Umbilical Cord Milking Versus Delayed Cord Clamping in Infants 28 to 32 Weeks: A Randomized Trial.

OBJECTIVES: To determine whether rate of severe intraventricular hemorrhage (IVH) or death among preterm infants receiving placental transfusion with UCM is noninferior to delayed cord clamping (DCC). METHODS: Noninferiority randomized controlled trial comparing UCM versus DCC in preterm infants born 28 to 32 weeks recruited between June 2017 through September 2022 from 19 university and private medical centers in 4 countries. The primary outcome was Grade III/IV IVH or death evaluated at a 1% noninferiority margin. RESULTS: Among 1019 infants (UCM n = 511 and DCC n = 508), all completed the trial from birth through initial hospitalization (mean gestational age 31 weeks, 44% female). For the primary outcome, 7 of 511 (1.4%) infants randomized to UCM developed severe IVH or died compared to 7 of 508 (1.4%) infants randomized to DCC (rate difference 0.01%, 95% confidence interval: (-1.4% to 1.4%), P = .99). CONCLUSIONS: In this randomized controlled trial of UCM versus DCC among preterm infants born between 28 and 32 weeks' gestation, there was no difference in the rates of severe IVH or death. UCM may be a safe alternative to DCC in premature infants born at 28 to 32 weeks who require resuscitation.

Perinatal Outcomes of Subjects Enrolled in a Multicenter Trial with a Waiver of Antenatal Consent.

OBJECTIVE: This study aimed to determine whether outcomes differed between infants enrolled in the PREMOD2 trial and those otherwise eligible but not enrolled, and whether the use of waiver effected these differences. STUDY DESIGN: The multicenter PREMOD2 (PREmature infants receiving Milking Or Delayed cord clamping) trial was approved for waiver of antenatal consent by six of the nine sites institutional review boards, while three sites exclusively used antenatal consent. Every randomized subject delivered at a site with a waiver of consent was approached for postnatal consent to allow for data collection. Four of those six sites IRBs required the study team to attempt antenatal consent when possible. Three sites exclusively used antenatal consent. RESULTS: Enrolled subjects had higher Apgar scores, less use of positive pressure ventilation, a lower rate of bronchopulmonary dysplasia, and a less frequent occurrence of the combined outcome of severe intraventricular hemorrhage or death. A significantly greater number of infants were enrolled at sites with an option of waiver of consent (66 vs. 26%, risk ratio = 2.54, p < 0.001). At sites with an option of either approaching families before delivery or after delivery with a waiver of antenatal consent, those approached prior to delivery refused consent 40% (range 15-74% across six sites) of the time. CONCLUSION: PREMOD2 trial demonstrated analytical validity limitations because of the variable mix of antenatal consent and waiver of consent. A waiver of antenatal consent for minimal risk interventional trials conducted during the intrapartum period will be more successful in enrolling a representative sample of low and high-risk infants if investigators are able to enroll all eligible subjects. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03019367. KEY POINTS: · Waiver of consent is when informed consent cannot be obtained prior to delivery.. · Cord milking is a procedure in which blood is pushed (stripped) two to four times towards the newborn.. · Delayed clamping means the umbilical cord is not clamped immediately after birth..

Identifying Ways to Fix Outcome Disparities among Outborns Needing Therapeutic Hypothermia.

OBJECTIVE: This study examined patterns of care after birth in newborns treated with therapeutic hypothermia to identify remediable causes for the poorer outcomes observed in outborn infants. STUDY DESIGN: This was a secondary analysis of 150 newborns (68 outborn) prospectively enrolled at our center in the Vermont Oxford Neonatal Encephalopathy Registry from January 2008 to October 2016. RESULTS: The 5-minute Apgar's score and cord pH value did not differ, but cord blood gases were obtained far less frequently in outborns (p = 0.002). Outborns needed more chest compressions (p = 0.01) and epinephrine (p = 0.04), and had more brain injury on neuroimaging (p = 0.05). Outborns took longer to reach target hypothermia temperature (p < 0.0001). CONCLUSION: The lack of cord gas values and longer time to reach target temperature observed in the outborns are two observed differences in care that can be potentially remedied by providing education and resources at delivering hospitals in rapid identification of hypothermia candidates, though further research is needed to define the effects of such measures. Possible solutions are also discussed here.

