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225]

Original Article

Evaluation of Risk Factors for Exchange Range Hyperbilirubinemia and

Neurotoxicity in Neonates from Hilly Terrain of India

Abstract Deeksha A Singla,

Background and Aim: Neonatal hyperbilirubinemia continues to be the most common cause Seema Sharma,
of hospital admissions and readmissions in the neonatal population worldwide and this pattern Milap Sharma,
continues despite attempts to identify neonates at risk of pathological hyperbilirubinemia.
Therefore, this study aimed to study the risk factors for severe hyperbilirubinemia in neonates. Sanjeev Chaudhary
Materials and Methods: An observational prospective study was undertaken for 1 year in neonates Department of Pediatrics,
with hyperbilirubinemia requiring double volume exchange transfusion in neonatology unit of a Dr. Rajendra Prasad
Government Medical College,
tertiary rural health care hospital. Results: Risk factors included ABO incompatibility in 14 (28.5%), Tanda, Himachal Pradesh, India
Rh incompatibility in 14  (28%). Other risk factors for hyperbilirubinemia were, jaundice in elder
sibling, oxytocin use, birth asphyxia, hypothyroidism, ABO along with Rh incompatibility, Glucose‑6
phosphate Dehydrogenase deficiency, cephalhematoma, and sepsis in neonates. Ten  (20%) neonates
were neurologically abnormal with signs of encephalopathy. Significant association of risk factors
with neurotoxicity were also found. All neurologically abnormal neonates were small for date and
none was appropriate for date (P = 0.05). There were no neurologically abnormal neonates with
A+  and O−  mothers  (P = 0.04). Conclusion: The high rate of exchange transfusion warrants
aggressive management of neonatal hyperbilirubinemia by health‑care providers by adequate
dissemination of information, strict following of hour‑based normograms, performing total serum
bilirubin assessment in all icteric neonates, and stratification into risk groups thereafter.

Keywords: Kernicterus, neonatal hyperbilirubinemia, risk factors

Introduction Written informed consent was obtained

from all the parents/guardians of the
In neonates with severe hyperbilirubinemia,
enrolled subjects. All neonates presenting
indications for exchange transfusion with neonatal hyperbilirubinemia
include exchange range hyperbilirubinemia, with gestation  ≥35  weeks with
phototherapy failures, and features of hyperbilirubinemia in exchange range
acute bilirubin encephalopathy (ABE) in according to the AAP (American Academy
neonates.[1‑3] However, despite increasing of Pediatrics) guidelines were included in
knowledge about risk factors, the prevalence the present study. Exclusion criteria were
continues to be more in developing nations. As neonates with gestation <35 weeks, neonates Received: 29 August, 2016.
a result, a sentinel event alert was issued by the with conjugated hyperbilirubinemia
Accepted: 14 September, 2017.

US centers for disease control and prevention and persistence of hyperbilirubinemia Address for correspondence:
to identify cases of kernicterus in healthy term beyond 4  weeks of life. Detailed history, Dr. Seema Sharma,
infants.[4] The study attempts to study the risk examination, and investigations were Department of Pediatrics,
Dr. Rajendra Prasad
factors for severe hyperbilirubinemia due to its performed, followed by classification of Government Medical College,
mortality and long‑term neurological sequlae. neonates into zones according to total Tanda, Himachal Pradesh,
serum bilirubin levels as per the AAP India.
Materials and Methods guidelines. The total serum bilirubin levels E‑mail: seema406@rediffmail.
com
This was a hospital‑based prospective were measured using Pearlman and Lee
observational study, conducted in the Diazo method.
neonatology unit, of a tertiary care hospital Investigations conducted in all neonates Access this article online
(2013–2014). requiring exchange were total serum Website:
www.ijabmr.org
The study commenced after approval bilirubin (TSB), conjugated and DOI:
from protocol and ethical committee. unconjugated fractions of TSB, ABO 10.4103/ijabmr.IJABMR_298_16
and Rhesus blood group, direct coombs Quick Response Code:
This is an open access article distributed under the terms of the
Creative Commons Attribution-NonCommercial-ShareAlike 3.0
License, which allows others to remix, tweak, and build upon the How to cite this article: Singla DA, Sharma S,
work non-commercially, as long as the author is credited and the Sharma M, Chaudhary S. Evaluation of risk factors for
new creations are licensed under the identical terms. exchange range hyperbilirubinemia and neurotoxicity
in neonates from hilly terrain of India. Int J App Basic
For reprints contact: reprints@medknow.com Med Res 2017;7:228-32.

