0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Review Article |

Neurodevelopmental Outcomes of Very Low-Birth-Weight Infants With Necrotizing Enterocolitis:  A Systematic Review of Observational Studies FREE

Sven M. Schulzke, MD; Girish C. Deshpande, DNB, FCPS; Sanjay K. Patole, FRACP, DrPH
[+] Author Affiliations

Author Affiliations: Department of Neonatal Paediatrics, King Edward Memorial Hospital for Women (Drs Schulzke, Deshpande, and Patole), and Division of Neonatal Paediatrics, University of Western Australia (Dr Patole), Perth, Australia.


Arch Pediatr Adolesc Med. 2007;161(6):583-590. doi:10.1001/archpedi.161.6.583.
Text Size: A A A
Published online

Objective  To systematically review observational studies reporting long-term neurodevelopmental outcomes in very low-birth-weight neonates surviving after necrotizing enterocolitis (NEC).

Data Sources  The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL (Cumulative Index to Nursing and Allied Health), and proceedings of the Pediatric Academic Societies (published in Pediatric Research since 1970) were searched in June and September 2006. The reference lists of identified studies and personal files were searched.

Study Selection  All studies with a control group were eligible for inclusion.

Main Outcome Exposure  Necrotizing enterocolitis (stage II or higher) vs no NEC.

Main Outcome Measure  Neurodevelopmental impairment at 1 year or older of corrected age.

Results  Eleven nonrandomized studies, including 5 with “matched controls,” were included in the analyses. The risk of long-term neurodevelopmental impairment was significantly higher in the presence of at least stage II NEC vs no NEC (odds ratio, 1.82; 95% confidence interval, 1.46-2.27). Significant heterogeneity (I2 = 47.9%; P = .06) between the studies indicated variations in patient, illness, and intervention characteristics and in follow-up methods. Patients with NEC requiring surgery were at higher risk for neurodevelopmental impairment vs those managed medically (odds ratio, 1.99; 95% confidence interval, 1.26-3.14). Results of analyses based on study design, follow-up rate, and year of birth were not statistically significantly different from those of the overall analysis. Risk of cerebral palsy and cognitive and severe visual impairment was significantly higher in neonates with NEC.

Conclusion  Survivors of stage II or higher NEC are at risk for long-term neurodevelopmental impairment, especially if they require surgery for the illness.

Figures in this Article

Necrotizing enterocolitis (NEC) is the most common neonatal gastrointestinal emergency. It is mainly associated with prematurity, with full-term neonates accounting for only 5% to 25% of all cases.1,2 The incidence of this potentially fatal illness is reported to be 5% to 10% in very low-birth-weight (VLBW) neonates.2 Extremely low-birth-weight (ELBW) neonates (birth weight <1000 g) with gestation less than 28 weeks are most susceptible.3 The mortality (20%-40%) and morbidity rates after a diagnosis of definite NEC continue to be high, especially in ELBW neonates.4 Preterm and VLBW neonates with NEC may be at high risk for long-term neurodevelopmental impairment (NDI) given the role of inflammatory cytokines in the illness and associated comorbidities, such as sepsis and nutritional deprivation. Survivors of surgically managed NEC may especially be at a higher risk after exposure to higher levels of pro-inflammatory cytokines for a longer duration.59 Several observational studies6,1013 have reported long-term NDI in NEC survivors. Generalization of the studies’ individual results is difficult owing to variations in study design, patient population, severity of illness, type of surgical intervention, method of follow-up, age at follow-up, and possibly the standard of neonatal intensive care and clinical practices at the time. However, this variability provides a unique opportunity to pool these data and evaluate the generalizability of the results. A systematic review and meta-analysis was undertaken to assess whether (1) NEC is associated with an increased risk of long-term NDI and (2) the risk of such an impairment is even higher in surgically compared with medically managed NEC in preterm VLBW neonates.

The standard search strategy of the Cochrane Neonatal Review Group was followed. The Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2006), MEDLINE (using the PubMed interface offered by the US National Library of Medicine), EMBASE (Excerpta Medica), CINAHL (Cumulative Index to Nursing and Allied Health), and proceedings of the Pediatric Academic Societies (published in Pediatric Research since 1970) were searched in June and September 2006. The reference lists of identified studies and personal files (proceedings of the European Society for Pediatric Research and Pediatric Gastroenterology conferences) were searched. All study designs with a control group were eligible for inclusion in the review. No language restriction was applied. The following PubMed search strategy was used: (neonate or infant, newborn [Medical Subject Headings (MeSH)]) and (necrotizing enterocolitis or necrotising enterocolitis or enterocolitis, necrotizing [MeSH]) and (mental retardation [MeSH] or psychomotor disorders [MeSH] or cerebral palsy [MeSH] or blindness [MeSH] or deafness [MeSH] or impair or long-term or outcome or neurodevelopment). The following preselected criteria justified inclusion of any study in the analysis:

  1. Studies involving VLBW infants, that is, gestational age less than 32 complete weeks or birth weight less than 1500 g.

  2. Use of modified Bell staging for defining stages of NEC.14,15 Only studies reporting on stage II or higher NEC were eligible for inclusion.

  3. Long-term follow-up at 1 year or older using a validated method for neurodevelopmental assessment, such as the Bayley16 or Griffiths17 scale.

  4. The presence of an a priori definition of moderate to severe NDI that included 1 or more of the following: scores less than 2 SDs of normal on the Bayley or Griffiths scale of assessment, cerebral palsy (CP), severe visual impairment, and severe hearing impairment. Clear definitions of CP, severe visual impairment, and severe hearing impairment were required.

