stout2015 pdf Review The Utility of 12 Hour Urine Collection for the Diagnosis of Preeclampsia A Systematic Review and Meta analysis Molly J Stout, MD, MSCI, Shayna N Conner, MD, MSCI, Graham A Coldit.
Review The Utility of 12-Hour Urine Collection for the Diagnosis of Preeclampsia A Systematic Review and Meta-analysis Molly J Stout, MD, MSCI, Shayna N Conner, MD, MSCI, Graham A Colditz, George A Macones, MD, MSCE, and Methodius G Tuuli, MD, MPH OBJECTIVE: To systematically review the literature and synthesize data on the diagnostic performance of a 12hour urine collection for proteinuria in pregnant women with suspected preeclampsia DATA SOURCES: We performed a literature search of PubMed, Embase, Scopus, ClinicalTrials.gov, and CINAHL through February 2014 using key words related to gestational hypertension, preeclampsia, and proteinuria METHODS OF STUDY SELECTION: Studies that contained results of both the 12-hour and 24-hour urine collection in the same patients were eligible TABULATION, INTEGRATION, AND RESULTS: Three independent reviewers abstracted test performance characteristics from each study for the performance of a 12-hour urine collection for the diagnosis of proteinuria defined as 300 mg in 24 hours Diagnostic meta-analysis was performed to obtain summary statistics Heterogeneity was assessed using the Cochrane Q or I2 Receiver operating characteristic curve analysis was used to assess the optimal diagnostic cutpoint for proteinuria from a 12-hour urine collection Stratified analysis was performed based on whether patients were on bed rest during urine collection A total of seven studies met inclusion criteria The 12-hour urine protein was From the Departments of Obstetrics and Gynecology and Surgery, Washington University School of Medicine in St Louis, St Louis, Missouri Dr Stout and Dr Tuuli are supported by a Women’s Reproductive Health Research Career Development grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development—1K12HD063086-01) Corresponding author: Molly J Stout, MD, MSCI, Washington University School of Medicine, Campus Box 8064, 4566 Scott Avenue, St Louis, MO 63110; e-mail: stoutm@wudosis.wustl.edu Financial Disclosure The authors did not report any potential conflicts of interest © 2015 by The American College of Obstetricians and Gynecologists Published by Wolters Kluwer Health, Inc All rights reserved ISSN: 0029-7844/15 VOL 126, NO 4, OCTOBER 2015 MD, DrPH, overall highly predictive of proteinuria on 24-hour urine collection area under receiver operating characteristic curve: 0.97 (95% confidence interval [CI] 0.95–0.98) The pooled sensitivity was 92% (95% CI 86–96) and specificity was 99% (95% CI 75–100) The optimal cutpoint based on the receiver operating characteristic curve was 150 mg of protein on 12-hour collection CONCLUSION: A 12-hour urine collection compares favorably with a 24-hour urine collection for the diagnosis of proteinuria in women with suspected preeclampsia and has the advantage of convenience and improved clinical efficiency (Obstet Gynecol 2015;126:731–6) DOI: 10.1097/AOG.0000000000001042 P reeclampsia complicates 5–8% of pregnancies, is characterized by hypertension and other endorgan injury, and remains a leading cause of maternal morbidity and mortality in the United States.1,2 A recent American College of Obstetricians and Gynecologists Task Force on hypertension in pregnancy removed the requirement of proteinuria for the diagnosis of preeclampsia if there are other findings suggestive of end organ involvement (thrombocytopenia, elevated liver transaminases, renal insufficiency, pulmonary edema, or new-onset neurologic symptoms).2 However, in the absence of these severe features, quantification of urinary protein remains an important diagnostic step for evaluation of hypertension in pregnancy Urine protein can be quantified using either a 24hour urine collection or a spot urine protein-tocreatinine ratio.2 Several studies have investigated urine protein-to-creatinine ratio as a rapid test to obviate the need for a 24-hour urine collection.3–12 Although the data show that extremely high or low urine protein-to-creatinine ratio values may be a substitute for a 24-hour urine collection,6,13 there are OBSTETRICS & GYNECOLOGY Copyright ª by The American College of Obstetricians and Gynecologists Published by Wolters Kluwer Health, Inc Unauthorized reproduction of this article is prohibited 731 clinical circumstances that may still require a 24-hour urine collection Several studies have investigated the use of a 12hour urine collection as opposed to a 24-hour urine collection for the diagnosis of proteinuria.14–20 