Journal of Perinatology (2013), 1–7

& 2013 Nature America, Inc. All rights reserved 0743-8346/13

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ORIGINAL ARTICLE
Neurodevelopmental outcomes of very low birth weight infants
with neonatal sepsis: systematic review and meta-analysis
B Alshaikh1,2, K Yusuf2 and R Sauve1,2

OBJECTIVE: To study the impact of neonatal sepsis on the long-term neurodevelopmental outcome in very low birth weight
(VLBW) infants.
STUDY DESIGN: Systematic review and meta-analysis of observational studies comparing neurodevelopmental outcomes in
VLBW infants exposed to culture-proven sepsis in the neonatal period with similar infants without sepsis.
RESULT: Seventeen studies involving 15 331 infants were included in the meta-analysis. Sepsis in VLBW infants was associated with
an increased risk of one or more long-term neurodevelopmental impairments (odds ratio (OR) 2.09; 95% confidence interval
(CI) 1.65 to 2.65) including cerebral palsy (CP; OR 2.09; 95% CI 1.78 to 2.45). Heterogeneity (I2 ¼ 36.9%; P ¼ 0.06) between the studies
was significant and related to variations in patient characteristics, causative pathogens and follow-up methods. Sensitivity analyses
based on study design, follow-up rate and year of birth were not significantly different from the overall analysis.
CONCLUSION: The meta-analysis suggests that sepsis in VLBW infants is associated with a worse neurodevelopmental outcome
including higher incidence of CP.

Journal of Perinatology advance online publication, 17 January 2013; doi:10.1038/jp.2012.167

Keywords: sepsis; long-term neurodevelopmental outcome; cerebral palsy; premature infants

INTRODUCTION important in determining the impact of neonatal sepsis on

Sepsis is a clinical syndrome characterized by systemic signs
of infection accompanied by bacteremia.1 The sepsis rate in
premature infants has significantly risen in the last three decades
because of increased survival of very low birth weight (VLBW)
infants,2 prolonged stay in neonatal intensive care units3 and
frequent exposure to protracted instrumentation, such as
intravascular lines and endotracheal tubes. Neonatal literature
indicates that 11 to 46% of VLBW infants experience a culture-
proven infection during hospitalization, and this incidence is
inversely proportional to gestational age and birth weight.3,4
The relationship between infection and neurodevelopmental
outcome of surviving VLBW infants has been correlated to cerebral
white matter injury, particularly periventricular leukomalacia.5–7 The
white matter injury resulting from sepsis is a multifactorial process
involving the production of pro-inflammatory cytokines, increased
blood–brain barrier permeability and hypoxic ischemic events
resulting from hypotension and impaired autoregulation of cerebral
blood flow.5,8,9 Systematic review on association between
intrauterine infection and poor neurodevelopmental outcome has
shown increased risk of cerebral palsy (CP) and periventricular
leukomalacia in preterm infants.10 However, studies on relationships
between neonatal infection and poor neurodevelopmental outcome
have conflicting results.
Advances in immunology and microbiology have opened the
door for researchers to produce drugs containing immunogloblins
and anti-cytokines to prevent sepsis or to protect infected infants
from brain injury.11–13
The objective of our review was to systematically evaluate the
current data reporting associations between neonatal sepsis and
neurodevelopmental outcome in preterm infants. This is critically
long-term prognosis, and for guiding development of therapeutic
interventions.
METHODS
Search strategy
Both manual and electronic search strategies were used to identify
relevant studies that evaluated the association between neonatal sepsis
and neurodevelopmental outcome. Our search was done initially in
January 2012 and updated in June 2012 including: MEDLINE, PUBMED,
EMBASE, and CINAHL (Cumulative Index to Nursing and Allied Health). In
addition, we searched the reference list of retrieved articles and abstracts
of two major pediatric international annual meetings (American Pediatric
Society and the European Society for Pediatric Research) in the last 2 years.
Searches were limited to observational trials in human newborn infants
but no language restrictions were applied. All studies including neonates
were considered for this review. Authors were contacted for additional or
missing information, first by sending two emails and if no reply we tried to
contact the author by phone. A combination of text words and exploded
medical subject headings were used to maximize the volume of retrieved
literature. Searches were performed using the following search themes
that created using the Boolean search term ‘or’ then combined by the
Boolean operator ‘and’ in varying combination:
(1) Sepsis: sepsis or infection or pathogen.
(2) Neurodevelopmental outcome: mental retardation or CP or blindness
or deafness or neurodevelopment* or impairment or long-term
outcome.
(3) Newborn: newborn or neonate or premature or preterm or very low
*birth weight or VLBW or extremely low* birth weight or ELBW.
(4) Four-study design: prevalence or cohort or follow-up or incidence or
case control or prognosis.

