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Objective To assess the relationship between cerebral oxygenation in the first 72 h of life and neurodevelopmental impairment (NDI) at 2 years corrected age in former premature infants. Study design Prospective observational cohort study of 127 infants

Delayed cord clamping and umbilical cord milking provide placental transfusion to vigorous newborns. Delayed cord clamping in nonvigorous newborns may not be provided owing to a perceived need for immediate resuscitation. Umbilical cord milking is an alternative, as it can be performed more quickly than delayed cord clamping and may confer similar benefits.We hypothesized that umbilical cord milking would reduce admission to the neonatal intensive care unit compared with early cord clamping in nonvigorous newborns born between 35 and 42 weeks' gestation.This was a pragmatic cluster-randomized crossover trial of infants born at 35 to 42 weeks' gestation in 10 medical centers in 3 countries between January 2019 and May 2021. The centers were randomized to umbilical cord milking or early cord clamping for approximately 1 year and then crossed over for an additional year or until the required number of consented subjects was reached. Waiver of consent as obtained in all centers to implement the intervention. Infants were eligible if nonvigorous at birth (poor tone, pale color, or lack of breathing in the first 15 seconds after birth) and were assigned to umbilical cord milking or early cord clamping according to their birth hospital randomization assignment. The baseline characteristics and outcomes were collected following deferred informed consent. The primary outcome was admission to the neonatal intensive care unit for predefined criteria. The main safety outcome was hypoxic-ischemic encephalopathy. Data were analyzed by the intention-to-treat concept.Among 16,234 screened newborns, 1780 were eligible (905 umbilical cord milking, 875 early cord clamping), and 1730 had primary outcome data for analysis (97% of eligible; 872 umbilical cord milking, 858 early cord clamping) either via informed consent (606 umbilical cord milking, 601 early cord clamping) or waiver of informed consent (266 umbilical cord milking, 257 early cord clamping). The difference in the frequency of neonatal intensive care unit admission using predefined criteria between the umbilical cord milking (23%) and early cord clamping (28%) groups did not reach statistical significance (modeled odds ratio, 0.69; 95% confidence interval, 0.41-1.14). Umbilical cord milking was associated with predefined secondary outcomes, including higher hemoglobin (modeled mean difference between umbilical cord milking and early cord clamping groups 0.68 g/dL, 95% confidence interval, 0.31-1.05), lower odds of abnormal 1-minute Apgar scores (Apgar ≤3, 30% vs 34%, crude odds ratio, 0.72; 95% confidence interval, 0.56-0.92); cardiorespiratory support at delivery (61% vs 71%, modeled odds ratio, 0.57; 95% confidence interval, 0.33-0.99), and therapeutic hypothermia (3% vs 4%, crude odds ratio, 0.57; 95% confidence interval, 0.33-0.99). Moderate-to-severe hypoxic-ischemic encephalopathy was significantly less common with umbilical cord milking (1% vs 3%, crude odds ratio, 0.48; 95% confidence interval, 0.24-0.96). No significant differences were observed for normal saline bolus, phototherapy, abnormal 5-minute Apgar scores (Apgar ≤6, 15.7% vs 18.8%, crude odds ratio, 0.81; 95% confidence interval, 0.62-1.06), or a serious adverse event composite of death before discharge.Among nonvigorous infants born at 35 to 42 weeks' gestation, umbilical cord milking did not reduce neonatal intensive care unit admission for predefined criteria. However, infants in the umbilical cord milking arm had higher hemoglobin, received less delivery room cardiorespiratory support, had a lower incidence of moderate-to-severe hypoxic-ischemic encephalopathy, and received less therapeutic hypothermia. These data may provide the first randomized controlled trial evidence that umbilical cord milking in nonvigorous infants is feasible, safe and, superior to early cord clamping.

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

The etiology of age-related cortical cataracts is not well understood but is speculated to be related to alterations in cell adhesion and/or the changing mechanical stresses occurring in the lens with time. The role of cell adhesion in maintaining lens transparency with age is difficult to assess because of the developmental and physiological roles that well-characterized adhesion proteins have in the lens. This report demonstrates that Arvcf, a member of the p120-catenin subfamily of catenins that bind to the juxtamembrane domain of cadherins, is an essential fiber cell protein that preserves lens transparency with age in mice. No major developmental defects are observed in the absence of Arvcf, however, cortical cataracts emerge in all animals examined older than 6-months of age. While opacities are not obvious in young animals, histological anomalies are observed in lenses at 4-weeks that include fiber cell separations, regions of hexagonal lattice disorganization, and absence of immunolabeled membranes. Compression analysis of whole lenses also revealed that Arvcf is required for their normal biomechanical properties. Immunofluorescent labeling of control and Arvcf-deficient lens fiber cells revealed a reduction in membrane localization of N-cadherin, β-catenin, and αN-catenin. Furthermore, super-resolution imaging demonstrated that the reduction in protein membrane localization is correlated with smaller cadherin nanoclusters. Additional characterization of lens fiber cell morphology with electron microscopy and high resolution fluorescent imaging also showed that the cellular protrusions of fiber cells are abnormally elongated with a reduction and disorganization of cadherin complex protein localization. Together, these data demonstrate that Arvcf is required to maintain transparency with age by mediating the stability of the N-cadherin protein complex in adherens junctions.

