Journal of Clinical Neonatology

ORIGINAL ARTICLE
Year
: 2020  |  Volume : 9  |  Issue : 2  |  Page : 138--142

Neurodevelopmental outcome at 6 months of age in full-term healthy newborns with neonatal hyperbilirubinemia


Amit Agrawal, Shilpa Pandya, Jyotsna Shrivastava 
 Department of Pediatrics, Gandhi Medical College and Kamla Nehru Hospital, Bhopal, Madhya Pradesh, India

Correspondence Address:
Dr, Amit Agrawal
28, Ravidas Nagar, Near Nizamuddin Colony, Indrapuri, Bhopal - 462 023, Madhya Pradesh
India

Abstract

Background: Neonatal hyperbilirubinemia (NNH) is an important cause of preventable brain damage among infants. Neurodevelopmental assessment and Brainstem-Evoked Response Audiometry (BERA) may help in the early identification and management of neurodevelopmental sequelae. Objectives: The objectives of this study were to find the association between neonatal peak serum bilirubin levels and the neurodevelopmental outcomes at 6 months in term infants with NNH and to assess the changes in BERA of these neonates. Methodology: A prospective cohort study was conducted in the Department of Pediatrics, Gandhi Medical College, Bhopal. All healthy, full-term, appropriate-for-date neonates, admitted from December 2014 to June 2015 with hyperbilirubinemia and serum bilirubin >12 mg/dL, were included in the study and were followed up till 6 months of age. The neurodevelopmental assessment was done using the Denver Developmental Screening Test II and BERA was done at an average age of 69 ± 6 days. Results: A total of 77 newborns were enrolled, and 73 completed the study. Of these 77 neonates, 40 (51.65%) had abnormal BERA results, whereas 3 (3.9%) had neurodevelopmental abnormalities. BERA and neurodevelopmental abnormalities were associated with a mean serum bilirubin of 22.58 mg/dL and 31.33 mg/dL, respectively. The cutoff value of serum bilirubin was 16.3 mg/dL and 23.8 mg/dL, respectively, to detect BERA and neurodevelopmental abnormalities, respectively. All patients (11) who received exchange transfusion had BERA abnormalities, and 3/11 (27.3%) had neurodevelopmental abnormalities. The association of ABO incompatibility was significant (P < 0.001) with abnormal BERA. Conclusion: Serum bilirubin is linearly associated with BERA and neurodevelopmental abnormalities. Patients receiving exchange transfusion have higher odds of neurodevelopmental sequelae. Regular follow-up and early intervention may help infants to have better neurodevelopmental and auditory outcomes.



How to cite this article:
Agrawal A, Pandya S, Shrivastava J. Neurodevelopmental outcome at 6 months of age in full-term healthy newborns with neonatal hyperbilirubinemia.J Clin Neonatol 2020;9:138-142


How to cite this URL:
Agrawal A, Pandya S, Shrivastava J. Neurodevelopmental outcome at 6 months of age in full-term healthy newborns with neonatal hyperbilirubinemia. J Clin Neonatol [serial online] 2020 [cited 2020 Jul 15 ];9:138-142
Available from: http://www.jcnonweb.com/text.asp?2020/9/2/138/283028


Full Text



 Introduction



Chemical hyperbilirubinemia, defined as total serum bilirubin (TSB) ≥2.0 mg/dL, is virtually universal in newborns during the 1st week of life. Neonates characteristically do not appear jaundiced until TSB exceeds 5–7 mg/dL.[1] Neonatal hyperbilirubinemia (NNH) is an important cause of preventable brain damage among infants. Emerging current practices such as early hospital discharges have led to a rise in the rate of preventable neurodevelopmental sequelae resulting from untreated NNH.

