CORD BLOOD BILIRUBIN CAN BE USED

AS AN EARLY PREDICTOR OF NEONATAL

HYPERBILIRUBINEMIA

By
Dr. BHARATH A.P., M.B.B.S.

Dissertation Submitted to the

Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore
In partial fulfillment of the requirements for the degree of

DOCTOR OF MEDICINE
IN
PEDIATRICS

Under the guidance of

Dr. SUDHA RUDRAPPA., MD
Professor

DEPARTMENT OF PEDIATRICS
MYSORE MEDICAL COLLEGE AND RESEARCH INSTITUTE
MYSORE-570 001
APRIL - 2011
ii
iii
iv
v
 ACKNOWLEDGEMENTS

With humble gratitude and great respect, I would like to thank my teacher and

guide, Dr. Sudha Rudrappa, Professor, Department of Pediatrics, Mysore Medical

College and Research Institute, Mysore, for her able guidance, constant

encouragement, immense help and valuable advices which went a long way in

moulding and enabled me to complete this work successfully.

I have great pleasure in expressing my deep sense of gratitude to

Dr. B. Krishnamurthy, Professor and Head, Department of Pediatrics, Mysore

Medical College and Research Institute, Mysore without whose initiative and constant

encouragement, this study would not have been possible. His vast experience,

knowledge, able supervision and valuable advices have served as a constant source of

inspiration during the entire course of my study.

I would like to thank Dr. Vijay Kumar Professor, Dr. Kumar G.M.,

Professor, Department of Pediatrics, Mysore Medical College and Research Institute,

Mysore, for their guidance during the study period.

I would like to thank Dr. Savitha M.R., Dr. Ragavendra Rao,

Dr. Manjunath and Dr. Usha Kiran and Dr. Rajendra Kumar, Assistant

Professors, Department of Pediatrics, Mysore Medical College and Research Institute,

Mysore, for their help during the study period.

I thank Dr. Shylaja., Senior Specialist, Department of Pediatrics, Mysore

Medical College and Research Institute, Mysore, for her cooperation during the

course of the study period.

vi
 I thank Dr. Prashanth S., Dr. Pradeep, Dr. Nagendra, Dr. Srinivas and

Dr. Prashanth M.R., Senior Residents, Department of Pediatrics, Mysore Medical

College and Research Institute, Mysore, for their cooperation during the course of the

study period.

Special thanks to my senior colleagues, Dr. Pradeep, Dr. Ullas, Dr. Jyothi,

Dr. Sharad Shresti, Dr. Chaitra and Dr. Deepa for their constant moral support and

encouragement during the study.

It is pleasure to thank my Postgraduate Colleagues, Dr. Rohini K. Patil, Dr.

Sheby Puthukkara, Dr. Kumar, Dr. Sanjay, Dr. Murulidharan and Dr. Iregouda

Patil.

I am extremely grateful to the technical staff, Mr. Wasim, Mr. Uday for their

valuable assistance during the study period.

I owe a debt of gratitude to my parents Shri Paraswanath A.N.,

Smt. Pankaja S.R., wife Krithika Prasad, for their moral support and constant

encouragement during the study.

I thank Dr. Lancy D’Souza, Statistician, Mysore for providing me the

statistical guidance.

My special thanks to Mr. Praveen Kumar, Softouch DTP Centre, Mysore for

working hard on shaping the dissertation book.

Last, but not the least, I am very much grateful to all patients without whom

this study would not have been completed.

Dr. BHARATH A.P.

Postgraduate in Pediatircs
Date: Mysore Medical College and Research Institute
Place : Mysore Mysore

vii
 LIST OF ABBREVIATIONS

ATP → Adenosine Tri Phosphate

BEAR → Brain Evoked Auditory Response

BNR → Band Neutrophil Ratio

C.I → Confidence Interval

CB → Conjugated Bilirubin

CID → Chronic Inflammatory Disease

CPD → Citrate Phosphate Dextrose

CS → Caesarean Section

DCT → Direct Coomb Test

DIC → Disseminated Intra Vascular Coagulation

ETCOc → End Tidal Carbon Monoxide

G6PD → Glucose-6-Phosphate Dehydrogenase

ICT → Indirect Coomb Test

P-gp → P-glycoprotein

PRBC → Packed Red Blood Cell

RBC → Red Blood Cell

STB → Serum Total Bilirubin

TcB → Trans Cutaneous Bilirubin

TSB → Total Serum Bilirubin

UCB → Unconjugated Bilirubin

UDPG-T → Uridine Di Phosphate Glucuronyl Transferase

VD → Vaginal Delivery

viii
 ABSTRACT

Background

Discharging healthy term newborns from the hospitals after delivery at

increasingly earlier postnatal ages has recently become a common practice due to

medical, social and economic reasons, however it contributes to readmission because

of jaundice.

Objectives

Usefulness of cord blood bilirubin estimation as an early predictor of neonatal

hyperbilirubinemia among healthy term newborns.

Methods

Observation study was performed on 100 healthy term newborns. Cord blood

was collected from the healthy term newborns delivered either vaginally or cesarean

section for the total bilirubin, conjugated bilirubin and unconjugated bilirubin level

measurements. Measurements of total bilirubin, conjugated bilirubin and

unconjugated bilirubin were repeated on the first day (24 hrs), third day (72 hrs) and

fifth day (120 hrs) with serum sampling of peripheral venous blood.

Results

Subjects were categorized into hyperbilirubinemia and non-hyperbilirubinemia

newborns. Babies with serum bilirubin level of ≥17mg/dl after 72 hrs of life were

considered for phototherapy and it is taken as neonatal hyperbilirubinemia in the

present study. By ROC analysis Cord blood bilirubin level of ≥2.15mg/dl was

ix
determined to have high sensitivity of 73% specificity of 74% and negative predictive

value of 90%.

Conclusion

There is a correlation between Cord blood bilirubin level and

hyperbilirubinemia in healthy term newborns. Cord blood bilirubin level of

≥2.15mg/dl can predict the development of hyperbilirubinemia.

Keywords : Cord Blood Bilirubin, Hyperbilirubinemia, Prediction and Newborns.

x
 TABLE OF CONTENTS

CONTENTS

Sl. No Page No.

1. INTRODUCTION 1-2
2. AIMS OF THE STUDY 3
3. REVIEW OF LITERATURE 4-41
a. History review
b. Prediction of Hyperbilirubinemia
c. Bilirubin metabolism
d. Foetal bilirubin metabolism
e. Etiology of Hyperbilirubinemia in newborn
f. Complications of Neonatal jaundice
g. Evaluation, prediction and Diagnosis of Neonatal jaundice
h. Laboratory evaluation
i. Treatment of Hyperbilirubinemia
4. MATERIALS AND METHODS 42-45
5. RESULTS 46-57
6. DISCUSSION 58-68
7. CONCLUSION 69
8. LIMITATIONS OF THE STUDY 70
9. RECOMMENDATIONS 71
10. SUMMARY 72-73
11. BIBLIOGRAPHY 74-79
12. ANNEXURES
i. Performa 80-81
ii. Statistical Methods Applied 82-83
iii. Master Chart 84-88
iv. Key to the Master Chart 89

xi
 LIST OF TABLES

Sl. No. Tables Pages

1. Showing sex wise distribution of cases 46

2. Association between the serum bilirubin level and the sex 47
of the newborn
3. Association between the mode of delivery and the 48
neonatal hyperbilirubinemia( ≥17mg/dl)
4. Association between the the Oxytocin induction of labour 49
and neonatal hyperbilirubinemia ( ≥17mg/dl)
5. Association between the time of initiation of breast 50
feeding and neonatal hyperbilirubinemia( ≥17mg/dl)
6. Association between the gestational hypertension and the 51
neonatal hyperbilirubinemia ( ≥17mg/dl)
7. Showing bilirubin profile in the first 5 postnatal days 52
8. Association between the neonatal hyperbilirubinemia 53
(≥17mg/dl) and the critical cord bilirubin level
(≥2.15mg/dl)
9. Association of the neonatal hyperbilirubinemia (≥17mg/dl) 55
with the first day(24hrs) bilirubin level(≥5mg/dl)
10. Characteristics of cases who did and who did not develop 57
significant hyperbilirubinemia(≥17mg/dl) after 72 hrs of
postnatal life
11. Comparison Studies on the mode of delivery and neonatal 59
hyperbilirubinemia (≥ 17mg/dl)
12. Comparison Studies on the initiation of breast feeding and 61
neonatal hyperbilirubinemia (≥ 17mg/dl)
13. Comparison Studies on the Maternal gestational 61
hypertension and neonatal hyperbilirubinemia
(≥ 17mg/dl)
14. Comparison Studies on the predictive ability of cord 64
blood bilirubin level (≥ 2.15mg/dl) and the neonatal
hyperbilirubinemia (≥ 17mg/dl)
15. Comparison Studies on the 1st day bilirubin level 66
(≥5mg/dl) and the neonatal hyperbilirubinemia
(≥ 17mg/dl)

xii
 LIST OF FIGURES

Sl. No. Figures Page No.

1. Bilirubin metabolism. 16

2. Risk designation of term and near-term well newborns 29

based on their hour-specific serum bilirubin values.

3. Schematic approach to the diagnosis of neonatal jaundice. 30

4. Guidelines for phototherapy in hospitalized infants of 35 32

or more weeks’ gestation.

5. Guidelines for exchange transfusion in hospitalized 33

infants of 35 or more weeks’ gestation.

6. Fully Automated Random Access Chemistry Analyser 45

Olympus AU 400.

xiii
 LIST OF GRAPHS

Sl. No. Graphs Pages

1. Showing sex wise distribution of cases 46

2. Association between the serum bilirubin level and the sex 47
of the newborn
3. Association between the mode of delivery and the 48
neonatal hyperbilirubinemia ( ≥17mg/dl)
4. Association between the neonatal hyperbilirubinemia 49
(≥17mg/dl) and the Oxytocin induction of labour
5. Association between the time of initiation of breast 50
feeding and neonatal hyperbilirubinemia( ≥17mg/dl)
6. Association between the gestational hypertension and the 51
neonatal hyperbilirubinemia ( ≥17mg/dl)
7. Showing bilirubin profile in the first 5 postnatal days 52
8(a). Receiver Operating Characteristics Curve Analysis of the 53
critical cord bilirubin level (≥2.15mg/dl)
8(b). Association between the neonatal hyperbilirubinemia 54
(≥17mg/dl) and the critical cord bilirubin level
(≥2.15mg/dl)
9(a). Receiver Operating Characteristics Curve Analysis of the 55
first day (24 hrs) bilirubin level (≥5mg/dl)
9(b). Association of the neonatal hyperbilirubinemia (≥17mg/dl) 56
with the first day(24hrs) bilirubin level (≥5mg/dl)
10. Characteristics of cases who did and who did not develop 57
significant hyperbilirubinemia(≥17mg/dl) after 72 hrs of
postnatal life

xiv
 INTRODUCTION

Health is defined as a state of complete physical, mental and social well being

and not merely an absence of disease or immunity. Health is a fundamental human

right.1

Inspite of completing 60 years of Independence and with so many prevailing

health programmes, IMR is high compared to developed countries. Infant mortality

rate is one of the most universally accepted indicator of health status not only of

infants but also the whole population.2

Developing countries like India must be fully aware of this limitation on the

development of neonatal care, particularly neonatal intensive care. The ultimate aim

should be to benefit maximum number of newborn babies with improved survival and

reduced mortality.

Clinical jaundice is seen in 60-70% of term and about 80% of preterm

newborns.3 6.1% of well term newborn have a serum bilirubin over 12.9 mg%. Serum

bilirubin over 15 mg% is found in 3% of normal term newborns.4

The potential risk of developing bilirubin encephalopathy or even kernicterus

is high in babies with elevated serum bilirubin level. The sequalae could be serious as

patients may develop cerebral palsy, sensorineural deafness and mental retardation.

1
 Treatment of severe neonatal jaundice by exchange transfusion is costly, labor

intensive, time consuming and associated with complications. Early treatment with

phototherapy is effective, simple and cheap. This technology is appropriate in treating

neonatal jaundice.

Financial constraints, family and medical consideration has led to early

discharge of the healthy term neonates after delivery. Thus the recognition, follow up

and early treatment of Jaundice has become more difficult as a result of earlier

discharge from the hospital.5

The concept of prediction of Jaundice offers an attractive option to pick up

babies at risk of neonatal hyperbilirubinemia. Physical examination is not a reliable

measure of the serum bilirubin. Under these circumstances it would be desirable to be

able to predict the risk of jaundice, in order to implement early treatment and thereby

minimize the risk of bilirubin dependent brain damage.5

2
 AIMS OF THE STUDY

Neonatal hyperbilirubinemia is a cause of concern for the parents as well as

the pediatricians. Early discharge of healthy term newborns after delivery has become

a common practice because of medical and social reasons and economic constraints. It

is significant that most common cause for readmission during the early neonatal

period is Hyperbilirubinemia.5

Aim of the study

a. To assess the usefulness of the cord blood bilirubin as an early predictor of

neonatal hyperbilirubinemia.

b. To assess the usefulness of 1st day bilirubin in predicting the neonatal

hyperbilirubinemia.

3
 REVIEW OF LITERATURE

a. History Review

Jaundice is a well known clinical entity in the Indian Medicine (Ayurveda).

Since the Vedic Era (1500 BC – 800 BC) this disease has been described. This has

been mentioned among diseases in Atharvaveda. Ayurveda is based on “Tridosha

theory of disease” – Vata (wind), Pitta (gall) and Kapha (mucus). Charaka Samhita

(200AD) described one of the first references to skin icterus. Jaundice (kamale) is a

specific condition, which arises due to aggravation of bile.

Greek Medicine was based on four humors – phlegm, yellow bile, blood and

black bile. Hippocrates (460-370 BC) “Father of Medicine” – made frequent

references to jaundice as a serious disease.6

Word “bile” is derived from latin bilis (“bile”). Word ‘Bilirubin’ and

‘Biliverdin’- means “red bile” and “green bile” Latinized. Icterus from Greek iketros,

meaning “yellow colored”, a word applied to a yellow bird as well. Word ‘Jaundice’-

from Old French jaundice, a word rooted in the Latin galbinus, meaning “greenish

yellow”, from galbus (“yellow”).7

The first reference to jaundice in newborns is from a book published in the

mid 15th century by Mettlinger, Germany entitled “Ein Regiment Der Jungenlannder”

[Aurberg – 1473].

