Intravenous Immunoglobulin and Necrotizing Enterocolitis in Newborns With

Hemolytic Disease
Josep Figueras-Aloy, José M. Rodríguez-Miguélez, Martin Iriondo-Sanz,
María-Dolores Salvia-Roiges, Francesc Botet-Mussons and Xavier Carbonell-Estrany
Pediatrics 2010;125;139; originally published online November 30, 2009;
DOI: 10.1542/peds.2009-0676

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/125/1/139.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org by guest on November 2, 2012


Intravenous Immunoglobulin and Necrotizing
Enterocolitis in Newborns With Hemolytic Disease
AUTHORS: Josep Figueras-Aloy, MD, PhD,a José M.
Rodríguez-Miguélez, MD, PhD,a Martin Iriondo-Sanz, MD,
PhD,b María-Dolores Salvia-Roiges, MD, PhD,a Francesc
Botet-Mussons, MD, PhD,a and Xavier Carbonell-Estrany,
MD, PhDa
aDepartment of Obstetrics and Neonatology, Institut Clínic de
Ginecologia, Hospital Clínic, Institut d’Investigacions
Biomèdiques August Pi I Sunyer, and bNeonatology Service,
Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona,
Spain
KEY WORDS
necrotizing enterocolitis, ABO blood-group system, intravenous/
therapeutic use of immunoglobulins, Rh isoimmunization/drug
therapy
ABBREVIATIONS
IVIG—intravenous immunoglobulin
NEC—necrotizing enterocolitis
OR— odds ratio
CI— confidence interval
www.pediatrics.org/cgi/doi/10.1542/peds.2009-0676
doi:10.1542/peds.2009-0676
Accepted for publication Jul 28, 2009
Address correspondence to Josep Figueras-Aloy, MD, PhD,
Neonatology Service, Hospital Clínic (sede Maternitat), C/Sabino
de Arana 1, E-08028 Barcelona, Spain. E-mail: jfiguer@clinic.ub.es
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2009 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have
no financial relationships relevant to this article to disclose.
PEDIATRICS Volume 125, Number 1, January 2010
Downloaded from pediatrics.aappublications.org by guest on November 2, 2012
ARTICLES
WHAT’S KNOWN ON THIS SUBJECT: Treatment with
phototherapy and high-dose IVIG for newborns with significant
hyperbilirubinemia caused by isoimmune hemolytic jaundice (Rh
or ABO incompatibility) reduces the need for exchange
transfusion.
WHAT THIS STUDY ADDS: The use of high-dose IVIG for severe
isoimmune hemolytic jaundice in late-preterm and term infants is
associated with a higher incidence of necrotizing enterocolitis.
abstract
OBJECTIVE: The objective of this study was to assess whether the use
of high-dose intravenous immunoglobulin (IVIG) in late-preterm and
term newborns with severe isoimmune hemolytic jaundice caused by
Rh and ABO incompatibility was a risk factor for necrotizing enteroco-
litis (NEC).
METHODS: An observational, retrospective study that encompassed 16
years was conducted. A total of 492 liveborn infants who were of ⱖ34
weeks’ gestation and had severe isoimmune hemolytic jaundice
caused by Rh (n ⫽ 91) and ABO (n ⫽ 401) incompatibility and were
treated with phototherapy were included in the study. IVIG (500 mg/kg
over 2– 4 hours) was indicated when total serum bilirubin level plus 2
points reached 85% of the cutoff value for performing exchange trans-
fusion.
RESULTS: A total of 167 (34%) infants received IVIG. NEC was diagnosed
in 11 (2.2%) patients: 10 (6%) in the IVIG-treated group and 1 (0.3%) in
the non–IVIG-treated group. Five patients required urgent operation,
and 1 of them died as a result of massive intestinal necrosis. Another
patient died 2 years later as a result of short bowel syndrome. In the
multivariate analysis, cesarean delivery (odds ratio [OR]: 3.76 [95%
confidence interval (CI): 1.10 –12.90), Apgar test at 5 minutes (OR: 0.50
[95% CI: 0.40 – 0.64), and IVIG (OR: 31.66 [95% CI: 3.25–308.57]) were
independent factors significantly associated with NEC.
