accuracy of circulating placental growth factor, vascular endothelial growth factor, a systematic...

8/10/2019 Accuracy of Circulating Placental Growth Factor, Vascular Endothelial Growth Factor, A Systematic Review and Meta-Analysis

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Accuracy of circulating placental growth factor,vascular endothelial growth factor, soluble

fms-like tyrosine kinase 1 and soluble endoglinin the prediction of pre-eclampsia: a systematicreview and meta-analysisCE Kleinrouweler,a MMJ Wiegerinck,a C Ris-Stalpers,a,b PMM Bossuyt,c JAM van der Post,a

P von Dadelszen,d BWJ Mol,a E Pajkrta for the EBM CONNECT Collaborationa Department of Obstetrics and Gynaecology b Reproductive Biology Laboratory c Department of Clinical Epidemiology, Biostatistics and

Bioinformatics, Academic Medical Center, Amsterdam, the Netherlands d Department of Obstetrics and Gynaecology, University of British

Columbia, Vancouver, BC, Canada

Correspondence:Ms CE Kleinrouweler, Department of Obstetrics and Gynaecology, Academic Medical Center, Room H4-232, Meibergdreef 9,

1105 AZ Amsterdam, the Netherlands. Email [email protected]

Accepted 8 February 2012. Published Online 20 March 2012.

Background Biomarkers have been proposed for identification of

women at increased risk of developing pre-eclampsia.

ObjectivesTo investigate the capacity of circulating placental

growth factor (PlGF), vascular endothelial growth factor (VEGF),

soluble fms-like tyrosine kinase-1 (sFLT1) and soluble endoglin

(sENG) to predict pre-eclampsia.

Search strategyMedline and Embase through October 2010 and

reference lists of reviews, without constraints.

Selection criteria We included original publications on testing of

PlGF, VEGF, sFLT1 and sENG in serum or plasma of pregnant

women at


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preterm. Expectant management of preterm pre-eclampsia

focuses on safely prolonging pregnancy through intensive

monitoring to prevent maternal and fetal complications.1

Screening for pregnant women to identify those at risk

of developing pre-eclampsia should substantially improve

the quality, focus, resource use and efficacy of antenatal

care, with the prospect of improving maternal and perina-

tal outcomes.2,3 Moreover, preventive treatment such as

aspirin would probably be more beneficial when started in

early pregnancy.4

The pathogenesis of pre-eclampsia, especially that of

early onset, begins at the time of trophoblast invasion and

remodelling of the spiral arteries during the first 12 weeks

of pregnancy.1 Inadequate placentation and subsequent

hypoxia are thought to be followed by an increased release

of the placenta-produced anti-angiogenic factor soluble

fms-like tyrosine kinase-1 (sFLT1) into the maternal circu-

lation.5 The sFLT1 binds to the angiogenic proteins placen-

tal growth factor (PlGF) and vascular endothelial growth

factor (VEGF), thereby blocking their actions through theplasma-membrane-bound form of the receptor, that con-

tains the tyrosine kinase domain essential to its biological

activity.69 Soluble endoglin (sENG), the extracellular

domain of the co-receptor endoglin, impairs binding of

transforming growth factor-b1 to cell surface receptors and

decreases endothelial nitric oxide signalling, hence inhibit-

ing angiogenesis and promoting vascular dysfunction.5

Dysfunction of the maternal endothelium ultimately results

in the clinical syndrome of pre-eclampsia.10,11

A number of studies have been performed to investigate

circulating levels of these factors in pre-eclamptic pregnan-

cies and to compare them with uncomplicated pregnancies.

A recent Health Technology Assessment report that investi-

gated the accuracy of predictive tests for pre-eclampsia and

their possible cost-effectiveness expressed the need for sys-

tematic reviews on new tests not considered in the report,

including biomarkers.12 In a systematic review from 2007,

sFLT1 levels were found to be elevated and PlGF levels to

be reduced in pre-eclamptic pregnancies, but absolute levels

varied markedly between studies.13 Because the number of

studies on sFLT1 and PlGF has increased substantially since

that review and the evidence on VEGF and sENG has not

been summarised previously, we undertook a systematic

review of the literature on the accuracy of the biomarkers

PlGF, VEGF, sFLT1 and sENG in the prediction of pre-eclampsia.

