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Original Article

Indomethacin Doseinterruption and Maternal

Chorioamnionitis are Risk Factors for Indomethacin
Treatment Failure in Preterm Infants with Patent Ductus
Arteriosus
Souvik Mitra, Muzafar Gani Abdul Wahab
Department of Pediatrics, Division of Neonatology, McMaster University, Hamilton, Ontario, Canada

ABSTRACT
Background: Indomethacin has been used as the primary pharmacotherapeutic agent for the closure of patent ductus arteriosus(PDA) in preterm
infants. However, it is commonly observed that infants often respond differently to indomethacin treatment with some requiring multiple courses of
the drug and subsequently surgical ligation. Objectives: To explore common variables that could be associated with failure of a primary course of
indomethacin for PDA in preterm infants. Methods: We examined 83 preterm infants who received intravenous indomethacin for PDA treatment
from 2010 to 2013. We identified those who failed primary pharmacotherapy and required subsequent courses or surgical ligation. Anumber of
perinatal/neonatal variables in the infants with and without primary indomethacin failure were compared initially for univariate analysis. Following
the univariate analysis, those variables which had a significant difference between the two groups were selected to carry out logistic regression
analysis to find out independent risk factors for indomethacin failure. Results: Of 77 infants analyzed, 36(46.7%) had a primary indomethacin
failure and nine infants(11.7%) underwent surgical ligation. Univariate analysis revealed that infants with primary indomethacin failure were
significantly more preterm, were more likely to be males, did not receive a complete course of antenatal corticosteroids, their mothers had clinical
chorioamnionitis and indomethacin dose interruption was documented during clinical care. The multivariate logistic regression analysis showed
that dose interruption(odds ratio[OR]: 27.14; 95% confidence interval[CI]: 5.94, 124.07) and clinical chorioamnionitis(OR: 7.80; 95% CI: 1.73,
35.00) were independent risk factors for indomethacin failure. Conclusion: Indomethacin dose interruption and clinical chorioamnionitis appear
to be independent risk factors for primary indomethacin failure in preterm infants.

Key words:
Chorioamnionitis, doseinterruption, indomethacin, patent ductus arteriosus

INTRODUCTION primary pharmacotherapeutic agent for the closure of a

Patent ductus arteriosus (PDA) is one of the most
controversial topics in the management of preterm
infants. It is a wellknown fact that more preterm the
infant is, more likely it is that the infant would have a
persistent and often clinically significant PDA that would
require treatment.[1] Indomethacin has been used as the
Address for correspondence:
Dr.Muzafar Gani Abdul Wahab,
Department of Pediatrics, Division of Neonatology, McMaster
University Medical Centre, HSC4F, 1280 Main Street West,
Hamilton, Ontario L8S 4K1, Canada.
Email:abdulwmg@mcmaster.ca
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hemodynamically significant PDA. However, it is commonly
observed that infants with similar gestational age and
clinical profile often respond differently to Indomethacin
treatment with some requiring multiple courses of the drug
and subsequently surgical ligation. Over the last few years,
management of PDA in preterm infants has undergone a
paradigm shift. Moving away from the prophylactic or early
interventional approach, a number of Neonatal Intensive
Care Units (NICUs) have adopted a more conservative,
individualized and targeted approach to the management
of the patent duct in a premature infant.[2] The adjunctive
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How to cite this article: Mitra S, Wahab MG. Indomethacin

DOI: dose-interruption and maternal chorioamnionitis are risk factors
10.4103/2249-4847.165688 for indomethacin treatment failure in preterm infants with patent
ductus arteriosus. J Clin Neonatol 2015;4:250-5.

