Research

ajog.org

OBSTETRICS

Antenatal exposure to indomethacin increases

the risk of severe intraventricular hemorrhage,
necrotizing enterocolitis, and periventricular
leukomalacia: a systematic review with
metaanalysis
Amy L. Hammers, MD; Luis Sanchez-Ramos, MD; Andrew M. Kaunitz, MD
OBJECTIVE: The purpose of this study was to provide an updated

summary of the literature regarding the effects of tocolysis with

indomethacin on neonatal outcome by systematically reviewing previously and recently reported data.
STUDY DESIGN: All previously reported studies pertaining to indomethacin tocolysis and neonatal outcomes along with recently reported data were identified with the use of electronic databases that
had been supplemented with references that were cited in original
studies and review articles. Observational studies that compared
neonatal outcomes among preterm infants who were exposed and not
exposed to indomethacin were included in this systematic review. Data
were extracted and quantitative analyses were performed on those
studies that assessed the neonatal outcomes of patients that received
antenatal tocolysis with indomethacin.
RESULTS: Twenty-seven observational studies that met criteria for

systematic review and metaanalysis were identified. These studies

included 8454 infants, of whom 1731 were exposed to antenatal
indomethacin and 6723 were not exposed. Relative risks with 95%

confidence intervals were calculated for dichotomous outcomes with

the use of random and fixed-effects models. Metaanalysis revealed no
statistically significant differences in the rates of respiratory distress
syndrome, patent ductus arteriosus, neonatal mortality rate, neonatal
sepsis, bronchopulmonary dysplasia, or intraventricular hemorrhage
(all grades). However, antenatal exposure to indomethacin was
associated with an increased risk of severe intraventricular hemorrhage (grade III-IV based on Papiles criteria; relative risk, 1.29; 95%
confidence interval, 1.06e1.56), necrotizing enterocolitis (relative
risk, 1.36; 95% confidence interval, 1.08e1.71), and periventricular
leukomalacia (relative risk, 1.59; 95% confidence interval,
1.17e2.17).
CONCLUSION: The use of indomethacin as a tocolytic agent for pre-

term labor is associated with an increased risk for severe intraventricular hemorrhage, necrotizing enterocolitis, and periventricular
leukomalacia.
Key words: intraventricular hemorrhage, necrotizing enterocolitis,
periventricular leukomalacia

Cite this article as: Hammers AL, Sanchez-Ramos L, Kaunitz AM. Antenatal exposure to indomethacin increases the risk of severe intraventricular hemorrhage,
necrotizing enterocolitis, and periventricular leukomalacia: a systematic review with metaanalysis. Am J Obstet Gynecol 2015;212:



.

reterm birth represents an important perinatal health problem

across the globe, not only in terms of
associated mortality rates but also
with regard to short- and long-term
morbidity and nancial costs. 1,2 In
the Unites States, the preterm birth
rate reached its peak in 2006 (12.8%).
However, despite a gradual decline for

the seventh straight year in 2013

(11.4%), 3 the United States ranks as 1
of the top 10 countries in the world
with the highest number of preterm
births.4 In the United States, premature birth accounts for nearly 35% of
deaths in the rst year of life at an
estimated annual cost that exceeds $26
billion. In addition, preterm birth

From the Department of Obstetrics and Gynecology, University of Florida College of

MedicineeJacksonville, Jacksonville, FL.
Received June 27, 2014; revised Oct. 8, 2014; accepted Oct. 28, 2014.
The authors report no conict of interest.
Corresponding author: Amy Hammers, MD. amy.hammers@jax.u.edu
0002-9378/$36.00
2015 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2014.10.1091

contributes to substantial neurobehavioral impairment.5

Major recent progress has been made
toward the early diagnosis,6 prediction,7-9
and prevention of spontaneous preterm
birth.10-13 However, the mainstay of
therapy for the treatment of acute preterm labor continues to be the employment of pharmacologic agents with the
aim of arrest of or decrease of uterine
contractility and thereby delaying preterm birth. Although tocolytic agents
have been shown to delay delivery for 48
hours to 7 days,14,15 their use has not led
to an improvement in neonatal outcomes. Nonetheless, this short prolongation of pregnancy allows for the
maternal transfer to a tertiary center and

