Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial.

IMPORTANCE: Invasive candidiasis in premature infants causes death and neurodevelopmental impairment. Fluconazole prophylaxis reduces candidiasis, but its effect on mortality and the safety of fluconazole are unknown. OBJECTIVE: To evaluate the efficacy and safety of fluconazole in preventing death or invasive candidiasis in extremely low-birth-weight infants. DESIGN, SETTING, AND PATIENTS: This study was a randomized, blinded, placebo-controlled trial of fluconazole in premature infants. Infants weighing less than 750 g at birth (N = 361) from 32 neonatal intensive care units (NICUs) in the United States were randomly assigned to receive either fluconazole or placebo twice weekly for 42 days. Surviving infants were evaluated at 18 to 22 months corrected age for neurodevelopmental outcomes. The study was conducted between November 2008 and February 2013. INTERVENTIONS: Fluconazole (6 mg/kg of body weight) or placebo. MAIN OUTCOMES AND MEASURES: The primary end point was a composite of death or definite or probable invasive candidiasis prior to study day 49 (1 week after completion of study drug). Secondary and safety outcomes included invasive candidiasis, liver function, bacterial infection, length of stay, intracranial hemorrhage, periventricular leukomalacia, chronic lung disease, patent ductus arteriosus requiring surgery, retinopathy of prematurity requiring surgery, necrotizing enterocolitis, spontaneous intestinal perforation, and neurodevelopmental outcomes-defined as a Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy at 18 to 22 months corrected age. RESULTS: Among infants receiving fluconazole, the composite primary end point of death or invasive candidiasis was 16% (95% CI, 11%-22%) vs 21% in the placebo group (95% CI, 15%-28%; odds ratio, 0.73 [95% CI, 0.43-1.23]; P = .24; treatment difference, -5% [95% CI, -13% to 3%]). Invasive candidiasis occurred less frequently in the fluconazole group (3% [95% CI, 1%-6%]) vs the placebo group (9% [95% CI, 5%-14%]; P = .02; treatment difference, -6% [95% CI, -11% to -1%]). The cumulative incidences of other secondary outcomes were not statistically different between groups. Neurodevelopmental impairment did not differ between the groups (fluconazole, 31% [95% CI, 21%-41%] vs placebo, 27% [95% CI, 18%-37%]; P = .60; treatment difference, 4% [95% CI, -10% to 17%]). CONCLUSIONS AND RELEVANCE: Among infants with a birth weight of less than 750 g, 42 days of fluconazole prophylaxis compared with placebo did not result in a lower incidence of the composite of death or invasive candidiasis. These findings do not support the universal use of prophylactic fluconazole in extremely low-birth-weight infants. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00734539.

The effect of recombinant human erythropoietin on the development of retinopathy of prematurity.

In addition to its hematopoietic effects, erythropoietin causes an increased release of endothelin-1 and the stimulation of angiogenesis and thereby it may have possible role in development of retinopathy of prematurity (ROP). Our objective was to determine if an association exists between recombinant human erythropoietin (rhEPO) treatment and the development of ROP. Our case-control study involved 85 very low birthweight infants with birthweights <1500 g born during 2003 and 2004. All the infants were divided into two groups on the basis of whether they got rhEPO or not. The rhEPO was given at the dose of 200 to 250 units/kg/dose three times a week for 10 doses. Further duration of rhEPO therapy was decided on the basis of the clinical response. Ophthalmological examinations were done at the age of 5 to 6 weeks and were repeated 1 to 4 weeks after the first examination according to the severity of the ROP disease during their in-hospital stay. Of 85 infants, 56 (66%) received rhEPO and 29 (34%) did not. In the rhEPO-treated group, 12 infants (21%) had ROP; in the non-rhEPO group, 11 infants (38%) developed ROP. This difference is not statistically significant (odds ratio = 2.63; P = 0.10). There was no correlation between the use of rhEPO and the stage of ROP (random sample = -0.01; P = 0.89). There was no significant difference in the incidence of plus, prethreshold, or threshold disease and the treatment required for ROP between the rhEPO-treated and the nontreated group. The study showed there is no significant difference in the incidence and severity of ROP between the rhEPO-treated and nontreated group.