Health Policy Advisory Committee on

Technology

Technology Brief

Antenatal Placental Growth Factor screening for

pre-eclampsia toxaemia

August 2013

© State of Queensland (Queensland Department of Health) 2013

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This brief was prepared by Hong Ju from HPACT Secretariat.

Antenatal PIGF screening for pre-eclampsia: August 2013 1

Technology, Company and Licensing

Register ID WP168

Technology name Antenatal Placental Growth Factor screening for pre- eclampsia toxaemia

Patient indication First-trimester pregnant women

Description of the technology

Placental growth factor (PlGF) is an angiogenic factor which is mainly expressed in placental

trophoblasts. It has a major role during pregnancy and pathological conditions including

ischemia, wound healing, and tumour progression.1 Research has demonstrated that

circulating angiogenic proteins may have an important biologic role in preeclampsia

toxaemia (PET) as women with low concentrations of PlGF during early gestation have a

much greater risk of early-onset PET.2

The DELFIA® Xpress PlGF kit (PerkinElmer Inc.) is used for the quantitative determination of

PlGF in maternal serum during the first trimester (first three months) of pregnancy, using a

technique called time-resolved fluorescence. The kit is used as an aid in screening pregnant

women for early-onset PET and for screening for risk of Down syndrome. The kit may be

used with either the DELFIA® Xpress random access platform or the AutoDELFIA automatic

immunoassay system. DELFIA Xpress is designed for fast random access sampling, suitable

for smaller clinics or laboratories. The AutoDELFIA is designed for larger batch throughput,

with results produced at a slower

speed. DELFIA Xpress has become

the most preferred platform

worldwide. This solid-phase, two-

site fluoro-immunometric assay is

based on the direct sandwich

technique in which monoclonal

antibodies and polyclonal

antibodies are directed against two

separate antigenic determinants on

the PlGF molecule.1

Figure 1 DELFIA® Xpress (http://www.perkinelmer.com)

The test can be conducted in antenatal clinics or hospital laboratories. Blood samples are

taken between week nine and 13 of pregnancy. Samples can be processed in 30 minutes

and a batch of 40 samples can be processed at a rate of 40 per hour. PerkinElmer provide a

free web-based computer programme package called the Pre-eclampsia Predictor™, which

is used to analyse the results in conjunction with information about the woman’s medical

history, blood pressure, level of another blood biomarker called pregnancy-associated

plasma protein-A (PAPP-A), and ultrasound/ultrasound Doppler results. The program gives

predictions of high or low risk for individual women for both early- and late-onset PET.1

In normal uncomplicated pregnancy free, unbound PlGF levels increase during the first and

second trimester and then decline. In women who later develop PET, however, the level of

PlGF is typically decreased in maternal serum during both the first and the second

trimesters of pregnancy.2 In addition, severe PET cases appear to have lower PlGF levels at

10–13 weeks of gestation than mild cases.3

Currently there are other PET tests which measure the PIGF levels (eg. Alere PlGF test and

the Roche sFlt-1/PlGF ratio tests), which may provide earlier and more accurate diagnosis of

PET in pregnant women who have signs and symptoms of the condition. However they are

not designed for screening purposes to predict the risk of PET before it occurs.4

Company or developer

There are several different technologies used in screening studies for the measurement of

first-trimester PIGF levels in serum. Some of the commonly used ones are

DELFIA®Xpress PlGF kit: PerkinElmer, Inc.

Quantikine® human PIGF immunoassay: R&D Systems

KRYPTOR automated immunofluorescent assays kit: Pantec

Reason for assessment

An accurate test that can identify women at high risk of pre-eclampsia toxaemia may

improve management of this potentially serious condition.

Stage of development in Australia

Yet to emerge Established

Experimental Established but changed indication or modification of technique

Investigational Should be taken out of use

Nearly established

Licensing, reimbursement and other approval

The DELFIA® Xpress PlGF kit is CE marked and is available for screening for Down syndrome

in the first trimester in the European Union and the UK, but is not currently available for use

in the USA and Canada.

