Chorioamnionitis as a Risk Factor for Necrotizing Enterocolitis: A Systematic Review and Meta-Analysis

Jasper V. Been, MD, MPH, PhD1,2, Sanne Lievense, MD1, Luc J. I. Zimmermann, MD, PhD1,3, Boris W. Kramer, MD, PhD1,3, and Tim G. A. M. Wolfs, PhD1,3 Objective To accumulate available evidence regarding the association between antenatal inammation and necrotizing enterocolitis (NEC).

Study design A systematic literature search was performed using Medline, Embase, Cochrane Library, ISI Web of
Knowledge, and reference hand searches. Human studies published in English that reported associations between chorioamnionitis or other indicators of antenatal inammation and NEC were eligible. Relevant associations were extracted and reported. Studies reporting associations between histological chorioamnionitis (HC) and NEC, HC with fetal involvement and NEC, and clinical chorioamnionitis and NEC were pooled in separate meta-analyses. Results A total of 33 relevant studies were identied. Clinical chorioamnionitis was signicantly associated with NEC (12 studies; n = 22 601; OR, 1.24; 95% CI, 1.01-1.52; P = .04; I2 = 12%), but the association between HC and NEC was not statistically signicant (13 studies; n = 5889; OR, 1.39; 95% CI, 0.95-2.04; P = .09; I2 = 49%). However, HC with fetal involvement was highly associated with NEC (3 studies; n = 1640; OR, 3.29; 95% CI, 1.87-5.78; P # .0001; I2 = 10%). Selection based on study quality did not affect the results. No indications of publication bias were apparent. Multivariate analyses in single studies generally attenuated the reported associations. Several associations between other markers of antenatal inammation and NEC are reported. Conclusion Currently available evidence supports a role for antenatal inammation in NEC pathophysiology. This nding emphasizes the need to further study the underlying mechanisms and evaluate potential interventions to improve postnatal intestinal outcomes. (J Pediatr 2012;-:---). reterm birth is the leading cause of neonatal morbidity and mortality. The majority of extremely preterm births are associated with chorioamnionitis, an inammation of the placenta and fetal membranes.1 This antenatal inammatory process is often clinically silent and is detected through histological examination of the placenta after birth. Histological signs of a fetal inammatory response, as well as clinically apparent chorioamnionitis, are thought to reect the more serious side of the continuum. Chorioamnionitis is classically recognized for its modulating effects on lung development.2 However, recent studies provide evidence that chorioamnionitis results in developmental changes in a whole range of organs including the gut, and thus may be considered a multiorgan disease of the fetus.3 Necrotizing enterocolitis (NEC) is the most serious gut-related complication of preterm birth. It affects between 5% and 10% of very low birth weight infants and is associated with a mortality rate of 20%-30% and considerable morbidity among survivors.4 Gastrointestinal (GI) inammation is one of the hallmarks of NEC, and postnatal inammatory processes, including sepsis, are highly associated with its development.4 The contribution of chorioamnionitis, a proinammatory process starting antenatally, is less clear. Several studies have reported an association between chorioamnionitis and NEC,5-7 while others have failed to reproduce this.8-17 In an attempt to clarify this issue, we aimed to accumulate the available evidence regarding the association between chorioamnionitis or other indicators of antenatal inammation and NEC.

Methods
We performed a systematic literature search in accordance with the Meta-Analysis of Observational Studies in Epidemiology criteria for a meta-analysis of observational studies.18 Databases for medical literature (Medline, Embase, and Cochrane Database of Systematic Reviews) were searched independently by 2 investigators
From the 1Department of Pediatrics, 2School for Public Health and Primary Care (CAPHRI), and 3School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, The Netherlands J.B. is funded by a Maastricht University MC Kootstra Talent Fellowship. The authors declare no conicts of interest.
0022-3476/$ - see front matter. Copyright 2012 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2012.07.012

BPD CC GI HC IL NEC

Bronchopulmonary dysplasia Clinical chorioamnionitis Gastrointestinal Histological chorioamnionitis Interleukin Necrotizing enterocolitis

