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Background Globally, the majority of newborns requiring resuscitation at birth are full term or late-preterm infants. These infants typically have their umbilical cord clamped early (ECC) before moving to a resuscitation platform, losing the potential support of the placental circulation. Physiologically based cord clamping (PBCC) is clamping the umbilical cord after establishing lung aeration and holds promise as a readily available means of improving early newborn outcomes. In mechanically ventilated lambs, PBCC improved cardiovascular stability and reduced hypoxia. We hypothesised that PBCC compared to ECC would result in higher heart rate (HR) in infants needing resuscitation, without compromising safety. Methods and findings Between 4 July 2018 and 18 May 2021, infants born at ≥32+0 weeks’ gestation with a paediatrician called to attend were enrolled in a parallel-arm randomised trial at 2 Australian perinatal centres. Following initial stimulation, infants requiring further resuscitation were randomised within 60 seconds of birth using a smartphone-accessible web link. The intervention (PBCC) was to establish lung aeration, either via positive pressure ventilation (PPV) or effective spontaneous breathing, prior to cord clamping. The comparator was early cord clamping (ECC) prior to resuscitation. The primary outcome was mean HR between 60 to 120 seconds after birth, measured using 3-lead electrocardiogram, extracted from video recordings blinded to group allocation. Nonrandomised infants had deferred cord clamping (DCC) ≥120 seconds in the observational study arm. Among 508 at-risk infants enrolled, 123 were randomised (n = 63 to PBCC, n = 60 to ECC). Median (interquartile range, IQR) for gestational age was 39.9 (38.3 to 40.7) weeks in PBCC infants and 39.6 (38.4 to 40.4) weeks in ECC infants. Approximately 49% and 50% of the PBCC and ECC infants were female, respectively. Five infants (PBCC = 2, ECC = 3, 4% total) had missing primary outcome data. Cord clamping occurred at a median (IQR) of 136 (126 to 150) seconds in the PBCC arm and 37 (27 to 51) seconds in the ECC arm. Mean HR between 60 to 120 seconds after birth was 154 bpm (beats per minute) for PBCC versus 158 bpm for ECC (adjusted mean difference −6 bpm, 95% confidence interval (CI) −17 to 5 bpm, P = 0.39). Among 31 secondary outcomes, postpartum haemorrhage ≥500 ml occurred in 34% and 32% of mothers in the PBCC and ECC arms, respectively. Two hundred ninety-five nonrandomised infants (55% female) with median (IQR) gestational age of 39.6 (38.6 to 40.6) weeks received DCC. Data from these infants was used to create percentile charts of expected HR and oxygen saturation in vigorous infants receiving DCC. The trial was limited by the small number of infants requiring prolonged or advanced resuscitation. PBCC may provide other important benefits we did not measure, including improved maternal–infant bonding and higher iron stores. Conclusions In this study, we observed that PBCC resulted in similar mean HR compared to infants receiving ECC. The findings suggest that for infants ≥32+0 weeks’ gestation who receive brief, effective resuscitation at closely monitored births, PBCC does not provide additional benefit over ECC (performed after initial drying and stimulation) in terms of key physiological markers of transition. PBCC was feasible using a simple, low-cost strategy at both cesarean and vaginal births. The percentile charts of HR and oxygen saturation may guide clinicians monitoring the transition of at-risk infants who receive DCC. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12618000621213.

Background Delayed umbilical cord clamping (UCC) after birth is thought to cause placental to infant blood transfusion, but the mechanisms are unknown. It has been suggested that uterine contractions force blood out of the placenta and into the infant during delayed cord clamping. We have investigated the effect of uterine contractions, induced by maternal oxytocin administration, on umbilical artery (UA) and venous (UV) blood flows before and after ventilation onset to determine whether uterine contractions cause placental transfusion in preterm lambs. Methods and findings At ~128 days of gestation, UA and UV blood flows, pulmonary arterial blood flow (PBF) and carotid arterial (CA) pressures and blood flows were measured in three groups of fetal sheep during delayed UCC; maternal oxytocin following mifepristone, mifepristone alone, and saline controls. Each successive uterine contraction significantly (p<0.05) decreased UV (26.2±6.0 to 14.1±4.5 mL.min.sup.-1 .kg.sup.-1) and UA (41.2±6.3 to 20.7 ± 4.0 mL.min.sup.-1 .kg.sup.-1) flows and increased CA pressure and flow (47.1±3.4 to 52.8±3.5 mmHg and 29.4±2.6 to 37.3±3.4 mL.min.sup.-1 .kg.sup.-1). These flows and pressures were partially restored between contractions, but did not return to pre-oxytocin administration levels. Ventilation onset during DCC increased the effects of uterine contractions on UA and UV flows, with retrograde UA flow (away from the placenta) commonly occurring during diastole. Conclusions We found no evidence that amplification of uterine contractions with oxytocin increase placental transfusion during DCC. Instead they decreased both UA and UV flow and caused a net loss of blood from the lamb. Uterine contractions did, however, have significant cardiovascular effects and reduced systemic and cerebral oxygenation.