1
Department of Community Health Sciences, Faculty of Medicine, University of Calgary, Calgary, AB, Canada and 2Department of Pediatrics, University of Calgary, Calgary, AB,
Canada. Correspondence: Dr B Alshaikh, Department of Pediatrics, Faculty of Medicine, University of Calgary, Room C211, 1403 29th Street NW Calgary, AB T2N 2T9, Canada.
E-mail: belal.alshaikh@albertahealthservices.ca
Received 15 August 2012; accepted 10 December 2012
 Neurodevelopmental outcomes of VLBW infants with neonatal sepsis
B Alshaikh et al
2
Study selection criteria
Two authors (BA and KY) searched the literature independently and
assessed the eligibility of identified articles for this systematic review
and meta-analysis. All following preselected criteria were considered for
including any study in the analysis: (1) studies on VLBW infants (o1500 g).
(2) Studies involving infants with neonatal culture-proven sepsis, that is,
sepsis accompanied by the presence of an organism in the blood during
the admission period in the neonatal intensive care unit. (3) Long-term
follow-up for a minimum of 12 months. (4) A priori definition of moderate-
to-severe neurodevelopmental impairment (NDI) that included at least one
of the following: CP, cognitive delay (cognitive score 2 s.d. less than mean
on standardized psychological testing), vision loss or deafness. In addition,
only studies reported original data (that is, no review articles) were
included.
Data extraction
Data extraction was performed independently by two reviewers (BA and
KY) using a standardized data collection form. Any discrepancies in
extracted data were solved by consensus. The following data were
collected: journal name, year of publication, single-center or multicenter
status, demographic data, year of birth, number of infants in both proven
sepsis and comparison groups, definitions adopted, inclusion and
exclusion criteria, and methods and duration of follow-up. The primary
outcome was one or more of NDIs in VLBW infants with culture-proven
sepsis in neonatal period as assessed by odds ratio (OR) in individual
studies. We used the OR, lower and upper limit of the 95% confidence
interval (CI) as reported in the studies. In the studies where ORs for the
association between neonatal sepsis and long-term NDI were not reported,
we calculated ORs using 2  2 tables.
Data synthesis and analysis
STATA version 11 (Stata, College Station, TX, USA) was used for all statistical
analysis. Estimates for OR together with the corresponding 95% CIs and
the percentage weight contributed to the overall meta-analysis from each
study were calculated. For each outcome of interest, effect estimates were
pooled assuming a random-effect modeling approach given that the data
were retrieved from the literature and expected to have variable size-
effect. Heterogeneity across the observational studies was evaluated using
both the I2 statistics; Po0.1 was defined to note statistical significance in
the analysis of heterogeneity. In addition, we assessed for potential
evidence of publication bias through visual inspection of the Begg’s funnel
plot and the Egger test for funnel plot asymmetry. Finally, the following
sensitivity and subgroup analyses were planned:
(1) Studies in which at least 80% of infants had follow-up because follow-
up rate is crucial in accurate interpretation of long-term neurodevelop-
mental outcome.
(2) Studies involving only neonates born in the post-surfactant era given
that long-term outcome of VLBW infants improved significantly after
introducing surfactant.
(3) Analysis of studies reporting long-term outcome for infants with
coagulase negative staphylococcus (CoNS) infection given that CoNS is
the most common cause of infection in VLBW infants.
(4) Comparison between the components of neurodevelopmental
outcome.
RESULTS
Our specified search strategy identified 1362 abstracts (Figure 1). In
