BACKGROUND AND OBJECTIVES: Caffeine is effective in the treatment of apnea of prematurity. Although caffeine therapy has a benefit on gross motor skills in school-aged children, effects on neurobehavioral outcomes are not fully understood. We aimed to investigate effects of neonatal caffeine therapy in very low birth weight (500-1250 g) infants on neurobehavioral outcomes in 11-year-old participants of the Caffeine for Apnea of Prematurity trial. METHODS: Thirteen academic hospitals in Canada, Australia, Great Britain, and Sweden participated in this part of the 11-year follow-up of the double-blind, randomized, placebo-controlled trial. Measures of general intelligence, attention, executive function, visuomotor integration and perception, and behavior were obtained in up to 870 children. The effects of caffeine therapy were assessed by using regression models. RESULTS: Neurobehavioral outcomes were generally similar for both the caffeine and placebo group. The caffeine group performed better than the placebo group in fine motor coordination (mean difference [MD] = 2.9; 95% confidence interval [CI]: 0.7 to 5.1; P = .01), visuomotor integration (MD = 1.8; 95% CI: 0.0 to 3.7; P < .05), visual perception (MD = 2.0; 95% CI: 0.3 to 3.8; P = .02), and visuospatial organization (MD = 1.2; 95% CI: 0.4 to 2.0; P = .003). CONCLUSIONS: Neonatal caffeine therapy for apnea of prematurity improved visuomotor, visuoperceptual, and visuospatial abilities at age 11 years. General intelligence, attention, and behavior were not adversely affected by caffeine, which highlights the long-term safety of caffeine therapy for apnea of prematurity in very low birth weight neonates.

(JAMA. 2018;319(21):2190–2201) Oxygen saturation is almost universally measured by pulse oximetry (SpO2) in neonatal intensive care units. While a lower SpO2 target (≤90%) may reduce retinopathy of prematurity (ROP), it also may impair neurodevelopment or increase the risk of death. On the other hand, higher oxygen levels (SpO2 target >90%) may increase the risk of adverse pulmonary sequelae. In 2003, 5 investigators planning separate randomized prospective clinical trials using similar study designs agreed to provide data after completion for a meta-analysis. This article detailed the results of the meta-analysis.

IMPORTANCE Caffeine citrate therapy for apnea of prematurity reduces the rates of bronchopulmonary dysplasia, severe retinopathy, and neurodevelopmental disability at 18 months and may improve motor function at 5 years.OBJECTIVE To evaluate whether neonatal caffeine therapy is associated with improved functional outcomes 11 years later.DESIGN, SETTING, AND PARTICIPANTS A follow-up study was conducted at 14 academic hospitals in Canada, Australia, and the United Kingdom from May 7, 2011, to May 27, 2016, of English-or French-speaking children who had been enrolled in the randomized, placebo-controlled Caffeine for Apnea of Prematurity trial between October 11, 1999, and October 22, 2004. A total of 1202 children with birth weights of 500 to 1250 g were eligible for this study; 920 (76.5%) had adequate data for the main outcome.INTERVENTIONS Caffeine citrate or placebo until drug therapy for apnea of prematurity was no longer needed.MAIN OUTCOMES AND MEASURES Functional impairment was a composite of poor academic performance (defined as at least 1 standard score greater than 2 SD below the mean on the Wide Range Achievement Test-4), motor impairment (defined as a percentile rank of <= 5 on the Movement Assessment Battery for Children-Second Edition), and behavior problems (defined as a Total Problem T score >= 2 SD above the mean on the Child Behavior Checklist).RESULTS Among the 920 children (444 females and 476 males; median age, 11.4 years [interquartile range, 11.1-11.8 years]), the combined rates of functional impairment were not significantly different between the 457 children assigned to receive caffeine compared with the 463 children assigned to receive placebo (145 [31.7%] vs 174 [37.6%]; adjusted odds ratio, 0.78; 95% CI, 0.59-1.02; P=.07). With all available data, including those from up to 24 Swedish trial participants, the rates of poor academic performance on 1 or more of 4 subtests (66 of 458 [14.4%] vs 61 of 462 [13.2%]; adjusted odds ratio, 1.11; 95% CI, 0.77-1.61; P=.58) and behavior problems (52 of 476 [10.9%] vs 40 of 481 [8.3%]; adjusted odds ratio, 1.32; 95% CI, 0.85-2.07; P=.22) were broadly similar between the group that received caffeine and the group that received placebo. However, caffeine therapy was associated with a reduced risk of motor impairment compared with placebo (90 of 457 [19.7%] vs 130 of 473 [27.5%]; adjusted odds ratio, 0.66; 95% CI, 0.48-0.90; P=.009).CONCLUSIONS AND RELEVANCE Caffeine therapy for apnea of prematurity did not significantly reduce the combined rate of academic, motor, and behavioral impairments but was associated with a reduced risk of motor impairment in 11-year-old children with very low birth weight. At the doses used in this trial, neonatal caffeine therapy is effective and safe into middle school age.

