ORIGINAL ARTICLE Year : 2021  |  Volume : 10  |  Issue : 1  |  Page : 19-23

The predictive factors for poor outcomes in preterm infants with coagulase-negative staphylococci infection

Abdulrahman Al-Matary, Roya Huseynova, Mostafa Qaraqe, Faisal K Aldandan
Department of Neonatology, King Fahad Medical City, Riyadh, Saudi Arabia

Date of Submission16-Jul-2019Date of Decision12-Sep-2020Date of Acceptance22-Nov-2020Date of Web Publication08-Feb-2021

Correspondence Address:
Dr. Abdulrahman Al-Matary
Department of Neonatology, King Fahad Medical City, PO Box 59046, Riyadh
Saudi Arabia

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jcn.JCN_105_20

Background: The main pathogen for neonatal nosocomial infections is coagulase-negative staphylococci (CoNS), particularly in very low-birth-weight and premature newborns. The current study is aimed to assess the outcomes of preterm infants with CoNS infection via a retrospective analysis, to determine the correlation between the clinical profile and mortality and morbidity, and to determine the factors associated with poor outcomes. Materials and Methods: This retrospective case–control study was conducted in the Children's and Women's Health Centre of King Fahad Medical City neonatal intensive care unit in Saudi Arabia. The study period was from January 2013 to December 2019. Results: There were 1333 controls and 137 cases of CoNS infection. There was a significant association between total parenteral nutrition use, surgical insertion of a central line, inotrope use, and spontaneous intestinal perforation and CoNS infection. There was a significant association between umbilical vein catheter (UVC) and peripherally inserted central catheter (PICC) line use and CoNS infection. The use of a UVC or PICC line significantly impacted. The presence of patent ductus arteriosus also significantly impacted. Conclusions: There was a significant association between UVC and PICC line use and outcome. The presence of patent ductus arteriosus or a perforated bowel and the need for inotrope use in CoNS infection was associated with poor outcomes. Mortality, retinopathy of prematurity, and necrotizing enterocolitis requiring surgery were more common in infants with CoNS infections.

Keywords: Coagulase-negative staphylococci, intraventricular hemorrhage, necrotizing enterocolitis, neonatal sepsis, retinopathy of prematurity, very low-birth-weight

How to cite this article:
Al-Matary A, Huseynova R, Qaraqe M, Aldandan FK. The predictive factors for poor outcomes in preterm infants with coagulase-negative staphylococci infection. J Clin Neonatol 2021;10:19-23
How to cite this URL:
Al-Matary A, Huseynova R, Qaraqe M, Aldandan FK. The predictive factors for poor outcomes in preterm infants with coagulase-negative staphylococci infection. J Clin Neonatol [serial online] 2021 [cited 2021 Dec 5];10:19-23. Available from: https://www.jcnonweb.com/text.asp?2021/10/1/19/308837   Introduction 

Infections cause an estimated 1.6 million deaths per year; among which 40% are neonatal deaths.[1],[2],[3] Approximately 12% of children, including 2% of very low-birth-weight (VLBW) infants, are born prematurely worldwide. Neonatal infections and prematurity are the most prominent reasons for neonatal deaths.[1] The most significant pathogens of nosocomial infections are coagulase-negative staphylococci (CoNS),[4] particularly in premature newborns or those hospitalized in intensive care units where they undergo antibiotic treatment and invasive procedures.[5],[6] CoNS are part of the mucosal and normal skin flora and are one of the most significant culture contaminants, which challenges the interpretation of blood culture results.[7]

