Histological chorioamnionitis – implication for bacterial colonization,laboratory markers of infection, and early onset sepsis in very-low-birth-weight neonates

SHING YAN ROBERT LEE & CHI WAI LEUNG

Department of Pediatrics and Adolescent Medicine, Princess Margaret Hospital, Kwai Chun, New Territories, Hong Kong, People’s Republic

of China

AbstractObjective. The objective of this study was to evaluate the relationship between histological chorioamnionitis and laboratorymarkers of infection and congenital sepsis in very-low-birth-weight (VLBW) premature neonates.Method. This study is a retrospective review of laboratory results of VLBW neonates with birth weight less than 1500 g in ourneonatal intensive care unit (NICU) in the last 5 years.Results. Ninety-nine VLBW neonates had histological chorioamnionitis, and 50 of them further had funisitis. One hundred andsixty-two VLBW neonates did not have chorioamnionitis. The chorioamnionitis group was more likely than the ‘nochorioamnionitis’ group to have raised C-reactive proteins (23% versus 9.9%; p¼ 0.006) and neutrophilia (41% versus 4.3%;p 5 0.001). White blood cells were more likely to be present in gastric lavage of the former group than the latter group (70% versus50%; p¼ 0.002). Ear swab and gastric lavage were more likely to yield positive growth of micro-organisms from the former groupthan the latter group (34% versus 9.9% and 22% versus 2.7%; p 5 0.001 and p 5 0.001, respectively). Congenital sepsis provenby positive blood culture was also more likely to occur (3% versus 0%; p¼ 0.027). Presence of funisitis further increased thelikelihood of the above abnormal laboratory results.Conclusions. Histological chorioamnionitis increases the likelihood of having markers of infection, bacterial colonization, andcongenital sepsis. Only 3% of histological chorioamnionitis resulted in congenital sepsis confirmed by blood culture.

Keywords: Histological chorioamnionitis, congenital sepsis, very-low-birth-weight, newborns, C-reactive protein, neutrophilia, bacterialcolonization

Introduction

It is almost a daily activity in neonatal intensive care unit

(NICU) that premature babies on admission are evaluated for

sepsis using laboratory investigations, and the duration of

antibiotics depends on the results of these investigations. The

treatment principle is based on the knowledge that chor-

ioamnionitis carries increased risk of congenital sepsis.

Clinical chorioamnionitis is a known risk factor for neonatal

sepsis, and actually, a guideline has been established

advocating the use of intrapartum antibiotics to prevent

neonatal sepsis in case of clinical chorioamnionitis [1].

However, according to a retrospective review, only 8% of

histological chorioamnionitis presents with signs of clinical

chorioamnionitis, and the prevalence of histological chor-

ioamnionitis in premature birth is high with proportion up to

80% at gestation of 24 weeks and declining to 20% at

gestation of 36 weeks [2]. In face with this common problem

of histological chorioamnionitis in premature birth, which is

mostly subclinical, there is an inclination to presume that

histological chorioamnionitis has the same implication as

clinical chorioamnionitis in relation to the development of

neonatal sepsis. However, to date, the evidence for this

presumption is not well grounded, and study on the relation-

ship between the histological chorioamnionitis and the

laboratory results of sepsis evaluation is scarce in the

literature. In a study, preterm babies with severe neonatal

morbidity were more likely to have histological chorioamnio-

nitis in the placentas [3], but in addition to neonatal sepsis,

other conditions such as respiratory distress syndrome,

pneumonia, bronchopulmonary dysplasia, intraventricular

hemorrhage, periventricular leukomalacia, and necrotizing

enterocolitis were lumped together to define severe neonatal

morbidity, blurring the picture of correlation between

histological chorioamnionitis and congenital sepsis. In an-

other study, congenital sepsis with positive blood culture

occurred in 12% of preterm babies having histological funisitis

(which often occurs concurrently with histological chorioam-

nionitis) versus 1% of cases without funisitis [4]. Wu et al.

