Survival and Neurodevelopmental Outcomes of Preterms Resuscitated With Different Oxygen Fractions
BACKGROUND AND OBJECTIVES: Stabilization of preterm infants after birth frequently requires oxygen supplementation. At present the optimal initial oxygen inspiratory fraction (Fio2) for preterm stabilization after birth is still under debate. We aimed to compare neurodevelopmental outcomes of extremely preterm infants at 24 months corrected age randomly assigned to be stabilized after birth with an initial Fio2 of 0.3 versus 0.6 to 0.65 in 3 academic centers from Spain and the Netherlands.
METHODS: Randomized, controlled, double-blinded, multicenter, international clinical trial enrolling preterm infants <32 weeks’ gestation assigned to an initial Fio2 of 0.3 (Lowox group) or 0.6 to 0.65 (Hiox group). During stabilization, arterial pulse oxygen saturation and heart rate were continuously monitored and Fio2 was individually titrated to keep infants within recommended ranges. At 24 months, blinded researchers used the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) to assess visual acuity, neurosensory deafness, and language skills.
RESULTS: A total of 253 infants were recruited and 206 (81.4%) completed follow-up. No differences in perinatal characteristics, oxidative stress, or morbidities during the neonatal period were assessed. Mortality at hospital discharge or when follow-up was completed didn’t show differences between the groups. No differences regarding Bayley-III scale scores (motor, cognitive, and language composites), neurosensorial handicaps, cerebral palsy, or language skills between groups were found.
CONCLUSIONS: The use of an initial lower (0.3) or higher (0.6–0.65) Fio2 during stabilization of extremely preterm infants in the delivery room does not influence survival or neurodevelopmental outcomes at 24 months.
- Bayley-III —
- Bayley Scales of Infant and Toddler Development, Third Edition
- BPD —
- bronchopulmonary dysplasia
- CI —
- confidence interval
- CP —
- cerebral palsy
- Fio2 —
- oxygen inspiratory fraction
- GMFCS —
- Gross Motor Function Classification System
- ILCOR —
- International Liaison Committee on Resuscitation
- IVH —
- intraventricular hemorrhage
- OR —
- odds ratio
- RCT —
- randomized controlled trial
- ROP —
- retinopathy of prematurity
- Spo2 —
- arterial pulse oxygen saturation
What’s Known on This Subject:
Oxygen supplementation in the delivery room to preterm infants is relatively common and should be individually titrated to avoid hyperoxia or hypoxia. Hence, an initial oxygen inspiratory fraction of 0.21 to 0.3 is recommended.
What This Study Adds:
Follow-up at 24 months corrected age shows no differences in mortality, morbidity, or Bayley Scales of Infant and Toddler Development, Third Edition composite scores for preterm infants <32 weeks' gestation stabalized in the delivery room with initial oxygen respiratory fractions of 0.3 versus 0.60 to 0.65.
The 2015 International Liaison Committee on Resuscitation (ILCOR) neonatal resuscitation guidelines strongly recommend that preterm infants <35 weeks’ gestation should be stabilized at birth with a lower (0.21–0.3) and not higher (>0.65) initial oxygen inspiratory fraction (Fio2).1 Arterial partial pressure of oxygen increases twofold during fetal to neonatal transition, causing oxidative stress. However, antioxidant defenses are not fully functional until the end of the third trimester,2 and therefore free radical–associated conditions are more likely in very preterm infants.3 The use of high oxygen load during resuscitation has been associated with increased and prolonged oxidative stress, bronchopulmonary dysplasia (BPD), and prolonged need for oxygen or mechanical ventilation.4–8
Newborn infants achieve arterial pulse oxygen saturation (Spo2) around 90% at ∼5 minutes after birth.9 In 2010, Dawson et al10 published a Spo2 nomogram with preductal values collected in the first 10 minutes after birth from healthy newborn infants’ who did not need resuscitation. This database was comprised of 66% term infants and 34% preterm infants, with only 16% <32 weeks’ gestation.10 Of note, preterm infants needed significantly more time to achieve a Spo2 plateau than term infants.10 In 2010, the American Heart Association recommended Spo2 targets between 60% to 65% at 1 minute, 65% to 70% at 2 minutes, 70% to 75% at 3 minutes, 75% to 80% at 4 minutes, 80% to 85% at 5 minutes, and 85% to 95% at 10 minutes.11 However, these targets were not achieved by a substantial number of preterm infants that were at risk for unnecessary oxygen supplementation.10 In a recent systematic review and meta-analysis, Saugstad et al12 compared stabilization of 677 newborn infants ≤32 weeks’ gestation resuscitated/stabilized with an initial lower (0.21–0.3) versus higher (0.6–1.0) Fio2. No differences in the incidence of BPD or intraventricular hemorrhage (IVH) was assessed, but reduced mortality in the lower oxygen group approached significance.12 No long-term neurocognitive and sensorial follow-up was performed in any of these studies.
