exposicion antenatal a indometacina incrementa el riesgo a hemorragia intraventricular,...

8/10/2019 Exposicion Antenatal a Indometacina Incrementa El Riesgo a Hemorragia Intraventricular, Enterocolitis Necrotizante y Periventricular Leucomalasia

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OBSTETRICS

Antenatal exposure to indomethacin increasesthe risk of severe intraventricular hemorrhage,

necrotizing enterocolitis, and periventricularleukomalacia: a systematic review withmetaanalysisAmy L. Hammers, MD; Luis Sanchez-Ramos, MD; Andrew M. Kaunitz, MD

OBJECTIVE: The purpose of this study was to provide an updatedsummary of the literature regarding the effects of tocolysis withindomethacin on neonatal outcome by systematically reviewing pre-viously and recently reported data.

STUDY DESIGN: All previously reported studies pertaining to indo-methacin tocolysis and neonatal outcomes along with recently re-ported data were identied with the use of electronic databases thathad been supplemented with references that were cited in originalstudies and review articles. Observational studies that comparedneonatal outcomes among preterm infants who were exposed and notexposed to indomethacin were included in this systematic review. Datawere extracted and quantitative analyses were performed on thosestudies that assessed the neonatal outcomes of patients that receivedantenatal tocolysis with indomethacin.

RESULTS: Twenty-seven observational studies that met criteria for

systematic review and metaanalysis were identied. These studiesincluded 8454 infants, of whom 1731 were exposed to antenatalindomethacin and 6723 were not exposed. Relative risks with 95%

condence intervals were calculated for dichotomous outcomes withthe use of random and xed-effects models. Metaanalysis revealed nostatistically signicant differences in the rates of respiratory distresssyndrome, patent ductus arteriosus, neonatal mortality rate, neonatal

sepsis, bronchopulmonary dysplasia, or intraventricular hemorrhage(all grades). However, antenatal exposure to indomethacin wasassociated with an increased risk of severe intraventricular hemor-rhage (grade III-IV based on Papiles criteria; relative risk, 1.29; 95%condence interval, 1.06e 1.56), necrotizing enterocolitis (relativerisk, 1.36; 95% condence interval, 1.08e 1.71), and periventricularleukomalacia (relative risk, 1.59; 95% condence interval,1.17e 2.17).

CONCLUSION: The use of indomethacin as a tocolytic agent for pre-term labor is associated with an increased risk for severe intraven-tricular hemorrhage, necrotizing enterocolitis, and periventricularleukomalacia.

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: .

P reterm birth represents an impor-tant perinatal health problemacross the globe, not only in terms of associated mortality rates but also

with regard to short- and long -te rmmorbidity and nancial costs. 1,2 Inthe Unites States, the preterm birthrate 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 1of the top 10 countries in the worldwith the highest number of preterm

births.4

In the United States, prema-ture birth accounts for nearly 35% of deaths in the rst year of life at anestimated annual cost that exceeds $26billion. In addition, preterm birth

contributes to subst antial neuro-behavioral impairment. 5

Major recent progress has been madetoward the early diagnosis, 6 prediction, 7-9

and prevention of spontaneous pretermbirth. 10-13 However, the mainstay of therapy for the treatment of acute pre-term labor continues to be the employ-ment of pharmacologic agents with theaim of arrest of or decrease of uterinecontractility and thereby delaying pre-term birth. Although tocolytic agentshave been show n to delay delivery for 48hours to 7 days,14,15 their use has not ledto an improvement in neonatal out-comes. Nonetheless, this short prolon-

gation of pregnancy allows for thematernal transfer to a tertiary center and

From the Department of Obstetrics and Gynecology, University of Florida College of Medicinee Jacksonville, Jacksonville, FL.Received June 27, 2014; revised Oct. 8, 2014; accepted Oct. 28, 2014. The authors report no con ict of interest.Corresponding author: Amy Hammers, MD. [email protected] .edu

0002-9378/$36.00 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2014.10.1091

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the administration of cortic osteroids toenhance fetal lung maturity. 16

A variety of pharmacologic agents thathave been used, most off-label, to sup-press uter ine contractility include b eta-mimetics, 17-21 magnesium sulfa te,22-25

oxytocin receptor antago nists,15,26-29

calcium channel blockers, 30-34 cyclo-oxygenase inhibitors, 35-41 and nitric ox-ide donors. 42-46 Each of these agents hasa unique mechanism of action and side-effects. A recent metaanalysis suggestedthat the calcium channel blocker nifed-ipine appears to meet several chara cter-istics of an ideal tocolytic agent.30 A systematic review and network meta-analysis47 and a metaanalysis with deci-sion analysis48 concluded that calcium

channel blockers and prostaglandin in-hibitors had the highest probability of delaying delivery and improving neonatal and maternal outcomes.

