THE JOURNAL OF PEDlATRICS • www.jpeds.com
Neurodevelopment of Extremely Preterm Infants who had Necrotizing ?
Enterocolitis with or without Late Bacteremia ?
Camilia R. Martin, MO, MS, Olaf Oammann, MO, Elizabeth N. Allred, MS, Sonal Patel, MD, T. Michael O'Shea, MD, MPH,
Karl C. K. Kuban, MO, SMEpi, and Alan Leviton, MD
Objective To evaluate neurodevelopment after necrotizing enterocolitis (NEC) and late bacteremia, alone and ?
Study design Sample included 1155 infants born at 23 to 27 weeks' gestation. NEC was classified by the mod ?
ified Bell's staging criteria and grouped as medical NEC or surgical NEC. Late bacteremia was defined as a positive ?
blood culture result after the first postnatal week. Neurodevelopment was assessed at 24 months corrected age. ?
Multivariable models estimated the risk of developmental dysfunction and microcephaly associated with medical ?
or surgical NEC with and without late bacteremia. ?
Results Children who had surgical NEC unaccompanied by late bacteremia were at increased risk of psychomo ?
tor developmental indexes <70 (OR =2.7 [1.2, 6.4]), and children who had both surgical NEC and late bacteremia ?
were at increased risk of diparetic cerebral palsy (OR =8.4 [1.9, 39]) and microcephaly (OR =9.3 [2.2, 40]). In con ?
trast, children who had medical NEC with or without late bacteremia were not at increased risk of any developmen ?
tal dysfunction. ?
Conclusion The risk of neurodevelopmental dysfunction and microcephaly is increased in children who had sur ?
gical NEC, especially if they also had late bacteremia. These observations support the hypothesis that bowel injury ?
might initiate systemic inflammation potentially affecting the developing brain. (J Pediatr 2010;157:751-6). ?
mong preterm infants followed up to almost 2 years corrected age, those who had necrotizing enterocolitis (NEC) were
at higher risk for poor cognitive and psychomotor development than infants without NEC. J-8 The risks were especially
high for children who had an advanced stage of NEC or needed surgery. 1 ,7,9
Poor neurodevelopment might be a primary consequence of NEC or caused by comorbidities of NEC such as bacteremia.
Like preterm infants with NEC, infants with bacteremia are more likely than those without to have impaired cognitive and
motor development at 2 years of age. IO Among infants with NEC, 30% to 60% also have a diagnosis of bacteremia during
their stay in the neonatal intensive ca re unit (NICU). \'5,7,11 Due to the significant overlap of these 2 diagnoses, the contri
bution to neurodevelopment of NEC alone versus NEC with bacteremia has been difficult to evaluate. The Extremely Low
Gestational Age Newborn (ELGAN) Study provided us with an opportunity to evaluate the developmental correlates of
NEC with and without accompanying bacteremia in a cohort of more than 1000 infants born before the 28th week of
The sample for this analysis is a subset of the 1506 infants enrolled in the ELGAN
Study, a prospective cohort study designed to identify characteristics and expo
sures that increase the risk of structural and functional neurologic disorders in
preterm infants.12 During the years 2002-2004, women delivering between 23
and 27 6/7 weeks of gestation at 1 of 14 participating institutions in 11 cities
in 5 states were enrolled in the study. The enrollment and consent processes
were approved by the individual institutional review boards.
Extremely low gestational age newborn
Mental Oevelopment Index
Neonatal intensive care unit
Psychomotor Oevelopment Index
From the Oepartment or Neonatology, Beth Israel
Oeaconess Medical Center (C.M.), the Oivision or
Newborn Medicine and the Neuroepidemiology Unit.
Oepartment or Neurology (EA, A.l.), Boslon. MA; and
Ihe Oepartment or Bioslatistics. Harvard School or Public
Heallh. Harvard University, Boston, MA (EA); the
Division of Newborn Medicine, Floating Hospital for
Children al Tufts Medical Center. Tufts University (0.0..
