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Home , Hypotonia, Kernicterus, Neonatal jaundice

Journal of Perinatology (2011) 31, 392–396 r 2011 Nature America, Inc. All rights reserved. 0743-8346/11 www.nature.com/jp ORIGINAL ARTICLE Acute neurological findings in a national cohort of neonates with severe neonatal hyperbilirubinemia

M Sgro1,2, D Campbell2, T Barozzino2 and V Shah3 1Keenan Research Centre of the Li Ka Shing Knowledge Institute, University of Toronto, Toronto, ON, Canada; 2Department of , St Michael’s Hospital, University of Toronto, Toronto, ON, Canada and 3Department of Pediatrics, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada

Introduction Objective: To describe and compare with severe Neonatal hyperbilirubinemia remains the most common cause hyperbilirubinemia, who presented with and without abnormal neurological of readmission in the neonatal period, despite attempts to identify findings and to identify associated risk factors. at-risk newborns for severe hyperbilirubinemia before initial Study Design: Data on infants with severe hyperbilirubinemia discharge from the hospital.1–10 Long-term sequelae of severe (>425 mmol lÀ1 and/or received ) were collected hyperbilirubinemia, including encephalopathy and prospectively through the Canadian Paediatric Surveillance Program , were thought to be rare since the advent of maternal (CPSP) from 2002 to 2004. Cases were categorized into two groups on the rhesus immunoglobulin prophylaxis, phototherapy and exchange basis of information provided by the reporting physician: neurologically transfusions.11–13 However, cases of bilirubin encephalopathy and normal or abnormal. Demographic characteristics were compared and kernicterus continue to be reported in healthy near-term and term univariate logistic regression was performed to identify factors associated infants in North America and Europe.1,11–20 with acute neurological abnormalities in infants. We recently reported on 258 infants with severe Result: Of the initial cohort of 258 infants, 32 (12.4%) were identified to hyperbilirubinemia in Canada from 2002 to 2004 through the 10 have neurological abnormalities. Infants in the highest peak bilirubin CPSP. The most common identifiable etiology of severe level group (>550 mmol lÀ1) had the greatest risk of acute neurological hyperbilirubinemia in our cohort was ABO incompatibility followed abnormalities. The mid range (451 to 550 mmol lÀ1) and lowest level by glucose-6-phosphate dehydrogenase deficiency, with many (p450 mmol lÀ1) groups were less likely to have abnormalities (odds infants presenting with abnormal neurological symptoms and signs ratio (OR) ¼ 0.174; P ¼ 0.0013 and 0.402; P ¼ 0.0613, respectively). on admission. Exchange transfusion and presentation within the first 2 days of age were Acute bilirubin encephalopathy occurs when bilirubin levels 9,12 positively associated with abnormal neurological findings in infants become neurotoxic in infants. Three phases of acute bilirubin (OR ¼ 3.332, P ¼ 0.003 and OR ¼ 2.572, P<0.0001, respectively). encephalopathy have been described. The early acute phase is characterized by lethargy, and poor suck; intermediate Conclusion: In this national cohort of infants with severe phase by (including and retrocollis), hyperbilirubinemia, a significant percentage of infants developed acute high-pitched cry, fever, moderate stupor or irritability, whereas in bilirubin encephalopathy. Long-term neurodevelopmental follow-up is the advanced phase infants present with , coma, apnea, necessary to determine the incidence of permanent neurological sequelae. pronounced retrocollis and opisthotonus, with death occurring in Journal of Perinatology (2011) 31, 392–396; doi:10.1038/jp.2010.137; severe cases.9,12 Although the acute neurological abnormalities of published online 9 December 2010 hyperbilirubinemic infants can be transient, the intermediate and Keywords: severe hyperbilirubinemia; bilirubin encephalopathy; advanced phases have been strongly linked to long-term -newborn neurological sequelae.21 The inability of physicians to recognize bilirubin encephalopathy early may lead to delays in treatment, thereby increasing the risk of long-term sequelae.22 The objective of this study was to describe and compare Correspondence: Dr D Campbell, Department of Pediatrics, St Michael’s Hospital, University the clinical course of infants with and without abnormal of Toronto, 30 Bond Street, Rm 15-014 Cardinal Carter, Toronto, ON M5B 1W8, Canada. neurological findings on admission to identify and better refine E-mail: [email protected] or [email protected] risk factors associated with the occurrence of acute neurological Received 10 June 2010; revised 11 August 2010; accepted 16 August 2010; published online 9 December 2010 findings. Neonatal hyperbilirubinemia and neurological findings M Sgro et al 393

