Preeclampsia is a disorder characterized by new-onset hypertension and proteinuria that develops after 20 weeks of gestation in pregnant women. The criterion standard in the evaluation of proteinuria for diagnosis of preeclampsia is the finding of greater than 300 mg protein in a 24-hour urine collection.1 However, single-specimen random protein/creatinine ratios have also been used as a method to quantify proteinuria.2–7 Protein/creatinine ratios have the advantage of ease of collection, patient convenience, and importantly, rapid results when compared with 24-hour urine collections. Prior studies in women undergoing evaluation for preeclampsia have generally shown good correlation between protein/creatinine ratios and 24-hour urine total protein,2–7 although a few recent studies have challenged this premise.8,9 The optimal cutoff point of the protein/creatinine ratio that maximizes sensitivity and minimizes false positivity has also been debated,10 with some studies suggesting a cutoff of 0.19,3,9 0.20,5 or 0.21,11 whereas another study supports a cutoff of 0.3.6
Most studies using protein/creatinine ratios involve random urine specimens, but typically do not specify the collection method. Among these studies, only one specifically stated that the protein/creatinine urine sample was collected midstream.7 However, contamination from vaginal secretions, particularly in pregnancy, may falsely elevate quantification of proteinuria. It is therefore possible that differences in collection method may contribute to some of the seemingly contradictory results among published studies correlating protein/creatinine ratios with 24-hour urine results.
Historically, our institution catheterized pregnant women when assessing protein/creatinine ratio in evaluation of suspected preeclampsia. Because good correlation has been reported between catheterized and clean catch urine specimens in the diagnosis of urinary tract infections among nonpregnant women12,13 in the absence of vaginal bleeding,13 we posited that midstream clean catch specimens may also be an acceptable substitute to catheterized urine specimens to evaluate proteinuria in pregnant women. This study was designed to examine whether a clean catch urine specimen protein/creatinine ratio correlates with a catheterized specimen among pregnant patients undergoing evaluation for preeclampsia.
MATERIALS AND METHODS
This was a prospective trial comparing clean catch and catheterized urine specimens in determination of protein/creatinine ratios in pregnant women with new onset of hypertension, or worsening hypertension in the case of women with preexisting hypertension undergoing evaluation for preeclampsia. This study was conducted between July 2005 and May 2006 at Magee-Womens Hospital. The study was approved by the University of Pittsburgh Institutional Review Board.
All pregnant women aged 14–50 years, greater than 20 weeks of gestation, and undergoing evaluation for preeclampsia were eligible for the study. This included women with coexisting medical conditions such as chronic hypertension, diabetes, and renal disease. Participants were recruited from the Magee-Womens Hospital Outpatient Clinic and the Labor and Delivery Unit.
Participants with rupture of membranes, vaginal bleeding or spotting, preexisting urinary tract infection, or prior enrollment in this study were excluded. Participants diagnosed with a concurrent urinary tract infection based on culture were also excluded. All participants gave informed consent before enrollment.
Participants were first instructed to collect a midstream clean catch urine specimen and then catheterized for a urine specimen after cleansing the urethra with an antiseptic solution. Only the catheterized urine specimen results were reported to and used by the primary obstetrician for clinical management as per standard practice at our institution. The clean catch specimen results were reported only to the investigators. The medical records were reviewed by the investigators after delivery for pregnancy outcomes, including development and diagnosis of preeclampsia.
All urine samples were analyzed for protein, creatinine, urinalysis, and urine culture by the Magee-Womens Hospital clinical laboratory. Urinary protein was determined using the Dade Behring Dimension RXL Analyzer (Newark, DE) by the pyrogallol red spectrophotometric method. Creatinine was analyzed using the alkaline picrate reaction with the same analyzer. The protein/creatinine ratio was calculated by dividing protein (mg/dL) by creatinine (mg/dL). Urinalysis and microscopic evaluation was analyzed using the Clinitek 100 (Bayer, Pittsburgh, PA) analyzer.
The primary outcome was the correlation between protein/creatinine ratios for clean catch and catheterized urine specimens. Because the protein/creatinine ratio is often used clinically to categorize patients by degree of proteinuria, the results were also analyzed by categorization of proteinuria as above or below a critical threshold. Because there is some controversy regarding the definition of the optimal ratio for predicting significant proteinuria,10 results were analyzed using a protein/creatinine ratio of 0.3, which is often used and considered by some to be comparable to urinary protein excretion of 300 mg/24 hours, and a protein/creatinine ratio of 0.19, which has also been reported to be predictive of significant proteinuria in prior studies.3,9
We aimed to demonstrate a high correlation between catheterized and clean catch protein/creatinine ratios. A sample size of 60 would provide a correlation coefficient of 0.9 with 80% power and α of 0.05. Statistical analysis was performed using Stata 9.0 (StataCorp LP, College Station, TX). Demographic data were summarized using descriptive statistics. Spearman’s rho and kappa statistics were used to estimate the degree of correlation and variance between the clean catch and catheterized urine specimen results for each participant. An intraclass correlation coefficient was used to estimate the degree of reproducibility between the two urine collection methods.
