Assay of procalcitonin in umbilical cord blood: a way of reducing exposure of extremely premature newborns to antibiotic therapy

doi:10.21203/rs.3.rs-2817307/v1

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Research Article

Assay of procalcitonin in umbilical cord blood: a way of reducing exposure of extremely premature newborns to antibiotic therapy

https://doi.org/10.21203/rs.3.rs-2817307/v1

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Objective

The diagnosis of early-onset neonatal sepsis (EOS) remains difficult. The early administration of antibiotic therapy though not without risk is still the most common practice. The main aim was to study the effect of a new algorithm for EOS, which includes the level of procalcitonin (PCT) in umbilical cord blood, on the exposure to antibiotic therapy of premature neonates of gestational age below 33 weeks of gestation who show signs of a risk of EOS.

Materials and methods

This is a monocentric, observational and retrospective study “before and after” of the evaluation of daily professional practices. The study was performed over two periods from the 1st of May to the 30th of November 2015, for the group of neonates not receiving PCT “no PCT” and from the 1st of November 2016 to the 30th of May 2017 for the group of neonates receiving PCT “PCT”. The duration and dose of antibiotic therapy provided as well as the morbidity and mortality were compared.

Results

Sixty neonates were included in the “no PCT” group and 54 in the “PCT” group. Antibiotic therapy was stopped after 24 hours for 18 neonates in the “PCT” group and 4 in the “no PCT” group (p = 0.001), and after 48 hours for 26 neonates in the “PCT” group and 10 in “no PCT” group (p = 0.0009). The average number of days of antibiotics was 3 for the “no PCT” group and one for the “PCT” group.

Conclusion

The implementation of a new decision making algorithm including PCT in the umbilical cord blood of preterm neonates at less than 33 weeks of gestation significantly reduced exposure to antibiotics without modifying mortality or morbidity.

neonatal sepsis

procalcitonin

antibiotic therapy

Early onset neonatal sepsis (EOS) is the main cause of morbidity and mortality in premature newborns [1]. The increased susceptibility to infection, the birthing situation and the absence of specific signs of sepsis in premature neonates drive neonatologists to prescribe probabilistic antibiotic therapy on admission into the neonatal intensive care unit. Seventy-eight percent of newborns of less than 1500 grams and 87% of newborns of less than 1000 grams received immediate postnatal broad spectrum antibiotic therapy [2]. However, unnecessary treatment increases the risk of subsequent infection, necrotising enterocolitis, death and retinopathy [3,4]. Delays in intestinal colonization and changes in the diversity of the microbiota also occur, resulting in a long-term risk of obesity, atopy and inflammatory bowel diseases [8].

The diagnosis of EOS is still complex, particulary for premature newborns for whom the risk of perinatal infection and clinical symptoms are not very specific [9,10]. The leucocyte count, the absolute number of polynuclear neutrophils and the level of C-reactive protein (CRP) have low sensitivity [11–13]. The diagnosis of EOS depends on the identification of the microorganism from samples (blood or cerebrospinal fluid (CSF)) [14] that have low levels of bacteria, are from a small volume of the sample and from only one culture [15].

PCT is a marker of specific bacterial infection with a good negative predictive value in newborns [16,17]. The sensitivity is higher than that of CRP and the leucocyte count, such that PCT has recently become more commonly used for the diagnosis of EOS, in particular using umbilical cord blood [18–20]. The PCT level of the umbilical cord avoids the postnatal physiological increase.

The most recent recommendations of the “Société Française de Néonatologie” (SFN) and the “Société Française de Pédiatrie” (SFP) concerning newborns at term recommend starting postnatal antibiotic therapy only in the case of symptoms [21].

The main objective of our study was to examine the effect of a new algorithm for the screening for EOS that includes the assay of PCT in umbilical cord blood during early exposure to antibiotics in the postnatal period for premature newborns of gestational age less than or equal to 33 weeks of gestation and showing signs of risk factors for infection.