Methods with acute bilirubin encephalopathy.12 Six of these infants Subjects were identified from a previously reported national had intermediate or advanced bilirubin encephalopathy database on infants with severe hyperbilirubinemia with seizures and/or opisthotonus during the initial (>425 mmol lÀ1 and/or received exchange transfusion) through presentation. the CPSP for the period July 2002 to June 2004.10 The methodology The baseline characteristics of the two cohorts (neonates with that was utilized to obtain data has been previously described.10 and without abnormal neurological findings) were similar The protocol and questionnaire were reviewed and approved by the (Table 1). The clinical presentation of the 32 infants with acute CPSP Steering Committee panel of experts, and by the Research neurological abnormalities is presented in Table 2. The peak Ethics Boards of two hospitals (St Michael’s Hospital and Mount bilirubin was higher in those who were neurologically abnormal À1 Sinai Hospital, Toronto, ON). A subsequent protocol was reviewed ((508.2 (104.5) vs 466.8 (71.8) mmol l )). Infants that presented and approved by the Research Ethics Boards of both institutions at <48 h of age had significantly lower serum bilirubin levels À1 for this secondary analysis. (median peak bilirubin ¼ 444 mmol l s.d. 88.6) compared Cases in which the reporting physician identified neurological with infants that presented after 48 h (median peak À1 abnormalities in the neonatal period were identified and compared bilirubin ¼ 460 mmol l s.d. 69.7) using the non-parametric with those without neurological abnormalities. Acute neurological test with P<0.0001. abnormalities were defined as infants having a clinical syndrome In all, 13 (41%) of the 32 infants with neurological findings consistent with acute bilirubin encephalopathy (early, intermediate had an identifiable etiology established for the hyperbilirubinemia or advanced).11,12 These include seizures, hypertonia, hypotonia, (Table 2). A total of 80 (35%) of the 226 infants without irritability, apnea, retrocollis, opisthotonus and poor suck.11,12 neurological findings had a diagnosis established for the Data on demographic characteristics, clinical course and hyperbilirubinemia. Exchange transfusions were performed in management were collected on a standardized data collection 14 (44%) of the 32 neonates with neurological abnormalities and form.10 Data were summarized using descriptive statistics for 43 (19%) of the 226 infants without abnormalities, respectively. All baseline characteristics. To compare babies with and without were treated with phototherapy. abnormalities and normal infants, the w2 test was used and the Univariate logistic regression analysis identified that infants in À1 non-parametric, Wilcoxon test was used for continuous variables. the highest peak bilirubin level group (>550 mmol l ) had the Univariate logistic regression analysis was performed to evaluate greatest risk of acute neurological abnormalities (9/27 or 30%). À1 the effect of predictors (age of infant presentation, peak serum The mid range (451 to 550 mmol l ) group had a lower rate of bilirubin, need for readmission, etiology of hyperbilirubinemia and neurological abnormalities (9/132 or 6.8%) OR of 0.174 À1 need for exchange transfusion) on neurological abnormities. The (P ¼ 0.0013). The lowest bilirubin level group (p450 mmol l ) final results are reported as OR along with their 95% confidence had 15 babies who were abnormal (15/99 or 15%) with an OR intervals. Owing to missing data in the predictors and the low of 0.402 (P ¼ 0.0613). Need for exchange transfusion and number of cases (N ¼ 32), we did not attempt to conduct presentation at p2 days of age was also associated with a multivariate analyses. The age of presentation was categorized as higher risk of acute neurological findings (Table 3). p2 days of age and >2 days of age. This time point was chosen as those with severe hyperbilirubinemia presenting early are likely to have hemolytic disease. Peak serum bilirubin was categorized as: À1 À1 À1 p450 mmol l , 451 to 550 mmol l and >550 mmol l ,as Table 1 Baseline characteristics of infants with and without abnormal these levels of hyperbilirubinemia have previously been linked to neurological findings abnormal outcomes. The significance level was set at P<0.05. a Statistical analysis was performed using the statistical software Characteristics Neurologically Neurologically P-value abnormal normal package SAS version 9.2 (SAS Institute, Cary, NC, USA). infants infants (N ¼ 32) (N ¼ 226)

Results Male (%) 22 (68.8) 140 (61.9) 0.46 The initial cohort consisted of data on 258 infants with severe (g) 3250.0 (459.0) 3391.0 (492.1) 0.13 hyperbilirubinemia, of which 52 were reported to have some degree Age at presentation (days) 4.17 (2.7) 4.73 (2.8) 0.29 of neurological abnormalities.10 A total of 20 of these infants had Breast-feeding (%) 22 (75.9) 171 (82.6) 0.38 non-specific neurological findings: either isolated irritability Readmission (%) 20 (62.5) 165 (73.0) 0.22 (N ¼ 8) or poor feeding (N ¼ 12), and were not considered to Weight loss from birth (10–15%) 3 (18) 25 (19) 1.00 have enough symptoms to be included with confidence.11,12 In all, Weight loss from birth (>15%) 1 (6) 11 (8) 1.00 32 infants therefore had neurological abnormalities consistent aResults are presented as mean (s.d.)/or as N (% relative to reported data).

