Early Human Development 87 (2011) 253257

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Early Human Development

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev

Impact of histological chorioamnionitis, funisitis and clinical chorioamnionitis on

neurodevelopmental outcome of preterm infants
Nuria Rovira a,, Ana Alarcon a, Marti Iriondo a, Margarita Ibaez b, Pilar Poo c, Victoria Cusi d, Thais Agut a,
Africa Pertierra a, Xavier Krauel a
a
Department of Neonatology, Sant Joan de Du University Hospital, Barcelona, Spain
b
Department of Psychology, Sant Joan de Du University Hospital, Barcelona, Spain
c
Department of Neurology, Sant Joan de Du University Hospital, Barcelona, Spain
d
Department of Pathology, Sant Joan de Du University Hospital, Barcelona, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Background: The role of chorioamnionitis in neurodevelopment of preterm infants is not fully understood.
Received 2 September 2010 Aim: To examine the association between different indicators of intrauterine inammation (clinical
Received in revised form 20 December 2010 chorioamnionitis, histological chorioamnionitis and funisitis) and neurodevelopmental impairment in very
Accepted 3 January 2011 preterm infants.
Methods: Preterm infants with a birth weight of b 1500 g or a gestational age of b 32 weeks were included.
Keywords:
Follow-up evaluation up to 2 years of age consisted of neurological examination, neurodevelopmental
Chorioamnionitis
Funisitis
assessment and visual and audiologic tests. Outcome data were compared between the chorioamnionitis and
Neurodevelopmental outcome the control groups, controlling for gestational age, birth weight and Apgar score at 5 min.
Premature infant Results: One hundred seventy-seven patients comprised the study population (mean gestational age 29
Cerebral palsy 2 weeks, mean birth weight 1167 344 g). Histological chorioamnionitis was present in 49% of placentas,
Intraventricular hemorrhage whereas funisitis was observed in 25%. In 57% cases clinical maternal chorioamnionitis was suspected.
Periventricular leukomalacia Follow-up was available for 130 (82%) patients. Infants with funisitis, compared with controls, had a
signicantly higher incidence of moderate to severe disability (18% vs 5%, OR 4.07; 95% CI 1.1015.09).
Conclusion: The results of this study suggest that, unlike a broad denition of histological chorioamnionitis
including inammation of maternal or fetal placental tissues, funisitis may entail a higher risk of moderate to
severe disability at 2 years of age in preterm infants.
2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Preterm infants born to mothers with chorioamnionitis are at risk

Chorioamnionitis is the condition of intrauterine infection/
inammation, dened as the presence of an invasion of polymorphonu-
clear leukocytes in the membranes, the umbilical cord and/or the
chorionic plate [1]. It is most often a subclinical condition, but occasionally
it produces clinical chorioamnionitis, characterized by maternal fever,
maternal or fetal tachycardia, uterine tenderness, malodorous amniotic
uid, maternal leukocytosis and/or elevated C-Reactive Protein (CRP) [1].
Exposure to intraamniotic infection/inammation may lead to a fetal
inammatory response syndrome, which is associated with funisitis
(umbilical vasculitis) and elevated proinammatory cytokines in the fetal
circulation [2,3]. Chorioamnionitis is a frequent cause of preterm birth
[1,47].
Corresponding author. Department of Neonatology, Sant Joan de Du Hospital,
Passeig Sant Joan de Du, 2 Esplugues de Llobregat, 08950 Barcelona, Spain. Tel.: + 34
93 600 63 33; fax: + 34 93 203 39 59.
E-mail address: nroviragirabal@hotmail.com (N. Rovira).
for adverse neurodevelopmental outcome [5,818]. Several authors
have observed an increased risk of severe intraventricular hemor-
rhage (IVH) [1924] and/or periventricular leukomalacia (PVL)
[20,21,25] in preterm infants exposed to chorioamnionitis. A meta-
analysis showed that clinical chorioamnionitis was signicantly
associated with the development of cystic PVL and cerebral palsy
(CP), but histological chorioamnionitis was only associated with
development of PVL in preterm infants [26]. Nevertheless, after
matching or adjustment for confounding factors, there seems to be a
signicant but limited association between histological chorioamnio-
nitis and CP [1,12].
A number of studies have not shown an unfavorable impact of
chorioamnionitis on neurodevelopmental outcome in preterm infants
[23,2732]. This variation may be due in part to the use of different
proxies of intrauterine infection/inammation. Funisitis indicating
fetal inammatory involvement seems to be more predictive of brain
injury than is inammation of placental tissues of maternal origin
[11,3336].

