Controversies in oxygen treatment in the delivery room for preterm infants—a narrative review

Introduction

Background

Oxygen is an essential component of cellular respiration. At birth, the newborn lung must eliminate carbon dioxide and accept oxygen to complete the transition from placental support. These physiologic understandings have driven over a century of delivery room management. Consequently, oxygen therapy has been utilized since the early 1900s to facilitate a safe transition from fetal to neonatal physiology (1).

Unfortunately, our early tools for neonatal resuscitation were crude. Neonatal mortality was high (Figure 1) (2). The standard therapy, 100% fraction of inspired oxygen (FiO₂ 1.0) (3), was eventually determined to be associated with both significant morbidity and mortality. In the 1950s, there was growing recognition of potential harms of oxygen therapy (4). The “first epidemic” of retinopathy of prematurity (ROP) was caused directly by protracted exposure to high oxygen therapy in preterm infants (5). By the 1990s, the utility and safety of FiO₂ 1.0 in term infants was under active investigation (6). Yet, it was not until 2010 that the International Liaison Committee on Resuscitation (ILCOR) recommended against the routine use of FiO₂ 1.0 in the resuscitation of term and near term newborns (7).

Figure 1 Global trend of neonatal mortality. Mortality rates (per 1,000) within the first month of life for newborns globally. Data were obtained from the UNICEF (45) (WHO, World Bank, UN DESA Population Division) for the years 1990 through 2020 (45). UN DESA, United Nations Department of Economic and Social Affairs; UNICEF, United Nations Inter-agency Group for Child Mortality Estimation; WHO, World Health Organization.

This transition of oxygen from a solitary therapy to a potential source of harm reflects a history of dramatic improvements in preterm neonatal outcomes (Figure 2) (8,9). Understanding the pathophysiology of respiratory distress syndrome has led to some of the most important therapies, including maternal corticosteroid administration and postnatal surfactant. Technological advancements have made precision care of small patients possible, with innovations such as continuous positive airway pressure, volume-targeted ventilation, and pulse oximetry. Parallel to these technological advancements, statistical techniques and trial designs within medicine have advanced. Meta-analyses provided the necessary statistical power required to demonstrate higher mortality in term neonates receiving initial FiO₂ 1.0 therapy (10,11). In surviving preterm infants, hyperoxia was found to be associated not just with ROP (4) but bronchopulmonary dysplasia (BPD) (12). Given that high oxygen concentration is not only unnecessary for many newborn resuscitations but also deleterious, the initial use of high FiO₂ has significantly decreased across all gestations.

Figure 2 Neonatal mortality in the USA according to gestational age with select advancements in neonatal care. Mortality rates (percentage of births) within the first month of life for infants with recorded gestational ages between 22–28 and 22–35 weeks. Data were collected from period/cohort data files as available from the National Center for Health Statistics (43,44). Each point is an average of the following 5-year period (with at least 2 years of data available) from 1985 through 2021. FiO₂, fraction of inspired oxygen; ILCOR, International Liaison Committee on Resuscitation; NICHD.

However, this progress in neonatal care has revealed new controversies for oxygen therapy in delivery room resuscitation. While there is clear evidence of harm in term and late preterm infants, studies in infants with lower gestational ages (GAs) have revealed possible divergent outcomes (13). Indeed, the proliferation of care for our extreme preterm (<28 weeks’ gestation) and periviable infants (<24 weeks) has again prompted the re-evaluation of oxygen therapy in delivery room management. We present this article in accordance with the Narrative Review reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-24-58/rc).

Objective

This narrative review article synthesizes the current scientific literature and clinical perspectives on oxygen treatment in the delivery room with particular focus on very preterm infants, defined as GA less than 32 weeks. The discussion follows on how improving techniques of neonatal resuscitation have changed the balance of harm to benefit of oxygen therapy. It aims to elucidate the controversies, examine the evidence supporting various approaches, and identify areas where further research is needed.

Methods

We did a non-systematic narrative review with a focused search in PubMed, EMBASE, and Google Scholar for articles in English available by December 2024. The following terms were used: “infant, preterm, delivery room, resuscitation, oxygen saturation, pulse oximetry”. No restriction was placed on the year of publication considered, but research completed within the last 5 years was prioritized. No formal inclusion/exclusion criteria were applied beyond the focus on preterm infants and oxygen therapy in the delivery room, and articles were selected based on unanimous agreement among all authors. Our search strategy summary is provided in Table 1.

