Urinary Tract Infection in Asymptomatic Newborns with Prolonged Unconjugated Hyperbilirubunemia: A Hospital based Observational study from Western Region of Nepal

Abstract

Background Urine culture is usually not a part of work-up for neonatal unconjugated hyperbilirubinemia; hence its prevalence remains unknown. Objective This study was done to determine the incidence of urinary tract infection (UTI) in asymptomatic newborns with prolonged unconjugated hyperbilirubinemia and to evaluate which other laboratory parameters are associated with UTIs. Method A prospective observational study where jaundiced newborns otherwise clinically well, were evaluated for UTI. The study was carried out in neonatal intensive care unit of Manipal Teaching Hospital, Pokhara from June 2012 -April 2013. The babies were divided in two groups group I- late prolonged jaundice and Group II - early physiological jaundice. Serum bilirubin, Septic screening and suprapubic urine sample analysis was performed for all subjects. Data was analyzed using SPSS version 16 and p 7lt; 0.05 was considered statistically significant. Result Of the 85 neonates, 33(38.8%) were females and 52(61.2%) males; 68(80%) were of term gestation and 17(20%) were preterms. The age at onset of jaundice for group I (n=53) was 13.6±4.88 days and for Group II (n= 32) was 5.0± 1.04 days. 11 /85 (12.9%) were diagnosed to have UTI [10 (90.9%) in group I and 1 in group II (9.01%] (p=0.04). UTI was more prevalent in group I [OR 7.20, 95% CI (0.87, 59.27)], more prevalent in male [OR 8.40, 95% CI (0.59, 74.13) and term babies of group I [OR 4.39, 95% CI (0.48, 39.82) when compared to Group II. Among other lab parameters only total WBC count was statistically significant (p=0.03). Escherichia coli was the predominant pathogen (45.45%) isolated. The sensitive antibiotics were aminoglycosides, fluroquinolones, nitrofurantoin and vancomycin and resistant antibiotics were most cephalosporins and penicillins for the isolated organisms. Conclusion The present study highlights significant association between late prolonged unconjugated hyperbilirubinemia and UTI. It is suggested that evaluation for UTI may be considered as a screening test for such cases.

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VOL. 14 | NO. 1 | ISSUE 53 | JAN-MAR 2016
1Department of Pediatrics
2Department of Community Medicine
Manipal College of medical science,
Pokhara, Nepal.
Corresponding Author
Tejesh Malla
Department of Pediatrics
Manipal College of Medical Science,
Pokhara, Nepal.
E-mail: tejeshmalla@hotmail.com
Citaon
Malla T, Sathian B, Malla KK, Adhikari S. Urinary tract
infecon in asymptomac newborns with prolonged
unconjugated hyperbilirubunemia: a hospital based
observaonal study from Western Region of Nepal.
Kathmandu Univ Med J 2016;53(1):41-6.
ABSTRACT
Background
Urine culture is usually not a part of work-up for neonatal unconjugated
hyperbilirubinemia; hence its prevalence remains unknown.
Objecve
This study was done to determine the incidence of urinary tract infecon (UTI) in
asymptomac newborns with prolonged unconjugated hyperbilirubinemia and to
evaluate which other laboratory parameters are associated with UTIs.
Method
A prospecve observaonal study where jaundiced newborns otherwise clinically
well, were evaluated for UTI. The study was carried out in neonatal intensive care
unit of Manipal Teaching Hospital, Pokhara from June 2012 -April 2013. The babies
were divided in two groups group I- late prolonged jaundice and Group II - early
physiological jaundice. Serum bilirubin, Sepc screening and suprapubic urine
sample analysis was performed for all subjects. Data was analyzed using SPSS version
16 and p < 0.05 was considered stascally signicant.
Result
Of the 85 neonates, 33(38.8%) were females and 52(61.2%) males; 68(80%) were of
term gestaon and 17(20%) were preterms. The age at onset of jaundice for group I
(n=53) was 13.6±4.88 days and for Group II (n= 32) was 5.0± 1.04 days. 11 /85 (12.9%)
were diagnosed to have UTI [10 (90.9%) in group I and 1 in group II (9.01%] (p=0.04).
UTI was more prevalent in group I [OR 7.20, 95% CI (0.87, 59.27)], more prevalent in
male [OR 8.40, 95% CI (0.59, 74.13) and term babies of group I [OR 4.39, 95% CI (0.48,
39.82) when compared to Group II. Among other lab parameters only total WBC count
was stascally signicant (p=0.03). Escherichia coli was the predominant pathogen
(45.45%) isolated. The sensive anbiocs were aminoglycosides, uroquinolones,
nitrofurantoin and vancomycin and resistant anbiocs were most cephalosporins
and penicillins for the isolated organisms.
Conclusion
The present study highlights signicant associaon between late prolonged
unconjugated hyperbilirubinemia and UTI. It is suggested that evaluaon for UTI
may be considered as a screening test for such cases.
KEY WORDS
Neonatal hyperbilirubinemia, newborn, sepc screening, urinary tract infecon
Urinary Tract Infecon in Asymptomac Newborns with
Prolonged Unconjugated Hyperbilirubunemia: A Hospital
based Observaonal study from Western Region of Nepal
Malla T,1 Sathian B,2 Malla KK,1 Adhikari S1
Original Arcle