0378-3782/$ see front matter 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.earlhumdev.2011.01.024
254 N. Rovira et al. / Early Human Development 87 (2011) 253257
Although the relationship between chorioamnionitis, PVL and CP
in the preterm infant has been more extensively studied, there is
less information on the effect of choriomionitis on other areas of
neurodevelopment, such as cognitive and speech development and
sensorineural functions [13,15,17,23,31,36].
We hypothesized that exposure to chorioamnionitis would be
associated with unfavorable neurodevelopmental outcome among
children born very preterm. The objective of our study was to examine
the relationship between in utero (maternal or fetal) infection/
inammation and neurodevelopment at 2 years of age, differentiating
between clinically apparent and subclinical processes.
2. Methods
All preterm infants born at Sant Joan de Du Hospital, a University
Tertiary Hospital, from January 2002 to December 2004 with a
gestational age of b32 weeks or a birth weight of b1500 g were
included. Patients were excluded if: malformations, genetic or
chromosomal syndromes or other causes of neurodevelopmental
disability or sensorineural decit not related to prematurity were
present; histopathological evaluation of the placenta had not been
performed; or infants were products of multiple pregnancy, histolog-
ical characteristics of the placentas were discordant and had not been
assigned to each of the siblings.
Neonatal and neurodevelopmental outcome data were collected
from a prospective data base. Information regarding maternal clinical
status at delivery was obtained by reviewing maternal clinical records.
For the purpose of this study, histology of the placentas was reviewed
by a pathologist (VC).
Histological chorioamnionitis was dened as neutrophil inltration
of amniotic membranes, umbilical cord or chorionic plate. Funisitis
was considered if neutrophil inltration of umbilical vessel walls or
Whartons jelly was found. Clinical chorioamnionitis was dened as
maternal fever (38 C) during labor or maternal leukocytosis or
elevated CRP ( 15,000 leukocytes/mm3 + CRP 30 mg/L, CRP
60 mg/L or 20,000 leukocytes/mm3), without another cause, or by
the presence of foul-smelling or purulent amniotic uid.
Follow-up consisted in evaluations up to 24 months' corrected
age performed by pediatrician, pediatric neurologist, psychologist,
othorhinolaryngologist and ophthalmologist. Patients underwent
neurological examinations and screening of developmental deviations
[37] at 2, 4, 8, 12, 18 and 24 months' corrected age. Visual evaluation
included evoked potential and screening for refractive errors. Hearing
screening was performed by brainstem auditory evoked potential. At
2 years' corrected age, a pediatric psychologist evaluated psychomo-
tor development via the Bayley Scales of Infant Development II [38] or
the BrunetLezine Scale [39] and performed behavioural assessment.
Disabilities were classied as absent, mild, moderate or severe [40,41]
(Table 1).
Table 1
Classication of disabilities in preterm infants.
No disabilities
Mild disabilities Isolated speech disorder.
Minor motor abnormality (tremor, clumsiness).
Mild sensorineural decit (partial and unilateral).
Mild behavioral disorder (hyperactivity).
Refractive disorders.
Moderate disabilities Hemiplegia, diplegia or tetraparesis not impairing the
ability to walk.
Partial sensorineural decit (partial bilateral or total
unilateral).
Developmental quotient 7084.
Severe disabilities Motor decit impairing the ability to walk.
Total sensorineural decit (blindness or deafness).
Seizures requiring anticonvulsant treatment.
Severe behavioral disorder (psychosis, autism).
Developmental quotient b 70.
Outcome data were compared between groups: histological
chorioamnionitis present/absent; funsitis present/absent; and clinical
chorioamnionitis present/absent. Categorical variables were expressed
