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  • 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 This work is licensed under a Creative Commons Attribution Non-Commercial No Derivatives 2.5 Australia licence. In essence, you are free to copy and communicate the work in its current form for non-commercial purposes, as long as you attribute the authors and abide by the licence terms. You may not alter or adapt the work in any way. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/2.5/au/. For further information, contact the HealthPACT Secretariat at: HealthPACT Secretariat c/o Clinical Access and Redesign Unit, Health Service and Clinical Innovation Division Department of Health, Queensland Level 13, Block 7 Royal Brisbane and Women’s Hospital HERSTON QLD 4029 Postal Address: GPO Box 48, Brisbane Qld 4001 Email: HealthPACT@health.qld.gov.au Telephone: +61 7 3646 9100 For permissions beyond the scope of this licence contact: Intellectual Property Officer, Queensland Health, GPO Box 48, Brisbane Qld 4001, email ip_officer@health.qld.gov.au, phone (07) 3234 1479. Electronic copies can be obtained from: http://www.health.qld.gov.au/healthpact DISCLAIMER: This brief is published with the intention of providing information of interest. It is based on information available at the time of research and cannot be expected to cover any developments arising from subsequent improvements to health technologies. This brief is based on a limited literature search and is not a definitive statement on the safety, effectiveness or costeffectiveness of the health technology covered. The State of Queensland acting through Queensland Health (“Queensland Health”) does not guarantee the accuracy, currency or completeness of the information in this brief. Information may contain or summarise the views of others, and not necessarily reflect the views of Queensland Health. This brief is not intended to be used as medical advice and it is not intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for a health professional's advice. It must not be relied upon without verification from authoritative sources. Queensland Health does not accept any liability, including for any injury, loss or damage, incurred by use of or reliance on the information. This brief was commissioned by Queensland Health, in its role as the Secretariat of the Health Policy Advisory Committee on Technology (HealthPACT). The production of this brief was overseen by HealthPACT. HealthPACT comprises representatives from health departments in all States and Territories, the Australian and New Zealand governments and MSAC. It is a sub-committee of the Australian Health Ministers’ Advisory Council (AHMAC), reporting to AHMAC’s Hospitals Principal Committee (HPC). AHMAC supports HealthPACT through funding. This brief was prepared by Hong Ju from HPACT Secretariat.
  • 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
  • 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)
  • 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 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
  • (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.
  • 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
  • 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
  • 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,
  • 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
  • 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
  • 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
  • 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
  • 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), 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.