Pediatrics and Neonatology (2018) 59, 231e237

Available online at www.sciencedirect.com

ScienceDirect

journal homepage: http://www.pediatr-neonatol.com

Review Article

Intrauterine inflammation, infection, or

both (Triple I): A new concept for
chorioamnionitis
Chun-Chih Peng a,b,c, Jui-Hsing Chang a,b,c, Hsiang-Yu Lin d,e,
Po-Jen Cheng f,g, Bai-Horng Su d,e,*

a
Department of Medicine, Mackay Medical College, Taipei, Taiwan
b
Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan
c
Mackay Medicine, Nursing and Management College, Taipei, Taiwan
d
Department of Neonatology, China Medical University Children’s Hospital, Taichung, Taiwan
e
School of Medicine, China Medical University, Taichung, Taiwan
f
Department of Obstetrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan
g
College of Medicine, Chang Gung University, Taoyuan, Taiwan

Received Jan 16, 2017; received in revised form Jun 19, 2017; accepted Sep 1, 2017
Available online 19 September 2017

Key Words Chorioamnionitis is a common cause of preterm birth and may cause adverse neonatal out-
chorioamnionitis; comes, including neurodevelopmental sequelae. Chorioamnionitis has been marked to a het-
intrauterine erogeneous setting of conditions characterized by infection or inflammation or both,
inflammation or followed by a great variety in clinical practice for mothers and their newborns. Recently, a
infection; descriptive term: “intrauterine inflammation or infection or both” abbreviated as “Triple I”
Triple I has been proposed by a National Institute of Child Health and Human Development expert
panel to replace the term chorioamnionitis. It is particularly important to recognize that an
isolated maternal fever does not automatically equate to chorioamnionitis. This article will re-
view the current literature on chorioamnionitis, and introduce the concept of Triple I, as well
as recommendations for assessment and management of pregnant women and their newborns
with a diagnosis of Triple I.
Copyright ª 2017, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).

* Corresponding author. Department of Neonatology, China Medical University Children’s Hospital, 2, Yuh-Der Road, Taichung, 404,
Taiwan. Fax: þ886 4 2203 2798.
E-mail address: subh1168@gmail.com (B.-H. Su).

https://doi.org/10.1016/j.pedneo.2017.09.001
1875-9572/Copyright ª 2017, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
232
1. Introduction
Chorioamnionitis is a common cause of preterm birth and may
causes adverse neonatal outcomes, including neuro-
developmental sequelae.1e3 Clinically, chorioamnionitis has
been marked to a heterogeneous setting of conditions char-
acterized by infection or inflammation or both, followed by a
great variety in clinical practice for mothers and their new-
borns. Recently, the term “intrauterine inflammation or
infection or both” abbreviated as “Triple I” has been suggested
by a National Institute of Child Health and Human Develop-
ment (NICHD) expert panel including maternal and neonatal
experts in a workshop to replace the term chorioamnionitis.4
This article will review the current literature on cho-
rioamnionitis, and introduce the concept of Triple I, as well as
recommendations for assessment and management of preg-
nant women and their newborns with a diagnosis of Triple I.
2. Current understanding of chorioamnionitis
Preterm birth is a major cause of perinatal mortality and
long-term morbidity. Chorioamnionitis is a common cause
of preterm birth. A recent prospective study of 871 preg-
nancies found that those with histologic chorioamnionitis,
premature delivery occurred nearly twice as often as those
without chorioamnionitis.3 Chorioamnionitis may induce
preterm delivery by a maternal inflammatory response.1,2
Bacterial infection, via the release of endotoxins and exo-
toxins, stimulates the release of cytokines from the decidua
and fetal membranes, which induce uterine contractions
and/or rupture of fetal membranes.
According to the presence or absence of clinical signs
and laboratory evidence, chorioamnionitis may be catego-
rized as clinical chorioamnionitis and subclinical/histologic
chorioamnionitis.1,2,5e7 Clinical chorioamnionitis is char-
acterized by maternal fever, leukocytosis, maternal and/or
fetal tachycardia, uterine tenderness, and preterm rupture
of membranes (PROM). Subclinical/histologic chorioamnio-
nitis is asymptomatic and defined by inflammation of the
chorion, amnion, and placenta, which is more common than
clinical chorioamnionitis.1,2
The inflammation of the chorioamnion (histologic cho-
rioamnionitis) and umbilical cord (funisitis) are the mani-
festations of the maternal and fetal immune responses in
condition of intra-amniotic infection.6,7 Histological and
microbiological evidence of inflammation or infection may
not always accompany one another. And maternal clinical
signs may not be present.