CONCLUSIONS: The use of high-dose IVIG for severe isoimmune hemo-
lytic jaundice in late-preterm and term infants was associated with a
higher incidence of NEC. Pediatrics 2010;125:139–144
139
Isoimmune hemolytic jaundice in the
newborn is mainly attributable to Rh or
ABO incompatibility. Phototherapy and,
in severe cases, exchange transfusion
are used to prevent kernicterus and to
reduce perinatal mortality. Treatment
with heme oxygenase inhibitors and in-
travenous immunoglobulin (IVIG) for
newborns with significant hyperbiliru-
binemia has been shown to reduce the
need for exchange transfusion.1–3
IVIG is a concentrated, purified solu-
tion of immunoglobulins derived from
pooled plasma of the donor popula-
tion. IVIG is indicated as replacement
therapy for patients with primary and
selected secondary immunodeficiency
diseases that are characterized by ab-
sent or deficient antibody production4
but is also useful for severe isoim-
mune thrombocytopenia and isoim-
mune hemolytic jaundice in neo-
nates.5,6 IVIG is usually given at a dose
of 500 to 1000 mg/kg infused over 2 to
6 hours, and additional doses can be
given at approximately every 24 hours.
The use of IVIG in neonates has been
extensively studied, particularly as ad-
juvant in the treatment of fulminant
sepsis, and has been shown to be safe
and well tolerated6–9; however, a case
of necrotizing enterocolitis (NEC) in a
term newborn with isoimmune neona-
tal thrombocytopenia after 3 days of
treatment with high-dose IVIG has been
reported and was attributed to a
thrombotic effect as a result of hyper-
viscosity of IVIG solution.10 In a con-
trolled trial of IVIG to reduce nosoco-
mial infection in very low birth weight
infants, the rate of NEC was 12.0% in
the IVIG group and 9.5% in the control
(placebo) group.8
To explore further the occurrence of
NEC in association with high-dose IVIG
treatment in hemolytic disease, we
conducted an observational, retro-
spective study. The objective of the
study was to determine whether the
use of high-dose IVIG in late-preterm
140 FIGUERAS-ALOY et al
Downloaded from pediatrics.aappublications.org by guest on November 2, 2012
TABLE 1 Cutoff Values of Total Serum
Bilirubin Levels for Phototherapy
Hours Total Serum Bilirubin
of Life Concentration (mg/dL)
31–36 wk or ⱖ37 wk or
1500–2500 g ⱖ2500 g
12 9 11
24 10 13
48 12 16
72 14 18
ⱖ96 15 20
and term newborns with severe isoim-
mune hemolytic jaundice caused by Rh
and ABO incompatibility was a risk fac-
tor for NEC.
METHODS
Population
This observational, retrospective study
was conducted at 3 high-risk neonatal
referral centers of acute care teaching
hospitals in Barcelona, Spain. Between
January 1993 and December 2008, a
total of 492 liveborn infants who were
of ⱖ34 week’s gestation, had isoim-
mune hemolytic jaundice, needed at
least phototherapy, and were consec-
utively attended at the participating
units were included in the study. Isoim-
mune hemolytic jaundice was attribut-
able to ABO incompatibility in 401 pa-
tients and to Rh incompatibility in the
remaining 91.
Medical Treatment
The therapeutic protocol of infants
with nonhemolytic and hemolytic jaun-
dice was the same in the 3 hospitals
during the 16-year study period. Table
1 shows the cutoff values for total se-
rum bilirubin concentrations accord-
ing to the hours of life and the gesta-
tional age or the birth weight that was
used for the indication of photother-
apy in nonhemolytic jaundice. Ex-
change transfusion was performed
when total serum bilirubin level was 5
points above the phototherapy limit. In
infants with isoimmune hemolytic
jaundice caused by Rh incompatibility,
phototherapy was started on admis-
sion, whereas in infants with ABO
incompatibility, phototherapy was
started when total serum bilirubin
level plus 2 points reached the cutoff
value. Phenobarbital was adminis-
tered intramuscularly or intrave-
nously at the same time (5 mg/kg every
12 hours for 3 days). In infants with
either Rh or ABO incompatibility, ex-
change transfusion was indicated
when total serum bilirubin level plus 2
points reached the cutoff value. In both
Rh and ABO incompatibility, high-dose
IVIG (500 mg/kg over 2– 4 hours and
repeated if necessary every 24 – 48
hours) was indicated when the total
serum bilirubin plus 2 points reached
85% of the cutoff value for performing
exchange transfusion. Total serum bil-
irubin levels, however, should never
surpass 20 mg/dL.
