Edition: April 2011

Bibliography

Placental Growth Factor (PlGF) in first trimester of pregnancy

2

Pre-eclampsia and SGA Screening for pre-eclampsia–lessons from aneuploidy screening ..............................................6Cuckle 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. ................................................................7Akolekar 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* ............................................................................8Audibert 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* ...............................9Wortelboer 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* ...10Cowans 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. ..........................................................................................11Poon 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 .....................................................................................................12Kasdaglis 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.

First-trimester prediction of hypertensive disorders in pregnancy ...........................................13Poon 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. .............14Savvidou 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. ......................................................................................15Poon LC, Zaragoza E, Akolekar R, Anagnostopoulos E, Nicolaides KH.Prenat Diagn. 2008 Dec;28(12):1110-5.

Index

*DELFIA Chemistry used in PlGF assay

3

Maternal serum placental growth factor at 11 + 0 to 13 + 6 weeks of gestation in the prediction of pre-eclampsia. ........................................................................16Akolekar 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? ................................................................................................................................17Sibai 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. ..................................................18Erez 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. .............................................................................................................20Romero 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. ............................22Smith 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. ..........................................................................................................23Vatten LJ, Eskild A, Nilsen TI, Jeansson S, Jenum PA, Staff AC.Am J Obstet Gynecol. 2007 Mar;196(3):239.e1-6.

Circulating angiogenic factors and the risk of preeclampsia.....................................................24Levine 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

Correlations of placental perfusion and PlGF protein expression in early human pregnancy. ...........................................................................................................25Welch 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.

4

Insulin resistance and alterations in angiogenesis: additive insults that may lead to preeclampsia. ................................................................................................................................26Thadhani 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.

First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia. ............................................................................................................27Thadhani 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. ............................................................................28Ong 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. ...............................................................................................................29Tidwell SC, Ho HN, Chiu WH, Torry RJ, Torry DS.Am J Obstet Gynecol. 2001 May;184(6):1267-72.

TrisomiesFirst trimester maternal serum placental growth factor in trisomy 21 pregnancies* .............30Cowans 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. ......................................................................................31Zaragoza E, Akolekar R, Poon LC, Pepes S, Nicolaides KH.Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital, London, UK.Ultrasound Obstet Gynecol. 2009 Apr;33(4):382-6.

Circulating angiogenic proteins in trisomy 13. ...........................................................................32Bdolah 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. ..................................................................33Spencer K, Liao AW, Ong CY, Geerts L, Nicolaides KH.Prenat Diagn. 2001 Sep;21(9):718-22.

*DELFIA Chemistry used in PlGF assay

5

Fetal DeathAn imbalance between angiogenic and anti-angiogenic factors precedes fetal death in a subset of patients: results of a longitudinal study. .............................................................34Romero 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.

6

Pre-eclampsia and SGA

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.

7

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.

8

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 β-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.

Pre-eclampsia and SGA

DELFIA Chemistry used in PlGF assay

9

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 β subunit of human chorionic gonadotrophin (fβ-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 fβ-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 fβ-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 fβ-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

10

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. The

AutoDELFIA IVD kit will be available during 2011.

Pre-eclampsia and SGA

DELFIA Chemistry used in PlGF assay

11

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.

12

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

13

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.

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. 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. This method of screening is far superior to the

traditional approach, which relies entirely on maternal history.

Index

14

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

15

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.

16

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

17

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.

18

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.

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

Pre-eclampsia and SGA

19

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.

20

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.

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).

Pre-eclampsia and SGA

21

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.

22

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

23

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.

24

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

25

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.

26

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

27

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.

28

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

29

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.

30

Trisomies

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

31

Maternal serum placental growth factor at 11-13 weeks in chromosomally abnormal pregnancies.

Zaragoza E, Akolekar R, Poon LC, Pepes S, Nicolaides KH.

Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital, London, UK.

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 (beta-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 beta-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.

32

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

33

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.

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 (beta-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. In the normal

pregnancies maternal serum PIGF levels increased exponentially with gestation. 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 beta-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 beta-hCG (r=+0.1024) and PAPP-A (r=+0.2288). In the trisomy

18 group there was a significant association between PIGF and free beta-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 beta-hCG (r=+0.0339). 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 beta-hCG. Copyright 2001 John Wiley & Sons, Ltd.

34

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.

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.

35

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

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