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Singla, et al.: Evaluation of risk factors for exchange range hyperbilirubinemia and neurotoxicity in neonates

test (DCT), reticulocyte count and peripheral blood smear Table 1: Baseline parameters of neonates with exchange
examination. Glucose‑6‑phosphate dehydrogenase (G6PD) range hyperbilirubinemia
levels, thyroid profile, and sepsis screen were done Parameter Mean±SD Minimum Maximum
wherever indicated. Age at which icterus noted (h) 51±39 6 189
Statistical analysis Age of presentation in hospital (h) 98±49 6 192
TSB (mg/dl) 27.1±10 13 38.6
Microsoft office (excel) 2010 Home edition  was used for Weight (kg) 2.58±0.38 1.8 3.5
statistical analysis. Chi‑square test was used for categorical Length (cm) 49±1.55 46 53
variables. The value of P < 0.5 was considered statistically Occipitofrontal 33.45±1 31 35
significant. circumference (cm)
TSB: Total serum bilirubin; SD: Standard deviation
Results
Out of the total 1970 neonates admitted to the neonatal unit, Table 2: Risk factors for exchange range
432 (21.9%) had neonatal jaundice requiring phototherapy. hyperbilirubinemia
While 60 (13.8%) neonates required exchange transfusion Risk factor n (%) Males Females
and 49  (11.3%) neonates who fulfilled the inclusion Small for gestation 37 (76) 18 (48.6) 19 (51.4)
criteria were studied. Of these, 22 (45%) were females ABO incompatibility 14 (28.5) 8 (57.2) 6 (42.8)
and 27 (55%) were males. Male‑to‑female ratio was 1.2:1. Rh incompatibility 14 (28.5) 6 (42) 8 (57)
Majority of total infants i.e., 37 (76%) were SFD, whereas ABO + Rh incompatibility 4 (8) 2 (50) 2 (50)
12 (24%) were appropriate for date (AFD) [Table 1]. G6PD deficiency 2 (4) 2 (100) 0
The family history of jaundice in elder sibling was present Sepsis 4 (8) 2 (50) 2 (50)
in 7 (14%) cases, whereas oxytocin use in 7 (14%) Cephalhematoma 2 (4) 2 (100) 0
neonates. There was no history of delayed cord clamping Jaundice in elder sibling 7 (14) 3 (42.85) 4 (57)
in any patient. History of oxytocin use was present in Hypothyroidism 3 (6) 2 (66.7) 1 (33.3)
7 (14%) neonates. History of birth asphyxia was present Oxytocin use 7 (14) 2 (28.5) 5 (71.5)
in 2 (4%). In both cases, it was mild. History of delayed G6PD: Glucose‑6‑phosphate dehydrogenase
feeding or meconium passage was not present in any of the
neonates. On examination, cephalhematoma was present in could be ascertained in 2 neonates. The mortality among the
2 (04%) neonates. studied neonates was 2 (4%) of the total. Both of these were
female neonates with features of ABE. There were total 10
Out of the total 49 neonates, ABO incompatibility was
neurologically abnormal neonates among 49 [Table 3].
present in 14 (28.5%) neonates and Rh incompatibility in
14 (28%) neonates. ABO along with Rh incompatibility Discussion
was present in 4 (8%) neonates. DCT was positive in
12 (85.7%) neonates with ABO incompatibility and This prospective study focused on studying the risk
13 (92.8%) neonates in Rh incompatibility. G6PD deficiency factors for exchange range hyperbilirubinemia. Till date,
was present in 2 (4%) neonates. History of hypothyroidism only two Indian studies have outlined these risk factors
was present in 5 (10%) mothers, and these mothers were and none so in the last decade.[5,6] The risk factors were
receiving treatment for the same. Three (06%) neonates studied for a high rate of exchange transfusion in this
had abnormal thyroid profile on investigations [Table 2]. hilly part of India.
Among the total 49 mothers distribution of various The mean period of gestation of neonates in our study was
blood groups were A Rh−06  (12.2%), A Rh+  02  (4.1%), 38.3  ±  1  weeks which was identical to available studies.[7‑9]
AB Rh−01 (2.0%), AB Rh+ 03 (6.1%), B Rh−04 (8.2%), B While mean age of presentation in our study was 98 ± 49 h,
Rh+ 16 (32.7%), O Rh−04 (8.2%), and O Rh+ 13 (26.5%). available literature has reported the age of presentation in
Among the total 49 neonates blood groups were A days as 4 ± 1 days, 4.9 ± 2.2 days, and 111.6 ± 66 days.
Rh−01  (2.0%), A Rh+  15  (30.5%), AB Rh−0  (0%), AB [7,8,10]
This wide range in age of presentation can be
Rh+  03  (6.1%), B Rh−0  (0%), B Rh+  22  (44.9%), O explained due to differences in the basic etiology underlying
Rh−0 (0%), and O Rh+ 08 (16.3%). hyperbilirubinemia such as ABO incompatibility, G6PD
More than one double volume exchange transfusion deficiency, and extravasation in the form of cephalhematoma.
(DVET) was required in 4 (8%) patients. Of these, 3 (75%) Mean age at which icterus was first noticed either by relative
neonates required exchange transfusion twice and 1 (25%) or health‑care provider was 51 ± 39 h. However, the mean
neonates required exchange transfusion thrice. Of the 4 age of presentation was 98 ± 49 h showing a lag period
neonates who required more than one exchange transfusion, between first notice of icterus and presentation. This could
Rh incompatibility was present in 1 neonate; ABO along with be due to multifactorial causation like delay in seeking care,
Rh incompatibility was present in 1 neonate while no cause delayed referral, phototherapy failure, and sociocultural