The secondary objective was to ensure that the new algorithm had no consequences on the mortality or morbidity of very premature newborns.

Description of the study

As of May 2016, the PCT level in umbilical cord blood was evaluated for premature newborns of less than 33 weeks of gestation presenting at the “Centre Hospitalier Universitaire de Nice” with a risk of infection.

Before this period antibiotic therapy was initiated according to the clinical situation. Discontinuation of the antibiotic therapy was envisaged after two negative CRP results were obtained within 48 hours and/or after obtaining conclusive negative cultures of samples obtained at birth. Once the assay for PCT with umbilical cord blood was set up routinely, the algorithm was modified. The decision to discontinue the treatment depended on a negative umbilical cord PCT and a negative CRP at 18 hours of life and no clinical signs of infection. The decision to start antibiotic therapy, irrespective of the period of the study, was left to the discretion of the neonatologist. Any discontinuation or absence of administration of antibiotic therapy required rigorous clinical surveillance.

The study is a monocentric, observational and retrospective “before-after” study. The data were obtained within the neonatal critical care unit of the Nice University Hospital by examining written reports and computer databases. The study was presented to the “Commission Nationale de l’Informatique et des Libertés” (CNIL). Written or oral parental consent was obtained. The « Comité d’Ethique de la Recherche (CER) de l’Université Côte d’Azur » gave agreement for the study under number 2022-004. As the study was retrospective and observational, and according to French regulations on research, formal ethics committee approval was not required.

Inclusion and exclusion criteria

a. Inclusion criteria

Premature newborns of less than 33 weeks of amenorrhea showing signs or several risk factors for EOS born between the 1st of May and the 30th of November 2015 were included in the group for whom no umbilical cord blood PCT assay was performed, while those born between the 1st of November 2016 and the 30th of May 2017 were included in the group for whom the umbilical cord blood PCT level was assayed. An interval of one year was considered necessary for the setup by all the members of the team of the delivery room and neonatal department of the new algorithm integrating the assay of umbilical cord PCT.

The risk factors were defined by the “Agence Nationale d’Accréditation et d’Évaluation en Santé” (ANAES) in September 2002 [22].

b. Exclusion criteria

Newborns not showing signs of infection, born outside the type III perinatal center, those with triple or more pregnancies, and those with antenatal malformations or chromosomal anomalies were excluded. The PCT assay in cord blood was performed at birth or during the first hours of life using an inserted umbilical catheter sample or a peripheral sample (up to four hours) [23].

Population

a. “no PCT” group

Very premature newborns born between the 1st of May and the 30th of November 2015 with one or several risk factors for EOS were selected. Samples were taken for culture and for two assays of CRP: one at 12 hours and one at 48 hours of life. Intravenous antibiotic therapy was initiated immediately postnatal according to the paediatrician’s discretion (based on clinico-bacteriology). Treatment was discontinued when two negative results for CRP were obtained, i.e. a value below 10 mg/l and if the blood culture remained negative at 48 hours after sampling.

b. “PCT” group

Very premature newborns born between the 1st of November 2016 and the 30th of May 2017 were included after the set up of the algorithm integrating the PCT assay of samples from umbilical cord blood or from an inserted venous umbilical catheter. Intravenous antibiotic therapy was initiated immediately postnatal according to the discretion of the paediatrician. Treatment was discontinued if the PCT results obtained from the umbilical cord blood were negative i.e. below 0.6 ng/ml, and the CRP level at 18 hours of life was below 10 mg/l.

4. Collection of data

The data included the number of newborns exposed to antibiotic therapy immediately postnatal, the different types of antibiotics used, the calculated dose expressed as a function of the weight of the newborn, the number of doses of antibiotic administered and the number of days of antibiotic therapy.

The collected clinical data of the populations are given in Table 1.

Progression to death and the cause were also noted. If this occurred during the first week of life, it was defined as early death.