All of us searched the literature independently and assessed the inclusion criteria and quality of the trials (including completeness of follow-up and blinding of outcome assessors). Two of us (S.M.S. and G.C.D.) independently extracted the data. Inconsistencies were resolved by discussion. Data extraction, statistical calculations, and graphing of results of meta-analyses were performed using a software program (Review Manager version 4.2.8; The Cochrane Collaboration, Oxford, England). Odds ratios (ORs) (“matched-control” studies and pooling of all included studies) and relative risks (RRs) (subgroup analysis of cohort studies) with 95% confidence intervals (CIs) were calculated. A statistical model assuming the same exposure and treatment effect across pooled studies (fixed effects) rather than estimating exposure and treatment effects that follow a distribution across pooled studies (random effects) was used for summarizing effects. Heterogeneity was estimated by means of the I2 statistic.18

The following sensitivity and subgroup analyses were preplanned:

  1. Pooling of data from all studies (NEC vs no NEC, surgically managed NEC vs no NEC, and medically managed NEC vs no NEC) and separately for cohort studies and those with a matched-control design (NEC vs no NEC).

  2. Exclusion of studies with less than 80% follow-up given that follow-up is critical in correct interpretation of long-term neurodevelopmental outcomes.

  3. Exclusion of studies involving neonates born in the presurfactant era given that survival and long-term outcome of high-risk neonates has improved dramatically since the availability of surfactant in the 1990s.

  4. Comparison of surgically vs medically managed NEC.

  5. Comparison of the Bayley mental (MDI) and psychomotor (PDI) developmental indices was planned because psychomotor rather than cognitive impairment has been reported as a significant issue in survivors of NEC.19

The guidelines for reporting of the Meta-analysis Of Observational Studies in Epidemiology Group were followed where appropriate.20

We identified 695 abstracts using the prespecified search strategy. Eighteen studies5,6,1013,19,2131 (7 matched-control and 11 cohort studies) reporting long-term NDI outcomes in preterm VLBW neonates with stage II or higher NEC were retrieved for detailed evaluation. Seven studies reported as “case-control” studies used gestation- or birth weight–matched controls for each case of NEC, with NDI as the outcome of interest. However, in a true case-control study, the cases would be children with NDI, the controls would be children without NDI, and the exposure of interest would be NEC. We, therefore, labeled these 7 retrospective comparative studies as matched-control studies for the purpose of this review. They are, however, analyzed separately because they used matched controls, and data on the entire control cohort were not available. No interventional studies reporting long-term NDI were found.

The characteristics of 11 studies (5 matched-control6,11,13,23,27 and 6 cohort10,12,22,24,26,31 studies) involving 6480 VLBW survivors of NEC included in the analysis are summarized in Table 1 and Table 2. The characteristics of 7 studies5,19,21,25,2830 excluded from the analysis and the reasons for their exclusion are summarized in Table 3.

Table Graphic Jump LocationTable 1. Characteristics of the 11 Included Studies
Table Graphic Jump LocationTable 2. Methods of Assessment and Definitions of NDI
Table Graphic Jump LocationTable 3. Characteristics of the 7 Excluded Studies
ANALYSIS COMBINING ALL STUDIES (NEC VS NO NEC)

More neonates with stage II or higher NEC had long-term NDI compared with those without NEC (183/427 [42.9%] vs 1267/3812 [33.2%]). Meta-analysis of data from 8 studies (N = 4239) using a fixed-effects model estimated a significant risk of long-term NDI in the presence of stage II or higher NEC compared with no NEC (OR, 1.82; 95% CI, 1.46-2.27) (Figure 1). There was significant heterogeneity between the studies (I2 = 47.9%; P = .06), indicating variations related to several factors, including patient, illness, and surgical intervention characteristics and long-term follow-up methods, as mentioned previously. Use of a random-effects model did not indicate any significant difference in the results (NEC vs no NEC: OR, 2.37; 95% CI, 1.51-3.71). The median (range) survival rate using the available data was 56/79 (70.9%) (40/84-75/86 [47.6%-87.2%]) for the NEC group and 3556/4588 (77.5%) (766/1422-560/703 [53.9%-79.7%]) for the no NEC group.

Place holder to copy figure label and caption
Figure 1.

Meta-analysis of neurodevelopmental impairment data from 8 studies using a fixed-effects model: necrotizing enterocolitis (NEC) vs no NEC. Plot displays odds ratios (ORs) for all included studies and separately for cohort and matched-control studies. CI indicates confidence interval; VLBW, very low-birth-weight. Squares represent the point estimate of treatment effect of each study, with a horizontal line extending on either side of the square representing the 95% CI. Arrowheads indicate a wide CI that is compressed to fit the scale. Solid diamonds represent the overall and subgroup OR estimate of the studies presented in the meta-analysis. The widths of the diamonds represent the 95% CI of the OR. The midline of the forest plot, corresponding to an OR of 1, represents a no-effect line.

Graphic Jump Location
SURGICAL VS MEDICAL MANAGEMENT

Meta-analysis of data from 3 studies6,10,12 (N = 3495) showed a significant risk of NDI when comparing surgically managed NEC with no NEC (OR, 2.00; 95% CI, 1.43-2.79). There was no significant risk of NDI when comparing medically managed NEC with no NEC (N = 3498) (OR, 1.08; 95% CI, 0.76-1.54). Use of a random-effects model did not show any significant difference in the results (surgically managed NEC vs no NEC: OR, 2.0; 95% CI, 1.43-2.79; medically managed NEC vs no NEC: OR, 1.09; 95% CI, 0.77-1.55). Subgroup analysis assessing the risk of NDI by method of NEC management estimated a pooled OR of 1.99 (95% CI, 1.26-3.14) for patients requiring surgery compared with those managed medically (Figure 2).