We conducted a systematic review for relevant studies evaluating the diagnostic utility of a 12-hour urine collection compared with a 24-hour urine collection for the diagnosis of proteinuria in pregnant women with suspected preeclampsia We then performed a diagnostic meta-analysis of the data to obtain summary diagnostic characteristics and estimate the optimal cutpoint of protein on 12-hour urine collection for the diagnosis of proteinuria SOURCES We used a predesigned study protocol outlining the search strategy, study inclusion and exclusion criteria, quality assessment tool, and data analysis plan The protocol adhered to guidelines in the Cochrane Handbook for Systematic Reviews of Diagnostic Accuracy.21 We searched PubMed, Embase, Scopus, ClinicalTrials.gov, and CINAHL through February 2014 using the MeSH: “hypertension, pregnancyInduced,” “gestational hypertension,” “pregnancy transient hypertension,” “edema-proteinuria-hypertension gestosis,” “pregnancy toxemia,” “pre-eclampsia,” “proteinuria,” “albuminuria,” “protein,” “urinary protein,” “12-hour,” “12-h,” and “12-hours.” Two medical librarians with specific training in literature searches for systematic reviews led the search STUDY SELECTION Studies that contained results of both the 12-hour and 24-hour urine collection in the same patients were eligible We excluded unpublished studies, nonEnglish studies, conference proceedings, abstracts, case studies, and commentaries Two independent investigators (M.J.S and S.N.C.) filtered titles and abstracts identified from the initial search to determine whether the studies met inclusion criteria Citation lists from included articles were manually searched Once screening of titles and abstracts was performed, three independent reviewers (M.J.S., S.N.C., M.G.T.) read the article and recorded quality data, incidence of positive 24-hour urine protein (greater than 300 mg), cutpoint used to define positive 12-hour urine protein, true-positives and -negatives, and false-positives and -negatives To be included in the final analysis, the study must have been performed in pregnant patients at or beyond 20 weeks of gestation, included collections of both a 12-hour and a 24-hour urine specimen, reported total protein (not concentration), and 732 Stout et al 12-Hour Urine Protein provided enough diagnostic information (prevalence of proteinuria in sample, cutpoint used for 12-hour test, sensitivity, specificity, predictive values) that truepositives and -negatives, and false-positives and -negatives could be back-calculated The true-positives and -negatives and false-positives and -negatives were based on the cutpoint used in the individual studies Disagreements were resolved by consensus of all three reviewers We assessed study quality based on the QUADAS tool for diagnostic meta-analysis The QUADAS tool was designed specifically to assess bias and study quality specifically related to studies on diagnostics tests and includes yes or no questions such as whether the spectrum of patients who underwent the test is representative of those who would have the clinical disease, whether the reference test and the index test were interpreted blindly, whether enough information is provided about the reference and index tests to replicate them, and other questions specifically pertinent to diagnostic test studies All reviewers extracted quality data based on the QUADAS tool.22 One QUADAS question (“Was the reference standard independent of the index test?”) was not pertinent to this study and was not assessed Results of the 12-hour urine results were compared with those of the gold standard 24-hour urine for each individual study to create two-by-two tables containing true- and false-positive and -negatives Meta-analysis was used to calculate pooled sensitivity and specificity of 12-hour urine compared with 24hour urine for quantification of proteinuria We used the Dersimonian and Laird randomeffects models to pool data irrespective of demonstrable statistical heterogeneity Heterogeneity was Fig Flowchart of studies examined for inclusion in the meta-analysis Stout 12-Hour Urine Protein Obstet Gynecol 2015 OBSTETRICS & GYNECOLOGY Copyright ª by The American College of Obstetricians and Gynecologists Published by Wolters Kluwer Health, Inc Unauthorized reproduction of this article is prohibited Table Characteristics of Studies Included in the Meta-analysis Comparing 12-Hour Urine Protein With 24-Hour Urine Protein for the Diagnosis of Preeclampsia Incidence of Bed Rest Cutpoint 24-h or Used for Greater Modified TrueTrueFalseFalse12-h U.S Than 300 Study Urine Location Inpatient Bed Rest Positive