Methods

Data sourcesWe performed an electronic search on 26 October 2010 in

Medline (from 1948) and Embase (from 1980) without lan-

guage or publication date restrictions to identify all articles

reporting on the prediction of pre-eclampsia using one or

more of the markers PlGF, VEGF, sFLT1 and sENG. The

electronic search strategy was based on MeSH terms and

keywords related to pre-eclampsia and to each of the four

markers, combined with methodological filters, allowing

efficient identification of studies on diagnostic and prog-

nostic tests (see Appendix S1). Reference lists of review

articles13 and eligible primary studies were checked to iden-

tify cited articles not captured by the electronic search.

This systematic review and meta-analysis was conducted

according to the Meta-analysis Of Observational Studies in

Epidemiology (MOOSE) guidelines.14

Eligibility criteriaEligible studies were those that reported on testing of PlGF,

VEGF, sFLT1 or sENG in serum or plasma of pregnant

women with blood sampling before clinical onset of pre-

eclampsia and before 30 weeks of gestation. To be

included, studies should describe the occurrence of pre-

eclampsia conditional on the test result in such a way that2 2 classification tables could be (re-)constructed, or

should describe the test results conditional on the occur-

rence of pre-eclampsia as means and standard deviations in

pregnancies before pre-eclampsia and uncomplicated preg-

nancies.

Study selectionStudies were selected in a staged process. First, two reviewers

(EK and MW) independently scrutinised titles and abstracts

of all retrieved references to select potentially eligible arti-

cles. Full text papers of references selected by at least one

reviewer were obtained. Second, both reviewers indepen-

dently examined these full text papers to see whether they

met the inclusion and exclusion criteria. In case of multiple

publications of one dataset we included only the most

recent or most complete paper. Disagreements about inclu-

sion were resolved by consensus or by consulting a third

reviewer (BM). We did not contact authors for further

information.

Data extractionFor each included study, data on clinical characteristics of

the women (age, obstetric history), characteristics of the

index test (marker, medium, test kit and manufacturer),

reference standard and test accuracy were extracted inde-pendently by two experienced reviewers (EK and MW)

using standardised data extraction forms.

Quality assessmentBoth reviewers assessed the methodological quality of the

included studies using the quality assessment of diagnostic

accuracy studies (QUADAS) criteria.15 In addition, we

assessed whether the study participants had received

Biomarkers for prediction of pre-eclampsia

2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG

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preventive treatment. Acceptable reference standards for

pre-eclampsia were persistent high systolic (140 mmHg)

or diastolic (90 mmHg) blood pressure and proteinuria

(0.3 g/24 hours or a dipstick result of 1+, equivalent to

30 mg/dl in a single urine sample or spot urine protein/

creatinine ratio 30 mg protein/mmol creatinine) of new

onset after 20 weeks of gestation, according to the Interna-

tional Society for the Study of Hypertension in Pregnancy

criteria.16

Data synthesisFor the studies with marker concentration reported as a

continuous variable, we assessed the differences in marker

concentration between women who did and did not

develop pre-eclampsia and expressed the results in standar-

dised mean differences. For uniform presentation in the

tables, all reported marker concentrations were converted

into pg/ml, as this is the most frequently reported unit. For

pooling of the results, we used an inverse-variance

weighted random effect approach in Review Manager5.0.17

Results of studies reporting sensitivities and specificities

were plotted in receiver operating characteristics spaces

with summary receiver operating characteristics curves that

correspond to summary diagnostic odds ratios. Analogous

to the odds ratio for expressing the strength of association

between exposure and disease, the diagnostic odds ratio

can be applied to express the strength of the association

between test result and disease. The diagnostic odds ratio

describes the odds of positive test results in patients with

disease compared with the odds of positive test results in

those without disease. Higher diagnostic odds ratios repre-

sent higher test accuracies: a test with a sensitivity and

specificity of 90% has a diagnostic odds ratio of 81. A diag-

nostic odds ratio value of 1 indicates that a test does not

discriminate between women with the disease and those

without the disease. Values


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(95% CI 3.113.7). This corresponds to a 0.72 sensitivity

and specificity, or a sensitivity of 0.26 for a 5% false-posi-

tive rate.

