Figure 1 summarises the process of identification and selection of studies. Of the 3213 potential citations, we included 20 primary articles in the critical appraisal and systematic review.10
Appendix B details the individual characteristics of the included studies. The 20 studies reported on 2978 pregnant women and produced 88 two by two tables. Thirteen were cohort studies, four were cross sectional studies, one was a case-control study, and two were purposely designed diagnostic accuracy studies. Ten studies used prospective recruitment of patients, four stated that consecutive recruitment was used, one was retrospective, and nine studies had unclear design. Thirteen studies excluded patients with proven urinary tract infections, five excluded those with chronic hypertension, and 11 excluded patients with chronic renal disease. Four papers included only inpatients on bed rest.
Fig 1Process from initial search to final inclusion for albumin to creatinine ratio or protein to creatinine ratio in management of pre-eclampsia (up to January 2011)
For the 24 hour urine collection, five papers reported that they excluded patients with inadequate urine collections, and one paper gave specific details on the tests for this. We noted significant heterogeneity in method of protein measurement. One study used the trichloroacetic acid method, five used the Biuret reaction, five used the pyrogallol red reaction, one used the Bradford assay, two used the turbidimetric method, and one used benzamethonium chloride. Methods of creatinine measurement included 12 studies using the Jaffe methods, one using the two pint rate methods, and one using the iminohydrolase reaction.
Quality of studies
Figure 2 shows a summary of the quality assessment of the included studies. We found good compliance with appropriate population spectrum, selection criteria adequately described, appropriate reference standard, and adequate description of index and reference standard. Blinding of the assessors of the outcome measure to the results of the albumin to creatinine ratio or protein to creatinine ratio was poorly reported (3/20 studies). No studies reported on the use of any treatment in between the albumin to creatinine ratio or protein to creatinine ratio and delivery or whether the results of the tests were used in determining patients’ management. Verification bias was minimised, as the number of eligible women progressing to the reference standard in included studies was more than 90% in 18/20. Five out of the 20 included studies used less than 80% of included women in the final analysis; reasons for this included exclusion after trial entry, lack of verification with reference standard, and loss to follow-up. In 379 (13%) cases this was due to incomplete 24 hour urine collection.
Fig 2Bar chart showing quality assessment using QUADAS criteria of included papers in systematic review of albumin to creatinine ratio and protein to creatinine ratio in management of pre-eclampsia. Availability of clinical data refers to “Were (more ...)
Summary results for protein to creatinine ratio to detect significant proteinuria compared with 24 hour urine collection
Fifteen studies compared protein to creatinine ratio with 24 hour urine collection (2790 women). No studies evaluated protein to creatinine ratio and adverse pregnancy outcome. Of the 15 studies using 24 hour collection as the outcome measure, 10 were in pregnant women with hypertension, four were in a population with hypertension and proteinuria on dipstick analysis, and in one the population was not clear. Thirteen of the 15 papers reported the approximate time during the day that the spot test was taken, and nine of the 15 reported the timing with respect to the 24 hour urine collection.
Tables 1 and 2 show the results for the constrained sensitivity, specificity, and likelihood ratios using the multivariate meta-analysis. Thirteen studies reported adequate data on the threshold of the reference standard for inclusion in this analysis. For sensitivity, no threshold gave a summary sensitivity estimate above 90%. Threshold values between 0.31 and 0.13 gave summary estimates between 80% and 90%, and the summary estimate was below 70% for thresholds of 0.45 and above. For specificity, no threshold gave a summary specificity estimate above 90%, but thresholds between 0.39 and 0.50 gave summary estimates between 81% and 87%. The summary specificity estimate was 70% or more for a threshold of 0.22 or above.
Table 1 Constrained summary sensitivity and specificity of protein to creatinine ratio
Table 2 Constrained summary likelihood ratios of protein to creatinine ratio
We found considerable heterogeneity at any threshold for which two or more studies provided evidence; for example, the between study standard deviation for sensitivity was estimated at between 0.41 and 1.58 in such studies. This heterogeneity may cause the performance of protein to creatinine ratio in an individual study setting to be somewhat different from the summary “average” results presented here (table 1).
Figure 3 shows the summary receiver operating characteristics curve for the constrained estimates. The area under the curve was 0.69, which indicates a good discriminatory ability on average across studies. The question arises as to which threshold for protein to creatinine ratio gives, on average across all studies, the best summary results for sensitivity and specificity combined. No threshold gave a summary estimate above 80% for both sensitivity and specificity. Threshold values between 0.22 and 0.40 gave summary estimates above 70% for both sensitivity and specificity (table 1). The optimum threshold (that which maximises both sensitivity and specificity jointly) seems to be somewhere between 0.30 and 0.35 inclusive (fig 3).
Fig 3Summary receiver operating characteristics curve for constrained estimates of sensitivity and specificity for protein to creatinine ratio. Open circles indicate most promising thresholds for use, as they optimise both sensitivity and specificity (more ...)
The prevalence of proteinuria varied across studies from 14% to 87% owing to the variability in severity of the included populations, so we did a subgroup analysis using only those studies that included women with hypertension and proteinuria on dipstick analysis (n=4 studies, 279 women). The only threshold for which we could do this analysis was a protein to creatinine ratio above 0.2 (n=3 studies, 237 women). The results were sensitivity 0.86 (95% confidence interval 0.79 to 0.91), specificity 0.95 (0.89 to 0.98), positive likelihood ratio 14.11 (6.29 to 31.67), and negative likelihood ratio 0.13 (0.06 to 0.29). To determine the predicted probability of disease given a positive test result and also the predicted probability of non-disease given a negative test result, we considered a range of different prevalences (0.2, 0.5, and 0.8) and combined each with the summary sensitivity and specificity estimates from our meta-analysis. The results in appendices C-E show that the predicted values clearly depend on the cut-off value chosen and the prevalence assumed. Higher prevalences lead to higher estimates of positive predictive value and lower estimates of negative predictive value, and vice versa. These values are based on using the average sensitivity and specificity from the meta-analysis, but these also vary across settings.
Albumin to creatinine ratio
For albumin to creatinine ratio, we had five included studies (620 women). Four studies used 24 hour total protein as the reference standard and one used adverse pregnancy outcome. Of the four studies that used 24 hour collection as the reference standard, two were in a hypertensive population and two were in a population with hypertension and proteinuria on dipstick. The study using adverse pregnancy outcome was in a population with hypertension only. Three studies described the timing of the sample, and one described the relation of the timing of the 24 hour collection. Three papers reported the use of automatic dipstick analysers for albumin to creatinine ratio.
Summary results for albumin to creatinine ratio to detect significant proteinuria compared with 24 hour urine collection
Meta-analysis of results from studies of albumin to creatinine ratio was not possible owing to different thresholds and study characteristics. Table 3 shows the results for the individual studies. The most promising result was with the DCA 2000 quantitative analyser (>2 mg/mmol) with sensitivity 0.94 (0.86 to 0.98), specificity 0.94 (0.87 to 0.98), positive likelihood ratio 14.65 (6.74 to 31.84), and negative likelihood ratio 0.07 (0.03 to 0.16).
Table 3 Summary of results of studies using albumin to creatinine ratio (ACR) in management of women with suspected pre-eclampsia
Summary results for albumin to creatinine ratio to predict adverse outcome
One study (Gangaram et al39
) reported results for adverse outcome, including maternal morbidity, for which the sensitivity was 0.55 (0.23 to 0.83) and specificity was 0.57 (0.48 to 0.65), and perinatal death, for which the sensitivity was 0.82 (0.48 to 0.98) and specificity was 0.59 (0.51 to 0.67).