REVIEW ARTICLE

Neurodevelopmental Outcomes
of Very Low-Birth-Weight Infants
With Necrotizing Enterocolitis
A Systematic Review of Observational Studies
Sven M. Schulzke, MD; Girish C. Deshpande, DNB, FCPS;
Sanjay K. Patole, FRACP, DrPH

Objective: To systematically review observational stud-

ies 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, 1.462.27). 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.

Arch Pediatr Adolesc Med. 2007;161:583-590

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.

ECROTIZING ENTERO colitis (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 inflamma-

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583

tory 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.5-9 Several observational
studies6,10-13 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

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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.
METHODS
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 metaanalyses 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 highrisk 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
RESULTS

We identified 695 abstracts using the prespecified search

strategy. Eighteen studies5,6,10-13,19,21-31 (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
weightmatched controls for each case of NEC, with NDI
as the outcome of interest. However, in a true casecontrol 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 matchedcontrol6,11,13,23,27 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 studies5,19,21,25,28-30 excluded from the analysis and
the reasons for their exclusion are summarized in Table 3.
ANALYSIS COMBINING ALL STUDIES
(NEC VS NO NEC)
More neonates with stage II or higher NEC had longterm 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.

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Table 1. Characteristics of the 11 Included Studies

Follow-up, No./Total No. (%)
Study
Cohort
Hintz et al,10 2005
Castro et al,22 2004
Waugh et al,31 1996
Holmsgaard and
Petersen,24 1996
Simon et al,26 1993
Walsh et al,12 1989
Matched-control
Soraisham et al,11 2006
Yeh et al,13 2004
Sonntag et al,27 2000
Chacko et al,23 1999
Tobiansky et al,6 1995

Design

Survivors,
Total No.

MC
MC
SC
SC

3725
1151
224
140

SC
SC
SC
SC
SC
SC
SC

Population

Birth Year

NEC

Control

ELBW
ELBW
ELBW
GA 28 wk

1995-1998
1993-1994
1977-1990
1987-1990

234/305 (76.7)
1008/1151 (87.6)
199/224 (88.8)
138/140 (98.6)

2703/3420 (79.0)
1008/1151 (87.6)
199/224 (88.8)
138/140 (98.6)

18
806

VLBW
VLBW

1986-1988
1975-1983

18/18 (100)
36/40 (90.0)

153
58
62
28
115

BW 1250 g
VLBW
VLBW
ELBW
VLBW

1995-2000
1991-2002
1992-1996
1990-1993
1986-1991

46/51 (90.2)
15/28 (53.6)
20/22 (90.9)
28/28 (100)
49/75 (65.3)

Age at
Assessment, mo

Blinding
of Outcome
Assessors
Yes
Yes
Yes
Unclear

No control group
766/766 (100)

18-22*
18-22*
24
Disabled: 10-68*
Healthy: 24-71*
24
20

100/102 (98.0)
30/30 (100)
40/40 (100)
No control group
40/40 (100)

36
18
20
12-59*
45

Unclear
Unclear
Unclear
Unclear
Unclear

Unclear
Unclear

Abbreviations: BW, birth weight; ELBW, extremely low BW; GA, gestational age; MC, multicenter; NEC, necrotizing enterocolitis; SC, single center; VLBW, very
low BW.
*Corrected age, range.
Follow-up rate for the entire cohort. Specific follow-up rates for the NEC and control groups are not provided.
Corrected age (unspecified).
Medically managed vs surgically managed NEC.
Retrospective comparative studies.
Uncorrected age, mean.

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, 1.263.14) for patients requiring surgery compared with those
managed medically (Figure 2).
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.
COMMENT

These results indicate that the diagnosis of stage II or

higher NEC is associated with an increased risk of longterm 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 matchedcontrol 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 with-

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Table 2. Methods of Assessment and Definitions of NDI

Study

Scale

Cohort
Hintz et al,10 2005

BSID 2

Castro et al,22 2004

BSID 2

Holmsgaard
and Petersen,24 1996

Undefined (clinical assessment)

