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Background: Immediately after birth, the oxygen saturation is between 30 and 50%, which then increases to 85-95% within the first 10 min. Over the last 10 years, recommendations regarding the ideal level of the initial fraction of inspired oxygen (FiO 2 ) for resuscitation in preterm infants have changed from 1.0, to room air to low levels of oxygen (< 0.3), up to moderate concentrations (0.3-0.65). This leaves clinicians in a challenging position, and a large multi-center international trial of sufficient sample size that is powered to look at safety outcomes such as mortality and adverse neurodevelopmental outcomes is required to provide the necessary evidence to guide clinical practice with confidence., Methods: An international cluster, cross-over randomized trial of initial FiO 2 of 0.3 or 0.6 during neonatal resuscitation in preterm infants at birth to increase survival free of major neurodevelopmental outcomes at 18 and 24 months corrected age will be conducted. Preterm infants born between 23 0/7 and 28 6/7  weeks' gestation will be eligible. Each participating hospital will be randomized to either an initial FiO 2 concentration of either 0.3 or 0.6 to recruit for up to 12 months' and then crossed over to the other concentration for up to 12 months. The intervention will be initial FiO 2 of 0.6, and the comparator will be initial FiO 2 of 0.3 during respiratory support in the delivery room. The sample size will be 1200 preterm infants. This will yield 80% power, assuming a type 1 error of 5% to detect a 25% reduction in relative risk of the primary outcome from 35 to 26.5%. The primary outcome will be a composite of all-cause mortality or the presence of a major neurodevelopmental outcome between 18 and 24 months corrected age. Secondary outcomes will include the components of the primary outcome (death, cerebral palsy, major developmental delay involving cognition, speech, visual, or hearing impairment) in addition to neonatal morbidities (severe brain injury, bronchopulmonary dysplasia; and severe retinopathy of prematurity)., Discussion: The use of supplementary oxygen may be crucial but also potentially detrimental to preterm infants at birth. The HiLo trial is powered for the primary outcome and will address gaps in the evidence due to its pragmatic and inclusive design, targeting all extremely preterm infants. Should 60% initial oxygen concertation increase survival free of major neurodevelopmental outcomes at 18-24 months corrected age, without severe adverse effects, this readily available intervention could be introduced immediately into clinical practice., Trial Registration: The trial was registered on January 31, 2019, at ClinicalTrials.gov with the Identifier: NCT03825835., (© 2024. The Author(s).)

Objective: To compare cost-effectiveness of oral sildenafil citrate, administered after onset of labor, with standard care to health system funders in the UK and Australia., Methods: We conducted a modeled cost-effectiveness analysis, measuring costs and quality adjusted life years (QALYs), using a decision-analytic model covering onset of labor to 1 month post-birth. The relative risk of emergency cesarean section and operative vaginal birth was taken from a Phase 2 placebo controlled double blinded randomized control trial., Results: Both options of care resulted in the same QALYs gained over the model time period (0.08). Sildenafil citrate was cost-saving compared with standard care, saving £92 per birth in the UK (AU$303 per birth in Australia). Sensitivity analyses did not identify any areas of uncertainty that stopped sildenafil citrate being cost saving compared with standard care. Threshold analysis revealed that sildenafil citrate would be cost saving up to a per birth drug or administration cost of £152.32 in the UK (AU$333.61 in Australia)., Conclusion: Oral sildenafil citrate may be cost saving compared with standard care; however, the effects on neonatal outcomes still need to be demonstrated in large randomized trials., (© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Introduction: Cerebral palsy (CP) is the most common physical disability of childhood worldwide. Historically the diagnosis was made between 12 and 24 months, meaning data about effective early interventions to improve motor outcomes are scant. In high-income countries, two in three children will walk. This evaluator-blinded randomised controlled trial will investigate the efficacy of an early and sustained Goals-Activity-Motor Enrichment approach to improve motor and cognitive skills in infants with suspected or confirmed CP., Methods and Analysis: Participants will be recruited from neonatal intensive care units and the community in Australia across four states. To be eligible for inclusion infants will be aged 3-6.5 months corrected for prematurity and have a diagnosis of CP or 'high risk of CP' according to the International Clinical Practice Guideline criteria. Eligible participants whose caregivers consent will be randomly allocated to receive usual care or weekly sessions at home from a GAME-trained study physiotherapist or occupational therapist, paired with a daily home programme, until age 2. The study requires 150 participants per group to detect a 0.5 SD difference in motor skills at 2 years of age, measured by the Peabody Developmental Motor Scales-2. Secondary outcomes include gross motor function, cognition, functional independence, social-emotional development and quality of life. A within-trial economic evaluation is also planned., Ethics and Dissemination: Ethical approval was obtained from the Sydney Children's Hospital Network Human Ethics Committee in April 2017 (ref number HREC/17/SCHN/37). Outcomes will be disseminated through peer-reviewed journal publications, presentations at international conferences and consumer websites., Trial Registration Number: ACTRN12617000006347., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Neonates, particularly if born preterm or with congenital anomalies, are among the pediatric patients most likely to need blood transfusion. However, they are also particularly vulnerable to adverse consequences of blood transfusion. Aiming to clamp the umbilical cord for at least a minute after birth is a simple safe procedure that is being increasingly adopted worldwide, although may be associated with increased rates of polycythemia and jaundice. It may also reduce the proportion of preterm babies who need a blood transfusion. The mechanisms for this are not fully understood. Potential mechanisms could include an increased volume of blood transfusion from the placenta to the baby after birth, and an overall reduction in the severity of illness in the first weeks after birth, which could lead to fewer blood tests and greater tolerance of anemia, or enhanced erythropoiesis. Objectives To investigate the mechanism behind the reduced need for blood transfusions after deferral of cord clamping. Methodology This protocol outlines the methods and data analysis plan for a study using nested retrospective data from a large randomized trial combined with additional data collected from patient medical and pathology records. The additional data items to be collected all relate to the receipt of transfusion and the factors that affect the risk for transfusion in preterm babies. The analysis will include all randomized babies from Australia and New Zealand for whom data are available. Causal mediation analysis is planned to estimate the effects of mediators on the relationship between the timing of cord clamping and the need for blood transfusion. The analysis is designed to discern whether initial severity of illness or the magnitude of placental transfusion mediates red blood cell transfusion dependence. Anticipated outcomes and dissemination We expect the study will identify potential strategies for reducing blood transfusions and associated negative outcomes in preterm infants. This will be relevant to researchers, clinicians, and parents. The results will be disseminated through publications, presentations, and inclusion in evidence-based guidelines., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Tan-Koay et al.)

Objective: To determine the effects of lower (≤0.3) versus higher (≥0.6) initial fractional inspired oxygen (FiO 2 ) for resuscitation on death and/or neurodevelopmental impairment (NDI) in infants <32 weeks' gestation., Design: Meta-analysis of individual patient data from three randomised controlled trials., Setting: Neonatal intensive care units., Patients: 543 children <32 weeks' gestation., Intervention: Randomisation at birth to resuscitation with lower (≤0.3) or higher (≥0.6) initial FiO 2 ., Outcome Measures: Primary: death and/or NDI at 2 years of age.Secondary: post-hoc non-randomised observational analysis of death/NDI according to 5-minute oxygen saturation (SpO 2 ) below or at/above 80%., Results: By 2 years of age, 46 of 543 (10%) children had died. Of the 497 survivors, 84 (17%) were lost to follow-up. Bayley Scale of Infant Development (third edition) assessments were conducted on 377 children. Initial FiO 2 was not associated with difference in death and/or disability (difference (95% CI) -0.2%, -7% to 7%, p=0.96) or with cognitive scores <85 (2%, -5% to 9%, p=0.5). Five-minute SpO 2 >80% was associated with decreased disability/death (14%, 7% to 21%) and cognitive scores >85 (10%, 3% to 18%, p=0.01). Multinomial regression analysis noted decreased death with 5-minute SpO 2 ≥80% (odds (95% CI) 09.62, 0.98 to 0.96) and gestation (0.52, 0.41 to 0.65), relative to children without death or NDI., Conclusion: Initial FiO 2 was not associated with difference in risk of disability/death at 2 years in infants <32 weeks' gestation but CIs were wide. Substantial benefit or harm cannot be excluded. Larger randomised studies accounting for patient differences, for example, gestation and gender are urgently needed., Competing Interests: Competing interests: YR has patents for technology to guide oxygen titration during newborn resuscitation. He did not contribute to any aspects of the manuscript related to the targeting of oxygen saturation., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Optimal starting oxygen concentration for delivery room resuscitation of extremely preterm infants (<29 weeks) remains unknown, with recommendations of 21-30% based on uncertain evidence. Individual patient randomized trials designed to answer this question have been hampered by poor enrolment., Hypothesis: It is feasible to compare 30% vs. 60% starting oxygen for delivery room resuscitation of extremely preterm infants using a change in local hospital policy and deferred consent approach., Study Design: Prospective, single-center, feasibility study, with each starting oxygen concentration used for two months for all eligible infants., Population: Infants born at 23 + 0-28 + 6 weeks' gestation who received delivery room resuscitation. Study interventions: Initial oxygen at 30% or 60%, increasing by 10-20% every minute for heart rate < 100 bpm, or increase to 100% for chest compressions., Primary Outcome: Feasibility, defined by (i) achieving difference in cumulative supplied oxygen concentration between groups, and (ii) post-intervention rate consent >50%., Results: Thirty-four infants were born during a 4-month period; consent was obtained in 63%. Thirty ( n = 12, 30% group; n = 18, 60% group) were analyzed, including limited data from eight who died or were transferred before parents could be approached. Median cumulative oxygen concentrations were significantly different between the two groups in the first 5 min., Conclusion: Randomized control trial of 30% or 60% oxygen at the initiation of resuscitation of extremely preterm neonates with deferred consent is feasible., Trial Registration: Clinicaltrials.gov NCT03706586.

About half of Australian women have a body mass index in the overweight or obese range at the start of pregnancy, with serious consequences including preterm birth, gestational hypertension and diabetes, caesarean section, stillbirth, and childhood obesity. Trials to limit weight gain during pregnancy have had limited success and reducing weight before pregnancy has greater potential to improve outcomes. The PreBabe Pilot study was a randomised controlled pilot trial to assess the feasibility, acceptability and potential weight loss achieved using a commercial online partial meal replacement program, (MR) vs. telephone-based conventional dietary advice, (DA) for pre-conception weight-loss over a 10-week period. Women 18-40 years of age with a BMI ≥ 25 kg/m 2 planning pregnancy within the next 6 to 12 months were included in the study. All participants had three clinic visits with a dietitian and one obstetric consultation. In total, 50 women were enrolled in the study between June 2018 and October 2019-26 in MR and 24 in DA. Study retention at the end of 10 week intervention 81% in the MR arm and 75% in the DA arm. In the-intention-to-treat analysis, women using meal replacements lost on average 5.4 ± 3.1% body weight compared to 2.3 ± 4.2% for women receiving conventional advice ( p = 0.029). Over 80% of women in the MR arm rated the support received as excellent, compared to 39% in the DA arm ( p < 0.001). Women assigned to the MR intervention were more likely to achieve pregnancy within 12 months of the 10 week intervention (57% (12 of 21) women assigned to MR intervention vs. 22% (4 of 18) assigned to the DA group ( p = 0.049) became pregnant). The findings suggest that a weight loss intervention using meal replacements in the preconception period was acceptable and may result in greater weight loss than conventional dietary advice alone.

Background and Objective: Sildenafil citrate is a vasodilator used in erectile dysfunction and pulmonary hypertension. We tested whether it reduces emergency operative births for fetal compromise and improves fetal or uteroplacental perfusion in labor in a phase 2 double-blind randomized controlled trial., Study Design: Women at term in early labor or undergoing scheduled induction of labor at Mater Mother's Hospital, Brisbane, Australia, were randomly allocated 50 mg of sildenafil citrate orally 8 hourly up to 150 mg or placebo. Intrapartum fetal monitoring followed Royal Australian and New Zealand College of Obstetricians and Gynaecologists guidelines. Primary outcomes were (1) emergency operative birth (by cesarean delivery or instrumental vaginal birth) for intrapartum fetal compromise and (2) mean indices of fetal and uteroplacental perfusion using Doppler ultrasound. Analysis was by intention-to-treat., Trial Registration Number: ANZCTRN12615000319572 RESULTS: Between September 2015 and January 2019, 300 women were randomized equally to sildenafil citrate or placebo. Sildenafil citrate reduced the risk of emergency operative birth by 51% (18% vs 36.7%; relative risk, 0.49, 95% confidence interval, 0.33-0.73, P=.0004, number needed to treat = 5 [3-11]). There was no difference in indices of fetal and uteroplacental perfusion, but these were ascertained in only 71 women. Sildenafil citrate reduced the risk of meconium-stained liquor or pathologic fetal heart rate patterns by 43% (25.3% vs 44.7%; relative risk, 0.57, 95% confidence interval, 0.41-0.79, P=.0005), but its effects on fetal scalp sampling rates (2.0% vs 6.7%; relative risk, 0.30, 95% confidence interval, 0.08-1.07, P=.06) and adverse neonatal outcome (20.7% vs 21.3%; relative risk, 0.97, 95% confidence interval, 0.62-1.50, P=.89) were inconclusive. Only 3.6% of maternal levels of sildenafil citrate or its metabolite were detected in cord blood. No differences in maternal adverse events were seen., Conclusion: Sildenafil citrate reduced operative birth for intrapartum fetal compromise, but much larger phase 3 trials of its effects on mother and child are needed before it can be routinely recommended., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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., Registration Number: Australian New Zealand Clinical Trials Registry (ANZCTR) (ACTRN12619001305112) and International Prospective Register of Systematic Reviews (PROSPERO, CRD42019136640)., Competing Interests: Competing interests: LD, ACK, CDPM, ED, HR, JK, JM, JJ, KF, OA, SH, VS, VD, WE-N and WT-M are Chief Investigators for potentially eligible trials., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Objective: To describe the trend and risk factors for severe intraventricular haemorrhage (IVH) among infants <32 weeks gestation., Design: Population-based cohort study., Setting: Australia and New Zealand., Patients: All preterm infants <32 weeks gestation in the Australian and New Zealand Neonatal Network (ANZNN) from 1995 to 2012., Interventions: Comparison of IVH incidence between 6-year epochs., Main Outcome Measures: Overall IVH and severe IVH incidence., Results: A total of 60 068 infants were included, and overall survival to discharge increased from 89% to 93% over the three epochs. As the percentage of infants with IVH decreased from 23.6% to 21.3% and 21.4% (p<0.001) from epoch 1 to 3, respectively, fewer survivors had severe IVH (4.0%, 3.3% and 2.8%, respectively, p<0.001). Over time, there were fewer antenatal complications, higher antenatal steroid usage and more caesarean-section births. Fewer infants were intubated at birth, had low 5 min Apgar score, had sepsis or pneumothorax needing drainage. Adjusted for perinatal confounders, there was significant reduction in odds of severe IVH from epoch 1 to 3 (adjusted OR (AOR) 0.8, 95% CI 0.7 to 0.9). Factors associated with development of severe IVH include no antenatal steroids (AOR 1.7, 95% CI 1.5 to 1.9), male (AOR 1.3, 95% CI 1.2 to 1.4), 5 min Apgar score <7 (AOR 2.0, 95% CI 1.9 to 2.2), intubated at birth (AOR 2.0, 95% CI 1.8 to 2.2), extremely low gestational age (AOR 4.0, 95% CI 3.7 to 4.4), outborn (AOR 1.6, 95% CI 1.5 to 1.8) and vaginal delivery (AOR 1.4, 95% CI 1.3 to 1.6)., Conclusions: Along with increased survival among infants born <32 weeks gestation, the incidence of severe IVH has decreased over the 18 years, especially in the most recent period. This coincided with reduction in rates of risk factors for severe IVH development., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In Canada alone, almost 3000 VLBW infants are born and treated annually with almost 1200 going onto death or survival with severe brain injury, chronic lung disorders, aggressive retinopathy of prematurity, late-onset sepsis, or significant necrotizing enterocolitis. Lactoferrin is an antimicrobial, antioxidant, anti-inflammatory iron-carrying, bifidogenic glycoprotein found in all vertebrates and in mammalian milk, leukocytes and exocrine secretions. Lactoferrin aids in creating an environment for growth of beneficial bacteria in the gut, thus reducing colonization with pathogenic bacteria. It is hypothesized that oral bovine lactoferrin (bLF), through its antimicrobial, antioxidant and anti-inflammatory properties, will reduce the rate of mortality or major morbidity in very low birth weight preterm infants., Method: Lactoferrin Infant Feeding Trial&#95;Canada (LIFT&#95;Canada) is a multi-centre, double-masked, randomized controlled trial with the aim to enroll 500 infants whose data will be combined with the data of the 1542 infants enrolled from Lactoferrin Infant Feeding Trial&#95;Australia/New Zealand (LIFT&#95;ANZ) in a pooled intention-to-treat analysis. Eligible infants will be randomized and allocated to one of two treatment groups: 1) a daily dose of 200 mg/kg bLF in breast/donor human milk or formula milk until 34 weeks corrected gestation or for a minimum of 2 weeks, whichever is longer, or until discharge home or transfer, if earlier; 2) no bLF with daily feeds. The primary outcome will be determined at 36 weeks corrected gestation for the presence of neonatal morbidity and at discharge for survival and treated retinopathy of prematurity. The duration of the trial is expected to be 36 months., Discussion: Currently, there continues to be no clear answer related to the benefit of bLF in reducing mortality or any or all of the significant neonatal morbidities in very low birth weight infants. LIFT&#95;Canada is designed with the hope that the pooled results from Australia, New Zealand, and Canada may help to clarify the situation., Trial Registration: Clinical Trials.Gov, Identifier: NCT03367013, Registered December 8, 2017.

This narrative review identified 23 publications in 2011 to 2019 discussing randomized trials of oxygen saturation targets of 85% to 89% versus 91% to 95% in infants below 28 weeks' gestation. Of 18 commentaries or consensus statements, 17 recommended saturation targets above 89%. Five systematic reviews reported that the 85% to 89% target increased mortality but not the composite of death or disability. The evidence for increased mortality was assessed as of "high", "moderate," or "low," quality, reflecting substantial differences in interpreting the GRADE guidelines. Systematic reviews and guidelines without biostatisticians or epidemiologists as co-authors should be considered potentially problematic., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Lactoferrin is the major antimicrobial protein in human milk. In our randomized controlled trial (RCT) of bovine lactoferrin (BLF) supplementation in preterm neonates, BLF reduced late-onset sepsis (LOS). Mother's own milk (MM) contains higher concentrations of lactoferrin than donor milk or formula, but whether BLF is more effective in infants who receive formula or donor milk is uncertain., Aim: To evaluate the incidence of LOS in preterm infants fed MM and in those fed formula and/or donor milk., Study Design: This is a (A) post hoc subgroup analysis, in our RCT of BLF, of its effects in preterm infants fed MM, with or without formula, versus those fed formula and/or donor milk (no-MM) and (B) post hoc meta-analysis, in our RCT of BLF and in the ELFIN (Enteral Lactoferrin in Neonates) RCT, of the effect of BLF in subgroups not exclusively fed MM., Results: (A) Of 472 infants in our RCT, 168 were randomized to placebo and 304 were randomized to BLF. Among MM infants, LOS occurred in 22/133 (16.5%) infants randomized to placebo and in 14/250 (5.6%) randomized to BLF (relative risk or risk ratio (RR): 0.34; relative risk reduction (RRR): 0.66; 95% confidence interval (95% CI) for RR: 0.18-0.64; p  < 0.0008). Among no-MM infants, LOS occurred in 7/35 (20.0%) randomized to placebo and in 2/54 (3.7%) randomized to BLF (RR: 0.19; RRR: 0.81; 95% CI for RR: 0.16-0.96; p  = 0.026). In multivariable logistic regression analysis, there was no interaction between BLF treatment effect and type of feeding ( p  = 0.628). (B) In 1,891 infants not exclusively fed MM in our RCT of BLF and in the ELFIN RCT, BLF reduced the RR of LOS by 18% (RR: 0.82; 95% CI: 0.71-0.96; p  = 0.01)., Conclusion: Adequately powered studies should address the hypothesis that BLF is more effective in infants fed formula or donor milk than those fed MM. Such studies should evaluate whether a specific threshold of total lactoferrin intake can be identified to protect such patients from LOS., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: To determine associations of low superior vena cava (SVC) flow (≤55 ml/kg/min) and low right ventricular output (RVO) (≤150 ml/kg/min) in preterm infants., Design/methods: An observational study in infants <30 weeks gestation randomized to receive immediate (<10 s) or delayed cord clamping (DCC) (≥60 s)., Results: The study enrolled 265 infants with a mean (SD) gestation 28 (2) weeks. Eighty-six (33%) infants had low SVC flow and 81 (31%) infants had low RVO. In multivariate analysis, low SVC flow was associated with gestation; low RVO was associated with DCC, gender and 5-minute Apgar; whereas mean RVO was negatively associated with both FiO 2 and mean airway pressure (MAP) at 9 h and 24 h. Low SVC flow was associated with ductus arteriosus (DA) treatment. Infants with low RVO had higher mortality on univariate analysis, but this was not significant after adjusting for gestation., Conclusions: SVC flow was associated with gestation, whilst RVO was associated with placental transfusion, gender, condition at birth, and early respiratory adaptation. Compared to infants with normal values, more infants with low SVC flow were treated for DA, but infants with low RVO had no significant difference in mortality or morbidity.

Introduction: Very-low birthweight (VLBW, <1500 g) infants comprise about 1%-1.4% of all births in high-income countries. Every year, about 3000 VLBW babies in Australia and New Zealand receive intensive care. Many die or else survive with severe brain injury, retinopathy, late-onset sepsis or necrotising enterocolitis (NEC), each of which carries substantial risk of disability., Methods and Analysis: This trial tests whether adding bovine lactoferrin (bLF) to feeds in VLBW infants improves (1) survival to hospital discharge free from brain injury, late-onset sepsis, NEC and treated retinopathy of prematurity (primary composite end point); (2) each component of the primary composite end point and (3) time to reach full enteral feeds, number of blood transfusions, chronic lung disease and length of hospital stay. It includes a cost-effectiveness analysis of bLF in improving survival free from major morbidity, and evaluates the effect of bLF on survival and developmental outcomes at 24 to 36 months corrected gestational age.This is a multicentre, two-arm, randomised trial comparing the treatment group receiving bLF added to breast milk or formula milk daily (up to 250 mg/kg/day bLF) versus the control group receiving no bLF supplementation. The intervention is administered until 34 completed weeks corrected gestation or for 2 weeks, whichever is longer, or until discharge home, if earlier. The target sample size of 1500 participants yields 85% power, at the two-sided 5% level significance, to detect a difference in proportions meeting the primary outcome assuming the true probability is 74% in controls and 80.5% in the bLF group., Ethics and Dissemination: This protocol was approved by Northern Sydney Local Human Research Ethics Committee in January 2017 (Version 2.0, Reference 1003-118M) and other relevant ethics committees. The findings of the trial will be disseminated through peer-reviewed journals and conference presentations., Trial Registration Number: ACTRN12611000247976; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine rates of death or neurodevelopmental impairment (NDI) at 2 years corrected age (primary outcome) in children <32 weeks' gestation randomized to initial resuscitation with a fraction of inspired oxygen (FiO 2 ) value of 0.21 or 1.0., Study Design: Blinded assessments were conducted at 2-3 years corrected age with the Bayley Scales of Infant and Toddler Development, Third Edition or the Ages and Stages Questionnaire by intention to treat., Results: Of the 290 children enrolled, 40 could not be contacted and 10 failed to attend appointments. Among the 240 children for whom outcomes at age 2 years were available, 1 child had a lethal congenital anomaly, 1 child had consent for follow-up withdrawn, and 23 children died. The primary outcome, which was available in 238 (82%) of those randomized, occurred in 47 of the 117 (40%) children assigned to initial FiO 2 0.21 and in 38 of the 121 (31%) assigned to initial FiO 2 1.0 (OR, 1.47; 95% CI, 0.86-2.5; P = .16). No difference in NDI was found in 215 survivors randomized to FiO 2 0.21 vs 1.0 (OR, 1.26; 95% CI, 0.70-2.28; P = .11). In post hoc exploratory analyses in the whole cohort, children with a 5-minute blood oxygen saturation (SpO 2 ) <80% were more likely to die or to have NDI (OR, 1.85; 95% CI, 1.07-3.2; P = .03)., Conclusions: Initial resuscitation of infants <32 weeks' gestation with initial FiO 2 0.21 had no significant effect on death or NDI compared with initial FiO 2 1.0. Further evaluation of optimum initial FiO 2 , including SpO 2 targeting, in a large randomized controlled trial is needed., Trial Registration: Australian and New Zealand Clinical Trials Network Registry ACTRN 12610001059055 and the National Malaysian Research Registry NMRR-07-685-957., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To determine the association between SpO 2 at 5 min and preterm infant outcomes., Design: Data from 768 infants <32 weeks gestation from 8 randomised controlled trials (RCTs) of lower (≤0.3) versus higher (≥0.6) initial inspiratory fractions of oxygen (FiO 2 ) for resuscitation, were examined., Setting: Individual patient analysis of 8 RCTs INTERVENTIONS: Lower (≤0.3) versus higher (≥0.6) oxygen resuscitation strategies targeted to specific predefined SpO 2 before 10 min of age., Patients: Infants <32 weeks gestation., Main Outcome Measures: Relationship between SpO 2 at 5 min, death and intraventricular haemorrhage (IVH) >grade 3., Results: 5 min SpO 2 data were obtained from 706 (92%) infants. Only 159 (23%) infants met SpO 2 study targets and 323 (46%) did not reach SpO 2 80%. Pooled data showed decreased likelihood of reaching SpO 2 80% if resuscitation was initiated with FiO 2 <0.3 (OR 2.63, 95% CI 1.21 to 5.74, p<0.05). SpO 2 <80% was associated with lower heart rates (mean difference -8.37, 95% CI -15.73 to -1.01, *p<0.05) and after accounting for confounders, with IVH (OR 2.04, 95% CI 1.01 to 4.11, p<0.05). Bradycardia (heart rate <100 bpm) at 5 min increased risk of death (OR 4.57, 95% CI 1.62 to 13.98, p<0.05). Taking into account confounders including gestation, birth weight and 5 min bradycardia, risk of death was significantly increased with time taken to reach SpO 2 80%., Conclusion: Not reaching SpO 2 80% at 5 min is associated with adverse outcomes, including IVH. Whether this is because of infant illness or the amount of oxygen that is administered during stabilisation is uncertain and needs to be examined in randomised trials., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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 <85) at a corrected age of 18 to 24 months. There were 16 secondary outcomes including the components of the primary outcome and other major morbidities., 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 < .001). Severe necrotizing enterocolitis occurred in 227 of 2464 infants (9.2%) in the lower Spo2 target group and 170 of 2465 infants (6.9%) in the higher Spo2 target group (risk difference, 2.3% [95% CI, 0.8% to 3.8%]; RR, 1.33 [95% CI, 1.10 to 1.61], P = .003)., 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.

Objectives: To compare effect of placental transfusion by delayed cord clamping (DCC) or cord milking (CM) with early cord clamping (ECC) on a composite of mortality or abnormal neurological status at 40 weeks' post-menstrual age (PMA) and 24-30 months' chronological age in neonates of 30-33 weeks' gestation., Study Design: Randomized, controlled trial., Outcomes: A composite of mortality or abnormal neurological status at 40 weeks PMA and survival free of neurodevelopmental abnormalities at 24-30 months' chronological age., Results: A total of 461 neonates were randomized to placental transfusion (n = 233) or to ECC (n = 228). Among those assigned to placental transfusion group, 173 underwent DCC while in the remaining 60, CM was done. Incidence of mortality or abnormal neurological status at 40 weeks PMA (43 (18%) vs 35 (15%), RR (95% CI) 1.2 (0.8, 1.8), p = 0.4) and survival free of neurodevelopmental impairment at 24-30 months of chronological age (99 (47%) vs. 100 (50%); RR (95% CI): 0.9 (0.8, 1.2); P = 0.9) was similar between the study groups. The placental transfusion group showed a trend towards lower incidence of necrotizing enterocolitis., Conclusion: In 30-33 weeks' gestation preterm neonates, placental transfusion as compared to early cord clamping resulted in similar mortality or abnormal neurological status at 40 weeks PMA and at 24-30 months of chronological age.

Objective: Functional cardiac ultrasound measures are used clinically and in trials for assessing the haemodynamic status of newborn infants. Superior vena cava (SVC) flow and right ventricular output (RVO) are established measures of systemic blood flow on the first postnatal day. The objective was to assess image quality and interobserver agreement of these measures in preterm infants enrolled in a randomised trial of immediate versus delayed cord clamping., Design and Setting: Image quality and interobserver agreement for SVC flow, RVO and ductus arteriosus (DA) size were assessed on measurements taken at 3-6, 6-12 and 20-28 hours for the first 10 infants enrolled at each of four sites (total 40). Bland-Altman plots were constructed; mean difference (bias) and limits of agreement (LOA) were calculated. Potential sources of variation were explored., Results: Quality was judged satisfactory for >97% of images. The mean difference and LOA between the observers were 5.4 mL/kg/min and -49.0 to 59.8 mL/kg/min for SVC flow, -26.6 mL/kg/min and -131.4 to 78.2 mL/kg/min for RVO, and 0 mm and -0.8 to 0.8 mm for DA diameter, respectively. The principal source of measurement error for SVC flow was diameter, and for RVO, diameter and velocity time integral. The difference between observers for both SVC and RVO was significantly associated with site., Conclusion: Interobserver variability for SVC flow is consistent with that previously reported, but higher for RVO. The findings should be incorporated into clinical practice, training, accreditation and trial design., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Despite evidence suggesting that parent involvement was beneficial for infant and parent outcomes, the Family Integrated Care (FICare) programme was one of the first pragmatic approaches to enable parents to become primary caregivers in the neonatal intensive care unit (NICU). We aimed to analyse the effect of FICare on infant and parent outcomes, safety, and resource use., Methods: In this multicentre, cluster-randomised controlled trial, we stratified 26 tertiary NICUs from Canada, Australia, and New Zealand by country and size, and assigned them, using a computer-generated random allocation sequence, to provide FICare or standard NICU care. Eligible infants were born at 33 weeks' gestation or earlier, and had no or low-level respiratory support; parents gave written informed consent for enrolment. To be eligible, parents in the FICare group had to commit to be present for at least 6 h a day, attend educational sessions, and actively care for their infant. The primary outcome, analysed at the individual level, was infant weight gain at day 21 after enrolment. Secondary outcomes were weight gain velocity, high frequency breastfeeding (≥6 times a day) at hospital discharge, parental stress and anxiety at enrolment and day 21, NICU mortality and major neonatal morbidities, safety, and resource use (including duration of oxygen therapy and hospital stay). This trial is registered with ClinicalTrials.gov, number NCT01852695., Findings: From Oct 1, 2012, 26 sites were randomly assigned to provide FICare (n=14) or standard care (n=12). One site assigned to FICare discontinued because of poor site enrolment. Parents and infants were enrolled between April 1, 2013, and Aug 31, 2015, with 895 infants being eligible in the FICare group and 891 in the standard care group. At day 21, weight gain was greater in the FICare group than in the standard care group (mean change in Z scores -0·071 [SD 0·42] vs -0·155 [0·42]; p<0·0002). Average daily weight gain was significantly higher in infants receiving FICare than those receiving standard care (mean daily weight gain 26·7 g [SD 9·4] vs 24·8 g [9·5]; p<0·0001). The high-frequency exclusive breastmilk feeding rate at discharge was higher for infants in the FICare group (279 [70%] of 396) than those in the standard care group (394 [63%] of 624; p=0·016). At day 21, parents in the FICare group had lower mean stress scores than did parents in the standard care group (2·3 [SD 0·8] vs 2·5 [0·8]; p<0·00043), and lower mean anxiety scores (70·8 [20·1] vs 74·2 [19·9]; p=0·0045). There were no significant differences between groups in the rates of the secondary outcomes of mortality, major morbidity, duration of oxygen therapy, and duration of hospital stay. Although the safety assessment was not completed, there were no adverse events., Interpretation: FICare improved infant weight gain, decreased parent stress and anxiety, and increased high-frequency exclusive breastmilk feeding at discharge, which together suggest that FICare is an important advancement in neonatal care. Further research is required to examine if these results translate into better long-term outcomes for families., Funding: Canadian Institutes of Health Research Partnerships for Health System Improvement, and Ontario Ministry of Health and Long-Term Care., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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 FiO 2 and target SpO 2 for the first 10 minutes of life., Results: A total of 45 CPGs were identified: 36 provided gestation specific recommendations (<28 to <37 weeks) while eight distinguished only between 'preterm' and 'term'. The most frequently recommended initial FiO 2 were between 0.21 and 0.3 (n = 17). Most countries suggested altering FiO 2 to meet SpO 2 targets recommended by expert committees, However, specific five-minute SpO 2 targets differed by up to 20% (70-90%) between guidelines. Five countries did not specify SpO 2 targets., Conclusion: CPG recommendations for delivery room oxygen management of preterm infants vary greatly, particularly in regard to gestational ages, initial FiO 2 and SpO 2 targets and most acknowledge the lack of evidence behind these recommendations. Sufficiently large and well-designed randomised studies are needed to inform on this important practice., (©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: The effects of delayed cord clamping of the umbilical cord in preterm infants are unclear., Objective: We sought to compare the effects of delayed vs early cord clamping on hospital mortality (primary outcome) and morbidity in preterm infants using Cochrane Collaboration neonatal review group methodology., Study Design: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Chinese articles, cross-referencing citations, expert informants, and trial registries to July 31, 2017, for randomized controlled trials of delayed (≥30 seconds) vs early (<30 seconds) clamping in infants born <37 weeks' gestation. Before searching the literature, we specified that trials estimated to have cord milking in >20% of infants in any arm would be ineligible. Two reviewers independently selected studies, assessed bias, and extracted data. Relative risk (ie, risk ratio), risk difference, and mean difference with 95% confidence intervals were assessed by fixed effects models, heterogeneity by I 2 statistics, and the quality of evidence by Grading of Recommendations, Assessment, Development, and Evaluations., Results: Eighteen randomized controlled trials compared delayed vs early clamping in 2834 infants. Most infants allocated to have delayed clamping were assigned a delay of ≥60 seconds. Delayed clamping reduced hospital mortality (risk ratio, 0.68; 95% confidence interval, 0.52-0.90; risk difference, -0.03; 95% confidence interval, -0.05 to -0.01; P = .005; number needed to benefit, 33; 95% confidence interval, 20-100; Grading of Recommendations, Assessment, Development, and Evaluations = high, with I 2  = 0 indicating no heterogeneity). In 3 trials in 996 infants ≤28 weeks' gestation, delayed clamping reduced hospital mortality (risk ratio, 0.70; 95% confidence interval, 0.51-0.95; risk difference, -0.05; 95% confidence interval, -0.09 to -0.01; P = .02, number needed to benefit, 20; 95% confidence interval, 11-100; I 2  = 0). In subgroup analyses, delayed clamping reduced the incidence of low Apgar score at 1 minute, but not at 5 minutes, and did not reduce the incidence of intubation for resuscitation, admission temperature, mechanical ventilation, intraventricular hemorrhage, brain injury, chronic lung disease, patent ductus arteriosus, necrotizing enterocolitis, late onset sepsis or retinopathy of prematurity. Delayed clamping increased peak hematocrit by 2.73 percentage points (95% confidence interval, 1.94-3.52; P < .00001) and reduced the proportion of infants having blood transfusion by 10% (95% confidence interval, 6-13%; P < .00001). Potential harms of delayed clamping included polycythemia and hyperbilirubinemia., Conclusion: This systematic review provides high-quality evidence that delayed clamping reduced hospital mortality, which supports current guidelines recommending delayed clamping in preterm infants. This review does not evaluate cord milking, which may also be of benefit. Analyses of individual patient data in these and other randomized controlled trials will be critically important in reliably evaluating important secondary outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The preferred timing of umbilical-cord clamping in preterm infants is unclear., Methods: We randomly assigned fetuses from women who were expected to deliver before 30 weeks of gestation to either immediate clamping of the umbilical cord (≤10 seconds after delivery) or delayed clamping (≥60 seconds after delivery). The primary composite outcome was death or major morbidity (defined as severe brain injury on postnatal ultrasonography, severe retinopathy of prematurity, necrotizing enterocolitis, or late-onset sepsis) by 36 weeks of postmenstrual age. Analyses were performed on an intention-to-treat basis, accounting for multiple births., Results: Of 1634 fetuses that underwent randomization, 1566 were born alive before 30 weeks of gestation; of these, 782 were assigned to immediate cord clamping and 784 to delayed cord clamping. The median time between delivery and cord clamping was 5 seconds and 60 seconds in the respective groups. Complete data on the primary outcome were available for 1497 infants (95.6%). There was no significant difference in the incidence of the primary outcome between infants assigned to delayed clamping (37.0%) and those assigned to immediate clamping (37.2%) (relative risk, 1.00; 95% confidence interval, 0.88 to 1.13; P=0.96). The mortality was 6.4% in the delayed-clamping group and 9.0% in the immediate-clamping group (P=0.03 in unadjusted analyses; P=0.39 after post hoc adjustment for multiple secondary outcomes). There were no significant differences between the two groups in the incidences of chronic lung disease or other major morbidities., Conclusions: Among preterm infants, delayed cord clamping did not result in a lower incidence of the combined outcome of death or major morbidity at 36 weeks of gestation than immediate cord clamping. (Funded by the Australian National Health and Medical Research Council [NHMRC] and the NHMRC Clinical Trials Centre; APTS Australian and New Zealand Clinical Trials Registry number, ACTRN12610000633088 .).

Background and Objectives: Lower concentrations of oxygen (O 2 ) (≤30%) are recommended for preterm resuscitation to avoid oxidative injury and cerebral ischemia. Effects on long-term outcomes are uncertain. We aimed to determine the effects of using room air (RA) or 100% O 2 on the combined risk of death and disability at 2 years in infants <32 weeks' gestation., Methods: A randomized, unmasked study designed to determine major disability and death at 2 years in infants <32 weeks' gestation after delivery room resuscitation was initiated with either RA or 100% O 2 and which were adjusted to target pulse oximetry of 65% to 95% at 5 minutes and 85% to 95% until NICU admission., Results: Of 6291 eligible patients, 292 were recruited and 287 (mean gestation: 28.9 weeks) were included in the analysis (RA: n = 144; 100% O 2 : n = 143). Recruitment ceased in June 2014, per the recommendations of the Data and Safety Monitoring Committee owing to loss of equipoise for the use of 100% O 2 . In non-prespecified analyses, infants <28 weeks who received RA resuscitation had higher hospital mortality (RA: 10 of 46 [22%]; than those given 100% O 2 : 3 of 54 [6%]; risk ratio: 3.9 [95% confidence interval: 1.1-13.4]; P = .01). Respiratory failure was the most common cause of death (n = 13)., Conclusions: Using RA to initiate resuscitation was associated with an increased risk of death in infants <28 weeks' gestation. This study was not a prespecified analysis, and it was underpowered to address this post hoc hypothesis reliably. Additional data are needed., (Copyright © 2017 by the American Academy of Pediatrics.)

Objective: To systematically review outcomes of infants ≤28+6 weeks gestation randomised to resuscitation with low (≤0.3) vs high (≥0.6) fraction of inspired oxygen (FiO 2 ) at delivery., Design: Systematic review of randomised controlled trials of low (≤0.3) vs high (≥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 ≤28+6 weeks gestation were independently extracted and pooled using a random effects model. Analyses were performed with Revman V.5., Main Outcome Measures: Death in hospital, bronchopulmonary dysplasia (BPD), retinopathy of prematurity >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 (≤0.30) or higher (≥0.6) FiO 2 in infants ≤28+6 weeks gestation. The opposing results for masked and unmasked trials may represent a Type I error, emphasising the need for larger, well designed studies., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objective: To determine whether delayed cord clamping improves systemic blood flow compared with immediate cord clamping in very preterm infants in the first 24 hours., Study Design: Women delivering at <30 weeks' gestation at 5 tertiary centers were randomized to receive immediate cord clamping (<10 seconds) or delayed cord clamping (≥60 seconds). Echocardiography and cardiorespiratory data were collected at 3, 9, and 24 hours after birth. The primary outcome was mean lowest superior vena cava (SVC) flow., Results: Of 266 infants enrolled, 133 were randomized to immediate cord clamping and 133 to delayed cord clamping. The 2 groups were similar at baseline, including mean gestation (immediate cord clamping 28 weeks vs delayed cord clamping 28 weeks) and birth weight (immediate cord clamping 1003 g vs delayed cord clamping 1044 g). There was no significant difference between groups in the primary outcome of mean lowest SVC flow (immediate cord clamping 71.4 mL/kg/min [SD 28.1] vs delayed cord clamping 70.2 mL/kg/min [SD 26.9]; P = .7). For secondary outcomes, hemoglobin increased by 0.9 g/dL at 6 hours in the group with delayed cord clamping (95% CI 3.9, 14.4; P = .0005, adjusted for baseline). The group with delayed cord clamping had lower right ventricular output (-21.9 mL/kg/min, 95% CI -39.0, -4.7; P = .01). Rates of treated hypotension, ductus arteriosus size and shunt direction, and treatment of the ductus arteriosus were similar., Conclusions: Delayed cord clamping had no effect on systemic blood flow measured as mean lowest SVC flow in the first 24 hours in infants <30 weeks' gestation., Trial Registration: Australia New Zealand Clinical Trials Registry: ACTRN12610000633088., (Copyright © 2016 Elsevier Inc. All rights reserved.)