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Edition: November 2013
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Placental Growth Factor (PLGF) in the first trimester of pregnancy–Pre-eclampsia, SGA and trisomies
2
Pre-eclampsia and SGA Combined Screening for Preeclampsia and Small for Gestational Age at 11–13 Weeks* .........8Poon L.C.Y., Syngelaki A., Akolekar R., Lai J., Nicolaides K.H.Vol. 33, No. 1, 2013 Issue release date: January 2013Fetal Diagn Ther 2013;33:16–27
Maternal Characteristics, Mean Arterial Pressure and Serum Markers in Early Prediction of Preeclampsia* .............................................................................................................................9Sylwia Kuc, Maria P. H. Koster, Arie Franx, Peter C. J. I. Schielen, Gerard H. A. VisserPLOS ONE, 2013; 8(5): e63546
Prediction of early and late pre-eclampsia from maternal characteristics, uterine artery Doppler and markers of vasculogenesis during first trimester of pregnancy .........................10M. PARRA-CORDERO, R. RODRIGO†, P. BARJA, C. BOSCO†, G. RENCORET,A. SEPÚ LVEDA-MARTINEZ and S. QUEZADAUltrasound Obstet Gynecol 2013; 41: 538–544
Competing Risks Model in Early Screening for Preeclampsia by Biophysical and Biochemical Markers* .......................................................................................11R Akolekar, A Syngelaki, L Poon, D Wright, K. H. NicolaidesFetal Diagn Ther. 2013, 33:8-15
Can changes in angiogenic biomarkers between the first and second trimesters of pregnancypredict development of pre-eclampsia in a low-risk nulliparous patient population? ..........12L Myatt, RG Clifton, JM Roberts, CY Spong, RJ Wapner, JM Thorp Jr, BM Mercer, AM Peaceman, SM Ramin, MW Carpenter, A Sciscione, JE Tolosa, G Saade, Y Sorokin, GD Anderson, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units NetworkDOI: 10.1111/1471-0528.12128. www.bjog.org. Accepted 20 November 2012. Published Online 18 January 2013.
Low placental growth factor across pregnancy identifies a subset of women with preterm preeclampsia: type 1 versus type 2 preeclampsia? .............................................13Powers RW, Roberts JM, Plymire DA, Pucci D, Datwyler SA, Laird DM, Sogin DC, Jeyabalan A, Hubel CA, Gandley RE.Hypertension. 2012 Jul; 60(1):239-46.
A Comparison of Two Immunoassay Methods for the Measurement of Maternal Serum Placental Growth Factor in Early Pregnancy* ............................................14 N.J. Cowans, M. Kisanga, A. Khan, K. SpencerFetal Diagn Ther 2012;31:254-259
First trimester maternal serum PIGF, free ß-hCG, PAPP-A, PP-13, uterine arteryDoppler and maternal history for the prediction of preeclampsia* .........................................15Di Lorenzo G, Ceccarello M, Cecotti V, Ronfani L, Monasta L, Vecchi Brumatti L, Montico M, D’Ottavio G.Placenta 2012, 1-7
Uterine artery Doppler and biochemical markers (PAPP-A, PIGF, sFlt-1, P-selectin, NGAL) at 11 + 0 to 13 + 6 weeks in the prediction of late (> 34 weeks) pre-eclampsia. ..........................16Youssef A, Righetti F, Morano D, Rizzo N, Farina A.Prenat Diagn 2011 Dec;31(12):1141-6. doi: 10.1002/pd.2848. Epub 2011 Oct 28
Contents
*DELFIA Chemistry used in PlGF assay
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Stability of first trimester placental growth factor in serum and whole blood* ....................17N. J. Cowans, H. Alfthan, U. H. Stenman and K. SpencerPrenat Diagn. 2011 Dec;31(12):1193-7. doi: 10.1002/pd.2894. Epub 2011 Oct 26.
First trimester screening for intra-uterine growth restriction and early-onset pre-eclampsia* ..............................................................................................................................18G. Vandenberghe, I. Mensink, J. W. R. Twisk, M. A. Blankenstein, A. C. Heijboer and J. M. G. van VugtPrenat Diagn 2011; 31: 955–961.
Longitudinal trends in fetoplacental biochemical markers, uterine artery pulsatility index and maternal blood pressure during the first trimester of pregnancy* ...................................19E. J. Wortelboer, M. P. H. Koster, S. Kuc, M. J. C. Eijkemans, C. M. Bilardo,P. C. J. I. Schielen and G. H. A. VisserUltrasound Obstet Gynecol 2011; 38: 383–388
Screening for pre-eclampsia–lessons from aneuploidy screening ............................................20Cuckle HS.Placenta. 2011 Feb;32 Suppl:S42-8
Prediction of early, intermediate and late pre-eclampsia from maternal factors, biophysical and biochemical markers at 11-13 weeks. ..............................................................21Akolekar R, Syngelaki A, Sarquis R, Zvanca M, Nicolaides KH.Prenat Diagn 2011 Jan;31(1):66-74.
Screening for preeclampsia using first-trimester serum markers and uterine artery Doppler in nulliparous women* ..........................................................................22Audibert F, Boucoiran I, An N, Aleksandrov N, Delvin E, Bujold E, Rey E.Am J Obstet Gynecol. 2010 Oct;203(4):383.e1-8.
First-trimester placental protein 13 and placental growth factor: markers for identification of women destined to develop early-onset pre-eclampsia* .............................23Wortelboer EJ, Koster MP, Cuckle HS, Stoutenbeek PH, Schielen PC, Visser GH.BJOG. 2010 Oct;117(11):1384-9.
First-trimester placental growth factor as a marker for hypertensive disorders and SGA* ...24Cowans NJ, Stamatopoulou A, Matwejew E, von Kaisenberg CS, Spencer K.Prenat Diagn 2010 Jun;30(6):565-70.
Hypertensive disorders in pregnancy: screening by biophysical and biochemical markers at 11-13 weeks. ..........................................................................................25Poon LC, Akolekar R, Lachmann R, Beta J, Nicolaides KH.Ultrasound Obstet Gynecol. 2010 Jun;35(6):662-70.
Placental growth factor in the first trimester: relationship with maternal factors and placental Doppler studies .....................................................................................................26Kasdaglis T, Aberdeen G, Turan O, Kopelman J, Atlas R, Jenkins C, Blitzer M, Harman C, Baschat AA.Ultrasound Obstet Gynecol. 2010 Mar;35(3):280-5.
Contents
*DELFIA Chemistry used in PlGF assay
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First-trimester prediction of hypertensive disorders in pregnancy ...........................................27Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides KH.Hypertension. 2009 May;53(5):812-8. Epub 2009 Mar 9.
First trimester urinary placental growth factor and development of pre-eclampsia. .............28Savvidou MD, Akolekar R, Zaragoza E, Poon LC, Nicolaides KH.BJOG. 2009 Apr;116(5):643-7. Epub 2009 Feb 10.
Maternal serum placental growth factor (PlGF) in small for gestational age pregnancy at 11(+0) to 13(+6) weeks of gestation. ......................................................................................29Poon LC, Zaragoza E, Akolekar R, Anagnostopoulos E, Nicolaides KH.Prenat Diagn. 2008 Dec;28(12):1110-5.
Maternal serum placental growth factor at 11 + 0 to 13 + 6 weeks of gestation in the prediction of pre-eclampsia. ........................................................................30Akolekar R, Zaragoza E, Poon LC, Pepes S, Nicolaides KH.Ultrasound Obstet Gynecol. 2008 Nov;32(6):732-9.
Serum inhibin A and angiogenic factor levels in pregnancies with previous preeclampsia and/or chronic hypertension: are they useful markers for prediction of subsequent preeclampsia? ................................................................................................................................31Sibai BM, Koch MA, Freire S, Pinto e Silva JL, Rudge MV, Martins-Costa S, Bartz J, de Barros Santos C, Cecatti JG, Costa R, Ramos JG, Spinnato JA 2nd.Am J Obstet Gynecol. 2008 Sep;199(3):268.e1-9.
The change in concentrations of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters in risk assessment for the subsequent development of preeclampsia and small-for-gestational age. ............................................ 32-33Erez O, Romero R, Espinoza J, Fu W, Todem D, Kusanovic JP, Gotsch F, Edwin S, Nien JK, Chaiworapongsa T, Mittal P, Mazaki-Tovi S, Than NG, Gomez R, Hassan SS.J Matern Fetal Neonatal Med. 2008 May;21(5):279-87.
A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate. ................................................................................................. 34-35Romero R, Nien JK, Espinoza J, Todem D, Fu W, Chung H, Kusanovic JP, Gotsch F, Erez O, Mazaki-Tovi S, Gomez R, Edwin S, Chaiworapongsa T, Levine RJ, Karumanchi SA.J Matern Fetal Neonatal Med. 2008 Jan;21(1):9-23.
Circulating angiogenic factors in early pregnancy and the risk of preeclampsia, intrauterine growth restriction, spontaneous preterm birth, and stillbirth. ............................36Smith GC, Crossley JA, Aitken DA, Jenkins N, Lyall F, Cameron AD, Connor JM, Dobbie R.Obstet Gynecol. 2007 Jun;109(6):1316-24.
Changes in circulating level of angiogenic factors from the first to second trimester as predictors of preeclampsia. ..........................................................................................................37Vatten LJ, Eskild A, Nilsen TI, Jeansson S, Jenum PA, Staff AC.Am J Obstet Gynecol. 2007 Mar;196(3):239.e1-6.
Contents
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Correlations of placental perfusion and PlGF protein expression in early human pregnancy ...........................................................................................................38Welch PC, Amankwah KS, Miller P, McAsey ME, Torry DS.Am J Obstet Gynecol. 2006 Jun;194(6):1625-9; discussion 1629-31. Epub 2006 Apr 25.
Insulin resistance and alterations in angiogenesis: additive insults that may lead to preeclampsia ....................................................................................................39Thadhani R, Ecker JL, Mutter WP, Wolf M, Smirnakis KV, Sukhatme VP, Levine RJ, Karumanchi SA.Hypertension. 2004 May;43(5):988-92. Epub 2004 Mar 15.
Circulating angiogenic factors and the risk of preeclampsia.....................................................40Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA.N Engl J Med. 2004 Feb 12;350(7):672-83. Epub 2004 Feb 5
First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia. ............................................................................................................41Thadhani R, Mutter WP, Wolf M, Levine RJ, Taylor RN, Sukhatme VP, Ecker J, Karumanchi SA.J Clin Endocrinol Metab. 2004 Feb;89(2):770-5.
First-trimester maternal serum levels of placenta growth factor as predictor of preeclampsia and fetal growth restriction .............................................................................42Ong CY, Liao AW, Cacho AM, Spencer K, Nicolaides KH.Obstet Gynecol. 2001 Oct;98(4):608-11.Comment in: Obstet Gynecol. 2001 Oct;98(4):596-9.
Low maternal serum levels of placenta growth factor as an antecedent of clinical preeclampsia ................................................................................................................43Tidwell SC, Ho HN, Chiu WH, Torry RJ, Torry DS.Am J Obstet Gynecol. 2001 May;184(6):1267-72.
TrisomiesImprovements in antenatal screening for Down’s syndrome* .................................................44NJ Wald, JP Bestwickand, WJ HuttlyJ Med Screen 2013:1–21, DOI: 10.1177/0969141313476496
Maternal serum placental growth factor and a-fetoprotein testingin first trimester screening for Down syndrome* ......................................................................45Kim Donalson, Steve Turner, Lesley Morrison, Päivi Liitti, Christel Nilsson and Howard CucklePrenatal Diagnosis 2013, 33, 457–461, DOI: 10.1002/pd.4087
First-trimester contingent screening for trisomy 21 by biomarkers and maternal blood cell-free DNA testing* ..................................................................................................................46K. H. NICOLAIDES, D. WRIGHT, L. C. POON, A. SYNGELAKI and M. GILUltrasound Obstet Gynecol 2013Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.12511
Contents
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Contents
Antenatal Screening for Down Syndrome Using Serum Placental Growth Factor with the Combined, Quadruple, Serum Integrated and Integrated Tests* .......................................47Nicholas J. Wald, Jonathan P. Bestwick, Lynne M. George, Wayne J. HuttlyPLoS ONE 7 (10): e46955
First trimester combined screening for trisomy 21 with different combinations of placental growth factor, free ß-hCG and PAPP-A* ......................................................................................48KO Kagan, M Hoopmann, H Abele, R Alkier, K LüthgensUltrasound in Obstetrics & Gynecology 2012
Maternal Serum Placental Growth Factor in Prospective Screening for Aneuploidies at 8–13 Weeks’ Gestation ......................................................................................49 Pranav Pandya, David Wright, Argyro Syngelaki, Ranjit Akolekar, Kypros H. NicolaidesFetal Diagn Ther, Published online: January 27, 2012, DOI: 10.1159/000335684
Fetal Diagn Ther, Published online: January 27, 2012Modeling Down syndrome screening performance using first-trimester serum markers* ............................................................................................................................50M. P. H. Koster, E. J. Wortelboer, P. Stoutenbeek, G. H. A. Visser and P. C. J. I. SchielenUltrasound Obstet Gynecol 2011; 38: 134–139
First trimester maternal serum placental growth factor in trisomy 21 pregnancies* .............51Cowans NJ, Stamatopoulou A, Spencer K.Prenat Diagn. 2010 May;30(5):449-53.
Maternal serum placental growth factor at 11-13 weeks in chromosomally abnormal pregnancies .......................................................................................52Zaragoza E, Akolekar R, Poon LC, Pepes S, Nicolaides KH.Ultrasound Obstet Gynecol. 2009 Apr;33(4):382-6.
