Journal of Perinatology (2014) 34, 125–129 & 2014 Nature America, Inc. All rights reserved 0743-8346/14 www.nature.com/jp
ORIGINAL ARTICLE
Coagulase-negative staphylococcus sepsis in preterm infants and long-term neurodevelopmental outcome B Alshaikh1,2, W Yee2, A Lodha2, E Henderson1, K Yusuf2 and R Sauve1,2 OBJECTIVE: The objective of this study was to examine the impact of Coagulase-negative staphylococcus (CoNS) sepsis in preterm infants on the neurodevelopmental outcomes at 30 to 42 months corrected age (CA). STUDY DESIGN: This is a retrospective cohort study. All preterm infants born at o29 weeks gestational age between 1995 and 2008 and had a neurodevelopmetnal assessment at 30 to 42 months CA were eligible. The neurodevelopmetnal outcomes of infants exposed to CoNS sepsis were compared with infants unexposed to any type of neonatal sepsis. RESULT: A total of 105 eligible infants who were exposed to CoNS sepsis were compared with 227 infants with no neonatal sepsis. In univariate analysis, infants with CoNS sepsis were more likely to have total major disability (odds ratio (OR) ¼ 1.9; 95% CI: 1.07 to 3.38) and cognitive delay (OR ¼ 2.53; 1.26 to 5.14).There was no significant difference in the incidence of cerebral palsy, blindness and deafness between the two groups. After correcting for potential confounders, CoNS sepsis was associated with increased risk of cognitive delay (adjusted odds ratio (aOR) ¼ 2.23; 95% CI 1.01 to 4.9), but not with the total major disability (aOR ¼ 1.14; 95% CI: 0.55 to 2.34). CONCLUSION: Our study suggests that CoNS sepsis in preterm infants might be associated with increased risk for cognitive delay at 36 months CA. Journal of Perinatology (2014) 34, 125–129; doi:10.1038/jp.2013.155; published online 19 December 2013 Keywords: preterm; Coagulase-negative staphylococcus; neurodevelopmental outcome
INTRODUCTION The increased survival of extremely preterm infants has highlighted the importance of assessing and improving long-term outcomes of these infants. Long-term neurodevelopmental outcome studies have shown that about half of the extremely preterm infants develop cognitive impairment and as many as 15% develop cerebral palsy (CP).1 Cerebral white matter injury (WMI) is a valuable predictor of neurodevelopmental deficits in extremely preterm infants.2,3 WMI frequently results from inflammatory responses to many factors including antenatal and postnatal infection.4,5 Coagulase-negative staphylococcus (CoNS) is the most commonly isolated agent of postnatal infection in preterm infants.6–8 The incidence of CoNS infection in neonatal intensive care units (NICUs) varies between 1.3 and 30.9%, depending on gestational age (GA), birth weight and presence of intravascular catheters.9–11 CoNS typically demonstrate low virulence and low mortality rate compared with other bacterial infection.9 However, recent reports raised concerns about potential poor neurodevelopmental outcome in preterm infants exposed to CoNS sepsis in the neonatal period.12,13 These reports showed a higher incidence of CP13,14 and lower psychomotor developmental index12 on assessment at 18 to 24 months of age. This potential association between CoNS sepsis and neurodevelopmental outcome has never been studied beyond 2 years of age.12–14 We hypothesize that exposure to CoNS sepsis in extremely preterm infants born at o29 weeks GA would be associated with neurodevelopmental disability. The objective of our study was to describe the long-term neurodevelopmental outcome at 30 to 42
months corrected age among preterm infants exposed to CoNS sepsis in the neonatal period. Having a better understanding of the relationship between CoNS sepsis and long-term neurodevelopmental outcome will guide future management, prevention and prognostication of these extremely preterm infants.
METHODS Study design and study population This single-center, retrospective cohort study was conducted at Foothills Medical Centre in Calgary with B7000 deliveries annually. The study was approved by the conjoint health research ethics board. All infants born at o29 weeks GA and admitted to the NICU between 1 January 1995 and 31 December 2008 were identified from the neonatal database. We identified all blood, cerebral spinal fluid (CSF) and urine cultures obtained from all infants during their stay in NICU. Infants without available blood culture results, those with major congenital anomalies, and infants with Gram-negative organisms isolated from bloodstream, CSF or urine were excluded. CoNS sepsis was defined by a combination of1 suggestive clinical signs (temperature instability, irritability, hypotonia, feeding difficulties, poor perfusion, apnea, tachycardia and tachypnea),2 a positive single-organism sterile body fluids (blood, CSF or urine) culture for CoNS3 appropriate antibiotic treatment of X5 days. Each infant with CoNS sepsis was compared with subsequent two infants born at o29 weeks GA who were admitted to the NICU and never had positive blood, CSF or urine culture. The neonatal and neurodevelopmental outcomes of all eligible infants were obtained from the Perinatal Follow Up (PNFU) database. Every subject identified in the neonatal database to be eligible for the study was given a study number. Alberta Healthcare numbers of these subjects were used temporally to link neonatal and PNFU databases.
1 Department of Community Health Sciences, Faculty of Medicine, University of Calgary, Calgary, AB, Canada and 2Department of Pediatrics, University of Calgary, Calgary, AB, Canada. Correspondence: Dr B Alshaikh, Department of Pediatrics, Faculty of Medicine, University of Calgary, Room 780-1403 29th St NW, Calgary, T2N 2T9 AB, Canada. E-mail: [email protected] Received 12 August 2013; revised 26 October 2013; accepted 6 November 2013; published online 19 December 2013
Coagulase-negative staphylococcus sepsis B Alshaikh et al
126 The PNFU database contains pregnancy, delivery and neonatal morbidities abstracted from the hospital charts at death or discharge from the hospital by a trained research assistant. These include maternal age, maternal education, antenatal risk factors like smoking and alcohol use, GA, birth weight, sex, antenatal steroids, mode of delivery, multiple or singleton pregnancy, Apgar scores, umbilical arterial pH, respiratory distress syndrome, use of surfactant, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia (PVL), patent ductus arteriosus, necrotizing enterocolitis, retinopathy of prematurity (ROP) and duration of hospital stay in NICU. The neurodevelopmental outcome data were also collected from the PNFU database. During the study period, preterm infants were prospectively followed up with longitudinal multidisciplinary examinations at adjusted ages of 4, 8, 12, 18 and 36 months in the PNFU clinic at Alberta Children’s Hospital. Neurodevelopmental assessments were performed independently by neonatologist/developmental pediatrician, physiotherapist, certified psychologist, ophthalmologist and audiologist on every child. The neurological assessment included evaluation of tone, strength, reflexes and posture. All neurological and neurodevelopmental assessments were performed by individuals who were unaware that a study on association between CoNS sepsis in preterm infants and long-term neurodevelopmental outcome would be conducted in the population.
