Clin. Exp. Obstet. Gynecol. 2022; 49(7): 160
https://doi.org/10.31083/j.ceog4907160

Original Research

Association between Chorioamnionitis Severity and Procalcitonin
Levels in Umbilical Venous Blood
Masatoki Kaneko1,2, *, Junsuke Muraoka1 , Naoshi Yamada1 , Yuki Kodama1
1 Department of Obstetrics and Gynecology, University of Miyazaki, 889-1692 Miyazaki, Japan
2 Graduate School of Nursing Science, University of Miyazaki, 889-1692 Miyazaki, Japan*Correspondence: mkaneko@med.miyazaki-u.ac.jp (Masatoki Kaneko)
Academic Editor: Luca Roncati
Submitted: 1 March 2022 Revised: 14 April 2022 Accepted: 19 April 2022

Published: 12 July 2022

Abstract
Background: Procalcitonin can effectively differentiate between bacterial sepsis and a systemic inflammatory response syndrome ofnoninfectious origins in the adult. However, the usefulness of procalcitonin in perinatal field is not determined. Thus, the purpose ofthis study was to determine whether procalcitonin levels in the umbilical blood reflect the severity of chorioamnionitis and to assess theircorrelation with perinatal outcomes. Methods: A retrospective study was conducted in 145 pregnant women with singleton pregnancies
and their neonates at a tertiary center between September 2010 and March 2013. Procalcitonin levels in the umbilical blood were measured by an immunoluminometric assay. The severity of chorioamnionitis was classified by the histological stage and grade for maternal
and fetal inflammatory responses. Procalcitonin levels were evaluated according to the severity of chorioamnionitis; and the association
with neonatal sepsis, intraventricular hemorrhage (IVH), neonatal death within 28 days of life, and periventricular leukomalacia wasinvestigated. Results: In total, 28 women (19%) had chorioamnionitis, of which 21 (75%) delivered at less than 34 weeks of gestation.
Fetal response in those with chorioamnionitis was correlated with maternal response. Procalcitonin levels in the group with fetal stage 2
and 3 or grade 2 responses were significantly higher than those infants with any other stage or grade. The frequency of neonatal sepsis,
IVH stage III or IV, and neonatal death significantly increased (p < 0.01), when a Procalcitonin level of ≥2 ng/mL was obtained. Conclusions: Procalcitonin levels in the umbilical blood reflect the severity of chorioamnionitis and are associated with neonatal outcomessuch as neonatal sepsis, neonatal death, and severe IVH. When PCT level in umbilical venous blood show the high value of ≥2 ng/mL,
it might be required that antibiotics therapy is initiated immediately after birth.
Keywords: chorioamnionitis; intraventricular hemorrhage; neonatal sepsis; neonatal death; procalcitonin; prematurity; periventricularleukomalacia

1. Introduction
The term chorioamnionitis is used to describe a clinical symptom complex suggestive of intrauterine infection.
There is now considerable evidence supporting the relationship between placental inflammation and important clinicaloutcomes such as neurological impairment and chronic lungdisease [1–3]. This requires a more active clinical approachto the management of chorioamnionitis. Once chorioamnionitis is diagnosed, the fetus may benefit from immediatedelivery rather than intrauterine treatment with antibiotics.
Unfortunately, there are no useful clinical signs or biomarkers that reflect histological chorioamnionitis to help determine the appropriate timing of delivery in the presence ofchorioamnionitis.
Procalcitonin (PCT) can effectively differentiate between bacterial sepsis and a systemic inflammatory response syndrome of noninfectious origins [4]. PCT has several advantages over other potential biomarkers such as awide biological range, short induction time after bacterial
stimulus, and long half-life [5]. However, the use of PCT
as a marker of sepsis during pregnancy is controversial. Because, the general reference values for PCT in pregnancy,

which are essential for clinical decision-making, have notbeen established [6]. Additionally, pregnancy conditions
such as elevation of progesterone and immune state canlead to a resistant to lipopolysaccharide-induced productionof PCT [6,7]. On the other hand, the serum PCT levels in
pregnant women are significantly higher than those in nonpregnant women [8], probably due to the physiological synthesis by trophoblast and stromal cell of the decidua [6,9].
Histological chorioamnionitis is most commonly associated with intrauterine bacterial infection. It is believedthat the fetal inflammatory response syndrome (FIRS), as aresult of infection pathways and increasing cytokines activate an inflammatory response that potentially lead to fetal
vasculitis, fetal death, preterm labor, or preterm rupture of
the membranes [10,11]. It is considered that this cytokine
activation lead to production of PCT in the fetus.
With respect to the sequence of maternal and fetal inflammation, histological chorioamnionitis has repeatedly
been shown to be both sensitive and specific for infection,and it is considered the gold standard against which otherclinical predictors of infection should be measured [10–14].
Recently, Redline et al. [15] proposed a clinically relevant

Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Publisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

and pathologically reproducible grading and staging system
for acute chorioamnionitis.
The objective of this study was to determine thechanges in PCT levels in the umbilical cord blood according to the histological progression of the disease (stage) andgradations of intensity (grade) for maternal and fetal inflammatory responses in chorioamnionitis and assess these correlations with perinatal outcomes.

2. Materials and Methods
2.1 Study Group
This retrospective study was conducted at a tertiary perinatal center, the University of Miyazaki, between
September 1, 2010 and March 31, 2013. The pregnant
women with singleton pregnancies and their neonates, whowere managed at our center in this period, were enrolled inthis study. The mothers delivered the neonates with chromosomal abnormalities, life-threatening structural anomalies, and hydrops were excluded from the study. The gestational age was based on the last menstrual period and wasconfirmed by ultrasonographic examination. We used medical charts and discharge forms to investigate the following
items: (1) maternal and neonatal characteristics, (2) clinical signs of maternal infection such as fever and any othermaternal complications during the intrapartum period, (3)presence of premature rupture of membranes (PROM), (4)culture for pathogens in the amniotic fluid or umbilical cord
blood, and (5) clinical signs of neonatal infection.
Early-onset neonatal bacterial infection was diagnosed during the first 72 h of life based on the presence of
three or more of the following categories of clinical signs
in the neonate: (1) skin color (pallor, jaundice, cyanosis);(2) respiratory (apnea, tachypnea >60 breaths/min, grunting, nasal flaring, intercostal or sternal retractions, or theneed for high ventilator settings or oxygen); (3) cardiovascular (bradycardia, tachycardia, poor peripheral perfusion, or hypotension); (4) neurological symptoms (hypotonia, irritability, lethargy, or seizures), (5) gastrointestinal(abdominal distension, green or bloody residuals, or vomiting); (6) temperature instability; and/or (7) positive blood
culture for the bacteria or yeast.

2.3 Placental Histological Examination
Following admission of neonate to the center, all placentas were subjected to histological analysis by pathologists blind to this study including the umbilical cord PCTlevels. Placental findings consistent with chorioamnionitis were defined by the presence of an inflammatory neutorophilic infiltrate at two or more sites on the chorionic plate and extraplacental membrane. The histologicalprogression of disease (stage) and gradations of intensity(grade) for the maternal and fetal inflammatory responses
were classified according to the definition reported by Redline et al. [15]. This scheme utilized three-tiered staging
and two-tiered grading of both the maternal and fetal inflammatory responses, respectively.
We investigated whether the PCT levels of the umbilical cord blood reflected the severity of placental inflammation. We also investigated the relationship between
PCT levels in the umbilical cord blood and neonatal outcomes such as early-onset sepsis, intraventricular hemorrhage (IVH), frequency of intubation, death within 28 daysof life, and cystic periventricular leukomalacia (PVL).
2.4 Statistical Analysis
Between-group differences were assessed using theMann–Whitney U test, χ2 analysis, Fisher exact test, or the
Kruskal–Wallis test followed by a post-hoc paired t-test using the Dunn Procedure. Results with p value < 0.05 wereconsidered statistically significant.
A multiple logistic regression analysis was performed
to identify any independent predictive factors of the neonatal outcomes. Only predictive variables with a p value <0.1 in the univariate analysis were entered into a logistic
regression model. A stepwise forward procedure using the
likelihood ratio test was used in the multivariable logistic
regression analysis. Variables with p value < 0.05 in the
final model of the multivariable logistic regression were
determined to be independent predictive factors of neonatal outcomes. A statistical analysis was performed using
the SPSS version 27 software program for Windows (IBMSPSS Statistics, Tokyo, Japan). Date are presented as mean
± standard deviation.