Circulating angiogenic proteins in trisomy 13. ...........................................................................53Bdolah Y, Palomaki GE, Yaron Y, Bdolah-Abram T, Goldman M, Levine RJ, Sachs BP, Haddow JE, Karumanchi SA.Am J Obstet Gynecol. 2006 Jan;194(1):239-45.
First trimester maternal serum placenta growth factor (PIGF) concentrations in pregnancies with fetal trisomy 21 or trisomy 18 ...................................................................54Spencer K, Liao AW, Ong CY, Geerts L, Nicolaides KH.Prenat Diagn. 2001 Sep;21(9):718-22.
*DELFIA Chemistry used in PlGF assay
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*DELFIA Chemistry used in PlGF assay
Fetal DeathAn imbalance between angiogenic and anti-angiogenic factors precedes fetal death in a subset of patients: results of a longitudinal study. ....................................................... 55-56Romero R, Chaiworapongsa T, Erez O, Tarca AL, Gervasi MT, Kusanovic JP, Mittal P, Ogge G, Vaisbuch E, Mazaki-Tovi S, Dong Z, Kim SK, Yeo L, Hassan SS.J Matern Fetal Neonatal Med. 2010 May 12.
Macrosomia Prediction of macrosomia at birth in type-1 and 2 diabetic pregnancies with biomarkers of early placentation* ..............................................................................................57S Kuc, EJ Wortelboer, MPH Koster, HW de Valk, PCJI Schielen, GHA VisserbJ Matern Fetal Neonatal Med. 2010 May 12.
Contents
8
Combined Screening for Preeclampsia and Small for Gestational Age at 11–13 Weeks
Poon L.C.Y., Syngelaki A., Akolekar R., Lai J., Nicolaides K.H.
Vol. 33, No. 1, 2013 Issue release date: January 2013
Fetal Diagn Ther 2013;33:16–27
OBJECTIVE: To combine a specific algorithm for small for gestational age (SGA) without preeclampsia
(PE) and another algorithm for PE in the prediction of SGA and PE.
METHODS: This was a screening study of singleton pregnancies at 11–13 weeks including 1,426
(2.3%) that subsequently developed PE, 3,168 (5.1%) that delivered SGA neonates and 57,458
that were unaffected by PE and SGA. We developed a prediction algorithm for SGA requiring
delivery before 37 weeks’ gestation (preterm-SGA) from maternal characteristics, uterine artery
pulsatility index, mean arterial pressure, serum pregnancy-associated plasma protein-A and placental
growth factor multiple of the median values. We then examined the performance of this algorithm
individually and in combination with a previously reported algorithm for early-PE in the prediction of
SGA and PE.
RESULTS: When screen positivity was defined by risk cutoff of 1:200 using the algorithm for early-PE
and the risk cutoff of 1:150 using the algorithm for preterm-SGA, the false positive rate was 10.9%
and the detection rates of early-PE, late-PE, preterm-SGA and term-SGA were 95.3, 45.6, 55.5 and
44.3%, respectively.
Pre-eclampsia and SGA
DELFIA Chemistry used in PlGF assay
9
Maternal Characteristics, Mean Arterial Pressure and Serum Markers in Early Prediction of Preeclampsia
Sylwia Kuc, Maria P. H. Koster, Arie Franx, Peter C. J. I. Schielen, Gerard H. A. Visser
PLOS ONE, 2013; 8(5): e63546
OBJECTIVE: In a previous study, we have described the predictive value of first-trimester Pregnancy-
Associated Plasma Protein-A (PAPP-A), free b-subunit of human Chorionic Gonadotropin (fb-hCG),
Placental Growth Factor (PlGF) and A Disintegrin And Metalloprotease 12 (ADAM12) for early onset
preeclampsia (EO-PE; delivery, 34 weeks). The objective of the current study was to obtain the
predictive value of these serum makers combined with maternal characteristics and first-trimester
maternal mean arterial blood pressure (MAP) in a large series of patients, for both EO-PE and late
onset PE (LO-PE; delivery, 34 weeks).
METHODS: This was a nested case-control study, using stored first-trimester maternal serum
from women who developed EO-PE (n = 68) or LO-PE (n = 99), and 500 uncomplicated singleton
pregnancies. Maternal characteristics, MAP, and pregnancy outcome were collected for each
individual woman and used to calculate prior risks for PE in a multiple logistic regression model.
Models containing prior PE risks, serum markers, and MAP were developed for the prediction of
EO-PE and LO-PE. The model-predicted detection rates (DR) for fixed 10% false-positive rates were
calculated for EO-PE and LO-PE with or without the presence of a small-for-gestational age infant
(SGA, birth weight,10th centile).
RESULTS: The best prediction model included maternal characteristics, MAP, PAPP-A, ADAM12, and
PlGF, with DR of 72% for EO-PE and 49% for LO-PE. Prediction for PE with concomitant SGA was
better than for PE alone (92% for EO-PE and 57% for LO-PE).
CONCLUSION: First-trimester MAP, PAPP-A, ADAM12, and PlGF combined with maternal
characteristics and MAP are promising markers in the risk assessment of PE, especially for EO-PE
complicated by SGA.
DELFIA Chemistry used in PlGF assay
Pre-eclampsia and SGA
10
Pre-eclampsia and SGA
Prediction of early and late pre-eclampsia from maternal characteristics, uterine artery Doppler and markers of vasculogenesis during first trimester of pregnancy
M. PARRA-CORDERO, R. RODRIGO†, P. BARJA, C. BOSCO†, G. RENCORET,
A. SEPÚ LVEDA-MARTINEZ and S. QUEZADA
Ultrasound Obstet Gynecol 2013; 41: 538–544
OBJECTIVE: To develop a predictive model for preeclampsia using clinical, biochemical and ultrasound
markers during the first trimester of pregnancy.
METHODS: This was a nested case–control study within a pre-eclampsia screening project that
involved 5367 asymptomatic pregnant women undergoing routine transvaginal uterine artery (UtA)
Doppler at 11+0 to 13+6weeks. Following exclusions, there were 70 pregnant women who later
developed pre-eclampsia and 289 control patients enrolled during the first trimester who had serum or
plasma samples taken at enrolment available for the purposes of this study. Of these, 17 pregnancies
were diagnosed with early-onset (delivery<34 weeks) pre-eclampsia and 53 with lateonset (delivery≥34
weeks) pre-eclampsia. The lowest, highest and mean of left and right UtA pulsatility indices (PI)
were calculated. Blood samples were stored at −84 °C until biochemical analysis for markers of
vasculogenesis was performed. The distributions of the lowest UtA-PI and the biochemical markers
were adjusted for maternal characteristics, expressed as multiples of the median (MoM), and compared
between groups. Logistic regression analysis was used to evaluate if any variable was significantly
associated with pre-eclampsia.
RESULTS: Pregnancies that later developed pre-eclampsiawere associated with higher maternal
prepregnancy body mass index. An increased lowest UtA-PI was significantly associated with both
early- and late-onset disease. Placental growth factor (PlGF) MoM was significantly reduced in women
who later developed early- or late-onset pre-eclampsia compared with controls (median (interquartile
range), 0.69 (0.33–1.46) and 1.10 Correspondence to: Dr M. Parra-Cordero, UnidadMedicina
Fetal,Hospital Cl´ınico Universidad de Chile, SantosDumont 999, Independencia, Santiago, Chile
(e-mail: [email protected]) Accepted: 6 July 2012 (0.39–1.56), respectively, vs 1.19 (0.65–
1.84), P<0.05). Different combined models were generated by logistic regression analysis, and the
detection rate with a fixed 10% false-positive rate was 47% and 29% for early- and late-onset pre-
eclampsia, respectively.
CONCLUSION: Pregnancies that later developed early or late pre-eclampsia were characterized by
impaired placentation and an anti-angiogenic state during the first trimester of pregnancy. Regression
models which include maternal characteristics, UtA Doppler and PlGF can apparently predict
approximately half of pregnancies that will be complicated by early-onset pre-eclampsia.We believe
more research in several areas is needed to aid in the creation of a better and more population-specific
screening test for pre-eclampsia during the first trimester of pregnancy.
11
Pre-eclampsia and SGA
Competing Risks Model in Early Screening for Preeclampsia by Biophysical and Biochemical Markers
R Akolekar, A Syngelaki, L Poon, D Wright, K. H. Nicolaides
Fetal Diagn Ther. 2013; 33: 8-15
OBJECTIVE: To develop models for prediction of preeclampsia (PE) based on maternal characteristics,
biophysical and biochemical markers at 11–13 weeks’ gestation in which the gestation at the time of
delivery for PE is treated as a continuous variable.
METHODS: This was a screening study of singleton pregnancies at 11–13 weeks including 1,426
(2.4%) that subsequently developed PE and 57,458 that were unaffected by PE. We developed a
survival time model for the time of delivery for PE in which Bayes’ theorem was used to combine the
prior information from maternal characteristics with uterine artery pulsatility index (PI), mean arterial
pressure (MAP), serum pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor
(PLGF) multiple of the median (MoM) values.
RESULTS: In pregnancies with PE, there was a linear correlation between MoM values of uterine artery
PI, MAP, PAPP-A and PLGF with gestational age at delivery and therefore the deviation from normal
was greater for early than late PE for all four biomarkers. Screening by maternal characteristics,
biophysical and biochemical markers detected 96% of cases of PE requiring delivery before 34 weeks
and 54% of all cases of PE at a fixed false-positive rate of 10%.
CONCLUSION: A new model has been developed for effective first-trimester screening for PE.
DELFIA Chemistry used in PlGF assay
12
Pre-eclampsia and SGA
Can changes in angiogenic biomarkers between the first and second trimesters of pregnancy predict development of pre-eclampsia in a low-risk nulliparous patient population?
L Myatt, RG Clifton, JM Roberts, CY Spong, RJ Wapner, JM Thorp Jr, BM Mercer, AM
Peaceman, SM Ramin, MW Carpenter, A Sciscione, JE Tolosa, G Saade, Y Sorokin, GD
Anderson, for the Eunice Kennedy Shriver National Institute of Child Health and Human
Development Maternal–Fetal Medicine Units Network.
DOI: 10.1111/1471-0528.12128. www.bjog.org. Accepted 20 November 2012.
Published Online 18 January 2013.
OBJECTIVE: To determine if change in maternal angiogenic biomarkers between the first and second
trimesters predicts pre-eclampsia in low-risk nulliparous women.
METHODS: Luminex assays for PlGF, sFlt-1 and sEng performed on maternal EDTA plasma collected
at 9–12, 15–18 and 23–26 weeks of gestation. Rate of change of analyte between first and either
early or late second trimester was calculated with and without adjustment for baseline clinical
characteristics.
RESULTS: Rates of change of PlGF, sEng and sFlt-1 between first and either early or late second
trimesters were significantly different in women who developed pre-eclampsia, severe pre-eclampsia
or early-onset pre-eclampsia compared with women who remained normotensive. Inclusion of clinical
characteristics (race, body massindex and blood pressure at entry) increased sensitivity for detecting
severe and particularly early-onset pre-eclampsia but not preeclampsia overall. Receiver operating
characteristics curves for change from first to early second trimester in sEng, PlGF and sFlt-1 with
clinical characteristics had areas under the curve of 0.88, 0.84 and 0.86, respectively, and for early-
onset pre-eclampsia with sensitivities of 88% (95% CI 64–99), 77% (95% CI 50–93) and 77% (95%
CI 50–93) for 80% specificity, respectively. Similar results were seen in the change from first to late
second trimester.
CONCLUSION: Change in angiogenic biomarkers between first and early second trimester combined
with clinical characteristics has strong utility for predicting early-onset pre-eclampsia.
13
Low placental growth factor across pregnancy identifies a subset of women with preterm preeclampsia: type 1 versus type 2 preeclampsia?
Powers RW, Roberts JM, Plymire DA, Pucci D, Datwyler SA, Laird DM, Sogin DC,
Jeyabalan A, Hubel CA, Gandley RE.
Hypertension. 2012 Jul;60(1):239-46.
OBJECTIVE: Preeclampsia is a heterogeneous syndrome affecting 3% to 5% of all pregnancies. An
imbalance of the antiangiogenic and proangiogenic factors, soluble receptor fms-like tyrosine kinase 1
and placental growth factor (PGF), is thought to contribute to the pathophysiology of preeclampsia.
METHODS: Maternal plasma PGF and soluble receptor fms-like tyrosine kinase 1 were quantified
by specific immunoassays in cross-sectional samples from 130 preeclamptic subjects and 342
normotensive controls at delivery and longitudinally in samples from 50 women who developed
preeclampsia and 250 normotensive controls. Among women who developed preeclampsia, 46%
(n=23) evidenced a pattern of consistently low maternal PGF across pregnancy below the lower 95%
CI of controls from 15 weeks’ gestation to term. In contrast, the remaining 54% (n=27) of women
who developed preeclampsia had maternal PGF concentrations similar to or above (n=7) those
of normotensive controls. Subjects with low PGF across pregnancy who developed preeclampsia
evidenced significantly higher blood pressure in early pregnancy (P<0.05) and, after diagnosis, earlier
gestational age at delivery (P<0.05) and more preterm birth (P<0.05) compared with preeclamptic
patients with high PGF.
RESULTS: A significant subset of women who develop preeclampsia show evidence of consistently
low PGF across pregnancy. Low PGF with preeclampsia was associated with preterm delivery
compared with preeclamptic patients with high PGF.
CONCLUSION: Identifying women with consistently low plasma PGF during pregnancy may provide a
greater understanding of preeclampsia pathophysiology and may provide more focused research and
clinical activities.
