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Original Article

Adverse Events Following Blood Exchange Transfusion for Neonatal

Hyperbilirubinemia: A Prospective Study
Swathi Chacham, Jogender Kumar, Sourabh Dutta, Praveen Kumar

Department of Pediatrics, Background: Exchange transfusion (ET) for hyperbilirubinemia is associated with

Abstract
Division of Neonatology,
Postgraduate Institute of
Medical Education and
Research, Chandigarh, India
many complications. The complications are underreported as most of the published
studies are retrospective, used varying definitions of adverse events  (AEs)
and variable follow‑up periods. Aim: We evaluated the incidence of clinical,
biochemical, hematological, and radiological AEs, including serious AEs, within
2  weeks of ET for hyperbilirubinemia in neonates, using standard definitions.
Materials and Methods: This prospective observational study was conducted in
level III newborn unit of north India from February 2008 to February 2009. We
enrolled consecutive inborn and outborn neonates admitted with hyperbilirubinemia
and required ET. Babies requiring partial exchange for anemia/polycythemia
or ET for indications other than hyperbilirubinemia were excluded. They were
prospectively monitored for clinical, biochemical, hematological, and radiological
AEs up to 2 weeks following the procedure. We calculated the incidence/AE
rate (AER) as the rate of events per 100 ET and compared them among various
groups using the Chi‑square test. The SPSS v20 was used for the analysis,
and value of P <  0.05 was considered as statistically significant. Results: A
total of 202 neonates were screened and 141 neonates (182 ET) were enrolled.
The overall AER was 112/100 ETs. The most common AE was biochemical
(45.6/100 ET), followed by hematological (44.5/100 ETs), clinical (15.9/100 ETs),
and radiological (8.9/100 ETs). Severe AER was 12.6/100 ETs. The AER was
significantly more in lower gestation and birth weight groups. Conclusion: ET
is a high‑risk procedure and should be performed only when the benefit of the
procedure offsets the risks.
Keywords: Adverse events, biochemical adverse events, clinical adverse events,
exchange transfusion, hematological adverse events, hyperbilirubinemia, neonate

Introduction
B lood exchange transfusion  (BET) was introduced in
the late 1940s to decrease mortality and morbidity
associated with hemolytic disease of the newborn,
but subsequently, it was used for the treatment of
severe hyperbilirubinemia due to any cause.[1] In due
course, its use extended to the treatment of other
conditions such as severe sepsis, drug intoxication,
hydrops fetalis, hyperammonemia, and refractory
hyperkalemia. However, tremendous progress in prenatal
(intrauterine transfusion and anti‑D immunoglobulin)
and postnatal care of Rh iso‑immunized fetuses along
with efficient phototherapy has substantially reduced the
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need for BET over the years.[2] The frequency of BET
in developed countries has decreased to such an extent
that with a decrease in experience with this age‑old
procedure, there is a risk of increase in the number of
BET‑related complications.[3] In developing countries of
Asia and Africa, despite advancements in phototherapy,
the rates of BET still continue to be high, as several
Address for correspondence: Prof. Praveen Kumar,
Department of Pediatrics, Division of Neonatology,
Postgraduate Institute of Medical Education and Research,
Chandigarh ‑ 160 012, India.
E‑mail: drpkumarpgi@gmail.com
This is an open access journal, and articles are distributed under the terms of the
Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows
others to remix, tweak, and build upon the work non-commercially, as long as
appropriate credit is given and the new creations are licensed under the identical
terms.
For reprints contact: reprints@medknow.com

DOI: How to cite this article: Chacham S, Kumar J, Dutta S, Kumar P.

10.4103/jcn.JCN_96_18 Adverse events following blood exchange transfusion for neonatal
hyperbilirubinemia: A prospective study. J Clin Neonatol 2019;8:79-84.