To determine differences in the duration and level of resuscitation between infants that achieve a peripheral oxygen saturation (SpO2) of 80% by 5 min compared with those who remain below 80% saturation. Infants

Objective Delayed cord clamping (DCC) and 21 to 30% O2 resuscitation is recommended for preterm infants but is commonly associated with low pulmonary blood flow (Qp) and hypoxia. 100% O2 supplementation during DCC for 60 seconds followed by 30% O2 may increase Qp and oxygen saturation (SpO2). Study design Preterm lambs (125-127 days of gestation) were resuscitated with 100% O2 with immediate cord clamping (ICC, n = 7) or ICC + 30% O2, and titrated to target SpO2 (n = 7) or DCC + 100% O2 for 60 seconds, which followed by cord clamping and 30% O2 titration (n = 7). Seven preterm (23-27 weeks of gestation) human infants received continuous positive airway pressure (CPAP) + 100% O2 for 60 seconds during DCC, cord clamping, and 30% O2 supplementation after cord clamping. Results Preterm lambs in the ICC + 100% O2 group resulted in PaO2 (77 ± 25 mmHg), SpO2 (77 ± 11%), and Qp (27 ± 9 mL/kg/min) at 60 seconds. ICC + 30% O2 led to low Qp (14 ± 3 mL/kg/min), low SpO2 (43 ± 26%), and PaO2 (19 ± 7 mmHg). DCC + 100% O2 led to similar Qp (28 ± 6 mL/kg/min) as ICC + 100% O2 with lower PaO2. In human infants, DCC + CPAP with 100% O2 for 60 seconds, which followed by weaning to 30% resulted in SpO2 of 92 ± 11% with all infants >80% at 5 minutes with 100% survival without severe intraventricular hemorrhage. Conclusion DCC + 100% O2 for 60 seconds increased Qp probably due to transient alveolar hyperoxia with systemic normoxia due to "dilution" by umbilical venous return. Larger translational and clinical studies are warranted to confirm these findings. Key points · Transient alveolar hyperoxia during delayed cord clamping can enhance pulmonary vasodilation.. · Placental transfusion buffers systemic oxygen tension and limits hyperoxia.. · Use of 100% oxygen for 60 seconds during DCC was associated with SpO2 ≥80% by 5 minutes..

Introduction Respiratory distress syndrome (RDS) or surfactant deficiency occurs primarily in premature infants resulting in composite outcomes of death or bronchopulmonary dysplasia. Initial management strategies for preterm infants with RDS includes early initiation of continuous positive airway pressure (CPAP) and titration of fractional inspired oxygen (FiO2), and may include the use of less invasive surfactant administration (LISA) to avoid the need for mechanical ventilation. In order to optimise success of non-invasive support, the use of early caffeine therapy may be critical to the success of LISA. The objective of our trial is to evaluate whether infants that receive early caffeine, CPAP and surfactant via the LISA method compared with infants that receive caffeine and CPAP alone, have a decreased need for invasive mechanical ventilation in the first 72 hours of life. Methods and analysis CaLI is an unblinded multicentre, randomised controlled, trial of 180 preterm infants (24+0–29+6 weeks corrected GA). Criteria for intubation/treatment failure will follow guidelines for the management of RDS, including: (1) CPAP level of 6–8 cmH20 and FiO2>0.40 required to maintain saturations 90%–95% for 2 hours after randomisation; (2) a pH of 7.15 or less or a paCO2>65 mm Hg on any (2) blood gases (arterial/capillary/or venous) at least 2 hours after randomisation and in the first 72 hours of life; (3) continued apnoea/bradycardia/desaturation events despite nasal intermittent minute ventilation mode of ventilation. Infants will be randomised by 1 hour of life and caffeine/LISA treatments administered by 2 hour of life. Caffeine will be administered prior to surfactant in the LISA arm and before 2 hours of life in the control arm. Ethics and dissemination Chiesi Farmaceutici, S.p.A is the sponsor of CaLI. Ethical approval has been obtained. Results will be submitted for publication in peer reviewed journals. Trial registration number www.Clinicaltrials.gov:NCT04209946; Pre-results.

Objective: To determine whether hospital mortality (primary outcome) is associated with duration of bradycardia without chest compressions during delivery room (DR) resuscitation in a retrospective cohort study of randomized controlled trials (RCTs) in preterm infants assigned low versus high initial oxygen concentration. Methods: Medline and EMBASE were searched from 01/01/1990 to 12/01/2020. RCTs of low vs high initial oxygen concentration which recorded serial heart rate (HR) and oxygen saturation (SpO2) during resuscitation of infants 2 < 80% at 5 min after birth had higher odds of hospital mortality. [OR 18.6 (4.3, 79.7)]. Conclusion: In preterm infants who did not receive chest compressions in the DR, prolonged bradycardia is associated with hospital mortality.