as counts and percentages. Continuous variables were expressed as
mean and standard deviation (M SD) if normally distributed and as
median and range if not normally distributed. Categorical variables
were compared between groups using chi-square or Fisher exact test
where appropriate. Continuous variables were compared using Student
T test or MannWhitney U test. Univariate analysis was performed to
look for an association between outcome variables and multiple birth,
gestational age, birth weight or Apgar score at 5 min. We performed
binomial logistic regression or linear regression analysis to adjust for
statistically signicant dichotomous or continuous confounding vari-
ables. A P valueb 0.05 was considered signicant. For risk estimates
odds ratios (ORs) and 95% condence intervals (CIs) were calculated
and adjusted for confounding variables by logistic regression analysis.
ORs were considered to represent a signicant association if the CIs did
not include 1.00. Statistical analysis was performed using the SPSS
package.
3. Results
During the study period, 225 preterm infants with a gestational
age of b32 weeks or a birth weight of b1500 g were born in our center.
Nineteen were excluded due to the following clinical criteria: 2
central nervous system malformations, 3 multiple congenital anoma-
lies syndromes, 2 pulmonary malformations, 7 congenital heart
diseases, 1 neuromuscular disorder, 1 middle ear malformation, 1
congenital CMV infection and 2 trisomies; in 18 cases histological
analysis of the placenta was not available; and 11 were product of
multiple pregnancy, histological characteristics of the placentas were
discordant and had not been assigned to each of the siblings. Thus, 177
patients met the study entry criteria. The mean gestational age at birth
was 29.2 2.6 weeks and the mean birth weight was 1167 344 g.
Analysis of the placentas showed histological choriamnionitis in
87 (49.2%) and funisitis in 45 (25.4%). In 36/45 (80%) cases of funisitis
inammation involved the arteries, the vein and the Wharton's jelly;
5 (11.1%) showed inammation of the arteries and the vein; 2 (4.4%)
inammation of the arteries alone; 1 (2.2%) inammation of the
arteries and the surrounding jelly and 1 (2.2%) isolated vein
involvement. Clinical chorioamnionitis was diagnosed in 50/87
(57.5%) cases of histological chorioamnionitis, whereas in 6 cases of
56 suspected clinical chorioamnionitis (10.7%) pathological analysis
of the placenta did not show inammation. Funisitis was more
frequently present when chorioamnionitis was clinically apparent
(68.0% vs 29.7%, P b 0.0001).
Neonatal characteristics of patients are shown in Table 2. Cranial
ultrasound scans revealed higher rates of IVH in infants exposed to
histological chorioamnionitis (P = 0.044), funisitis (P = 0.036) and
clinical chorioamnionitis (P = 0.003). In addition, the rate of grade 3
IVH or parenchymal cerebral hemorrhage was higher in the groups of
infants exposed to histological chorioamnionitis (P = 0.028) and
clinical chorioamnionitis (P = 0.043). Severe cerebral lesions (grade
3 IVH, parenchymal haemorrhage and/or cystic PVL) were more
frequently observed amongst patients exposed to histological chor-
ioamnionitis (P = 0.013), funisitis (P = 0.025) and maternal clinical
sings of chorioamnionitis (P = 0.014). However, adjustment for
gestational age, birth weight and Apgar scores at 5 min by means of
multivariate logistic regression analysis revealed no signicant
association between the different indicators of intraamniotic infec-
tion/inammation and cranial ultrasonographic ndings.
Of the 158 patients who survived the neonatal period, follow-up
evaluations up to 2 years of age were available for 130 (82.2%).
Patients with neurodevelopmental assessment at 2 years and patients
lost to follow-up were comparable for gestational age, Apgar scores at
5 min, IVH, days of mechanical ventilation, days of oxygen,
 N. Rovira et al. / Early Human Development 87 (2011) 253257 255