Australian Therapeutic Goods Administration approval

Yes ARTG number (s)

No

Not applicable

Technology type Diagnostic

Technology use Diagnostic

Patient Indication and Setting

Disease description and associated mortality and morbidity

Preeclampsia is defined as de novo hypertension (≥140/90 mmHg) developing after 20

weeks of gestation in a woman with previously normal blood pressure and co-existing

significant proteinuria (≥0.3 g in a 24-hour urine specimen).5 It is a multi-system disorder

involving one or more other systems, such as renal, haematological, liver, neurological,

pulmonary and/or placental abruption. Raised blood pressure is often, but not always, the

first manifestation. Proteinuria is the most commonly recognised additional feature after

hypertension.6 As a serious complication of pregnancy, it is a leading cause of maternal and

perinatal morbidity and mortality, particularly when it occurs at a gestational age of less

than 34 weeks.7 Compared to normal pregnancy, women with de novo hypertension in

pregnancy were found at increased risk of a major morbidity or mortality, with studies

reporting from 30 per cent increased risk for women with gestational hypertension to 400

per cent for women with PET. In addition, fetus growth restriction and preterm birth are

often the accompany conditions.8

The aetiology of PET is not clear, although it has been associated with the trophoblastic

invasion by the placenta or significant alterations in the immune system.5 One factor

contributing to the development of PET is endothelial dysfunction caused by imbalance

between angiogenic (e.g.PlGF) and anti-angiogenic factors (e.g. sFlt1) released from the

placenta.6

Preeclampsia is a progressive disorder that will inevitably worsen if pregnancy continues

and delivery is the definitive management.6 Early-onset PET develops relatively early in

pregnancy and necessitates delivery before 34 weeks’ gestation, compared to late-onset

PET which requires delivery at or after 34 weeks of gestation. After delivery, all clinical and

laboratory signs of PET recover, but there is often a delay of several days, and sometimes

longer, in return to normality.7 Anti-hypertensive treatment may be considered when

systolic blood pressure reaches 140-160 mmHg systolic and/or 90-100 mmHg diastolic on

more than one occasion. Prolongation of pregnancy in the presence of PET carries no

benefit for the mother but is desirable at early gestations to improve the fetal prognosis.

Continuation of PET also carries fetal risk and stillbirth may occur despite careful

monitoring.6 If not well controlled, PET can proceed to eclampsia which characterised by

seizure. Not all seizures will have early warning symptoms such as headache, visual

disturbances or epigastric pain.6

All women who develop PET are at increased risk of the disorder in future pregnancies.

Many risk factors for PET have been identified (Table 1) but to date no accurate predictive

tool, using either clinical or laboratory markers, has been developed. In addition, a number

of other factors are also associated with an increased risk of PET including chronic

hypertension, pre-existing renal disease, autoimmune disease, >10 years since previous

pregnancy, short sexual relationship prior to conception, other thrombophilias eg Factor V

Leiden and possibly periodontal disease.6

Table 1 Risk factors associated with preeclampsia 6

In Australia in 2010, hypertension or PET were also responsible for a significant number of

caesarean sections: 469 in Queensland (3.1% of total caesarean sections in the state), 155 in

South Australia (12.8%) and 86 in Tasmania (4.8%).9

Number of patients

The reported incidence of PET varies in the literature however it is approximately within the

range 2-10 per cent of all pregnancies.4, 5 Similarly, there is a large variability in the

estimated rates for PET between jurisdictions in Australia due to the lack of a standardised

definition and non-differentiation of gestational hypertension and PET in some jurisdictions.

An estimated prevalence of 1.5-7.7 per cent was reported in one study.10 Another

population-based study from NSW reported a rate of 4.2 per cent for PET, 0.3 per cent for

chronic hypertension with superimposed PET, and 4.3 per cent for gestational

hypertension.8 Overall, about one in 10 pregnancies in NSW is complicated by hypertension:

about 3-4 per cent have PET, a similar proportion have gestational hypertension and 1-2 per

cent have pre-existing chronic hypertension.9 Eclampsia complicates 1 in 200-300 cases of

preeclampsia in Australia. Currently there are no reliable clinical markers to predict

eclampsia and conversely, the presence of neurological symptoms and/or signs is rarely

associated with seizures.6

Speciality Pregnancy and childbirth

Technology setting General hospital and ambulatory care

Impact

Alternative and/or complementary technology

PIGF is intended to be used as a complementary technology, in addition to clinical

characteristics, Doppler ultrasound and other serum biomarkers, in predicting PET in the

first-trimester.

Current technology

According to the UK National Screening Committee, a nationally managed screening

programme for PET is not recommended currently due to the lack of appropriate predictive

tests or preventive treatments with suitably safe profiles.11

Currently women at risk of developing PET are identified based on clinical characteristics.

Risk factors are recommended to be determined by 10 weeks through history taking, blood

pressure and proteinuria measurements.12 A range of maternal risk factors have been

identified (see Table 1 for details). However screening by maternal characteristics alone will

only identify about 30 per cent of women who will develop PET.13 Blood pressure

measurement and urine tests are done at every antenatal visit to detect any early signs of

PET in the UK, however urine tests are only recommended for women with other risk factors

in Australia.12 Women who are considered to be at increased risk are offered more frequent

antenatal check-ups.12 Doppler velocimetry of uterine arteries has not been shown to be

useful by itself to screen pregnant women at low risk for PET.5

Diffusion of technology in Australia

Personal communication with the company indicated that most states in Australia, except

Victoria, already have one of the DELFIA platforms for prenatal screening (mainly for Down

syndrome).

