Association between sepsis and retinopathy of prematurity: a systematic review and meta-analysis.

OBJECTIVE: To explore the association between sepsis and retinopathy of prematurity (ROP) in premature infants. DESIGN: A systematic review and meta-analysis. DATA SOURCES: We performed a systematic search of PubMed, the Cochrane Library and Embase from 1 January, 2000, to 1 January, 2018, with no language restrictions and reported the relationship between sepsis and ROP. ELIGIBILITY CRITERIA: Original observational studies, including cohort studies and case-control studies. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently completed the study selection and data extraction. The OR and corresponding 95% CI were used to measure the risk of sepsis in patients with ROP. The heterogeneity between studies was evaluated using Cochran's Q test and the I2 statistic. The Newcastle-Ottawa Scale was adopted to evaluate the quality of each of the included studies, and the Grading of Recommendations Assessment, Development and Evaluation approach was used to assess the quality of the evidence. RESULTS: Sixteen studies with a total sample size of 12 466 premature infants and 2494 cases of ROP were included in this meta-analysis. Adjusted analysis showed that sepsis was closely related to any stage of ROP (OR = 1.57, 95% CI 1.31 to 1.89) and severe stage of ROP (OR = 2.33, 95% CI 1.21 to 4.51) in premature infants, with 56.3% and 81.8% heterogeneity, respectively. Subgroup analyses showed that heterogeneity was obvious in prospective cohort studies (I2 = 62.1%, p<0.001). In a sensitivity analysis, we found that removing any single study did not significantly change the overall effect value. The quality of the evidence was rated as low for both any stage of ROP and severe stage of ROP. CONCLUSIONS: Sepsis increases the risk of ROP in preterm infants. However, considering that all included studies are observational and causality can rarely be established, additional evidence is needed to substantiate this finding and provide advice for practice.

Beyond sepsis: Staphylococcus epidermidis is an underestimated but significant contributor to neonatal morbidity.

Staphylococcus epidermidis accounts for the majority of cases of neonatal sepsis. Moreover, it has been demonstrated to be associated with neonatal morbidities, such as bronchopulmonary dysplasia (BPD), white matter injury (WMI), necrotizing enterocolitis (NEC) and retinopathy of prematurity (ROP), which affect short-term and long-term neonatal outcome. Imbalanced inflammation has been considered to be a major underlying mechanism of each entity. Conventionally regarded as a harmless commensal on human skin, S. epidermidis has received less attention than its more virulent relative Staphylococcus aureus. Particularities of neonatal innate immunity and nosocomial environmental factors, however, may contribute to the emergence of S. epidermidis as a significant nosocomial pathogen. Neonatal host response to S. epidermidis sepsis has not been fully elucidated. Evidence is emerging regarding the implication of S. epidermidis sepsis in the pathogenesis of neonatal inflammatory diseases. This review focuses on the interplay among S. epidermidis, neonatal innate immunity and inflammation-driven organ injury.

Perinatal infection, inflammation, and retinopathy of prematurity.

The major known risk factors for retinopathy of prematurity (ROP) are extremely low gestational age, exposure to high levels of oxygen early after birth (phase I) and relatively lower oxygen levels later (phase II). In this review, we summarize recent data suggesting that exposure to perinatal infection/inflammation is associated with an increased risk for ROP. Part of this effect might be due to direct exposure of the developing retina to circulating products of infection and/or inflammation. Another potential mechanism that deserves exploration is that inflammation and/or oxidative stress can modify the known increased risk of oxygen-associated ROP. Taken together, accumulating evidence suggests that prenatal, perinatal, and postnatal systemic inflammation contribute to a 'pre-phase', sensitizing the pre-ROP retina for subsequent insults, setting the stage for what are now called phase I and phase II of ROP pathogenesis. Strategies targeting inflammatory responses might help reduce the risk for ROP in extremely low gestational age newborns.

Neonatal bacteremia and retinopathy of prematurity: the ELGAN study.

OBJECTIVE: To explore whether early or late and presumed or definite neonatal bacteremia are associated with an increased risk of severe retinopathy of prematurity (ROP). METHODS: We evaluated 1059 infants born before week 28 of gestation for ROP. Infants were classified as having early (postnatal week 1) or late (weeks 2-4) definite (culture-proven) or presumed (antibiotics taken for >72 hours despite negative blood culture results) bacteremia. Severe ROP was defined as stage 3 to 5, zone 1, prethreshold/threshold, or plus disease. We used time-oriented risk models to adjust for confounders. RESULTS: In univariable, but not multivariable, analysis, newborns with presumed early bacteremia were at increased risk for plus disease (odds ratio [OR], 1.7; 95% CI, 1.1-2.7), and those with definite early bacteremia were at increased risk for stage 3 to 5 disease (1.9; 1.1-3.2). Infants who had presumed or definite late bacteremia were at increased risk for all 4 indicators of severe ROP in univariable analysis. In multivariable analysis, newborns with presumed late bacteremia were at increased risk for prethreshold/threshold ROP (OR, 1.8; 95% CI, 1.02-3.2), and those with definite late bacteremia were at increased risk for prethreshold/threshold ROP (1.8; 1.1-2.9) and plus disease (1.8; 1.05-2.9). CONCLUSIONS: Definite late neonatal bacteremia seems to be an independent risk factor for prethreshold/threshold ROP and plus disease, and presumed late bacteremia seems to be related to prethreshold/threshold ROP.