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the administration of corticosteroids to

enhance fetal lung maturity.16
A variety of pharmacologic agents that
have been used, most off-label, to suppress uterine contractility include betamimetics,17-21 magnesium sulfate,22-25
oxytocin receptor antagonists,15,26-29
calcium channel blockers,30-34 cyclooxygenase inhibitors,35-41and nitric oxide donors.42-46 Each of these agents has
a unique mechanism of action and sideeffects. A recent metaanalysis suggested
that the calcium channel blocker nifedipine appears to meet several characteristics of an ideal tocolytic agent.30 A
systematic review and network metaanalysis47 and a metaanalysis with decision analysis48 concluded that calcium
channel blockers and prostaglandin inhibitors had the highest probability
of delaying delivery and improving
neonatal and maternal outcomes.
There is strong evidence that prostaglandins are involved intimately in the
initiation and progression of term and
preterm labor in humans.49-53 Prostaglandins affect myometrial contractility
by direct effect with their own receptors50,51 by an increase in the sensitivity of the myometrium to oxytocin52
and by regulation of myometrial gap
junctions.49 They also stimulate the
inux of intracellular calcium that
activates the enzyme myosin light
chain kinase that results in myometrial
contractility.53
Indomethacin, a cyclooxygenase inhibitor that decreases uterine contractility by blocking the conversion of
arachidonic acid to prostaglandin, has
been used as a tocolytic agent since
1974.54 Many obstetricians continue to
use indomethacin as a rst-line tocolytic
agent, which is an indication that is
supported by the American College of
Obstetricians and Gynecologists.55 A
number of studies have raised concerns
about the safety of indomethacin because
it crosses the placenta and inhibits prostaglandin synthesis in fetal organs.56,57
Case reports and observational studies
have suggested that indomethacin may
cause adverse neonatal outcomes that
include necrotizing enterocolitis (NEC),
intraventricular hemorrhage, periventricular leukomalacia, and other cardiac,

ajog.org
pulmonary, and renal abnormalities.58-61
Accordingly, indomethacins role as a
current option by obstetricians in the
treatment for possible preterm labor is
controversial. Since 2005, 2 systematic
reviews with metaanalyses that assessed
neonatal outcomes after indomethacin
tocolysis, while using similar sources,
have reported conicting results.58,59 The
rst of these reports included both
observational studies and randomized
trials; the subsequent report included
only observational studies. Subsequent to
these publications, more recent observational and prospective studies that
assessed indomethacin tocolysis have
been published.62-67 The goal of this
current study was to review these new
studies, to reanalyze studies that were
included in the 2 previous reviews, and to
pool the data to determine more accurately the neonatal effects of indomethacin exposure, thus providing needed
guidance regarding the use of this medication for tocolysis.

M ATERIALS

AND

M ETHODS

This systematic review and metaanalysis

was conducted according to the Metaanalysis of Observational Studies in
Epidemiology (MOOSE) guidelines.68
Searches were conducted for published
literature from January 1966 to March
2014. The key words indomethacin and
tocolysis were used in the search independently and then in conjunction with
the following other key words: bronchopulmonary dysplasia, intraventricular
hemorrhage, patent ductus arteriosus,
necrotizing enterocolitis, and neonatal
mortality. Prospective and retrospective
observational studies and clinical trials
that evaluated tocolysis with indomethacin as an exclusive agent or in combination with other tocolytics for preterm
labor vs a comparison group without
tocolytics or with a different tocolytic
agent were identied. In addition to
including those studies that were
assessed in the previous systematic reviews, we identied more recent observational studies and clinical trials that
evaluated neonatal outcomes with
the use of indomethacin for tocolysis
in patients with preterm labor using
the following computerized databases:

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PubMed, MEDLINE, and Cochrane. All

of the included studies assessed 1 of the
following neonatal outcomes: intraventricular hemorrhage (IVH) that was
graded by Papiles classication based on
head ultrasound scanning, NEC that was
based on Bells staging criteria or x-ray
ndings of pneumatosis intestinalis
and/or intestinal perforation, patent
ductus arteriosus (PDA) that was diagnosed by echocardiography, bronchopulmonary dysplasia (BPD) that was
based on oxygen requirements of the
neonate at 36 weeks postmenstrual age,
respiratory distress syndrome (RDS)
that was based on clinical and/or chest xray ndings, periventricular leukomalacia (PVL) that was diagnosed on head
ultrasound scanning or other imaging,
neonatal sepsis that was evidenced
by positive cultures and/or clinical
symptoms, or neonatal death that represented death during initial hospitalization after birth. Because each report
did not assess all outcomes of interest,
specic outcome metaanalyses were
performed that were based on a variable
number of studies that were related to
that outcome. Studies were excluded if
they lacked a comparison group, lacked
assessment of neonatal outcomes of interest, or lacked sufcient quantitative
data for extraction.
Each study was scored for quality by
the primary author and a second obstetrician with the use of the NewcastleOttawa Quality Assessment scale.69
Data that were collected from each
study included rst author, study design,
publication year, control group denition, gestational age at birth of subjects,
neonatal outcomes that were measured,
number of subjects in the study and
control group, other tocolytics that were
used, neonatal birthweight and gender,
and the administration of steroids for
fetal lung maturity. Raw data were
extracted by the primary author using
2  2 tables for each neonatal outcome
that was measured in the antenatal
indomethacin exposure group and in the
comparison group. Two other independent researchers then conrmed these
data.
Metaanalyses were performed for
each neonatal outcome with a Stata

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were identied.62-67 Randomized clinical trials were not included in this

updated analysis. The study selection
process is detailed in Figure 1. One previously reported study97 was excluded
because it contained data on postnatal

statistical software package (version

11.0; Stata Corp, College Station, TX).
Relative risk (RR) for each outcome
and 95% condence intervals (CI)
were calculated for the antenatal
indomethacin-exposed group compared
with the no-exposure comparison group
for dichotomous outcomes. Estimates of
RR were calculated with xed-effects
(Mantel-Haenszel) and random-effects
(DerSimonian and Laird) models.70,71
Random effects models were used
whenever there was evidence of heterogeneity (P < .10). The null hypothesis
underlying the overall test of association
was that the overall RR was equal to 1.
Publication bias was evaluated with
the Egger test and by inspection of
funnel plots, which plot RR against
study sample size.72 When biases and
heterogeneity are absent, the variation
in the estimated effect decreases with
increasing sample size, and the plot resembles a symmetric funnel. Asymmetric funnel plots are caused by small
trials that report greater effects than
larger trials, which suggests publication
or other biases.
The Breslow-Day method was used to
test the homogeneity treatment effect
across the studies to determine the
combinability of the individual studies.73
In addition, LAbbe plots were inspected
visually to assess homogeneity across
studies.74 Sensitivity analyses were performed by sequential omission of each
study and analysis of the overall impact
of that particular study on the pooled
results. Metaregression analysis was
performed to identify causes of heterogeneity among any statistically signicant neonatal outcomes by examination
of the study variables of neonatal birthweight, antenatal steroid use, sex, gestational age at delivery, delivery within 48
hours of last indomethacin dose, other
tocolytic use in control infants, and
mean dosage of indomethacin that was
administered. The number needed to
treat or harm with 95% CIs was calculated for any outcome that revealed statistical signicance.75

were reported in the 2005 metaanalysis

by Loe et al58 and in 2007 by Amin et al,59
7 new observational studies that evaluated antenatal indomethacin tocolysis
and its impact on neonatal outcomes
and that met the inclusion criteria

R ESULTS

MOOSE (68) flow diagram for inclusion of the studies examining the association between antenatal
indomethacin and neonatal outcomes.

In addition to the overall total of 21

observational studies76-96 that previously

Hammers. Neonatal effects of indomethacin tocolysis. Am J Obstet Gynecol 2014.