Sydney − Sonic Healthcare (Douglass Hanly Moir): DELFIA Xpress (covering 65% of

NSW prenatal screening):

Adelaide − Women’s and Children’s Hospital: DELFIA Xpress (covering 100% of SA

and Southern NT prenatal screening);

Perth − Princess Margaret Hospital: AutoDELFIA (covering 20% of WA prenatal

screening); CliniPath Pathology: DELFIA Xpress (covering 25% of WA prenatal

screening); and

Brisbane − Mater Hospital: DELFIA Xpress (covering 10% of QLD prenatal screening).

However none have yet introduced PlGF kit into routine screening for PET, although several

sites have done, or are doing, some research on PIGF. In addition, AutoDELFIA is also

available in sites in Auckland and Christchurch and covers 100 per cent of NZ prenatal

screening.

International utilisation

Country Level of Use

Trials underway or

completed

Limited use Widely diffused

USA

Canada

Europe

Brazil

Turkey

Asia

It is indicated that DELFIA Xpress PlGF kit has already been in use in more than 40 countries

around the world, mainly in the Europe, for screening for Down syndrome.

Cost infrastructure and economic consequences

In general, no additional cost-related to infrastructure is anticipated as the DELFIA

instruments are table-top size machines which are already in use in a number of

laboratories.

According to the company, the cost of a PlGF kit depends on a number of factors, including

the volume of samples. As an estimate, the cost per test using the PIGF assay is

approximately $10 and the DELFIA Xpress costs approximately AU$60,000 to purchase.

Ethical, cultural or religious considerations

None identified.

Evidence and Policy

Safety and effectiveness

A large number of retrospective studies reported on the performance of PIGF, either alone

or in combination with other markers, in predicting PET during the first-trimester. There was

limited prospective screening evidence evaluating the predictive value of PIGF identified.

Results from a systematic review of mainly retrospective studies and six cohort studies were

presented here.

A systematic review evaluated the predictive value of the seven most studied first-trimester

placental serum markers, uterine artery Doppler velocity waveform assessment (Ut-A

Doppler) measurements and maternal characteristics, either individually or combined

(screening level III-2).7 The vast majority of the included studies were retrospective studies

after PET had been diagnosed clinically. The review defined early-onset PET as pregnancies

that required delivery before 34 weeks of gestation, and late-onset PET as those that

required delivery at, or after, 34 weeks of gestation. The primary outcome was the

detection rate (DR) of the tests at a fixed false positive rate of 10 per cent to facilitate the

comparisons among the selected markers. A meta-analysis was not performed due to

significant heterogeneity among the included studies. Four of the 35 included studies

evaluated the performance of PIGF, three of which were case-control studies with the

population comprising mainly of women with low prior risk. PIGF levels were measured by

different technologies including DELFIA® Xpress PlGF kit (PerkinElmer Inc.).

The review found that the median multiples of expected median1 (MoMs) for PIGF were

significantly lower in PET cases, compared with the controls, especially for early-onset PET

(Table 2).

Table 2 Median MoMs of first-trimester PIGF in PET cases and controls from the included studies in the systematic

review7

Study ID Gestational age

(weeks) PET Control P value

N Median MoM N Median MoM

Early-onset PET

Akolekar (2008) 11-14 29 0.61 609 0.99 <0.0001

Audibert (2010) 11-13 9 0.68 833 0.94 NS

Foidart (2010) 11-14 30 0.61 180 1.01 <0.0167

Wortelboer (2010) 8-14 88 0.73 478 1.00 <0.0001

Late-onset PET

Akolekar (2008) 11-14 98 0.82 609 0.99 <0.0001

Foidart (2010) 11-14 60 0.82 180 1.01 <0.0167

PET (not specified)

Audibert (2010) 11-13 40 0.74 833 0.94 <0.05

MoM=multiples of expected median; PET=pre-eclampsia toxaemia;

The reported detection rate of PIGF alone in the first trimester for predicting PET was

modest at a false positive rate of 10 per cent, varying between 41-59 per cent for early-

onset PET and 33 per cent for late-onset PET (Figure 2), making it unsuitable as a stand-

alone screening test for unselected populations in clinical practice.

1 A multiple of the median (MoM) is a measure of how far an individual test result deviates from the median.

MoM and is commonly used to report the results of medical screening tests, particularly where the results of the

individual tests are highly variable.

