Journal of Infection (1992) 25, 55-62
Urinary-tract infections in African neonates A b d u l k a r e e m I. Airede*
Department of Paediatrics, Jos University Teaching Hospital, Murtala Mohammed Way, Jos, Plateau State, Nigeria Accepted for publication I9 December I99I Summary During a 4-year period between January I987 and December I99o, 4I high-risk neonates with proven urinary tract infections (UTIs) were studied prospectively and compared with 55 control neonates. An incidence of 2"6 U T I s per Iooo live births was noted, amongst whom no obvious radiological abnormalities of the urinary tract were found. Significantly, more males than females developed UTIs, the ratio being 4"5 : I. Low-birth-weight babies were significantly more often affected than those of normal weight (P < 0"05). Staphylococcus aureus and Klebsiella spp. were the predominant pathogens isolated. Aetiologically, bacteraemia from sepsis was important. Most of the infants presented with a significantly higher incidence of pyrexia, abdominal distension, lethargy and jaundice (P < o.oi). The overall mortality rate of I7"I % was closely related to these associated problems. The relatively high incidence of U T I and the rarity of radiological abnormalities of the urinary tract in the African neonate contrast with previous reports in the literature and the reason is worthy of consideration. Despite the rarity of urinary-tract anomalies, a continuous surveillance of the trend of neonatal U T I and its outcome is recommended.
Introduction T h e urinary tract is often the site of bacterial infection during childhood. U r i n a r y - t r a c t infection ( U T I ) is fairly c o m m o n in infants and children, in w h o m there is a female p r e p o n d e r a n c e except during early infancy. In view of the frequent association with anomalies of the urinary tract, Smellie et al. 1 described 200 children with U T I , of w h o m I88 ( 9 4 % ) were investigated b y excretory u r o g r a p h y or micturating (voiding) cysto-urethrography, or both. U r i n a r y - t r a c t infection is responsible for approximately 20 % of the endstage renal failure which occurs in E u r o p e a n p a t i e n t s ) Vesico-ureteral reflux is k n o w n to be causally related to such infections and therefore the early identification of patients with reflux could offer the prospect of preventing some cases of renal failure b y appropriate intervention before severe damage has occurred. T h e bulk of the p u b l i s h e d evidence suggests that scarring is present at the first investigation in most of those children in w h o m renal damage develops. 3'4 A further study also showed unequivocally that n e w scars can develop in previously u n d a m a g e d and d a m a g e d kidneys. ~ It is difficult to estimate the exact incidence of U T I in the neonate, and yet diagnosis at this time m a y reduce morbidity. T h e condition has long been said * Address correspondence to : Dr A. I. Airede, Department of Paediatrics, College of Medical Sciences, University of Maiduguri, Barna Road, Maiduguri, Borno State, Nigeria.
o163-4453/92./o4oo55 +08 $03.00/0
© I99z The British Society for the Study of Infection
56
A.I. AIREDE
to have a serious prognosis. 6'7 Reports of U T I in the neonate have dwelt mainly on the frequency, signs, symptoms and associated urological abnormalities. 8-11 T h e value of leucocyturia as an indication of U T I remains a matter for discussion and the final diagnosis depends on quantitative bacterial culture of the urine. 1~-14 T h e pattern of U T I in European and North American neonates suggested that it would be appropriate to investigate prospectively the trend of this type of infection in the African neonate, especially in relation to the incidence and prognosis. Materials a n d m e t h o d s
T h e study cohort comprised all high-risk infants admitted to the Special Care Baby Unit (SCBU) of the Jos University Teaching Hospital ( J U T H ) , Plateau State of Nigeria, during the 4 years between I January 1987 and 31 December 1990. T h e S C B U and J U T H are active Regional, Tertiary (Referral) intensivecare centres subserving contiguous states in the Middle-Belt of the country. J U T H also has an active obstetric service capable of handling all complicated cases, and has over 2ooo live births a year. Referrals are readily accepted and come from general, missionary and cottage hospitals and maternity homes. High-risk infants in this study comprised babies who were asphyxiated at birth, preterm, low birth weight (less than 25oo g), septicaemic, infants of diabetic mothers, those delivered by caesarean section (admitted as routine unit policy for 24-48 h observation), infants born after prolonged rupture of the fetal membranes (PROM) occurring more than 24 h before delivery, babies born of pre-eclamptic and eclamptic mothers, those with suspected sepsis and those with pathological hyperbilirubinaemia. Infants with congenital malformations a n d / o r obstructive uropathy were excluded. Such exclusions were based on clinical grounds, with radiological confirmation in some cases, e.g. presence of any malformation involving the gastro-intestinal or urogenital systems, lower intestinal obstruction, volvulus, m e c o n i u m plugs/ileus, prune-belly syndrome, posterior urethral valves and palpable renal masses, etc. These exclusions were an attempt to reduce the contribution of factors that might enhance the pathogenesis of U T I . It was also worth noting the progress/outcome of U T I that commenced ab initio without interplay of hereditary components. Infants who presented with suspected sepsis, delivery following P R O M or maternal peripartum pyrexia were screened for possible infection. This included blood, urine and C S F cultures, and, when indicated, stool culture. T h e C S F was also analysed for glucose, protein and cells. Each baby also had a blood count and glucose estimation. Radiographs were taken when clinically appropriate. T h e diagnosis of U T I was based on clinical grounds plus abnormal urinary findings. All urine samples were obtained by suprapubic bladder aspiration as described elsewhere. 14 Freshly obtained urine was collected into a sterile receptacle containing IO m g of boric acid and was analysed within 90 min. An aliquot of centrifuged urine was subjected to microscopic examination. A mixed uncentrifuged sample was plated on to MacConkey's agar and cysteine lactose electrolyte-deficient m e d i u m ( C L E D ) and incubated for 18-24 h at