S.P.). Medrord. MA; and the Oivision or Pedialric
Neurology. Department of Pedlatrics, Bastan Medical
Cenler. Boston University (K.K.). Boston . MA; Ihe
Oepartment or Neonatology. Wake Forest University.
Winslon-Salem. NC (T.O·S.): and Ihe Perinalal
Neuroepidemiology Unit, Hannover Medical School,
Hannover. Germany (0.0.)
AII authors are members 01 Ihe ELGAN Study Group.
Supported by a cooperative agreement with the National
Institute of Neurological Diseases and Stroke
(5U01 NS040069-05) and a program project grant rrom
Ihe National Institute or Child Health and Human Oevel
opmenl (NIH-P30-HO-18655). The authors declare no
conflicts of interest.
0022-3476/$ - see front maller. Copyright ~ " 20 ' 0 MOSby Ine.
Al! righls reserved. 10.101 6Jj.jpeds.2010.05.042
Vol. 157, No. 5
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Mothers were approached for consent either on antenatal
admission or shortly after delivery, depending on c1inical cir
cumstance and institutional preference. A total of 1249
(83%) mothers consented, and approximately 260 women
were either missed or did not consent to participate for a total
population of 1506 infants. After excluding 143 infants whose
NEC or late bacteremia status was unknown, 49 who had an
isolated perforation, 3 who did not undergo a protocol head
ultrasound scanning, and 156 who did not survive to 2 years
and thus were not eligible for the 2-year evaluation, we stud
ied a sample of 1155 infants.
Gestational age (GA) estimates were based on a hierarchy of
the quality of available information. Most desirable were es
timates based on the dates ofembryo retrieval or intrauterine
insemination or fetal ultrasonography before the 14th week
of gestation (62%). When these were not available, reliance
was placed sequentially on a fetal ultrasound scan obtained
at 14 or more weeks ofgestation (29%), last menstrual period
without fetal ultrasonography (7%), and GA recorded in the
log ofthe NICU (1%).
NEC Definition and Staging
NEC was defined by the modified Bell's staging criteria. 13 NEC
"watch" referred to evaluations for NEC for a brief period (48
to 72 hours), without abdominal radiographs that demon
strated pneumatosis. Stage 1 included infants who had "sus
pected" NEC and, despite the absence of pneumatosis on
abdominal radiographs, were treated with antibiotics, and sus
pension ofenteral feedings for at least 1 week. Stage IIa repre
sented infants who had pneumatosis but did not experience
c1inical deterioration or laboratory derangements. Stage IIb in
c1uded infants with pneumatosis and metabolic (acidosis) or
hematologic changes (thrombocytopenia). Stage IIIa included
infants with stage IIb criteria plus respiratory or cardiovascular
deterioration (eg, increased need for respiratory support, new
vasopressor requirement, oliguria, disseminated intravascular
coagulation). Finally, stage IIIb identified those infants who re
quired surgical intervention, an exploratory laparotomy or
placement of a Penrose drain. For analysis, we c1assify NEC
as medical (stages lIa, IIb, and II1a) or surgical (stage I1Ib).
Early and Late Bacteremia
Because results from bacterial cultures were collected weekly
on days 7, 14,21, and 28, we do not know the precise day on
which a positive blood culture result was obtained, although
we do know the week. This led us to define early bacteremia
as a positive blood culture result in the first postnatal week
and late bacteremia as a positive blood culture result in weeks
2, 3, or 4. Al! positive culture results were considered in the
analyses regardless of species.
Neurodevelopmental Diagnoses and Correlates at
Two Years Corrected Age
Cerebral Palsy. When infants were 24 months corrected
age, a certified examiner who was unaware ofthe neuroimag
ing findings in the NICU completed a comprehensive, stan
dardized neurologic examination. 14 The findings from this
examination were used to diagnose cerebral palsy and c1assify
children with regard to cerebral palsy type (quadriparesis,
hemiparesis, and diparesis).lS
Gross Motor Functional Classification System. The
neurologic examiners rated each child using the Gross Motor
Function Classification System. 16 AlI children with a Gross
Motor Functional Classification System of 2 or higher had
been given a diagnosis of severe cerebral palsy.
