Neonatal Hyperbilirubinemia and Neurodevelopmental Delay Assessment at Six Months of Age

Document Type : Original Article


1 Department of Pediatrics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Epidemiology, Faculty of Health, Mashhad University of Medical Sciences, Mashhad, Iran

3 Student of Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran


Background: Being toxic to the developing central nervous system, hyperbilirubinemia may cause neurological damage or developmental delay. This study aimed to assess the relationship between hyperbilirubinemia and developmental delay at six months of age in infants with neonatal severe hyperbilirubinemia.
Methods: A prospective cohort study was conducted on infants with a gestational age of >35 weeks and hyperbilirubinemia from 2014 to 2020. The neurodevelopmental assessment was performed using the Denver Developmental Screening Test II (DAS II). The collected data were statistically analyzed by SPSS software (version 26).
Results: Among the three main causes of hyperbilirubinemia, 9.6% of the neonates had blood group incompatibility; ABO, Rh, and ABO +Rh were observed in 7.5%, 1.6%, and 1.1% of the neonates, respectively, and 1.1% of the infants were diagnosed with glucose-6-phosphate dehydrogenase deficiency.  The correlation between hyperbilirubinemia and developmental delay in all four domains according to the DAS II test was statistically significant (P<0.001). Moreover, the severity of hyperbilirubinemia was proved to have a positive correlation with the severity of the developmental delay. Furthermore, this study found a significant correlation (P<0.001) between the causes of icterus and the probability of neurodevelopmental delay at six months of age (Correlation Coefficient=0.470, sig=0.000).
Conclusion: There is a strong correlation between hyperbilirubinemia and developmental delay at six months of age in infants with neonatal hyperbilirubinemia. The severity of hyperbilirubinemia is significantly associated with the cause of jaundice. It is also demonstrated that the severity of hyperbilirubinemia has a positive correlation with the severity of the developmental delay.


  1. Boskabadi H, Maamouri G, Bagheri S. Significant Neonatal Weight Loss Related to Idiopathic Neonatal Hyperbilirubinemia. Int J Pediatr. 2014;
  2. Yilmaz Y, Karadeniz L, Yildiz F, Degirmenci SY, Say A. Neurological prognosis in term newborns with neonatal indirect hyperbilirubinemia. Indian 2001;38(2):165–8.
  3. Soorani-Lunsing I, Woltil HA, Hadders-Algra M. Are moderate degrees of hyperbilirubinemia in healthy term neonates really safe for the brain? Pediatr Res. 2001;50(6):701–5.
  4. Mitra S, Rennie J. Neonatal jaundice: aetiology, diagnosis and treatment. Br J Hosp Med (Lond). 2017;78(12):699–704.
  5. Boskabadi H, Ashrafzadeh F, Azarkish F, Khakshour A. Complications of Neonatal Jaundice and the Predisposing Factors in ‎Newborns Complications of neonatal jaundice and the predisposing factors in‎ J Babol Univ Med Sci. 2015;17(9):7–13.
  6. Agrawal A, Pandya S, Shrivastava J. Neurodevelopmental outcome at 6 months of age in full-term healthy newborns with neonatal hyperbilirubinemia. J Clin Neonatol. 20201;
  7. Boskabadi H, Masoud O, Shahin M. Prevalence and Clinical Manifestation of Glucose-6-Phosphate Dehydrogenase Deficiency in Newborns with Hyperbilirubinemia in Mashhad, Iran. Maced J Med Sci. 2010;3(4):383-7.
  8. Boskabadi H, Akhondian J, Afarideh M, Maamouri G, Bagheri S, Parizadeh SM, et al. Long-term neurodevelopmental outcome of neonates with hypernatremic dehydration. Breastfeeding Med. 2017;12(3):163-8.
  9. Oh W, Tyson JE, Fanaroff AA, Vohr BR, Perritt R, Stoll BJ, et al. Association between peak serum bilirubin and neurodevelopmental outcomes in extremely low birth weight infants. Pediatrics. 2003;
  10. Wiradharma W, Windiani IG, Haksari E. Developmental delay in 3-month-old low birth weight infants with hyperbilirubinemia. Paediatr Indones. 201331;53(4):228-31.
  11. Amin SB, Prinzing D, Myers G. Hyperbilirubinemia and language delay in premature infants. Pediatrics. 2009;123(1):327-31.
  12. Arimbawa IM, Soetjiningsih S, Kari IK. Adverse effects of hyperbilirubinemia on the development of healthy term infants. Paediatr Indones. 2006;
  13. Tsao P-C, Yeh H-L, Shiau Y-S, Chang Y-C, Chiang S-H, Soong W-J, et al. Long-term neurodevelopmental outcomes of significant neonatal jaundice in Taiwan from 2000–2003: a nationwide, population-based cohort study. Sci Rep. 2020;10(1):11374.
  14. Jangaard KA, Fell DB, Dodds L, Allen AC. Outcomes in a population of healthy term and near-term infants with serum bilirubin levels of >or=325 micromol/L (>or=19 mg/dL) who were born in Nova Scotia, Canada, between 1994 and 2000. Pediatrics. 2008;122(1):119–24.
  15. Özgürhan G, Comert S. Neurodevelopmental Evaluation of Term Newborns with Significant Istanbul Med J. 2020;21(5):370–4.
  16.  Boskabadi H, Zakerihamidi M, Moradi A, Bakhshaee M. Risk Factors for Sensorineural Hearing Loss in Neonatal Hyperbilirubinemia. Iran J Otorhinolaryngol. 2018;30(99):195–202.