Definitions True CoNS sepsis was defined as described previously. Persistent CoNS sepsis defined as three or more consecutive positive blood cultures at least 48 h apart with the same CoNS species during a single septic episode.15,16 Meningitis was defined as positive CSF culture, white blood cell count of 430 cells mm 3, or baby treated with therapeutic course of antibiotics based on the other CSF findings.12 GA was defined as the best obstetric estimate that is based on early prenatal ultrasound, and obstetric history, unless the postnatal pediatric estimate of gestation age based on Ballard score differed from the obstetric estimate by 42 weeks. Respiratory distress syndrome was defined as the presence of respiratory signs including tachypnea, grunting and chest retraction, typical chest X-ray findings and/or treatment by surfactant with the need for mechanical ventilation for 424 h in the first 3 days of life. Intraventricular hemorrhage was defined according to the criteria of Papile et al.17 from head ultrasound. Patent ductus arteriosus was defined as clinical diagnosis plus treatment with indomethacin or surgical ligation or both. Bronchopulmonary dysplasia was defined as oxygen dependency at 36 weeks postmenstrual age for preterm infant who is born p32 weeks’ gestation.18 PVL was defined as parenchymal echo densities or lucencies around the ventricles from head ultrasound performed after 32 weeks postmenstrual age. Necrotizing enterocolitis was defined according to the modified criteria of Bell et al.19 (stage II or higher). ROP was defined according to the International Classification for ROP.20 CP was defined as a non-progressive motor impairment characterized by abnormal muscle tone in at least one extremity and decreased range or control of movements.21 Cognitive delay was defined as a score of 42 standard deviation below the mean on standardized assessment (Wechsler Preschool and Primary Scale of Intelligence-Revised, Bayley Scales of Infant Development II or Stanford-Binet IV).22 Deafness was defined as sensorineural hearing loss requiring amplification. Milder form of neurosensory hearing loss was defined when the impairment does not require amplification. Blindness was defined as visual acuity o20/200 following refractive correction.
Statistical analysis Descriptive statistics including means, medians and standard deviations were used to describe the study population. In order to compare between continuous variables in infants exposed and unexposed to CoNS sepsis, two-sample t-test or Mann–Whitney test were used. Chi-square test (contingency table method) was used to compare discrete variables unless the expected cell frequency was less than five and then Fisher’s exact test was performed. The association between CoNS sepsis and the presence of neurodevelopmental outcomes (CP, cognitive delay, deafness, blindness and total major disability) was examined using multivariable logistic regression with backward selection. Because of small event numbers in deafness and blindness, their association with CoNS sepsis were adjusted for GA only. For CP, cognitive delay and major disabilities, which had a greater number of outcome events, the associations were adjusted for GA, chorioamnionitis, severe intraventricular hemorrhage and use of postnatal Journal of Perinatology (2014), 125 – 129
steroids. These covariates were selected using a cautious approach consists of including them in the model if the P-value is o0.20 on the univariate analysis or if its inclusion resulted in change of 15% or more in the estimate of the main effect of CoNS sepsis exposure. In addition, any variable identified as confounder in the literature is highly considered for inclusion in the final model. Odds ratio (OR) and 95% confidence interval (CI) were computed for the outcomes. Significance for all tests was established at a P-value of o0.05. All P-values were based on two-sided test results. Stata version 11.0 software (Stata Corporation, College Station, TX, USA) was used for all data analyses.
RESULTS Study population From 1995 to 2008, a total of 1224 preterm infants o29 weeks were admitted to the regional NICU at Foothills Medical Centre. Of these, 181 infants were identified to have at least one blood, urine or CSF positive culture for CoNS based on the neonatal database. A total of 121 (66.8%) survival infants had true CoNS sepsis. The cumulative incidence of true CoNS sepsis was 13.1% over the 14 years period of the study. Of the 121, 118 (97.5%) infants had bloodstream infection. There were four cases of meningitis resulting from CoNS. Of the four, only one infant had positive blood culture. The other three infants who had meningitis and negative blood cultures had ventriculoperitoneal shunt. All collected urine samples in infants with CoNS sepsis were negative for CoNS organisms. The median (interquartile range) age for CoNS sepsis was 15 (9,21) days. Infants who had true CoNS sepsis were compared with 227 survival infants with no CoNS sepsis who met the inclusion/exclusion criteria for the study, and came to follow up clinic at age of 36 months. The proportion of infants who were lost to follow up was similar between the two groups (13.2 vs 13.4%). Eleven infants died in the CoNS group, of which 7 infants died during the initial hospitalization and 4 infants died after discharge from the hospital. In the uninfected group, 61 infants died, of which 49 infants died during the initial hospitalization and 12 infants died after discharge. Twenty-eight infants in the no CoNS group died in the first week of life whereas no one in the CoNS group died in the first week of life. There was no difference in the proportion of infants who died after the first week of life between the two groups (P ¼ 0.36). Figure 1 shows the flow diagram of the subjects in the study. The maternal characteristics were similar between preterm infants exposed and not exposed to CoNS sepsis. Infants with CoNS sepsis had lower GA (25.9±1.7 vs 26.2±1.7), lower birth weight (834±211 g vs 900±197 g), more likely to be small for gestational age (13.4 vs 5.7%) and to have lower cord pH (7.28±0.09 vs 7.30±0.09) and lower Apgar score at 5 min (median 7 vs 8). Table 1 shows the maternal and neonatal characteristics of infants with and without CoNS sepsis in the neonatal period. The common neonatal morbidities between the two groups are presented in Table 2. CoNS sepsis was more likely to associate with respiratory distress syndrome (89.5 vs 80.6%), severe ROP (37.1 vs 22.5%) and use of postnatal steroid (36.2 vs 18.5%). All these differences were no longer significant after adjusting for GA. The median length of hospital stay was longer in infants with CoNS sepsis (38 (20, 59) vs 24 (7, 46); Po0.001). This difference continued to be significant after adjusting for GA (12 days; 95% CI 7.1 to 16.9). Neurodevelopmental outcomes The mean age at neurodevelopmental follow-up was similar between the infants exposed and unexposed to CoNS sepsis (37.1±2.1 months in the CoNS group vs 36.9±1.85 months in the group without CoNS; P ¼ 0.4). On bivariate analysis, infants with CoNS sepsis had increased rate of total major neurodevelopmental impairment (NDI) (24.7 vs 14.9%; P ¼ 0.03) and cognitive delay (17.1 vs 7.5%, P ¼ 0.01) when compared with infants without CoNS & 2014 Nature America, Inc.
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127
Figure 1.
Flow diagram of the subjects in the study.
Table 1.
Comparison of maternal and neonatal characteristics between infants exposed and unexposed to CoNS sepsis No CoNS group (n ¼ 227) Maternal characteristics Maternal age, mean (s.d.) Antenatal steroids, n (%) Multiple births, n (%) Chorioamnionitis, n (%) Cesearean section, n (%) Use of antibiotics during labor, n (%) Mothers completed high school, n (%) Smoking, n (%) Neonatal characteristics Gestational age, mean (week)±s.d. Birth weight, mean (g)±s.d. Male (%) SGA (%) Apgar score at 5 min, median (IQR) Cord pH, mean±s.d.
