Artikel Penelitian

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

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
76
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.
Maj Kedokt Indon, Volum: 61, Nomor: 2, Februari 2011 77
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
Asymptomatic UTIs occur in 5% to 10% of all pregnan-
cies. It becomes more frequent because of the remarkable
changes in the structure and function of the urinary tract
during pregnancy. Urinary stasis and the presence of
vesicoureteral reflux predispose pregnant women to upper
tract UTI.
1
Asymptomatic UTI is defined as a positive urine cul-
ture without specific symptoms. To diagnose asymptomatic
UTIs, urine culture is used as a gold standard test.
1-3
Unfor-
tunately, this diagnostic method is expensive, time-consum-
ing, laboratory- and microbiologist-dependent. These limi-
tations have led many physicians to use urinalysis as initial
step to evaluate the diagnosis of asymptomatic UTI.
1
There are numbers of other diagnostic tests those have
wide range of specificity and sensitivity for diagnosing as-
ymptomatic UTI, such as urine dipstick, dip slide, and direct
microscopy.
1,3
A urine dipstick measures specific gravity and
pH of the urine, as well as the presence of urobilinogen,
ketones, glucose, hemoglobin, leukocyte esterase and ni-
trite in the urine.
4
The urine dipstick is valued as a quick and
inexpensive test that requires little expertise to perform cor-
rectly.
5
Nitrite is one of the most useful indicators for asymp-
tomatic UTI diagnosis. Nitrite is produced from dietary ni-
trate by bacteria containing nitrate reductase.
4-6
Clinical Question
Is nitrite test accurate as diagnostic tools in pregnant
woman?
Methods
Search strategy
The search was conducted on PubMed,

Proquest,

Cochrane,

and Embase

on July 13
th
2010, using the search
tools containing keywords pregnant or gravid or pregnancy,
and urinalysis or nitrate, and urine culture and urinary tract
infections with synonyms and related terms (Table 1). Search
strategy, results and the inclusion and exclusion criteria are
shown in a flowchart (Figure 1).
Selection
After obtaining a result, a first selection was done by
using exclusion criteria (nonpregnant, therapeutic study, ex-
posure difference, comparison difference, review). There was
Nitrite Test for Optimizing Diagnosis of Asymptomatic Urinary Tract Infection in Pregnant Women
Nitrite Test for Optimizing Diagnosis of Asymptomatic Urinary Tract Infection in Pregnant Women
Maj Kedokt Indon, Volum: 61, Nomor: 2, Februari 2011 78
Table 1. Search Strategy Used in PubMed, Cochrane, Embase, and Proquest (Conducted on July 13
th
2010)
Engine Search Terms Resul ts
PubMed (pregnant OR pregnancyOR gravid) AND (urinalysisOR nitrateAND urine cultureAND 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.
From the selection and filtration, sixteen articles were ob-
tained, out of which only four full-text articles were avail-
able.
Critical Appraisal
Four relevant articles, Mignini et al.,
1
Lorentzon et al.,
2
Norstrands et al.,
3
and Tincello et al.,
7
were each appraised
in groups by 6 authors using standardized validity criteria
for diagnostic research. Several aspects were critically re-
viewed comprising of its validity, importance, and applicabil-
ity. The checklists used were obtained from www.bmj.com.
Results
Mignini, et al.
1
performed a study to evaluate the sensi-
tivity and specificity of chemical dipstick compared with urine
culture. This study was conducted in parallel with the WHO
multicentre double-blind randomized trial for asymptomatic
UTIs treatment. Dipstick test considered positive if both of
leukocyte and nitrite or either one positive. They reported,
Nitrite Test for Optimizing Diagnosis of Asymptomatic Urinary Tract Infection in Pregnant Women
Maj Kedokt Indon, Volum: 61, Nomor: 2, Februari 2011 79
Table 2. Critical Appraisal from 4 Useful Articles Based on Their Validity, Importance and Applicability
Cri teri a Relevance Validity Importance
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
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from 3032 dipsticks, a probability of asymptomatic UTIs was

