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BMC Pregnancy and Childbirth
Published in: BMC Pregnancy and Childbirth 1/2018

Open Access 01-12-2018 | Research article

Assessing the sensitivity of placental growth factor and soluble fms-like tyrosine kinase 1 at 36 weeks’ gestation to predict small-for-gestational-age infants or late-onset preeclampsia: a prospective nested case-control study

Authors: Teresa M. MacDonald, Chuong Tran, Tu’uhevaha J. Kaitu’u-Lino, Shaun P. Brennecke, Richard J. Hiscock, Lisa Hui, Kirsten M. Dane, Anna L. Middleton, Ping Cannon, Susan P. Walker, Stephen Tong

Published in: BMC Pregnancy and Childbirth | Issue 1/2018

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Abstract

Background

Fetal growth restriction is a disorder of placental dysfunction with three to four-fold increased risk of stillbirth. Fetal growth restriction has pathophysiological features in common with preeclampsia. We hypothesised that angiogenesis-related factors in maternal plasma, known to predict preeclampsia, may also detect fetal growth restriction at 36 weeks’ gestation. We therefore set out to determine the diagnostic performance of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and the sFlt-1:PlGF ratio, measured at 36 weeks’ gestation, in identifying women who subsequently give birth to small-for-gestational-age (SGA; birthweight <10th centile) infants. We also aimed to validate the predictive performance of the analytes for late-onset preeclampsia in a large independent, prospective cohort.

Methods

A nested 1:2 case-control study was performed including 102 cases of SGA infants and a matched group of 207 controls; and 39 cases of preeclampsia. We determined the diagnostic performance of each angiogenesis-related factor, and of their ratio, to detect SGA infants or preeclampsia, for a predetermined 10% false positive rate.

Results

Median plasma levels of PlGF at 36 weeks’ gestation were significantly lower in women who subsequently had SGA newborns (178.5 pg/ml) compared to normal birthweight controls (326.7 pg/ml, p < 0.0001). sFlt-1 was also higher among SGA cases, but this was not significant after women with concurrent preeclampsia were excluded. The sensitivity of PlGF to predict SGA infants was 28.8% for a 10% false positive rate. The sFlt-1:PlGF ratio demonstrated better sensitivity for preeclampsia than either analyte alone, detecting 69.2% of cases for a 10% false positive rate.