There is strong evidence that prosta-glandins are involved intimately in theinitiation and progression of term andpreterm labor in humans. 49-53 Prosta-glandins affect myometrial contractility by direct effect with their own re-ceptors 50,51 by an increase in the sens i-tivity of the myometrium to oxytocin 52

and by reg ulation of myometrial gap junctions. 49 They also stimulate thein ux of intracellular calcium thatactivates the enzyme myosin lightchain kinase that results in myometrialcontractility. 53

Indomethacin, a cyclooxygenase in-hibitor that decreases uterine contrac-tility by blocking the conversion of arachidonic acid to prostaglandin, hasbeen used as a tocolytic agent since1974.54 Many obstetricians continue to

use indomethacin as a

rst-line tocolyticagent, which is an indication that issupported by the American Colle ge of Obstetricians and Gynecologists. 55 A number of studies have raised concernsabout thesafety of indomethacin becauseit crosses the placenta and inhibits p ros-taglandin synthesis in fetal organs. 56,57

Case reports and observational studieshave suggested that indomethacin may cause adverse neonatal outcomes thatinclude necrotizing enterocolitis (NEC),

intraventricular hemorrhage, periven-tricular leukomalacia, and other cardiac,

pulmonary, and renal abnormalities. 58-61

Accordingly, indomethacin s role as acurrent option by obstetricians in thetreatment for possible preterm labor iscontroversial. Since 2005, 2 systematicreviews with metaanalyses that assessed

neonatal outcomes after indomethacintocolysis, while using similar sources,have reported con icting results. 58,59 The

rst of these reports included bothobservational studies and randomizedtrials; the subsequent report includedonly observational studies. Subsequent tothese publications, more recent observa-tional and prospective studies thatassessed indom ethacin tocolysis havebeen published. 62-67 The goal of thiscurrent study was to review these new

studies, to reanalyze studies that wereincluded in the2 previousreviews, and topool the data to determine more accu-rately the neonatal effects of indometh-acin exposure, thus providing neededguidance regarding the use of this medi-cation for tocolysis.

MATERIALS AND METHODSThis systematic review and metaanalysiswas conducted according to the Meta-analysis of Observational Studies in

Epidemiology (MOOSE) guidelines.68

Searches were conducted for publishedliterature from January 1966 to March2014. The key words indomethacin andtocolysis were used in the search inde-pendently and then in conjunction withthe following other key words: bronchopulmonary dysplasia, intraventricular hemorrhage , patent ductus arteriosus ,necrotizing enterocolitis , and neonatal mortality . Prospective and retrospectiveobservational studies and clinical trials

that evaluated tocolysis with indometh-acin as an exclusive agent or in combi-nation with other tocolytics for pretermlabor vs a comparison group withouttocolytics or with a different tocolyticagent were identi ed. In addition toincluding those studies that wereassessed in the previous systematic re-views, we identi ed more recent obser-vational studies and clinical trials thatevaluated neonatal outcomes withthe use of indomethacin for tocolysis

in patients with preterm labor using the following computerized databases:

PubMed, MEDLINE, and Cochrane. Allof theincluded studies assessed 1ofthefollowing neonatal outcomes: intraven-tricular hemorrhage (IVH) that wasgraded by Papile s classi cation based onhead ultrasound scanning, NEC that was

based on Bell

s staging criteria or x-ray ndings of pneumatosis intestinalisand/or intestinal perforation, patentductus arteriosus (PDA) that was diag-nosed by echocardiography, broncho-pulmonary dysplasia (BPD) that wasbased on oxygen requirements of theneonate at 36 weeks postmenstrual age,respiratory distress syndrome (RDS)that was based on clinical and/or chest x-ray ndings, periventricular leukomala-cia (PVL) that was diagnosed on head

ultrasound scanning or other imaging,neonatal sepsis that was evidencedby positive cultures and/or clinicalsymptoms, or neonatal death that rep-resented death during initial hospitali-zation after birth. Because each reportdid not assess all outcomes of interest,speci c outcome metaanalyses wereperformed that were based on a variablenumber of studies that were related tothat outcome. Studies were excluded if they lacked a comparison group, lacked

assessment of neonatal outcomes of in-terest, or lacked suf cient quantitativedata for extraction.

