Noureen Afzal  ( Department of Pediatrics and Child Health, The Aga Khan University Hospital, Karachi. )
Maqbool Qadir  ( Department of Pediatrics and Child Health, The Aga Khan University Hospital, Karachi. )
Sonia Qureshi  ( Department of Pediatrics and Child Health, The Aga Khan University Hospital, Karachi. )
Rehan Ali  ( Department of Pediatrics and Child Health, The Aga Khan University Hospital, Karachi. )
Shakeel Ahmed  ( Department of Pediatrics and Child Health, the Aga Khan University Hospital, Karachi. )
Khalil Ahmad  ( Department of Pediatrics and Child Health, The Aga Khan University Hospital, Karachi. )

Neonatal Hyperbilirubinaemia is a common finding during the first postnatal week. Physiological jaundice occurs in first week of life in 60% of term and 80% of premature neonates. Non physiologic or pathologic jaundice occurs in 5-10% of newborns which require intervention. According to AAP guidelines laboratory investigation for jaundice include total serum bilirubin, blood Type and coombs test and if the baby has an elevation of direct reacting or conjugated bilirubin, there should be a urine analysis and urine culture. Here we are presenting 5 cases that developed indirect hyperbilirubinaemia and routine workup done according to AAP guidelines were normal. On extensive investigation all cases found to have urinary tract infection despite of having indirect bilirubin and they needed course of antibiotics according to sensitivities and follow up ultrasound. From our experience we suggest that UTI should be considered as a cause of neonatal jaundice especially when indirect bilirubin peaks after one week of life at mean age of 10.8 ± 2.38 days.
Keywords: Hyperbilirubenemia. UTI (urinary tract infection).

Hyperbilirubenemia is the commonest morbidity in neonatal period. The incidence of jaundice in the first week of birth is 60% among term and 80% among premature neonates. About 5-10% of newborns required intervention.^1-3 Jaundice attributable to physiological immaturity, usually appears between 24 to72hrs of age in term and by 5th to7th day in preterm neonates and disappears by 10-14 days of life.² Most jaundice is benign, but because of potential toxicity of bilirubin to developing brain, newborn infants must be monitored to identify those who might develop severe hyperbilirubinaemia and in rare cases acute bilirubin encephalopathy or kernicterus.¹ AAP has published guidelines outlining the management of healthy newborn with hyperbilirubinaemia, which includes maternal and infant blood grouping, Rh typing, direct coombs test and total serum bilirubin level and if the baby has direct hyperbilirubinaemia then investigate for urinary tract infection. Urinary tract infections (UTIs) are a common problem in febrile infants younger than 8 weeks of age, with prevalence between 5% and 11%. Jaundice can be one of the earliest symptoms of urinary tract infection therefore investigating for UTI in the infants with unexplained hyperbilirubinaemia is suggested as part of the workup for jaundice.² Complete clinical assessment is needed in all cases of prolonged jaundice, however the indications and extent of investigation remain unclear.³ With the literature review it is somehow clear that unexplained, prolonged and direct hyperbilirubinaemia requires urine analysis but the question remains, should one investigate urine in case of indirect hyperbilirubinaemia. Clinical manifestations of UTI are non specific in neonates. The incidence of UTI is between 0.1% and 1% of all newborn, with higher incidence in premature infants.³ The manifestation of sepsis and UTI are nonspecific in neonates and the consequences of misdiagnosis and delayed treatment could lead to significant morbidity. Here we are presenting summary of five newborns who developed indirect hyperbilirubinaemia after one week of life. Hyperbilirubinaemia workup was found to be normal. However on extensive investigation they were found to have positive urine culture with gram negative organism.

We are reporting 5 cases that presented with neonatal jaundice in the second week of life at mean age of 10.8 ± 2.38 days and were treated with photo therapy. On examination no signs of infection were found and on investigation no common cause like ABO incompatibility, Rh incompatibility, and G6PD deficiency was detected. On further investigating the babies, Case 1, 2, 4 and 5 had proven urinary tract infection with positive urine C/S with different sensitivities. Case 3 although had no growth in urine culture (Baby had received antibiotic at another hospital) but her urine detailed report was significant for TLC count of 16/HPF. On follow up ultrasound KUB all were reported as normal. All specimens were collected aseptically through bladder catherization. Details of cases are illustrated in the table.

Nearly 60% of full term and 80%of premature infants develop jaundice^1-4 which in most cases is benign and considered physiologic. Jaundice in breast fed, healthy babies usually appears between 24-72 hours of age, peaks by 5-15 days of life and disappear by the third week of life.⁴ Sepsis is a well known cause of neonatal jaundice in seriously ill newborns and it may be the only sign of sepsis.^2,3
Garcia et al⁴ reported that patients with an elevated conjugated bilirubin fraction were more likely to have UTI and AAP also recommend urine analysis and culture in patient with conjugated and prolonged jaundice. But in our reported cases neither has prolonged jaundice (>2 weeks), nor have direct hyperbilirubinaemia; rather all of the them have predominantly indirect hyperbilirubinaemia.
Incidence of UTI in asymptomatic, afebrile, jaundiced infants younger than 8 weeks age was reported as 7.5%⁴ in one study from USA. In another study from Turkey Hulya Bilgen et al⁵  emphasized on the importance that UTI can occur in asymptomatic jaundiced neonates even in the first week of life and urine culture should be in the workup of neonatal jaundice, they have reported UTI in 8% of 102 asymptomatic unexplained hyperbilirubinaemia. Jafarzaden M et al.⁶ found UTI in 8.2% of asymptomatic unexplained afebrile jaundiced infants and mean age of presentation was 8.9 days. To the best of our knowledge these are the first reported cases of indirect hyperbilirubinaemia, secondary to urinary tract infection in neonates. Most of them presented in the second week of life and none of them had prolonged history of jaundice.
From the literature review above and with our reported cases, urine culture should also be included in the workup of indirect hyperbilirubinaemia not explained by other causes. We do not know the exact mechanism of haemolysis and subsequent hyperbilirubinaemia secondary to UTI. Clinically, none of these infants are septic and all of them have negative blood cultures. To the best of our knowledge these are the first reported cases from Pakistan of neonatal UTI which has presented as jaundice predominantly indirect hyperbilirubenaemia in the second week of life.

Urine analysis should be the part of investigation for neonatal hyperbilirubinaemia especially when indirect bilirubin peaks after one week of life because untreated UTI can cause severe morbidity.

1. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004; 114: 297-316.
2. Eslami Z, Sheikhha MH. Investigation of Urinary Tract Infection in Neonates with Hyperbilirubinemia. J Med Sci 2007; 7: 909-12.
3. Pashapour N, Nikibahksh AA, Golmohammadlou S. Urinary tract infection in term neonates with prolonged jaundice. Urol J 2007; 4: 91-4.
4. Garcia FJ, Nager AL. Jaundice as an early diagnostic sign of urinary tract infection in infancy. Pediatrics 2002; 109: 846-51.
5. Bilgen H, Ozek E, Unver T, Biyikli N, Alpay H, Cebeci D. Urinary tract infection and hyperbilirubinemia. Turk J Pediatr 2006; 48: 51-5.
6. Jafarzadeh M, Mohammadzadeh A. Should urine culture be considered in the hyperbilirubinemia workup of neonate. J Chinese Clin Med 2009; 4: 136-8.