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Singla, et al.: Evaluation of risk factors for exchange range hyperbilirubinemia and neurotoxicity in neonates

Table 3: Risk factor assessment for neurotoxicity in The percentage of male neonates among those requiring
neonatal hyperbilirubinemia exchange were 55% and female neonates were 44%
Patient variable Neurologically Neurologically P with male‑to‑female ratio of 1.2:1. This was almost
normal (%) abnormal (%) identical to the available literature.[8‑10] All studies
Gestation showed male preponderance among neonates with
35‑37 38 (97.4) 9 (90.0) 0.289 severe hyperbilirubinemia. Hence, male sex has emerged
37‑41 1 (2.6) 1 (10.0) as a well recognized risk factor for exchange range
Place of birth hyperbilirubinemia in neonates.[11] The mean of preexchange
Inborn 19 (48.7) 2 (20.0) 0.102 TSB level was 27.1 ± 10 mg/dl. This was reported to be
Outborn 20 (51.3) 8 (80.0) 30 mg/dl by Bhat et al.,[7] 25.9 ± 7.5 mg/dl by Badiee
Mode of delivery et  al.,[12] 28.1  ±  6.4 by Davutoğlu et  al.[8] All these
NVD 30 (76.95) 9 (90.0) 0.360 studies showed bilirubin levels >25 mg/dl to be uniformly
LSCS 9 (23.1) 1 (10.0) present in neonates requiring exchange transfusion. In the
G6PD status current study majority of total infants, that is, 76% were
Negative 37 (94.4) 10 (100) 0.465 SFD and rest, 24% were AFD. The study demonstrates a
Positive 2 (5.1) 0 preponderance of small for date neonates to develop severe
History of jaundice hyperbilirubinemia requiring exchange transfusion with
Present 6 (15.4) 1 (10) 0.664 statistically significant results.
Absent 33 (84.6) 9 (21.4)
Oxytocin use
ABO incompatibility was the most common reason
Used 6 (15.4) 1 (10) 0.664
for exchange range hyperbilirubinemia in all available
Not used 33 (84.6) 9 (90) studies. It was defined as DCT positivity and or evidence
Birth asphyxia of hemolysis in the peripheral blood film. In the present
Present 2 (5.1) 0 0.465 study, it was present in 32% infants (62% male and 38%
Absent 37 (94.9) 10 (100) of female neonates). Variable incidence of35.9%, 5%, 25%,
AFD/SFD 38%, 32%, 22%, and 15% has been reported in available
AFD 11 (28.9) 0 0.053 literature.[5‑9,12,13]
SFD 27 (71.1) 10 (100) Rh incompatibility defined as DCT positivity and or
Cephalhematoma evidence of hemolysis in peripheral blood film was present
Present 2 (5.1) 0 0.465 in 28% of patients. Studies by Bhat et  al.,[7] Davutoğlu
Absent 37 (94.9) 10 (100) et  al.,[8] Badiee,[12] Dikshit et  al.,[5] Narang et  al.,[6] and
Maternal blood group Chitlangia et  al.,[9] had reported Rh incompatibility in
A− 3 (7.7) 3 (30) 0.042 20.6%, 12.6%, 11.7%, 10.7%, 9.2%, and 6.7%, respectively.
A+ 2 (5.1) 0
AB− 0 1 (10) Rh incompatibility was the second most common reason
AB+ 1 (2.6) 2 (20) for exchange transfusion in neonates. Among all the studies
B− 3 (7.7) 1 (10) our study reflected the highest rate of Rh incompatibility
B+ 14 (35.9) 2 (20) in neonates reflecting geographical and racial variations.
O− 4 (10.3) 0 G6PD deficiency was detected in 4% of the total subjects
O+ 12 (30.8) 1 (10) while previous studies show rates of 19.1%, 17.2%, 11.4%,
Baby blood group 6.2%, and 0% by Badiee,[12] Narang et  al.,[6] Davutoğlu
A− 0 1 (10) 0.077 et al.,[8] Dikshit et al.,[5] and Chitlangia et al.,[9] respectively.
A+ 10 (25.6) 5 (50) The percentages of neonates with G6PD deficiency remain
AB− 0 0 low in our study. This can be explained by low detection
AB+ 2 (5.1) 1 (10) rate during the acute hemolytic episode as young red blood
B− 0 0 cells have higher G6PD activity. More accurate assessment
B+ 19 (48.7) 3 (30.0) can be done if these neonates are followed up for G6PD
O+ 8 (20.5) 0 deficiency testing subsequently.
O− 0 0
Sepsis was present in 8.1% of the total patients in our
NVD: Normal vaginal delivery; LSCS: Lower section cesarean section;
G6PD: Glucose‑6‑phosphate dehydrogenase; AFD: Appropriate for
study. Only two other studies by Narang et  al.[6] and
date; SFD: Small for date Dikshit et  al.[5] have reported the incidence of sepsis in
neonates requiring exchange transfusion. It was reported
beliefs of parents. The mean body weight in our study was to be 24% and 8%, respectively. However, the higher rate
2.58 ± 0.38 kg. Previous studies show mean body weight to reported by Dikshit et  al. may be due to more number
be 2.81  ±  0.67 with minimum of 1.2  kg and maximum of of sick infants referred to their hospital. Extravasation
4.3,[8] 2.53 ± 0.52,[7] and 3.36 ± 0.48 kg.[10] in the form of Cephalhematoma in the current study was

