NIHR Signal Single urine samples are just as good as 24-hour collections for diagnosing pre-eclampsia

Published on 17 January 2018

The urine spot albumin-creatinine ratio (which is done on a single, on-the-spot sample) reliably identified 99% of pregnant women with high blood pressure who went on to develop severe pre-eclampsia. The spot protein-creatinine ratio, as currently recommended by NICE, was slightly less sensitive identifying over 90% of women. Both spot tests were good value for money.

Nearly 1,000 women, suspected of having pre-eclampsia, took part in this NIHR-funded study, in 36 UK obstetric units. They had high blood pressure and protein detected in their urine (by dipstick) beyond 20 weeks of pregnancy. The study compared the diagnostic accuracy of newer ways of ‘spot’ testing a single sample of urine for predicting severe pre-eclampsia with traditional tests on a urine sample taken over 24-hours.

The findings suggest that spot albumin-creatinine or protein-creatinine ratios could be used in place of 24-hour urine collection and testing. Each can potentially rule-out women at risk of severe pre-eclampsia while being cheaper, quicker and more acceptable to women.

The study supports current NICE recommendations on the use of spot protein-creatinine ratio. Further guideline updates may consider the feasibility of the spot albumin-creatinine ratio test, though this test required analysis at a central laboratory.

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Why was this study needed?

Pre-eclampsia is a serious complication of late pregnancy involving raised blood pressure (hypertension) and kidney dysfunction, detected by protein in the urine (proteinuria). It occurs in around 4-5% of pregnancies in the UK.

Pre-eclampsia is the second most common cause of maternal death and accounts for around 20% of stillbirths and up to 10% of preterm births. Early detection and active management are therefore essential.

Measuring the urine protein excreted over 24 hours is one way of quantifying the proteinuria. However, other tests on single samples, are more convenient and less time-consuming. They could also be a more accurate measure of protein excretion and better tests for ruling out pre-eclampsia.

This study aimed to see whether the spot protein-creatinine ratio (SPCR) and spot albumin-creatinine ratio (SACR) were more accurate at diagnosing severe pre-eclampsia than the 24-hour collection. Both tests only require a single urine sample. If these tests are more efficient and accurate, they may enable better management of pre-eclampsia, reduce adverse outcomes, and spare healthcare resources.

What did this study do?

Pregnant women (aged 16 and over) who were over 20 weeks were recruited from 36 UK centres. All had new hypertension (blood pressure of 140/90 mmHg or more) and at least a trace of proteinuria when tested by urine dipstick.

Participants provided a single urine spot sample and then collected urine for 24 hours in a container. SPCR was tested in three ways: at the local laboratory, and at the central laboratory using two different assays. SACR was tested at the central laboratory using an automated chemistry analyser. The 24-hour urine sample was tested at the central laboratory.

Tests were assessed for their ability to predict severe pre-eclampsia (the reference standard) according to the NICE definition, which includes severe hypertension (≥160/110), symptoms and/or blood abnormalities.

What did it find?

  • Of 1,823 women with hypertension initially recruited, 959 had complete data available on all tests and could be included in the analysis. Half of these women (475) with pre-eclampsia, of which 417 cases were severe.
  • The three SPCR tests (using a cut-off threshold of 30 mg/mmol) had good accuracy for reliably identifying those who would develop severe pre-eclampsia. Sensitivity (the proportion with the diagnosis correctly identified by the test) ranged from 93% to 95% depending on test assay and laboratory. However, not everyone testing positive would develop severe pre-eclampsia. Specificity (the proportion of women without the condition who correctly tested negative) was only 56% to 61% depending on the test.
  • The SACR test (using a cut-off threshold of 2 mg/mmol) had a very high sensitivity of 99% so identified almost all women with severe pre-eclampsia. Specificity of SACR, however, was much poorer at 23%, so at this threshold the test would also pick up about three-quarters of women who wouldn’t develop severe pre-eclampsia (false positive results).
  • All test strategies had similar overall costs.

What does current guidance say on this issue?

NICE guidelines on the diagnosis and management of hypertension in pregnancy (2010) recommend using SPCR to diagnose proteinuria in the hospital setting, alternatively 24-hour urine collection. NICE advise diagnosing significant proteinuria if the urinary protein:creatinine ratio is greater than 30 mg/mmol or a validated 24-hour urine collection result shows greater than 300 mg protein.

NICE does not currently give any recommendation about the use of SACR testing. Their 2010 guideline called for more research into the different tests for measuring proteinuria, including SACR.

What are the implications?

Spot testing using SACR or SPCR at the currently recommended threshold seem reliable for ruling out severe pre-eclampsia in pregnant women with new-onset hypertension.

The findings seem to support the withdrawal of 24-hour urine collection as a means to diagnose proteinuria. The spot tests are likely to be more acceptable and easier to carry and save time and resources.