29.2 183 46 60 106 148
(5.9) (82.8) (20.3) (27.9) (46.9) (67.9)
CoNS group (n ¼ 105) 29.4 82 31 19 55 66
P-value
(5.4) (79.6) (29.5) (18.8) (52.4) (63.5)
0.79 0.49 0.06 0.08 0.35 0.43
177 (84.3)
83 (81.3)
0.51
35 (15.8)
16 (15.5)
0.94
26.2±1.4
25.9±1.7
0.04
900±197
834±211
0.01
116 (51.1) 13 (5.7) 8 (6, 8)
63 (60) 14 (13.4) 7 (6, 8)
0.13 0.02 0.03
7.30±0.09
7.28±0.09
0.02
Abbreviations: CoNS, Coagulase-negative staphylococcus; IQR, interquartile range; SGA, small for gestational age.
sepsis (Table 3). However, adjusting for potential confounders including GA, chorioamnionitis, severe intraventricular hemorrhage and the use of postnatal steroids showed increased risk for cognitive delay (OR ¼ 2.23; 95% CI: 1.01 to 4.9), but not for total major disability (OR ¼ 1.14; 95% CI: 0.55 to 2.34). Since a significant proportion of study infants had CoNS sepsis before receiving postnatal steroids (which could be involved in the causal pathway linking CoNS and adverse neurodevelopmental outcome), we elected to report the outcomes without plugging the steroid in the models. The OR for cognitive delay was 2.36 (95% CI: 1.1 to 5.07), and for major disability was 1.85 (95% CI: 0.96 to 3.57). Of the 332 infants included in the study, 304 (91.5%) had cognitive testing. The mean cognitive score was 90.8±21 in the CoNS group as compared with 94.7±16.3 in infants without CoNS sepsis. There were no significant differences in the rates of CP (10.6 vs 10.4%), & 2014 Nature America, Inc.
blindness (1 vs 1.7%) and deafness (5 vs 2.2%) between the two groups. Of interest, when we include the milder form of neurosensory deafness looking for any neurosensory impairment, children exposed to CoNS sepsis were at risk (9.6 vs 3.1%; P ¼ 0.01). Excluding the four infants with meningitis from the analysis did not alter the results of neurodevelopmental outcome.
DISCUSSION The cumulative incidence of CoNS sepsis in the current study (13.1%) is similar to that reported previously.6 Our study shows that CoNS sepsis is associated with respiratory distress syndrome, patent ductus arteriosus and severe ROP (grade 3 and 4). This association turned out to be no longer significant after correcting for GA. In the current study, CoNS sepsis has no association with total major NDI in extremely preterm infants. However, the assessment of the type-specific NDI showed that CoNS sepsis is independently associated with a 2.2-fold increased odds for cognitive delay in this population. Our study supports the findings reported by Shah et al.12 who found a significant difference in the psychomotor developmental index at 2 years of age in infants exposed to CoNS sepsis when compared with unexposed infants. The mean difference after correcting for potential confounders in the former study was 5.8 points (95% CI: 0.3 to 11.2; P ¼ 0.04). The lower psychomotor developmental index in infants with sepsis was mediated by WMI.12 In contrast to our findings, a study by Schlapbach et al.13 showed increased risk for developing CP in infants exposed to CoNS sepsis. However, the total number of infants with CP was limited to 14 children in this study.14 Our study revealed similar proportion of CP in infants exposed and unexposed to CoNS sepsis. Cerebral lesion and particularly PVL are the most important predictors of CP in very preterm infants.23 Silveira et al.24 reported that neonatal sepsis (61% resulted from CoNS) is an independent risk factor for PVL in very preterm infants. However, the proportion of infants with PVL in their study was high (57.8%) compared with only (3%) in our cohort. Similarly, Stoll et al.14 reported increased risk of CP (OR ¼ 1.4; 95% CI 1.0 to 1.9) in infants exposed to CoNS sepsis, but no difference in cognitive delay. The cognitive outcome of Stoll’s study was a result of a single-point follow-up at 18 to 22 months corrected age. Assessment of cognitive outcome at 18 to 22 months corrected age may encounter many difficulties as the rate of acquiring new skills in these infants differs largely during this period.25 Journal of Perinatology (2014), 125 – 129
Coagulase-negative staphylococcus sepsis B Alshaikh et al
128 Table 2.
Comparison of neonatal outcomes between infants exposed and unexposed to CoNS sepsis No CoNS group (n ¼ 227)
Characteristics RDS, n (%) Severe IVH, n (%) PDA, n (%) NEC, n (%) Severe ROP Xstage 3, n (%) BPD, n (%) Postnatal steroid, n (%) Length of stay day, median (IQR)
183 22 141 31 51 170 42 81
CoNS group (n ¼ 105)
(80.6) (9.6) (62.1) (13.6) (22.5) (74.9) (18.5) (70, 100)
94 13 84 23 39 86 38 98
P-value
(89.5) (12.3) (80) (21.9) (37.1) (81.9) (36.2) (79, 124)
0.047 0.46 0.001 0.06 0.005 0.16 0.001 o0.001
Abbreviations: BPD, bronchopulmonary dysplasia; CoNS, Coagulase-negative staphylococcus; IQR, interquartile range; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; RDS, respiratory distress syndrome; ROP, retinopathy of prematurity.
Table 3.
Neurodevelopmental outcomes
Neurodevelopmental outcome
CP Cognitive delay Blindness Deafness Major NDI
Unadjusted OR
Adjusted OR
OR
95% CI
P-value
OR
95% CI
P-value
0.99 2.53 0.54 2.7 1.9
0.46–2.10 1.24–5.14 0.06–4.93 0.8–9.07 1.07–3.38
0.97 0.01 0.59 0.10 0.03
0.63 2.23 0.35 2.24 1.14
0.24–1.64 1.01–4.9 0.03–3.37 0.64–7.73 0.55–2.34
0.34 0.048 0.36 0.20 0.71
Abbreviations: CP, cerebral palsy; GA, gestational age; IVH, intraventricular hemorrhage; NDI, neurodevelopmental impairment. CP, cognitive outcome and major NDI were adjusted for GA, severe IVH, chorioamnionitis and postnatal steroids. Deafness and blindness were adjusted for GA only as severe IVH, chorioamnionitis and sex did not seem to alter the outcome.
