Coronavirus disease (COVID-19) can present with various symptoms and can involve multiple organs. Women infected during pregnancy have a higher incidence of obstetrical complications and infants born to “positive” mothers may get the infection with different manifestations. Presepsin seems to be a promising sepsis biomarker in adults and neonates. The aim of this study was to assess if presepsin levels in neonatal cord blood could be influenced by maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
A total of 119 neonates born from women with a confirmed diagnosis of SARS-CoV-2 infection were enrolled and presepsin levels of cord blood samples were collected. All neonates were tested for SARS-CoV-2 infection at birth and after 48–72 h.
The median presepsin value in umbilical cord blood samples collected after birth was 455 pg/mL. Presepsin levels were not influenced by maternal symptoms of COVID-19, weight for gestational age, or delivery mode, and did not significantly differ between infants with and without adverse neonatal outcomes. Infants hospitalized for more than 5 days had a significantly higher presepsin level at birth rather than those discharged up to 4 days of life. Three infants with positive nasopharyngeal swab at birth had higher Presepsin levels than two infants tested positive at 48 h.
This is the first study reporting cord presepsin levels in term and preterm infants born to mothers with COVID-19, that appeared to be not influenced by maternal clinical presentation. However, further studies are needed to explain the mechanisms of P-SEP increase in neonates exposed to perinatal maternal SARS-CoV-2 infection or with an indeterminate/possible SARS-CoV-2 infection in the same neonates.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the global ongoing coronavirus disease 2019 (COVID-19) pandemic. COVID-19 may affect different organs and systems, but it mostly affects the respiratory system, where it can induce symptoms ranging from normal cold to severe respiratory distress. The condition is more severe and lethal in older adults and especially in those who have pre-existing comorbidities .
Pregnancy is a particular condition, in which women undergo physiological and immunological changes in order for their immune systems to be able to tolerate pregnancy . Furthermore, viral infections, such as SARS-CoV-2, could influence innate immune responses during pregnancy . Given the higher incidence of obstetrical complications in pregnant women infected with SARS-CoV-2 , neonates born to infected mothers with a more severe clinical course may have a worse outcome, mainly due to neonatal morbidity and mortality associated with prematurity . Moreover, neonates infected with SARS-CoV-2 can range from mild to severe manifestations, up to multisystem inflammatory syndrome (MIS-C) .
Presepsin (P-SEP) is a small soluble regulatory peptide generated from a soluble cluster of differentiation 14 (CD14), that modulates immune responses through the interaction with T and B cells . The principal ligand of CD14 is bacterial lipopolysaccharide (LPS), and this explains why P-SEP seems to be accurate in discriminating bacterial sepsis, whereas it does not show the same accuracy in the diagnosis of viral forms from current literature. The use of P-SEP as a novel biomarker for early diagnosis, risk stratification, and prognosis prediction appeared promising not only in septic adult patients , but also in neonates , , .
The aim of this work was to assess if P-SEP values in cord blood of neonates born to positive COVID-19 mothers were influenced by maternal viral infection.
Materials and methods
In this prospective study, we initially considered for enrolment all neonates delivered by women with a confirmed diagnosis of SARS-CoV-2 infection by a real-time Polymerase Chain Reaction (RT-PCR) test performed on nasopharyngeal swab at the time of delivery, assessed at Fondazione Policlinico Universitario “A. Gemelli” IRCCS (Rome, Italy) from March 1, 2020 to November 30, 2021. We finally enrolled in the study all neonates (born to RT-PCR positive mothers) for whom a blood sample was collected from the clamped umbilical cord after the delivery and P-SEP values were assessed in this sample.
Exclusion criteria were: (1) preterm birth before 30 weeks of gestational age; (2) perinatal asphyxia; (3) absence of written informed consent to participate from a legal guardian.
All neonates underwent Cobas® 6800 SARS-CoV-2 rt-PCR (Roche, USA), intend for the qualitative detection of nucleic acids, on nasopharyngeal swab at birth and between 48 and 72 h of life.