Neonatal urinary-tract infections
57
37 °C. All pathogens isolated were identified by standard microbiological techniques. U T I was considered to be present if there was a positive culture from the suprapubic urine (SPU). Babies with leucocyturia in the absence of positive S P U culture were excluded. All infants with proven U T I were evaluated radiologically with intravenous urography (IVU) and micturating cystourethrography (MCU) within 2-4 weeks after treatment. Controls
One or two babies were selected as controls for each infant with U T I . T h e y had no congenital abnormality. T h e y had been admitted consecutively before or after each infant with U T I and were matched in respect of birth weight and gestational age. No attempt was made to match the controls and infants with U T I for any other morbidity. Treatment regimen
A standard protocol of treatment prevailed t h r o u g h o u t the study period. This included a combination of gentamicin 5"o-7"5 m g / k g / d a y Iv or IM in two or three divided doses and cloxacillin Ioo m g / k g / d a y Iv in four divided doses for IO days. Other antimicrobials were substituted according to the organisms and their sensitivity patterns when these became available. A final confirmatory sterile S P U was obtained before the antibiotics were discontinued. Statistical analysis was by Student's t and Chi-square (X2) tests with 95 % confidence intervals. Results
D u r i n g the 4-year study period there were 839I live births of which IOiI ( I 2 % ) were of low birth weight (less than 25o0 g). T h e total n u m b e r of neonates admitted into SCBU was 2797, of which I64O (58"6%) were delivered in J U T H (in-born). Forty-one neonates had proven U T I ; 22 (53"7 %) were in-born while I9 (46"3 %) were out-born, having been referred from peripheral hospitals (Table I). T h e r e was no significant difference in birth weight between those in the study and control groups; with a mean (S.D.) of 2950 g (9Io) and 3 I5o g (97o), respectively. T h e mean (S.D.) gestational age in weeks was also similar: 38"5 (3"7) and 38.7 (2"7), respectively. Incidence
T h e overall incidence of U T I s in the S C B U was I 4 ' 7 / I o o o admissions. T h e out-born neonates had a slightly higher incidence: I6"4/IOOO admissions (Table I). T h e incidence during individual years of the study period was fairly constant. T h e r e were 2183, 2250, 2284 and I674 live births, with 2"7, 2"7, 2.6 and 2"4 U T I s per thousand respectively. T h e overall incidence of U T I s among the 839I neonates was 2"6/IOOO live births and was m u c h higher among babies of low birth weight than in those of normal weight: I4"8/IOOO vs. I.o/IOOO live births, and this difference was significant (X2 --- 4'84; P < o'o5).
A. I. AIREDE
58
T a b l e I Incidence of urinary tract infections in neonates admitted to the Special Care Baby Unit
Live births Birth weights 2500 g Birth weight/> 25oo g Total admissions to SCBU In-born Out-born
Total
Babies with UTI
Incidence of UTI (per lOOO)
8391 IOI I 738o 2797 164o i I57
22 15 7 41 22 19
2-6 14"8 I.O 14"7 13.4 I6"4
T a b l e II Sex distribution and outcome of neonatal urinary-tract infections
Survived Died
M
F
31
3
I
6
The difference was highly significant; X2 = 20'03 ; P < o.oooi. P r e d i s p o s i n g p e r i n a t a l factors
T h e r e was no significant difference between the study cohort and the control group in respect o f antepartum haemorrhage, P R O M , chorioamnionitis, prolonged labour, maternal eclampsia and maternal p e r i p a r t u m pyrexia, all well-known adverse obstetric factors. Sex d i s t r i b u t i o n
T h e sex ratio of the infants with U T I was M : F 3"6:1. T h u s there was male p r e p o n d e r a n c e in this group, in contrast to the 2" I : I ratio in the control group. T h i s difference is not statistically significant. H o w e v e r , the male preponderance was significant in the group o f in-born infants, 18 males to four females (4"5:1), in view of the fact that the usual sex ratio for live births at J U T H during the period of study was I'3 : I. D e s p i t e this, most of the cases that died were females in a highly significant ratio of M : F I : 6 (Table II). Seventeen (77"3 %) of the in-born babies presented within the first 48 h of life while five (22"7 %) presented thereafter. In contrast, I5 (79 %) of the outborn cases presented after 48 h of life. T a b l e I I I summarises the clinical features of neonates with U T I and the controls. T h e y were similar in respect o f birth weight and gestational age. T h o s e with U T I presented with a significantly higher incidence of pyrexia, abdominal distension, jaundice and lethargy. T h e study further highlighted the fact that failure to thrive, t h o u g h not a specific feature of U T I , was of some importance. T a b l e IV lists the associated p r o b l e m s causing most concern in both groups. Septicaemia, omphalitis and osteomyelitis were significantly
Neonatal urinary-tract infections
59
Table I I I Summary of features in 4I neonates with U T I and 55 controls
Features
4I neonates with UTI N u m b e r (%)
55 controls N u m b e r (%)
Pyrexia T >~ 38 °C Hypotherrnia, T < 36 °C Iaundice Abdominal distension Asphyxia ( A P G A R ~< 5) Failure to thrive Vomiting Diarrhoea Lethargy
26 (63"4) 14 (34-i) 3o (73"2) I3 (3I'7) I t (26.8) IO (24"4) 9 (22.o) 9 (22-o) 8 (I9"5)
7 (I2"7) o (o) 5 (9"I) o (o) 9 (I6"4) Io (I8'2) 7 (I2'7) 4 (7"3) o (o)
These differences were significant (X2 = 8I'72; P < o'ooI).