A recent systematic review and meta-analysis on neonatal sepsis in very low birth weight infants and long-term neurodevelopmental outcomes showed that neonatal sepsis increases the risk of any type NDI by twofold.26 The subgroup analysis of NDI in infants exposed to CoNS sepsis showed similar findings to the overall sepsis, but the magnitude was smaller (OR 1.3; 95% CI 1.09 to 1.57). However, the studies included in this meta-analysis were heterogeneous, and the number of studies reporting the NDI in CoNS sepsis group was very limited. Number of children with blindness was very small. The findings of no difference in deafness requiring amplification between the two groups were consistent with Stoll’s study.14 However, including the milder form of neurosensory deafness in the total hearing impairment revealed that children exposed to CoNS sepsis were at risk for any hearing loss. Use of antibiotics such as vancomycin and gentamicin in preterm infants is shown to increase the risk of neurosensory hearing impairment.27,28 These antibiotics are commonly used to treat CoNS sepsis and are proposed to be a possible cause of hearing impairment in this population. Recent studies have shown that 15 to 20% of very preterm infants are at risk for severe neurodevelopmental delay, and 40 to 50% of this population have some degree of cognitive delay.29,30 Cognitive delay is highly correlated with WMI.31 Diagnosis of WMI needs a brain magnetic resonance imaging at term equivalent gestation. Yet, there is no agreement on the routine use of brain magnetic resonance imaging for extremely preterm infants. Alternatively, cranial ultrasound is a screening tool for PVL, but its ability to detect other white matter abnormalities is limited.32 The pathogenesis of WMI resulting from CoNS sepsis is thought to be similar to other postnatal sepsis in preterm infants. It has two related mechanisms (upstream and downstream).33 Production of pro-inflammatory cytokines, increase of blood–brain barrier permeability, hypoxic ischemic events resulting from hypotension and impaired autoregulation of cerebral blood flow represent the upstream mechanisms to stimulate the brain’s microglia.4,24,34,35 This leads to activation of downstream mechanisms which include excitotoxicity and free radical attack caused by reactive oxygen Journal of Perinatology (2014), 125 – 129
and nitrogen species.33 This activation subsequently leads to the death of the vulnerable pre-myelinating oligodendrocytes.33 Evidence from animal studies showed that signaling toll-like receptor 2 (TLR2) and TLR6 presented on microglia (the resident immune cells of the brain) by staphylococcus bacteria leads to increase in lysosomal activity and massive production of IL-10 followed by apoptosis of these cells.36 Subsequently, this participates in the damage to other precious neurons around the microglia. Critical care studies in adult patients and animal studies have demonstrated a permanent cognitive impairment in severe sepsis survivors.37 This impairment has correlated with hippocampus atrophy.37–39 The strengths of the current study include a high rate (86%) of comprehensive multidisciplinary follow up. All neurodevelopmental assessments were performed by individuals who were unaware that this study would be conducted in the perinatal follow up clinic. The neurodevelopmental assessment at 36 months corrected age provided more accurate diagnosis than all assessments of outcome at less than 24 months of age. This is particularly important for assessment of cognitive outcome as all earlier tests are not highly predictive and transient neurological abnormalities seen before 24 months will be avoided. Use of a priori operational definitions provided an accurate tool to protect the study from measurement bias. There are several limitations of our study, including being a single report of the only perinatal follow up clinic of southern Alberta, thus it reflected the unique diagnostic and follow-up experience of this ‘single’ center. Using single blood culture to define CoNS sepsis could have resulted in including infants with contaminant blood culture in the study; however, this would have resulted in dilution of the effect toward null. Use of additional criteria to the definition including changes in infection laboratory indicators such as complete blood cell count, C-reactive protein and so on was thought to be helpful in lowering the risk of CoNS contamination, but was not feasible as the data on complete blood cell count and C-reactive protein were not available. In addition, the fact that many preterm infants have a decreased & 2014 Nature America, Inc.
Coagulase-negative staphylococcus sepsis B Alshaikh et al
129 inflammatory response to various types of CoNS organism limits the benefit of using these markers.40 The retrospective design limits the ability to investigate the biological pathways of the association between the CoNS sepsis and cognitive impairment. In conclusion, CoNS sepsis might be associated with an increased risk of cognitive delay in preterm infants born at o29 weeks GA. This study alerts health care providers to actively use infection control strategies to protect all preterm infants in NICU from CoNS sepsis. It also emphasizes the importance of long-term follow-up of preterm infants with CoNS sepsis, and helps clinicians for counseling parents of preterm infants with CoNS sepsis. CONFLICT OF INTEREST The authors declare no conflict of interest.
REFERENCES 1 Hack M, Wilson-Costello D, Friedman H, Taylor GH, Schluchter M, Fanaroff AA. Neurodevelopment and predictors of outcomes of children with birth weights of less than 1000 g: 1992-1995. Arch Pediatr Adolesc Med 2000; 154(7): 725–731. 2 Pinto-Martin JA, Riolo S, Cnaan A, Holzman C, Susser MW, Paneth N. Cranial ultrasound prediction of disabling and nondisabling cerebral palsy at age two in a low birth weight population. Pediatrics 1995; 95(2): 249–254. 3 Volpe JJ. Cerebral white matter injury of the premature infant-more common than you think. Pediatrics 2003; 112(1 Pt 1): 176–180. 4 Volpe JJ. Postnatal sepsis, necrotizing entercolitis, and the critical role of systemic inflammation in white matter injury in premature infants. J Pediatr 2008; 153(2): 160–163. 5 Volpe JJ. Neonatal encephalitis and white matter injury: more than just inflammation? Ann Neurol 2008; 64(3): 232–236. 6 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(1): 63–71. 7 Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA et al. Lateonset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics 2002; 110(2 Pt 1): 285–291. 8 Klein JO. Bacteriology of neonatal sepsis. Pediatr Infect Dis J 1990; 9(10): 778–779. 9 Orsi GB, d’Ettorre G, Panero A, Chiarini F, Vullo V, Venditti M. Hospital-acquired infection surveillance in a neonatal intensive care unit. Am J Infect Control 2009; 37(3): 201–203. 10 Van der Lugt NM, Steggerda SJ, Walther FJ. Use of rifampin in persistent coagulase negative staphylococcal bacteremia in neonates. BMC Pediatr 2010; 10: 84–89. 11 Isaacs D, Australasian Study Group For Neonatal I. A ten year, multicentre study of coagulase negative staphylococcal infections in Australasian neonatal units. Arch Dis Child Fetal Neonatal Ed 2003; 88(2): F89–F93. 12 Shah DK, Doyle LW, Anderson PJ, Bear M, Daley AJ, Hunt RW et al. Adverse neurodevelopment in preterm infants with postnatal sepsis or necrotizing enterocolitis is mediated by white matter abnormalities on magnetic resonance imaging at term. J Pediatr 2008; 153(2): 170–175. 13 Schlapbach LJ, Aebischer M, Adams M, Natalucci G, Bonhoeffer J, Latzin P et al. Impact of sepsis on neurodevelopmental outcome in a Swiss National Cohort of extremely premature infants. Pediatrics 2011; 128(2): e348–e357. 14 Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr B et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004; 292(19): 2357–2365. 15 Khashu M, Osiovich H, Henry D, Al Khotani A, Solimano A, Speert DP. Persistent bacteremia and severe thrombocytopenia caused by coagulase-negative Staphylococcus in a neonatal intensive care unit. Pediatrics 2006; 117(2): 340–348. 16 Dimitriou G, Fouzas S, Giormezis N, Giannakopoulos I, Tzifas S, Foka A et al. Clinical and microbiological profile of persistent coagulase-negative staphylococcal bacteraemia in neonates. Clin Microbiol Infect 2011; 17(11): 1684–1690. 17 Papile LA, Munsick-Bruno G, Schaefer A. Relationship of cerebral intraventricular hemorrhage and early childhood neurologic handicaps. J Pediatr 1983; 103(2): 273–277.
& 2014 Nature America, Inc.
