In this large, multicenter, national retrospective cohort, the IFI rate among all admitted neonates was extremely low at approximately 1 in every 500 admitted neonates; however, the incidence was higher among lower GA and lower BW groups. CFR was approximately 1 in 3 for all categories of patient characteristics and IFI subtypes. Compared with those without IFI, preterm neonates of <33 weeks GA who had an IFI were associated with higher odds of mortality, NEC and severe ROP. C. albicans and C. parapsilosis were responsible for 80% of IFI cases.
Our reported IFI incidences of 0.12%–0.28% of IFI throughout the study period, including 0.64% among infants <33 weeks GA, 0.90% among the VLBW group and 1.78% among the ELBW group, were lower in comparison to other large population cohort studies including those from the National Epidemiology of Mycosis Survey study group,22 Pediatrix Medical Group,23 Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network from United States,24 though similar to the National prospective surveillance study from United Kingdom.8 Our CFRs of 30.8%–36.2% are not different to the 27.6%–48.0% reported mortality rates associated with Candida bloodstream infections in other cohorts.4 , 5 , 25 We speculate that our country’s lower overall rates of late-onset sepsis and antibiotic utilization may be responsible for our observed trends, considering that antibiotic utilization is a major risk factor for developing IFI.1 , 26 It is well known that antibacterial therapy increases the density of Candida colonization by reducing the competitive pressure exerted by commensal bacteria.1 , 27
In our study, risk factors identified for IFI were lower gestation, male sex, higher illness severity, maternal diabetes and birth via vaginal route. Neonates born at lower GA and BW have immature gastrointestinal tracts and skin, impaired immune function, frequent sepsis evaluations and exposure to antibiotics and increased need for central venous catheterization. All of these factors contribute to the pathogenesis of IFIs.1 Moreover, preterm infants are more likely to require postnatal rescue steroids, which alter the number and function of T-lymphocytes and inhibit phagocytosis of Candida spp.14 , 28 Studies have shown that risk of vaginal Candida colonization in pregnant women is much higher in women with diabetes29 and birth via vaginal route increases the likelihood for colonization by pathogens of the Candida species,11 which were reflected in our findings.
IFI is associated with substantial adverse neonatal outcomes, with at least one-fifth of cases developing ophthalmologic, visceral or cardiac complications.30 In our cohort, infants with IFI had increased odds of mortality, NEC and severe ROP. Meta-analyses have shown that systemic fungal infections are associated with the development of all degrees of retinopathy in VLBW infants, which could be related to the increased production of inflammatory cytokines, resulting in damage to the developing blood vessels in the retina.2 , 31 NEC and other gastrointestinal pathologies are known to be associated with candidiasis among premature infants, which is likely because of translocation of the pathogen across the colonized gastrointestinal tract.10 , 15 Moreover, infants with NEC often receive broad-spectrum intravenous antibiotics for varying periods of time, which by itself, also raises the risk of IFI.1 , 19
In the literature, most infant cases of IFIs are caused by relatively few species.1 In the 10-year population study of neonatal and pediatric candidemia in England and Wales, C. albicans and C. parapsilosis account for most infections in all age groups. In our cohort, C. albicans and C. parapsilosis accounted for 4 of 5 cases of IFI, a pattern similar to other published studies.10 , 32 , 33 Unlike the concerning rising trend of candidemia caused by species with inherent or potential resistance to fluconazole in adult populations, C. krusei and C. glabrata accounted only for a relatively small proportion, if any, of our cases, which is comparable to other neonatal cohorts.10 , 11 , 32 Less than 5% of our isolates were identified as C. lusitaniae, which may bring additional challenges to treatment because of their resistance to amphotericin B, a commonly used broad-spectrum antifungal agent.34
The main strength of our study is the inclusion of a large number of infants from a national neonatal network that captured the majority of tertiary level NICU admissions over a decade period. This enabled us to conduct a comprehensive analysis of IFI rates to determine whether prophylactic antifungal therapy should be revisited in Canada. However, our study has some limitations. First, data on the duration and type of antibiotics received before the development of IFI were not available. This is important information to achieve a better understanding of the chronology of IFI, as well as specific antibiotic risk categories for the development of IFI. Second, information on the insertion of a central catheter in situ at the time of development of IFI was not captured, which may have played a critical role in its pathogenesis.5 , 10 , 22 , 24 Third, we did not use an active surveillance study design to capture details of risk factors at the time of identification of infection; therefore, this prevents us from providing more conclusive results. There could be different approaches to the initiation and choice of antifungals across the whole study period and between sites, which might potentially affect the development of IFI. Neither did we capture the susceptibility of organisms to the antifungal agents. Also, we cannot rule out a minority of infants with fungi grown at sterile sites other than blood or CSF, as quoted in another study.24 We did not include positive urine growth of fungi as cases of invasive infection because of lack of standardized definitions of urinary tract infection in neonatal populations.35 Including these infants may underestimate the case-fatality. Also, CNN started collecting the data of NEC and spontaneously intestinal perforation (SIP) separately since 2010. Thus, neonates with SIP would not be included in our analysis during 2010–2013. However, for admissions between 2003 and 2009, we might include neonates who had SIP in the group classified as NEC. Finally, there is the possibility of ascertainment bias in our study, particularly among neonates who presented with significant systemic compromise and could not provide proper samples for evaluation of an IFI. However, this is probably unlikely given the fact that >85% of neonates born and admitted to NICUs were included in our population.