Table IV Problems causing most concern in 4I neonates with U T I and 55 controls
Clinical problems Septicaemia* Osteomyelitis* Bronchopneumonia Meningitis* Omphalitis* Anaemia Hypocalcaemia Impetigo
Neonates with UTI N u m b e r (%) 20 5 4 I 7 I I i
(48'8) (I2.2) (9 '8) (2'4) (IT"I) (2"4) (2'4) (2"4)
Controls N u m b e r (%) o I 3 o 2 2 3 2
(I.8) (5"5) (o) (3"6) 3'6) (5"5) (3"6)
* These associated clinical problems were present in significantly greater numbers in neonates with U T I (X~ = 20"5; P < o.oi).
more frequent in neonates with U T I than in the controls. Most of these problems were of infective origin. T h e r e was no relation between leucocyturia and positive urine culture. T w e n t y - s e v e n (65"8%) neonates with positive cultures had less than 5 W B C / r a m 3 on urine microscopy, io (24"4 %) had more than Io W B C / m m 3 and the remaining four (9"8 %) had 5 - I o W B C / m m 3. T h e pathogens isolated from the urine were: Klebsiella spp. I5 neonates (36"6 ~/o); Escherichia coli 6 (I4"6 %); Pseudomonas aeruginosa 5 (I2-2 %); Alkaligenesfaecalis 3 (7"3 ~/o) and Staphylococcus aureus 12 (29"3 %). These pathogens were all sensitive to gentamicin while 83"3 % of the S. aureus were sensitive to cloxacillin.
Prognosis Intravenous urography and micturating cysto-urethrography were normal in the babies with U T I . In particular, all grades of VUR/~,ls other features of neuropathic bladder with functional obstruction a n d / o r bladder-neck narrow-
60
A.I. AIREDE
ing were excluded. A further episode of bacteriuria after treatment was not observed during follow-up periods of between 3 months and 3 years. T h e overall mortality from U T I was I7"1%. T h e mortality was frequently related to the associated problems (Table IV). F o u r (2o %) of the neonates with septicaemia and two (4o %) with osteomyelitis died, as did the infant with meningitis. Discussion
This study has revealed a relatively high incidence of U T I s of 2-6/Iooo live births. T h e incidence found in this high-risk population contrasts with previous findings of I ' I - I ' 4 per Iooo births. 1'1°'17'18 Furthermore, the failure to demonstrate urinary-tract abnormalities in spite of radiological evaluation differs from findings reported from Europe and N o r t h America. 1,2A°'11,18 These reports have stressed the high frequency of V U R and other obstructive uropathies associated with neonatal U T I . Smellie e t a l . ~ had noted 35-5o % abnormalities in those investigated after their first infection. T h e reason for the high incidence of U T I and the associated rarity of urinary-tract abnormalities in the African neonate is uncertain. It can be postulated that it may relate to an inherent genetic e n d o w m e n t of a more mature muscularity. T h e detrusor muscle could thereby be more easily relaxed, and hence assist in reducing residual urine. An important but poorly recognised feature of recurrent urinary-tract infections and V U R is constipation, ~9 though it was not found in this study. T h e poor perineal muscular relaxation that accompanies detrusor instability impedes both bladder and rectal emptying. Although the prognosis in respect of the immediate outcome of U T I s in neonates was poor, the mortality being I7"I %, the long-term result at 3"5 years follow-up is good. Unlike the findings of previous reports, ~°'~s'19 no case of progressive renal scarring was seen. This was understandable in view of the absence of recurrent U T I s and urinary-tract anatomical abnormalities and was in contrast to a recurrence rate of 26 ~o noted elsewhere. 10 T h e poor immediate outcome was associated with intercurrent problems but the mortality rate compares favourably with other studies. 9,1°,17,1s T h e belief that positive bacterial urine cultures are not proportional to the leucocyturia ~2'17 was confirmed in this study, and indicates that the diagnosis of urinary-tract infections required positive urine cultures. 1~.,3 T h e m e t h o d of urine collection is also important, and the suprapubic aspiration used in this study is satisfactory and allows reliable interpretation. 18'~4 T h e significant finding (P < o'ooI) of non-specific signs such as pyrexia, jaundice, abdominal distension, omphalitis and lethargy should suggest U T I in high-risk neonates. T h e importance of omphalitis has previously been noted 2° and the finding of jaundice as one of the major signs is in agreement with other reports, ls'2~ Adverse perinatal conditions such as P R O M , chorioamnionitis, antepartum, haemorrhage, maternal peripartum pyrexia and birth asphyxia were not significant factors in predisposing to neonatal U T I in our series, which is at variance with other reports. 9 T h e increased predisposition to U T I of infants with septicaemia and osteomyelitis supports the concept that haematogenous invasion of the kidney is a frequent cause of neonatal U T I . 22
N e o n a t a l u r i n a r y - t r a c t infections
61
K l e b s i e l l a spp., followed by E. coli, were the p r e d o m i n a n t G r a m - n e g a t i v e pathogens isolated. T h i s t r e n d has been reported elsewhere. I°'18 H o w e v e r , S. a u r e u s ranked second amongst all pathogens and was the only Gram-positive microbe isolated in this study. T h i s is f u r t h e r evidence for the haematogenous invasion of the kidney because m a n y of our babies also had S . aureus septicaemia as an associated problem. T h i s finding, although at variance with other reports, was u n d e r s t a n d a b l e in view of a previous outbreak of this p a t h o g e n in our Unit. 23 M u c h still needs to be done in this c o u n t r y to p r o m o t e good health care during delivery and reduce the high incidence of bacteraemia. T h e m a r k e d overall male preponderance, in agreement with virtually all other studies, is w o r t h noting. T h e difference was statistically significant (P < o'o5) w h e n the i n - b o r n infant findings were analysed. However, given the susceptibility of males to sepsis because of their possession of a single X - c h r o m o s o m e t h o u g h t to contain a gene which regulates the synthesis of i m m u n o g l o b u l i n s , 2a'~5 it is surprising that the mortality rate was significantly higher in females (P < o.0oi): T a b l e II. T h e sexes may have been infected with equal frequency, but the infection m a y have been more self-limited or better contained in the males. Other, as yet u n d e t e r m i n e d factors m a y be operative in this mortality bias. I n conclusion, a relatively high incidence of neonatal U T I s but with u r i n a r y - t r a c t abnormalities a rarity in Nigerian neonates, suggests that the incidence of end-stage renal disease consequent u p o n infection will be low. Despite this rarity of u r i n a r y - t r a c t anomalies, a continuous surveillance of the t r e n d of U T I and its outcome is r e c o m m e n d e d . S i x - m o n t h l y and yearly evaluations with I V U and M C U is suggested.