KATHMANDU UNIVERSITY MEDICAL JOURNAL
Page 42
INTRODUCTION
Urinary tract infecon (UTI) is the most common disease
of the urogenital system.1 Its incidence varies from 0.1 to
1% among neonates.2,3 Hyperbilirubinemia in newborns
may be associated with bacterial infecon especially
UTI.4 Hence evaluaon of UTI should be a part workup
for neonatal hyperbilirubinemia but the current scienc
guidelines, that of the American Academy of Pediatrics
(AAP) do not recommend any evaluaon for UTI among
babies with hyperbilirubinemia.5 Above that the clinical
presentaon of UTI in neonates are nonspecic hence
the diagnosis may be missed. Considering these points
this study aimed to determine whether late prolonged
unconjugated hyperbilirubinemia in asymptomac
newborns is associated with UTI.
METHODS
A hospital based observaonal study was undertaken in
NICU of Manipal Teaching Hospital, Pokhara for a period of
10 months from June 2012 to April 2013. Ethical approval
was taken from the Instuonal Review Commiee,
Manipal Teaching hospital (IRC/MTH). The purpose of the
study was explained to the parents and a wrien consent
from parents of the neonates was also obtained before
the commencement of the study. Sample size was based
in a pilot study done before original study which showed
standard deviaon of age at onset of late prolonged
jaundice to be 4.9 and 1.2 for early physiological jaundice.
Sample size required for 95% condence interval and
allowable Error 1.5 and 0.5 were 41 and 23 respecvely.
But we have taken 53 for late jaundice and 32 for early
jaundice. Of the 85/200 (42.5%) who fullled the criteria
for inclusion were selected for the study. Inclusion criteria
was the newborns who presented with jaundice aer 24
hours of life and had no clinical symptoms and signs of any
disease. The Exclusion criteria were : a) Jaundice on rst 24
hours of life, b) those having clinical features of sepsis, c)
congenital and chromosomal anomalies ,d) Gestaon age ≤
28 weeks, e) preterm with complicaons, f) any features of
hemolysis, g) Rh and ABO incompability and h) suspected
metabolic diseases.
The populaon was divided in two groups: Group I [late
prolonged jaundice] – jaundice appearing or prolonged
more than 10 days for term and 14 days or later for preterm.
Group II [early physiological jaundice] – jaundice on 2-9
days for term and 2-13 days for preterm which is the me
for physiological jaundice to appear and then disappear.6
Detailed informaon including gestaon age, sex and
blood group for baby and mother were recorded. Then
all babies were examined and serum bilirubin (direct,
indirect), sepc screening (complete blood count with
peripheral smear, C-reacve protein,blood culture and
where required Cerebrospinal uid culture) and suprapubic
urine sample (taken under strict asepc precauon) was
analysed. Centrifuged samples of urine were stained and
then studied with High power eld; leukocyte count (more
than ve) and bacterial count (many, moderate, few, none)
were reported. All samples were sent for quantave
urine culture - single pathogen, obtained by suprapubic
puncture was considered as posive. In cases where the
urine culture was posive, ultrasound and renal funcon
tests were performed.
Data was collected, tabulated and analyzed using stascal
package SPSS 16.0 version. Microso Excel (2003) and SPSS
were used for plong gures. Chi- square test was used
to compare the parameters and p <0.05 was considered
stascally signicant.
RESULTS
Out of total 85 cases of neonatal hyperbilirubunemia there
were 52(61.20%) males and 33(38.80%) females, 68(80%)
were of term gestaon and 17(20%) were preterms.
Fiy three had late prolonged (Group I) and 32 had early
physiological jaundice (Group II) with mean age at onset of
jaundice 13.60±4.88 days and 5.00±1.04 days respecvely
(Table1).
Of the 11/85 (12.90%) cases had UTI based on posive urine
culture. Ten (90.90%) were in group I and only 1(9.09%)
was in group II (p<0.046) [g1 and table 2]. Escherichia
coli was the predominant pathogen (45.45%) isolated
followed by Klebsiella (27.27%), Enterococcus (18.18%) and
Staphylococcus aureus (9.09% %) shown in Table 1.
Table 1. Sample characteriscs.
Variables N % Total
Sex :
Male 52 61.20
85
Female 33 38.80
Gestaon age
Term 68 80
Preterm 17 20
Age at onset -jaundice
Group I (Late jaundice) 53 62.40
Group II (Early jaundice) 32 37.60
UTI
Yes 11 12.90
No 74 87.10
Growth in urine C/S
11
Escherichia coli 5 45.45
Enetrococcus 2 18.18
Klebsiella 327.27
Staphylococcus aureus 19.09
**Mean age at onset of jaundice
Group I (late) = 13.60±4.88 days
Group II (Early) = 5.00±1.04 days