CRP was assayed with samples obtained at 12 and 48 hours of life for the “no PCT” group. The level of PCT in umbilical cord blood as well as that of CRP at 18 hours of life were determined for the “PCT” group. Definitive infection was defined as a positive sample (blood culture). Maternal samples for bacteriology were also collected.

5. Statistical analyses

A descriptive analysis of the characteristics of the exposed population was performed, expressed as frequencies (percentages) for qualitative variables and averages (minimal-maximal values) for quantitative variables. Fisher’s exact test was used to compare the characteristics of the population, Student’s t test was used for quantitative variables, and the non-parametric Mann-Whitney test was used for small-sized samples. The threshold of significance p was set at 5%.

Statistical analysis was performed with Easy Med Stat (Asnières-sur-Seine, France) software.

Description of the population

Sixty newborns were included in the “no PCT” group and 54 in the “PCT” group after exclusion of four newborns for whom the assay for PCT could not be done (Figure 1).

	no PCT (n=60)	PCT (n=54)	p-value
Weeks of gestation, median (min-max)	29.9 (25 - 32.7)	29.6 (24.1 - 32.8)	0.89
Number of newborns according to the gestational age (weeks of gestation) - 24– 27, n (%) - 28– 32, n (%)	16 (26.7) 44 (73.3)	14 (25.9) 40 (74)	0.57 0.53
Weight at birth (grams), median (min-max)	1407.5 (700 -2250)	1445 (580 - 2300)	0.79
Sex ratio M/F	1.31	2.17	0.25
Complete antenatal corticosteroid therapy, n (%)	42 (70)	37 (68.5)	1
Administration of magnesium sulphate, n (%)	40 (66.7)	35 (64.8)	0.85
Amniotic fluid not transparent or coloured or meconial, n (%)	3 (5.1)	2 (3.7)	1
Premature rupture of membranes, n (%)	34 (56.7)	23 (42.6)	0.19
Risk of premature birth, n (%)	48 (80)	40 (74.1)	0.50
Prolonged rupture of membranes (≥ 12h), n (%)	33 (55)	22 (40.7)	0.14
Suspicion of chorioamniotis, n (%)	15 (25)	11 (20.4)	0.65
Anomalous fœtal heart rate, n (%)	6 (10)	10 (18.5)	0.28
Streptocoque B positive vaginal sample, n (%)	7 (11.7)	6 (11.1)	1
Cesarian delivery, n (%)	31 (51.7)	28 (52.8)	1
Exogenous surfactant therapy, n (%)	24 (40)	16 (29.6)	0.32
Positive PCT (> 0.6 ng/mL), n (%)	/	14 (25.9)
CRP > 10 mg/L at H12 (“no PCT” group) or H18 of life (“PCT” group), n (%)	6 (10)	11 (20.8)	0.12
Confirmed infection (positive blood culture), n (%)	3 (5.3)	1 (2.3)	0.63

Table 1: Characteristics of the populations of the “no PCT” and “PCT” groups

Exposure toantibiotic therapy

Forty-eight newborns (80%) in the “no PCT” group received immediate postnatal antibiotic therapy, 93.8% of whom were in the 24-27 weeks of gestation subgroup and 75% in the 28-32 weeks of gestation subgroup. Forty-six newborns (85.2%) in the “PCT” group received antibiotic therapy immediately postnatal. All very premature newborns in this group and 80% of severely premature newborns received antibiotic therapy.