all, 33 studies reporting sepsis in neonates and long-term
neurodevelopment impairment were retrieved for full detailed
evaluation. Seventeen studies met the inclusion criteria. There was
an excellent agreement for the inclusion of individual studies (kappa
0.94, 95% CI (0.92 to 0.96)). The characteristics of these 17 studies (14
cohort and 3 case–control studies) involving 15 331 VLBW survivors
of neonatal sepsis are summarized in Tables 1 and 2.
Analysis combining all studies
VLBW infants with sepsis in the neonatal period had poor long-
term neurodevelopment outcome compared with those without
Journal of Perinatology (2013), 1 – 7
1362 Citation screened
1329 Articles excluded:
Abstracts not including neurodevelopmental
outcome of neonates with sepsis
33 Potentially relevant citations
identified for further review
16 Articles excluded:
4 All patients were included in other studies
8 No data for VLBW infants or neonatal sepsis
2 Sepsis was diagnosed clinically
1 Follow up was at < 12 months post menstrual age
1 Some data on NDI were collected by phone
17 Studies included in the analysis
Figure 1. Flow diagram of study selection process. NDI, neurodeve-
lopmental impairment; VLBW, very low birth weight.
sepsis (OR 2.09; 95% CI 1.65 to 2.65; Figure 2). There was
considerable heterogeneity within the studies (I2 ¼ 36.9; P ¼ 0.06),
representing variations related to a number of factors, including
patient characteristics, specifics of the illness and long-term
follow-up rates.
There was some evidence to suggest probable publication bias
in Egger’s test (coefficient 0.80, 95% CI 0.03 to 1.52, P ¼ 0.04);
however, this was not evident in Begg’s test (P ¼ 0.53, with
continuity correction) although it appeared highly likely in the
funnel plot. Figure 3 displays this bias graphically, as there is
asymmetry in the funnel plot with a predominance of studies with
large standard errors (small studies) showing positive effect
studies and a paucity of small negative studies.
Sensitivity analysis
Results of sensitivity analyses based on the year of birth before
1990 showed similar association between neonatal sepsis and NDI
to studies included patients after 1990. However, the magnitude
of association was higher in infants born before 1990; OR 2.74
(1.66 to 4.53) vs 1.82 (1.48 to 2.24). Results of using follow-up rate
of 80% as a cutoff were not significantly different from the
combined analysis of sepsis vs no sepsis (OR 2.06 (1.53 to 2.77) for
follow-up 480% vs 2.18 (1.52 to 3.12) for o80%). In regard to
study design, cohort studies (OR 2.01; 95% CI 1.69 to 2.39) yield
similar result to the combined studies, but the three case–control
studies showed higher association between sepsis and NDI (OR
2.89; 95% CI 1.75 to 4.77).
Analysis of components of NDI
Analysis of individual components of NDI indicated a significantly
increased risk of CP (11 studies: OR 2.09; 95% CI 1.78 to 2.45;
Figure 4), low psychomotor developmental index (PDI) (3
studies(14,18,22): OR 1.55; 95% CI 1.25 to 1.92) and deafness (2
studies(22,42): OR 2.07; 95% CI 1.09 to 2.94). Analysis for the
mental developmental index component revealed no significant
difference between sepsis and no sepsis groups (4 stu-
dies14,18,22,24: OR 1.16; 95% CI 0.84 to 1.61). Data on visual
impairment were limited to one study22 OR 2.7 (2.14 to 3.41).
Analysis of CoNS sepsis and candida infection
Analysis of the relationship between neonatal sepsis caused by
CoNS and neurodevelopmental outcome showed a similar
association to that seen in any culture-proven sepsis and NDI
(three studies14,20,22: OR 1.31; 95% CI 1.09 to 1.57) and with CP
(three studies14,20,22: OR 1.7; 95% CI 1.02 to 2.87). Data on mental
& 2013 Nature America, Inc.
 Neurodevelopmental outcomes of VLBW infants with neonatal sepsis
B Alshaikh et al
3
Table 1. Characteristics of the included studies