Current guidelines support the use of a cardiac monitor during neonatal resuscitation. Preterm infants randomized to a novel ECG algorithm displayed a heart rate sooner than the conventional ECG algorithm. Although resuscitation outcomes were not different, availability of an earlier heart rate may benefit neonatal providers during high-risk resuscitations.

BACKGROUND: Permissive hypercapnia is a lung-protection strategy. We sought to review our current clinical practice for the range of permissive hypercapnia and identify the relationship between PaCO2 and pH and adverse outcomes. METHODS: A secondary analysis of a delayed cord-clamping clinical trial was performed on all arterial blood gas tests in the first 72 h in infants RESULTS: 147 infants with birthweight of 1,206 ± 395 g and gestational age of 28 ± 2 weeks were included. Of the 1,316 total samples, CONCLUSION: The routine targeting of higher than normal PaCO2 goals may lead to a low incidence of hypocapnia and associated adverse events. Hypercapnia is common, and moderate hypercapnia may increase the risk of neurologic injury and provide little pulmonary benefit.

OBJECTIVE: To evaluate the effects of early treatment with CPAP on nutritional intake and in-hospital growth rates of extremely preterm (EPT) infants. STUDY DESIGN: EPT infants (24–0/7 to 27–6/7 weeks of gestation) enrolled in the Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT) were included. EPT infants who died before 36 weeks’ postmenstrual age (PMA) were excluded. The growth rates from birth to 36 weeks’ PMA and follow-up outcomes at 18–22 months’ corrected age of EPT infants randomized at birth to either early CPAP (intervention group) or early intubation for surfactant administration (control group) were analyzed. RESULTS: 810 of 1316 infants enrolled in SUPPORT (414 in intervention group, 396 in control group) had growth data analyzed. Median gestational age was 26 weeks and mean birthweight was 839 grams. Baseline characteristics, total nutritional intake, and in-hospital comorbidities were not significantly different between groups. In a regression model, growth rates between birth and 36 weeks’ PMA as well as growth rates during multiple intervals from birth to day 7, day 7 to14, day 14 to 21, day 21 to 28, day 28 to 32 weeks’ PMA, and 32 weeks’ PMA to 36 weeks’ PMA did not differ between treatment groups. Independent of treatment group, higher growth rates from day 21 to day 28 were associated with a lower risk of Bayley III cognitive score

To determine if umbilical cord milking is detrimental in compromised term/near-term infants. A retrospective analysis of infants with abnormal cord gases (cord arterial or venous pH of ≤ 7.1 or base deficit > −12). We collected maternal risk factors, cord management, birth, and neonatal outcomes during hospitalization. We found 157 infants who met the criteria for abnormal cord gases. Thirty-six of those had umbilical cord milking at delivery. There was no significant difference in neonatal outcomes, but fewer infants in the cord milking group needed resuscitation (38 vs. 56%, p = 0.07) and ongoing respiratory support (19 vs. 31%, p = 0.16) compared to the immediate clamping group. While not significant, infants who received cord milking at birth needed less resuscitation and ongoing respiratory support. This study suggests that umbilical cord milking appears to be a safe therapy when acidosis is present and when resuscitation is needed.

The current recommendation for umbilical cord management of non-vigorous infants (limp, pale, and not breathing) who need resuscitation at birth is to immediately clamp the umbilical cord. This recommendation is due in part to insufficient evidence for delayed cord clamping (DCC) or umbilical cord milking (UCM). These methods may provide a neuroprotective mechanism that also facilitates cardiovascular transition for non-vigorous infants at birth.

Informed consent is a process ensuring that subjects enrolled in research are appropriately informed of the risks and benefits. While this process is well-defined when it is possible and practical to obtain consent prior to the research intervention, it can be less clear in cases of deferred or waived consent. Defining minimal risk, such as when research is attempting to determine which of two currently practiced interventions is safest and/or most effective, is critical to moving forward in establishing appropriate care in newborns. For perinatal/neonatal research the challenge lies between the ethical justification for approaching women in labor or under medication vs. the scientific integrity of excluding a number of subjects that may potentially benefit the most from an intervention. Researchers must work with their IRBs as well as families who have participated in trials to determine the most appropriate method for obtaining informed consent from expectant parents. Clinical researchers and IRBs ultimately need to find a middle ground for the appropriate use of deferred or waived consent.

OBJECTIVE: To evaluate neurodevelopmental outcomes of preterm infants with need for Child Protective Services (CPS) supervision at hospital discharge compared with those discharged without CPS supervision. STUDY DESIGN: For infants born at