Early Cardiac and Cerebral Hemodynamics with Umbilical Cord Milking Compared with Delayed Cord Clamping in Infants Born Preterm.

OBJECTIVE: To evaluate changes in cerebral oxygenation, peripheral arterial oxygenation, respiratory status, and administered fraction of inspired oxygen during the first 10 minutes of life in premature infants receiving umbilical cord milking compared with delayed cord clamping (DCC). STUDY DESIGN: Premature infants born at 230/7 to 276/7 weeks of gestation were randomized to umbilical cord milking or DCC. A near infrared spectroscopy sensor, pulse oximeter, and electrocardiogram electrodes were placed. Pulse rate, cerebral tissue oxygenation, peripheral oxygen saturation, airway pressure, and fraction of inspired oxygen were collected for 10 minutes in the delivery room. Longitudinal models were used to compare effects of umbilical cord milking and DCC. RESULTS: Fifty-six infants had cerebral oximetry and advanced monitoring at birth. There was an increased incidence of severe intraventricular hemorrhage in infants who received umbilical cord milking compared with DCC (P = .0211). Longitudinal models suggested that peripheral oxygen saturation was higher in the umbilical cord milking group in the first 4 minutes (P = .0221) and that mean airway pressures were lower in the umbilical cord milking group after the first 7 minutes (P = .0072). No statistical differences were observed for fraction of inspired oxygen, cerebral tissue oxygenation, or heart rates. CONCLUSIONS: The data suggest that the rapid transfer of blood during umbilical cord milking may facilitate lung expansion with improved pulmonary blood flow, but may also increase cerebral blood flow, resulting in severe intraventricular hemorrhage. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03145142.

Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: There are no US Food and Drug Administration-approved therapies for neonatal seizures. Phenobarbital and phenytoin frequently fail to control seizures. There are concerns about the safety of seizure medications in the developing brain. Levetiracetam has proven efficacy and an excellent safety profile in older patients; therefore, there is great interest in its use in neonates. However, randomized studies have not been performed. Our objectives were to study the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment of neonatal seizures. METHODS: The study was a multicenter, randomized, blinded, controlled, phase IIb trial investigating the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment for neonatal seizures of any cause. The primary outcome measure was complete seizure freedom for 24 hours, assessed by independent review of the EEGs by 2 neurophysiologists. RESULTS: Eighty percent of patients (24 of 30) randomly assigned to phenobarbital remained seizure free for 24 hours, compared with 28% of patients (15 of 53) randomly assigned to levetiracetam (P < .001; relative risk 0.35 [95% confidence interval: 0.22-0.56]; modified intention-to-treat population). A 7.5% improvement in efficacy was achieved with a dose escalation of levetiracetam from 40 to 60 mg/kg. More adverse effects were seen in subjects randomly assigned to phenobarbital (not statistically significant). CONCLUSIONS: In this phase IIb study, phenobarbital was more effective than levetiracetam for the treatment of neonatal seizures. Higher rates of adverse effects were seen with phenobarbital treatment. Higher-dose studies of levetiracetam are warranted, and definitive studies with long-term outcome measures are needed.

Association of Umbilical Cord Milking vs Delayed Umbilical Cord Clamping With Death or Severe Intraventricular Hemorrhage Among Preterm Infants.