Pre-eclampsia and SGA
14
A Comparison of Two Immunoassay Methods for the Measurement of Maternal Serum Placental Growth Factor in Early Pregnancy.
N.J. Cowans, M. Kisanga, A. Khan, K. Spencer
Fetal Diagn Ther 2012;31:254-259
OBJECTIVE: To compare the DELFIA Xpress and Quantikine ELISA placental growth factor (PlGF)
immunoassay platforms by analysing the same set of early first-trimester maternal serum samples
from cases with trisomy 21 and euploid controls.
METHODS: Thirty-seven trisomy 21 cases and 243 euploid control serum samples, drawn at 8+0 to
10+6 weeks of gestation, were reanalysed by Quantikine PlGF ELISA following original analysis on the
DELFIA Xpress platform.
RESULTS: PlGF levels increased with gestation in the euploid controls when measured on both
platforms, although raw levels were in general lower on the DELFIA Xpress. After conversion to
multiples of the median (MoMs), PlGF was increased in trisomy 21 cases when measured on the
DELFIA Xpress platform (euploid: 1.00 MoM, trisomy 21: 1.32 MoM, p < 0.0001) but unchanged
when measured on the Quantikine ELISA (euploid: 1.01 MoM, trisomy 21: 1.06 MoM, p = 0.84).
CONCLUSION: Discrepancies exist in the measurement of PlGF when performed on these different
platforms, which may to some extent contribute to the inconsistencies found in the literature with
regard to PlGF in trisomy 21 pregnancies.
DELFIA Chemistry used in PlGF assay
Pre-eclampsia and SGA
15
Pre-eclampsia and SGA
First trimester maternal serum PIGF, free ß-hCG, PAPP-A, PP-13, uterine artery Doppler and maternal history for the prediction of preeclampsia
Di Lorenzo G, Ceccarello M, Cecotti V, Ronfani L, Monasta L, Vecchi Brumatti L, Montico M,
D’Ottavio G.
Placenta 2012, 1-7
OBJECTIVE: To evaluate the detection of pregnancy hypertensive disorders by integrating maternal
history, serum biomarkers and uterine artery Doppler in the first trimester.
METHODS: We prospectively recruited 2118 women that underwent an 11e13 weeks aneuploidy
screening. We gathered information on maternal history, uterine artery Doppler and serum
biomarkers (PAPP-A, PlGF, PP-13 and free ß-hCG). Models were developed for the prediction of overall
preeclampsia (PE), early-onset PE, late-onset PE and gestational hypertension (GH). For each outcome,
we performed a multivariate logistic regression starting from the saturated model: adopting a step-
down procedure we excluded all factors not statistically significant (p > 0.05). Sensitivity models only
for statistically significant parameters were calculated from the ROC curves for fixed false-positive
rates (FPR).
RESULTS: Among 2118 women, 46 (2.17%) developed GH and 25 (1.18%) were diagnosed with
PE, including 12 (0.57%) early-onset PE and 13 (0.61%) late-onset PE. For a fixed FPR of 10 and 5%,
serum PlGF, free ß-hCG and chronic hypertension identified respectively 67 and 75% of women who
developed early-onset PE. In the model for the prediction of overall PE the combination of the uterine
artery Doppler pulsatility index (UtA PI) with PlGF and chronic hypertension reached a sensitivity of
60% for a 20% of FPR.
CONCLUSION: An integration of maternal characteristics and first trimester maternal serum
biomarkers (free ß-hCG and PlGF) provided a possible screening for early-onset PE. In the overall PE
model, UtA PI turned out to be statistically significant but did not improve the detection rate.
DELFIA Chemistry used in PlGF assay
16
Pre-eclampsia and SGA
Uterine artery Doppler and biochemical markers (PAPP-A, PIGF, sFlt-1, P-selectin, NGAL) at 11 + 0 to 13 + 6 weeks in the prediction of late (> 34 weeks) pre-eclampsia.
Youssef A, Righetti F, Morano D, Rizzo N, Farina A.
Prenat Diagn 2011 Dec;31(12):1141-6. doi: 10.1002/pd.2848. Epub 2011 Oct 28
OBJECTIVE: To determine the performance of screening for late pre-eclampsia (PE) by maternal
characteristics, uterine artery Doppler and a set of biochemical markers at 11 + 0 to 13 + 6 weeks’
gestation.
METHODS: Prospectively enrolled women at 11 + 0 to 13 + 6 weeks. Maternal characteristics,
highest UtA pulsatility index and serum placental biomarkers including pregnancy-associated plasma
protein-A, placental growth factor, soluble fms-like tyrosine kinase 1, P-selectin and neutrophil
gelatinase-associated lipocalin were recorded.
RESULTS: The rate of PE was 2.5% (13/528). Four (0.8%) had severe PE. A combined screening
model that included placental growth factor, soluble fms-like tyrosine kinase 1 and neutrophil
gelatinase-associated lipocalin could detect 77% of PE at a 10% false-positive rate. Mean risk for mild
PE was 8.8% ± 6.4, mean risk for severe PE was 38.6% ± 4.3. Mean risk for controls was 2% ± 4.1.
CONCLUSION: This combination of maternal biochemical variables in the first trimester can detect a
consistent number of late PE. Further studies on a new and independent series of data could confirm
the presented results.
17
Stability of first trimester placental growth factor in serum and whole blood
N. J. Cowans, H. Alfthan, U. H. Stenman and K. Spencer
Prenat Diagn. 2011 Dec;31(12):1193-7. doi: 10.1002/pd.2894. Epub 2011 Oct 26.
BACkGROUND: Placental growth factor (PlGF) is a proposed first-trimester screening marker for
pre-eclampsia. This study investigates the stability of PlGF in serum and whole blood at typical
routine storage temperatures.
METHODS: Serum pools were stored at refrigerator temperature, room temperature or 30 °C
for up to 30 days, or exposed to up to six freeze–thaw cycles. Whole blood was stored at room
temperature or 30 °C for up to 6 days. PlGF was quantified using a DELFIA Xpress analyser.
RESULTS: Placental growth factor levels increased over time, seemingly because of the dissociation
of PlGF bound to a soluble binding protein, sFlt-1. Increase was slow in serum at refrigerator
temperature, remaining stable (less than 10% change from start point) for at least 30 days. At room
temperature PlGF was stable for 3.3 days and at 30 °C for 1 day. Serum PlGF remained stable for at
least six freeze–thaw cycles. In whole blood, instability was worse, being stable for only 19.4 h at
room temperature and just 3.3 h at 30 °C.
CONCLUSION: Routine screening of sample handling requires careful monitoring. However, no
extra precautions need to be taken when PlGF is used for pre-eclampsia screening run alongside
existing first trimester aneuploidy screening programs that include hCG.
DELFIA Chemistry used in PlGF assay
Pre-eclampsia and SGA
18
DELFIA Chemistry used in PlGF assay
First trimester screening for intra-uterine growth restriction and early-onset pre-eclampsia.
G. Vandenberghe, I. Mensink, J. W. R. Twisk, M. A. Blankenstein,
A. C. Heijboer and J. M. G. van Vugt
Prenat Diagn 2011; 31: 955–961.
OBJECTIVE: To assess first trimester placental growth factor (PlGF) and pregnancy-associated plasma
protein-A (PAPP-A) as screening markers for early-onset pre-eclampsia (PE) and intra-uterine growth
restriction (IUGR).
METHODS: PlGF concentration was retrospectively measured in first trimester serum specimens of 23
cases of early-onset PE (<34 weeks), 26 cases of IUGR (birth weight <5th centile) and 5 controls per case.
Levels were adjusted for gestational age (GA), ethnicity and smoking to obtain multiples of the expected
median (MoM). Logistic regression was used to assess PlGF, PAPP-A and maternal characteristics as
potential predictors of early-onset PE and IUGR.
RESULTS: PlGF MoM levels were significantly lower in the early-onset PE group (P < 0.0001) compared
with controls, but not in the IUGR group. PAPP-A MoM levels were significantly lower in the IUGR group
(P < 0.01) compared with controls but not in the early-onset PE group. PlGF significantly improved the
ability of systolic blood pressure at the first prenatal visit to predict early-onset PE [achieving a receiver-
operating characteristics curve with area under the curve (AUC) of 0.8]. Combining systolic blood
pressure at the first prenatal visit and PlGF did not significantly improve the predictive ability compared
with PlGF alone (AUC = 0.83).
CONCLUSION: Serum PlGF is an acceptable marker in first trimester screening for early-onset PE, but a
poor marker in screening for IUGR. Screening performance of serum PAPP-A is poor for both early-onset
PE and IUGR.
Pre-eclampsia and SGA
19
Longitudinal trends in fetoplacental biochemical markers, uterine artery pulsatility index and maternal blood pressure during the first trimester of pregnancy
E. J. Wortelboer, M. P. H. Koster, S. Kuc, M. J. C. Eijkemans, C. M. Bilardo, P. C. J. I. Schielen
and G. H. A. Visser
Ultrasound Obstet Gynecol 2011; 38: 383–388
OBJECTIVE: To assess trends in levels of biochemical markers, uterine artery (UtA) pulsatility index (PI)
and maternal blood pressure changes over time and study their relationships in uncomplicated first-
trimester pregnancies.
METHODS: The study population comprised 86 women with singleton pregnancies. In each woman,
a blood sample was collected at 6–7, 8–9, 10–11 and 12–13 weeks’ gestation. At the same visit
blood pressure was measured and ultrasound examination was performed to measure the crown–
rump length and Doppler flow velocity waveform patterns of both UtAs. Serum concentrations of
pregnancy-associated plasma protein-A (PAPP-A), free ß-human chorionic gonadotropin (ß-hCG),
A disintegrin and metalloprotease domain-containing protein-12 (ADAM-12), placental protein-13
(PP-13) and placental growth factor (PlGF) levels were measured in thawed specimens using an
automated time-resolved fluorescence assay. Summary curves were reated to describe normal ranges
and trends over time. The data were analyzed with a linear mixed model with the log-transformed
marker values as dependent variables. This allowed for flexible modeling of patterns over time.
RESULTS: Sixty-eight pregnancies had an uneventful outcome, with the birth of an appropriate-
for-gestationalage (AGA) infant. In these pregnancies serum PAPP-A, ADAM-12, PP-13 and PlGF
levels increased with gestational age. The UtA-PI decreased and the mean arterial blood pressure
remained constant. There were no significant correlations between maternal age, birth-weight
percentile, gender and blood pressure and any of the biochemical markers. The serum markers were
highly correlated with each other except for ß-hCG. A negative correlation was found between
most biomarkers and UtA-PI, especially from 10 weeks onwards. Serum concentrations of ADAM-
12 and PP-13 were lower in a small-for-gestational-age (SGA) subgroup born at term (n = 6), the
former statistically significantly (P = 0.031), the latter non-significantly (P = 0.054), whereas UtA-PI
was significantly higher (P = 0.02). Biomarker concentrations in 12 women delivering a large-for-
gestational age infant did not differ from those delivering AGA neonates.
CONCLUSION: There is a relationship between biochemical markers of early placentation and
downstream resistance to flow in theUtAs in low-risk uncomplicated pregnancies, indicating
differences in placentation. In a small series of SGA infants born at term we could demonstrate
differences as compared to normal pregnancies, with potential value for screening.
DELFIA Chemistry used in PlGF assay
Pre-eclampsia and SGA
20
Screening for pre-eclampsia–lessons from aneuploidy screening.
Cuckle HS.
Placenta. 2011 Feb;32 Suppl:S42-8
BACkGROUND: Antenatal screening for aneuploidy is an established routine clinical practice
worldwide. The same statistical methodology, developed and refined over three decades, might be
adapted to screening for pre-eclampsia.
METHODS: The published literature is reviewed for evidence that the methodology is valid for pre-
eclampsia using first trimester maternal serum PP13, PAPP-A, PlGF, ADAM12 and inhibin A, together
with MAP and uterine artery Doppler PI. Risk is estimated for both early onset pre-eclampsia, requiring
delivery before 34 weeks, or late onset disease. Prior risk from the background prevalence multiplied
by likelihood ratios (LRs) for ethnicity, parity, adiposity and family history is multiplied by an LR from
the screening marker profile. Markers are expressed in multiples of the gestation-specific median and
adjusted for body mass, ethnicity and smoking status as appropriate. A standardized population with
a fixed distribution of risk factors and a multi-variate Gaussian model of marker profiles is used to
predict performance.
RESULTS: There is sufficient published data to estimate individual risks reasonably well. Modeling
predicts that using PAPP-A and one other serum marker, together with the physical markers more
than two-thirds of early and one-third of late onset cases can be detected by classifying less than 2%
of pregnancies as high risk; three-quarters of early case could be detected with a 5% high risk rate.
CONCLUSION: Whilst more data on some markers is still required modeling so far suggests that
extending first trimester aneuploidy screening programs to include pre-eclampsia screening would
yield a high detection. However, prospective studies are needed to verify the model predictions.
Pre-eclampsia and SGA
21
Prediction of early, intermediate and late pre-eclampsia from maternal factors, biophysical and biochemical markers at 11-13 weeks.
Akolekar R, Syngelaki A, Sarquis R, Zvanca M, Nicolaides KH.
Prenat Diagn. 2011 Jan;31(1):66-74.
OBJECTIVE: To develop models for prediction of pre-eclampsia (PE) based on maternal factors and
biophysical and biochemical markers at 11-13 weeks’ gestation.
