Neurodevelopmental outcome of healthy term newborn with serum bilirubin >15 mg/dl at one year

1 Introduction

Neonatal hyperbilirubinemia (NNH) is a commonly faced clinical situation; especially, in the first week of life [1, 2]. Neonatal jaundice is defined as a yellowish discoloration of the skin and sclera in a newborn caused by bilirubin accumulation [3]. Approximately 60%of term babies and 85%of preterm babies develop clinically apparent jaundice [4, 5]. In most newborns, this is a transient phenomenon.

The unconjugated bilirubin is known to cross the blood-brain barrier and tends to deposit in the basal ganglia, brain stem nuclei, the vestibulocochlear nucleus, and causes neurotoxicity leading to developmental delay, behavioral and neurological impairment, even in term newborns [6–8]. Acute bilirubin encephalopathy may develop during hyperbilirubinemia and evolve into chronic neurodevelopmental sequelae of kernicterus. NNH is an important cause of preventable brain damage among infants. There are researches showing higher levels of bilirubin related to higher neurological deficits in neonates. Paludetto et al. observed that the self-quieting abilities of neonates were affected when total bilirubin levels > 13.2 mg/dl [6].

Several developmental screening tools are used by the health professionals to obtain structured fol-low-up of high-risk newborns, assess their neurodevelopmental outcome by a structured scale, and correlate factors affecting the outcome in developmental and behavioral pediatric practice. This enables feedback to NICU care, thus resulting in the improvement of NICU protocols and care. One such tool for the assessment of infantile neurodevelopment in the Indian Population is Development Assessment Scale for Indian Infants (DASII) [9]. The level of bilirubin associated with toxicity in healthy term or preterm infants is uncertain and appears to vary among infants and in different clinical circumstances [10–12]. Even a moderate level of serum bilirubin may affect the development; therefore, the present study was planned to evaluate the neurodevelopmental outcome in full-term healthy newborn at one year of age with serum bilirubin > 15mg/dl.

2 Material and methods

This prospective cohort study was conducted in the Department of Pediatrics of a tertiary care teaching institution of Central India from January 2018 to August 2019. Prior approval from the institutional ethics committee was obtained, and informed consent was taken from the parents/ legal guardians. 125 healthy term neonates, admitted to NICU for NNH with at least one serum bilirubin value of >15 mg/dl, were included in the study. Preterm or IUGR babies, babies with meningitis, suspected/ culture-positive sepsis, birth asphyxia, neonatal convulsions, conjugated hyperbilirubinemia, neonatal hypothyroidism, or congenital malformations affecting the neurodevelopmental outcome, were excluded from the study.

Keeping a 95%confidence interval and 80%power of the study with a 9%prevalence of NNH and the allowable error of 5%, the sample size was determined to be 125. Out of the total 125 recruited neonates, 17 patients did not complete the follow-up till one year; therefore, they were excluded and the final sample size was 108 with a dropout rate of 16.6%.

A detailed antenatal history, demographic data, anthropometry, vitals, gestational age, the systemic examination was recorded on a pretested proforma. Gestational age was assessed using the last menstrual period and available ultrasonography scans. Gestational age was confirmed by the new Ballard score in neonates. Appropriate for the date (as per the Fenton’sCharts) newborns with total serum bilirubin (TSB)>15 mg/dl were included in the study. A thorough clinical examination was done to assess the extent of Icterus (Cramer’s rule) and neurological status. Blood sample collection was done by venipuncture under all aseptic precautions at the time of admission. Serum was separated by centrifugation, and then, serum bilirubin estimation was done using the Modified Jendrassik and Grof’s Method kit [13]. Other investigations including complete hemogram, C-reactive protein (CRP), serum bilirubin, blood group, peripheral smear (PS) for typing of anemia, glucose-6-phosphate dehydrogenase (G6PD) assay, direct Coombs test, and thyroid profile were also done. Serum bilirubin estimation was done 12 hourly [14], and the peak TSB level was considered for inclusion in the study.

Newborns with hyperbilirubinemia were managed as per the guidelines for phototherapy and exchange transfusion published by the American Academy of Pediatrics Subcommittee on Hyperbilirubinemia [15]. An infant once discharged was then followed-up at three, six, nine, and 12 months of age and complete developmental assessment was done using DASII on each visit. DASII is a revised version of the Bayley Scale of Infant Development (BSID) and it was validated in subsequently conducted studies in different pediatric populations [9, 16].