Importance: Umbilical cord milking as an alternative to delayed umbilical cord clamping may provide equivalent benefits to preterm infants, but without delaying resuscitation. Objective: To determine whether the rates of death or severe intraventricular hemorrhage differ among preterm infants receiving placental transfusion with umbilical cord milking vs delayed umbilical cord clamping. Design, Setting, and Participants: Noninferiority randomized clinical trial of preterm infants (born at 23-31 weeks' gestation) from 9 university and private medical centers in 4 countries were recruited and enrolled between June 2017 and September 2018. Planned enrollment was 750 per group. However, a safety signal comprising an imbalance in the number of severe intraventricular hemorrhage events by study group was observed at the first interim analysis; enrollment was stopped based on recommendations from the data and safety monitoring board. The planned noninferiority analysis could not be conducted and a post hoc comparison was performed instead. Final date of follow-up was December 2018. Interventions: Participants were randomized to umbilical cord milking (n = 236) or delayed umbilical cord clamping (n = 238). Main Outcomes and Measures: The primary outcome was a composite of death or severe intraventricular hemorrhage to determine noninferiority of umbilical cord milking with a 1% noninferiority margin. Results: Among 540 infants randomized, 474 (88%) were enrolled and completed the trial (mean gestational age of 28 weeks; 46% female). Twelve percent (29/236) of the umbilical cord milking group died or developed severe intraventricular hemorrhage compared with 8% (20/238) of the delayed umbilical cord clamping group (risk difference, 4% [95% CI, -2% to 9%]; P = .16). Although there was no statistically significant difference in death, severe intraventricular hemorrhage was statistically significantly higher in the umbilical cord milking group than in the delayed umbilical cord clamping group (8% [20/236] vs 3% [8/238], respectively; risk difference, 5% [95% CI, 1% to 9%]; P = .02). The test for interaction between gestational age strata and treatment group was significant for severe intraventricular hemorrhage only (P = .003); among infants born at 23 to 27 weeks' gestation, severe intraventricular hemorrhage was statistically significantly higher with umbilical cord milking than with delayed umbilical cord clamping (22% [20/93] vs 6% [5/89], respectively; risk difference, 16% [95% CI, 6% to 26%]; P = .002). Conclusions and Relevance: In this post hoc analysis of a prematurely terminated randomized clinical trial of umbilical cord milking vs delayed umbilical cord clamping among preterm infants born at less than 32 weeks' gestation, there was no statistically significant difference in the rate of a composite outcome of death or severe intraventricular hemorrhage, but there was a statistically significantly higher rate of severe intraventricular hemorrhage in the umbilical cord milking group. The early study termination and resulting post hoc nature of the analyses preclude definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT03019367.

Assessing the Feasibility of Providing a Real-Time Response to Seizures Detected With Continuous Long-Term Neonatal Electroencephalography Monitoring.

PURPOSE: Continuous video electroencephalography (cEEG) monitoring is the recommended gold standard of care for at-risk neonates but is not available in many Neonatal Intensive Care Units (NICUs). To conduct a randomized treatment trial of levetiracetam for the first-line treatment of neonatal seizures (the NEOLEV2 trial), we developed a monitoring infrastructure at five NICUs, implementing recent technological advancements to provide continuous video EEG monitoring and real-time response to seizure detection. Here, we report on the feasibility of providing this level of care. METHODS: Twenty-five key informant interviews were conducted with study neurologists, neonatologists, coordinators, and EEG technicians from the commercial EEG monitoring company Corticare. A general inductive approach was used to analyze these qualitative data. RESULTS: A robust infrastructure for continuous video EEG monitoring, remote review, and real-time seizure detection was established at all sites. At the time of this survey, 260 babies had been recruited and monitored for 2 to 6 days. The EEG technician review by the commercial EEG monitoring company was reassuring to families and neonatologists and led to earlier detection of seizures but did not reduce work load for neurologists. Neurologists found the automated neonatal seizure detector algorithm provided by the EEG software company Persyst useful, but the accuracy of the algorithm was not such that it could be used without review by human expert. Placement of EEG electrodes to initiate monitoring, especially after hours, remains problematic. CONCLUSIONS: Technological advancements have made it possible to provide at-risk neonates with continuous video EEG monitoring, real-time detection of and response to seizures. However, this standard of care remains unfeasible in usual clinical practice. Chief obstacles remain starting a recording and resourcing the real-time specialist review of suspect seizures.