By pathologic criteria, kernicterus develops in 30% of infants with bilirubin levels >25–30 mg/dL.[1] In the clinical setting, kernicterus denotes the chronic and permanent sequelae of bilirubin toxicity. Acute bilirubin encephalopathy is the clinical manifestation of bilirubin toxicity in the neonatal period. It has been well recognized that once “acute bilirubin encephalopathy” develops, babies sustain a varying degree of neurodevelopmental sequelae. Hyperbilirubinemia in term infants has been associated with abnormalities in Brainstem-Evoked Response Audiometry (BERA), cry characteristics, and neurobehavioral measures. There has been conflicting evidence regarding the proportionate association of peak serum bilirubin with the future neurodevelopmental delay. 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.[2],[3],[4]

This study was aimed to assess the association between neonatal peak TSB levels and the neurodevelopmental outcome at 6 months of age in healthy term infants with NNH. The study also aimed to assess changes, if any, in BERA of neonates with hyperbilirubinemia.

 Methodology



This prospective cohort study was conducted in the department of pediatrics of a tertiary care teaching institution of Central India from December 2014 to June 2015. Prior approval from the institutional ethics committee was obtained, and informed consent was taken from the parents/legal guardians. All healthy, full-term, appropriate-for-date (completed 37–42 weeks) neonates, admitted during the study period with jaundice and serum bilirubin >12 mg/dL, were included in the study. Premature or postterm, low birth weight, small-for-date, Babies with Intra-uterine growth restriction and those with hypoglycemia, perinatal asphyxia, neonatal sepsis, seizures, metabolic disorders, hypothyroidism, or congenital malformations affecting the neurodevelopmental outcome were excluded from the study.

Gestational age (completed 37–42 weeks) was assessed using the last menstrual period and available ultrasonography scans. Gestational age was confirmed by the Ballard scoring in neonates of age <7 days. Anthropometric measurements were taken of all enrolled neonates. Appropriate-for-date (as per the Fenton's Charts) newborns with serum bilirubin >12 mg/dL were included in the study as physiological jaundice rarely exceeds 12 mg/dL in full-term neonates and 15 mg/dL in preterm neonates.[2]

The thorough clinical examination was done to assess the extent of icterus (Cramer's rule) and neurological status. Blood sample collection was done by venepuncture 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.[5] Other investigations including blood group, glucose-6-phosphate dehydrogenase (G6PD), direct Coombs test, thyroid profile, liver function test, hematocrit, and C-reactive protein were also done. Serum bilirubin estimation was done 12 hourly,[1] and the peak serum bilirubin level was considered.

Newborns with hyperbilirubinemia were managed as per the guidelines for phototherapy and exchange transfusion published by the American Academy of Pediatrics Subcommittee on Hyperbilirubinemia.[6] An infant once discharged was then followed up fortnightly till 3 months of age and then monthly till 6 months of age. In each follow-up visit, the thorough clinical examination was done and neurodevelopment was assessed using the Denver Developmental Screening Test II. The test was applied as per instructions given in manual, and results were plotted on the form provided. Individual items in the test were interpreted as advanced, normal, caution, delayed, or no opportunity. The test subjects were interpreted as normal with no delay or one caution, as suspects with two or more cautions and/or one or more delays, and as untestable with one or more refusal scores. In each visit, the results were analyzed, and in the case of caution, early follow-up was done within 1–2 weeks.

BERA[7] was planned in both ears at 3 months of age. The machine used was RMS EMG EP MARK II, and the test was carried out in the Department of Physiology at the same institution. Infants were sedated using syrup chloral hydrate at a dose of 20 mg/kg. Middle ear examination for wax impaction or any other ear defects was done. The guidelines published by the Joint Committee on Infant Hearing[8] were followed. Increased latencies of waves as per the age limits and increased threshold in either ear were considered to be abnormal.

The study population was divided into three groups according to serum bilirubin levels, namely Group 1 (bilirubin: 12–15 mg/dl), Group 2 (15–20 mg/dl), and Group 3 (>20 mg/dl). The outcome was compared between these groups. Statistical analysis was done using appropriate tests including the Chi-square test and t-test. Statistical significance was tested at 95% confidence level, found significant if P < 0.05. All the statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) software version 20.0 (IBM corporation, NY, USA).