Journal of Perinatology Neonatal hyperbilirubinemia and neurological findings M Sgro et al 394

Table 2 Description of cases with acute neurological abnormalities (N ¼ 32)

Case Etiology Gestational Age Peak bilirubin Abnormal neurological findings Seizures Abnormal auditory age (weeks) (days) (mmol lÀ1) yes (Y)/no (N) evoked responses yes (Y)/no (N)

1 Unknown 37 2 506 Hypotonia, irritability N N 2 Other antibodies 38 1 362 Y N 3 Unknown 39 5 444 Hypotonia, irritability N N 4 ABOa 39 0.4 424 Hypotonia N Y 5 G6PDb 39 4 564 Hypotonia N Y 6 Unknown 38 4 430 Poor suck, hypotonia, lethargy N N 7 Unknown 37 6 446 Hypotonia, lethargy N N 8 Unknown 37 8 645 Poor suck, lethargy Y N 9 Unknown 37 7 755 Hypotonia, hypertonia, poor suck Y Y 10 Unknown 40 4 613 Seizure Y N 11 Unknown 39 5 435 Hypotonia N N 12 ABOa 38 2 503 Lethargy N Y 13 ABOa 40 3 500 Hypotonia, lethargy N N 14 ABOa 38 1 570 Hypotonia, poor suck N N 15 Unknown 40 7 732 Hypertonia, poor suck N Y 16 Sphero-cytosis 38 7 506 Retrocollis N N 17 Unknown 38 2 437 Hypotonia N N 18 Unknown 40 11 773 Opisthotonus Y Y 19 ABOa 38 18 466 Hypotonia, poor suck N N 20 G6PDb 40 1 423 Opisthotonus, irritability N N 21 G6PDb 37 5 564 Opisthotonus, hypertonia, lethargy, abnormal NY visual evoked responses 22 Unknown 40 5 438 Poor suck, lethargy, hypotonia N N 23 Unknown 41 5 468 Hypotonia, lethargy N N 24 Unknown 40 2 429 Poor suck, hypotonia N N 25 39 5 645 Hypotonia N Y 26 Unknown 39 4 476 Hypotonia N Y 27 Other antibodies 39 1 445 Apnea, hypotonia N N 28 Other antibodies 38 7 450 Poor suck, lethargy, hypotonia N Y 29 Unknown 37 7 426 Lethargy, poor suck N Y 30 Unknown 37 4 437 Lethargy, hypotonia N N 31 Unknown 39 8 501 Hypotonia, poor suck, lethargy N N 32 Unknown 39 4 450 Hypotonia N Y aABO incompatibility. bGlucose-6-phosphate dehydrogenase (G6PD) deficiency.

Discussion previous studies that have failed to show a strong correlation Our study highlights the association between severe neonatal between serum bilirubin levels and kernicterus.6,9,11,13,14 In our hyperbilirubinemia and acute bilirubin encephalopathy. In our cohort, early presentation (<2 days) was a significant risk factor, cohort, the presence of acute neurological findings correlated with and this group’s mean peak serum bilirubin levels were lower than higher peak bilirubin, the need for exchange transfusion and an that of the older newborns. early age of presentation (first 2 days of life). The trend to more We were unable to demonstrate a relationship between etiology neurological abnormalities in the lower bilirubin level group and the likelihood of acute bilirubin encephalopathy. Previous (<450 mmol lÀ1) compared with the mid-range group (450 to studies have shown that both acute bilirubin encephalopathy and 550 mmol lÀ1) is likely related to the fact that early presentation kernicterus were more likely to occur if the hyperbilirubinemia was and therefore a rapid rise in serum bilirubin levels increases the secondary to and a specific etiology, such as glucose-6- risk of acute bilirubin encephalopathy even at lower serum phosphate dehydrogenase deficiency or ABO incompatibility.1,11,16 bilirubin levels23 (Table 3). These data may help to explain It is possible that the reason we were unable to show a relationship