METHODS: Screening study of singleton pregnancies at 11-13 weeks including 752 (2.2%) that
subsequently developed PE and 32,850 that were unaffected by PE. Models were developed for
the prediction of early PE, requiring delivery before 34 weeks, intermediate PE with delivery at
34-37 weeks and late PE delivering after 37 weeks. The data used for the models were firstly,
maternal characteristics and history, uterine artery pulsatility index, mean arterial pressure and serum
pregnancy-associated plasma protein-A obtained from the screening study and secondly, maternal
serum or plasma concentration of placental growth factor, placental protein-13, inhibin-A, activin-A,
soluble endoglin, pentraxin-3 and P-selectin obtained from case-control studies.
RESULTS: In screening for PE by maternal factors only at a fixed false positive rate of 5%, the
estimated detection rates were 33.0% for early PE, 27.8% for intermediate PE and 24.5% for late
PE. The respective detection rates in screening by a combination of maternal factors, biophysical and
biochemical markers were 91.0, 79.4 and 60.9%.
CONCLUSION: Effective prediction of PE can be achieved at 11-13 weeks’ gestation.
Pre-eclampsia and SGA
22
Pre-eclampsia and SGA
Screening for preeclampsia using first-trimester serum markers and uterine artery Doppler in nulliparous women.
Audibert F, Boucoiran I, An N, Aleksandrov N, Delvin E, Bujold E, Rey E.
Am J Obstet Gynecol. 2010 Oct;203(4):383.e1-8.
OBJECTIVE: To evaluate the screening accuracy of pregnancy hypertensive disorders by maternal
serum biomarkers and uterine artery Doppler in the first trimester.
STUDY DESIGN: Prospectively enrolled nulliparous women had uterine artery Doppler and serum
measured at 11-13 weeks. Maternal characteristics, uterine artery Doppler, and serum placental
biomarkers (pregnancy-associated plasma protein-A, Inhibin-A, placental protein 13, A disintegrin and
metalloprotease 12, free ß-hCG, placental growth factor) were recorded.
RESULTS: Among 893 women, 20 (2.2%) had gestational hypertension developed and 40 (4.5%)
had preeclampsia developed, including 9 (1.0%) early-onset preeclampsia and 16 (1.8%) severe
preeclampsia. A combined screening model with clinical characteristics, pregnancy-associated plasma
protein-A, Inhibin-A, and placental growth factor could detect 75% of early-onset preeclampsia at
a 10% false-positive rate. After adjustment for clinical variables, uterine artery Doppler, placental
protein 13, and A disintegrin and metalloprotease 12 did not improve the diagnostic accuracy.
CONCLUSION: A combination of clinical characteristics and first-trimester maternal serum biomarkers
(pregnancy-associated plasma protein-A, Inhibin-A, and placental growth factor) provides an accurate
screening for early-onset preeclampsia in nulliparous women.
DELFIA Chemistry used in PlGF assay
23
First-trimester placental protein 13 and placental growth factor: markers for identification of women destined to develop early-onset pre-eclampsia.
Wortelboer EJ, Koster MP, Cuckle HS, Stoutenbeek PH, Schielen PC, Visser GH.
BJOG. 2010 Oct;117(11):1384-9.
OBJECTIVE: To investigate the predictive value of maternal serum pregnancy-associated plasma
protein A (PAPP-A), free ß subunit of human chorionic gonadotrophin (fß-hCG), placental protein 13
(PP13), placental growth factor (PlGF) and a desintegrin and metalloproteinase 12 (ADAM12), for first-
trimester identification of early-onset pre-eclampsia.
DESIGN: Nested case-control study.
SETTING: Routine first-trimester screening for trisomy 21 in the Netherlands.
POPULATION: Eighty-eight women who developed pre-eclampsia or haemolysis, elevated liver
enzymes, low platelets (HELLP) syndrome before 34 weeks of gestation and 480 controls
METHODS: PP13, PlGF and ADAM12 were measured in stored first-trimester serum, previously tested
for PAPP-A and fß-hCG. All marker levels were expressed in multiples of the gestation-specific normal
median (MoMs). Model predicted detection rates for fixed false-positive rates were obtained for
statistically significant markers alone and in combination.
MAIN OUTCOME MEASURES: Development of pre-eclampsia or HELLP syndrome.
RESULTS: PP13 and PlGF were reduced in women with pre-eclampsia, with medians 0.68 MoM and
0.73 MoM respectively (P < 0.0001 for both). PAPP-A was reduced (median 0.82 MoM, P < 0.02)
whereas ADAM12 and fß-hCG did not differ between control women and those with pre-eclampsia.
In pre-eclampsia complicated by a small-for-gestational-age fetus, all markers except fß-hCG had
lower values, compared with pregnancies involving fetuses of normal weight. The model-predicted
pre-eclampsia detection rate for a combination of PP13 and PlGF was 44% and 54%, respectively, for
a fixed 5% and 10% false-positive rate.
CONCLUSION: This study demonstrates that PP13 and PlGF in the first-trimester might be promising
markers in risk assessment for early pre-eclampsia/HELLP syndrome but for an adequate screening test
additional characteristics are necessary.
DELFIA Chemistry used in PlGF assay
Pre-eclampsia and SGA
24
First-trimester placental growth factor as a marker for hypertensive disorders and SGA.
Cowans NJ, Stamatopoulou A, Matwejew E, von Kaisenberg CS, Spencer K.
Prenat Diagn. 2010 Jun;30(6):565-70.
OBJECTIVE: The objective of this study was to examine first-trimester maternal serum placental
growth factor (PlGF) levels in pregnancies which later develop hypertensive and growth complications.
METHODS: In this case-control study, PlGF levels were measured by AutoDELFIA immunoassay
platform. There were 47 cases of at least one of the following adverse outcomes: pre-eclampsia (PE),
small for gestational age (SGA), haemolysis elevated liver enzymes and low platelets (HELLP) and
gestational hypertension (GH) and 452 matched controls.
RESULTS: PlGF levels were significantly lower in cases of all PE, early PE, HELLP, all SGA, early SGA and
SGA without PE, but not in GH, late PE, late SGA, PE with SGA or PE without SGA or HELLP.
CONCLUSION: Low levels of first-trimester PlGF provide a good indicator of SGA complications and
some hypertensive disorders, in particular severe cases of PE such as early onset and HELLP syndrome.
A prototype version of the PerkinElmer AutoDELFIA PlGF assay kit was used in this study.
Pre-eclampsia and SGA
DELFIA Chemistry used in PlGF assay
25
Hypertensive disorders in pregnancy: screening by biophysical and biochemical markers at 11-13 weeks.
Poon LC, Akolekar R, Lachmann R, Beta J, Nicolaides KH.
Ultrasound Obstet Gynecol. 2010 Jun;35(6):662-70.
OBJECTIVE: To examine the performance of screening for pre-eclampsia (PE) and gestational
hypertension (GH) by a combination of maternal factors and various biophysical and biochemical
markers at 11-13 weeks’ gestation.
METHODS: This was a case-control study of 26 cases of early PE, 90 of late PE, 85 of GH and 201
unaffected controls. Maternal history was recorded, the uterine artery with the lowest pulsatility index
(L-PI) and mean arterial pressure (MAP) were measured and stored plasma and serum were analyzed
for placental growth factor (PlGF), inhibin-A, activin-A, tumor necrosis factor receptor-1, matrix
metalloproteinase-9, pentraxin-3 and P-selectin.
RESULTS: Multivariate logistic regression analysis demonstrated that significant prediction for early PE
was provided by maternal factors, MAP, uterine artery L-PI and serum PlGF. Significant prediction of
late PE was provided by maternal factors, MAP, uterine artery L-PI, PlGF, activin-A and P-selectin. For
GH significant prediction was provided by maternal factors, MAP, uterine artery L-PI and activin-A. In
screening by a combination of maternal factors, biophysical and biochemical markers the estimated
detection rates, at a 5% false-positive rate, were 88.5% (95% CI, 69.8-97.4%) for early PE, 46.7%
(95% CI, 36.1-57.5%) for late PE and 35.3% (95% CI, 25.2-46.4%) for GH.
CONCLUSION: Combined biophysical and biochemical testing at 11-13 weeks could effectively
identify women at high risk for subsequent development of hypertensive disorders in pregnancy.
Pre-eclampsia and SGA
26
Placental growth factor in the first trimester: relationship with maternal factors and placental Doppler studies.
Kasdaglis T, Aberdeen G, Turan O, Kopelman J, Atlas R, Jenkins C, Blitzer M, Harman C,
Baschat AA.
Ultrasound Obstet Gynecol. 2010 Mar;35(3):280-5.
OBJECTIVE: Placental growth factor (PlGF) is a potent angiogenic factor that impacts on early
placental vascular development. It was our aim to clarify relationships between PlGF and first-trimester
maternal/placental factors that are related to placental development.
METHODS: Prospectively enrolled patients at 11-14 weeks’ gestation had serum PlGF measurement
by enzyme-linked immunosorbent assay. Results were related to maternal age, parity, race, body mass
index, mean arterial blood pressure (MAP), smoking/caffeine use and parameters of placental blood
flow resistance.
RESULTS: In 110 consecutive patients PlGF levels ranged between 1.0 and 176.1 pg/mL, showing
a linear relationship with gestational age (GA) (PlGF = (1.4251 x GA) -74.951, r(2) = 0.0765, F =
8.941, P = 0.03). PlGF did not relate to maternal demographics but negatively correlated with MAP
(Spearman rho = -0.191, P < 0.05). Bilateral uterine artery notching was associated with lower PlGF
(40.7 (range, 1.01-131.6) vs. 51.1 (range, 6.4-176.1) pg/mL; Mann-Whitney P = 0.034.). A trend to
lower levels was also observed when umbilical artery end-diastolic flow was absent (37.1 (range, 6.8-
95) vs. 49.3 (range, 1.01-176.1) pg/mL; P = 0.05).
CONCLUSION: PlGF in the first trimester is related to maternal cardiovascular factors and placental
Doppler findings that are associated with subsequent placental dysfunction. The utility of this
parameter as a first-trimester screening tool on a population basis requires further investigation.
Pre-eclampsia and SGA
27
First-trimester prediction of hypertensive disorders in pregnancy.
Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides KH.
Hypertension. 2009 May;53(5):812-8. Epub 2009 Mar 9.
OBJECTIVE: This study aimed to establish a method of screening for pregnancy hypertension by
a combination of maternal variables, including mean arterial pressure, uterine artery pulsatility
index, pregnancy-associated plasma protein-A, and placental growth factor in early pregnancy. The
base-cohort population constituted of 7797 singleton pregnancies, including 34 case subjects who
developed preeclampsia (PE) requiring delivery before 34 weeks (early PE) and 123 with late PE,
136 with gestational hypertension, and 7504 cases subjects (96.3%) who were unaffected by PE or
gestational hypertension. Maternal history, uterine artery pulsatility index, mean arterial pressure,
and pregnancy-associated plasma protein-A were recorded in all of the cases in the base cohort,
but placental growth factor was measured only in the case-control population of 209 cases who
developed hypertensive disorders and 418 controls.
METHODS: In each case the measured mean arterial pressure, uterine artery pulsatility index,
pregnancy-associated plasma protein-A, and placental growth factor were converted to a multiple
of the expected median (MoM) after correction for maternal characteristics found to affect the
measurements in the unaffected group. Early PE and late PE were associated with increased mean
arterial pressure (1.15 MoM and 1.08 MoM) and uterine artery pulsatility index (1.53 MoM and
1.23 MoM) and decreased pregnancy-associated plasma protein-A (0.53 MoM and 0.93 MoM) and
placental growth factor (0.61 MoM and 0.83 MoM). Logistic regression analysis was used to derive
algorithms for the prediction of hypertensive disorders. It was estimated that, with the algorithm for
early PE, 93.1%, 35.7%, and 18.3% of early PE, late PE, and gestational hypertension, respectively,
could be detected with a 5% false-positive rate and that 1 in 5 pregnancies classified as being screen
positive would develop pregnancy hypertension.
CONCLUSION: This method of screening is far superior to the traditional approach, which relies
entirely on maternal history.
Pre-eclampsia and SGA
28
First trimester urinary placental growth factor and development of pre-eclampsia.
Savvidou MD, Akolekar R, Zaragoza E, Poon LC, Nicolaides KH.
BJOG. 2009 Apr;116(5):643-7. Epub 2009 Feb 10.
OBJECTIVE: To compare urinary placental growth factor (PlGF) concentration at 11(+0) to 13(+6)
weeks of gestation in women who subsequently develop pre-eclampsia with normotensive controls.
DESIGN: Nested case-control study within a prospective study for first trimester prediction of pre-
eclampsia.
SETTING: Routine antenatal visit in a teaching hospital.
POPULATION: Fifty-two women who developed pre-eclampsia and 52 controls matched for
gestational age and sample storage time.
METHODS: Urinary PlGF concentration and PlGF to creatinine ratio were measured in women who
developed pre-eclampsia and their matched controls. Comparisons between groups were performed
using Student’s t test.
MAIN OUTCOME MEASURES: Development of pre-eclampsia.
RESULTS: In the pre-eclampsia group, the median urinary PlGF concentration (20.6 pg/ml,
interquartile range [IQR] 9.1-32.0 pg/ml) and median urinary PlGF to creatinine ratio (1.6 pg/mg, IQR
1.2-2.5 pg/mg) were not significantly different from the control group (11.8 pg/ml, IQR 5.5-29.8
pg/ml, P=0.1 and 1.7 pg/mg, IQR 1.2-2.3 pg/mg, P=0.3, respectively). There were no significant
differences between women with early-onset pre-eclampsia requiring delivery before 34 weeks (n=13)
and those with late-onset pre-eclampsia (n=39) and between women with pre-eclampsia and fetal
growth restriction (FGR) (n=25) and those with pre-eclampsia and no FGR (n=27) in either median
PlGF concentration or median urinary PlGF to creatinine ratio.