Table 2
Neonatal characteristics of 177 infants grouped by the presence or absence of histological chorioamnionitis, funisitis and clinical chorioamnionitis.

Histological chorioamnionitis Histological funisitis Clinical chorioamnionitis

Yes (n = 87) No (n = 90) P Yes (n = 45) No (n = 132) P Yes (n = 56) No (n = 121) P

Mltiple pregnancy no. (%) 15 (17.4%) 36 (40%) 0.001 8 (17.8%) 43 (32.5%) ns 13 (23.2%) 38 (31.4%) ns
Male sex no. (%) 48 (55.1%) 46 (51.1%) ns 22 (48.9%) 72 (54.5%) ns 29 (51.7%) 65 (53.7%) ns
Gestational age M SD wk 28.3 2.5 30.1 2.3 b 0.001 27.9 2.5 29.7 2.4 b 0.001 27.9 2.3 29.8 2.5 b0.001
Birth weight M SD g 1168 373 1165 316 ns 1145 413 1174 318 ns 1153 391 1173 322 ns
Apgar score at 5 min median (range) 9 (510) 9 (410) ns 9 (510) 9 (410) ns 9 (610) 9 (410) ns
Days of oxygen median (range) 2 (0144) 2 (070) ns 4 (080) 1.42 (0144) ns 4 (0144) 1 (080) ns
Days of MV median (range) 0.5 (054) 0.02 (090) ns 0.75 (054) 0.08 (090) ns 1 (028) 0 (090) ns
Death no. (%) 12 (13.8%) 7 (7.7%) nsa 7 (15.5%) 12 (9.0%) nsa 9 (16.0%) 10 (8.3%) nsa
Cranial ultrasonographic ndings (n = 85) (n = 89) (n = 43) (n = 131) (n = 54) (n = 120)
Any grade IVH [42] no. (%) 18 (21.1%) 9 (10.1%) nsa 11 (25.6%) 16 (12.2%) nsa 15 (27.8%) 12 (10.0%) nsa
Grade 3 IVH or PH no. (%) 12 (14.1%) 4 (4.5%) nsa 6 (13.9%) 10 (7.6%) nsa 9 (16.7%) 7 (5.8%) nsa
Cystic PVL [43] no. (%) 3 (3.5%) 2 (2.2%) ns 3 (7.0%) 2 (1.5%) ns 2 (3.7%) 3 (2.5%) ns
Grade 3 IVH, PH or cystic PVL no. (%) 15 (17.6%) 5 (5.6%) nsa 9 (20.0%) 11 (8.3%) nsa 11 (20.3%) 9 (7.5%) nsa

VM, mechanical ventilation; IVH, intraventricular hemorrhage; PH, parenchymal hemorrhage; PVL, periventricular leukomalacia.
a
Logistic regression analysis performed to adjust for gestational age, birth weight and Apgar score at 5 min.