DASII is applied for infants between zero months and two and a half years of age and development is assessed in two domains; namely, motor and mental domain. The motor development items cover the child’s development from supine to erect posture, neck control, locomotion, and basic locomotive skills, such as climbing, jumping, skipping, etc. It also includes the record for manipulative behavior such as reaching, picking up things, handling and manipulating them, putting, or throwing them in a directed manner, etc. The mental development items record the child’s cognizance of objects in the surroundings, the perceptual pursuit of moving objects, exploring them to meaningful manipulation. It also covers the development of communication and language comprehension, spatial relationship and manual dexterity, imitative behavior and social interaction, etc.

The motor and mental developmental quotients (DQ) were calculated and correlated in each cluster group. DQ <70 was taken as delay and the neonates who had DQ <70 were enrolled in the developmental neurology clinic where they were assessed monthly and appropriate therapy was started.

Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) software version 20.0 (IBM corporation, NY, USA). Data comparison was done by applying specific statistical tests to find out the statistical significance of the comparisons. Quantitative variables were compared using mean values and qualitative variables using proportions. Quantitative data were compared with help of the student t-test. Qualitative data were compared with the Chi-square test and Fisher’s exact test. The significance level was fixed at p≤0.05.

3 Results

Out of a total of 108 cases enrolled in the study, the peak serum bilirubin was observed at three to seven days of age in 84.3%(n = 91) and between 8–14 days in 15.7%(n = 17) neonates. Weight of babies was between 2.5–3.0 kg in 83.3%(n = 90) and more than 3 kg in 16.7%(n = 18). Based on the bilirubin level, all cases were stratified into three groups as shown in Table 1.

Motor developmental outcomes by DASII at three and six months of age, 100 (92.6%) out of 108 neonates had normal motor development and four (3.7%) cases had a mild delay while four (3.7%) had a severe delay. At nine months, an improvement was seen in one patient with mild delay; therefore at nine months, three (2.8%) cases had a mild delay and four (3.7%) had a significant delay. At 12 months of age, out of 108 cases, 101 (93.5%) had normal motor development and two (1.9%) cases had a mild delay while one case with mild delay progressed to severe delay; thus, a total of five (4.6%) had a significant delay in motor development at 12 months of age (Table 2).

In the present study, Locomotion-I (coordinated movements) score was found >70 among 89 (82.4%) cases and it was <70 in 19(17.6%) cases. Locomotion-I score >70 was found in 74 (87%) cases with 15–20 mg/dl bilirubin (group 1) and it was <70 among 11(13%) cases and this association was statistically significant (P = 0.003) [Table 3]. Manipulation score was >70 among 95 (88.0%) cases and it was <70 in 13 (12.0%) neonates. Manipulation score >70 was found in 79 (92.9%) cases with 15–20 mg/dl bilirubin and it was <70 among 6 (7.1%) cases and this association was statistically significant (p = 0.001) (Table 3).

Table 4 reveals the mean TSB according to the mental and motor neurodevelopmental outcomes. The mean TSB was significantly higher among cases with the delayed mental neurodevelopmental outcome as compared to those with normal development. A statistically significant association was found between TSB and the mental and motor neurodevelopmental outcomes (p = 0.001).

Neurodevelopmental disability is a group of interrelated, chronic, non-progressive disorders of the central nervous system caused by injury of the developing brain. It is constituted of a spectrum ranging from motor impairment to cognitive impairment and sensory impairment. Numerous retrospective studies have attempted to support or refute the relationship of NNH with the abnormal neurodevelopmental outcome. A particular challenge in understanding this relationship has been the use of varying measures of neurodevelopmental assessment. Paludetto et al observed that the self-quieting abilities of neonates were affected when total bilirubin levels >13.2 mg/dl [6].