Figure 2 Forest plot with the detection rates of the screening tests, including PIGF as a single marker or combined with

other markers, fixed at 10% false-positive rates in prediction of pre-eclampsia in the first-trimester in studies

included in the systematic review7

When combining more than two markers, including maternal characteristics, Ut-A Doppler

and multiple serum markers, detection rates of early-onset PET were improved with rates

reaching 75 per cent or higher. The best results were observed with the combination of five

makers (inhibin A, PIGF, pregnancy-associated plasma protein-A, Ut-A Doppler and maternal

characteristics)with a detection rate of 100 per cent, however only one study reported on

this combination with a small number of PET cases. For the detection of late-onset PET,

detection rates appeared to be lower, with the combination of four makers (inhibin A, PIGF,

pregnancy-associated plasma protein-A and maternal characteristics) yielding a detection

rate of only 49 per cent. Similarly, the reported detection rate for predicting unspecified PET

Study ID PE SP Marker DR fixed at 10% fixed FPR DR (95% CI)

Early-onset PE

Late-onset PE

PE (not specified)

DR=detection rate; FPR=false positive rate; MC=maternal characteristics; PAPP-A=pregnancy-associated plasma protein-

A;PE=pre-eclampsia; PIGF=placental growth factor; SP=study population

was low for both single and combined markers at a rate of 40 per cent, at a fixed false

positive rate of 10 per cent. The review concluded that currently there is no validated

screening test that accurately predicts PET early in the pregnancy, although a combination

of serum markers, Ut-A Doppler measurements and maternal characteristics may help to

identify high-risk patients. Large prospective studies are called for to evaluate potential

combination strategies.

One study 13 included in the systematic review was based on a cohort study for screening

Down syndrome at 11 to 13 weeks (screening evidence level III-2). Among the 893

nulliparous women included in the study, PIGF was only measured in 531 women due to the

initial study design, which did not include PIGF, and additional serum was not available for

women included in the first year of study. PIGF levels were measured by DELFIA Xpress

(PerkinElmer). Among the 531 women, only 22 developed PET, with early-onset PET

(diagnosed before 34 weeks) in four and severe PET (HP ≥160/110 mmHg, proteinuria ≥5

g/day or the presence of an adverse condition) in 13 women. The study showed that PIGF

generally performed better in predicting early-onset PET (Table 3).

Table 3 Summary results for performance of the tests13

Variable PET Early-onset PET Severe PET

AUC [95% CI]

PIGF, Doppler 0.654 [0.521, 0.787] 0.747 [0.509, 0.984] 0.711 [0.541, 0.882]

PIGF, MC 0.790 [0.702, 0.878] 0.847 [0.593, 1.000] 0.786 [0.645, 0.926]

PIGF, PAPP-A, MC 0.795 [0.710, 0.880] 0.844 [0.584, 1.000] 0.814 [0.695, 0.933]

PIGF, Inhibin A, MC 0.794 [0.713, 0.876] 0.958 [0.877, 1.000] 0.815 [0.690, 0.941]

PIGF, Inhibin A, PAPP-A, MC 0.793 [0.714, 0.873] 0.969 [0.910, 1.000] 0.851 [0.749, 0.953]

PIGF, Inhibin A, PAPP-A, L-PI,

MC

0.815 [0.737-0.893] 0.994 [0.982, 1.000] 0.890 [0.803, 0.977]

Sensitivity LR+ LR- Sensitivity LR+ LR- Sensitivity LR+ LR-

PIGF, MC 40.9% 4.1 0.7 75.0% 7.5 0.3 61.5% 6.1 0.4

PIGF, PAPP-A, MC 40.9% 4.1 0.7 75.0% 7.5 0.3 53.8% 5.4 0.5

PIGF, Inhibin A, MC 40.9% 4.1 0.7 75.0% 7.5 0.3 53.8% 5.4 0.5

PIGF, Inhibin A, PAPP-A, MC 31.8% 3.2 0.8 75.0% 7.5 0.3 53.8% 5.4 0.5

PIGF, Inhibin A, PAPP-A, L-PI,

MC

40.0% 4.0 0.7 100.0% 10.0 0.00 54.5 5.5 0.5

AUC=area under the ROC curve; L-PI=lowest of uterine artery Doppler pulsatility indices; LR+=likelihood ratio for a positive test; LR-=likelihood ratio for a

negative test; MC=maternal characteristics; PAPP-A= pregnancy-associated plasma protein-A; PET=pre-eclampsia toxaemia; PlGF=placental growth

factor. Sensitivity and LR results are calculated at a fixed false-positive rate of 10%

As a single serum marker, PIGF did not substantially improve the accuracy of maternal

characteristics in predicting PET. The best predictors of PET during first-trimester were a

combined model of PIGF, Inhibin A and pregnancy-associated plasma protein-A (PAPP-A),

