Assessment of proteinuria in pregnancy

Abstract

Urinary spot protein:creatinine ratio can reliably rule out proteinuria in pregnancy

Pre-eclampsia is a global problem—it affects 2-8% of pregnancies, and an estimated 8.3 million women develop the disease each year. For developing countries, the priority is preventing maternal deaths from multiorgan complications of the disease. The difference in case fatality rates from eclampsia between developing countries and developed countries (5.2% v 0.72%) suggests that mortality is easily avoidable.¹ In developed countries where death is rarer, research is directed towards improving prediction and prevention of pre-eclampsia and minimising morbidity. Accurate diagnosis is needed to accomplish this. In the accompanying systematic review, Côté and colleagues assess urinary spot protein:creatinine and albumin:creatinine ratios as diagnostic tests for significant proteinuria in women with hypertension in pregnancy.²

Pre-eclampsia is a multiorgan syndrome, the clinical characteristics of which may include kidney, liver, and cerebral damage, an altered coagulant state, and fetal growth restriction.³ It is defined by two imperfect measures of end organ involvement—hypertension and proteinuria.⁴ Early blood markers of the disease can now be identified many weeks before these clinical manifestations,⁵ but antenatal diagnosis still relies on measuring blood pressure and urine dipstick inspection. In the United Kingdom alone, 660 000 women each year will have at least 7-10 such antenatal checks during each pregnancy, according to the schedule recommended by the National Institute for Health and Clinical Excellence.⁶ In other developed countries, women are seen even more often.

The classic clinical presentation of pre-eclampsia is initial hypertension and subsequent proteinuria, which is a cue to seek other manifestations of the disease. The likelihood of adverse pregnancy outcomes escalates in women with pre-eclampsia rather than gestational hypertension alone, so proteinuria often dictates the need to admit women to hospital or deliver the baby.⁷ Screening for proteinuria has traditionally been by urine dipstick, but this method is prone to considerable error.

A previous systematic review reported the pooled negative likelihood ratio for 1+ protein or greater on urine dipstick for predicting 300 mg/24 h proteinuria as 0.6 (95% confidence interval 0.45 to 0.8), with a pooled positive likelihood ratio of 3.48 (1.66 to 7.27).⁸ This implies that the test often misleads the healthcare professional but, as no easy alternative is available at point of care, it continues to be used widely in clinical practice.

Comparison of urine dipstick with 24 hour collection is complicated by 24 hour collection not being a precise gold standard. Healthcare professionals and the women rarely follow the correct procedure at the start and end of collection, and because women micturate so often during pregnancy they may forget to add all the samples to the collection. Different laboratory assays for measuring protein give varying results,⁹ and the threshold of 300 mg/24 h is not based on reaching a distinct clinicopathological state, but on the 95th centile for normal pregnant women. Proteinuria is key to management, but current clinical assessment is far from perfect. Can we improve on this situation?

In their systematic review, Côté and colleagues report a pooled negative likelihood ratio for a cut-off of 30 mg/mmol of 0.21 (0.13 to 0.31).² They conclude that the test is useful for ruling out significant proteinuria but do not advocate its use for quantification as the positive likelihood ratio was only poor to fair (3.53, 2.83 to 4.49). However, assessment of the value of the test must include comparison with its alternatives and the implications of both a positive and missed diagnosis, which are considerable.

Quantification is not crucial to obstetricians, because once a threshold is breached the diagnosis is made. Unlike blood pressure (which is related to risk of a cerebrovascular event), serial assessment of proteinuria after the diagnosis of pre-eclampsia rarely influences management because the rate of increase is not an important predictor of adverse pregnancy outcomes.¹⁰ Ruling out proteinuria is key, and the protein:creatinine ratio performs well in this respect. Detection of proteinuria above the threshold in a pregnant woman with hypertension differentiates between relatively innocuous gestational hypertension and pre-eclampsia and dictates a considerable step-up in surveillance, often including admission. The social and financial repercussions of this for the woman and the economic consequences for the healthcare system are considerable.

The protein:creatinine ratio is most likely to improve the initial screening of proteinuria by dipstick assessment. It may have a more limited role in precluding the need for 24 hour collection. When the protein:creatinine ratio is above 30 mg/mmol, the 24 hour collection will still be used in many units to quantify proteinuria and confirm the diagnosis, but when the ratio is below the threshold it could replace 24 hour collection in excluding significant proteinuria. Although it is currently a laboratory test, it is quick; obstetric day care units could use it to improve accuracy and speed of diagnosis. Fully quantitative point of care devices exist for measuring albumin:creatinine ratio¹¹; a similar one for protein:creatinine ratio may be an easy and more accurate alternative to current urinalysis screening in the future.

Côté and colleagues rightly highlight the need for future research into the validity of the 30 mg/mmol threshold for the protein:creatinine ratio in predicting adverse pregnancy outcome.² Further work is also needed to compare the use of urinary spot protein:creatinine ratio with current urine dipstick analysis in the management of pregnant women with hypertension, particularly with respect to accuracy of diagnosis and the effect on inappropriate admissions and discharges. The 24 hour collection system will still be needed for those women who require accurate quantification of proteinuria. New technology in the assessment of proteinuria that incorporates the protein:creatinine ratio has the potential to improve the lives of many pregnant women, while reducing wrong diagnoses and therefore enhancing safety.