Outcome Measures
Variables were collected from the da-
tabase of infants who were admitted to
the neonatal units, which is shared by
the 3 hospitals. Maternal- and labor-
related variables included medical
center, date of delivery, outborn, ma-
ternal age, use of intravenous antibiot-
ics during the labor, diabetes, pre-
eclampsia, drug addiction, multiple
gestation, and cesarean delivery. Neo-
natal characteristics and outcome in-
cluded gestational age, gender of the
newborn, and resuscitation maneu-
vers (bag and mask or endotracheal
intubation) at the time of delivery, Ap-
gar test at 1 and 5 minutes, birth
weight, small for gestational age (birth
weight ⬍10th percentile by gesta-
tional age by using the neonatal curves
from Catalonia11), polycythemia (ve-
nous hematocrit ⬎70% at 6 hours af-
ter birth), maximum total serum biliru-
bin level, any volume of formula
feeding given initially, use of high-dose
IVIG, exchange transfusion, evidence of
NEC (diagnosed with the accepted
combination of clinical signs and ra-
 ARTICLES

TABLE 2 Salient Characteristics of 11 Infants With Necrotizing Enterocolitis

Gender Cause Birth Gestational Maximum Total IVIG Dosage and Feeding (Diet IVIG Hours NEC, Hours Surgery Outcome
Weight, g Age, wk Serum Bilirubin, Perfusion Duration, h) of Life of Life for NEC
mg/dL Duration
Female Rh 2700 34 9.4 1000 mg/kg, 2 h Formula (2 h) 14 58 No Alive
Male ABO 2760 39 20.0 1000 mg/kg, 2 h Breastfeeding (2 h) 52 54 No Alive
Female Rh 2720 35 19.8 500 mg/kg, 2 h Formula 106 148 No Alive
500 mg/kg, 2 h No diet 144
Female ABO 2930 39 7.3 500 mg/kg, 3 h No feeding 10 40 Yes Alivea
Female Rh 2770 37 14.5 500 mg/kg, 2 h Breastfeeding (2 h) 4 132 No Alive
500 mg/kg, 4 h 14
500 mg/kg, 4 h 36
Female ABO 3210 39 19.0 500 mg/kg, 4 h Formula, no diet 51 56 Yes Deceased
Female ABO 1850 35 12.0 500 mg/kg, 4 h Formula, no diet 31 104 Yes Alive
Female ABO 3300 41 15.0 500 mg/kg, 4 h Formula (3 h) 33 78 No Alive
500 mg/kg, 4 h 51
Female Rh 2830 38 17.1 500 mg/kg, 4 h Formula (2 h) 48 84 No Alive
Female ABO 1660 37 14.5 500 mg/kg, 4 h Formula (10 h) 54 74 Yes Alive
Male ABO 3070 37 14.3 No Breastfeeding 100 Yes Alive
a Died at 2 years of age as a result of short bowel syndrome.

diographic findings), and surgical
treatment of NEC, if needed. All out-
comes, including death, were re-
corded until infants were discharged
from the hospital.
Statistical Analysis
The null hypothesis was that neonates
who were born at ⱖ34 weeks’ gesta-
tion and affected by isoimmune hemo-
lytic jaundice that presented NEC had
the same probability of being treated
with high-dose IVIG as newborns with-
out NEC. Bivariate analyses included
the comparison of maternal and labor
data as well as neonatal characteris-
tics and outcome between the groups
with and without IVIG therapy and be-
tween the groups with and without
NEC. Categorical variables were ana-
lyzed with the ␹2 test and 2-sided
Fisher’s exact test, and continuous
variables were measured with the
Mann-Whitney U test. Results were ex-
pressed as number and percentage
(categorical data) or as median and
interquartile range (25th–75th per-
centiles). Because IVIG was not admin-
istered in a randomized manner and
despite a common protocol for the 3
participating centers, the use of IVIG
could have been conditioned by differ-
ent circumstances (eg, medical cen-
ter, period of time, outborn); there-
fore, to avoid attributing to IVIG what
may be attributable to other variables,
we established a propensity score12
for IVIG (administered or not). This
score was obtained with a logistic re-
gression model that included the de-
mographic variables that in the bivari-
ate analysis were associated with IVIG
(P ⬍ .3) and not considered covari-
ables or confounders. Covariables
were the variables that were probably
related to NEC at P ⬍ .1 in bivariate
analysis, whereas confounders were
the variables that at the same time had a
P ⬍ .3 in infants who were classified by
exposure (IVIG) and by outcome (NEC).