 Results



Of total admissions during the study period, 77 neonates fulfilled the inclusion criteria and 73 completed the study [Figure 1]. Of these 77 neonates, 52 (67.5%) were male and 25 (32.5%) were female. As per weight, 53 (68.8%) neonates were between 2.5 and 3 kg and 24 (31.2%) were ≥3 kg. The mean serum bilirubin levels in neonates of all the three groups are presented in [Table 1].{Figure 1}{Table 1}

There were no admissions with NNH in <24 h of life. The maximum patients (42, 54.56%) had their peak serum bilirubin levels on day 4 in all the three groups. None of the studied neonates had G6PD deficiency, and blood group incompatibility was observed in 37.7% of neonates with ABO, Rh, and ABO +Rh accounting to 31.2%, 5.2%, and 1.3%, respectively.

In Group 3, 17 (60.71%) patients received only phototherapy, whereas exchange transfusion was performed in 11 (39.29%) patients. In Group 2, all 30 (100%) patients received only phototherapy. In Group 1, 18 (94.74%) patients received phototherapy and one patient did not require any treatment.

BERA was done in 70 patients (three patients did not consent for BERA) at an average age of 69 ± 6 days. Forty had abnormal BERA and 30 had normal BERA. The most common abnormalities seen were increased latencies of waves V and III. BERA findings in different groups are shown in [Figure 2]. Correlation of BERA with serum bilirubin was analyzed using Student's t-test. The mean bilirubin of 22.58 ± 6.08 mg/dL was significantly associated with abnormal BERA (P < 0.001). The receiver operating characteristic (ROC) curve for abnormal BERA and serum bilirubin level showed the area under the curve (AUC) as 93.5% (95% confidence interval [CI]: 88.2%–98.5%), and the cutoff was 16.3 mg/dL. Age at peak serum bilirubin did not correlate significantly with BERA abnormalities (P = 0.62).{Figure 2}

The P value for correlation of ABO incompatibility with abnormal BERA was significant (< 0.05) when compared with no and Rh incompatibility. Significantly higher (P = 0.0061) abnormal BERA was seen in cases with exchange transfusion when compared to phototherapy (odds ratio: 8.43, 95% CI: 1.02–31.64, and relative risk: 1.93).

In 77 patients, 70 (90.91%) patients had a normal neurodevelopmental screening at 6 months of age. Three (3.90%) patients were suspected to have a neurodevelopmental delay. Four (5.19%) patients lost to follow-up; hence, the assessment could not be done. Distribution as per neurodevelopmental outcome in different groups is shown in [Figure 3].{Figure 3}

At mean indirect bilirubin level of 31.33 ± 7.02 mg/dL, an association of suspected neurodevelopmental delay was significantly high (P < 0.001). ROC curve for the abnormal neurodevelopmental outcome and serum bilirubin level showed AUC as 95.2%, 95% CI: 88.5%–100%, and the cutoff was 23.8 mg/dL. There was no significant correlation between blood group incompatibility and neurodevelopmental delay in any of the groups except in patients with both ABO with Rh incompatibility (P < 0.001).

Significantly higher (P < 0.001) suspect cases were seen with exchange transfusion when compared to phototherapy (odds ratio: 31.2, 95% CI: 2.6–55.3). On correlating neurodevelopmental outcome and BERA [Table 2], the odds ratio of suspect neurodevelopmental delay with abnormal BERA was 3.21 (95% CI: 0.31–21.4).{Table 2}

 Discussion



Unconjugated bilirubin crosses blood–brain barrier and causes damage in terms of hearing and neurodevelopment. Indirect bilirubin is strongly neurotoxic for underdeveloped neural system, especially when the indirect bilirubin concentration exceeds the albumin-binding capacity. The phenomenon of deposited indirect bilirubin in the basal ganglia as well as in the vestibule-cochlear nucleus causes a neurological syndrome called kernicterus as well as sensorineural hearing loss (SNHL). BERA detects SNHL and aids in early diagnosis and management.

