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NIHR Signal Placental growth factor testing can speed up diagnosis of pre-eclampsia

Published on 9 July 2019

doi: 10.3310/signal-000787

Measuring the level of placental growth factor (PlGF) in women with suspected pre-eclampsia helps to reduce the time to diagnose pre-eclampsia from 4 days to 2 days. PlGF testing is also associated with fewer adverse outcomes for mothers.

In this NIHR-funded trial, the test results were used alongside the NICE clinical management algorithm to help clinicians make a diagnosis.

Pre-eclampsia can lead to serious complications for mothers and babies. Women with suspected pre-eclampsia require further tests and monitoring. A quicker diagnosis should reduce delays in management for those affected, and reduce unnecessary monitoring and worry for others.

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Why was this study needed?

Hypertension affects 10% of pregnancies, with pre-eclampsia complicating 3% of singleton pregnancies. It is thought to be caused by a problem with the development of the placenta. Early effects include high blood pressure and protein in the urine, but are often without symptoms. Pre-eclampsia is both difficult to diagnose and can lead to serious complications for both mother and baby.

Blood pressure and urine protein levels are checked routinely throughout pregnancy. From 20 weeks gestation, if these results suggest pre-eclampsia, a PlGF blood test can be used to help rule it out. If PlGF levels are high, it’s very unlikely to be pre-eclampsia. If they are low, it indicates a potential problem with the placenta, but not necessarily pre-eclampsia.

This is the first randomised controlled trial to assess whether knowing PlGF levels, along with a clinical management algorithm, speeds up a diagnosis of pre-eclampsia, and whether this had an impact on the mothers’ and babies’ health.

What did this study do?

This randomised controlled trial compared usual care using the NICE management algorithm with usual care plus PIGF level. It was carried out in eleven maternity units in the UK between 2016 and 2017. The trial included women with singleton pregnancies before 37 weeks gestation with suspected pre-eclampsia.

From the start of the trial, PlGF measurements were taken, but results were concealed from clinicians and women. The maternity units were randomised to reveal ongoing local test results to clinicians at six-week intervals.

Of 1,023 eligible participants, 447 women (44%) were randomised to receive usual care (with PlGF test results concealed), and 576 women (56%) were randomised to have test results revealed to clinicians.

The pragmatic, stepped-wedge study design is particularly suited to this sort of complex intervention and ensures that every participating maternity unit can test the management algorithm. This trial did not address the value of repeated PlGF testing, nor whether using PlGF as a continuous measure could improve risk assessments or prognostic stratification.

What did it find?

  • The median time to pre-eclampsia diagnosis was 2.2 days less in the revealed PlGF testing group; 1.9 days compared with 4.1 days in the usual care group. After adjustment for risk factors (such as gestational age, previous pre-eclampsia, chronic hypertension and chronic kidney disease) this corresponded to a 64% reduction in time to diagnosis (95% confidence interval (CI) 13% to 85% reduction).
  • Maternal adverse outcomes appeared to occur in fewer women in the revealed testing group: 4% (22/573) compared with 5% (24/447) of women in the usual care group (adjusted odds ratio [aOR] 0.32, 95% CI 0.11 to 0.96).
  • There was no difference demonstrated in perinatal adverse outcomes, which affected 14% of each group (aOR 1.45, 95% CI 0.73 to 2.90), and no difference in gestation at delivery.
  • Before 35 weeks gestation, low PlGF measurements (<100 pg/ml) had a sensitivity of 94.9% in detecting pre-eclampsia requiring delivery within 14 days, and a negative predictive value of 98.3%.

What does current guidance say on this issue?

NICE published guidance in 2016 on PlGF-based testing to help diagnose suspected pre-eclampsia. PlGF testing, in combination with clinical assessment and follow-up, is recommended to help rule-out pre-eclampsia in women in whom it is suspected between 20 weeks and 34+6 weeks gestation. The guidance notes there is insufficient evidence to recommend routine adoption of PlGF testing to rule-in pre-eclampsia.

NICE’s 2019 guideline on the diagnosis and management of hypertension in pregnancy recommends that PlGF testing is carried out once, to help rule out pre-eclampsia in women presenting with suspected pre-eclampsia after 20 weeks and before 35 weeks gestation.

What are the implications?

The study supports the use of PlGF testing in women with suspected pre-eclampsia.

Commissioners and providers of antenatal care should note that PlGF testing has been shown to be a useful diagnostic adjunct in women presenting with pre-eclampsia. It reduces the time to diagnosis of pre-eclampsia, and so promotes more timely management. This may be expected to lead to reduced adverse events for mothers and babies.

Citation and Funding

Duhig K, Myers J, Seed P et al. Placental growth factor testing to assess women with suspected pre-eclampsia: a multicentre, pragmatic, stepped-wedge cluster-randomised controlled trial. Lancet. 2019;393:1807-18

This project was funded by the NIHR Research for Patient Benefit Programme (project number PB-PG-0214-33054) and an NIHR professorship (number RP-2014-05-019).

