Urinary Tract Infections and Vesicoureteral Reflux

Epidemiology

Neonates, by virtue of their immature immune system, are at a higher risk for urinary tract infections (UTIs). In the United States, the prevalence of UTI within the first 30 days of life is estimated at 0.1% to 1%, while in developing countries, it is as high as 1.8%. UTI is the second most common bacterial infection in children after otitis media.

In febrile children less than 2 months of age without an obvious source of infection, the prevalence of UTI is 5% to 20%. There is a male predominance in the neonatal period, with males comprising 70% to 90% of all cases of neonatal UTI before the age of 6 months, irrespective of their degree of prematurity. Hispanics and whites are more likely to be diagnosed with a UTI than children of African descent.

Pathophysiology

The natural pathophysiology of UTI is dependent on the migration of uropathogenic bacteria through the fecal–perineal–urethral route with subsequent entry into the bladder. Iatrogenic instrumentation and hematogenous seeding are alternative modes of entry into the urinary system. Once in the bladder, these uropathogens may ascend into the ureter and kidney in a retrograde manner. The effectiveness of this process is determined by both pathogen and host factors.

Host factors in the neonate often relate to anatomy and involve urogenital malformations such as posterior urethral valves, vesicoureteral reflux (VUR), phimosis, ureteropelvic junction obstruction, and neurogenic bladder dysfunction secondary to spinal dysraphism. These conditions ultimately disturb the washout effect of antegrade urinary flow that would normally clear the uropathogens. Additional host factors include the neonatal immune function and the antimicrobial properties of urine, such as low pH.

Uropathogens have a number of virulence factors that are used to overcome the defense of the host. Escherichia coli serotypes with P-fimbriae are commonly isolated in infected urine. These are adhesion proteins at the tip of the bacterium’s attachment structures that enhance binding to receptors on the host urothelium. These increase the bacteria’s ability to ascend the urinary tract, even in the absence of VUR.

Epidemiologic studies have shown that 76% to 94% of pyelonephritic strains of E. coli are P-fimbriated, compared with 19% to 23% of strains causing cystitis and 14% to 18% of strains isolated from patients with asymptomatic bacteriuria. In one study, P-fimbriated E. coli was isolated in only 36% of girls with VUR and recurrent pyelonephritis, as compared with 71% of girls with pyelonephritis without VUR.

However, in the presence of VUR, P-fimbriated E. coli is not necessary for infection of the upper urinary tract. Other virulence factors from uropathogenic E. coli include the release of alpha hemolysin and cytotoxic necrotizing factor-1, as well as the ability to form a protective glycosylated polysaccharide capsule.

Clinical Presentation

The signs and symptoms of UTI in newborns differ from those of older children. The familiar symptoms of dysuria, frequency, urgency, malodorous urine, incontinence, suprapubic pain, and hematuria are often absent or not recognized. The clinician must retain a high index of suspicion for the diagnosis of a UTI in a neonate. In full-term infants the most common presentation is a fever of greater than 38.5°C followed by poor feeding, tachypnea, and lethargy. In contrast, premature infants commonly present with apnea, hypoxia, tachypnea, and fevers with a temperature greater than 39°C. Other nonspecific signs and symptoms, such as abdominal distention, diarrhea, vomiting, and failure to thrive, have also been described in infants with UTIs.

Neonatal jaundice, especially with an onset after 8 days of life, has been associated with neonatal UTIs. Mutlu et al. found that the incidence of UTI in children with hyperbilirubinemia was 18%. This is an important association, as Xinias et al. showed that approximately 50% of neonates with UTI-induced jaundice had renal cortical changes on dimercaptosuccinic acid (DMSA) scan.

Bacteriology

Neonatal UTIs are commonly caused by gram-negative rods, with E. coli (40% to 72%) and Klebsiella species (7% to 40%) responsible for over 80% of cases. Enterococcus, a gram-positive coccus, is the third most common organism, with an incidence of 10% to 16%.