sENGIn the ten studies that reported concentrations of sENG,

higher concentrations were found in pregnancies before

pre-eclampsia: SMD 0.54 (95% CI 0.240.84). In studies

testing before 16 weeks of gestation, these differences were

smaller (SMD 0.18, 95% CI )0.02 to 0.38) compared with

studies testing between 7 and 26 weeks of gestation (SMD

0.70, 95% CI 0.301.10) (see Appendix S3D).

We identified four studies that reported sensitivity and

specificity of sENG testing (see Appendix S4C). The sum-

mary diagnostic odds ratio was 4.2 (95% CI 2.47.2). This

corresponds to a sensitivity and specificity of 0.67, or a

sensitivity of 0.18 for a 5% false-positive rate.

Highly significant between-study heterogeneity was

recorded for all markers, with I2 statistics of 84% (PlGF),

96% (VEGF), 93% (sFLT1) and 91% (sENG). Sensitivity

analyses taking into account differences in gestational ageat testing (see Appendix S3), study design and selection of

study population, and selection of eligible controls in case

control studies (see Appendix S5) did not explain this

heterogeneity. In a sensitivity analysis with only studies that

used the most frequently used ELISA kits from R&D Sys-

tems (Abingdon, UK), I2 statistics decreased to 80% for

PlGF (15/18 studies, SMD )0.60, 95% CI )0.84 to )0.30)

and 70% for sFLT1 (14/17 studies, SMD 0.33, 95% CI

0.160.49) but remained 91% for sENG (eight of nine

studies, SMD 0.42, 95% CI 0.080.76). All studies on VEGF

used R&D Systems assays. We could not find any evidence

that commercial participation in a study influenced the

predictive ability of the markers.

Discussion

This systematic review provides an overview of the discrim-

inatory performance and predictive capacity of the pro-

angiogenic and anti-angiogenic biomarkers PlGF, VEGF,

sFLT1 and sENG for pre-eclampsia before 30 weeks of ges-

tation. We included studies that investigated differences in

marker concentration between women who developed pre-

eclampsia and those who remained healthy throughout

pregnancy and studies that provided details on the accuracy

of such tests. In 34 such studies with overall good quality,

we found that mean concentrations of PlGF were modestly

but significantly lower before pre-eclampsia and concentra-

tions of sFLT1 and sENG were higher. In studies that com-

pared the timing of testing (16 weeks, 19 weeks orboth), differences between the groups were largest from

19 weeks of gestation onwards and significant for all three

markers, whereas for sFLT1 and sENG, the differences in

marker concentration were not significantly different

16 weeks of gestation. However, the test accuracy of the

markers PlGF, sFLT1 and sENG in terms of sensitivity and

specificity was too poor for accurate identification of pre-

eclampsia cases in clinical practice, and we recommend that

Yes or not applicable No Unclear

Figure 2. Summary of quality assessment.

Kleinrouweleret al.

782 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG


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these markers should not be used alone for the prediction

of pre-eclampsia.

Some methodological aspects of this study require com-

ment. This systematic review revealed a considerable

amount of heterogeneity between studies, which is reflected

in the high values of I2 in the meta-analyses. We propose

several mechanisms through which this might have

occurred. First, eligible studies reported on testing in dis-

similar and overlapping periods of gestational age, which

hampered the distinction between first-trimester and sec-

ond-trimester assessments, and concentrations of the mark-

ers are known to change with gestational age as the result

of biological variability.55,56 In addition, the majority of

studies24 of 27 for PlGF and two out of three for

VEGFdid not report exactly what was measured by the

test kit, i.e. whether it concerned the total circulating level

of the marker, the free fraction or a subset of either one of

these. Also, different ELISA test kits were used. A combina-

tion of these factors may have resulted in varying levels of

the same circulating factor, even in similar populations andat similar gestational ages, which makes it possible to

express the results only as SMD.