CONCLUSIONS: The development of pre-eclampsia is not preceded by altered urinary PlGF
concentration in the first trimester of pregnancy.
Pre-eclampsia and SGA
29
Maternal serum placental growth factor (PlGF) in small for gestational age pregnancy at 11(+0) to 13(+6) weeks of gestation.
Poon LC, Zaragoza E, Akolekar R, Anagnostopoulos E, Nicolaides KH.
Prenat Diagn. 2008 Dec;28(12):1110-5.
OBJECTIVE: To investigate the pathogenesis of pregnancies delivering small for gestational age (SGA)
neonates by examining biochemical and Doppler indices of placental development during the first
trimester of pregnancy.
METHOD: The concentration of placental growth factor (PlGF) at 11(+0)-13(+6) weeks was measured
in 296 cases, which delivered SGA neonates, and 609 controls. The newborn was considered to be
SGA if the birth weight was less than the fifth percentile after correction for gestation at delivery and
sex, maternal racial origin, weight, height and parity. The distributions of uterine artery pulsatility
index (PI), PlGF and PAPP-A, expressed in multiples of the median (MoM), in the control and SGA
groups were compared. Logistic regression analysis was used to determine if significant contribution is
provided by maternal factors, PlGF, PAPP-A and uterine artery PI in predicting SGA.
RESULTS: The median PlGF (0.900 MoM) and PAPP-A (0.778 MoM) were lower and uterine artery PI
was higher (1.087 MoM) in the SGA group than in the controls (PlGF: 0.991 MoM; PAPP-A: 1.070
MoM; uterine artery PI: 1.030 MoM). In the SGA group there was a significant association between
PlGF and PAPP-A (r = 0.368, p < 0.0001) and uterine artery PI (r = 0.191, p = 0.001). Significant
contributions for the prediction of SGA were provided by maternal factors, PlGF and PAPP-A and with
combined screening the detection rate was 27% at a false-positive rate of 5%.
CONCLUSION: Birth weight is predetermined by placental development during the first trimester of
pregnancy. Copyright (c) 2008 John Wiley & Sons, Ltd.
Pre-eclampsia and SGA
30
Maternal serum placental growth factor at 11 + 0 to 13 + 6 weeks of gestation in the prediction of pre-eclampsia.
Akolekar R, Zaragoza E, Poon LC, Pepes S, Nicolaides KH.
Ultrasound Obstet Gynecol. 2008 Nov;32(6):732-9.
OBJECTIVE: To investigate the potential value of maternal serum placental growth factor (PlGF) in
first-trimester screening for pre-eclampsia (PE).
METHODS: The concentration of PlGF at 11 + 0 to 13 + 6 weeks’ gestation was measured in samples
from 127 pregnancies that developed PE, including 29 that required delivery before 34 weeks
(early PE) and 98 with late PE, 88 cases of gestational hypertension (GH) and 609 normal controls.
The distributions of PlGF multiples of the median (MoM) in the control and hypertensive groups
were compared. Logistic regression analysis was used to determine the factors with a significant
contribution for predicting PE.
RESULTS: In the control group significant independent contributions for log PlGF were provided by
fetal crown-rump length, maternal weight, cigarette smoking and racial origin, and after correction
for these variables the median MoM PlGF was 0.991. In the early-PE and late-PE groups PlGF (0.611
MoM and 0.822 MoM, respectively; P < 0.0001) and pregnancy-associated plasma protein-A (PAPP-A)
(0.535 MoM; P < 0.0001 and 0.929 MoM; P = 0.015, respectively) were reduced but in GH (PlGF:
0.966 MoM; PAPP-A: 0.895 MoM) there were no significant differences from controls. Significant
contributions for the prediction of PE were provided by maternal characteristics and obstetric history,
serum PlGF and uterine artery pulsatility index (PI) and with combined screening the detection rates
for early PE and late PE were 90% and 49%, respectively, for a false-positive rate of 10%.
CONCLUSION: Effective screening for PE can be provided by a combination of maternal
characteristics and obstetric history, uterine artery PI and maternal serum PlGF at 11 + 0 to 13 + 6
weeks’ gestation. (c) 2008 ISUOG. Published by John Wiley & Sons, Ltd.
Pre-eclampsia and SGA
31
Serum inhibin A and angiogenic factor levels in pregnancies with previous preeclampsia and/or chronic hypertension: are they useful markers for prediction of subsequent preeclampsia?
Sibai BM, Koch MA, Freire S, Pinto e Silva JL, Rudge MV, Martins-Costa S, Bartz J, de Barros
Santos C, Cecatti JG, Costa R, Ramos JG, Spinnato JA 2nd.
Am J Obstet Gynecol. 2008 Sep;199(3):268.e1-9.
OBJECTIVE: Our objective was to determine whether measurement of placenta growth factor (PLGF),
inhibin A, or soluble fms-like tyrosine kinase-1 (sFlt-1) at 2 times during pregnancy would usefully
predict subsequent preeclampsia (PE) in women at high risk.
STUDY DESIGN: We analyzed serum obtained at enrollment (12(0/7) to 19(6/7) weeks) and follow-up
(24-28 weeks) from 704 patients with previous PE and/or chronic hypertension (CHTN) enrolled in a
randomized trial for the prevention of PE. Logistic regression analysis assessed the association of log-
transformed markers with subsequent PE; receiver operating characteristic analysis assessed predictive
value.
RESULTS: One hundred four developed preeclampsia: 27 at 37 weeks or longer and 77 at less than
37 weeks (9 at less than 27 weeks). None of the markers was associated with PE at 37 weeks or
longer. Significant associations were observed between PE at less than 37 weeks and reduced PLGF
levels at baseline (P = .022) and follow-up (P < .0001) and elevated inhibin A (P < .0001) and sFlt-1
(P = .0002) levels at follow-up; at 75% specificity, sensitivities ranged from 38% to 52%. Using
changes in markers from baseline to follow-up, sensitivities were 52-55%. Associations were observed
between baseline markers and PE less than 27 weeks (P < or = .0004 for all); sensitivities were 67-
89%, but positive predictive values (PPVs) were only 3.4-4.5%.
CONCLUSION: Inhibin A and circulating angiogenic factors levels obtained at 12(0/7) to 19(6/7)
weeks have significant associations with onset of PE at less than 27 weeks, as do levels obtained at
24-28 weeks with onset of PE at less than 37 weeks. However, because the corresponding sensitivities
and/or PPVs were low, these markers might not be clinically useful to predict PE in women with
previous PE and/or CHTN.
Pre-eclampsia and SGA
32
The change in concentrations of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters in risk assessment for the subsequent development of preeclampsia and small-for-gestational age.
Erez O, Romero R, Espinoza J, Fu W, Todem D, Kusanovic JP, Gotsch F, Edwin S, Nien JK,
Chaiworapongsa T, Mittal P, Mazaki-Tovi S, Than NG, Gomez R, Hassan SS.
J Matern Fetal Neonatal Med. 2008 May;21(5):279-87.
INTRODUCTION: An imbalance between angiogenic and anti-angiogenic factors has been proposed
as central to the pathophysiology of preeclampsia (PE). Indeed, patients with PE and those delivering
small-for-gestational age (SGA) neonates have higher plasma concentrations of soluble vascular
endothelial growth factor receptor-1 (sVEGFR-1) and the soluble form of endoglin (s-Eng), as well
as lower plasma concentrations of vascular endothelial growth factor (VEGF) and placental growth
factor (PlGF) than do patients with normal pregnancies. Of note, this imbalance has been observed
before the clinical presentation of PE or the delivery of an SGA neonate. The objective of this study
was to determine if changes in the profile of angiogenic and anti-angiogenic factors in maternal
plasma between the first and second trimesters are associated with a high risk for the subsequent
development of PE and/or delivery of an SGA neonate.
METHODS: This longitudinal case-control study included 402 singleton pregnancies in the following
groups: (1) normal pregnancies with appropriate for gestational age (AGA) neonates (n = 201);
(2) patients who delivered an SGA neonate (n = 145); and (3) patients who developed PE (n = 56).
Maternal plasma samples were obtained at the time of each prenatal visit, scheduled at 4-week
intervals from the first or early second trimester until delivery. In this study, we included two samples
per patient: (1) first sample obtained between 6 and 15 weeks of gestation (‘first trimester’ sample),
and (2) second sample obtained between 20 and 25 weeks of gestation (‘second trimester’ sample).
Plasma concentrations of s-Eng, sVEGFR-1, and PlGF were determined by specific and sensitive
immunoassays. Changes in the maternal plasma concentrations of these angiogenesis-related
factors were compared among normal patients and those destined to develop PE or deliver an SGA
neonate while adjusting for maternal age, nulliparity, and body mass index. General linear models
and polytomous logistic regression models were used to relate the analyte concentrations, ratios, and
product to the subsequent development of PE and SGA.
Pre-eclampsia and SGA
33
RESULTS: (1) An increase in the maternal plasma concentration of s-Eng between the first and second
trimesters conferred risk for the development of preterm PE and SGA (OR 14.9, 95% CI 4.9-45.0
and OR 2.9, 95% CI 1.5-5.6, respectively). (2) An increase in the maternal plasma concentration of
sVEGFR-1 between the first and second trimester conferred risk for the development of preterm PE
(OR 3.9, 95% CI 1.2-12.6). (3) A subnormal increase in maternal plasma PlGF concentration between
the first and the second trimester was a risk factor for the subsequent development of preterm and
term PE (OR 4.3, 95% CI 1.2-15.5 and OR 2.7, 95% CI 1.2-5.9, respectively). (4) In addition, the
combination of the three analytes into a pro-angiogenic versus anti-angiogwenic ratio (PlGF/(s-Eng x
VEGFR-1)) conferred risk for the subsequent development of preterm PE (OR 3.7, 95% CI 1.1-12.1).
(5) Importantly, patients with a high change in the s-Eng x sVEGFR-1 product had an OR of 10.4 (95%
CI 3.2-33.8) for the development of preterm PE and 1.6 (95% CI 1.0-2.6) for the development of
SGA.
CONCLUSIONS: Changes in the maternal plasma concentrations of s-Eng, sVEGFR-1, PlGF or their
ratios between the first and second trimesters of pregnancy confer an increased risk to deliver an SGA
neonate and/or develop PE.
Pre-eclampsia and SGA
34
A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate
Romero R, Nien JK, Espinoza J, Todem D, Fu W, Chung H, Kusanovic JP, Gotsch F, Erez O,
Mazaki-Tovi S, Gomez R, Edwin S, Chaiworapongsa T, Levine RJ, Karumanchi SA.
J Matern Fetal Neonatal Med. 2008 Jan;21(1):9-23.
INTRODUCTION: Accumulating evidence suggests that an imbalance between pro-angiogenic
(i.e., vascular endothelial growth factor (VEGF) and placental growth factor (PlGF)) and anti-
angiogenic factors (i.e., soluble VEGF receptor-1 (sVEGFR-1, also referred to as sFlt1)) is involved in
the pathophysiology of preeclampsia (PE). Endoglin is a protein that regulates the pro-angiogenic
effects of transforming growth factor beta, and its soluble form has recently been implicated in
the pathophysiology of PE. The objective of this study was to determine if changes in maternal
plasma concentration of these angiogenic and anti-angiogenic factors differ prior to development
of disease among patients with normal pregnancies and those destined to develop PE (preterm and
term) or to deliver a small for gestational age (SGA) neonate.
METHODS: This longitudinal nested case-control study included 144 singleton pregnancies in
the following groups: (1) patients with uncomplicated pregnancies who delivered appropriate
for gestational age (AGA) neonates (n = 46); (2) patients who delivered an SGA neonate but
did not develop PE (n = 56); and (3) patients who developed PE (n = 42). Longitudinal samples
were collected at each prenatal visit, scheduled at 4-week intervals from the first or early second
trimester until delivery. Plasma concentrations of soluble endoglin (s-Eng), sVEGFR-1, and PlGF were
determined by specific and sensitive ELISA.
Pre-eclampsia and SGA
35
RESULTS: (1) Patients destined to deliver an SGA neonate had higher plasma concentrations of s-Eng
throughout gestation than those with normal pregnancies; (2) patients destined to develop preterm
PE and term PE had significantly higher concentrations of s-Eng than those with normal pregnancies
at 23 and 30 weeks, respectively (for preterm PE: p < 0.036 and for term PE: p = 0.002); (3) patients
destined to develop PE (term or preterm) and those who delivered an SGA neonate had lower plasma
concentrations of PlGF than those with a normal pregnancy throughout gestation, and the maternal
plasma concentration of this analyte became detectable later among patients with pregnancy
complications, compared to normal pregnant women; (4) there were no significant differences in the
plasma concentrations of sVEGFR-1 between patients destined to deliver an SGA neonate and those
with normal pregnancies; (5) patients destined to develop preterm and term PE had a significantly
higher plasma concentration of sVEGFR-1 at 26 and 29 weeks of gestation than controls (p = 0.009
and p = 0.0199, respectively); and (6) there was no significant difference in the increment of sVEGFR-1
between control patients and those who delivered an SGA neonate (p = 0.147 at 25 weeks and p =
0.8285 at 40 weeks).
CONCLUSIONS: (1) Changes in the maternal plasma concentration of s-Eng, sVEGFR-1, and PlGF
precede the clinical presentation of PE, but only changes in s-Eng and PlGF precede the delivery of
an SGA neonate; and (2) differences in the profile of angiogenic and anti-angiogenic response to
intrauterine insults may determine whether a patient will deliver an SGA neonate, develop PE, or both.