In 1654, Panaroli reported apparent case of hemolytic disease of the newborn.8

4
 Erythroblastosis fetalis may well have been described in 1609 in France, a

report by a midwife named Bourgeois described an hydropic infant girl died 15 min

after birth with severe jaundice of the placenta and blood.9

Juncker in 1724, speaks of true jaundice “the icteric tinge which may be

observed in infants, immediately after birth” The latter, he says, is of no account and

disappears spontaneously after the meconium is passed.10

A quote from Bracken’s 1737 text book entitled “The midwives companion”

gives a perspective on the 18th century view of neonatal jaundice.11

Dewees writes in his 1825 American text book “Jaundice in the newborn

infant is but too often fatal, with whatever property or energy we may attempt to

relieve it”.12

In 1847 Virchow isolated bilirubin crystals from hematomas and suggested

that bilirubin was derived from blood.13

The relationship between the clinical encephalopathy associated with elevated

serum bilirubin concentration and gross pathological changes seen as yellow staining

of specific areas of the CNS was observed and described by Orth in 1875.14

In 1903, Schmorl coined the term ‘Kernikterus’ and described the pathology

of the jaundice in the brain.15

In text book on diseases of liver by Murchison in 1885, made frequent

references to jaundice in newborn.16

5
 In the first edition of Holt’s “The diseases of Infancy and Childhood”

published in 1897, the clinical description of physiologic jaundice is entirely

compatible with modern concepts.17

The first use of the term “Erythroblastosis fetalis” was by Rautmann in 1912

in reference to an hydropic still born.18

Halban in 1900 suggested that isoimmunization of the mother could be basis

of erythroblastosis.19

Ottenberg in 1923 proposed that feto-maternal transfusion was etiologically

responsible,20 later Levine and Colleagues in 1941, demonstrated the role of Rh

antibodies in the etiology of erythroblastosis fetalis.21

In 1913, Yllpo demonstrated that the newborn had an elevated serum bilirubin

concentration.22

In 1916, Ilymann Van den Bergh, developed a definitive test for measurement

of bilirubin and its separation into two chemically distinct compounds labeled by Van

den Bergh as direct and indirect reacting bilirubin.23

In 1932, Diamond and Colleagues found that generalized edema of the fetus,

icterus gravis and congenital anemia of the newborn were in fact all part of a single

condition, which they termed Erythroblastosis fetalis.24

6
 In 1939, Landsteiner and Weiner, Levine and Stetson demonstrated the

serological basis of maternal fetal blood group incompatibility and the identification

of the Rh system of antigens.25

In 1952, Crigler and Najjar described Congenital familial nonhemolytic

jaundice with Kernicterus.26

In 1944, Halbrecht coined the term “Icterus Precox” for jaundice developed

within 24 hours of birth.27

The first exchange transfusion in a newborn was performed in 1925 by Hart

for treatment of erythroblastosis fetalis28 and in 1946, Wallerstein reported the

successful exchange transfusion of three infants with erythroblastosis fetalis.29

Cremer and Colleagues in 1958, observed the effect of sunlight on the serum

bilirubin level of premature infant nursed outdoors, prompted the first use of a ‘Cradle

illumination machine’.30

b. Prediction of neonatal hyperbilirubinemia

Neonatal hyperbilirubinemia is a cause of concern for the parents and for

pediatricians. The recognition, follow up and the early treatment of jaundice has

become difficult as a result of earlier discharge from the hospital. Severe jaundice,

and even kernicterus can occur in some full term healthy newborns discharged early

with no apparent early findings of hemolysis. The concept of prediction of jaundice

offers an attractive option to pick up babies at risk of neonatal hyperbilirubinemia.5

7
 Of all conditions found to account for readmission to the hospital within first

14 days only hyperbilirubinemia and dehydration / failure to thrive are susceptible to

some kind of intervention that might prevent readmission.31

A length of stay of <72 hours was also an important factor associated with the

risk of readmission and in particular readmission for jaundice.31

There is also evidence that mothering competence may be affected by early

discharge. Eidelman32 et al., have demonstrated that women on the first post partum

day score significantly lower than non pregnant women on standardized tests of

cognitive function. Mothers discharged early on the second day manifest some degree

of confusion and forgetfulness. Such mothers will not be reliably integrated

information given to them by care givers and this could have an impact on the infant’s

well being in the next several days. Whether infants discharged at 30 or 60 hours of

life, those infants who are readmitted on days 4 to 6 with hyperbilirubinemia have not

achieved their peak bilirubin level by the time they leave the hospital. Thus if we want

to be sure we do not miss very severe hyperbilirubinemia (that even in a healthy term

newborn, on occasion have disastrous consequences) then infants discharged <72 hrs

after birth also be seen within 2 to 3 days of discharge , perhaps current guidelines for

the follow up of infants should be reevaluated.31

In 1977, Risemberg et al. established a correlation between bilirubin levels in

the umbilical cord blood and hyperbilirubinemia in newborns with ABO

incompatibility. These researchers concluded that newborns presenting levels higher

than 4 mg/100ml were a group at risk of developing severe hyperbilirubinemia and

8
should be followed up and reassessed, since all of them presented serum bilirubin

levels that were higher than 16 mg/100ml between 12 and 36 hours of life. In the

present study, phototherapy was significantly associated with the presence of blood

group incompatibility between mother and child, as well as with the unconjugated

bilirubin level in cord blood. There was also a significant association between the

unconjugated bilirubin in cord blood and the newborn’s bilirubin level.33

In 1986, Rosenfeld analyzed a group of 108 full-term newborns according to

their risk of developing severe hyperbilirubinemia and concluded that babies with an

umbilical cord blood bilirubin level of lower than 2 mg/100 ml had a 4% chance of

developing significant jaundice, in comparison with a 25% chance presented by the

ones with levels higher than 2 mg/100ml. In addition, the latter group also presented a

higher chance of needing to undergo phototherapy.34

In 1989, Aage Kundsen in his study on umbilical cord serum bilirubin

concentration as a predictor of subsequent jaundice on 291 newborns he found it was

possible to define subgroups of infants with significantly higher or lower risks of

developing jaundice. If cord bilirubin was below 20 µmo1/1, 2.9% became jaundiced

as opposed to 85% if cord bilirubin was above 40 µmo1/1,, Furthermore, 57% of

jaundiced infants with cord bilirubin above 40 µmo1/1 required phototherapy, but

only 9% if cord bilirubin was 40 µmo1/1, or lower (p>0.003). Knowledge of infants at

risk of developing jaundice allows simple bilirubin reducing methods to be

implemented before jaundice is present and could influence a decision regarding early

discharge from hospital. Since the ability of plasma to bind bilirubin in cord blood

from jaundiced and non-jaundiced infants showed no significant differences, the

9
increased cord bilirubin among infants who later became jaundiced is presumably

caused by increased fetal bilirubin production or decreased removal of bilirubin from

the fetal circulation.35

In 1994, Rataj et al carried out a study in 800 healthy term newborns and the

results showed that critical bilirubin level in the cord blood of >2.5 mg/dl had a

probability of 69% for the development of significant hyperbilirubinemia in

newborns.36

In 1998, M.Jeffey Maisal et al carried out a study to evaluate the effect of

postnatal age at the time of discharge on the risk of readmission to the hospital with

specific reference to readmission for hyperbilirubinemia. Newborn infants born

between December 1st 1988 and November 30th 1994 who were readmitted to hospital

within 14 days of discharge were compared with a randomly selected control group

who were not readmitted. He concluded that the major reason for readmission to the

hospital in the first 2 weeks of life is Hyperbilirubinemia (incidence 4.2 per 1000

discharges). The risk of readmission is similar for infants discharged < 48 hours or

≥ 48 hours to < 72 hours, suggesting that infants discharged at < 72 hours should be

seen by a health care professional within 2 to3 days of discharge.31

In 1998, Shally Awasthi and Hasibur Rehman carried out a study on early

prediction of neonatal hyperbilirubinemia. The study was conducted on a prospective

cohort of 274 neonates born in north India. The main outcome measures were (a)

hyperbilirubinemia and (b) phototherapy. Serum bilirubin level was estimated at 18-

24 hours of age and then daily from second to fifth postnatal day. Exclusion criteria

were Rh incompatibility, asphyxia and life threatening congenital malformations; and

10
neonates of women with gestational diabetes or history of intake of drugs affecting

the fetal liver. Hyperbilirubinemia was found in 12.8% and 19.3% neonates received

phototherapy. Dichotomous SB 18-24, using a cut-off of > 3.99 mg/dL, as the

“prediction test” had the following sensitivity and specificity for predicting (a)

hyperbilirubinemia : 67% and 67%, respectively, and (b) the treatment with

phototherapy : 64% and 68%, respectively. They concluded that by using SB 18-24 as

the “prediction test”, approximately two-thirds of neonates were test negative and had

about one in ten chances of readmission for the treatment of hyperbilirubinemia, if

discharged.37

In 1999, Johnson and Brown attributed the incidence of kernicterus to shorter

hospitals stays, decreased vigilance in diagnosing jaundice, lack of physician

perception of the toxicity of bilirubin.38

In 2000, Alpay F et al carried out a study on the value of first-day bilirubin

measurement in predicting the development of significant hyperbilirubinemia in

healthy term newborns. A total of 498 healthy term newborns were followed with

daily serum total bilirubin measurements for the first 5 days of life, and cases with

serum bilirubin levels of ≥ 17 mg/dL after 24 hours of life were defined to have

significant hyperbilirubinemia. In his study, mean serum bilirubin level ≥ 6mg/dL on

the first day had the highest sensitivity (90%) with negative predictive value was very

high (97.9%) and the positive predictive value was fairly low (26.2%). So he

concluded a serum bilirubin measurement and the use of the critical bilirubin level of

6 mg/dL in the first 24 hours of life will predict nearly all of the term newborns who

will have significant hyperbilirubinemia and will determine all those who will require

a phototherapy treatment later during the first days of life.39

11
 In 2004, Bernaldo and Segre carried out a prospective study to evaluate

whether bilirubin levels in cord blood could predict neonatal hyperbilirubinemia that

would require treatment in full-term newborns up to their third day of life.

Participants were 380 full-term newborns considered normal with or without ABO/Rh

blood group incompatibility and without other complications. Results showed the

mean value for unconjugated bilirubin in cord blood was significantly higher in

newborns whose unconjugated bilirubin required phototherapy. The presence of ABO

blood group incompatibility was a significant variable in relation to unconjugated

bilirubin that required phototherapy. The most useful cutoff point for unconjugated

bilirubin in cord blood was 2.0 mg/100ml. He concluded blood group incompatibility

between mother and child was a predictor for the appearance of hyperbilirubinemia

that required treatment. Considering a cut off point of 2.0mg/100ml, it could be

concluded that 53% of the newborns who had greater unconjugated bilirubin levels in

cord blood would reach levels requiring phototherapy by the third day of life.40

In 2005, Amar Taksande et al., in a study on 200 healthy term neonates with

gestation > 37 weeks, in the absence of significant illness or Rh hemolysis cord

bilirubin was estimated by micromethod using calorimeterically using green filter

with 540nm wavelength. Neonates were followed up clinically every 12 hrs till

discharge and then after 72 hour total serum bilirubin (TSB) level was estimated again.

He concluded that increased cord blood bilirubin can be used as a predictor of the

development of neonatal hyperbilirubinemia. Cord bilirubin level of >2mg/dl had the

highest sensitivity (89.5%), and this critical bilirubin level had a very high (98.7%)

negative predictive value and fairly low (38.6%) positive predictive value.5

12
 Rostami et al 2005, on their study to identify healthy newborns at risk for

developing significant hyperbilirubinemia by measuring bilirubin level in cord blood

in 643 full term infants. Serum bilirubin level was obtained on umbilical cord serum

and on day three of age. The total bilirubin ≥ 239µmo1/1 (14 mg/dl) was defined as

significant hyperbilirubinemia. Data were analyzed using t-test, chi-square, and

receiver operating characteristics (ROC) curve. Result showed mean and standard

deviation of cord bilirubin level was 34.2± 15.9 µmol/1 (2.00 ±0.93 mg/dl). There

was a statistically significant relation between use of oxytocin and subsequent

significant hyperbilirubinemia (p < 0.04). 92.4% of neonates with cord bilirubin levels

below 51.3 µmol/1 (3 mg/dl) did not develop significant hyperbilirubinemia. A cord

serum bilirubin level above 51.3 µmol/1 is not a useful predictor of neonatal jaundice.

They concluded that cord serum bilirubin level cannot identify newborns with

subsequent significant hyperbilirubinemia.

In 2007, Sun et al found that cord blood bilirubin level could predict the

development of significant hyperbilirubinemia in healthy term newborns. This study

showed the bilirubin in cord blood critical level of > 2 mg/dl had positive predictive

value of 45.68% and sensitivity of 68.27 (P < 0.001). 42

In 2009, Rudy Satrya et al., in his prospective observational study on 88 health

term newborns, Cord blood was collected for the total bilirubin, conjugated bilirubin,

unconjugated bilirubin level measurement and blood group test. Measurements of

total bilirubin, conjugated bilirubin, and unconjugated bilirubin were repeated on the

5th day with serum sampling, or as soon as the newborn appeared to be jaundiced.

Subjects were categorized into hyperbilirubinemia and non-hyperbilirubinemia

13
newborns. There was a correlation between cord blood and the 5th day bilirubin level.

By ROC analysis, cord blood bilirubin level of ≥2.54 mg/dl was determined to have

high sensitivity (90.5%), specificity of 85%, and accuracy of 86.4%. He concluded

there is a correlation between cord blood bilirubin level and hyperbilirubinemia in

healthy term newborns. Cord blood bilirubin level at or greater than 2.54 mg/dl can

predict the development of hyperbilirubinemia.43

Zakia Nahar et al 2009 carried a study on the value of umbilical cord blood

bilirubin measurement in predicting the development of significant

hyperbilirubinemia in healthy newborn. For this purpose 84 healthy newborn infants

were enrolled and followed up for first 5 days of life. Study subjects were divided into

two groups. Group-I consisted of 71 subjects, who did not develop significant

hyperbilirubinemia (bilirubin <17mg/dl); Group-II consisted of 13 newborns, who

developed significant hyperbilirubinemia (bilirubin >17mg/dl) during the follow up.