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Vol. -, No. fetal involvement and NEC, resulting in a prominent pooled OR (Figure 2, B). CC and NEC Pooling of the studies on CC revealed a signicant association with NEC (Figure 2, C). Exclusion of a study that contributed 39.4% of the total weight in the meta-analysis slightly augmented the association (OR, 1.29; 95% CI, 1.04-1.59). The point estimate was lower for casecontrol studies compared with cohort studies (OR, 1.13; 95% CI, 0.60-2.13 vs OR, 1.29; 95% CI, 1.02-1.63), and for retrospective studies compared with prospective studies (OR, 1.21; 95% CI, 0.91-1.61 vs OR, 1.38; 95% CI, 0.99-1.93). Omission of a study that pooled HC and CC9 slightly augmented the association between CC and NEC (OR, 1.27; 95% CI, 1.02-1.58). Studies including only patients with preterm premature rupture of the membranes22,26 had a higher point estimate than those without this restriction (OR, 1.91; 95% CI, 1.13-3.29 vs OR, 1.12; 95% CI, 0.95-1.32). We found no statistical indications for publication bias in any comparison. Overall study quality was moderate to high (Table II; available at www.jpeds.com). Restriction of the analyses to high-quality studies (Newcastle-Ottawa Scale score $7) did not greatly alter point estimates of the association between HC or CC and NEC (OR, 1.48; 95% CI, 0.96-2.30 and OR, 1.22; 95% CI, 0.95-1.57, respectively). A minority of studies performed multivariate analyses to adjust for potential confounders affecting the association between chorioamnionitis and NEC.5,6,8,15,22 This resulted in somewhat attenuated ORs in most studies,5,6,15,22 and a loss of statistical signicance of the association in 2 studies.5,6 Other Indicators of Antenatal Inammation and NEC Fifteen studies associated one or more indicators of antenatal inammation other than chorioamnionitis with NEC (Tables I and III). Signicant positive associations have been reported between NEC and umbilical cord polymorphonuclear cell inltration,27 NEC and positive amniotic uid microbial polymerase chain reaction,28,29 NEC and Ureaplasma urealyticum colonization,21 and NEC and increased cord blood interleukin (IL)-630,31 and IL-8 levels.32 Several of these associations remained signicant after multivariate analysis.7,21,29,31 However, other studies have been unable to detect similar associations with chorioamnionitis severity,14,33 fetal vasculitis,7,21 U urealyticum colonization,30,34,35 or cord blood IL-6 levels.21,32,36 Additional Studies Interpretation of results from 2 additional small studies is complex because normal controls are missing. One of the studies reported no signicant difference in NEC incidence between selected infants with necrotizing funisitis versus those with acute funisitis (22% vs 7%).37 A second study
Been et al

(J.B. and S.L.) in April 2012. We used broad search terms to identify potentially relevant articles: (chorioamnionitis OR intrauterine infection OR intrauterine inammation OR prenatal infection OR prenatal inammation OR antenatal infection OR antenatal inammation) AND (gut OR necrotizing entercolitis OR NEC OR gastrointestinal OR intestine OR ileum OR jejunum OR stomach OR colon). We performed additional searches by screening reference lists from articles of interest as well as citations to articles of interest, using the ISI Web of Knowledge. Articles written in English that reported associations between chorioamnionitis or other indicators of antenatal inammation and NEC in humans were eligible for inclusion. Study selection and data extraction were performed independently by 2 investigators (J.B. and S.L.), and any disagreements were resolved by consensus. We performed meta-analyses for the association between chorioamnionitis and NEC. We used Mantel-Haenszel analysis to calculate aggregate ORs and 95% CIs using a randomeffects model. Study quality was assessed independently by 2 investigators (J.B. and S.L.) using the Newcastle-Ottawa Scale for observational studies, and disagreement was resolved by consensus. We used the Eggers regression test and funnel plots to assess publication bias. We applied an a level of 0.05 in all analyses, and performed all calculations using RevMan 5.1 software (Cochrane Library; ims.cochrane.org/ revman).