18 Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988; 82(4): 527–532. 19 Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978; 187(1): 1–7. 20 The International Committee for the Classification of the Late Stages of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. II. The classification of retinal detachment. Arch Ophthalmol 1987; 105(7): 906–912. 21 Levine MS. Cerebral palsy diagnosis in children over age 1 year: standard criteria. Arch Phys Med Rehabil 1980; 61(9): 385–389. 22 Thorndike RHE, Sattler J. The Stanford-Binet intelligence scale, fourth edition. Guide for administering and scoring. Riverside Pub. Co: Chicago, IL, 1986, 192 p. 23 Beaino G, Khoshnood B, Kaminski M, Pierrat V, Marret S, Matis J et al. Predictors of cerebral palsy in very preterm infants: the EPIPAGE prospective population-based cohort study. Dev Med Child Neurol 2010; 52(6): e119–e125. 24 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 2008; 84(3): 211–216. 25 Hack M, Taylor HG, Drotar D, Schluchter M, Cartar L, Wilson-Costello D et al. Poor predictive validity of the Bayley Scales of Infant Development for cognitive function of extremely low birth weight children at school age. Pediatrics 2005; 116(2): 333–341. 26 Alshaikh B, Yusuf K, Sauve R. Neurodevelopmental outcomes of very low birth weight infants with neonatal sepsis: systematic review and meta-analysis. J Perinatol 2013; 33(7): 558–564. 27 Vella-Brincat JW, Begg EJ, Robertshawe BJ, Lynn AM, Borrie TL, Darlow BA. Are gentamicin and/or vancomycin associated with ototoxicity in the neonate? A retrospective audit. Neonatology 2011; 100(2): 186–193. 28 Coenraad S, Goedegebure A, van Goudoever JB, Hoeve LJ. Risk factors for auditory neuropathy spectrum disorder in NICU infants compared to normal-hearing NICU controls. Laryngoscope 2011; 121(4): 852–855. 29 Woodward LJ, Moor S, Hood KM, Champion PR, Foster-Cohen S, Inder TE et al. Very preterm children show impairments across multiple neurodevelopmental domains by age 4 years. Arch Dis Child Fetal Neonatal Ed 2009; 94(5): F339–F344. 30 Litt J, Taylor HG, Klein N, Hack M. Learning disabilities in children with very low birthweight: prevalence, neuropsychological correlates, and educational interventions. J Learn Disabil 2005; 38(2): 130–141. 31 Woodward LJ, Clark CA, Bora S, Inder TE. Neonatal white matter abnormalities an important predictor of neurocognitive outcome for very preterm children. PLoS One 2012; 7(12): e51879. 32 Leijser LM, de Bruine FT, van der Grond J, Steggerda SJ, Walther FJ, van WezelMeijler G. Is sequential cranial ultrasound reliable for detection of white matter injury in very preterm infants? Neuroradiology 2010; 52(5): 397–406. 33 Khwaja O, Volpe JJ. Pathogenesis of cerebral white matter injury of prematurity. Arch Dis Child Fetal Neonatal Ed 2008; 93(2): F153–F161. 34 Graham EM, Holcroft CJ, Rai KK, Donohue PK, Allen MC. Neonatal cerebral white matter injury in preterm infants is associated with culture positive infections and only rarely with metabolic acidosis. Am J Obstet Gynecol 2004; 191(4): 1305–1310. 35 Procianoy RS, Silveira RC. Association between high cytokine levels with white matter injury in preterm infants with sepsis. Pediatr Crit Care Med 2012; 13(2): 183–187. 36 Chau TA, McCully ML, Brintnell W, An G, Kasper KJ, Vines ED et al. Toll-like receptor 2 ligands on the staphylococcal cell wall downregulate superantigen-induced T cell activation and prevent toxic shock syndrome. Nat Med 2009; 15(6): 641–648. 37 Semmler A, Widmann CN, Okulla T, Urbach H, Kaiser M, Widman G et al. Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors. J Neurol Neurosurg Psychiatry 2013; 84(1): 62–69. 38 Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 2010; 304(16): 1787–1794. 39 Chavan SS, Huerta PT, Robbiati S, Valdes-Ferrer SI, Ochani M, Dancho M et al. HMGB1 mediates cognitive impairment in sepsis survivors. Mol Med 2012; 18: 930–937. 40 Klingenberg C, Aarag E, Ronnestad A, Sollid JE, Abrahamsen TG, Kjeldsen G et al. Coagulase-negative staphylococcal sepsis in neonates. Association between antibiotic resistance, biofilm formation and the host inflammatory response. Pediatr Infect Dis J 2005; 24(9): 817–822.
Journal of Perinatology (2014), 125 – 129
ORIGINAL ARTICLE
Coagulase-negative staphylococcus sepsis in preterm infants and long-term neurodevelopmental outcome B Alshaikh1,2, W Yee2, A Lodha2, E Henderson1, K Yusuf2 and R Sauve1,2 OBJECTIVE: The objective of this study was to examine the impact of Coagulase-negative staphylococcus (CoNS) sepsis in preterm infants on the neurodevelopmental outcomes at 30 to 42 months corrected age (CA). STUDY DESIGN: This is a retrospective cohort study. All preterm infants born at o29 weeks gestational age between 1995 and 2008 and had a neurodevelopmetnal assessment at 30 to 42 months CA were eligible. The neurodevelopmetnal outcomes of infants exposed to CoNS sepsis were compared with infants unexposed to any type of neonatal sepsis. RESULT: A total of 105 eligible infants who were exposed to CoNS sepsis were compared with 227 infants with no neonatal sepsis. In univariate analysis, infants with CoNS sepsis were more likely to have total major disability (odds ratio (OR) ¼ 1.9; 95% CI: 1.07 to 3.38) and cognitive delay (OR ¼ 2.53; 1.26 to 5.14).There was no significant difference in the incidence of cerebral palsy, blindness and deafness between the two groups. After correcting for potential confounders, CoNS sepsis was associated with increased risk of cognitive delay (adjusted odds ratio (aOR) ¼ 2.23; 95% CI 1.01 to 4.9), but not with the total major disability (aOR ¼ 1.14; 95% CI: 0.55 to 2.34). CONCLUSION: Our study suggests that CoNS sepsis in preterm infants might be associated with increased risk for cognitive delay at 36 months CA. Journal of Perinatology (2014) 34, 125–129; doi:10.1038/jp.2013.155; published online 19 December 2013 Keywords: preterm; Coagulase-negative staphylococcus; neurodevelopmental outcome
INTRODUCTION The increased survival of extremely preterm infants has highlighted the importance of assessing and improving long-term outcomes of these infants. Long-term neurodevelopmental outcome studies have shown that about half of the extremely preterm infants develop cognitive impairment and as many as 15% develop cerebral palsy (CP).1 Cerebral white matter injury (WMI) is a valuable predictor of neurodevelopmental deficits in extremely preterm infants.2,3 WMI frequently results from inflammatory responses to many factors including antenatal and postnatal infection.4,5 Coagulase-negative staphylococcus (CoNS) is the most commonly isolated agent of postnatal infection in preterm infants.6–8 The incidence of CoNS infection in neonatal intensive care units (NICUs) varies between 1.3 and 30.9%, depending on gestational age (GA), birth weight and presence of intravascular catheters.9–11 CoNS typically demonstrate low virulence and low mortality rate compared with other bacterial infection.9 However, recent reports raised concerns about potential poor neurodevelopmental outcome in preterm infants exposed to CoNS sepsis in the neonatal period.12,13 These reports showed a higher incidence of CP13,14 and lower psychomotor developmental index12 on assessment at 18 to 24 months of age. This potential association between CoNS sepsis and neurodevelopmental outcome has never been studied beyond 2 years of age.12–14 We hypothesize that exposure to CoNS sepsis in extremely preterm infants born at o29 weeks GA would be associated with neurodevelopmental disability. The objective of our study was to describe the long-term neurodevelopmental outcome at 30 to 42
months corrected age among preterm infants exposed to CoNS sepsis in the neonatal period. Having a better understanding of the relationship between CoNS sepsis and long-term neurodevelopmental outcome will guide future management, prevention and prognostication of these extremely preterm infants.