Pre-eclampsia and SGA
36
Circulating angiogenic factors in early pregnancy and the risk of preeclampsia, intrauterine growth restriction, spontaneous preterm birth, and stillbirth. Smith GC, Crossley JA, Aitken DA, Jenkins N, Lyall F, Cameron AD, Connor JM, Dobbie R.
Obstet Gynecol. 2007 Jun;109(6):1316-24.
OBJECTIVE: To estimate the relationship between maternal serum levels of placental growth factor
(PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in early pregnancy with the risk of subsequent
adverse outcome.
METHODS: A nested, case-control study was performed within a prospective cohort study of Down
syndrome screening. Maternal serum levels of sFlt-1 and PlGF at 10-14 weeks of gestation were
compared between 939 women with complicated pregnancies and 937 controls. Associations were
quantified as the odds ratio for a one decile increase in the corrected level of the analyte.
RESULTS: Higher levels of sFlt-1 were not associated with the risk of preeclampsia but were associated
with a reduced risk of delivery of a small for gestational age infant (odds ratio [OR] 0.92, 95%
confidence interval [CI] 0.88-0.96), extreme (24-32 weeks) spontaneous preterm birth (OR 0.90, 95%
CI 0.83-0.99), moderate (33-36 weeks) spontaneous preterm birth (OR 0.93, 95% CI 0.88-0.98), and
stillbirth associated with abruption or growth restriction (OR 0.77, 95% CI 0.61-0.95). Higher levels of
PlGF were associated with a reduced risk of preeclampsia (OR 0.95, 95% CI 0.90-0.99) and delivery of
a small for gestational age infant (OR 0.95, 95% CI 0.91-0.99). Associations were minimally affected
by adjustment for maternal characteristics.
CONCLUSION: Higher early pregnancy levels of sFlt-1 and PlGF were associated with a decreased risk
of adverse perinatal outcome.
Pre-eclampsia and SGA
37
Changes in circulating level of angiogenic factors from the first to second trimester as predictors of preeclampsia. Vatten LJ, Eskild A, Nilsen TI, Jeansson S, Jenum PA, Staff AC.
Am J Obstet Gynecol. 2007 Mar;196(3):239.e1-6.
OBJECTIVE: This study was undertaken to assess changes in placenta growth factor and soluble fms-
like tyrosine kinase-1 as predictors of preeclampsia.
STUDY DESIGN: Nested case-control study of 154 preeclampsia cases delivered preterm and 190
delivered at term, and 392 controls.
RESULTS: Comparing the lowest and highest quartile of placenta growth factor increase from first to
second trimester, the odds for preterm preeclampsia was 13.8 (95% CI, 4.4-43.2) higher for women
with the lowest increase. Compared with controls, women with preterm preeclampsia had lower
soluble fms-like tyrosine kinase-1 in the first, but higher in second trimester. Comparing highest and
lowest quartile of increase, the odds for preterm preeclampsia was 9.2 (95% CI 3.4-25.0) higher for
women with highest increase. Low placenta growth factor and high soluble fms-like tyrosine kinase-1
increase combined yielded extremely high relative risk of preterm preeclampsia (odds ratio, 35.3, 95%
CI, 7.6-164.2), compared with the combination of high (placenta growth factor) and low (soluble fms-
like tyrosine kinase-1) increase.
CONCLUSION: Low placenta growth factor and high soluble fms-like tyrosine kinase-1 increase from
first to second trimester are strong predictors of preeclampsia.
Pre-eclampsia and SGA
38
Correlations of placental perfusion and PlGF protein expression in early human pregnancy.
Welch PC, Amankwah KS, Miller P, McAsey ME, Torry DS.
Am J Obstet Gynecol. 2006 Jun;194(6):1625-9; discussion 1629-31. Epub 2006 Apr 25.
OBJECTIVE: The purpose of this study was to investigate temporal correlations between maternal
serum placenta growth factor levels and placental perfusion in early human pregnancies.
STUDY DESIGN: Systolic umbilical artery Doppler blood flow velocity indices at fetal and placental
insertion sites were measured between 7 and 22 weeks of gestation from normal singleton
pregnancies. Maternal serum placenta growth factor levels were determined by enzyme-linked
immunosorbent assay.
RESULTS: Maternal serum placenta growth factor levels showed an exponential increase at
approximately 14 weeks of gestation. Placenta perfusion, as estimated by systolic Doppler blood
flow indices, significantly increased with gestational age (P < .0001). There was a close association
between placenta growth factor expression levels and evidence of increased placenta perfusion
(P < .033).
CONCLUSION: The significant increase in serum placenta growth factor coincides with the increased
perfusion of the maternal/fetal interface at approximately 12 to 14 weeks of gestation. Correlation of
placenta growth factor expression and placental perfusion suggests that placenta growth factor may
contribute to assuring adequate vascular development/function of the placenta early in gestation.
Pre-eclampsia and SGA
39
Insulin resistance and alterations in angiogenesis: additive insults that may lead to preeclampsia.
Thadhani R, Ecker JL, Mutter WP, Wolf M, Smirnakis KV, Sukhatme VP, Levine RJ,
Karumanchi SA.
Hypertension. 2004 May;43(5):988-92. Epub 2004 Mar 15.
Altered angiogenesis and insulin resistance, which are intimately related at a molecular level,
characterize preeclampsia. To test if an epidemiological interaction exists between these two
alterations, we performed a nested case-control study of 28 women who developed preeclampsia
and 57 contemporaneous controls. Serum samples at 12 weeks of gestation were measured for
sex hormone binding globulin (SHBG; low levels correlate with insulin resistance) and placental
growth factor (PlGF; a proangiogenic molecule). Compared with controls, women who developed
preeclampsia had lower serum levels of SHBG (208+/-116 versus 256+/-101 nmol/L, P=0.05) and
PlGF (16+/-14 versus 67+/-150 pg/mL, P<0.001), and in multivariable analysis, women with serum
levels of PlGF < or =20 pg/mL had an increased risk of developing preeclampsia (odds ratio [OR] 7.6,
95% CI 1.4 to 38.4). Stratified by levels of serum SHBG (< or =175 versus >175 mg/dL), women with
low levels of SHBG and PlGF had a 25.5-fold increased risk of developing preeclampsia (P=0.10),
compared with 1.8 (P=0.38) among women with high levels of SHBG and low levels of PlGF. Formal
testing for interaction (PlGFxSHBG) was significant (P=0.02). In a model with 3 (n-1) interaction
terms (high PlGF and high SHBG, reference), the risk for developing preeclampsia was as follows:
low PlGF and low SHBG, OR 15.1, 95% CI 1.7 to 134.9; high PlGF and low SHBG, OR 4.1, 95% CI
0.45 to 38.2; low PlGF and high SHBG, OR 8.7, 95% CI 1.2 to 60.3. Altered angiogenesis and insulin
resistance are additive insults that lead to preeclampsia.
Pre-eclampsia and SGA
40
Circulating angiogenic factors and the risk of preeclampsia.
Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs
BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA.
N Engl J Med. 2004 Feb 12;350(7):672-83. Epub 2004 Feb 5
BACkGROUND: The cause of preeclampsia remains unclear. Limited data suggest that excess
circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and
vascular endothelial growth factor (VEGF), may have a pathogenic role.
METHODS: We performed a nested case-control study within the Calcium for Preeclampsia
Prevention trial, which involved healthy nulliparous women. Each woman with preeclampsia was
matched to one normotensive control. A total of 120 pairs of women were randomly chosen.
Serum concentrations of angiogenic factors (total sFlt-1, free PlGF, and free VEGF) were measured
throughout pregnancy; there were a total of 655 serum specimens. The data were analyzed
cross-sectionally within intervals of gestational age and according to the time before the onset of
preeclampsia.
RESULTS: During the last two months of pregnancy in the normotensive controls, the level of sFlt-1
increased and the level of PlGF decreased. These changes occurred earlier and were more pronounced
in the women in whom preeclampsia later developed. The sFlt-1 level increased beginning
approximately five weeks before the onset of preeclampsia. At the onset of clinical disease, the mean
serum level in the women with preeclampsia was 4382 pg per milliliter, as compared with 1643
pg per milliliter in controls with fetuses of similar gestational age (P<0.001). The PlGF levels were
significantly lower in the women who later had preeclampsia than in the controls beginning at 13 to
16 weeks of gestation (mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01), with the greatest
difference occurring during the weeks before the onset of preeclampsia, coincident with the increase
in the sFlt-1 level. Alterations in the levels of sFlt-1 and free PlGF were greater in women with an
earlier onset of preeclampsia and in women in whom preeclampsia was associated with a small-for-
gestational-age infant.
CONCLUSIONS: Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent
development of preeclampsia. Copyright 2004 Massachusetts Medical Society
Pre-eclampsia and SGA
41
First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia.
Thadhani R, Mutter WP, Wolf M, Levine RJ, Taylor RN, Sukhatme VP, Ecker J, Karumanchi SA.
J Clin Endocrinol Metab. 2004 Feb;89(2):770-5.
An imbalance of pro- and antiangiogenic factors may lead to preeclampsia (PE). In this prospective
nested case-control study, we investigated whether first trimester serum levels of placental growth
factor (PlGF), a potent angiogenic factor, and its soluble inhibitor, soluble fms-like tyrosine kinase
1 (sFlt1), distinguished women who developed PE (n = 40) from those who developed gestational
hypertension (n = 40), delivered a small for gestational age (SGA) newborn (n = 40), or completed
a full term normal pregnancy (n = 80). Compared with controls, serum PlGF levels were lower
among women who developed PE (23 +/- 24 pg/ml vs. 63 +/- 145 pg/ml; P < 0.01) or gestational
hypertension (27 +/- 19 pg/ml; P = 0.03), or who delivered a SGA newborn (21 +/- 16 pg/ml; P <
0.01). In contrast, serum sFlt1 levels did not markedly differ between the groups: PE, 1048 +/- 657
pg/ml; gestational hypertension, 942 +/- 437 pg/ml; SGA newborns, 1011 +/- 479 pg/ml; and normal
controls, 973 +/- 490 pg/ml. Multivariable analysis adjusting for potential confounders and serum
sFlt1 levels demonstrated a 3.7-fold (95% confidence interval, 1.2-12.5) increase in risk for PE for
every log unit decrease in serum levels of PlGF compared with controls. Analyses for gestational
hypertension and SGA were not significant. Examined in tertiles, the risk for PE was increased 28.7-
fold (95% confidence interval, 2.3-351.0) in the third (<12 pg/ml) compared with the first (>39 pg/ml)
PlGF tertile. First trimester serum levels of PlGF and sFlt1 may identify women at high risk for PE.
Pre-eclampsia and SGA
42
First-trimester maternal serum levels of placenta growth factor as predictor of preeclampsia and fetal growth restriction.
Ong CY, Liao AW, Cacho AM, Spencer K, Nicolaides KH.
Obstet Gynecol. 2001 Oct;98(4):608-11.
Comment in: Obstet Gynecol. 2001 Oct;98(4):596-9.
OBJECTIVE: To determine whether the reported decrease in maternal serum placenta growth factor
concentration in preeclampsia is evident from the first trimester and before clinical onset of the
disease. We also examined levels in pregnancies that subsequently resulted in fetal growth restriction
(FGR).
METHODS: Placenta growth factor concentration was measured in stored maternal serum samples
obtained at 11-14 weeks of gestation from 131 women who subsequently developed preeclampsia,
137 women who subsequently developed FGR, and 400 randomly selected controls who did not
develop preeclampsia or FGR. Preeclampsia was defined as diastolic blood pressure of 90 mmHg
or more on two occasions 4 hours apart, accompanied by proteinuria (more than 300 mg of total
protein in a 24-hour urine collection or a positive test for albumin on reagent strip) in women with no
pre-existing hypertensive or renal disease. Fetal growth restriction was considered present if a woman
subsequently delivered a live infant with a birth weight below the fifth centile for gestation.
RESULTS: In the control group, maternal serum placenta growth factor concentration increased with
gestation. Compared with the controls (median multiple of the median 0.98, standard deviation
[SD] 0.51), levels in the preeclampsia group (median multiple of the median 1.09, SD 0.52) were not
significantly different (t = 1.83, P = .07), but in the FGR group (median multiple of the median 1.57,
SD 0.74), levels were significantly increased (t = 10.85, P < .001).
CONCLUSION: The previously reported decrease in serum placenta growth factor levels in women
with preeclampsia might not precede clinical onset of the disease and is not apparent in the first
trimester of pregnancy. Levels are significantly increased in pregnancies resulting in FGR.
Pre-eclampsia and SGA
43
Low maternal serum levels of placenta growth factor as an antecedent of clinical preeclampsia.
Tidwell SC, Ho HN, Chiu WH, Torry RJ, Torry DS.
Am J Obstet Gynecol. 2001 May;184(6):1267-72.
OBJECTIVE: Maternal serum placenta growth factor levels have been shown to be significantly
reduced in women with established preeclampsia. However, the temporal change in serum placenta
growth factor levels before the clinical onset of preeclampsia is not known.
STUDY DESIGN: Serum samples were collected from patients at the first prenatal (5-15 weeks’
gestation), second-trimester (16-20 weeks’ gestation), and third-trimester (26-30 weeks’ gestation)
visits. Serum placenta growth factor levels were determined and analyzed according to pregnancy
outcome.
RESULTS: Maternal placenta growth factor levels during normal gestation increased dramatically from
the first to the third trimester. At the same gestational time points, in contrast, significantly lower
serum placenta growth factor levels were found in patients in whom mild or severe preeclampsia
eventually developed (P <.01). Low maternal serum placenta growth factor levels during early
gestation were associated with a significant odds ratio for development of preeclampsia (P <.005).