We aimed to evaluate neurocognitive and sensorial outcomes of 2 populations of preterm infants randomly assigned to be blindly stabilized with higher (0.60–0.65) or lower (0.30) initial Fio2s in 3 academic centers in Europe at 24 months after birth.
Eligible patients were preterm infants <32 weeks’ gestation recruited in 2 randomized, controlled, and double-blinded studies13,14 performed in 2 academic centers in Spain (University and Polytechnic Hospital La Fe and Hospital Sant Joan de Deu), and 1 academic center in the Netherlands (Sophia Children’s Hospital, Erasmus Medical Center). Patients were recruited immediately after birth from January 2008 to December 2012. The primary outcome was survival without neurodevelopmental impairment at a corrected age of 2 years. The Spanish study13 included preterm infants of ≤30 weeks’ gestation randomly assigned to resuscitation with an initial Fio2 of 0.3 (Lowox group) versus 0.6 (Hiox group). The Dutch study14 included infants <32 weeks’ gestation randomly assigned to be resuscitated with an initial Fio2 of 0.3 (Lowox group) verus 0.65 (Hiox group).
Power calculation required 30 infants per group in the Spanish trial and 90 per group in the Dutch study to find a statistically significant reduction with an α value of 0.05 and a power of 0.80.13,14 The Spanish study13 was registered with the European Clinical Trials Database (No. 2088-005047-42) and the Dutch study14 was registered with the Netherlands Trial Registry (No. NTR243). The ethics committees of the 3 participating hospitals approved the study, and parents of all recruited infants signed informed consent forms.
Inclusion criteria included inborn preterm infants <30 weeks’ gestation in the Spanish study13 and <32 weeks gestation in the Dutch study14 needing oxygen supplementation for postnatal stabilization and completing follow-up at 24 months corrected age in the participating hospitals. Exclusion criteria included major congenital malformations or chromosome defects identified before or immediately after birth, or loss to/incomplete follow-up.
Postnatal stabilization was performed according to the ILCOR 2010 guidelines. Initial Fio2 in both studies was titrated to keep heart rate and Spo2 within the ranges reflected in the recommendations of the American Heart Association.11 Resuscitation parameters (Fio2, respiratory rate, positive pressure, end expiratory pressure, Spo2, heart rate) were continuously monitored and stored, and biomarkers of oxidative stress were determined in blood and urine at the Research Laboratory of the University and Polytechnic Hospital La Fe and Department of Pediatrics, Obstetrics and Reproductive Medicine (University of Siena, Siena, Italy).13,14
Different domains of development were recorded at 24 months corrected age according to standardized protocols as follows:
A clinical, specific, and structured neurologic examination was performed and recorded by using standardized forms. Items were grouped in categories (tone, tone patterns, reflexes, movements, abnormal signs, and behavior). Blinded examiners performed patient assessments.
Ophthalmologic and audiological assessments were performed by blinded specialists.
Certified and blinded psychologists and/or neonatologists performed developmental assessments at 24 months corrected age that included cognitive, language, and motor development using Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III).17 Scales were standardized to a mean (SD) score of 100 points.
Children in each group were compared for cognition, language, and motor function according to the Bayley-III scales18 as follows: “normal” if the composite score of the respective function scale was greater than or equal to mean – 1 SD; “mildly impaired” if the respective score was less than the mean – 1 SD and greater than or equal to the mean – 2 SD; “moderately impaired” if the score was less than the mean – 2 SD and greater than or equal to the mean – 3 SD; and “severely impaired” if the score was less than mean – 3 SD.