Results

Oxygenation of very and extremely preterm infants in the delivery room: start high or low?

Today, the evidence supporting the use of an FiO₂ of 0.21 for initial resuscitation in term infants is consistent and reflected in treatment recommendations (14,15). For preterm infants, ILCOR recommended in 2019 an initial FiO₂ of 0.21 to 0.30 for all infants with a GA <35 weeks (15). National guidelines vary with regards to initial FiO₂ (16-20) (Table 2), reflecting the lack of evidence of benefit for FiO₂ 1.0, a lack of studies comparing different intermediate O₂ concentrations (e.g., FiO₂ 0.3–0.6), and a goal of minimizing the known toxicities of hyperoxia.

Meta-analyses reflect the difficulty of performing studies with such brief exposure window that delivery room stabilization represents. The large ILCOR-associated meta-analysis in 2019, assessed 5,697 preterm infants (<35 weeks) and concluded that there was no difference in mortality between initial oxygen therapy concentrations (21). Subgroup analysis also failed to demonstrate a difference for those <28 weeks’ gestation, in contrast to prior studies (13), but like a prior meta-analysis (22). A meta-analysis in 2022 was unable to demonstrate differences in neurodevelopmental outcome or mortality in 2-year follow-up between high and low oxygenation treatment groups within the delivery room (23). All the above analyses describe high uncertainty of the evidence as a primary concern, recommending future studies with larger sample sizes.

The NETwork Meta-analysis Of Trials of Initial Oxygen in preterm Newborns (NETMOTION) study was an individual participant data network meta-analysis and pooled outcomes across 1,055 infants born GA <32 weeks (24). The study compared low (0.3), intermediate (0.5–0.65), or high (0.90–1.0) FiO₂ with regards to the outcomes all-cause mortality upon discharge, and morbidities including BPD, intraventricular hemorrhage (IVH) grade III or IV and ROP, as well as oxygen saturation (SpO₂) 80–85% at 5 min of age. The 12 (10 from high-income countries; two from middle-income countries) included studies were conducted 2005–2019. With low to very-low certainty, very preterm infant mortality was reduced when high initial FiO₂ was used compared with both low and intermediate FiO₂. There was no evidence of a difference in morbidity between treatment arms.

After having performed an updated study-level meta-analysis and appraised the NETMOTION study according to the method of adolopment, ILCOR released the 2025 Consensus on Science with Treatment Recommendations: “Among newborn infants <32 weeks’ gestation, it is reasonable to begin resuscitation with ≥30% oxygen (weak recommendation, low-certainty evidence).” (25). The anticipated PROspective Meta-analysis Of Trials of Initial Oxygen in preterm Newborns (PROMOTION) will include two ongoing randomized control trials (RCTs), the Targeted Oxygenation in the Respiratory care of Premature Infants at Delivery: Effects on Outcome (TORPIDO 30/60) and the 30% or 60% Oxygen at Birth to Improve Neurodevelopmental Outcomes in Very Low Birthweight Infants (HiLo) trials (26-28). Both TORPIDO 30/60 and HiLo compare FiO₂ 0.30 with 0.60.

Achieving SpO₂ goals: move quick or slow?

Current guidelines recommend using SpO₂ targets of 80–85% at 5 minutes of life (19). Failure to reach this target in newborn infants <32 weeks GA has been associated with increased mortality, severe IVH and poor neurodevelopmental outcomes (29-31). The details of how to obtain such targets are unclear. A recent, prospective observational study of healthy preterm infants placed the median time to SpO₂ >90% at just over 5 minutes (32). Interestingly, while the NETMOTION study demonstrated no difference in achievement of target SpO₂ (80–85%) at five minutes of life, patients in the high FiO₂ arm demonstrated a higher SpO₂ at 5 minutes of life as compared to low FiO₂ as a secondary outcome (very low certainty). While this meta-analysis initially intended to analyze oxygenation titration strategies, study heterogeneity precluded such planned analysis. Results are waited for the ongoing Optimization of Saturation Targets And Resuscitation Trial (OptiSTART) which is an RCT comparing a higher (75^th) and routine (50^th) percentile SpO₂ target for preterm newborn resuscitation (33).