Negative Positive Negative mg (%) (n) Study Rinehart et al,15 1999 Adelberg et al,16 2001 Schubert and Abernathy,17 2006 Rabiee,18 2006 Moslemizadeh et al,19 2008 Tun et al,14 2012 Rani Singhal et al,20 2014 29 86 150 Yes Yes No 24 62 65 165 Yes Mixed Yes 34 20 15 60 150 Yes Yes Yes 57 36 14 72 100 148 No No Mixed Yes Yes No 24 49 2 86 33 165 Yes Yes Yes 27 58 125 85 150 No Yes Unknown 102 16 assessed using the Higgin’s I2 statistic and Cochrane’s Q test Stratified analysis according to bed rest status during the urine collection was performed A summary receiver operating characteristic (ROC) curve was used to estimate the optimal cutpoint for the 12-hour urine protein that maximized both sensitivity and specificity The optimal cutpoint on the ROC curve was identified as the left uppermost point The 12-hour protein cutpoint used in the study closest to this point was considered the optimal cutpoint Publication bias was assessed using Deek’s funnel plot for small study effect This is a regression plot of the diagnostic log odds ratio against the inverse of the sample size weighted by the effective sample size.23 P,.10 was considered significant to take into account the modest statistical power of this test Analysis was performed using the MIDAS package in Stata12 12-hour urine test results that were false-negative (Table 1) The proportion of studies complying with each of the criteria of the QUADAS tool is shown graphically in Figure All included studies were a prospective cohort design, had both 12- and 24-hour analysis performed by same laboratory, and included patients who by definition underwent both the index (12hour urine protein) and referent (24-hour urine protein) tests All studies included patients who represent RESULTS A total of 87 studies were identified from the initial search, of which seven were included in the final analysis (Fig 1) The incidence of 24-hour urine protein greater than 300 mg ranged from 14% to 86% The cutpoint used for a positive 12-hour urine collection ranged from 100 to 165 mg Studies varied with respect to inpatient or outpatient status as well as the use of bed rest or not during the urine collection Of the 410 total number of patients in the studies included, five (1.2%) had 2-hour urine protein test results that were false-positive and 16 (3.9%) had VOL 126, NO 4, OCTOBER 2015 Fig Bar chart showing quality assessment using quality assessment of diagnostic accuracy studies criteria Stout 12-Hour Urine Protein Obstet Gynecol 2015 Stout et al 12-Hour Urine Protein Copyright ª by The American College of Obstetricians and Gynecologists Published by Wolters Kluwer Health, Inc Unauthorized reproduction of this article is prohibited 733 Fig Forest plot of pooled sensitivity (A) and specificity (B) Stout 12-Hour Urine Protein Obstet Gynecol 2015 those who would likely be undergoing testing in typical clinical practice (eg, hypertensive disease beyond 20 weeks of gestation) and had clinical data available that would routinely be available in clinical practice Studies differed as to whether the 12- and 24-hour urines were interpreted blindly The pooled sensitivity was 92% (95% confidence interval [CI] 86–96%), and specificity was 99% (95% CI 75–100%) (Fig 3) There was significant heterogeneity between studies (I2553%, Q test P,.04 and I2575%, Q test P,.01, respectively) A planned stratified analysis according to bed rest status was performed because clinical characteristics such as bed rest compared with ambulation may alter protein excretion.24,25 Bed rest during the urine collection was associated with a nominally lower sensitivity (88% compared with 94%) and slightly higher specificity (100% compared with 86%) (Table 2) However, overlapping CIs suggest a nonstatistical difference The summary ROC curve (comparing sensitivity on the Y-axis and 1-specificity [false-positives] on the X-axis) showed that the 12-hour urine protein was highly predictive of proteinuria on 24-hour urine Table Pooled Sensitivity and Specificity by Bed Rest Subgroup Sensitivity (95% CI) Subgroup Bed rest (n54 studies, 220 patients) No bed rest (n52 studies, 65 patients) 88 (80–96) 94 (88–100) CI, confidence interval; NA, not applicable 734 Stout et al 12-Hour Urine Protein Specificity (95% CI) 100 (NA) 86 (67–100) collection (area under ROC curve 0.97, 95% CI 0.95–0.98; Fig 4) The 12-hour protein cutpoint used in the study closest to the optimal cutpoint (located in the upper left most region of the ROC curve where sensitivity is maximized and false-positives are minimized) was 150 mg.17 The Deek’s funnel plot showed no significant correlation between the diagnostic odds ratio and