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VOL. 14 | NO. 1 | ISSUE 53 | JAN-MAR 2016
Table 2. Relaon of variables in group I and group II with UTI
Variables UTI p value Odds rao
(95% CI)
Yes No
Total (N=85)
Group I(n=53) 10
18.9%
43
81.1%
0.04 7.21(0.87, 59.27)
Group II (n=32) 1
3.1%
31
96.9%
1
Male (n=52)
Group I(n=27) 7
25.9%
20
74.1%
0.055 8.40(0.59, 74.13)
Group II(n=25) 1
4%
24
96%
1
Female (n=33)
Group I (n=26) 3
11.5%
23
88.5%
1 -
Group II(n=7) 0
0%
7
100%
Term (n=68)
Group I(n=38) 5
13.2%
33
86.8%
0.218 4.39(0.48, 39.82)
Group II(n=30) 1
3.3%
29
96.7%
1
Preterm (n=17)
Group I(n=15) 5
33.3%
10
66.7%
1 -
Group II(n=2) 0
0%
2
100%
Table 3. Lab parameters of two groups.
Lab parameters Group Chi-
square
test
p value
I (n=53): II (n=32)
Total count
High 16(30.2%) 2(6.2%)
13.53 0.001
Normal 30 (56.6%) 30 93.8%)
Low 7(13.2%) 0 (0%)
Neutrophil count
High 18(34%) 4(12.5%) 4.72 0.029
Normal 35(66%) 28(87.5%)
CRP
Posive 38(71.7%) 15(46.9%)
5.24 0.022
Negave 15(28.3%) 17(53.1%)
Urine C/S
No growth 43(81.1%) 31(96.9%) 4.39 0.036
Growth 10 18.9%) 1 (3.1%)








GroupI GroupII
90.90%
9.09%
Fig1PercentageofUTIintwogroups(n=11)
GroupIGroupII
Figure 1. Percentage of UTI in two groups (n=11)
Table 4. The mean values ± SD of lab parameters in two groups:
Lab parameters Group N Mean ±SD p value
Total count Group I 53 10996 ±6844 0.01
Group II 32 8187±2757
Neutrophil Group I 53 64.566±18.49 0.005
Group II 32 3.750±15.25
CRP Group I 53 21.056±18.62 0.001
Group II 32 8.625 ±12.92
Total bilirubin Group I 53 18.611 ±3.05 0.497
Group II 32 18.196±2.48
Direct bilirubin Group I 53 1.196 ±0.52 0.073
Group II 32 1.450 ±0.67
Indirect bilirubin Group I 53 17.226 ±3.11 0.429
Group II 32 16.747 ±2.39