We obtained clinical data of mothers and neonates from medical electronic records, collecting variables such as gestational age (GA, weeks), birthweight (grams), incidence of weight appropriate for GA (AGA, 10°–90° centile) or small for GA (SGA, <10° centile) or large for GA (LGA, >10° centile) according to INTERGROWTH-21st reference values, maternal age (years), days between positive maternal nasopharyngeal swab and delivery, delivery mode (vaginal delivery vs. vacuum-assisted delivery/elective caesarean section/emergency caesarean section), Apgar score at 1st and 5th minute, in-hospital mortality, length of stay (days). We analyzed also adverse neonatal outcomes: neonatal fever, feeding intolerance (inability to digest enteral feedings associated to increased gastric residuals, abdominal distension and/or emesis), tone anomalies (hypotonia/hypertonia), hypoglycaemia (if blood glucose level was less than 46 mg/dL) and hyperglycaemia (if blood glucose level was higher than 180 mg/dL), respiratory distress, need of mechanical ventilation, bradycardia (heart rate below 80 beats per minute) and tachycardia (heart rate above 220 beats per minute), jaundice (elevated total serum bilirubin for GA and hours of life according to Italian recommendations for treatment of jaundice), thrombocytopenia (defined as a platelet count <150000/µL), abdominal distension, cyanosis, seizures, clinical early-onset sepsis (including all signs and symptoms before mentioned).
The primary outcome was to assess if presepsin levels in neonatal cord blood could be influenced by maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We further assessed differences in P-SEP values according to maternal and neonatal characteristics.
We also explored P-SEP values in neonates with indeterminate SARS-CoV-2 infection and in those with possible SARS-CoV-2 infection, according to the WHO definition available at https://www.who.int/publications/i/item/WHO-2019-nCoV-mother-to-child-transmission-2021.1).
Measurement of presepsin
P-SEP was measured on 100 μL of blood collected in ethylenediaminetetraacetic acid (EDTA) tubes and immediately processed after the withdrawal. We used the PATHFAST point-of-care device (Mitsubishi, Tokyo, Japan), with a fully automated method, based on a chemiluminescence enzyme immunoassay (CLEIA) and providing results in 17 min .
In order to avoid any bias related to the wide range in neonatal hematocrit values , we corrected P-SEP values according to the current hematocrit of our patients (previously measured for routine test and entered for each of them) when whole blood was placed in the device , as recommended by the manufacturer for an accurate measurement.
We considered as reference ranges of presepsin those provided by Pugni et al., the largest cohort of healthy term and preterm neonates used to establish the reference ranges, which reported average values of PSEP in healthy term and preterm neonates of 604 and 620 pg/mL, respectively .
Statistical analysis and ethical issues
Data were analyzed using JASP software – version 0.16.1 (Amsterdam, Netherlands). Categorical variables are presented as numbers and percentages, while continuous variables are presented as mean and standard deviation (if they were normally distributed) or as median and interquartile range (if normality could not be accepted). Data distribution was evaluated by the Shapiro-Wilk test.
Categorical variables were compared using the Fisher’s exact test, whereas Mann-Whitney was used to compare non-normal data. Firstly, we compared cord P-SEP values between term neonates and preterm neonates. Furthermore, we ruled out differences in cord P-SEP values between neonates born to mothers with symptomatic COVID-19 and their peers born to mothers with asymptomatic COVID-19, between AGA neonates and SGA/LGA ones, between neonates vaginally delivered and those born via caesarean section, between neonates without adverse outcomes and those who have suffered them, between neonates discharged before 4 days of life and those later discharged. A p-value <0.05 was considered significant: two-sided p-values are reported.
The study was approved by the Ethics Committee of the Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy (ID 4023). All patients’ caregivers provided written consent to participate in the study.
