Introduction
At present, the main role of placental growth factor (PlGF) in antenatal care has been in screening women for risk of preterm pre-eclampsia (PE) in the late first trimester or at later gestations. It is used on its own or in conjunction with soluble fms-like tyrosine kinase-1 (sFlt-1) as indicators for PE in asymptomatic women or in women who present with signs or symptoms of PE.11Rolnik DL, Wright D, Poon LC, O’Gorman N, Syngelaki A, et al. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. N Engl J Med 2017;377:613-22 22Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, et al. Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia. N Engl J Med 2016;374):13-22 The finding that reduced levels of PlGF in maternal circulation is not only associated with PE but also with other adverse pregnancy and fetal outcomes such as being small for gestational age and aneuploidy has led to the discussion as to whether PlGF can fulfill a dual function. Specifically, the key research questions are whether PlGF can be used to screen for both PE and aneuploidy at 11-13 weeks of gestation and by replacing pregnancy associated plasma protein-A (PAPP-A) with PlGF the overall cost of screening is reduced. Alternatively, can PlGF be used as an additional biomarker as part of the first trimester combined test to increase the detection of trisomy 21.
There are similarities between PAPP-A and PlGF where both are produced by the placenta and are dependent on gestational age as well as maternal and pregnancy characteristics such as weight, smoking, mode of conception and ethnicity. However, whilst PAPP-A is shown to be consistently reduced in pregnancies affected by trisomies 13, 18 and 21, studies assessing the association between the level of PlGF and trisomy 21 have shown discordant findings. Maternal serum levels of PlGF have been reported as being both increased, reduced or no different in trisomy 21 affected pregnancies as compared to non-aneuploidy affected pregnancies.33Debieve F, Moiset A, Thomas K, Pampfer S, Hubinont, et al endothelial growth factor and placenta growth factor concentrations in Down’s syndrome and control pregnancies. Mol Hum Reprod 2001;7:765-70 44Spencer K, Liao AW, Ong CY, L Geerts L, Nicolaides KH. First trimester maternal serum placenta growth factor (PIGF) concentrations in pregnancies with fetal trisomy 21 or trisomy 18. Prenat Diagn 2001;21:718-22 55Lambert-Messerlian GM, Canick JA. Placenta growth factor levels in second-trimester maternal serum in Down syndrome pregnancy and in the prediction of preeclampsia. Prenat Diagn 2004;24:876-80 66Zaragoza E, Akolekar R, Poon LCY, Pepes S, Nicolaides KH. Maternal serum placental growth factor at 11-13 weeks in chromosomally abnormal pregnancies. Ultrasound Obstet Gynecol 2009;33:382-6 Earlier studies have reported that the addition of PlGF to the conventional first trimester combined test of nuchal translucency (NT), free β-human chorionic gonadotropin (hCG) and PAPP-A has improved the detection rates of trisomy 21 by 1 to 2% for a given false positive rate. Possible reasons for the PlGF divergence include method used in PlGF measurement, ELISA or immunoassays, as well as underlying differences between assay PlGF isomer recovery and cross-reactivity. 77Cheng YKY, Poon LCY, Shennan A, Leung TY, Sahota DS. Inter-manufacturer comparison of automated immunoassays for the measurement of soluble FMS-like tyrosine kinase-1 and placental growth factor. Pregnancy Hypertens 2019;17:165-71 Other factors which could have impacted on the earlier findings are PlGF stability due to length of time before processing and environmental temperatures in samples while being transported to central laboratories.88Cowans NJ, Alfthan H, Stenman UH, Spencer K. Stability of first trimester placental growth factor in serum and whole blood. Prenat Diagn 2011;31:1193-7 One factor common in many studies was that analysis was based on previously stored, as opposed to freshly acquired, serum samples with unknown number of freeze–thaw cycles and unknown length of storage time, if reported, and modelling of screening performance based on case-control findings.99Kagan KO, Hoopmann M, Abele H, Alkier R, Lüthgens K. First-trimester combined screening for trisomy 21 with different combinations of placental growth factor, free ß-human chorionic gonadotropin and pregnancy-associated plasma protein-A. Ultrasound Obstet Gynecol 2012;40:530-5 Furthermore, samples in prolonged storage could be subject to freezer burn due to loss of water molecules resulting in increased measured concentrations.1010Blow, N. Biobanking: freezer burn. Nat Methods 2009:6; 173–178
The objective of this study was to determine whether incorporating PlGF as an additional or alternative marker for trisomy 21 screening would be clinically justifiable and of added benefit.