CONCLUSION: Relatively decreased levels of serum placenta growth factor occur before the onset
of clinical preeclampsia, which suggests that placenta growth factor measurement could be used to
discriminate those pregnancies predisposed to development of preeclampsia.
Pre-eclampsia and SGA
44
Improvements in antenatal screening for Down’s syndrome Wald NJ, Bestwickand JP, Huttly WJ
J Med Screen 2013:1–21 DOI: 10.1177/0969141313476496
OBJECTIVE: To estimate improvements to four antenatal screening tests for Down’s syndrome (first
trimester Combined, second trimester Quadruple, and first and second trimester Integrated and
Serum Integrated tests) based on adding ductus venosus pulsatility index (DVPI), fetal nasal bone
examination (NBE) and serum placental growth factor (PlGF). Setting Statistical analysis of data from
several sources modelled using the maternal age distribution of live births in England and Wales from
2006 to 2008.
METHODS: Monte Carlo simulation carried out to estimate the screening performance of tests with
the addition of combinations of DVPI, NBE and PlGF. Results At a 95% detection rate (DR), with first
trimester markers measured at 11 completed weeks’ gestation, the addition of DVPI, NBE and PlGF
decreased the false-positive rate (FPR) of the Combined test from 16.1% to 3.0%, the addition of
PlGF to the Quadruple test decreased the FPR from 15.7% to 15.3%, the addition of DVPI, NBE
and PlGF to the Integrated test decreased the FPR from 4.1% to 0.6% and the addition of PlGF to
the Serum Integrated test decreased the FPR from 15.1% to 11.1%. At a 90% detection rate, the
reductions in the FPR were from 6.8% to 0.8%, 7.7% to 7.4%, 1.2% to 0.1% and 6.2% to 4.8%,
respectively.
CONCLUSION: The addition of DVPI, NBE and PlGF to the Combined and Integrated tests significantly
improves screening performance, reducing the FPRs by over 80%. The Integrated test with DVPI, NBE
and PlGF is significantly better than the Combined test with DVPI, NBE and PlGF.
DELFIA Chemistry used in PlGF assay
Trisomies
45
DELFIA Chemistry used in PlGF assay
Pre-eclampsia and SGA
Maternal serum placental growth factor and a-fetoprotein testing in first trimester screening for Down syndrome.
Kim Donalson, Steve Turner, Lesley Morrison, Päivi Liitti, Christel Nilsson and Howard Cuckle
Prenatal Diagnosis 2013, 33, 457–461, DOI: 10.1002/pd.4087
OBJECTIVE: The aim of this research was to evaluate the addition of first trimester maternal serum
placental growth factor (PlGF) and a-fetoprotein (AFP) to the combined test for Down syndrome and
a serum only protocol of PlGF, AFP, free ß-human chorionic gonadotropin and pregnancy-associated
plasma protein-A.
METHODS: Samples were from 92 Down syndrome cases with 552 matched controls. All women
had a combined test at 11–14 weeks gestation. PlGF and AFP were measured and expressed in
multiples of the gestation-specific median (MoM), adjusting for maternal weight and smoking status.
Multivariate Gaussian modeling was used to predict detection and false-positive rates.
RESULTS: The median PlGF level in the cases was 0.694 MoM and controls 1.000 MoM (p =<0.0001).
The corresponding values for AFP were 0.764 MoM and 0.990 MoM (p<0.0001). Statistical modeling
predicted that for a given false-positive rate, the addition of PlGF to the combined test increases the
detection rate by 4–7%. For a given detection rate, the false-positive rate could be almost halved.
When both PlGF and AFP are used, the detection rate increase is 5–8%. A serum only protocol had a
predicted a detection rate of 71% for a false-positive rate of 5%.
CONCLUSION: Results suggest a substantial benefit of adding PlGF to the combined test.
46
First-trimester contingent screening for trisomy 21 by biomarkers and maternal blood cell-free DNA testing K. H. Nicolaides, D. Wright, L. C. Poon, A. Syngelaki and M. Gil
Ultrasound Obstet Gynecol 2013
Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.12511
OBJECTIVE: To define risk cut-offs with corresponding detection rates (DR) and false-positive rates
(FPR) in screening for trisomy 21 using maternal age and combinations of first-trimester iomarkers
in order to determine which women should undergo contingent maternal blood cell-free (cf)
DNA testing.
METHODS: From singleton pregnancies undergoing screening for aneuploidies at three UK hospitals
between March 2006 and May 2012, we analyzed prospectively collected data on the following
biomarkers: fetal nuchal translucency thickness (NT) and ductus venosus pulsatility index for veins
(DV-PIV) at 11+0 to 13+6 weeks’ gestation and serum free ß-human chorionic gonadotropin (ß-hCG),
pregnancy-associated plasma protein-A (PAPPA), placental growth factor (PlGF) and alpha-fetoprotein
(AFP) at 8+0 to 13+6 weeks. Estimates of risk cutoffs, DRs and FPRs were derived for combinations of
biomarkers and these were used to define the best strategy for contingent cfDNA testing.
RESULTS: In contingent screening, detection of 98% of fetuses with trisomy 21 at an overall invasive
testing rate <0.5% can be potentially achieved by offering cfDNA testing to about 36%, 21% and
11% of cases identified by first-line screening using the combined test alone, using the combined test
with the addition of serum PlGF and AFP and using the combined test with the addition of PlGF, AFP
and DV-PIV, respectively.
CONCLUSION: Effective first-trimester screening for trisomy 21, with DR of 98% and invasive testing
rate <0.5%, can be potentially achieved by contingent screening incorporating biomarkers and
cfDNA testing.
DELFIA Chemistry used in PlGF assay
Trisomies
47
Antenatal Screening for Down Syndrome Using Serum Placental Growth Factor with the Combined, Quadruple, Serum Integrated and Integrated Tests
Wald NJ, Bestwick JP, George LM, Huttly WJ.
PLoS ONE 7 (10): e46955
OBJECTIVE: To estimate the value of first or second trimester placental growth factor (PlGF) as an
additional antenatal screening marker for Down syndrome.
DESIGN: Nested case-control study.
SETTING: Antenatal screening service.
POPULATION OR SAMPLE : 532 Down syndrome pregnancies and 1,155 matched
unaffected pregnancies.
METHODS: Stored maternal serum samples (−40°C) were assayed for PlGF. Monte Carlo simulation
was used to estimate the screening performance of PlGF with the Combined, Quadruple, serum
Integrated and Integrated tests.
MAIN OUTCOME MEASURES : Median PlGF levels in affected and unaffected pregnancies and
screening performance (detection rates [DR] for specified false-positive rates [FPR] and vice versa).
RESULTS: First trimester median PlGF was 15%, 28% and 39% lower in Down syndrome than
unaffected pregnancies at 11, 12 and 13 completed weeks’ gestation respectively (all p<0.001).
Second trimester median PlGF was 31% lower at 14 weeks (p<0.001), and the difference decreased
(6% lower at 17 weeks). At a 90% DR with first trimester markers measured at 13 weeks, adding
PlGF decreased the FPR from 11.1 to 5.1% using the Combined test, 9.3% to 4.5% using the serum
Integrated test, and 3.4% to 1.5% using the Integrated test (or 1.5 to 1.4% with first trimester
markers measured at 11 weeks). Adding PlGF to the Quadruple test (measured at 15 weeks)
decreased the FPR from 10.0% to 9.6% at a 90% DR.
CONCLUSION: First trimester PlGF measurements improve the performance of antenatal screening for
Down syndrome using the Combined, serum Integrated and Integrated tests. Second trimester PlGF
measurements are of limited value.
DELFIA Chemistry used in PlGF assay
Trisomies
48
First trimester combined screening for trisomy 21 with different combinations of placental growth factor, free ß-hCG and PAPP-A
KO Kagan, M Hoopmann, H Abele, R Alkier, K Lüthgens
Ultrasound in Obstetrics & Gynecology 2012
OBJECTIVE: To examine placental growth factor (PlGF) in euploid and trisomy 21 pregnancies at 11-
13 weeks of gestation and to model the impact on first trimester combined screening.
METHODS: PlGF was measured in the surplus of 509 (409 euploid and 100 trisomic fetuses) serum
samples that have been derived from prospective first trimester combined screening for trisomy 21
at 11 to 13 weeks. The serum samples were stored at -80° C following the measurement of free
ß-hCG and PAPP-A and were only thawed for the measurement of PlGF. In euploid and trisomy 21
pregnancies, the samples were stored for a median time span from 0.9 to 4.1 years. The effect of the
additional measurement of PlGF at the time of combined screening was investigated by simulating
fetal NT measurements and MoM values for PAPP-A, free ß-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 and in addition either free ß-hCG, PAPP-A and PlGF, PAPP-A and PlGF or free ß-hCG
and PlGF. Detection and false-positive rates were calculated as proportion of cases above certain
thresholds.
RESULTS: In euploid fetuses, median PlGF MoM was 1.0 (95% CI 0.96 – 1.04). In trisomy 21, median
PlGF MoM was 0.73 (95% CI 0.70 – 0.80) MoM, which was significantly lower than in euploid
pregnacies (p<0.0001). There was no significant dependency neither between PlGF and gestational
age at the time of blood sampling (r=0.087; p=0.392) nor between PlGF and the storage time
(r=0.028; p=0.785). Modelled 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 incresed the detection rate
to 87% and reduced the false-positive rate to 2.6%, respectively. Screening by maternal and fetal NT
in combination with PlGF and PAPP-A or in combination with PlGF and free ß-hCG provides detection
rates of 82% and 79% for false-positive rates of 2.7% and 3.0%, respectively.
CONCLUSION: n pregnancies with trisomy 21 PlGF is reduced. The impact on the overal screening
performance for trisomy 21 is low and does not justify the measurement of PlGF solely for trisomy 21.
However, as the measurement of PlGF aims to assess the risk for preeclampsia rather than for trisomy
21, a further improvement in screening for trisomy 21 can be considered as a positive side effect.
Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.
DELFIA Chemistry used in PlGF assay
Trisomies
49
Trisomies
Maternal Serum Placental Growth Factor in Prospective Screening for Aneuploidies at 8–13 Weeks’ Gestation
Pranav Pandya, David Wright, Argyro Syngelaki, Ranjit Akolekar, Kypros H. Nicolaides
Fetal Diagn Ther, Published online: January 27, 2012, DOI: 10.1159/000335684
OBJECTIVES: To investigate whether measurement of maternal serum placental growth factor (PLGF)
can improve the performance of first-trimester combined screening for trisomy- 21 by fetal nuchal
translucency (NT) thickness and serum free ß -human chorionic gonadotropin (ß-hCG) and PAPP-A.
METHODS: In singleton pregnancies attending for routine care, serum PLGF, free ß-hCG and PAPP-A
were measured at 8 +0 –13 +6 weeks’ gestation, and fetal NT was measured at 11 +0 –13 +6 weeks.
The population included 12,154 normal and 44 trisomy-21 pregnancies. We examined the effect of
adding PLGF on the performance of screening by the combined test.
RESULTS: In the trisomy-21 pregnancies the median multiple of the normal median PLGF, adjusted
for gestational age, maternal weight, racial origin, smoking status and method of conception, was
significantly reduced (0.6070, 95% CI 0.5543–0.6648), and this did not change significantly with
gestational age. Adding PLGF to combined testing with a risk cut-off of 1 in 100 reduced the false
positive rate from 2.7% (95% CI 2.5–3.0) to 2.6% (95% CI 2.4–2.8) and increased the detection rate
from 85% (95% CI 75–93) to 88% (95% CI 78–95).
CONCLUSIONS: Inclusion of serum PLGF improves the performance of the first-trimester combined
test in screening for trisomy-21.
DELFIA Chemistry used in PlGF assay
50
DELFIA Chemistry used in PlGF assay
Modeling Down syndrome screening performance using first-trimester serum markers
M. P. H. Koster, E. J. Wortelboer, P. Stoutenbeek, G. H. A. Visser and P. C. J. I. Schielen
Ultrasound Obstet Gynecol 2011; 38: 134–139
OBJECTIVES: To evaluate the modeled predictive value of three current screening markers
(pregnancy-associated plasma protein-A (PAPP-A), free ß-human chorionic gonadotropin (free ß-hCG),
and nuchal translucency (NT)) and four potential screening markers (a disintegrin and metalloprotease
12 (ADAM12), total hCG, placental protein 13 (PP13), and placental growth factor (PlGF)) for Down
syndrome using different screening strategies.
METHODS: All markers were measured in stored first trimester serum of 151 Down syndrome cases
and 847 controls. All marker levels were expressed as gestational age-specific multiples of the median
(MoMs) and comparisons were made using the Mann-Whitney Utest. Detection rates (DRs) for fixed
false-positive rates (FPRs) were modeled using different screening strategies.
RESULTS: Significantly different median MoMs for Down syndrome cases compared to controls were
found for PAPP-A (0.49 vs. 1.00; P < 0.0001), free ß-hCG (1.70 vs. 1.01; P < 0.0001), ADAM12 (0.89
vs. 1.00; P < 0.0001), total hCG (1.28 vs. 1.00; P < 0.0001), PlGF (0.80 vs. 1.00; P < 0.0001) and NT
(1.74 vs. 1.01; P < 0.0001). The lower PP13 MoM in Down syndrome cases (0.91 vs. 1.00) was not
statistically significant (P = 0.061). Adding the four new markers to the current screening strategy (i.e.
first-trimester ombined test) led to an increase in DR from 77% to 80% at a 5%FPR. The modeled
application of a two-sample screening strategy (with some markers assessed early and others later
in the first trimester) increased the DR to 89%. In a two-step contingent screening model, using an
intermediate risk range of 1 in 100 to 1 in 2000 at biochemical screening (using all markers), the
overall DR was 77%, but it was predicted that only 33% of women would require referral for NT
measurement.