2.2 PCT Measurements
The umbilical cord bloods were routinely collected ina standardized fashion at the time of delivery to measure
PCT levels for all patients. The measurement of PCT levels
were conducted at the laboratory in University of Miyazaki.
The umbilical cord blood was collected into collection tubes
containing ethylenediaminetetraacetic acid. All tubes wereimmediately centrifuged and assayed within 1 h after collection. An immunoluminometric assay was performed tomeasure the PCT levels in the umbilical cord blood usinga PCT kit (Roche Diagnostics Japan, Tokyo, Japan) anda fully automated chemiluminescence analyzer (cobas®,
Roche, Germany). Using this method, the lowest detection
limit of PCT was 0.02 ng/mL.
2

3. Results
A total of 145 pregnant women with singleton pregnancies and their neonates were enrolled in this study. The
maternal and neonatal characteristics of this study group areshown in Table 1. Ten women (6.9%) were febrile within
2 h before or during delivery, but only four women had
histological chorioamnionitis. Twenty-eight (19%) women
had PROM, 10 of which had histological chorioamnionitis. Twenty-eight (19%) had histological chorioamnionitis.
The gestational age at delivery varied from 22 to 41 weeks
of gestation, and 21 (75%) women delivered at less than 34
weeks of gestation. Two of 28 women did not show the fetal
inflammatory response in the placenta.

Table 1. Characteristics of the mother and neonate.
Patients
total n = 145
Age (year)
Primipara (%)
G.W at delivery
Cesarean section (%)
Maternal fever (≥38 °C)
PROM (%)
Male (%)
Birth weight (g)Histological CAM (%)
Positive culture (%)
Pathogen
GBS
Bacteroides ureolyticus
CandidaFusobacterium nucleatum
Capnocytophaga
Hemophilus influenzae

30.9 ± 5.2
68 (47)32.3 ± 5.0
102 (70)
10 (6.9)28 (19)61 (42)1816 ± 891
28 (19)7 (25)
1
1
2
1
1
1

GW, gestational week; PROM, premature rupture of membranes; CAM, chorioamnionitis; GBS, group B streptococcus.
Data shown mean ± SD.

3.1 Comparison between Chorioamnionitis and Non
Chorioamnionitis (Table 2)
PCT level and CRP level in chorioamnionitis groupwere significantly higher than those in no chorioamnionitis
group (p < 0.01). Significant differences in the gestational
age at birth and the birthweight were found between two
groups (p < 0.01). Eighteen cases (64.3%) in chorioamnionitis group was born at less than 29 weeks of gestation.
Table 2. Comparison between CAM and non CAM.
CAM
(n = 28)

non CAMp value(n = 117)

PCT (ng/mL)
8.4 ± 18.58 0.22 ± 0.15 <0.01
CRP (mg/dL)
0.34 ± 0.59 0.08 ± 0.77 <0.01
Gestational age at birth (weeks) 28 ± 6
33 ± 4<0.01
Birthweight (g)1283 ± 951 1916 ± 831 <0.01
CAM, chorioamnionitis; PCT, procalcitonin; CRP, c-reactive protein.

3.2 Relationship between Umbilical PCT Level andSeverity of Placental Inflammation
The relationship between the histological progressionof the disease and maternal and fetal inflammatory responses is shown in Fig. 1. The fetal inflammatory response in chorioamnionitis progressed as the maternal response progressed. However, the maternal response was
equal to or more severe than the fetal response.

Fig. 1. Relationship between the maternal inflammatory response and fetal inflammatory response in chorioamnionities. Circle, <0.5 ng/mL; triangle, 0.5–2.0 ng/mL; square, 2.0–10
ng/mL; black circle, ≥10 ng/mL.