Journal of Perinatology Neonatal hyperbilirubinemia and neurological findings M Sgro et al 395

Table 3 Results of univariate logistic regression analysis for acute neurological report on whether all of these infants had permanent sequelae on findings (N ¼ 258) follow-up. We tried to account for this by only including infants Variable OR 95% CI P-value who had significantly abnormal neurological features, for example, hypotonia and abnormal auditory evoked responses. It is likely that Readmission 0.616 (0.284, 1.336) 0.2199 the voluntary reporting system underestimates the true incidence of Diagnosis 1.249 (0.586, 2.66) 0.5649 acute bilirubin encephalopathy, as not all cases may have been Exchange transfusion 3.332 (1.527, 7.272) 0.003 captured, and reported cases were not completely described. Age of infant <2 daysa 2.572 (1.136–5.821) <0.0001 b Peak bilirubin level <450 mmol lÀ1 0.402 (0.155, 1.044) 0.0613 b 451–550 mmol lÀ1 0.174 (0.060, 0.504) 0.0013 Conclusion Abbreviations: CI, confidence interval; OR, odds ratio. a Our study had a significant number of infants with neurological The reference group is infants >2 days of age. bThe reference group is infants with peak bilirubin >550 mmol lÀ1. findings secondary to acute bilirubin encephalopathy, putting them at significant risk of adverse long-term neurological outcomes. We feel that physician recognition of the clinical syndrome of acute in our study was the low rate of reported etiology for the bilirubin encephalopathy is of utmost importance. When these hyperbilirubinemia. This limitation was difficult to avoid because symptoms present, aggressive treatment of the acute neonatal of the fact that we were relying on voluntary reporting; many hyperbilirubinemia is urgently required. infants with an ‘unknown etiology’ may not have been completely investigated. The incidence of acute bilirubin encephalopathy is unknown, Conflict of interest 22,24 but is thought to be rare. The Canadian birth rate was The authors declare no conflict of interest. B330 000 infants per year at the time of our study.25 Our data therefore suggest an incidence of acute bilirubin encephalopathy of B 1 in 20 000 live births. It is likely that the infants excluded from Acknowledgments our initial analysis with ‘non-specific findings’ (isolated irritability Supported in part by a Grant from the Ontario Federation for . (N ¼ 8) and poor feeding (N ¼ 12)) also had early acute bilirubin We thank Dr Danielle Grenier and the Canadian Pediatric Surveillance Program encephalopathy, given the very high bilirubin levels necessary to be (CPSP) for their support of this research. entered into the database (>425 mmol lÀ1).10,12 If these infants were included, the incidence of acute bilirubin encephalopathy B would be 1/10 000 live births. This estimate is in keeping with References two national cohorts reported from Denmark in 2000–2001 and 2002–2005.26,27 A recent study from the United Kingdom reported 1 Tan-Dy C, Moore A, Satodia P, Blaser S, Fallagh S. Predicting kernicterus in severe 16 unconjugated hyperbilirubinemia. Paediatr Child Health 2004; 9(Suppl A): 17A. a much lower incidence of 0.9/100 000 live births. In this study 2 Lee KS, Perlman M. The impact of early obstetric discharge on newborn health care. however, only infants with peak serum bilirubin levels of Curr Opin Pediatr 1996; 8(2): 96–101. >510 mmol lÀ1 were included.16 Six infants in our study had 3 Lee KS, Perlman M, Ballantyne M, Elliott I, To T. Association between duration of intermediate and/or advanced signs of encephalopathy neonatal hospital stay and readmission rate. J Pediatr 1995; 127(5): 758–766. corresponding to a incidence of 1.8/100 000. This is higher than 4 Liu S, Wen SW, McMillan D, Trouton K, Fowler D, McCourt C. Increased neonatal readmission rate associated with decreased length of hospital stay at birth in Canada. what has previously been reported by the British and Danish Can J Public Health 2000; 91(1): 46–50. 16,26,27 groups. 5 Brown AK, Damus K, Kim MH, King K, Harper R, Campbell D et al. Factors relating to The occurrence of acute bilirubin encephalopathy may not readmission of term and near term neonates in the first two weeks of life. J Perinat translate into permanent neurological sequelae, but is concerning Med 1999; 27(4): 263–275. nonetheless.20,28 Of the 14 infants with acute bilirubin 6 Bhutani VK, Johnson LH. Urgent clinical need for accurate and precise bilirubin encephalopathy evaluated at 12 months in the study by Manning measurements in the United States to prevent kernicterus. Clin Chem 2004; 50(3): 16 477–480. et al., 7 had significant adverse neurological outcomes 7 Bhutani VK, Johnson LH, Keren R. Diagnosis and management of hyperbilirubinemia (including cerebral palsy), 3 died, whereas 3 were normal and in the term neonate: for a safer first week. Pediatr Clin North Am 2004; 51: 843–861. 1 was lost to follow-up. We would suggest that all infants with 8 Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific peak bilirubin levels >425 mmol lÀ1 be followed long-term as part serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and of neonatal follow-up programs. near-term newborns. Pediatrics 1999; 103(1): 6–14. 9 Johnson LH, Bhutani VK, Brown AK. System-based approach to management of The main limitation of our study is related to information neonatal and prevention of kernicterus. J Pediatr 2002; 140(4): 396–403. collected via a voluntary reporting system. We were neither able to 10 Sgro M, Campbell D, Shah V. Incidence and causes of severe neonatal corroborate the acute abnormal neurological findings nor could we hyperbilirubinemia in Canada. CMAJ 2006; 175(6): 587–590.