The Neu-Prem Trial: Neuromonitoring of Brains of Infants Born Preterm During Resuscitation-A Prospective Observational Cohort Study.

OBJECTIVE: To determine whether monitoring cerebral oxygen tissue saturation (StO2) with near-infrared spectroscopy (NIRS) and brain activity with amplitude-integrated electroencephalography (aEEG) can predict infants at risk for intraventricular hemorrhage (IVH) and death in the first 72 hours of life. STUDY DESIGN: A NIRS sensor and electroencephalography leads were placed on 127 newborns <32 weeks of gestational age at birth. Ten minutes of continuous NIRS and aEEG along with heart rate, peripheral arterial oxygen saturation, fraction of inspired oxygen, and mean airway pressure measurements were obtained in the delivery room. Once the infant was transferred to the neonatal intensive care unit, NIRS, aEEG, and vital signs were recorded until 72 hours of life. An ultrasound scan of the head was performed within the first 12 hours of life and again at 72 hours of life. RESULTS: Thirteen of the infants developed any IVH or died; of these, 4 developed severe IVH (grade 3-4) within 72 hours. There were no differences in either cerebral StO2 or aEEG in the infants with low-grade IVH. Infants who developed severe IVH or death had significantly lower cerebral StO2 from 8 to 10 minutes of life. CONCLUSIONS: aEEG was not predictive of IVH or death in the delivery room or in the neonatal intensive care unit. It may be possible to use NIRS in the delivery room to predict severe IVH and early death. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02605733.

The 30-second rule: the effects of prolonged intubation attempts on oxygen saturation and heart rate in preterm infants in the delivery room.

BACKGROUND: A duration of 30 seconds has been shown to improve the success rate of intubation attempts without any decompensation. There is limited data regarding the detrimental effects of prolonged intubation attempts in preterm infants. The aim was to determine the effect of prolonged intubation attempts on heart rate and oxygen saturation in preterm infants. METHODS: We retrospectively reviewed videos and physiologic data collected during delivery room (DR) resuscitations. Infants who had a functioning pulse oximeter at the time of intubation in the delivery room were analyzed using video and analog recordings. The duration of the intubation attempt was defined as the time the laryngoscope blade was in the infant's mouth. Prolonged intubations were defined as intubations over 30 seconds. Baseline heart rate and saturations were defined as the heart rate and saturation immediately prior to the intubation attempt. Video recording was used to determine time laryngoscope was in the mouth, what other procedures were performed, and whether there was recovery between attempts. Analog data including heart rate, airway pressure and saturation was also recorded. RESULTS: There were 52 intubation attempts in 28 infants. The median (IQR) birth weight and gestational age were 795 (705, 972) grams and 25 (25, 27) weeks. The duration of an intubation attempt was 35 (27, 46) seconds with number of attempts 2 (1, 2). There were 34 intubation attempts greater than 30 seconds (prolonged group) and 18 attempts less than or equal to 30 seconds (short group). Longer attempts did not affect intubation success (successful 34 [25,37] seconds vs. unsuccessful 41[29, 53] seconds; P=0.05). Infants in the prolonged group had a greater decrease in oxygen saturation percentage from baseline (5±8 percent, short intubation group and 13±27 prolonged intubation group; P=0.004). There was also a significant decrease in heart rate beats per minute between the two groups (6±9 in the short intubation group and 23±29 prolonged group; P=0.004). CONCLUSIONS: The currently recommended guideline by the Neonatal Resuscitation Program limiting intubation attempts to less than 30 seconds is supported by stable oxygen saturations and heart rate. Prolonging the intubation more than 30 seconds leads to greater hypoxia and may contribute to increased neonatal morbidity, with no effect on success rate.