Although we maintained high quality standards for the

conduct of this systematic review and meta-analysis, we

realise that the results and their implications are only as

good as the source of the data. In the absence of a suffi-

cient number of well-designed marker evaluation studies,

we had to include studies that differed in design: nested or

matched casecontrol studies as well as cohort studies, with

widely ranging sample sizes. Furthermore, selection of the

study population (at lower or higher risk) in cohort studies

and selection of eligible controls (completely healthy or

without pre-eclampsia) in casecontrol studies differed

between studies. Despite these likely sources of heterogene-

ity, sensitivity analyses did not point to a single most

important factor. Other factors that may partly explain the

heterogeneity are the endpoint of disease and the definition

of pre-eclampsia used in the original studies, although we

minimised this by only including studies that defined pre-

eclampsia according to the International Society for the

Study of Hypertension in Pregnancy criteria,16 and we

found that almost all studies used all pre-eclampsia as the

endpoint of disease. Because only a few studies have pro-

vided results for subgroups with onset of disease before or

after a certain (varying) gestational age, we did not performsensitivity analyses taking this factor into account. The end-

point of disease and selection criteria used in the original

studies can be found in Tables S1S7.

We identified several studies that reported the results in

medians and ranges or multiples of the medians, which

cannot be compared directly with the included studies, so

we were not able to include all existing evidence in this

paper.

We also investigated the test accuracy of the markers

PlGF, sFLT1 and sENG in terms of their sensitivity and

specificity. Because of different or unreported positivity

thresholds, a meta-analysis of sensitivities and specificities

was inappropriate because this would ignore threshold dif-

ferences and underestimate diagnostic performance. Instead

we used the diagnostic odds ratio as a single measure of

test performance. A disadvantage of this method is that it

does not result in unique summary estimates of sensitivity

and specificity: summary estimates of one value can only

be obtained by specifying the value of the other.18,19 Hence,

for each of the biomarkers, we reported two possible esti-

mates of sensitivity and specificity that corresponded to the

pooled diagnostic odds ratios: one in which sensitivity and

specificity were equal, and the other in which there was a

false-positive rate of 5% (or a specificity of 95%), which is

common in screening studies.

Identifying women at risk for pre-eclampsia remains an

important aspect of antenatal care57 because it can not only

contribute to the development and evaluation of preventivetreatments, but can also guide the structure of antenatal

care. A recent meta-analysis showed that aspirin started

at 16 weeks or earlier in pregnancy was associated with a

significant and greater reduction in pre-eclampsia in women

at moderate or high risk than aspirin started after 16 weeks

of gestation.4 In addition, early estimation of patient-spe-

cific risks for pregnancy complications could shift antenatal

care from a series of routine visits for everyone to an

approach in which care, in terms of schedule and content,

is given to those who need it and others are reassured at an

early stage. Women identified as being at high risk can have

close surveillance, but the great majority of women are safe

with a substantially reduced number of visits.58

Our findings that concentrations of PlGF, sFLT1 and

sENG are significantly different before the onset of pre-

eclampsia and that these differences are greatest from

19 weeks of gestation onwards would be unfavourable in

the clinical situation because it would not allow for early

intervention. Moreover, using these markers as a discrimi-

native test proved to be more difficult and had only limited

accuracy.

In addition, all pre-eclampsia cases do not appear to

have the same origin.1 While early-onset pre-eclampsia is

most closely associated with inadequate placentation and

may well be associated with alterations in angiogenic bal-ance, as suggested by this review, term pre-eclampsia is

most commonly associated with normal placental develop-

ment and likely to be predicted by factors associated with

long-term cardiovascular risk, such as obesity, diabetes and

chronic hypertension.59 However, most studies included in

this review did not describe subgroups of early-onset and

late-onset pre-eclampsia and we did not make this distinc-

tion in our analyses.



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Ramon y Cajal, Spain; C Fox, J Daniels, University of

Birmingham, UK; and KS Khan, S Thangaratinam, C

Meads, Barts and the London School of Medicine, Queen

Mary University of London, UK. No funders were involved

in the design and conduct of the study; collection, manage-

ment, analysis and interpretation of the data; or in the

preparation, review or approval of the manuscript.