Of the enrolled subjects, 46 (55%) were male and rest 38(45%) were female; 64

(76%) were term babies and 20 (24%) were pre-term babies. Significantly higher

percentage of pre-term babies developed hyperbilirubinemia. ROC(receiver operating

characteristic) analysis demonstrates that the critical value ofcord blood bilirubin

>2.5mg/dl had the high sensitivity (77%) and specificity (98.6%)to predict the

newborn who would develop significant hyperbilirubinemia. At this level the negative

predictive value was 96% and positive predictive value 91%.44

A cord serum bilirubin measurement and the use of critical cord serum

bilirubin level can be used to predict nearly all the term newborns who will have

significant hyperbilirubinemia and will determine all those who will require

phototherapy later.

14
c. Bilirubin metabolism

Jaundice is the commonest abnormal physical finding during first week of life.

Between 25 to 50% of all term newborns and a higher percentage of premature

newborns develop clinical jaundice.4

Sources of bilirubin

Bilirubin is derived from the breakdown of heme containing protein in the

reticuloendothelial system.4

a. The major heme containing protein is red blood cell hemoglobin. This is the

source of 75% of all bilirubin production.

b. The other 25% of bilirubin is called early labeled bilirubin. It is derived from

hemoglobin released by ineffective erythropoiesis in the bone marrow, from

other heme containing proteins in tissues (ex: myoglobin, cytochromes,

catalase, peroxidase) and from free heme.

15
Fig. 1 : Bilirubin metabolism45

16
Bilirubin Metabolism4

The conversion of heme to bilirubin requires two closely linked enzymatic

steps.

Bilirubin synthesis

1st step is conversion of heme to a linear tetrapyrrole biliverdin ,1 molecule of

ferrous ion and 1 mol of carbonmonoxide is released by enzyme Heme oxygenase. It

is the rate limiting step and upregulated during hemolysis.46

2nd step of bilirubin synthesis involves Biliverdin reductase found in cystosol

of most cells. Biliverdin is converted to Bilirubin.46

Bilirubin transport in the plasma

Bilirubin in plasma is tightly bound to serum albumin, usually does not enter

the central nervous system and is thought to be nontoxic.4

Bilirubin uptake

Non polar, fat, soluble bilirubin (dissociated from albumin) crosses the

hepatocyte plasma membrane and is bound mainly to cytoplasmic ligandin (Y

protein) for transport to the smooth endoplasmic reticulum. Phenobarbital increases

the concentration of ligandin.4

Bilirubin conjugation

Unconjugated bilirubin (UCB) is converted to water soluble conjugated

(direct) bilirubin (CB) in the smooth endoplasmic reticulum by uridine diphosphate

glucuronyl transferase (UDPG-T). This enzyme is inducible by phenobarbital and

17
catalyzes the formation of bilirubin monoglucuronide. Both mono and diglucuronide

forms of conjugated bilirubin are able to be excreted into the bile canaliculi against a

concentration gradient.4

Bilirubin excretion

Conjugated bilirubin in the biliary tree enters the gastrointestinal tract and is

thus eliminated from the body in the stool, which contains large amount of bilirubin.

Excretion is considered to be the rate limiting step of overall bilirubin clearance from

the plasma.4

Enterohepatic circulation of bilirubin

Conjugated bilirubin is not normally reabsorbed from the bowel unless it is

converted back to unconjugated bilirubin by the intestinal enzyme β-glucuronidase.

Intestinal bacteria can prevent the enterohepatic circulation by converting the

conjugated bilirubin to urobilinoids, which are not substrates of β-glucuronidase.4

d. Fetal bilirubin metabolism

Most unconjugated bilirubin formed by the fetus is cleared by the placenta into

the maternal circulation. Formation of conjugated bilirubin is limited in the fetus

because of decreased fetal hepatic blood flow, decreased hepatic ligandin and

decreased UDPG-T activity. The small amount of conjugated bilirubin excreted is

usually hydrolyzed by β-glucuronidase and reabsorbed.4

Bilirubin is normally found in the amniotic fluid by 12 weeks gestation and is

usually gone by 37 weeks gestation. Increased amniotic fluid bilirubin is found in

hemolytic disease of the newborn and in fetal intestinal obstruction below the bile

ducts. 4

18
e. Etiology of hyperbilirubinemia in newborn

Any process that increases the production or impairs the elimination of

bilirubin can exacerbate the normally occurring physiologic jaundice in newborn. 4

Etiology

I. Physiologic jaundice4

a. Increased bilirubin production due to

- Increased RBC volume per kilogram and decreased RBC survival (90 days

versus 120 days) in infants.

- Increased ineffective erythropoiesis and increased turnover of non

hemoglobin heme proteins.

b. Increased enterohepatic circulation due to high levels of intestinal β-

glucuronidase enzyme, decreased intestinal bacteria, decreased gut motility.

c. Defective uptake of bilirubin from plasma due to decreased ligandin and binding

of ligandin by other anions.

d. Defective conjugation due to decreased UDPG-T activity.

e. Decreased hepatic excretion of bilirubin.

II Non physiologic jaundice4

a. Over production

- Feto maternal blood group incompatibility.

- Hereditary Spherocytosis, Elliptocytosis, Stomatocytosis.

- Nonspherocytic hemolytic anemias.

- G6 PD deficiency and drugs.

- Pyruvate kinase deficiency.

19
 - Other red cell enzyme deficiencies

- α - Thalassemia

- δ - β-Thalassemia

- Acquired hemolysis due to vitamin K, Nitrofurantoin, Sulfonamides,

Antimalarials, Penicillin, Oxytocin, Bupivacaine or Infection.

- Extra vascular blood : Petechiae, hematomas, pulmonary, cerebral or

occult hemorrhage.

- Polycythemia : Fetomaternal or fetofetal transfusion. Delayed

clamping of the umbilical cord.

- Increased enterohepatic circulation

- Pyloric stenosis,

- Intestinal atresia or stenosis including annular pancreas,

- Hirschsprung disease,

- Meconium ileus or Meconium plug syndrome,

- Swallowed blood.

b. Undersecretion

- Metabolic or endocrine conditions

- Galactosemia

- Familial Nonhemolytic jaundice (crigler-Najjar syndrome and

Gilbert syndrome)

- Hypothyroidism

- Tyrosinosis

- Hypermethioninemia

- Drugs and Harmones – Novobiocin, Pregnanediol

- Lucy – Driscoll syndrome

20
 - Infants of diabetic mothers

- Prematurity, Hypopitutarism and Anencephaly.

- Obstructive disorders

- Biliary atresia

- Dubin Johnson and Rotor syndrome

- Choledochal cyst

- Cystic fibrosis (inspissated bile)

- Tumor or band (extrinsic compression)

- Parenteral nutrition

- α1 – antitrypsin deficiency

c. Mixed

- Sepsis

- Intrauterine infections

- Toxoplasmosis

- Rubella

- CID

- Herpes simplex

- Syphilis, Hepatitis

- Respiratory distress syndrome

- Asphyxia

- Infant of diabetic mothers

- Severe erythroblastosis fetalis

d. Uncertain mechanism

Breast milk jaundice

Chinese, Japanese, Korean and American indian infants.

21
Causes of jaundice on the basis of age of onset47

Within 24 hours : Rh and ABO incompatibility, G6 PD and PK enzyme deficiency.

Infections – Bacterial, Malarial, TORCH, Hereditary Spherocytosis, α-thalassemia,

Administration of large amount of drugs – vitamin K, salicylates, sulfisoxazole etc. to

the mother.

24 – 72 hours after birth : Physiologic jaundice, Blood group incompatibility,

Polycythemia, Extra vascular bleed – cephalohematoma, subgaleal hemorrhage,

breast feeding jaundice, neonatal sepsis, Increased enterohepatic circulation –

intestinal obstruction.

After 72 hours of birth : Neonatal sepsis, Cephalohematoma, Neonatal hepatitis,

Biliary atresia, Breast milk jaundice, Metabolic - Hypothyroidism, Hypopitutarism,

Galactosemia, Tyrosinemia, Cystic Fibrosis, Hereditary fructosemia, Crigler - Najjar

Syndrome, Gilbert Disease.

f. Complications of neonatal jaundice

Bilirubin encephalopathy refers to the clinical manifestations of the effects of

bilirubin on the central nervous system, where as kernicterus refers to the

neuropathologic changes that are characterized by pigment deposition in specific

areas of the CNS such as basal ganglia, pons and cerebellum.7

Bilirubin encephalopathy is a multifactorial process that requires a critical

level of free bilirubin, access to the brain across the blood-brain barrier, and presence

of susceptible nerve cells. The severity and duration of hyperbilirubinemia, the

maturity of the structures involved, the binding capacity of albumin, the physiologic

environment, and the cell membrane composition and metabolic state probably all are

critical to the development of neurodysfunction.3

22
Entry of bilirubin into the brain

The mechanism by which uncojugated bilirubin enters the brain and damages

it is unclear. Several hypotheses regarding entrance of bilirubin into the brain have

been proposed.7

One hypothesis is the lipophilic nature of free bilirubin, in equilibrium with

bound bilirubin, has access to tissues. Thus, any increase in the amount of free

bilirubin or reduction in the amount or binding capacity of albumin could increase the

level of unbound bilirubin within the brain tissue, saturating membranes and causing

precipitation of bilirubin acid within the nerve cell membrane.7

Second hypothesis is based on close examination of the chemical nature of

bilirubin in solution and seeks to explain the increased risk in acidotic infants. In this

theory, the rate of tissue uptake of bilirubin depends on both the concentration of

albumin-bound bilirubin and the pH, with low pH enhancing precipitation and tissue

uptake.7

Third theory suggests that bound bilirubin enters the brain mainly through a

damaged blood-brain barrier.7

Recent studies suggest that unconjugated bilirubin is a substrate for P-

glycoprotein (P-gp) and that the blood-brain barrier P-gp may play a role in limiting

the passage of bilirubin into the CNS. P-gp is an ATP – dependent integral plasma

membrane transport protein that translocates a wide range of substrates across

biologic membranes.7

23
Factors that increase susceptibility to Neurotoxicity associated with

Hyperbilirubinemia

Asphyxia, Hyperthermia, Septicemia, Hypoalbuminemia, Acidosis, Calorie

deprivation, Prolonged Hyperbilirubinemia, Low birth weight, Young gestational age,

Excessive hemolysis. 7

Bilirubin toxicity at cellular level7

Four possible mechanisms have been proposed:

• Interruption of normal neurotransmission

• Mitochondrial dysfunction

• Cellular and intracellular membrane impairment

• Interference with enzyme activity

Clinical features4

Early : Lethargy, poor feeding, high pitched cry, hypotonia.

Intermediate : Irritability, opisthonous, seizures, apnea, oculogyric crisis,

hypertonia , fever, retrocollis.

All infants who survive this phase develop chronic bilirubin

encephalopathy (clinical diagnosis of kernicterus)

Advanced phase : Pronounced opisthonous, shrill cry, apnea, seizures, coma and

death.

Chronic bilirubin encephalopathy (kernicterus)

It is marked by athetosis, athetoid cerebral palsy, partial or complete high

frequency sensorineural hearing loss, paralysis of upward gaze, dental dysplasia and

intellectual deficits.4

24
Predicting Encephalopathy and Reversibility of damage7

ƒ Brainstem Evoked Auditory Response- Because auditory pathway of the

newborn is particularly vulnerable to insult from the bilirubin, BEAR testing has

been suggested as a tool that could identify or predict early effects of

hyperbilirubinemia. Studies have shown increased bilirubin concentrations with

changes in the amplitude and latency of these responses. BEAR is accurate and

non invasive and assesses the functional status of the auditory nerve in the

brainstem pathway. In a study of 50 full term infants with moderate

hyperbilirubinemia, the latency of BEAR waves lV and V was longer than in

those infants with lower STB levels (Shapiro and Nakamura, 2001).48 BEAR

testing could be used to screen hyperbilirubinemic full-term and premature

infants for sensorineural hearing loss and could be incorporated into the

assessment of need for exchange transfusions (Nwaesei et al, 1984;49 Wennberg

et al, 1982).50

ƒ Infant Cry Analysis - It has been shown that with moderately elevated STB

levels, there is interference with neural conduction, as demonstrated by the

BEAR, and changes in neural function in adjoining pathways, with resultant

effects on the vocal cords (increased tension on phonation).7

ƒ Nuclear Magnetic Resonance Techniques – Nuclear magnetic resonance (NMR)

techniques, both imaging and spectroscopy, have been proposed as a rapid,

noninvasive measure of impending or actual brain cell injury in the face of

hyperbilirubinemia7 (Palmer and Smith, 1990).51

25
g. Evaluation, prediction and diagnosis of neonatal jaundice

Between 25% and 50% of all term newborns and a higher percentage of

premature infants develop clinical jaundice. A serum bilirubin level of >15 mg/dl is

found in 3% of normal term babies. Physical examination is not a suitable measure of

serum bilirubin estimation.4

Kramer criterion

Visual assessment of serum bilirubin levels as suggested by Kramer (1969) ,

which relies on the cephalocaudal progression of jaundice with the raising serum

bilirubin levels, head and neck,4 to 8 mg/dl ; upper trunk,5-12 mg/dl ; lower trunk and

thighs,8 to 16 mg/dl ; palms and soles, greater than 15 mg/dl ; is now known to be

fraught with error.52

Hour specific nomogram

Bhutani and colleagues (1999) generated a percentile based bilirubin

nomogram using hour specific pre discharge STB levels from a racially diverse group

of term healthy newborns with no ABO or Rh incompatibility who did not need

phototherapy before 60 hours of age and of whom 60% were breastfed. Post discharge

STB levels were measured by a hospital based bilirubin assay within 3 days after

discharge. The risk for significant hyperbilirubinemia (STB greater than 17 mg/dl) for

infants with a pre-discharge STB above the 95th percentile (high risk zone) was

57%,for infants with STB between the 75th and 95th percentiles (high intermediate

risk) it was 13%, for infants with STB between the 40th and 75th percentiles (low

intermediate risk zone) it was 2.1%, and for infants below 40th percentiles (low risk) it

was 0. Limitations of this approach are the need for blood sampling and the cost of

STB measurement.53

26
Transcutaneous bilirubin measurement (TcB)

Transcutaneous (TcB) is based on the measurement of light reflected from the

skin. Many devices (Bilicheck ,Norcross ,Georgia) that measures the entire spectrum

of visible light reflected from the skin has been shown to provide an accurate

assessment of STB in term and near term newborn infants of diverse races and

ethnicities. It is important to note that TcB measured is not the serum bilirubin but the

amount of bilirubin that has moved into the tissues.7

End tidal carbon monoxide (ETCOc) measurement

The breakdown of Heme by the rate limiting enzyme Heme Oxygenase leads

to the formation of equimolar amounts of CO and Biliverdin.The measurement of CO

in the exhaled breath in the newborn can be used as an index of heme degradation and

bile production in vivo. It can help to distinguish between cases of increased bilirubin

production versus decreased elimination or impaired bilirubin conjugation.7

Risk factors for development of neonatal hyperbilirubinemia in infants of 35 or

more week’s gestation4

- Major risk factors

- Pre-discharge TSB or TcB level in high risk zone

- Jaundice observed in the first 24 hours

- Blood group incompatibility with positive DCT or elevated ETCOc.