Doppler and maternal characteristics, especially for early-onset PET, with an AUC of 0.994

(95% CI 0.982, 1.000). Similarly, at a fixed false-positive rate of 10 per cent, the same

combination yielded a sensitivity of 100 per cent and a positive likelihood ratio of 10.0 and

negative likelihood ratio of 0. The combination model was indicated as a good predictive

test for early-onset PET. The authors concluded that the combination of maternal

characteristics and first-trimester serum biomarkers provided an accurate screening for

early-onset PET in nulliparous women. Caution should apply when interpreting results from

this screening study as only a subsample from the original prospective study was available

for this study and the number of PET cases (n=22), especially early-onset PET (n=4), was very

small thus the accuracy of the estimates may be questionable.

A recent screening study of singleton pregnancies at 11-13 weeks’ gestation reported the

performance of models for predicting PET based on maternal characteristics, biophysical

and biochemical markers (screening level III-2).14 The study was part of a prospective

screening study for adverse obstetric outcomes in women attending their routine first

hospital visit during pregnancy in the UK. The 14,252 women with singleton pregnancies

included in the study were part of the 58,884 women in the original study who had available

serum PlGF. Pregnancies with aneuploidies and major fetal abnormalities, and those ending

in termination, miscarriage or fetal death before 24 weeks of gestation and pregnancies

delivering small for gestational age neonates in the absence of PET were excluded. Among

the included women, 385 (2.7%) developed PET. PlGF levels were measured by DELFIA

Xpress (PerkinElmer). As demonstrated in Table 4, during the first-trimester screening for

PET, the tests performed better for early-onset (requiring delivery before 34 weeks) rather

than late-onset PET. Table 4 Estimated detection rates of preeclampsia requiring delivery

before 34 and 37 weeks’ gestation at false-positive rates of 5% and 10%

Screening test FPR PET (requiring delivery <34 weeks) PET (requiring delivery <37 weeks)

Risk cut-off Detection rate Risk cut-off Detection rate

MC, PlGF 5%

10%

1:95

1:170

59.3%

72.4%

1:33

1:55

40.8%

54.4%

MC, Doppler, PlGF 5%

10%

1:126

1:261

87.4%

95.8%

1:36

1:67

60.6%

77.3%

MC, Doppler, PAPP-A, PlGF 5%

10%

1:128

1:269

93.4%

96.3%

1:36

1:67

61.1%

76.6%

MC=maternal characteristics; PAPP-A=pregnancy-associated plasma protein-A; PET=pre-eclampsia toxaemia; PlGF=placental growth factor.

In screening for early-onset PET, the addition of PlGF to maternal characteristics achieved a

detection rate of approximately 72 per cent at a 10 per cent false-positive rate. This was

improved to over 95 per cent using an algorithm combining maternal characteristics,

Doppler and biochemical markers (PAPP-A and PlGF), providing a relatively effective first-

trimester screening tool for early-onset PET.

Another recent prospective cohort study enrolled 2,118 women with a singleton pregnancy

to evaluate a model for the detection of gestational hypertension using maternal history,

serum biomarkers and uterine artery Doppler between 11-13 weeks (screening level III-2).15

Pregnancies with major fetal abnormalities, miscarriage and termination of pregnancy were

excluded. PIGF levels were measured by DELFIA Xpress (PerkinElmer). Among 25 PET cases,

12 were early-onset (diagnosed before 34 weeks of gestation) and 13 were late-onset

(diagnosed after 34 weeks of gestation). The study developed two models, with model A

including all maternal characteristics, Doppler and biomarkers studied regardless of whether

they are significantly related with PET in the regression analysis, whereas model B included

only significant factors. The reported sensitivities for identifying PET cases at various fixed

false-positive rates for both models are presented in Table 5. The best performance was

observed using model B for identifying early-onset PET, with serum PIGF, free β-hCG and

chronic hypertension identifying 67 and 75 per cent of women who developed early-onset

PET at a fixed false-positive rate of 5 and 10 per cent, respectively. The corresponding values

for model A were 60 and 58 per cent. The performance of both models for PET and late-

onset PET were poorer, especially for the later. The authors concluded that there is

potential of first-trimester screening for early-onset PET with a combination of PIGF, free β-

hCG and chronic hypertension yielding a reasonable detection rate and an area under the

ROC curve of 0.893. However further research is needed to evaluate the prediction markers

and models for PET.