(I thank the resident doctors and nursing personnel for the high standard of care given to my patients and Mr Williams Orji for secretarial assistance.) References
i. Smellie JM, Hodson CJ, Edwards D, Normand ICS. Clinical and radiological features of urinary infection in childhood. Br Med J 1964; ii: 1222-1226. 2. Broyer M, Rizzoni G, Brunner FP et al. Combined report on regular dialysis and transplantation of children in Europe, XIV, 1984. Proc Eur Dial Transplant Assoc I984; 5: 55-79. 3. Hodson J. Reflux nephropathy: a personal historical review. A J R I98I; 137: 451-461. 4. Berg UB, Johansson SB. Age as a main determinant of renal functional damage in urinary tract infection. Arch Dis Child 1983; 58:963-969 • 5. Smellie JM, Ransley PG, Normand ICS, Prescod N, Edwards D. Development of new renal scars : a collaborative study. Br Med J 1985; 29o : I957-I96O. 6. Smallpiece V. Urinary tract infection in childhood and its relevance to disease in adult life. London : W. Heinemann, 1968. 7. Lincoln K, Winberg J. Studies of urinary tract infections in infancy and childhood. II. Quantitative estimation of bacteria in unselected neonates with special reference to occurrence of asymptomatic infections. Aeta Paediatr Scand I964; 53: 3o7-321. 8. James U. Urinary infection in the newborn. Lancet 1959; ii: Iooo-loo2. 9. Littlewood JM. 66 infants with urinary tract infection in first month of life. Arch Dis Child 1972; 47: 218-225. IO. Bergstrom T, Larson H, Lincoln K, Winberg J. Studies of urinary tract infections in infancy and childhood. XII. Eighty consecutive patients with neonatal infection. J Pediatr 1972; 8o: 858-866.
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I I. Drew JH, Acton CM. Radiological findings in newborn infants with urinary infection. Arch Dis Child r976; 5x : 528-53 o. I2. Littlewood JM. White cells and bacteria in voided urine of healthy newborns. Arch Dis Child z97I ; 46: r67-I72. r 3. Bailey RR, Little PJ. Suprapubic bladder aspiration diagnosis of urinary tract infection. Br M e d J I969; I: 293-295. I4. Saccharov L, Pryles CV. Further experience with the use of percutaneous suprapubic aspiration of the urinary bladder. Bacteriological studies in 654 infants and children. Pediatrics i969; 43: ioi8-IO22. IS. Shah KJ, Robins DG, White RHR. Renal scarring and vesicoureteric reflux. Arch Dis Child I978; 53: 2IO-217. I6. Lebowitz RL, Olbing H, Parkkulainen KV, Smellie JM, Tamminen-Mobius TE. International system of radiographic grading of vesicoureteric reflux. Pediatr Radiol I985; 15: I05-I09. I7- Gower PE, Husband P, Coleman JC, Snodgrass GJA. Urinary infection in two selected neonatal populations. Arch Dis Child I97O; 45: 259-263, I8. Maherzi M, Guidard JP, Torrado A. Urinary tract infection in high-risk newborn infants. Pediatrics I978; 62 : 521-523. I9. White RHR. Management of urinary tract infection. Arch Dis Child I987; 62: 42z-427. 20. Airede A'KI. Pathogens in neonatal omphalitis. J Trop Pediatr I992; 38(I). 2I. Ng SH, Rawstron. Urinary tract infections presenting with jaundice. Arch Dis Child x97I ; 46: z73-I76. 22. Klein JO. Bacterial infections of the urinary tract. In: Remington JS, Klein JO, Eds, Infectious Diseases of the Fetus and Newborn 2rid ed., Philadelphia : WB Saunders, z983. 23. Airede A'KI. Neonatal septicemia in an African city of high altitude. J Trop Pediatr I992; 38(4). 24. Alojipan LC, Andrews BF. Neonatal sepsis. Clin Pediatr I98I; 14: I8I-I83. 25. Rhodes K, Markham RL, Maxwell PM, Monk-Jones ME. Immunoglobulins and the Xchromosome. Br M e d J I969; 3: 439-44I.
