title: First-trimester combined screening for trisomy 21 with different combinations of placental growth factor, free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A.
abstract: OBJECTIVE
  To examine placental growth factor (PlGF) in euploid and trisomy 21 pregnancies at 11-13 weeks' gestation and to model the impact on first-trimester combined screening.
  
  
  METHODS
  PlGF was measured in 509 (409 euploid and 100 trisomic) fetal serum samples derived from prospective first-trimester combined screening for trisomy 21 at 11-13 weeks' gestation. The serum samples were stored at -80°C, following the measurement of free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) levels, for median time spans of 0.9 and 4.1 years in the euploid and trisomy 21 pregnancies, respectively. The effect of additional PlGF measurement at the time of combined screening was investigated by simulating fetal nuchal translucency (NT) measurements and multiples of the median (MoM) values for PAPP-A, free β-hCG and PlGF for 20,000 euploid and 20,000 trisomy 21 pregnancies. Patient-specific combined risks were calculated based on maternal age and fetal NT in addition to free β-hCG, PAPP-A and PlGF, PAPP-A and PlGF or free β-hCG and PlGF, and detection and false-positive rates were calculated.
  
  
  RESULTS
  Median PlGF-MoM was 1.0 (95% confidence interval (CI), 0.96-1.04) in euploid fetuses and significantly lower, at 0.73 (95% CI, 0.70-0.76), in trisomy-21 fetuses (P < 0.0001). There was no significant dependency between PlGF-MoM and either gestational age at the time of blood sampling (r = 0.087, P = 0.392) or sample storage time (r = 0.028, P = 0.785). Modeled detection and false-positive rates for first-trimester combined screening (based on maternal and gestational age, fetal NT and maternal serum biochemistry) without PlGF were 85% and 2.7% for a fixed risk cut-off of 1:100. The addition of PlGF increased the detection rate to 87% and reduced the false-positive rate to 2.6%. Screening by maternal age and fetal NT in combination with PlGF and PAPP-A or in combination with PlGF and free β-hCG provided detection rates of 82% and 79%, with false-positive rates of 2.7% and 3.0%, respectively.
  
  
  CONCLUSIONS
  In pregnancies with trisomy 21 PlGF is reduced. The impact on the overall screening performance for trisomy 21 is low and does not justify the measurement of PlGF solely for trisomy 21 screening. However, as PlGF is measured with the aim of assessing the risk for pre-eclampsia, further improvement in screening for trisomy 21 can be considered as an added benefit.
authors.affiliation: Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen, Germany. KOKagan@gmx.de
authors.forename: K O
authors.initials: KO
authors.lastname: Kagan
authors.forename: M
authors.initials: M
authors.lastname: Hoopmann
authors.forename: H
authors.initials: H
authors.lastname: Abele
authors.forename: R
authors.initials: R
authors.lastname: Alkier
authors.forename: K
authors.initials: K
authors.lastname: Lüthgens
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000097:blood; D004314:Down Syndrome / Q000097:blood*; D005260:Female; D006801:Humans; D048208:Nuchal Translucency Measurement; D000072483:Placenta Growth Factor; D011225:Pre-Eclampsia / Q000097:blood; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000097:blood*; D011261:Pregnancy Trimester, First; D011266:Pregnancy-Associated Plasma Protein-A / Q000378:metabolism*; D011296:Prenatal Diagnosis; D012044:Regression Analysis; D012307:Risk Factors; D018709:Statistics, Nonparametric
chemical_list: D018997:Chorionic Gonadotropin, beta Subunit, Human; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; D011266:Pregnancy-Associated Plasma Protein-A