Moderate Hyperbilirubinemia Induces a Transient Alteration of Neonatal Behavior
Objective. To investigate the behavioral changes induced by moderate hyperbilirubinemia in the otherwise healthy, untreated newborn infant.
Methods. Fifty term neonates (23 boys) with untreated moderate hyperbilirubinemia (median: 14.3 mg/dL; range: 13.2–20 mg/dL) and 50 matched control subjects with lower bilirubin concentrations (median: 9.1 mg/dL; range: 5.3–12 mg/dL) were administered the Brazelton Neonatal Behavioral Scale at 87 hours of life (range: 72–110 hours). A subgroup analysis was also performed at 104 hours of life (range: 96–134 hours) and at 3 weeks of age.
Results. At the first examination, all behavioral clusters were significantly altered in the group with moderate hyperbilirubinemia. The visual and auditory capabilities of the hyperbilirubinemic infant were especially compromised. Although social-interactive cluster scores significantly correlated both with serum bilirubinemia and birth weight, the former accounted for 8.7% of the variance and the latter accounted for only 4.7%. The moderate hyperbilirubinemia neonates’ scores also showed a negative correlation with the autonomic system and more frequent presence of tremors. After 24 hours, a decrease in serum bilirubin within the moderate hyperbilirubinemic group was associated with improved scores. At 3 weeks of age, the behavioral assessment of the 2 groups did not show significant differences.
Conclusions. Untreated moderate hyperbilirubinemia is associated with a transient and apparently reversible alteration of neonatal behavior, particularly in the social-interactive area.
Bilirubin is a heme catabolite known for its potential toxicity to the neonatal central nervous system (CNS). Although extreme hyperbilirubinemia (>30 mg/dL) has been associated with adverse neurodevelopmental consequences in term newborns without hemolytic disease,1 lower bilirubin concentrations (<8 mg/dL) have not been associated with significant alterations of CNS function.2,3 The effects of intermediate or moderate bilirubin concentrations, formerly treated with phototherapy, are unclear. In this respect, medical intervention itself can represent a source of bias, as different groups4,5 have shown that phototherapy can influence the neurobehavioral assessment of the newborn. In 1994, new guidelines on the use of phototherapy to treat neonatal jaundice issued by the American Academy of Pediatrics moved upward the bilirubin concentration that warrants treatment.6 This revision has allowed us to perform a prospective, observational study to examine the possible effects of moderate hyperbilirubinemia per se on neonatal behavior using a well-validated tool, the Brazelton Neonatal Behavioral Assessment Scale (BNBAS).
This study was approved by the Ethical Committee of Università “Federico II” Hospital. In the period of the study (January 1, 1999, to December 1, 2000), we routinely measured total bilirubinemia when screening every infant for phenylketonuria and hypothyroidism (after 72 hours of age and before the discharge from the hospital). Moreover, in jaundiced neonates, total bilirubinemia was repeated according to the clinical judgment of the attending pediatrician. Our study inclusion criteria were singleton, white, term newborn infant; birth weight appropriate for gestational age; delivered spontaneously from uneventful pregnancy; no drug administered peripartum to either mother or child; Apgar score >7 at 1 minute and ≥9 at 5 minutes; normal appearance at routine clinical or laboratory examination until the moment of observation (ie, no clinical evidence of tremors, malformations, metabolic imbalances, etc); exclusive breastfeeding; not treated with phototherapy; without evidence of hemolytic disease; age from 72 to 110 hours of life; and with a bilirubin level ≥13 mg/dL. We excluded from the study those infants who were born to mothers with diabetes or with a history of illicit drugs use or excessive tobacco (>3 cigarettes/day) or caffeine (>1 cup/day) consumption during pregnancy. After informed consent was obtained from a parent, the enrolled neonate was paired to an appropriate control infant, who had to have a bilirubin concentration <13 mg/dL and be matched for gender, birth weight (±150 g), gestational age (±1 week), hours of life (±5 hours), maternal age (±2.5 years), parity, and paternal occupation. The BNBAS was then administered between feedings and no later than 3 hours after the bilirubin determination. All studies were performed under a dim light to minimize the bias represented by the icteric skin. The examiner, experienced in neonatal neurology and specifically trained to administer the BNBAS, was unaware of the purpose of the study and was blinded to the group allocation. At the first observation, we evaluated 50 pairs of neonates. The number of studied pairs was designed so as to achieve 90% power to detect a difference as small as 25% in behavioral response, at the 5% level of significance. The characteristics of the groups at the first observation are indicated in Table 1. A second score after 24 hours was obtained from those jaundiced neonates whose bilirubin concentration had decreased at least of 1 mg/dL. Finally, a third observation at 3 weeks of age was obtained from 16 newborn pairs who returned to our clinic (Fig 1).