FIGURE 1

Flow diagram of study selection process

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indomethacin treatment only and was

included inadvertently in the study by
Loe.58 There were 2 new observational
studies by Soraisham et al62,98 that
included overlapping populations of infants; each of the studies looked at
different primary outcomes but also reported on the secondary neonatal outcomes that were relevant to this study.
Therefore, only the study that included
the largest number of subjects was

included.62 The characteristics of the

studies that were included are detailed in
Table 1. The 27 observational studies
that were included assessed 8454 infants
overall, which is an increase of 2375 from
the previously reported metaanalyses. Of
these infants, 1731 were exposed to
antenatal indomethacin, and 6723 were
not exposed. The studies varied with
respect to size, cause of preterm delivery,
use of other tocolytics in the study

groups and in the comparison groups,

the dose and duration of indomethacin
therapy, and the time from last dose of
indomethacin to delivery.
Data on neonatal outcomes were
pooled (Table 2). Signicant heterogeneity among studies was noted for all
neonatal outcomes, except PVL and
neonatal sepsis. For all other outcomes, a
random-effects model was used because
of the presence of heterogeneity. The risk

TABLE 1

Characteristics of included studiesa

Comparison group tocolytic

Gestational
age, wk

Indo  Mg, b-mimetic

None, Mg, or b-mimetic

30

Indo  salbutamol or nifedipine

None, salbutamol, or nifedipine

30

124

Indo  Mg, b-mimetic

None, Mg, or b-mimetic

<32

225

Indo Mg

Mg

32

Study

Year

Norton et al76

1993

114

Souter et al77

1998

79

1996
1999

78

Gardner et al

Vermillion and Newman

Van Overmeire et al

80

Ojala et al81
Weintraub et al
Gerson et al
Abbasi et al

82

83

84

Niebyl and Witter

85

Iannucci et al86
Suarez et al
Major et al

87

88

Hammerman et al
Al-Alaiyan et al90
91

Parilla et al

92

Baerts et al

93

Pietrantoni et al
Friedman et al

94

Murata et al95
Doyle et al

96
65

Baerts et al

66

Cordero et al

89

79

Infant, n

Study group tocolytic

1998

76

Indo b-mimetic

b-mimetic

33

2000

176

Indo

Not Specified

<33

2001

2794

Indo

None, Mg, or b-mimetic

32

1990

57

Indo Terb and Mg or ritodrine

Terbutaline Mg or ritodrine

<33

2003

248

Indo  Mg, terbutaline

None, Mg or terbutaline

<34

1986

135

Indo

None or other

34

1996

56

Indo Mg

Mg

<30

2001

70

Indo

Mg

<33

1994

759

Indo  Mg

Mg  b-mimetic

<30

1998

105

Indo

Not specified

<33

1996

30

Indo

None

33

2000

110

Indo

None or Mg

<37

1990

159

Indo fenoterol

None or fenoterol

<30

1995

280

Indo

Not specified

32

2005

236

Indo

None

<32

2005

201

Indo ritodrine

Mg  ritodrine

<33

2005

549

Indo Mg

Mg

<34

2013

36

Indo

None or other

<30

2007

116

Indo  Mg, terbutaline

Mg  terbutaline

28

2008

248

Indo  Mg

None or Mg

29

Soraisham et al98

2011

462

Indo

Not specified

28

Sood et al63

2011

628

Indo  Mg

None or Mg

<32

2010

381

Indo

Not specified

<36

Amin et al

67

Sharma et al

64

Indo, indomethacin; Mg, magnesium sulfate.

a

All of these studies were observational studies.

Hammers. Neonatal effects of indomethacin tocolysis. Am J Obstet Gynecol 2014.

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Relative risk
(95% confidence
interval)

Heterogeneity
(P value)

83/1432

1.59 (1.17e2.17)a

.974

.000

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TABLE 2

Pooled estimates of neonatal outcomes

Study group,
n/N

Comparison
group, n/N

Outcome

References

Periventricular leukomalacia

63, 65, 67, 77, 84, 92, 94, 95, 98

Respiratory distress syndrome

67, 76-78, 80, 81, 83-85, 88, 92, 98

366/708

668/1581

0.92 (0.77e1.08)

All grades

77-79, 81, 83, 84, 87, 90, 92-93, 98

181/751

194/1018

1.17 (0.89e1.56)b

.006

Grade III-IV

63, 66, 67, 76-79, 81, 82, 84, 86, 90,

147/1179

245/2794

1.29 (1.06e1.56)

.011

134/720

319/2172

1.12 (0.94e1.34)a

.140

168/1013

379/2337

1.04 (0.77e1.41)

