This nationwide study of 1306 infants with UTI provides a comprehensive overview of current diagnostic procedures, treatment, and management in Swedish pediatric care. According to national recommendations, infants with a suspected UTI are referred to and managed by pediatricians and we believe that the study population is representative for this age group.

Compared to the Swedish quality assurance project in the mid-1990s, a nationwide study of children < 2 years with first time UTI, our study revealed a remarkable shift in urine sampling method in favor of the clean catch technique, practiced in 93% of cases compared to only 11% in the 1990s, while bag samples, previously used in 50% of urine cultures, have virtually disappeared [19]. Bag samples, known to carry a high risk of contamination, are rarely used nowadays. However, it is surprising that SPA was infrequently performed in this population of young infants despite being recommended in the national guidelines. Clearly, clean catch urine has become the method of choice in pediatric specialist care in Sweden, a trend seen also in other parts of the world. This sampling technique has been proposed as an alternative to invasive techniques for infants in good clinical condition by the Italian, Indian, Australian and Swiss guidelines [5, 7, 20, 21] and is the recommended method in the NICE guidelines [2]. Clean catch urine combined with a standardized stimulation technique has shown similar contamination risk as urethral catheterization [22] while others advocate SPA or catheter specimens to avoid contamination [23].

Similar to other reports, we found non-E. coli in 10% of the infants, with comparable rates of Enterococcus and Klebsiella species, known to be associated with lower bacterial counts and less pyuria [24,25,26]. Eighteen percent of infants in our cohort had bacterial numbers less than 100,000 CFU/mL. This was in line with the frequency of 19–20% found in other studies [27,28,29]. These results indicate that disregarding urine cultures with low bacterial counts or low-grade pyuria in this age group could lead to a missed or delayed diagnosis and treatment.

From an international perspective, our study showed a low frequency of resistant uropathogens. A meta-analysis of antimicrobial resistance in children 0–5 years treated for UTI in primary care showed that the pooled prevalence of resistance in E. coli isolates was 29.8% for trimethoprim sulphamethoxazole, 9.6% for amoxicillin/clavulanic acid, and 4.9% for third generation cephalosporins [30].

Initial intravenous treatment was given to 37% of infants and was more frequent in younger age groups. Although 40% of the study subjects were younger than 3 months, we anticipated a more frequent use of oral antibiotics as initial treatment. The use of oral antibiotics for UTI in Swedish pediatric care has not changed since the 1990s despite evidence of oral antibiotic treatment being equally effective as intravenous administration in well appearing children [31, 32]. In the former Swedish study, the proportions of initial intravenous treatment in age groups 0– < 3 months, 3– < 6 months and 6– < 12 months were 51%, 31% and 24%, respectively, and in the current study 56%, 28%, and 21% [19]. In our study, there were similar rates of permanent kidney damage between oral and intravenous treatment groups, thereby supporting the evidence of safe oral antibiotic treatment in infant UTI. The practice of initial empirical treatment with oral antibiotics in infants in our study, however, was in sharp contrast to the standard practice of care in Japan. This was presented in a recent study on children aged < 36 months with UTI where almost all patients were hospitalized and initially treated with intravenous antibiotics and 81% of the patients were switched to oral antibiotics as late as day 4 to 8 of hospitalization [33].

Long-term antimicrobial prophylaxis was used in 16% of the patients, similar to the 1990s Swedish quality assurance study where it was used in 20% of the cases [19]. However, the use of prophylaxis while awaiting the initial imaging to be performed, has dropped from 79 to only 2%.

During the study period, prenatal ultrasound screening was offered to pregnant women at gestational week 12–14 (combined ultrasound and blood test for chromosomal anomalies) and week 18–19 (including organ screening) in most parts of the country. We did not ask for the information on any prenatal ultrasound in this study. Recommendations in the national UTI guidelines were to perform RBUS in all infants with first time UTI, justified by the need to identify children with major congenital abnormalities or obstruction of the kidneys and urinary tract. We used high creatinine as a risk factor that could indicate a more severely ill child with prerenal acute kidney injury, congenital hypo/dysplasia, known to be more common in boys, or kidneys that are more vulnerable to consequences of the infection. This should alert the caregiver to pay extra attention to that child and motivate further assessment and imaging.

Our study included a multivariable analysis of risk factors for recurrent UTI showing female gender as a significant independent risk factor. The higher recurrence rate in girls than in boys (21% vs. 14%) was in accordance with the Swedish reflux trial where recurrent UTIs were seen more frequently in girls (33%) than in boys (9%), although these children were all above 1 year of age [13]. Other studies on gender as a risk factor for recurrent UTI, however, are scarce and results not conclusive, partly due to small studies and diverging populations. A large pediatric primary care study by Conway et al. found no significant gender difference although children up to 6 years of age were included [34]. Neither could two smaller studies including younger children with first time UTI find significant differences in recurrence rate between males and females [35, 36].