Each study was scored for quality by the primary author and a second obste-trician with the use of the Newcastl e-Ottawa Quality Assessment scale. 69

Data that were collected from eachstudy included rst author, study design,publication year, control group de ni-tion, gestational age at birth of subjects,neonatal outcomes that were measured,

number of subjects in the study andcontrol group, other tocolytics that wereused, neonatal birthweight and gender,and the administration of steroids forfetal lung maturity. Raw data wereextracted by the primary author using 2 2 tables for each neonatal outcomethat was measured in the antenatalindomethacin exposure group and in thecomparison group. Two other indepen-dent researchers then con rmed thesedata.

Metaanalyses were performed foreach neonatal outcome with a Stata

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statistical software package (version11.0; Stata Corp, College Station, TX).Relative risk (RR) for each outcomeand 95% con dence intervals (CI)were calculated for the antenatalindomethacin-exposed group compared

with the no-exposure comparison groupfor dichotomous outcomes. Estimates of RR were calculated with xed-effects(Mantel-Haenszel) and random-eff ects(DerSimonian and Laird) models. 70,71

Random effects models were usedwhenever there was evidence of hetero-geneity (P < .10). The null hypothesisunderlying the overall test of associationwas that the overall RR was equal to 1.Publication bias was evaluated withthe Egger test and by inspection of

funnel plots, which plot RR againststudy sample size.72 When biases andheterogeneity are absent, the variationin the estimated effect decreases withincreasing sample size, and the plot re-sembles a symmetric funnel. Asym-metric funnel plots are caused by smalltrials that report greater effects thanlarger trials, which suggests publicationor other biases.

The Breslow-Day method was used totest the homogeneity treatment effect

across the studies to determine t hecombinability of the individual studies. 73

In addition, L Abbe plots were inspectedvisually to assess homogeneity acrossstudies.74 Sensitivity analyses were per-formed by sequential omission of eachstudy and analysis of the overall impactof that particular study on the pooledresults. Metaregression analysis wasperformed to identify causes of hetero-geneity among any statistically signi -cant neonatal outcomes by examination

of the study variables of neonatal birth-weight, antenatal steroid use, sex, gesta-tional age at delivery, delivery within 48hours of last indomethacin dose, othertocolytic use in control infants, andmean dosage of indomethacin that wasadministered. The number needed totreat or harm with 95% CIs was calcu-lated for any outco me that revealed sta-tistical signi cance. 75

R ESULTS

In addition to the overall total of 21observational studies 76-96 thatpreviously

were repor ted in the 2005 metaanalys isbyLoe et al58 and in2007 byAmin etal, 59

7 new observational studies that evalu-ated antenatal indomethacin tocolysisand its impact on neonatal outcomesand that met the inclusion criteria

were identi ed.62-67 Randomized clini-cal trials were not included in thisupdated analysis. The study selectionprocess is detailed in Figure 1. One pre-viously reported study 97 was excludedbecause it contained data on postnatal

FIGURE 1Flow diagram of study selection process

MOOSE (68) ow diagram for inclusion of the studies examining the association between antenatindomethacin and neonatal outcomes.

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

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indomethacin treatment only and wasincluded inadvertently in the study by Loe.58 There were 2 new observationalstudies by Soraisham et al62,98 thatincluded overlapping populations of in-fants; each of the studies looked at

different primary outcomes but also re-ported on the secondary neonatal out-comes that were relevant to this study.Therefore, only the study that includedthe largest number of subjects was

included. 62 The characteristics of thestudies that were included are detailed inTable 1. The 27 observational studiesthat were included assessed 8454 infantsoverall,which is an increaseof 2375 fromthe previously reported metaanalyses.Of

these infants, 1731 were exposed toantenatal indomethacin, and 6723 werenot exposed. The studies varied withrespect to size, cause of preterm delivery,use of other tocolytics in the study

groups and in the comparison groups,the dose and duration of indomethacintherapy, and the time from last dose of indomethacin to delivery.

