Indian J Pediatr (February 2012) 79(2):202206 DOI 10.

1007/s12098-011-0501-2

ORIGINAL ARTICLE

Association between Peak Serum Bilirubin and Neurodevelopmental Outcomes in Term Babies with Hyperbilirubinemia
Thirunavukkarasu Arun Babu & Vishnu Bhat B & Noyal Mariya Joseph

Received: 25 November 2010 / Accepted: 10 June 2011 / Published online: 25 June 2011 # Dr. K C Chaudhuri Foundation 2011

Abstract Objective To find the association between neonatal Peak serum bilirubin (PSB) levels and the neurodevelopmental outcomes at 6 months in term infants with neonatal hyperbilirubinemia. Methods Term neonates who developed jaundice with atleast one PSB value of above 15 mg/dl within first wk of life were included. Babies with any condition affecting the neurodevelopment, like prematurity, convulsions or asphyxia were excluded from the study. This prospective cohort study included 66 term babies out of the 6548 newborns delivered during the study period. Results The incidence of abnormal developmental quotient gradually increased with increase in the level of PSB. Based on univariate analysis, a PSB22 mg/dl (the cut off obtained based on Receiver operating characteristic curve), Rh incompatibility and occurrence of jaundice within 2 days of life were found to be significant risk factors for abnormal developmental quotient. These three risk factors were also independently associated with abnormal development by multivariate logistic regression analysis. Conclusions PSB level of 22 mg/dl, Rh incompatibility and occurrence of jaundice within 2 days of life are independent predictors of abnormal development in babies with neonatal jaundice. Keywords Neonatal hyperbilirubinemia . Jaundice . Peak serum bilirubin . Neurodevelopment
T. Arun Babu : V. Bhat B (*) : N. M. Joseph Department of Pediatrics, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Puducherry 605 006, India e-mail: drvishnubhat@yahoo.com

Introduction Neonatal hyperbilirubinemia is an important cause of preventable brain damage and early death among infants. Emerging current practices like early hospital discharges have led to a rise in the rate of preventable neurodevelopmental sequelae resulting from untreated hyperbilirubinemia [1]. The current understanding on the development of bilirubin encephalopathy is that when the level of serum unconjugated bilirubin exceeds the bilirubin binding capacity of albumin, the excess unconjugated unbound bilirubin, due to its lipophilic nature readily crosses the bloodbrain barrier, resulting in neuronal injury [24]. Since the albumin levels and the conjugating ability are relatively constant, the amount of unbound unconjugated bilirubin is directly proportional to the total serum bilirubin. It is now clear that the risk of developing acute bilirubin encephalopathy is more when the bilirubin level increases beyond 20 mg/dL [5]. It has been well recognized that once acute bilirubin encephalopathy develops, babies sustain varying degree of neurodevelopmental sequlae. It is still not clear whether bilirubin levels falling short of developing acute bilirubin encephalopathy affects neurodevelopmental outcome or not [6]. There has been conflicting evidence regarding the proportionate association of peak serum bilirubin with the future neurodevelopmental delay [7, 8]. The purpose of this study was to assess the association between peak total serum bilirubin (PSB) during the first wk of life and the neurodevelopmental outcome among term infants at 6 months of age.

Material and Methods The present study was conducted over a 2 year period from March 2007 through March 2009, at a tertiary care teaching

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hospital in South India. All the term neonates who developed jaundice with atleast one total serum bilirubin value of above 15 mg/dl within first wk of life were enrolled in the study. Babies with acute bilirubin encephalopathy, major congenital anomalies, prematurity (less than 37 wks), intra uterine growth retardation, suspected or culture positive sepsis, birth asphyxia, convulsions or any other disease process which could possibly affect the neurodevelopment were excluded from the study. An informed written consent was obtained from all the parents before their babies were included in the study. This study was approved by the Institute Research and Ethics committee. Baseline characteristics of neonates including sex, gestational age, and anthropometry were recorded at admission. Investigations including total and direct bilirubin concentration, hemoglobin levels, peripheral smear, blood counts, blood grouping, and coombs test were done for the cases. The highest value of total serum bilirubin was considered as Peak serum bilirubin (PSB) for that case. Septic screen and blood culture were done in suspected cases of sepsis. Standard institutional protocol for treatment of neonatal jaundice was followed. Treatment modalities started and response to treatment were recorded. After discharge all cases were followed up till 6 months of age and assessed using Baroda developmental screening test (BDST) [9]. Developmental age and quotients were calculated for each case according to BDST. BDST is a standardized version of The Bayley Scales of Infant Development (BSID) for Indian children [10]. It contains, 54 items arranged sequentially by their 97% pass age-placements and grouped monthly for 12 months. The point where the score crosses the upper (50%) standardized curve gives the developmental age of the infant. The Development Quotient was calculated using the formula (Developmental Age x 100/Chronological Age) and a score of 80 was taken as normal [10]. Statistical Analysis Data entry and analysis were done using statistical software SPSS for Windows Version 16.0 (SPSS Inc, Chicago, IL, USA). Percentages were calculated for categorical variables. Receiver operating characteristic (ROC) curve was generated to evaluate the role of PSB level as a prognostic factor and the co-ordinate of the ROC curve was used to determine the cut-off of PSB for predicting poor neurodevelopmental outcome. Univariate analysis of the various risk factors for poor neurodevelopmental outcome was performed using the chi-square test or Fishers exact test. The authors confirmed the results of these tests, with logistic regression analysis. This step was necessary to avoid producing spuriously significant results with multiple comparisons. Results of the logistic regression analyses