250 2015 Journal of Clinical Neonatology | Published by Wolters Kluwer - Medknow

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Mitra and Wahab:Clinical chorioamnionitis and doseinterruption are risk factors for indomethacin failure
perinatal and neonatal management strategies have also
undergone significant changes over the last few years.
Therefore, a number of antenatal and postnatal factors may
affect the infants response to indomethacin treatment for
PDA.
A number of studies have tried to look into different
variables associated with indomethacin failure.
A PubMed/MEDLINE search (Search details: (Ductus
Arteriosus, Patent [Mesh] AND Infant,
Newborn [Mesh]) AND Indomethacin [Mesh])
yielded 660 articles out of which 9 articles have tried
to explore risk factors associated with indomethacin
failure and persistent ductus in the past decade.[311] The
antenatal factors that have been studied include exposure
to antenatal betamethasone, gestational diabetes,
preeclampsia, chorioamnionitis.[9] Out of these lack of
antenatal steroids was found to be a significant risk factor
for pharmacotherapeutic failure.[9] In a recent study by
Arayici etal., histological chorioamnionitis was found to
be an important risk factor for persistent PDA.[12] Among
the postnatal factors, the most commonly studied factors
include birth weight, gestational age, sex, race, postnatal
age at indomethacin treatment, respiratory distress
syndrome, excess fluid administration, platelet counts and
treatment with furosemide, caffeine and phototherapy.
[811,1315]
However, almost all these studies included a
population dating back to 2009 or earlier except one by
Sallmon etal. which included a population between 2005
and 2010.[3] With the advent of ibuprofen, the research
focus has largely shifted away from indomethacin in the
past few years. For example a recent study by BasSurez
et al. has looked into factors associated with failure
of prostaglandin inhibitors in PDA, but in their study
neonates from 2006 to 2009 received indomethacin and
neonates thereafter (20092012) received ibuprofen.[16]
Similar studies in recent times by Dani etal. and Alyamac
Dizdar etal. have focused on factors related to ibuprofen
failure.[17,18] However, for institutions that continue to
use indomethacin, it is important to identify the factors
associated with indomethacin failure, especially with the
currently adopted conservative management protocols.
With this background, we conducted a study to explore
common variables that could be associated with failure of
a primary course of indomethacin for hemodynamically
significant PDA in the preterm population in a tertiary
care center.
METHODS
Design and data sources
We performed a singlecenter retrospective study of
infants who received indomethacin for treatment PDA at
McMaster Childrens Hospital, Hamilton, Ontario, Canada.
Journal of Clinical Neonatology | Vol. 4 | Issue 4 | October-December 2015
Data was collected for the period between 2010 and 2013.
Infants who have received Indomethacin during the period
were identified using the Canadian Neonatal Network
database. Subsequently, details regarding perinatal and
neonatal variables were obtained using medical records
and electronic lab results. This study was approved by the
Hamilton Integrated Research Ethics Board.
Infants admitted to the NICU during the study period and
meeting both the following criteria were included in the
study: (i) Neonates who completed a primary course of
indomethacin for a significant PDA, and(ii) also required
a second course of indomethacin or surgical ligation
following a primary course of indomethacin. Infants who
did not receive all three doses of indomethacin to complete
a primary course were excluded. Those eligible infants who
died during the NICU stay were also excluded from the
final analytical sample.
Definitions
A complete course of indomethacin was defined as
three doses of indomethacin (0.2 mg/kg/dose) infused
over20min at 12 hourly intervals in accordance with the
hospital policy. Failure of primary course of indomethacin
was defined as infants requiring more than one full course
of indomethacin for closure of PDA or received one full
course of indomethacin followed by surgical ligation for
the closure of PDA. Infants who did not require more than
one course of indomethacin during their hospital stay were
deemed as those who did not have primary indomethacin
failure. The decision to treat PDA was at the discretion
of the attending neonatologist in the presence of clinical
symptoms attributable to PDA along with fulfilment of
predefined echocardiographic criteria. The clinical criteria
include any two of the following:
FiO2 requirement >30% to maintain target SpO2
between 91% and 95%
Escalation of ventilator parameters from baseline to