To characterize behavior of 2-year-old children based on the severity of bronchopulmonary dysplasia (BPD).We studied children born at 22-26 weeks of gestation and assessed at 22-26 months of corrected age with the Child Behavior Checklist (CBCL). BPD was classified by the level of respiratory support at 36 weeks of postmenstrual age. CBCL syndrome scales were the primary outcomes. The relationship between BPD grade and behavior was evaluated, adjusting for perinatal confounders. Mediation analysis was performed to evaluate whether cognitive, language, or motor skills mediated the effect of BPD grade on behavior.Of 2310 children, 1208 (52%) had no BPD, 806 (35%) had grade 1 BPD, 177 (8%) had grade 2 BPD, and 119 (5%) had grade 3 BPD. Withdrawn behavior (P .001) and pervasive developmental problems (P .001) increased with worsening BPD grade. Sleep problems (P = .008) and aggressive behavior (P = .023) decreased with worsening BPD grade. Children with grade 3 BPD scored 2 points worse for withdrawn behavior and pervasive developmental problems and 2 points better for externalizing problems, sleep problems, and aggressive behavior than children without BPD. Cognitive, language, and motor skills mediated the effect of BPD grade on the attention problems, emotionally reactive, somatic complaints, and withdrawn CBCL syndrome scales (P values .05).BPD grade was associated with increased risk of withdrawn behavior and pervasive developmental problems but with decreased risk of sleep problems and aggressive behavior. The relationship between BPD and behavior is complex. Cognitive, language, and motor skills mediate the effects of BPD grade on some problem behaviors.

To determine differences in the duration and level of resuscitation between infants that achieve a peripheral oxygen saturation (SpOInfants 32 weeks GA were analyzed. Pulse rate, SpOTwo hundred and eighty-four infants were analyzed of which 100 had SpOInfants32 weeks GA that do not achieve a peripheral arterial saturation of 80% by 5 min of life experience more death or severe IVH. This association is amongst the strongest seen of any predictor of morbidity in the delivery room.

Objective To systematically review outcomes of infants = 0.6) fraction of inspired oxygen (FiO(2)) at delivery. Design Systematic review of randomised controlled trials of low (= 0.6) FiO(2) resuscitation. Information was obtained from databases (Medline/Pub Med, EMBASE, ClinicalTrials.gov, Cochrane) and meeting abstracts between 1990 to 2015. Search index terms: preterm/resuscitation/oxygen. Data for infants grade 2 (ROP), intraventricular haemorrhage >grade 2 (IVH), patent ductus arteriosus (PDA) and necrotising enterocolitis (NEC). Results A total of 251 and 253 infants were enrolled in 8 studies (6 masked, 2 unmasked) in the lower and higher oxygen groups, respectively, (mean gestation 26 weeks) between 2005 and 2014. There were no differences in BPD (relative risk, 95% CIs 0.88 (0.68 to 1.14)), IVH (0.81 (0.52 to 1.27)), ROP (0.82 (0.46 to 1.46)), PDA (0.95 (0.80 to 1.14)) and NEC (1.61 (0.67 to 3.36)) and overall mortality (0.99 (0.52 to 1.91)). Mortality was lower in low oxygen arms of masked studies (0.46 (0.23 to 0.92), p=0.03) and higher in low oxygen arms of unmasked studies (1.94 (1.02 to 3.68), p=0.04). Conclusions There is no difference in the overall risk of death or other common preterm morbidities after resuscitation is initiated at delivery with lower (= 0.6) FiO(2) in infants

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

ObjectiveTo identify achieved oxygen saturations (SpO2) associated with increased risk of severe retinopathy of prematurity (ROP).DesignThis is a secondary analysis of the Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT)randomised controlled trial. SpO2was recorded up to 36 weeks’ postmenstrual age. Saturations through 9 postnatal weeks were explored graphically, and logistic regression models were created to predict severe ROP.Setting20 centres of theEunice Kennedy ShriverNational Institute of Child Health and Human Development Neonatal Research Network.Patients984 surviving infants of 24–27 weeks’ gestational age born in 2005–2009.InterventionsSUPPORT targeted SpO2to a lower (85%–89%) or higher (91%–95%) range through 36 weeks’ postmenstrual age or off respiratory support.Main outcome measuresSevere ROP defined as threshold ROP, ophthalmological surgery or bevacizumab treatment.ResultsThere were statistically significant interactions between duration of oxygen supplementation and percentage of time in certain achieved saturation ranges. Specifically, for infants who spent at least 2 weeks on oxygen in postnatal weeks 1–5, a higher percentage of time at 91%–96% SpO2was associated with increased odds of severe ROP. For infants who spent at least 3 weeks on oxygen in postnatal weeks 6–9, a higher percentage of time at 97%–100% SpO2was associated with increased odds of severe ROP. Other significant risk factors were lower gestational age and birth weight, non-Hispanic white versus black race, prospectively defined severe illness, late-onset sepsis or meningitis, and clinical centre.ConclusionsAmong extremely preterm survivors to discharge, the association between SpO2and severe ROP depended on the timing and duration of oxygen supplementation.

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.