- Gestational age 35-36 weeks

- Previous sibling received phototherapy

- Cephalohematoma or significant bruising

- Exclusive breast feeding, particularly if nursing is not going well and weight loss

in excessive.

- East Asian race.

27
Minor risk factors

- Pre discharge TCB or TcB level on the high intermediate risk zone

- Gestational age 37-38 weeks

- Jaundice observed before discharge

- Previous sibling with jaundice

- Macrosomic infant of a diabetic mother

- Maternal age ≥ 25 years

- Male gender

Decreased risk

- TSB or TcB level in low risk zone

- Gestational age ≥ 41 weeks

- Exclusive bottle feeding

- Black race

- Discharge from hospital after 72 hours.

28
Total serum bilirubin (mg/dL)

Fig 2 : Risk designation of term and near-term well newborns based

on their hour-specific serum bilirubin values. The high-risk
zone is subdivided by the 95th percentile track. The
intermediate at risk zone is subdivided into upper and lower
risk zones by the 75th percentile track. The low-risk zone has
been electively and statistically defined by the 40th percentile.3

29
Fig 3 : Schematic approach to the diagnosis of neonatal jaundice7

30
Criterion for physiological jaundice54

- Type of bilirubin – Indirect bilirubin,

- Direct bilirubin never more than 2mg/dl or less than 15% of total bilirubin,

- Appearance - after 36 hours of age,

- Rate of rise of bilirubin – less than 5mg / dl/day,

- Severity of jaundice – Usually does not exceed 15 mg/dl,

- Natural course – Peak STB levels seen between 3rd – 5th days of life and 3rd – 7th

day in preterm and disappears by 2 weeks.

- Clinical condition – Healthy newborn.

Pathological jaundice is suspected in the newborn with54

- Clinical jaundice in the first 24 hours of life.

- STB > 15 mg/dl

- Rate of STB increase > 0.2 mg/dl/hr or 5mg/dl/day.

- Direct serum bilirubin > 2mg/dl or > 15% of total bilirubin

- Clinical jaundice persisting for > 2 weeks.

Guidelines for Phototherapy and Exchange transfusion in hospitalized infants

of 35 or more weeks’ gestation are depicted in Fig. 4 and Fig. 5 respectively.55 (From

American Academy of Pediatrics Subcommittee on Hyperbilirubinemia: Management

of hyperbilibubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics

2004; 114:297-316).

31
 Fig. 4 : Guidelines for phototherapy in hospitalized infants of 35 or
more weeks’ gestation3

• Use total bilirubin. Do not subtract direct reacting or conjugated bilirubin.

• Risk factors = isoimmune hemolytic disease, G6PD deficiency, asphyxia,

significant lethargy, temperature instability, sepsis, acidosis, or albumin <3.0 g/dL

(if measured).

• For well infants 35-37 6/7 wk can adjust TSB levels for intervention around the

medium risk line. It is an option to intervene at lower TSB levels for infants closer

to 35 wks and at higher TSB levels for those closer to 37 6/7 wk.

• It is an option to provide conventional phototherapy in hospital or at home at TSB

levels 2-3 mg/dl (35-50mmol/L) below those shown but home phototherapy

should not be used in any infant with risk factors.

32
 Fig. 5 : Guidelines for exchange transfusion in hospitalized infants of 35
or more weeks’ gestation3

• The dashed lines for the first 24 hours indicate uncertainty due to a wide range of

clinical circumstances and a range of responses to phototherapy.

• Immediate exchange transfusion is recommended if infant shows signs of acute

bilirubin encephalopathy (hypertonia, arching, retrocollis, opisthotonos, fever,

high pitched cry) or if TSB is ≥ 5 mg/dl (85 µmol/L) above these lines.

• Risk factors – isoimmune hemolytic disease, G6PD deficiency, asphyxia,

significant lethargy, temperature instability, sepsis, acidosis.

• Measure serum albumin and calculate B/A ratio.

• Use total bilirubin. Do not subtract direct reacting or conjugated bilirubin.

• If infant is well and 35-37 6/7 wk (median risk) can individualize TSB levels for

exchange based on actual gestational age.

33
h. Laboratory evaluation7

I. Maternal: Blood grouping and Indirect Coombs Test (ICT) to test for Isoimmune

hemolytic disease, Serology to rule out syphilis.

II. Infant :

- Total serum bilirubin and or Transcutaneous bilirubin.

- Blood grouping, Rh typing and Direct coomb test to test for isoimmune

hemolytic disease.

- Hemoglobin and Hematocrit.

Anemia suggests hemolytic disease and large entrapped hemorrhage.

- Polycythemia cause jaundice.

- Reticulocyte count is elevated in hemolytic anemia.

- Red cell morphology – By peripheral blood smear

- Red cell fragmentation seen in disseminated intravascular coagulation (DIC)

- Spherocytes suggests ABO incompatibility or Hereditery Spherocytosis.

- Platelet count is decreased in infections.

- White blood cell count less than 50,000 cells/cumm or BNR> 0.2 suggest

infection.

- Urine analysis for reducing substance to diagnose Galactosemia.

- Screening of G6 PD deficiency.

- Serum protein and albumin to estimate albumin binding capacity and reserve

albumin binding site.

- pH

- Protein binding (2,4 hydroxybenzene azobenzoic acid (HABA), Salicylates)

These tests helps to measure the quantity of binding of bilirubin in the serum

of jaundice infants.

34
i. Treatment of Neonatal Hyperbilirubinemia47

The aim of the therapy is to ensure that serum bilirubin is kept at a safe level

and brain damage is prevented. Neonatal Hyperbilirubinemia is a medical emergency

and delay in its management can lead to irreversible brain damage and death.

Preventive and suggestive measures

• Drugs known to aggravate jaundice or block the bilirubin binding sites on albumin

should be withheld.

• Vitamin K in large doses should be avoided.

• Perinatal distress factors such as hypoxia, acidosis, hypothermia, hypoglycemia

should be prevented or adequately managed.

• Use of phenolic detergents are avoided in nursery as they may enhance the

jaundice in the babies.

Adequate feeding

Early feeding augments colonization of the gut and reduces the enterohepatic

circulation. Effective evacuation of meconium is associated with elimination of

conjugated bilirubin and stercobilin.

Pharmacological management

Phenobarbitone

Barbiturates have been shown to induce the maturation of microsomal

enzymes, ligandin (Y-acceptor protein) and glucuronyl transferase (UDPG-T), thus

improving the uptake, conjugation and excretion of bilirubin by the liver.

35
 Phenobarbitone in a single dose of 10 mg/kg im or 5mg/kg/day in two divided

doses orally for 3 days is indicated in cases of cord serum bilirubin level of > 2.5

mg/dl, early onset of jaundice due to any cause, difficult or instrumental delivery,

Oxytocin induced delivery with bruising and cephalohematoma.

Clofibrate

It is a potent enhancer of glucuronyl transferase. It is more efficacious but it is

slow in its action and takes several days to show the beneficial effect.

Agar

It is a sea weed extensively used in processing of food. In dose of 250mg 6th

hourly orally it binds conjugated bilirubin in the gut and blocks the enterohepatic

circulation. Its use is unpredictable and variable.

Cholestyramine

In dose of 1.5 mg/kg/day in 4 divided doses mixing in milk feeds has been

shown to enhance fecal exertion of bilirubin and thus blocking enterohepatic

circulation. Infant should be watched for constipation – intestinal obstruction and

hypercholeremic acidosis.

Orotic acid

It is a metabolic precursor of uridine diphosphate glucuronic acid and thus

promotes the conjugation of bilirubin. Its ability is limited and cost is prohibitive.

36
Tin-mesoporphyrin (SnMP)

Metalloporphyrins (Tin and Zinc) are structural analogs of heme and they

inhibit heme oxygenase. It diminish the production of bile pigments by competitive

inhibition. Heme oxygenase is a rate limiting enzyme in heme metabolism. Tin

mesoporphyrin (6 µmol/kg/single dose im) has been shown to significantly reduce

bilirubin production. It is associated with high incidence of photosensitive skin

reactions and potential risk of hepatic and renal toxicity.

Albumin infusion

When administered (1 gm/kg), half an hour before exchange transfusion it

facilitates more effective removal of bilirubin and also improves the bilirubin binding

capacity of the baby. Use is avoided in babies with congestive cardiac failure because

of risk of overloading the circulation. Rarely used due to exorbitant cost and risk of

transmission of viral infections.

Inhibiting hemolysis4

IvIg (500-1gm/kg) used to reduce bilirubin levels in infants with Isoimmune

Hemolytic disease. The immunoglobulins act by occupying the Fc receptors of

reticuloendothelial cells, there by preventing them from taking up and lysing antibody

coated Red Blood Cells.

37
Phototherapy47

Widely accepted, relatively safe and effective method for treatment of

neonatal hyperbilirubinemia. Bilirubin absorbs light maximally at 420-460 nm and

light sources with peak emissions in this range lower serum bilirubin levels by several

mechanisms.

Photo oxidation

Photo oxidation of bilirubin into water soluble colorless form of bilirubin is

very slow, ineffective.

Configurational photoisomerization

Here E-isomers (4Z 15E, 4E 15E, 4E 15Z) which are more polar water soluble

diazo negative compounds are produced. E isomers are nontoxic and after 8-12 hours

of phototherapy they constitute about 25% of total serum bilirubin.

Structural isomerization

It is the production of stable water soluble structural isomers of bilirubin like

lumirubin. These photocatabolites are readily excreted in bile, feces and to a lesser

extent in urine. The conversion of bilirubin to lumirubin is irreversible and it cannot

be reabsorbed. It is most important pathway for the lowering of serum bilirubin levels

and strongly related to the dose of phototherapy used in the range of 6 to 12

µw/cm2/nm.

Procedure of phototherapy

The narrow spectral blue light is most effective for phototherapy but it

interferes with proper observation of the infant. White day light fluorescent lamps are

quite effective and commonly used in our country. Blue and white tubes phototherapy

unit are also available.

38
 Nude infant is exposed to a portable or fixed light source kept at 45cm from

the skin. Distance between the baby and phototherapy unit can be reduced to 15-20

cms to provide effective and more intensive phototherapy.

During phototherapy eyes must be shielded to prevent retinal damage and a

diaper should be kept on to cover the genitals. For effective phototherapy, the

minimal spectral irradiance or ‘flux’ of 4 to 6 µw/cm2/nm is available and maintained

at the level of the infant’s skin.

Side effects

- Passage of loose green stools because of transient lactose intolerance and irritant

effect of photocatabolites causes increased colonic secretory losses.

- Hyperthermia

- Irritability

- Dehydration

- Flea bite rash on the trunk or extremities

- Risk of opening up to PDA in preterm babies.

- Hypocalcemia due to secretion of melatonin from pineal gland

- Bronze baby syndrome – Infants with parenchymal liver disease with biliary

obstruction, due to excessive accumulation of bilifucin (Polymerized form of

lumirubin) imparting brownish discoloration to the skin.

- Theoretically increased risk of skin malignancy later in life.

- Exposure to light may disturb the Circadian rhythm of the sex hormones thus

having potential implications on onset of puberty and disturbances in future sex

behavior.

39
Exchange transfusion4

There is no single reliable laboratory parameter that can predict with certainty

the potentiality for development of brain damage due to bilirubin.47

Need for exchange transfusion is based on level of unconjugated serum

bilirubin, gestational maturity, postnatal age, existence of or otherwise perinatal

distress factors and the cause of jaundice.47

Choice of blood4

- O Rh negative blood in emergency situations.

- Fresh (<7 days old) type O cells with AB plasma to ensure that no anti A and anti

B antibodies are present.

- In non immune hyperbilirubinemia, blood is typed and cross matched against the

plasma and red cells of the infant. Exchange transfusion usually involve double

the volume of the infant’s blood and is known as a Two volume exchange. [160

ml/kg]. This replaces the 87% of infant’s blood volume with new blood.

Technique

a) Exchange transfusion is done by push pull technique through the umbilical vein

inserted only as far as required to permit the free blood exchange.

b) Isovolumetric exchange transfusion –Simultaneously pulling blood out of the

umbilical artery and pushing new blood in the umbilical vein may be better

tolerated in small sick or hydropic infants.

c) Exchange transfusion can be accomplished through central venous pressure line

placed through the anticubital fossa or into the femoral vein through the

saphenous vein and radial artery.

40
- In push pull method, blood is removed in aliquots that are tolerated by the infant.

Usually 5ml for <1500gms, 10ml for infants 1500-2500gms, 15ml for 2500-

3500gms and 20ml for >3.5kgs.

- The recommended time for the exchange transfusion is 1 hour.

Complications of Exchange transfusion

1) Hypocalcaemia and Hypomagnesemia : The citrated blood used binds ionic

calcium and magnesium.

2) Hypoglycemia : High glucose content of CPD (300mg/dl) stimulates insulin

secretion and causes hypoglycemia 1-2 hours after exchange.

3) Acid base balance : Citrate in CPD blood is metabolized to alkali resulting in late

metabolic alkalosis.