The frequency of histologic chorioamnionitis is higher
than that of clinical chorioamnionitis with positive bacterial
cultures. The treatment with antibiotics and the difficulty
of growing fastidious organisms may lead to negative cul-
tures even in the presence of histological evidence of
placental inflammation.6 Therefore, pathological evalua-
tion of the placenta is essential for definite diagnosis.
Different authors have shown higher positive cultures
rates of amniotic fluid in women with preterm labor at
earlier gestational ages,8 higher interleukin (IL)-6 levels in
the amniotic fluid in women with spontaneous labor in
pregnancies less than 34 weeks,9 and higher IL-6 levels in
cord blood in preterm compared with term newborns born
C.-C. Peng et al
after microbial invasion of the amniotic cavity.10 The fetal
inflammatory response syndrome (FIRS) is a condition
characterized by systemic activation of the fetal immune
system. FIRS was originally defined as an elevation of the
fetal plasma IL-6 concentration in fetuses of mothers with
preterm labor and PROM.11
PROM refers to rupture of membranes (ROM) prior to the
onset of labor but beyond 37 weeks’ gestation. ROM prior to
37 weeks’ gestation is called preterm PROM (PPROM). PPROM
is responsible for one-third of preterm deliveries.12 Pro-
longed ROM is any ROM that persists for more than 24 h and
prior to the onset of labor; it increases incidence of neonatal
sepsis 2e10 times because of the facilitated ascending
infection to the uterine cavity, and this risk becomes 4 times
higher when ROM is accompanied by chorioamnionitis.13 The
incidence of histological chorioamnionitis increases up to
50% with PPROM6,7 and is inversely related to gestational
age.14e16
Histological chorioamnionitis is most commonly associ-
ated with intrauterine bacterial infection, and may coexist
with umbilical infiltration (funisitis).17 It is believed that
FIRS, as a result of infection pathways and increasing cy-
tokines activate an inflammatory response that potentially
lead to fetal vasculitis, congenital anomalies, fetal death,
fetal hydrops, spontaneous abortion, preterm labor, or
preterm rupture of the membranes.18,19 Chorioamnionitis
has been suggested to affect neonatal outcome adversely
by increasing the risk of bronchopulmonary dysplasia,
necrotizing enterocolitis, intraventricular hemorrhage,
patent ductus arteriosus, neonatal sepsis, and neuro-
developmental sequelae.16,20e23
3. Current management of chorioamnionitis
Chorioamnionitis is an acute condition requiring a high
index of suspicion, and the threshold for antibiotics treat-
ment is low in the pregnant woman and their neonates
because both are severely affected by the organisms
leading to infection.24 Clinical chorioamnionitis is diag-
nosed when following clinical signs are present: maternal
fever, maternal and/or fetal tachycardia, maternal leuko-
cytosis, uterine tenderness, and foul-smelling or purulent
amniotic fluid.25 However, these subjective findings are
generally neither sensitive nor specific.