Place holder to copy figure label and caption
Figure 2.

Meta-analysis of neurodevelopmental impairment data from 4 studies using a fixed-effects model: surgically vs medically managed necrotizing enterocolitis (NEC). Plot displays odds ratios (ORs) for all included studies and separately for cohort and matched-control studies. CI indicates confidence interval; VLBW, very low-birth-weight. Squares represent the point estimate of treatment effect of each study, with a horizontal line extending on either side of the square representing the 95% CI. Arrowheads indicate a wide CI that is compressed to fit the scale. Solid diamonds represent the overall and subgroup OR estimate of the studies presented in the meta-analysis. The widths of the diamonds represent the 95% CI of the OR. The midline of the forest plot, corresponding to an OR of 1, represents a no-effect line.

Graphic Jump Location
SENSITIVITY ANALYSES

Results of the different sensitivity analyses based on the study design, follow-up rate, and year of birth were not significantly different from those of the combined analysis of NEC vs no NEC: (1) matched-control studies (OR, 3.09; 95% CI, 1.76-5.41) or cohort studies (RR, 1.33; 95% CI, 1.17-1.51; and OR, 1.64; 95% CI, 1.29-2.09); (2) studies with follow-up rates of 80% or greater (OR, 2.60; 95% CI, 1.67-4.05); and (3) studies involving only neonates born in 1990 or later (OR, 1.79; 95% CI, 1.40-2.29).

ANALYSIS OF COMPONENTS OF NDI

Analysis of individual components of NDI showed a significantly increased risk of CP and cognitive and severe visual impairment but not of severe hearing impairment in neonates with NEC (Table 4). Assessment of mean Bayley PDI and MDI scores was possible only for the comparison of surgically vs medically managed NEC owing to lack of data. In this analysis, pooled data from 2 studies10,26 incorporating 248 neonates showed a significant reduction in mean PDI scores (weighed mean difference, −6.56; 95% CI, −10.82 to −2.30) but not MDI scores (weighed mean difference, −2.69; 95% CI, −6.14 to 0.75) in those with surgically vs medically managed NEC.

Table Graphic Jump LocationTable 4. Meta-analysis of Individual Components of Neurodevelopmental Impairment: NEC vs No NEC

These results indicate that the diagnosis of stage II or higher NEC is associated with an increased risk of long-term NDI in preterm VLBW neonates. The risk is even higher in the presence of surgically managed (usually stage III) NEC. Caution is necessary in interpretation of these results given the variability in the study, patient, and illness characteristics mentioned previously. The fact that the results are based on matched-control and cohort studies rather than on randomized controlled trials is important. Pooling of data from matched-control studies requires the use of ORs rather than RRs for effect estimation, which can lead to overestimation of the effect size, particularly if the baseline risk is high.32 However, all significant ORs calculated in this meta-analysis are less than 2.8, and calculation of RRs instead of ORs for cohort studies did not change the results significantly.

This systematic review included the large National Institute of Child Health and Human Development study by Hintz et al,10 with a follow-up rate of 77% in the NEC group. Although this study received a weight of 75% in the overall analyses, its exclusion in a sensitivity analysis owing to a follow-up rate less than 80% merely widened CIs without changing the results significantly. The differences in the definition of NDI are an important issue. In the most recent studies,10,11,22 neonates with mild to moderate CP were classified as having moderate to severe impairment, whereas other studies12,24 regarded only nonambulatory CP as a component of moderate to severe impairment. Most studies defined cognitive and psychomotor impairment as a score greater than 2 SDs below the mean of a validated scale of neurodevelopmental assessment. However, Walsh et al12 used a cutoff point of a Bayley score less than 80. The definition of moderate to severe impairment based on mild to moderate CP and Bayley scores less than 80 can overestimate the impairment rates. Holmsgaard and Petersen24 did not use a standardized score for overall assessment of NDI, but the description of impairment indicates it to be severe. In any case, their study is not significant in terms of the present overall results given that it contributes only 1 case with NDI.

The role of a range of confounding factors, including prematurity, intrauterine growth restriction, sepsis, postnatal growth restriction, and exposure to glucocorticoids, as well as hyperbilirubinemia, apnea, preterm rupture of membranes, and chorioamnionitis, also must not be forgotten in such high-risk, especially ELBW, neonates.29,3342 Mere pooling of data on neurodevelopmental outcomes does not assess the impact of these confounding factors. The frequently observed interplay among prematurity, intrauterine growth restriction, sepsis, NEC, and postnatal growth restriction due to nutrient deprivation is especially important when evaluating long-term NDI in extremely preterm neonates.

Interpretation of these results is difficult because they relate to follow-up at a younger age, which may not reflect the true “long-term” outcomes.26 Simon et al26 reported a higher incidence of motor delays at 8 and 15 months of corrected age in VLBW neonates requiring surgery for NEC. The motor delays, however, had resolved by 24 months in 5 of the 6 cases, highlighting the importance of longer follow-up.26 Last, the impact of reporting bias and changes (known/unknown) in clinical practice across time also cannot be denied. Castro et al22 investigated possible bias in neurodevelopmental and somatic growth assessment at 18 to 22 months' postmenstrual age among 1483 ELBW survivors (born in 1993-1994) from many centers. Compared with children who were lost to follow-up, those who were compliant with follow-up were more likely to have been 1 of a multiple birth, to have received postnatal glucocorticoids, and to have had chronic lung disease. Chronic lung disease was associated with increased risk of CP. Scores less than 70 on the MDI and PDI were found in 37% and 29% of children evaluated at follow-up, respectively. Prediction models revealed that 34% and 26% of those in the no-visit group would have had MDI and PDI scores less than 70, respectively. Compliant children tended to have a greater incidence of MDI scores less than 70 compared with those predicted in the no-visit group but not of PDI scores less than 70. Cerebral palsy was identified in 17% of the compliant group and was predicted for 18% of the no-visit group. Predicted probabilities of having CP were marginally higher in no-visit infants compared with those who were compliant with follow-up. Overall, the results indicate that follow-up results based on those who are compliant with follow-up might be an overestimation of adverse outcomes in ELBW survivors.22 Despite all the issues discussed herein, the consistency of the association between NEC and NDI across all studies and sensitivity analyses and the biological plausibility of cerebral white matter injury from proinflammatory cytokines (implicated in the pathogenesis of NEC), however, support the present results.4349