Variables that were entered in the log-
istic regression model included the
covariables, the potential confounding
variables, and the propensity score. A
forward stepwise approach was used.
Data were analyzed with the Statistical
Package for the Social Sciences (SPSS
13.0, Chicago, IL).
RESULTS
Of the total 492 infants included in the
study and treated with phototherapy,
167 received high-dose IVIG. NEC was
diagnosed in 11 (2.2%) patients: 10
(6%) of 167 in IVIG-treated patients and
1 (0.3%) of 325 in the non–IVIG-treated
group (P ⬍ .001). There were 9 female
infants and 2 male infants. Five pa-
tients required urgent operation, and
1 of them died as a result of massive
intestinal necrosis. NEC developed be-
tween 40 and 148 hours after birth and
between 2 and 96 hours after IVIG ad-
ministration. The characteristics of
these patients are detailed in Table 2.
Seven newborns received formula
feeding (any volume), 3 received
breastfeeding only, and 1 was never
fed. Apart from this last newborn, a
diet period during/after IVIG admin-
istration was not indicated for 3 new-
borns who were formula-fed. Two in-
fants with NEC received exchange
transfusion, which was performed
before IVIG therapy in 1 and after op-
eration for NEC as a result of high
serum bilirubin level (23 mg/dL) in
the other. No infant needed mechan-
ical ventilation or presented arterial
hypotension before the diagnosis of
NEC. All of them were healthy, except
for 2 girls with Rh incompatibility,
who were born with anemia and
needed to receive a transfusion in
the first hour after birth.
Treatment with high-dose IVIG was
more significantly frequent in infants
with Rh incompatibility (50.5%) than in

PEDIATRICS Volume 125, Number 1, January 2010 141

Downloaded from pediatrics.aappublications.org by guest on November 2, 2012
TABLE 3 Variables Associated With the Administration of High-Dose IVIG and With the Occurrence of NEC
Variable Treatment of Isoimmune Hemolytic Jaundice NEC
Phototherapy and Phototherapy P Present Absent P
IVIG (n ⫽ 167) Only (n ⫽ 325) (n ⫽ 11) (n ⫽ 481)
Maternal and labor data
Medical center .057 .417
1 34 (45.9) 40 (54.1) 3 (4.1) 71 (95.9)
2 101 (31.4) 221 (68.6) 7 (2.2) 315 (97.8)
3 32 (33.3) 64 (66.7) 1 (1.0) 95 (99.0)
Period of study .375 .620
1993–1999 53 (35.1) 98 (64.9) 4 (2.6) 147 (97.4)
2000–2004 74 (36.3) 130 (63.7) 3 (1.5) 201 (98.5)
2005–2008 40 (29.2) 97 (70.8) 4 (2.9) 133 (97.1)
Outborn 53 (31.7) 81 (24.9) .108 2 (18.2) 132 (27.4) .495
Antimicrobials during labor 49 (32.2) 105 (33.5) .778 3 (33.3) 151 (33.1) .999
Diabetes in the mother 9 (5.4) 23 (7.1) .472 0 (0.0) 32 (6.7) .999
Preeclampsia 1 (0.6) 10 (3.1) .108 0 (0.0) 11 (2.3) .999
Drug addiction 1 (0.6) 2 (0.6) .999 0 (0.0) 3 (0.6) .999
Multiple gestation 3 (1.9) 9 (2.8) .759 0 (0.0) 12 (2.5) .999
Cesarean delivery 34 (21.0) 75 (23.4) .544 6 (54.5) 103 (21.9) .020
Neonatal characteristics
Male gender 77 (46.1) 166 (51.1) .297 2 (18.2) 241 (50.1) .036
Gestational age, median (IQR), wk 38.7 (37.0–39.5) 39.0 (38.0–40.0) .003 37.1 (36.0–39.0) 39.0 (37.4–40.0) .054
Birth weight, mean (IQR), g 3189 (2773–3460) 3190 (2875–3530) .542 2770 (2710–3000) 3200 (2870–3530) .006
Resuscitation maneuvers 7 (4.3) 15 (4.8) .811 3 (27.3) 19 (4.1) .011
Apgar score at 1 min, median (IQR) 9 (9–9) 9 (9–9) .842 9 (8–9) 9 (9–9) .052
Apgar score at 5 min, median (IQR) 10 (10–10) 10 (10–10) .722 10 (9–10) 10 (10–10) .060
Small for gestational age 14 (8.4) 29 (8.9) .841 3 (27.3) 40 (8.3) .063
Polycythemia 2 (1.2) 2 (0.6) .607 0 (0.0) 4 (8.3) .999
Serum bilirubin, maximum (IQR), mg/dL 18.6 (15.6–20.6) 15.5 (13.5–18.0) .000 15.0 (14.5–17.3) 16.2 (14.0–19.2) .601
Formula feeding (any volume) 102 (63.8) 227 (71.7) .079 7 (63.6) 323 (69.1) .806
Death 1 (0.6) 1 (0.3) .999 1 (9.1) 1 (0.2) .044
Data are n (%) unless otherwise stated. IQR indicates interquartile range.