Maternal fever complicates up to one-third of labors and
has diverse causes including infection, epidural anesthesia,
and inflammation. Because not every maternal fever is
caused by infection, to treat all fevers with antibiotics will
result in overtreatment of mothers.24e26
Many intrauterine or extrauterine factors may cause
maternal fever. Intrauterine infection can result in preterm
birth, increased risk of operative delivery, maternal
bacteremia and sepsis, postcesarean wound infection, need
for hysterectomy, postpartum hemorrhage, admission to
intensive care unit, and rarely maternal mortality.25 How-
ever, a clear differentiation between infectious and non-
infectious fever during labor is difficult; therefore, intra-
partum fever frequently results in evaluation and treat-
ment of neonates for possible sepsis.27,28
The clinical signs and laboratory data usually used to di-
agnose chorioamnionitis have poor predictive value, may be
Triple I: A new concept for chorioamnionitis
absent or appear late, and are unreliable for identification of
acute chorioamnionitis. In addition, the term “rule out
chorioamnionitis” and maternal antibiotic treatment itself
often results in evaluation and antibiotic treatment of neo-
nates for possible sepsis for varying duration.29e31
3.1. Guidelines for neonates born to women with
suspected chorioamnionitis
The effects of intrauterine infection on the fetus and the
newborn depend on the duration and timing of the in-
flammatory process. Acute infection is a risk factor for
early-onset neonatal sepsis. However, chronic infection
usually is subclinical and has been associated with a wide
variety of neonatal organ injury, including brain, lung, eye,
intestine, and thymus.26
Once maternal chorioamnionitis is diagnosed, in spite of
the duration of intrapartum antibiotics, the current
recommendation from the Centers for Disease Control and
Prevention (CDC),32 and the Committee on Fetus and
Newborn of the American Academy of Pediatrics (AAP)33
required a full sepsis workup and initiation of antibiotics
treatment even in well-appearing infants. The actual in-
trauterine transmission of microorganisms to the fetus is
very low and limited to high virulent bacteria such as gram-
negative bacilli, aerobic streptococci, and Listeria.34 These
guidelines significantly increase the neonatal exposure to
antibiotics in an attempt to treat rare possibility of early-
onset sepsis. It is worth to emphasize that maternal fever
or suspected chorioamnionitis without evidence of fetal
infection is unlikely to cause fetal or neonatal injury.35
Therefore, it is important to reevaluate the policy for this
group of women and newborns.4
4. Intrauterine inflammation, infection, or
both (Triple I)
On January 26e27, 2015, the Eunice Kennedy Shriver
NICHD, the Society for Maternal-Fetal Medicine, the
American College of Obstetricians and Gynecologists, and
the American Academy of Pediatrics invited a group of
maternal and neonatal experts to a workshop to address
numerous knowledge gaps and to provide evidence-based
guidelines for the diagnosis and management of pregnant
women with chorioamnionitis and their neonates. The
expert panel agreed that isolated maternal fever should not
lead to a diagnosis of infection (or chorioamnionitis) and to
antibiotics therapy.4
The expert panel recommended to use the term “in-
trauterine inflammation or infection or both” or “Triple I”
as shown in Table 1 to replace the term chorioamnionitis.
4.1. Diagnosis of Triple I
According to the recommendation, Triple I is diagnosed
when maternal fever is present with one or more of the
following4:
1. Fetal tachycardia (>160 beats/min for 10 min or
longer)36
233
Table 1 Features of isolated maternal fever and Triple I
with classification.
Terminology Features and comments
Isolated Maternal oral temperature 39.0  C or
maternal fever greater (102.2  F) on any one
(“documented” occasion is documented fever. If the
fever) oral temperature is between 38.0  C
(100.4  F) and 39.0  C (102.0  F),
repeat the measurement in 30 min; if
the repeat value remains at least
38.0  C (100.4  F), it is documented
fever
Suspected Triple I Fever without a clear source plus any
of the following:
1) baseline fetal tachycardia (greater
that 160 beats per min for 10 min
or longer, excluding accelerations,
decelerations, and periods of
marked variability)
2) maternal white blood cell count
greater than 15,000 per mm3 in the
absence of corticosteroids
3) definite purulent fluid from the
cervical os
Confirmed Triple I All the above plus:
1) amniocentesis-proven infection
through a positive Gram stain
2) low glucose or positive amniotic
fluid culture
3) placental pathology revealing
diagnostic features of infection
*Discontinue the use of the term “Chorioamnionitis.” See the
text for discussion.
Copyright 2016, The American College of Obstetricians and
Gynecologists and Wolters Kluwer Health, Inc. Reproduced from
Higgins RD et al.4 with permission.
2. Maternal WBC count >15,000 cells/mm3 without using
corticosteroids
3. Purulent discharge from the cervical os confirmed visu-
ally on speculum examination
4. Biochemical or microbiologic evidence in amniotic fluid
consistent with amniotic infection (see subsequently).