Bayley Scales of Infant Development-Second Edition.
The Bayley Scales ofInfant Development-Second Edition was
administered by certified examiners who were unaware ofthe
infant's medical history, including neuroimaging results. In
fants were scheduled for assessment at 24 months postterm
Table I. The percent of all infants with or without late baeteremia who also had the NEC stage that heads eaeh eolumn
who were given the neurodevelopmental diagnosis listed on the left (Column pereents)
NEC Stage grouping
No Surg Med
No Overall %
Cerebral palsy diagnosis
MOl < 70
POI < 70
Surg, Surgical NEC (Stage IIIb); Med, medical NEC (Stage Ila, IIb, lila); Overal! %, the percent 01 inlants with the neurodevelopmental diagnosis listed on the left regardless 01 the diagnostic stratum
(column headings); Row N, the actual number 01 inlants who were given the neurodevelopmental diagnosis Iisted on the left regardless 01 the diagnostic stratum; Column N, the actual number 01
inlants placed within each 01 the 6 diagnostic stratums (column headings).
Martin et al
equivalent, with 77% evaluated between 23.5 and 27.9
months of age. A score of < 70, more than 2 standard devia
tions below the mean, represents significant mental (Mental
Development Index [MDI]) or psychomotor delay (Psycho
motor Development Index [POI]).
Head Growth. The head circumference (HC) was mea
sured as the largest possible occipital-frontal circumference
and rounded to the closest 0.1 cm. The HC Z-score represents
the number ofstandard deviations the infant's HC is aboye or
below the median HC of infants at the same GA in a referent
StatisticaI Analyses. The generalized form of the major
null hypothesis evaluated is that neither NEC, nor docu
mented late bacteremia, is associated with the risk ofdevelop
mental dysfunctions (cerebral palsy diagnoses, Grass Motor
Functional Classification System seo re, and low MOI and
POI scores) and small He. We selected variables as con
founders if they had be en identified in the literature or if in
our data they were associated with both the exposure (late
bacteremia or NEC) and with one of the developmental out
comes with probabilities :s .25. 18
Findings from Table 1 prompted us to model the
contribution of late bacteremia and NEC (Bell stage Ha and
higher) to the occurrence of developmental dysfunctions
and microcephaly in 2 different ways. One model has
variables for late bacteremia only, medical NEC only, and
the combination of late bacteremia and medical NEC
(TabJe 11) . Another model is identical but replaces medical
NEC with surgical NEC (Table III). Both of these models
excluded children who had other forms of NEC (ie,
children with surgical NEC were excluded from the first
mode!, and children with medical NEC were excluded from
the second model).
The contributions of these variables are presented as odds
ratios and 95% confidence intervals. AlI models are adjusted
for public insurance (determined at the time of enrollment),
maternal or fetal initiator of delivery, gestational age (23-24,
25-26, 27 weeks), birth weight Z-score <-1 and thrombosis
of fetal stem vessels (including a missingness indicator). To
account for the possibility that infants born at a particular
hospital are more like each other than like infants born at
other hospitals, a hospital cluster ter m (random effect) was
included in all models. Empty cells prohibited our creating
models of hemiparetic cerebral palsy risk.
Ofthe 1155 eligible children, 59 (5%) had medical NEC, 42
(4%) had surgical NEC, 70 (6%) had culture-proven early
bacteremia, and 279 (24%) had culture-proven late bacter
emia. The incidence of early bacteremia was not different
in infants with and without NEe. In contrast, the incidence
of late bacteremia was higher in infants with NEC than in
those without NEC (34% vs 23%).
