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Articles |
Divisions of
1
Neonatology and
2
Obstetrics, S. Camillo Hospital, 00152 Rome, Italy.
3
Institute of Experimental Medicine, National Research
Council, 00161 Rome, Italy.
a Address correspondence to this author at: Institute of Pediatrics, La Sapienza University of Rome, Viale R. Elena, 324 00161 Rome, Italy. Fax 39-06-49-218-480; e-mail Claudio.Chiesa{at}Uniroma1.it
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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24 h of age, and many questions
remain regarding maternal and perinatal factors that may influence the
normal PCT kinetics during the immediate postnatal period. Methods: We prospectively investigated the association between the serum PCT values obtained from 121 mothers at delivery and serum PCT in their healthy, term offspring at birth as well as at 24 and 48 h of age. We also analyzed whether obstetric and perinatal factors would alter maternal and neonatal PCT response.
Results: PCT concentrations in the babies at birth were
significantly higher than in the mothers (P
<0.0001), with even larger differences at 24 and 48 h of age.
None of the variables identified from maternal and perinatal histories
had a significant effect on maternal PCT response. In the healthy
neonate, the variables that significantly affected the concentration of
PCT at birth were the mothers’ PCT (P <0.01), maternal
group B streptococcus colonization (P <0.05), and
rupture of membranes 
18 h (P <0.01). The coefficient
of linear correlation between the mother’s PCT concentration and that
of the baby at birth was 0.32 (P <0.01). The only
variable that significantly altered the PCT concentration at both 24
(P <0.01) and 48 (P <0.01) h of age was
rupture of membranes 18 h. Nonetheless, the PCT response observed
during the 48-h period after birth among healthy babies born to mothers
with risk factors for infection was well below that reported previously
among age-matched neonates with sepsis.
Conclusions: The postnatal increase of PCT observed in the healthy neonate with peak values at 24 h of age most likely represents endogenous synthesis. In estimating the sensitivities and specificities of PCT for diagnosis of sepsis throughout the initial 48 h of life, it is important to consider the normal PCT kinetics and the pattern(s) of PCT response in the healthy neonate.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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12
kDa) of PCT (15), it is not surprising that transplacental
passage has been suggested as a possible source of the postnatal
increase of PCT (16), although we are not aware of any study
dealing specifically with this issue. The main objective of the present study was to investigate the association, if any, between serum PCT concentrations in mothers at delivery and serum PCT in their healthy babies at birth as well as at 24 and 48 h of age. The three fixed neonatal ages 0, 24, and 48 h could provide this information given that the half-life of PCT is 22–29 h (17). Also, we investigated whether maternal and perinatal factors could confound these associations.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2500 g) and with normal results
on physical examination at birth implying, therefore, no need of
empiric management. The mother-infant pair was included in the present
study if all the following criteria were met: (a) a blood
sample was collected at the time of delivery from the mother;
(b) a blood sample was obtained at birth, at 24 h, and
at 48 h after birth from each infant; and (c) the
neonate had a continuous, uncomplicated hospital stay until discharge
on day 3 after vaginal or day 4 after cesarean delivery and also normal
assessments at the 2- and 4-week follow-up visits. We excluded
parturients with: (a) multiple pre-existent or
pregnancy-related noninfectious complications; or (b)
clinically evident intraamniotic infection [defined as intrapartum
fever (38 °C) accompanied by at least two of the following:
tachycardia (maternal, 100 beats/min; fetal, 160 beats/min),
uterine tenderness, purulent amniotic fluid, or increased peripheral
white blood cell count (>15 000/mm3)].
All antepartum and intrapartum data were collected prospectively and
included maternal age, pre-existent or pregnancy-related diseases, mode
of delivery, use of anesthesia, duration of active labor
(18), interval between rupture of membranes and delivery,
maternal group B streptococcus (GBS) colonization, intrapartum
antimicrobial administration, and abnormalities in intrapartum fetal
heart monitoring. The institutional policy was to give term women with
rupture of membranes 18 h intrapartum penicillin or broad-spectrum
antibiotics, if results of GBS cultures were not known at the time of
labor (19). Late prenatal cultures (35–37 weeks) including
vaginal specimens for GBS culture (20) were considered a
part of good antenatal care. For those with poor or no antenatal care,
intrapartum vaginal specimens were obtained for culture. For term women
with rupture of membranes <18 h, the institutional policy was to treat
those patients with late prenatal cultures positive for GBS. Neonatal
data collected included gestational age, birth weight, gender, and
Apgar scores at 1 and 5 min.
pct determination
Blood for PCT determination was centrifuged within 30 min of
collection, and the serum was stored at -70 °C until analysis. PCT
was first determined by the LUMItest® PCT method (BRAHMS Diagnostica)
as described in detail elsewhere (9). According to the
manufacturer, this immunoluminometric assay has a detection limit of
0.1 µg/L. Interassay and intraassay variations at both low and high
concentrations were <8% and 7%, respectively. Samples with PCT
concentrations below the detection limit of the LUMItest PCT assay were
subsequently tested with the LUMItest ProCa-S assay (BRAHMS
Diagnostica), which has been developed in a prototype format only. This
immunoluminometric test is more sensitive (limit of detection, 0.005
µg/L) than the LUMItest PCT assay. Duplicate determinations of PCT
were performed for each serum sample, without knowledge of the maternal
and neonatal clinical characteristics.