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Chacham, et al.: Adverse events following blood exchange transfusion

neonates are brought late to the hospital when they
already have extreme hyperbilirubinemia and/or signs of
acute bilirubin encephalopathy (ABE).
BET; however, can lead to complications such as
life‑threatening bleeding, sepsis, cardiac arrhythmias
and even death, apart from transient hypocalcemia,
hyperkalemia, bradycardia, and thrombocytopenia.[4,5]
The adverse events (AEs) associated with BET may be
attributable to fluctuations in blood volume and blood
pressure, changes in the acid–base status, alterations in
platelet count due to use of packed red cells which lack
platelets and coagulation factors, electrolyte disturbances
and the introduction of infectious agents. Although BET
has been considered as a major procedure akin to major
surgery, accurate information regarding the incidence
of these morbidities is lacking. Most of the published
studies are retrospective, have used varying definitions
of AEs and have had inconsistent follow‑up periods.[1,6,7]
It is vital to have accurate information about AEs, using
standard definitions for fair comparisons with any newer
modality of treatment and to evaluate any improvement
strategies. Hence, we prospectively assessed the
incidence of clinical, biochemical, hematological,
and radiological AEs, including serious AEs (SAEs),
occurring within 14 days of BET for hyperbilirubinemia
in neonates, using standard definitions.
Materials and Methods
This prospective observational study was conducted in
a level III neonatal unit in north India. All consecutive
inborn, as well as outborn neonates admitted in the
newborn unit for a single or double volume ET, were
screened. Neonates requiring BET for hyperbilirubinemia
were enrolled after getting informed written consent
from one of the parents. For phototherapy and BET,
we followed the American Academy of Pediatrics 2004
recommendations[8] for the infants ≥35 weeks of gestation
and Maisel’s charts[9] for preterm infants <35 weeks
gestation. We excluded babies who underwent partial
ET for anemia or polycythemia, or who underwent
BET for indications other than hyperbilirubinemia.
We prospectively monitored all enrolled neonates for
clinical, biochemical, hematological, and radiological
AEs for 14 days following BET. Ethical clearance was
obtained from the Institute Ethics Committee.
Fresh  (<5  days old) compatible blood, cross‑matched
with both mother and baby was used. All BETs
were double volume. Patient demographics, cause of
hyperbilirubinemia, indication for BET, comorbidities
which could influence the AEs, details of donor
blood (blood group, age, and biochemical parameters),
details of the procedure (personnel, route, and
duration), clinical, hematological, and biochemical
monitoring (before, during and after procedure),
neurological status and BET‑related complications
were recorded in predesigned performa. Neonates were
investigated for biochemical parameters (ionized calcium,
sodium, potassium, pH, and bicarbonate) before the
procedure and at one, two, six, 12, and 24  h after
BET. Platelet count was assessed before, at 24 h and
72 h after BET. In neonates, who underwent repeat
BET within 24 h of the first exchange, platelet count
was repeated at 24 and 72 h after the last BET. In
preterm neonates undergoing BET, ultrasound head
was performed before and at six and 24  h after BET, to
look for intracranial/intraventricular hemorrhage (IVH).
Blood glucose was checked 2 h after the procedure.
Neonates were actively monitored for clinical
AEs (CAEs) such as sepsis, apnea, bleeding, cardiac
arrest, and seizures manifesting immediately after the
procedure and until 14 days.
Definitions used in the study
Healthy neonate
Neonate who did not have any associated morbidity, and
who did not require any supplemental oxygen and who had
normal hemodynamic and neurologic status at admission.
Sick neonate
Neonate who had other comorbidity or who was on
supplemental oxygen or other respiratory support or had
critical hemodynamic status or abnormal neurological
status at admission.
Adverse event
Any abnormal alteration in the physiologic status and/or
variation in the laboratory parameters (done in relation
to the procedure) during or within 14 days of performing
BET, which normally would not have occurred in the
absence of the procedure.
AEs were further classified as follows:
Clinical adverse events
Apnea, bradycardia, seizures, hypothermia, new
onset/increase in need of respiratory support,
hypotension, significant clinical bleeding from any site,
sepsis, arrhythmia, and death.
Biochemical adverse events
Hypocalcemia  (ionized Ca  <1 mmol/L);
hyponatremia (Na +
<135 meq/L);
hyperkalemia (K+ >6.5 meq/L with ECG changes);
acidosis (pH < 7.20 or base excess >‑10 meq/L).
Hematological adverse events
Thrombocytopenia (platelet count <100,000/mm3); severe
thrombocytopenia (platelet count <50,000/mm3). In