4) Hyperkalemia : Potassium levels may be greatly elevated in stored PRBC’s.

5) Cardiovascular : Perforation of vessels, embolisation, vasospasm, thrombosis,

infarction, arrhythmia, volume overload, arrest.

6) Bleeding : Thrombocytopenia, deficient clotting factors.

7) Infections : Bacteremia, hepatitis, CMV, HIV, West Nile virus and malaria.

8) Hemolysis : Hemoglobinemia, hemoglobinuria, and hyperkalemia caused by

over heating of the blood have been reported.

9) Graft-versus-host disease. This is prevented by using irradiated blood.

10) Miscellaneous: Hypothermia, hyperthermia and possibly necrotizing

enterocolitis.

41
 MATERIALS AND METHODS

The present study was conducted in Cheluvamba hospital attached to Mysore

Medical College and Research Institute. The study group consisted of 100 consecutive

term neonates delivered at Cheluvamba Hospital, Mysore from December 1st 2008 to

May 31st 2010. These neonates were followed from birth to 5th postnatal day.

Inclusion criteria

1) Healthy term neonates delivered at Cheluvamba Hospital, Mysore.

2) Hospital stay of more than 5 days.

3) Cases with informed, written parental consent.

Exclusion criteria

1) Clinical jaundice on the first postnatal day

2) Sick babies or babies admitted to NICU

3) Babies receiving drugs that are known to affect serum bilirubin levels.

4) Birth asphyxia APGAR <7 at 5th min

5) Major congenital anomalies in newborn.

6) Maternal gestational diabetes mellitus.

7) Pathological jaundice.

Informed written parental consent was obtained from all cases. Data was

collected as per the Performa. Questionnaire method, maternal case file, and

examination of the newborn were used to obtain the required data.

42 
 Maternal variables like history of jaundice, first trimester bleeding, gestational

hypertension, mode of delivery and uses of drugs during pregnancy were collected.

Medication during labour, details of delivery, APGAR score and maternal blood

group were collected from the maternal file.

Babies were examined daily and looked for evidence of jaundice, sepsis,

illness or birth trauma. Weight of the newborn was recorded and gestational age

calculated. All the babies were followed up daily for first 5 postnatal days because

peak serum bilirubin occurs between 3rd to 5th day.

Cord blood was collected at birth. First day serum bilirubin was estimated

using blood drawn between 12-24 hours after birth. Blood was also drawn on 3rd and

5th day. Peripheral venous blood was used to measure serum bilirubin.

Blood sample collected was stored away from light. The sample was

refrigerated between 2 -8degree C till serum bilirubin estimation is done. Serum

bilirubin estimation was done within 12 hours of collection of sample by Diazotized

sulfanilic test.

Principle - Bilirubin reacts with diazotized sulfanilic acid to produce

azobilirubin which is quantified by spectrometry. Both direct and indirect bilirubin

couple with diazo in the presence of cetremide. The terms ‘direct’ and ‘indirect’ are

approximately equivalent to conjugated and unconjugated fractions.

43 
 The main outcome of the study was inferred in terms of hyperbilirubinemia.

Serum bilirubin ≥17 mg/dl after 72 hours of life was taken as hyperbilirubinemia

needing phototherapy and treatment is advised to all those full term healthy babies

with serum bilirubin level of ≥17mg/dl after 72 hours of life, as per the American

academy of paediatrics practice parameter, 2004. IAP-NNF also recommends

considering phototherapy with neonatal serum bilirubin levels of ≥17mg/dl after 72

hours of life. So in the present study babies with serum bilirubin level of ≥17mg/dl are

considered hyperbilirubinemia and needs phototherapy after 72 hours of postnatal life.

Maternal, neonatal and natal variables were compared between neonates with

5 days follow up.

Statistical analysis- Statistical data were analyzed with the independent sample

t test and the descriptive analysis and chi-square tests. Sensitivity, specificity,

negative and positive predictive value of the test were calculated.

The critical cord bilirubin level having the highest sensitivity and specificity

was determined with the Receiver operating characteristics (ROC) curve analysis.

Cord serum bilirubin and first day serum bilirubin concentration were used for

developing ‘prediction test’. The sensitivity and specificity were calculated for

predicting hyperbilirubinemia.

44 
Fig. 6 : Fully Automated Random Access Chemistry Analyser Olympus AU 400

45 
 RESULTS

The following results were made from the study. The study group consisted of

100 healthy term newborns that were followed up for first 5 postnatal days. The study

results were analyzed using appropriate statistical methods and compared with the

previous studies.

Table 1 : Showing sex wise distribution of cases

n=100

Sex Cases Percent (%)

Male 45 45
Female 55 55
Total 100 100

Graph 1 : Showing sex wise distribution of cases

In the present study, there is no significant difference in the number of male and

female babies.

This implies uniform distribution of cases in the study group.

46 
 Table 2 : Association between the serum bilirubin level and
the sex of the newborn
n=100
Neonatal
Hyperbilirubinemia
Sex (≥17mg/dl) Total
No Yes
Male 35 10 45
Female 50 05 55
Total 85 15 100

Group Statistics

Sex Mean Std. Deviation Std. Error Mean

Male 8.0316 5.62992 0.41963
Female 7.0216 4.89113 0.32976

Graph 2 : Association between the serum bilirubin level and

the sex of the newborn

In the present study, there is no significant difference (p value 0.67) in the

serum bilirubin level of both the sexes.

Hence the present study infers that the serum bilirubin level is independent of

the sex of the newborn.

47 
 Table 3 : Association between the mode of delivery and the neonatal
hyperbilirubinemia(≥17mg/dl)
n=100

Neonatal
Hyperbilirubinemia
Delivery (≥17mg/dl) Total

No Yes
Vaginal 33 7 40
Caesarean 52 8 60
Total 85 15 100

Graph 3 : Association between the mode of delivery and the neonatal

hyperbilirubinemia

In the present study there is no significant association (p 0.568) between the

neonatal hyperbilirubinemia (≥17mg/dl) and the mode of the delivery either the

vaginal delivery or the caesarean section.

This implies that neonatal hyperbilirubinemia is independent of the mode of

delivery.

48 
 Table 4 : Association between the neonatal hyperbilirubinemia(≥17mg/dl) and
the Oxytocin induction of labour
n=100

Neonatal
Hyperbilirubinemia
Medication (≥17mg/dl) Total

No Yes
With oxytocin 10 04 14
With out oxytocin 75 11 86
Total 85 15 100

Graph 4 : Association between the neonatal hyperbilirubinemia(≥17mg/dl) and

the Oxytocin induction of labour

In the present study, there is no significant correlation (>p 0.05) between the

babies given fluids and other medications (except Oxytocin) with the neonatal

hyperbilirubinemia (≥17mg/dl). But there is significant correlation (<0.05) between

the neonatal hyperbilirubinemia and the Oxytocin induction of labour.

49 
 Table 5 : Association between the time of initiation of breast feeding and
neonatal hyperbilirubinemia(≥17mg/dl)

n=100

Neonatal
Timing of Initiation of Hyperbilirubinemia
(≥17mg/dl) Total
breast feeding
No Yes
< 30 min 34 07 41
> 30 min 51 08 59
Total 85 15 100

Graph 5 : Association between the time of initiation of breast feeding and

neonatal hyperbilirubinemia(≥17mg/dl)

Time of intitation of breast feeding (min)

In the present study, the timing of initiation of breast feeding is not

significantly associated (p 0.628) with neonatal hyperbilirubinemia.

This infers that the neonatal hyperbilirubinemia is independent of timing of

initiation of breast feeding.

50 
 Table 6 : Association between the gestational hypertension and the neonatal
hyperbilirubinemia ( ≥17mg/dl)
n=100

Neonatal
Maternal Gestational Hyperbilirubinemia
(≥17mg/dl) Total
Hypertension
No Yes
Yes 11 02 13
No 74 13 87
Total 85 15 100

Graph 6 : Association between the gestational hypertension and the neonatal

hyperbilirubinemia ( ≥17mg/dl)

In the present study the maternal gestational hypertension has no significant

correlation (p 0.967) with the development of neonatal hyperbilirubinemia.

Hence the study infers that the neonatal hyperbilirubinemia is independent of

the maternal gestational hypertension.

51 
 Table 7 : Showing bilirubin profile in the first 5 postnatal days

n=100

Neonatal Std.
Std.
Hyperbilirubinemia N Mean Error
Deviation
(≥17mg/dL) Mean
Yes 15 2.5967 .72665 .18762
Cord bilirubin
No 85 1.9465 .79656 .08640
Yes 15 5.9933 1.23547 .31900
First Day bilirubin
No 85 4.3200 1.36798 .14838
Yes 15 15.7533 1.04872 .27078
Third Day bilirubin
No 85 9.5556 2.87562 .31190
Yes 15 20.3667 1.20099 .31009
Fifth Day bilirubin
No 85 11.4694 3.38980 .36768

Graph 7 : Showing bilirubin profile in the first 5 postnatal days

The present study infers that the cord serum bilirubin levels of the babies with

neonatal hyperbilirubinemia (≥17mg/dl) is significantly higher than the babies

without hyperbilirubinemia.

Bilirubin profile in the first 5 days of postnatal life infers that the babies with

neonatal hyperbilirubinemia has significantly higher bilirubin levels compared to

babies without hyperbilirubinemia.

52 
Table 8 : Association between the neonatal hyperbilirubinemia(≥17mg/dl) and
the critical cord bilirubin level (≥2.15mg/dl)
n=100

Neonatal Cord Blood

Hyperbilirubinemia Bilirubin(mg/dl) Total
(≥17mg/dl) ≥2.15 <2.15
Absent 31 54 85
Present 11 04 15
Total 42 58 100

Graph 8(a) : Receiver Operating Characteristics Curve Analysis

ROC Curve
1.00

.75

.50

.25
Sensitivity

0.00
0.00 .25 .50 .75 1.00

1 - Specificity
Diagonal segments are produced by ties.

53 
 Graph 8(b) : Association between the neonatal hyperbilirubinemia(≥17mg/dl)
and the critical cord bilirubin level (≥2.15mg/dl)

Cord bilirubin level of ≥2.15mg/dl cut off value is chosen based on the

Receiver operating characteristics (ROC) analysis.

In the present study cord serum bilirubin of ≥2.15mg/dl having the sensitivity

73%, specificity 74%, positive predictive value 26% and the negative predictive value

90% in prediction of neonatal hyperbilirubinemia. (P value is 0.008)

So the cord bilirubin level of ≥ 2.15mg/dl can be used as an early predictor of

neonatal hyperbilirubinemia.

54 
Table 9 : Association of the neonatal hyperbilirubinemia(≥17mg/dl) with the first
day(24hrs) bilirubin level(≥5mg/dl)

n=100

Neonatal First Day (24 hrs)

Hyperbilirubinemia Bilirubin (mg/dl) Total
(≥17mg/dl) ≥5 <5
Absent 24 61 85
Present 13 2 15
Total 37 63 100

Graph 9(a) : Receiver Operating Characteristics Curve Analysis

ROC Curve
1.00

.75

.50

.25
Sensitivity

0.00
0.00 .25 .50 .75 1.00

1 - Specificity
Diagonal segments are produced by ties.

55 
 Graph 9(b) : Association between the neonatal hyperbilirubinemia(≥17mg/dl)
and first day (24 hrs) bilirubin level (≥5 mg/dl)

 
≥5 
<5 
 

First day serum bilirubin level of ≥5mg/dl cut off value is chosen based on the

receiver operating characterstics (ROC) analysis. In the present study first day serum

bilirubin level of ≥5mg/dl has sensitivity 86%, specificity 71%, positive predictive

value of 35% and negative predictive value of 96%.

So the first day (24hours) serum bilirubin of ≥5mg/dl can also be used as an

early predictor of neonatal hyperbilirubinemia (≥17mg/dl).

56 
 Table 10 : Characteristics of cases who did and who did not develop significant
hyperbilirubinemia(≥17mg/dl) after 72 hrs of postnatal life
n=100

Variables <17mg/dl ≥17mg/dl P value

Males/Females 35/50 10/5 0.067
Vaginal 33 07
Delivery 0.568
Caesarean 52 08
<30min 34 07
Breast feeding 0.628
>30min 51 08
PIH in the mother 11 2 0.967
Oxytocin induction 10 4 0.004
Cord bilirubin level 1.9465 2.5967 0.004
1st day bilirubin level 4.3200 5.9933 0.000

Graph 10 : Characteristics of cases who did and who did not develop significant
hyperbilirubinemia(≥17mg/dL) after 72 hrs of postnatal life

Mode of Time of Gestational Oxytocin

delivery
    Induction
breast feeding hypertension

So, there is no significant association between the sex of the neonate, mode of

delivery either vaginal or caesarean delivery, timing of initiation of breast feeding,

and maternal gestational hypertension with neonatal hyperbilirubinemia.

There is a significant correlation between the Oxytocin induction of labour,

cord serum bilirubin levels, 1st day serum bilirubin levels with the neonatal

hyperbilirubinemia(≥17mg/dl).
57 
 DISCUSSION

There is a concern about increasing incidence of kernicterus in healthy term

neonates, and hyperbilirubinemia is one of the most common causes for readmission

of the newborns. The need for early detection of hyperbilirubinemia in the early

discharged newborns from the hospital is therefore important. Knowledge of the

infants at risk for developing jaundice allows simple bilirubin reducing methods to be

implemented before bilirubin reaches critical levels.

In this present study, we assessed the ability of cord bilirubin level to be a tool

for screening for the risk of subsequent neonatal jaundice.

1. Sex of the newborn

Studies Female Male p Value

Present 55 45 0.056
Amar Taksande et al5 (2005) 118 82 0.323
Rudy Satrya et al43 (2009) 39 50 0.040

In the present study, study group is uniformly distributed with 45 male and 55

female babies. There is no significant correlation (p 0.056) in the serum bilirubin

levels and the sex of the newborn. Hence the present study infers that the neonatal

hyperbilirubinemia (≥ 17mg/dl) is independent of the sex of the newborn.

Maisal et al31 1998, showed in a study consisting of 29934 infants, factors

associated with readmission for jaundice. Male sex in the study group is 74.8%

compared to control with 49.6%, with p value 0.007, showing that male sex has more

risk of readmission for neonatal hyperbilirubinemia.