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11 AlOtaibi SF, Blaser S, MacGregor DL. Neurological complications of kernicterus. (eds). The Year Book of Neonatal and Perinatal Medicine. Mosby Year Book: Can J Neurol Sci 2005; 32(3): 311–315. St Louis, MO, 1996, pp 17–28. 12 American Academy of Pediatrics Clinical practice guideline. Management of 21 Johnson L, Brown AK, Bhutani VK. BIND-A clinical score for bilirubin induced hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics neurologic dysfunction in newborns. Pediatr Suppl 1999; 104: 746. 2004; 114(1): 297–316. 22 Canadian Paediatric Society. Guidelines for detection, management and prevention of 13 Maisels MJ, Newman TB. Kernicterus in otherwise healthy, breast-fed term newborns. hyperbilirubinemia in term and late preterm newborn infants (35 or more weeks’ Pediatrics 1995; 96(4): 730–733. gestation). Paediatr Child Health 2007; 12(5): 401–407. 14 Penn AA, Enzmann DR, Hahn JS, Stevenson DK. Kernicterus in a full term infant. 23 Johnson L, Bhutani VK, Karp K, Sivieri EM, Shapiro SM. Clinical report from Pediatrics 1994; 93(6): 1003–1006. the pilot USA Kerniterus Registry (1992 to 2004). J Perinatol 2009; 29(Suppl 1): 15 Johnson L, Bhutani VK. Guidelines for management of the jaundiced term and near S25–S45. term infant. Clin Perinatol 1998; 25(3): 555–574. 24 American Academy of Pediatrics, Provisional Committee for Quality Improvement 16 Manning D, Todd P, Maxwell M, Jane Platt M. Prospective surveillance study of severe and Subcommittee on Hyperbilirubinemia. Practice parameter: management hyperbilirubinaemia in newborn in the UK and Ireland. Arch Dis Child Fetal Neonatal of hyperbilirubinemia in the healthy term newborn. Pediatrics 1994; 94(4): Ed 2007; 92(5): 341–346. 558–565. 17 Harris MC, Bernbaum JC, Polin JR, Zimmerman R, Polin RA. Developmental follow-up 25 Statistics Canada. Canadian Statistics. Birth rate 2004 to 2005 http://www40.statcan. of breastfed term and near-term infants with marked hyperbilirubinemia. Pediatrics gc.ca/l01/cst01/demo02a-eng.htmAccessed 11 November, 2009. 2001; 107(5): 1075–1080. 26 Bjerre JV, Petersen JR, Ebbesen F. Surveillance of extreme hyperbilrubinaemia in 18 Newman TB, Maisels MJ. Less aggressive treatment of and reports Denmark. A method to identify the newborn infants. Acta Paediatr 2008; 97(8): of kernicterus: lessons about practice guidelines. Pediatrics 2000; 105(1 part 3): 1030–1034. 242–245. 27 Ebbesen F, Andersson C, Verder H, Grytter C, Pedersen-Bjergaard L, Petersen JR et al. 19 Dennery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinemia. N Engl J Med Extreme hyperbilirubinemia in term and near-term infants in Denmark. Acta Paediatr 2001; 344(8): 581–590. 2005; 94(1): 59–64. 20 Brown AK, Johnson L. Loss of concern about jaundice and the re-emergence of 28 Johnson LH, Bhutani VK, Brown AK. System-based approach to management of kernicterus in full-term infants in an era of managed care. In: Fanarof A, Klaus M neonatal jaundice and prevention of kernicterus. J Pediatr 2002; 140(4): 396–403.

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