CONCLUSIONS: First-trimester Down syndrome screening may be improved by adding new markers
to the current screening test and by applying different screening strategies. The application of a
two-sample screening model resulted in the highest predicted DR, but this should be confirmed in
population-based prospective studies.
Trisomies
51
First trimester maternal serum placental growth factor in trisomy 21 pregnancies
Cowans NJ, Stamatopoulou A, Spencer K.
Prenat Diagn. 2010 May;30(5):449-53.
OBJECTIVE: To examine placental growth factor (PlGF) levels in first trimester maternal serum in
trisomy 21 pregnancies and to investigate the potential value of PlGF in a first trimester screening test.
METHODS: First trimester maternal serum from 70 trisomy 21 cases and 375 euploid controls
were retrospectively analyzed for PlGF using a DELFIA Xpress immunoassay platform. Results were
expressed as multiples of medians (MoM) for comparison.
RESULTS: PlGF levels were significantly decreased in pregnancies with trisomy 21, 0.76 MoM
versus 0.98 MoM in controls. Inclusion of PlGF into the first trimester combined test [maternal age,
pregnancy associated plasma protein-A (PAPP-A), free-beta human chorionic gonadotrophin (beta-
hCG) and nuchal translucency] would increase the detection rate by 0.5% at a 5% false positive rate.
CONCLUSION: PlGF at 11 weeks to 13 weeks 6 days has the potential to be included as a marker for
the detection of pregnancies with trisomy 21.
DELFIA Chemistry used in PlGF assay
Trisomies
52
Maternal serum placental growth factor at 11-13 weeks in chromosomally abnormal pregnancies
Zaragoza E, Akolekar R, Poon LC, Pepes S, Nicolaides KH.
Ultrasound Obstet Gynecol. 2009 Apr;33(4):382-6.
OBJECTIVES: To investigate the potential value of maternal serum placental growth factor (PlGF) in
first-trimester screening for trisomy 21 and other major chromosomal abnormalities.
METHODS: The maternal serum concentration of PlGF at 11 + 0 to 13 + 6 weeks was measured
in 609 euploid and 175 chromosomally abnormal pregnancies, including 90 with trisomy 21, 28
with trisomy 18, 19 with trisomy 13, 28 with Turner syndrome and 10 with triploidy. The levels of
PlGF were compared in cases and controls, and were assessed for association with free beta-human
chorionic gonadotropin (ß-hCG) and pregnancy-associated plasma protein-A (PAPP-A).
RESULTS: Logistic regression analysis demonstrated in the euploid group that significant independent
contributions for log PlGF were provided by fetal crown-rump length, maternal weight, cigarette
smoking and ethnic origin; after correction for these variables the median multiple of the median
(MoM) PlGF was 0.991. Significantly lower values were observed in pregnancies with trisomy 21
(0.707 MoM), trisomy 18 (0.483 MoM), trisomy 13 (0.404 MoM), triploidy (0.531 MoM) and Turner
syndrome (0.534 MoM). Significant contributions in the prediction of trisomy 21 were provided by
maternal age, serum PlGF, PAPP-A and free ß-hCG, and the detection rates of screening with the
combination of these variables were 70% and 80% at respective false-positive rates of 3% and 5%.
CONCLUSIONS: Maternal serum PlGF concentration at 11-13 weeks of gestation is potentially useful
in first-trimester screening for trisomy 21 and other major chromosomal abnormalities. (c) 2009
ISUOG. Published by John Wiley & Sons, Ltd.
Trisomies
53
Circulating angiogenic proteins in trisomy 13.
Bdolah Y, Palomaki GE, Yaron Y, Bdolah-Abram T, Goldman M, Levine RJ, Sachs BP,
Haddow JE, Karumanchi SA.
Am J Obstet Gynecol. 2006 Jan;194(1):239-45.
OBJECTIVE: Women who are carrying a trisomy 13 fetus are more prone to develop preeclampsia.
Excess circulating soluble fms-like tyrosine kinase-1 has been implicated recently in the pathogenesis
of preeclampsia. Since the fms-like tyrosine kinase-1/soluble fms-like tyrosine kinase-1 gene is located
on chromosome 13q12, we hypothesized that the extra copy of this gene in trisomy 13 may lead to
excess circulating soluble fms-like tyrosine kinase-1, reduced free placental growth factor level, and
increased soluble fms-like tyrosine kinase-1/placental growth factor ratio. This may then contribute
to the increased risk of preeclampsia that has been observed in these patients. Our objective was to
characterize the maternal circulating angiogenic proteins in trisomy 13 pregnancies.
STUDY DESIGN: Maternal serum samples of trisomy 13, 18, 21 and normal karyotype pregnancies
were obtained from first and second trimester screening programs. We chose 17 cases of trisomy
13 that were matched for maternal age, freezer storage time, and parity with 85 normal karyotype
control samples. Additionally, 20 cases of trisomy 18 and 17 cases of trisomy 21 were included.
Cases and control samples were assayed for levels of soluble fms-like tyrosine kinase-1 and placental
growth factor by enzyme-linked immunosorbent assay in a blinded fashion. Because of the skewed
distributions of soluble fms-like tyrosine kinase-1 and placental growth factor, nonparametric analytic
techniques were used, and the results are reported as median and ranges.
RESULTS: In early pregnancy trisomy 13 cases and control samples, the median circulating soluble
fms-like tyrosine kinase-1/placental growth factor ratios were 17.0 (range, 1.2-61.3) and 6.7 (range,
0.8-62.9), respectively (P = .003). The median soluble fms-like tyrosine kinase-1/placental growth
factor ratios in trisomy 18 and 21 were 4.8 (range, 0.9-53.9) and 5.1 (range, 1.0-18.1), which were
not significantly different than the control samples. Furthermore, the differences between trisomy 13
and control samples were more pronounced in the second trimester specimens than in the specimens
from the first trimester.
CONCLUSION: These data suggest that alterations in circulating angiogenic factors may be involved
intimately in the pathogenesis of preeclampsia in trisomy 13. A larger clinical study that measures
these factors longitudinally and correlates them with pregnancy outcomes is needed to further
establish the link between trisomy 13, altered angiogenic factors, and preeclampsia.
Trisomies
54
First trimester maternal serum placenta growth factor (PIGF)concentrations in pregnancies with fetal trisomy 21 or trisomy 18. Spencer K, Liao AW, Ong CY, Geerts L, Nicolaides KH.
Prenat Diagn. 2001 Sep;21(9):718-22.
OBJECTIVE: Placenta growth factor (PIGF), an angiogenic factor belonging to the vascular
endothelial growth factor family, pregnancy-associated plasma protein A (PAPP-A) and free beta-
human chorionic gonadotrophin (ß-hCG) were measured in maternal serum from 45 pregnancies with
trisomy 21, 45 with trisomy 18 and 493 normal controls at 10-13 completed weeks of gestation.
METHODS: In the normal pregnancies maternal serum PIGF levels increased exponentially with
gestation.
RESULTS: The median multiple of the median (MoM) PIGF concentration in the trisomy 21 group
(1.26 MoM) was significantly higher (p<0.0001) than in the control group (1.00 MoM). In the
trisomy 18 group the median PIGF was lower (0.889 MoM) but this did not quite reach significance
(p=0.064). The corresponding median MoM values for PAPP-A were 1.00 MoM for the controls, 0.49
MoM for trisomy 21 and 0.16 MoM for trisomy 18. The median MoM values for free ß-hCG were
1.00 MoM for the controls, 2.05 MoM for trisomy 21 and 0.38 MoM for trisomy 18. In the control
group there was a small but significant correlation of PIGF with free ß-hCG (r=+0.1024) and PAPP-A
(r=+0.2288). In the trisomy 18 group there was a significant association between PIGF and free
ß-hCG (r=+0.2629) but not with PAPP-A (r=+0.0038). In the trisomy 21 group there was a small but
significant association with PAPP-A (r=+0.1028) but not with free ß-hCG (r=+0.0339).
CONCLUSION: The separation of affected and unaffected pregnancies in maternal serum PIGF
is small, and therefore it is unlikely that measurement of PIGF would improve screening for these
abnormalities provided by the combination of fetal nuchal translucency and maternal serum PAPP-A
and free ß-hCG.
Trisomies
55
Fetal Death
An imbalance between angiogenic and anti-angiogenic factors precedes fetal death in a subset of patients: results of a longitudinal study.
Romero R, Chaiworapongsa T, Erez O, Tarca AL, Gervasi MT, Kusanovic JP, Mittal P, Ogge G,
Vaisbuch E, Mazaki-Tovi S, Dong Z, Kim SK, Yeo L, Hassan SS.
J Matern Fetal Neonatal Med. 2010 May 12. [Epub ahead of print]
OBJECTIVE: Women with a fetal death at the time of diagnosis have higher maternal plasma
concentrations of the anti-angiogenic factor, soluble vascular endothelial growth factor receptor
(sVEGFR)-1, than women with a normal pregnancy. An important question is whether these
changes are the cause or consequence of fetal death. To address this issue, we conducted a
longitudinal study and measured the maternal plasma concentrations of selective angiogenic and
anti-angiogenic factors before the diagnosis of a fetal death. The anti-angiogenic factors studied
were sVEGFR-1 and soluble endoglin (sEng), and the angiogenic factor, placental growth factor
(PlGF).
METHODS: This retrospective longitudinal nested case-control study included 143 singleton
pregnancies in the following groups: (1) patients with uncomplicated pregnancies who delivered
a term infant with an appropriate weight for gestational age (n = 124); and (2) patients who had
a fetal death (n = 19). Blood samples were collected at each prenatal visit, scheduled at 4-week
intervals from the first trimester until delivery. Plasma concentrations of sVEGFR-1, sEng, and
PlGF were determined by specific and sensitive ELISA. A linear mixed-effects model was used for
analysis.
56
RESULTS: (1) The average profiles of analyte concentrations as a function of gestational age for
sVEGFR-1, sEng and PlGF were different between women destined to have a fetal death and those
with a normal pregnancy after adjusting for covariates (p < 0.05); (2) Plasma sVEGFR-1 concentrations
in patients destined to have a fetal death were significantly lower between 7 and 11 weeks of
gestation and became significantly higher than those of women with a normal pregnancy between
20 and 37 weeks of gestation (p < 0.05); (3) Similarly, plasma sEng concentrations of women destined
to have a fetal death were lower at 7 weeks of gestation (p = 0.04) and became higher than those of
controls between 20 and 40 weeks of gestation (p < 0.05); (4) In contrast, plasma PlGF concentrations
were higher among patients destined to develop a fetal death between 7 and 14 weeks of gestation
and became significantly lower than those in the control group between 22 and 39 weeks of
gestation (p < 0.05); (5) The ratio of PlGF/(sVEGFR-1 x sEng) was significantly higher in women
destined to have a fetal death between 7 and 13 weeks of gestation (94-781%) and significantly
lower (44-75%) than those in normal pregnant women between 20 and 40 weeks of gestation (p
< 0.05); (6) Similar results were obtained when patients with a fetal death were stratified into those
who were diagnosed before or after 37 weeks of gestation.
CONCLUSIONS: Fetal death is characterised by higher maternal plasma concentrations of PlGF during
the first trimester compared to normal pregnancy. This profile changes into an anti-angiogenic one
during the second and third trimesters
Fetal Death
57
Macrosomia
Prediction of macrosomia at birth in type-1 and 2 diabetic pregnancies with biomarkers of early placentation
S Kuc, EJ Wortelboer, MPH Koster, HW de Valk, PCJI Schielen, GHA Visserb
BJOG An International Journal of Obstetrics and Gynaecology,
DOI: 10.1111/j.1471-0528.2011.02904.x
OBJECTIVE: To evaluate the value of first trimester placental biomarkers (fb-hCG, PAPP-A,
ADAM12, PP13 and PlGF) and fetal nuchal translucency (NT) in the prediction of macrosomia at
birth in pregestational type-1 and type-2 diabetes (PGDM). Design Nested case–control study.
Setting Routine first-trimester combined test. Population A total of 178 PGDM and 186 control
pregnancies.
METHODS: ADAM12, PP13 and PlGF concentrations were measured in stored first-trimester
serum, previously tested for fb-hCG and PAPP-A. All concentrations were expressed as multiples of
the median (MoM). Where applicable, the median MoMs of PGDM and control pregnancies were
compared in relation to birthweight centiles (£90th centile, non-macrosomic, versus >90th centile,
macrosomic). Model- redicted detection rates for fixed false positive rates were obtained for
statistically significant markers, separately and in combination. Main outcome measures Prediction
of macrosomia in diabetic pregnancies.
RESULTS: In the PGDM group, median ADAM12 MoM (0.88; P = 0.007) was lower than in the
controls. Subgroup analyses showed that median MoMs of PAPP-A (0.65), ADAM12 (0.85), PP13
(0.81) and PlGF (0.91) were only reduced in the PGDM non-macrosomic birthweight subgroup (n =
93) compared with other weight subgroups. In the PGDM macrosomic birthweight subgroup (n =
69), MoMs of all markers were comparable with the control birthweight subgroups. The screening
performance for macrosomia at birth in the PGDM group provided a detection rate of 30% for a
5% false-positive rate (FPR) and 43% for a 10% FPR. Conclusions Macrosomia at birth in PGDM
pregnancies may be predicted by normal levels of PAPP-A, ADAM12, PP13 and PlGF already
in the first trimester of pregnancy. Fetal birthweight in PGDM offspring is partially determined
by placental development during the first trimester of pregnancy. The present increase in fetal
macrosomia may be related to better early glycemic control and placentation.
DELFIA Chemistry used in PlGF assay
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