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Pediatrics and Neonatology (2018) 59, 231e237
Available online at
journal homepage:
Review Article
Intrauterine inflammation, infection, or
both (Triple I): A new concept for
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,*
Department of Medicine, Mackay Medical College, Taipei, Taiwan
Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan
Mackay Medicine, Nursing and Management College, Taipei, Taiwan
Department of Neonatology, China Medical University Children’s Hospital, Taichung, Taiwan
School of Medicine, China Medical University, Taichung, Taiwan
Department of Obstetrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan
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
inflammation or
Triple I
Chorioamnionitis is a common cause of preterm birth and may cause adverse neonatal outcomes, including neurodevelopmental sequelae. Chorioamnionitis has been marked to a heterogeneous setting of conditions characterized by infection or inflammation or both,
followed by a great variety in clinical practice for mothers and their newborns. Recently, a
descriptive term: “intrauterine inflammation or infection or both” abbreviated as “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 review 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 (
* 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: [email protected] (B.-H. Su).
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 (
1. Introduction
Chorioamnionitis is a common cause of preterm birth and may
causes adverse neonatal outcomes, including neurodevelopmental sequelae.1e3 Clinically, chorioamnionitis has
been marked to a heterogeneous setting of conditions characterized by infection or inflammation or both, followed by a
great variety in clinical practice for mothers and their newborns. 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 Development (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 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.
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 pregnancies 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 exotoxins, 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 categorized as clinical chorioamnionitis and subclinical/histologic
chorioamnionitis.1,2,5e7 Clinical chorioamnionitis is characterized by maternal fever, leukocytosis, maternal and/or
fetal tachycardia, uterine tenderness, and preterm rupture
of membranes (PROM). Subclinical/histologic chorioamnionitis 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 chorioamnionitis) and umbilical cord (funisitis) are the manifestations 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 cultures even in the presence of histological evidence of
placental inflammation.6 Therefore, pathological evaluation 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 Prolonged 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
Histological chorioamnionitis is most commonly associated 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 cytokines 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 neurodevelopmental sequelae.16,20e23
3. Current management of chorioamnionitis
Chorioamnionitis is an acute condition requiring a high
index of suspicion, and the threshold for antibiotics treatment is low in the pregnant woman and their neonates
because both are severely affected by the organisms
leading to infection.24 Clinical chorioamnionitis is diagnosed when following clinical signs are present: maternal
fever, maternal and/or fetal tachycardia, maternal leukocytosis, 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 However, a clear differentiation between infectious and noninfectious fever during labor is difficult; therefore, intrapartum fever frequently results in evaluation and treatment of neonates for possible sepsis.27,28
The clinical signs and laboratory data usually used to diagnose 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 neonates 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 inflammatory 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 intrauterine transmission of microorganisms to the fetus is
very low and limited to high virulent bacteria such as gramnegative bacilli, aerobic streptococci, and Listeria.34 These
guidelines significantly increase the neonatal exposure to
antibiotics in an attempt to treat rare possibility of earlyonset 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 “intrauterine 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
1. Fetal tachycardia (>160 beats/min for 10 min or
Table 1 Features of isolated maternal fever and Triple I
with classification.
Features and comments
maternal fever
Maternal oral temperature 39.0 C or
greater (102.2 F) on any one
occasion is documented fever. If the
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 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
All the above plus:
1) amniocentesis-proven
through a positive Gram stain
2) low glucose or positive amniotic
fluid culture
3) placental pathology revealing
diagnostic features of infection
Suspected Triple I
Confirmed Triple I
*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
3. Purulent discharge from the cervical os confirmed visually 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
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 findings. 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 management for mother.4 Antenatal markers confirmation of chorioamnionitis 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 corticosteroid, biomarks assessment may be of value in establishing 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
4.3.2. Postnatal markers
Postnatal markers should have the role to guide the postnatal 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 examination 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 additions, currently there is no established consensus definition for neonatal sepsis. New biomarkers should be
developed and evaluated on the basis of neonatal
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
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 beneficial 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 preterm 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 antibiotics treatment and reduce unnecessary antibiotic
4.7. Communication between neonatal team and
obstetric team
Close communication between neonatal team and obstetric
team can ensure appropriate maternal and neonatal management. 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.
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
inflammation or infection or both while restricting the term
chorioamnionitis to a pathologic diagnosis. Chorioamnionitis is usually diagnosed based on subjective findings or by
histopathologic examination of the placenta and the umbilical 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.
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