The PCT levels in the umbilical blood according to thestage (S) and grade (G) for maternal and fetal inflammatory
responses in chorioamnionitis are shown in Table 3. Sevencases with the most severe maternal inflammatory response(S3/G2) showed variable PCT levels, but four (57%) had
PCT levels higher than 2 ng/mL. Two of the seven cases
showed low PCT levels (0.43 and 0.44 ng/mL) and both ofthese had Candida neonatal sepsis. In nine women showing moderate S1/G1 responses, two had PCT levels higher
than 2 ng/mL. One (PCT, 7.76 ng/mL) of the two delivered at 27 weeks of gestation had neonatal Haemophilus
influenzae sepsis. The remaining one (PCT, 43.22 ng/mL)
delivered at 40 weeks of gestation with an umbilical arterial
blood of pH 6.9 and base excess of –14.8 mmol/L. Of the
117 women without maternal inflammatory responses, 114(97%) showed PCT levels lower than 0.5 ng/mL.
Similarly, the PCT levels were analyzed according to
the fetal inflammatory responses in the placenta (Table 3).
There was only one case that showed a fetal S3/G2 responsewith a PCT level higher than 2 ng/mL. Two Candidal sepsis cases showed S2/G2 and S2/G1 responses. In the 16
women showing fetal S1/G1 responses, two had PCT levels higher than 10 ng/mL; one had 43.22 ng/mL (the term
asphyxia case) and the other had 13.09 ng/mL (22 weeks ofgestation with diffuse chorioamniotic hemosiderosis). Of
the 119 women without maternal inflammatory responses,
114 (97%) showed PCT levels lower than 0.5 ng/mL andthe remaining four had PCT levels between 0.5–2 ng/mL(0.57–1.07 ng/mL).
PCT levels of the umbilical blood were compared according to the maternal and fetal inflammatory responses(Table 4). In the maternal inflammatory responses, the PCTlevels in S3 or G2 cases were significantly higher than those3

Table 3. PCT level according to placental inflammatory
response.
Placental response

PCT level (ng/mL)
<0.5
total

129

145

n (%)

0.5–2

2–10

≥10

5

6

5

n (%) n (%) n (%)

Maternal response
Stage 3, Grade 2 ; n (%) 7
2 (1.6) 1 (20) 1 (16.7) 3 (60)Stage 2, Grade 2 ; n (%) 200 2 (33.3) 0Stage 2, Grade 1 ; n (%) 10 7 (5.4)
0 2 (33.3) 1 (20)Stage 1, Grade 1 ; n (%) 9
6 (4.7) 1 (20) 1 (16.7) 1 (20)without response; n (%) 117 114 (88.4) 3 (60)00Fetal response
Stage 3, Grade 2 ; n (%) 100 1 (16.7) 0Stage 2, Grade 2 ; n (%) 5
1 (0.8)0 1 (16.7) 3 (60)Stage 2, Grade 1 ; n (%) 4
2 (1.6) 1 (20) 1 (16.7) 0Stage 1, Grade 1 ; n (%) 16 11 (8.5)
0 3 (50.0) 2 (40)without response; n (%) 119 115 (89.1) 4 (80)00of any other stages or grades. Because only one case had a
S3 fetal inflammatory response, the PCT levels were analyzed after combined S2 and S3, which were significantly
higher than those at any other stage. Similarly, as the fetal
grades advanced, the PCT levels also increased.
Table 4. Relationship between inflammatory response and

3.3 Relationship between Umbilical PCT Level andNeonatal Outcomes
The frequencies of neonatal complications were compared among the four PCT levels (Table 5). The frequencyof early-onset sepsis in cases with PCT levels higher than 2
ng/mL was greater than that in those with PCT levels lower
than 2 ng/mL. There were nine neonates with IVH grades
III or IV, six of which had PCT levels higher than 2 ng/mL;
this was a significantly higher incidence than in cases with
PCT levels higher than 2 ng/mL. There were five deaths
within 28 days of life, four of which were cases that had
PCT levels higher than 2 ng/mL. There was no relationshipbetween the PCT level and PVL frequency.
Table 5. Relationship between PCT and neonatal outcome.
PCT (ng/mL)
<0.5

0.5–2

2–10

≥10

Outcometotal n = 129 (%) n = 5 (%) n = 6 (%) n = 5 (%)
Early-onset sepsis
13
2 (1.6)
1 (20)∗ 6 (100)∗† 4 (90)∗†
Intubation
21
6 (4.7)5 (100)∗ 6 (100)∗ 5 (90)∗
IVH III or IV
9
2 (1.7)
1 (20) 3 (50)∗ 3 (60)∗†
Death <28 days of life 5
1 (0.8)0 (0) 3 (50)∗† 1 (20)∗PVL
7
6 (4.7)0 (0)1 (17)0 (0)IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia.
* p < 0.01 vs group of < 0.5 ng/mL, † p < 0.01 vs group of 0.5–2
ng/mL.