AcknowledgementWe thank Faridi van Etten, clinical librarian, for her help

with the electronic search.

Supporting Information

Additional Supporting Information may be found in the

online version of this article.

Tables S1S7. Study characteristics, characteristics of

women and test results of all 34 included studies, grouped

by biomarker and presentation of results.

Appendix S1. Search strategy for MEDLINE andEMBASE.

Appendix S2. References of studies excluded after

screening of full text, as described in Figure 1.

Appendix S3. Forest plots showing standardised mean

differences in marker concentration between women

who would develop pre-eclampsia and women with

uncomplicated pregnancies in all studies reporting data as

continuous variables. Negative values indicate lower con-

centrations; positive values indicate higher concentrations

before pre-eclampsia. (A) PlGF; (B) VEGF; (C) sFLT1; and

(D) sENG.

Appendix S4. Results of studies on PlGF (A), sFLT1 (B)

and sENG (C) reporting sensitivity and specificity of the

test, plotted in receiver operating characteristics (ROC)

spaces with summary ROC curves. Area of circles is pro-

portional to study sample size.

Appendix S5. Sensitivity analyses that are not reported

in the paper.

Please note: Wiley-Blackwell are not responsible for the

content or functionality of any supporting information

supplied by the authors. Any queries (other than missing

material) should be directed to the corresponding

author.j

References

1 Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclamp-

sia. Lancet 2010;376:63144.

2 Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents

for preventing pre-eclampsia and its complications. Cochrane Data-

base Syst Rev 2007;:CD004659.

3 Askie LM, Duley L, Henderson-Smart DJ, Stewart LA. Antiplatelet

agents for prevention of pre-eclampsia: a meta-analysis of individual

patient data. Lancet 2007;369:17918.

4 Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S,

et al. Prevention of preeclampsia and intrauterine growth restriction

with aspirin started in early pregnancy: a meta-analysis. Obstet

Gynecol 2010;116:40214.

5 James JL, Whitley GS, Cartwright JE. Pre-eclampsia: fitting together

the placental, immune and cardiovascular pieces. J Pathol

2010;221:36378.

6 Gu Y, Lewis DF, Wang Y. Placental productions and expressions of

soluble endoglin, soluble fms-like tyrosine kinase receptor-1, andplacental growth factor in normal and preeclamptic pregnancies.

J Clin Endocrinol Metab 2008;93:2606.

7 Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, et al.

Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may con-

tribute to endothelial dysfunction, hypertension, and proteinuria in

preeclampsia.J Clin Invest 2003;111:64958.

8 Tsatsaris V, Goffin F, Munaut C, Brichant JF, Pignon MR, Noel A,

et al. Overexpression of the soluble vascular endothelial growth fac-

tor receptor in preeclamptic patients: pathophysiological conse-

quences. J Clin Endocrinol Metab 2003;88:555563.

9 Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hyper-

tension with bevacizumab, an antibody against vascular endothelial

growth factor: systematic review and meta-analysis. Am J Kidney Dis

2007;49:18693.

10 Roberts JM, Hubel CA. The two stage model of preeclampsia: varia-tions on the theme. Placenta 2009;30(Suppl.):327.

11 Huppertz B. Placental origins of preeclampsia: challenging the cur-

rent hypothesis. Hypertension 2008;51:9705.

12 Meads CA, Cnossen JS, Meher S, Juarez-Garcia A, ter Riet G, Duley

L, et al. Methods of prediction and prevention of pre-eclampsia:

systematic reviews of accuracy and effectiveness literature with

economic modelling. Health Technol Assess 2008;12:iiiiv, 1270.

13 Widmer M, Villar J, Benigni A, Conde-Agudelo A, Karumanchi SA,

Lindheimer M. Mapping the theories of preeclampsia and the role

of angiogenic factors: a systematic review. Obstet Gynecol

2007;109:16880.