Table 1 documents the percent of infants in ea eh
diagnostic stratum (column headings) who were given the
neurodevelopmental diagnosis listed
Children who had both late bacteremia and surgical NEC
were almost 8 times more likely to have development of
diparetic cerebral palsy than children who had neither
(23% vs 3%). Among newborns who had late bacteremia,
those who had medical NEC were twice as likely to have
development of diparetic cerebral palsy as newborns who
did not have NEC (6 vs 3%). Compared with newborns
who had neither late bacteremia nor NEC, those who had
both (regardless of whether the NEC was medical or
surgical) were twice as likely to ha ve an MDI <70. The risk
of a POI <70 was less prominently increased among
newborns who had the combinatian of NEC and late
bacteremia (50% vs 27%). HC more than 2 SD below the
median occurred 4 times more frequently among children
who had both late bacteremia and surgical NEC (38%) and
twice as frequently among children who had both late
bacteremia and medical NEC (17%) than among than
children who had neither late bacteremia nar NEC (8%).
The central tendency and dispersion of MOI and POI
scores are presented in box and whiskers displays (Figure).
The distribution of MDI values among children with
Table n. Odds ratios and 95% confidence intervals obtained from multivariable logistic regression models" ofthe risk of
each individual neurodevelopmental correlate/diagnosis associated with medical NEC unaccompanied by late bacteremia
and late bacteremia unaccompanied by medical NEC and the cooccurrence of both medical NEC and late bacteremia
Med NEC and late
bacteremia (n =20)
1.6 (0.2, 14)
1.4 (0.2, 12)
2.6 (0.9, 7.4)
2.2 (0.8, 6.0)
2.0 (0.5, 8.4)
1.5 (0.5. 4.8)
Med NEC only
0.6 (0.1, 4.6)
1.5 (0.3, 7.5)
0.6 (0.1, 4.3)
1.0 (0.4, 2.4)
0.8 (0.3, 1.9)
1.0 (0.3, 3.9)
0.9 (0.3, 2.4)
only (n =245)
Bayley MOl < 70
Bayley POI < 70
HC Z-score < -2
HC Z-score ~
1.3 (0.7, 2.6)
0.9 (0.4, 2.3)
1.5 (0.8 , 2.9)
1.5 (1.1, 2.2)
1.4 (0.95, 2.0)
1.5 (0.9, 2.6)
1.4 (0.9, 2.2)
-2, < -1
Each outcome is a dichotomy. For quadriparesis and diparesis the relerent group is no cerebral palsy. For head circumlerence Z·score < -2 and head Clfcumlerence Z·score ;e: -2, < -1 the ?
referent group is head circumlerence Z·score > - 1. ?
'AII models are adjusted lor public insurance, maternal or letal initiator lor delivery, gestational age (23·24, 25·26, 27 weeksj, birth weighl Z-score < -1 and Ihrombosis 01 Ihe letal stem vessels 01 ?
the placenta and include a random ellect cluster term lar birth hospital. ?
Neurodevelopment of Extremely Preterm Infants who had Necrotizing Enterocolitis with or without Late Bacteremia 753
Vol. 157, No. 5
THE JOURNAL OF PEDIATRICS • www.jpeds.com
Table lIl. Odds ratios and 95% confidence intervals from multivariable logistic regression models" of the risk of each
individual neurodevelopmental correlate/diagnosis associated with surgical NEC unaccompanied by late bacteremia and
late bacteremia unaccompanied by surgical NEC and the cooccurrence of both surgical NEC and late bacteremia
Surg NEC and late
bacteremla (n =14)
only (n =28)
only (n =245)
Bayley MOl < 70
Bayley POI < 70
HC Z·score < -2
HC Z-score '=: -2, < -1
8.4 (1,9, 39)
2,2 (0,9, 5,2)
1.4 (0,3, 5,9)
1,9 (0,7, 5.4)
1.4 (0,7, 2,7)
0,9 (0.4, 2.4)
1,5 (0,8, 2,9)
1,5 (1,05, 2,2)
1,5 (0,9, 2,6)
1,5 (0,98, 2,3)
2,7 (0,8, 8,9)
9,3 (2,2, 40)
2,6 (0,5, 13)
Each outcome is a dicholomy, For Quadriparesis and diparesis the referent group is no cerebral palsy, For head circumference Z·score < -2 and head circumference Z-score
referenl group is head circumference Z·score > -1
'AII models are adjusted for public insurance, maternal or fetal initiator for delivery, gestational age (23·24, 25-26, 27 weeks), birth weighl Z·score < -1 and thrombosis of the fetal stem vessels of
the placenta and include a random effect cluster term for birth hospital.