4.2. Clinical category of Triple I (Table 1)
1. Isolated maternal fever (not Triple I)
2. Suspected Triple I
3. Confirmed Triple I.
4.2.1. Isolated maternal fever
Fever without any criteria (listed in Section 4.1.) should be
defined as “isolated maternal fever.” The criteria of
maternal fever were defined as follows: maternal
temperature  39.0  C or 102.2  F on one reading. If the
temperature is 38.0  C or 100.4  F but <39.0  C or
234
102.2  F, the temperature should be rechecked in 30 min. A
repeat temperature 38.0  C or 100.4  F constitutes a
documented fever.25,37 Oral temperature measurement
was recommended.38 In labor accompanied with fever and
unknown GBS status at gestation 37 weeks, intrapartum
prophylaxis should be given according to CDC guidelines.32
4.2.2. Suspected Triple I
Without confirmation, Triple I should be qualified with the
term “suspected.”
4.2.3. Confirmed Triple I
To diagnose a confirmed Triple I, infection in amniotic fluid
(AF) or histopathologic evidence of infection or inflammation
or both in the placenta, fetal membranes, or the umbilical
cord vessels (funisitis) should be proved by laboratory find-
ings. These findings include positive Gram stain for bacteria
in AF, low AF glucose, high WBC count in the absence of a
bloody tap, or positive AF culture results.34,40,41
4.3. Biomarkers
Objective biomarkers that can precisely assess the risk for
early-onset neonatal sepsis is very important. Potential
biomarkers to guide neonatal management can either be
antenatal or postnatal.
4.3.1. Antenatal markers
Antenatal markers accompanied with gestational age and
clinical manifestations can be used to guide the manage-
ment for mother.4 Antenatal markers confirmation of cho-
rioamnionitis is not routinely necessary in women at term
who are progressing to delivery. However, in women with
preterm labor being evaluated for tocolysis or using corti-
costeroid, biomarks assessment may be of value in estab-
lishing the diagnosis of chorioamnionitis. The different
biomarkers that have been evaluated are far from ideal,
either because the accuracy is not sufficient to define a
specific threshold or because of the invasiveness of an
amniocentesis. Investigational studies have noted IL-6 has
promise as a marker of intrauterine inflammation.34,39
However, current data remain controversial. A recent
Cochrane review revealed that using AF analysis to exclude
Triple I in women with PPROM has low quality of evidence.42
In contrast, some recent studies recommend to rule out
Triple I using AF analysis before doing cervical
cerclage.43e45
4.3.2. Postnatal markers
Postnatal markers should have the role to guide the post-
natal care of the newborn in 1) to objectively confirm the
presence of neonatal sepsis, 2) to help to decide whether
admission to NICU and antibiotics therapy is necessary or
not, and to guide the duration of antibiotics therapy, and 3)
to facilitate maternal and family counseling about the
probable cause of preterm birth and future pregnancies.4
Umbilical cord blood and neonatal blood taken within
72 h of birth are the most often used for biomarkers ex-
amination for early-onset sepsis. The cord blood has
advantage because it can obtain a relatively large amount
C.-C. Peng et al
immediately on delivery. The disadvantage is that some
biomarkers of placental origin may be higher than neonatal
blood. CRP, procalcitonin, IL-6, IL-8, haptoglobin and
haptoglobin-related protein in cord blood have been widely
studied and used in association with hematologic indices to
predict early-onset neonatal sepsis.46e50
The amount of blood that can be safely obtained for
biomarkers examination is limited, especially in very low
birth weight infants. Some biomarkers such as CRP and IL-6
are affected by postnatal physiologic changes that reduce
their specificity.51,52 Blood cultures are known as the gold
standard for early-onset sepsis, however, their use is
limited by false negative or false-positive results.53 In ad-
ditions, currently there is no established consensus defini-
tion for neonatal sepsis. New biomarkers should be
developed and evaluated on the basis of neonatal
outcomes.
4.4. Maternal management
The management for mother includes 1) to consider
admission or transfer to facilities with maternalefetal care
and grade 3 or 4 NICU if indicated by clinical evaluation, 2)
to decide whether to take expectant management or to
expeditious delivery, 3) to decide whether to perform a
cervical cerclage or not, 4) to decide whether to initiate
tocolytic treatment or not, 5) to decide whether antibiotics
treatment should be given or not, and 6) when to give
steroid.4,32,54
4.5. Neonatal management
Neonatal management should be guided by the clinical
category of isolated fever, suspected Triple I or confirmed
Triple I, gestational age at birth, and neonatal conditions
(Fig. 1, Algorithm).4 Communication between obstetric and
neonatal teams is essential for the appropriate neonatal
treatment. Clinical management is different for term and
late preterm neonates as compared with preterm neonates
with gestational age <34 weeks.