Deferred (also known as delayed) cord clamping can improve survival of infants born preterm (before 37 weeks of gestation), but the optimal duration of deferral remains unclear. We conducted a systematic review and individual participant data network meta-analysis with the aim of comparing the effectiveness of umbilical cord clamping strategies with different timings of clamping or with cord milking for preterm infants. We searched medical databases and trial registries from inception until Feb 24, 2022 (updated June 6, 2023) for randomised controlled trials comparing cord clamping strategies for preterm infants. Individual participant data were harmonised and assessed for risk of bias and quality. Interventions were grouped into immediate clamping, short deferral (≥15 s to <45 s), medium deferral (≥45 s to <120 s), long deferral (≥120 s), and intact cord milking. The primary outcome was death before hospital discharge. We calculated one-stage, intention-to-treat Bayesian random-effects individual participant data network meta-analysis. This study was registered with PROSPERO, CRD42019136640. We included individual participant data from 47 trials with 6094 participants. Of all interventions, long deferral reduced death before discharge the most (compared with immediate clamping; odds ratio 0·31 [95% credibility interval] 0·11–0·80; moderate certainty). The risk of bias was low for 10 (33%) of 30 trials, 14 (47%) had some concerns, and 6 (20%) were rated as having a high risk of bias. Heterogeneity was low, with no indication of inconsistency. This study found that long deferral of clamping leads to reduced odds of death before discharge in preterm infants. In infants assessed as requiring immediate resuscitation, this finding might only be generalisable if there are provisions for such care with the cord intact. These results are based on thoroughly cleaned and checked individual participant data and can inform future guidelines and practice. Australian National Health and Medical Research Council.

Umbilical cord clamping strategies at preterm birth have the potential to affect important health outcomes. The aim of this study was to compare the effectiveness of deferred cord clamping, umbilical cord milking, and immediate cord clamping in reducing neonatal mortality and morbidity at preterm birth. We conducted a systematic review and individual participant data meta-analysis. We searched medical databases and trial registries (from database inception until Feb 24, 2022; updated June 6, 2023) for randomised controlled trials comparing deferred (also known as delayed) cord clamping, cord milking, and immediate cord clamping for preterm births (<37 weeks' gestation). Quasi-randomised or cluster-randomised trials were excluded. Authors of eligible studies were invited to join the iCOMP collaboration and share individual participant data. All data were checked, harmonised, re-coded, and assessed for risk of bias following prespecified criteria. The primary outcome was death before hospital discharge. We performed intention-to-treat one-stage individual participant data meta-analyses accounting for heterogeneity to examine treatment effects overall and in prespecified subgroup analyses. Certainty of evidence was assessed with Grading of Recommendations Assessment, Development, and Evaluation. This study is registered with PROSPERO, CRD42019136640. We identified 2369 records, of which 48 randomised trials provided individual participant data and were eligible for our primary analysis. We included individual participant data on 6367 infants (3303 [55%] male, 2667 [45%] female, two intersex, and 395 missing data). Deferred cord clamping, compared with immediate cord clamping, reduced death before discharge (odds ratio [OR] 0·68 [95% CI 0·51–0·91], high-certainty evidence, 20 studies, n=3260, 232 deaths). For umbilical cord milking compared with immediate cord clamping, no clear evidence was found of a difference in death before discharge (OR 0·73 [0·44–1·20], low certainty, 18 studies, n=1561, 74 deaths). Similarly, for umbilical cord milking compared with deferred cord clamping, no clear evidence was found of a difference in death before discharge (0·95 [0·59–1·53], low certainty, 12 studies, n=1303, 93 deaths). We found no evidence of subgroup differences for the primary outcome, including by gestational age, type of delivery, multiple birth, study year, and perinatal mortality. This study provides high-certainty evidence that deferred cord clamping, compared with immediate cord clamping, reduces death before discharge in preterm infants. This effect appears to be consistent across several participant-level and trial-level subgroups. These results will inform international treatment recommendations. Australian National Health and Medical Research Council.