Data on neonatal outcomes werepooled ( Table 2). Signi cant heteroge-

neity among studies was noted for allneonatal outcomes, except PVL andneonatal sepsis. Forall other outcomes, arandom-effects model was used becauseof thepresence of heterogeneity. Therisk

TABLE 1Characteristics of included studies a

Study Year Infant, n Study group tocolytic Comparison group tocolyticGestationalage, wk

Norton et al76

1993 114 Indo Mg, b-mimetic None, Mg, or b-mimetic 30Souter et al77 1998 79 Indo salbutamol or nifedipine None, salbutamol, or nifedipine 30

Gardner et al78 1996 124 Indo Mg, b-mimetic None, Mg, or b-mimetic < 32

Vermillion and Newman79 1999 225 Indo Mg Mg 32

Van Overmeire et al80 1998 76 Indo b-mimetic b-mimetic 33

Ojala et al81 2000 176 Indo Not Specied < 33

Weintraub et al82 2001 2794 Indo None, Mg, or b-mimetic 32

Gerson et al83 1990 57 Indo Terb and Mg or ritodrine Terbutaline Mg or ritodrine < 33

Abbasi et al84 2003 248 Indo Mg, terbutaline None, Mg or terbutaline < 34

Niebyl and Witter 85 1986 135 Indo None or other 34

Iannucci et al86 1996 56 Indo Mg Mg < 30

Suarez et al87 2001 70 Indo Mg < 33

Major et al88 1994 759 Indo Mg Mg b-mimetic < 30

Hammerman et al89 1998 105 Indo Not specied < 33

Al-Alaiyan et al90 1996 30 Indo None 33

Parilla et al91 2000 110 Indo None or Mg < 37

Baerts et al92 1990 159 Indo fenoterol None or fenoterol < 30

Pietrantoni et al93 1995 280 Indo Not specied 32

Friedman et al94 2005 236 Indo None < 32

Murata et al95

2005 201 Indo ritodrine Mg ritodrine < 33Doyle et al96 2005 549 Indo Mg Mg < 34

Baerts et al65 2013 36 Indo None or other < 30

Cordero et al66 2007 116 Indo Mg, terbutaline Mg terbutaline 28

Amin et al67 2008 248 Indo Mg None or Mg 29

Soraisham et al98 2011 462 Indo Not specied 28

Sood et al63 2011 628 Indo Mg None or Mg < 32

Sharma et al64 2010 381 Indo Not specied < 36

Indo , indomethacin; Mg , magnesium sulfate.a All of these studies were observational studies.





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of severe IVH, which was de ned withPapile s classi cation stage III and IV,was signi cantly higher among infants

who received tocolysis with indometh-acin (RR, 1.29; 95% CI, 1.06e 1.56),compared with those who received notocolysis or tocolysis with other agents(Figure 2). The number needed to harmfor this outcome was 26. A signi cantincreased risk for NEC was also notedamong infants who were exposed toantenatal indomethacin (RR, 1.36; 95%CI, 1.08e 1.71; Figure 3). The numberneeded to harm for this outcome was30. In addition, the incidence of PVL

was increased signi cantly among those infants who were exposed toantenatal indomethacin (RR, 1.59; 95%CI, 1.17e 2.17; Figure 4). The numberneeded to harm for this outcome was 28.No signi cant differences were found forthe risk of RDS, PDA, BPD, IVH (allgrades), neonatal sepsis, or neonataldeath.

The results of the metaregressionanalysis did not alter the ndings of the statistically signi cant increases in

severe grade IVH, NEC, and PVL(Table 3). Visual inspection of funnel

plots did not identify evidence of pub-lication bias.

COMMENTPrincipal ndings of this studyOur study included the following main

ndings: (1) Neonates whose motherswere exposed to antenatal indomethacinwere noted to have signi cantly increased risks for NEC, severe IVH(grades III-IV), and PVL. (2) Metare-gression analysis for important cova-riates 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 thoseinfants who were exposed to antenatalindomethacin, these differences did notachieve statistical signi cance.