histological chorioamnionitis, funisitis and clinical chorioamnionitis.
Birth weight was signicantly higher in patients lost to follow-up
(1324 375 g vs 1189 302 g; P = 0.042). Neurodevelopmental out-
comes are shown in Table 3. The risk of moderate to severe disability
was increased by factor 4 in patients with funisitis (OR 4.07; 95% CI
1.1015.09), whereas the risk of disability of any grade was doubled in
patients exposed to clinical chorioamnionitis compared to controls
(OR 2.33; 95% CI 1.035.25). Association between outcome variables
and placental lesions remained unchanged when analysis was
performed excluding multiple births.
4. Discussion
In our study histological chorioamnionitis was present in the
placentas of 49% of very low birth weight infants, a gure similar to
that found by other authors [17,22,33,44]. Apart from a marginally
signicant association with motor abnormalities, this condition was
not associated with an increased risk for adverse neurodevelopmental
outcome. Nevertheless, the presence of funisitis signicantly in-
creased the odds of development of moderate to severe disabilities.
Our diagnostic criteria for clinical chorioamnionitis detected 57% of
cases of histological chorioamnionitis, whereas we had a 10% rate of
false positive clinical diagnoses of chorioamionitis. Our results are
comparable to those of Redline et al., who also found an association
between clinically recognized cases of chorioamnionitis and fetal
inammatory involvement [33]. Furthermore, our study showed a
relationship between clinical chorioamnionitis and development of
disabilities.
Gestational age was lower in our group of infants with chor-
ioamnionitis, suggesting that intrauterine infection/inammation is
usually associated to birth at earlier gestational ages than vascular or
other causes of prematurity. We therefore controlled for gestational
age in analysis, as well as for multiple pregnancy, birth weight and
Apgar score at 5 min. The lack of rigorous adjustment for confounding
factors, mainly gestational age, may in part explain the relationship
between histological chorioamnionitis and neurodevelopmental

Table 3
Neurodevelopmental outcomes of 130 infants grouped by the presence or absence of histological chorioamnionitis, funisitis and clinical chorioamnionitis.

Histological chorioamnionitis Histological funisitis Clinical chorioamnionitis

Yes (n = 62) No (n = 68) P Yes (n = 33) No (n = 97) P Yes (n = 39) No (n = 91) P

Speech abnormalities no. (%) 15 (24.2%) 13 (19.1%) ns 12 (36.3%) 16 (16.5%) 0.05 13 (33.3%) 15 (16.5%) 0.039
Motor abnormalities
Any grade no. (%) 9 (14.5%) 3 (4.4%) 0.047 6 (18.2%) 6 (6.2%) ns 6 (15.4%) 6 (6.5%) ns
Cerebral palsy no. (%) 5 (8%) 2 (2.9%) ns 4 (12.1%) 3 (3.1%) 0.047 3 (7.7%) 4 (4.4%) ns
Cerebral palsy impairing walking no. (%) 2 (3.2%) 0 ns 2 (6%) 0 ns 1 (2.5%) 1 (1.1%) ns
Refractive disorder no. (%) 10 (16.1%) 12 (17.6%) ns 6 (18.1%) 16 (16.5%) ns 8 (20.5%) 14 (15.4%) ns
VEP abnormal result no. (%) 2 (3.2%) 0 ns 1 (3.0%) 1 (1.0%) ns 1 (2.5%) 1 (1.1%) ns
Hearing loss no. (%) 2 (3.2%) 3 (4.4%) ns 1 (3.0%) 4 (4.1%) ns 1 (2.5%) 4 (4.4%) ns
Behavioral disorder no. (%) 9 (14.5%) 8 (11.7%) nsa 4 (12.1%) 13 (13.4%) nsa 9 (23%) 8 (8.8%) nsa
Seizures no. (%) 3 (4.8%) 1 (1.5%) ns 3 (9.0%) 1 (1.0%) 0.05 2 (5.1%) 2 (2.2%) Ns
Disability
Any grade no. (%) 24 (38.7%) 23 (33.8%) nsb 14 (42.4%) 33 (34.0%) nsb 19(48.7%) 28 (30.7%) 0.045b
Moderate to severe no. (%) 7 (11.3%) 4 (5.9%) nsb 6 (18.1%) 5 (5.1%) 0.03b 5 (12.8%) 6 (6.6%) nsb
Severe no. (%) 2 (3.2%) 1 (1.5%) nsb 2 (6.0%) 1 (1.0%) nsb 1 (2.5%) 2 (2.2%) nsb
Developmental quotient (n = 40) (n = 51) (n = 21) (n = 70) (n = 22) (n = 69)
Median (range) 111 (75156) 108 (52133) ns 112 (75150) 108 (52156) ns 111 (75150) 108 (52156) ns
b70 no. (%) 0 (0%) 2 (3.9%) ns 0 (0%) 2 (2.9%) ns 0 (0%) 2 (2.9%) ns
7084 no. (%) 2 (5%) 1 (2.0%) ns 2 (9.5%) 1 (1.4%) ns 2 (9.1%) 1 (1.4%) ns
85 no. (%) 38 (95.0%) 48 (94.1%) ns 19 (90.5%) 67 (95.7%) ns 20 (90.9%) 66 (75.8%) ns