Systemic fungal infection is associated with the development of retinopathy of prematurity in very low birth weight infants: a meta-review.

OBJECTIVE: To study the association between systemic fungal infection (SFI) and the development of retinopathy of prematurity (ROP) and severe ROP in very low birth weight (VLBW) infants by systematic review and meta-analysis. STUDY DESIGN: A meta-review was performed using a fixed effects model. The exposure and outcomes studied were SFI and all ROP/severe ROP, respectively in VLBW infants. Results and effect sizes analyzed with Review Manager 4.2 software are expressed as relative risk (RR), odds ratio (OR), risk difference (RD) and number needed to harm (NNH) with 95% confidence intervals. RESULT: Data for severe ROP were available from eight studies and on all ROP from seven of those eight studies. Estimated gestational age ranged from 24.7+/-1.6 to 28.6+/-4 weeks and birth weight from 673 (median) (range 426 to 995) to 1108+/-266 g (mean+/-s.d.). A total of 261 of 303 babies with SFI had all ROP vs 1081 of 1648 babies without SFI (OR 3.4(*), 2.34-4.95) and 118 of 330 babies with SFI had severe ROP vs 235 of 1951 babies without SFI (OR 4.06(*), 3.05-5.42). The NNH was 5.56(*) (4.54-7.14) for all ROP and 4.54(*) (3.70 to 5.88) for severe ROP ((*) P<0.00001). CONCLUSION: SFIs are associated with the development of all degrees of ROP and severe ROP in VLBW infants.

Association of candidemia and retinopathy of prematurity in very low birthweight infants.

OBJECTIVE: To determine if the presence of candidemia in infants is associated with an increased incidence of threshold retinopathy of prematurity (ROP). DESIGN: Retrospective, case-controlled study. PARTICIPANTS AND CONTROLS: Forty-six infants admitted to the Texas Children's Hospital Neonatal Intensive Care Unit between 1989 and 1999 with a birth weight 1500 g or less, estimated gestational age (EGA) 28 weeks or less, and in whom candidemia developed were matched to a control group of 46 infants based on corresponding birth weight, EGA, and year of birth. METHODS: Records of each infant were reviewed to determine the presence and severity of ROP. MAIN OUTCOME MEASURES: Development of threshold ROP, including retinal detachment. RESULTS: Forty-three infants (93.5%) with candidemia and 39 (84.8%) without candidemia had ROP. Twenty-four infants (52.2%) with candidemia reached threshold and required surgical intervention, compared with 11 infants (23.9%) without candidemia (adjusted odds ratio [OR], 7.4; 95% confidence interval [CI], 1.7-32.1; P = 0.008). Retinal detachment developed in 10 of 24 candidemic infants (41.7%) who reached threshold ROP, compared with 2 of 11 infants (18.2%) without candidemia (OR, 4.4; 95% CI, 0.73-26.9; P = 0.1). CONCLUSIONS: Candidemia is associated with increased risk of threshold ROP. Infants with Candida sepsis should be monitored closely for the development of ROP and progression after treatment.

Does candidemia predict threshold retinopathy of prematurity in extremely low birth weight (

BACKGROUND: Extreme prematurity is a risk factor for both candidemia and threshold retinopathy of prematurity (ROP) and may confound the reported association between these conditions. OBJECTIVE: To determine if candidemia is an independent risk factor for threshold ROP. METHODS: A cohort study was conducted of infants weighing 3 days of age, and 5 were discharged or transferred before ROP screening. A total of 449 infants were included in the study; 58 (13%) developed threshold ROP. Candidemia occurred in 58 (13%) infants before developing the worst stage of ROP. Candidemia occurred in 27 of 73 (37%) at 23 to 24 weeks' gestational age (GA), 25 of 197 (13%) at 25 to 26 weeks' GA, and 6 of 129 (5%) at 27 to 28 weeks' GA, 0 of 50 >28 weeks' GA. Similarly, threshold ROP occurred in 25 of 73 (34%) at 23 to 24 weeks' GA, 26 of 197 (13%) at 25 to 26 weeks' GA, and 6 of 129 (5%) at 27 to 28 weeks' GA, and 1 of 50 (2%) >28 weeks' GA. Threshold ROP developed in 19 of 58 (33%) infants with a history of candidemia and 39 of 391 (10%) without candidemia. Proportional hazards analysis indicated that GA in weeks (hazard ratio =.75; 95% confidence interval [CI]:. 61,.93) and non-black ethnicity (hazard ratio = 1.8; 95% CI: 1.05, 3. 08) were significantly associated with threshold ROP. After controlling for GA and other factors, candidemia did not remain significantly associated with threshold ROP (hazard ratio = 1.6; 95% CI:.89, 2.89). CONCLUSION: Candidemia may not be an independent risk factor for threshold ROP in extremely low birth weight infants. The magnitude of the previously reported association between candidemia and threshold ROP (more than fivefold) is unlikely and much of the clinically observed association appears to be mediated by gestational age.

Systemic candidiasis in babies with retinopathy of prematurity.

Fifteen premature babies developed systemic candidiasis during the administration of intravenous hyperalimentation in the Beilinson Neonatal Intensive Care Unit. Candida albicans was found in the blood cultures of all the babies and in the urine cultures of 66.7% of them. Repeated funduscopic examinations revealed no evidence of septic embolization in the retinal or choroidal circulation. It should be noted that acute retinopathy of prematurity (ROP) grade 2 or 3 was found in all the babies.