tried to find out in what way histological chorioamnionitis is

related to clinical features and laboratory findings in

premature babies [5]. Unfortunately, with a small sample size

of 77 patients, they were only able to show that C-reactive

(Received 18 May 2010; revised 20 February 2011; accepted 5 April 011)

Correspondence: Shing Yan Robert Lee, Department of Pediatrics and Adolescent Medicine, Princess Margaret Hospital, Lai King Hill Road, Kwai Chun,

NT, Hong Kong, People’s Republic of China. Tel: þ852-29903244. Fax: þ852-29903481. E-mail: leesyr@netvigator.com

The Journal of Maternal-Fetal and Neonatal Medicine, 2012; 25(4): 364–368

� 2012 Informa UK, Ltd.

ISSN 1476-7058 print/ISSN 1476-4954 online

DOI: 10.3109/14767058.2011.579208

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protein was more likely to be raised in the group with

histological chorioamnionitis.

Objective: In this study, we try to find out the relationship

between histological chorioamnionitis and the results of

laboratory evaluation of sepsis and the occurrence of

congenital sepsis.

Methods

This is a retrospective review of very-low-birth-weight

(VLBW) neonates (birth weight 51500 g) admitted to our

NICU in the last 5 years. It is a routine practice of having

placental pathological sections for VLBW births in public

hospitals in Hong Kong. In our cohort, all the recruited

neonates were born in public hospitals, with availability of

reports of placental pathological sections. A few VLBW

neonates were excluded from this study as they were born in

private hospitals before transport to our hospital. The

placentas were sectioned at four sites: proximal umbilical

cord and placental membrane, distal umbilical cord and

placental membrane, and two random blocks of the placentas.

The diagnosis of chorioamnionitis and funisitis was adapted

from the criteria recommended by the Perinatal Section of the

Society for Pediatric Pathology [6]. Chorioamnionitis was

defined as the presence of neutrophils in the fibrous amnion

and/or chorion, irrespective of severity grade. Funisitis was

defined as umbilical phlebitis or vasculitis of one or two

arteries, irrespective of severity grade.

Sepsis evaluation included blood culture, and blood tests

for white cell count, platelet count and C-reactive protein.

The test for C-reactive protein was repeated 12 to 48 hours

later. Lumbar puncture was not a routine procedure of sepsis

evaluation. The laboratory data of VLBW neonates were

reviewed. Neutropenia was defined as neutrophil count less

than 1 6 109/l [7]. Neutrophilia was defined using the graph

of Mouzinho et al. [8], which has a cutoff value of 6.3 6 109/l

at 0 h of life rising to the peak of 14.4 6 109/l at 22 h of life.

Thrombocytopenia was defined as platelet count less than 150

6 109/l [9]. C-reactive protein greater than 10 mg/l was

considered raised [10]. In our laboratory, microscopic

examination for white blood cells in gastric lavage was semi-

quantitatively classified into ‘a few number’, ‘a moderate

number’, and ‘a large number’ according to the number of

white blood cells seen in low power view of microscope.

Congenital sepsis was diagnosed in the presence of a positive

blood culture result within 72 h of delivery. Our laboratory

did not perform microscopic examination of blood film for

immature neutrophil and thus immature and total neutrophil

(I/T) ratio was not available in this study.

Results

The cohort consisted of 261 VLBW neonates. Ninety-nine

neonates had placentas showing histological chorioamnionitis,

and amongst 50 of them, funisitis was also present. All the

cases of funisitis were concurrent with chorioamnionitis and

did not occur alone. In most of the specimens showing

funisitis, neutrophilic infiltration was quite diffuse, involving

the umbilical arteries and veins. Occasionally, the Wharton’s

jelly was involved as well. Only in four cases was there pure

involvement of the umbilical veins only.