4.5.1. Term and late preterm neonates4
1. When isolated maternal fever, treatment is not benefi-
cial for well-appearing term and late preterm neonates
according to current evidence
2. When suspected Triple I, care should be decided by
clinical conditions. The majority of well-appearing term
and late preterm neonates can be observed without
receiving antibiotics treatment if remain asymptomatic
3. When confirmed Triple I, these neonates should be
treated according to current guidelines32,33
All neonates born to women with suspected or confirmed
Triple I who are not treated require close observations.
4.5.2. Neonates born at <34 0/7 weeks of gestation4
1. When isolated maternal fever, well-appearing preterm
neonates with gestational age <34 weeks might be
Triple I: A new concept for chorioamnionitis
Figure 1 Proposed algorism for neonatal management.
Copyright 2016, The American College of Obstetricians and Gynecologists and Wolters Kluwer Health, Inc. Reproduced from Higgins
RD et al.4 with permission.
observed if laboratory data is not favor of sepsis, but this
recommendation is not evidence-based
2. When suspected or confirmed Triple I, neonates with
gestational age <34 weeks should be given antibiotics
treatment as soon as cultures are done
3. The more the prematurity is, the more likely the pre-
term neonates will be symptomatic and should not be
treating as “well-appearing”.
4.6. Duration of neonatal antimicrobial therapy
In most well-appearing neonates, there is no evidence that
antibiotics treatment should be continued more than 48 h
when blood cultures are negative. However, there are
concerns about the validity of blood cultures in neonates
when their mother received broad-spectrum antibiotics
before delivery. It is a common reason for newborns being
treated with antibiotics for more than 5 days. To develop
more rigorous diagnostic criteria may better identify those
women and their neonates most likely to benefit from an-
tibiotics treatment and reduce unnecessary antibiotic
exposure.35
4.7. Communication between neonatal team and
obstetric team
Close communication between neonatal team and obstetric
team can ensure appropriate maternal and neonatal man-
agement. Box 1 provides items that could be included on a
checklist for every shift change to ensure continuity of
care.4 The education of obstetric and pediatric or neonatal
staff is important for the communication, identification,
and appropriate treatment of women at risk for Triple I and
their newborns.
235
Box 1. Checklist of items to include in communication
between the obstetric and neonatal teams.
 Gestational age
 Maternal tachycardia
 Fetal tachycardia
 Maternal white blood cell count greater than 15,000
 Maternal group B streptococci status
 Duration of rupture of membranes
 Duration of labor
 Purulent fluid
 Amniotic fluid evaluation
 Highest maternal temperature
 Epidural anesthesia use
 Prostaglandin use
 Antimicrobial agent(s) used
 Antipyretic used
 Spontaneous preterm birth
 Prior spontaneous preterm birth
Copyright 2016, The American College of Obstetricians
and Gynecologists and Wolters Kluwer Health, Inc.
Reproduced from Higgins RD et al.4 with permission.
5. Conclusion
In clinical practice, the term chorioamnionitis has been
used excessively and implies the presence of infectious and
inflammatory conditions affecting the mother, fetus and
newborn. In order to achieve better fetal, maternal and
neonatal care, the NICHD expert panel has recommended
the new concept “Triple I” to indicate intrauterine
236
inflammation or infection or both while restricting the term
chorioamnionitis to a pathologic diagnosis. Chorioamnioni-
tis is usually diagnosed based on subjective findings or by
histopathologic examination of the placenta and the um-
bilical cord. To develop more rigorous diagnostic criteria
may better identify those women and their neonates most
likely to benefit from antibiotics treatment and reduce
unnecessary antibiotic exposure. A prospective study to
determine whether clinical parameters combined with
biomarkers accurately predict the presence of Triple I
would be beneficial to improve maternal and neonatal
health care.
Conflict of interest
None.
References
1. Su BH. Histologic chorioamnionitis and neonatal outcome in
preterm infants. Pediatr Neonatol 2014;55:154e5.