Urinary-tract infections in African neonates A b d u l k a r e e m I. Airede*
Department of Paediatrics, Jos University Teaching Hospital, Murtala Mohammed Way, Jos, Plateau State, Nigeria Accepted for publication I9 December I99I Summary During a 4-year period between January I987 and December I99o, 4I high-risk neonates with proven urinary tract infections (UTIs) were studied prospectively and compared with 55 control neonates. An incidence of 2"6 U T I s per Iooo live births was noted, amongst whom no obvious radiological abnormalities of the urinary tract were found. Significantly, more males than females developed UTIs, the ratio being 4"5 : I. Low-birth-weight babies were significantly more often affected than those of normal weight (P < 0"05). Staphylococcus aureus and Klebsiella spp. were the predominant pathogens isolated. Aetiologically, bacteraemia from sepsis was important. Most of the infants presented with a significantly higher incidence of pyrexia, abdominal distension, lethargy and jaundice (P < o.oi). The overall mortality rate of I7"I % was closely related to these associated problems. The relatively high incidence of U T I and the rarity of radiological abnormalities of the urinary tract in the African neonate contrast with previous reports in the literature and the reason is worthy of consideration. Despite the rarity of urinary-tract anomalies, a continuous surveillance of the trend of neonatal U T I and its outcome is recommended.
Introduction T h e urinary tract is often the site of bacterial infection during childhood. U r i n a r y - t r a c t infection ( U T I ) is fairly c o m m o n in infants and children, in w h o m there is a female p r e p o n d e r a n c e except during early infancy. In view of the frequent association with anomalies of the urinary tract, Smellie et al. 1 described 200 children with U T I , of w h o m I88 ( 9 4 % ) were investigated b y excretory u r o g r a p h y or micturating (voiding) cysto-urethrography, or both. U r i n a r y - t r a c t infection is responsible for approximately 20 % of the endstage renal failure which occurs in E u r o p e a n p a t i e n t s ) Vesico-ureteral reflux is k n o w n to be causally related to such infections and therefore the early identification of patients with reflux could offer the prospect of preventing some cases of renal failure b y appropriate intervention before severe damage has occurred. T h e bulk of the p u b l i s h e d evidence suggests that scarring is present at the first investigation in most of those children in w h o m renal damage develops. 3'4 A further study also showed unequivocally that n e w scars can develop in previously u n d a m a g e d and d a m a g e d kidneys. ~ It is difficult to estimate the exact incidence of U T I in the neonate, and yet diagnosis at this time m a y reduce morbidity. T h e condition has long been said * Address correspondence to : Dr A. I. Airede, Department of Paediatrics, College of Medical Sciences, University of Maiduguri, Barna Road, Maiduguri, Borno State, Nigeria.
o163-4453/92./o4oo55 +08 $03.00/0
© I99z The British Society for the Study of Infection
56
A.I. AIREDE
to have a serious prognosis. 6'7 Reports of U T I in the neonate have dwelt mainly on the frequency, signs, symptoms and associated urological abnormalities. 8-11 T h e value of leucocyturia as an indication of U T I remains a matter for discussion and the final diagnosis depends on quantitative bacterial culture of the urine. 1~-14 T h e pattern of U T I in European and North American neonates suggested that it would be appropriate to investigate prospectively the trend of this type of infection in the African neonate, especially in relation to the incidence and prognosis. Materials a n d m e t h o d s
T h e study cohort comprised all high-risk infants admitted to the Special Care Baby Unit (SCBU) of the Jos University Teaching Hospital ( J U T H ) , Plateau State of Nigeria, during the 4 years between I January 1987 and 31 December 1990. T h e S C B U and J U T H are active Regional, Tertiary (Referral) intensivecare centres subserving contiguous states in the Middle-Belt of the country. J U T H also has an active obstetric service capable of handling all complicated cases, and has over 2ooo live births a year. Referrals are readily accepted and come from general, missionary and cottage hospitals and maternity homes. High-risk infants in this study comprised babies who were asphyxiated at birth, preterm, low birth weight (less than 25oo g), septicaemic, infants of diabetic mothers, those delivered by caesarean section (admitted as routine unit policy for 24-48 h observation), infants born after prolonged rupture of the fetal membranes (PROM) occurring more than 24 h before delivery, babies born of pre-eclamptic and eclamptic mothers, those with suspected sepsis and those with pathological hyperbilirubinaemia. Infants with congenital malformations a n d / o r obstructive uropathy were excluded. Such exclusions were based on clinical grounds, with radiological confirmation in some cases, e.g. presence of any malformation involving the gastro-intestinal or urogenital systems, lower intestinal obstruction, volvulus, m e c o n i u m plugs/ileus, prune-belly syndrome, posterior urethral valves and palpable renal masses, etc. These exclusions were an attempt to reduce the contribution of factors that might enhance the pathogenesis of U T I . It was also worth noting the progress/outcome of U T I that commenced ab initio without interplay of hereditary components. Infants who presented with suspected sepsis, delivery following P R O M or maternal peripartum pyrexia were screened for possible infection. This included blood, urine and C S F cultures, and, when indicated, stool culture. T h e C S F was also analysed for glucose, protein and cells. Each baby also had a blood count and glucose estimation. Radiographs were taken when clinically appropriate. T h e diagnosis of U T I was based on clinical grounds plus abnormal urinary findings. All urine samples were obtained by suprapubic bladder aspiration as described elsewhere. 14 Freshly obtained urine was collected into a sterile receptacle containing IO m g of boric acid and was analysed within 90 min. An aliquot of centrifuged urine was subjected to microscopic examination. A mixed uncentrifuged sample was plated on to MacConkey's agar and cysteine lactose electrolyte-deficient m e d i u m ( C L E D ) and incubated for 18-24 h at
