The Journal of Maternal-Fetal & Neonatal Medicine

ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmf20

Procalcitonin for prediction of chorioamnionitis in

preterm premature rupture of membranes

Loralei L. Thornburg, Ruthanne Queenan, Brianne Brandt-Griffith & Eva K.

Pressman

To cite this article: Loralei L. Thornburg, Ruthanne Queenan, Brianne Brandt-Griffith & Eva
K. Pressman (2015): Procalcitonin for prediction of chorioamnionitis in preterm premature
rupture of membranes, The Journal of Maternal-Fetal & Neonatal Medicine

To link to this article: http://dx.doi.org/10.3109/14767058.2015.1077224

Published online: 28 Aug 2015.

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 http://informahealthcare.com/jmf
ISSN: 1476-7058 (print), 1476-4954 (electronic)

J Matern Fetal Neonatal Med, Early Online: 16

! 2015 Taylor & Francis. DOI: 10.3109/14767058.2015.1077224

ORIGINAL ARTICLE

Procalcitonin for prediction of chorioamnionitis in preterm premature

rupture of membranes*
Loralei L. Thornburg, Ruthanne Queenan, Brianne Brandt-Griffith, and Eva K. Pressman

Department of Obstetrics & Gynecology, University of Rochester Medical Center, Rochester, NY, USA

Abstract Keywords
Objective: To assess serum procalcitonin (PCT), a marker of monocyte activity, in predicting Funisitis, infection, pregnancy, preterm
chorioamnionitis in preterm premature rupture of membranes (PPROM). delivery, preterm premature rupture of
Downloaded by [ETH Zurich] at 23:09 02 November 2015

Methods: Prospective cohort study in singleton gestation patients with PPROM between 2 2 + 0 membranes
to 3 3 + 6 weeks gestation. Two blood samples were taken admission and delivery or
diagnosis of clinical chorioamnionitis. Maternal serum PCT40.1 ng/mL was considered positive. History
Patients were divided into four groups: clinical evidence of chorioamnionitis confirmed by
placental pathology (group C + P); pathological evidence of chorioamnionitis without clinical Received 10 February 2015
signs (group P); clinical signs only (group C); and patients without clinical or pathological Revised 20 July 2015
findings (group N). Groups were compared to gestational age matched controls. Accepted 24 July 2015
Results: Forty eight patients recruited, with 28 eligible for analysis: 10 in C + P group, 10 P group, Published online 28 August 2015
3 C group, and 5 N group. None of the control or PPROM patients had positive PCT on
admission. At delivery, 3 of 10 group C + P and 4 of 10 group P had positive PCT. Maternal
serum PCT sensitivity was 50% and specificity 55.6% for diagnosis of pathological
chorioamnionitis.
Conclusions: Maternal serum PCT is not detectable in PPROM patients at admission or in
uncomplicated pregnant controls and is a poor predictor for clinical or pathological
chorioamnionitis.