METHODS Study design and study population This single-center, retrospective cohort study was conducted at Foothills Medical Centre in Calgary with B7000 deliveries annually. The study was approved by the conjoint health research ethics board. All infants born at o29 weeks GA and admitted to the NICU between 1 January 1995 and 31 December 2008 were identified from the neonatal database. We identified all blood, cerebral spinal fluid (CSF) and urine cultures obtained from all infants during their stay in NICU. Infants without available blood culture results, those with major congenital anomalies, and infants with Gram-negative organisms isolated from bloodstream, CSF or urine were excluded. CoNS sepsis was defined by a combination of1 suggestive clinical signs (temperature instability, irritability, hypotonia, feeding difficulties, poor perfusion, apnea, tachycardia and tachypnea),2 a positive single-organism sterile body fluids (blood, CSF or urine) culture for CoNS3 appropriate antibiotic treatment of X5 days. Each infant with CoNS sepsis was compared with subsequent two infants born at o29 weeks GA who were admitted to the NICU and never had positive blood, CSF or urine culture. The neonatal and neurodevelopmental outcomes of all eligible infants were obtained from the Perinatal Follow Up (PNFU) database. Every subject identified in the neonatal database to be eligible for the study was given a study number. Alberta Healthcare numbers of these subjects were used temporally to link neonatal and PNFU databases.
1 Department of Community Health Sciences, Faculty of Medicine, University of Calgary, Calgary, AB, Canada and 2Department of Pediatrics, University of Calgary, Calgary, AB, Canada. Correspondence: Dr B Alshaikh, Department of Pediatrics, Faculty of Medicine, University of Calgary, Room 780-1403 29th St NW, Calgary, T2N 2T9 AB, Canada. E-mail: [email protected] Received 12 August 2013; revised 26 October 2013; accepted 6 November 2013; published online 19 December 2013
Coagulase-negative staphylococcus sepsis B Alshaikh et al
126 The PNFU database contains pregnancy, delivery and neonatal morbidities abstracted from the hospital charts at death or discharge from the hospital by a trained research assistant. These include maternal age, maternal education, antenatal risk factors like smoking and alcohol use, GA, birth weight, sex, antenatal steroids, mode of delivery, multiple or singleton pregnancy, Apgar scores, umbilical arterial pH, respiratory distress syndrome, use of surfactant, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia (PVL), patent ductus arteriosus, necrotizing enterocolitis, retinopathy of prematurity (ROP) and duration of hospital stay in NICU. The neurodevelopmental outcome data were also collected from the PNFU database. During the study period, preterm infants were prospectively followed up with longitudinal multidisciplinary examinations at adjusted ages of 4, 8, 12, 18 and 36 months in the PNFU clinic at Alberta Children’s Hospital. Neurodevelopmental assessments were performed independently by neonatologist/developmental pediatrician, physiotherapist, certified psychologist, ophthalmologist and audiologist on every child. The neurological assessment included evaluation of tone, strength, reflexes and posture. All neurological and neurodevelopmental assessments were performed by individuals who were unaware that a study on association between CoNS sepsis in preterm infants and long-term neurodevelopmental outcome would be conducted in the population.
Definitions True CoNS sepsis was defined as described previously. Persistent CoNS sepsis defined as three or more consecutive positive blood cultures at least 48 h apart with the same CoNS species during a single septic episode.15,16 Meningitis was defined as positive CSF culture, white blood cell count of 430 cells mm 3, or baby treated with therapeutic course of antibiotics based on the other CSF findings.12 GA was defined as the best obstetric estimate that is based on early prenatal ultrasound, and obstetric history, unless the postnatal pediatric estimate of gestation age based on Ballard score differed from the obstetric estimate by 42 weeks. Respiratory distress syndrome was defined as the presence of respiratory signs including tachypnea, grunting and chest retraction, typical chest X-ray findings and/or treatment by surfactant with the need for mechanical ventilation for 424 h in the first 3 days of life. Intraventricular hemorrhage was defined according to the criteria of Papile et al.17 from head ultrasound. Patent ductus arteriosus was defined as clinical diagnosis plus treatment with indomethacin or surgical ligation or both. Bronchopulmonary dysplasia was defined as oxygen dependency at 36 weeks postmenstrual age for preterm infant who is born p32 weeks’ gestation.18 PVL was defined as parenchymal echo densities or lucencies around the ventricles from head ultrasound performed after 32 weeks postmenstrual age. Necrotizing enterocolitis was defined according to the modified criteria of Bell et al.19 (stage II or higher). ROP was defined according to the International Classification for ROP.20 CP was defined as a non-progressive motor impairment characterized by abnormal muscle tone in at least one extremity and decreased range or control of movements.21 Cognitive delay was defined as a score of 42 standard deviation below the mean on standardized assessment (Wechsler Preschool and Primary Scale of Intelligence-Revised, Bayley Scales of Infant Development II or Stanford-Binet IV).22 Deafness was defined as sensorineural hearing loss requiring amplification. Milder form of neurosensory hearing loss was defined when the impairment does not require amplification. Blindness was defined as visual acuity o20/200 following refractive correction.
Statistical analysis Descriptive statistics including means, medians and standard deviations were used to describe the study population. In order to compare between continuous variables in infants exposed and unexposed to CoNS sepsis, two-sample t-test or Mann–Whitney test were used. Chi-square test (contingency table method) was used to compare discrete variables unless the expected cell frequency was less than five and then Fisher’s exact test was performed. The association between CoNS sepsis and the presence of neurodevelopmental outcomes (CP, cognitive delay, deafness, blindness and total major disability) was examined using multivariable logistic regression with backward selection. Because of small event numbers in deafness and blindness, their association with CoNS sepsis were adjusted for GA only. For CP, cognitive delay and major disabilities, which had a greater number of outcome events, the associations were adjusted for GA, chorioamnionitis, severe intraventricular hemorrhage and use of postnatal Journal of Perinatology (2014), 125 – 129
steroids. These covariates were selected using a cautious approach consists of including them in the model if the P-value is o0.20 on the univariate analysis or if its inclusion resulted in change of 15% or more in the estimate of the main effect of CoNS sepsis exposure. In addition, any variable identified as confounder in the literature is highly considered for inclusion in the final model. Odds ratio (OR) and 95% confidence interval (CI) were computed for the outcomes. Significance for all tests was established at a P-value of o0.05. All P-values were based on two-sided test results. Stata version 11.0 software (Stata Corporation, College Station, TX, USA) was used for all data analyses.