2. Galinsky R, Polglase GR, Hooper SB, Black MJ, Moss TJ. The
consequences of chorioamnionitis: preterm birth and effects
on development. J Pregnancy 2013;2013:412831.
3. Bastek JA, Weber AL, McShea MA, Ryan ME, Elovitz MA. Pre-
natal inflammation is associated with adverse neonatal out-
comes. Am J Obstet Gynecol 2014;210. 450.e1e10.
4. Higgins RD, Saade G, Polin RA, Grobman WA, Buhimschi IA,
Watterberg K, et al. Evaluation and management of women
and newborns with a maternal diagnosis of chorioamnionitis:
summary of a workshop. Obstet Gynecol 2016;127:426e36.
5. Erdemir G, Kultursay N, Calkavur S, Zekioglu O, Koroglu OA,
Cakmak B, et al. Histological chorioamnionitis: effects on
premature delivery and neonatal prognosis. Pediatr Neonatol
2013;54:267e74.
6. Smulian JC, Shen-Schwarz S, Vintzileos AM, Lake MF,
Ananth CV. Clinical chorioamnionitis and histologic placental
inflammation. Obstet Gynecol 1999;94:1000e5.
7. Steel JH, O’donoghue K, Kennea NL, Sullivan MH, Edwards AD.
Maternal origin of inflammatory leukocytes in preterm fetal
membranes, shown by fluorescence in situ hybridisation.
Placenta 2005;26:672e7.
8. Watts DH, Krohn MA, Hillier SL, Eschenbach DA. The association
of occult amniotic fluid infection with gestational age and
neonatal outcome among women in preterm labor. Obstet
Gynecol 1992;79:351e7.
9. Andrews WW, Hauth JC, Goldenberg RL, Gomez R, Romero R,
Cassell GH. Amniotic fluid interleukin-6: correlation with upper
genital tract microbial colonization and gestational age in
women delivered after spontaneous labor versus indicated
delivery. Am J Obstet Gynecol 1995;173:606e12.
10. Yoon BH, Romero R, Moon J, Chaiworapongsa T, Espinoza J,
Kim YM, et al. Differences in the fetal interleukin-6 response to
microbial invasion of the amniotic cavity between term and
preterm gestation. J Matern Fetal Neonatal Med 2003;13:
32e8.
11. Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. The
fetal inflammatory response syndrome. Am J Obstet Gynecol
1998;179:194e202.
12. Parry S, Strauss 3rd JF. Premature rupture of the fetal mem-
branes. N Engl J Med 1998;338:663e70.
13. Edwards MS. Postnatal bacterial infections. In: Martin RJ,
Fanaroff AA, Walsh MC, editors. Fanaroff and Martin’s
neonatal perinatal medicine disease of the fetus and ınfant.
8th ed., vol. 2. Philadelphia: Mosby Elsevier; 2006. p. 791e804.
C.-C. Peng et al
14. Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR,
Walsh MC, et al. Neonatal outcomes of extremely preterm in-
fants from the NICHD neonatal research network. Pediatrics
2010;126:443e56.
15. Lahra MM, Jeffery HE. A fetal response to chorioamnionitis is
associated with early survival after preterm birth. Am J Obstet
Gynecol 2004;190:147e51.
16. Dammann O, Allred EN, Leviton A, Shen-Schwarz S, Heller D,
Genest DR, et al. Fetal vasculitis in preterm newborns: in-
terrelationships, modifiers, and antecedents. Placenta 2004;
25:788e96.
17. Redline RW. Inflammatory responses in the placenta and um-
bilical cord. Semin Fetal Neonatal Med 2006;11:296e301.
18. Pacora P, Chaiworapongsa T, Maymon E, Kim YM, Gomez R,
Yoon BH, et al. Funisitis and chorionic vasculitis: the histo-
logical counterpart of the fetal inflammatory response syn-
drome. J Matern Fetal Neonatal Med 2002;11:18e25.
19. Yoon BH, Romero R, Park JS, Kim M, Oh SY, Kim CJ, et al. The
relationship among inflammatory lesions of the umbilical cord
(funisitis), umbilical cord plasma interleukin 6 concentration,
amniotic fluid infection, and neonatal sepsis. Am J Obstet
Gynecol 2000;183:1124e9.