While SACR, in particular, had excellent sensitivity, specificity was very poor at the 2mg/mmol threshold. The researchers suggest further evaluation of an 8mg/mmol threshold if the test is used to ”rule out” significant proteinuria and severe pre-eclampsia. This may reduce the number of women at low risk who are put through further testing.

Citation and Funding

Waugh J, Hooper R, Lamb E, et al. Spot protein-creatinine ratio and spot albumin-creatinine ratio in the assessment of pre-eclampsia: a diagnostic accuracy study with decision-analytic model-based economic evaluation and acceptability analysis. Health Technol Assess. 2017;21(61).

This project was funded by the National Institute for Health Research Health Technology Assessment (HTA) programme (project number 10/65/02).

Bibliography

NICE. Hypertension in pregnancy: the management of hypertensive disorders during pregnancy. CG107. London: National Institute for Health and Care Excellence; 2010.

Why was this study needed?

Pre-eclampsia is a serious complication of late pregnancy involving raised blood pressure (hypertension) and kidney dysfunction, detected by protein in the urine (proteinuria). It occurs in around 4-5% of pregnancies in the UK.

Pre-eclampsia is the second most common cause of maternal death and accounts for around 20% of stillbirths and up to 10% of preterm births. Early detection and active management are therefore essential.

Measuring the urine protein excreted over 24 hours is one way of quantifying the proteinuria. However, other tests on single samples, are more convenient and less time-consuming. They could also be a more accurate measure of protein excretion and better tests for ruling out pre-eclampsia.

This study aimed to see whether the spot protein-creatinine ratio (SPCR) and spot albumin-creatinine ratio (SACR) were more accurate at diagnosing severe pre-eclampsia than the 24-hour collection. Both tests only require a single urine sample. If these tests are more efficient and accurate, they may enable better management of pre-eclampsia, reduce adverse outcomes, and spare healthcare resources.

What did this study do?

Pregnant women (aged 16 and over) who were over 20 weeks were recruited from 36 UK centres. All had new hypertension (blood pressure of 140/90 mmHg or more) and at least a trace of proteinuria when tested by urine dipstick.

Participants provided a single urine spot sample and then collected urine for 24 hours in a container. SPCR was tested in three ways: at the local laboratory, and at the central laboratory using two different assays. SACR was tested at the central laboratory using an automated chemistry analyser. The 24-hour urine sample was tested at the central laboratory.

Tests were assessed for their ability to predict severe pre-eclampsia (the reference standard) according to the NICE definition, which includes severe hypertension (≥160/110), symptoms and/or blood abnormalities.

What did it find?

  • Of 1,823 women with hypertension initially recruited, 959 had complete data available on all tests and could be included in the analysis. Half of these women (475) with pre-eclampsia, of which 417 cases were severe.
  • The three SPCR tests (using a cut-off threshold of 30 mg/mmol) had good accuracy for reliably identifying those who would develop severe pre-eclampsia. Sensitivity (the proportion with the diagnosis correctly identified by the test) ranged from 93% to 95% depending on test assay and laboratory. However, not everyone testing positive would develop severe pre-eclampsia. Specificity (the proportion of women without the condition who correctly tested negative) was only 56% to 61% depending on the test.
  • The SACR test (using a cut-off threshold of 2 mg/mmol) had a very high sensitivity of 99% so identified almost all women with severe pre-eclampsia. Specificity of SACR, however, was much poorer at 23%, so at this threshold the test would also pick up about three-quarters of women who wouldn’t develop severe pre-eclampsia (false positive results).
  • All test strategies had similar overall costs.

What does current guidance say on this issue?

NICE guidelines on the diagnosis and management of hypertension in pregnancy (2010) recommend using SPCR to diagnose proteinuria in the hospital setting, alternatively 24-hour urine collection. NICE advise diagnosing significant proteinuria if the urinary protein:creatinine ratio is greater than 30 mg/mmol or a validated 24-hour urine collection result shows greater than 300 mg protein.

NICE does not currently give any recommendation about the use of SACR testing. Their 2010 guideline called for more research into the different tests for measuring proteinuria, including SACR.

What are the implications?

Spot testing using SACR or SPCR at the currently recommended threshold seem reliable for ruling out severe pre-eclampsia in pregnant women with new-onset hypertension.

The findings seem to support the withdrawal of 24-hour urine collection as a means to diagnose proteinuria. The spot tests are likely to be more acceptable and easier to carry and save time and resources.

While SACR, in particular, had excellent sensitivity, specificity was very poor at the 2mg/mmol threshold. The researchers suggest further evaluation of an 8mg/mmol threshold if the test is used to ”rule out” significant proteinuria and severe pre-eclampsia. This may reduce the number of women at low risk who are put through further testing.

Citation and Funding

Waugh J, Hooper R, Lamb E, et al. Spot protein-creatinine ratio and spot albumin-creatinine ratio in the assessment of pre-eclampsia: a diagnostic accuracy study with decision-analytic model-based economic evaluation and acceptability analysis. Health Technol Assess. 2017;21(61).

