REBOUND HYPERBILIRUBINEMIA AFTER PHOTOTHERAPY

Thesis Submitted For Fulfillment of MSc Degree in Pediatrics

By Mohamed Abd El-Halim Abd El-Aal (M.B., B.Ch)

Supervised by Prof. Dr. Zahraa Mohamed Ezz-Eldin Professor of Pediatrics Faculty of Medicine Cairo University

Prof. Dr. Yasmeen Amr Mansi Assistant Professor of Pediatrics Faculty of Medicine Cairo University

Dr. Reem Ibrahim Ismail Lecturer of Pediatrics Faculty of Medicine Cairo University

Faculty of Medicine Cairo University 2012

‫ن الّرَحِيمِ‬ ‫هلل الّرَحْم ِ‬ ‫بِسْمِ ا ِ‬

‫سبْحَانكَ الَعلِ َم َلنَا إِالّمَا‬ ‫قَالُوا ُ‬ ‫ت الْ َعلِي ُم الْحَكِيمُ‬ ‫ك أَن َ‬ ‫علّ ْم َتنَا ِإ َن َ‬ ‫َ‬ ‫﴿‬

‫﴾‬

‫صدق اهلل العظيم‬ ‫البقّرة ‪ ..‬آيت رقم ‪٣٢‬‬

Acknowledgement First of all and above all great thanks to ALLAH. It is a great honor to me to express my deepest gratitude, extreme thankfulness and deep appreciation to Prof. Dr. Zahraa Mohamed Ezz-

Eldin, Professor of Pediatrics, Faculty of Medicine, Cairo University for her generous help, continuous guidance and supervision, kind encouragement and valuable advice throughout the work. I would like to express my deepest gratitude and thanks to

Dr. Yasmeen Amr Mansi, Assistant Professor of Pediatrics, Faculty of Medicine, Cairo University for her close observation, generous guidance, effective help and valuable supervision. I wish to express my full thanks to Dr. Reem Ibrahim Ismail, Lecturer of Pediatrics, Faculty of Medicine, Cairo University for her continuous interest, generous guidance and for her kind help, that I will remain always remembering.   



ABSTRACT

I

ntroduction: Neonatal hyperbilirubinemia is a common problem. Approximately 60% of term infants and 80% of preterm infants develop jaundice in the first week of life. Despite hyperbilirubinemia being a common morbidity among neonates, few studies have systematically studied the phenomenon of post‐phototherapy rebound, data about the phenomenon of bilirubin rebound is lacking. Objectives: The aim of this study was to determine whether a rebound in serum bilirubin level occurs within 24 hours after discontinuation of phototherapy in neonates with hyperbilirubinemia and to identify aetiological factors for hyperbilirubinemia that could be used to select infants at risk for rebound. Study design: A prospective clinical survey was performed on 133 term and preterm neonates treated with phototherapy. Neonates were tested for T.S.B 24(±6) hours after discontinuation of phototherapy, with additional testing as clinically indicated. The main outcome measure, significant bilirubin rebound, was defined as a post-phototherapy T.S.B ≥15 mg/dl. Phototherapy was not reinstituted in all cases of rebound, but rather according to clinical indications. Results: A total of 29 (21.8%) neonates developed significant rebound, mean (±SD) T.S.B was 16.45 (±0.99) mg/dl. Multiple logistic regression analysis for risk factors for significant bilirubin rebound showed significant risk for aetiological risk factors including hemolysis (odds ratio 1.241, 95% CI 1.117 to 2.496) and positive direct Coombs test (odds ratio 6.392, 95% CI 1.530 to 26.706). Sixteen of those (55.2%) were retreated with phototherapy, mean (±SD) T.S.B was 16.9 (±1.1) mg/dl. Multiple Logistic regression analysis for risk factors for re-admission for phototherapy showed significant risk for aetiological risk factors including hemolysis (odds ratio 1.121, 95% CI 1.048 to 2.307) and positive direct Coombs test (odds ratio 7.162, 95% CI 1.571 to 32.658). Also there was a trend for re-admission for phototherapy with weight < 2kg (odds ratio 5.976, 95% CI 0.818 to 43.685). Conclusion: Post-phototherapy neonatal bilirubin rebound to clinically significant levels may occur, especially in cases of hemolysis, direct Coombs test positivity and low birth weight < 2kg. These risk factors should be taken into account when planning post-phototherapy follow up. Key words: Neonatal hyperbilirubinemia – Bilirubin rebound.