Seventy-six women were enrolled in the study. Two participants were excluded due to incomplete enrollment documents. An additional 11 participants were excluded due to incomplete laboratory results (eg, lost clean catch urine results). Two women were excluded from the study due to urinary tract infection diagnosed after enrollment. One participant was excluded due to vaginal bleeding at the time of presentation upon retrospective review of records. Thus in total, 16 participants were excluded from final analysis, leaving protein/creatinine results for 60 participants.
Demographic characteristics and medical history are depicted in Table 1. The mean age of the participants was 27.0 years (range 17–39 years). Approximately 57% of the participants received care at the resident clinic, 40% with private obstetricians, and 3% with maternal–fetal medicine specialists. The mean gestational age at enrollment was 35.9 weeks (range 23.1–41.7 weeks). Twelve participants (20%) had a history of preeclampsia in a prior pregnancy.
Delivery outcomes are included in Table 1. Thirty participants (50.8%) developed preeclampsia by the time of delivery. Of these 30 women, 36.7%, 43.3%, and 20.0% were diagnosed with mild preeclampsia, severe preeclampsia, and superimposed preeclampsia, respectively. The mean time to diagnosis of preeclampsia from study enrollment was 1.3 weeks (range 0–15 weeks), and the median time to development of preeclampsia was less than 24 hours. Delivery outcome for one participant was not available because she did not deliver at our institution. One participant delivered twins.
The median clean catch and catheterized protein/creatinine ratios were 0.204 (0.089–3.465) and 0.181 (0.067–3.335). Because the data were not normally distributed, Spearman’s rho was used to calculate a correlation coefficient of 0.897 (P<.001, Fig. 1). The intraclass correlation coefficient was 0.998, indicating excellent reproducibility.
When results were categorized by degree of proteinuria using the 0.3 cutoff, 38 participants were classified as positive by both clean catch and catheterized protein/creatinine, and 20 participants were classified as negative (Table 2). For one patient with a negative catheterized protein/creatinine and positive clean catch protein/creatinine, the values were close to the 0.3 threshold with a catheterized protein/creatinine of 0.291 and a clean catch protein/creatinine of 0.314. For another patient with a positive catheterized specimen but a negative clean catch specimen, the catheterized protein/creatinine was 0.372 and the clean catch was 0.276. Interestingly, this patient had a body mass index of 68. Thus, the sensitivity and specificity of the clean catch protein/creatinine were 95.2% and 97.4%. The kappa reproducibility coefficient calculation was 0.93 (95% confidence interval 0.75–0.98), indicating excellent agreement between the two methods of assessment.
When using the more conservative threshold of 0.19, 24 participants were classified as positive by both clean catch and catheterized protein/creatinine ratios and 27 participants were classified as negative (Table 3). Sensitivity and specificity of the clean catch protein/creatinine ratios were 96.4% and 75.0%. The kappa reproducibility coefficient calculation was 0.70 (95% confidence interval 0.48–0.84), indicating good agreement.
We found strong correlation with high reproducibility between clean catch and catheterized urine protein/creatinine ratios when evaluating women with suspected preeclampsia in the third trimester, with a correlation coefficient of 0.9. In addition, when the degree of proteinuria was categorized as positive or negative, there was excellent agreement between clean catch and catheterized protein/creatinine ratios using the cutoff of 0.3 and good agreement when using the more conservative cutoff of 0.19.
At our institution, the protein/creatinine ratio is commonly used by obstetric care providers to make decisions about hospitalization or outpatient management, need for 24-hour urine collection and occasionally even delivery if clinical suspicion for preeclampsia is otherwise high. Before our study, transurethral catheterization was standard practice at our institution for the collection of urine specimens for protein/creatinine ratios.
Because routine catheterization entails patient discomfort, burden to nursing or medical staff, economic costs of catheterization equipment, and a small risk of urinary tract infection, an alternative method to minimize these risks when evaluating suspected preeclampsia would be preferable. Prior studies have demonstrated that catheterized and clean catch urine specimens correlate well in nonpregnant women in the diagnosis of urinary tract infections.12,13 Our study was designed to directly compare clean catch and catheterized urine results to evaluate whether clean catch urine collection is an acceptable substitute for catheterization in pregnant women undergoing evaluation for preeclampsia. Our findings support the hypothesis that routine catheterization of women is not necessary in women without ruptured membranes, vaginal bleeding or spotting, or urinary tract infection.
One limitation of our study is the possibility of measurement bias. Although participants were given standard instructions for clean catch urine collection by the nursing staff, it is possible that the actual collection may have been performed more carefully in the context of the clinical trial in comparison with usual clinical care. However, some studies suggest that clean catch urine specimens do not reduce bacterial contamination when compared with urine specimen collection without cleansing.14,15 Also, because clean catch urine collection is a common obstetric procedure, we do not feel that it is likely to greatly affect its correlation with catheterized specimens.
Another limitation of our study is that we compared clean catch to catheterized protein/creatinine ratios and not to 24-hour urinary protein, the criterion standard for diagnosis of preeclampsia. There were also few patients with high protein excretion who were enrolled in the study. However, given the excellent correlation between the protein/creatinine ratios in our study, we contend that the protein/creatinine ratio threshold value selected by an institution for clinical decision-making should not be affected by the collection method of the sample, and if the degree of proteinuria is critical to decision-making, then a timed urine collection may be warranted. Likewise, we suggest that sample collection method alone does not explain the disparate results in published studies relating protein/creatinine ratios and 24-hour urinary protein.
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