Neonatal urinary-tract infections
57
37 °C. All pathogens isolated were identified by standard microbiological techniques. U T I was considered to be present if there was a positive culture from the suprapubic urine (SPU). Babies with leucocyturia in the absence of positive S P U culture were excluded. All infants with proven U T I were evaluated radiologically with intravenous urography (IVU) and micturating cystourethrography (MCU) within 2-4 weeks after treatment. Controls
One or two babies were selected as controls for each infant with U T I . T h e y had no congenital abnormality. T h e y had been admitted consecutively before or after each infant with U T I and were matched in respect of birth weight and gestational age. No attempt was made to match the controls and infants with U T I for any other morbidity. Treatment regimen
A standard protocol of treatment prevailed t h r o u g h o u t the study period. This included a combination of gentamicin 5"o-7"5 m g / k g / d a y Iv or IM in two or three divided doses and cloxacillin Ioo m g / k g / d a y Iv in four divided doses for IO days. Other antimicrobials were substituted according to the organisms and their sensitivity patterns when these became available. A final confirmatory sterile S P U was obtained before the antibiotics were discontinued. Statistical analysis was by Student's t and Chi-square (X2) tests with 95 % confidence intervals. Results
D u r i n g the 4-year study period there were 839I live births of which IOiI ( I 2 % ) were of low birth weight (less than 25o0 g). T h e total n u m b e r of neonates admitted into SCBU was 2797, of which I64O (58"6%) were delivered in J U T H (in-born). Forty-one neonates had proven U T I ; 22 (53"7 %) were in-born while I9 (46"3 %) were out-born, having been referred from peripheral hospitals (Table I). T h e r e was no significant difference in birth weight between those in the study and control groups; with a mean (S.D.) of 2950 g (9Io) and 3 I5o g (97o), respectively. T h e mean (S.D.) gestational age in weeks was also similar: 38"5 (3"7) and 38.7 (2"7), respectively. Incidence
T h e overall incidence of U T I s in the S C B U was I 4 ' 7 / I o o o admissions. T h e out-born neonates had a slightly higher incidence: I6"4/IOOO admissions (Table I). T h e incidence during individual years of the study period was fairly constant. T h e r e were 2183, 2250, 2284 and I674 live births, with 2"7, 2"7, 2.6 and 2"4 U T I s per thousand respectively. T h e overall incidence of U T I s among the 839I neonates was 2"6/IOOO live births and was m u c h higher among babies of low birth weight than in those of normal weight: I4"8/IOOO vs. I.o/IOOO live births, and this difference was significant (X2 --- 4'84; P < o'o5).
A. I. AIREDE
58
T a b l e I Incidence of urinary tract infections in neonates admitted to the Special Care Baby Unit
Live births Birth weights 2500 g Birth weight/> 25oo g Total admissions to SCBU In-born Out-born
Total
Babies with UTI
Incidence of UTI (per lOOO)
8391 IOI I 738o 2797 164o i I57
22 15 7 41 22 19
2-6 14"8 I.O 14"7 13.4 I6"4
T a b l e II Sex distribution and outcome of neonatal urinary-tract infections
Survived Died
M
F
31
3
I
6
The difference was highly significant; X2 = 20'03 ; P < o.oooi. P r e d i s p o s i n g p e r i n a t a l factors
T h e r e was no significant difference between the study cohort and the control group in respect o f antepartum haemorrhage, P R O M , chorioamnionitis, prolonged labour, maternal eclampsia and maternal p e r i p a r t u m pyrexia, all well-known adverse obstetric factors. Sex d i s t r i b u t i o n
T h e sex ratio of the infants with U T I was M : F 3"6:1. T h u s there was male p r e p o n d e r a n c e in this group, in contrast to the 2" I : I ratio in the control group. T h i s difference is not statistically significant. H o w e v e r , the male preponderance was significant in the group o f in-born infants, 18 males to four females (4"5:1), in view of the fact that the usual sex ratio for live births at J U T H during the period of study was I'3 : I. D e s p i t e this, most of the cases that died were females in a highly significant ratio of M : F I : 6 (Table II). Seventeen (77"3 %) of the in-born babies presented within the first 48 h of life while five (22"7 %) presented thereafter. In contrast, I5 (79 %) of the outborn cases presented after 48 h of life. T a b l e I I I summarises the clinical features of neonates with U T I and the controls. T h e y were similar in respect o f birth weight and gestational age. T h o s e with U T I presented with a significantly higher incidence of pyrexia, abdominal distension, jaundice and lethargy. T h e study further highlighted the fact that failure to thrive, t h o u g h not a specific feature of U T I , was of some importance. T a b l e IV lists the associated p r o b l e m s causing most concern in both groups. Septicaemia, omphalitis and osteomyelitis were significantly
Neonatal urinary-tract infections
59
Table I I I Summary of features in 4I neonates with U T I and 55 controls
Features
4I neonates with UTI N u m b e r (%)
55 controls N u m b e r (%)
Pyrexia T >~ 38 °C Hypotherrnia, T < 36 °C Iaundice Abdominal distension Asphyxia ( A P G A R ~< 5) Failure to thrive Vomiting Diarrhoea Lethargy
26 (63"4) 14 (34-i) 3o (73"2) I3 (3I'7) I t (26.8) IO (24"4) 9 (22.o) 9 (22-o) 8 (I9"5)
7 (I2"7) o (o) 5 (9"I) o (o) 9 (I6"4) Io (I8'2) 7 (I2'7) 4 (7"3) o (o)
These differences were significant (X2 = 8I'72; P < o'ooI).