Neonatal intensive care has been one of the successful areas in modern medicine; and with progressively advancing technology and the development of interventions, there has been an ongoing improvement in survival of preterm infants, including those born at the limit of viability at 23 and 24 weeks’ gestation. As these infants have high risk of adverse neonatal outcomes and long-term neurodevelopmental impairments, it remains important also to monitor the changing trends in survivors free of major neonatal morbidity and long-term neurodisability.There have been several reports in the perinatal literature, looking at the changing trends in important neonatal morbidities: bronchopulmonary dysplasia (BPD), grades 3 and 4 intraventricular haemorrhage (IVH), cystic periventricular leucomalacia (PVL), severe retinopathy of prematurity (ROP) and necrotising enterocolitis (NEC). The data quality of such reports vary however, depending on whether the report was a hospital unit based or a large population based, data collection was retrospective or prospective and also depending on the ascertainment of the outcomes.The article by Pfister et al 1 provides useful information on trends in some important major neonatal morbidities, but not severe ROP. There are several strengths of this study: being a …

Neonatal intensive care has been one of the successful areas in modern medicine; and with progressively advancing technology and the development of interventions, there has been an ongoing improvement in survival of preterm infants, including those born at the limit of viability at 23 and 24 weeks’ gestation. As these infants have high risk of adverse neonatal outcomes and long-term neurodevelopmental impairments, it remains important also to monitor the changing trends in survivors free of major neonatal morbidity and long-term neurodisability. There have been several reports in the perinatal literature, looking at the changing trends in important neonatal morbidities: bronchopulmonary dysplasia (BPD), grades 3 and 4 intraventricular haemorrhage (IVH), cystic periventricular leucomalacia (PVL), severe retinopathy of prematurity (ROP) and necrotising enterocolitis (NEC). The data quality of such reports vary however, depending on whether the report was a hospital unit based or a large population based, data collection was retrospective or prospective and also depending on the ascertainment of the outcomes. The article by Pfister et al 1 provides useful information on trends in some important major neonatal morbidities, but not severe ROP. There are several strengths of this study: being a …

BACKGROUNDThe safest ranges of oxygen saturation in preterm infants have been the subject of debate.METHODSIn two trials, conducted in Australia and the United Kingdom, infants born before 28 weeks' gestation were randomly assigned to either a lower (85 to 89%) or a higher (91 to 95%) oxygen-saturation range. During enrollment, the oximeters were revised to correct a calibration-algorithm artifact. The primary outcome was death or disability at a corrected gestational age of 2 years; this outcome was evaluated among infants whose oxygen saturation was measured with any study oximeter in the Australian trial and those whose oxygen saturation was measured with a revised oximeter in the U.K. trial.RESULTSAfter 1135 infants in Australia and 973 infants in the United Kingdom had been enrolled in the trial, an interim analysis showed increased mortality at a corrected gestational age of 36 weeks, and enrollment was stopped. Death or disability in the Australian trial (with all oximeters included) occurred in 247 of 549 infants (45.0%) in the lower-target group versus 217 of 545 infants (39.8%) in the higher-target group (adjusted relative risk, 1.12; 95% confidence interval [CI], 0.98 to 1.27; P=0.10); death or disability in the U.K. trial (with only revised oximeters included) occurred in 185 of 366 infants (50.5%) in the lower-target group versus 164 of 357 infants (45.9%) in the higher-target group (adjusted relative risk, 1.10; 95% CI, 0.97 to 1.24; P=0.15). In post hoc combined, unadjusted analyses that included all oximeters, death or disability occurred in 492 of 1022 infants (48.1%) in the lower-target group versus 437 of 1013 infants (43.1%) in the higher-target group (relative risk, 1.11; 95% CI, 1.01 to 1.23; P=0.02), and death occurred in 222 of 1045 infants (21.2%) in the lower-target group versus 185 of 1045 infants (17.7%) in the higher-target group (relative risk, 1.20; 95% CI, 1.01 to 1.43; P=0.04). In the group in which revised oximeters were used, death or disability occurred in 287 of 580 infants (49.5%) in the lower-target group versus 248 of 563 infants (44.0%) in the higher-target group (relative risk, 1.12; 95% CI, 0.99 to 1.27; P=0.07), and death occurred in 144 of 587 infants (24.5%) versus 99 of 586 infants (16.9%) (relative risk, 1.45; 95% CI, 1.16 to 1.82; P=0.001).CONCLUSIONSUse of an oxygen-saturation target range of 85 to 89% versus 91 to 95% resulted in nonsignificantly higher rates of death or disability at 2 years in each trial but in significantly increased risks of this combined outcome and of death alone in post hoc combined analyses. (Funded by the Australian National Health and Medical Research Council and others; BOOST-II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry number, ACTRN12605000055606.)