effective sample size, suggesting no significant publication bias (Fig 5) DISCUSSION The findings of this systematic review and diagnostic meta-analysis suggest that a 12-hour urine protein collection performs well compared with a 24-hour urine collection for the diagnosis of preeclampsia with high sensitivity and specificity Hypertensive disease continues to be a major source of pregnancy-related morbidity The differentiation of preeclampsia from gestational hypertension depends in part on quantification of proteinuria A recent American College of Obstetricians and Gynecologists Task Force document recommends against the use of dipstick quantification of urine protein.2 Other rapid quantification methodologies such as urine protein-to-creatinine ratio are useful in certain circumstances, but recent meta-analyses suggest that urine protein-to-creatinine ratio may have most utility in ruling out (rather than ruling in) significant proteinuria.6,13 Thus, 24-hour urine collection for protein is still clinically relevant and required for some patients This analysis has several strengths including use of a predefined protocol adhering to guidelines for metaanalysis of diagnostic studies,21 the comprehensive OBSTETRICS & GYNECOLOGY Copyright ª by The American College of Obstetricians and Gynecologists Published by Wolters Kluwer Health, Inc Unauthorized reproduction of this article is prohibited 10 Inverse of the effective sample size Sensitivity 1.0 0.5 15 20 25 10 100 1,000 Diagnostic odds ratio 0.0 0.0 0.5 1-specificity Rinehart 199916 Adelberg 200117 Schubert 200618 Rabiee 200619 Moslemizadeh 200820 Tun 201215 Singhal 201421 1.0 Summary operating point SROC curve 95% confidence contour 95% prediction contour Fig Summary receiver operating characteristic (SROC) curve for summary sensitivity and specificity for diagnosis of proteinuria by 12-hour urine protein The colored circles represent the individual studies Summary operating point: sensitivity50.92 (95% confidence interval [CI] 0.86–0.96), specificity50.99 (95% CI 0.75–1.00) Summary receiver operating characteristic curve: area under the curve50.97 (95% CI 0.95–0.98) Stout 12-Hour Urine Protein Obstet Gynecol 2015 literature search performed by trained medical librarians, and use of the ROC curve to objectively estimate the optimal cutpoint The study also has a number of limitations We included only seven studies with relatively small samples sizes that met inclusion criteria Moreover, there was also significant between study heterogeneity likely resulting from the varied cutpoints used and differences in the use of bed rest during urine collection We used the random-effects model to account for this heterogeneity and obtain conservative estimates of the diagnostic characteristics In addition, because of the small number of studies in subgroups, it is unclear whether urine collection during the day or night and bed rest or no bed rest alter the prediction of proteinuria In conclusion, results of this systematic review and diagnostic meta-analysis suggest that a 12-hour urine collection performs well for the diagnosis of proteinuria in hypertensive women during pregnancy A clinically applicable cutpoint based on the data avail- VOL 126, NO 4, OCTOBER 2015 Rinehart 199916 Adelberg 200117 Schubert 200618 Rabiee 200619 Moslemizadeh 200820 Tun 201215 Singhal 201421 Regression line Fig Deek’s funnel plot for publication bias The colored circles represent the individual studies The regression line represents the relationship between the inverse of the effective sample size and the effect estimate (diagnostic odds ratio) The nonsignificant correlation suggests absence of publication bias, P5.23 Stout 12-Hour Urine Protein Obstet Gynecol 2015 able would be 150 mg per 12-hour collection This cutpoint is associated with 99% specificity and 92% sensitivity Use of the 12-hour urine collection would be more convenient and expedite diagnosis, clinical management, and decrease cost Future studies 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DISCUSSION The findings of this systematic review and diagnostic meta- analysis suggest that a 12- hour urine protein collection performs well compared with a 24 -hour urine collection for the diagnosis of. .. diagnosis of proteinuria in pregnant women with suspected preeclampsia We then performed a diagnostic meta- analysis of the data to obtain summary diagnostic characteristics and estimate the optimal... preeclampsia: which sample is more suitable? Pak J Biol Sci 2008;11:2584–8 20 Rani Singhal S, Ghalaut V, Lata S, Madaan H, Kadian V, Sachdeva A Correlation of hour, hour, hour and 12 hour urine