The present study found a significant association between peak serum bilirubin levels and BERA changes. The percentage of abnormal BERA in the present study (51.95%) was higher as compared to studies conducted by Agrawal et al.[9] (23.3%) and Sharma et al.[10] (22.5%). Saluja et al.[11] found that 6/13 (46.15%) had abnormal BERA after phototherapy or exchange transfusion. The observation was similar to the present study, in which 89.67% of neonates who underwent exchange transfusion had abnormal BERA. Studies in Iran by Baradaranfar et al.[12] and Okhravi et al.[13] also showed a significant association between BERA and hyperbilirubinemia. Martínez Cruzet al.[14] also found that the frequency of SNHL in children with a history of exchange transfusion treated at a 3rd-level hospital in Mexico City was high (15%). Shankar and Manjunath[15] found the incidence of hearing the loss in NNH to be 8.6%. However, the studies, done by Wong et al.[16] and Duman et al.,[17] were not in concordance with the present study. [Table 3] summarizes the results of BERA in different studies.{Table 3}

In the present study, 3 of 77 newborns (3.90%) were categorized as a suspect and required further neurodevelopmental assessment. All of these had abnormal BERA. These children are being managed in the high-risk clinic of the department.

Babu and Bhat[20] in their study concluded that peak serum bilirubin >25 mg/dl, need for exchange transfusion, Rh incompatibility, and onset of jaundice within 2 days of birth are independent predictors of abnormal neurodevelopmental at 6 months. As per the study by Maimburg et al.,[21] the excess risk of infantile autism was 67%. Hokkanen et al.[22] and Jangaard et al.[23] also found an association of hyperbilirubinemia with cognitive abnormalities and attention deficit disorder. However, studies by Newman et al.,[24] Wong et al.,[16] and Croen et al.[25] either showed reversibility after treatment or no significant association with neurodevelopmental. Vandborget al.[26] also found no developmental delay at 1–5 years of age in children with hyperbilirubinemia.

The present study had certain limitations as repeat BERA could not be done in abnormal BERA cases to assess the reversibility and longer follow-up can give us the better predictive outcome. Confirmatory tests such as DASII would have resulted in the better assessment of neurodevelopmental outcome.