Neonatal sepsis is defined as a bloodstream infection in newborn infants <28 days old. The leading cause of mortality and morbidity among newborn infants is sepsis, particularly in lower and middle-income countries.[8] Neonatal sepsis is mainly classified into two types based on the time of presentation after childbirth: late-onset sepsis (LOS) and early-onset sepsis (EOS). After 72 h of life, neonatal sepsis is referred to as LOS, and before 72 h of life, it is referred to as EOS. However, several experts use 7 days as the cut-off timepoint for neonatal sepsis.[9] Over the last century, mortality due to neonatal sepsis has significantly declined because of advances in the medical field. The incidence of neonatal sepsis cases was extremely high in the preantibiotic era (before 1940), exceeding 80% of all birth. After the 1960s, the rate of neonatal sepsis decreased as low as to 20% due to modern perinatal care development and the introduction of antibiotics.[10] Over the last century, the pathogens causing neonatal sepsis have dramatically changed.[10],[11],[12],[13],[14] Before the 1930s, group A streptococci, followed by Streptococcus pneumonia caused almost half of LOS cases.[10],[11] Currently, the main pathogen of LOS, specifically in newborns, is CoNS. According to a report from the National Institutes of Child Health and Development, infection-related deaths in VLBW neonates BW <1500 g) averages 10%,[13] but it can reach 40% based on the pathogen involved.[15],[16],[17] The incidence of neonatal sepsis ranges from 6 to 9/1000 newborns, but the incidence is significantly higher among neonates with a LBW.[18] Sepsis caused by bacteria is considered the most significant cause of neonatal mortality. Approximately 5 million neonatal deaths occur annually, of which 98% occur in developing countries according to the estimations of the World Health Organization.[19] Despite recent developments in neonatal care, the effects of neonatal sepsis remain substantial in developing countries.[20],[21],[22] Therefore, recognizing the risk and prognosis factors that exist in different geographical contexts has become a crucial issue to improve neonatal care. The current research aimed to assess the outcomes of CoNS infection in preterm infants via a retrospective analysis, to determine the correlation between the clinical profile and mortality and morbidity, and to determine the factors associated with poor outcomes.

  Materials and Methods 

Study design, setting, and population

This study was a retrospective case–control study conducted in the Children's and Women's Health Centre of King Fahad Medical City (KFMC) neonatal intensive care unit (NICU) in Saudi Arabia. The study period was from January 2013 to December 2019.

Inclusion criteria

All preterm infants < 32 weeks' gestation at birth or < 1500 g with CoNS infection admitted to the NICU from January 2013 to December 2019 were included.

Exclusion criteria

Preterm infants with Do not Resuscitate (DNR) or a congenital anomaly were excluded from the study.

Demographic data

The demographic data, including gender, age, gestational age (GA), BW, and age at first positive blood culture, were recorded. The medical history, examination findings, and laboratory results, including the complete blood count and blood culture results, were collected. The duration of the incubation of blood cultures and the sequence of antibiotic sensitivity were collected. Data on the antibiotic treatment were collected. CoNS bacteremia was characterized as one to two positive blood cultures in a single sepsis episode at least 48 h apart.

Evaluation of clinical manifestations

A range in the temperature from 36.5°C to 37.5°C or 1°C change in 24 h was termed an unstable temperature. Respiratory deterioration was characterized by a requirement of O2 or an increase in O2 necessary for escalation of respiratory therapy, enhanced bradycardia, or episodes of apnea and/or oxygen desaturation at presentation. Feeding intolerance was characterized by abdominal distension requiring at least 24 h of cessation of feeding or significant gastric fluid retention aspiration.

Evaluation of risk factors

The following risk factors were evaluated in preterm infants: GA, BW, Apgar score, chorioamnionitis, mode of delivery, surgically inserted central line use, peripherally inserted central catheter (PICC) line use, inotrope use, gastrointestinal (GI) perforation, maternal antibiotics, spontaneous intestinal perforation (SIP), total parenteral nutrition (TPN) use, need for a platelet transfusion due to thrombocytopenia, and patent ductus arteriosus (PDA).

Clinical analysis

An abnormal peripheral white blood cell count (WCC) was >20 ×109 cells/L when the ratio of immature to total neutrophils was <0.2 or when the count of neutrophils was <1.5 × 109 cells/LThrombocytopenia was defined as <80 ×109 platelets, and extreme thrombocytopenia was defined as <30 plateletsThe neutrophil count and WCC cut-offs depended on what we used to test for sepsis in clinical practiceIn consideration of the lower platelet counts in the first weeks of life, we used a threshold of 80 ×109 cells/L instead of 150 × 109 cells/L for thrombocytopenia in a large percentage of extremely low BW infantsThe determination of severe thrombocytopenia cut-offs depended on the cut-offs we used for platelet transfusion in a sick neonate in clinical practice.