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Singla, et al.: Evaluation of risk factors for exchange range hyperbilirubinemia and neurotoxicity in neonates
present in 4% of all the neonates. Narang et al.[6] reported
that 1.4% of neonates had extravasation. However,
no other recent studies have described the association
between the exchange range hyperbilirubinemia and
extravasation among their patients. History of jaundice
in eldersibling was present in 14% of cases in our study
which has not been described in any previous study.
This is a pointer towards the role of genetic factors in
the causation of severe hyperbilirubinemia requiring
exchange transfusion. Documented hypothyroidism was
present in 6% of the neonates in our study. Only Sgro
et al.[10] have reported hypothyroidism in neonates with
severe hyperbilirubinemia in 1% of neonates in whom
the causes could be found. No cause for exchange range
hyperbilirubinemia could be ascertained in 16% of the
total study patients in our study. Previous studies have
reported rates of 9.3% by Dikshit et  al.,[5] 13.9% by
Davutoğlu et  al.,[8] 27.5% by Chitlangia et  al.,[9] 35.4%
by Narang et  al.[6] The wide variation in the percentage
of idiopathic cases can be due to genetic mutations in
enzymes involved in bilirubin production and metabolism
in addition to the regional differences and resource
availability among various studies.
The mortality rate among the study subjects was 2 (4%)
and these were two female neonates who presented
with features of ABE i: eabnormal tone, retrocollis,
seizures, poor feeding and lethargy and died within 24  h
of presentation. This mortality was chiefly attributed to
ABE as suggested by signs and symptoms. The mortality
rate in other studies has been documented to be 1.5% by
Badiee,[12] 2% by Bhat et al.,[7] 1.5% by Chitlangia et al.,[9]
zero by Davutoğlu et  al.,[8] zero by Narang et  al.[6] All
these studies show that exchange transfusion is a relatively
safe procedure, especially in experienced hands. However,
with decreasing rates of exchange, increasing rate of
complications is expected, more so in developed nations
where the residencies may be completed without seeing or
performing even a single exchange transfusion.
More than one DVET was required in 8% of patients in
our study. In one of these Rh incompatibility was present,
in another both ABO plus Rh incompatibility were present
while in two no cause could be ascertained. Total 6% of
neonates required DVET twice and 2% of neonates required
DVET thrice. The percentage of neonates requiring more
than DVET are 12.6% by Davutoğlu et al.,[8] 12.3% Badiee
et al.,[12] and 11.7% by Chitlangia et al.[9] Chitlangia et al.[9]
have also described their findings that DVET was done
twice in 9.2%, thrice in 1.7%, 5 times in 0.8% of the total
neonates. These findings show declining trend for multiple
DVET which can be best explained by more intensive
phototherapy and availability of alternate modalities like
immunoglobulins.
In the present study, total of 49 subjects, 20% of neonates
were neurologically abnormal with signs of encephalopathy.
International Journal of Applied and Basic Medical Research | Volume 7 | Issue 4 | October-December 2017
Other studies have reported the percentage of neurologically
abnormal neonates as 7.3%, 16.5%, and 19.8%.[8,10,12]
In the current study, 90% of neonates were between
35 and 37  weeks, whereas 10% of neonates were between
37 and 41  weeks  (P  =  0.289) reflecting differences