The BNBAS7 includes 28 behavioral items, each scored on a 9-point scale, and 18 elicited reflexes scored on a 3-point scale. The BNBAS evaluates the best performance during the examination. On the reliability session between 2 observers, a 1-point difference is admitted on the behavioral items. Studies that have addressed the issue of test-retest reliability during repeated BNBAS exami-nations reveal low to moderate test-retest correlations.8,9 However, because the neonatal period is characterized by rapid changes in physical, physiologic, and behavioral systems, the test-to-test reliability issue may not be appropriate for the BNBAS.10 The infant’s performance is summarized according to 6 factors: habituation, social-interactive, motor behavior, state organization, regulation of state, and autonomic stability. For the analysis, we followed the indications of the scale to convert all of the scores from curvilinear to linear such that a low score indicated a low-intensity response and a high score indicated a high-energy-level response. Other characteristics and limits of the BNBAS can be found in the manual.7 Total bilirubin was assessed using a commercial spectrophotometer (Neobil, das, Milan, Italy).
Data analysis variables were compared by nonparametric Wilcoxon Test for paired data. Pearson coefficient was calculated to evaluate any correlations between quantitative variables. Regression analysis was used to evaluate the contribution of possibly confounding factors, such as gestational age, birth weight, Apgar scores, and hours of life, on the dependent variables. A level of P < .05 was chosen as statistically significant.
At the first observation, the group with moderate hyperbilirubinemia (median: 14.3 mg/dL; range: 13.2–20) was examined at 88 hours of life (range: 72–110), and the group with low bilirubinemia (9.1 mg/dL; range: 5.3–12 mg/dL) was examined at 87 hours of life (range: 72–110). The comparison of the 27 behavioral items between the 2 groups showed significant differences in most items of all clusters and particularly in the social-interactive cluster; all 7 items that gather the visual and auditory capabilities of the neonate were (Table 2) significantly poorer in the moderate hyperbilirubinemia group. Social-interactive cluster scores significantly correlated with serum bilirubinemia (r = −0.295; P = .003) and birth weight (r = 0.240; P = .01) but did not correlate with hours of age, gestational age and Apgar score at 1 minute. When a multiple regression analysis including serum bilirubinemia and birth weight was performed, serum bilirubinemia accounted for 8.7% of the variance, whereas birth weight only for 4.7%. The correlation between social-interactive scores at the first observation and serum bilirubin is reported in Fig 2A. The moderate hyperbilirubinemia group also showed a negative correlation with the autonomic system (r = −0.383; P = .001) and more frequent presence of tremors. Figure 2B shows the correlation between bilirubin and tremors in the 2 groups. Motor system (r = 330; P = .001) and state organization scores (r = 0.215; P = .032) significantly correlated with birth weight. Twenty-four hours later, at the second observation, a subgroup of 22 subjects (10 girls) with decreasing bilirubinemia and 22 matched control subjects showed an average bilirubin of 13.1 mg/dL (range: 10.2–15.5 mg/dL) and 9 mg/dL (range: 2.2–12 mg/dL), respectively. No significant variation in the BNBAS was noted between the groups (data not shown). However, to understand whether a variation of BNBAS scores was associated with decreasing serum bilirubin levels, we compared scores from the 22 jaundiced infants who had been evaluated twice. Serum bilirubin had dropped significantly from 15.5 mg/dL (range: 13.2–16.8) to 13.1 mg/dL (range: 10.2–15.3) (t = 8.494; P = .001) and BNBAS scores had improved (Table 3). At 3 weeks of age—19.5 days (range: 16–25) versus 19.3 days (range: 18–25)—a third evaluation was obtained in 16 matched pairs of the original sample. Infants of both groups appeared pink, and serum bilirubin determination was not performed. BNBAS scores did not show significant differences (data not shown). At the time, 2 subjects in the moderate hyperbilirubinemia and 1 in the low bilirubin group were still partially breastfed.