Table IV Problems causing most concern in 4I neonates with U T I and 55 controls
Clinical problems Septicaemia* Osteomyelitis* Bronchopneumonia Meningitis* Omphalitis* Anaemia Hypocalcaemia Impetigo
Neonates with UTI N u m b e r (%) 20 5 4 I 7 I I i
(48'8) (I2.2) (9 '8) (2'4) (IT"I) (2"4) (2'4) (2"4)
Controls N u m b e r (%) o I 3 o 2 2 3 2
(I.8) (5"5) (o) (3"6) 3'6) (5"5) (3"6)
* These associated clinical problems were present in significantly greater numbers in neonates with U T I (X~ = 20"5; P < o.oi).
more frequent in neonates with U T I than in the controls. Most of these problems were of infective origin. T h e r e was no relation between leucocyturia and positive urine culture. T w e n t y - s e v e n (65"8%) neonates with positive cultures had less than 5 W B C / r a m 3 on urine microscopy, io (24"4 %) had more than Io W B C / m m 3 and the remaining four (9"8 %) had 5 - I o W B C / m m 3. T h e pathogens isolated from the urine were: Klebsiella spp. I5 neonates (36"6 ~/o); Escherichia coli 6 (I4"6 %); Pseudomonas aeruginosa 5 (I2-2 %); Alkaligenesfaecalis 3 (7"3 ~/o) and Staphylococcus aureus 12 (29"3 %). These pathogens were all sensitive to gentamicin while 83"3 % of the S. aureus were sensitive to cloxacillin.
Prognosis Intravenous urography and micturating cysto-urethrography were normal in the babies with U T I . In particular, all grades of VUR/~,ls other features of neuropathic bladder with functional obstruction a n d / o r bladder-neck narrow-
60
A.I. AIREDE
ing were excluded. A further episode of bacteriuria after treatment was not observed during follow-up periods of between 3 months and 3 years. T h e overall mortality from U T I was I7"1%. T h e mortality was frequently related to the associated problems (Table IV). F o u r (2o %) of the neonates with septicaemia and two (4o %) with osteomyelitis died, as did the infant with meningitis. Discussion
This study has revealed a relatively high incidence of U T I s of 2-6/Iooo live births. T h e incidence found in this high-risk population contrasts with previous findings of I ' I - I ' 4 per Iooo births. 1'1°'17'18 Furthermore, the failure to demonstrate urinary-tract abnormalities in spite of radiological evaluation differs from findings reported from Europe and N o r t h America. 1,2A°'11,18 These reports have stressed the high frequency of V U R and other obstructive uropathies associated with neonatal U T I . Smellie e t a l . ~ had noted 35-5o % abnormalities in those investigated after their first infection. T h e reason for the high incidence of U T I and the associated rarity of urinary-tract abnormalities in the African neonate is uncertain. It can be postulated that it may relate to an inherent genetic e n d o w m e n t of a more mature muscularity. T h e detrusor muscle could thereby be more easily relaxed, and hence assist in reducing residual urine. An important but poorly recognised feature of recurrent urinary-tract infections and V U R is constipation, ~9 though it was not found in this study. T h e poor perineal muscular relaxation that accompanies detrusor instability impedes both bladder and rectal emptying. Although the prognosis in respect of the immediate outcome of U T I s in neonates was poor, the mortality being I7"I %, the long-term result at 3"5 years follow-up is good. Unlike the findings of previous reports, ~°'~s'19 no case of progressive renal scarring was seen. This was understandable in view of the absence of recurrent U T I s and urinary-tract anatomical abnormalities and was in contrast to a recurrence rate of 26 ~o noted elsewhere. 10 T h e poor immediate outcome was associated with intercurrent problems but the mortality rate compares favourably with other studies. 9,1°,17,1s T h e belief that positive bacterial urine cultures are not proportional to the leucocyturia ~2'17 was confirmed in this study, and indicates that the diagnosis of urinary-tract infections required positive urine cultures. 1~.,3 T h e m e t h o d of urine collection is also important, and the suprapubic aspiration used in this study is satisfactory and allows reliable interpretation. 18'~4 T h e significant finding (P < o'ooI) of non-specific signs such as pyrexia, jaundice, abdominal distension, omphalitis and lethargy should suggest U T I in high-risk neonates. T h e importance of omphalitis has previously been noted 2° and the finding of jaundice as one of the major signs is in agreement with other reports, ls'2~ Adverse perinatal conditions such as P R O M , chorioamnionitis, antepartum, haemorrhage, maternal peripartum pyrexia and birth asphyxia were not significant factors in predisposing to neonatal U T I in our series, which is at variance with other reports. 9 T h e increased predisposition to U T I of infants with septicaemia and osteomyelitis supports the concept that haematogenous invasion of the kidney is a frequent cause of neonatal U T I . 22
N e o n a t a l u r i n a r y - t r a c t infections
61
K l e b s i e l l a spp., followed by E. coli, were the p r e d o m i n a n t G r a m - n e g a t i v e pathogens isolated. T h i s t r e n d has been reported elsewhere. I°'18 H o w e v e r , S. a u r e u s ranked second amongst all pathogens and was the only Gram-positive microbe isolated in this study. T h i s is f u r t h e r evidence for the haematogenous invasion of the kidney because m a n y of our babies also had S . aureus septicaemia as an associated problem. T h i s finding, although at variance with other reports, was u n d e r s t a n d a b l e in view of a previous outbreak of this p a t h o g e n in our Unit. 23 M u c h still needs to be done in this c o u n t r y to p r o m o t e good health care during delivery and reduce the high incidence of bacteraemia. T h e m a r k e d overall male preponderance, in agreement with virtually all other studies, is w o r t h noting. T h e difference was statistically significant (P < o'o5) w h e n the i n - b o r n infant findings were analysed. However, given the susceptibility of males to sepsis because of their possession of a single X - c h r o m o s o m e t h o u g h t to contain a gene which regulates the synthesis of i m m u n o g l o b u l i n s , 2a'~5 it is surprising that the mortality rate was significantly higher in females (P < o.0oi): T a b l e II. T h e sexes may have been infected with equal frequency, but the infection m a y have been more self-limited or better contained in the males. Other, as yet u n d e t e r m i n e d factors m a y be operative in this mortality bias. I n conclusion, a relatively high incidence of neonatal U T I s but with u r i n a r y - t r a c t abnormalities a rarity in Nigerian neonates, suggests that the incidence of end-stage renal disease consequent u p o n infection will be low. Despite this rarity of u r i n a r y - t r a c t anomalies, a continuous surveillance of the t r e n d of U T I and its outcome is r e c o m m e n d e d . S i x - m o n t h l y and yearly evaluations with I V U and M C U is suggested.