statistical analysis
The PCT values (Fig. 1
) were distributed with a long tail to the right (positive
skew), but the logarithms of the values of PCT were approximately
normally distributed. Thus, the data were analyzed after a logarithmic
transformation, and the results were expressed as geometric means with
95% confidence intervals (CIs). The geometric mean concentration of
PCT in the mothers was compared with that of the babies at birth and at
24 and 48 h of age by applying a matched-pairs t-test
to the logarithms of the PCT values, from which the mean percentage
difference and its CI can be derived. The nonparametric Wilcoxon test
was also applied to confirm the result of the t-test.
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The association between the serum PCT values obtained from mothers and serum PCT in their healthy offspring at birth and at ages 24 and 48 h were investigated by multiple regression of the log PCT of the baby on the log PCT of the mother, whereas dummy variables were used to take account of the possible confounding effects of: gestational diabetes, pregnancy-induced hypertension, intrapartum fetal distress, maternal GBS colonization, type of delivery (spontaneous vaginal, elective cesarean section, emergency cesarean section, and induced delivery), duration of active labor, interval (h) between rupture of the membranes and delivery, intrapartum antimicrobial administration, and use of epidural or general anesthesia. All statistical tests were considered significant if P <0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The characteristics of mothers and their healthy infants are summarized
in Table 1
. Table 2
shows the geometric mean PCT concentration in delivering
mothers and in their healthy newborns at each postnatal age. PCT
concentrations in the babies at birth were significantly higher than in
the mothers (P <0.0001 by t-test; P
<0.0001 by Wilcoxon test), with even larger differences at 24 and
48 h of life. At 24 and 48 h after birth, the geometric mean
concentration of PCT in the babies was 220 and 76 times higher than the
concentration observed in the delivering mothers, respectively (Table 2
).
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By multiple regression analysis, none of the variables identified from
maternal and perinatal history had a significant effect on PCT response
in parturient mothers. Multiple regression analysis of PCT values
observed in the babies at delivery on the mother’s PCT and the
confounders identified from antepartum and intrapartum data (see
Statistical Analysis) revealed that the variables that
significantly affected PCT concentrations in the babies at birth were
the PCT concentrations in the delivering mothers, maternal GBS
colonization, and rupture of membranes for 18 h or longer. The
crude product–moment coefficient of linear correlation, r,
between the mother’s PCT values and those of the baby at birth was
0.32 (P <0.01), and the Spearman rank correlation was 0.38.
The baby’s PCT concentration at birth was increased by a factor of
1.45 (95% CI, 1.05–1.99; P <0.05) if the mother had GBS
colonization and 1.50 (95% CI, 1.12–2.0; P <0.01) if the
time from rupture of the membranes was 18 h. In contrast, the
multiple regression showed that the mothers’ PCT had no significant
association with the baby’s concentration at both 24
(r = 0.021; P = 0.41) and 48
(r = 0.025; P = 0.40) h of age.
Likewise, the rank correlation coefficients were 0.023 and 0.004,
respectively. Indeed, at both postnatal hours 24 and 48, the only
variable found to be associated with the babies’ values of PCT was the
time since rupture of the membranes. If this time was 18 h, the
concentration of PCT was increased by a factor of 2.84 (95% CI,
1.50–5.48; P <0.01) at 24 h of life and by 2.47 (95%
CI, 1.29–4.73; P <0.01) at 48 h. In fact, for babies
born to mothers with rupture of the membranes 18 h, the geometric
mean PCT values were 5.96 µg/L (95% CI, 2.50–14.18) at 24 h of
age and 1.82 µg/L (95% CI, 0.73–4.53) at 48 h. In contrast, if
the time since rupture of the membranes was <18 h, the geometric mean
values of PCT were 2.16 µg/L (95% CI, 1.74–2.69) at 24 h of
age and 0.74 µg/L (95% CI, 0.61–0.92) at 48 h.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Most previous studies did not assess the postnatal course of PCT (7)(8)(10)(11)(12)(13)(14) in the healthy term baby, neither did they provide information as to whether maternal and perinatal factors may affect the interpretation of what constitutes the abnormal (and as importantly the normal) postnatal PCT value. Consequently, the reported "normal" ranges have been relatively broad and have made uncertain the use of PCT as a discriminatory tool for differentiating infected from uninfected neonates during the immediate postnatal period. The present study, which is the first to analyze the PCT response of a cohort of healthy, full-term neonates born under different clinical scenarios, shows that pathologic prenatal noninfectious conditions, such as gestational diabetes or pregnancy-induced hypertension, do not affect the babies’ PCT concentration during the 48-h period after birth. Additionally, perinatal stress, surgical trauma, and anesthesia did not significantly alter PCT response in such neonatal population. However, the novel finding observed in the current investigation is that neonates born to intrapartum-treated mothers with isolated risk factors for infection, although totally asymptomatic, had significantly increased PCT concentrations when compared with those who were born to mothers who were either risk factor negative or who had only noninfectious clinical conditions.