List of Contents Page List of Abbreviations

I

List of Figures

III

List of Tables

V

Introduction

1

Aim of The Work

2

Review of Literature Chapter (1): Neonatal Hyperbilirubinemia Chapter (2): Rebound Hyperbilirubinemia

3 74

Patients and Methods

78

Results

82

Discussion

88

Summary

94

Conclusion and Recommendations

96

References

97

Arabic Summary

١

List of Abbreviations ADCC

Antibody Dependent Cell mediated Cytotoxicity

AHT

Allogenic Hepatocyte Transplantation

ATP

Adenosine Tri-Phosphate

BIND

Bilirubin Induced Neurologic Disorders

CN

Crigler-Najjar

CO

Carbon mono-Oxide

CT

Computed Tomography

DAT

Direct Antiglobin Test

DWI

Diffusion-Weighted Imaging

ET

Exchange Transfusion

FFA

Free Fatty Acids

GA

Gestational Age

G6PD

Glucose-6-Phosphate Dehydrogenase

HDN

Hemolytic Disease of the Newborn

HO

Heme Oxygenase

HS

Hereditary Spherocytosis

IgG

Immunoglobulin G

IgM

Immunoglobulin M

IVIG

IntraVenous ImmunoGlobulin

LBW

Low Birth Weight

LEDs

Light-Emitting Diodes

MRI

Magnetic Resonance Imaging

NICU

Neonatal Intensive Care Unit

N.J

Neonatal Jaundice

NMR

Nuclear Magnetic Resonance I

OD

Optical Density

PK

Pyruvate Kinase

RBCs

Red Blood Cells

Rh

Rhesus

SBR

Significant Bilirubin Rebound

TcB

Transcutaneous Bilirubin

T.S.B

Total Serum Bilirubin

UDPGT

Uridine Di-Phosphate Glucuronyl Transferase

UVC

Umbilical Vein Catheter

WHO

World Health Organization

2,3-DPG

2,3-Di-Phospho Glycerate

II

List of Figures Page Figure (1)

Anatomy of biliary system

5

Figure (2)

Bilirubin metabolism

8

Figure (3)

Gene Therapy

18

Figure (4)

Pentose phosphate pathway

24

Figure (5)

Spherocytosis in comparison with normal RBCs

28

Figure (6)

Elliptocytosis

30

Figure (7)

Mechanism of maternal sensitization in Rh incompatibility and its prevention with anti-D

32

Figure (8)

Difference between Rh and ABO incompatibility

37

Figure (9)

Marked retrocollis and opisthotonus in a baby with kernicterus

44

Figure (10) Bilirubin encephalopathy Figure (11)

Guidelines for phototherapy in hospitalized infants of 35 or more weeks’ gestation

Figure (12) A neonate on conventional phototherapy

III

47 61 62

Figure (13) A neonate using bili-blanket

62

Figure (14) Exchange transfusion in a jaundiced neonate

66

Figure (15)

Guidelines for exchange transfusion in infants 35 or more weeks’ gestation

69

Figure (16)

Percentage of different aetiological subgroups of hyperbilirubinemia in neonates included in the study

83

Figure (17)

Percentage of different aetiological subgroups in neonates with significant bilirubin rebound

84

Figure (18)

Percentage of different aetiological subgroups in neonates re-admitted for phototherapy

86

IV

List of Tables Page Table (1)

Differential diagnosis of neonatal hyperbilirubinemia

9

Table (2)

Possible mechanisms involved in physiologic jaundice

11

Table (3)

Congenital non-hemolytic unconjugated hyperbilirubinemia: clinical syndrome

19

Table (4)

Drugs that cause significant displacement of bilirubin from albumin

21

Table (5)

WHO classification of G6PD enzyme variants

25

Table (6)

Comparison of the two most common variants of G6PD deficiency

26

Table (7)

Clinical and laboratory features of immune hemolysis due to Rh and ABO incompatibility

38

Table (8)

Factors that increase susceptibility to neuro-toxicity associated with hyperbilirubinemia

42

Table (9)

BIND-score system

46

Table (10) Guide to dermal staining with level of bilirubin

49

Table (11) Laboratory evaluation of neonatal hyperbilirubinemia

52

Table (12) Follow-up assessment of hyperbilirubinemia

55

Risk factors for development of severe Table (13) hyperbilirubinemia in infants 35 or more weeks' gestation

56

V

Table (14)

Recommendations for prevention of neonatal hyperbilirubinemia

57

Table (15)

Bilirubin level and management guidelines in LBW babies based on birth weight

70

Table (16)

Number of days for maturation of reticulocytes in the marrow and blood

80

Table (17) Mode of delivery and gender

82

Table (18) Neonatal descriptive data

82

Table (19) Jaundice descriptive data

83

Table (20)

Association between neonatal risk factors and significant bilirubin rebound

85

Table (21)

Logistic regression analysis for risk factors for significant bilirubin rebound

85

Table (22)