Introduction
Preterm premature rupture of membranes (PPROM) compli-
cates approximately 3% of births in the USA [1]. Delivery
timing is a balance between prevention of maternal and fetal
infection and maximization of gestational age to prevent
sequel of prematurity [1]. Clinically evident infection
develops in 1525% of women antepartum [2] and 1520%
postpartum [3]. In general, patients are maintained on
hospitalized bedrest after PPROM until developing clinical
symptoms consistent with chorioamnionitis or reaching 34
35 weeks gestation, at which time they are delivered [1,4].
However, waiting for delivery until the development of severe
chorioamnionitis can result in severe maternal and fetal
inflammatory response, with intrapartum infection considered
the single greatest risk factor of the development of cerebral
palsy [5]. Given this, the ability to predict impending or pre-
clinical chorioamnionitis may allow the delivery of infants
*Prior Presentation: This original research was presented in abstract
(poster) form at Society for Maternal Fetal Medicine Annual meeting,
San Francisco, CA, 2011.
Address for correspondence: Loralei L. Thornburg, MD, Department of
Obstetrics & Gynecology, Maternal Fetal Medicine, University of
Rochester Medical Center, 601 Elmwood Avenue, Box 668, Rochester,
NY 14642, USA. Tel: +1 5852757480/+1 5852753727. Fax: +1
5852561416. E-mail: loralei_thornburg@urmc.rochester.edu
before the onset of severe sepsis and therefore prevention of
infection related neonatal sequelae.
Accurate prediction of chorioamnionitis in pregnancy can
be very difficult [4]. White blood cell counts, which can be
used as marker of early infection, are of limited utility in
pregnancy, especially after the administration of steroids for
fetal lung maturity both of which raise the white cell count
[6]. Amniotic fluid levels of IL-6, glucose and white cells can
be used to assess for intra-amniotic infection but require
amniocentesis which is invasive, carries a risk of
introducing infection, and can be difficult if there is minimal
remaining amniotic fluid [7]. Clinical signs such as mildly
elevated temperatures and fundal tenderness are nonspecific
and extremely subjective [8]. Development of a specific and
easily administered assay for detection of early bacterial
infection in PPROM would allow care providers to inter-
vene before the onset of severe sepsis and clinical
chorioamnionitis.
Procalcitonin (PCT) is a marker of monocyte activity and
an acute phase reactant, which has been used to predict
bacterial infection in those patients with congestive heart
failure where the diagnosis of pneumonia can be particularly
challenging, in order to reduce antibiotic overtreatment and
development of antibiotic resistance [9]. PCT appears to be a
relatively specific marker of mononuclear activity and
 2 L. L. Thornburg et al.
bacterial infection in the non-obstetrical patient [10]. One
previous study has shown that levels of 50.05 ng/mL are
suggestive of a low risk of bacterial infection, and elevated
levels remain a relatively specific (rule-in) tool even in
patients with chronic autoimmune processes [11]. However,
in clinical practice, typically 0.1 or  0.15 ng/mL are
considered the appropriate cutoffs for distinguishing bacterial
infection when a patient with chronic lung disease presents
with increased symptomatology [9].
PCT does not appear to be elevated in the maternal serum
in women undergoing term uncomplicated delivery, with
mean levels of 0.01 ng/mL [12]. It has been shown to be
elevated in patients with septic abortion [13], but does not
appear to be elevated in vaginal fluid in patients with
chorioamnionitis [14]. There are conflicting data on eleva-
tions in women with preterm labor who deliver at term
compared with those going onto spontaneous preterm birth
[15]. On the neonatal side, PCT does appear to be elevated in
the umbilical cord blood of preterm infants born to women
with chorioamnionitis [16], but there are also data suggesting
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that prematurity also raises neonatal PCT in the absence of
infection and needs a gestational age specific nomogram [17].
Although alone PCT in infants does not appear to be a reliable
single test for diagnosis of sepsis [18], when combined with
C-reactive protein umbilical cord levels of PCT appear to be a
marker of early onset neonatal sepsis [1921].
Therefore, if PCT elevations in maternal serum were to be
present before the onset of clinically apparent symptoms of
chorioamnionitis, this could potentially serve as trigger for
delivery before the onset of severe neonatal infection. We
therefore sought to evaluate the levels of PCT in women with
PPROM with clinical chorioamnionitis compared to those
with placental chorioamnionitis without maternal or fetal
systemic response, and unruptured, unlabored, control
patients at the same gestational age.
Methods
Patients between 2 3 + 0 and 3 3 + 6 weeks gestation with a
singleton pregnancy between August 2008 and October 2010
at the University of Rochester, Strong Memorial Hospital
were offered enrollment into the study. The study was
approved by the Institutional Review Board. Those who had
evidence on admission of concurrent bacterial infection from
any source, acute chorioamnionitis, or a cerclage in place
were excluded. Additionally, as the goal was to assess PCT
from patients with rupture of membranes before labor or the
onset of symptoms for chorioamnionitis, those patients in
active labor, or those that delivered within 24 h were also
excluded as they did not have a sample from a unlabored afebrile, and had to be without complaints of contractions,
state for analysis. PPROM was determined by the presence of
vaginal pool, fern and nitrazine testing on speculum
examination.
Maternal serum was drawn at both admission and delivery
aliquotted and frozen for batch analysis of PCT levels by a
national reference laboratory (Mayo Clinical Laboratories)
using standard illuminometer techniques after completion of
the study. All PCT testing was preformed after completion of
the study in order to blind clinical personnel and avoid any
influence on care or treatment by knowledge of PCT levels.
J Matern Fetal Neonatal Med, Early Online: 16
At delivery, all placentas were collected and assessed for the
presence of histologic chorioamnionitis and funisitis (inflam-
mation of the umbilical cord) which suggests evidence of
a fetal inflammatory response to infection [22].
Chorioamnionitis was defined on routine pathologic examin-
ation criteria with the finding of Stage 2 acute chorioam-
nionitis with neutrophils in connective tissue plane between
chorion and amnion or Stage 3 (severe) necrotizing
chorioamnionitis with necrosis, amnion sloughing, thickening
of amnion basement membrane and neutrophilic karyorrhexis,
and/or multifocal abscesses were considered as having
chorioamnionitis [23]. Because of the difficulty of making
the distinction between Stage 1 (some neutrophils in