The exact site of PCT release during sepsis is unclear. Recently,
Brunkhorst et al. (23) mentioned that one possible site of
PCT production during inflammation is peripheral blood mononuclear
cells, whereas Nijsten et al. (24) suggested that the liver
is a major source of PCT production. There are few data to support
either possibility. Likewise, the mechanism of PCT release remains
uncertain. Dandona et al. (25) first showed that when
endotoxin was administered to apparently healthy human
volunteers, the expected release of tumor necrosis factor (TNF)-
and
interleukin (IL)-6 was followed by an increase and prolonged peak of
concentrations of circulating PCT. A tenable interpretation was that
endotoxin might release PCT directly, without cytokine mediation. More
recently however, Nijsten et al. (24) showed that, directly
or indirectly, IL-6 and TNF- release PCT. Whatever the site(s) and
mechanism(s) of PCT release, the amount of PCT produced and the degree
of increase in serum concentrations have been correlated with the
extent of the inflammatory reaction to infection
(1)(26).
Al-Nawas et al. (2) reported higher PCT concentrations in
adult patients with clinically documented infection than in those
merely fulfilling the criteria of systemic inflammatory response
syndrome. Similar observations have been reported recently by
Martin-Denavit et al. (27) in neonates with unspecified
gestational age. These authors showed that, among neonates born to
intrapartum-treated mothers who presented a risk factor for infection
(including premature rupture of membranes or maternal GBS
colonization), mean PCT values at both 24 and 72 h of life were
much higher in those with clinical signs of infection than in the ones
without. In the current study, the magnitude of PCT response observed
during the first 48 h of life among healthy term babies born to
mothers with either rupture of membranes 18 h or GBS colonization
remained modest, being well below the concentrations reached in
symptomatic neonates with early-onset (i.e., within the first 48 h
of life) infection (9). Nonetheless, it would be reasonable
to postulate that the increased PCT concentrations in such neonates
specifically represent a host inflammatory response to the infectious
stimuli, and their presence may then remain a potential marker of
infection. We cannot rule out subclinical infection in some of these
infants born to intrapartum-treated mothers; however, none of them
became symptomatic or received antibiotic treatment. Serum PCT values
obtained in this longitudinal study from healthy neonates born to
mothers without infectious risk factors are comparable with those
reported in a previous cross-sectional study of the whole population of
healthy neonates born after uncomplicated pregnancy and labor
(9). The pattern(s) of PCT response and temporal course of
the increase in PCT concentrations in the healthy neonate should be
taken into account to optimize the use of PCT in the diagnosis of
early-onset neonatal sepsis.
Mothers delivering at term had circulating PCT concentrations similar
to those observed in the apparently healthy adult population
(1)(3). The maternal concentration of PCT did
not appear to be affected by pregnancy-related disorders, mode of
delivery, use and type of anesthesia, duration of active labor, and
stressful labor. Importantly, although maternal GBS colonization per se
or rupture of membranes 18 h per se appeared to be associated with a
significant increase in the neonatal PCT concentration at or after
birth, neither risk factor was associated with a significant increase
in maternal PCT concentration at the time of delivery. Possibly the
fetal compartment responds differently than the maternal compartment in
the presence of such infectious risk factors. Future studies would be
useful to clarify the role of maternal serum PCT in preterm and term
labor under conditions of clinically overt or subclinical
chorioamnionitis.
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Footnotes |
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1 Nonstandard abbreviations: PCT, procalcitonin; GBS, group B streptococcus; CI, confidence interval; TNF-, tumor necrosis factor-; and IL-6, interleukin-6. 
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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for differentiation of bacterial vs. viral infections. Pediatr Infect Dis J 1999;18:875-881.[Web of Science][Medline]
[Order article via Infotrieve]
The following articles in journals at HighWire Press have cited this article:
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  D Turner, C Hammerman, B Rudensky, Y Schlesinger, C Goia, and M S Schimmel Procalcitonin in preterm infants during the first few days of life: introducing an age related nomogram Arch. Dis. Child. Fetal Neonatal Ed., July 1, 2006; 91(4): F283 - F286. [Abstract] [Full Text] [PDF]
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 S. D. Carrigan, G. Scott, and M. Tabrizian Toward Resolving the Challenges of Sepsis Diagnosis Clin. Chem., August 1, 2004; 50(8): 1301 - 1314. [Abstract] [Full Text] [PDF]
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C. Chiesa, A. Panero, J. F. Osborn, A. F. Simonetti, and L. Pacifico Diagnosis of Neonatal Sepsis: A Clinical and Laboratory Challenge Clin. Chem., February 1, 2004; 50(2): 279 - 287. [Full Text] [PDF]
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, 10 subjects; •, 1 subject.