Association between neonatal risk factors and readmission for phototherapy

87

Table (23)

Logistic regression analysis for risk factors for readmission for phototherapy

87

VI

INTRODUCTION & AIM OF THE WORK

Introduction &Aim of the work

INTRODUCTION Neonatal hyperbilirubinemia is a common problem. Approximately 60% of term infants and 80% of preterm infants develop jaundice in the first week of life (Gomella et al., 2009). Jaundice is a common cause of readmission to hospital after early discharge of newborn babies, but fortunately only few babies have an underlying disease (Gale et al., 2001). Although most newborns with jaundice are otherwise healthy, they need to be monitored because bilirubin is potentially toxic to the central nervous system. Sufficiently elevated levels of bilirubin can lead to bilirubin encephalopathy and subsequently kernicterus with devastating permanent neurodevelopmental handicaps. Fortunately, phototherapy is an effective method for the prevention or treatment of neonatal hyperbilirubinemia (Luchtman-Jones et al., 2006). Phototherapy is the primary treatment in neonates with unconjugated hyperbilirubinemia and is now arguably the most widespread therapy of any kind (excluding prophylactic treatments) used in newborns. Phototherapy often averts the need for exchange transfusion and is generally regarded as safe method, the reported side effects have been subjected to extensive and controversial debate (Vreman et al., 2004). Decreasing hospital length of stay is an objective sought by physicians and administrators alike and it is recommended that infants need not be kept in the hospital after discontinuation of phototherapy. However they should be followed-up to measure rebound bilirubin levels following the discontinuation of phototherapy (Maisels and Kring, 2002). Data available are inadequate to formulate recommendations for or against post‐phototherapy bilirubin testing. Many reports on the subject have been flawed by comprising retrospective chart reviews, analysis of rebound by determining the mean bilirubin value rather than peak post‐treatment values. Lack of preset definitions for rebound or indications for retreatment are issues for further investigations (Bansal et al., 2010).

1

Introduction &Aim of the work

AIM OF THE WORK The aim of this study was to determine whether a rebound in serum bilirubin level occurs within 24 hours after discontinuation of phototherapy in

neonates with hyperbilirubinemia and to identify

aetiological factors for hyperbilirubinemia that could be used to select infants at risk for rebound.

2

REVIEW OF LITERATURE

Review of literature

NEONATAL HYPERBILIRUBINEMIA Introduction: Hyperbilirubinemia is a common and, in most cases, benign problem in neonates. Jaundice is observed during the 1st week of life in approximately 60% of term infants and 80% of preterm infants (Ambalavanan and Carlo, 2012). Neonatal hyperbilirubinemia is defined as a total serum bilirubin level above 5 mg per dl (85 μmol per L) is a frequently encountered problem. Jaundice is an important problem in the first week of life. It is a cause of concern for the physician and a source of anxiety for the parents. High bilirubin levels may be toxic to the developing nervous system and may cause neurological impairment even in term newborns. Nearly 60% of term newborns become visibly jaundiced in the first week of life. In most cases it is benign and no intervention is required. Approximately 510% of them have clinical significant hyperbiliubinemia mandating the use of phototherapy (Mishra et al., 2008). Jaundice typically results from the deposition of unconjugated bilirubin pigment in the skin and mucous membranes. Depending on the underlying etiology, this condition may present throughout the neonatal period with permanent clinical sequelae. Fortunately, the approaches to prevention, detection and treating hyperbilirubinemia had changed over time aiming at decreasing the permanent clinical sequelae (Porter and Dennis, 2002). Few term newborns with hyperbilirubinemia have serious underlying pathology. Jaundice is considered pathologic if it presents within the first 24 hours after birth, the total serum bilirubin level rises by more than 5 mg per dl (85 μmol per L) per day or an infant has signs and symptoms suggestive of serious illness. The management goals are to exclude pathologic causes of hyperbilirubinemia and initiate treatment to prevent bilirubin neurotoxicity (Porter and Dennis, 2002).

3

Review of literature

Epidemiology: Neonatal hyperbilirubinemia is extremely common. Incidence figures are difficult to compare because authors of different studies do not use the same definitions for significant neonatal hyperbilirubinemia or jaundice (Hansen, 2011). Internationally, incidence varies with ethnicity and geography. Incidence is higher in East Asians and American Indians and lower in blacks. Greeks living in Greece have a higher incidence than those of Greek descent living outside of Greece (Yusoff et al., 2006). Studies suggest that the variability in the incidence and severity in neonatal jaundice may be related to the difference in the distribution of genetic variants in bilirubin metabolism (Huang et al., 2004). Sixty percent of term infants and 80% of preterm infants have clinical jaundice (Gomella et al., 2009). Significant jaundice (values