Two previous systematic reviews withmetaanalysis assessment of the safety of indomethacin that was used f or tocolysishave been published. Loe et al58 analyzed6008 infants from 17 observationalstudies and 11 randomized controlledtrials. Pooled estimates of observationalstudies, which included 5380 infants,

revealed no signi cant differences forIVH, severe IVH (grades III and IV),

BPD, PDA, NEC, or perinatal death.Pooled estimates from the 11 random-ized trials, which included 628 infants,

revealed a signi cantly increased risk of BPD for infants who were exposed toindomethacin. However, no differenceswere noted for IVH, PDA, NEC, orperinatal death. The statistical powerfor the assessment of neonatal outcomein these 11 RCTs remained low. PVLwas not included in the outcomes thatwere assessed in the observationalstudies or the RCTs. A similar met a-analysis was published by Amin et al59

in 2007. They analyzed 21 studies (15

retrospective cohort studies and 6 case-control studies) that included 6079 in-fants. Pooled results indicated a signif-icantly increased risk for PVL (oddsratio, 2.08; 95% CI, 1.38e 3.14) but nodifference in IVH, NEC, BPD, PDA,RDS, or perinatal death. Althoughthere was a trend that suggested anincreased risk for NEC (odds ratio, 1.4;95% CI, 0.91e 2.3), this pooled esti-mate did not achieve statistical signi -cance. The principal difference between

the

ndings of these 2 previous meta-analyses was the nding of an increased

TABLE 2Pooled estimates of neonatal outcomes

Outcome ReferencesStudy group,n/N

Comparisongroup, n/N

Relative risk (95% condenceinterval)

Heterogeneity( P value)

Periventricular leukomalacia 63, 65, 67, 77, 84, 92, 94, 95, 98 66/595 83/1432 1.59 (1.17 e 2.17)a .974

Respiratory distress syndrome 67, 76-78, 80, 81, 83-85, 88, 92, 98 366/708 668/1581 0.92 (0.77 e 1.08)b .000

Intraventricular hemorrhage

All grades 77-79, 81, 83, 84, 87, 90, 92-93, 98 181/751 194/1018 1.17 (0.89 e 1.56)b .006

Grade III-IV 63, 66, 67, 76-79, 81, 82, 84, 86, 90,92, 93, 96, 98

147/1179 245/2794 1.29 (1.06 e 1.56)b .011

Sepsis 63, 67, 76, 79, 81, 84-86, 88, 90, 92, 98 134/720 319/2172 1.12 (0.94 e 1.34)a .140

Death 63, 66, 67, 76-79, 80, 81, 83-85, 92,96, 98

168/1013 379/2337 1.04 (0.77 e 1.41)b .001

Bronchopulmonarydysplasia

63, 79, 80, 81, 83, 90, 98 119/372 321/1141 1.12 (0.79 e 1.59)b .015

Patent ductus arteriosus 63, 67, 76-79, 80, 83-85, 88-90, 92,93, 96, 98

376/1031 871/2895 1.14 (0.97 e 1.35)b .001

Necrotizing enterocolitis 63, 64, 66, 67, 76-79, 80, 81, 84, 86,88, 90, 91, 93, 96, 98

112/1090 256/3183 1.36 (1.08 e 1.71)b .031

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





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r isk for PVL by Amin et al,59 anoutcome that was not assessed by Loeet al.58

The current metaanalysis con rmedthe signi cantly increased risk of PVLamong fetuses that were exposed to

indomethacin and also, as a new nding,signi cantly increased risks of severeIVH (grades III and IV) and NEC. Thesenew ndings likely re ect our inclusionof studies that were published subse-quent to previous metaanalyses, adding 2375 infants, so that the overall numberof infants included is 8454.

Possible pathophysiologicmechanismsIndomethacin freely crosses the

placenta, inhibits fetal prostaglandinsynthesis, and alters the normal

physiologic condition of the fetal car-diovascular system. 56,99 Antenatalexposure to indomethacin and othernonsteroidal antiin ammatory drugs(NSAIDs) have been shown to affectcereb ral, mesenteric, and renal blood

ow,61

and platelet and neutrophilfunction. 100 These pathophysiologicmechanisms may explain the higherrisks of severe IVH, PVL, and NECnoted in our metaanalysis.

Intraventricular hemorrhageThe particular vulnerability of preterminfants to IVH may stem from a sub-ependymal germinal matrix that is richin immature vessels but p oorly sup-ported by connective tissue, 101 mark ed

uctuations in cerebral blood

ow,102

and major swings in intrathoracic and

venouspressure that is t ransmitted to thefragile germinal matrix. 103

Indomethacin has important effectson fetal and neonatal cerebral circula-tions, both in animal and humanmodels. 104-106 Studies on fetal lambs,

newborn piglets, and preterm infantshave shown that indomethacin causessigni cant reductions of cerebral blood