Data for the clinical outcome

Necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP) requiring surgery, and death with CoNS sepsis were the clinical outcomes.

Data analysis

Means, medians, and standard deviations were used to describe the study population using descriptive statistics. A two-sample t-test was used to compare the continuous variables between the cases and the controls. To compare two categorical variables, a Chi-square test (contingency table method) was used. The association between periventricular leukomalacia (PVL), PDA, NEC, umbilical vein catheter (UVC) use, PICC use, and IVH and CONS infection were tested using binary logistic regression. An odds ratio and 95% confidence interval were computed for the outcomes. All data analyses were conducted using IBM SPSS 25.0, Armonk, New York, USA. P < 0.05 was considered statistically significant. All P values were based on two-sided test results.

  Results 

The prevalence of CoNS infections in the study period is presented in [Table 1]. CoNS infections occurred in 137 infants (9.3%) in the total study population.

The GA, BW, gender distribution, and Apgar score were compared between the cases and the controls [Table 2].

Table 2: Comparison of demographic characteristics between the cases and the controls (n=1470)

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TPN use (P < 0.001), surgically inserted line use (P < 0.001), PICC line use (P < 0001), SIP (P < 0.001), and PDA (P < 0.01) were significantly higher in the cases than in the controls [Table 3].

Table 3: Comparison of risk factors between the cases and the controls (n=1470)

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Among the cases, four infants died. PVL (P < 0.003), ROP with surgery (P < 0.001), LOS (P < 0.001), bronchopulmonary dysplasia (BPD) (P < 0.001), need for inotropes (P < 0.001), and postnatal need for steroids (P < 0.001) were significantly associated with CoNS sepsis exposure in preterm infants [Table 4].

Table 4: Association of outcomes between the controls and cases (n=1470)

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The studied characteristics of the CoNS cases significantly exceeded the controls by 18.9% in TPN use, 11.1% in GI perforation, 12.5% in PICC line use, 10.4% in UAC use, 21.8% in PDA, 12.6% in ROP with surgery, 7.8% in PVL, 8.7% in SIP, 32.7% in BPD, 22.8% in PLT, and 10.6% in postnatal steroid use for BPD. Moreover, the mean length of stay was 40.4 days longer and the BW was 84 g less in the CoNS cases than in the controls. The incidence of NEC was 2.4% higher in the CoNS cases, but its association with CoNS was not significant [Table 5].

Table 5: Predicting the most significant association of the studied variables with septicemia

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  Discussion 

CoNS are pathogens that play an important role in neonatal nosocomial infections. It is critical to determine the main factors associated with CoNS infections in preterm infants. In the present work, 1470 preterm infants were evaluated to determine the prevalence of CoNS infection. All the selected preterm infants had VLBWs and were born at < 32 weeks' gestation. The prevalence of CoNS infection was 9.3%. Previously, several studies demonstrated that prematurity and LBW are significantly associated with CoNS sepsis.[23],[24]

The studied characteristics significantly associated with CoNS infection were GA, TPN use, GI perforation, PICC line use, UAC use, and the presence of PDA. The infection rate was inversely proportional to the BW according to our findings, which were similar to the findings of Shrestha et al.[27],[28]

Four infants with CoNS infection died, and ROP with surgery, PVL, SIP, BPD, need for platelet transfusion, postnatal steroids for BPD, mean length of stay were more associated with CoNS infection. NEC and IVH were not significantly associated. Guida et al.[25] studied 943 VLBW neonates to observe the relationship between sepsis and thrombocytopenia. Among these 943 patients, sepsis was diagnosed in 154 (16%) patients.