between preterms and term neonates and higher
predisposition for neurological damage in preterms.
Previous studies have reported the number of preterms with
respect to the total study subjects as 6.3% by Davutoğlu
et  al.[8] who has also described prematurity and other
factors. His study also reported prematurity and kernicterus
40%, prematurity and ABO incompatibility 5.1%,
prematurity and Rh incompatibility 1.3%, prematurity and
polycythemia 1.3%, prematurity and hypothyroidism 1.3%
of the total neonates. Crosse et  al.[14] reported that 73.6%
of preterm babies with kernicterus died as compared to
25.6% of all preterm infants. However, limited studies
have compared prematurity versus risk for neurological
abnormality in neonates.
Of the total 10 neurologically abnormal neonates all
100% were SFD and none was AFD (P = 0.50) showing
differences between the two however not significant
statistically. However To the best of our knowledge, detailed
comparison of growth retardation versus neurological
Abnormality in neonates with severe hyperbilirubinemia
was not found in the previous studies.
This calls for better screening and more intensive
management of growth retarded neonates. The distribution
of blood groups among the total 49 neonates was
A Rh−01  (2.0%), A Rh+  15  (30.5%), AB Rh−0  (0%),
AB Rh+  03  (6.1%), B Rh−0  (0%), B Rh+  22  (44.9%),
O Rh−0  (0%), and O Rh+  08  (16.3%). Among 10
neurologically abnormal neonates, 5 (50%) had blood
Group A Rh+, 3 (30%) had blood Group B Rh+,
1 (10%) each had blood Group AB Rh+ and A Rh+ and
none of the neonates were O Rh+, O Rh−, AB Rh−and
B Rh−  (P  =  0.77) showing no significant differences in
rates of neurological abnormality with different blood
groups. The relation of blood groups to neurological
status has not been described in detail in neonates with
hyperbilirubinemia requiring exchange transfusion in the
available literature.
Among the total 10 neonates with abnormal neurological
examination, 3  (30%) neonates had mothers with A Rh−
blood Group, 2 (20%) had mothers with AB Rh+ blood
Group, 2 (20%) had mothers with B Rh+ blood group
and 1 (10%) each had mother with blood Groups AB
Rh−, B Rh−and O Rh+. While there were no
neurologically abnormal neonates with A Rh+ and O
Rh−mothers  (P  =  0.042) showing statistically significant
differences in rates of neurological abnormality. So far no
studies have discussed the detailed analysis of maternal
blood group with the abnormal neurological status of
the neonate. However, the current study has reflected
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Singla, et al.: Evaluation of risk factors for exchange range hyperbilirubinemia and neurotoxicity in neonates
the significant influence of maternal blood group in
predisposition for neurotoxicity. This warrants further
studies to document such evidence and the management
thereafter. Hence, this study is important for studying
the risk factors for exchange range hyperbilirubinemia in
neonates requiring exchange transfusion.
Conclusion
Identification of risk factors predisposing to exchange
range hyperbilirubinemia and neurotoxicity prediction
in healthy near term and term neonates can help in
the stratification of high‑risk group. Management of
neonatal hyperbilirubinemia with strict following of hour
based normograms can further result in decrease into
morbidity, mortality, and neurotoxicity resulting into
neurodevelopmental disorders.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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