Objective To investigate associations in toddlers born extremely preterm ( Study design Cohort analysis from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Surfactant Positive Airway Pressure and Pulse Oximetry Trial Neuroimaging and Neurodevelopmental Outcomes Study of infants born extremely preterm. Subjects underwent cranial ultrasonography and near-term magnetic resonance imaging (MRI). At 18-22 months of corrected age, the assessment included the Brief Infant Toddler Social Emotional Assessment (BITSEA) Problem and Competence Scale scores and the Bayley Scales of Infant Development, Third Edition (Bayley-III). The BITSEA Problem Scale assesses dysregulation; the Competence Scale assesses social-emotional competence. We examined associations of Problem and Competence scores and positive screen rates with cranial ultrasonography and near-term MRI. Mean BITSEA and Bayley-III scores were compared using ANOVA and positive screen rates with the χ2 test. We computed correlations between BITSEA and Bayley-III scores. Results Of the 397 children, positive BITSEA screens were found in 34% for the Problem score and 26% for the Competence score. Presence of lesions on near-term MRI that included cerebellar lesions were significantly associated with lower BITSEA Competence but not with Problem scores; Competence scores were inversely related to the presence/significance of lesions. Positive screens on Competence scores and on both Competence and Problem scores were significantly associated with Bayley-III cognitive and language scores Conclusions Social–emotional competence contributes to deficits in cognitive and language development. Presence of injury on near-term MRI that includes cerebellar lesions is associated with later social–emotional competence and may be a useful predictor to guide early assessment and intervention. Trial registration ClinicalTrials.gov : NCT00063063 and NCT00233324 .

BACKGROUND: Extremely preterm infants are at risk for neurodevelopmental impairment (NDI). Early cranial ultrasound (CUS) is usual practice, but near-term brain MRI has been reported to better predict outcomes. We prospectively evaluated MRI white matter abnormality (WMA) and cerebellar lesions, and serial CUS adverse findings as predictors of outcomes at 18 to 22 months’ corrected age. METHODS: Early and late CUS, and brain MRI were read by masked central readers, in a large cohort (n = 480) of infants RESULTS: Of 480 infants, 15 died and 20 were lost. Increasing severity of WMA and significant cerebellar lesions on MRI were associated with adverse outcomes. Cerebellar lesions were rarely identified by CUS. In full multivariable models, both late CUS and MRI, but not early CUS, remained independently associated with NDI or death (MRI cerebellar lesions: odds ratio, 3.0 [95% confidence interval: 1.3–6.8]; late CUS: odds ratio, 9.8 [95% confidence interval: 2.8–35]), and significant gross motor impairment or death. In models that did not include late CUS, MRI moderate-severe WMA was independently associated with adverse outcomes. CONCLUSIONS: Both late CUS and near-term MRI abnormalities were associated with outcomes, independent of early CUS and other factors, underscoring the relative prognostic value of near-term neuroimaging.

Importance Studies of cranial ultrasonography and early childhood outcomes among cohorts of extremely preterm neonates have linked periventricular-intraventricular hemorrhage and cystic periventricular leukomalacia with adverse neurodevelopmental outcomes. However, the association between nonhemorrhagic ventriculomegaly and neurodevelopmental and behavioral outcomes is not fully understood. Objective To characterize the outcomes of extremely preterm neonates younger than 27 weeks’ gestational age who experienced nonhemorrhagic ventriculomegaly that was detected prior to 36 weeks’ postmenstrual age. Design, Setting, and Participants This longitudinal observational study was conducted at 16 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants born prior to 27 weeks’ gestational age in any network facility between July 1, 2006, and June 30, 2011, were included if they had a cranial ultrasonogram performed prior to 36 weeks’ postmenstrual age. Comparisons were made between those with ventriculomegaly and those with normal cranial sonograms. Data analysis was completed from August 2013 to August 2017. Main Outcomes and Measures The main outcome was neurodevelopmental impairment, defined as a Bayley Scales of Infant and Toddler Development III cognitive score less than 70, moderate/severe cerebral palsy, a Gross Motor Function Classification System score of level 2 or more, vision impairment, or hearing impairment. Secondary outcomes included Bayley Scales of Infant and Toddler Development III subscores, components of neurodevelopmental impairment, behavioral outcomes, and death/neurodevelopmental impairment. Logistic regression was used to evaluate the association of ventriculomegaly with adverse outcomes while controlling for potentially confounding variables and center differences as a random effect. Linear regression was used similarly for continuous outcomes. Results Of 4193 neonates with ultrasonography data, 300 had nonhemorrhagic ventriculomegaly (7%); 3045 had normal cranial ultrasonograms (73%), 775 had periventricular-intraventricular hemorrhage (18.5%), and 73 had cystic periventricular leukomalacia (1.7%). Outcomes were available for 3008 of 3345 neonates with ventriculomegaly or normal scans (90%). Compared with normal cranial ultrasonograms, ventriculomegaly was associated with lower gestational age, male sex, and bronchopulmonary dysplasia, late-onset sepsis, meningitis, necrotizing enterocolitis, and stage 3 retinopathy of prematurity. After adjustment, neonates with ventriculomegaly had higher odds of neurodevelopmental impairment (odds ratio [OR], 3.07; 95% CI, 2.13-4.43), cognitive impairment (OR, 3.23; 95% CI, 2.09-4.99), moderate/severe cerebral palsy (OR, 3.68; 95% CI, 2.08-6.51), death/neurodevelopmental impairment (OR, 2.17; 95% CI, 1.62-2.91), but not death alone (OR, 1.09; 95% CI, 0.76-1.57). Behavioral outcomes did not differ. Conclusions and Relevance Nonhemorrhagic ventriculomegaly is associated with increased odds of neurodevelopmental impairment among extremely preterm neonates.