subchorionic fibrin or interface between deciduas and chor-
ion) and normal PPROM inflammatory findings [24], these
patients were considered negative.
Chorioamnionitis or other diagnoses requiring delivery
were at the discretion of the treating team. All women
underwent the routine care for PPROM at our institution
including inpatient monitoring, latency antibiotic therapy
(intravenous ampicillin and erythromycin for 48 h followed by
oral ampicillin and azithromycin for 6 days), betamethazone
therapy for fetal lung maturity if more than 22 5/7 weeks and
less than 32 weeks gestation, nifidipine or indomethacine for
tocolysis for the first 48 h with evidence of contractions. All
patients received cervical testing for gonorrhea and chlamydia
as well as rectovaginal testing for group B strep and urine
culture. Delivery by 35 0/7 weeks is the standard at our
institution.
Clinical evidence of chorioamnionitis necessitating deliv-
ery was defined by the team rendering care. Those for whom
delivery blood was not drawn for any reason were excluded.
Women were divided into five groups:
Group C+P: Clinical chorioamnionitis confirmed by patho-
logical examination of the placenta.
Group P: No evidence of clinical chorioamnionitis, but
pathological evidence on examination of the placenta.
Group C: Clinical evidence of chorioamnionitis without
confirmation on pathological evaluation of the placenta.
Group N: No clinical or pathologic evidence of
chorioamnionitis.
Controls: Patients without infection, PPROM or preterm labor
gestational aged matched to Group C+P within 1 week of
PPROM presentation.
For each patient with the group C + P, a control patient was
enrolled and matched to the admission gestational age within
1 week (i.e. the gestational age of PPROM). The control
group was chosen from patients presenting for evaluation or
care for routine prenatal care. All control patients were
urinary symptoms, vulvo-vaginal discharge, labor or evidence
of rupture of membranes, cerclage or other bacterial infection.
For cost and logistic reasons, the study was halted when there
were 10 patients with complete data in the clinical group. It
was determined that this number would allow at 80% power to
detect an increase in positive PCT rates of more than 50%
(more than half of women testing positive) over the control
samples.
Elevations in PCT levels 40.1 ng/mL were defined as
positive. Neonatal sepsis was defined by the NICU personal.
 DOI: 10.3109/14767058.2015.1077224
Only patients diagnosed with sepsis within 48 h of delivery
were included. Sepsis criteria included  2 of the following:
respiratory signs (tachypnea, apnea or cyanosis), cardiovas-
cular signs (bradycardia or tachycardia), shock (poor perfu-
sion or low blood pressure), consciousness (irritability,
lethargy, poor feeding, hypotonia, seizures), other signs
(hepatosplenomegally, jaundice, fever).
Differences between maternal and infant groups were
evaluated at admission and delivery, with ANOVA for
evaluation of differences of continuous variable, Kruskal
Wallis for non-parametric data and chi-square/Fishers exact
for categorical variables. The rates and mean value of positive
values of PCT at admission and delivery for each group were
evaluated and compared by ANOVA and Fishers exact
testing. Additionally, associations between maternal PCT and
funisitis, as well as between PCT and subsequent diagnosis of
neonatal sepsis were evaluated by Fishers exact. Sensitivity
and specificity of PCT for prediction of chorioamnionitis,
neonatal sepsis, and funisitis was calculated.
Results
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The results of the enrollment process are described in
Figure 1 and demographics of the five groups are shown in
Table 1. A total of 86 women were screened, of them 48
eligible met inclusion criteria and consented to sudy proced-
ures. Eight patients were withdrawn two with subsequent
negative dye testing for rupture, three left against medical
advice and three elected for home management. Among the
remaining 40 women with PPROM, there were 10 women
with clinical evidence of chorioamnionitis, confirmed on
placental evaluation (group C + P: Clinical chorioamnionitis
confirmed by pathologic evaluation of the placenta). There
were 22 women with no clinical chorioamnionitis, but
pathological evidence in the placenta, and 10 of these had
available delivery blood draws (group P: Pathologic chor-
ioamnionitis group). There were three with clinical diagnosis
of chorioamnionitis, but no pathological evidence of chor-
ioamnionitis on placental evaluation (group C: Clinical
chorioamnionitis only) and five women without clinical or
Figure 1. Flowchart detailing enrollment of women with PPROM in the study.
Procalcitonin 3
pathological chorioamnionitis (group N: No evidence of
chorioamnionitis). There were no women meeting sepsis or
systemic inflammatory response (SIRS) criteria.
Outcomes for the PPROM patients are shown in Figure 2
and Table 2. There were no infants with sepsis or funisitis in
the control group. There were no positive PCT at admission
for any patient in any PPROM group, or in the controls.
Among patients with clinical and pathologic chorioamnionitis
(Group C + P) there were only three with positive PCT levels
at delivery, and among the pathologic group (Group P) there
were four. When Group C + P and Group P were combined
(all patients with positive pathological testing), there were
significantly more patients with a positive PCT (40% positive)
than in control patients (0% positive) (p 0.04) but not when
compared to PPROM patients with negative pathology (37%
positive) (p 0.8). When comparing Group C + P, Group C
and Group P (those with clinical or pathological signs) to
those with negative symptomatology (Group N) there was no
difference in rates of positive PCT (p 0.6).
Of the seven infants with sepsis including one sepsis related
death, all mothers had negative PCT testing at delivery; while
10 of the 20 infants with negative sepsis evaluations had
detectable maternal PCT. The maternal serum level of PCT
was also not predictive of fetal inflammatory response as noted
by funisitis. Among infants with funisitis, there was a positive
maternal serum PCT prior to delivery in 5 of the mothers of the
15 infants with funisitis and 5 women had a positive PCT
among the 13 infants without funisitis (p 0.8). Maternal
serum PCT was neither sensitive nor specific for pathological
chorioamnionitis (sensitivity 50%; specificity 55.6%), funisitis
(sensitivity 50%; specificity 44.4%) or infant sepsis (sensitivity
0%; specificity 61.1%). The delivering teams clinical diagno-
sis of chorioamnionitis performed equally well to PCT for
predication of pathological chorioamnionitis, with a sensitivity
of 77% and specificity of 29%.
Discussion
Our data suggest that despite PCT being a relatively specific
marker of bacterial infection and inflammation in the non-
 4 L. L. Thornburg et al. J Matern Fetal Neonatal Med, Early Online: 16

