Abstract
SummaryBackgroundPrevious 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.MethodsWe 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.FindingsBetween 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).InterpretationWe 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.FundingNational Institute for Health Research.
Highlights
Hypertension affects 10% of pregnant women, and pre-eclampsia complicates around 3% of singleton pregnancies.[1,2] Women with pre-eclampsia are often asymptomatic, even those with severe disease
Where placental growth factor (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
We found no published trials that evaluated the implementation of angiogenic factors as a diagnostic adjunct in women presenting with suspected pre-eclampsia
Summary
Hypertension affects 10% of pregnant women, and pre-eclampsia complicates around 3% of singleton pregnancies.[1,2] Women with pre-eclampsia are often asymptomatic, even those with severe disease. Diagnosis is based on clinical features such as hypertension and raised urinary protein excretion, both of which are subject to observer error,[3] heterogeneity in test accuracy,[4,5] and an insufficient ability of clinicians to predict important adverse pregnancy outcomes.[6] The presentation of pre-eclampsia is often clinically ambiguous, and risk stratification of women with suspected pre-eclampsia is complex. This ambiguity leads to repeated hospital attendances for antenatal monitoring, increased use of health resources,[7] and considerable anxiety for women, while missing at-risk cases.[8]. The area under the receiver operating characteristic curve for low PlGF concentrations in determining preeclampsia was 0·87 (SE 0·03), which is greater than all commonly used tests in the maternity assessment setting (such as for blood pressure, alanine transaminase, and urate)
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