Results
Our search identied a total of 33 relevant studies (Table I). The selection process is summarized in Figure 1 (available at www.jpeds.com). Studies reporting associations between histological chorioamnionitis (HC) and NEC (13 cohort studies),5-14,19-21 between HC with fetal involvement and NEC (3 cohort studies),5,7,11 and between clinical chorioamnionitis (CC) and NEC (9 cohort and 3 case-control studies)5,9,10,15-17,21-26 were pooled in separate meta-analyses. Many of these studies, as well as other studies, reported associations between indicators of antenatal inammation other than chorioamnionitis and NEC, which are reported separately. HC and NEC Pooling of the studies on HC revealed no signicant overall association with NEC (Figure 2, A). Considerable heterogeneity was present among the studies (Figure 2, A). Findings were similar in retrospective studies and prospective studies (OR, 1.38; 95% CI, 0.81-2.36 vs OR, 1.39; 95% CI, 0.76-2.54). Likewise, the point estimate was not greatly altered by the exclusion of one study that pooled HC and CC (OR, 1.43; 95% CI, 0.96-2.13).9 Severe cases of chorioamnionitis may exhibit signs of fetal involvement. Three of the studies of HC compared the incidence of NEC between infants with chorioamnionitis plus fetal involvement and infants without chorioamnionitis.5,7,11 All demonstrated a signicant association between HC with
2

Chorioamnionitis as a Risk Factor for Necrotizing Enterocolitis: A Systematic Review and Meta-Analysis
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Table I. Characteristics of clinical studies associating antenatal inammation with NEC

Author and year Andrews et al (2006) * Aziz et al (2009)
22 27,

Study period 1996-2001 1980-2001 2001-2003 2006-2008 1963-1985 1989-1999 1995-2003 1997-2007 1990-1997 1997-2001 1996-2001 1996-2001 Not reported

Inclusion criteria 23-32 weeks, singleton 24-34 weeks, singleton, PPROM #32 weeks 24-32 weeks Unclear <30 weeks NEC 15-37 weeks, singleton, PPROM 500-1750 g <28 weeks/<1000 g 24-31 + 6 weeks 23-32 weeks, singleton Singleton, preterm labor/ PPROM, born <7 days after amniocentesis/ cordocentesis 24-29 weeks #34 weeks, preterm labor <34 weeks <34 weeks, singleton, cesarean section Neonatal intensive care unit admission >2000 g VLBW 24-32 weeks 23-32 weeks, singleton <33 weeks, <1501 g <32 weeks 22-37 weeks, PPROM <32 weeks #1500 g, intubated within 12 hours

Exclusion criteria

Study design Prospective cohort

N 446 1153 301 96 90 342 79 cases, 158 controls 204 1260 388 309 446 73

NEC criteria (Bell) stage $2 Not stated Bell stage $2 Bell criteria Not stated Radiologic/surgery/autopsy Modied Bell stage $2b Not mentioned Clinical and radiologic, surgery/autopsy Radiologic (Bell) stage $2 (Bell) stage $2 Clinical and radiologic/ autopsy/surgery Clinical and radiologic Clinical and radiologic/ autopsy/surgery Not reported Bell stage $2 Bell stage $2 Denite NEC/Walsh and Kliegman stage 2/3 Radiologic/surgery/autopsy Clinical and radiologic and surgical ndings Not reported Bell stage $2 (Bell) stage $2 Clinical/radiologic Bell criteria Not reported

Antenatal inammation indicators PMN membrane; PMN fetal plate; PMN cord CC HC; HC with fetal involvement; CC HC Necrotizing/acute funisitis HC CC AF PCR-positive, culture-negative; AF culture-positive HC HC or CC Cord IL-6 HC; CC; placental culture-positive Fetal plasma IL-6 (cutoff >11 pg/mL)

Immediate delivery, fetal demise/anomalies Fetal anomalies, antenatal infection, cerebral infarction

Retrospective cohort Prospective cohort Prospective cohort Case-control Retrospective cohort Matched case-control