- 2, < -1 Ihe
medical NEC unaccompanied by late bacteremia does not
differ from the distribution among children with neither
bacteremia nor any NEC. The distribution tends to be
modestly shifted to the left (lower MOI values) among
children with bacteremia alone. The distribution is
prominently shifted to the left among children who had
surgical NEC (with or without bacteremia) and those with
both medical NEC and bacteremia. In contrast, the
differences among groups are much less prominent for PDI.
Surg NEC & bact
Svrg NEC only
Med NEC & bacl
Me<:! NEC only
NoNECor bact t = j ~ ~ ~ ~ = = = ~ - = - - ~ - - -
70 90 110 130 150
eSID Mental Developmenllndex
Surg NEC only
Med NEC & bacl
No NECor bact t = ~ 2 ~ ~ ~ = = = :
eSlo Psychomolor Development Index
Figure. In these box and whisker displays of the distribution
of MOl and POI , the median is indicated by the verticalline
close to the middle of each box and the 25th and 75th centiles
by the sides of each box. The dispersion of the MOl and POI
scores is indicated by the length of the horizontallines that
emanate from the box, as well as by the large dots, which
identify outliers. There is a box for each combination of NEC
and late bacteremia.
In multivariable models that adjusted for potential con
founders, medical NEC, regardless of whether or not accom
panied by late bacteremia, was not statistically significantly
associated with any of the outcomes of interest (Table II).
The combination of medical NEC and late bacteremia was
associated with a doubling of the risk a low MDI and a low
POI, but beca use only 20 children had this combination,
statistical significance was not achieved. Late bacteremia
alone, however, was associated with an increased risk of an
In similar models with surgical NEC replacing medical
NEC, 3 odds ratios associated with surgical NEC achieved
statistical significance (Table nI). Compared with children
without any surgical NEC or late bacteremia, those who
had both late bacteremia and surgical NEC were at
increased risk for diparetic CP and microcephaly, and the
children who had surgical NEC unaccompanied by late
bacteremia were at increased risk for a PD¡ <70.
In this large prospective cohort ofextremely preterm infants,
infants who had development of medical NEC were not at
statistically significantly increased risk of ei ther any of the de
velopmental disorders we assessed or of microcephaly. On
the other hand, children who had surgical NEC without ac
companying late bacteremia were at an increased risk of
a PDI <70. Children who had development of surgical
NEC and had culture-proven late bacteremia were at prom
inently increased risk of diparetic cerebral palsy and micro
cephaly. Children who had late bacteremia unaccompanied
by surgical NEC were at increased risk of an MOI <70.
Despite the large size of our sample, only 59 children had
medical NEC and 42 had surgical NEC. Consequently, the
confidence intervals for the odds ratios are wide. In addition,
the precise timing of the NEC diagnosis relative to the late
bacteremia diagnosis is unknown. Strengths of our study in
elude the large multicenter cohort, prospective collection of
data about NEC and bacteremia, and outcome assessments
by examiners who were unaware of neonatal exposures.