.001

119/372

321/1141

1.12 (0.79e1.59)b

.015

376/1031

871/2895

1.14 (0.97e1.35)b

.001

112/1090

256/3183

1.36 (1.08e1.71)b

.031

66/595

Intraventricular hemorrhage

92, 93, 96, 98

Sepsis

63, 67, 76, 79, 81, 84-86, 88, 90, 92, 98

Death

63, 66, 67, 76-79, 80, 81, 83-85, 92,

96, 98

Bronchopulmonary
dysplasia

63, 79, 80, 81, 83, 90, 98

Patent ductus arteriosus

63, 67, 76-79, 80, 83-85, 88-90, 92,

93, 96, 98

Necrotizing enterocolitis

63, 64, 66, 67, 76-79, 80, 81, 84, 86,

88, 90, 91, 93, 96, 98

Mantel-Haenzsel pooled relative risk, fixed effects model; b DerSimonian and Laird pooled relative risk, random effects model.

Hammers. Neonatal effects of indomethacin tocolysis. Am J Obstet Gynecol 2014.

of severe IVH, which was dened with

Papiles classication stage III and IV,
was signicantly higher among infants
who received tocolysis with indomethacin (RR, 1.29; 95% CI, 1.06e1.56),
compared with those who received no
tocolysis or tocolysis with other agents
(Figure 2). The number needed to harm
for this outcome was 26. A signicant
increased risk for NEC was also noted
among infants who were exposed to
antenatal indomethacin (RR, 1.36; 95%
CI, 1.08e1.71; Figure 3). The number
needed to harm for this outcome was
30. In addition, the incidence of PVL
was increased signicantly among
those infants who were exposed to
antenatal indomethacin (RR, 1.59; 95%
CI, 1.17e2.17; Figure 4). The number
needed to harm for this outcome was 28.
No signicant differences were found for
the risk of RDS, PDA, BPD, IVH (all
grades), neonatal sepsis, or neonatal
death.
The results of the metaregression
analysis did not alter the ndings of
the statistically signicant increases in
severe grade IVH, NEC, and PVL
(Table 3). Visual inspection of funnel

plots did not identify evidence of publication bias.

C OMMENT
Principal findings of this study
Our study included the following main
ndings: (1) Neonates whose mothers
were exposed to antenatal indomethacin
were noted to have signicantly
increased risks for NEC, severe IVH
(grades III-IV), and PVL. (2) Metaregression analysis for important covariates did not alter these results. (3)
Although the rates of RDS, all grades of
IVH, neonatal sepsis, perinatal death,
BPD, and PDA were increased in those
infants who were exposed to antenatal
indomethacin, these differences did not
achieve statistical signicance.
Two previous systematic reviews with
metaanalysis assessment of the safety of
indomethacin that was used for tocolysis
have been published. Loe et al58 analyzed
6008 infants from 17 observational
studies and 11 randomized controlled
trials. Pooled estimates of observational
studies, which included 5380 infants,
revealed no signicant differences for
IVH, severe IVH (grades III and IV),

BPD, PDA, NEC, or perinatal death.

Pooled estimates from the 11 randomized trials, which included 628 infants,
revealed a signicantly increased risk of
BPD for infants who were exposed to
indomethacin. However, no differences
were noted for IVH, PDA, NEC, or
perinatal death. The statistical power
for the assessment of neonatal outcome
in these 11 RCTs remained low. PVL
was not included in the outcomes that
were assessed in the observational
studies or the RCTs. A similar metaanalysis was published by Amin et al59
in 2007. They analyzed 21 studies (15
retrospective cohort studies and 6 casecontrol studies) that included 6079 infants. Pooled results indicated a significantly increased risk for PVL (odds
ratio, 2.08; 95% CI, 1.38e3.14) but no
difference in IVH, NEC, BPD, PDA,
RDS, or perinatal death. Although
there was a trend that suggested an
increased risk for NEC (odds ratio, 1.4;
95% CI, 0.91e2.3), this pooled estimate did not achieve statistical signicance. The principal difference between
the ndings of these 2 previous metaanalyses was the nding of an increased