maintain normal pCO2 levels
Feeding intolerance defined as inability to increase
feeds as per institutional feeding guidelines due to
increased residuals/abdominal distension
Need for inotropes for hypotension management.
The echocardiographic criteria include presence of two or
more of the following:[19]
Transductal PDA diameter>1.4mm/kg
Unrestrictive pulsatile transductal flow (PDA
maximum velocity[Vmax] <2.0m/s)
Mildtomoderate left heart volume loading (left
atrium/aorta[LA/Ao] ratio>1.4)
Increased pulmonary perfusion, that is, mean and
enddiastolic flow velocity in the left pulmonary
artery0.42 and0.20m/s, respectively
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Mitra and Wahab:Clinical chorioamnionitis and doseinterruption are risk factors for indomethacin failure
Increased left ventricular output(LVO) and consistent
peripheral hypoperfusion in the superior vena
cava(SVC), that is, LVO/SVC flow ratio4.
Antenatal and postnatal variables
The antenatal variables that were studied included(i) complete
course of antenatal steroids;(ii) clinical chorioamnionitis in
the mother. Definition of variables: Clinical chorioamnionitis
was defined as presence of maternal fever >38C and >2 of
following: Maternal heart rate>100/min; fetal heart rate>160/
min; uterine tenderness; foul smelling amniotic fluid and
maternal leukocytosis (>15,000/cumm).[20] Complete
course of antenatal steroids were defined as two doses of
betamethasone(12mg each) given 24h apart or four doses of
dexamethasone(6mg each) given intramuscularly 12h apart
to the mother with the last dose being given at least 24h prior
to delivery.[21] The postnatal variables included(i) gestational
age;(ii) birth weight; (iii) sex;(iv) presence of respiratory distress
syndrome requiring surfactant therapy; (v) prophylactic
indomethacin administration;(vi) postnatal age at the start of
primary course of indomethacin;(vii) any interruption in the
dosage schedule during the primary course;(viii) total fluid
intake at start of therapy; (ix) blood culture positive sepsis
receiving antibiotics at start of treatment;(x) platelet counts
at the start of the primary indomethacin course; whether the
baby was receiving; (xi) caffeine citrate; (xii) phototherapy
at the start of the primary course. An interruption in dosage
was defined as any deviation from the prescribed frequency
of doses in a complete course of indomethacin as defined
above. Only cases, where the course was completed in spite of
interruption, were included for analysis.
Data analysis
Variables of infants with and without primary indomethacin
failure were compared initially for univariate analysis. The
Chisquare test was used for analysis of categorical variables.
For continuous variables, the Students ttest(unpaired) was
used for analysis of variables with normal distribution and
the MannWhitney Utest for analysis of variables with
skewed distribution. Following the univariate analysis, those
variables which had a significant difference between the two
groups were selected to carry out logistic regression analysis
to find out independent risk factors for indomethacin failure.
All data were entered into Excel spreadsheet and analyzed
using Minitab 17 Statistical Software (2010). [Computer
software]. State College, PA: Minitab, Inc. P <0.05 was
considered to be statistically significant. Odds ratio (OR)
and 95% confidence intervals (CIs) were calculated for
independent factors in the regression analysis.
RESULTS
Eightythree infants received indomethacin during
the study period out of which six infants died during
252
NICU stay. The remaining 77 infants formed the final
analytical sample. The mean birth weight was 840246g
(mean standard deviation) and gestational age was
252weeks(2331weeks). The overall male:female ratio
was 0.97 (38:39). Mean postnatal age at indomethacin
treatment was 7.2 3.8 days. Out of the 77 infants,
36 (46.7%) had primary indomethacin failure and nine
infants (11.7%) underwent surgical ligation. None of the
infants received prophylactic indomethacin nor received
antibiotics for blood culture positive sepsis at the start of
indomethacin treatment. The distribution of the cases
according to their gestational age is shown in Figure1.
Univariate analysis of the perinatal and neonatal variables
revealed that infants with primary indomethacin failure were
significantly more preterm with a lower birth weight, were
more likely to be males, did not receive a complete course
of antenatal corticosteroids, their mothers had documented
clinical chorioamnionitis and indomethacin dose interruption
was documented during clinical care (P < 0.05) [Table 1].
A total of 36 infants had documented dose interruption.
In 20 of them(55.6%), doses were interrupted due to new
onset oliguria (<1 ml/kg/h), nine infants (25%) had rising