 Conclusion



The study concludes that NNH is a recognizable cause of auditory neuropathy and neurodevelopmental sequelae. Peak serum bilirubin is linearly associated with BERA changes and neurodevelopmental sequelae. Patients having ABO incompatibility and receiving exchange transfusion have higher odds of neurodevelopmental and BERA abnormalities. Regular follow-up and early intervention may help infants with NNH to have better neurodevelopmental and auditory outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Mitra S, Rennie J. Neonatal jaundice: Aetiology, diagnosis and treatment. Br J Hosp Med (Lond) 2017;78:699-704.
2Karimzadeh P, Fallahi M, Kazemian M, Taslimi Taleghani N, Nouripour S, Radfar M. Bilirubin Induced Encephalopathy. Iran J Child Neurol 2020;14:7-19.
3Watchko JF. Bilirubin-induced neurotoxicity in the preterm neonate. Clin Perinatol 2016;43:297-311.
4Olusanya BO, Kaplan M, Hansen TW. Neonatal hyperbilirubinaemia: A global perspective. Lancet Child Adolesc Health 2018;2:610-20.
5Slusher TM, Vaucher YE. Management of neonatal jaundice in low- and middle-income countries. Paediatr Int Child Health 2020;40:7-10.
6Ip S, Chung M, Kulig J, O'Brien R, Sege R, Glicken S, et al. An evidence-based review of important issues concerning neonatal hyperbilirubinemia. Pediatrics 2004;114:e130-53.
7Misra UK, Kalita J. Brainstem Auditory Evoked Potentials in Clinical Neurophysiology. 2nd ed. New Delhi: Elsevier Publishers; 2008. p. 329-46.
8American Academy of Pediatrics, Joint Committee on Infant Hearing. Year 2007 position statement: Principles and guidelines for early hearing detection and intervention programs. Pediatrics 2007;120:898-921.
9Agrawal VK, Shukla R, Misra PK, Kapoor RK, Malik GK. Brainstem auditory evoked response in newborns with hyperbilirubinemia. Indian Pediatr 1998;35:513-8.
10Sharma R, Grover N, Sankhyan N, Sharma ML. Auditory brainstem responses in neonatal hyperbilirubinemia and effect of therapy. Indian J Otolaryngol Head Neck Surg 2006;58:340-2.
11Saluja S, Agarwal A, Kler N, Amin S. Auditory neuropathy spectrum disorder in late preterm and term infants with severe jaundice. Int J Pediatr Otorhinolaryngol 2010;74:1292-7.
12Baradaranfar MH, Atighechi S, Dadgarnia MH, Jafari R, Karimi G, Mollasadeghi A, et al. Hearing status in neonatal hyperbilirubinemia by auditory brain stem evoked response and transient evoked otoacoustic emission. Acta Med Iran 2011;49:109-12.
13Okhravi T, Tarvij Eslami S, Hushyar Ahmadi A, Nassirian H, Najibpour R. Evaluation of auditory brain stems evoked response in newborns with pathologic hyperbilirubinemia in Mashhad, Iran. Iran Red Crescent Med J 2015;17:e18288.
14Martínez-Cruz CF, García Alonso-Themann P, Poblano A, Cedillo-Rodríguez IA. Hearing and neurological impairment in children with history of exchange transfusion for neonatal hyperbilirubinemia. Int J Pediatr 2014;2014:605828.
15Shankar P, Manjunath VC. A study of hearing evaluation for neonates with hyperbilirubinemia using otoacoustic emission and brain stem auditory evoked response. J Evol Med Dent Sci 2014;3:2403-7.
16Wong V, Chen WX, Wong KY. Short- and long-term outcome of severe neonatal nonhemolytic hyperbilirubinemia. J Child Neurol 2006;21:309-15.
17Duman N, Ozkan H, Serbetçioglu B, Ogün B, Kumral A, Avci M. Long-term follow-up of otherwise healthy term infants with marked hyperbilirubinaemia: Should the limits of exchange transfusion be changed in Turkey? Acta Paediatr 2004;93:361-7.
18Bhagya V, Brid SV, Doddamani M. Incidence of hearing loss in infants at risk. Int J Biol Med Res 2011;2:1102-5.
19Vinodh M, Ambikapathy P, Aravind MA, Ganesh J. Reversibility of brainstem evoked response audiometry abnormalities at 3 months in term newborns with hyperbilirubinemia. Indian Pediatr 2014;51:134-5.
20Babu A, Bhat VB. Predictors of abnormal neurodevelopmental at 6 months in term babies with early neonatal hyperbilirubinemia. A prospective cohort study from South India. Curr Pediatr Res 2011;15:93-5.
21Maimburg RD, Bech BH, Vaeth M, Møller-Madsen B, Olsen J. Neonatal jaundice, autism, and other disorders of psychological development. Pediatrics 2010;126:872-8.
22Hokkanen L, Launes J, Michelsson K. Adult neurobehavioral outcome of hyperbilirubinemia in full term neonates-a 30 year prospective follow-up study. PeerJ 2014;2:e294.
23Jangaard KA, Fell DB, Dodds L, Allen AC. Outcomes in a Population of healthy term and near-term infants with serum bilirubin levels of ≥325 μmol/L (≥19 mg/dL) who were born in nova scotia, Canada, Between 1994 and 2000. Pediatrics 2008;122:119-24.
24Newman TB, Liljestrand P, Jeremy RJ, Ferriero DM, Wu YW, Hudes ES, et al. Outcomes among newborns with total serum bilirubin levels of 25 mg per deciliter or more. N Engl J Med 2006;354:1889-900.
25Croen LA, Yoshida CK, Odouli R, Newman TB. Neonatal hyperbilirubinemia and risk of autism spectrum disorders. Pediatrics 2005;115:e135-8.
26Vandborg PK, Hansen BM, Greisen G, Jepsen M, Ebbesen F. Follow-up of neonates with total serum bilirubin levels ≥25 mg/dL: A Danish population-based study. Pediatrics 2012;130:61-6.