those with ABO incompatibility (30.2%;
P ⬍ .001). Newborns who were treated
with IVIG had a more severe hemolytic
disease, with higher total serum biliru-
bin levels (Table 3), and needed more
exchange transfusions than infants
who were treated only with photother-
apy (19.2% vs 7.4%; P ⬍ .001). Maxi-
mum total serum bilirubin level in the
24 newborns who needed exchange
transfusion and were treated only with
phototherapy was 23.8 mg/dL (inter-
quartile range: 17.9 –29.4 mg/dL). Ex-
change transfusion was performed in
18.2% (2 of 11) of infants with NEC and
in 11.2% (54 of 481) of newborns with-
out NEC (P ⫽ .362). As shown in Table 3,
gestational age and male gender were
independent variables associated with
both IVIG therapy and NEC (P ⬍ .3, con-
founders), whereas cesarean delivery,
resuscitation maneuvers, birth weight,
Apgar test at 1 and 5 minutes, small for
gestational age, and IVIG administra- DISCUSSION
tion were independent variables asso- One of the modes of action of immuno-
ciated with NEC (P ⬍ .1, covariates). globulin involves modulation of the ex-
Medical center, outborn, serum bili-
pression and function of Fc receptors
rubin level, exchange transfusion,
in reticuloendothelial cells,13 by occu-
and formula feeding (P ⬍ .3 only for
pying these receptors and preventing
IVIG therapy) were used to obtain the
them from lysing antibody-coated red
propensity score. In the multivariate
cells; therefore, IVIG administration re-
analysis, cesarean delivery (odds ra-
tio [OR]: 3.76 [95% confidence inter- duces the need for exchange transfu-
val (CI: 1.10 –12.90]), Apgar test at 5 sion in isoimmune hemolytic jaundi-
minutes (OR: 0.50 [95% CI: 0.40 – ces. In our experience, when IVIG was
0.64]), and high-dose IVIG (OR: 31.66 administered to infants with severe
[95% CI: 3.25–308.57]) were indepen- forms of isoimmune hemolytic dis-
dent factors significantly associated ease, exchange transfusion was per-
with NEC (Table 4). formed in 19.2% (32 of 167), a percent-
TABLE 4 Results of Multivariate Analysis
Variable Coefficient (␤) SE P OR 95% CI
Cesarean delivery 1.325 0.629 .035 3.76 1.10–12.90
Apgar score at 5 min ⫺.682 0.120 .000 0.50 0.40–0.64
High-dose IVIG treatment 3.455 1.162 .003 31.66 3.25–308.57
Nagelkerke R2 ⫽ 0.942.

142 FIGUERAS-ALOY et al
Downloaded from pediatrics.aappublications.org by guest on November 2, 2012

age similar to 14.6% found in
systematic reviews,6,14 although higher
than 7.1% reported by Miqdad et al9 in
hemolytic disease caused by ABO in-
compatibility. The meta-analysis of Al-
cock and Liley6 published in 2002 con-
cluded that the role of IVIG remains
uncertain, although its use reduces
the need for exchange transfusion. IVIG
may play a role in special circum-
stances, such as parental refusal or
unavailability of blood components for
exchange transfusion. In contrast, the
meta-analysis of Gottstein and Cooke14
showed that IVIG is an effective treat-
ment for neonatal hemolytic disease
because it reduces the need for ex-
change transfusion, duration of photo-
therapy, and length of hospital stay.
