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.