Been et al (2009)5 Chau et al (2009)19 Craver and Baldwin (1992)37 Dempsey et al (2005)8 Desfrere et al (2005)23 DiGiulio et al (2010)28 Elimian et al (2000)
6

Fetal anomalies CC Fetal anomalies CC, fetal distress, signicant vaginal haemorrhage High-order multiplets, AF infection Fetal anomalies Died <36 weeks PMA

Retrospective cohort Retrospective cohort Prospective cohort Prospective cohort Prospective cohort Prospective cohort

Fung et al (2003)9 Goepfert et al (2004)31,* Goldenberg et al (2006)10,* Gomez et al (1998)36

Gray et al (1997)24 Hitti et al (2001)29 Holcroft et al (2004)11 Kasper et al (2011)34 Lau et al (2005)7 Martinez-Tallo et al (1997) Mu et al (2008)20 Ogunyemi et al (2003)12 Ohyama et al (2002)33 Okogbule-Wonodi et al (2011)21 Ozdemir et al (2011)30 Osmana gao glu et al (2005)26 Perrone et al (2012)13 Perzigian et al (1998)35
25

1988-1990 1991-1997 19992002 20012005 1996-1997 1990-1993 2000-2004 1992-2000 1993-1996 1999-2003; 2007-2009 ? 1995-2003 2008-2011 1993-1994

Retrospective cohort Prospective cohort Retrospective cohort Prospective cohort Prospective cohort Matched case- control

158 151 354 257 1296 24 cases, 48 controls 119 774 143 197 224 254 105 105

CC AF culture-positive; AF culturepositive TNF-a >30 pg/mL HC; HC + funisitis Uu-positive AF/placenta/amniotic membrane HC; HC + fetal response CC HC HC Stage 3 acute HC, subacute HC, subacute necrotizing funisitis HC; fetal vasculitis, CC; Uu colonization; cord IL-1b; cord IL-6 Uu colonization; cord IL-6; cord CRP; cord WBC CC HC Uu colonization (TAF or nasopharyngeal culture) (continued )

Fetal anomalies Died < 28 days Fetal neurological defect, congenital viral infection

Retrospective cohort Retrospective cohort Retrospective cohort Prospective cohort Not reported Retrospective cohort

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Fetal anomalies, incompatibility group Fetal anomalies, died <7 days

Prospective cohort Cohort

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AF, amniotic uid; CRP, C-reactive protein; PCR, polymerase chain reaction; PMA, postmenstrual age; PMN, polymorphonuclear; PPROM, preterm premature rupture of membranes; TAF, tracheal aspirate uid; TNF, tumor necrosis factor; Uu, Ureaplasma urealyticum; VLBW, very low birth weight; WBC, white blood cells. *Same cohort. Partly unpublished. zAll NEC cases combined.

CC Cord IL-6, cord IL-8, cord TNF-a

Discussion
Our current systematic review and meta-analysis demonstrates that HC with fetal involvement is associated with a threefold increased risk of NEC, and CC is associated with a modest increase in NEC risk. Although the observed magnitude of association between HC and NEC was slightly higher, the difference was not statistically signicant. Several additional studies have reported evidence of associations between NEC and other markers of antenatal inammation. Methodological aspects affect interpretation of these ndings. The incidence of both chorioamnionitis and NEC is inversely associated with gestational age at birth.4,39 Thus, differences in gestational age between infants with and without chorioamnionitis may explain part of its association with NEC. Another potential confounder may be the lower rate of breast-feeding in chorioamnionitisaffected mothers. Clearly, NEC is a multifactorial disease, and additional factors contribute to its pathogenesis. Individual studies that adjusted for confounding have suggested that its association with chorioamnionitis may in fact be attenuated. It is important to note that there were considerable differences in chorioamnionitis and NEC incidence among studies. These may be related to differences in inclusion and exclusion criteria among studies, in standards of care among centers, and in diagnostic criteria for both entities. Random-effects models were used in both comparisons to minimize bias resulting from heterogeneity. Of note, the number of studies included by hand search was relatively high. This implies that additional potentially relevant studies may have been missed by our search strategy, which might affect the analyses. This is probably related to the fact that NEC was a secondary outcome in most studies, which, on the other hand, decreases the probability of publication bias in the meta-analysis. This is further supported by the notion that ndings were similar across different levels of study quality. Several studies have identied additional markers of inammation other than chorioamnionitis associated with NEC.21,27-29,31 These include other histological markers of inammation,27 microbial presence at the fetalmaternal interface,21,28,29 and inammatory markers in umbilical cord blood.30-32 Additional clinical as well as experimental observations support an association between chorioamnionitis and adverse GI outcomes. Along with NEC, chorioamnionitis was recently shown to be associated with spontaneous intestinal perforation in preterm infants.40 Increased GI neutrophil counts and IL-6 levels have been demonstrated in chorioamnionitis-exposed preterm infants, reecting a proinammatory state of the gut shortly after birth.41 Moreover, microbial presence in the gut has been
Been et al

