Supplementary Material for: Optimal Oxygenation of Extremely Low Birth Weight Infants: A Meta-Analysis and Systematic Review of the Oxygen Saturation Target Studies

<b><i>Background:</i></b> The optimal oxygen saturation for extremely low birth weight infants in the postnatal period beyond the delivery room is not known. <b><i>Objectives:</i></b> To summarize and discuss the results of the randomized trials, constituting the NEOPROM (Neonatal Oxygenation Prospective Meta-analysis) collaborative study, examining the effect of low versus high functional oxygen saturation targets in the postnatal period in premature infants with gestational age <28 weeks. <b><i>Methods:</i></b> A meta-analysis of SUPPORT (Surfactant, Positive Pressure and Pulse Oximetry Randomized Trial), the three BOOST II (Benefits of Oxygen Saturation Targeting) studies and the COT (Canadian Oxygen Trial) was performed including a total of 4,911 infants randomized to either a low (85-89%) or high (91-95%) functional oxygen saturation (SpO₂) within the first 24 h after birth. <b><i>Results:</i></b> Relative risks (RR; 95% CIs) comparing a low versus a high oxygen saturation target were 1.41 (1.14-1.74) for mortality at discharge or at follow-up, 0.74 (0.59-0.92) for severe retinopathy of prematurity, 0.95 (0.86-1.04) for physiologic bronchopulmonary dysplasia, 1.25 (1.05-1.49) for necrotizing enterocolitis, 1.02 (0.88-1.19) for brain injury, and 1.01 (0.95-1.08) for patent ductus arteriosus. RR >1.0 favors a high oxygen saturation. <b><i>Conclusions:</i></b> RRs for mortality and necrotizing enterocolitis are significantly increased and severe retinopathy of prematurity significantly reduced in low compared to high oxygen saturation target infants. There are no differences regarding physiologic bronchopulmonary dysplasia, brain injury or patent ductus arteriosus between the groups. Based on these results, it is suggested that functional SpO₂ should be targeted at 90-95% in infants with gestational age <28 weeks until 36 weeks' postmenstrual age. However, there are still several unanswered questions in this field

Supplementary Material for: Chorioamnionitis as a Risk Factor for Retinopathy of Prematurity: A Systematic Review and Meta-Analysis

<b><i>Background:</i></b> The role of chorioamnionitis (CA) in the development of retinopathy of prematurity (ROP) has not been well established. <b><i>Objective:</i></b> To conduct a systematic review and meta-analysis of the association between CA and ROP in preterm infants. <b><i>Data Sources:</i></b> The authors searched MEDLINE, Embase, CINAHL, Cochrane Central Register of Controlled Trials and PubMed, reviewed reference lists of relevant articles, abstracts and conference proceedings (Society for Pediatric Research, European Society for Paediatric Research 1990-2012), sought results of unpublished trials, and contacted the primary authors of relevant studies. <b><i>Study Selection:</i></b> Studies were included if they had a comparison group, examined preterm infants, and reported primary data that could be used to measure the association between exposure to CA and the development of ROP. <b><i>Data Extraction:</i></b> Two reviewers independently screened the search results, applied inclusion criteria and assessed methodological quality using the Newcastle-Ottawa Scale. One reviewer extracted data and a second reviewer checked data extraction. Summary relative risks (RRs) were calculated using a random effects model. <b><i>Data Synthesis:</i></b> We identified 1,249 potentially relevant studies from the electronic databases. Twenty-seven studies involving 10,590 preterm neonates with 2,562 cases of ROP were included. Taking into account all included studies without adjusting for gestational age (GA), CA was significantly associated with ROP (any stage) [summary RR 1.33 (95% CI 1.14-1.55, I² = 77%, p_{heterogeneity} < 0.0001)], and a borderline significant association was observed for severe ROP (stage ≥3) [summary RR 1.27 (95% CI 0.99-1.63, I² = 74%, p_{heterogeneity} < 0.0001)]. There was no publication bias with Begg's test. However, subgroup analysis of studies adjusting for GA showed no significant association on CA with ROP [summary RR 0.98 (95% CI 0.77-1.26, I² = 0%, p_{heterogeneity} = 0.89)]. <b><i>Conclusion:</i></b> Unadjusted analyses showed that CA was significantly associated with ROP (any stage) as well as with severe ROP (stage ≥ 3). However, the association disappeared on analysis of studies adjusting for GA. Hence, CA cannot be definitively considered as a risk factor for ROP, and further studies should adjust for potential confounding factors and report results by stage to clarify the association with severe ROP