The finding that an increased risk of NDI is even more relevant to neonates with surgically managed NEC probably reflects the severity of illness with resultant exposure to a higher level of proinflammatory cytokines for a longer duration and the fact that surgical intervention itself is associated with proinflammatory cytokine surge and NDI.59 Survivors of surgical NEC are also expected to be subjected to longer and possibly more significant exposure to suboptimal nutrition and multiple episodes of sepsis29 due to prolonged enteral feed intolerance and dependence on central venous catheters for parenteral nutrition, and, in some cases, short bowel syndrome. Note that bias may have been introduced by separating patients into groups based on the need for surgery. However, analysis by an objective criterion, such as the presence or absence of bowel perforation, could not be performed because of lack of specific data.

The clinical relevance of the present results needs to be discussed. Because the diagnosis of definite NEC is associated with long-term NDI and the risk is even higher with surgically managed NEC, prevention, early diagnosis, optimal treatment, and long-term follow-up after the illness is important. Experts have already pointed out the need to emphasize the importance and significance of the “risky business” of long-term follow-up while counseling the parents of neonatal survivors of NEC.50 Given the poorly understood and multifactorial pathogenesis of the illness and the fact that prematurity is the single most important risk factor, primary prevention of NEC is expected to be difficult.51 Early diagnosis and prevention of progression of stage II NEC to perforation and peritonitis (stage III) are, thus, equally important. Advances in laparoscopic techniques for the tiny patients are expected to be helpful in early diagnosis.52 The results of recent experimental studies53 indicate the potential role of immunomodulators in secondary prevention of the illness. Current evidence54 indicates that the early outcomes in preterm neonates with perforated NEC are not significantly different using either peritoneal drains or laparotomy. Long-term follow-up results of such studies are important because the less invasive nature of peritoneal drains and laparoscopy may be associated with less NDI.

Just at the time of reporting these results, Rees et al55 also reported their meta-analysis on neurodevelopmental outcomes of preterm neonates with medically and surgically managed NEC with almost identical results. The differences in methods, however, need to be pointed out. Rees et al did not address the critical issue of variations in the definition of NDI in the studies. Sensitivity analyses (analyzing cohort and matched-control studies separately, assessing cohort studies by means of ORs and RRs, and excluding studies from the presurfactant era and studies with follow-up rates <80%) are lacking. These data also include the most recent study by Soraisham et al11 evaluating the impact of NEC on the neurodevelopmental and growth outcomes in preterm neonates with birth weight of 1250 g or less.

In summary, these results indicate that survivors of stage II or higher NEC are at high risk for NDI. The risk is even higher in survivors of NEC who require surgical intervention. The need for continued long-term follow-up and counseling of the parents about its importance is emphasized. Continued research toward primary and secondary prevention of NEC is critical in avoiding or at least minimizing NDI associated with the illness.

Correspondence: Sanjay K. Patole, FRACP, DrPH, Department of Neonatal Paediatrics, King Edward Memorial Hospital for Women, 374 Bagot Rd, Subiaco, Perth, Western Australia 6008, Australia (sanjay.patole@health.wa.gov.au).

Accepted for Publication: January 15, 2007.

Author Contributions: All the authors had full access to all the data in the systematic review and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Patole. Acquisition of data: Schulzke, Deshpande, and Patole. Analysis and interpretation of data: Schulzke, Deshpande, Patole. Drafting of the manuscript: Schulzke and Patole. Critical revision of the manuscript for important intellectual content: Schulzke, Deshpande, and Patole. Statistical analysis: Schulzke, Deshpande, and Patole. Administrative, technical, and material support: Schulzke. Study supervision: Patole.

Financial Disclosure: None reported.

Acknowledgment: We thank Ross Haslam, FRACP, for clarification of existing data.