14 Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D,

et al. Meta-analysis of observational studies in epidemiology: a pro-

posal for reporting. Meta-analysis Of Observational Studies in Epide-

miology (MOOSE) group. JAMA 2000;283:200812.15 Whiting PF, Weswood ME, Rutjes AW, Reitsma JB, Bossuyt PN, Kleij-

nen J. Evaluation of QUADAS, a tool for the quality assessment of

diagnostic accuracy studies. BMC Med Res Methodol 2006;6:9.

16 Brown MA, Lindheimer MD, de SM, Van AA, Moutquin JM. The

classification and diagnosis of the hypertensive disorders of preg-

nancy: statement from the International Society for the Study of

Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy 2001;20:

IXXIV.

17 Review Manager (RevMan) [Computer program]Version 5.0. Copen-

hagen: The Nordic Cochrane Centre, The Cochrane Collaboration,

2008.

18 Deeks JJ. Systematic reviews in health care: systematic reviews

of evaluations of diagnostic and screening tests. BMJ 2001;323:

15762.

19 Glas AS, Lijmer JG, Prins MH, Bonsel GJ, Bossuyt PM. The diagnosticodds ratio: a single indicator of test performance. J Clin Epidemiol

2003;56:112935.

20 Zamora J, Abraira V, Muriel A, Khan K, Coomarasamy A. Meta-

DiSc: a software for meta-analysis of test accuracy data. BMC Med

Res Methodol 2006;6:31.

21 Akolekar R, Zaragoza E, Poon LCY, Pepes S, Nicolaides KH. Maternal

serum placental growth factor at 11 + 0 to 13 + 6 weeks of gesta-

tion in the prediction of pre-eclampsia. Ultrasound Obstet Gynecol

2008;32:7329.



785


9/10

22 Audibert F, Boucoiran I, An N, Aleksandrov N, Delvin E, Bujold E,

et al. Screening for preeclampsia using first-trimester serum markers

and uterine artery Doppler in nulliparous women. Am J Obstet

Gynecol 2010;203:3838.

23 Baumann MU, Bersinger NA, Mohaupt MG, Raio L, Gerber S, Surbek

DV. First-trimester serum levels of soluble endoglin and soluble fms-

like tyrosine kinase-1 as first-trimester markers for late-onset pre-

eclampsia.Am J Obstet Gynecol 2008;199:266.

24 Bersinger NA, Odegard RA. Serum levels of macrophage colonystimulating, vascular endothelial, and placenta growth factor in rela-

tion to later clinical onset of pre-eclampsia and a small-for-gesta-

tional age birth. Am J Reprod Immunol 2005;54:7783.

25 Bills VL, Varet J, Millar A, Harper SJ, Soothill PW, Bates DO. Failure

to up-regulate VEGF165b in maternal plasma is a first trimester pre-

dictive marker for pre-eclampsia. Clin Sci (Lond) 2009;116:26572.

26 Bosio PM, Wheeler T, Anthony F, Conroy R, OHerlihy C, McKenna

P. Maternal plasma vascular endothelial growth factor concentra-

tions in normal and hypertensive pregnancies and their relationship

to peripheral vascular resistance. Am J Obstet Gynecol 2001;184:

14652.

27 Chaiworapongsa T, Romero R, Kim YM, Kim GJ, Kim MR, Espinoza

J, et al. Plasma soluble vascular endothelial growth factor receptor-1

concentration is elevated prior to the clinical diagnosis of pre-

eclampsia.J Matern Fetal Neonatal Med 2005;17:318.28 Crispi F, Llurba E, Dominguez C, Martin-Gallan P, Cabero L, Grata-

cos 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;31:3039.

29 Diab AE, El-Behery MM, Ebrahiem MA, Shehata AE. Angiogenic fac-

tors for the prediction of pre-eclampsia in women with abnormal

midtrimester uterine artery Doppler velocimetry. Int J Gynaecol

Obstet 2008;102:14651.

30 Espinoza J, Romero R, Nien JK, Gomez R, Kusanovic JP, Goncalves

LF, et al. Identification of patients at risk for early onset and/or

severe preeclampsia with the use of uterine artery Doppler velocime-

try and placental growth factor. Am J Obstet Gynecol 2007;196:

326.e113.