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Chacham, et al.: Adverse events following blood exchange transfusion

neonates with preexchange platelet count <100,000/mm3, These 141 neonates underwent 182 BETs. Out of
>2% fall from baseline was considered an HAE, as the 141, 105 (74%) underwent one, 31 (22%) underwent
coefficient of variation of the platelet analyzer was two two, and rest five  (4%) underwent three BETs. The
percentages. baseline characteristics of the study population are
described in Table 1. Most of the neonates were
Serious adverse event
outborn as our center serves as the referral institute
Any AE that resulted in death need for readmission, for neighboring states. The most common causes for
prolongation of existing hospitalization, a persistent or hyperbilirubinemia were G6PD deficiency  (n‑38,27%),
significant disability or incapacity within 14  days of Rh isoimmunization (n‑33,23.4%), and ABO
BET. incompatibility (n‑17,12.1%). In 53 (37.6%) infants,
Blood exchange transfusion‑related mortality no cause could be determined (labeled idiopathic).
Any death which occurred within 14 days after BET Forty  (28.4%) neonates had ABE at presentation and
was considered as BET-related mortality. The attribution most (80%) had mild encephalopathy.
to BET was further defined as: definite if the AE was AEs were observed in 96 (68.1%) neonates. There were
clearly related to the BET; possible if the AE was likely a total of 204 AEs following 182 BETs, which included
related to the BET; probable if the AE may be related to 83 (40.6% of total AEs, n‑60 neonates) biochemical
the BET; and unlikely if the AE was doubtfully related AEs (BAEs), 81 (39.7% of total AEs, n‑81 neonates)
to the BET. hematological AEs (HAEs), 29 (14.2% of total AEs,
Acute bilirubin encephalopathy n‑27 neonates) CAEs, and 11 (5.4% of total AEs, n‑11
Acute clinical manifestations of elevated bilirubin in neonates) radiological AEs (RAEs). Therefore, the
the central nervous system manifesting as lethargy, poor
feeding, hypo/hypertonia, high‑pitched cry, torticollis, No. of subjects screened = 202
opisthotonus, setting‑sun sign, and seizures, etc. It was
further classified into mild, moderate, and severe ABE Excluded -61
• Underwent partial exchange -9
based on the bilirubin‑induced neurologic dysfunction • Consent not given- 10
score.[10] • Underwent BET for other
reasons- 42
• Sepsis- 39
Sample size • Hydrops fetalis - 3
From previously reported studies, the incidence of AEs
following blood ET varied from 12% to 44%. To detect Enrolled subjects- 141
Hyperbilirubinemia without sepsis- 124
12% AEs, with an allowable error of 5%, (alpha error of Hyperbilirubinemia with sepsis - 17
5% and power of 80%), a total of 168 BETs needed to
be studied.
Statistical analysis Follow up - 141 neonates (182 ET)
Outcome analysis – 141 neonates (182 ET)
We described categorical variables as percentages,
normally distributed numerical variables as Figure 1: Flow of the study
mean (standard deviation), and numerical variables with
skewed distributions as median (1st and 3rd quartile).
Table 1: Baseline characteristics of the study population
Skewness of distributions was determined by the Parameter n=141
Shapiro–Wilk test and Q–Q plot. We calculated the Gestation (weeks), mean±SD 35.5±3.8
incidence of AE rate (AER) as the number of events per Birth weight (g), mean±SD 2126±735
100 ET and compared them in various groups using the Male sex, n (%) 90 (63.8)
Chi‑square test. The Statistical Package for the Social Outborn, n (%) 84 (59.6)
Sciences version 20 (IBM Inc., Armonk, NY, USA) Age at admission (days), median (1st and 3rd quartile) 3 (1, 4)
was used for the analysis, and P < 0.05 was taken as Age of onset of hyperbilirubinemia (days), 2.4 (1.8, 3.3)
statistically significant. median (1st and 3rd quartile)
Age at BET (days), median (1st and 3rd quartile) 4.7 (3.1, 5.9)
Results Status before procedure, n (%)
Sick neonates 61 (43.3)
A total of 202 neonates underwent 257 BETs during Healthy neonates 80 (56.7)
the study period and were screened for possible ABE before exchange, n (%) 40 (28.4)
inclusion. Of them, 61 neonates were excluded due SD – Standard deviation; BET – Blood exchange transfusion;
to various reasons  [Figure  1] and 141 were enrolled. ABE – Acute bilirubin encephalopathy