Ng  S Necrotizing enterocolitis in the full-term neonate. J Paediatr Child Health 2001;371- 4
PubMed Link to Article
Stoll  BJ Epidemiology of necrotizing enterocolitis. Clin Perinatol 1994;21205- 218
PubMed
Rowe  MIReblock  KKKurkchubasche  AGHealey  PJ Necrotizing enterocolitis in the extremely low birth weight infant. J Pediatr Surg 1994;29987- 990
PubMed Link to Article
Motil  KJ Necrotising enterocolitis. Eigin  RDedDeAngelis  CDOski's Pediatrics Principles and Practice. Philadelphia, Pa Lippincott Williams & Wilkins2006;389- 397
Blakely  MLTyson  JELally  KP  et al.  Laparotomy versus peritoneal drainage for necrotizing enterocolitis or isolated intestinal perforation in extremely low birth weight infants: outcomes through 18 months adjusted age. Pediatrics 2006;117e680- e687
PubMed Link to Article
Tobiansky  RLui  KRoberts  SVeddovi  M Neurodevelopmental outcome in very low birthweight infants with necrotizing enterocolitis requiring surgery. J Paediatr Child Health 1995;31233- 236
PubMed Link to Article
Lodha  AKAsztalos  EMoore  AM Elevated cytokines and poor neurodevelopmental outcome in prematurity and NEC [abstract]. Pediatr Res 2003;53386A
Ni Choileain  NRedmond  HP Cell response to surgery. Arch Surg 2006;1411132- 1140
PubMed Link to Article
Victorian Infant Collaborative Study Group, Surgery and the tiny baby: sensorineural outcome at 5 years of age. J Paediatr Child Health 1996;32167- 172
PubMed Link to Article
Hintz  SRKendrick  DEStoll  BJ  et al.  Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis. Pediatrics 2005;115696- 703
PubMed Link to Article
Soraisham  ASAmin  HJAl-Hindi  MYSinghal  NSauve  RS Does necrotising enterocolitis impact the neurodevelopmental and growth outcomes in preterm infants with birthweight ≤1250 g? J Paediatr Child Health 2006;42499- 504
PubMed Link to Article
Walsh  MCKliegman  RMHack  M Severity of necrotizing enterocolitis: influence on outcome at 2 years of age. Pediatrics 1989;84808- 814
PubMed
Yeh  TCChang  JHKao  HAHsu  CHHung  HYPeng  CC Necrotizing enterocolitis in infants: clinical outcome and influence on growth and neurodevelopment. J Formos Med Assoc 2004;103761- 766
PubMed
Bell  MJTernberg  JLFeigin  RD  et al.  Neonatal necrotizing enterocolitis: therapeutic decisions based upon clinical staging. Ann Surg 1978;1871- 7
PubMed Link to Article
Walsh  MCKliegman  RM Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986;33179- 201
PubMed
Bayley  N Bayley Scales of Infant Development-II.  San Antonio, Tex Psychological Corporation1993;
Griffiths  R The Abilities of Young Children: A Comprehensive System of Mental Measurement for the First Eight Years of Life.  High Wycombe, England Test Agency1970;
Higgins  JPThompson  SG Quantifying heterogeneity in a meta-analysis. Stat Med 2002;211539- 1558
PubMed Link to Article
Salhab  WAPerlman  JMSilver  LBroyles  RS Necrotizing enterocolitis and neurodevelopmental outcome in extremely low birth weight infants <1000 g. J Perinatol 2004;24534- 540
PubMed Link to Article
Stroup  DFBerlin  JAMorton  SC  et al. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) Group, Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA 2000;2832008- 2012
PubMed Link to Article
Adesanya  OAO'Shea  TMTurner  CSAmoroso  RMMorgan  TMAschner  JL Intestinal perforation in very low birth weight infants: growth and neurodevelopment at 1 year of age. J Perinatol 2005;25583- 589
PubMed Link to Article
Castro  LYolton  KHaberman  B  et al.  Bias in reported neurodevelopmental outcomes among extremely low birth weight survivors. Pediatrics 2004;114404- 410
PubMed Link to Article
Chacko  JFord  WDHaslam  R Growth and neurodevelopmental outcome in extremely-low-birth-weight infants after laparotomy. Pediatr Surg Int 1999;15496- 499
PubMed Link to Article
Holmsgaard  KWPetersen  S Infants with gestational age 28 weeks or less. Dan Med Bull 1996;4386- 91
PubMed
Mayr  JFasching  GHollwarth  ME Psychosocial and psychomotoric development of very low birthweight infants with necrotizing enterocolitis. Acta Paediatr Suppl 1994;39696- 100
PubMed Link to Article
Simon  NPBrady  NRStafford  RLPowell  RW The effect of abdominal incisions on early motor development of infants with necrotizing enterocolitis. Dev Med Child Neurol 1993;3549- 53
PubMed Link to Article
Sonntag  JGrimmer  IScholz  TMetze  BWit  JObladen  M Growth and neurodevelopmental outcome of very low birthweight infants with necrotizing enterocolitis. Acta Paediatr 2000;89528- 532
PubMed Link to Article
Stevenson  DKKerner  JAMalachowski  NSunshine  P Late morbidity among survivors of necrotizing enterocolitis. Pediatrics 1980;66925- 927
PubMed
Stoll  BJHansen  NIAdams-Chapman  I  et al.  Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004;2922357- 2365
PubMed Link to Article
Vohr  BRWright  LLPoole  WKMcDonald  SA Neurodevelopmental outcomes of extremely low birth weight infants <32 weeks' gestation between 1993 and 1998. Pediatrics 2005;116635- 643
PubMed Link to Article
Waugh  JO'Callaghan  MJTudehope  DI  et al.  Prevalence and aetiology of neurological impairment in extremely low birthweight infants. J Paediatr Child Health 1996;32120- 124
PubMed Link to Article
Davies  HTCrombie  IKTavakoli  M When can odds ratios mislead? BMJ 1998;316989- 991
PubMed Link to Article
Adams-Chapman  IStoll  BJ Neonatal infection and long-term neurodevelopmental outcome in the preterm infant. Curr Opin Infect Dis 2006;19290- 297
PubMed Link to Article
Amin  HSinghal  NSauve  RS Impact of intrauterine growth restriction on neurodevelopmental and growth outcomes in very low birthweight infants. Acta Paediatr 1997;86306- 314
PubMed Link to Article
Barrington  KJ The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. BMC Pediatr 2001;11
PubMed Link to Article