Adverse events were mild and usually
clinically irrelevant. The authors con-
cluded that “it may be considered un-
ethical to delay wider use of high-dose
IVIG while carrying out further re-
search.”14 Nasseri et al15 reported that
the administration of IVIG to newborns
with significant hyperbilirubinemia
caused by Rh hemolytic disease re-
duced the need for exchange transfu-
sion, but in ABO hemolytic disease,
there was no significant difference be-
tween IVIG and double-surface blue-
light phototherapy.
Adverse events that were reported af-
ter the use of IVIG include pyrogenic
reactions, volume overload (with tran-
sient tachycardia or hypertension), hy-
poglycemia, and hypotension that dis-
appeared after stopping the infusion.
Because of the purification processes,
currently used IVIG products have a
very low risk for transmitting infec-
tious diseases5; however, hemolysis16
can be an uncommon complication as
well as acute renal failure and
NEC.8,10,17 Renal failure seems related
to tubular damage induced by sucrose
in the IVIG preparation.18 Wittstock et
al19 and Go et al20 reported that IVIG
may produce severe deep vein throm-
PEDIATRICS Volume 125, Number 1, January 2010
Downloaded from pediatrics.aappublications.org by guest on November 2, 2012
bosis in adults with immunomediated
diseases. The thrombosis developed
within 3 days after infusion of IVIG19
and was attributed to hyperviscosity of
the IVIG preparation. The pathophysio-
logic process and clinical presentation
of NEC in late-preterm infants or term
newborns is different from standard
NEC in more immature preterm infants
because it is especially attributable to in-
testinal hypoxia-ischemia (as a result of
thrombosis) instead of infection.21 Hy-
perviscosity of the IVIG solutions may in-
crease the risk for intestinal thrombosis.
Because IVIG is administered during the
first days of life, its prothrombotic effect
may also increase the physiologic hyper-
coagulability of the fetus and newborn
after birth.
In our experience, high-dose IVIG ad-
ministration was associated with NEC
in 6% of newborns who were of ⱖ34
week’s gestation, had isoimmune he-
molytic jaundice, and were already
treated with phototherapy. Moreover,
NEC was severe enough to require ur-
gent surgery (40% of the cases) and to
cause 2 deaths. When isoimmune he-
molytic disease was not severe enough
to justify IVIG administration, NEC oc-
curred in only 0.3% of the patients.
Newborns with ⬍34 weeks’ gesta-
tional age and affected by isoimmune
hemolytic jaundice were excluded
from the study because in these cases,
NEC could have been related to their
immaturity. In our experience, in no
case was treatment with IVIG given
prophylactically. The indication of im-
munoglobulin therapy was delayed un-
til the need for exchange transfusion
was imminent. This was possible
thanks to the common protocol at the 3
hospitals during these 16 years. The
frequency of IVIG treatment varied
from 31.4% to 45.9% among the cen-
ters, probably in relation to the sever-
ity of the infants’ conditions. Before
2000, IVIG was administered during 2
hours instead of 4 hours, but the treat-
ARTICLES
ment schedule was the same in the
groups with and without NEC.
Our study was observational and ret-
rospective, and treatment with IVIG
was not assigned at random. Despite
the common protocol at the 3 partici-
pating centers, the probability of re-
ceiving the IVIG treatment might have
been influenced by clinical or demo-
graphic factors. From the clinical point
of view, the infants with the most se-
vere conditions were the ones who re-
ceived the IVIG therapy. To control this
bias, we considered that severity of he-
molysis was proportional to total se-
rum bilirubin level, and this variable
was included in the calculation of the
propensity score for IVIG treatment.
Propensity scores are used in observa-
tional studies to adjust for nonrandom
treatment allocations,12 minimizing
the likelihood of attributing to IVIG an
effect that was related to other factors
that influenced the decision of giving
IVIG. By reducing the 5 variables that
were included in the propensity
score to 1 summary score, the de-
grees of freedom in the logistic re-
gression model were also dimin-
ished. Moreover, it was adjusted for
a number of potentially confounding
factors, although it is still possible
that unmeasured risk factors can be
responsible for some of the associa-
tions observed.