A study by Alshaikh et al.[29] reported a significant association between CoNS sepsis and severe ROP, PDA, and respiratory distress syndrome, which is similar to the present findings of our research. In addition, Ohlin et al.[30] demonstrated CoNS-induced sepsis has become the most common cause of neonatal sepsis. Because these strains are often resistant to multiple antibiotics, there is clinical concern. In contrast, Stoll et al. demonstrated that CoNS infections were not significantly associated with morbidity and mortality.[31],[32]

In this study, the positive significant impact of PDA had a high risk of CoNS infection, while NEC did not significantly impact CoNS infection. In contrast, a report by Isaacs[33] demonstrated a significant association between NEC and CoNS, with 2.3% of all infected neonates having NEC at the same time and 8 neonates who died of NEC having blood cultures positive for CoNS. Ohlin et al.[30] reported IVH was not significantly associated with neonatal sepsis. In our study, there was a significant association between UVC use, PICC use, and IVH and CoNS infection.

In this study, there was a significant association between extended LOS and CoNS, while there was no significant association between BPD and thrombocytopenia requiring transfusion and CoNS. Ohlin et al.[30] demonstrated sepsis is a risk factor for BPD, but this finding was only on the boundary of statistical significance. They found no statistical evidence that CoNS sepsis is more likely to cause BPD than other bacteria. Previously, Dong et al.[34] reported that in terms of disease burden and the clinical path of LOS induced by Gram-negative bacteria, VLBW infants differ from more developed neonates.

  Conclusions 

TPN, surgically inserted central line use, UAC use, PICC line use, GI perforation, SIP, and the presence of PDA are significantly associated with CoNS infection in preterm infants. Mortality and poor outcomes, including ROP, the need for inotropes, and thrombocytopenia, in preterm infants mainly depended on CoNS sepsis. There is a significantly prolonged length of stay in infants with CoNS sepsis.

Acknowledgments

The authors would like to thanks the Research Centre, KFMC, Riyadh, Saudi Arabia, for providing support in preparing this manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 