Clark  RHThomas  PPeabody  J Extrauterine growth restriction remains a serious problem in prematurely born neonates. Pediatrics 2003;111986- 990
PubMed Link to Article
Cooke  RWFoulder-Hughes  L Growth impairment in the very preterm and cognitive and motor performance at 7 years. Arch Dis Child 2003;88482- 487
PubMed Link to Article
Fattal-Valevski  ALeitner  YKutai  M  et al.  Neurodevelopmental outcome in children with intrauterine growth retardation: a 3-year follow-up. J Child Neurol 1999;14724- 727
PubMed Link to Article
Janvier  AKhairy  MKokkotis  ACormier  CMessmer  DBarrington  KJ Apnea is associated with neurodevelopmental impairment in very low birth weight infants. J Perinatol 2004;24763- 768
PubMed Link to Article
Oh  WTyson  JEFanaroff  AA  et al.  Association between peak serum bilirubin and neurodevelopmental outcomes in extremely low birth weight infants. Pediatrics 2003;112773- 779
PubMed Link to Article
Polam  SKoons  AAnwar  MShen-Schwarz  SHegyi  T Effect of chorioamnionitis on neurodevelopmental outcome in preterm infants. Arch Pediatr Adolesc Med 2005;1591032- 1035
PubMed Link to Article
Spinillo  AMontanari  LSanpaolo  PBergante  CChiara  AFazzi  E Fetal growth and infant neurodevelopmental outcome after preterm premature rupture of membranes. Obstet Gynecol 2004;1031286- 1293
PubMed Link to Article
Back  SA Perinatal white matter injury: the changing spectrum of pathology and emerging insights into pathogenetic mechanisms. Ment Retard Dev Disabil Res Rev 2006;12129- 140
PubMed Link to Article
Edelson  MBBagwell  CERozycki  HJ Circulating pro- and counterinflammatory cytokine levels and severity in necrotizing enterocolitis. Pediatrics 1999;103766- 771
PubMed Link to Article
Ellison  VJMocatta  TJWinterbourn  CCDarlow  BAVolpe  JJInder  TE The relationship of CSF and plasma cytokine levels to cerebral white matter injury in the premature newborn. Pediatr Res 2005;57282- 286
PubMed Link to Article
Harris  MCD'Angio  CTGallagher  PRKaufman  DEvans  JKilpatrick  L Cytokine elaboration in critically ill infants with bacterial sepsis, necrotizing entercolitis, or sepsis syndrome: correlation with clinical parameters of inflammation and mortality. J Pediatr 2005;147462- 468
PubMed Link to Article
Hsueh  WCaplan  MSTan  XMacKendrick  WGonzalez-Crussi  F Necrotizing enterocolitis of the newborn: pathogenetic concepts in perspective. Pediatr Dev Pathol 1998;12- 16
PubMed Link to Article
Markel  TACrisostomo  PRWairiuko  GMPitcher  JTsai  BMMeldrum  DR Cytokines in necrotizing enterocolitis. Shock 2006;25329- 337
PubMed Link to Article
Morecroft  JASpitz  LHamilton  PAHolmes  SJ Plasma cytokine levels in necrotizing enterocolitis. Acta Paediatr Suppl 1994;39618- 20
PubMed Link to Article
Bedrick  AD Necrotizing enterocolitis: neurodevelopmental “risky business.” J Perinatol 2004;24531- 533
PubMed Link to Article
Patole  S Prevention of necrotising enterocolitis: year 2004 and beyond. J Matern Fetal Neonatal Med 2005;1769- 80
PubMed Link to Article
Pierro  AHall  NAde-Ajayi  ACurry  JKiely  EM Laparoscopy assists surgical decision making in infants with necrotizing enterocolitis. J Pediatr Surg 2004;39902- 906
PubMed Link to Article
Travadi  JPatole  SCharles  ADvorak  BDoherty  DSimmer  K Pentoxifylline reduces the incidence and severity of necrotizing enterocolitis in a neonatal rat model. Pediatr Res 2006;60185- 189
PubMed Link to Article
Moss  RLDimmitt  RABarnhart  DC  et al.  Laparotomy versus peritoneal drainage for necrotizing enterocolitis and perforation. N Engl J Med 2006;3542225- 2234
PubMed Link to Article
Rees  CMPierro  AEaton  S Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis [published online ahead of print September 19, 2006]. Arch Dis Child Fetal Neonatal Ed doi:10.1136/adc.2006.099929
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Meta-analysis of neurodevelopmental impairment data from 8 studies using a fixed-effects model: necrotizing enterocolitis (NEC) vs no NEC. Plot displays odds ratios (ORs) for all included studies and separately for cohort and matched-control studies. CI indicates confidence interval; VLBW, very low-birth-weight. Squares represent the point estimate of treatment effect of each study, with a horizontal line extending on either side of the square representing the 95% CI. Arrowheads indicate a wide CI that is compressed to fit the scale. Solid diamonds represent the overall and subgroup OR estimate of the studies presented in the meta-analysis. The widths of the diamonds represent the 95% CI of the OR. The midline of the forest plot, corresponding to an OR of 1, represents a no-effect line.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Meta-analysis of neurodevelopmental impairment data from 4 studies using a fixed-effects model: surgically vs medically managed necrotizing enterocolitis (NEC). Plot displays odds ratios (ORs) for all included studies and separately for cohort and matched-control studies. CI indicates confidence interval; VLBW, very low-birth-weight. Squares represent the point estimate of treatment effect of each study, with a horizontal line extending on either side of the square representing the 95% CI. Arrowheads indicate a wide CI that is compressed to fit the scale. Solid diamonds represent the overall and subgroup OR estimate of the studies presented in the meta-analysis. The widths of the diamonds represent the 95% CI of the OR. The midline of the forest plot, corresponding to an OR of 1, represents a no-effect line.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Characteristics of the 11 Included Studies
Table Graphic Jump LocationTable 2. Methods of Assessment and Definitions of NDI
Table Graphic Jump LocationTable 3. Characteristics of the 7 Excluded Studies
Table Graphic Jump LocationTable 4. Meta-analysis of Individual Components of Neurodevelopmental Impairment: NEC vs No NEC