Table 5 Sensitivity for identifying PET at fixed false-positive rates15

Variable PET Early-onset PET Late-onset PET

Model A (including all maternal characteristics, Doppler and biomarkers)

False-positive rate 5% 10% 15% 5% 10% 15% 5% 10% 15%

Sensitivity 36% 52% 60% 60% 58% 67% 23% 31% 38%

Model B* (including markers with p<0.05)

False-positive rate 5% 10% 15% 5% 10% 15% 5% 10% 15%

Sensitivity 32% 40% 48% 67% 75% 75% 23% 31% 31%

PET=pre-eclampsia toxaemia *Model B: for PET it included chronic hypertension, Doppler and PIGF; for early-onset PET it included hypertension, free β-hCG and PIGF; for late-onset PET, it included Doppler only.

Another small prospective cohort study evaluated the screening accuracy of late-onset PET

(defined as PET diagnosed at, or after, 34 weeks) by maternal characteristics, Doppler and a

combination of biomarkers (PAPP-A, PIGF, soluble fms-like tyrosine kinase-1 (sFlt-1) and P-

selection and neutrophil gelatinase-associated lipocalin (NDAL)) in 528 pregnant women

who decided to deliver in the centre with a complete follow-up (screening level III-2).16

Cases of early-onset PET, multiple pregnancy, pregnancy with fetal chromosomal and major

structural anomaly and miscarriage before 20 weeks were excluded. The study was

conducted at time of screening for Down syndrome at 11 to 13 weeks. PIGF levels were

measured using a Pantec solid-phase ELISA (Pantec, Turin, Italy). Late-onset PET occurred in

13 women (2.5%). The study found that, among the biomarkers studied, PIGF yielded the

best detection rate of 61.5 per cent at a fixed false-positive rate of 10 per cent for predicting

late-onset PET. When combined with two other better performing markers (NGAL and sFlt-

1), the detection rate was improved to 77.0 per cent. The AUC for detection rate for

predicting late-onset PET by screening based on PIGF, NGAL and sFlt-1 was 0.815 (95% CI

0.637, 0.993). Maternal characteristics such as parity did not add any consistent

discriminate power between cases and controls and was thus excluded from the model. The

study concluded that the model of biomarkers including PIGF, NGAL and sFlt-1 for late-onset

PET prediction yielded a sufficient detection rate to allow its prospective extensive use.

However, the better detection rate for late-onset PET screening than other literature that

was attributed to the homogeneous population included should be interpreted with caution

due to the small sample for a screening study.

In addition, two studies from the same group of authors examined the predictive accuracy

of PlGF for PET screening through repeated measures (at both first- and second-trimesters)

and in singleton and multiple pregnancies. One study included 893 nulliparous women, 40

(4.5%) of whom developed PET, with singleton pregnancies at the time of screening for

Down syndrome at 11-13 weeks of gestation in Canada.17 The second blood sample was

taken during the second-trimester ultrasound between 18-23 weeks. Serum PlGF, placental

protein 13 (P13) and A disintegrin and metalloprotease (ADAM12) levels were measured at

each visit with DELFIA Xpress PlGF kit (PerkinElmer) used for PlGF measurement. The study

reported that, at a 10 per cent false-positive rate, the detection rate of maternal

characteristics plus PlGF at 11-13 weeks was 35.3 per cent and the AUC was 0.73 (95% CI

0.65-0.81). The addition of PlGF at 18-23 weeks did not significantly improve the predictive

value (detection rate 38.2%, p=0.901; AUC0.71 (95% CI 0.63-0.80), p=0.301) and

discriminative ability of the model with PlGF during the first-trimester. Therefore the first-

trimester measurement of PlGF was a promising marker of PET however its screening

accuracy is limited in an unselected population even with repeated measures.

In another prospective cohort study nested in a multicentre randomised controlled trial of

antioxidant supplementation for the prevention of PET, the authors evaluated the accuracy

of PlGF, sFlt-1 and inhibin A in multiple, compared with singleton, pregnancies in prenatal

screening for PET and small for gestational age (screening level III-2).18 The study included

772 pregnant women between 12-18 weeks of gestation, among whom 34 (4.4%) developed

PET including five multiple pregnancies. Two maternal blood samples were collected

between 12-18 weeks (visit 1) and between 24-26 weeks (visit 2), and plasma PlGF levels

were measured with DELFIA Xpress PlGF kit (PerkinElmer). The study found that, compared

to the other biomarkers, PlGF yielded best predictive accuracy for PET in both singleton

(AUC 0.67 (95% CI 0.57-0.77), detection rate 21.4%) and multiple (AUC 0.81 (95% CI 0.62-

1.00), detection rate 60.0%) pregnancies during visit 1. In addition, the screening

performance of PIGF for PET at visit 1 were higher among multiple pregnancies than among

singleton pregnancies, however the difference was not significant (AUC 0.81 vs 0.67,

respectively, p=0.237). The authors concluded that PlGF was a good predictor of PET in

multiple pregnancies but was not clinically useful enough to be used as a single marker.