  References 
1.The State of the World's Children report 2009: Maternal and Newborn Health, UNICEF, New York, USA.  
    2.World Health Organization. World Health Statistics 2010. Geneva: World Health Organization; 2010.  
    3.Liu L, Johnson HL, Cousens S, Perin J, Scott S, Lawn JE, et al. Global, regional, and national causes of child mortality: An updated systematic analysis for 2010 with time trends since 2000. Lancet 2012;379:2151-61.  
    4.Srivastava S, Shetty N. Healthcare-associated infections in neonatal units: Lessons from contrasting worlds. J Hosp Infect 2007;65:292-306.  
    5.Cunha ML, Lopes CA, Rugolo LM, Chalita LV. Clinical significance of coagulase-negative staphylococci isolated of neonates. J Pediatr (Rio J) 2002;78:279-88.  
    6.Schwab F, Geffers C, Bärwolff S, Rüden H, Gastmeier P. Reducing neonatal nosocomial bloodstream infections through participation in a national surveillance system. J Hosp Infect 2007;65:319-25.  
    7.Hira V, Sluijter M, Estevão S, Horst-Kreft D, Ott A, de Groot R, et al. Clinical and molecular epidemiologic characteristics of coagulase-negative staphylococcal bloodstream infections in intensive care neonates. Pediatr Infect Dis J 2007;26:607-12.  
    8.Wynn JL. Defining neonatal sepsis. Curr Opin Pediatr 2016;28:135-40.  
    9.Simonsen KA, Anderson-Berry AL, Delair SF, Davies HD. Early-onset neonatal sepsis. Clin Microbiol Rev 2014;27:21-47.  
    10.Bizzarro MJ. Seventy-five years of neonatal sepsis at Yale: 1928-2003. Pediatrics 2005;116:595-602.  
    11.Donowitz LG. Nosocomial infection in neonatal intensive care units. Am J Infect Control 1989;17:250-7.  
    12.Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010;126:443-56.  
    13.Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, et al. Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants. N Engl J Med 2002;347:240-7.  
    14.Vergnano S, Menson E, Kennea N, Embleton N, Russell AB, Watts T, et al. Neonatal infections in England: The NeonIN surveillance network. Arch Dis Child Fetal Neonatal Ed 2011;96:F9-14.  
    15.Hornik CP, Fort P, Clark RH, Watt K, Benjamin DK, Smith PB, et al. Early and late onset sepsis in very-low-birth-weight infants from a large group of neonatal intensive care units. Early Hum Dev 2012;88:S69-74.  
    16.Makhoul IR, Sujov P, Smolkin T, Lusky A, Reichman B. Pathogen-specific early mortality in very low birth weight infants with late-onset sepsis: A national survey. Clin Infect Dis 2005;40:218-24.  
    17.Weston EJ, Pondo T, Lewis MM, Martell-Cleary P, Morin C, Jewell B, et al. The burden of invasive early-onset neonatal sepsis in the United States, 2005-2008. Pediatr Infect Dis J 2011;30:937-41.  
    18.Janer AL. Applied thrapeutics: The clinical use of drugs. Am J Pharm Educ 2002;66:94.  
    19.Melamed N, Hod M. Perinatal mortality in pregestational diabetes. Int J Gynecol Obstet 2009;104:S20-4.  
    20.Zupan J. Neonatal and Perinatal Mortality: Country, Regional and Global Estimates. Geneva: World Health Organization; 2006.  
    21.Vergnano S. Neonatal sepsis: An international perspective. Arch Dis Child Fetal Neonatal Ed 2005;90:F220-4.  
    22.Barros FC, Bhutta ZA, Batra M, Hansen TN, Victora CG, Rubens CE. Global report on preterm birth and stillbirth (3 of 7): Evidence for effectiveness of interventions. BMC Pregnancy Childbirth 2010;10:S3.  
    23.Gladstone I, Ehrenkranz RA, Edberg SC, Baltimore RS. A ten-year review of neonatal sepsis and comparison with the previous fifty-year experience. Pediatr Infect Dis J 1990;9:819-90.  
    24.Grauel EL, Halle E, Bollmann R, Buchholz P, Buttenberg S. Neonatal septicaemia incidence, etiology and outcome a 6-year analysis. Acta Paediatr 1989;78:113-9.  
    25.Guida JD, Kunig AM, Leef KH, McKenzie SE, Paul DA. Platelet count and sepsis in very low birth weight neonates: Is there an organism-specific response? Pediatrics 2003;111:1411-5.  
    26.Mukhopadhyay S, Puopolo KM. Risk assessment in neonatal early onset sepsis. Semin Perinatol 2012;36:408-15.  
    27.Shrestha S, Adhikari N, Rai BK, Shreepaili A. Antibiotic resistance pattern of bacterial isolates in neonatal care unit. JNMA J Nepal Med Assoc 2010;50:277-81.  
    28.Cheng YW, Nicholson JM, Nakagawa S, Bruckner TA, Washington AE, Caughey AB. Perinatal outcomes in low-risk term pregnancies: Do they differ by week of gestation? Am J Obstet Gynecol 2008;199:370.e1-7.  
    29.Alshaikh B, Yee W, Lodha A, Henderson E, Yusuf K, Sauve R. Coagulase-negative staphylococcus sepsis in preterm infants and long-term neurodevelopmental outcome. J Perinatol 2014;34:125-9.  
    30.Ohlin A, Björkman L, Serenius F, Schollin J, Källén K. Sepsis as a risk factor for neonatal morbidity in extremely preterm infants. Acta Paediatr 2015;104:1070-6.  
    31.Stoll BJ, Gordon T, Korones SB, Shankaran S, Tyson JE, Bauer CR, et al. Late-onset sepsis in very low birth weight neonates: A report from the National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr 1996;129:63-71.  
    32.Silveira RC, Procianoy RS, Dill JC, da Costa CS. Periventricular leukomalacia in very low birth weight preterm neonates with high risk for neonatal sepsis. J Pediatr (Rio J) 2008;84:211-6.  
    33.Isaacs D. A ten year, multicentre study of coagulase negative staphylococcal infections in Australasian neonatal units. Arch Dis Child Fetal Neonatal Ed 2003;88:F89-93.  
    34.Dong Y, Glaser K, Speer CP. Late-onset sepsis caused by Gram-negative bacteria in very low birth weight infants: A systematic review. Expert Rev Anti Infect Ther 2019;17:177-88.  
    

 
 

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]