ObjectiveUmbilical cord milking (UCM) at birth may benefit preterm infants, but the physiological effects of UCM are unknown. We compared the physiological effects of two UCM strategies with immediate umbilical cord clamping (UCC) and physiological-based cord clamping (PBCC) in preterm lambs.MethodsAt 126 days’ gestational age, fetal lambs were exteriorised, intubated and instrumented to measure umbilical, pulmonary and cerebral blood flows and arterial pressures. Lambs received either (1) UCM without placental refill (UCMwoPR); (2) UCM with placental refill (UCMwPR); (3) PBCC, whereby ventilation commenced prior to UCC; or (4) immediate UCC. UCM involved eight milks along a 10 cm length of cord, followed by UCC.ResultsA net volume of blood was transferred into the lamb during UCMwPR (8.8 mL/kg, IQR 8–10, P=0.01) but not during UCMwoPR (0 mL/kg, IQR −2.8 to 1.7) or PBCC (1.1 mL/kg, IQR −1.3 to 4.3). UCM had no effect on pulmonary blood flow, but caused large fluctuations in mean carotid artery pressures (MBP) and blood flows (CABF). In UCMwoPR and UCMwPR lambs, MBP increased by 12%±1% and 8%±1% and CABF increased by 32%±2% and 15%±2%, respectively, with each milk. Cerebral oxygenation decreased the least in PBCC lambs (17%, IQR 13–26) compared with UCMwoPR (26%, IQR 23–25, P=0.03), UCMwPR (35%, IQR 27–44, P=0.02) and immediate UCC (34%, IQR 28–41, P=0.02) lambs.ConclusionsUCMwoPR failed to provide placental transfusion, and UCM strategies caused considerable haemodynamic disturbance. UCM does not provide the same physiological benefits of PBCC. Further review of UCM is warranted before adoption into routine clinical practice.

BackgroundPhysiologically based cord clamping (PBCC) has advantages over immediate cord clamping (ICC) during preterm delivery, but its efficacy in asphyxiated infants is not known. We investigated the physiology of PBCC following perinatal asphyxia in near-term lambs.MethodsNear-term sheep fetuses (139±2 (SD) days’ gestation) were instrumented to measure umbilical, carotid, pulmonary and femoral arterial flows and pressures. Systemic and cerebral oxygenation was recorded using pulse oximetry and near-infrared spectroscopy, respectively. Fetal asphyxia was induced until mean blood pressure reached ~20 mm Hg, where lambs underwent ICC and initiation of ventilation (n=7), or ventilation for 15 min prior to umbilical cord clamping (PBCC; n=8). Cardiovascular parameters were measured and white and grey matter microvascular integrity assessed using qRT-PCR and immunohistochemistry.ResultsPBCC restored oxygenation and cardiac output at the same rate and in a similar fashion to lambs resuscitated following ICC. However, ICC lambs had a rapid and marked overshoot in mean systemic arterial blood pressure from 1 to 10 min after ventilation onset, which was largely absent in PBCC lambs. ICC lambs had increased cerebrovascular injury, as indicated by reduced expression of blood–brain barrier proteins and increased cerebrovascular protein leakage in the subcortical white matter (by 86%) and grey matter (by 47%).ConclusionPBCC restored cardiac output and oxygenation in an identical time frame as ICC, but greatly mitigated the postasphyxia rebound hypertension measured in ICC lambs. This likely protected the asphyxiated brain from cerebrovascular injury. PBCC may be a more suitable option for the resuscitation of the asphyxiated newborn compared with the current standard of ICC.

ObjectiveIntraosseous access is recommended as a reasonable alternative for vascular access during newborn resuscitation if umbilical access is unavailable, but there are minimal reported data in newborns. We compared intraosseous with intravenous epinephrine administration during resuscitation of severely asphyxiated lambs at birth.MethodsNear-term lambs (139 days’ gestation) were instrumented antenatally for measurement of carotid and pulmonary blood flow and systemic blood pressure. Intrapartum asphyxia was induced by umbilical cord clamping until asystole. Resuscitation commenced with positive pressure ventilation followed by chest compressions and the lambs received either intraosseous or central intravenous epinephrine (10 μg/kg); epinephrine administration was repeated every 3 min until return of spontaneous circulation (ROSC). The lambs were maintained for 30 min after ROSC. Plasma epinephrine levels were measured before cord clamping, at end asphyxia, and at 3 and 15 min post-ROSC.ResultsROSC was successful in 7 of 9 intraosseous epinephrine lambs and in 10 of 12 intravenous epinephrine lambs. The time and number of epinephrine doses required to achieve ROSC were similar between the groups, as were the achieved plasma epinephrine levels. Lambs in both groups displayed a similar marked overshoot in systemic blood pressure and carotid blood flow after ROSC. Blood gas parameters improved more quickly in the intraosseous lambs in the first 3 min, but were otherwise similar over the 30 min after ROSC.ConclusionsIntraosseous epinephrine administration results in similar outcomes to intravenous epinephrine during resuscitation of asphyxiated newborn lambs. These findings support the inclusion of intraosseous access as a route for epinephrine administration in current guidelines.