Another interesting aspect is whether
more severe hemolysis might predis-
pose to intestinal compromise, such
that NEC may be associated with hemo-
lysis rather than with IVIG therapy. In
our series, no statistically significant
differences in total serum bilirubin lev-
els according to the presence or ab-
sence of NEC were observed. This find-
ing suggests that NEC was unrelated to
the severity of hemolysis.
CONCLUSIONS
Although the infants with the most se-
vere conditions were the ones who re-
143
ceived the IVIG therapy, the administra-
tion of high-dose IVIG for severe
isoimmune hemolytic jaundice was as-
sociated with a higher incidence of NEC
in late-preterm and term infants, par-
ticularly in the presence of cesarean
delivery and low Apgar score at 5 min-
utes. Other factors that also related to
the development of this complication
were female gender, low birth weight,
and need for resuscitation maneuvers
REFERENCES
1. American Academy of Pediatrics Subcom-
mittee on Hyperbilirubinemia. Management
of hyperbilirubinemia in the newborn infant
35 or more weeks of gestation [published
correction appears in Pediatrics. 2004;
114(4):1138]. Pediatrics. 2004;114(1):297–
316
2. Hansen TW. Recent advances in the pharma-
cotherapy for hyperbilirubinaemia in the
neonate. Expert Opin Pharmacother. 2003;
4(11):1939 –1948
3. Smits-Wintjens VE, Walther FJ, Lopriore E.
Rhesus haemolytic disease of the newborn:
postnatal management, associated mor-
bidity and long-term outcome. Semin Fetal
Neonatal Med. 2008;13(4):265–271
4. Orange JS, Hossny EM, Weiler CR, et al. Use
of intravenous immunoglobulin in human
disease: a review of evidence by members
of the Primary Immunodeficiency Commit-
tee of the American Academy of Allergy,
Asthma and Immunology.[published cor-
rection appears in J Allergy Clin Immunol.
2006;117(6):1483]. J Allergy Clin Immunol.
2006;117(4 suppl):S525–S553
5. Sloan SR. Blood products used in the new-
born. In: Cloherty JP, Eichenwald EC, Stark
AR, eds. Manual of Neonatal Care. 6th ed.
Philadelphia, PA: Wolters Kluwer, Lippincott
Williams & Wilkins; 2008:463– 469
6. Alcock GS, Liley H. Immunoglobulin infusion
for isoimmune haemolytic jaundice in neo-
nates. Cochrane Database Syst Rev. 2002;
(3):CD003313
7. Ohlsson A, Lacy JB. Intravenous immuno-
globulin for preventing infection in preterm
144 FIGUERAS-ALOY et al
Downloaded from pediatrics.aappublications.org by guest on November 2, 2012
at the time of delivery. In these circum-
stances, clinicians should be cautious
before prescribing IVIG to a newborn. If
it is considered necessary, then the in-
fusion should be administered slowly
(at least during 4 hours) to reduce the
effects of hyperviscosity; however, in
the present era, in which more potent
phototherapy devices are available, we
agree with Alcock and Liley6 that it is
warranted to perform a multicenter,
and/or low-birth-weight infants. Cochrane
Database Syst Rev. 2004;(1):CD000361
8. Fanaroff AA, Korones SB, Wright LL, et al. A
controlled trial of intravenous immune
globulin to reduce nosocomial infections in
very-low-birth-weight infants. National In-
stitute of Child Health and Human Develop-
ment Neonatal Research Network. N Engl
J Med. 1994;330(16):1107–1113
9. Miqdad AM, Abdelbasit OB, Shaheed MM,
Seidahmed MZ, Abomelha AM, Arcala OP. In-
travenous immunoglobulin G (IVIG) therapy
for significant hyperbilirubinemia in ABO
hemolytic disease of the newborn. J Matern
Fetal Neonatal Med. 2004;16(3):163–166
10. Merlob P, Litmanovitch I, Mor N, Litwin A,
Wielunsky E. Necrotizing enterocolitis after
intravenous immunoglobulin treatment for
neonatal isoimmune thrombocytopenia.