Study Year Design Population Birth Survivors Follow Proven Comparison Age at Blinding
year total no. up sepsis group no. assessment, of
rate/ no. months outcome
total assessors
no.

Cohort
Schlapbach et al.14 2011 MC GA 24–27 2000–2007 702 77% 161 236 18–24 NS
Jang et al.15 2011 SC VLBW 1989–2007 817 81% NA NA 24 NS
Kono et al.16 2011 MC VLBW 2003–2004 2847 64% 113 1714 36–48 NS
Gocer et al.17 2010 SC VLBW or 2002 117 45.7% 24 93 36 NS
o32GA
Addison et al.18 2009 SC VLBW 1999–2001 65 98.4% 46 19 12–18 No
Chen et al.19 2008 SC VLBW 1998–2005 160 76.3% 25 197 18–36 NS
Shah et al.20 2008 SC VLBW 2001–2003 183 94% 66 119 24 NS
Saw et al.21 2005 SC VLBW 1998–2005 215 100% 33 182 6–24 NS
Stoll et al.22 2004 MC 401–1000 1993–2001 8853 80% 1825 2144 18–22 NS
Hoekstra et al.23 2004 SC GA 23–26 1986–2000 675 87% NA NA 36–60 NS
Hack et al.24 2000 SC ELBW 1992–1995 241 92% 109 112 20 NS
Friedman et al.25 2000 SC ELBW 1988–1996 299 90% 27 272 24 NS
TapiaCollados 1997 SC VLBW 1986–1991 174 87% 12 125 18–60 NS
et al.26
Msall et al.27 1994 SC GA 23–28 1983–1986 153 97% 18 131 52±9.9 Yes

Case–control
Lee et al.28 1998 SC o1250 1990–1995 50 25 25 9–50 NS
Murphy et al.29 1997 SC GAo32 1984–1990 293 68 227 36–60 NS
Grether et al.30 1996 SC VLBW 1983–1985 117 45 72 36 NS
Abbreviations: GA, gestational age; MC, multicenter; NA, not available; NS, not specified; SC, single center; VLBW, very low birth weight.

developmental index and PDI were reported in only one study22.
Analysis of the impact of candida infection on NDI showed similar
association (three studies22,25,28: OR 2.62; 95% CI 1.37 to 5.0).
DISCUSSION
Our meta-analysis of 17 studies indicates that the diagnosis of
neonatal sepsis in VLBW infants is associated with an increased
risk of one or more long-term NDIs. Analyzing the components of
NDI revealed a higher association with CP, low PDI and deafness.
With the exception of CP, which was included in 11 studies in this
analysis, results on PDI and deafness are based on small number
of studies. Analyzing data from CoNS and candida infection
yielded the same association. Neurodevelopmental outcome of
VLBW infants with candida infection was reported separately in
three studies.22,25,28 Two of them restricted their studies to fungal
infection only. Analysis for infection resulting from bacterial or
fungal infection elucidates the same kind of association seen in
the combined analysis.
Careful interpretation of these results is necessary given the
previously mentioned variability in characteristics of the studies,
patients and causative pathogens. In addition, the difference in
definition of NDI is particularly an important issue. The two largest
studies14,22 have similar definitions, whereas the other studies
have one or more components from the NDI. Saw and Chen,21
Murphy et al.29 and Grether et al.30 limited their testing to hearing
loss or CP. Our systematic review examined the association
between neonatal sepsis and one or more of the NDI taking into
account the variety and number of neurodevelopmental
disabilities included in each study. Most studies defined
psychomotor and cognitive impairment as a score of o70 or
42 s.d. below the mean of a validated scale of
neurodevelopmental evaluation. Chen et al.19 used a cutoff
point of a Bayley score o84, whereas Collados et al.26 used a
developmental coefficient of o80 on Denver and Amiel Tison
test. The definition of moderate-to-severe impairment based
on cognitive function o2 s.d. below the mean can overestimate
the rates of disability. However, excluding these two
studies did not have any impact on the results of the meta-
analysis.
The results of our meta-analysis are based on cohort and case–
control studies because randomized controlled trials do not exist
given that a randomized controlled trial is ethically not possible.
Pooling of data from case–control studies requires the use of ORs
rather than relative risks, this may lead to overestimation of the
effect size, particularly if the risk of NDI is high among infants with
sepsis. Nonetheless, using relative risks instead of ORs in cohort
studies showed similar association between neonatal sepsis and
NDI, however, the magnitude of this effect was less (relative risk
1.43; 95% CI 1.22 to 1.67).
The fact that the studies in our systematic review have
differently adjusted for one or more of the potential confounding
factors including gestational age, birth weight, sex, cesarean
delivery, multiple birth, antenatal and postnatal steroid exposure,
intrauterine growth restriction, bronchopulmonary dysplasia,
necrotizing enterocolitis and chorioamnionitis required us to use
the unadjusted ORs when pooling the data on neurodevelop-
mental outcomes, therefore, we could not assess the impact of
these confounding factors. However, the available adjusted ORs
from studies reporting them14,15,22,27 were consistent with our
results. The presence of publication bias must not be forgotten as
the small studies elucidate a higher risk for NDI.
Neonatal meningitis is frequently accompanied with bacter-
emia. In all, 19.8 to 55% of affected neonates could have NDI.43–45
Included studies in our systematic review did not exclude babies
with meningitis from the analysis. Thus, the impact of sepsis
without meningitis on long-term outcome could not be assessed
separately and represents a limitation to our meta-analysis.
Recent biological studies suggest that sepsis-causing pathogens
in neonates have the ability to stimulate microglia (brain’s resident
immune cells) resulting in excitotoxicity and activation to
free radical attack by reactive oxygen and nitrogen species,
leading to the death of the vulnerable pre-myelinating
oligodendrocytes.46–50