Bibliography

NHS website. Pre-eclampsia. London: Department of Health and Social Care; 2018.

NICE. Hypertension in pregnancy. Clinical Knowledge Summary. London: National Institute for Health and Care Excellence; 2016.

NICE. Hypertension in pregnancy: diagnosis and management. NG133. London: National Institute for Health and Care Excellence; 2019.

NICE. PlGF-based testing to help diagnose suspected pre-eclampsia. DG23. London: National Institute for Health and Care Excellence; 2016.

Why was this study needed?

Hypertension affects 10% of pregnancies, with pre-eclampsia complicating 3% of singleton pregnancies. It is thought to be caused by a problem with the development of the placenta. Early effects include high blood pressure and protein in the urine, but are often without symptoms. Pre-eclampsia is both difficult to diagnose and can lead to serious complications for both mother and baby.

Blood pressure and urine protein levels are checked routinely throughout pregnancy. From 20 weeks gestation, if these results suggest pre-eclampsia, a PlGF blood test can be used to help rule it out. If PlGF levels are high, it’s very unlikely to be pre-eclampsia. If they are low, it indicates a potential problem with the placenta, but not necessarily pre-eclampsia.

This is the first randomised controlled trial to assess whether knowing PlGF levels, along with a clinical management algorithm, speeds up a diagnosis of pre-eclampsia, and whether this had an impact on the mothers’ and babies’ health.

What did this study do?

This randomised controlled trial compared usual care using the NICE management algorithm with usual care plus PIGF level. It was carried out in eleven maternity units in the UK between 2016 and 2017. The trial included women with singleton pregnancies before 37 weeks gestation with suspected pre-eclampsia.

From the start of the trial, PlGF measurements were taken, but results were concealed from clinicians and women. The maternity units were randomised to reveal ongoing local test results to clinicians at six-week intervals.

Of 1,023 eligible participants, 447 women (44%) were randomised to receive usual care (with PlGF test results concealed), and 576 women (56%) were randomised to have test results revealed to clinicians.

The pragmatic, stepped-wedge study design is particularly suited to this sort of complex intervention and ensures that every participating maternity unit can test the management algorithm. This trial did not address the value of repeated PlGF testing, nor whether using PlGF as a continuous measure could improve risk assessments or prognostic stratification.

What did it find?

  • The median time to pre-eclampsia diagnosis was 2.2 days less in the revealed PlGF testing group; 1.9 days compared with 4.1 days in the usual care group. After adjustment for risk factors (such as gestational age, previous pre-eclampsia, chronic hypertension and chronic kidney disease) this corresponded to a 64% reduction in time to diagnosis (95% confidence interval (CI) 13% to 85% reduction).
  • Maternal adverse outcomes appeared to occur in fewer women in the revealed testing group: 4% (22/573) compared with 5% (24/447) of women in the usual care group (adjusted odds ratio [aOR] 0.32, 95% CI 0.11 to 0.96).
  • There was no difference demonstrated in perinatal adverse outcomes, which affected 14% of each group (aOR 1.45, 95% CI 0.73 to 2.90), and no difference in gestation at delivery.
  • Before 35 weeks gestation, low PlGF measurements (<100 pg/ml) had a sensitivity of 94.9% in detecting pre-eclampsia requiring delivery within 14 days, and a negative predictive value of 98.3%.

What does current guidance say on this issue?

NICE published guidance in 2016 on PlGF-based testing to help diagnose suspected pre-eclampsia. PlGF testing, in combination with clinical assessment and follow-up, is recommended to help rule-out pre-eclampsia in women in whom it is suspected between 20 weeks and 34+6 weeks gestation. The guidance notes there is insufficient evidence to recommend routine adoption of PlGF testing to rule-in pre-eclampsia.

NICE’s 2019 guideline on the diagnosis and management of hypertension in pregnancy recommends that PlGF testing is carried out once, to help rule out pre-eclampsia in women presenting with suspected pre-eclampsia after 20 weeks and before 35 weeks gestation.

What are the implications?

The study supports the use of PlGF testing in women with suspected pre-eclampsia.

Commissioners and providers of antenatal care should note that PlGF testing has been shown to be a useful diagnostic adjunct in women presenting with pre-eclampsia. It reduces the time to diagnosis of pre-eclampsia, and so promotes more timely management. This may be expected to lead to reduced adverse events for mothers and babies.

Citation and Funding

Duhig K, Myers J, Seed P et al. Placental growth factor testing to assess women with suspected pre-eclampsia: a multicentre, pragmatic, stepped-wedge cluster-randomised controlled trial. Lancet. 2019;393:1807-18

This project was funded by the NIHR Research for Patient Benefit Programme (project number PB-PG-0214-33054) and an NIHR professorship (number RP-2014-05-019).

Bibliography

NHS website. Pre-eclampsia. London: Department of Health and Social Care; 2018.

NICE. Hypertension in pregnancy. Clinical Knowledge Summary. London: National Institute for Health and Care Excellence; 2016.

NICE. Hypertension in pregnancy: diagnosis and management. NG133. London: National Institute for Health and Care Excellence; 2019.