References

Ng  S Necrotizing enterocolitis in the full-term neonate. J Paediatr Child Health 2001;371- 4
PubMed Link to Article
Stoll  BJ Epidemiology of necrotizing enterocolitis. Clin Perinatol 1994;21205- 218
PubMed
Rowe  MIReblock  KKKurkchubasche  AGHealey  PJ Necrotizing enterocolitis in the extremely low birth weight infant. J Pediatr Surg 1994;29987- 990
PubMed Link to Article
Motil  KJ Necrotising enterocolitis. Eigin  RDedDeAngelis  CDOski's Pediatrics Principles and Practice. Philadelphia, Pa Lippincott Williams & Wilkins2006;389- 397
Blakely  MLTyson  JELally  KP  et al.  Laparotomy versus peritoneal drainage for necrotizing enterocolitis or isolated intestinal perforation in extremely low birth weight infants: outcomes through 18 months adjusted age. Pediatrics 2006;117e680- e687
PubMed Link to Article
Tobiansky  RLui  KRoberts  SVeddovi  M Neurodevelopmental outcome in very low birthweight infants with necrotizing enterocolitis requiring surgery. J Paediatr Child Health 1995;31233- 236
PubMed Link to Article
Lodha  AKAsztalos  EMoore  AM Elevated cytokines and poor neurodevelopmental outcome in prematurity and NEC [abstract]. Pediatr Res 2003;53386A
Ni Choileain  NRedmond  HP Cell response to surgery. Arch Surg 2006;1411132- 1140
PubMed Link to Article
Victorian Infant Collaborative Study Group, Surgery and the tiny baby: sensorineural outcome at 5 years of age. J Paediatr Child Health 1996;32167- 172
PubMed Link to Article
Hintz  SRKendrick  DEStoll  BJ  et al.  Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis. Pediatrics 2005;115696- 703
PubMed Link to Article
Soraisham  ASAmin  HJAl-Hindi  MYSinghal  NSauve  RS Does necrotising enterocolitis impact the neurodevelopmental and growth outcomes in preterm infants with birthweight ≤1250 g? J Paediatr Child Health 2006;42499- 504
PubMed Link to Article
Walsh  MCKliegman  RMHack  M Severity of necrotizing enterocolitis: influence on outcome at 2 years of age. Pediatrics 1989;84808- 814
PubMed
Yeh  TCChang  JHKao  HAHsu  CHHung  HYPeng  CC Necrotizing enterocolitis in infants: clinical outcome and influence on growth and neurodevelopment. J Formos Med Assoc 2004;103761- 766
PubMed
Bell  MJTernberg  JLFeigin  RD  et al.  Neonatal necrotizing enterocolitis: therapeutic decisions based upon clinical staging. Ann Surg 1978;1871- 7
PubMed Link to Article
Walsh  MCKliegman  RM Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986;33179- 201
PubMed
Bayley  N Bayley Scales of Infant Development-II.  San Antonio, Tex Psychological Corporation1993;
Griffiths  R The Abilities of Young Children: A Comprehensive System of Mental Measurement for the First Eight Years of Life.  High Wycombe, England Test Agency1970;
Higgins  JPThompson  SG Quantifying heterogeneity in a meta-analysis. Stat Med 2002;211539- 1558
PubMed Link to Article
Salhab  WAPerlman  JMSilver  LBroyles  RS Necrotizing enterocolitis and neurodevelopmental outcome in extremely low birth weight infants <1000 g. J Perinatol 2004;24534- 540
PubMed Link to Article
Stroup  DFBerlin  JAMorton  SC  et al. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) Group, Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA 2000;2832008- 2012
PubMed Link to Article
Adesanya  OAO'Shea  TMTurner  CSAmoroso  RMMorgan  TMAschner  JL Intestinal perforation in very low birth weight infants: growth and neurodevelopment at 1 year of age. J Perinatol 2005;25583- 589
PubMed Link to Article
Castro  LYolton  KHaberman  B  et al.  Bias in reported neurodevelopmental outcomes among extremely low birth weight survivors. Pediatrics 2004;114404- 410
PubMed Link to Article
Chacko  JFord  WDHaslam  R Growth and neurodevelopmental outcome in extremely-low-birth-weight infants after laparotomy. Pediatr Surg Int 1999;15496- 499
PubMed Link to Article
Holmsgaard  KWPetersen  S Infants with gestational age 28 weeks or less. Dan Med Bull 1996;4386- 91
PubMed
Mayr  JFasching  GHollwarth  ME Psychosocial and psychomotoric development of very low birthweight infants with necrotizing enterocolitis. Acta Paediatr Suppl 1994;39696- 100
PubMed Link to Article
Simon  NPBrady  NRStafford  RLPowell  RW The effect of abdominal incisions on early motor development of infants with necrotizing enterocolitis. Dev Med Child Neurol 1993;3549- 53
PubMed Link to Article
Sonntag  JGrimmer  IScholz  TMetze  BWit  JObladen  M Growth and neurodevelopmental outcome of very low birthweight infants with necrotizing enterocolitis. Acta Paediatr 2000;89528- 532
PubMed Link to Article
Stevenson  DKKerner  JAMalachowski  NSunshine  P Late morbidity among survivors of necrotizing enterocolitis. Pediatrics 1980;66925- 927
PubMed
Stoll  BJHansen  NIAdams-Chapman  I  et al.  Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004;2922357- 2365
PubMed Link to Article