ow.107-110 This prostaglandin inhibitorhas also been shown to produce cerebralarterial vasoconstriction and to increasethe mean arterial blood pressure of thepreterm neonate. 65 Moreover, indo-methacin increases bleeding through itsinhibitory effect on platelet aggrega-tion. 111 Decreased cerebral perfusion,vasoconstriction, loss of cerebral auto-

regulation, and the combination of uctuations in intracranial pressure

FIGURE 2Relative 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 infantantenatal indomethacin exposure. The boxes indicate the point estimate of effect with the area of the box proportional to each studys assigned weighThe horizontal lines represent the 95% condence intervals. The diamond and broken vertical line represent the overall summary estimate. The solid vertical line represents null effect.CI , condence interval.





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weaken the resistance of th e intestinalmucosa to microorganisms. 121

A number of studies in animals

and humans have observed that indo-methacin and other NSAIDs increase thesynthesis of proin ammatory cyto-kines.122 Certain proin ammatory cy-tokines, in particular the platelet-activating factor and tumor necrosisfactor, have been shown t o play a role inthe pathogenesis of NEC. 123

Some investigators have suggestedthat the intestinal complication of recentantenatal exposure to indomethacin may be, in fact, spontane ous intestinal perfo-

ration and not NEC.124

Spontaneous in-testinal perforation occurs predominantly

in infants with birthweights < 1000 g;NEC occurs over a larger birthweightrange. Nonetheless, both of these gastro-

intestinal complications are associatedwith major morbidity and a substantialrisk of death.

Periventricular leukomalaciaThe cause and pathophysiologic con-dition of PVL in the preterm neo-nate remains partially understood,with a variety of factors potentially involved. Perinatal infections and in-

ammatory conditions have been im-plicated in the pathogenesis of PVL.

If infection and in ammation play arole in the development of PVL, why

do antiin ammatory agents such asindomethacin increase the risk of thiscondition?

Proin ammatory interleukins, mainly tumor necrosis factor e alpha andinterleukin-1 play an important role inthe pathogenesis of PVL. These cyto-kines, which are well-characterized early responders in in ammation, participatein neonatal central nervous systemdamage by induction of the productionof other in ammatory and cytotoxicmediators, promotion of leukocytein ltration, and expression of adhesionmolecules. These actions in uence glial

gene expression and cause damage tooligodendrocytes. 125,126

FIGURE 4Relative risk of periventricular leukomalacia

Forest plot shows the pooled effect estimate (relative risk) of periventricular leukomalacia in preterm infants after antenatal indomethacin exposureboxes indicate the point estimate of effect with the area of the box proportional to each studys assigned weight. The horizontal lines represent the 95%condence intervals. The diamond and broken vertical line represent the overall summary estimate. The solid vertical line represents null effect.CI , condence interval.





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Various studies in animals and

humans have shown that indomethacinand other NSAIDs increase the s yn-thesis of proin ammatory cytokines. 122

NSAIDs up-regulate messenger RNA expression and the production of cyto-kines that are produced by Th1 cells(proin ammatory), whereas those thatare regulated by Th2 (a ntiin ammatory)were down-regulated. 127 By decreasing the availability of antiin ammatory cy-tokines, mainly interleukin-4 and-10, NSAIDs have the potential to exac-

erbate in ammation. In addition, thein ammatory cytokine interleukin-6is required to increase the number of neural stem-cell progenitors. 128

How might the antenatal exposureof indomethacin increase the incidenceof PVL? (1) Marked reductions in ce-rebral blood ow can cause infarctionand ischemic necrosis that leads tocystic PVL. (2) Increased productionof proin ammatory cytokines can da-mage the central nervous system

directly. (3) Decreased production of antiin ammatory cytokines results in

the increased potential to exacerbate

in ammation. (4) Lack of interleukin-6synthesis reduces the number of neuralstem-cell progenitors; such suppres-sion of neural stem-cell expansion may rob the damaged brain of factors thatare necessary to the launch of a robustendogenous repair response. 128

Strengths of this studyThe strengths of this study include (1)the use of rigorous methods for theperformance of systematic reviews of

observational studies that are conductedaccording to the MOOSE guidelines; (2)an extensive literature search with theuse of various computerized databasesthat included sources of grey literature,without language restrictions; (3) theinclusion of large numberof studies withan overall total of 8454 infants; (4) astudy quality assessment that was basedon strict predetermined criteria; (5) theperformance of sensitivity analysis thatincluded the sequential omission of

1 study at a time that did not show any signi cant in uence of an individual

study on the overall effect size; (5) the

nding of symmetric funnel plots thatthereby excluded publication bias; and(6) performance of metaregression forimportant covariates, a process that didnot alter the results.