Despite the advances in the field of perinatal medicine over the past few decades, neonatal infections remain as one of the major factors responsible for neonatal morbidity and mortality. These infections can have their origin in the antenatal, perinatal or early infantile period with the potential to cause lifelong sequelae. Neonatal mortality is still a significant global burden with a major gap within the developed and the developing world. It remains extremely important for clinicians caring for sick newborn infants to be up-to-date with the information available in the field of neonatal sepsis.

AimTo evaluate the efficacy of automated control of the fraction of inspired oxygen (FiO(2)) in comparison with manual FiO(2) control in maintaining target pulse oxygen saturation (SpO(2)) range.MethodsCrossover physiological study involving preterm infants requiring mechanical ventilation and supplemental oxygen. Each infant was studied for two consecutive 12hours in a random sequence. Outcome measures included the proportion of time with SpO(2) within and outside the target range of 90-95%, extreme hypoxaemia (<80%) and hyperoxaemia (98%).ResultsComplete data set was available in 27 infants. The percentage of time (median, IQR) within the target range was higher during automated control 72.8 (58.8-82.6) compared to manual control 59.6 (49.3-73.3), p=0.031. Corresponding reduction in per cent time below the target range was 18.1 (12.7-23.6) versus 25.9 (17.8-30.7), p=0.028, and above the target range 4.8 (3-16) versus 10.1 (6.4-22.5), p=0.026. Median (IQR) per cent time spent with severe hypoxaemia (SpO(2)<80%) and severe hyperoxaemia (SpO(2)98%) was 1.3 (0.1-2.9) versus 3.2 (1.4-6.1), p=0.022 and 0.08 (0.05-0.36) versus 1.7 (0.7-6.8), p=0.001, respectively. Median number of manual adjustments of FiO(2) per 12hour was 0 and 63, respectively.ConclusionAutomated control of FiO(2) significantly improved compliance of oxygen saturation targeting and significantly reduced exposure to hypoxaemia as well as hyperoxaemia.

OBJECTIVE:To determine whether the ability to predict severe motor impairment at age 5 years improves between birth and 18 months.DESIGN:Ancillary study of the Caffeine for Apnea of Prematurity Trial.SETTING AND PATIENTS:International cohort of very low birth weight children who were assessed sequentially from birth to 5 years.OUTCOME MEASURES:Severe motor impairment was defined as a score <5th percentile on the Movement Assessment Battery of Children (MABC), or inability to complete the MABC because of cerebral palsy. Multivariable logistic regression cumulative risk models used four sets of predictor variables: early neonatal risk factors, risk factors at 36 weeks' postmenstrual age, risk factors at a corrected age of 18 months, and sociodemographic variables. A receiver operating characteristic curve (ROC) was generated for each model, and the four ROC curves were compared to determine if the addition of the new set of predictors significantly increased the area under the curve (AUC).RESULTS:Of 1469 children, 291 (19.8%) had a severe motor impairment at 5 years. The AUC increased from 0.650 soon after birth, to 0.718 (p<0.001) at 36 weeks' postmenstrual age, and to 0.797 at 18 months (p<0.001). Sociodemographic variables did not significantly improve the AUC (AUC=0.806; p=0.07).CONCLUSIONS:Prediction of severe motor impairment at 5 years of age using a cumulative risk model improves significantly from birth to 18 months of age in children with birth weights between 500 g and 1250 g.TRIAL REGISTRATION NUMBER:ClinicalTrials.gov number NCT00182312.

To evaluate the efficacy of automated control of the fraction of inspired oxygen (FiO 2 ) in comparison with manual FiO 2 control in maintaining target pulse oxygen saturation (SpO 2 ) range. Crossover physiological study involving preterm infants requiring mechanical ventilation and supplemental oxygen. Each infant was studied for two consecutive 12 hours in a random sequence. Outcome measures included the proportion of time with SpO 2 within and outside the target range of 90–95%, extreme hypoxaemia (<80%) and hyperoxaemia (≥98%). Complete data set was available in 27 infants. The percentage of time (median, IQR) within the target range was higher during automated control 72.8 (58.8–82.6) compared to manual control 59.6 (49.3–73.3), p = 0.031. Corresponding reduction in per cent time below the target range was 18.1 (12.7–23.6) versus 25.9 (17.8–30.7), p = 0.028, and above the target range 4.8 (3–16) versus 10.1 (6.4-22.5), p = 0.026. Median (IQR) per cent time spent with severe hypoxaemia (SpO 2 <80%) and severe hyperoxaemia (SpO 2 ≥98%) was 1.3 (0.1–2.9) versus 3.2 (1.4–6.1), p = 0.022 and 0.08 (0.05–0.36) versus 1.7 (0.7–6.8), p = 0.001, respectively. Median number of manual adjustments of FiO 2 per 12 hour was 0 and 63, respectively. Automated control of FiO 2 significantly improved compliance of oxygen saturation targeting and significantly reduced exposure to hypoxaemia as well as hyperoxaemia.