Cerebral palsy (CP) was defined as a nonprogressive central nervous system disorder characterized by abnormal muscle tone in at least 1 extremity and abnormal control of movement and posture that interfered with or prevented age-appropriate motor activity. CP was classified according to the Gross Motor Function Classification System (GMFCS).19 The 5 levels of function were: (I) Walks without restrictions; limitations in more advanced gross motor skills; (II) Walks without assistive devices; limitations walking outdoors and in the community; (III) Walks with assistive mobility devices; limitations walking outdoors and in the community; (IV) Self-mobility with limitations; children are transported or use power mobility outdoors and in the community; and (V) Self-mobility is severely limited even with the use of assistive technology.
For sensorial assessment, we included children with severe sensorial impairment. Thus, blindness was defined as the absence of response to fixate or follow a light.20 Severe hearing loss was defined as permanent hearing loss with no response to amplification.21
Finally, summarized outcome was classified as: no disability, mild disability (defined as scores between –1 and –2 SD from the mean in any of the Bayley III scales or mild CP [I and II]), moderate disability (scores between –2 and –3 SD from the mean in any of the Bayley III scales, moderate CP [III]), and severe disability (scores less than the mean –3 SD in any of the Bayley III scales, severe CP [IV and V] or bilateral blindness or deafness).
Data were summarized by using mean (SD) and median (first and third quartile) in the case of continuous variables and with relative and absolute frequencies in the case of categorical variables. The association of Fio2 with the different items (cognition, language, and motor function) of the Bayley III scales was assessed by using linear regression models to adjust for gestational age and gender. Differences in disability grades were assessed between both groups by using ordinal regression models. Logistic regression was used to assess differences in blindness and deafness risk. P values < .05 were considered statistically significant. All statistical analyses were performed by using R Statistical Software, version 3.2.3 (Western Ecology Division, Corvallis, OR).
Figure 1 shows the flow diagram of the patients who were initially included in the study and randomized to lower (Lowox group) or higher (Hiox group) initial Fio2. In addition, Fig 1 shows patients who died before and after discharge from the hospital. The mortality rate at 24 months corrected age was 8.27% for the Lowox group and 14.04% for the Hiox group. Figure 1 also shows the number of infants lost to follow-up and those who were finally assessed in the Lowox and in the Hiox groups. With respect to gestational age, 55 patients were ≤28 weeks’ gestation and 54 patients were >29 weeks’ gestation in the Lowox group; 47 patients were ≤28 weeks’ gestation and 52 patients were >29 weeks’ gestation in the Hiox group.
Table 1 shows the clinical and obstetric baseline characteristics of participating individuals. Table 1 also shows the major complications during hospital stay and mortality at 24 months corrected age. No differences in the incidence of BPD, patent ductus arteriosus, retinopathy of prematurity (ROP), intra-peri-ventricular hemorrhage, or mortality before hospital discharge were detected between both groups. Only 1 infant from the Spanish study13 died after hospital discharge. Of the survivors, 15 infants in the Lowox group and 5 infants in the Hiox group were lost to follow-up.
Table 2 shows the baseline characteristics at follow-up. The median corrected age and children’s growth charts were similar in both groups.
Table 3 shows the Bayley-III scoring results. Of the 207 patients eligible for assessment in the follow-up clinic, 170 (81.7%) completed the cognitive scale, 144 (69.2%) completed the motor scale, and 142 (68.2%) completed the language evaluation of the Bayley-III test. A total of 32 patients (15.4%) missed the appointment and, of those who attended, 6 patients (2.9%) did not perform the Bayley-III evaluation because of lack of cooperation. Of the 38 patients who did not attend or perform the follow-up assessment, 34 (16.4% of the eligible [n = 207] and 89.5% of the nonevaluated patients) were immigrants with low socioeconomic and educational status. Table 3 shows the mean (SD) for cognitive, motor, and language scoring for the entire population. In addition, we also performed a subanalysis of the results taking into consideration gestational age and gender. There were no statistical differences between groups for cognitive scale scores by gestational age (odds ratio [OR], 0.46; 95% confidence interval [CI], –0.52 to 1.46) or sex (1.91; 95% CI, –2.25 to 6.07; P = .37), for motor scale by gestational age (0.36; 95% CI, –0.69 to 1.42) or sex (1.31; 95% CI, –3.02 to 5.63; P = .55), or for language evaluation by gestational age (1.06; 95% CI, –0.15 to 2.27) or sex (-4.01; 95% CI, –9.13 to 1.10; P = .12).