Delayed cord clamping

When the umbilical cord is cut, the infant is separated from the low-resistance placental circulation, the systemic vascular resistance and blood pressure increase and right-to-left ductal shunting decreases (34). Lung aeration after birth results in a reduced pulmonary vascular resistance and increased pulmonary blood flow. Thus, lung aeration prior to umbilical cord clamping ensures that left ventricular pre-load and -output are maintained when the umbilical cord is clamped (35). Outcomes for preterm infants can be stratified along the time between birth and the clamping of the umbilical cord. Long deferral (>120 seconds) of cord clamping, as compared with immediate clamping (<15 seconds), reduced mortality in a recent individual-patient network meta-analysis (36). However, the sample size was very low, and the infants were analyzed per intention-to-treat, not actual cord clamping time. A recent clinical trial randomizing preterm infants to respiratory therapy before cord clamping demonstrated a decreased need for delivery room intubation. While this study failed to show primary benefit (mortality or reduced rates of IVH), the decreased intubation requirement supports the unique transitional physiology between delivery and separation from the placenta (37).

Observational data indicate that deferred cord clamping (DCC) is associated with a lower initial heart rate (HR) and a more gradual increase in the HR (38-40). In contrast, a recent study by Badurdeen et al. found similar trajectories in HR and SpO₂ for preterm infants (GA ≥32 weeks) undergoing either physiologically based cord clamping or early cord clamping (41). A prospective observational study of healthy infants born between 32–36 weeks GA receiving routine DCC reported that although preterm infants typically had lower HR and SpO₂ during the first 5 minutes after birth, infants below the 25^th percentiles of SpO₂ at 2 minutes of age did not reach an SpO₂ of 80% by 5 minutes (42).

DCC may limit the exposure to hyperoxia during resuscitation. In a study by Chandrasekharan et al. in 2021, asphyxiated preterm lambs were randomized to immediate or DCC (43). Resuscitation was completed with FiO₂ 0.30–0.60. In lambs randomized to DCC, they demonstrated earlier achievement of target SpO₂, lower FiO₂ requirements, and decreased oxygen load. This “differential oxygenation”, whereby the placenta acts as an additional organ of PaO₂ regulation during resuscitation, may provide protection from higher initial FiO₂ exposure. Consistent with this potential for placental protection, the ongoing Delayed Cord Clamping with Oxygen In Extremely Low Gestation Infants (DOXIE) is comparing FiO₂ 1.0 to 0.3 during DCC (44).

How to oxygenate during chest compressions?

International guidelines direct the use of FiO₂ 1.0 during chest compressions, ideally administered through a definitive airway (19). However, a systematic review and meta-analysis from 2018 did not identify any human studies comparing an FiO₂ of 1.0 with lower oxygen concentrations during neonatal chest compression (45). Eight animal studies in term models were meta-analyzed and showed no difference in mortality or adverse effects resulting from an FiO₂ of 0.21 versus 1.0 (45). A similar conclusion was made by an ILCOR scoping review on neonatal chest compressions from 2023 (46).

There is consistent evidence that post resuscitation oxygenation, both within neonatal and pediatric populations, may influence mortality (47). A study in 2023 compared FiO₂ 0.21 to 1.0, and gradual vs. abrupt weaning protocols, in lambs asphyxiated through umbilical cord occlusion (48). At return of spontaneous circulation (ROSC), the low FiO₂ treatment arm demonstrated significant lactic acid burden and depressed PaO₂. Rapid weaning obviated supraphysiologic oxygenation (48).

Monitoring oxygen therapy

The physical examination of preterm infants presents unique challenges. Unlike their term counterparts, preterm infants lack reciprocal interaction during examination, making it difficult to assess their condition through traditional signs of recognition and response. Consequently, modern neonatology has increasingly relied on objective measurements to guide therapy. The refinement of these measurements has significantly improved the quality of care, often by limiting the use of potentially harmful therapies. By the 1970s, use of intermittent transcutaneous oxygen monitoring was “routine” (49). While it was known that excessive FiO₂ therapy could cause ROP, the appropriate level of oxygen therapy remained unclear. Flynn et al. in 1987 compared continuous monitoring vs. scheduling monitoring of transcutaneous oxygenation on ROP risk (50). Initial oxygen concentrations for these infants were “almost always greater than 40%”. They found benefit in prevention of ROP only in those >1,000 g with continuous oxygen monitoring, but the accuracy of early continuous monitoring in the smallest infants was at question. Almost four decades later, the accuracy of SpO₂ measurement is still in question, particularly for patients of color and preterm infants (51-53).