(I thank the resident doctors and nursing personnel for the high standard of care given to my patients and Mr Williams Orji for secretarial assistance.) References
i. Smellie JM, Hodson CJ, Edwards D, Normand ICS. Clinical and radiological features of urinary infection in childhood. Br Med J 1964; ii: 1222-1226. 2. Broyer M, Rizzoni G, Brunner FP et al. Combined report on regular dialysis and transplantation of children in Europe, XIV, 1984. Proc Eur Dial Transplant Assoc I984; 5: 55-79. 3. Hodson J. Reflux nephropathy: a personal historical review. A J R I98I; 137: 451-461. 4. Berg UB, Johansson SB. Age as a main determinant of renal functional damage in urinary tract infection. Arch Dis Child 1983; 58:963-969 • 5. Smellie JM, Ransley PG, Normand ICS, Prescod N, Edwards D. Development of new renal scars : a collaborative study. Br Med J 1985; 29o : I957-I96O. 6. Smallpiece V. Urinary tract infection in childhood and its relevance to disease in adult life. London : W. Heinemann, 1968. 7. Lincoln K, Winberg J. Studies of urinary tract infections in infancy and childhood. II. Quantitative estimation of bacteria in unselected neonates with special reference to occurrence of asymptomatic infections. Aeta Paediatr Scand I964; 53: 3o7-321. 8. James U. Urinary infection in the newborn. Lancet 1959; ii: Iooo-loo2. 9. Littlewood JM. 66 infants with urinary tract infection in first month of life. Arch Dis Child 1972; 47: 218-225. IO. Bergstrom T, Larson H, Lincoln K, Winberg J. Studies of urinary tract infections in infancy and childhood. XII. Eighty consecutive patients with neonatal infection. J Pediatr 1972; 8o: 858-866.
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I I. Drew JH, Acton CM. Radiological findings in newborn infants with urinary infection. Arch Dis Child r976; 5x : 528-53 o. I2. Littlewood JM. White cells and bacteria in voided urine of healthy newborns. Arch Dis Child z97I ; 46: r67-I72. r 3. Bailey RR, Little PJ. Suprapubic bladder aspiration diagnosis of urinary tract infection. Br M e d J I969; I: 293-295. I4. Saccharov L, Pryles CV. Further experience with the use of percutaneous suprapubic aspiration of the urinary bladder. Bacteriological studies in 654 infants and children. Pediatrics i969; 43: ioi8-IO22. IS. Shah KJ, Robins DG, White RHR. Renal scarring and vesicoureteric reflux. Arch Dis Child I978; 53: 2IO-217. I6. Lebowitz RL, Olbing H, Parkkulainen KV, Smellie JM, Tamminen-Mobius TE. International system of radiographic grading of vesicoureteric reflux. Pediatr Radiol I985; 15: I05-I09. I7- Gower PE, Husband P, Coleman JC, Snodgrass GJA. Urinary infection in two selected neonatal populations. Arch Dis Child I97O; 45: 259-263, I8. Maherzi M, Guidard JP, Torrado A. Urinary tract infection in high-risk newborn infants. Pediatrics I978; 62 : 521-523. I9. White RHR. Management of urinary tract infection. Arch Dis Child I987; 62: 42z-427. 20. Airede A'KI. Pathogens in neonatal omphalitis. J Trop Pediatr I992; 38(I). 2I. Ng SH, Rawstron. Urinary tract infections presenting with jaundice. Arch Dis Child x97I ; 46: z73-I76. 22. Klein JO. Bacterial infections of the urinary tract. In: Remington JS, Klein JO, Eds, Infectious Diseases of the Fetus and Newborn 2rid ed., Philadelphia : WB Saunders, z983. 23. Airede A'KI. Neonatal septicemia in an African city of high altitude. J Trop Pediatr I992; 38(4). 24. Alojipan LC, Andrews BF. Neonatal sepsis. Clin Pediatr I98I; 14: I8I-I83. 25. Rhodes K, Markham RL, Maxwell PM, Monk-Jones ME. Immunoglobulins and the Xchromosome. Br M e d J I969; 3: 439-44I.