58 
 Amar Taksande et al5 2005, in a study on 200 neonates with 82 males and 118

females, 8 males and 11 females have serum bilirubin level of (≥17mg/dl) with p

value of 0.323. So they found no correlation between the sex of the newborn and the

neonatal hyperbilirubinemia (≥17mg/dl).

Rudy Satrya et al43 2009, showed significant correlation between the sex of

the newborn and neonatal hyperbilirubinemia with p <0.05. Off 88 newborns 21

develop hyperbilirubinemia, 16 were males and 5 females.

Rostami et al41 in 2005, in Iran in a study showed that there is no correlation

between the neonatal hyperbilirubinemia and the sex of the newborn.

The present study is in correlation with the study done by Amar Taksande et

al5 (2005) and Rostami et al41 (2005).

2. Mode of delivery

Table 11 : Comparison Studies on the mode of delivery and neonatal

hyperbilirubinemia

Total Cut-off neonatal Vaginal Caesarean

Studies p Value
cases hyperbilirubinemia delivery section
Present 100 ≥17mg/dl 7/33 8/52 0.568
5
Amar taksande et al 200 ≥17mg/dl 11/103 8/58 0.527
(2005)
Rudy Satrya et al43 88 ≥12.9mg/dl 16/50 5/17 0.885
(2009)
Knudsen35 (1989) 291 >15mg/dl NS

In the present study association between the neonatal hyperbilirubinemia and

the mode of delivery was studied. 40 cases with vaginal delivery 7 developed serum

bilirubin ≥17mg/dl and off 60 cases with caesarean section 8 developed significant
59 
jaundice (≥17mg/dl). With p value of 0.568, there is no significant association

between the neonatal hyperbilirubinemia (≥17mg/dl) and the mode of the delivery.

Knudsen35 (1989) showed in his study on 291 cases, with cut off neonatal

hyperbilirubinemia of 15mg/dl, no significant association between the mode of

delivery and neonatal hyperbilirubinemia.

Amar Taksande et al5 (2005), in their study on 200 newborns,11 cases of 114

vaginal delivery and 8 cases of 66 caesarean section developed significant

hyperbilirubinemia.With p value of 0.527, showed no correlation between the mode

of delivery and neonatal hyperbilirubinemia.

Rostami et al41 2005, in their study found that there is no significant

association between neonatal hyperbilirubinemia and the mode of delivery.

Awasthi et al37 1998, peak serum bilirubin level >15mg/dl was found in 35 of

274 cases (12.8%;95% C. I. :9.2-17.1). hyperbilirubinemia was seen in 12.3%

preterms (95% C.I. 6.9-22.2) and 12.6% terms (95% C.I. :8.5-17.8). Peak serum

bilirubin was compared between the neonates with presence or absence of certain

maternal, natal and neonatal variables. Peak serum bilirubin was higher in neonates

born by vaginal route.

Rudy Satrya et al43 2009, in a study on 88 newborns, with cut off neonatal

hyperbilirubinemia of ≥14.9mg/dl, showed that there is no association (p 0.885)

between the mode of delivery and neonatal hyperbilirubinemia.

The present study is in correlation with the other studies.

60 
3. Association between the time of initiation of breast feeding and neonatal

hyperbilirubinemia (≥17mg/dl)

Table 12 : Comparison Studies on the initiation of breast feeding and neonatal

hyperbilirubinemia

< 30 minutes >30 minutes

Studies P value Inference
Mean SD Mean SD

Present 12.07 4.77 13.30 4.24 0.179 NS

Awasthi et al37 11.52 2.89 11.5 3.69 0.9 NS

(1998)

In the present study, the timing of initiation of breast feeding is not

significantly associated with neonatal hyperbilirubinemia with p value 0.628.

Awasthi et al37 1998, showed there is no significant correlation between the

timing of initiation of breast feeding and neonatal hyperbilirubinemia.

4. Association between the Gestational hypertension and neonatal

hyperbilirubinemia (≥17mg/dl)

Table 13 : Comparison Studies on the Maternal gestational hypertension and

neonatal hyperbilirubinemia

Maternal No Maternal
gestational gestational
Studies hypertension hypertension P value Inference

Mean SD Mean SD
Present 13.1769 4.89 12.7483 4.45 0.750 NS
Awasthi et al37(1998) 12.1 3.3 11.9 3.4 0.5 NS
Amar Taskasande et - - - - 0.06 NS
al5(2005)

61 
 In the present study there is significant association between the neonatal

hyperbilirubinemia and maternal gestational hypertension with p value 0.750.

Other studies are, Awasthi et al37 1998, with p value of 0.5 showed no

association between the neonatal hyperbilirubinemia and maternal gestational

hypertension.

Amar Taksande et al5 2005, with p value p 0.06 showed no correlation

between the neonatal hyperbilirubinemia and maternal gestational hypertension.

So, the present study is in correlation with the other studies.

5. Association between the neonatal hyperbilirubinemia (≥17mg/dl) and the

Oxytocin induction of labour
In the present study, there is no significant association (p >0.05) between the

babies given fluids and other medications with the development of neonatal

hyperbilirubinemia. But there is a significant association between the induction of

labour with Oxytocin and the neonatal hyperbilirubinemia (p <0.05) .The present

study is in correlation with the other studies.

Rostami et al41 2005, in his study on 643 full term infants, bilirubin level

>14mg/dl were observed in 16.9% of infants whose mother had received Oxytocin

during delivery and in 10.6% of infants whose mother had not received it.

Oral E et al53 2003, in their study, a total of 80 patients managed with oxytocin

during labour, patients randomly divided into isotonic 0.9% saline (Group 1) and 5%

glucose solutions (Group 2) by a consecutive order using a balanced block

62 
randomization scheme. Forty multiparous patients delivering without oxytocin

infusion formed the control group (Group 3). Sodium and initial bilirubin levels were

measured in the cord blood. Later on, capillary blood bilirubin and hematocrit

concentrations were measured on day 1 and 2 in the newborn nursery. The results

showed the cord plasma bilirubin levels and day 2 plasma bilirubin levels were

significantly higher in the accelerated group. So they concluded that there is no

significant effect of Oxytocin infusion on neonatal hyperbilirubinemia unless it was

for the augmentation of labour.

Awasthi et al37 1998 showed significant correlation between the neonatal

hyperbilirubinemia with the Oxytocin induction of labour (p 0.004).

Amar Taksande et al5 (2005) in his study showed no significant association

(p 0.245) between the Oxytocin induction of labour and neonatal hyperbilirubinemia.

Knudsen35 (1989) found no correlation among the jaundiced and non

jaundiced infants with Oxytocin induction of labour.

Mechanism of hyperbilirubinemia with Oxytocin induction of labour-

Oxytocin induces hyponatremia and hypo-osmolality in the mother by virtue of its

anti-diuretic and saluretic effects. These biochemical changes are aggravated by the

infusion of electrolyte-free dextrose solution used as a vehicle for administration of

oxytocin. Transplacentally transmitted hypo-osmlality in the fetal blood, leads to

enhanced osmotic fragility of the red blood cells. The swollen and hyper fragile

63 
erythrocytes are easily trapped by the spleen resulting in net higher bilirubin

production.

The present study is correlation with the studies of Oral E et al53 (2003) and

Rostami et al41 (2005).

6. Association between the cord blood bilirubin level of ≥2.15mg/dl with

neonatal hyperbilirubinemia(≥17mg/dl)

Table 14 : Comparison Studies on the predictive ability of cord blood bilirubin

level and the neonatal hyperbilirubinemia
Cut off Neonatal

Predictive Value
Predictive Value
inemia (mg/dL)
Hyperbilirib-
Cut off Cord

Specificity
Sensitivity

Negative
(mg/dL)

Positive

p value
STB

Studies

Present ≥2.15 ≥17 73% 74% 26% 90% 0.008

Amar Taksande et5 >2 ≥17 89.5% 85% 38.8% 98.7% 0.000
al (2005)
Knudsen35 (1989) >2.35 >15 13% 99% 85% 72% <0.001
Zakia Nahar et al44 ≥2.5 ≥17 77% 98.6% 96% <0.05
(2009)
Sun et al42 (2007) >2 ≥17 68% 45.08% <0.001
Rudy Satrya et al43 ≥2.54 ≥12.9 90.5% 85% 0.001
(2009)

In the present study, on ROC curve analysis critical cord bilirubin level

(≥2.15mg/dl) with high sensitivity and high specificity is selected. The probability

that a neonate with cord bilirubin ≥2.15mg/dl would later become hyperbilirubinemia

(positive predictive value) was 26%. The negative predictive value,the probability of

64 
nonhyperbilirubinemia given a cord bilirubin lower than 2.15mg/dl was 90%. If a

child become hyperbilirubinemic, the probability that the cord bilirubin was

≥2.15mg/dl was 73% (sensitivity). Given a non-hyperbilirubinemic child, the

probability that the cord bilirubin was <2.15mg/dl was 90% (specificity).

Several studies are published on the usefulness of cord bilirubin concentration

in prediction of hyperbilirubinemia.

Knudsen35 1989, established that if the cord bilirubin was below 20 µmol/l,

2.9% became jaundiced, as opposed to 85% if the cord bilirubin was above 40 µmol/l.

Furthermore, 57% of jaundiced infants with cord bilirubin above 40 µmol/l required

phototherapy, but only 9% if the cord bilirubin was 40 µmol/l or lower (0.008) in

correlation with the present study.

Amar Taksande et al5 2005, showed that the cord bilirubin level >2mg/dl has

a sensitivity 89.5%, specificity 85%, negative predictive value of 98.7% and positive

predictive value of 38.8% in correlation with the present study.

Zakia Nahar et al44 2009, showed that the cord bilirubin level ≥2.5mg/dl has a

sensitivity 77%, specificity 98.6%, with negative predictive value of 96% in

correlation with the present study.

Bernaldo and Segre40 in 2005 showed that the cut off point for unconjugated

bilirubin in cord blood was ≥2.0mg/dl the probability that the newborn would need

phototherapy was 53%. When cord blood bilirubin was 2.5mg/dl the probability

needing phototherapy was 72%, when the level was 3.0mg/dl, the probability of

needing treatment was 86%, and if it was 3.5mg/dl, the probability went up to 93%.
65 
 Sun et al42 (2007), Rudy Satrya et al43 (2009) studies are in correlation with

the present study.

Rostami et al41 2005, on their study to identify healthy newborns at risk for

developing significant hyperbilirubinemia by measuring bilirubin level in cord blood

in 643 full term infants. Serum bilirubin level was obtained on umbilical cord serum

and on day three of age. The total bilirubin ≥ 239µmo1/1 (14 mg/dl) was defined as

significant hyperbilirubinemia. They concluded that cord serum bilirubin level cannot

identify newborns with subsequent significant hyperbilirubinemia.

7. Association between the 1st day bilirubin (24hrs) and the neonatal
hyperbilirubinemia(≥17mg/dl)

Table 15 : Comparison Studies on the 1st day bilirubin level and the neonatal
hyperbilirubinemia
Cut off Neonatal

Predictive Value

Predictive Value
Cut of First Day
inemia (mg/dL)
Hyperbilirib-

(24 hrs) STB

Sensitivity

Specificity

Negative
(mg/dL)

Positive

p value
Studies

Present ≥17 ≥5 86% 71% 35% 96% 0.000

37
Awasthi et al >15 ≥3.99 68.6 65 22.6 93.45 <0.05
(1998)
Alpay et al39 ≥17 ≥6 90 65.3 26.3 97.9 <0.05
(2000)
Shivani Randev ≥17 >6.4 87 80.11 37.5 97.92 0.000
et al58 (2010)
Rina Triasih et ≥12.9 >4.5 90 71.9 50 96.8 <0.05
al57 (2003)

In the present study, on ROC curve analysis critical 1st day bilirubin level

with high sensitivity and high specificity ≥5mg/dl is selected. The probability that a

66 
neonate with 1st day bilirubin higher than ≥5mg/dl would later become

hyperbilirubinemia (positive predictive value) was 35%. The negative predictive

value,the probability of nonhyperbilirubinemia given a 1st day bilirubin lower than

5mg/dl was 96%. If a child become hyperbilirubinemic, the probability that the 1st

day bilirubin was ≥5mg/dl was 86% (sensitivity). Given a non-hyperbilirubinemic

child, the probability that the 1st day bilirubin was <5mg/dl was 71% (specificity).

Shivani Randev et al58 2010, in a study, a total of 200 neonates were enrolled,

24 neonates (i.e., 12%) developed hyperbilirubinemia. The mean first day TSB value

in the neonates who subsequently developed hyperbilirubinemia was 7.716 mg/dl as

compared to a value of 5.154 mg/dl in those who did not. The difference was

significant (p=0.000). Using Receiver operating characteristic (ROC) curve analysis, a

value of 6.4 mg/dl (first day TSB) was determined to have the best predictive ability

for subsequent hyperbilirubinemia with a sensitivity of 87.5%, specificity of 80.11%,

positive predictive value of 37.5% and a negative predictive value of 97.92%.

Awasthi et al37 1998, with the 1st day bilirubin level of ≥3.99mg/dl showed

that it has a sensitivity 68.6%, specificity 71%, positive predictive value 35% and

negative predictive value of 96% in predicting neonatal hyperbilirubinemia.

Alpay et al39 2000, with the 1st day bilirubin level of ≥6mg/dl showed that it

has a sensitivity 90%, specificity 65.3%, positive predictive value 26.3% and negative

predictive value of 97.9% in predicting neonatal hyperbilirubinemia.

67 
 Rina Trisiah et al57 2003, with the 1st day bilirubin level of >4.5mg/dl showed

that it has a sensitivity 90%, specificity 71.9%, positive predictive value 50% and

negative predictive value of 96.8% in predicting neonatal hyperbilirubinemia.

The present study infers that 1st day (24hrs) bilirubin ≥5mg/dl can also be used

as an early predictor of neonatal hyperbilirubinemia.

68 
 CONCLUSION

Hyperbilirubinemia is one of the common problems encountered in neonatal

wards.

Babies delivered by Vaginal/Caesarean section, Oxytocin is used with caution

in view of its ability to develop neonatal hyperbilirubinemia by inducing hemolysis.