Eur J Pediatr. 1990;149(6):432– 433
11. Ramos F, Prats R, Jané M, Plasència A, Pérez
G. Neonatal weight, height, and head cir-
cumference reference curves for single-
tons, twins, and triplets in Catalonia [in
Spanish]. General Direction of Public
Health, Autonomous Government of Catalo-
nia. Prous Science, 2007
12. Rubin DB. Estimating causal effects from
large data sets using propensity scores.
Ann Intern Med. 1997;127(8 pt 2):757–763
13. Kazatchkine MD, Kaveri SV. Immunomodula-
tion of autoimmune and inflammatory dis-
eases with intravenous immune globulin.
N Engl J Med. 2001;345(10):747–755
14. Gottstein R, Cooke RW. Systematic review of
randomized, controlled trial to exam-
ine the safety and efficacy of high-dose
IVIG treatment to assess the incidence
of adverse events, short-term results,
and long-term neurodevelopmental
outcomes.
ACKNOWLEDGMENTS
We thank Marta Pulido, MD, for edit-
ing the manuscript and for editorial
assistance.
intravenous immunoglobulin in haemolytic
disease of the newborn. Arch Dis Child Fetal
Neonatal Ed. 2003;88(1):F6 –F10
15. Nasseri F, Mamouri GA, Babaei H. Intrave-
nous immunoglobulin in ABO and Rh hemo-
lytic diseases of newborn. Saudi Med J.
2006;27(12):1827–1830
16. Copelan EA, Strohm PL, Kennedy MS, Tut-
schka PJ. Hemolysis following intravenous
immune globulin therapy. Transfusion.
1986;26(5):410 – 412
17. Ward RM. Drugs. In: Taeusch HW, Ballard RA.
Gleason CA, eds. Avery’s Diseases of the
Newborn. 8th ed. Philadelphia, PA: Elsevier
Saunders; 2005:1557–1572
18. Decocq G, de Cagny B, Andréjak M, Desablens
B. Acute kidney failure secondary to intrave-
nous immunoglobulin administration: 4 cases
and review of the literature [in French]. Thera-
pie. 1996;51(5):516 –526
19. Wittstock M, Benecke R, Zettl UK. Therapy
with intravenous immunoglobulins: compli-
cations and side-effects. Eur Neurol. 2003;
50(3):172–175
20. Go RS, Call TG. Deep venous thrombosis of
the arm after intravenous immunoglobulin
infusion: case report and literature review
of intravenous immunoglobulin-related
thrombotic complications. Mayo Clin Proc.
2000;75(1):83– 85
21. Owens L, Berseth CL. Clinical presentation
of necrotizing enterocolitis (NEC) differs be-
tween very low birth weight (VLBW) and low
birth weight (LBW) infants. J Clin Investigat
Med. 1996;44(1):14A
 Intravenous Immunoglobulin and Necrotizing Enterocolitis in Newborns With
Hemolytic Disease
Josep Figueras-Aloy, José M. Rodríguez-Miguélez, Martin Iriondo-Sanz,
María-Dolores Salvia-Roiges, Francesc Botet-Mussons and Xavier Carbonell-Estrany
Pediatrics 2010;125;139; originally published online November 30, 2009;
DOI: 10.1542/peds.2009-0676
Updated Information & including high resolution figures, can be found at:
Services http://pediatrics.aappublications.org/content/125/1/139.full.ht
ml
References This article cites 18 articles, 2 of which can be accessed free
at:
http://pediatrics.aappublications.org/content/125/1/139.full.ht
ml#ref-list-1
Citations This article has been cited by 5 HighWire-hosted articles:
http://pediatrics.aappublications.org/content/125/1/139.full.ht
ml#related-urls
Post-Publication 3 P3Rs have been posted to this article
Peer Reviews (P3Rs) http://pediatrics.aappublications.org/cgi/eletters/125/1/139
Subspecialty Collections This article, along with others on similar topics, appears in
the following collection(s):
Premature & Newborn
http://pediatrics.aappublications.org/cgi/collection/premature
_and_newborn
Permissions & Licensing Information about reproducing this article in parts (figures,
tables) or in its entirety can be found online at:
http://pediatrics.aappublications.org/site/misc/Permissions.xht
ml
Reprints Information about ordering reprints can be found online:
http://pediatrics.aappublications.org/site/misc/reprints.xhtml

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org by guest on November 2, 2012