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Chacham, et al.: Adverse events following blood exchange transfusion
AER in the study population was 112/100 BETs. BAEs
occurred in 60 (42.5%) neonates (45.6/100 BETs) and
the most common event was hypocalcemia (n‑41)
followed by hypernatremia (n‑26), hyponatremia (n‑8),
hyperkalemia (n‑7), and acidosis (n‑1). All BAEs
except hyperkalemia occurred most commonly at 1  h
post‑BET and showed a declining trend over the next
24 h [Table 2]. The incidence of hyperkalemia was
highest at 2 h post‑BET and showed improvement
by 6 h post‑BET. Thrombocytopenia was observed
in 81 (57.4%) neonates (44.5/100 BETs), of which
25 (17.7%) had severe thrombocytopenia. The incidence
of thrombocytopenia was the highest at 24 h post‑BET
and improved by 72 h. None of the infants had clinical
bleeding. Twenty‑nine CAEs occurred in 27 (19.2%)
neonates (15.9/100 BETs). Common benign AEs were
jitteriness due to symptomatic hypocalcemia (n‑3)
followed by symptomatic hyperkalemia (n‑1),
hypothermia (n‑1), and multiple soft‑tissue
abscesses (n‑1). The rest of the 23 CAEs were SAEs that
occurred in 23 (16%) neonates (12.6/100 ETs). These
included death in nine, sepsis in seven (meningitis‑two,
culture positive‑four, and culture negative‑one), seizures
in five, and cardiac arrest and intravascular hemolysis
in one neonate each. All nine (6.4%) neonates who
died (7.5/100 BETs) within 14 days of BET were
sick before the procedure. Out of nine, one death was
classified as possibly related, five as probably related,
and rest three as unlikely to be due to the procedure. Of
the infants who died, three died within 6 h of procedure,
four between 24 and 48 h, and rest two between 1 and
2 weeks after the procedure.
Only preterm neonates (n‑66) were screened for RAEs.
Eight (9.1%) babies had IVH (8.9 per 100 BETs). Seven
out of these eight were sick neonates, and none of them
had severe (grade III/IV) IVH. Two‑third of all IVH was
observed within 6 h post‑BET.
AERs were significantly higher in lower gestation
and birth weight groups  [Table  3]; and sick
neonates [Table 4]. Among the sick neonates, those with
ABE at admission had more AEs as compared to those
without encephalopathy.
Table 2: Timing of biochemical adverse events
Parameters
Pre‑BET (n=141) 1 h (n=136)
Hypocalcemia 93 (66) 106 (78)
Hyponatremia 14 (10) 10 (7.3)
Hypernatremia 18 (12.8) 33 (24.1)
Hyperkalemia 1 (0.1) 2 (0.2)
Metabolic acidosis 3 (2) 2 (0.2)
BET – Blood exchange transfusion
82 Journal of Clinical Neonatology ¦ Volume 8 ¦ Issue 2 ¦ April-June 2019
We also recorded donor blood and BET
procedure‑related details. Median age of the donor
blood was 2 (1–3) days, mean donor blood pH
was 6.89 ± 0.98, HCO3 was 13.89 ± 4.3 meq/L,
SBE was  −15.39  ±  6 meq/L, potassium was
5.75 ± 1.43 meq/L, sodium was 149.38 ± 6.3 meq/L, and
ionized calcium was 0.03 ± 0.05 mmol/L. Mean duration
of the procedure was 75.22 ± 25 min (range 60–90 min).
Mean aliquot volume (ml/kg) was 3.58 ± 0.98.
Majority (53.5%) of BETs were performed by the
3rd year postgraduate residents, followed by 2nd year
residents (36.5%). All were supervised by neonatology
fellows. Umbilical venous route n = 157 (86.3%)
followed by peripheral arterial route n = 24 (13.1%)
was used for BET. One neonate (0.6%) had undergone
BET through the umbilical artery catheter and peripheral
vein. Twenty‑two neonates (15.8%) had catheter block
during the procedure and required reinsertion.
Discussion
In this prospective study of 182 BETs in 141 neonates,
AEs were assessed systematically for 14 days.
Overall AER was 112/100 BETs. Most common
AE was biochemical (45.6/100 BETs), followed by
hematological (44.5/100 BETs), clinical (15.9/100 BETs),
and radiological (8.9/100 BETs). Severe AER was
12.6/100 BETs. The AER was significantly higher in
infants with lower gestation, lower birth weight, and
sickness. We included only those neonates who required
BET primarily for neonatal hyperbilirubinemia as the AEs
following BET for other indications, for example, sepsis,
hydrops, an inborn error of metabolism, etc., will be quite
different because of the underlying conditions and many
confounders. We included all gestations and also those
neonates with who were sick, but BET was being done for
the primary indication of hyperbilirubinemia, to improve
generalizability of our results. We stratified the results
according to gestation, weight, and sickness at admission
for better comparison with other studies.[11,12] Ours being
a large government tertiary care center in north India, the
majority of enrolled neonates were outborn.
Previous studies either did not describe any time
limit, or used a time frame of 3–7  days for reporting
Number of hours post‑BET, n (%)
2 h (n=137) 6 h (n=136) 12 h (n=126) 24 h (n=115)
104 (76) 103 (75.7) 84 (66.7) 68 (59)
9 (6.6) 6 (4.4) 4 (3.2) 2 (1.7)
20 (14.6) 11 (8) 2 (0.2) 1 (0.1)
5 (0.4) 2 (0.2) 1 (0.2) 1 (0.1)
0 1 (0.1) 1 (0.1) 1 (0.1)
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Chacham, et al.: Adverse events following blood exchange transfusion

