Neonatal Sepsis Episodes and Retinopathy of Prematurity in Very Preterm Infants.

Importance: Retinopathy of prematurity (ROP) is a major morbidity of preterm infants causing visual impairment, including blindness, for which timely treatment is vital and prevention is key. Increasing evidence suggests that exposure to neonatal sepsis contributes to ROP development. Objective: To investigate the association between neonatal sepsis and ROP in 2 large-scale cohorts of preterm infants born at less than 29 weeks' gestation. Design, Setting, and Participants: This retrospective cohort study was conducted using data from the German Neonatal Network (GNN) and Norwegian Neonatal Network (NNN). The GNN involves 68 and the NNN includes 21 level III neonatal intensive care units. Participants were infants born at a gestation of 22 weeks and 0 days to 28 weeks and 6 days and enrolled in the GNN between January 1, 2009, and December 31, 2022, and NNN between January 1, 2009, and December 31, 2018. Data were analyzed from February through September 2023. Exposure: Single or multiple episodes of culture-proven sepsis. Main Outcomes and Measures: Any ROP and treatment-warranted ROP. Results: Among 12 794 infants in the GNN (6043 female [47.2%] and 6751 male [52.8%]; mean [SD] gestational age, 26.4 [1.5] weeks) and 1844 infants in the NNN (866 female [47.0%] and 978 male [53.0%]; mean [SD] gestational age, 25.6 [1.5] weeks), the mean (SD) birth weight was 848 (229) g and 807 (215) g, respectively. Any ROP was present in 6370 infants (49.8%) in GNN and 620 infants (33.6%) in NNN, and treatment-warranted ROP was present in 840 infants (6.6%) in GNN and 140 infants (7.6%) in NNN. In both cohorts, there were increasing rates of treatment-warranted ROP with each sepsis episode (no sepsis: 572 of 10 658 infants [5.4%] in GNN and 85 of 1492 infants (5.7%) in NNN; 1 episode: 190 of 1738 infants in GNN [10.9%] and 29 of 293 infants [9.9%] in NNN; 2 episodes: 53 of 314 infants in GNN [16.9%] and 13 of 49 infants [26.5%] in NNN; 3 episodes: 25 of 84 infants [29.8%] in GNN and 3 of 10 infants [30.0%] in NNN). After adjusting for multiple confounders in the GNN dataset, the number of sepsis episodes was associated with ROP and treatment-warranted ROP compared with 0 episodes (1 episode: adjusted odds ratio [aOR], 1.44 [95% CI, 1.27-1.63]; P < .001 and OR, 1.60 [95% CI, 1.31-1.96]; P < .001, respectively; 2 episodes: OR, 1.81 [95% CI, 1.35-2.42]; P < .001 and OR, 2.38 [95% CI, 1.68-3.37]; P < .001, respectively; 3 episodes: OR, 4.39 [95% CI, 2.19-8.78]; P < .001 and OR, 3.88 [95% CI, 2.29-6.55]; P < .001, respectively). These associations were confirmed for any ROP by propensity score matching (for example, the aOR with propensity score matching was 1.76 [95% CI, 1.54-2.02]; P < .001 for 1 episode vs 0 episodes and 1.58 [95% CI, 1.12-2.22]; P = .007 for 3 episodes vs 0 or 1 episode). In the NNN dataset, surgical NEC was associated with treatment-warranted ROP (multivariable analysis: aOR, 3.37 [95% CI, 1.78-6.37]; P < .001). Conclusions and Relevance: This study found that in the large-scale GNN cohort, recurrent culture-proven sepsis was associated with ROP and treatment-warranted ROP in infants born at less than 29 weeks.

Association of ApoE Genotypes and Recovery From Intracerebral Hemorrhage in Very Low Birth Weight Infants.

BACKGROUND AND PURPOSE: Associations of APOE genotypes with intracerebral hemorrhage (ICH) in preterm infants were previously described. In adults, APOE-ε4 genotype has been proposed as susceptibility factor for impaired recovery after cerebral insult. We here aim to determine APOE genotype-specific neurological consequences of neonatal ICH at school age. METHODS: In this multicenter observational cohort study, very low birth weight (<1500 g, <32 weeks gestational age) children were studied for cerebral palsy (CP) after ultrasound diagnosed ICH stratified by APOE genotype. Follow-up examination was done at the age of 5 to 6 years. Study personnel were blinded for perinatal information and complications. Participants were born between January 1, 2009 and December 31, 2013 and enrolled in the German Neonatal Network. Of 8022 infants primarily enrolled, 2467 children were invited for follow-up between January 1, 2014 and December 31, 2019. Univariate analyses and multivariate logistic regression models were used to assess the impact of APOE genotype (APOE-ε2, APOE-ε3, APOE-ε4) on CP after ICH. RESULTS: Two thousand two hundred fifteen children participated at follow-up, including 363 children with ultrasound diagnosed neonatal ICH. In univariate analyses of children with a history of ICH, APOE-ε3 carriers had lower frequencies of CP (n=33/250; 13.2 [95% CI, 9.4%-17.8%]), as compared to APOE-ε2 (n=15/63; 23.8 [14.6%-35.3%], P=0.037) and -ε4 carriers (n=31/107; 29.0 [21.0%-38.0%], P<0.001), respectively. Regression models revealed an association of APOE-ε4 genotype and CP development (odds ratio, 2.77 [1.44-5.32], P=0.002) after ICH. Notably, at low-grade ICH (grade I) APOE-ε4 expression resulted in an increased rate of CP (n=6/39; 15.4 [6.7-29.0]) in comparison to APOE-ε3 (n=2/105; 1.9 [0.4%-6.0%], P=0.002). CONCLUSIONS: APOE-ε4 carriers have an increased risk for long-term motor deficits after ICH. We assume an effect even after low-grade neonatal ICH, but more data are needed to clarify this issue.

Prevalence of Congenital CMV Infection and Antiviral Therapy in Very-Low-Birth-Weight Infants: Observations of the German Neonatal Network.

BACKGROUND: To determine the prevalence of congenital CMV infection (cCMV) in very-low-birth-weight infants (VLBWI) and to evaluate epidemiological characteristics of VLBWI with antiviral therapy (AT). METHODS: CMV-specific PCR in umbilical cord tissue was performed (n=3330). Univariate analyses and logistic regression models were used to identify associations with outcome. RESULTS: 22/3330 VLBWI received AT (0.66%). 4 of these (0.12%) were PCR positive, with 2 VLBWI showing pathological screening for hearing loss. VLBWI with AT and negative PCR had significantly reduced mean birth weight (BW) and higher rates of small-for-gestational-age (SGA). Clinical sepsis, bronchopulmonary dysplasia (BPD), use of reserve antibiotics (RA) and treatment for retinopathy of prematurity were significantly increased. We further observed a higher need of transfusion of red blood cells (RBC), fresh frozen plasma and platelets. Logistic regression (controlled for gender, gestational age, SGA and BW) showed associations for AT and BPD (OR 3.4 [1.2-10.1], p=0.024), RA (OR 20.4 [4.2-98.9], p≤0.001), transfusions of RBC (OR 11.9 [1.3-105.7], p=0.026) and platelets (OR 8.7 [2.9-26.4], p≤0.001). DISCUSSION: All VLBWI with positive PCR received AT. We hypothesize from our data by assuming a postnatal aquired CMV infection in VLBWI with AT and negative PCR that VLBWI born SGA have a different risk profile. CONCLUSION: Further prospective studies concerning postnatal transmission should take VLBWI born SGA into account and should study the impact of infection on short- and long-term complications in this supposed vulnerable group.