HC severity Clinical and radiologic 302 <30 weeks 2000-2008 Sato et al (2011)14

NEC criteria

34 83

Cohort Case-control PPROM vs no PPROM Retrospective cohort NEC requiring surgery 29-35 weeks, singleton 1987-1999 ? Ruangtrakool et al (2001)38 Satar et al (2008)32

Inclusion criteria

Study period

Table I. Continued

Soraisham et al (2009)15 Thompson et al (2011)16 Yee et al (2012)17

Author and year

2005-2006 1991-2007 2003-2008

<33 weeks <37 weeks <33 weeks

Maternal viral or urinary tract infection Fetal anomalies, referred or died <28 days Fetal anomalies Fetal GI anomalies

Exclusion criteria

Prospective cohort Case-control Retrospective cohort

Study design

3094 385 16 669

Bell stage $2 Bell stage $2z Bell stage $2

Not stated Kliegman

CC CC CC

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Figure 2. Forest plots for associations between A, HC and NEC, B, HC with fetal involvement (HCF) and NEC, and C, CC and NEC.

shown to reect that of the amniotic uid when chorioamnionitis is present.42 In concert with a disturbed barrier function, this may increase the guts susceptibility to secondary hits, such as sepsis and circulatory instability, leading to an increased incidence of NEC. Accumulating

evidence suggests that a similar multihit model applies to the effects of antenatal inammation on the lung, where chorioamnionitis alone may protect against bronchopulmonary dysplasia (BPD), and additional postnatal inammation caused by mechanical ventilation and sepsis
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Table III. Individual quality of studies included in the meta-analysis as assessed by the Newcastle-Ottawa Scale
NOS subscale score (maximum score) Cohort studies Aziz et al (2009)22 Been et al (2009)5 Chau et al (2009)19 Dempsey et al (2005)8 Elimian et al (2000)6 Fung et al (2003)9 Goldenberg et al (2006)10 Gray et al (1997)24 Holcroft et al (2004)11 Lau et al (2005)7 Mu et al (2008)20 Ogunyemi et al (2003)12 OkogbuleWonodi et al (2011)21 Osmana gao glu et al (2005)26 Perrone et al (2012)13 Sato et al (2011)14 Soraisham et al (2009)15 Yee et al (2012)17 Selection (4) 0111=3 1111=4 0111=3 1111=4 0111=3 1111=4 1111=4 1111=4 1111=4 1111=4 1111=4 1111=4 1111=4 0111=3 1111=4 0111=3 1111=4 1111=4 Selection (4) 0111=3 0111=3 0111=3 Comparability (2)* 11=2 11=2 00=0 11=2 11=2 00=0 00=0 00=0 00=0 11=2 10=1 00=0 00=0 00=0 00=0 00=0 11=2 11=2 NOS subscale score (maximum score) Case-control studies Desfrere et al (2005) Martinez-Tallo et al (1997)25 Thompson et al (2011)16
23

Outcome (3) 111=3 111=3 101=2 111=3 111=3 110=2 111=3 111=3 111=3 110=2 111=3 111=3 111=3 111=3 110=2 111=3 111=3 110=2