are reported as estimated odd ratios with their 95% confidence intervals. P value<0.05 was considered statistically significant.

Results Out of the total 6548 newborns delivered during the study period, 66 term babies developed jaundice within the first wk of life with at least one value of PSB more than 15 mg/dl fulfilling the inclusion criteria. Out of the total 66 included cases, 19 cases were lost to follow up and two cases died due to causes unrelated to jaundice. The remaining 45 cases that completed the study were taken for analysis. Of these 24 (53.3%) were boys and 21 (46.7%) were girls. Of the 45 babies, 22 had a peak serum bilirubin (PSB) level > 21 mg/dl. None of these babies had kernicterus or obvious neurological abnormality at discharge. Majority (66.7%) of the neonates presented with jaundice within 3 days of life. In 16 (35.5%) babies, the developmental quotient was abnormal (< 80) at 6 months of age. The authors observed that the proportion of babies with abnormal developmental quotient gradually increased with increase in the level of PSB (Fig. 1). The ROC curve was generated to determine if the PSB can be used as prognostic marker of abnormal development quotient (Fig. 2). Based on the co-ordinates of the ROC curve, a PSB level of 22 mg/dl was considered as cut off for predicting abnormal development quotient. Based on univariate analysis, a PSB22 mg/dl had a relative risk of 4.53 (95% CI, 1.49 to 13.76) with a P value 0.0036. The authors studied the various other factors which could also be responsible for poor neurodevelopmental outcome. The results of univariate analysis of the various

Fig. 1 The association between Peak serum bilirubin (PSB) and abnormal developmental quotient

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Indian J Pediatr (February 2012) 79(2):202206

Fig. 2 Receiver operating characteristic (ROC) curve for determining the PSB cut-off for predicting abnormal development

factors which could contribute to poor neurodevelopmental outcome are summarised in Table 1. Rh incompatibility and occurrence of jaundice within 2 days of life were found to be statistically significant risk factors for abnormal developmental quotient. Sex, birth weight and head circumference were not found to significantly influence the developmental quotient of the babies with neonatal jaundice. Multivariate logistic Regression analysis identified PSB above 22 mg/dl, Rh incompatibility and occurrence of jaundice within 2 days of life as independent risk factors associated with abnormal developmental outcome (Table 2).

Discussion It is clinically difficult to accurately predict the neurodevelopmental outcome of babies with neonatal jaundice. The authors studied the role of PSB as a prognostic factor in predicting the neurodevelopmental outcome of babies with hyperbilirubinemia.

The major strength of the present study rests in excluding all possible confounding factors causing neurodevelopmental delay and a good follow up rate of 75%. But, this would have lead to a relatively small sample size. The cases in the present study were followed up till 6 months of age and were screened for abnormal neurodevelopment. Ideally, longer follow ups are desirable in order to pick up mild cases of abnormal neurodevelopment and to know the overall neurodevelopment. Other limitation of the present study is that the PSB is a single value, and the duration of hyperbilirubinemia, which might also have influenced the outcome, was not documented as it is practically cumbersome and requires multiple blood sampling. Preterm babies were excluded from the study since prematurity itself is a significant confounding factor which can contribute to neurodevelopmental sequlae. In a study done among preterm infants, two thirds of them demonstrated neurodevelopmental impairments [11]. Other possible conditions affecting neurodevelopment like sepsis, birth asphyxia etc. were excluded from the study. Studies have identified that severe jaundice with bilirubin levels of more than 15 mg/dl can be associated with neurodevelopmental delay [12]. A cut off value of 15 mg/dl was chosen in the present study to exclude physiological jaundice in term newborns and to include the potentially at risk newborns with higher peak serum bilirubin levels. The authors observed that the number of babies with abnormal developmental quotient increased proportionately with increase in the level of PSB. A similar study done in extremely low birth weight babies identified that increased bilirubin levels were proportionately associated with neurodevelopmental impairment [13]. Studies have shown that besides PSB levels, other factors such as birth weight and male sex can also influence the neurological outcome of the babies with neonatal jaundice [14]. Hence, the authors evaluated if factors such as sex, birth weight, head circumference, diagnosis and day of onset of jaundice had any influence on the neurodevelopmental outcome of the