Supplementary Material for: Temporal Patterns of Gene Expression Profiles in the Neonatal Mouse Lung after Hypoxia-Reoxygenation

<p><b><i>Background:</i></b> One out of four children with neonatal asphyxia has lung involvement. Still, there has been little research on injury mechanisms of hypoxia-reoxygenation in the neonatal lung. <b><i>Objectives:</i></b> To make a temporal profile of the gene expression changes of 44 a priori selected genes after hypoxia-reoxygenation in the newborn mouse lung, and to compare the changes after hyperoxic and normoxic reoxygenation. <b><i>Methods:</i></b> Postnatal day 7 mice were randomized to 2-hour hypoxia (8% O₂) and 30-min reoxygenation in either 60% O₂ or air. After 0-72 h of observation, gene expression changes and protein concentrations in whole lung homogenates were examined. <b><i>Results:</i></b> Immediately after completed reoxygenation, 7 genes of mediators of inflammation were downregulated, and there was an antiapoptotic gene expression pattern. Three DNA glycosylases were downregulated, while genes involved in cell cycle renewal indicated both increased and decreased cell cycle arrest. <i>Sod1</i> (T2.5h median H60: 1.01, H21: 0.88, p = 0.005; T5h median H60: 1.04, H21: 0.85, p = 0.038) and <i>Il1b</i> (T0h median H60: 0.86, H21: 1.08, p = 0.021) were significantly differentially expressed when comparing hyperoxic and normoxic reoxygenation. <b><i>Conclusion:</i></b> In this newborn mouse lung hypoxia-reoxygenation model, we found downregulation of genes of mediators of inflammation, an antiapoptotic gene expression pattern, and downregulation of DNA glycosylases. <i>Sod1</i> and <i>Il1b</i> were significantly differentially expressed when comparing reoxygenation using 60% O₂ with air.</p><br

Supplementary Material for: Association between Brain and Kidney Near-Infrared Spectroscopy and Early Postresuscitation Mortality in Asphyxiated Newborn Piglets

<p><b><i>Background:</i></b> Early outcome predictors after delivery room cardiopulmonary resuscitation (CPR) of asphyxiated newborns are needed. <b><i>Objectives:</i></b> To investigate if cerebral (rScO₂) and renal (rSrO₂) tissue oxygen saturation 30 min after return of spontaneous circulation (ROSC) are different between surviving versus nonsurviving piglets with asphyxia-induced cardiac arrest and CPR. Further, to investigate the relationship of rScO₂ and rSrO₂ to cardiac output (CO), blood pressure (BP), and biochemical variables 30 min and 4 h after ROSC. <b><i>Methods:</i></b> Anesthetized, mechanically ventilated piglets (1-3 days, 1.7-2.4 kg) were used. rScO₂, rSrO₂, SpO₂, right common carotid artery flow, and arterial BP were measured continuously. CO was measured with echocardiography. The piglets were asphyxiated until cardiac arrest and resuscitated. Piglets that survived 4 h after ROSC (<i>n</i> = 12) were compared with piglets that died before planned euthanasia at 4 h (<i>n</i> = 13). Left ventricular, and kidney and brain tissue lactate were analyzed. Correlations between variables were assessed. <b><i>Results:</i></b> Thirty minutes after ROSC, median rSrO₂ (43% [<i>n</i> = 10] vs. 25% [<i>n</i> = 2], <i>p</i> = 0.003) but not rScO₂ (46% [41-55] [<i>n</i> = 10] vs. 40% [22-45] [<i>n</i> = 5], <i>p</i> = 0.08) was higher in survivors than in nonsurvivors. Arterial lactate was negatively correlated and pH positively correlated with rScO₂ and rSrO₂. Left ventricular, but not kidney or brain lactate was negatively correlated with rScO₂ and rSrO₂. There was no correlation between CO or BP and rScO₂ or rSrO₂. <b><i>Conclusions:</i></b> Despite satisfactory CO and BP vital organ oxygenation can be poor. Tissue oxygen saturation, pH, and lactate, as measures of anaerobic metabolism, may reflect vital organ oxygenation and outcome.</p