A comprehensive literature review was performed by the New England Medical Center Evidence-Based Practice Center to answer the following key questions:
- Question 1: What is the relationship between peak bilirubin levels and/or duration of hyperbilirubinemia and neurodevelopmental outcome?
- Question 2: What is the evidence for effect modification of the results in question 1 by gestational age (GA), hemolysis, serum albumin, and other factors?
- Question 3: What are the quantitative estimates of efficacy treatment for 1) reducing peak bilirubin levels (e.g., number needed to treat [NNT] at 20 mg/dL to keep total serum bilirubin [TSB] from rising); 2) reducing the duration of hyperbilirubinemia (e.g., average number of hours by which time TSB is higher than 20 mg/dL may be shortened by treatment); and 3) improving neurodevelopmental outcomes?
- Question 4: What is the efficacy of various strategies for predicting hyperbilirubinemia, including hour-specific bilirubin percentiles?
- Question 5: What is the accuracy of transcutaneous bilirubin [TcB] measurements?
The Medline database was searched on September 25, 2001, for publications from 1966 to the present using relevant medical subject heading terms ("hyperbilirubinemia"; "hyperbilirubinemia, hereditary"; "bilirubin"; "jaundice, neonatal"; and "kernicterus") and text words ("bilirubin," "hyperbilirubinemia," "jaundice," kernicterus," and "neonatal"). The abstracts were limited to human subjects and English-language studies focusing on newborns between birth and 1 month of age. In addition, the same text words used for the Medline search were used to search the Pre-Medline database. The strategy yielded 4,280 Medline and 45 PreMedline abstracts. Domain experts were consulted and relevant review articles were examined for additional studies. A supplemental search for case reports of kernicterus in reference lists of relevant articles and reviews was performed also.
Screening and Selection Process
In the preliminary screening of abstracts, more than 600 potentially relevant articles were identified in total for questions 1, 2, and 3. To handle this large number of articles, the following scheme was devised to address the key questions and ensure that the report was completed within the time and resource constraints. The Evidence-Based practice Center included only studies that measured neurodevelopmental or behavioral outcomes (except for question 3, part 1, for which they evaluated all studies addressing the efficacy of treatment). For the specific question of quantitative estimates of efficacy of treatment, all studies concerning therapies designed to prevent hyperbilirubinemia (generally bilirubin greater than or equal to 20 mg/dL) were included in the review.
Inclusion Criteria
The target population of this review was healthy, term infants. For the purpose of this review, articles concerning infants who were at least 34 weeks’ estimated gestational age (EGA) at the time of birth were included. From studies that reported birth weight rather than age, infants whose birth weight was greater than or equal to 2,500 g were included. This cutoff was derived from findings of the National Institute of Child Health and Human Development (NICHD) hyperbilirubinemia study, in which none of the 1,339 infants weighing greater than or equal to 2,500 g were less than 34 weeks’ EGA. Articles were selected for inclusion in the systematic review based on the following additional criteria:
Question 1 or 2 (Risk Association)
- Population: infants greater than or equal to 34 weeks’ EGA or birth weight greater than or equal to 2,500 g
- Sample size: more than 5 subjects per arm
- Predictors: jaundice or hyperbilirubinemia
- Outcomes: at least 1 behavioral/neurodevelopmental outcome reported in the article
- Study design: prospective cohorts (more than 2 arms), prospective cross-sectional study, prospective longitudinal study, prospective single-arm study, or retrospective cohorts (more than 2 arms)
Case Reports of Kernicterus
- Population: kernicterus case
- Study design: case reports with kernicterus as a predictor or an outcome
Kernicterus, as defined by authors, included any of the following: acute phase of kernicterus (poor feeding, lethargy, high-pitched cry, increased tone, opisthotonos, or seizures), kernicterus sequelae (motor delay, sensorineural hearing loss, gaze palsy, dental dysplasia, cerebral palsy, or mental retardation), necropsy finding of yellow staining in the brain nuclei.
Question 3 (Efficacy of Treatment at Reducing Serum Bilirubin)
- Population: infants greater than or equal to 34 weeks’ EGA or birth weight greater than or equal to 2,500 g
- Sample size: more than 10 subjects per arm
- Treatments: any treatment for neonatal hyperbilirubinemia
- Outcomes: serum bilirubin level higher than or equal to 20 mg/dL or frequency of blood exchange transfusion specifically for bilirubin level higher than or equal to 20 mg/dL
- Study design: randomized or nonrandomized, controlled trials
For All Other Issues
- Population: infants greater than or equal to 34 weeks’ EGA or birth weight greater than or equal to 2,500 g
- Sample size: more than 10 subjects per arm for phototherapy; any sample size for other treatments
- Treatments: any treatment for neonatal hyperbilirubinemia
- Outcomes: at least 1 neurodevelopmental outcome was reported in the article
Question 4 or 5 (Diagnosis)
- Population: infants greater than or equal to 34 weeks’ EGA or birth weight greater than or equal to 2,500 g
- Sample size: more than 10 subjects
- Reference standard: laboratory-based TSB
Exclusion Criteria
Case reports of kernicterus were excluded if they did not report serum bilirubin level or GA and birth weight.
Results of Screening of Titles and Abstracts
There were 158, 174, 99, 153, and 79 abstracts for questions 1, 2, 3, 4, and 5, respectively. Some articles were relevant to more than 1 question.