Martin et al
Our findings lead to several inferences. In one set, NEC
pathophysiology is not in the causal chain. Rather, NEC con
veys information about other risk factors. For example, NEC
(as an indicator of bowel immaturity) might provide infor
mation about brain immaturity/vulnerability beyond that
identified by gestational age, or it might be a marker for over
all severity of illness during the NICU stay, or it might convey
information about exposure to associated risk factors such as
anesthesia during abdominal surgery.19 Conversely, NEC
might be associated with the absence of factors that are asso
ciated with improved neurodevelopmental outcome, such as
In a second set of inferences, NEC pathophysiology is in
the causal chain. This set is especially plausible because our
findings support the view that NEC can be classified by sever
ity with no NEC as the referent, and increasing with medical
NEC, surgical NEC without accompanying late bacteremia,
and culminating with surgical NEC accompanied by late bac
The more severe the NEC, the greater the likelihood of in
testinal wall inflammation22 and the greater the likelihood of
intestinal barrier dysfunction.23,24 Intestinal barrier dysfunc
tion manifests as the translocation of inflammatory media
tors into the systemic circulation. For example, platelet
activating factor plasma leve\s are significantly higher in
NEC patients than in control subjects and correlate with
NEC severity.25 Likewise, plasma levels of interleukin-6,
a monocyte-derived cytokine, correlated with disease severity
in infants with NEC26; and, in another study, were highest
among infants with severe NEC and in infants who had
both sepsis and NEC, and less elevated among infants with
either sepsis or NEC alone.27
As one of the largest defense barriers of the infant, the neo
natal gut regulates immune function and the inflammatory
response. Disruption or injury to this barrier, as can occur
in severe NEC, leads to an increased risk for bacterial trans
location, leading to bacteremia, and increased production
of proinflammatory mediators, which can initiate, as well
as propagate, a systemic inflammatory response.28 Unmiti
gated systemic inflammation contributes to neuronal injury
and to the pathogenesis of other comorbidities such as reti
nopathy ofprematuritl9and chronic lung disease.30 The ob
servation of adverse neurodevelopment with increased
severity of disease (surgical versus medical NEC) or with
the prolonged presence of diseased bowel (management
with a Penrose drain)31 supports the hypothesis that the in
jured gut contributes to a systemic inflammatory response,
which, in turn, can affect the developing brain.
In previously published studies of premature infants, NEC
predicted poor neurodevelopmental outcomes, 1,3,5-9,11,32 as
well as cystic periventricular leukomalacia on head ultra
sound 1 and white matter injury on magnetic resonance imag
ing.33 Our findings may support sorne of these earlier studies.
Furthermore, the relationship between NEC and poor neuro
developmental outcomes is strongest among the more ill in
fants, as demonstrated by an advanced stage of NEC or need
for surgical intervention. 1 ,7,9.32 Our findings are also consis
tent with these previous reports that children with NEC who
required surgery were at greater risk for adverse neurodeve!
opment than infants with NEC who did not require surgery.
In a large study ofextremely low birth weight infants, those
who were infected were more likely to have cerebral palsy,
low MDI and PDI scores, and microcephaly than children
who did not have a neo natal infection.10 In our large sample
of ELGANs, we found that in the absence of NEC, late
bacteremia was associated with an increased risk of low
MDI scores. Potential explanations for the outcome differ
ences between these 2 studies are that the former study was
a birth weight defined cohort of < 1000 g, and our study
was defined by a gestational age of < 28 weeks' gestation;
and the former study included the diagnoses of early-onset
sepsis, suspected sepsis (culture negative), and NEC in their
A unique contribution of our study to the NEC-sepsis lit
erature is our distinction between early and late-onset sepsis,
proven and clinically suspected sepsis, and NEC with or with
out late-onset bacteremia. Each of these designations helped
us evaluate the influence of NEC alone and NEC plus late
bacteremia on later neurodevelopment. •
Acknowledgments available at www.jpeds.com.
Submitted for publieation Dee 28, 2009; last revision reeeived Apr 2, 2010;
aeeepted May 25, 2010. ?
Reprint requests: Camilia R. Martin, MD 330 Brookline Ave, Rose-318, ?
Boston, MA 02215. E-mail: firstname.lastname@example.org. ?
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