Table 1 Univariate analysis of the various risk factors for poor neurodevelopmental outcome

Parameter

Normal developmental quotient (n=29) (%) 2 2

Abnormal developmental quotient (n=16) (%) 9 8

Relative risk (95% confidence limits)

P value

Rh incompatibility Jaundice within first 2 days of life Male sex Birth weight ( 2.50 Kg) Head circumference ( 33 cm)

3.97 (1.94 to 8.14) 3.50 (1.77 to 6.93)

0.0005 0.0017

14 5

10 3

1.46 (0.64 to 3.33) 1.07 (0.39 to 2.89)

0.5462 1.0000

1.20 (0.54 to 2.67)

0.9123

Indian J Pediatr (February 2012) 79(2):202206 Table 2 Logistic regression analysis of PSB controlling for the other risk factors P value Adjusted 95% confidence interval Odds ratio Lower Upper PSB22 mg/dl Rh incompatibility Jaundice within first 2 days of life 0.028 0.047 0.037 7.750 8.815 12.010 1.248 1.027 1.156 48.132 75.676 124.746

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outcome. In addition, Rh incompatibility and occurrence of jaundice within 2 days of life can also predict abnormal developmental outcome in babies with neonatal jaundice.

Contributions ABT,VBB; conceived and conducted the study, ABT, NMJ; literature search and drafted the manuscript, VBB; critically reviewed and approved the manuscript.

Conflict of Interest None.

babies included in the present study. Of the various factors evaluated, only Rh incompatibility as an etiology and occurrence of jaundice within 2 days of life were associated with abnormal developmental quotient in our study. Therefore, logistic regression analysis for the above mentioned two risk factors was performed to find out if PSB levels can be used as an independent prognostic factor of poor neurodevelopmental outcome. It showed that PSB 22 mg/dl was a significant predictor of abnormal developmental quotient, even in the absence of the other two risk factors. Two similar studies have also showed proportionate impairment in neurodevelopment with increasing PSB in the first wk of life [13, 15]. Studies have shown that Rh incompatibility significantly impairs the neurodevelopmental outcome when compared to the other etiologies, similar to the present study [16]. In babies with Rh incompatibility, the excessive hemolysis results in an enormous production of unconjugated bilirubin which could not be effectively eliminated by the hepatic conjugation. Rh incompatibility frequently causes high PSB levels than other etiologies. The lipid cells in the brain later take up this excess bilirubin, which remains unbound to albumin, resulting in serious neurological damage [17]. This could be the reason for the association between Rh incompatibility and abnormal development quotient of babies with neonatal jaundice. The neonatal jaundice presenting within the first 2 days of life are usually pathological, while the milder self limiting form of physiological jaundice presents usually after the first 48 h [18]. This explains the increased risk of abnormal developmental quotient associated with jaundice occurring within 2 days of life. But, another study done on term neonates with hyperbilirubinemia failed to show any significant association between the day of onset of jaundice and neurodevelopment, but there was significant difference in PSB between developmentally normal and abnormal infants at follow up [19].

Role of Funding Source None.

References
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Conclusions A PSB level of 22 mg/dl can be relied upon as an independent prognostic factor for poor neurodevelopmental

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Indian J Pediatr (February 2012) 79(2):202206 18. Martin CR, Cloherty JP. Neonatal hyperbilirubinemia. In: Cloherty JP, Eichenwald EC, Stark AR, editors. Manual of neonatal care. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2004. pp. 181212. 19. Yilmaz Y, Karadeniz L, Yildiz F, Degirmenci SY, Say A. Neurological prognosis in term newborns with neonatal indirect hyperbilirubinemia. Indian Pediatr. 2001;38:1658.