PCT.
Inflammatory response
Maternal stage
without response
Stage 1
Stage 2
Stage 3
Maternal grade
without response
Grade 1
Grade 2
Fetal stage
without response
Stage 1
Stage 2
3
Fetal grade
without response
Grade 1
Grade 2

PCT (ng/mL)
0.22 ± 0.15*
5.97 ± 14.18*
2.75 ± 4.0*
29.45 ± 34.52
0.22 ± 0.15 †4.15 ± 10.09 †22.16 ± 30.84
0.23 ± 0.16*
4.84 ± 10.90*

Table 6. Comparison between the poor and good infant
outcome groups.

21.36 ± 31.40

Variables

0.23 ± 0.17 †, ‡4.30 ± 10.04 †36.34 ± 35.68

PCT (ng/mL)
12.72 ± 22.19 0.25 ± 0.36
CRP (mg/dL)
0.33 ± 0.51 0.11 ± 0.77
CAM n (%)
16 (88.9)
12 (9.4)
Early-onset sepsis n (%)
12 (66.7)
1 (0.8)
Gestational age at birth (week)
26 ± 633 ± 4Birthweight (g)984 ± 895
1908 ± 829
Male n (%)
8 (44.4)
53 (41.7)

Neonatal outcome
poor (n = 18) good (n = 127) p value* p < 0.01 vs Stage 3 or Stage 2&3, † p < 0.01
vs Grade 2, ‡ p < 0.05 vs Grade 1, Data shows
mean ± SD.

4

The study subjects were divided into the poor infant outcome (neonatal death and abnormal ultrasonography findings) and good infant outcome groups (Table 6).
PCT and CRP levels in umbilical venous blood in the pooroutcome group were significantly higher than that in goodoutcome group (p < 0.01). Significant differences were observed in the proportion of chorioamnionitis and early-onset
sepsis between the two groups (p < 0.01). There were alsosignificant differences in the gestational age at birth andbirthweight between the two groups (p < 0.01).

<0.01
<0.01
<0.01
<0.01
<0.01
<0.01

0.85

The findings from the multiple logistic regression
analysis are shown in Table 7. Six predictive factors,
namely PCT level, CRP level, chorioamnionitis, earlyonset sepsis, gestational age at birth and birthweight, wereentered into the multivariate model. As a result, two predictive factors, namely early-onset sepsis and chorioamnionitis, were found to be independent factors of poor infant outcome.
Table 7. Multivariable logistic regression analysis regarding
the infant’s prognosis.
Bvariablep valueOR

95% CI
Lower Upper

Early-onset sepsis 3.15 0.002 23.38 3.31 165.2
Chorioamnionitis 3.26 <0.001 25.91 4.53 148.32
Constant–2.23 0.011

As mentioned above, one infant who was deliveredat term had birth asphyxia and mild chorioamnionitis andshowed a high PCT level (43.22 ng/mL). MRI revealed that
this infant had white matter injury with neurological impairment.

4. Discussion
We evaluated the PCT levels in the umbilical cord
blood according to the maternal and fetal inflammatory responses in the placenta and investigated the relationship between PCT levels and neonatal outcomes. We found that theumbilical PCT level reflected the histological progressionof disease (stage) and the gradations of intensity (grade) for
both maternal and fetal inflammatory responses. Furthermore, the prevalence of early-onset sepsis, IVH grades III
or IV, and neonatal death significantly increased when theumbilical PCT levels became higher than 2 ng/mL.
Intrauterine infection induces fetal inflammatory responses, resulting in elevated levels of proinflammatory
cytokines and an increased incidence of preterm birth andneonatal lung and brain injury [1,2,16,17]. The fetal inflammatory response syndrome (FIRS) is characterized by theactivation of the innate fetal immune system after in utero
exposure to infection/inflammation [18]. FIRS was originally defined on the basis of increased cord blood concentrations of interleukin (IL)-6, which was shown to be associated with adverse neonatal outcome [19]. However, it
is difficult to clinically diagnose chorioamnionitis. Clinicalchorioamnionitis, variably defined by the presence of maternal fever, tachycardia, leukocytosis, foul-smelling vaginal discharge, or fetal tachycardia, is present only in a minority of cases with either histologically, microbiologically,or biochemically proven chorioamnionitis [20–23]. Moreover, there are no highly sensitive and specific biomarkers
for detecting chorioamnionitis.