This project was funded by the National Institute for Health Research Health Technology Assessment (HTA) programme (project number 10/65/02).

Bibliography

NICE. Hypertension in pregnancy: the management of hypertensive disorders during pregnancy. CG107. London: National Institute for Health and Care Excellence; 2010.

Spot protein-creatinine ratio and spot albumin-creatinine ratio in the assessment of pre-eclampsia: a diagnostic accuracy study with decision-analytic model-based economic evaluation and acceptability analysis

Published on 24 October 2017

Waugh J, Hooper R, Lamb E, Robson S, Shennan A, Milne F, Price C, Thangaratinam S, Berdunov V & Bingham J.

Health Technology Assessment Volume 21 Issue 61 , 2017

Background: The National Institute for Health and Care Excellence (NICE) guidelines highlighted the need for ‘large, high-quality prospective studies comparing the various methods of measuring proteinuria in women with new-onset hypertensive disorders during pregnancy’. Objectives: The primary objective was to evaluate quantitative assessments of spot protein–creatinine ratio (SPCR) and spot albumin–creatinine ratio (SACR) in predicting severe pre-eclampsia (PE) compared with 24-hour urine protein measurement. The secondary objectives were to investigate interlaboratory assay variation, to evaluate SPCR and SACR thresholds in predicting adverse maternal and fetal outcomes and to assess the cost-effectiveness of these models. Design: This was a prospective diagnostic accuracy cohort study, with decision-analytic modelling and a cost-effectiveness analysis. Setting: The setting was 36 obstetric units in England, UK. Participants: Pregnant women (aged ≥ 16 years), who were at > 20 weeks’ gestation with confirmed gestational hypertension and trace or more proteinuria on an automated dipstick urinalysis. Interventions: Women provided a spot urine sample for protein analysis (the recruitment sample) and were asked to collect a 24-hour urine sample, which was stored for secondary analysis. A further spot sample of urine was taken immediately before delivery. Main outcome measures: Outcome data were collected from hospital records. There were four index tests on a spot sample of urine: (1) SPCR test (conducted at the local laboratory); (2) SPCR test [conducted at the central laboratory using the benzethonium chloride (BZC) assay]; (3) SPCR test [conducted at the central laboratory using the pyrogallol red (PGR) assay]; and (4) SACR test (conducted at the central laboratory using an automated chemistry analyser). The comparator tests on 24-hour urine collection were a central test using the BZC assay and a central test using the PGR assay. The primary reference standard was the NICE definition of severe PE. Secondary reference standards were a clinician diagnosis of severe PE, which is defined as treatment with magnesium sulphate or with severe PE protocol; adverse perinatal outcome; one or more of perinatal or infant mortality, bronchopulmonary dysplasia, necrotising enterocolitis or grade III/IV intraventricular haemorrhage; and economic cost and outcomes. Health service data on service use and costs followed published economic models. Results: In total, 959 women were available for primary analysis and 417 of them had severe PE. The diagnostic accuracy of the four assays on spot urine samples against the reference standards was similar. The three SPCR tests had sensitivities in excess of 90% at prespecified thresholds, with poor specificities and negative likelihood ratios of ≥ 0.1. The SACR test had a significantly higher sensitivity of 99% (confidence interval 98% to 100%) and lower specificity. Receiver operating characteristic (ROC) curves were similar (area under ROC curve between 0.87 and 0.89); the area under the central laboratory’s SACR curve was significantly higher (p = 0.004). The central laboratory’s SACR test was the most cost-effective option, generating an additional 0.03 quality-adjusted life-years at an additional cost of £45.07 compared with the local laboratory’s SPCR test. The probabilistic analysis showed it to have a 100% probability of being cost-effective at the standard willingness-to-pay threshold recommended by NICE. Limitations: Implementation of NICE guidelines has led to an increased intervention rate in the study population that affected recruitment rates and led to revised sample size calculations. Conclusions: Evidence from this clinical study does not support the recommendation of 24-hour urine sample collection in hypertensive pregnant women. The SACR test had better diagnostic performance when predicting severe pre-eclampsia. All four tests could potentially be used as rule-out tests for the NICE definition of severe PE. Future work: Testing SACR at a threshold of 8 mg/mmol should be studied as a ‘rule-out’ test of proteinuria. Funding: This project was funded by the National Institute Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology

Expert commentary

Proteinuria is a well-recognised feature of pre-eclampsia, but the best way to measure it is not clear, although we already know that quick bedside dipstick tests are unreliable.

This study has shown that a spot albumin-creatinine ratio (SACR) has the highest test accuracy for predicting severe disease. Spot protein creatinine ratio (SPCR) is only slightly inferior. Either can be used for diagnosis.

Those hospitals that currently perform a full 24-hour urine collection, for this reason, can safely stop doing so. This will be convenient for patients and save money.

Jim Thornton, Professor of Obstetrics and Gynaecology, University of Nottingham