A pilot randomized controlled trial of EKG for neonatal resuscitation.

BACKGROUND: The seventh edition of the American Academy of Pediatrics Neonatal Resuscitation Program recommends the use of a cardiac monitor in infants that need resuscitation. Previous trials have shown that EKG heart rate is available before pulse rate from a pulse oximeter. To date no trial has looked at how the availability of electrocardiogram (EKG) affects clinical interventions in the delivery room. OBJECTIVE: To determine whether the availability of an EKG heart rate value and tracing to the clinical team has an effect on physiologic measures and related interventions during the stabilization of preterm infants. DESIGN/METHODS: Forty (40) premature infants enrolled in a neuro-monitoring study (The Neu-Prem Trial: NCT02605733) who had an EKG monitor available were randomized to have the heart rate information from the bedside EKG monitor either displayed or not displayed to the clinical team. Heart rate, oxygen saturation, FiO2 and mean airway pressure from a data acquisition system were recorded every 2 seconds. Results were averaged over 30 seconds and the differences analyzed using two-tailed t-test. Interventions analyzed included time to first change in FiO2, first positive pressure ventilation, first increase in airway pressure, and first intubation. RESULTS: There were no significant differences in time to clinical interventions between the blinded and unblinded group, despite the unblinded group having access to a visible heart rate at 66 +/- 20 compared to 114 +/- 39 seconds for the blinded group (p < .0001). Pulse rate from oximeter was lower than EKG heart rate during the first 2 minutes of life, but this was not significant. CONCLUSION(S): EKG provides an earlier, and more accurate heart rate than pulse rate from an oximeter during stabilization of preterm infants, allowing earlier intervention. All interventions were started earlier in the unblinded EKG group but these numbers were not significant in this small trial. Earlier EKG placement before pulse oximeter placement may affect other interventions, but this needs further study.

Providing a Placental Transfusion in Newborns Who Need Resuscitation.

Over the past decade, there have been several studies and reviews on the importance of providing a placental transfusion to the newborn. Allowing a placental transfusion to occur by delaying the clamping of the umbilical cord is an extremely effective method of enhancing arterial oxygen content, increasing cardiac output, and improving oxygen delivery. However, premature and term newborns who require resuscitation have impaired transitional hemodynamics and may warrant different methods to actively provide a placental transfusion while still allowing for resuscitation. In this review, we will provide evidence for providing a placental transfusion in these circumstances and methods for implementation. Several factors including cord clamping time, uterine contractions, umbilical blood flow, respirations, and gravity play an important role in determining placental transfusion volumes. Finally, while many practitioners agree that a placental transfusion is beneficial, it is not always straightforward to implement and can be performed using different methods, making this basic procedure important to discuss. We will review three placental transfusion techniques: delayed cord clamping, intact umbilical cord milking, and cut-umbilical cord milking. We will also review resuscitation with an intact cord and the evidence in term and preterm newborns supporting this practice. We will discuss perceived risks versus benefits of these procedures. Finally, we will provide key straightforward concepts and implementation strategies to ensure that placental-to-newborn transfusion can become routine practice at any institution.

Neonatal Resuscitation with an Intact Cord: A Randomized Clinical Trial.