In summary, we found the overall incidence of IFI in neonates was low in Canada in comparison to other large population cohort studies; however, the mortality and morbidity remained high.
The authors gratefully acknowledge all site investigators of the Canadian Neonatal Network (CNN). We would also like to thank the data abstractors of the CNN, as well as the staff at the Maternal-Infant Care Research Centre at Mount Sinai Hospital, Toronto, ON, for providing organizational support for this project. Specifically, we extend our thanks to Philip Ye, MSc, for statistical support, and Natasha Musrap, PhD, for editorial assistance.
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Investigators of the Canadian Neonatal Network: Prakesh S. Shah, MD, MSc (Director, Canadian Neonatal Network and site investigator), Mount Sinai Hospital, Toronto, ON, Canada; Adele Harrison, MD, MB ChB, Victoria General Hospital, Victoria, BC, Canada; Anne Synnes, MDCM, MHSC, and Joseph Y. Ting, MD, B.C. Women’s Hospital and Health Centre, Vancouver, BC, Canada; Zenon Cieslak, MD, Royal Columbian Hospital, New Westminster, BC, Canada; Rebecca Sherlock, MD, Surrey Memorial Hospital, Surrey, BC, Canada; Wendy Yee, MD, Foothills Medical Centre, Calgary, AB, Canada; Khalid Aziz, MBBS, MA, MEd, and Jennifer Toye, MD, Royal Alexandra Hospital, Edmonton, AB, Canada; Carlos Fajardo, MD, Alberta Children’s Hospital, Calgary, AB, Canada; Zarin Kalapesi, MD, Regina General Hospital, Regina, Saskatchewan; Koravangattu Sankaran, MD, MBBS, and Sibasis Daspal, MD, Royal University Hospital, Saskatoon, Saskatchewan, Canada; Mary Seshia, MB ChB, Winnipeg Health Sciences Centre, Winnipeg, MB, Canada; Ruben Alvaro, MD, St. Boniface General Hospital, Winnipeg, MB, Canada; Amit Mukerji, MD, Hamilton Health Sciences Centre, Hamilton, ON, Canada; Orlando da Silva, MD, MSc, London Health Sciences Centre, London, ON, Canada; Chuks Nwaesei, MD, Windsor Regional Hospital, Windsor, ON, Canada; Kyong-Soon Lee, MD, MSc, Hospital for Sick Children, Toronto, ON, Canada; Michael Dunn, MD, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; Brigitte Lemyre, MD, Children’s Hospital of Eastern Ontario and Ottawa General Hospital, Ottawa, ON, Canada; Kimberly Dow, MD, Kingston General Hospital, Kingston, ON, Canada; Victoria Bizgu, MD, Jewish General Hospital, Montréal, QC, Canada; Keith Barrington, MB ChB, Hôpital Sainte-Justine, Montréal, QC, Canada; Christine Drolet, MD, and Bruno Piedboeuf, MD, Centre Hospitalier Universitaire de Québec, Sainte Foy, QC, Canada; Martine Claveau, MSc, LLM, NNP, and Marc Beltempo, MD, McGill University Health Centre, Montréal, QC, Canada; Valerie Bertelle, MD, and Edith Masse, MD, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada; Roderick Canning, MD, Moncton Hospital, Moncton, NB, Canada; Hala Makary, MD, Dr. Everett Chalmers Hospital, Fredericton, NB, Canada; Cecil Ojah, MBBS, and Luis Monterrosa, MD, Saint John Regional Hospital, Saint John, NB, Canada; Akhil Deshpandey, MBBS, MRCPI, Janeway Children’s Health and Rehabilitation Centre, St. John’s, Newfoundland; Jehier Afifi, MB BCh, MSc, IWK Health Centre, Halifax, NS, Canada; Andrzej Kajetanowicz, MD, Cape Breton Regional Hospital, Sydney, NS, Canada; Shoo K. Lee, MBBS, PhD (Chairman, Canadian Neonatal Network), Mount Sinai Hospital, Toronto, ON, Canada.