& 2013 Nature America, Inc. Journal of Perinatology (2013), 1 – 7

 Neurodevelopmental outcomes of VLBW infants with neonatal sepsis
B Alshaikh et al
4
Table 2. Methods of assessment and definitions of NDI and CP

Study Scale Definitions

Cohort
Schlapbach et al.14 BSID II NDI: X1of the following: CP; MDIp 70; PDIp70; deafness or blindness.
CP: a nonprogressive motor disorder characterized by abnormal tone in at
least 1 extremity and abnormal control of movement and posture.
Blindness: not defined but bilateral.
Deafness: severe hearing loss requiring auditory amplification.
Jang et al.15 BSID II Non-CP NDI: 46 month of motor or mental development including cognitive
impairment, psychomotor impairment or neurosensory impairment.
CP: a permanent, but not unchanging, disorder of movement or posture and
of motor function, caused by a non-progressive interference, lesion or
abnormality of the developing premature brain.
Blindness and deafness: not assessed.
Kono et al.16 KSPD test31 Cognitive delay: developmental quotient on KSPD scale o70
CP: non-progressive central nervous system disorder characterized by
abnormal muscle tone in at least one extremity and abnormal control of
movement and position.
Blindness: unilateral or bilateral based on diagnosis of ophthalmologist.
Deafness: severe impairment required hearing aids.
Gocer et al.17 DDST32 NDI (severe): CP, mental retardation, blindness, deafness, hydrocephalus or
convulsion,33 balance disorders, myopia, mild hearing loss, perception
difficulties, behavioral problem.
Blindeness and deafness: not defined.
Addison et al.18 BSID II NDI: Either CP or a BSID MDI or PDIo70
CP: a non-progressive central nervous system disorder characterized by
abnormal muscle tone in at least one extremity and abnormal control of
movement and posture resulting in impaired motor function
Chen et al.19 BSID II MDI or PDI o84 (mild and moderate: 70–83, severe: o70)
CP, blindness and deafness: not assessed.
Shah et al.20 BSID II MDI or PDI o70 (mean of 100 and s.d. of 15)
CP: not defined
Blindness and deafness: not assessed.
Saw et al.21 Hearing only Deafness: absent of reliable hearing response to a sound pulse intensity of
40 dB delivered bilaterally using BAEP examination.
Others: not assessed.
Stoll et al.22 BSID II NDI: MDI o70, PDIo70, CP, bilateral blindness or bilateral hearing impairment.
CP: a nonprogressive disorder characterized by abnormal tone in at least 1
extremity and abnormal control of movement and posture.
Vision impairment: blindness in one or both eyes or need for corrective lenses.
Hearing impairment: hearing aids in one or both ears.
Hoekstra et al.23 BSID II (first 36 month). NDI: mild-to-moderate impairment if examination revealed only minor
DDST, Early Language Millstone abnormalities and developmental assessments were 6 to 12 months below
scale,34 and Zimmerman their chronological age. Severe impairment if examination revealed severe