NICE. PlGF-based testing to help diagnose suspected pre-eclampsia. DG23. London: National Institute for Health and Care Excellence; 2016.

Placental growth factor testing to assess women with suspected pre-eclampsia: a multicentre, pragmatic, stepped-wedge cluster-randomised controlled trial

Published on 1 April 2019

K Duhig, J Myers, P Seed, J Sparkes, J Lowe, R Hunter, A Shennan, L Chappell

The Lancet , 2019

Background Previous prospective cohort studies have shown that angiogenic factors have a high diagnostic accuracy in women with suspected pre-eclampsia, but we remain uncertain of the effectiveness of these tests in a real-world setting. We therefore aimed to determine whether knowledge of the circulating concentration of placental growth factor (PlGF), an angiogenic factor, integrated with a clinical management algorithm, decreased the time for clinicians to make a diagnosis in women with suspected pre-eclampsia, and whether this approach reduced subsequent maternal or perinatal adverse outcomes. Methods We did a multicentre, pragmatic, stepped-wedge cluster-randomised controlled trial in 11 maternity units in the UK, which were each responsible for 3000–9000 deliveries per year. Women aged 18 years and older who presented with suspected pre-eclampsia between 20 weeks and 0 days of gestation and 36 weeks and 6 days of gestation, with a live, singleton fetus were invited to participate by the clinical research team. Suspected pre-eclampsia was defined as new-onset or worsening of existing hypertension, dipstick proteinuria, epigastric or right upper-quadrant pain, headache with visual disturbances, fetal growth restriction, or abnormal maternal blood tests that were suggestive of disease (such as thrombocytopenia or hepatic or renal dysfunction). Women were approached individually, they consented for study inclusion, and they were asked to give blood samples. We randomly allocated the maternity units, representing the clusters, to blocks. Blocks represented an intervention initiation time, which occurred at equally spaced 6-week intervals throughout the trial. At the start of the trial, all units had usual care (in which PlGF measurements were also taken but were concealed from clinicians and women). At the initiation time of each successive block, a site began to use the intervention (in which the circulating PlGF measurement was revealed and a clinical management algorithm was used). Enrolment of women continued for the duration of the blocks either to concealed PlGF testing, or after implementation, to revealed PlGF testing. The primary outcome was the time from presentation with suspected pre-eclampsia to documented pre-eclampsia in women enrolled in the trial who received a diagnosis of pre-eclampsia by their treating clinicians. This trial is registered with ISRCTN, number 16842031. Findings Between June 13, 2016, and Oct 27, 2017, we enrolled and assessed 1035 women with suspected pre-eclampsia. 12 (1%) women were found to be ineligible. Of the 1023 eligible women, 576 (56%) women were assigned to the intervention (revealed testing) group, and 447 (44%) women were assigned to receive usual care with additional concealed testing (concealed testing group). Three (1%) women in the revealed testing group were lost to follow-up, so 573 (99%) women in this group were included in the analyses. One (<1%) woman in the concealed testing group withdrew consent to follow-up data collection, so 446 (>99%) women in this group were included in the analyses. The median time to pre-eclampsia diagnosis was 4·1 days with concealed testing versus 1·9 days with revealed testing (time ratio 0·36, 95% CI 0·15–0·87; p=0·027). Maternal severe adverse outcomes were reported in 24 (5%) of 447 women in the concealed testing group versus 22 (4%) of 573 women in the revealed testing group (adjusted odds ratio 0·32, 95% CI 0·11–0·96; p=0·043), but there was no evidence of a difference in perinatal adverse outcomes (15% vs 14%, 1·45, 0·73–2·90) or gestation at delivery (36·6 weeks vs 36·8 weeks; mean difference −0·52, 95% CI −0·63 to 0·73). Interpretation We found that the availability of PlGF test results substantially reduced the time to clinical confirmation of pre-eclampsia. Where PlGF was implemented, we found a lower incidence of maternal adverse outcomes, consistent with adoption of targeted, enhanced surveillance, as recommended in the clinical management algorithm for clinicians. Adoption of PlGF testing in women with suspected pre-eclampsia is supported by the results of this study. Funding National Institute for Health Research.

Expert commentary

This important trial has potential to improve outcomes for thousands of pregnant women in high-income countries. Pre-eclampsia is a disease of the placenta. Onset may be sudden and insidious (not all women present with ‘typical’ symptoms), with significant health impacts if diagnosis is delayed.

In this trial, time from presenting with suspected pre-eclampsia to primary diagnosis was shorter by a median of 2.2 days in women in whom results of a blood test to identify maternal placental growth factor data were known by their clinicians, compared with those whose data were not known, with no differences in other outcomes of interest.

A test which could accurately and quickly distinguish between non-harmful blood pressure increases in pregnancy and onset of pre-eclampsia could be very important to improve outcomes of antenatal care. 

Debra Bick, Professor of Clinical Trials in Maternal Health, Warwick Clinical Trials Unit, University of Warwick

The commentator collaborates with two of the study authors on other work