VEP, visual evoked potential.

a
Logistic regression performed to adjust for gestational age and birth weight.
b
Logistic regression performed to adjust for birth weight and Apgar score at 5 min.
256 N. Rovira et al. / Early Human Development 87 (2011) 253257
disability in preterm infants observed in some studies [14,17,18]. Our
data are in agreement with other studies which suggest that funisitis
appears to be more predictive of adverse outcome than is maternal
placental inammation [10,11,33,35,36]. Chorionic plate vasculitis is
equivalent and strongly related to umbilical vasculitis [45,46]. It has
also been shown to be associated with high levels of fetal plasma
interleukin-6, as well as neonatal morbidity [45]. Nevertheless,
chorionic vessels are present in a limited number of placental biopsies
routinely obtained following clinical protocols rather than prospec-
tive research [46].
Not all authors have found an association of histologic evidence
of fetal inammation and long term neurodevelopmental disability
in preterm infants [28,30,31]. Apart from methodological differ-
ences, this disparity may be somewhat explained by a variable
distribution of genetic polymorphisms associated with inammato-
ry response that might be related to the risk of brain injury in the
presence of intrauterine infection/inammation [47,48]. The obser-
vation that the risk of cerebral palsy associated with exposure to
chorioamnionitis may vary between ethnic groups supports this
hypothesis [30].
Investigations on the effect of intrauterine infection/inammation
on areas of neurodevelopment other than gross motor function, such
as cognitive functions, speech development and sensorineural
functions, are scarce and present disparate results [15,17,23,31,36].
Our data further support a relationship between funisitis and cerebral
palsy, and show an association of marginal signicance between fetal
intraamniotic infection and both speech delay and seizures. In
contrast, we did not demonstrate a higher risk of visual or hearing
decits. One limitation of our study is the restricted number of
patients (57%) available for evaluation of developmental index at
2 years of age. As observed for patients lost to global follow-up (18%),
birth weight was higher in patients not evaluated, but gestational age,
Apgar scores at 5 min, rates of IVH, days of mechanical ventilation,
days of oxygen, rates of histological chorioamnionitis, funisitis and
clinical chorioamnionitis were comparable between patients with and
without developmental quotient available. Therefore, selection bias is
unlikely. However, we are unaware whether a larger sample size
would have shown lower developmental scores in patients exposed to
funisitis conditioned by the risk of disabilities.
Although ultrasonographic cerebral lesions were more frequently
detected in patients exposed to intraamniotic inammation, adjust-
ment for confounding variables showed no association between the
different indicators of chorioamnionitis and IHV nor cystic PVL. Other
single center studies have failed to demonstrate such association
[17,23], which has been observed in larger single center or
population-based studies [1925], as well as in systematic reviews
[26,49]. It is unknown whether a relationship would have been
observed between funsitis and more subtle and frequent white matter
abnormalities detected by brain magnetic resonance image [50].
We are unaware whether our results are inuenced by the fact that
causes of prematurity other than fetal inammation, such as
preeclampsia or placental insufciency, could precondition the fetus
for a better outcome. To address this matter, studies evaluating the
impact of different etiologies of preterm birth on long-term
neurodevelopmental outcome are needed.
In conclusion, unlike a broad denition of histological chorioam-
nionitis including inammation of maternal or fetal placental tissues,
funisitis was associated with a higher risk of moderate to severe
disability at 2 years of age, compared with controls.
Conict of interest statement
The authors have no nancial and personal relationship with other
people or organisations that could inappropriately inuence (bias)
their work.
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