Respiratory distress syndrome is a disease of prematurity and is caused by a relative deficiency of endogenous surfactant production. Respiratory distress syndrome is the most common cause of mortality and morbidity in the newborn population and the standard of care is to provide exogenous surfactant therapy. This saves lives and reduces respiratory complications but, despite treatment, a significant proportion of these infants go onto develop chronic lung disease, the severest form of which is bronchopulmonary dysplasia. Once developed, this is a multisystem disease and treatment is mostly supportive by using various therapeutic adjuncts. Some of these have been proven to be safe and effective in large randomized, controlled trials but similar evidence for other drugs is lacking. The aim of this paper is to provide an overview and critically appraise the available scientific evidence for or against their use in routine practice.

BACKGROUND:The clinically appropriate range for oxygen saturation in preterm infants is unknown. Previous studies have shown that infants had reduced rates of retinopathy of prematurity when lower targets of oxygen saturation were used. METHODS:In three international randomized, controlled trials, we evaluated the effects of targeting an oxygen saturation of 85 to 89%, as compared with a range of 91 to 95%, on disability-free survival at 2 years in infants born before 28 weeks' gestation. Halfway through the trials, the oximeter-calibration algorithm was revised. Recruitment was stopped early when an interim analysis showed an increased rate of death at 36 weeks in the group with a lower oxygen saturation. We analyzed pooled data from patients and now report hospital-discharge outcomes. RESULTS:A total of 2448 infants were recruited. Among the 1187 infants whose treatment used the revised oximeter-calibration algorithm, the rate of death was significantly higher in the lower-target group than in the higher-target group (23.1% vs. 15.9%; relative risk in the lower-target group, 1.45; 95% confidence interval [CI], 1.15 to 1.84; P=0.002). There was heterogeneity for mortality between the original algorithm and the revised algorithm (P=0.006) but not for other outcomes. In all 2448 infants, those in the lower-target group for oxygen saturation had a reduced rate of retinopathy of prematurity (10.6% vs. 13.5%; relative risk, 0.79; 95% CI, 0.63 to 1.00; P=0.045) and an increased rate of necrotizing enterocolitis (10.4% vs. 8.0%; relative risk, 1.31; 95% CI, 1.02 to 1.68; P=0.04). There were no significant between-group differences in rates of other outcomes or adverse events. CONCLUSIONS:Targeting an oxygen saturation below 90% with the use of current oximeters in extremely preterm infants was associated with an increased risk of death. (Funded by the Australian National Health and Medical Research Council and others; BOOST II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry numbers, ACTRN12605000055606 and ACTRN12605000253606.).

CONTEXT:Very preterm infants are prone to apnea and have an increased risk of death or disability. Caffeine therapy for apnea of prematurity reduces the rates of cerebral palsy and cognitive delay at 18 months of age.OBJECTIVE:To determine whether neonatal caffeine therapy has lasting benefits or newly apparent risks at early school age.DESIGN, SETTING, AND PARTICIPANTS:Five-year follow-up from 2005 to 2011 in 31 of 35 academic hospitals in Canada, Australia, Europe, and Israel, where 1932 of 2006 participants (96.3%) had been enrolled in the randomized, placebo-controlled Caffeine for Apnea of Prematurity trial between 1999 and 2004. A total of 1640 children (84.9%) with birth weights of 500 to 1250 g had adequate data for the main outcome at 5 years.MAIN OUTCOME MEASURES:Combined outcome of death or survival to 5 years with 1 or more of motor impairment (defined as a Gross Motor Function Classification System level of 3 to 5), cognitive impairment (defined as a Full Scale IQ<70), behavior problems, poor general health, deafness, and blindness.RESULTS:The combined outcome of death or disability was not significantly different for the 833 children assigned to caffeine from that for the 807 children assigned to placebo (21.1% vs 24.8%; odds ratio adjusted for center, 0.82; 95% CI, 0.65-1.03; P = .09). The rates of death, motor impairment, behavior problems, poor general health, deafness, and blindness did not differ significantly between the 2 groups. The incidence of cognitive impairment was lower at 5 years than at 18 months and similar in the 2 groups (4.9% vs 5.1%; odds ratio adjusted for center, 0.97; 95% CI, 0.61-1.55; P = .89).CONCLUSION:Neonatal caffeine therapy was no longer associated with a significantly improved rate of survival without disability in children with very low birth weights who were assessed at 5 years.