Sex, mode of delivery, time of initiation of breast feeding is not associated

with neonatal hyperbilirubinemia.

In the present study infants with neonatal hyperbilirubinemia (≥17mg/dl) had

significantly higher levels of cord bilirubin than neonates with serum bilirubin of

<17mg/dl. So it is possible to define a group of neonates at risk of developing

jaundice needing phototherapy already at birth. Simple knowledge of a increased risk

of neonatal hyperbilirubinemia in a child could influence a decision of early discharge

vs. prolonged observation.

From the present study, cord bilirubin level of ≥2.15mg/dl has a correlation

with incidence of significant hyperbilirubinemia in term newborns. So this

≥2.15mg/dl of cord bilirubin level could predict the development of significant

hyperbilirubinemia. 1st post natal day (24 hrs) bilirubin estimation with bilirubin level

of ≥5mg/dl can also be used as an early predictor of neonatal hyperbilirubinemia.

69 
 LIMITATIONS OF THE PRESENT STUDY

Present study was conducted to assess the usefulness of cord blood bilirubin in

predicting neonatal hyperbilirubinemia requiring phototherapy.

Limitations of the study

ƒ In the present study only full term healthy neonates were taken for the study.

ƒ Since the peak bilirubin level reaches on 3rd and 5th postnatal days, babies are

followed till 5 days of delivery.

ƒ In view of early discharge of the babies delivered vaginally, increased

representation of babies extracted by caesarean section are taken.

70 
 RECOMMENDATIONS

The present study was done to assess the usefulness of the cord blood bilirubin

estimation as a predictor of subsequent neonatal hyperbilirubinemia in a healthy term

infants who require phototherapy.

Since the cord blood bilirubin level of more than ≥2.15mg/dl has a sensitivity

of 73% and specificity of 74%, babies having serum cord bilirubin level of

≥2.15mg/dl can be followed up in the hospital for 5 days, the time of peak neonatal

hyperbilirubinemia to prevent the babies discharged early and later readmission for

neonatal hyperbilirubinemia.

Since the 1st day (24 hrs) bilirubin level of ≥5mg/dl has a sensitivity of 86%

and specificity of 71%, 1st day (24 hrs) bilirubin estimation with serum bilirubin level

of ≥5mg/dl can also be used as an early predictor of neonatal hyperbilirubinemia.

It is recommended to have cord blood bilirubin estimation of all healthy term

babies delivered in an institution to prevent the dangerous consequences of neonatal

hyperbilirubinemia like Kernicterus. This can reduce the morbidity and mortality due

to hyperbilirubinemia.

71 
 SUMMARY

The study group consisted of 100 full term neonates delivered in the

Cheluvamba hospital attached to Mysore Medical College and Research Institute,

from December 1st 2008 to May 31st 2010.

• Neonates were followed from birth to 5th postnatal day.

• Healthy term neonates with hospital stay of upto 5 days were selected for the

study.

• Informed written consent was taken from the parents.

• All the babies were followed up daily for the development of jaundice during

postnatal visits.

• Cord blood was collected at birth and bilirubin estimation was done within 12

hours of collection of the blood.

• 1st day, 3rd day and 5th day bilirubin estimation was done. Peripheral venous

blood was collected for estimation of bilirubin.

• Main outcome of the study was inferred in terms of neonatal

hyperbilirubinemia of ≥17mg/dl as per the American academy of paediatrics

practice guidelines 2004 and IAP-NNF recommendations.

• Maternal, neonatal and natal variables were compared between neonates with

5 days of follow-up using appropriate statistical methods.

• There is no association between the development of neonatal

hyperbilirubinemia and the sex of the newborn.

• There is no association between the development of neonatal

hyperbilirubinemia and the mode of delivery either the normal vaginal

delivery or the caesarean section.

72 
• There is no association between the development of neonatal

hyperbilirubinemia and the timing of initiation of breast feeding in the

newborn.

• There is significant association between the neonatal hyperbilirubinemia and

the medications used. Oxytocin induction of labour has significant correlation

with the later development of hyperbilirubinemia in the newborn due to

hemolysis.

• Cord blood bilirubin level of ≥2.15mg/dl has a sensitivity of 73% and

specificity of 74%, positive predictive value 26% and negative predictive

value of 90% in predicting the risk of neonatal hyperbilirubinemia.

• 1st day bilirubin level of ≥5mg/dl has a sensitivity of 86% and specificity of

71% and positive predictive value of 35% and negative predictive value of

96% in predicting the risk of neonatal hyperbilirubinemia.

73 
 BIBLIOGRAPHY

1. Concept of Health and Disease. K. Park. Parks Text Book of Preventive and

Social Medicine edn. 20th. M/s Banarsidas Bhonat publishers 2003, 12-16.

2. Preventive Medicine in Obstetrics, Paediatrics and Geriatrics. K. Park. Parks

Text Book of Preventive and Social Medicine edn. 20th. M/s Banarsidas Bhonat

publishers 2003, 12-16.

3. Anthony J Piazza and Barbara J Stoll. Jaundice and Hyperbilirubinemia in the

Newborn. In: Behrman,Kliegman,Jenson,Stanton ed. Nelson Text Book of

Pediatrics 18th edn,WB Saunders Company,2008:756-765

4. Hinkes MT, Cloharty JP. Neonatal hyperbilirubinemia. In : Cloharty JP, Stork

AR ed. Manual of neonatal care 5th edn, Lippincott Willams and Wilkins,

Philadelphia 1998 ; 175 – 211.

5. Amar Taksande, Krishna Vilhekar, Manish Jain, Preeti Zade, Suchita Atkari,

Sherin Verkey. Prediction of the development of neonatal hyperbilirubinemia by

increased umbilical cord blood bilirubin. Ind Medica 2005 ; 9(1) : 5-9.

6. Niki Papavramidou, Elizabeth Fee and Helen Christopoulou-Aletra. Jaundice in

the Hippocratic Corpus. Springer New York, Journal of Gastrointestinal Surgery

2007; 11(12) : 1728-1731.

7. Ashima Madan,James R.Macmohan, and David K. Stevenson.Neonatal

Hyperbilirubinemia in the Newborn. In : Taeusch,Ballard,Gleason. Avery’s

Diseases of the Newborn 8th edn,1226-1257.

8. Panaroli D. Iatrologismorum sive observationum medicinalium. Pentacostae

quarta. Obs 1654; 44 : 137.

9. Bourgeois L. Observations Diverse sur la Sterilite Perte de Fruiot, Foecondite,

Accouchments, et Maladies de Femmes, et Enfants Nouveaux-naiz, Paris 1609.

74 
10. Juncker DL. Conspectus Medicinae Theoreticopracticae. Halae Magdeburgeicae

1724; 717.

11. Bracken H. The Midwives Companion. Book 3, London 1737.

12. Dewees WP. Treatise on the Physical and Medical Treatment of Children. First

Edition. Philadelphia. Carey and Lea 1825.

13. Virchow R. Die Pathologischen pigmente. Arch Pathol Anat 1847; 1:379.

14. Orth J. Uber das vorkommen von bilirubinkrystallen bei neugebornen kinder.

Arch Path Anat Phys u f Klin Med (virchows Arch) 1875; 63 : 477.

15. Schmorl CG. Zur kenntnis des ikterus neonatorum, insbesondere der dabei

auftretenden gehirnveranderungen. Vehandl d Dent Path Gesell 1904; 6 : 109.

16. Murchison C. Clinical Lectures on Diseases of the Liver, Jaundice and

Abdominal Dropsy. Third Edition. William Wood and Co. New York 1885.

17. Holt LE. Diseases of Infancy and Childhood. First Edition, D Appleton Co. New

York 1897.

18. Rautmann H. Ueber blutbildung bei fotaler allgemeiner wassersuch. Beit Z Path

Anat u z alleg Path 1912; 54 : 332.

19. Halban J. Agglutinationsversuche mit muuterlichen and kinderlichen blute.

Wien Klin Woch 1900; 13 : 545.

20. Ottenberg R. The etiology of eclampsia : historical and critical notes. J Amer

Med Ass 1923 ; 81 : 295.

21. Levine P, Burnham L, Katzin EM et al. The role of isoimmunisation in the

pathogenesis of erythroblastosis fetalis. Amer J Obstet and Gynec 1942; 42 :

925.

22. Ylppo A. Icterus neonatorum and Gallenfarbstoffsekretion beim foetus and

neugenborenen. Z f Kinderh 1913; 9 : 208.

75 
23. Van den Bergh AAH, Muller P. Uber eine direkte and eine indirekte

diazoreaktionen auf bilirubin. Biochem Z 1916; 77 : 90.

24. Diamond LK, Blackfan KD, Baty JM. Erythrobalstosis fetalis and its association

with universal edema of fetus, icterus gravis neonatorum andanemia of the

newborn. J Pediatr 1932; 1 : 269.

25. Landsteiner K. Wiener AJ. An agglutinable factor in human blood recognized

by immune sera for rhesus blood. Proc Soc Exp Biol and Med 1940 ; 74 : 309.

26. Crigler JF, Najjar VA. Congenital familial nonhemolytic jaundice with

kernicterus. Pediatrics 1952 ; 10 : 169.

27. Halbrecht L. Role of hemagglutinins anti-A and anti-B in pathogenesis of

jaundice of newborn (icterus neonatorum precox). Amer J Dis Child 1944 ; 68 :

248.

28. Hart AP. Familial icterus gravis of the newborn and its treatment. Canad Med

Assn J 1925 ; 15 : 1008.

29. Wallerstein H. Treatment of severe erythroblastosis fetalis by simultaneous

removal and replacement of the blood of the newborn infant. Science 1946 ; 103

: 583.

30. Cremer RJ, Perryman PW, Richards DH. Influence of light on the

hyperbilirubinemia of infants. Lancet 1958 ; 1 : 1094.

31. Maisels MJ, Kring E Length of stay, Jaundice and hospital readmission.

Pediatrics 1998; 101 : 995-998.

32. Eidelmen AL, Hoffman NW, Kaitz M. Cognitive deficits in women after

childbirth. Obstet Gynecol 1993; 81 : 764-767.

76 
33. Risemberg HM, Mazzi E, Macdonald MG, Peralta M, Heldrich F. Correlation

cord bilirubin levels with hyperbilirubinemia in ABO incompatibility. Arch Dis

Child 1977; 57 : 219-222.

34. Rosenfeld J. Umbilical cord bilirubin levels as predict-or of subsequent

hyperbilirubinemia. J Fam Pract 1986 ; 23 : 556-58.

35. Knudsen A. Prediction of the development of neonatal jaundice by increased

umbilical cord blood bilirubin. Acta Paediatr Scand 1989 ; 78 : 217-221.

36. Rataj J. Kornacka M, Korman E. Usefulness of measuring bilirubin levels in

cord blood for predicting hyperbilirubinemia in newborns Ginekol Pol 1994 ; 65

: 276-280.

37. Shally Awasthi and Hasibur Rehman. Early Prediction of Neonatal

Hyperbilirubinemia. Indian J Pediatr 1998 ; 65 : 131-139.

38. Johnson LH, Brown AK. A pilot registry for acute and chronic kernicterus in

term and near-term infants. Pediatrics 1999 ; 104 : 736.

39. Alpay F, Sarici SU, Tosuncuk HD, Serdar MA, Inanc N, Gokcay E. The value

of First Day Bilirubin Measurement in Predicting the Development of

Significant Hyperbilirubinemia in Healthy Term New borns. Pediatrics 2000 ;

106 (2) : 16.

40. Bernaldo AJN, Segre CAM. Bilirubin dosage in cord blood : could it predict

neonatal hyperbilirubinemia? Sao Paulo Med J 2004 ; 122 : 99-103.

41. Rostami N, Mehrabi Y. Identifying the newborns at risk for developing

significant hyperbilirubinemia by measuring cord bilirubin levels. J Arab

Neonatal Forum 2005 ; 2 : 81-5.

77 
42. Sun G, Wang YL, Liang JF, Du LZ. Predictive value of umbilical cord blood

bilirubin level for subsequent neonatal jaundice. Zhonghua Er Ke Za Zhi 2007;

45 : 848-52.

43. Rudy Satrya, Sjarif Hidayat Effendi, Dida Akhmad Gurnida. Correlation

between cord blood bilirubin level and incidence of hyperbilirubinemia in term

newborns. Paediatrica Indonesiana 2009 ; 49(6) : 349-354.

44. Zakia Nahar MD. Shahidukkah,Abdul Mannan, Sanjoy Kumar Dey,Ujjal

Mitra,SM Selimuzzaman: The value of umbilical cord blood bilirubin

measurement in predicting the development of significant hyperbilirubinemia in

healthy Newborn.Bangladesh J Child Health 2009: Vol 33(2):50-54

45. James M.Crawford. Liver and biliary tract. In: Kumar,Abbas,Fausto ed. Robbins

and Cotran Pathologic basis of disease 7th edn, Saunders Company 2004:877-

954

46. Peter F.Whitington, Estella M.Alonso. Disorder of Bilirubin Metabolism. In

David G.Nathan, Staurt H.Orkin,David Ginsberg,A.Thomas Look .Hematology

of Infancy and Childhood 6th edn, Saunders Company,2003:86-120.

47. Jaundice. Meharban Singh. Care of the New Born edn 6th. Sagar Publications

2004,239-255.

48. Shapiro Sm, Nakamura H. Bilirubin and the auditory system. J Perinatol

21:S52-S55,2001

49. Nwaesei CG, Van Aerde J, Boyden M et al. Changes in auditory brainstem

responses in hyperbilirubinemic infants before and after exchange transfusion.

Pediatrics 1984 ; 74 : 800-803.

78 
50. Wennberg RP, Ahlfors CE, Bickers R et al. Abnormal auditory brainstem

response in a newborn infant with hyperbilirubinemia : improvement with

exchange transfusion. J Pediatr 1982 ; 100 : 624-626.

51. Palmer C, Smith MB. Assessing the risk of kernicterus using nuclear magnetic

resonance. Clin Perinatol 1990 ; 17 : 307-329.

52. Kramer LI. Advancement of dermal icterus in the jaundiced newborn. Am J Dis

Child 1969 ; 118 : 454-458.

53. Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour

specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy

term and near-term newborns. Pediatrics 1999; 103 : 6-14.