Ampicillin was given intrapartumly in 49% of cases as

prophylaxis against group B Streptococcal infection based on

the CDC (Centers for Disease Control and Prevention)

guidelines [11].

The neonates with chorioamnionitis tended to have lower

maturity and birth weight (Table I). When compared with

neonates without chorioamnionitis, they were more likely to

have raised C-reactive protein from 12 to 48 h of life (23%

versus 9.9%) and neutrophilia (41% versus 4.3%) (Table I).

White blood cells were not uncommonly found in gastric

lavage (65 of 92 in chorioamnionitis group and 73 of 147 in

the ‘no chorioamnionitis’ group), but the finding of white

blood cells was more common in the chorioamnionitis group.

The number of white blood cells when present tended to be

more in this group as well (Table I). Surface cultures and

blood culture were more likely to be positive. In the subgroup

analysis, the chorioamnionitis group was divided into sub-

groups with or without funisitis (Table II). The above positive

findings of sepsis evaluation became less statistically signifi-

cant in the subgroup without funisitis than the subgroup with

funisitis on comparison with ‘no chorioamnionitis’ group. In

other words, presence of funisitis increased the likelihood of

having these positive findings.

Table I. Comparison between neonates with or without histological chorioamnionitis.

Chorioamnionitis + funisitis (n¼ 99) No chorioamnionitis (n¼162) p

Birth weight (grams, mean + SD) 979 + 313 1088 + 280 0.004

Gestation (weeks, mean + SD) 27.7 + 3 29.7 + 2.8 50.001

Congenital sepsis with positive blood culture in first 72 h 3/98 (3%) 0/160 (0%) 0.027

Neutropenia (5109/l) 1/83 (1.2%) 9/138 (6.5%) 0.066

Neutrophilia 34/83 (41%) 6/138 (4.3%) 50.001

Platelet count 5150 6 109/l 8/98 (8.2%) 24/162 (15%) 0.114

Ear swab with positive growth 32/95 (34%) 15/152 (9.9%) 50.001

Gastric lavage with positive growth 20/92 (22%) 4/147 (2.7%) 50.001

White blood cells in gastric lavage

A few number 24/92 (26%) 38/147 (26%) 0.97

A moderate number 14/92 (15%) 13/147 (8.8%) 0.51

A large number 27/92 (29%) 16/147 (11%) 50.001

Any number 65/92 (70%) 73/147 (50%) 0.002

Raised C-reactive protein (410 mg/l)

Within 12 h 6/74 (8.1%) 5/123 (4.1%) 0.23

12–48 h 21/93 (23%) 15/152 (9.9%) 0.006

Any time in first 48 h of life 24/97 (25%) 18/159 (11%) 0.005

Student’s t-test for parametric data. Mann–Whitney test for non-parametric data.

From histological chorioamnionitis to congenital sepsis 365

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Gastric lavage yielded growth of organisms with bracketed

frequency as follows: Escherichia coli (11), Citrobacter (3),

Klebsiella (2), Enterobacter (2), Staphylococcus aureus (2),

Candida albicans (2), Acinetobacter (1), Morganella morgani

(1), Roseomonas sp. (1), and Streptococcus milleri (1). Ear swab

yielded growth of organisms with bracketed frequency as

follows: E. coli (16), C. albicans/yeasts (7), Klebsiella (4),

Citrobacter (3), Group B Streptococcus (3), Enterobacter (2),

Enterococci (2), Proteus (2), S. aureus (1), M. morgani (1),

Roseomonas sp. (1), S. milleri (1), Gardnerella vaginalis (1), and

mixed growth of more than three organisms (6).

Congenital sepsis proven by positive blood culture only

occurred in three patients, which were far fewer than the

number of neonates having laboratory evidence of bacterial

colonization with positive growth from gastric lavage and ear

swab and increased C-reactive protein and neutrophilia. The

positive predictive value of histological chorioamnionitis for

culture-proven congenital sepsis was 3% and negative

predictive value was 100%.All these three patients had

pathology reports of placentas showing histological chorioam-

nionitis, with funisitis being present in two of them as well.