pregnant patient [10], it did not perform well for prediction of
chorioamnionitis in our population. The presence of a
negative PCT at admission as well as in non-pregnant controls
suggests that systemic inflammation was not present in these
patients at baseline. Patients with chorioamnionitis confirmed
by pathological examination of the placenta did have more
positive PCT test results than controls, but not more than
other PPROM patients. This suggests that subclinical bacter-
ial infection is present in many of these patients, and
consistent with literature suggesting that more than 30% of
PPROM patients have subclinical infection at presentation
[7]. Additionally, pathological diagnosis of chorioamnionitis
is also variable, with some studies suggesting that only 60% of
clinical chorioamnionitis can be confirmed pathologically
[24]. However, the overall sensitivity of histologic chorioam-
nionitis is high (83100%) in most studies, suggesting that
when present on pathologic evaluation of the placenta there is
indeed at least some degree of placental infection [25].
Funisitis, the presence of inflammation within the umbilical
Downloaded by [ETH Zurich] at 23:09 02 November 2015
cord, suggests a fetal response to intra-amniotic infection.
Although funisitis is seen in only 60% of chorioamnionitis,
chorioamnionitis is seen in nearly all funisitis [22].
Many patients in our study with both pathologic chorioam-
nionitis and even funisitis were asymptomatic on clinical
examination. Additionally, there was no change in maternal
PCT levels even when there was funisitis suggesting a strong
fetal response to infection. These findings suggest that for
many women there may not be a strong maternal response to
this compartmentalized infection. Our data suggest that
chorioamnionitis even with a strong fetal response does not
reliability increase maternal PCT levels.
It is possible that the physiologic changes of pregnancy
themselves may also alter the response to systemic infection
and therefore prevent the use of this marker for early detection
of bacterial infections in pregnant women. It is interesting that
all patients with chorioamnionitis confirmed by pathological
examination of the placenta had funisitis (i.e. fetal SIRS),
compared to only half of those with pathological

