3. Technology, Company and Licensing
Register ID
WP168
Technology name
Antenatal Placental Growth Factor screening for preeclampsia 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, twosite 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
Antenatal PIGF screening for pre-eclampsia: August 2013
1
4. 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
Should be taken out of use
Investigational
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
No
ARTG number (s)
5. 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
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
7. 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).
8. 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
USA
Widely diffused
Canada
Limited use
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
9. (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
PET
(weeks)
Control
N
Median MoM
N
P value
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
Akolekar (2008)
11-14
98
0.82
609
0.99
<0.0001
Foidart (2010)
11-14
60
0.82
180
1.01
<0.0167
11-13
40
0.74
833
0.94
<0.05
Late-onset PET
PET (not specified)
Audibert (2010)
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 earlyonset PET and 33 per cent for late-onset PET (Figure 2), making it unsuitable as a standalone 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.
10. 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 proteinA;PE=pre-eclampsia; PIGF=placental growth factor; SP=study population
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
11. 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,
0.815 [0.737-0.893]
0.994 [0.982, 1.000]
0.890 [0.803, 0.977]
MC
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,
40.0%
4.0
0.7
100.0%
10.0
0.00
54.5
5.5
0.5
MC
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
12. 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
5%
1:95
59.3%
1:33
40.8%
1:170
72.4%
1:55
54.4%
5%
1:126
87.4%
1:36
60.6%
1:261
95.8%
1:67
77.3%
5%
1:128
93.4%
1:36
61.1%
10%
MC, Doppler, PAPP-A, PlGF
Detection rate
10%
MC, Doppler, PlGF
Risk cut-off
10%
MC, PlGF
Detection rate
1:269
96.3%
1:67
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,
13. Doppler and biochemical markers (PAPP-A and PlGF), providing a relatively effective firsttrimester 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 lateonset 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 βhCG 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 Pselection and neutrophil gelatinase-associated lipocalin (NDAL)) in 528 pregnant women
14. 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 sFlt1), 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 firsttrimester 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
15. 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 0.621.00), 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 earlyonset 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
16. 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 lowrisk 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 falsepositive 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
17. 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.
18. 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), 28597.
11.
The UK National Screening Committee. The UK NSC policy on Pre-eclampsia
screening in pregnancy2011: Available from: http://www.screening.nhs.uk/preeclampsia [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 firsttrimester 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.