(Table III)

In our cohort, a neonate had clinical features of sepsis but

blood culture was negative. At birth, there was clinical

chorioamnionitis as evidenced by maternal fever and fetal

tachycardia. The baby had intractable hypotension, and

subsequently multi-organ failure set in. She succumbed in

the first day of life. Placental section showed histological

chorioamnionitis and funisitis. Surface swab and placental

swab grew E. coli. Because of negative blood culture, this

patient was not counted as a case with congenital infection

according to our definition.

Discussion

In a study of term or near-term neonates, the following clinical

signs were used as criteria for classifying suspected sepsis:

respiratory distress, poor feeding, poor perfusion, hypoten-

sion, lethargy, hyperthermia, hypothermia, and low Apgar

scores [12]. However, in our population of VLBW premature

neonates, the above signs commonly occurred with or without

sepsis, and prematurity with factors other than sepsis could

result in these signs as well. Hence, in our study, we chose to

focus on the laboratory results of sepsis evaluation.

It is known that lower the gestation, higher the incidence of

histological chorioamnionitis [2], which is in line with our

result of lower gestational age and lower birth weight in the

chorioamnionitis group than ‘no chorioamnionitis’ group.

Classically, neutropenia and thrombocytopenia are re-

garded as markers for neonatal sepsis [13], but in our cohort,

they were not more common in histological chorioamnionitis.

Neutropenia and thrombocytopenia can also result from

placental insufficiency and pre-eclampsia, which is a common

indication for preterm delivery brought about by obstetricians.

This may explain why neutropenia and thrombocytopenia

were not more frequent in histological chorioamnionitis as

other markers of infection were.

Our result showed that some laboratory markers were more

likely to occur in VLBW neonates with histological chor-

ioamnionitis: neutrophilia, raised C-reactive protein, and the

presence and the abundance of white blood cells in gastric

lavage. Despite the common occurrence of laboratory markers

of infection in neonates with histological chorioamnionitis as

mentioned, only three neonates had congenital sepsis in our

Tab

leII

.S

ub

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up

of

cho

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Ch

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Val

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nit

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(n¼

49)

Ch

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is

wit

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(n¼

50)

No

cho

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(n¼

16

2)

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9

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tati

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(wee

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+3

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Co

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wit

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osi

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rst

72

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13

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366 S. Y. R. Lee & C. W. Leung

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cohort, which constituted 3% of histological chorioamnionitis.

This finding of more cases with infection markers than with

culture-proven congenital infection has three possible expla-

nations. First, the commonest organism in chorioamnionitis is

Ureaplasma urealyticum, and Mycoplasma hominis could be

occasionally identified [14]. These organisms cannot be

recovered by routine laboratory culture method. Second, in

our cohort, intrapartum antibiotics were administered in 49%

of the cases. This could have prevented bacterial invasion of

fetus/neonates and reduced the incidence of congenital sepsis

in histological chorioamnionitis. Besides, we speculate that in

some neonates with septicemia, intrapartum antibiotics could

have inhibited the growth of bacteria in blood culture

producing a false negative result. Third, chorioamnionitis

progresses in several stages as far as its pathogenetic

mechanism is concerned [15]. Initially, there is excessive

growth of organisms in vagina causing deciduitis. Infection

then spreads to involve amnion (amnionitis), chorion (chor-

ionitis), and umbilical vessels (funisitis). Later, bacteria

multiply in intra-amniotic fluid causing intra-amniotic infec-

tion (53% of funisitis in premature birth) [4]. Finally, these

organisms are inhaled or ingested by fetus and may end up in

bacteremia in the fetus and subsequently neonatal sepsis [15].