20. Ogunyemi D, Murillo M, Jackson U, Hunter N, Alperson B. The
relationship between placental histopathology findings and
perinatal outcome in preterm infants. J Matern Fetal Neonatal
Med 2003;13:102e9.
21. Dexter SC, Malee MP, Pinar H, Hogan JW, Carpenter MW,
Vohr BR. Influence of chorioamnionitis on developmental
outcome in very low birth weight infants. Obstet Gynecol 1999;
94:267e73.
22. Salas AA, Faye-Petersen OM, Sims B, Peralta-Carcelen M,
Reilly SD, McGwin Jr G, et al. Histological characteristics of the
fetal inflammatory response associated with neuro-
developmental impairment and death in extremely preterm
infants. J Pediatr 2013;163:652e7.
23. Malaeb S, Dammann O. Fetal inflammatory response and brain
injury in the preterm newborn. J Child Neurol 2009;24:
1119e26.
24. Kourtis AP, Read JS, Jamieson DJ. Pregnancy and infection. N
Engl J Med 2014;370:2211e8.
25. Tita AT, Andrews WW. Diagnosis and management of clinical
chorioamnionitis. Clin Perinatol 2010;37:339e54.
26. Lieberman E, Lang J, Richardson DK, Frigoletto FD, Heffner LJ,
Cohen A. Intrapartum maternal fever and neonatal outcome.
Pediatrics 2000;105:8e13.
27. Evers AC, Nijhuis L, Koster MP, Bont LJ, Visser GH. Intrapartum
fever at term: diagnostic markers to individualize the risk of
fetal infection: a review. Obstet Gynecol Surv 2012;67:
187e200.
28. Impey LW, Greenwood CE, Black RS, Yeh PS, Sheil O, Doyle P.
The relationship between intrapartum maternal fever and
neonatal acidosis as risk factors for neonatal encephalopathy.
Am J Obstet Gynecol 2008;198:49.
29. Mukhopadhyay S, Dukhovny D, Mao W, Eichenwald EC,
Puopolo KM. 2010 perinatal GBS prevention guideline and
resource utilization. Pediatrics 2014;133:196e203.
30. Kiser C, Nawab U, McKenna K, Aghai ZH. Role of guidelines on
length of therapy in chorioamnionitis and neonatal sepsis.
Pediatrics 2014;133:992e8.
31. Mukherjee A, Davidson L, Anguvaa L, Duffy DA, Kennea N. NICE
neonatal early onset sepsis guidance: greater consistency, but
more investigations, and greater length of stay. Arch Dis Child
Fetal Neonatal Ed 2015;100:F248e9.
32. Verani JR, McGee L, Schrag SJ. Division of bacterial diseases,
national center for immunization and respiratory diseases,
centers for disease control and prevention (CDC). Prevention
of perinatal group B streptococcal diseasedrevised guidelines
from CDC, 2010. MMWR Recomm Rep 2010;59:1e36.
Triple I: A new concept for chorioamnionitis
33. Polin RA, Committee on fetus and newborn. Management of
neonates with suspected or proven early-onset bacterial
sepsis. Pediatrics 2012;129:1006e15.
34. Redline RW. Inflammatory response in acute chorioamnionitis.
Semin Fetal Neonatal Med 2012;17:20e5.
35. Polin RA, Randis TM. Chorioamnionitis. In: Martin RJ,
Fanaroff AA, Walsh MC, editors. Fanaroff and Martin’s
neonatal-perinatal medicine. 10th ed. Philadelphia, PA:
Elsevier; 2015. p. 355e64.
36. Macones GA, Hankins GD, Spong CY, Hauth J, Moore T. The 2008
National Institute of Child Health and Human Development
workshop report on electronic fetal monitoring: update on
definitions, interpretation, and research guidelines. J Obstet
Gynecol Neonatal Nurs 2008;37:510e5.
37. Avila C, Willins JL, Jackson M, Mathai J, Jabsky M, Kong A,
et al. Usefulness of two clinical chorioamnionitis definitions in
predicting neonatal infectious outcomes: a systematic review.
Am J Perinatol 2015;32:1001e9.
