Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants

Abstract

Objectives To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18–22 months corrected age in extremely low birth weight infants. Method Total plasma biirubin and unbound biirubin were measured in 1,101 extremely low birth weight infants at 5±1 day of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18–22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow-up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors. Results Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow-up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow-up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants. Conclusions In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma and unbound bilirubin and death or adverse neurodevelopmental outcomes at 18–22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants.

An approach to the management of hyperbilirubinemia in the preterm infant less than 35 weeks of gestation

“…Use the lower range of the listed TSB levels for infants at greater risk for bilirubin toxicity, for example, (1) lower gestational age, (2) serum albumin levels <2.5 g dl À1 , (3) rapidly rising TSB levels, suggesting hemolytic disease and (4) those who are clinically unstable. 31 When a decision is being made about the initiation of phototherapy or exchange transfusion, infants are considered to be clinically unstable if they have one or more of the following conditions: (a) blood pH <7.15; (b) blood culture positive sepsis in the prior 24 h; (c) apnea and bradycardia requiring cardio-respiratory resuscitation (bagging and or intubation) during the previous 24 h; (d) hypotension requiring pressor treatment during the previous 24 h; and (e) mechanical ventilation at the time of blood sampling. 31 Recommendations for exchange transfusion apply to infants who are receiving intensive phototherapy to the maximal surface area but whose TSB levels continue to increase to the levels listed.…”

“…31 When a decision is being made about the initiation of phototherapy or exchange transfusion, infants are considered to be clinically unstable if they have one or more of the following conditions: (a) blood pH <7.15; (b) blood culture positive sepsis in the prior 24 h; (c) apnea and bradycardia requiring cardio-respiratory resuscitation (bagging and or intubation) during the previous 24 h; (d) hypotension requiring pressor treatment during the previous 24 h; and (e) mechanical ventilation at the time of blood sampling. 31 Recommendations for exchange transfusion apply to infants who are receiving intensive phototherapy to the maximal surface area but whose TSB levels continue to increase to the levels listed. For all infants, an exchange transfusion is recommended if the infant shows signs of acute bilirubin encephalopathy (hypertonia, arching, retrocollis, opisthotonos, highpitched cry) although it is recognized that these signs rarely occur in VLBW infants.…”

“…The concentration of UB is believed to dictate the biological effects of bilirubin in jaundiced newborns, including its neurotoxicity, and elevations of UB have been associated with kernicterus or NDI in sick, preterm infants. [29][30][31] Routine, clinical laboratory measurement of UB is not commercially available in the United States, so that even if there was agreement regarding UB levels that require intervention, such recommendations, currently, could not be implemented. Some experts have recommended using the ratio of bilirubin (mg dl À1 ) to albumin (g dl À1 ) as an approximate surrogate for the measurement of UB.…”

Severe Neonatal Hyperbilirubinemia and Kernicterus: Are These Still Problems in the Third Millennium?

“…More recently, in the post-Rh isoimmunization era, it has become clear that the serum total bilirubin value correlates poorly with the subsequent development of kernicterus. There is also no single cutoff point above which an infant will categorically develop bilirubin encephalopathy and/or kernicterus, or below which a baby will remain safe [34][35][36] . Many factors, including prematurity or the presence of hemolysis, may interact with the total bilirubin to precipitate or prevent the development of kernicterus.…”

Unbound Free Fatty Acids from Preterm Infants Treated with Intralipid Decouples Unbound from Total Bilirubin Potentially Making Phototherapy Ineffective

“…Extremely low birth weight (ELBW; <1,000 g) infants have poor outcomes; approximately 50% of these infants die or have severe neurologic deficits [1,2]. In an effort to improve these outcomes, the NICHD Neonatal Research Network assigned 1,974 ELBW infants to either aggressive or conservative phototherapy, but found that aggressive phototherapy did not improve outcomes substantially [1].…”