Waugh et al,31 1996

Griffiths and McCarthy Index

Simon et al,26 1993

BSID 1

Walsh et al,12 1989

BSID 1 and Stanford-Binet

Matched-control*
Soraisham et al,11 2006

BSID 2 and Stanford-Binet

Yeh et al,13 2004

Sonntag et al,27 2000
Chacko et al,23 1999

BSID 2
Griffiths
Griffiths and Stanford-Binet

Tobiansky et al,6 1995

Griffiths and Stanford-Binet

Definitions
NDI: 1 of the following: MDI 70, PDI 70, CP, blindness, deafness.
CP: Nonprogressive central nervous system disorder characterized by abnormal
muscle tone in 1 extremity and abnormal control of movement and posture.
Blindness: No useful vision in either eye.
Deafness: Hearing aids in both ears.
NDI: Includes MDI 70, PDI 70, and CP.
CP: Nonprogressive central nervous system disorder characterized by abnormal
muscle tone in 1 extremity and abnormal control of movement and posture.
Blindness and deafness: Not assessed.
NDI: 1 of the following: severe mental retardation or autism, severe CP
(unable to walk), blindness, deafness.
CP: Severe, unable to walk; moderate, walks with support; mild, walks well.
Blindness and deafness: Not defined.
NDI: GQ 76 (2 SDs below mean).
CP: Severe, unable to function independently even with assistance; moderate,
impaired but able to function independently with assistance; mild, minimal
or no functional impairment.
Visual impairment: Absent or minimal light perception in 1 or both eyes at the
last assessment.
Deafness: Sensorineural hearing impairment requiring amplification.
NDI: No clear definition. Data on mean MDI and PDI given.
CP: Decreased lower extremity/trunk flexor tone; able to walk, but poor balance
reactions; wide-based, clumsy gait.
Blindness and deafness: Not assessed.
NDI: Bayley score 80 or the presence of neurosensory abnormality, including
hypotonia, severe CP, hydrocephalus, severe visual or severe hearing impairment.
CP: Spastic diplegia or quadriplegia.
Severe visual and hearing impairment: Not defined.
NDI: 1 of the following: cognitive delay (MDI or IQ 2 SDs below mean), CP, visual
impairment, deafness.
CP: Nonprogressive motor impairment characterized by abnormal muscle tone
in 1 extremity and decreased range or control of movements.
Visual impairment (after refractive correction): Vision in best eye 20/60;
blindness: vision 20/200.
Deafness: Sensorineural hearing loss requiring hearing aids.
NDI: MDI or PDI 70.
NDI: GQ 2 SDs below mean.
NDI: 1 of the following: GQ or IQ 71, moderate or severe CP, blindness, deafness.
CP: Severe, nonambulatory; moderate, ambulatory with aids only; mild,
ambulatory without aids.
Blindness: Bilateral vision 6/60.
Deafness: Bilateral sensorineural hearing loss requiring hearing aids.
NDI: 1 of the following: GQ or IQ 71, moderate or severe CP, blindness, deafness.
CP: Moderate to severe, walking aids needed/child unlikely ever to walk; mild,
ambulatory, motor impairment interfering only slightly with daily activities.
Blindness: Bilateral vision 6/60.
Deafness: Bilateral sensorineural hearing loss requiring hearing aids.

Abbreviations: BSID, Bayley Scales of Infant Development; CP cerebral palsy; GQ, Griffiths quotient; MDI, mental developmental index; NDI, neurodevelopmental impairment; PDI, psychomotor developmental index.
*Retrospective comparative studies.

out 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, neo-

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Table 3. Characteristics of the 7 Excluded Studies

Study

Design

Cohort
Blakely et al,5 2006

Reason for Exclusion

Large randomized multicenter trial of peritoneal drainage vs

laparotomy in ELBW infants with either NEC or isolated
perforation
NICHD study assessing neurodevelopment in ELBW infants
NICHD study assessing neurodevelopment in ELBW infants
with infections
Retrospective cohort study assessing neurodevelopment in
VLBW infants with either NEC or isolated perforation
Retrospective cohort study assessing growth and
neurodevelopment in survivors of NEC

Vohr et al,30 2005

Stoll et al,29 2004
Adesanya et al,21 2005
Stevenson et al,28 1980
Matched-control*
Salhab et al,19 2004

No control group

All participants are included in Hintz et al,10 2005

All participants are included in Hintz et al,10 2005
No control group
No control group

All participants are included in Hintz et al,10 2005

NICHD study assessing neurodevelopment in ELBW infants

with NEC
Single-center study assessing psychosocial and psychomotor
development in VLBW infants with NEC

Mayr et al,25 1994

NDI and hearing and visual impairment not defined,

some tests of neurodevelopment not validated

Abbreviations: ELBW, extremely low-birth-weight; NDI, neurodevelopmental impairment; NEC, necrotizing enterocolitis; NICHD, National Institute of Child Health
and Human Development; VLBW, very low-birth-weight.
*Retrospective comparative studies.

Review:
Comparison:
Outcome:

Neurodevelopmental Outcome of Preterm VLBW Survivors of Severe NEC

01 Neurodevelopmental Follow-up at >12 mo: NEC vs No NEC
01 Neurodevelopmental Impairment

Study
or Subcategory

NEC,
No./Total No.

No NEC,
No./Total No.

