Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr

Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr B, Higgins RD; National Institute
of Child Health and Human Development Neonatal Research Network. Neurodevelopmental and
growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA. 2004 Nov
17;292(19):2357-65.!
Late%onset%sepsis%and%the%preemie%
!  Risk!of!infec+on!greatest!a0er!first!week!of!life!
!  21%!of!VLBW!infants!develop!culture!proven!sepsis!
!  Meningi+s!documented!in!3B5%!which!is!likely!an!
underes+mate!
!  One!third!of!infants!have!meningi+s!without!sepsis!
!
!
!
!
!Stoll!BJ!et!al.!Pediatrics!(2004)!
!  The!rate!of!sepsis!has!doubled!over!last!decade!due!
increasing!survival!in!this!popula+on!and!this!adds!
another!risk!factor!for!NDI!
!
!
!
!
!Doctor!BA,!et!al.!Clin!Pediatr!(2001)!
Postnatal%infec3on%and%CNS%injury%
!  Matura+on!dependent!vulnerability!of!brain!
par+cularly!the!preBoligodentrocyte!cell!line!
!  Sensi+ve!to!oxida+ve!stress!and!inflamma+on!
!  Cytokines!inhibit!prolifera+on!of!neuronal!precursor!
cells,!ac+vate!astrogliosis,!and!s+mulate!
oligodentrocyte!cell!death,!increasing!the!risk!of!
WMI!!
!  White!maYer!is!important!in!neural!networking!and!
connec+vity.!
echniques have allowed researchers to understand the
data implicating cytokines in the causal pathway lead
Figure 2 Graphic representation of the complex interaction of cytokines and central nervous system injury due to both
neurotoxic and neurotrophic effects. (Reprinted with permission from Rezaie and Dean.26)
Neurodevelopmental%and%growth%
impairment%in%ELBW%infants%with%infec3on%
!  Infants!401B1000!g!born!1993B2001!at!Neonatal!
Research!Network!centers!
!  Assessed!at!18B22!months!of!age!and!compared!by!
infec+on!group!
!  Infec+on!groups:!
!Uninfected !n=2161!
!Clinical!infec+on!!n=1538!
!Sepsis!n=1922!
!!!!!!!Sepsis!and!NEC!n=279!
!Meningi+s!with!or!without!sepsis!!n=193!
Stoll!BJ!et!al.!JAMA!(2004)!
Neurodevelopmental%and%growth%
impairment%in%ELBW%infants%with%infec3on%
I. Adams-Chapman
466
Table 3 Neurodevelopment and Growth Outcomes Assessed by ORs for Infants with Infection vs Uninfected Infants by Logistic
Regression Analysis*
Clinical Infection
Outcomes
MDI < 70 (n ! 5385)
PDI < 70 (n ! 5314)
CP (n ! 5740)
Vision impairment
(n ! 5719)
Hearing impairment
(n ! 5674)
NDI (n ! 5346)
Weight < 10th percentile
(n ! 5722)
Length < 10th percentile
(n ! 5710)
Head circumference <
10th percentile
(n ! 5721)
Sepsis Alone
Sepsis Plus NEC
Meningitis with or
Without Sepsis
No. of
Infants
OR (95% CI)
No. of
Infants
OR (95% CI)
No. of
Infants
OR (95% CI)
No. of
Infants
OR (95% CI)
1349
1329
1438
1438
1.3 (1.1-1.15)†
1.6 (1.3-2.0)‡
1.3 (1.0-1.6)
1.3 (1.0-1.8)‡
1716
1687
1825
1813
1.3 (1.1-1.6)†
1.5 (1.2-1.9)‡
1.4 (1.1-1.8)‡
1.7 (1.3-2.2)†
251
247
266
264
1.6 (1.2-2.2)†
2.4 (1.7-3.4)‡
1.7 (1.2-2.5)‡
2.0 (1.3-3.0)§
174
174
184
184
1.6 (1.1-2.3)†
1.7 (1.1-2.5)§
1.6 (1.0-2.5)§
2.2 (1.4-3.6)†
1432
1.2 (0.6-2.2)
1802
1.8 (1.0-3.1)§
260
3.4 (1.6-7.3)†
182
0.8 (0.2-2.8)
1340
1433
1.3 (1.1-1.6)‡
1.0 (0.9-1.2)
1703
1819
1.5 (1.2-1.7)‡
1.0 (0.9-1.1)
256
265
1.8 (1.4-2.5)‡
1.7 (1.3-2.2)§
175
184
1.6 (1.1-2.3)†
0.9 (0.7-1.3)
1431
1.1 (0.9-1.3)
1809
1.2 (1.0-1.3)†
265
1.8 (1.4-2.4)‡
183
1.6 (1.2-2.3)†
1433
1.3 (1.1-1.6)†
1819
1.5 (1.2-1.7)§
266
2.0 (1.5-2.6)§
183
1.6 (1.1-2.3)‡
Reprinted with permission from Stoll et al.33
CI, confidence interval; CP, cerebral palsy; MDI, Mental Development Index; NEC, necrotizing enterocolitis; NDI, neurodevelopmental impairment; OR, odds ratio;
PDI, Psychomotor Developmental Index.