For the population exposed to antibiotics and those who did not die at an early stage, antibiotic therapy was discontinued after 24 hours for 18 newborns in the “PCT” (41.9%) group versus four in the “no PCT” (9.3%) (p=0.001) group and after 48 hours for 26 newborns in the “PCT” group versus 10 (23%) in the “no PCT” (p=0.0009) (table2).

no PCT (n=60)

PCT (n=54)

p-value

Antibiotherapy, n (%)

- 24 – 27 weeks, n (%)

- 28 – 32 weeks, n (%)

48 (80)

15 (93.8)

33 (75)

46 (85.2)

14 (100)

32 (80)

0.62

0.6

Monotherapy

Bitherapy

Tritherapy

1 (1.7)

38 (63.3)

9 (15)

1 (1.9)

37 (68.5)

8 (14.8)

0.70

Cephalosporine, n (%)

- 24 – 27 weeks, n (%)

- 28 – 32 weeks, n (%)

48 (80)

15 (93.8)

33 (75)

44 (81.5)

14 (100)

30 (75)

Gentamicine, n (%)

- 24 – 27 weeks, n (%)

- 28 – 32 weeks, n (%)

47 (78.3)

14 (87.5)

33 (75)

45 (83.3)

14 (100)

31 (77.5)

0.63

0.48

0.8

Amoxicilline, n (%)

- 24 – 27 weeks, n (%)

- 28 – 32 weeks, n (%)

9 (15)

2 (12.5)

7 (15.9)

9 (16.7)

4.(28.6)

5.(12.5)

0.38

0.76

Meropenem, n (%)

- 24 – 27 weeks, n (%)

- 28 – 32 weeks, n (%)

2 (3.7)

2 (5)

0.22

Table 2: Description of the antibiotic therapy administered immediately postnatal

for the “no PCT” and “PCT” groups

3. Exposure to third-generation cephalosporines

Exposure to third-generation cephalosporines, the main antibiotic therapy prescribed to our population, is given in Table 3 for each group.

Initially, the analysis was performed for the total population. The median number of doses received by the “no PCT” group was 12 compared to four for the “PCT” (p = 0.04) group. The median number of days of antibiotic therapy was three in the “no PCT” group and one in the “PCT” group. The accumulated dose in milligrams per weight of the newborn was 603 mg/kg for the “no PCT” group versus 198 mg/kg in the “PCT” (p = 0.003) group. There was a general decrease in exposure to antibiotic therapy in our population.

No PCT survivals (n=54)

PCT survivals

(n=51)

p-value

Medium number of doses of cephalosporine, (interquartile)

- 24 - 27 weeks

- 28 - 33 weeks

12 (4 - 16)

16 (12 - 16)

10 (1 - 16)

4 (3 - 16)

9 (8 - 18)

4 (3 - 7)

0.03

0.23

0.05

Medium cumulated cephalosporine dose in mg/kg (interquartile)

- 24 - 27 weeks

- 28 - 33 weeks

612 (200 - 790)

780 (651 - 800)

488 (50 - 734)

197 (100 - 400)

300 (210 - 650)

152 (75 - 330)

0.002

0.02

Medium number of days of cephalosporine (interquartile)

- 24 - 27 weeks

- 28 - 33 weeks

3 (1 – 4)

4 (3.5 – 4 )

2.5 (0.25 - 4)

1 (0.75 - 3.15)

2.25 (2 - 4.5)

1 (0.75 - 1.75)

0.02

0.13

0.04

Table 3 : Duration of exposure and cumulative dose of third-generation cephalosporine for survivors of the “no PCT” and “PCT” groups.

4. Mortality

Ten deaths, i.e. 16.7% of newborns occurred in the “no PCT” group, one of which was due to infection, versus five in the “PCT” group, i.e. 9.3% (p = 0.27), one of which was due to infection. Nine deaths occurred within the first seven days of life (six in the “no PCT” and three in the “PCT” group).

5. Morbidity

The details concerning morbidity and progression of the newborns in each group are illustrated in table 4.