54. IAP-NNF Guidelines 2006 on Jaundice in Newborn. 188-209.

55. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia :

Management of hyperbilirubinemia in the newborn infant 35 or more weeks of

gestation. Pediatrics. 2004 ; 114 : 297-316.

56. Oral E, Gezer A, Cagdas A, Pakkal N. Oxytocin infusion in labor: the effect

different indications and the use of different diluents on neonatal bilirubin

levels. Archgynecol Obstet 2003 Jan:267(3):117-20.

57. Rina Triasih, MD; Ekawaty L Haksari, MD; Achmad Surjono, MD. The first

24-hour bilirubin level as a predictor of hyperbilirubinemia in healthy term

newborns.Pediatrica Indonesaina, May-June 2003,Vol 43. No 5-6.

58. Shivani Randev nad Neelam Grover: predicting Neonatal Hyperbilirubinemia

Using First Day Serum Bilirubin Levels. Indian J Pediatr 2010; 77(2): 147-150.

79 
 PROFORMA

Case no : Guide :

Name : DOA :

Age : Date & Time of Delivery :

Sex : IP No :

Address :

History

1. Mother s age: Gravida: Para:

2. Jaundice in the mother/other siblings: Y/N

3. Toxemia of Pregnancy/Eclampsia: Y/N

4. Medications during pregnancy:

5. Premature rupture of membranes: Y/N Duration:

6. Mode of Delivery:

7. If Vaginal: Spontaneous/Instrumental/Induced

8. Medications during pregnancy: IV fluids/Oxytocin/PG/Others

9. Any other significant maternal history:

10. Resuscitation: Done/Not done

11. APGAR score 1st min: 5th min:

12. Medications given to the baby: Y/N

13. Feeding history: A. Breast feeding : Exclusive/ or not

B .Timing of initiation:

C. Prelacteal feeds : Top feeds/Sugar water/castor oil/honey

14. Colour of the Urine :

Colour of the Stools:

Duration after delivery when meconium was first passed :

15. Any other significant history :

80 
Examination: Weight: Length: Gestational age:

Heart rate: Respiratory rate: Activity:

Evidence of birth trauma:

2nd day 3nd day 4th day 5th day

Face
Trunk
Extremities
Palms& soles

Systemic Examination:

Investigations

1. Blood group and Rh typing: Mother: Baby:

2. Serum Bilirubin

Cord 1st day 3rd day 5th day

Total
Date

3. Any other investigations:

• Final diagnosis :

• Treatment : Phototherapy/Exchange transfusion/Drugs/Others

• Follow up :

• Sign of the PG :

• Informed written consent :

• Sign of the Guide :

81 
 STATISTICAL METHODS APPLIED

Descriptive statistics

The Descriptives procedure displays univariate summary statistics for several

variables in a single table and calculates standardized values (z scores). Variables can

be ordered by the size of their means (in ascending or descending order),

alphabetically, or by the order in which you select the variables (the default).

Frequencies

The Frequencies procedure provides statistics and graphical displays that are

useful for describing many types of variables. For a first look at your data, the

Frequencies procedure is a good place to start.

Independent-Samples T Test

The Independent-Samples T Test procedure compares means for two groups

of cases. Ideally, for this test, the subjects should be randomly assigned to two groups,

so that any difference in response is due to the treatment (or lack of treatment) and not

to other factors. This is not the case if you compare average income for males and

females.

Crosstabs

The Crosstabs procedure forms two-way and multi-way tables and provides a

variety of tests and measures of association for two-way tables. The structure of the

table and whether categories are ordered determine what test or measure to use.

82 
Chi-Square Test

The Chi-Square Test procedure tabulates a variable into categories and

computes a chi-square statistic. This goodness-of-fit test compares the observed and

expected frequencies in each category to test either that all categories contain the

same proportion of values or that each category contains a user-specified proportion

of values.

ROC curve

This procedure is a useful way to evaluate the performance of classification

schemes in which there is one variable with two categories by which subjects are

classified.

p value calculated by appropriate statistical analysis with ≥ 0.05 indicates no

significant correlation in a study and p value with <0.05 indicates significant

correlation in a study.

All the statistical methods were carried out through the SPSS for Windows

(version 16.0)

83 
 MASTER CHART

Time of
Medication Serum 1st 3rd 5th
Sl. Gestational Nature of the initiation of
Name of the Baby IP No Sex during bilirubin
No Hypertension delivery breast day day day
delivery cord
feeding
1 B/0 Savithamma 13004 M 1 3 6,7 8 2 4.4 10.8 13.5
2 B/o Mangala 12976 F 1 3 6 8 1.3 2.1 4.5 8.2
3 B/oLakshmi 12866 F 1 3 6 8 2.65 6.6 13 10
4 B/o Soumya 11404 M 1 3 6,7 8 1.9 5.2 10.1 12
5 B/oSangeetha 11460 F 1 3 5,6 8 2.3 5.8 15 19.5
6 B/o Lakshmi 11587 M 1 3 6 8 1.4 3.5 5.1 8
7 B/o Geetha 11523 M 1 3 6,7 8 3.65 7 17 21.2
8 B/o Saraswathi 11321 M 1 4 5,6 9 1 4.5 10.2 12.6
9 B/o Jyothi 11276 F 1 3 6,7 8 2.2 5.1 9 12
10 B/o Meenakshi 11430 F 1 3 6,7 8 1.9 4.3 8.5 11.8
11 B/o Divya 10003 M 1 4 6 9 2.4 4.9 7.7 10.2
12 B/o Soumya 10125 F 1 3 6,7 8 1.7 5 7.5 7.1
13 B/oMangala 10435 M 1 3 5,6 8 3.9 7.5 16 19.8
14 B/o Manjula 10753 F 1 4 6 9 0.6 2.8 7 6.1
15 B/o Savitha 11674 M 1 4 6,7 9 2 4.9 11 13.2
16 B/o Jamuna 12643 M 2 3 6,7 8 2.5 6.2 14.6 20
17 B/o Gayana 12098 F 1 3 5,6 8 2.2 5.7 12 16.6

84 
18 B/o Mangalamma 13867 F 1 4 6 9 1.2 4.1 6.6 9
19 B/o Devi 13324 F 1 3 6 8 0.3 3.5 6 6.5
20 B/o Rathanamma 11675 M 1 4 6,7 9 2.3 5 9.1 13.5
21 B/o Kamakshi 12597 M 2 3 6 8 2.7 5.6 15 18.8
22 B/o Aisha 13376 F 1 3 5,6 8 3.4 5.8 11.6 10.2
23 B/o Krithika 13890 M 1 3 6,7 8 1.1 3.7 8.2 7
24 B/o Swathi 13645 F 1 3 6,7 8 0.3 4.1 7.5 8
25 B/o Pankaja 13086 M 1 3 6,7 8 1.9 6.2 10.1 13.5
26 B/o Nagu 13775 F 2 3 6 8 2 4.5 8.2 11
27 B/o Satyavathi 14678 F 1 3 6 8 1.9 3.1 5 8.4
28 B/o Jayamma 13676 M 1 4 6 9 3 6.1 11.5 13.2
29 B/o Padma 13974 F 1 3 6 8 0.7 4.2 9.1 10
30 B/o Noor Fathima 14007 F 1 4 5,6 9 2.2 5 8.9 12
31 B/o Shalini 14554 M 1 3 6 8 1.7 5 14.5 19.1
32 B/o Sameena 14352 M 1 4 5,6 9 2.4 6.1 15.3 17.3
33 B/o Mala 14898 F 1 4 6 9 2.9 6.5 9 11.7
34 B/o Gagana 14212 F 1 4 6,7 9 2 5.1 9.2 11.9
35 B/o Ambika 12356 M 1 3 6,7 8 3.5 4.4 9.8 8.1
36 B/o Jaya 12975 M 2 3 6 8 1.7 2.2 5.3 10.5
37 B/o Gowri 12753 F 1 4 6 9 2.9 3.2 11.3 7.1
38 B/o Lakshamamma 13589 M 1 3 6,7 8 2.7 3.8 8.8 9.1
39 B/o Savitha 13451 M 1 3 6,7 8 2 3.8 8.9 13.3

85 
40 B/o Lakshmi 13678 M 2 4 6 9 1.1 4.4 7 8.7
41 B/o Saraswathi 13943 F 1 4 6 9 2.8 4.4 8 8.6
42 B/o Pooja 12546 M 1 4 6 9 3.4 4.5 6.5 5.5
43 B/o Sharada 15979 F 1 4 6,7 9 1.7 2.3 6.6 12.7
44 B/o Varsha 15368 F 1 3 6 8 3.5 3.8 9.1 12.2
45 B/o Megha 15957 M 1 3 6 8 1.1 3.4 8.3 7.6
46 B/o Malini 15765 F 1 4 9 0.2 1.1 6.5 9.8
47 B/o Sulthana 15387 F 1 3 6,7 8 3.2 6.6 16.5 19
48 B/o Sangeetha 15080 M 1 3 6,7 8 1.4 2.8 5.6 8.9
49 B/o Janaki 12568 M 1 3 6 8 2.6 4.5 7.5 9
50 B/o Ashwini 14098 F 2 3 6 8 0.9 2.1 7.4 8.2
51 B/o Bhagya 15889 F 2 4 6,7 9 1.4 3.8 8.7 7.5
52 B/o Akshatha 16987 M 1 4 5,6 9 3.2 6 15.7 21
53 B/o Manasa 16000 F 1 4 6 9 2.1 2.4 12 11.5
54 B/o Mariya 16979 F 1 4 6 9 1.3 4 6.5 10.2
55 B/o Uma 16687 F 1 4 6 9 1.9 2.8 8.4 6
56 B/o Rashmi 16395 M 1 3 6,7 8 2 3.7 10.3 12
57 B/o Shruthi 16673 F 1 3 6,7 8 2.2 6.4 17 22.6
58 B/o Soumya 16892 M 1 3 6 8 1.7 1.9 7.05 7.7
59 B/o Lalitha 16343 M 1 4 5,6 9 3.1 5.9 11.6 16.4
60 B/o Madhuri 15203 M 1 4 6,7 9 2.8 6 9.18 15.4
61 B/o Aisha 15969 F 1 4 6 9 1.1 1.5 9 8.7

86 
62 B/o Prema 16943 F 1 4 6,7 9 2.8 6.3 17.3 21.4
63 B/o Savithramma 13444 F 2 4 6 9 3.6 5.6 13.4 15.7
64 B/o Sangeetha 21600 M 1 4 6 9 1.4 4.3 9.5 13.4
65 B/o Shalini 21489 F 1 4 5,6 9 2.1 6.1 14.6 18.8
66 B/o Nagamma 21428 F 1 4 6 9 2.6 4.9 9.9 12.5
67 B/o Padmaja 21617 M 1 4 6 9 1.9 7.3 11.7 11.4
68 B/o Geetha 21894 F 1 4 6 9 2.1 5.8 11.2 14.2
69 B/o Shaziya 21750 F 1 4 5,6 9 2 7 12 15
70 B/o Bhagya 21788 M 1 4 5,6 9 1 5.8 11 11.4
71 B/o Devamma 21996 M 2 4 6,7 9 1.5 6.1 16 22.4
72 B/o Rajamma 22042 M 1 4 6 9 1.7 6 14.9 16
73 B/o Shruthi 21976 M 1 4 6 9 1.7 5.1 18 20
74 B/o Nagarathanamma 21951 F 2 4 6 9 2.1 6.4 14.1 14.9
75 B/o Tejaswini 21950 F 1 4 6,7 9 1 2.4 7.5 8.6
76 B/o Jaya 21428 F 1 4 6,7 9 2.6 4.9 9.9 12.5
77 B/o Arsiya Banu 21602 M 1 4 5,6 9 2.2 6.4 14.6 19.5
78 B/o Kumari 25148 F 1 4 6 9 2 4..8 11.2 14.4
79 B/o Cethana 12458 F 1 4 6 9 2.8 5.2 8.8 10.6
80 B/o Bhanukumari 13343 M 1 4 6 9 2.5 5.2 11.5 10.1
81 B/o Nagamma 19484 F 2 4 6,7 9 1.5 4.9 8.6 11.3
82 B/o Priyanka 1002 F 1 4 6,7 9 2.1 3.9 11.7 18.4
83 B/o Prema 1333 M 1 4 5,6,7 9 3.2 6.5 16.6 20.9

87 
84 B/o Rani 17533 F 1 4 6 9 1.9 5.1 12 14.5
85 B/o Lalitha 17021 F 1 4 6,7 9 0.8 3.4 6.9 8
86 B/o Rathanamma 18333 M 1 4 5,6,7 9 2.8 5.6 14.5 19
87 B/o Sharada 18939 F 2 3 6,7 8 0.5 4.1 8 8.5
88 B/o Deepa 19685 F 1 4 6 8 1.6 3.5 6.3 6
89 B/o Swathi 18384 F 1 4 6,7 9 2.3 3.7 12 15
90 B/o Deepa 18723 M 1 4 6,7 9 1.8 4.5 9 13.5
91 B/o Mythri 18745 F 1 4 6,7 9 2 6 14.5 20.8
92 B/o Usna Banu 19432 F 1 4 6 9 2.2 4.1 8.7 9
93 B/o Bhagya 27533 M 1 4 6 9 1.6 4.2 9 13.5
94 B/o Cethana 14002 F 1 3 6,7 8 2.9 6.5 14 18
95 B/o Puttamma 19344 F 1 3 6 8 0.4 3.2 5 7.5
96 B/o Siddamma 19879 F 1 4 5,6,7 9 2.3 4.8 8.5 13.1
97 B/o Rashmi ganesh 19854 M 1 4 6 9 1.8 6.1 16.5 19.3
98 B/o Manjula 19967 F 2 4 6 9 2.1 5 10.5 13.8
99 B/o Nagu 19000 M 1 4 6 9 3 4.4 14.4 12.5
100 B/o Jyothi 20191 M 1 3 6,7 8 2.9 5.6 16 14.8

88 
 KEY TO MASTER CHART

1. Without maternal hypertension

2. With maternal hypertension

3. Vaginal delivery

4. Caesarean section

5. Oxytocin induction of Labour

6. Fluids only

7. Fluids and other medications

8. Breast feeding within 30min of delivery

9. Breast feeding after 30 min of delivery

89