It is hypothesized that the incompletely developed neonatal immune system not only increases the newborn’s risk of infection but also makes the newborn susceptible to additional organisms compared to older children. In neonates with UTIs, group B streptococci have been found to be more common than in older children. Additionally, other gram-positive bacteria, such as coagulase-negative staphylococci, have been associated with UTIs in premature infants, although this remains controversial. Candida, as a causative agent for UTIs, has a reported incidence of 25% to 42% in premature children admitted to the neonatal intensive care unit.

Risk Factors

The important risk factors for UTIs in neonates are prematurity, uncircumcised males, white race, high-grade VUR, a maternal history of UTI, instrumentation of the urinary tract, and the existence of congenital anomalies of the kidney and urinary tract.

The decreased risk for UTI in circumcised males is supported by two metaanalyses. In febrile neonates, the incidence of UTI in uncircumcised males is 20% to 21% compared with 2% in circumcised males and 5% to 8% for females. This phenomenon is supported by studies showing a higher concentration of uropathogenic bacteria in the periurethral region of uncircumcised males. Laway et al. prospectively studied the effects of circumcision on the colonization of the periurethral area of 124 children. The authors found that the periurethral region was devoid of E. coli , Llebsiella, Proteus, Pseudomonas , and Enterococci after the children underwent circumcision, whereas these uropathogenic bacteria were present in 68% preoperatively.

In its 2012 Policy Statement on circumcision (current version at the time of this writing), the American Academy of Pediatrics (AAP) states that the health benefits of male newborn circumcision outweigh the risks of the procedure. Benefits include significant reductions in the risk of UTIs in the first year, as outlined above, and reductions in the risk of heterosexual acquisition of human immunodeficiency virus, and the transmission of other sexually transmitted infections. Despite the risk reduction, however, the AAP suggests that the health benefits are not great enough to recommend routine circumcision for all male newborns. Instead, the AAP recommends that clinicians routinely inform parents of the health benefits and risks of circumcision in an unbiased and accurate manner and that the parents should decide whether circumcision is in the best interests of their child.

A maternal history of UTI is a risk factor for neonatal UTI. Milas et al. studied 1200 newborns for a 6-month period and showed that neonates with UTIs were more likely to have mothers that were diagnosed with a UTI during the pregnancy (22.2% vs. 5.2%, P < .001). This was further supported by a cross-sectional study by Khalesi et al. who demonstrated a 5.9-fold increased risk for neonatal UTI in newborns where there was a history of maternal UTIs.

The overall reported incidence of genitourinary abnormalities in neonates is 5%. VUR is a common renal abnormality predisposing neonates to UTIs and pyelonephritis. Cleper et al. retrospectively studied 64 neonates with UTIs and found the incidence of VUR to be 20.3%, of which 31% represented high-grade VUR. However, other studies have reported rates between 20% and 50%. In male neonates with UTI, the most common anomaly was VUR. In neonates with UTI the incidence of VUR increases to 30% to 50%. Although other anatomic abnormalities, such as posterior urethral valves, congenital urethral strictures, ureteroceles, ureteropelvic junction obstruction, and neurologic bladder dysfunction, increase the risk of UTIs, these are less common than VUR. An obstructive pathology represents less than 1% to 2% of the abnormalities found in neonates with UTIs. A detailed discussion on VUR can be found in this chapter under the subheading “Vesicoureteral Reflux.”

A calculator was recently developed to help clinicians estimate the probability of UTI in febrile infants at the bedside ( https://uticalc.pitt.edu ). Although not specific to neonates, it is based on five risk factors that include age under 12 months, white race, female sex (or uncircumcised boy), maximum temperature of 39°C, and the absence of another source for fever. The calculator was validated in a cohort of 2000 children and was found to reduce unnecessary testing, to decrease missed UTIs, and to reduce treatment delays.

Evaluation

The diagnosis of UTI in neonates differs from older children. An initial assessment should involve a detailed history including birth and family history and findings on prenatal imaging, if performed. The focused physical examination should include vital signs, general appearance, as well as abdominal and genital examination. In girls, special attention should be paid to the presence of labial adhesions or intravaginal foreign bodies. In boys, special attention should be paid to the presence of phimosis or meatal stenosis, and testicular examination for signs of epididymoorchitis.

In febrile newborns with a UTI, 20% to 30% have associated bacteremia. For this reason, a comprehensive work-up for sepsis should be performed in all febrile neonates.