Vohr  BRWright  LLPoole  WKMcDonald  SA Neurodevelopmental outcomes of extremely low birth weight infants <32 weeks' gestation between 1993 and 1998. Pediatrics 2005;116635- 643
PubMed Link to Article
Waugh  JO'Callaghan  MJTudehope  DI  et al.  Prevalence and aetiology of neurological impairment in extremely low birthweight infants. J Paediatr Child Health 1996;32120- 124
PubMed Link to Article
Davies  HTCrombie  IKTavakoli  M When can odds ratios mislead? BMJ 1998;316989- 991
PubMed Link to Article
Adams-Chapman  IStoll  BJ Neonatal infection and long-term neurodevelopmental outcome in the preterm infant. Curr Opin Infect Dis 2006;19290- 297
PubMed Link to Article
Amin  HSinghal  NSauve  RS Impact of intrauterine growth restriction on neurodevelopmental and growth outcomes in very low birthweight infants. Acta Paediatr 1997;86306- 314
PubMed Link to Article
Barrington  KJ The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. BMC Pediatr 2001;11
PubMed Link to Article
Clark  RHThomas  PPeabody  J Extrauterine growth restriction remains a serious problem in prematurely born neonates. Pediatrics 2003;111986- 990
PubMed Link to Article
Cooke  RWFoulder-Hughes  L Growth impairment in the very preterm and cognitive and motor performance at 7 years. Arch Dis Child 2003;88482- 487
PubMed Link to Article
Fattal-Valevski  ALeitner  YKutai  M  et al.  Neurodevelopmental outcome in children with intrauterine growth retardation: a 3-year follow-up. J Child Neurol 1999;14724- 727
PubMed Link to Article
Janvier  AKhairy  MKokkotis  ACormier  CMessmer  DBarrington  KJ Apnea is associated with neurodevelopmental impairment in very low birth weight infants. J Perinatol 2004;24763- 768
PubMed Link to Article
Oh  WTyson  JEFanaroff  AA  et al.  Association between peak serum bilirubin and neurodevelopmental outcomes in extremely low birth weight infants. Pediatrics 2003;112773- 779
PubMed Link to Article
Polam  SKoons  AAnwar  MShen-Schwarz  SHegyi  T Effect of chorioamnionitis on neurodevelopmental outcome in preterm infants. Arch Pediatr Adolesc Med 2005;1591032- 1035
PubMed Link to Article
Spinillo  AMontanari  LSanpaolo  PBergante  CChiara  AFazzi  E Fetal growth and infant neurodevelopmental outcome after preterm premature rupture of membranes. Obstet Gynecol 2004;1031286- 1293
PubMed Link to Article
Back  SA Perinatal white matter injury: the changing spectrum of pathology and emerging insights into pathogenetic mechanisms. Ment Retard Dev Disabil Res Rev 2006;12129- 140
PubMed Link to Article
Edelson  MBBagwell  CERozycki  HJ Circulating pro- and counterinflammatory cytokine levels and severity in necrotizing enterocolitis. Pediatrics 1999;103766- 771
PubMed Link to Article
Ellison  VJMocatta  TJWinterbourn  CCDarlow  BAVolpe  JJInder  TE The relationship of CSF and plasma cytokine levels to cerebral white matter injury in the premature newborn. Pediatr Res 2005;57282- 286
PubMed Link to Article
Harris  MCD'Angio  CTGallagher  PRKaufman  DEvans  JKilpatrick  L Cytokine elaboration in critically ill infants with bacterial sepsis, necrotizing entercolitis, or sepsis syndrome: correlation with clinical parameters of inflammation and mortality. J Pediatr 2005;147462- 468
PubMed Link to Article
Hsueh  WCaplan  MSTan  XMacKendrick  WGonzalez-Crussi  F Necrotizing enterocolitis of the newborn: pathogenetic concepts in perspective. Pediatr Dev Pathol 1998;12- 16
PubMed Link to Article
Markel  TACrisostomo  PRWairiuko  GMPitcher  JTsai  BMMeldrum  DR Cytokines in necrotizing enterocolitis. Shock 2006;25329- 337
PubMed Link to Article
Morecroft  JASpitz  LHamilton  PAHolmes  SJ Plasma cytokine levels in necrotizing enterocolitis. Acta Paediatr Suppl 1994;39618- 20
PubMed Link to Article
Bedrick  AD Necrotizing enterocolitis: neurodevelopmental “risky business.” J Perinatol 2004;24531- 533
PubMed Link to Article
Patole  S Prevention of necrotising enterocolitis: year 2004 and beyond. J Matern Fetal Neonatal Med 2005;1769- 80
PubMed Link to Article
Pierro  AHall  NAde-Ajayi  ACurry  JKiely  EM Laparoscopy assists surgical decision making in infants with necrotizing enterocolitis. J Pediatr Surg 2004;39902- 906
PubMed Link to Article
Travadi  JPatole  SCharles  ADvorak  BDoherty  DSimmer  K Pentoxifylline reduces the incidence and severity of necrotizing enterocolitis in a neonatal rat model. Pediatr Res 2006;60185- 189
PubMed Link to Article
Moss  RLDimmitt  RABarnhart  DC  et al.  Laparotomy versus peritoneal drainage for necrotizing enterocolitis and perforation. N Engl J Med 2006;3542225- 2234
PubMed Link to Article
Rees  CMPierro  AEaton  S Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis [published online ahead of print September 19, 2006]. Arch Dis Child Fetal Neonatal Ed doi:10.1136/adc.2006.099929
PubMed

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 79

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles