Systematic review and network meta-analysis with individual participant data on cord management at preterm birth (iCOMP): study protocol

Introduction Timing of cord clamping and other cord management strategies may improve outcomes at preterm birth. However, it is unclear whether benefits apply to all preterm subgroups. Previous and current trials compare various policies, including time-based or physiology-based deferred cord clamping, and cord milking. Individual participant data (IPD) enable exploration of different strategies within subgroups. Network meta-analysis (NMA) enables comparison and ranking of all available interventions using a combination of direct and indirect comparisons. Objectives (1) To evaluate the effectiveness of cord management strategies for preterm infants on neonatal mortality and morbidity overall and for different participant characteristics using IPD meta-analysis. (2) To evaluate and rank the effect of different cord management strategies for preterm births on mortality and other key outcomes using NMA. Methods and analysis Systematic searches of Medline, Embase, clinical trial registries, and other sources for all ongoing and completed randomised controlled trials comparing cord management strategies at preterm birth (before 37 weeks’ gestation) have been completed up to 13 February 2019, but will be updated regularly to include additional trials. IPD will be sought for all trials; aggregate summary data will be included where IPD are unavailable. First, deferred clamping and cord milking will be compared with immediate clamping in pairwise IPD meta-analyses. The primary outcome will be death prior to hospital discharge. Effect differences will be explored for prespecified participant subgroups. Second, all identified cord management strategies will be compared and ranked in an IPD NMA for the primary outcome and the key secondary outcomes. Treatment effect differences by participant characteristics will be identified. Inconsistency and heterogeneity will be explored. Ethics and dissemination Ethics approval for this project has been granted by the University of Sydney Human Research Ethics Committee (2018/886). Results will be relevant to clinicians, guideline developers and policy-makers, and will be disseminated via publications, presentations and media releases

Ventilation Prior to Umbilical Cord Clamping Improves Cardiovascular Stability and Oxygenation in Preterm Lambs After Exposure to Intrauterine Inflammation

Background: Delaying umbilical cord clamping until after aeration of the lung (physiological-based cord clamping; PBCC) maintains cardiac output and oxygenation in preterm lambs at birth, however, its efficacy after intrauterine inflammation is not known. Given the high incidence of chorioamnionitis in preterm infants, we investigated whether PBCC conferred any benefits compared to immediate cord clamping (ICC) in preterm lambs exposed antenatally to 7 days of intrauterine inflammation.Methods: Ultrasound guided intraamniotic injection of 20 mg Lipopolysaccharide (from E. coli:055:B5) was administered to pregnant ewes at 0.8 gestation. Seven days later, ewes were anesthetized, preterm fetuses exteriorised via cesarean section, and instrumented for continuous measurement of pulmonary, systemic and cerebral pressures and flows, and systemic, and cerebral oxygenation. Lambs were then randomized to either PBCC, whereupon ventilation was initiated and maintained for 3 min prior to umbilical cord clamping, or ICC where the umbilical cord was cut and ventilation initiated 30 s later. Ventilation was maintained for 30 min.Results: ICC caused a rapid fall in systemic (by 25%) and cerebral (by 11%) oxygen saturation in ICC lambs, concurrent with a rapid increase in carotid arterial pressure and heart rate. The overshoot in carotid arterial pressure was sustained in ICC lambs for the first 20 min of the study. PBCC maintained cardiac output and prevented the fall in cerebral oxygen delivery at birth. PBCC lambs had lower respiratory compliance and higher respiratory requirements throughout the study.Conclusion: PBCC mitigated the adverse effects of ICC on oxygenation and cardiac output, and therefore could be more beneficial in preterm babies exposed to antenatal inflammation as it maintains cardiac output and oxygen delivery. The increased respiratory requirements require further investigation in this sub-group of preterm infants

Systematic review and network meta-analysis with individual participant data on cord management at preterm birth (iCOMP): study protocol

Timing of cord clamping and other cord management strategies may improve outcomes at preterm birth. However, it is unclear whether benefits apply to all preterm subgroups. Previous and current trials compare various policies, including time-based or physiology-based deferred cord clamping, and cord milking. Individual participant data (IPD) enable exploration of different strategies within subgroups. Network meta-analysis (NMA) enables comparison and ranking of all available interventions using a combination of direct and indirect comparisons. (1) To evaluate the effectiveness of cord management strategies for preterm infants on neonatal mortality and morbidity overall and for different participant characteristics using IPD meta-analysis. (2) To evaluate and rank the effect of different cord management strategies for preterm births on mortality and other key outcomes using NMA. Systematic searches of Medline, Embase, clinical trial registries, and other sources for all ongoing and completed randomised controlled trials comparing cord management strategies at preterm birth (before 37 weeks' gestation) have been completed up to 13 February 2019, but will be updated regularly to include additional trials. IPD will be sought for all trials; aggregate summary data will be included where IPD are unavailable. First, deferred clamping and cord milking will be compared with immediate clamping in pairwise IPD meta-analyses. The primary outcome will be death prior to hospital discharge. Effect differences will be explored for prespecified participant subgroups. Second, all identified cord management strategies will be compared and ranked in an IPD NMA for the primary outcome and the key secondary outcomes. Treatment effect differences by participant characteristics will be identified. Inconsistency and heterogeneity will be explored. Ethics approval for this project has been granted by the University of Sydney Human Research Ethics Committee (2018/886). Results will be relevant to clinicians, guideline developers and policy-makers, and will be disseminated via publications, presentations and media releases. Australian New Zealand Clinical Trials Registry (ANZCTR) (ACTRN12619001305112) and International Prospective Register of Systematic Reviews (PROSPERO, CRD42019136640)

Barriers to the Implementation of Newborn Pulse Oximetry Screening: A Different Perspective

Pulse oximetry screening of the well newborn to assist in the diagnosis of critical congenital heart disease (CCHD) is increasingly being adopted. There are advantages to diagnosing CCHD prior to collapse, particularly if this occurs outside of the hospital setting. The current recommended approach links pulse oximetry screening with the assessment for CCHD. An alternative approach is to document the oxygen saturation as part of a routine set of vital signs in each newborn infant prior to discharge, delinking the measurement of oxygen saturation from assessment for CCHD. This approach, the way that many hospitals which contribute to the Australian New Zealand Neonatal Network (ANZNN) have introduced screening, has the potential benefits of decreasing parental anxiety and expectation, not requiring specific consent, changing the interpretation of false positives and therefore the timing of the test, and removing the pressure to perform an immediate echocardiogram if the test is positive. There are advantages of introducing a formal screening program, including the attainment of adequate funding and a universal approach, but the barriers noted above need to be dealt with and the process of acceptance by a national body as a screening test can take many years

A Reply to Comment on Kluckow M. Barriers to the Implementation of Newborn Pulse Oximetry Screening: A Different Perspective. Int. J. Neonatal Screen. 2018, 4(1), 4

The commentary provided by Gentles et al. argues for the implementation of a universal pulse oximetry screening program, and I agree that, if it is possible, this is the optimum way to introduce this important health care measure for all of the reasons set out by the authors.[...

The Pathophysiology of Low Systemic Blood Flow in the Preterm Infant

Assessment and treatment of the VLBW infant with cardiovascular impairment requires understanding of the underlying physiology of the infant in transition. The situation is dynamic with changes occurring in systemic blood pressure, pulmonary pressures, myocardial function, and ductal shunt in the first postnatal days. New insights into the role of umbilical cord clamping in the transitional circulation have been provided by large clinical trials of early versus later cord clamping and a series of basic science reports describing the physiology in an animal model. Ultrasound assessment is invaluable in assessment of the physiology of the transition and can provide information about the size and shunt direction of the ductus arteriosus, the function of the myocardium and its filling as well as measurements of the cardiac output and an estimate of the state of peripheral vascular resistance. This information not only allows more specific treatment but it will often reduce the need for treatment

Functional echocardiography; from physiology to treatment

Functional echocardiography (fECHO) is the bedside use of ultrasound to longitudinally assess myocardial function, systemic and pulmonary blood flow, and intra and extracardiac shunts. This review will focus on fECHO as a tool for the clinician to assess the hemodynamic condition of sick neonates and describe situations where fECHO can help determine a pathophysiological choice for cardiovascular support. The very low birth weight infant with hypotension during the first 24 h of life, assessment and monitoring of the ductus arteriosus, assessment and response to treatment of infants with pulmonary hypertension, the infant with perinatal asphyxia and the infant with sepsis and cardiovascular compromise are reviewed. Close cooperation with pediatric cardiology, proper logistics and training programs are mandatory to achieve a 24 h a day fECHO service run by bedside clinicians

Weight corrected percentiles for blood vessel diameters used in flow measurements in preterm infants

Background: Blood flow measurements are an integral part of haemodynamic assessment of the newborn infant. Most variability of Doppler derived blood flow is caused by diameter measurements. Population based percentiles of diameter measurements would be useful for training of clinicians undertaking blood flow measurements and allow rapid identification of outliers. Methods: Diameter measurements of pulmonary valve annulus, ascending aorta and the superior vena cava using standardised methodology were collected retrospectively from 9 prospective studies on transitional haemodynamics in preterm infants. Data were analysed to calculate weight corrected percentiles of diameters used for blood flow measurements. Results: We analysed 2870 measurements in 694 preterm infants less than 1750 g. The median gestational age was 27 weeks (range 23 to 34 weeks) and the median time of measurement was 22 h after birth (range 0.5 h to 70 days). 76% of measurements were performed while the infant received mechanical ventilation and 20% received cardiovascular support. Mean diameters increased with weight and standard deviations were comparable over the weight range. Conclusion: Data from this large combined series provide a reference range for blood vessel diameters in the population most often measured. The data permits recognition of outliers and could be used to trigger review of measurements that fall outside the normal range