NOS total score (9) 8 9 5 9 8 6 7 7 7 8 8 7 7 6 6 6 9 8

Comparability (2)* 11=2 11=2 11=2

Exposure (3) 001=1 001=1 011=2

NOS total score (9) 6 6 7

NOS, Newcastle-Ottawa Scale. *Controlling for potential confounding was not incorporated in the meta-analysis. Hospital-based controls were considered appropriate.

signicantly increases the risk of BPD in infants exposed to chorioamnionitis.43-45 Much like BPD, NEC has a complex and multifactorial pathogenesis, with inammation playing a central role.4 Similarly, it is likely that interactions with additional risk factors inuence the association between chorioamnionitis and NEC. Given the low incidence of NEC, large multicenter cohort studies are needed to study such interactions. Animal studies have provided insight into the mechanisms possibly underlying these associations. Intraperitoneal lipopolysaccharide injection in pregnant rats decreased ileal mucosal thickness and increased mucosal permeability and inducible nitric oxide synthase expression in their offspring.46,47 Additional work from the same group suggested that this effect may be partly reversed by aminoguadine suppletion.47 Using an ovine chorioamnionitis model, we showed that intra-amniotic exposure to lipopolysaccharide or Ureaplasma (the most common isolate of chorioamnionitis) also resulted in fetal gut inammation.48 This inammatory response was largely mediated by IL-1a and resulted in mucosal damage and impaired intestinal development.48,49 In conclusion, the current systematic review demonstrates that chorioamnionitis is associated with an increased risk for the development of NEC. Appropriately sized clinical studies should evaluate the role of chorioamnionitis in a multihit model leading to NEC. The reported association between chorioamnionitis and NEC primes us to further study the mechanisms underlying the detrimental in utero alterations and evaluate
6

potential interventions to improve postnatal intestinal outcomes. n

Submitted for publication Apr 15, 2012; last revision received Jun 19, 2012; accepted Jul 9, 2012.

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Chorioamnionitis as a Risk Factor for Necrotizing Enterocolitis: A Systematic Review and Meta-Analysis

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Table II. Associations of antenatal inammation indicators other than chorioamnionitis with NEC
NEC association Author(s) and year Histological criteria Andrews et al (2006)27,* Ohyama et al (2002)33 Okogbule-Wonodi et al (2011)21 DiGiulio et al (2010)28 Goldenberg et al (2006)10,* Hitti et al (2001)29 Kasper et al (2011)34 Okogbule-Wonodi et al (2011)21 Ozdemir et al (2011)30 Perzigian et al (1998)35 Goepfert et al (2004)31 Gomez et al (1998)36 Hitti et al (2001)29 Okogbule-Wonodi et al (2011)21 Ozdemir et al (2011)30 Satar et al (2008)
32

Indicator PMN membranes PMN fetal plate PMN cord Stage 3 acute HC Subacute HC Subacute necrotizing funisitis Fetal vasculitis AF PCR-positive, culture-negative AF culture-positive Placenta culture-positive AF culture-positive AF culture negative/TNF-a >30 pg/mL Uu-positive placenta/AF/amniotic membrane Uu colonization (TAF/nasopharyngeal) Uu colonization (TAF/nasopharyngeal) Uu colonization (TAF) Cord IL-6 Fetal plasma IL-6 >11 pg/mL AF culture-positive + TNF-a >30 pg/mL Cord IL-1b Cord IL-6 Cord IL-6 Cord CRP Cord WBC count Cord IL-6 Cord IL-8 Cord TNF-a

Univariate NA NA

Multivariate ND ND ND ND ND ND ND ND ND ND ND

NA NA NA NA

Microbial presence

NA NA
z

NA NA

ND

NA NA
z

NA ND

Inammatory markers

NA NA NA NA
z

NA NA NA

NA

ND ND ND ND ND ND ND ND ND ND

NA, no association; ND, no data. *Same cohort. Increased, P < .05. zIncreased, P < .01.

Chorioamnionitis as a Risk Factor for Necrotizing Enterocolitis: A Systematic Review and Meta-Analysis

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