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Nitrite Test for Optimizing Diagnosis of


Asymptomatic Urinary Tract Infection in
Pregnant Women: An Evidence-based report

Article · February 2011

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Felix Firyanto Widjaja Dyah Purnamasari


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Artikel Penelitian

Nitrite Test for Optimizing


Diagnosis of Asymptomatic Urinary Tract
Infection in Pregnant Women:
An Evidence-based report

Felix Firyanto Widjaja,* Adly Nanda,* Dyah Widyowati,*


Retnani Budiningsih,* Nirk Faiz,* Dyah Purnamasari**

*Faculty of Medicine University of Indonesia, Jakarta


**Department of Internal Medicine Faculty of Medicine University of Indonesia/
Cipto Mangunkusomo Hospital, Jakarta

Abstract: Asymptomatic urinary tract infections (UTIs) in pregnant women who are not treated
appear more likely to develop serious complications on occassional life threatening and risk to
deliver more low birth weight neonates. Thus, it is necessary to test whether the infection is
really present or not. Urine culture as the gold standard examination still has limitations. This
report was made to examine nitrite as a component of urinalysis to be an alternative test for
asymptomatic UTIs. A search was conducted on PubMed,® Proquest,® Cochcrane® and Embase.®
After screening titles and abstracts by inclusion and exclusion criteria, 16 original articles were
found, but only 4 articles were used by author. All four articles showed high negative predictive
value (0.82-0.96) and three of them showed good post-test probability (<0.09) when the test
result was negative for asymptomatic UTIs. On the other hand, the positive predictive value (0.5-
0.69) was poor. Based on the results, nitrite is not strong enough as a sole test for diagnosing
asymptomatic UTIs. But, we found that nitrite is good enough to confidently rule out the asymp-
tomatic UTIs in pregnant woman.
Keywords: asymptomatic UTI, nitrite, diagnosis, pregnant woman.

76 Maj Kedokt Indon, Volum: 61, Nomor: 2, Februari 2011


Nitrite Test for Optimizing Diagnosis of Asymptomatic Urinary Tract Infection in Pregnant Women

Pemeriksaan Nitrit untuk Membantu Diagnosis Infeksi Saluran Kemih


tanpa Gejala pada Wanita Hamil: Laporan Berdasarkan Bukti

Felix Firyanto Widjaja,* Adly Nanda,* Dyah Widyowati,*


Retnani Budiningsih,* Nirk Faiz,* Dyah Purnamasari**

*Fifth Year Student, Faculty of Medicine Universitas Indonesia, Jakarta


**Staff Department of Internal Medicine Metabolic Endocrine Division
Cipto Mangunkusomo Hospital, Jakarta

Abstrak: Infeksi saluran kemih asimtomatik pada wanita hamil akan menyebabkan komplikasi
yang serius, mengancam nyawa serta berisiko tinggi melahirkan bayi dengan berat lahir rendah.
Oleh karena itu, pemeriksaan perlu dilakukan untuk mendeteksi adanya infeksi. Kultur urin
sebagai pemeriksaan baku emas masih memiliki keterbatasan. Laporan ini dibuat untuk melihat
nilai diagnostik nitrit dari pemeriksaan urinalisis sebagai modalitas diagnostik alternatif infeksi
saluran kemih asimtomatik. Pencarian dilakukan di PubMed,® Proquest,® Cochrane® dan
Embase.® Setelah dilakukan penapisan judul dan abstrak dengan kriteria inklusi dan eksklusi, 16
artikel ditemukan, tetapi hanya empat artikel yang digunakan oleh penulis. Keempat artikel
menunjukkan negative predictive value (0,82-0,96) yang tinggi dan tiga dari empat artikel tersebut
menunjukkan post-test probability yang baik saat hasil uji negatif untuk infeksi saluran kemih
tanpa gejala. Sementara positive predictive value (0,5-0,69) memperlihatkan nilai yang kurang
baik. Berdasarkan hasil tersebut, nitrit tidak cukup baik sebagai uji tunggal untuk diagnosis
infeksi saluran kemih asimtomatik. Tetapi, nitrit cukup baik untuk mengeksklusi infeksi saluran
kemih asimtomatik pada wanita hamil.
Kata kunci: ISK asimtomatik, nitrit, diagnosis, wanita hamil.