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FIGURE 2

Relative risk of severe grade intraventricular hemorrhage

Forest plot shows the pooled effect estimate (relative risk) of intraventricular hemorrhage, severe grade (III-IV of Papiles criteria) in preterm infants after
antenatal indomethacin exposure. The boxes indicate the point estimate of effect with the area of the box proportional to each studys assigned weight.
The horizontal lines represent the 95% confidence intervals. The diamond and broken vertical line represent the overall summary estimate. The solid
vertical line represents null effect.
CI, confidence interval.
Hammers. Neonatal effects of indomethacin tocolysis. Am J Obstet Gynecol 2014.

risk for PVL by Amin et al,59 an

outcome that was not assessed by Loe
et al.58
The current metaanalysis conrmed
the signicantly increased risk of PVL
among fetuses that were exposed to
indomethacin and also, as a new nding,
signicantly increased risks of severe
IVH (grades III and IV) and NEC. These
new ndings likely reect our inclusion
of studies that were published subsequent to previous metaanalyses, adding
2375 infants, so that the overall number
of infants included is 8454.

Possible pathophysiologic
mechanisms
Indomethacin freely crosses the
placenta, inhibits fetal prostaglandin
synthesis, and alters the normal

physiologic condition of the fetal cardiovascular system.56,99 Antenatal

exposure to indomethacin and other
nonsteroidal antiinammatory drugs
(NSAIDs) have been shown to affect
cerebral, mesenteric, and renal blood
ow,61 and platelet and neutrophil
function.100 These pathophysiologic
mechanisms may explain the higher
risks of severe IVH, PVL, and NEC
noted in our metaanalysis.

Intraventricular hemorrhage
The particular vulnerability of preterm
infants to IVH may stem from a subependymal germinal matrix that is rich
in immature vessels but poorly supported by connective tissue,101 marked
uctuations in cerebral blood ow,102
and major swings in intrathoracic and

1.e6 American Journal of Obstetrics & Gynecology MONTH 2015

venous pressure that is transmitted to the

fragile germinal matrix.103
Indomethacin has important effects
on fetal and neonatal cerebral circulations, both in animal and human
models.104-106 Studies on fetal lambs,
newborn piglets, and preterm infants
have shown that indomethacin causes
signicant reductions of cerebral blood
ow.107-110 This prostaglandin inhibitor
has also been shown to produce cerebral
arterial vasoconstriction and to increase
the mean arterial blood pressure of the
preterm neonate.65 Moreover, indomethacin increases bleeding through its
inhibitory effect on platelet aggregation.111 Decreased cerebral perfusion,
vasoconstriction, loss of cerebral autoregulation, and the combination of
uctuations in intracranial pressure

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FIGURE 3

Relative risk of necrotizing enterocolitis

Forest plot shows the pooled effect estimate (relative risk) of necrotizing enterocolitis in preterm infants after antenatal indomethacin exposure. The boxes
indicate the point estimate of effect with the area of the box proportional to each studys assigned weight. The horizontal lines represent the 95%
confidence intervals. The diamond and broken vertical line represent the overall summary estimate. The solid vertical line represents null effect.
CI, confidence interval.
Hammers. Neonatal effects of indomethacin tocolysis. Am J Obstet Gynecol 2014.

during active labor in the presence of

platelet dysfunction likely contribute to
the increased risk of IVH after antenatal
use of indomethacin.
The increased risk of IVH among infants
who are delivered of indomethacinexposed mothers in this study contrasts
with reports that indomethacin that is
administered to the newborn reduces the
risk of severe IVH in very preterm infants.
Indomethacin, by reducing baseline cerebral blood ow, has been found to reduce
the incidence and severity of IVH when
administered by continuous intravenous
infusion in the preterm neonate.112 However, indomethacin that is administered by

other routes of administration or schedules

has not been found to achieve these benets.113 Accordingly, the apparent paradoxic
increased risk of IVH among infants who
are delivered of indomethacin-exposed
mothers may reect variations in route as
well as schedule of drug administration.