Conclusions

Plasma PlGF at 36 weeks’ gestation is significantly lower in women who subsequently deliver a SGA infant. While the sensitivity and specificity of PlGF currently limit clinical translation, our findings support a blood-based biomarker approach to detect late-onset fetal growth restriction. Thirty-six week sFlt-1:PlGF ratio predicts 69.2% of preeclampsia cases, and could be a useful screening test to triage antenatal surveillance.
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Literature
1.
Flenady V, Koopmans L, Middleton P, Froen JF, Smith GC, Gibbons K, Coory M, Gordon A, Ellwood D, McIntyre HD, et al. Major risk factors for stillbirth in high-income countries: a systematic review and meta-analysis. Lancet. 2011;377:1331–40.CrossRefPubMed
2.
3.
Vashevnik S, Walker S, Permezel M. Stillbirths and neonatal deaths in appropriate, small and large birthweight for gestational age fetuses. Aust N Z J Obstet Gynaecol. 2007;47:302–6.CrossRefPubMed
4.
Mendez-Figueroa H, Truong VT, Pedroza C, Khan AM, Chauhan SP. Small-for-gestational-age infants among uncomplicated pregnancies at term: a secondary analysis of 9 maternal-fetal medicine units network studies. Am J Obstet Gynecol. 2016;215:628.e621–7.CrossRef
5.
Pattinson R, Kerber K, Buchmann E, Friberg IK, Belizan M, Lansky S, Weissman E, Mathai M, Rudan I, Walker N, Lawn JE. Stillbirths: how can health systems deliver for mothers and babies? Lancet. 2011;377:1610–23.CrossRefPubMed
6.
Sparks TN, Cheng YW, McLaughlin B, Esakoff TF, Caughey AB. Fundal height: a useful screening tool for fetal growth? J Matern Fetal Neonatal Med. 2011;24:708–12.CrossRefPubMed
7.
Hargreaves K, Cameron M, Edwards H, Gray R, Deane K. Is the use of symphysis-fundal height measurement and ultrasound examination effective in detecting small or large fetuses? J Obstet Gynaecol. 2011;31:380–3.CrossRefPubMed
8.
Goto E. Prediction of low birthweight and small for gestational age from symphysis-fundal height mainly in developing countries: a meta-analysis. J Epidemiol Community Health. 2013;67:999–1005.CrossRefPubMed
9.
Sovio U, White IR, Dacey A, Pasupathy D, Smith GC. Screening for fetal growth restriction with universal third trimester ultrasonography in nulliparous women in the pregnancy outcome prediction (POP) study: a prospective cohort study. Lancet. 2015;386:2089–97.CrossRefPubMedPubMedCentral
10.
Kwiatkowski S, Dolegowska B, Kwiatkowska E, Rzepka R, Marczuk N, Loj B, Torbe A. Maternal endothelial damage as a disorder shared by early preeclampsia, late preeclampsia and intrauterine growth restriction. J Perinat Med. 2016;
11.
Crispi F, Dominguez C, Llurba E, Martin-Gallan P, Cabero L, Gratacos E. Placental angiogenic growth factors and uterine artery Doppler findings for characterization of different subsets in preeclampsia and in isolated intrauterine growth restriction. Am J Obstet Gynecol. 2006;195:201–7.CrossRefPubMed
12.
Romero R, Nien JK, Espinoza J, Todem D, Fu W, Chung H, Kusanovic JP, Gotsch F, Erez O, Mazaki-Tovi S, et al. 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. J Matern Fetal Neonatal Med. 2008;21:9–23.CrossRefPubMedPubMedCentral
13.
Villa PM, Hamalainen E, Maki A, Raikkonen K, Pesonen AK, Taipale P, Kajantie E, Laivuori H. Vasoactive agents for the prediction of early- and late-onset preeclampsia in a high-risk cohort. BMC Pregnancy Childbirth. 2013;13:110.CrossRefPubMedPubMedCentral
14.
Verlohren S, Herraiz I, Lapaire O, Schlembach D, Moertl M, Zeisler H, Calda P, Holzgreve W, Galindo A, Engels T, et al. The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients. Am J Obstet Gynecol. 2012;206(58):e51–8.
15.
Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennstrom M, Olovsson M, Brennecke SP, Stepan H, Allegranza D, et al. Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia. N Engl J Med. 2016;374:13–22.CrossRefPubMed
16.
Sovio U, Gaccioli F, Cook E, Hund M, Charnock-Jones DS, Smith GC. Prediction of preeclampsia using the soluble fms-like tyrosine kinase 1 to placental growth factor ratio: a prospective cohort study of unselected nulliparous women. Hypertension. 2017;69:731–8.CrossRefPubMedPubMedCentral
17.
Schoofs K, Grittner U, Engels T, Pape J, Denk B, Henrich W, Verlohren S. The importance of repeated measurements of the sFlt-1/PlGF ratio for the prediction of preeclampsia and intrauterine growth restriction. J Perinat Med. 2014;42:61–8.CrossRefPubMed
18.
Triunfo S, Parra-Saavedra M, Rodriguez-Sureda V, Crovetto F, Dominguez C, Gratacos E, Figueras F. Angiogenic factors and Doppler evaluation in normally growing fetuses at routine third-trimester scan: prediction of subsequent low birth weight. Fetal Diagn Ther. 2016;40:13–20.CrossRefPubMed
19.
20.
The American College of Obstetricians and Gynecaologists. Task force on hypertension in pregnancy. Hypertension in pregnancy. Pp. 100. Acog.Org; 2013. p. 100.
21.
van Zaane B, Vergouwe Y, Donders AR, Moons KG. Comparison of approaches to estimate confidence intervals of post-test probabilities of diagnostic test results in a nested case-control study. BMC Med Res Methodol. 2012;12:166.CrossRefPubMedPubMedCentral
22.
The Royal College of Obstetricians and Gynaecologists. The investigation and management of the small-for-gestational-age fetus. In: RCOG Green-top Guideline No 31, 2nd edition; 2013.
23.
Gordijn SJ, Beune IM, Thilaganathan B, Papageorghiou A, Baschat AA, Baker PN, Silver RM, Wynia K, Ganzevoort W. Consensus definition of fetal growth restriction: a Delphi procedure. Ultrasound Obstet Gynecol. 2016;48:333–9.CrossRefPubMed