ObjectiveLung ultrasound (LUS) has shown promise as a diagnostic tool for the evaluation of the newborn with respiratory distress. No study has described LUS during ‘normal’ transition. Our goal was to characterise the appearance of serial LUS in healthy newborns from the first minutes after birth until airway liquid clearance is achieved.Study designProspective observational study.SettingSingle-centre tertiary perinatal centre in Australia.PatientsOf 115 infants born at ≥35 weeks gestational age, mean (SD) gestational age of 386/7 weeks±11 days, mean birth weight of 3380±555 g, 51 were delivered vaginally, 14 via caesarean section (CS) after labour and 50 infants via elective CS.InterventionsWe obtained serial LUS videos via the right and left axillae at 1–10 min, 11–20 min and 1, 2, 4 and 24 hours after birth.Main outcome measuresLUS videos were graded for aeration and liquid clearance according to a previously validated system.ResultsWe analysed 1168 LUS video recordings. As assessed by LUS, lung aeration and airway liquid clearance occurred quickly. All infants had an established pleural line at the first examination (median=2 (1–4) min). Only 14% of infants had substantial liquid retention at 10 min after birth. 49%, 78% and 100% of infants had completed airway liquid clearance at 2, 4 and 24 hours, respectively.ConclusionsIn healthy transitioning newborn infants, lung aeration and partial liquid clearance are achieved on the first minutes after birth with complete liquid clearance typically achieved within the first 4 hours of birth.Trial registration numberANZCT 12615000380594.

Background Cord-clamping strategies may modify blood pressure (BP) and cerebral tissue oxygen saturation (rStO 2 ) immediately after birth. Methods We conducted a sub-study nested within the Baby-Directed Umbilical Cord-Clamping trial. Infants ≥32 +0 weeks’ gestation assessed as requiring resuscitation were randomly allocated to either physiologically-based cord clamping (PBCC), where resuscitation commenced prior to umbilical cord clamping, or standard care where cord clamping occurred early (ECC). In this single-site sub-study, we obtained additional measurements of pre-ductal BP and rStO 2 . In a separate observational arm, non-randomised vigorous infants received 2 min of deferred cord clamping (DCC) and contributed data for reference percentiles. Results Among 161 included infants, n  = 55 were randomly allocated to PBCC ( n  = 30) or ECC ( n  = 25). The mean (SD) BP at 3–4 min after birth (primary outcome) in the PBCC group was 64 (10) mmHg compared to 62 (10) mmHg in the ECC group, mean difference 2 mmHg (95% confidence interval −3–8 mmHg, p  = 0.42). BP and rStO 2 were similar across both randomised arms and the observational arm ( n  = 106). Conclusion We found no difference in BP or rStO 2 with the different cord clamping strategies. We report reference ranges for BP and rStO 2 for late-preterm and full-term infants receiving DCC. Impact Among late-preterm and full-term infants receiving varying levels of resuscitation, blood pressure (BP, at 3–4 minutes and 6 min) and cerebral tissue oxygen saturation (rStO 2 ) are not influenced by timing of cord clamping in relation to establishment of ventilation. Infants in this study did not require advanced resuscitation, where cord clamping strategies may yet influence BP and rStO 2 . The reference ranges for BP and rStO 2 represent the first, to our knowledge, for vigorous late-preterm and full-term infants receiving deferred cord clamping. rStO 2  > 90% (~90 th percentile) may be used to define cerebral hyperoxia, for instance when studying oxygen supplementation after birth.

ObjectiveTo identify risk factors associated with delivery room respiratory support in at-risk infants who are initially vigorous and received delayed cord clamping (DCC).DesignProspective cohort study.SettingTwo perinatal centres in Melbourne, Australia.PatientsAt-risk infants born at ≥35+0 weeks gestation with a paediatric doctor in attendance who were initially vigorous and received DCC for >60 s.Main outcome measuresDelivery room respiratory support defined as facemask positive pressure ventilation, continuous positive airway pressure and/or supplemental oxygen within 10 min of birth.ResultsTwo hundred and ninety-eight infants born at a median (IQR) gestational age of 39+3 (38+2–40+2) weeks were included. Cord clamping occurred at a median (IQR) of 128 (123–145) s. Forty-four (15%) infants received respiratory support at a median of 214 (IQR 156–326) s after birth. Neonatal unit admission for respiratory distress occurred in 32% of infants receiving delivery room respiratory support vs 1% of infants who did not receive delivery room respiratory support (p<0.001). Risk factors independently associated with delivery room respiratory support were average heart rate (HR) at 90–120 s after birth (determined using three-lead ECG), mode of birth and time to establish regular cries. Decision tree analysis identified that infants at highest risk had an average HR of <165 beats per minute at 90–120 s after birth following caesarean section (risk of 39%). Infants with an average HR of ≥165 beats per minute at 90–120 s after birth were at low risk (5%).ConclusionsWe present a clinical decision pathway for at-risk infants who may benefit from close observation following DCC. Our findings provide a novel perspective of HR beyond the traditional threshold of 100 beats per minute.