Preschool Articulation Test abnormalities on physical and neurologic examinations and/or abnormalities
(between 3 and 6 year).35 on developmental assessment 1 year below their chronological age.
CP, blindness and deafness: not defined.
Hack et al.24 BSID II NDI: MDIo70, neurologic abnormality (CP, hypotonia hypertonia and/or
shunt-dependent hydrocephalus), unilateral or bilateral blindness or deafness.
CP: spastic diplegia, hemiplegia, hemidiplegia or quadriplegia (but did not
assessed separately).
Friedman et al.25 BSID II severe neurodevelopmental delay in infants with severe CP (not sitting
by 2 years of age, nonambulatory), bilateral blindness, aided sensorineural
hearing loss, severe cognitive delay with MDI, 70 (2s.d. below the mean)
or shunted hydrocephalus.
Tapia Collados et al.26 DDST and Amiel Tison test36 Moderate or severe: CP (hemiplegia, quadriplegia or diplegia), dystonia
development coefficient o80, educational delay, persistent hyperactivity.
Seizure or epilepsy, or hearing loss (o67 db).
Msall et al.27 McCarthy scales of children Major NDI: CP, mental retardation, blindness, deafness or multiple
abilities.37 impairments.
Cattell Infant Intelligence Test or CP: early onset, none progressive motor and posture delays.
the Clinical Linguistic Auditory Mental retardation: IQo67
Milestone Scale (for children Blindness: legal blindness or corrected vision worse than 20/200.
with a mental age o30 Deafness: bilateral hearing impairment of 485 db.
months)38
Case–control
Lee et al.28 BSID (o24 months), NDDs were diagnosed when one or more of the following were present: CP
Stanford–Binet Intelligence of all types or severity, (16,17) legal blindness (corrected visual acuity of the
Scale39 and the Peabody better eye, o20/200), hearing loss (neuro sensory hearing loss in the better
Developmental Motor Scales for ear 430 dB of better ear), and/or cognitive delay (MDI, 43 s.d. below the
older children40 mean).

Journal of Perinatology (2013), 1 – 7 & 2013 Nature America, Inc.

 Neurodevelopmental outcomes of VLBW infants with neonatal sepsis
B Alshaikh et al
5
Table 2. (Continued )

Study Scale Definitions

29
Murphy et al. CP only CP: a permanent of impairment of voluntary movement or posture presumed
to be damaged to the immature brain.
30
Grether et al. CP only CP: chronic disability of CNS origin characterized by aberrant control of
movement or posture, appearing early in life and not the result of progressive
disease.
Abbreviations: BAEP, brainstem auditory evoked potential; BSID, Bayley Scales of Infant Development 41; CP, cerebral palsy; DDST, Denver II developmental
screening test; IQ, intelligence quotient; KSPD, Kyoto Scale of Psychological Development; MDI, mental developmental index; NDD, neurodevelopmental
disability; NDI, neurodevelopmental impairment; PDI, psychomotor developmental index.