RESULTS Study population From 1995 to 2008, a total of 1224 preterm infants o29 weeks were admitted to the regional NICU at Foothills Medical Centre. Of these, 181 infants were identified to have at least one blood, urine or CSF positive culture for CoNS based on the neonatal database. A total of 121 (66.8%) survival infants had true CoNS sepsis. The cumulative incidence of true CoNS sepsis was 13.1% over the 14 years period of the study. Of the 121, 118 (97.5%) infants had bloodstream infection. There were four cases of meningitis resulting from CoNS. Of the four, only one infant had positive blood culture. The other three infants who had meningitis and negative blood cultures had ventriculoperitoneal shunt. All collected urine samples in infants with CoNS sepsis were negative for CoNS organisms. The median (interquartile range) age for CoNS sepsis was 15 (9,21) days. Infants who had true CoNS sepsis were compared with 227 survival infants with no CoNS sepsis who met the inclusion/exclusion criteria for the study, and came to follow up clinic at age of 36 months. The proportion of infants who were lost to follow up was similar between the two groups (13.2 vs 13.4%). Eleven infants died in the CoNS group, of which 7 infants died during the initial hospitalization and 4 infants died after discharge from the hospital. In the uninfected group, 61 infants died, of which 49 infants died during the initial hospitalization and 12 infants died after discharge. Twenty-eight infants in the no CoNS group died in the first week of life whereas no one in the CoNS group died in the first week of life. There was no difference in the proportion of infants who died after the first week of life between the two groups (P ¼ 0.36). Figure 1 shows the flow diagram of the subjects in the study. The maternal characteristics were similar between preterm infants exposed and not exposed to CoNS sepsis. Infants with CoNS sepsis had lower GA (25.9±1.7 vs 26.2±1.7), lower birth weight (834±211 g vs 900±197 g), more likely to be small for gestational age (13.4 vs 5.7%) and to have lower cord pH (7.28±0.09 vs 7.30±0.09) and lower Apgar score at 5 min (median 7 vs 8). Table 1 shows the maternal and neonatal characteristics of infants with and without CoNS sepsis in the neonatal period. The common neonatal morbidities between the two groups are presented in Table 2. CoNS sepsis was more likely to associate with respiratory distress syndrome (89.5 vs 80.6%), severe ROP (37.1 vs 22.5%) and use of postnatal steroid (36.2 vs 18.5%). All these differences were no longer significant after adjusting for GA. The median length of hospital stay was longer in infants with CoNS sepsis (38 (20, 59) vs 24 (7, 46); Po0.001). This difference continued to be significant after adjusting for GA (12 days; 95% CI 7.1 to 16.9). Neurodevelopmental outcomes The mean age at neurodevelopmental follow-up was similar between the infants exposed and unexposed to CoNS sepsis (37.1±2.1 months in the CoNS group vs 36.9±1.85 months in the group without CoNS; P ¼ 0.4). On bivariate analysis, infants with CoNS sepsis had increased rate of total major neurodevelopmental impairment (NDI) (24.7 vs 14.9%; P ¼ 0.03) and cognitive delay (17.1 vs 7.5%, P ¼ 0.01) when compared with infants without CoNS & 2014 Nature America, Inc.
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127
Figure 1.
Flow diagram of the subjects in the study.
Table 1.
Comparison of maternal and neonatal characteristics between infants exposed and unexposed to CoNS sepsis No CoNS group (n ¼ 227) Maternal characteristics Maternal age, mean (s.d.) Antenatal steroids, n (%) Multiple births, n (%) Chorioamnionitis, n (%) Cesearean section, n (%) Use of antibiotics during labor, n (%) Mothers completed high school, n (%) Smoking, n (%) Neonatal characteristics Gestational age, mean (week)±s.d. Birth weight, mean (g)±s.d. Male (%) SGA (%) Apgar score at 5 min, median (IQR) Cord pH, mean±s.d.
29.2 183 46 60 106 148
(5.9) (82.8) (20.3) (27.9) (46.9) (67.9)
CoNS group (n ¼ 105) 29.4 82 31 19 55 66
P-value
(5.4) (79.6) (29.5) (18.8) (52.4) (63.5)
0.79 0.49 0.06 0.08 0.35 0.43
177 (84.3)
83 (81.3)
0.51
35 (15.8)
16 (15.5)
0.94
26.2±1.4
25.9±1.7
0.04
900±197
834±211
0.01
116 (51.1) 13 (5.7) 8 (6, 8)
63 (60) 14 (13.4) 7 (6, 8)
0.13 0.02 0.03
7.30±0.09
7.28±0.09
0.02
Abbreviations: CoNS, Coagulase-negative staphylococcus; IQR, interquartile range; SGA, small for gestational age.
sepsis (Table 3). However, adjusting for potential confounders including GA, chorioamnionitis, severe intraventricular hemorrhage and the use of postnatal steroids showed increased risk for cognitive delay (OR ¼ 2.23; 95% CI: 1.01 to 4.9), but not for total major disability (OR ¼ 1.14; 95% CI: 0.55 to 2.34). Since a significant proportion of study infants had CoNS sepsis before receiving postnatal steroids (which could be involved in the causal pathway linking CoNS and adverse neurodevelopmental outcome), we elected to report the outcomes without plugging the steroid in the models. The OR for cognitive delay was 2.36 (95% CI: 1.1 to 5.07), and for major disability was 1.85 (95% CI: 0.96 to 3.57). Of the 332 infants included in the study, 304 (91.5%) had cognitive testing. The mean cognitive score was 90.8±21 in the CoNS group as compared with 94.7±16.3 in infants without CoNS sepsis. There were no significant differences in the rates of CP (10.6 vs 10.4%), & 2014 Nature America, Inc.
blindness (1 vs 1.7%) and deafness (5 vs 2.2%) between the two groups. Of interest, when we include the milder form of neurosensory deafness looking for any neurosensory impairment, children exposed to CoNS sepsis were at risk (9.6 vs 3.1%; P ¼ 0.01). Excluding the four infants with meningitis from the analysis did not alter the results of neurodevelopmental outcome.
DISCUSSION The cumulative incidence of CoNS sepsis in the current study (13.1%) is similar to that reported previously.6 Our study shows that CoNS sepsis is associated with respiratory distress syndrome, patent ductus arteriosus and severe ROP (grade 3 and 4). This association turned out to be no longer significant after correcting for GA. In the current study, CoNS sepsis has no association with total major NDI in extremely preterm infants. However, the assessment of the type-specific NDI showed that CoNS sepsis is independently associated with a 2.2-fold increased odds for cognitive delay in this population. Our study supports the findings reported by Shah et al.12 who found a significant difference in the psychomotor developmental index at 2 years of age in infants exposed to CoNS sepsis when compared with unexposed infants. The mean difference after correcting for potential confounders in the former study was 5.8 points (95% CI: 0.3 to 11.2; P ¼ 0.04). The lower psychomotor developmental index in infants with sepsis was mediated by WMI.12 In contrast to our findings, a study by Schlapbach et al.13 showed increased risk for developing CP in infants exposed to CoNS sepsis. However, the total number of infants with CP was limited to 14 children in this study.14 Our study revealed similar proportion of CP in infants exposed and unexposed to CoNS sepsis. Cerebral lesion and particularly PVL are the most important predictors of CP in very preterm infants.23 Silveira et al.24 reported that neonatal sepsis (61% resulted from CoNS) is an independent risk factor for PVL in very preterm infants. However, the proportion of infants with PVL in their study was high (57.8%) compared with only (3%) in our cohort. Similarly, Stoll et al.14 reported increased risk of CP (OR ¼ 1.4; 95% CI 1.0 to 1.9) in infants exposed to CoNS sepsis, but no difference in cognitive delay. The cognitive outcome of Stoll’s study was a result of a single-point follow-up at 18 to 22 months corrected age. Assessment of cognitive outcome at 18 to 22 months corrected age may encounter many difficulties as the rate of acquiring new skills in these infants differs largely during this period.25 Journal of Perinatology (2014), 125 – 129