creatinine without oliguria and the rest seven (19.4%)
developed thrombocytopenia(<100109/L).
Based on the results of the univariate analysis, multivariate
logistic regression analysis was performed with the
abovementioned variables that were significant on
univariate analysis. Gestational age and birth weight
were found to be significantly correlated on linear
regression(P<0.0001; Pearson correlation coefficient: 0.75
[95% CI: 0.640.84]; r2 = 0.57). Hence, only gestational
age was used as a covariate in the regression analysis
instead of both gestational age and birth weight. The
multivariate logistic regression analysis showed that dose
interruption(OR: 27.14; 95% CI: 5.94, 124.07) and clinical
Figure1: Distribution of indomethacin failure cases according to
gestational age
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Mitra and Wahab:Clinical chorioamnionitis and doseinterruption are risk factors for indomethacin failure
Table1: Baseline variables and univariate analysis of risk factors for indomethacin failure
Variables
Indomethacin failure (n=36)*
Gestational age (week) 241*
Birth weight (g) 748145*
Sex (male/female) 23/13
Antenatal corticosteroids 18
Clinical chorioamnionitis 22
RDS requiring surfactant 34
Postnatal age at indomethacin treatment (days) 7.64.4*
TFI at indomethacin treatment (ml/kg/day) 1439*
Platelet count at indomethacin start (109/L) 17775*
Dose interruption during indomethacin treatment 30
On caffeine during indomethacin treatment 35
On phototherapy during indomethacin treatment 21
PDA ligation 11
SDStandard deviation; RDSRespiratory distress syndrome; TFITotal fluid intake; PDAPatent ductus arteriosus; *[meanSD]; ** statistically significant (p<0.05)
chorioamnionitis (OR: 7.80; 95% CI: 1.73, 35.00) were
independent risk factors for indomethacin failure in this
population[Table2].
DISCUSSION
Variation in response to indomethacin in preterm infants
has always been an enigma to practicing neonatologists.
As a result, there have been several attempts over the
years to relate this variation to a number of perinatal and
postnatal variables. However, logistic factors play an equally
important role in the successful management of a preterm
infant as does associated physiologic variables. This study
is the first of its kind to test the interaction of operational
factors like indomethacin dosage interruption with relevant
physiologic variables to identify the risk factors for primary
indomethacin failure in this changing era of conservative
PDA management. Interestingly, we found that the presence
of maternal clinical chorioamnionitis and interruption in
indomethacin dosage were independent risk factors for
primary indomethacin failure.
It is often observed in clinical practice that indomethacin
doses are withheld due to poor urine output and resumed
once the urine output has improved. In fact this renal
effect of indomethacin along with its presumed role in
increasing in the incidence of necrotizing enterocolitis
have been cited as the reasons why ibuprofen should be
considered as the drug of choice for PDA pharmacotherapy
in the recent update of the Cochrane database of systematic
reviews.[22] However, in institutions which continue to
use indomethacin as the standard of care, this issue has
largely remained unresolved in spite of infusing the drug
over2030min. The primary reason for this is dearth of good levels and result in variable response to indomethacin
pharmacokinetic (PK)/pharamcodynamic (PD) studies to
guide clinicians on how long to stagger the dosing interval in
Journal of Clinical Neonatology | Vol. 4 | Issue 4 | October-December 2015
P
No indomethacin failure (n=41)
262* 0.001**
922287* 0.001**
15/26 0.01**
22 0.75
7 0.0002**
10 0.05
6.83.2* 0.36
14710* 0.10
18873* 0.53
6 <0.0001**
39 0.45
20 0.54
0 -
the face of a transient oliguria. This grey area in the clinical
practice guidelines could potentially lead to situations where
the plasma levels of indomethacin are subtherapeutic. In
fact, PK/PD studies on indomethacin in preterm infants
have shown that older the infant (>10 days), higher is the
dose required to maintain a critical concentration and
also infants with seconddose peak plasma indomethacin
level<800ng/ml required escalation of therapy to close the
PDA.[23,24] So the question is, is there any way to maintain
therapeutic plasma levels without causing the untoward
side effects? There have been studies which show that even
infusing indomethacin over2030min may also result in a
hemodynamic compromise in the regional microcirculation.
It has been shown by Austin et al. that indomethacin
infusion over 30 min was associated with a significant
reduction in timeaveraged mean velocity, peak systolic
velocity, and end diastolic velocity in both the anterior
cerebral artery and middle cerebral artery.[25] In a recent