OBJECTIVE: To assess whether providing ventilation during delayed cord clamping (V-DCC) increases placental transfusion compared with delayed cord clamping alone (DCC only). STUDY DESIGN: Inborn premature infants (230/7-316/7 weeks' gestational age) were randomized to receive at least 60 seconds of V-DCC (initial continuous positive airway pressure) with addition of positive pressure ventilation if needed) or without assisted ventilation (DCC only). For the DCC-only group, infants were dried and stimulated by gently rubbing the back if apneic. The primary outcome was the peak hematocrit in the first 24 hours of life. Delivery room outcomes were analyzed from video recordings and a data acquisition system. Hemodynamic measurements were performed with the use of functional echocardiography, near-infrared spectroscopy, and electrical cardiometry. RESULTS: There was no difference in the primary outcome of peak hematocrit in the first 24 hours of life. The onset of breathing was similar between both groups (25 ± 20 and 27 ± 28 seconds, P = .627); however, infants receiving DCC received a greater duration of stimulation than V-DCC (41 ± 19 and 20 ± 21 seconds P = .002). There were no differences in delivery room interventions, early hemodynamics (cerebral oxygenation by near-infrared spectroscopy, cardiac output and stroke volume by electrical cardiometry, or superior vena cava flow by of functional echocardiography), or neonatal outcomes. CONCLUSIONS: V-DCC was feasible but did not lead to any measurable clinical improvements immediately after delivery or reduce subsequent neonatal morbidity. Caretakers should consider providing adequate stimulation before cord clamping. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02231411.

Relationship Between Near-Infrared Spectroscopy and Transabdominal Ultrasonography: Noninvasive Monitoring of Intestinal Function in Neonates.

BACKGROUND: Near-infrared spectroscopy (NIRS) has the potential to continuously and noninvasively monitor intestinal function. This technology may be valuable because among neonates, intestinal maturity is highly variable and difficult to assess based solely on clinical signs. The aim of this study was to determine if there is an association between NIRS-based StO2 measurements and peristaltic activity assessed by transabdominal ultrasonography (US). MATERIAL/METHODS: Nineteen neonates of gestational age >32 weeks were categorized according to "no/low" versus "normal/hyperactive" motility levels, based on blinded US scan results. StO2 was recorded every 2 s for 24 h, following the ultrasound recording. Differences between the resulting estimates of average StO2 (bias of fits) and goodness-of-fit (residuals) were evaluated. RESULTS: Newborns with normal/hyperactive motility had higher mean StO2 than newborns with no/low motility (72.3±4.4 vs. 65.5±7.9, p<0.05, F=5.65). Residual errors were not significantly different between the 2 groups (p=0.213, F=0.213). A multivariate linear regression model using the means, residuals, and pairwise products of both, demonstrated more significant separation (0.47±0.26 vs. -0.24±0.33, p<0.01, F=27.4). A non-linear variant of the multivariate linear regression model demonstrated greatest separation (0.68±0.24 vs. -0.49±0.53, p<0.01, F=41.9). CONCLUSIONS: This is the first study to demonstrate an association between NIRS-based StO2 measurements and peristaltic activity visualized by ultrasound imaging. NIRS may offer a continuous, noninvasive method to assess motility. This may have significant implications in premature infants at risk for feeding intolerance or necrotizing enterocolitis.

Measuring cardiac changes using electrical impedance during delayed cord clamping: a feasibility trial.

BACKGROUND: To date no study has attempted to continuously evaluate changes in hemodynamics during delayed cord clamping in humans. We aimed to demonstrate 1. the feasibility of measurements of hemodynamics during delayed cord clamping and 2. to describe the changes that occur over each minute. RESULTS: After vaginal delivery, term infants (37(0)-41(6) weeks) were placed on a Life Start® bed 10-20 cm below the placenta. Transcutaneous sensors were placed on the neck and chest to determine heart rate, stroke volume and cardiac output at each beat. Once a signal was obtained, first 5 values (taken every beat) were averaged and the percent change for each subject from baseline was calculated. 20 infants were enrolled and all had a reliable signal obtained from transcutaneous sensors and had a delay in cord clamping for about 5 minutes. Cardiac output increased from 2 to 5 minutes of life (p = 0.008). For every minute of life the cord was kept unclamped, the stroke volume increased 13.1% ± 12.3 (p = 0.0001) and cardiac output increased 12.6% ± 6.3 from baseline (p < 0.0001). While the majority of infants continued to have an increase in cardiac output at 5 minutes of life, 7/20 infants reached their peak cardiac output at 188 ± 41 seconds of life. CONCLUSIONS: This study demonstrates that hemodynamic measures could be successfully obtained during the first five minutes of birth and while a newborn was receiving delayed cord clamping. This study also provides reference values for changes in cardiac output and stroke volume in well term infants during delayed cord clamping. TRIAL REGISTRATION: Clinical Trials.gov NCT02195037 Registered 17 July 2014.