Study ID (year) OR (95% CI) %Weight

Case-Control
Grether (1996) 2.30 (1.10, 5.00) 6.72
Murphy (1997) 3.97 (2.04, 7.65) 8.05
Lee (1998) 2.40 (0.32, 19.33) 1.24
Subtotal (I-squared = 0.0%, p = 0.550) 3.09 (1.90, 5.01) 16.01

Cohort
Msall (1994) 4.95 (1.53, 15.70) 3.45
Collados (1997) 1.37 (0.35, 7.02) 2.22
Friedman (2000) 4.98 (1.90, 12.50) 4.87
Hack (2000) 0.99 (0.54, 1.88) 8.65
Hoekstra (2004) 1.10 (0.40, 2.35) 5.35
Stoll (2004) 1.66 (1.46, 1.88) 20.70
Saw (2005) 4.45 (0.92, 21.55) 2.02
Chen (2008) 6.40 (1.65, 24.92) 2.65
Shah (2008) 1.78 (0.23, 13.67) 1.25
Addison (2009) 2.56 (0.71, 10.51) 2.68
Gocer (2010) 2.90 (0.54, 13.45) 1.95
Schlapbach (2011) 1.85 (1.12, 3.05) 11.02
Jang (2011) 1.65 (0.84, 3.21) 7.90
Kono (2011) 2.15 (1.16, 3.76) 9.27
Subtotal (I-squared = 31.0%, p = 0.128) 1.92 (1.51, 2.45) 83.99

Overall (I-squared = 36.9%, p = 0.064) 2.09 (1.65, 2.65) 100.00

0.25 0.5 1 2.5 5 10 20

Odds Ratio

Figure 2. Meta-analysis of neurodevelopmental outcome data from 17 studies using a random-effect model. CI, confidence interval; OR, odds
ratio.

Begg's funnel plot with pseudo 95% confidence limits

Strength and limitations
4 To our knowledge, this is the first review study examining the
pooled impact of sepsis in VLBW infants on long-term neurode-
velopmental outcome. The use of different NDI definitions and
2 follow-up methods resulted in significant heterogeneity during
the assessment of the primary outcome; however, this disap-
log[or]

peared when we examined the association between sepsis and

0
CP. Despite that our analysis used non-randomized studies and
unadjusted ORs, the sensitivity analyses and the biological
plausibility support our present findings.
In conclusion, our meta-analysis indicates that VLBW infants
-2 surviving sepsis in the neonatal period are at higher risk for
0 0.5 1 neurodevelopmental disability including CP. This emphasizes the
s.e. of: log[or] need for continued long-term follow-up of these infants. Avoiding
Figure 3. Evidence of publication bias by funnel plot. Funnel plot neurodevelopment impairments associated with the sepsis in
asymmetry is exhibited by evidence of small studies with higher VLBW infants requires more research toward prevention of sepsis
odds ratio and the paucity of small negative studies in the lower in this vulnerable population.
right of the funnel plot.

& 2013 Nature America, Inc. Journal of Perinatology (2013), 1 – 7

 Neurodevelopmental outcomes of VLBW infants with neonatal sepsis
B Alshaikh et al
6
Study (year) OR (95% CI) %Weight

Case-Control
Grether (1996) 2.30 (1.10, 5.00) 4.58
Murphy (1997) 3.60 (1.80, 7.40) 5.25
Lee (1998) 2.40 (0.32, 19.33) 0.62
Subtotal (I-squared = 0.0%, p = 0.687) 2.89 (1.75, 4.77) 10.45

Cohort
Hoekstra (2004) 1.10 (0.40, 2.50) 3.12
Stoll (2004) 2.04 (1.67, 2.48) 67.10
Shah (2008) 1.90 (0.25, 14.57) 0.63
Addison (2009) 1.83 (0.31, 19.41) 0.61
Gocer (2010) 2.90 (0.54, 13.45) 1.02
Schlapbach (2011) 2.90 (1.22, 6.89) 3.50
Kono (2011) 2.15 (1.16, 3.76) 7.59
Jang (2011) 1.65 (0.85, 3.20) 5.97
Subtotal (I-squared = 0.0%, p = 0.887) 2.01 (1.69, 2.39) 89.55

Overall (I-squared = 0.0%, p = 0.853) 2.09 (1.78, 2.45) 100.00

0.25 0.5 1 2.5 5 10 20

Odds Ratio

Figure 4. Meta-analysis of CP data from 11 studies using a random-effect model. CI, confidence interval; CP, cerebral palsy; OR, odds ratio.

CONFLICT OF INTEREST staphylococcal immunoglobulin, for prevention of nosocomial infections in very

The authors declare no conflict of interest.
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