This study shows that over a moderate range of concentrations, bilirubin can significantly affect neonatal behavior, particularly on its motor and sensorial components. Other investigators had described similar alterations induced by moderate hyperbilirubinemia.11,12 However, unlike those previous studies, we were able to exclude phototherapy as a significant confounder. Moreover, hypoxia, infection, acidosis, and other metabolic conditions that have been identified as possible cofactors of bilirubin neurotoxicity13 do not seem to play a role in our experimental setting.
Recently, Soorani-Lunsing et al14 observed an increased rate of minor motor dysfunctions in neonates with moderate hyperbilirubinemia. This is in good agreement with our findings that, indeed, offer a wider, behavioral perspective of the issue. The pattern of behavioral alterations that we describe has intriguing similarities with the CNS involvement for higher hyperbilirubinemia levels. In fact, both acute and chronic bilirubin encephalopathies show extrapyramidal and sensorial involvement while other cortical functions are relatively spared.13 This is attributable to the prevalent bilirubin deposition in the basal ganglia and mesencephalic formations13 for reasons that have recently become clearer. In fact, although a differential neuronal susceptibility to bilirubin has never been proved,13 experimental data from piglets and rats in metabolic equilibrium show that the CNS areas that are preferentially affected have an increased vascular permeability to bilirubin both in basal conditions and after a bilirubin injection.15,16 It is interesting that not only the increased permeability is more pronounced in the newborn rat than in older puppies15,16 but also, as reported by Roger et al,16 hyperbilirubinemia in the moderate concentration range is associated with the greatest increase in bilirubin-to-brain transfer in the auditory areas followed by the visual and extrapyramidal system.
Our work does not address whether the behavioral changes are clinically relevant by interfering with feeding, bonding, soothing, or fussiness, and we believe that additional studies are needed in this respect. In conclusion, moderate hyperbilirubinemia per se induces an apparently reversible alteration in neonatal behavior that is compatible with a transient involvement of the same CNS centers that are selectively affected by higher bilirubin concentrations.
- ↵Maisels MJ. Jaundice. In: Avery GB, Fletcher MA, Mac Donald MG, eds. Neonatology, Pathophysiology and Management of the Newborn. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins;1999:765– 820
- ↵American Academy of Pediatrics, Provisional Committee for Quality Improvement and Subcommittee on Hyperbilirubinemia. Practice parameter: management of hyperbilirubinemia in the healthy term newborn. Pediatrics.1994;94 :558– 565
- ↵Brazelton TB, Nugent JK. Neonatal Behavioral Assessment Scale. 3rd ed. Cambridge, UK: Cambridge University Press;1995
- ↵Lester BM. Data analysis and prediction. In: Brazelton TB, ed. Neonatal Behavioral Assessment Scale. 2nd ed. London, UK: Spastics International Medical Publications;1984:85– 96
- ↵Brazelton TB, Nugent JK, Lester BM. Neonatal Behavioral Assessment Scale. In: Osofoki J, ed. The Handbook of Infants Development. New York, NY: Wiley;1987:780– 817
- ↵Horowitz FD, Linn PL. Use of the NBAS in research. In: Brazelton TB, ed. Neonatal Behavioral Assessment Scale. 2nd ed. London, UK: Spastics International Medical Publications;1984:97– 104
- ↵Volpe JJ. Bilirubin and brain injury. In: Volpe JJ, ed. Neurology of the Newborn. Philadelphia, PA: Saunders;2001:521– 546
- Copyright © 2002 by the American Academy of Pediatrics