24.
Rajakumar A, Jeyabalan A, Markovic N, Ness R, Gilmour C, Conrad KP. Placental HIF-1 alpha, HIF-2 alpha, membrane and soluble VEGF receptor-1 proteins are not increased in normotensive pregnancies complicated by late-onset intrauterine growth restriction. Am J Physiol Regul Integr Comp Physiol. 2007;293:R766–74.CrossRefPubMed
25.
Miranda J, Rodriguez-Lopez M, Triunfo S, Sairanen M, Kouru H, Parra-Saavedra M, Crovetto F, Figueras F, Crispi F, Gratacos E. Prediction of fetal growth restriction using estimated fetal weight versus a combined screening model at 32-36 weeks of gestation. Ultrasound Obstet Gynecol. 2016;
26.
Crovetto F, Triunfo S, Crispi F, Rodriguez-Sureda V, Roma E, Dominguez C, Gratacos E, Figueras F. First-trimester screening with specific algorithms for early- and late-onset fetal growth restriction. Ultrasound Obstet Gynecol. 2016;48:340–8.CrossRefPubMed
27.
Triunfo S, Lobmaier S, Parra-Saavedra M, Crovetto F, Peguero A, Nadal A, Gratacos E, Figueras F. Angiogenic factors at diagnosis of late-onset small-for-gestational age and histological placental underperfusion. Placenta. 2014;35:398–403.CrossRefPubMed
28.
Margossian A, Boisson-Gaudin C, Subtil F, Rudigoz RC, Dubernard G, Allias F, Huissoud C. Intra-uterine growth restriction impact on maternal serum concentration of PlGF (placental growth factor): a case control study. Gynecol Obstet Fertil. 2016;44:23–8.CrossRefPubMed
29.
Herraiz I, Droge LA, Gomez-Montes E, Henrich W, Galindo A, Verlohren S. Characterization of the soluble fms-like tyrosine kinase-1 to placental growth factor ratio in pregnancies complicated by fetal growth restriction. Obstet Gynecol. 2014;124:265–73.CrossRefPubMed
30.
Benton SJ, McCowan LM, Heazell AE, Grynspan D, Hutcheon JA, Senger C, Burke O, Chan Y, Harding JE, Yockell-Lelievre J, et al. Placental growth factor as a marker of fetal growth restriction caused by placental dysfunction. Placenta. 2016;42:1–8.CrossRefPubMed
31.
Wallner W, Sengenberger R, Strick R, Strissel PL, Meurer B, Beckmann MW, Schlembach D. Angiogenic growth factors in maternal and fetal serum in pregnancies complicated by intrauterine growth restriction. Clin Sci (Lond). 2007;112:51–7.CrossRef
32.
Borras D, Perales-Puchalt A, Ruiz Sacedon N, Perales A. Angiogenic growth factors in maternal and fetal serum in pregnancies complicated with intrauterine growth restriction. J Obstet Gynaecol. 2014;34:218–20.CrossRefPubMed
33.
Semczuk-Sikora A, Krzyzanowski A, Stachowicz N, Robak J, Kraczkowski J, Kwiatek M, Semczuk M. Maternal serum concentration of angiogenic factors: PIGF, VEGF and VEGFR-1 and placental volume in pregnancies complicated by intrauterine growth restriction. Ginekol Pol. 2007;78:783–6.PubMed
34.
Kuhnel E, Kleff V, Stojanovska V, Kaiser S, Waldschutz R, Herse F, Plosch T, Winterhager E, Gellhaus A. Placental-specific overexpression of sFlt-1 alters trophoblast differentiation and nutrient transporter expression in an IUGR mouse model. J Cell Biochem. 2016;
35.
Zamarian AC, Araujo Junior E, Daher S, Rolo LC, Moron AF, Nardozza LM. Evaluation of biochemical markers combined with uterine artery Doppler parameters in fetuses with growth restriction: a case-control study. Arch Gynecol Obstet. 2016;294:715–23.CrossRefPubMed
36.
Fadigas C, Peeva G, Mendez O, Poon LC, Nicolaides KH. Prediction of small-for-gestational-age neonates: screening by placental growth factor and soluble fms-like tyrosine kinase-1 at 35-37 weeks. Ultrasound Obstet Gynecol. 2015;46:191–7.CrossRefPubMed
37.
Smith GC, Crossley JA, Aitken DA, Jenkins N, Lyall F, Cameron AD, Connor JM, Dobbie R. Circulating angiogenic factors in early pregnancy and the risk of preeclampsia, intrauterine growth restriction, spontaneous preterm birth, and stillbirth. Obstet Gynecol. 2007;109:1316–24.CrossRefPubMed
38.
Crispi F, Llurba E, Dominguez C, Martin-Gallan P, Cabero L, Gratacos E. Predictive value of angiogenic factors and uterine artery Doppler for early- versus late-onset pre-eclampsia and intrauterine growth restriction. Ultrasound Obstet Gynecol. 2008;31:303–9.CrossRefPubMed
39.
Schlembach D, Wallner W, Sengenberger R, Stiegler E, Mortl M, Beckmann MW, Lang U. Angiogenic growth factor levels in maternal and fetal blood: correlation with Doppler ultrasound parameters in pregnancies complicated by pre-eclampsia and intrauterine growth restriction. Ultrasound Obstet Gynecol. 2007;29:407–13.CrossRefPubMed
40.
Gaccioli F, Sovio U, Cook E, Hund M, Charnock-Jones DS, Smith GCS. Screening for fetal growth restriction using ultrasound and the sFLT1/PlGF ratio in nulliparous women: a prospective cohort study. The Lancet Child & Adolescent Health. 2018;2:569–81.CrossRef
41.
42.
43.
44.
Gardosi J, Francis A. Adverse pregnancy outcome and association with small for gestational age birthweight by customized and population-based percentiles. Am J Obstet Gynecol. 2009;201(28):e21–8.
Metadata
Title
Assessing the sensitivity of placental growth factor and soluble fms-like tyrosine kinase 1 at 36 weeks’ gestation to predict small-for-gestational-age infants or late-onset preeclampsia: a prospective nested case-control study
Authors
Teresa M. MacDonald
Chuong Tran
Tu’uhevaha J. Kaitu’u-Lino
Shaun P. Brennecke
Richard J. Hiscock
Lisa Hui
Kirsten M. Dane
Anna L. Middleton
Ping Cannon
Susan P. Walker
Stephen Tong
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Pregnancy and Childbirth / Issue 1/2018
Electronic ISSN: 1471-2393
DOI
https://doi.org/10.1186/s12884-018-1992-x

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