PCT is ubiquitously produced in response to endotoxin or mediators released during bacterial infections (forexample, tumor necrosis factor-α, IL-6, and IL-8). It has
several advantages over other potential biomarkers, such asa wide biological range, immediate induction after bacterial
stimuli, and long half-life [5]. In this study, we found thatumbilical PCT measurement at delivery could be a potential biomarker to predict neonatal outcomes including earlyonset sepsis, IVH, and neonatal death. However, interpreting the levels may require some considerations. First,
the PCT level did not increase in cases with neonatal Candida infection despite severe chorioamnionitis. Data regarding the role of PCT in invasive fungal infections remain limited and controversial [24]. Dornbusch et al. [24]speculated that there was a potential difference in the cytokine response to the respective fungal species and a potential delayed increase in PCT. These specific responses
to fungal infections may introduce different results in eachstudy. Second, a term acidemic newborn showed an extremely high PCT level despite having mild chorioamnionitis. In an animal model, repetitive severe fetal acidemia
induced the elevation of fetal plasma IL-1β values, indicating a systemic inflammatory response [25]. We speculated that fetal acidemia may have an impact on the umbilical PCT level. Furthermore, animal studies have shownthat PCT acts as the inflammatory mediator [26,27]. Highlevels of PCT may directly injure the brain white matterand induce neurological impairment in infants. Third, inneonatal H. influenzae infections, the umbilical PCT levels were significantly higher despite mild chorioamnionitis. PCT levels markedly increased in neutropenic children
with gram-negative bacteremia compared with those withgram-positive bacteremia (bacilli, mycoplasma or fungi)[28]. Different pathogens may induce distinct responses,
resulting in a variable up-regulation of the circulating PCTlevels.
The most important feature of a biomarker is its potential to change clinical decision making. Huetz et al. [29] reported the potential impact of umbilical cord blood procalcitonin based algorithm on antibiotics exposure in neonateswith suspected early-onset sepsis. They concluded that thisalgorithm could significantly help the clinicians in theirantibiotic prescription decision to decrease neonatal antibiotics exposure as compared with current practice [29].
However, they could not show the usefulness of PCT inumbilical cord blood as a diagnostic tool. The chief advantage of cord blood is that it is available in relatively large
quantities immediately upon delivery, its sampling is technically easy to perform and does not pose a risk of infection
or hemorrhage for the neonate. High PCT level in umbilical venous blood reflected sever chorioamnionitis in thisstudy. Additionally, the chorioamnionitis and early-onset
sepsis were the predictive factors for the infant’s outcomesin this study. Delay in diagnosis and treatment of sepsis increases mortality, prolongs length of hospital stay. Thus,5when PCT level in umbilical venous blood show the highvalue of more than 2 ng/mL, it might be required that antibiotics therapy is initiated immediately after birth. However,the precise cut-off value of PCT level is required to introduce PCT measurement in clinical practice. The limitationof this study is that we cannot show this cut-off value. Because, there are several influenced factors for PCT level inumbilical venous blood such as neonatal asphyxia and prematurity.
Seventy-five percent of our study population withchorioamnionitis delivered at less than 34 weeks of gestation. In a cohort study of 483 singletons with a mean gestational age of 34.5 weeks (range 24–42 weeks), histologicalchorioamnionitis significantly increased the odds ratio forearly abnormal brain sonography findings such as increased
periventricular echodensity or echolucency, severe IVH,
or ventriculomegaly [21]. This result is consistent with
our result. However, there remains a controversy about
whether prematurity-independent effects of chorioamnionitis on neonatal outcomes exist [30]. It is difficult to assess chorioamnionitis as a risk factor for adverse outcomesin extremely premature infants because prematurity can itself cause adverse outcomes. Regarding this point, we
could show that early-onset sepsis and chorioamnionitis
were independent variables by using multivariable logistic
regression analysis, although prematurity influenced on the
neonatal outcome in between-group difference’s analysis.
In this study, we did not show a relationship between
histological chorioamnionitis and PVL. However, our result
is consistent with the report by Soraisham et al. [31], inwhich no association between clinical chorioamnionitis and
PVL was observed in 477 infants born at less than 33 weeks
of gestation.

5. Conclusions
Early-onset sepsis and histological chorioamnionitis
were independent variables against the neonatal adverse
outcomes according to multivariable logistic regression
analysis. Umbilical PCT levels higher than 2 ng/mL reflected the severity of histological chorioamnionitis andwere associated with poor perinatal outcomes.