During the study period, P-SEP values were assessed in 119 neonates born to mothers with a documented SARS-CoV-2 infection (Table 1). Of the mothers, 43 (36.1%) had a symptomatic disease, according to the WHO classification . Seventy-eight neonates (65.6%) were vaginally delivered and forty-one (3.4%) by caesarean section.
|Neonates||n = 119|
|Gestational age, weeks||39.0 (38.0–40.0)|
|Preterm birth||12 (10.1%)|
|Birthweight, grams||3,195 (2,940–3,475)|
|Apgar at 1st minute||9 (9–9)|
|Apgar at 5th minute||10 (10–10)|
|Length of stay, days
|Mothers||n = 119|
|Maternal age, years||33.5 (29–38)|
|Asymptomatic COVID-19||76 (63.8%)|
|Mild COVID-19 disease||43 (36.2%)|
Data are expressed as median (min-max) or number (percentage). GA, gestational age; AGA, appropriate for GA; SGA, small for GA; LGA, large for GA.
Three neonates tested positive (2.5%) at the first swab performed at less than 24 h since birth, but all were negative at 48 h of age (indeterminate infection). The other two cases (1.7%) had a confirmed positive nasopharyngeal test (possible infection, since it was from a non-sterile sample.
We found a median P-SEP value of 455 pg/mL (IQR 292–762) in umbilical cord blood samples collected after the delivery. We found no significant differences in P-SEP values between term neonates (median: 461 pg/mL; IQR 292–771) and preterm neonates (median: 404 pg/mL; IQR 307–613). We observed that P-SEP values were not influenced by weight for gestational age (AGA vs SGA/LGA), or delivery mode (vaginal delivery vs. vacuum-assisted delivery/elective caesarean section/emergency caesarean section). In particular, we found no significant differences between neonates born to symptomatic COVID-19 mothers (median: 445 pg/mL; IQR 287–910) and neonates born to asymptomatic COVID-19 mothers (median: 458 pg/mL; IQR 302–716) (Figure 1).
Twenty-eight neonates (23.5%) had adverse neonatal outcomes during hospital stay (Table 2); a significantly higher incidence was observed among preterm neonates rather than in term neonates (91.7 vs 15.9% respectively, p < 0.001). P-SEP values did not significantly differ between neonates without adverse neonatal outcomes (median: 485 pg/mL; IQR 291–793) and those who have suffered them (median: 379 pg/mL; IQR 302–500) (p = 0.307).
|Adverse outcome||n = 28||Cord P-SEP value, pg/mL|
|Abdominal distension||3 (2.5%)||287 (237–375)|
|Brady/tachycardia||10 (8.4%)||427 (295–1,230)|
|Cyanosis||2 (1.7%)||963 (601–1,324)|
|Feeding intolerance||10 (8.4%)||334 (294–445)|
|Hypo/hyperglycaemia||9 (7.6%)||392 (294–445)|
|Jaundice||10 (8.4%)||379 (288–451)|
|Mechanical ventilation||2 (1.7%)||893 (678–1,108)|
|Neonatal fever||1 (0.8%)||368|
|Respiratory distress||10 (8.4%)||353 (292–452)|
|Suspected early-onset sepsis||1 (0.8%)||2,458|
|Thrombocytopenia||2 (1.7%)||1,147 (878–1,416)|
|Tone anomalies||2 (1.7%)||1,015 (680–1,350)|
Data are expressed as number (percentage).
We also found no significant differences in adverse neonatal outcomes and length of stay among those who had a P-SEP value higher than 95° centile or higher than 75° centile and those without. However, neonates with a length of stay greater than 5 days had a significantly higher P-SEP value at birth (median: 610 pg/mL; IQR 319–1,086) rather than neonates who have been discharged up to 4 days of life (median: 339 pg/mL; IQR 245–515) (p < 0.001).
We had no cases of confirmed SARS-CoV2- infection in this cohort. The three neonates with a positive nasopharyngeal swab at birth and indeterminate SARS-CoV-2 infection had a higher P-SEP value (median: 1,644 pg/mL; IQR 1045–2,599) than the two neonates with possible SARS-CoV-2 infection who later became positive at 48 h (median: 998 pg/mL; IQR 904–1,093) (Figure 2). Other 114 uninfected neonates had a median value of 439 pg/mL (IQR 291–708).