The emergence of complications such as bronchopulmonary dysplasia, enteropathies, retinopathies of the premature and periventricular leukomalacia, were comparable in the two groups. Infectious complications such as late onset sepsis were similar in the two groups (p=1). The average duration of a central catheter was similar (p = 0.7). There was a significant difference in removing umbilical venous catheters (p = 0.001) at an earlier stage in the “no PCT” group to be replaced by peripherally inserted central catheters (PICCs). No difference concerning the PICCs was noted (p=0.11). There was also no difference in the duration of enteral or parenteral nutritions (p = 0.71 and p = 0.73). The age at discharge, expressed as the corrected age, was 37.8 weeks of gestation for the “no PCT” group and 37.4 weeks of gestation for the “PCT” (p = 0.07) group.

	no PCT Survivors (n=54)	PCT Survivors (n=51)	p-values
Late onset sepsis, n (%)	2 (3.7)	1 (2)	1
Enteropathies, n (%)	4 (7.5)	4 (7.8)	1
Bronchopulmonary dysplasia, n (%)	13 (24)	15 (29.4)	0.66
Premature retinopathy, n (%)	1 (1.9)	0	1
Periventriculaire leucomalacia, n (%)	2 (3.7)	3 (5.88)	0.7
Duration of hospitalisation, median in days (min-max)	54 (10 - 220)	54.5 (15 - 123)	0.6
Duration of the central catheter, median in days (min-max) - umbilical venous catheter - PICCs	8.5 (0 - 29) 2.5 (0 - 5) 5.5 (0 - 26)	6 (0 - 30) 5 (0 - 7) 3 (0 - 26)	0.7 0.001 0.11
Enteral nutrition, median in days (min-max)	35.5 (12 - 209)	38 (8 - 108)	0.71
Parenterale nutrition, median in days (min-max)	5 (0 - 26)	6 (0 - 30)	0.73
Corrected age at discharge, median WE (min-max)	38.1 (35.4 - 41.2)	37.4 (35.6 - 43.3)	0.25

Table 4: Morbidity and progression of the survivors in the “no PCT” and “PCT” groups

The implementation of an algorithm integrating the assay of PCT from samples of umbilical cord blood for the care of very premature newborns allowed a significant decrease in exposure to antibiotic therapy of this population with early discontinuation of a antibiotic therapy before 24 hours of life in the “PCT” group. These results are in agreement with those of a multicentric study by Stocker et al. that included 1378 newborns with a gestational age higher than 34 weeks [24]. A study by Huetz et al. in newborns of more than 36 weeks born in three French maternities reported a decrease in exposure to antibiotics by 1.8% after using an algorithm that integrated the assay of PCT in cord blood [25]. These encouraging results can be explained by a protocol effect that induced more rigorous care of newborns presenting with a risk of EOS. After a subgroup analysis according to gestational age our study found a less pronounced decrease in exposure to antibiotic therapy for extremely premature newborns, including those of a gestational age less than 28 weeks. Antibiotic therapy was discontinued after 24 hours of treatment for only 41.9% of very premature newborns in the “PCT” group despite the lack of positivity of a central sample. The discordance between the prescription of antibiotic therapy and negative biological markers may call into question the practice concerning the use of antibiotic therapy. Ting et al. reported that 41% of newborns of less than 1500 grams received antibiotic therapy for more than three days without a positive bacteriological sample [4]. Despite the absence of an argument in favour of EOS, the extreme prematurity and non-specific clinic-biological signs of a bacterial infection probably lead to reticence in discontinuing antibiotic therapy in the subgroup of more immature newborns.

Despite the changes in our practices with respect to the duration of antibiotic therapy, the morbidity-mortality remained unchanged. The majority of deaths of babies in the two groups occurred early on within the first seven days of life. The present study did not find evidence of a significant difference between the “no PCT” and “PCT” groups concerning morbidity, which is in contrast to reports in the literature. This may be explained by the small number of newborns in the two populations. Cantey et al. reported that each additional day of antibiotic therapy was associated with a 24% increase in the risk of developing late-onset bacteremia, ulceronecrotic enterocolitis or death in a population of 374 newborns with a gestational age of less than or equal to 32 weeks and with a weight of less than or equal to 1500 grams [26]. Ting et al. reported an association of prolonged exposure to antibiotic therapy during a stay in an intensive care unit for a similar population with an increased risk of mortality and morbidity [27,28].