Necrotizing enterocolitis
Gastrointestinal complications, which
include NEC and spontaneous intestinal perforation, represent known
side-effects of indomethacin exposure.114,115 In newborn animals, postnatal treatment with indomethacin has
been shown to decrease the blood ow

in the terminal ileum and to block the

regulation of intestinal oxygen consumption.116 Other studies that have
been performed in animals suggest that
indomethacin administration may increase the risk of bowel necrosis after
temporary intestinal ischemia.117 Doppler studies in preterm infants who were
exposed to indomethacin have demonstrated a signicant reduction in the
superior mesenteric artery blood ow
velocity.118,119 The inhibition of prostaglandin synthesis that is induced by
indomethacin leads to vasoconstriction
and can compromise intestinal defense
mechanisms.120 Indomethacin also may

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FIGURE 4

Relative risk of periventricular leukomalacia

Forest plot shows the pooled effect estimate (relative risk) of periventricular leukomalacia in preterm infants after antenatal indomethacin exposure. The
boxes indicate the point estimate of effect with the area of the box proportional to each studys assigned weight. The horizontal lines represent the 95%
confidence intervals. The diamond and broken vertical line represent the overall summary estimate. The solid vertical line represents null effect.
CI, confidence interval.
Hammers. Neonatal effects of indomethacin tocolysis. Am J Obstet Gynecol 2014.

weaken the resistance of the intestinal

mucosa to microorganisms.121
A number of studies in animals
and humans have observed that indomethacin and other NSAIDs increase the
synthesis of proinammatory cytokines.122 Certain proinammatory cytokines, in particular the plateletactivating factor and tumor necrosis
factor, have been shown to play a role in
the pathogenesis of NEC.123
Some investigators have suggested
that the intestinal complication of recent
antenatal exposure to indomethacin may
be, in fact, spontaneous intestinal perforation and not NEC.124 Spontaneous intestinal perforation occurs predominantly

in infants with birthweights <1000 g;

NEC occurs over a larger birthweight
range. Nonetheless, both of these gastrointestinal complications are associated
with major morbidity and a substantial
risk of death.

Periventricular leukomalacia
The cause and pathophysiologic condition of PVL in the preterm neonate remains partially understood,
with a variety of factors potentially
involved. Perinatal infections and inammatory conditions have been implicated in the pathogenesis of PVL.
If infection and inammation play a
role in the development of PVL, why

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do antiinammatory agents such as

indomethacin increase the risk of this
condition?
Proinammatory interleukins, mainly
tumor necrosis factorealpha and
interleukin-1 play an important role in
the pathogenesis of PVL. These cytokines, which are well-characterized early
responders in inammation, participate
in neonatal central nervous system
damage by induction of the production
of other inammatory and cytotoxic
mediators, promotion of leukocyte
inltration, and expression of adhesion
molecules. These actions inuence glial
gene expression and cause damage to
oligodendrocytes.125,126

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Research

TABLE 3

Effects of covariates on heterogeneity of significant neonatal outcomes

Neonatal outcome

Covariate

Coefficient (95%
confidence interval)

P value

Intraventricular hemorrhage
grade III-IV

Gestational age at delivery

e0.71 (e1.57 to 0.14)

.09

1.87

0.004 (e0.003 to 0.01)

.21

1.35

Infant gender

0.49 (e0.06 to 0.16)

.35

0.99

Antenatal steroid exposure

0.02 (e0.04 to 0.08)

.52

0.68

Absence of other tocolytics in control subjects

0.52 (e1.50 to 2.54)

.59

0.56

Delivery within 48 hr of last indomethacin dose

0.76 (e1.66 to 3.20)

.51

0.68

e0.41 (e2.04 to 1.22)

Birthweight

Necrotizing enterocolitis

Gestational age at delivery

.56

0.62

Birthweight

0.002 (e0.01 to 0.02)

.72

0.37

Infant sex

0.03 (e0.11 to 0.18)

.58

0.58

0.01 (e0.05 to 0.08)

.63

0.50

0.66 (e2.83 to 4.16)

.71

0.37

4.73 (e16.15 to 25.62)

Antenatal steroid exposure

Low mean dose of indomethacin
Periventricular leukomalacia

s2a

Gestational age at delivery

.43

0.98

Birthweight

e0.03 (e0.17 to 0.11)

.43

0.98

Infant sex

e0.01 (e0.44 to 0.43)

.95

0.08

Delivery within 48 hr of last indomethacin dose

e0.13 (e1.93 to 1.67)

.89

e0.14

Smaller value of s2 indicates less between-study variability; b Defined as 250 mg.

Hammers. Neonatal effects of indomethacin tocolysis. Am J Obstet Gynecol 2014.