0.08 (negative predicting value of 0.92) when dipstick test
was negative to both and 0.537 when nitrite or leukocyte
esterase or both was positive (dipstick test positive). The
specificity is 0.92 and the sensitivity is 0.53.
Lorentzon et al.
2
conducted a cross-sectional evalua-
tion for nitrite test and others with urine culture to detect
bacteriuria in 865 pregnant women. They considered posi-
tive result for urine culture if the bacteria was >10
5
CFU/ml.
They reported a probability for bacteriuria of 0.058 (negative
predicting value = 0.94) when nitrite was negative and 0.64
when nitrite was positive. The sensitivity of nitrite test is
0.15, while the specificity is 0.99.
Norstrands et al.
3
conducted a cross-sectional study
to evaluate two groups of asymptomatic UTIs cases, one
group determined by urine culture (chemistrip urinalysis
strips) and others by nitrite using automated urinalysis. The
studied shown positive predictive value for nitrite was 0.50
and negative predictive value was 0.82. The pre- and post-
test probability could not be calculated because the data
was not available. The sensitivity is 0.19 and specificity is
0.95.
Tincello et al.
7
conducted a prospective case series to
evaluate the performance of reagent test strips in screening
pregnant women for asymptomatic UTIs at their first visit to
antenatal clinic. From 893 eligible samples, they reported the
probability for urinary tract infection of 0.046 (negative pre-
dicting value = 0.956) when nitrite was negative and 0.692
when nitrite was positive.
Discussion
Asymptomatic UTIs is defined as the presence of at
least 100 000 organisms per milliliter of urine in an asymp-
tomatic patient. Particularly in asymptomatic patients, a di-
agnosis of UTI should be supported by an uropathogen
found in the culture.
1,4-7
Mignini et al.,
1
Lorentzon et al.,
2
Norstrands et al.,
3
and
Tincello et al.
7
showed similar specificity ranging from 0.92-
0.995. The sensitivity were also similar ranging from 0.15-
0.192, but the sensitivity of Mignini et al.s
1
study cannot be
comparable since they used nitrite or/and leukocyte esterase.
Devile et al.
8
also showed in their systematic review that
nitrites had the lowest sensitivity in pregnant women.
In Indonesia, Cipto Mangunkusumo National General
Hospital particularly, the prevalence of asymptomatic UTIs
was 7.3%,
9
similar to the prevalence in other works that were
analyzed (ranging from 5-11%). Thus, the posttest probabil-
ity when nitrite was negative or positive would not also be
so different. We calculated the post-test probability with the
prevalence in Indonesia and we got the probability was 0.34-
0.59 when nitrite was positive and 0.04-0.06 when nitrite was
negative.
The tests used commonly in the primary care settings
(i.e., nitrite testing and leukocyte esterase testing) have poor
test characteristics for detecting bacteriuria in asymptomatic
persons.
10
It was similar in our findings that nitrite had low
positive predictive value (0.5-0.69) to become a diagnosis
tool for asymptomatic UTIs. Otherwise we found that nitrite
had high negative predictive value (0.82-0.96) which was
good to rule out rule out the infection. Simerville et al.
4
men-
tioned in his comprehensive review that nitrite test was spe-
cific but not highly sensitive. On the other hand, Graham
5
stated that the specificity of nitrite test was high and the
sensitivity ranges from 35% to 85%. Combined with the leu-
kocyte esterase test, the sensitivity rose to 70-100% with
only a small decrease in specificity. However, Norstrands et
al.
3
explained that when nitrite was analyzed as the single
independent variable, it was significantly related to infection
(p=0.019) and when nitrite and leukocyte esterase were ana-
lyzed together, nitrite was no significant statistically
Maj Kedokt Indon, Volum: 61, Nomor: 2, Februari 2011
Nitrite Test for Optimizing Diagnosis of Asymptomatic Urinary Tract Infection in Pregnant Women
80
(p=0.302).
Although nitrite was not useful for diagnosing asymp-
tomatic UTIs in pregnant women, it may be used as a mul-
tiple testing strategies. Increasing sensitivity has also been
seen by adding leukocyte esterase as the part of the test. On
the other hand, nitrite may be used to rule out asymptomatic
UTIs. On the results above, the post-test probabilities when
nitrite was negative were under 0.09 in three from four ar-
ticles whether we used their prevalence or prevalence in In-
donesia, while the other can not be calculated because of
the lack of data. The results guide us to convince that our
patients are not having asymptomatic UTIs if the nitrite test
is negative. Deville et al.
8
also stated that in pregnant woman
a negative result from both tests (nitrite and leukocyte es-
terase) rules out infection while a positive nitrite test still
needs confirmation from another tests.
Conclusion
Urine nitrite examination alone may not be used for di-
agnosing asymptomatic UTIs in pregnant women, but it may
help to decide which patients need further laboratory tests.
When nitrite test is positive, further laboratory tests or urine
culture should be performed. On the other hand, negative
nitrite examination can convince us that the patient does not
have asymptomatic UTI. Thus, it avoids further laboratory
test such as unnecessary urine culture to find asymptomatic
UTI. This finding can be applied as a cost effective method
to rule out urinary tract infection, especially in facility with
limited recourses, and to prevent inappropriate antibiotic
prescription.
Recommendation for Clinical Case
This new insight in ruling out the asymptomatic UTIs
may be translated to clinical practice. For example, the fol-
lowing case was presented to us. A 32 years-old-female,
G2P1A0 on 16
th
weeks age of gestations, came to the hospi-
tal for the first time in order to do antenatal care. There were
no complaints from the patients e.g.: vaginal discharge, con-
traction, dysuria, frequencies, fever, hematuria, and urgency
nocturial. In order to make sure that the patient did not have
any asymptomatic UTI, the physician planned to check urine
culture and it would be done to the patient monthly. But, the
patient refused to do so considering the financial problem.
Patient came from the low economic background. She can-
not afford to pay the urine culture which is quite expensive.
Because of it, the physician chose to do the urinalysis. The
nitrite test showed negative result implying the patient was
free from asymptomatic UTI. Urine culture could then be
avoided and the patient was also safe from the threat of
asymptomatic UTI.
References
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et al. Accuracy of diagnostic tests to detect asymptomatic bacte-
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diagnosis of bacteriuria during pregnancy. Scand J Prim Health
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3. Nostrand JD, Junkins AD, Bartholdi RK. Poor Predictive Ability
of Urinalysis and Microscopic Examination to Detect Urinary
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