OR
(95% CI)

Weight,
%

OR
(95% CI)

119/234

1014/2531

75.27

1.55 (1.18-2.02)

1/4

31/134

1.20

1.11 (0.11-11.03)

01 Cohort Studies
Hintz et al,10 2005
Holmsgaard and Petersen,24 1996
Waugh et al,31 1996

7/23

13/171

1.91

5.32 (1.86-15.24)

Walsh et al,12 1989

12/36

173/766

9.24

1.71 (0.84-3.50)

87.63

1.64 (1.29-2.09)

Subtotal

297

3602

Total Events: 139 (NEC), 1231 (No NEC)

Test for Heterogeneity: 2 = 5.10, df = 3 (P = .16), I2 = 41.1%
Test for Overall Effect: Z = 3.99 (P<.001)

02 Matched-Control Studies
Soraisham et al,11 2006

11/46

10/100

4.28

2.83 (1.10-7.25)

Yeh et al,13 2004

13/15

11/30

0.87

11.23 (2.13-59.26)

Sonntag et al,27 2000

11/20

9/40

2.41

4.21 (1.33-13.32)

Tobiansky et al,6 1995

9/49

6/40

4.81

1.28 (0.41-3.95)

210

12.37

3.09 (1.76-5.41)

3812

100.00

1.82 (1.46-2.27)

Subtotal

130

Total Events: 44 (NEC), 36 (No NEC)

Test for Heterogeneity: 2 = 4.98, df = 3 (P = .17), I2 = 39.7%
Test for Overall Effect: Z = 3.94 (P<.001)

Total
427
Total Events: 183 (NEC), 1267 (No NEC)
2
2
Test for Heterogeneity: = 13.44, df = 7 (P = .06), I = 47.9%
Test for Overall Effect: Z = 5.29 (P<.001)

0.1

0.2

0.5

No NEC

10

NEC

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.

nates.29,33-42 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 depri-

vation is especially important when evaluating longterm 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 re-

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Review:
Comparison:
Outcome:

Neurodevelopmental Outcome of Preterm VLBW Survivors of Severe NEC

02 Neurodevelopmental Follow-up at >12 mo: Surgically vs Medically Managed NEC
01 Neurodevelopmental Impairment

Study
or Subcategory

Surgical NEC,
No./Total No.

Medical NEC,
No./Total No.

Hintz et al,10 2005

69/121

Walsh et al,12 1989

6/17

OR
(95% CI)

Weight,
%

OR
(95% CI)

50/113

85.29

1.67 (1.00-2.80)

3/19

7.04

2.91 (0.60-14.18)

92.32

1.77 (1.08-2.88)

01 Cohort Studies

Subtotal

138
Total Events: 75 (Surgically managed NEC), 53 (Medically managed NEC)
Test for Heterogeneity: 2 = 0.42, df = 1 (P = .51), I2 = 0%
Test for Overall Effect: Z = 2.27 (P = .02)

132

02 Matched-Control Studies
Chacko et al,23 1999

2/6

1/22

1.10

10.50 (0.76-145.36)

Tobiansky et al,6 1995

6/20

3/29

6.58

3.71 (0.80-17.16)

Subtotal

26
Total Events: 8 (Surgically managed NEC), 4 (Medically managed NEC)
2
2
Test for Heterogeneity: = 0.45, df = 1 (P = .50), I = 0%
Test for Overall Effect: Z = 2.29 (P = .02)

51

7.68

4.68 (1.25-17.59)

Total
164
Total Events: 83 (Surgically managed NEC), 57 (Medically managed NEC)
2
2

Test for Heterogeneity: = 2.83, df = 3 (P = .42), I = 0%

Test for Overall Effect: Z = 2.95 (P = .003)

183

100.00

0.01

0.1

Medical NEC

10

1.99 (1.26-3.14)

100

Surgical NEC

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.

Table 4. Meta-analysis of Individual Components

of Neurodevelopmental Impairment: NEC vs No NEC
Studies,
No.

Outcome
Cerebral palsy
Cognitive impairment
Severe visual
impairment
Severe hearing
impairment

Participants,
No.

OR (95% CI)

5
310,11,13
36,10,11

4385
2954
3161

1.59 (1.23-2.07)
1.65 (1.27-2.15)
2.75 (1.30-5.85)

36,10,11

3165

1.74 (0.79-3.85)

6,10,11,22,31

Abbreviations: CI, confidence interval; NEC, necrotizing enterocolitis;

OR, odds ratio.

ported 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 19931994) 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.43-49
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.5-9 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

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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. Longterm 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.
Accepted for Publication: January 15, 2007.
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).

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.
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From where did Pop Goes the Weasel originate? The phrase initially referred to the opening and shutting of a pocketbook. Weasel
or weaselskin was a popular slang name for
pocketbook when the verse was written.
From Why Do We Say It? Castle Books, 1985

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