal age with first trimester measurements of  PAPP-A, total hCG, Free β-hCG and NT and maternal age with nuchal translucency and PAPP-A in the first trimester, and AFP, uE3, total or free ß hCG  in the second trimester combined in an Integrated test.   As an alternative to screening the risk of a pregnancy being affected with trisomy 18 can be shown on the report as an incidental result of screening for Down's syndrome.

The estimated trisomy 18 detection rate and false positive rate at an early second trimester cut-off of 1 in 100 is given in the table below.  The NT measurement was taken at 11 weeks and the maternal age distribution is that for England & Wales in 2006-2008.  (Reference 4).

Test Detection rate (%) False positive rate (%)
Combined
(NT, Free β-hCG & PAPP-A)
79 0.10
Triple
(AFP, uE3 and Free β-hCG)
48 0.11
Serum integrated
(PAPP-A in the first trimester and
AFP, uE3 and Free β-hCG in the second trimester)
78 0.08
Integrated
(NT and PAPP-A in the first trimester and
AFP, uE3 and Free β-hCG in the second trimester)
82 0.05

Screening tests for trisomy 13

αlpha can be used to screen for trisomy 13 using maternal age with first trimester measurements of PAPP-A, Free β-hCG and NT or maternal age with a second trimester measurement of inhibin-A and first trimester measurements of PAPP-A and NT combined in a Integrated test .  As an alternative to screening the risk of a pregnancy being affected with trisomy 13 can be shown on the report as an incidental result of screening for Down's syndrome.

The estimated trisomy 13 detection rate and false positive rate at an early second trimester cut-off of 1 in 100 is given in the table below.  The NT measurement was taken at 11 weeks and the maternal age distribution is that for England & Wales in 2006-2008.  (Reference 4)

Test Detection rate (%) False positive rate (%)
Combined
(NT, Free β-hCG & PAPP-A)
65 0.21
Serum integrated
(PAPP-A in the first trimester and 
inhibin-A  in the second trimester)
44 0.22
Integrated
(NT and PAPP-A in the first trimester and inhibin-A in the second trimester)
65 0.17

Screening tests for pre-eclampsia

The pre-eclampsia prevalence together with:

  • second trimester measurements of AFP, uE3, total hCG, Free β-hCG, inhibin-A and PlGF
  • first trimester measurements of PlGF, PAPP-A and mean arterial pressure (MAP)
  • previous history of pre-eclampsia, family history of pre-eclampsia and parity

can be used to calculate the risk of developing pre-eclampsia.   This provides an opportunity for closer monitoring of the pregnancy and preventive treatment in patients with a risk above a specified cut-off.

Assuming a pre-eclampsia prevalence of 4% and using the quadruple test markers plus a measurement of second trimester PlGF the estimated pre-eclampsia detection rate is 45% (all pre-eclampsia) and 52% (early pre-eclampsia) for a false positive rate of 5%.  If previous history of pre-eclampsia, family history and parity are taken into account, the estimated detection rate for all pre-eclampsia is 48% for a false positive rate of 5%. (Reference 2)

Using first trimester measurements of  PAPP-A and MAP together with the quadruple test markers plus a measurement of second trimester PlGF the estimated pre-eclampsia detection rate is 51% (all pre-eclampsisa) and 64% (early pre-eclampsia) for a false positive rate of 5%.  Taking the PlGf measurement in the first trimester reduces the detection rate by 5% for all pre-eclampsia and 1% for early pre-eclampsia (derived from references 6 & 7).  If previous history of pre-eclampsia, family history and parity are taken into account, the estimated detection rate for all pre-eclampsia is 56% for a false positive rate of 5%.

Single risk

Alpha can optionally screen using a single risk of Down's syndrome, trisomy 18 or trisomy 13 or using Down's syndrome risk and a single risk of trisomy 18 or  trisomy 13 (reference 9)

Other disorders

Smith Lemli Opitz syndrome (SLOS)

Pregnancies at high risk of SLOS can be identified using second trimester measurements of  AFP, uE3 and total hCG. (Reference 3)

References

1. Improvements in antenatal screening for Down’s syndrome (2013)
2. Screening for pre-eclampsia using serum placental growth factor and endoglin measurement with Down’s Syndrome Quadruple test markers (2012)
3. Assigning risk for Smith-Lemli-Opitz syndrome as part of 2nd trimester screening for Down's syndrome (2002)
4. Screening for trisomy 18 and trisomy 13 using first and second trimester Down syndrome screening markers (2013)
5. Adding ductus venosus blood flow as a categorical variable to the Combined and Integrated tests in Down’s syndrome screening (2012)
6. Prediction of early intermediate and late pre-eclampsia from maternal factors, biophysical and biochemical markers at 11-13 weeks (2011)
7. Competing risks model in early screening for preeclampsia by biophysical and biochemical markers (2013)
8. Neural tube defects (2000)
9. Antenatal screening for Down’s syndrome, trisomy 18, and trisomy 13: Reporting a single screening result for all three (2015)