Table 1. Demographic and delivery characteristics of groups.

Group P:
Group C+P: pathologic Group C:
clinical chorio chorio only clinical chorio Group N:
with pathologic (no clinical only (no pathologic no clinical or Control
confirmation evidence chorio) evidence chorio) pathologic chorio group
(n 10 (n 10) (n 3) (n 5) (n 10) p values
Age (years) 28.2 5.2 34.2 5.9 30 2.9 30.2 4.9 24 4.5 0.005*
GA at enrollment (weeks) 29.5 2.6 30.4 2.9 31.8 2.1 30.1 3 29.8 2.3 0.78*
Parity (median) 1 2 0 0 1 0.49y
Race Caucasian 3/10 8/10 3/3 5/5 5/10 0.44z
Delivery mode (number Cesarean Delivery) 1/10 5/10 3/3 1/5 4/10 0.99z

Data given as mean SD; or number/total. Chorio, chorioamnionitis; GA, gestational age; PPROM, preterm premature rupture of membranes.
*ANOVA.
yKruskalWallis.
zFishers exact all PPROM versus controls (groups C + P, P, C, N versus controls).

Figure 2. Flowchart detailing PPROM patient outcomes.

 DOI: 10.3109/14767058.2015.1077224 Procalcitonin 5
Table 2. Birth outcomes for PPROM patient groups.

Group P: pathologic Group C:

Group C+P: clinical chorio only clinical chorio Group N:
chorio with pathologic (no clinical only (no pathologic no clinical or
confirmation evidence chorio) evidence chorio) pathologic chorio
(n 10) (n 10) (n 3) (n 5) p values
GA at delivery (weeks) 30.9 2.3 32.1 2.9 32.7 2 32.3 1.3 0.4*
Latency (days) median (range) 10 (123) 11 (122) 9 (210) 10 (174) 0.8y
Birth weight (g) 1581 418 1851 499 1768 183 2047 514 0.19y
Positive procalcitonin at delivery 3/10 4/10 2/3 1/5 0.99z
Mean procalcitonin (positives only) 0.45 0.6 0.26 0.12 0.26 0.06 0.25 0.87*
Infant with sepsis 5/10 2/10 0/3 0/5 0.3z
Funisitis 10/10 5/10 0/3 0/5 0.03z

Data given as mean SD; or number/total unless noted. GA, gestational age; PPROM, preterm premature rupture of membranes; PCT, procalcitonin.
*ANOVA.
yKruskalWallis.
zFishers exact (C + P versus P only due to small numbers).

chorioamnionitis without evidence of systemic maternal marker of systemic bacterial infection in a non-pregnant
response. This again suggests that systemic maternal signs population, our study failed to demonstrate a role for PCT for
Downloaded by [ETH Zurich] at 23:09 02 November 2015

of infection, like fever, are likely a late markers of infection
and do not manifest until severe infection and fetal inflam-
matory response are already present. Strengths of our study
include the prospective collection and blinded comparison of
maternal levels both at the time of PPROM as well as at
delivery, allowing for assessment of changes in inflammation
through the events of PPROM until delivery. However, our
study is small, and the numbers of women with severe sepsis
and SIRS were low, which did not allow us to evaluate PCT in
relationship to maternal sepsis. Additionally, due to the small
study size there is variation in age and ethnicity between
groups, with group P being slightly older, and Controls
slightly younger than other groups, and groups C and N being
primarily Caucasian. It is possible that age and ethnicity alter
inflammatory responses; however, the groups are too small to
allow subanalysis. We do not have placental culture results to
confirm the presence of bacterial infection or further delineate
the species of the causative organism.
Our study results are similar to other work indicating PCT
alone was a poor marker for chorioamnionitis [14,26]. This
has been demonstrated from both maternal serum and vaginal
secretions. However, there are also data suggesting a 490%
sensitivity of serum PCT for intrauterine infection [27].
Similarly, one study suggests PCT from the vaginal fluid as a
marker for neonatal infection [28]. Evaluating PCT in the
vaginal fluid is logical given that fetal inflammation and
elevations of PCT should precede maternal elevations or
symptoms. This is further supported by the findings that both
CRP and PCT are useful in the early newborn period for
sepsis determination after PPROM [29,30]. However, similar
to prenatal testing, IL-6 remained the most sensitive marker
[7,31]. There are studies that have looked at the maternal-fetal
dyad in combination by evaluating the combination of CRP,
PCT and neopterin from both the maternal serum and
umbilical cord bloods samples [29]. These suggest that the
combination of maternal and neonatal testing is highly
accurate for determination of subsequent perinatal infection
[29]. However, this combination of testing is not possible
prior to birth for determination of the presence of chor-
ioamnionitis. Overall, despite PCT being a relatively sensitive
determination of chorioamnionitis. Even among patients with
clinically symptomatic chorioamnionitis after PPROM, PCT
did not appear to be consistent elevated within the maternal
serum. Additionally, in patients with evidence of infection
with fetal inflammation (funisitis), PCT was not consistently
elevated, suggesting that this infection is too compartmenta-
lized to allow maternal serum PCT to be clinically useful.
Declaration of interest
This work was made possible a grant from the Mae Stone
Goode foundation. None of the authors have any potential
conflicts of interest with regard to this manuscript.
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