Author Contributions
MK made the conception and design, analyzed and interpreted the patient data, and wrote the manuscript. JM
collected the data and analyzed the patient data. NY collected the data and analyzed the patient data. YK collected
the data and analyzed the patient data. All authors read andapproved the final manuscript.

Ethics Approval and Consent to Participate
The study conducted according to the guidelines of the
Declaration of Helsinki, and approved by the Ethics Committee of the Faculty of Medicine, University of Miyazaki,
6

Miyazaki Japan (approval number 2013-077). Informed
consent was obtained from all subjects involved in the
study.

Acknowledgment
The authors would like to thank Enago (www.enago.
jp) for the English language review.

Funding
This work was supported by JSPS KAKENHI Grant
Number JP25462566.

Conflict of Interest
The authors declare no conflict of interest. MK is serving as one of the Guest editors of this journal. We declarethat MK had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for thisarticle was delegated to LR.

References[1] Yoon BH, Romero R, Park JS, Kim CJ, Kim SH, Choi JH, etal. Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. American
Journal of Obstetrics and Gynecology. 2000; 182: 675–681.
[2] Leviton A, Allred EN, Kuban KCK, Hecht JL, Onderdonk AB,
O’Shea TM, et al. Microbiologic and Histologic Characteristicsof the Extremely Preterm Infant’s Placenta Predict White Matter
Damage and Later Cerebral Palsy. The ELGAN Study. PediatricResearch. 2010; 67: 95–101.
[3] Been JV, Rours IG, Kornelisse RF, Jonkers F, de Krijger RR,
Zimmermann LJ. Chorioamnionitis Alters the Response to Surfactant in Preterm Infants. The Journal of Pediatrics. 2010; 156:
10–15.e1.
[4] Schuetz P, Albrich W, Mueller B. Procalcitonin for diagnosis
of infection and guide to antibiotic decisions: past, present andfuture. BMC Medicine. 2011; 9: 107.
[5] Dandona P, Nix D, Wilson MF, Aljada A, Love J, Assicot M,
et al. Procalcitonin increase after endotoxin injection in normal
subjects. The Journal of Clinical Endocrinology & Metabolism.
1994; 79: 1605–1608.
[6] Mangogna A, Agostinis C, Ricci G, Romano F, Bulla R.
Overview of procalcitonin in pregnancy and in pre-eclampsia.
Clinical and Experimental Immunology. 2019; 198: 37–46.
[7] Rami D, La Bianca M, Agostinis C, Zauli G, Radillo O, Bulla R.
The first trimester gravida serum regulates procalcitonin expression in human macrophages skewing their phenotype in vitro.
Mediators of Inflammation. 2014; 2014: 248963.
[8] Hu Y, Yang M, Zhou Y, Ding Y, Xiang Z, Yu L. Establishment ofreference intervals for procalcitonin in healthy pregnant womenof Chinese population. Clinical Biochemistry. 2017; 50: 150–
154.
[9] Agostinis C, Rami D, Zacchi P, Bossi F, Stampalija T, Mangogna A, et al. Pre-eclampsia affects procalcitonin productionin placental tissue. American Journal of Reproductive Immunology. 2018; 79: e12823.
[10] Pacora P, Chaiworapongsa T, Maymon E, Kim YM, Gomez R,
Yoon BH, et al. Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome.
The Journal of Maternal-Fetal & Neonatal Medicine. 2002; 11:
18–25.