Objective To determine if preterm infants with moderate respiratory distress syndrome on continuous positive airway pressure (CPAP) who received surfactant via a laryngeal mask airway (LMA) would have a decreased rate of intubation and mechanical ventilation compared with those on CPAP who did not receive surfactant. Study design In this prospective, multicenter, randomized controlled trial, 103 premature infants 280/7-356/7 weeks gestation, ≥1250 g and ≤36 hours old on CPAP requiring fraction of inspired oxygen 0.30-0.40 were assigned to receive surfactant administered through an LMA then placed back on CPAP (LMA group) or maintained on CPAP with no surfactant administered (control group). The primary outcome was treatment failure necessitating intubation and mechanical ventilation in the first 7 days of life. Results Surfactant administration through an LMA (n = 50) significantly decreased the rate of intubation and mechanical ventilation compared with controls (n = 53): 38% vs 64%, respectively, OR 0.30 (95% CI 0.13, 0.70), P = .006, number needed to treat: 4). There were no serious adverse events associated with placement of the LMA or surfactant administration. Conclusions In premature neonates with moderate respiratory distress syndrome, surfactant administered through an LMA decreased the rate of intubation and mechanical ventilation. This intervention may have significant impact on clinical care in both high and low resource settings. Trial registration ClinicalTrials.gov : NCT01116921 .

Background: We have previously demonstrated that it is difficult to obtain a representative subject sample when conducting a randomized controlled trial (RCT) at or near the time of birth and obtaining antenatal consent. Deferred consent has been used in neonatal trials, but parents’ reactions to being enrolled in these trials have never been reported. Methods: The parents enrolled in a RCT involving a waiver of consent with a post-delivery discussion were asked to take part in a brief survey. The survey questions included the timing of when parents were informed about the study, and how they felt about their infants being included in the study. Results: Forty-nine (49) parents completed the online survey. Sixty-nine percent (n=34) remembered a physician discussing their premature baby with them prior to delivery. Thirty-four percent (17) indicated the physician had discussed participation in the study prior to delivery. Sixty nine percent (34) indicated that they had a positive or strongly positive feeling about the studies impact on their baby’s health. Conclusions: Our study demonstrates that the majority of responding parents of infants who have actually participated in a RCT with a waiver of consent process had a positive response, a minority had a neutral response, and none had a slightly negative or highly negative response to participation in the study.

AIM To collate and assess international clinical practice guidelines (CPG) to determine current recommendations guiding oxygen management for respiratory stabilisation of preterm infants at delivery. METHODS A search of public databases using the terms 'clinical practice guidelines', 'preterm', 'oxygen' and 'resuscitation' was made and complemented by direct query to consensus groups, resuscitation expert committees and clinicians. Data were extracted to include the three criteria for assessment: country of origin, gestation and initial FiO2 and target SpO2 for the first 10 minutes of life. RESULTS A total of 45 CPGs were identified: 36 provided gestation specific recommendations (

Heart rate is the most important indicator of infant well-being during neonatal resuscitation. The Nellcor Pedi-Cap turns gold when exposed to exhaled gas with CO₂15 mmHg. The aim of this study was to determine if Pedi-Cap gold color change during neonatal resuscitation precedes an increase in heart rate in babies with bradycardia receiving mask ventilation.This was a single-center retrospective review of video recordings and physiologic data of newborns with bradycardia receiving mask positive pressure ventilation during neonatal resuscitation. Subjects were included if the baby's HR100 BPM within the first 90 s of resuscitation. The primary outcome was the change in HR prior to Pedi-Cap gold color change compared to the HR after Pedi-Cap gold color change.Forty-one newborns during the study period had HR100 BPM and received mask positive pressure ventilation with a Pedi-Cap. The median heart rate 10s prior to Pedi-Cap gold color change was 75 BPM (IQR 62-85) and increased to 136 BPM (IQR 113-158) 30 s after gold color change (p0.001). SpO₂ increased from 45 ± 17% prior to Pedi-Cap gold color change to 52 ± 17% 30s after gold color change (p=0.001).Colorimetric CO₂ detection during mask positive pressure ventilation in neonatal resuscitation precedes a significant increase in heart rate and SpO₂. The Pedi-Cap can be easily applied during resuscitation, requires no electricity, provides immediate feedback and may be a useful, simple tool early in resuscitation and may be especially useful in resource limited settings.

Electrical cardiometry (EC) is a continuous noninvasive method for measuring cardiac output (CO), but there are limited data on premature infants. We evaluated the utility of EC monitoring by comparing the results obtained using EC to measurements of CO and systemic blood flow using echocardiography (ECHO).In this prospective observational study, 40 preterm neonates underwent 108-paired EC and ECHO measurements.There were correlations between EC-CO and left ventricular output (LVO, p0.005) and right ventricular output (RVO, p0.005) but not with superior vena cava (r = 0.093, p = 0.177). Both RVO and LVO correlated with EC with and without a hemodynamically significant ductus arteriosus (p = 0.001 and 0.008, respectively). The level of agreement was decreased in infants ventilated by high-frequency oscillation ventilators (HFOV). The bias in HFOV was also positive compared with the negative biases found in other modes of ventilation.Given the correlation of EC with LVO, RVO, and lack of confounding effects of the ductus, our results suggest that EC has promise for trending CO in the preterm infant. However, given the limitations with mode of ventilation and the lack of correlation at low LVO values, further study is needed before this technology can be for routine use.