0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
70.00%
80.00%
90.00%
100.00%
E.Coli Klebsiella Enterococcus S.aureus Nogrowth
GroupI7.50% 5.70% 3.80% 1.90% 81.10%
GroupII 3.10% 0% 0% 0% 96.90%
Percentage
Fig2.Growthpatterninurinecultureintwogroups
Figure 2. Growth paern of urine culture in two groups.
Determinants of sociodemographic factors and UTI with
two groups by logisc regression.
Logisc regression analysis revealed that UTI was more
prevalent in group I [OR 7.209, 95% CI (0.877, 59.278)]
when compared to group II. Again UTI was more prevalent
in male of group I [OR 8.400 (0.592, 74.138) and Term
gestaon newborn of group I [OR 4.394 (0.485, 39.823)
when compared to Group II.
Other lab parameters
Lab parameters with mean values ± standard deviaon
(SD) in two groups are shown in table 3 and 4 where
total white blood cell (WBC) count, neutrophil count and
C-reacve protein (CRP) levels are stascally signicant.
The growth paern of urine culture in two groups is
highlighted in gure 2. Table 5 shows the anbiogram of
isolated organisms.
Original Arcle

KATHMANDU UNIVERSITY MEDICAL JOURNAL
Page 44
Table 5. Anmicrobial suscepbility paern of isolated
organisms from urine samples:
Organism Type of anbioc Suscepbility level
Sensive Resistant Not done
Esch-
erichia
coli =5
Gentamycin 41 0
Amikacin/nelmycin 4 0 1
Nitrofurantoin/ Norox 3 1 1
Imipenem 2 0 3
Ciprooxacin/cefotaxim 2 1 2
Ceriaxone 2 2 1
Amoxicillin / Piperacillin 1 3 1
Penicillin/ Cotrimoxa-
zole
10 4
Cefexim 1 1 3
Ampicillin 0 4 1
Cefazolin 03 2
Cefalexin 0 2 3
Klebsiella
(n=3)
Imipenem 3 0 0
Amikacin/nelmycin 2 0 1
Gentamicin/Ciprooxa-
cin/ vancomycin
2 1 0
Ceriaxone/cefotaxim/
Piperacillin
1 1 1
Cefazolin 1 2 0
Nitrofurantoin 1 0 2
Cotrimoxazole/Norox/
Cloxacillin
0 3 0
Ampi/ Amoxycillin/Ce-
falexin/ penicillin
0 1 2
Entero-
coccus
(n=2)
Gentamicin/Nitrofuran-
toin/ Vancomycin
2 0 0
Imipenem/ Ciprooxa-
cin
1 1 0
Norox/ Penicillin 1 0 1
Cefazolin /cefalexin/
Piperacillin/ cloxacillin /
ampicillin
0 1 1
Ceriaxone/cefotaxim /
Amoxicillin
0 2 0
Staphy-
lococcus
aureus
(n=1)
Gentamicin/Nitrofuran-
toin/Cefazoli/Vancomy-
cin/ Erythromycin
1 0 0
Amikacin/Nelmycin/
Cefotaxim /cefalexin/
Amoxicillin/penicillin/
Ciprooxacin/piperacil-
lin/ampicillin/Cefexim
0 1 0
may possibly be missed in such cases. American Academy
of Pediatrics (AAP) has published guidelines where they
recommend invesgaon for urinary tract infecon only in
direct hyperbilirubinemia.5 Mulple studies have described
paents with proven bacterial infecon, who developed
jaundice during the course of their illness.10-12 Other
studies, have noted that jaundice may be one of the rst
signs of bacterial sepsis in neonates in the rst few days
of life.13 But none of these studies have menoned about
UTI. According to this study 12.9% cases of asymptomac
babies with indirect hyperbilirubinemia had UTI. This was
reported to be 15 and 18% in other studies.14,15 Ghaemi et
al. studies evaluated late and prolonged icterus and found
UTI in 5.8%.4 The reason for lower incidence of UTI in laer
study maybe due to the fact that they had evaluated only
late and prolonged jaundice and had excluded physiological
jaundice whereas other studies including our study had
included physiological jaundice. Most of the studies have
evaluated late jaundice with UTI where mean age was at
range of 5-12.1 days.3,16 In our study we compared early
physiological jaundice with mean age at onset of jaundice
5.0±1.04 days with late prolonged jaundice with mean
age 13.60±4.88. To our knowledge, very few studies have
compared the incidence of UTI in asymptomac jaundiced
newborns between early physiological and late prolonged
jaundice. The incidence of UTI was found to be double in
late than early icterus (27.2% Vs 14.2%) in one study.15 We
also had high incidence of UTI in late prolonged jaundice
10/11 (90.9%) Vs 1/11 (10.1%) with p<0.046 and [OR
7.210, 95% CI (0.870, 59.270)]. Another study where
mean age at onset of jaundice was 8.9 days the incidence
of jaundice was found to be 8.2%.17 In this study, one
case with early physiological jaundice had UTI, however
in this case sepsis could have been the cause of jaundice
as some asymptomac babies had high total WBC count
and posive CRP. In a study from Turkey Hulya Bilgen et al.
emphasized on the importance of urine culture as roune
workup in all neonatal jaundice.9
Neonatal hyperbilirubunemia was more frequent in males
in our study. Similar nding was noted in another study.4
Again, unlike our study UTI was more prevalent in females,
suggesng that there are no sex predominance for UTI in
newborns.18 UTI was noted more in term gestaon babies
with prolonged jaundice in this study. Supporng our
study all culture posive newborns were of term gestaon
in Chamdine Omar et al. study and other two studies
reported that hyperbilirubinemia was the main clinical
nding among term newborns with UTI.19-21
Although Garcia et al. reported that an elevated
conjugated bilirubin fracon was more likely to have
UTI; none of our paents had a high direct bilirubin
level.22 The hyperbilirubinemia associated with UTIs can
be unconjugated and related to hemolysis caused by
Escherichia coli and other Gram-negave organisms, or
conjugated secondary to cholestasis.10,23-26 The mechanism
by which a UTI causes cholestasis is not clear, but possible
DISCUSSION
Hyperbilirubinemia is one of the presenng signs of
bacterial infecon in newborns, and its associaon with
urinary tract infecon (UTI) has been reported by several
Authors.8,9 Urinary evaluaon is rounely done in seriously
ill jaundiced newborns who present with features of
sepsis But in cases where newborns are asymptomac
and present with indirect hyperbilirubinemia urine
evaluaon is not a roune test hence the diagnosis of UTI