[11] Yoon BH, Romero R, Park JS, Kim M, Oh S, 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. American Journalof Obstetrics and Gynecology. 2000; 183: 1124–1129.
[12] Rodrigo FGM, Henriquez GG, Aloy JF, Perz AGA. Outcomesof very-low-birth- weight infants exposed to maternal clinicalchorioamnionitis: A multicenter study. Neonatology. 2014; 106:229–234.
[13] Peng C, Chang J, Lin H, Cheng P, Su B. Intrauterine inflammation, infection, or both (Triple I): a new concept for chorioamnionitis. Pediatrics & Neonatology. 2018; 59: 231–237.
[14] Higgins RD, Saade G, Polin RA, Grobman WA, Buhimschi IA,
Watterberg K, et al. Evaluation and Management of Womenand Newborns with a Maternal Diagnosis of Chorioamnionitis:
Summary of a workshop. Obstetrics & Gynecology. 2016; 127:
426–436.
[15] Redline RW, Faye-Petersen O, Heller D, Qureshi F, Savell V,
Vogler C. Amniotic Infection Syndrome: Nosology and Reproducibility of Placental Reaction Patterns. Pediatric and Developmental Pathology. 2003; 6: 435–448.
[16] McElrath TF, Hecht JL, Dammann O, Boggess K, Onderdonk
A, Markenson G, et al. Pregnancy disorders that lead to delivery
before the 28th week of gestation: an epidemiologic approach
to classification. The American Journal of Epidemiology. 2008;
168: 980–989.
[17] Onderdonk AB, Delaney ML, DuBois AM, Allred EN, Leviton
A. Detection of bacteria in placental tissues obtained from extremely low gestational age neonates. American Journal of Obstetrics and Gynecology. 2008; 198: 110.e1–110.e7.
[18] Gotsch F, Romero R, Kusanovic JP, Mazaki-Tovi S, Pineles BL,
Erez O, et al. The Fetal Inflammatory Response Syndrome. Clinical Obstetrics & Gynecology. 2007; 50: 652–683.
[19] Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM.
The fetal inflammatory response syndrome. American Journalof Obstetrics and Gynecology. 1998; 179: 194–202.
[20] Hagberg H, Wennerholm U, Sävman K. Sequelae of chorioamnionitis. Current Opinion in Infectious Diseases. 2002; 15: 301–
306.
[21] De Felice C, Toti P, Laurini RN, Stumpo M, Picciolini E, Todros
T, et al. Early neonatal brain injury in histologic chorioamnioni-

tis. The Journal of Pediatrics. 2001; 138: 101–104.
[22] Dammann O, Allred EN, Leviton A, Shen-Schwarz S, Heller
D, Genest DR, et al. Fetal vasculitis in preterm newborns: interrelationships, modifiers, and antecedents. Placenta. 2004; 25:
788–796.
[23] Van Hoeven K, Anyaegbunam A, Hochster H, Whitty J, Distant
J, Crawford C, et al. Clinical Significance of Increasing Histologic Severity of Acute Inflammation in the Fetal Membranes
and Umbilical Cord. Fetal and Pediatric Pathology. 1996; 16:
731–744.
[24] Dornbusch HJ, Strenger V, Kerbl R, Lackner H, Schwinger W,
Sovinz P, et al. Procalcitonin—a marker of invasive fungal infection? Supportive Care in Cancer. 2005; 13: 343–346.
[25] Prout AP, Frasch MG, Veldhuizen RAW, Hammond R, Ross
MG, Richardson BS. Systemic and cerebral inflammatory response to umbilical cord occlusions with worsening acidosis in
the ovine fetus. American Journal of Obstetrics and Gynecology.
2010; 202: 82.e1–82.e9.
[26] Nylen ES, Whang KT, Snider RH, Steinwald PM, White JC,
Becker KL. Mortality is increased by procalcitonin and decreased by an antiserum reactive to procalcitonin in experimental sepsis. Critical Care Medicine. 1998; 26: 1001–1006.
[27] Christ-Crain M, Muller B. Procalcitonin in bacterial infectionhype, hope, more or less? Swiss Medical Weekly. 2005; 135:
451–460.
[28] Huetz N, Launay E, Gascoin G, Leboucher B, Savagner
C, Muller JB, et al. Potential impact of umbilical-cordblood procalcitonin-based algorithm on antibiotics exposure inneonates with suspected early-onset sepsis. Frontiers in Pediatrics. 2020; 8; 1–8.
[29] Fleischhack G, Cipic D, Juettner J, Hasan C, Bode U. Procalcitonin – a sensitive inflammation marker of febrile episodes
in neutropenic children with cancer. Intensive Care Medicine.
2000; 26: S202–S211.
[30] Bracci R, Buonocore G. Chorioamnionitis: a risk factor for fetala neonatal morbidity. Biology of the Neonate. 2003; 83: 85–96.
[31] Soraisham AS, Singhal N, McMillan DD, Sauve RS, Lee SK.
A multicenter study on the clinical outcome of chorioamnionitis
in preterm infants. American Journal of Obstetrics and Gynecology. 2009; 200: 372.e1–372.e6.

7