Introduction rectly.5 Nitrite is one of the most useful indicators for asymp-
Asymptomatic UTIs occur in 5% to 10% of all pregnan- tomatic UTI diagnosis. Nitrite is produced from dietary ni-
cies. It becomes more frequent because of the remarkable trate by bacteria containing nitrate reductase.4-6
changes in the structure and function of the urinary tract
Clinical Question
during pregnancy. Urinary stasis and the presence of
vesicoureteral reflux predispose pregnant women to upper Is nitrite test accurate as diagnostic tools in pregnant
tract UTI.1 woman?
Asymptomatic UTI is defined as a positive urine cul-
Methods
ture without specific symptoms. To diagnose asymptomatic
UTIs, urine culture is used as a gold standard test.1-3 Unfor- Search strategy
tunately, this diagnostic method is expensive, time-consum- The search was conducted on PubMed,® Proquest,®
ing, laboratory- and microbiologist-dependent. These limi- Cochrane,® and Embase® on July 13th 2010, using the search
tations have led many physicians to use urinalysis as initial tools containing keywords pregnant or gravid or pregnancy,
step to evaluate the diagnosis of asymptomatic UTI.1 and urinalysis or nitrate, and urine culture and urinary tract
There are numbers of other diagnostic tests those have infections with synonyms and related terms (Table 1). Search
wide range of specificity and sensitivity for diagnosing as- strategy, results and the inclusion and exclusion criteria are
ymptomatic UTI, such as urine dipstick, dip slide, and direct shown in a flowchart (Figure 1).
microscopy.1,3 A urine dipstick measures specific gravity and
pH of the urine, as well as the presence of urobilinogen, Selection
ketones, glucose, hemoglobin, leukocyte esterase and ni- After obtaining a result, a first selection was done by
trite in the urine.4 The urine dipstick is valued as a quick and using exclusion criteria (nonpregnant, therapeutic study, ex-
inexpensive test that requires little expertise to perform cor- posure difference, comparison difference, review). There was

Maj Kedokt Indon, Volum: 61, Nomor: 2, Februari 2011 77


Nitrite Test for Optimizing Diagnosis of Asymptomatic Urinary Tract Infection in Pregnant Women

Table 1. Search Strategy Used in PubMed, Cochrane, Embase, and Proquest (Conducted on July 13 th 2010)

Engine Search Terms Results

PubMed (“pregnant” OR “pregnancy”OR “gravid”) AND (“urinalysis”OR “nitrate”AND “urine culture”AND 7


(“UTI” OR “bacteriuria” OR “Urinary tract infection”)
Embase ‘pregnant’ OR ‘gravid’ OR ‘pregnancy’ AND ‘urinalysis’/exp OR ‘nitrite’/exp OR ‘nitrites’/exp AND 0
‘urine’/de AND ‘culture’/de AND urinary AND tract AND ‘infection’/exp OR uti OR ‘bacteriuria’/exp
AND [female]/lim AND [adult]/lim AND [humans]/lim AND [english]/lim
Cochrane (pregnant OR gravid OR pregnancy) AND (urinalysis OR nitrite) AND urine culture AND (urinary tract 25
infection OR UTI OR bacteriuria)
Proquest TEXT(((pregnant) OR (gravid) OR (pregnancy)) AND ((urinalysis) OR (nitrite)) AND ((urine culture)) 181
AND ((urinary tract infection) OR (UTI) OR (bacteriuria))) Database: Multiple databases.. Limit results
to: full text Look for terms in: citation and abstract Publication type: Scholarly journals

Figure 1. Flow Chart of Search Strategy

no same article found in four engines after filtering doubles. viewed comprising of its validity, importance, and applicabil-
From the selection and filtration, sixteen articles were ob- ity. The checklists used were obtained from www.bmj.com.
tained, out of which only four full-text articles were avail-
able. Results
Mignini, et al.1 performed a study to evaluate the sensi-
Critical Appraisal tivity and specificity of chemical dipstick compared with urine
Four relevant articles, Mignini et al.,1 Lorentzon et al.,2 culture. This study was conducted in parallel with the WHO
Norstrands et al.,3 and Tincello et al.,7 were each appraised multicentre double-blind randomized trial for asymptomatic
in groups by 6 authors using standardized validity criteria UTIs treatment. Dipstick test considered positive if both of
for diagnostic research. Several aspects were critically re- leukocyte and nitrite or either one positive. They reported,

78 Maj Kedokt Indon, Volum: 61, Nomor: 2, Februari 2011


Nitrite Test for Optimizing Diagnosis of Asymptomatic Urinary Tract Infection in Pregnant Women

Table 2. Critical Appraisal from 4 Useful Articles Based on Their Validity, Importance and Applicability

Criteria Relevance Validity Importance

Independent and blind comparison

Posterior Probability when +

Posterior Probability when “


Negative Predictive Value
Positive Predictive Value
Similarity Intervention

Similarity Comparison

Similarity Outcome

Difference standard
with gold standard
Similarity Patient

Appropriate

Prevalence
Sensitivity

Specificity
Article

Lorentzon, et al - + + + + + + 0.15 0.99 0.64 0.94 0.06 0.47 0.05


Mignin, et al - + + - + + + 0.53 0.92 0.53 0.92 0.11 0.44 0.06
Norstrands, et al - + - + + - + 0.19 0.95 0.5 0.82
Tincello, et al + + + + + + + 0.19 0.99 0.69 0.96 0.05 0.47 0.04