The transition from fetal to neonatal life is a dramatic and complex process involving extensive physiologic changes, which are most obvious at the time of birth. Individuals who care for newly born infants must monitor the progress of the transition and be prepared to intervene when necessary. In the majority of births, this transition occurs without a requirement for any significant assistance. If newborns require assistance, the majority of the time respiratory support is all that is required. In some instances, however, there are circulatory emergencies that need to be rapidly identified or there may be dire consequences including death in the delivery room. This chapter will review various pathologies that are circulatory emergencies, and discuss how to assess them. We will also review new technologies which may help providers better understand the circulatory status or hemodynamic changes in the delivery room including heart rate, cardiac output, cerebral oxygenation and echocardiography.

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

Importance There are potential benefits and harms of hyperoxemia and hypoxemia for extremely preterm infants receiving more vs less supplemental oxygen. Objective To compare the effects of different target ranges for oxygen saturation as measured by pulse oximetry (Spo2) on death or major morbidity. Design, Setting, and Participants Prospectively planned meta-analysis of individual participant data from 5 randomized clinical trials (conducted from 2005-2014) enrolling infants born before 28 weeks’ gestation. Exposures Spo2 target range that was lower (85%-89%) vs higher (91%-95%). Main Outcomes and Measures The primary outcome was a composite of death or major disability (bilateral blindness, deafness, cerebral palsy diagnosed as ≥2 level on the Gross Motor Function Classification System, or Bayley-III cognitive or language score Results A total of 4965 infants were randomized (2480 to the lower Spo2 target range and 2485 to the higher Spo2 range) and had a median gestational age of 26 weeks (interquartile range, 25-27 weeks) and a mean birth weight of 832 g (SD, 190 g). The primary outcome occurred in 1191 of 2228 infants (53.5%) in the lower Spo2 target group and 1150 of 2229 infants (51.6%) in the higher Spo2 target group (risk difference, 1.7% [95% CI, −1.3% to 4.6%]; relative risk [RR], 1.04 [95% CI, 0.98 to 1.09], P = .21). Of the 16 secondary outcomes, 11 were null, 2 significantly favored the lower Spo2 target group, and 3 significantly favored the higher Spo2 target group. Death occurred in 484 of 2433 infants (19.9%) in the lower Spo2 target group and 418 of 2440 infants (17.1%) in the higher Spo2 target group (risk difference, 2.8% [95% CI, 0.6% to 5.0%]; RR, 1.17 [95% CI, 1.04 to 1.31], P = .01). Treatment for retinopathy of prematurity was administered to 220 of 2020 infants (10.9%) in the lower Spo2 target group and 308 of 2065 infants (14.9%) in the higher Spo2 target group (risk difference, −4.0% [95% CI, −6.1% to −2.0%]; RR, 0.74 [95% CI, 0.63 to 0.86], P Conclusions and Relevance In this prospectively planned meta-analysis of individual participant data from extremely preterm infants, there was no significant difference between a lower Spo2 target range compared with a higher Spo2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower Spo2 target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.

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.

Objectives To identify variables associated with successful elective extubation, and to determine neonatal morbidities associated with extubation failure in extremely preterm neonates. Study design This study was a secondary analysis of the National Institute of Child Health and Human Development Neonatal Research Network's Surfactant, Positive Pressure, and Oxygenation Randomized Trial that included extremely preterm infants born at 240/7 to 276/7 weeks' gestation. Patients were randomized either to a permissive ventilatory strategy (continuous positive airway pressure group) or intubation followed by early surfactant (surfactant group). There were prespecified intubation and extubation criteria. Extubation failure was defined as reintubation within 5 days of extubation. Results Of 1316 infants in the trial, 1071 were eligible; 926 infants had data available on extubation status; 538 were successful and 388 failed extubation. The rate of successful extubation was 50% (188/374) in the continuous positive airway pressure group and 63% (350/552) in the surfactant group. Successful extubation was associated with higher 5-minute Apgar score, and pH prior to extubation, lower peak fraction of inspired oxygen within the first 24 hours of age and prior to extubation, lower partial pressure of carbon dioxide prior to extubation, and non-small for gestational age status after adjustment for the randomization group assignment. Infants who failed extubation had higher adjusted rates of mortality (OR 2.89), bronchopulmonary dysplasia (OR 3.06), and death/ bronchopulmonary dysplasia (OR 3.27). Conclusions Higher 5-minute Apgar score, and pH prior to extubation, lower peak fraction of inspired oxygen within first 24 hours of age, lower partial pressure of carbon dioxide and fraction of inspired oxygen prior to extubation, and nonsmall for gestational age status were associated with successful extubation. Failed extubation was associated with significantly higher likelihood of mortality and morbidities. Trial registration ClinicalTrials.gov : NCT00233324 .