In the present study, at 12 months of age, 101 (93.5%) out of 108 cases had normal motor development while two (1.9%) cases had a mild delay and five (4.6%) had a severe delay in motor development. In the present study, the mean TSB was significantly higher among cases with the delayed neurodevelopmental outcome as compared to those with normal development. A significant association was found between the higher mean TSB and adverse motor outcome (p = 0.001). Similarly, a study by Yilmaz Y et al. [17], found a significant relationship between the neurological outcome and bilirubin levels, neurologically disabled children with TSB levels of 20–23.9 mg/dl had only minor neurological dysfunction, whereas babies with TSB levels of >24 mg/dl had moderate to severe neurological sequelae.

In a separate study, Meredith L et al. [18], conclu-ded the risk of bilirubin toxicity is probably negligible in a healthy term newborn without hemolysis, the bilirubin level above 25 mg/dl (428μmol/L) is a con-cern, whereas, in the term newborn with hemolysis, a bilirubin level above 20 mg/dl (342μmol/L) is a concern. In the present study, the mean TSB was significantly higher among the children with blood group incompatibility. Babu and Bhat [19] in their study concluded that peak TSB >25 mg/dl, need for exchange transfusion, Rh incompatibility, and the onset of jaundice within two days of birth are independent predictors of abnormal neurodevelopmental at six months. As per the study by Maimburg et al. [20], the excess risk of infantile autism was 67%. Hokkanen et al. [21] and Jangaard et al. [22], also found an association of hyperbilirubinemia with cognitive abnormalities and attention deficit disorder.

In contrast to the above studies, results of which are similar to the present study, a study by Gamaleldin R et al. [23], concluded that in the absence of neurotoxicity risk factors, newborns tolerate bilirubin levels of 25 to 30 mg/dl with low risk for bilirubin encephalopathy; the TSB threshold for acute bilirubin encephalopathy was 31.5 mg/dl in 111 infants who had no risk factors; however, we had excluded the neurotoxicity risk factors in our study. In studies by Newman et al. [24] and Croen et al. [25], they showed reversibility after treatment or no significant association with neurodevelopmental outcome. Vandborg et al. [26], also found no developmental delay at one to five years of age in children with hyperbilirubinemia.

Hansen RL et al. [27], evaluated 74 children, who required neonatal intensive care, with a psychoeduca-tional test battery at ages nine to 11 years, and concluded that direct measures of hyperbilirubinemia, including peak TSB, did not have a significant relationship with the intelligence outcomes. However, they found a significant association between a measure of bilirubin-albumin binding and scores on the Kaufman Mental Processing Composite. The authors suggested that the overall TSB level may not be as important in determining neurotoxicity as is the free or unbound bilirubin level, or the bilirubin-albumin binding capacity.

In our study, we assessed the developmental outcome using DASII, and on cluster analysis, we found that six (7.1%) cases and 11 (13%) cases of group 1 were delayed in the manipulation score and locomotion-I score, respectively. A significant association between manipulation score and TSB (p = 0.001), as well as locomotion-I and TSB (p = 0.003), was found. We could not compare these results with other studies as we could not find studies on the cluster analysis of DASII in healthy full term newborns with NNH.

As even a moderate level of bilirubin significantly affects the developmental outcome, efforts should be made for the early detection as well as prevention of the rise in serum bilrubin levels before it reaches to the toxic levels. Antenatal screening of high risk mothers, cord blood bilirubin of high risk neonates, use of anti D antenatally and perinatally are measures which may prevent the development of significant hyperbilirubinemia and its sequelae at primary and secondary level [28].

The present study had some limitations such as a relatively shorter follow-up of only one-year. If the involvement of locomotion and manipulation clusters remain unattended and not intervined, it may give rise to various disabilities. With a longer follow-up, specific developmental disorders may be diagnosed early and a domain-specific early intervention can be planned to decrease the preventable neurological sequelae.

5 Conclusion

In the present study, a significant association was found between TSB and neurodevelopment outcomes. The present study had shown that the delay in individual clusters of motor and mental development can be diagnosed at an early age by DASII. Apart from a timely diagnosis and early intervention in newborns with hyperbilirubinemia, efforts should be made to prevent the increase in bilirubin levels to the neurotoxic levels.

Author’s contribution

PD: Acquisition and interpretation of data, data analysis, drafting the article, and literature review; JS: Concept, interpretation of data and data analysis, drafting the article, and literature review; AA: Data analysis, manuscript review, manuscript editing, revising the article critically for important intellectual content; JS will act as guarantor. All the authors approved the final manuscript.

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