As shown in Table 4, according to the results of the Bayley-III scales, patients were classified into 4 severity categories in each group: no disability and mildly, moderately or, severely disabled (see Methods). No differences between groups or severity categories were found (cognitive: OR, 1.05; 95% CI, 0.34–3.20; motor: OR, 1.69; 95% CI, 0.40–8.49; and language: OR, 1.58; 95% CI, 0.70–3.59). Detailed description of results by category is provided in Table 4. Figure 2, in addition, shows the composite scores’ differences for mean Bayley-III composites (cognitive, motor, and language).
Cerebral Palsy and Sensory Disabilities
Table 5 shows the incidence of cerebral palsy (CP) for both groups (Lowox and Hiox). CP was present in 4 patients (3.7%) in the Lowox group, all of whom were classified as mild by using the GMFCS. Hence, 3 patients pertained to group 1 (7.4%), and 1 patient to group 2 (2.6%). In the Hiox group, 4 patients (4.1%) were diagnosed with CP and classified each one for every group. As shown in Table 5, neurosensorial evaluation revealed that 1 patient in the Hiox group was impaired with blindness (1%) and 1 patient in the Lowox group was impaired with deafness (1%).
Overall Rate of Disabilities
The overall rate of disabilities (Table 6) included performance on the Bayley-III assessment, CP, and neurosensorial disability, as described above. Of the 208 patients evaluated, 67 children (75.3%) in the Lowox group were classified as normal (no disability) versus 61 patients (71.8%) in the Hiox group. Rates of moderate to severe disability were also similar between groups (8.99% in Lowox versus 9.41% in Hiox group). No statistical differences between groups (OR, 1.17; 95% CI, 0.60–2.30).
Survival of extremely preterm infants has improved in recent years; however, both neurodevelopmental and/or sensorial impairment still affect a substantial number of survivors.22 Term infants resuscitated with 100% oxygen exhibited prolonged oxidative stress after birth and had increased mortality.4,23 Moreover, epidemiologic studies have shown that exposure to oxygen even for brief periods of time immediately after birth is associated with an increased incidence of childhood cancer.24 The use of high oxygen concentrations in preterm infants has been associated with severe neonatal conditions, such as BPD, ROP and IVH.2,3,5–8 Furthermore, preterm infants stabilized with higher oxygen concentrations (Fio2 > 0.9) have higher levels of oxidative stress biomarkers and BPD.5–8
To date, the optimal initial Fio2 to stabilize preterm infants in the delivery room is still under debate.3,12,25–27 Although most experts agree that individually titrating Fio2 to achieve targeted Spo2 according to saturation ranges is the best applicable approach, it is not clear if the initial Fio2 should be set at a higher (>50%) or lower (<50%) oxygen concentration. In this scenario, ILCOR 2015 guidelines strongly recommend the use of an initial low Fio2 (0.21–0.3) for all preterm infants <35 weeks’ gestation.1 However, this recommendation has been questioned based on recently published information.28,29 Oei et al30 presented results of the largest randomized controlled trial (RCT) completed to date, which examined the effects of resuscitation with room air versus 100% oxygen in 289 preterm infants <32 weeks’ gestation. Mortality in the subgroup of infants <29 weeks’ gestation was 16.2% in the air group and 6% in the 100% oxygen group. This difference, although statistically marginal, emphasized the urgent need for larger RCTs to examine this question.30 In addition, the Canadian Neonatal Network, in a retrospective cohort study, compared major outcomes of infants ≤27 weeks’ gestation before and after 2006 when the policy regarding the initial Fio2 for preterm infants in the delivery room was changed from 100% to <100% oxygen.31 Adjusted OR for the primary outcome of severe neurologic injury or death was higher in the lower oxygen group and in those resuscitated with air when compared with 100% oxygen. Although no data about oxygen exposure for each individual infant were available, the investigators cautioned against a policy of initial stabilization of very preterm infants with lower oxygen that could imply a higher risk of severe neurologic injury or death compared with starting with 100% oxygen.31
Our study has evaluated for the first time neurodevelopmental and sensorial outcome of very preterm infants resuscitated with lower versus higher oxygen at 24 months corrected age. Infants in the Lowox group (initial Fio2, 0.3) received significantly less oxygen in the first few minutes of life compared with those in the HiOx group (initial Fio2, 0.6 to 0.65). As shown by Rook et al,14 differences in Fio2 were significant for the first 6 minutes after birth. However, we have found no statistical differences for survival and/or major morbidities in the neonatal period independent of the initial Fio2. Thus, mortality was 8.27% for the lower oxygen and 14.04% for the higher oxygen group. We also did not find differences in mortality when comparing our rates with those described by Oei et al30 for infants receiving air or pure oxygen.