from 3032 dipsticks, a probability of asymptomatic UTIs was found in the culture.1,4-7
0.08 (negative predicting value of 0.92) when dipstick test Mignini et al.,1 Lorentzon et al.,2 Norstrands et al.,3 and
was negative to both and 0.537 when nitrite or leukocyte Tincello et al.7 showed similar specificity ranging from 0.92-
esterase or both was positive (dipstick test positive). The 0.995. The sensitivity were also similar ranging from 0.15-
specificity is 0.92 and the sensitivity is 0.53. 0.192, but the sensitivity of Mignini et al.’s1 study cannot be
Lorentzon et al. 2 conducted a cross-sectional evalua- comparable since they used nitrite or/and leukocyte esterase.
tion for nitrite test and others with urine culture to detect Devile et al.8 also showed in their systematic review that
bacteriuria in 865 pregnant women. They considered posi- nitrites had the lowest sensitivity in pregnant women.
tive result for urine culture if the bacteria was >105 CFU/ml. In Indonesia, Cipto Mangunkusumo National General
They reported a probability for bacteriuria of 0.058 (negative Hospital particularly, the prevalence of asymptomatic UTIs
predicting value = 0.94) when nitrite was negative and 0.64 was 7.3%,9 similar to the prevalence in other works that were
when nitrite was positive. The sensitivity of nitrite test is analyzed (ranging from 5-11%). Thus, the posttest probabil-
0.15, while the specificity is 0.99. ity when nitrite was negative or positive would not also be
Norstrands et al.3 conducted a cross-sectional study so different. We calculated the post-test probability with the
to evaluate two groups of asymptomatic UTIs cases, one prevalence in Indonesia and we got the probability was 0.34-
group determined by urine culture (chemistrip urinalysis 0.59 when nitrite was positive and 0.04-0.06 when nitrite was
strips) and others by nitrite using automated urinalysis. The negative.
studied shown positive predictive value for nitrite was 0.50 The tests used commonly in the primary care settings
and negative predictive value was 0.82. The pre- and post- (i.e., nitrite testing and leukocyte esterase testing) have poor
test probability could not be calculated because the data test characteristics for detecting bacteriuria in asymptomatic
was not available. The sensitivity is 0.19 and specificity is persons.10 It was similar in our findings that nitrite had low
0.95. positive predictive value (0.5-0.69) to become a diagnosis
Tincello et al.7 conducted a prospective case series to tool for asymptomatic UTIs. Otherwise we found that nitrite
evaluate the performance of reagent test strips in screening had high negative predictive value (0.82-0.96) which was
pregnant women for asymptomatic UTIs at their first visit to good to rule out rule out the infection. Simerville et al. 4 men-
antenatal clinic. From 893 eligible samples, they reported the tioned in his comprehensive review that nitrite test was spe-
probability for urinary tract infection of 0.046 (negative pre- cific but not highly sensitive. On the other hand, Graham5
dicting value = 0.956) when nitrite was negative and 0.692 stated that the specificity of nitrite test was high and the
when nitrite was positive. sensitivity ranges from 35% to 85%. Combined with the leu-
kocyte esterase test, the sensitivity rose to 70-100% with
Discussion only a small decrease in specificity. However, Norstrands et
Asymptomatic UTIs is defined as the presence of at al.3 explained that when nitrite was analyzed as the single
least 100 000 organisms per milliliter of urine in an asymp- independent variable, it was significantly related to infection
tomatic patient. Particularly in asymptomatic patients, a di- (p=0.019) and when nitrite and leukocyte esterase were ana-
agnosis of UTI should be supported by an uropathogen lyzed together, nitrite was no significant statistically

Maj Kedokt Indon, Volum: 61, Nomor: 2, Februari 2011 79


Nitrite Test for Optimizing Diagnosis of Asymptomatic Urinary Tract Infection in Pregnant Women

(p=0.302). traction, dysuria, frequencies, fever, hematuria, and urgency


Although nitrite was not useful for diagnosing asymp- nocturial. In order to make sure that the patient did not have
tomatic UTIs in pregnant women, it may be used as a mul- any asymptomatic UTI, the physician planned to check urine
tiple testing strategies. Increasing sensitivity has also been culture and it would be done to the patient monthly. But, the
seen by adding leukocyte esterase as the part of the test. On patient refused to do so considering the financial problem.
the other hand, nitrite may be used to rule out asymptomatic Patient came from the low economic background. She can-
UTIs. On the results above, the post-test probabilities when not afford to pay the urine culture which is quite expensive.
nitrite was negative were under 0.09 in three from four ar- Because of it, the physician chose to do the urinalysis. The
ticles whether we used their prevalence or prevalence in In- nitrite test showed negative result implying the patient was
donesia, while the other can not be calculated because of free from asymptomatic UTI. Urine culture could then be
the lack of data. The results guide us to convince that our avoided and the patient was also safe from the threat of
patients are not having asymptomatic UTIs if the nitrite test asymptomatic UTI.
is negative. Deville et al.8 also stated that in pregnant woman
a negative result from both tests (nitrite and leukocyte es- References
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