Coagulase-negative staphylococcus sepsis B Alshaikh et al
128 Table 2.
Comparison of neonatal outcomes between infants exposed and unexposed to CoNS sepsis No CoNS group (n ¼ 227)
Characteristics RDS, n (%) Severe IVH, n (%) PDA, n (%) NEC, n (%) Severe ROP Xstage 3, n (%) BPD, n (%) Postnatal steroid, n (%) Length of stay day, median (IQR)
183 22 141 31 51 170 42 81
CoNS group (n ¼ 105)
(80.6) (9.6) (62.1) (13.6) (22.5) (74.9) (18.5) (70, 100)
94 13 84 23 39 86 38 98
P-value
(89.5) (12.3) (80) (21.9) (37.1) (81.9) (36.2) (79, 124)
0.047 0.46 0.001 0.06 0.005 0.16 0.001 o0.001
Abbreviations: BPD, bronchopulmonary dysplasia; CoNS, Coagulase-negative staphylococcus; IQR, interquartile range; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; RDS, respiratory distress syndrome; ROP, retinopathy of prematurity.
Table 3.
Neurodevelopmental outcomes
Neurodevelopmental outcome
CP Cognitive delay Blindness Deafness Major NDI
Unadjusted OR
Adjusted OR
OR
95% CI
P-value
OR
95% CI
P-value
0.99 2.53 0.54 2.7 1.9
0.46–2.10 1.24–5.14 0.06–4.93 0.8–9.07 1.07–3.38
0.97 0.01 0.59 0.10 0.03
0.63 2.23 0.35 2.24 1.14
0.24–1.64 1.01–4.9 0.03–3.37 0.64–7.73 0.55–2.34
0.34 0.048 0.36 0.20 0.71
Abbreviations: CP, cerebral palsy; GA, gestational age; IVH, intraventricular hemorrhage; NDI, neurodevelopmental impairment. CP, cognitive outcome and major NDI were adjusted for GA, severe IVH, chorioamnionitis and postnatal steroids. Deafness and blindness were adjusted for GA only as severe IVH, chorioamnionitis and sex did not seem to alter the outcome.
A recent systematic review and meta-analysis on neonatal sepsis in very low birth weight infants and long-term neurodevelopmental outcomes showed that neonatal sepsis increases the risk of any type NDI by twofold.26 The subgroup analysis of NDI in infants exposed to CoNS sepsis showed similar findings to the overall sepsis, but the magnitude was smaller (OR 1.3; 95% CI 1.09 to 1.57). However, the studies included in this meta-analysis were heterogeneous, and the number of studies reporting the NDI in CoNS sepsis group was very limited. Number of children with blindness was very small. The findings of no difference in deafness requiring amplification between the two groups were consistent with Stoll’s study.14 However, including the milder form of neurosensory deafness in the total hearing impairment revealed that children exposed to CoNS sepsis were at risk for any hearing loss. Use of antibiotics such as vancomycin and gentamicin in preterm infants is shown to increase the risk of neurosensory hearing impairment.27,28 These antibiotics are commonly used to treat CoNS sepsis and are proposed to be a possible cause of hearing impairment in this population. Recent studies have shown that 15 to 20% of very preterm infants are at risk for severe neurodevelopmental delay, and 40 to 50% of this population have some degree of cognitive delay.29,30 Cognitive delay is highly correlated with WMI.31 Diagnosis of WMI needs a brain magnetic resonance imaging at term equivalent gestation. Yet, there is no agreement on the routine use of brain magnetic resonance imaging for extremely preterm infants. Alternatively, cranial ultrasound is a screening tool for PVL, but its ability to detect other white matter abnormalities is limited.32 The pathogenesis of WMI resulting from CoNS sepsis is thought to be similar to other postnatal sepsis in preterm infants. It has two related mechanisms (upstream and downstream).33 Production of pro-inflammatory cytokines, increase of blood–brain barrier permeability, hypoxic ischemic events resulting from hypotension and impaired autoregulation of cerebral blood flow represent the upstream mechanisms to stimulate the brain’s microglia.4,24,34,35 This leads to activation of downstream mechanisms which include excitotoxicity and free radical attack caused by reactive oxygen Journal of Perinatology (2014), 125 – 129
and nitrogen species.33 This activation subsequently leads to the death of the vulnerable pre-myelinating oligodendrocytes.33 Evidence from animal studies showed that signaling toll-like receptor 2 (TLR2) and TLR6 presented on microglia (the resident immune cells of the brain) by staphylococcus bacteria leads to increase in lysosomal activity and massive production of IL-10 followed by apoptosis of these cells.36 Subsequently, this participates in the damage to other precious neurons around the microglia. Critical care studies in adult patients and animal studies have demonstrated a permanent cognitive impairment in severe sepsis survivors.37 This impairment has correlated with hippocampus atrophy.37–39 The strengths of the current study include a high rate (86%) of comprehensive multidisciplinary follow up. All neurodevelopmental assessments were performed by individuals who were unaware that this study would be conducted in the perinatal follow up clinic. The neurodevelopmental assessment at 36 months corrected age provided more accurate diagnosis than all assessments of outcome at less than 24 months of age. This is particularly important for assessment of cognitive outcome as all earlier tests are not highly predictive and transient neurological abnormalities seen before 24 months will be avoided. Use of a priori operational definitions provided an accurate tool to protect the study from measurement bias. There are several limitations of our study, including being a single report of the only perinatal follow up clinic of southern Alberta, thus it reflected the unique diagnostic and follow-up experience of this ‘single’ center. Using single blood culture to define CoNS sepsis could have resulted in including infants with contaminant blood culture in the study; however, this would have resulted in dilution of the effect toward null. Use of additional criteria to the definition including changes in infection laboratory indicators such as complete blood cell count, C-reactive protein and so on was thought to be helpful in lowering the risk of CoNS contamination, but was not feasible as the data on complete blood cell count and C-reactive protein were not available. In addition, the fact that many preterm infants have a decreased & 2014 Nature America, Inc.
Coagulase-negative staphylococcus sepsis B Alshaikh et al
129 inflammatory response to various types of CoNS organism limits the benefit of using these markers.40 The retrospective design limits the ability to investigate the biological pathways of the association between the CoNS sepsis and cognitive impairment. In conclusion, CoNS sepsis might be associated with an increased risk of cognitive delay in preterm infants born at o29 weeks GA. This study alerts health care providers to actively use infection control strategies to protect all preterm infants in NICU from CoNS sepsis. It also emphasizes the importance of long-term follow-up of preterm infants with CoNS sepsis, and helps clinicians for counseling parents of preterm infants with CoNS sepsis. CONFLICT OF INTEREST The authors declare no conflict of interest.
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