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VOL. 14 | NO. 1 | ISSUE 53 | JAN-MAR 2016
mechanisms include microcirculatory changes in the
liver, direct eects from bacterial products, and/or from
endotoxin-induced mediators.27,28 It is postulated that even
mild hemolysis can overload the immature liver conjugang
mechanism, leading to an increase in serum bilirubin levels.
Supporng the statement, E. coli is responsible for the
vast majority of UTI in young infants, E. coli (45.45%) was
the predominant pathogen isolated in this study followed
by Klebsiella (27.27%), enterococcus (18.18%) and Staph.
aureus (9.09% %). Similar organisms were isolated in other
studies but the anbioc sensivity paern diered.15 Other
lab parameters like total WBC count, neutrophil count and
CRP was signicantly elevated in prolonged jaundice cases
so maybe these could also be included as roune screening
tool even in asymptomac hyperbilirubinemic newborns.
CONCLUSION
UTI can occur in asymptomac, unconjugated neonatal
jaundice and was 12.9% in this study. In addion, UTI
was signicantly high in late prolonged unconjugated
hyperbilirubinema. Therefore, based on the result of this
study we suggest that urine culture to be considered as part
of the diagnosc evaluaon for asymptomac newborns
with late prolonged unconjugated hyperbilirubinemia.
Since this was just a hospital based study a sucient
large cohort study is essenal for beer conclusion. This
may help idenfy UTI before signs and symptoms become
evident and help in mely treatment.
ACKNOWLEDGEMENT
We thank the newborns and mothers of newborns who
parcipated in this study. We also express our gratude
to Professor and Head of department Dr. K Seshagiri
Rao, Manipal Teaching Hospital, Pokhara for granng us
permission to do the study. We are also thankful to Dr. Isha
Bhandari for her contribuon in collecng data.
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