Economic evaluation

None identified.

Ongoing research

The following trials were identified in the clinical trial registry:

NCT01348711(BIODOP-T1): aimed to assess the role of uterine artery and maternal

serum PIGF and sflt-1 and their combination in screening for pre-eclampsia and small

-for-gestational age (SGA) fetuses at 12-14 weeks of gestation in high-risk population

in France. The trial intended to recruit 300 women with the primary outcome being

occurrence of PET or SGA. The indicated completion date was May 2011. No relevant

publication identified.

NCT01387776: this prospective cohort study aims to evaluate the benefits of early-

onset PET risk assessment in the 1st-trimester (measuring PIGF, blood pressure and

Doppler ultrasound), and how the results can modify or influence the course of the

pre-eclampsia during pregnancy. The primary outcome is the level of PP13, PIGF,

PAPP-A combined with Doppler ultrasound and standardised blood pressure

measurements to see if they can be used as early risk markers in patients having a

delivery before 34 weeks gestation. The trial is currently recruiting in Canada with an

intended sample size of 2,000. The anticipated completion date is April 2017.

Other issues

Regardless of the performance of PIGF, alone or combined with other markers, in predicting

PET in the first trimester of pregnancy, there is concern as to whether any such prediction is

of value for the obstetricians and pregnant woman.19 On the one hand, there are as yet no

effective preventative strategies for PET. Among a range of agents studied for reducing the

risk of PET, there is some recent evidence for prophylactic use of low dose (50-150 mg)

aspirin before 16 weeks of gestation resulting in up to 50 per cent reduction of the

incidence of PET without increasing the rate of maternal and fetal complications.7 In a

population with baseline risk of PET of 8 per cent, 114 women will need to be treated to

prevent one case of PET. The number needed to treat reduces to 50 in a population with a

baseline risk of PET of 20 per cent. Thus low dose aspirin may be indicated for the secondary

prevention of PET in women at increased risk. On the other hand, an effective screening

may lead to better use of health resources in antenatal care and in selection of suitable

women for future trials investigating potential preventive measures.6

Feedback from clinicians indicate that currently early pregnancy prediction of PET remains

in the research domain and is not yet ready for routine clinical application. In addition, there

is no definitive management pathway of women at high-risk for PET through first-trimester

screening, thus it is unlikely that their identification will alter their care especially for low-

risk women based on clinical characteristics. All women with a pre-existing high risk for PET,

on the other hand, are closely followed and monitored. In addition, incorporating PIGF

screening would increase specialist referrals, with a significant impact on sonography,

nursing times and patient flow, resulting in approximately an additional 30 minutes per

patient. Nevertheless, some private ultrasound practices in Australia are already offering

such testing to women with significant out-of-pocket costs. It is recommended that more

evidence is required for improved outcome for women identified as high risk for PET.

Furthermore, more well-planned evaluations especially in a general population and in

populations such as nulliparous women are recommended.

In addition, it should be noted that the DELFIA® Xpress platform can be, and is currently,

used in a number of settings, with a potential benefit of increasing the detection rate of

Down syndrome by adding PlGF test.

Summary of findings

Currently only low level (III-2) screening studies are available. These studies mainly focus on

the performance of PlGF as a screening test during first trimester, alone or in combination

with other markers, in identifying women at risk of developing PET. No randomised

controlled trial has been identified which assesses the effect of screening on final patient

outcomes.

The available studies showed that, as a single biomarker, PlGF did not substantially improve

the accuracy of clinical characteristics in predicting PET. Using models combining PlGF, a

range of other biomarkers, uterine artery Doppler and maternal characteristics, a better

diagnostic performance was achieved especially for early-onset PET (diagnosed or requiring

delivery before 34 weeks), with a best detection rate reaching 96-100 per cent at a false-

positive rate of 10 per cent. However the performance varied considerably depending on

the markers included in the models. Furthermore, the screening performance of various

models was generally poorer for late-onset PET.

Although there is potential for PlGF as a first trimester screening test for early-onset PET,

currently evidence is limited on its clinical usefulness. Coupled with the limited body of

evidence on the effectiveness of preventative strategies for PET, further large randomised

controlled trials or prospective screening studies are needed to identify the best

combination of prediction markers and to evaluate the predictive models of PET on

maternal and perinatal outcomes.

HealthPACT assessment

PIGF test for early screening for PET currently has limited or no clinical utility. Even if the

assay can reliably predict PET, evidence on the effectiveness of management of PET is

sparse. Therefore it is recommended that no further research on behalf of HealthPACT on

PlGF assays for the detection of pre-eclampsia is warranted at this time.