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.

Objective To characterize actual achieved patterns of oxygenation in infants born appropriate vs small for gestational age (SGA) randomized to a lower (85-89%) vs higher (91%-95%) oxygen saturation target in the Surfactant Positive Pressure and Oxygen Trial. To determine the association between achieved oxygen saturation levels and survival in infants born appropriate vs SGA enrolled in the Surfactant Positive Pressure and Oxygen Trial. Study design Median oxygen saturation and intermittent hypoxemia events ( 0/7 -27 6/7 weeks of gestation while receiving supplemental oxygen during the first 3 days of life. Results Lower target infants who were small for gestational age had the lowest oxygen saturation and highest incidence of intermittent hypoxemia during the first 3 days of life. The lowest quartile of oxygen saturation (≤92%) during the first 3 days of life was associated with lower 90-day survival for both infants born appropriate and SGA. An increased incidence of intermittent hypoxemia events during the first 3 days of life was associated with lower 90-day survival only in infants born SGA. Conclusion Lower achieved oxygen saturation during the first 3 days of life was associated with lower 90-day survival in extremely preterm infants. Infants born SGA had enhanced vulnerability to lower oxygen saturation targets as evidenced by lower achieved oxygen saturation and an association between increased intermittent hypoxemia events and lower survival. Trial registration ClinicalTrials.gov: NCT00233324.

Objective To explore differences in blood cytokine profiles among distinct bronchopulmonary dysplasia (BPD) patterns. Study design We evaluated blood spots collected from 943 infants born at ≤1000 g and surviving to 28 days on postnatal days 1, 3, 7, 14, and 21 for 25 cytokines. Infants were assigned to the following lung disease patterns: (1) no lung disease (NLD); (2) respiratory distress syndrome without BPD; (3) classic BPD (persistent exposure to supplemental oxygen until 28 days of age); or (4) atypical BPD (period without supplemental oxygen before 28 days). Median cytokine levels for infants with BPD were compared with the IQR of results among infants with NLD. Results The distribution of enrolled infants by group was as follows: 69 (NLD), 73 (respiratory distress syndrome), 381 (classic BPD), and 160 (atypical BPD). The remaining 260 infants could not be classified because of missing data (104) or not fitting a predefined pattern (156). Median levels of 3 cytokines (elevated interleukin [IL]-8, matrix metalloproteinase-9; decreased granulocyte macrophage colony-stimulating factor) fell outside the IQR for at least 2 time points in both infants with atypical and classic BPD. Profiles of 7 cytokines (IL-6, IL-10, IL-18, macrophage inflammatory protein-1α, C-reactive protein, brain-derived neurotrophic factor, regulated on activation, normal T cell expressed and secreted) differed between infants with classic and atypical BPD. Conclusions Blood cytokine profiles may differ between infants developing classic and atypical BPD. These dissimilarities suggest the possibility that differing mechanisms could explain the varied patterns of pathophysiology of lung disease in extremely premature infants.

Despite advances in the understanding of fetal and neonatal physiology and the technology to monitor and treat premature and full-term neonates, little has changed in resuscitation rooms. The authors’ vision for the Fetal and Neonatal Resuscitation and Transition Suite of the future is marked by improvements in the amount of physical space, monitoring technologies, portable diagnostic and therapeutic technologies, communication systems, and capabilities and training of the resuscitation team. Human factors analysis will play an important role in the design and testing of the improvements for safe, effective, and efficient resuscitation of the newborn.

OBJECTIVE: To compare the time required to obtain a continuous audible heart rate signal from an electrocardiogram (ECG) monitor and pulse oximeter (PO) in infants requiring resuscitation. METHODS: Infants who had both ECG and PO placed during resuscitation were analyzed using video and analog recordings. The median times from arrival until the ECG electrodes and PO sensor were placed, and the time to achieve audible tones from the devices, were compared. RESULTS: Forty-six infants had ECG and PO data. Thirty infants were very low birth weight (23–30 weeks). There was a difference in the median total time to place either device (26 vs 38 seconds; P = .04), and a difference (P < .001) in the time to achieve an audible heart rate signal after ECG lead (2 seconds) versus PO probe (24 seconds) placement. In infants weighing >1500 g (n = 16), the median time (interquartile range) to place the ECG was 20 seconds (14–43) whereas the time to place the PO was 36 seconds (28–56) (P = .74). The median times (interquartile range) to acquire a signal from the ECG and PO were 4 seconds (1–6) and 32 seconds (15–40, P = .001), respectively. During the first minutes of resuscitation, 93% of infants had an ECG heart rate compared with only 56% for PO. CONCLUSIONS: Early application of ECG electrodes during infant resuscitation can provide the resuscitation team with a continuous audible heart rate, and its use may improve the timeliness of appropriate critical interventions.

(See the Editorial Commentary by Jacqz-Aigrain, on pages 1503–4.) Intra-abdominal infections in young infants (