Among the neonates of this cohort, we had no cases of culture-proven bacterial early-onset sepsis. Only a full-term newborn with a high value of P-SEP (2,458 pg/mL) had a clinically suspected early-onset sepsis and received empiric antibiotic treatment, which was stopped when blood cultures resulted to be negative. He was regularly discharged at 7 days of life.
In this study, we prospectively assessed presepsin values in umbilical cord blood in a cohort of neonates exposed to SARS-CoV-2 at the time of delivery. We found that P-SEP values in neonatal cord blood are not influenced by maternal SARS-CoV-2 infection, even in those neonates born to mothers with COVID-19 symptoms.
In recent years, P-SEP has gained increasing attention for its diagnostic accuracy in detecting neonatal sepsis [20, 21]. Interestingly, P-SEP seems to be not influenced by maternal and neonatal variables , which can bias the interpretation of the biomarker in symptomatic neonates or in neonates at risk for infection. It is well known that an elevation in values of C-reactive protein (CRP, the most widely used marker of sepsis in neonatology) is not necessarily diagnostic for sepsis but can physiologically occur in case of different conditions such as maternal intrapartum fever, premature rupture of membranes, vaginal delivery, fetal distress or perinatal asphyxia, respiratory distress syndrome [22, 23]. Similarly, procalcitonin (PCT) values show a physiologic increase 24–48 h after birth and decreases to normal values after 3 days . We confirm that in our cohort P-SEP values were not affected by weight for gestational age and delivery mode.
Considering that immune system dysregulation and cytokines release are pivotal pathogenetic mechanisms of COVID-19 [24, 25], in severe cases driving to a frank production of proinflammatory cytokines and markers , it was important to exclude the influence of the maternal infectious state in modifying the P-SEP values of the neonates, as we have made.
Conversely, Zhu et al. described a mild increase in neonatal values of CRP and PCT in some neonates born to mothers with COVID-19, without evidence of sepsis .
Similarly to Zaninotto’s findings in adult patients with COVID-19 , we found that neonates with a longer length of stay had significantly higher P-SEP values at birth, although we did not use a specific cut-off as in adults. Indeed, available neonatal reference ranges for P-SEP are related to healthy term neonates and preterm neonates without sepsis , and the definitive threshold in neonates is yet to be determined when there is something to possibly affect values.
The main limitation of our study is the lack of neonates born to mothers with SARS-CoV-2 infection who also had an overlapped early-onset bacterial sepsis, to confirm the diagnostic accuracy of P-SEP in case of bacterial infection when an infant is born in the context of a maternal immune system dysregulation. A second limitation is the lack of evaluation of neonatal P-SEP values according to maternal symptoms severity.
In this study, for the first time, we reported cord P-SEP values in an adequate sample of term and preterm neonates born to mothers with COVID-19, without any culture-proven bacterial infection that could have increased them. Cord P-SEP values appeared to be similar in neonates born to symptomatic COVID-19 mothers and in neonates born to asymptomatic ones. We found no differences between neonates with adverse neonatal outcomes and those without; the only neonate with suspected early-onset sepsis had a high value of cord P-SEP. Therefore, considering the need for a feasible biomarker of EOS not influenced by maternal characteristics and hours of life (such as CRP and PCT), we postulate that P-SEP can be used to rule out bacterial sepsis even in neonates born to mothers with COVID-19 at the time of delivery.
However, further studies are still needed to explain the mechanisms of P-SEP increase in neonates exposed to perinatal maternal SARS-CoV-2 infection or with an indeterminate/possible SARS-CoV-2 infection in the same neonates.
The authors would like to thank all women and their neonates who allowed the realization of this study.
Research funding: The authors received no financial support for the research, authorship, and/or publication of this article.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Declaration of conflicting interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Informed consent: Informed consent was obtained from all individuals included in this study.
Ethical approval: Research involving human subjects complied with all relevant national regulations, institutional policies and is in accordance with the tenets of the Helsinki Declaration (as revised in 2013), and has been approved by the authors’ Institutional Review Board (ID 4023).
Data availability: Datasets will be made available upon request.
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