Obviously, it takes time to progress to this final stage. Delivery

of the neonates before progression to this final stage and

prophylactic antibiotics delivered to mother could account for a

small proportion of neonates having neonatal sepsis. However,

in cases of histological chorioamnionitis and preterm labor,

numerous cytokines and mediators of inflammation were

implicated: interleukin (IL)-1, IL-2, IL-4, IL-6, IL-12, inter-

feron-g [16], and tumor necrosis factor (TNF) [17]. Studies

have shown that levels of IL-6 and TNF are high in blood

sampled from umbilical cord at the time of delivery in

histological chorioamnionitis [17]. IL-6 and TNF are potent

stimulators for the production of C-reactive protein, and these

cytokines thus generated could induce the production of C-

reactive protein in fetal/neonatal liver [18]. Cytokines can also

induce production of neutrophils in bone marrow. This explains

why raised C-reactive protein and neutrophilia were more likely

to occur in our cases with histological chorioamnionitis.

Our case of death of clinical sepsis with negative blood

culture is perplexing but is of educational value. First, we

strongly believe that the patient genuinely had sepsis. There

were clinical chorioamnionitis as well as histological chor-

ioamnionitis with funisitis. Ear swab, gastric lavage, and

placental swab yielded heavy growth of E. coli resistant to

ampicillin. There was no other overt cause, which could

explain multi-organ failure other than septicemic shock. The

mother received a week’s course of intravenous ampicillin for

group B Streptococcus prophylaxis, and this could have selected

out E. coli resistant to ampicillin in this case. It has been

known that cytokines are generated in the pathogenetic

process of chorioamnionitis and funisitis, which are respon-

sible for causing periventricular leukomalacia [19], broncho-

pulmonary dysplasia [19], and hypotension [20]. In these

original studies on cytokine effects in histological chorioam-

nionitis [19,20], the neonates usually did not have culture-

proven sepsis either, and the picture was just a fetal

inflammatory response syndrome. We speculate that in this

patient dying of clinical sepsis, cytokines could have produced

shock and multi-organ failure, which is possible when

cytokines are released in great amount, and this phenomenon

has been described once in literature [21]. An alternative

explanation is that the technique in blood culture might be

faulty in this patient, as in VLBW neonates, the amount of

blood taken for blood culture tends to be less than the

standard required.

In conclusion, histological chorioamnionitis in premature

VLBW birth is common. Often, it leads to inflammatory

response resulting in increased white blood cells in gastric

lavage fluid, increased neutrophil count, and raised C-reactive

protein. It leads to colonization of the neonates as evidenced

by the increased positive growth in gastric lavage and ear

swab. It increases the chance of congenital sepsis, but the

magnitude is just 3% amongst all cases of histological

chorioamnionitis.

Declaration of interest: The authors report no conflicts of

interest. The authors alone are responsible for the content and

writing of the paper.

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Academy of Pediatrics. Guidelines for perinatal care. 6th ed;

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3. Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM.

The fetal inflammatory response syndrome. Am J Obstet Gynecol

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Table III. Clinical information on the three cases of congenital sepsis.

Case

Birth weight

(grams)/gestation

Organisms in

blood culture

Growth from ear

swab/gastric lavage Chorioamnionitis Funisitis Clinical features/outcome

1 560 g/22 weeks E. coli E. coli Yes Neutrophilic infiltrate of

both umbilical veins and

arteries and Wharton’s jelly

Mild respiratory

distress/died of

severe

intraventricular

hemorrhage on

day 12

2 860 g/27 þ 6 weeks E. coli E. coli Yes Neutrophilic infiltrate of

both umbilical veins

and arteries and

Wharton’s jelly

Septic shock and

persistent

pulmonary

hypertension of

newborn/survived

3 673 g/25 þ 2 weeks Citrobacter Citrobacter Yes No Mild respiratory

distress/survived

From histological chorioamnionitis to congenital sepsis 367

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