procedure‑related AEs.[1,11‑13] In the present study, we study, their individuals were healthy and of higher
defined the limit of 14  days for reporting of AEs in gestation with assessment of AE up to 7 days only.
concordance with standard surgical care guidelines to On the contrary, complication rates reported by Steiner
make it more uniform and comparable. The incidence et  al.[1] were quite low (22.7/100 BETs) as compared
of AEs was quite high in the present study. This to the previous studies. These differences can be due to
can be explained by the fact that due to multimodal variation in the definitions used, level of sickness among
monitoring, >1 AE was detected in the majority of the the participants, health‑care system in various countries,
neonates. Furthermore, due to the prospective nature and delayed referral in the developing countries. All
of the study, meticulous protocolised monitoring, the studies showed that although BET is a commonly
more AEs were identified, which could have been performed procedure in neonates, it is not free of risks
otherwise missed by retrospective chart reviews. and is associated with significant complications.
Similar rates of AE have been reported from recent
prospective studies done in the Southeast Asian region In the present study, biochemical and hematological
and older studies from the western countries.[7,11,14] Two complications were the most common AEs. Previous
prospective studies from Nepal reported AER of 146 studies have also reported similar findings.[1,6,11,14,15]
and 210/100 BETs, respectively.[7,14] In a study by Patra Hypocalcemia was one of the most frequent AEs with
et al., 74% of BETs were associated with AEs and AER the incidence ranging from 22.5% to 98%.[1,6,7,11,14]
was 136/100 BETs.[11] Hakan et  al. reported the largest Hypocalcemia following BET is due to the calcium
prospective series from Turkey involving 306 patients.[6] chelating properties of citrate, which is present in a very
In this Turkish series, 337 BET‑related complications high concentration in the donor blood as a component
were observed in 306 patients (337 BETs), with an AER of anticoagulant. The citrate in donor blood binds ionic
of 100/100 BETs. However, compared to the present calcium and magnesium in the neonate and produces
significant hypocalcemia.[15,16] Thrombocytopenia was
seen in 57.4% neonates undergoing BET, of which
Table 3: Distribution of rate of adverse events (/100
blood exchange transfusion) according to sickness at almost one‑third had severe thrombocytopenia. A similar
admission frequency of thrombocytopenia was reported in other
Parameter Healthy Sick without Sick with P* studies.[1,6,7,11,14] We also observed that the incidence
ABE ABE of thrombocytopenia was highest at 24 h post‑ET
All adverse events 92.7 105 190 0.000 and showed improvement by 72 h. Jasso‑Gutiérrez
Severe adverse events 4.2 15.8 34.5 0.000 et  al. studied the pattern of recovery of platelet count
Clinical adverse events 7.3 19.3 38 0.001 after BET.[17] Like us, they also observed a decrease
Biochemical adverse 43.8 52.6 72.4 0.043 in platelet count following BET with a nadir at 24 h
events and full recovery at or after 72  h. This finding has
Hematological adverse 40.6 47.4 51.7 0.022
important implications in management and mandates
events
Radiological adverse 2 16.7 30 0.000
screening for this, at least in preterm infants. Post‑BET
events thrombocytopenia is due to the replacement of whole
*Chi‑square test was used. P<0.05 is considered as statistically blood with packed red blood cells, which are deficient
significant. ABE – Acute bilirubin encephalopathy in platelets. Furthermore, the process of BET can