In spite of the differences in oxygenation during the first minutes after birth, follow-up evaluation at 24 months corrected age did not show significant differences in Bayley-III scores in 88.6% of patients in the Lowox and in 95.0% of patients in the Hiox group. At follow-up, 73.6% of patients were nondisabled (75.3% in the Lowox group and 71.8% in Hiox group). Disabilities detected were mild in both groups (15%–20%) and the combined prevalence of moderate and severe disabilities was 9% in the Lowox group and 9.4% in the Hiox group, which is comparable to similar published studies.32–38 The rate of CP (3.8%) was not different between groups. Of note, subgroup analysis of infants according to gestational age did not find significant differences between groups in mortality, as opposed to Oei et al,30 or in sensorial or neurocognitive impairment.
Although the strengths of this study rely on the inclusion of randomized and blinded enrollment and multidisciplinary monitoring of patients with a relevant follow-up rate (total follow-up rate, 81.9%), there are some limitations that should be underscored.
Our patients were resuscitated with an initial Fio2 of 0.3 versus 0.6–0.65. This difference in oxygen load didn’t cause significant differences in mortality, biochemical results,13,14 short- and long-term outcomes (Table 1), and neurocognitive and sensorial assessment (Tables 2, 3, 4, 5, and 6). However, long-term results in preterm infants initially resuscitated with an Fio2 of 1.0 have not yet been performed. The use of pure oxygen provides a substantially greater total oxygen load at the end of resuscitation, which has been associated with increased levels of oxidative stress biomarkers, more prolonged use of oxygen, and/or BPD.7,13,14,39,40
Another limitation relates to the fact that 20% to 30% of patients did not come to the clinic to perform follow-up assessment or were not able to complete it. It has been shown that fidelity to appointments for follow-up greatly correlates with socioeconomic inequalities.41 A considerable number of infants were from immigrant families with low socioeconomic and educational status and frequent changes of residence. These factors may explain losses to follow-up.
To our knowledge, this is the first study that has compared neurocognitive and sensorial outcomes at 2 years corrected age in preterm infants stabilized with higher or lower initial Fio2. Both studies were randomized, controlled, and blinded trials, thus achieving a high grading of evidence. In addition, long-term follow-up of these patients, including academic, behavioral, and psychological assessment, is ongoing at all of the participating centers. We conclude that there are no differences in neurocognitive and sensorial outcomes at 24 months corrected age in preterm infants resuscitated with an initial Fio2 of 0.3 versus 0.6 to 0.65. Powered RCTs with saturation targets at specific time points for extremely preterm infants are required to assess if there are differences in mortality and/or long-term outcomes.
- Accepted September 21, 2016.
- Address correspondence to Máximo Vento, MD, PhD, Division of Neonatology, Health Research Institute La Fe, University and Polytechnic Hospital La Fe, Avenida Fernando Abril Martorell 101, 46026 Valencia, Spain. E-mail:
The trials in this article have been registered with the European Clinical Trials Database (https://eudract.ema.europa.eu/) (identifier 2088-005047-42) and with the Netherlands Trial Registry (http://www.trialregister.nl/trialreg/index.asp) (identifier NTR243).
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Drs Cernada and Cubells are both supported by a “Rio Hortega” (Health Research Institute Carlos III, Spanish Ministry of Economy and Competitiveness) grant; Dr Nuñez is supported by research contract RD12/0026/0012 from the Retic Red de Salud Materno Infantil y del Desarrollo; Dr Parra is supported by a research fellowship from Health Research Institute La Fe; and Dr Vento is supported by grant PI14/0443 from Health Research Institute Carlos III, Spanish Ministry of Economy and Competitiveness and by RETICS, funded by the PN 2018-2011 grant (Spain), Instituto de Salud Carlos III-Sub-Directorate General for Research Assessment and Promotion and the European Regional Development Fund (FEDER), reference RD12/0026/0011.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no conflicts of interest relevant to this article to disclose.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2016-3168.
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- Copyright © 2016 by the American Academy of Pediatrics