*Odds ratio were adjusted for study center, gestational age, birth weight, sex, race/ethnicity, rupture of membrane more than 24 hours before
Stoll!BJ,!et!al."JAMA"(2004)!
birth, cesarean delivery, multiple birth, antenatal antibiotic exposure, antenatal steroid exposure, postnatal steroid exposure, surfactant use,
respiratory distress syndrome, bronchopulmonary dysplasia, patent ductus arteriosus, intraventricular hemorrhage grade 3 or 4, periventricular leukomalacia, maternal age at the time of delivery, and caregiver’s level of education. Participant numbers shown in row headings
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.
17!studies!involving!15,331!newborns!were!included!
!
Studies!all!had!FU!rates!>80%!
!
Included!only!infants!born!in!postBsurfactant!era!!
Journal of Perinatology
(2013) 33, 558–564; doi:10.1038/jp.2012.167; published online 17 January 2013
!
Keywords: sepsis; long-term neurodevelopmental outcome; cerebral palsy; premature infants
Studies!used!different!defini+ons!of!neurodevelopmental!!
Impairment!(NDI)!
important in determining the impact of neonatal sepsis on
INTRODUCTION
!
long-term prognosis, and for guiding development of therapeutic
Sepsis is a clinical syndrome characterized by systemic signs
interventions.
of infection accompanied by bacteremia. The sepsis rate in
!
premature infants has significantly risen in the last three decades
1
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
METHODS
Search strategy
Neurodevelopmental outcomes of VLBW infants with neonatal
Sepsis!is!associated!with!a!2Bfold!higher!risk!of!CP!in!VLBW!infants!
B Alshaikh et al
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
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
Cohort
0.25
0.5
1
2.5
5
10
20
Odds Ratio
Meta-analysis of CP data from 11 studies using a random-effect model. CI, confidence interval; CP, cerebral palsy; OR, o
y; NDI, neurodevelopmental impairment; PDI, psychomotor developmental index.
Sepsis!is!associated!with!2!fold!higher!risk!of!NDI!in!VLBW!infants!
Study ID (year)
OR (95% CI)
Case-Control
Grether (1996)
Murphy (1997)
Lee (1998)
Subtotal (I-squared = 0.0%, p = 0.550)
2.30 (1.10, 5.00)
3.97 (2.04, 7.65)
2.40 (0.32, 19.33)
3.09 (1.90, 5.01)
6.72
8.05
1.24
16.01
Cohort
Msall (1994)
Collados (1997)
Friedman (2000)
Hack (2000)
Hoekstra (2004)
Stoll (2004)
Saw (2005)
Chen (2008)
Shah (2008)
Addison (2009)
Gocer (2010)
Schlapbach (2011)
Jang (2011)
Kono (2011)
Subtotal (I-squared = 31.0%, p = 0.128)
4.95 (1.53, 15.70)
1.37 (0.35, 7.02)
4.98 (1.90, 12.50)
0.99 (0.54, 1.88)
1.10 (0.40, 2.35)
1.66 (1.46, 1.88)
4.45 (0.92, 21.55)
6.40 (1.65, 24.92)
1.78 (0.23, 13.67)
2.56 (0.71, 10.51)
2.90 (0.54, 13.45)
1.85 (1.12, 3.05)
1.65 (0.84, 3.21)
2.15 (1.16, 3.76)
1.92 (1.51, 2.45)
3.45
2.22
4.87
8.65
5.35
20.70
2.02
2.65
1.25
2.68
1.95
11.02
7.90
9.27
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
%Weight
20
Odds Ratio
Meta-analysis of neurodevelopmental outcome data from 17 studies using a random-effect model. CI, confidence interval; O
Conclusion%
!  Neonatal!infec+ons!are!associated!with!poor!
neurodevelopmental!and!growth!outcomes!in!early!
childhood.!
!  Infec+on!control!is!another!neuroprotec+ve!
prac+ce!that!has!the!poten+al!to!improve!outcomes!
for!our!most!vulnerable!infants!