Table 4: Comparison of adverse event rate across various gestation and weight groups
Category Adverse event rate (/100 blood exchange transfusions)
All participants P Sick neonates P Healthy neonates P
Gestation (weeks)
<28 150 0.000 225 0.013 ‑ 0.048
28-30 165 179 134
31-33 146 244 86.7
34-36 115 117 114
≥37 89 102 76.1
Birth weight (g)
<1000 176 0.000 167 0.002 188 0.013
1000-1499 192 215 117
1500-1999 84 123 60
2000-2500 108 116 103
>2500 77.6 82.8 74

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Chacham, et al.: Adverse events following blood exchange transfusion
activate the coagulation system, leading to vascular
thrombosis and consumptive thrombocytopenia.[11] The
all‑cause mortality rate in the present study was 7.5/100
BETs. However, only one death was directly related to
the procedure (0.8/100 BETs). This rate is comparable
to other studies[1,6,13,14,18] and is lower than previously
reported from India.[19,20] All the neonates who died were
sick before BET. As expected, AEs were more frequent
in the infants of lower gestation and birth weights and
those who were sicker. These results are similar to the
other studies[11,19] and due to the fact that sicker and
smaller infants have multiple comorbidities, and hence,
are at risk of more complications.
The strength of the present study is that it was a
prospective study of a large number of BETs with
a preplanned protocol for monitoring, with clear
standard definitions of AEs and a follow‑up of 14  days.
However, we limited our laboratory testing to not so
frequent intervals to minimize the blood sampling.
We were able to provide AERs for various groups of
neonates undergoing BET for the primary indication of
hyperbilirubinemia. These AERs can be used for quality
improvement as well as comparison with any other
treatment options for critical hyperbilirubinemia.
Conclusion
Although BET is a commonly performed procedure
in the management of severe hyperbilirubinemia, the
frequency of associated AEs is quite high. AEs are
more common in infants of lower gestation, weight, and
those who are sicker. A clear protocol of monitoring
of these AEs can help early detection and treatment of
these complications.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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