The result of the Swedish quality assurance project [19] was a reflection of the management of infant UTI at that time, where most local guidelines were based on a bottom-up approach and kidney scarring was identified at follow-up with intravenous urography or DMSA scintigraphy. In comparison, we found a substantial reduction in the frequency of VCUGs in our study, 30% versus 85% in the 1990s. Furthermore, the use of intravenous urography has dropped from 25% of the patients to no urographies at all. On the other hand, 59% of children in our study were exposed to a DMSA scan, compared to 25% in the previous study and 13% had two DMSA scans during the study period. The radiation dose of a DMSA scan is approximately 0.7–1 mSv, equivalent to about 4–6 months of natural background radiation [37]. In light of the potential risks with exposure to ionizing radiation in early infancy it is prudent to continue the efforts of reducing the radiation burden for infants with UTI [38].

VUR grade 4 or 5, a major risk factor for scarring was detected in 78/1306 infants (6%) in our study population. In a meta-analysis by Shaik et al., where 1247 of 1280 children with a first UTI were examined by VCUG, 4% showed VUR grade 4 or 5 [39]. In a single center study of infants with UTI where VCUG was performed in all participants the detection rate of VUR grade 4 or 5 was 5% [40]. Our relatively high rate of VUR grade 4 and 5, despite only 30% of the cohort being subject to a VCUG indicates that the Swedish guidelines effectively identified infants with a high risk of dilating VUR.

Results from the DMSA and MAG3 scintigraphies identified permanent abnormalities of the kidneys in 126 of the 1306 infants (10%) which could result in further investigations or long-term follow-up. Since our study only had end point data for permanent kidney damage from 648 of the 1306 patients (50%) in the cohort, 10% is a minimum rate. Boys had significantly more severe kidney defects than girls. This yield is comparable to Hoberman et al., reporting 26 cases of renal damage after UTI in 275 children (9.5%) [17]. However, according to other studies, the expected rate of kidney scarring after a first UTI varies from 15 to up to 25% when discrete uptake defects on DMSA were also included [41, 42]. Furthermore, in a recent study of prophylaxis or no prophylaxis to infants with dilating VUR before any UTI, new parenchymal kidney defects occurred regardless of whether the children had a UTI or not during follow-up [43].

There were 25 infants excluded from the study, with no growth in the urine culture, yet diagnosed and treated as having UTI. Compared to the study population, these infants were younger and more likely to have affected kidney function by elevated creatinine (Table 4). Furthermore, dilatation on RBUS was more prevalent, as was dilating VUR and kidney damage although not reaching significance levels. These infants were reported to be ill appearing and, in the majority, a first dose of antibiotics was given prior to urine sampling. Thus, these infants comprise a clinically challenging group, although not fitting into the study requisite.

A limitation with the study was that imaging investigations and chemistry lab tests were analyzed and interpreted in the local laboratories with the risk of regional and individual differences or errors. There was no requirement of standardized protocol for the ultrasound examinations performed at the 29 different centers and reports often lacked data on APD. Yet, the rate of dilatation of the urinary tract in our study, 14%, was very similar to the 15% rate of dilatation found in a single center study with a standardized protocol on 290 infants with UTI [40].

The predominant use of clean catch urine sampling carries a risk of patients being included who did not suffer from a true UTI. In addition, as the guidelines did not define any specific limit for bacterial count, a few children with contaminated urine culture may have been falsely classified as having UTI. On the other hand, this makes the study more relevant for evaluating management and patient characteristics in every day clinical care of infants treated for UTI and evaluating the diagnostic yield, burden of investigations and functionality of clinical guidelines in routine pediatric practice.

From public demographic data and expected UTI incidence in infants, we estimate that there were roughly 5000 infants eligible for inclusion during the study period. However, there was no indication of systematic bias in the sample selection. A few centers in the country did not include any patients at all and when analyzing two of the largest centers, there was no difference in gender, age or temperature between the children included in the study and those not included.

In conclusion, this report describes current management of infants with first time UTI in pediatric centers in Sweden and provides data on the yield of the implemented investigations in a large and representative population. Since the 1990s, a major shift in urine collection method in favor of the clean catch technique was noted. Furthermore, the use of prophylactic antibiotics while awaiting investigation with VCUG, has virtually disappeared. Initial intravenous antibiotic treatment was surprisingly unchanged providing incentive for improvement by increased outpatient management or oral antibiotic use in inpatient care. This would render savings for the healthcare provider and less traumatic care.

The study results indicate that the Swedish UTI guidelines are able to identify important abnormalities such as permanent kidney damage and dilating VUR. We have reduced the number of VCUG considerably, however, the number of DMSA investigations on infants with UTI is still substantial. Our work continues with reducing the burden of investigations further, in particular radiation exposure, and developing individualized methods of risk assessment. The management of the very youngest infants should be more clearly addressed in future revisions of the guidelines.