Various studies in animals and

humans have shown that indomethacin
and other NSAIDs increase the synthesis of proinammatory cytokines.122
NSAIDs up-regulate messenger RNA
expression and the production of cytokines that are produced by Th1 cells
(proinammatory), whereas those that
are regulated by Th2 (antiinammatory)
were down-regulated.127 By decreasing
the availability of antiinammatory cytokines, mainly interleukin-4 and
-10, NSAIDs have the potential to exacerbate inammation. In addition, the
inammatory cytokine interleukin-6
is required to increase the number of
neural stem-cell progenitors.128
How might the antenatal exposure
of indomethacin increase the incidence
of PVL? (1) Marked reductions in cerebral blood ow can cause infarction
and ischemic necrosis that leads to
cystic PVL. (2) Increased production
of proinammatory cytokines can damage the central nervous system
directly. (3) Decreased production of
antiinammatory cytokines results in

the increased potential to exacerbate

inammation. (4) Lack of interleukin-6
synthesis reduces the number of neural
stem-cell progenitors; such suppression of neural stem-cell expansion may
rob the damaged brain of factors that
are necessary to the launch of a robust
endogenous repair response.128

Strengths of this study

The strengths of this study include (1)
the use of rigorous methods for the
performance of systematic reviews of
observational studies that are conducted
according to the MOOSE guidelines; (2)
an extensive literature search with the
use of various computerized databases
that included sources of grey literature,
without language restrictions; (3) the
inclusion of large number of studies with
an overall total of 8454 infants; (4) a
study quality assessment that was based
on strict predetermined criteria; (5) the
performance of sensitivity analysis that
included the sequential omission of
1 study at a time that did not show any
signicant inuence of an individual

study on the overall effect size; (5) the

nding of symmetric funnel plots that
thereby excluded publication bias; and
(6) performance of metaregression for
important covariates, a process that did
not alter the results.

Limitations of this study

There are several important limitations
to this metaanalysis: (1) Confounding
factors and selection bias are often
difcult to control in metaanalyses of
observational studies. However, metaregression of important covariates such
as gestational age at delivery, birthweight, infant sex, and delivery within 48
hours of the last indomethacin dose did
not alter the overall results. (2) Other
confounding variables, such as the use of
corticosteroids, could not be assessed
because some variables were not reported universally. (3) Many of the
women whose data were included in the
trial analyses received tocolysis with
indomethacin only after not responding
to rst-line therapy. However, when this
potential confounder was analyzed in

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metaregression, it did not appear to alter

the results. In the great majority of
studies aggregated in our metaanalysis,
tocolysis with indomethacin was not a
rst-line therapy. Accordingly, we were
unable to perform meaningful subgroup
analysis that focused on studies in which
indomethacin was the sole tocolytic
used. Unfortunately, in the context of
this metaanalysis, we are unable to estimate the effects attributable to other
specic tocolytics. (4) We found signicant heterogeneity for RDS, IVH, perinatal death, BPD, persistent ductus
arteriosus, and NEC, which indicated
that differences in the design of the
studies that were included in our systematic review likely contributed to this
nding. These studies differed with
respect to exposure to other tocolytics,
duration of exposure to indomethacin,
total dose of indomethacin, and interval
from last dose to delivery. Most of the
studies attempted to match comparison
patients by gestational age, birthweight,
maternal characteristics, and infant
characteristics that could affect outcome. However, there were still signicant baseline differences between the
indomethacin group and the comparison group. For outcomes that showed
evidence of heterogeneity, we used
random-effects models for metaanalysis.
(5) Because most of the studies did not
include a detailed denition for NEC, we
were unable to differentiate NEC from
spontaneous intestinal perforation.
Notwithstanding these limitations,
the pooled data from these observational
studies revealed increased risks of NEC,
severe grade IVH, and PVL that are
associated with maternal tocolysis by the
use of indomethacin. Although data
from observational studies are inherently more prone to bias, the paucity of
data from randomized trials indicates
that results of our metaanalysis merit
consideration. Based on the results of
this metaanalysis, the use of indomethacin for tocolysis should be avoided. ACKNOWLEDGMENT
We thank Mr Brendan Jannesen, BSN student,
Chamberlain College of Nursing, Jacksonville,
FL, for his assistance in reviewing and conrming
our data.

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