Guided imagery: an innovative approach to improving maternal sleep quality.

Mothers of preterm infants are at risk for poor sleep quality, which may adversely affect their health, maternal-infant attachment, and infant caretaking activities. This study examined the relationship of an 8-week relaxation guided imagery intervention on sleep quality and the association between sleep quality and maternal distress (perceived stress, depressive symptoms, and state anxiety) in 20 mothers of hospitalized preterm infants. Mothers received a CD (compact disc) with three 20-minutes recordings and were asked to listen to at least 1 recording daily for 8 weeks. This analysis used self-report data gathered at baseline and 8 weeks. Pearson correlations were used to examine the relationships between mean cumulative relaxation guided imagery use and measures of maternal distress and sleep quality scores at 8 weeks. Complete data on 19 mothers were available for analysis. At 8 weeks, higher mean relaxation guided imagery use was inversely correlated with sleep quality scores (r = -0.30); sleep quality scores were positively correlated with stress (r = 0.42), depressive symptoms (r = 0.34), and anxiety (r = 0.39) scores. In mothers of preterm infants, sleep quality was negatively affected by mental distress and may be improved by a guided imagery intervention.

Impact of a physiologic definition on bronchopulmonary dysplasia rates.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is the endpoint of many intervention trials in neonatology, yet the outcome measure when based solely on oxygen administration may be confounded by differing criteria for oxygen administration between physicians. We previously reported a technique to standardize the definition of BPD between sites by using a timed room-air challenge in selected infants. We hypothesized that a physiologic definition of BPD would reduce the variation in observed rates of BPD among different neonatal centers. Methodology. A total of 1598 consecutive inborn premature infants (501-1249 g birth weight) who remained hospitalized at 36 weeks' postmenstrual age were prospectively assessed and assigned an outcome with both a clinical definition and physiologic definition of BPD. The clinical definition of BPD was oxygen supplementation at exactly 36 weeks' postmenstrual age. The physiologic definition of BPD was assigned at 36 +/- 1 weeks' postmenstrual age and included 2 distinct subpopulations. First, neonates on positive pressure support or receiving >30% supplemental oxygen with saturations between 90% and 96% were assigned the outcome BPD and not tested further. Second, those receiving < or =30% oxygen or effective oxygen >30% with saturations >96% underwent a room-air challenge with continuous observation and oxygen-saturation monitoring. Outcomes of the room-air challenge were "no BPD" (saturations > or =90% during weaning and in room air for 30 minutes) or "BPD" (saturation <90%). At the conclusion of the room-air challenge, all infants were returned to their baseline oxygen levels. Safety (apnea, bradycardia, increased oxygen use) and outcomes of the physiologic definition versus the clinical definition were assessed. RESULTS: A total of 560 (35.0%) neonates were diagnosed with BPD by the clinical definition of oxygen use at 36 weeks' postmenstrual age. The physiologic definition diagnosed BPD in 398 (25.0%) neonates in the cohort. All infants were safely studied. There were marked differences in the impact of the definition on BPD rates between centers (mean reduction: 10%; range: 0-44%). Sixteen centers had a decrease in their BPD rate, and 1 center had no change in their rate. CONCLUSIONS: The physiologic definition of BPD reduced the overall rate of BPD and reduced the variation among centers. Significant center differences in the impact of the physiologic definition were seen, and differences remained even with the use of this standardized definition. The magnitude of the change in BPD rate is comparable to the magnitude of treatment effects seen in some clinical trials in BPD. The physiologic definition of BPD facilitates the measurement of BPD as an outcome in clinical trials and the comparison between and within centers over time.