31 Koga K, Osuga Y, Tajima T, Hirota Y, Igarashi T, Fujii T, et al. Ele-

vated serum soluble fms-like tyrosine kinase 1 (sFlt1) level in womenwith hydatidiform mole. Fertil Steril 2010;94:3058.

32 Kusanovic JP, Romero R, Chaiworapongsa T, Erez O, Mittal P, Vais-

buch E, et al. A prospective cohort study of the value of maternal

plasma concentrations of angiogenic and anti-angiogenic factors in

early pregnancy and midtrimester in the identification of patients

destined to develop preeclampsia. J Matern Fetal Neonatal Med

2009;22:102138.

33 Lim JH, Kim SY, Park SY, Yang JH, Kim MY, Ryu HM. Effective pre-

diction of preeclampsia by a combined ratio of angiogenesis-related

factors. Obstet Gynecol 2008;111:14039.

34 Lynch AM, Murphy JR, Gibbs RS, Levine RJ, Giclas PC, Salmon JE,

et al. The interrelationship of complement-activation fragments and

angiogenesis-related factors in early pregnancy and their association

with pre-eclampsia. BJOG 2010;117:45662.

35 Madazli R, Kuseyrioglu B, Uzun H, Uludag S, Ocak V. Prediction ofpreeclampsia with maternal mid-trimester placental growth factor,

activin A, fibronectin and uterine artery Doppler velocimetry. Int J

Gynaecol Obstet 2005;89:2517.

36 Park CW, Park JS, Shim SS, Jun JK, Yoon BH, Romero R. An elevated

maternal plasma, but not amniotic fluid, soluble fms-like tyrosine

kinase-1 (sFlt-1) at the time of mid-trimester genetic amniocentesis

is a risk factor for preeclampsia. Am J Obstet Gynecol 2005;193:

9849.

37 Parra M, Rodrigo R, Barja P, Bosco C, Fernandez V, Munoz H, et al.

Screening test for preeclampsia through assessment of uteroplacen-

tal blood flow and biochemical markers of oxidative stress and

endothelial dysfunction. Am J Obstet Gynecol 2005;193:148691.

38 Polliotti BM, Fry AG, Saller DN, Mooney RA, Cox C, Miller RK. Sec-

ond-trimester maternal serum placental growth factor and vascular

endothelial growth factor for predicting severe, early-onset pre-

eclampsia. Obstet Gynecol 2003;101:126674.

39 Powers RW, Jeyabalan A, Clifton RG, Van DP, Hauth JC, KlebanoffMA, et al. Soluble fms-Like tyrosine kinase 1 (sFlt1), endoglin and

placental growth factor (PlGF) in preeclampsia among high risk preg-

nancies.PLoS ONE 2010;5:e13263.

40 Rana S, Karumanchi SA, Levine RJ, Venkatesha S, Rauh-Hain JA, Ta-

mez H, et al. Sequential changes in antiangiogenic factors in early

pregnancy and risk of developing preeclampsia. Hypertension 2007;

50:13742.

41 Robinson CJ, Johnson DD. Soluble endoglin as a second-trimester

marker for preeclampsia. Am J Obstet Gynecol 2007;197:1745.

42 Savvidou MD, Noori M, Anderson JM, Hingorani AD, Nicolaides KH.

Maternal endothelial function and serum concentrations of placental

growth factor and soluble endoglin in women with abnormal

placentation. Ultrasound Obstet Gynecol 2008;32:8716.

43 Schmidt M, Dogan C, Birdir C, Kuhn U, Gellhaus A, Kimmig R, et al.

Placental growth factor: a predictive marker for preeclampsia? Gyna-kol Geburtshilfliche Rundsch 2009;49:949.

44 Shokry M, Bedaiwy MA, Fathalla MM, Alsemary A, Elwakil S, Mur-

phy A. Maternal serum placental growth factor and soluble fms-like

tyrosine kinase 1 as early predictors of preeclampsia. Acta Obstet

Gynecol Scand 2010;89:1436.