We have previously shown, in mechanically ventilated human infants in the neonatal intensive care unit (NICU) (54) and asphyxiated newborn piglets (55), that pulse oximetry overestimated the oxygen saturation compared with arterial blood gas analysis in these populations. Johnston et al. (56), representing the BOOST-II investigators (https://www.npeu.ox.ac.uk/boost), noticed a non-plausible distribution of SpO₂-values in preterm neonates monitored with the Masimo SET Radical pulse oximeter. The manufacturer acknowledged that this was due to an error in the pulse oximetry calibration algorithm, leading to more SpO₂ values than expected above 90%. New software was then supplied to the trials that investigated different oxygen targets for extremely preterm infants in the NICU (57).

While pulse oximetry has the potential for biased results, these objective measurements are more accurate than visual diagnosis of hypoxia in newborns with darker skin tones (58). To mitigate the risk of bias, it is advisable to select pulse oximetry platforms with a demonstrated history of good accuracy in diverse patient populations. Until such devices are readily available, a clinician’s assessment should consider both the reported saturation of the pulse oximeter and a holistic evaluation of the patient’s clinical status. Where possible, participation in open-access data monitoring programs could accelerate the improvement and validation process of these devices (59).

New advancements in oximetry may provide further nuance in managing newborn oxygen saturation. While standard oximetry provides critical signals of hypoxemia, it offers no insight into the degree of hyperoxia.

The oxygen reserve index (ORi^TM) is a noninvasive method that complements the information given by SpO₂. This method is a multiwavelength co-oximetry that analyzes the variation in the light absorption at arterial and venous level, which allows for a real time and continuous analysis of the patient oxygenation state. ORi^TM can detect moderate hyperoxia (PaO₂ >100 and <200 mmHg) even with SpO₂ levels within the desirable range. Thus, the method may also alert the provider about downward-trending saturation before the pulse oximeter does (60). If such new monitoring platforms can demonstrate consistent accuracy, they may provide the necessary clinical information to finally recognize the clinical utility of other therapies, such as automated oxygen control (61,62).

Discussion

First decisions

Despite over a century of progress, we are still learning how to help—not harm—the transition to extrauterine life. Before meeting the patient, the provider must make several decisions at delivery: the initial FiO₂ for resuscitation, the target SpO₂ at 5 minutes of life, and the timing of umbilical cord clamping. With very-low certainty, newer clinical data suggest that initial FiO₂ >0.30 administration is associated with less mortality in very preterm infants (24). Ongoing trials and the following planned individual participant meta-analysis (TORPIDO 30/60, Hilo, PROMOTION) aim to validate this key initial therapy. OptiSTART will add accuracy to the SpO₂ target, hopefully reducing invasive oxygen therapy and the associated lung injury. DCC reduces mortality and introduces a second organ of respiration into routine resuscitation. Upcoming studies, such as DOXIE, will allow an informed consideration of DCC in initial FiO₂ choice. It is notable that all the above studies include neurodevelopmental outcomes, allowing comparison of treatment options across a critical benchmark to minimize the impact of premature birth (63).

Rare events

A resuscitation with chest compressions is a complex event in neonatology. The rarity and ethical weight of chest compressions has almost precluded traditional research design. As such, more complex approaches will be needed to answer fundamental questions that improve ROSC, survival, and neurodevelopmental outcomes.

Ongoing monitoring

Despite several advantages, there are some limitations to the use of pulse oximetry during neonatal resuscitation. Overall, pulse oximetry is a fairly accurate method for delivery room HR measurement and should be routinely used to monitor HR and SpO₂ during neonatal resuscitation (64). However, there may be concerns about pulse oximetry bias with increased skin pigmentation. Such considerations, together with the fact that some lower resourced settings may not have access to oxygen blenders (65), contribute to disparity in the quality of care for preterm infants during delivery room stabilization. Hyperoxia is not detected with pulse oximetry, but use of the ORi^TM may hold promise.

Conclusions

A higher initial FiO₂ may be needed in the delivery room stabilization and resuscitation of very preterm infants. Ongoing research aims to determine both the ideal SpO₂ goals and the effect of DCC.

The management decisions required for chest compressions are based on particularly low certainty evidence. Continuous pulse oximetry, when its limitations are recognized and anticipated, will continue to serve as our standard tool to guide oxygen therapy. Future advancements in oximetry are expected to reduce the rate of occult hypoxemia and provide guidance on the degree of hyperoxia.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-24-58/rc

Peer Review File: Available at https://pm.amegroups.com/article/view/10.21037/pm-24-58/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-24-58/coif). O.D.S. serves as the unpaid Associate Editor-in-Chief of Pediatric Medicine from January 2024 to December 2025. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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