study by Bhatt etal. in 2012, it was found that slow infusion
of cyclooxygenase inhibitors were associated with significant
reduction in regional cerebral (rSO2C), renal (rSO2R),
and mesenteric (rSO2M) tissue oxygenation measured by
nearinfrared spectroscopy.[26] Hence, dose interruption as a
risk factor for indomethacin failure poses a unique question
that needs to be addressed with future prospective trials.
Ductus arteriosus tone is maintained in the perinatal
period by prostaglandins (PGE2) and prostacyclin
and their production is mediated by cyclooxygenase
enzyme.[2729] Indomethacin targets this enzyme and
downregulates prostaglandin production which facilitates
ductus closure. However, perinatal inflammation in
the form of chorioamnionitis may potentially alter PG
as observed in our study. This hypothesis was further
strengthened in a similar study by Kim et al., who not
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Mitra and Wahab:Clinical chorioamnionitis and doseinterruption are risk factors for indomethacin failure
Table2: Multivariate logistic regression analysis of
significant risk factors
Variable P OR (adjusted)
Gestational age ( 1-week) 0.302 0.82
Male sex 0.966 0.97
Clinical chorioamnionitis 0.007 7.80
Dose interruption <0.0001 27.14
OROdds ratio; CIConfidence interval
only showed that intrauterine inflammation was an
independent risk factor for persistence of PDA, but also
showed that cyclooxygenase1 expression in the umbilical
arteries and plasma 6keto prostaglandin F1 levels were
higher in nonresponders to indomethacin.[6]
Our univariate analysis revealed certain interesting
observations. Firstly our success rate with the primary course
of indomethacin was much lower(53.3%) as compared to a
randomized trial by Van Overmeire etal. where the closure
rate at day 6 was 73% in the early treatment group.[30] One
possible explanation is that with the conservative approach
of recent times, our mean postnatal age at treatment
initiation was 7.23.8days as compared to 3.1days in the
early treatment group in the Van Overmeire etal. trial. This
conforms to the observations by Shaffer etal. who suggested
that older neonates require higher doses to maintain similar
plasma levels of indomethacin.[23]
A number of other interesting findings were noted on
univariate analyses that were subsequently not found to be
independent risk factors on logistic regression. For example,
female sex was found to be protective on univariate analysis.
Higher incidence of PDA has also been previously reported
in preterm males in observational studies. However no
hypothesis for causality has been established.[31,32] There
has been some speculation that infants with lower platelet
counts respond poorly to indomethacin treatment.[10,33] The
theory has also been refuted in a few other observation
studies.[17,18] We did not find any relation between platelet
counts and primary indomethacin failure. Nor did we
find any relation between the total fluid intake at the start
of treatment and treatment failure which substantiate
the increasingly acknowledged practice of not overtly
restricting fluids during PDA treatment.[2]
We acknowledge the limitations of this being a retrospective
study which brings in an inherent bias of variation in practice
during the course of the study period. Hence we have tried
to strike a balance between limiting our study period to
as short as possible to ensure consistency of neonatal care
versus obtaining a decent sample size to run a logistic
regression with the most important covariates. However, this
has led to a smaller sample size for the study and hence has
limited our ability to test the effect of all potential variables
254
using a regression model. Thus we selected only those
variables that were most significantly different (P < 0.05)
on univariate analysis to build our multivariable regression
95% CI
model. Aprospective study of a similar nature, where all the
0.56, 1.20
variables are defined a priori, would lend more credibility to
0.23, 4.01
the study. Hence we would like to emphasize that our study
1.73, 35.00
only generates an important and previously unexplored
5.94, 124.07
hypothesis regarding the role of dosage interruption in
treatment failure along with the association of the latter with
maternal clinical chorioamnionitis This could pave the way
for future prospective cohort studies to better analyze these
interactions and also prospective randomized controlled
trials to potentially find a solution to the problem associated
with dose interruption.
Acknowledgments
We would like to thank Wendy Seidlitz(RN, BScN, MSc),
Data Management Specialist, Hamilton Health Sciences for
data collection.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflict of interest.
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