45 Sibai BM, Koch MA, Freire S, Pinto e Silva JL, Rudge MV, Martins-

Costa S, et al. Serum inhibin A and angiogenic factor levels in preg-

nancies with previous preeclampsia and/or chronic hypertension: are

they useful markers for prediction of subsequent preeclampsia? Am

J Obstet Gynecol 2008;199:2689.

46 Stepan H, Geipel A, Schwarz F, Kramer T, Wessel N, Faber R. Circu-

latory soluble endoglin and its predictive value for preeclampsia in

second-trimester pregnancies with abnormal uterine perfusion. Am J

Obstet Gynecol 2008;198:1756.

47 Stepan H, Unversucht A, Wessel N, Faber R. Predictive value ofmaternal angiogenic factors in second trimester pregnancies with

abnormal uterine perfusion. Hypertension 2007;49:81824.

48 Su YN, Lee CN, Cheng WF, Shau WY, Chow SN, Hsieh FJ.

Decreased maternal serum placenta growth factor in early second

trimester and preeclampsia. Obstet Gynecol 2001;97:898904.

49 Thadhani R, Mutter WP, Wolf M, Levine RJ, Taylor RN, Sukhatme

VP, et al. First trimester placental growth factor and soluble fms-like

tyrosine kinase 1 and risk for preeclampsia. J Clin Endocrinol Metab

2004;89:7705.

50 Thadhani R, Ecker JL, Mutter WP, Wolf M, Smirnakis KV, Sukhatme

VP, et al. Insulin resistance and alterations in angiogenesis: additive

insults that may lead to preeclampsia. Hypertension 2004;43:988

92.

51 Tidwell SC, Ho HN, Chiu WH, Torry RJ, Torry DS. Low maternal

serum levels of placenta growth factor as an antecedent of clinicalpreeclampsia.Am J Obstet Gynecol 2001;184:126772.

52 Tjoa ML, van Vugt JM, Mulders MA, Schutgens RB, Oudejans CB,

van WI. Plasma placenta growth factor levels in midtrimester preg-

nancies. Obstet Gynecol 2001;98:6007.

53 Wortelboer EJ, Koster MP, Cuckle HS, Stoutenbeek PH, Schielen PC,

Visser GH. First-trimester placental protein 13 and placental growth

factor: markers for identification of women destined to develop

early-onset pre-eclampsia. BJOG 2010;117:13849.

Kleinrouweleret al.

786 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG


10/10

54 Yu J, Shixia CZ, Wu Y, Duan T. Inhibin A, activin A, placental growth

factor and uterine artery Doppler pulsatility index in the prediction of

pre-eclampsia.Ultrasound Obstet Gynecol 2011;37:52833.

55 Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, et al.

Circulating angiogenic factors and the risk of preeclampsia. N Engl J

Med 2004;350:67283.

56 Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, et al.

Soluble endoglin and other circulating antiangiogenic factors in pre-

eclampsia.N Engl J Med 2006;355:9921005.57 National Collaborating Centre for Womens and Childrens Health.

Antenatal Care: Routine Care for the Healthy Pregnant Woman

[Clinical guideline]. London: National Institute for Health and Clinical

Excellence, 2008.

58 Nicolaides KH. A model for a new pyramid of prenatal care based

on the 11 to 13 weeks assessment. Prenat Diagn 2011;31:36.

59 Kenny LC, Broadhurst DI, Dunn W, Brown M, North RA, McCowan

L, et al. Robust early pregnancy prediction of later preeclampsia

using metabolomic biomarkers. Hypertension 2010;56:7419.

60 North RA, McCowan LM, Dekker GA, Poston L, Chan EH, Stewart

AW, et al. Clinical risk prediction for pre-eclampsia in nulliparous

women: development of model in international prospective cohort.

BMJ 2011;342:d1875.61 Poon LC, Stratieva V, Piras S, Piri S, Nicolaides KH. Hypertensive dis-

orders in pregnancy: combined screening by uterine artery Doppler,

blood pressure and serum PAPP-A at 1113 weeks. Prenat Diagn

2010;30:21623.



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