Birth within the context of chorioamniotitis is usually justification for continuing antibiotic therapy for premature newborns. Twenty percent of the newborns in our “PCT” group were born in the context of chorioamniotitis, which was comparable to that of the “no PCT” (25%) group. Early discontinuation of antibiotic therapy was possible for newborns in the “PCT” group without unfavorable progression and without delay in diagnosis of bacteremia. Several studies in the literature support our results. Randis et al. reported a very low frequency of EOS (0.7%) for newborns exposed to chorioamniotitis [29]. The scientists of the Kaiser Permanente Medical Center in the United States developed a tool to calculate the risk of developing EOS by using factors of risk of maternal infection as well as the clinical data of the newborn at birth and during the first 24 hours of life [30].

A retrospective study by Carola et al. including 1159 newborns of gestational age greater than or equal to 35 weeks and exposed to chorioamniotitis reported a two-thirds decrease in the exposure to probabilistic antibiotic therapy after using this approach [31].

When interpreting PCT, it is necessary to remain cautious. It has excellent specificity and a good negative predictive value to detect non-infected newborns and limits the prescription of antibiotic therapy. In contrast, the sensitivity and the positive predictive value seem to be less powerful, which does not allow its use as a positive diagnostic tool [19,30]. Two biomarkers of inflammation appear to be of interest for the diagnosis of EOS: interleukin-6 (IL-6) and interleukin-8 (IL-8).

Hendricks Munoz et al. reported that IL-6 had a higher sensitivity than CRP (90%) and a negative predictive value of 91% during the early phase of neonatal infection. A similar interesting result was found for IL-8, with a sensitivity of 90% and a specificity between 75 and 100% [32]. Integration into an algorithm for the diagnosis of EOS may be useful, particularly in association with the PCT assay in cord blood [33]. In addition, these interleukins seem to hold a high negative predictive value that allows more robust diagnostic exclusion [34]. These biomarkers are still being studied and are not used in daily practice.

Our study has its limits. First, it is a retrospective study that had difficulties in collecting the information, particularly concerning some missing or incomplete data. In contrast to some published studies, we did not find any change in morbidity due to the small number of patients. It would be interesting to perform a multi-centric prospective randomised study using a protocol recommending antibiotic therapy in the case of a positive PCT and/or clinical signs of EOS with the aim of decreasing exposure to antibiotics and reducing the deleterious effects.

Our study showed that the implementation of a new decisional algorithm including the assay of PCT with samples of umbilical cord blood from premature newborns of less than 33 weeks of gestation significantly reduced exposure to antibiotics without modifying either mortality or morbidity. Modification to the prescription and duration of antibiotic therapy during the postnatal period is possible even for extremely premature patients with a risk of EOS. This study obtained results in favour of the integration of cord PCT into screening for EOS in this population. It provides paediatricians with an additional argument for decision making with regard to early discontinuation of antibiotic therapy for premature babies.

ANAES : Agence Nationale d’Accréditation et d’Evaluation en Santé

CER : Comité d’Ethique et de la Recherche

CNIL : Commision Nationale de l’Informatioque et des Libertés

CRP : C-reactive protein

CSF : cerebrospinal fluid

EOS : early onset sepsis

PCT : procalcitonine

PICC : peripherally inserted central catheter

SFN : Société Française de Néonatologie

SFP : Société Française de Pédiatrie

Ethics approval: Approval was obtained from the ethics committee of Unisversity of Nice under number 2022-004.

Consent to participate: Parents were informed of the progress of the study.

Competing interest: The authors declare no competing interests.

Funding declaration : no funding was needed.

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Assay of procalcitonin in umbilical cord blood: a way of reducing exposure of extremely premature newborns to antibiotic therapy

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Abstract

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I. Introduction

II. Materials and Methods

III. Results

Description of the population

3. Exposure to third-generation cephalosporines

4. Mortality

5. Morbidity

IV. Discussion

V. Conclusion

Abbreviations

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References

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