Limitations of this studyThere are several important limitationsto this metaanalysis: (1) Confounding factors and selection bias are oftendif cult to control in metaanalyses of observational studies. However, meta-

regression of important covariates suchas gestational age at delivery, birth-weight, infant sex, and delivery within 48hours of the last indomethacin dose didnot alter the overall results. (2) Otherconfounding variables, such as the use of corticosteroids, could not be assessedbecause some variables were not re-ported universally. (3) Many of thewomen whose data were included in thetrial analyses received tocolysis withindomethacin only after not responding

to

rst-line therapy. However, when thispotential confounder was analyzed in

TABLE 3Effects of covariates on heterogeneity of signicant neonatal outcomes

Neonatal outcome CovariateCoefcient (95%condence interval) P value s 2 a

Intraventricular hemorrhagegrade III-IV

Gestational age at delivery e 0.71 (e 1.57 to 0.14) .09 1.87

Birthweight 0.004 (e 0.003 to 0.01) .21 1.35

Infant gender 0.49 (e 0.06 to 0.16) .35 0.99

Antenatal steroid exposure 0.02 (e 0.04 to 0.08) .52 0.68

Absence of other tocolytics in control subjects 0.52 (e 1.50 to 2.54) .59 0.56

Delivery within 48 hr of last indomethacin dose 0.76 (e 1.66 to 3.20) .51 0.68

Necrotizing enterocolitis Gestational age at delivery e 0.41 (e 2.04 to 1.22) .56 0.62

Birthweight 0.002 (e 0.01 to 0.02) .72 0.37

Infant sex 0.03 (e 0.11 to 0.18) .58 0.58

Antenatal steroid exposure 0.01 (e 0.05 to 0.08) .63 0.50

Low mean dose of indomethacinb 0.66 (e 2.83 to 4.16) .71 0.37Periventricular leukomalacia Gestational age at delivery 4.73 (e 16.15 to 25.62) .43 0.98

Birthweight e 0.03 (e 0.17 to 0.11) .43 0.98

Infant sex e 0.01 (e 0.44 to 0.43) .95 0.08

Delivery within 48 hr of last indomethacin dose e 0.13 (e 1.93 to 1.67) .89 e 0.14a Smaller value of s 2 indicates less between-study variability; b Dened as 250 mg.





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metaregression, it did not appear to alterthe results. In the great majority of studies aggregated in our metaanalysis,tocolysis with indomethacin was not a

rst-line therapy. Accordingly, we wereunable to perform meaningful subgroup

analysis that focused on studies in whichindomethacin was the sole tocolyticused. Unfortunately, in the context of this metaanalysis, we are unable to esti-mate the effects attributable to otherspeci c tocolytics. (4) We found signi -cant heterogeneity for RDS, IVH, peri-natal death, BPD, persistent ductusarteriosus, and NEC, which indicatedthat differences in the design of thestudies that were included in our sys-tematic review likely contributed to this

nding. These studies differed withrespect to exposure to other tocolytics,duration of exposure to indomethacin,total dose of indomethacin, and intervalfrom last dose to delivery. Most of thestudies attempted to match comparisonpatients by gestational age, birthweight,maternal characteristics, and infantcharacteristics that could affect out-come. However, there were still signi -cant baseline differences between theindomethacin group and the compari-

son group. For outcomes that showedevidence of heterogeneity, we usedrandom-effects models for metaanalysis.(5) Because most of the studies did notinclude a detailed de nition for NEC, wewere unable to differentiate NEC fromspontaneous intestinal perforation.

Notwithstanding these limitations,the pooled data from these observationalstudies revealed increased risks of NEC,severe grade IVH, and PVL that areassociated with maternal tocolysis by the

use of indomethacin. Although datafrom observational studies are inher-ently more prone to bias, the paucity of data from randomized trials indicatesthat results of our metaanalysis meritconsideration. Based on the results of this metaanalysis, the use of indometh-acin for tocolysis should be avoided. -

ACKNOWLEDGMENT

We thank Mr Brendan Jannesen, BSN student,Chamberlain College of Nursing, Jacksonville,

FL, forhis assistancein reviewingandcon rmingour data.

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