Number of studies included

All evidence included for assessment in this Technology Brief has been assessed according

to the revised NHMRC levels of evidence. A document summarising these levels may be

accessed via the HealthPACT web site.

Total number of studies 7

Total number of Level III-2 studies 7

Search criteria to be used (MeSH terms)

PE OR Preeclampsia OR “pre-eclampsia” OR (pre AND eclampsia)

PlGF OR “placental growth factor”

Screening OR screen

References

1. PerkinElmer (2012). DELFIA® Xpress PIGF kit, PerkinElmer Inc., Maryland.

2. Levine, RJ, Maynard, SE et al (2004). 'Circulating angiogenic factors and the risk of preeclampsia'. N Engl J Med, 350 (7), 672-83.

3. Akolekar, R, Zaragoza, E et al (2008). 'Maternal serum placental growth factor at 11 + 0 to 13 + 6 weeks of gestation in the prediction of pre-eclampsia'. Ultrasound Obstet Gynecol, 32 (6), 732-9.

4. National Horizon Scanning Centre (2012). DELFIA® Xpress PlGF kit antenatal screening test to predict risk of pre-eclampsia, National Horizon Scanning Centre (NHSC) Available from:

5. ACOG. Diagnosis and management of preeclampsia and eclampsia. Clinical management guidelines for obstetrician-gynecologist [serial on the Internet]. 2002: Available from: http://mail.ny.acog.org/website/SMIPodcast/DiagnosisMgt.pdf [Accessed.

6. Lowe, SA, Brown, MA et al (2009). 'Guidelines for the management of hypertensive disorders of pregnancy 2008'. Aust N Z J Obstet Gynaecol, 49 (3), 242-6.

7. Kuc, S, Wortelboer, EJ et al (2011). 'Evaluation of 7 serum biomarkers and uterine artery Doppler ultrasound for first-trimester prediction of preeclampsia: a systematic review'. Obstet Gynecol Surv, 66 (4), 225-39.

8. Roberts, CL, Algert, CS et al (2005). 'Hypertensive disorders in pregnancy: a population-based study'. Med J Aust, 182 (7), 332-5.

9. Metcalfe, A. Maternal morbidity data in Australia: an assessment of the feasibility of standardised collection. Cat no PER 56 [serial on the Internet]. 2012: Available from: http://www.aihw.gov.au/WorkArea/DownloadAsset.aspx?id=60129542382 [Accessed.

10. Roberts, CL, Bell, JC et al (2008). 'The accuracy of reporting of the hypertensive disorders of pregnancy in population health data'. Hypertens Pregnancy, 27 (3), 285-97.

11. The UK National Screening Committee. The UK NSC policy on Pre-eclampsia screening in pregnancy2011: Available from: http://www.screening.nhs.uk/pre-eclampsia [Accessed.

12. AHMAC (2012). Clinical Practice Guidelines: Antenatal Care – Module 1, Australian Health Ministers’ Advisory Council, Australian Government Department of Health and Ageing, Canberra Available from: http://www.health.gov.au/antenatal.

13. Audibert, F, Boucoiran, I et al (2010). 'Screening for preeclampsia using first-trimester serum markers and uterine artery Doppler in nulliparous women'. Am J Obstet Gynecol, 203 (4), 383 e1-8.

14. Akolekar, R, Syngelaki, A et al (2013). 'Competing risks model in early screening for preeclampsia by biophysical and biochemical markers'. Fetal Diagn Ther, 33 (1), 8-15.

15. Di Lorenzo, G, Ceccarello, M et al (2012). 'First trimester maternal serum PIGF, free beta-hCG, PAPP-A, PP-13, uterine artery Doppler and maternal history for the prediction of preeclampsia'. Placenta, 33 (6), 495-501.

16. Youssef, A, Righetti, F et al (2011). 'Uterine artery Doppler and biochemical markers (PAPP-A, PIGF, sFlt-1, P-selectin, NGAL) at 11 + 0 to 13 + 6 weeks in the prediction of late (> 34 weeks) pre-eclampsia'. Prenat Diagn, 31 (12), 1141-6.

17. Boucoiran, I, Suarthana, E et al (2013). 'Repeated measures of placental ggrowth factor, placental protein 13, and a disintegrin and metalloprotease 12 at first and second trimesters for preeclampsia Sscreening'. Am J Perinatol.

18. Boucoiran, I, Thissier-Levy, S et al (2012). 'Risks for preeclampsia and small for gestational age: predictive values of placental growth factor, soluble fms-like tyrosine kinase-1, and inhibin A in singleton and multiple-gestation pregnancies'. Am J Perinatol.

19. Huppertz, B&Kawaguchi, R (2012). 'First trimester serum markers to predict preeclampsia'. Wien Med Wochenschr, 162 (9-10), 191-5.