38. Banerjee S, Cashman P, Yentis SM, Steer PJ. Maternal tem-
perature monitoring during labor: concordance and variability
among monitoring sites. Obstet Gynecol 2004;103:287e93.
39. Genc MR, Ford CE. The clinical use of inflammatory markers
during pregnancy. Curr Opin Obstet Gynecol 2010;22:116e21.
40. Buhimschi CS, Bhandari V, Hamar BD, Bahtiyar MO, Zhao G,
Sfakianaki AK, et al. Proteomic profiling of the amniotic fluid to
detect inflammation, infection, and neonatal sepsis. PLoS Med
2007;4:e18.
41. Abdel-Razeq SS, Buhimschi IA, Bahtiyar MO, Rosenberg VA,
Dulay AT, Han CS, et al. Interpretation of amniotic fluid white
blood cell count in “bloody tap” amniocenteses in women with
symptoms of preterm labor. Obstet Gynecol 2010;116:344e54.
42. Sharp GC, Stock SJ, Norman JE. Fetal assessment methods for
improving neonatal and maternal outcomes in preterm prel-
abour rupture of membranes. Cochrane Database Syst Rev
2014;(10):CD010209.
43. Aguin E, Aguin T, Cordoba M, Aguin V, Roberts R, Albayrak S,
et al. Amniotic fluid inflammation with negative culture and
outcome after cervical cerclage. J Matern Fetal Neonatal Med
2012;25:1990e4.
44. Vaisbuch E, Hassan SS, Mazaki-Tovi S, Nhan-Chang CL,
Kusanovic JP, Chaiworapongsa T, et al. Patients with an
237
asymptomatic short cervix (15 mm) have a high rate of sub-
clinical intraamniotic inflammation: implications for patient
counseling. Am J Obstet Gynecol 2010;202:433.
45. Lisonkova S, Sabr Y, Joseph KS. Diagnosis of subclinical amni-
otic fluid infection prior to rescue cerclage using gram stain
and glucose tests: an individual patient meta-analysis. J Obstet
Gynaecol Can 2014;36:116e22.
46. Steinberger E, Hofer N, Resch B. Cord blood procalcitonin and
Interleukin-6 are highly sensitive and specific in the prediction
of early-onset sepsis in preterm infants. Scand J Clin Lab
Investig 2014;74:432e6.
47. Cobo T, Kacerovsky M, Andrys C, Drahosova M, Musilova I,
Hornychova H, et al. Umbilical cord blood IL-6 as predictor of
early-onset neonatal sepsis in women with preterm prelabour
rupture of membranes. PLoS One 2013;8:e69341.
48. Howman RA, Charles AK, Jacques A, Doherty DA, Simmer K,
Strunk T, et al. Inflammatory and haematological markers in
the maternal, umbilical cord and infant circulation in histo-
logical chorioamnionitis. PLoS One 2012;7:e51836.
49. Fan Y, Yu JL. Umbilical blood biomarkers for predicting early-
onset neonatal sepsis. World J Pediatr 2012;8:101e8.
50. Buhimschi CS, Bhandari V, Dulay AT, Nayeri UA, Abdel-
Razeq SS, Pettker CM, et al. Proteomics mapping of cord blood
identifies haptoglobin “switch-on” pattern as biomarker of
early-onset neonatal sepsis in preterm newborns. PLoS One
2011;6:e26111.
51. Chiesa C, Signore F, Assumma M, Buffone E, Tramontozzi P,
Osborn JF, et al. Serial measurements of C-reactive protein
and interleukin-6 in the immediate postnatal period: reference
intervals and analysis of maternal and perinatal confounders.
Clin Chem 2001;47:1016e22.
52. Chiesa C, Pellegrini G, Panero A, Osborn JF, Signore F,
Assumma M, et al. C-reactive protein, interleukin-6, and pro-
calcitonin in the immediate postnatal period: influence of
illness severity, risk status, antenatal and perinatal complica-
tions, and infection. Clin Chem 2003;49:60e8.
53. Wynn JL, Wong HR, Shanley TP, Bizzarro MJ, Saiman L,
Polin RA. Time for a neonatal-specific consensus definition for
sepsis. Pediatr Crit Care Med 2014;15:523e8.
54. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection
and preterm delivery. N Engl J Med 2000;342:1500e7.