Does the use of higher versus lower oxygen concentration improve neurodevelopmental outcomes at 18-24 months in very low birthweight infants?

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 (FiO2) 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 FiO2 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 230/7 and 286/7 weeks' gestation will be eligible. Each participating hospital will be randomized to either an initial FiO2 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 FiO2 of 0.6, and the comparator will be initial FiO2 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.

Intrapartum use of sildenafil citrate to prevent fetal compromise and emergency operative birth in term pregnancies in the United Kingdom and Australia: A preliminary cost-effectiveness analysis.

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.

To guide future practice, perinatal trials should be much larger, simpler and less fragile with close to 100% ascertainment of mortality and other key outcomes.

The Australian Placental Transfusion Study (APTS) randomised 1,634 fetuses to delayed (≥60 s) versus immediate (≤10 s) clamping of the umbilical cord. Systematic reviews with meta-analyses, including this and similar trials, show that delaying clamping in preterm infants reduces mortality and need for blood transfusions. Amongst 1,531 infants in APTS followed up at two years, aiming to delay clamping for 60 s or more reduced the relative risk of the primary composite outcome of death or disability by 17% (p = 0.01). However, this result is fragile because nominal statistical significance (p < 0.05) would be abolished by only 2 patients switching from a non-event to an event, and the primary composite outcome was missing in 112 patients (7%). To achieve more robust evidence, any future trials should emulate the large, simple trials co-ordinated from Oxford which reliably identified moderate, incremental improvements in mortality in tens of thousands of participants, with <1% missing data. Those who fund, regulate, and conduct trials that aim to change practice should repay the trust of those who consent to participate by doing everything possible to minimise missing data for key outcomes.

Lactoferrin for the postoperative management of term neonates after gastrointestinal surgery.

BACKGROUND: Neonates who have undergone gastrointestinal surgery are particularly susceptible to infectious complications in the postoperative period. This may be due in part to disruption of the integrity of the gut and its altered intestinal microflora. Lactoferrin is a whey protein found in milk and is an important innate mammalian defence mechanism. Lactoferrin has been reported to have antimicrobial and anti-inflammatory properties. It has also been reported to help establish a healthy gut microflora and aid in the intestinal immune system. Lactoferrin supplementation has been reported to decrease sepsis in preterm infants. There may be a role for lactoferrin to reduce the incidence of sepsis, thus reducing morbidity and mortality and improving enteral feeding in postoperative term neonates. OBJECTIVES: The primary objective of this review was to evaluate the efficacy of administering lactoferrin on the incidence of sepsis and mortality in term neonates after gastrointestinal surgery. The secondary objective was to assess the impact of administering lactoferrin on time to full enteral feeds, the intestinal microflora, duration of hospital stay, and mortality before discharge in the same population. SEARCH METHODS: The Cochrane Neonatal Information Specialist searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Embase Ovid, CINAHL, the WHO ICTRP and ClinicalTrials.gov trials registries. The date of the last search was February 2023. There were no restrictions to language, publication year or publication type. We checked references of potentially relevant studies and systematic reviews. SELECTION CRITERIA: We planned to include randomised controlled trials that studied infants born at 37 or more weeks of gestation who had one or more episodes of gastrointestinal surgery within 28 days of birth, and compared administration of lactoferrin with a placebo. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. We planned to use the GRADE approach to assess the certainty of evidence for each outcome. MAIN RESULTS: We identified no published randomised controlled studies that assessed the efficacy of lactoferrin for the postoperative management of term neonates following gastrointestinal surgery. AUTHORS' CONCLUSIONS: There is currently no evidence available from randomised controlled trials to show whether lactoferrin is effective or ineffective for the postoperative management of term neonates after gastrointestinal surgery. There is a need for randomised controlled trials to be performed to assess the role of lactoferrin in this setting.

Harnessing neuroplasticity to improve motor performance in infants with cerebral palsy: a study protocol for the GAME randomised controlled trial.

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.

PROspective Meta-analysis Of Trials of Initial Oxygen in preterm Newborns (PROMOTION): Protocol for a systematic review and prospective meta-analysis with individual participant data on initial oxygen concentration for resuscitation of preterm infants.

BACKGROUND: Clinicians favour low oxygen concentrations when resuscitating preterm infants immediately after birth despite inconclusive evidence to support this practice. Prospective meta-analysis (PMA) is a novel approach where studies are identified as eligible for inclusion in the meta-analysis before their results are known. AIMS: To explore whether high (60%) or low (30%) oxygen is associated with greater efficacy and safety for the initial resuscitation (immediately after birth) of preterm infants born at <29 weeks' gestation. METHODS: We will conduct a prospective meta-analysis (PMA) with individual participant data (IPD). We will perform a systematic search to identify ongoing RCTs including infants <29 weeks' gestation randomised to high (60%) or low (30%) oxygen for initial resuscitation after birth. IPD will be sought for all infants randomised for the purpose of meta-analysis. We will employ a one-stage random-effects approach to IPD meta-analysis. Potential heterogeneity and the differential effect of high or low oxygen will be explored through subgroup and interaction analyses. The primary outcome of this study is all-cause mortality prior to hospital discharge. There will be a follow-up analysis of neurodevelopmental outcomes once available. RESULTS/CONCLUSION: The results of neonatal outcomes at hospital discharge are expected by 2025, and neurodevelopmental outcomes by 2027.

Protocol for a Nested, Retrospective Study of the Australian Placental Transfusion Study Cohort.

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.

Neurodevelopmental outcomes of preterm infants after randomisation to initial resuscitation with lower (FiO2 <0.3) or higher (FiO2 >0.6) initial oxygen levels. An individual patient meta-analysis.

OBJECTIVE: To determine the effects of lower (≤0.3) versus higher (≥0.6) initial fractional inspired oxygen (FiO2) 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 FiO2. 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 (SpO2) 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 FiO2 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 SpO2 >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 SpO2 ≥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 FiO2 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.

Effects of delayed versus immediate umbilical cord clamping in reducing death or major disability at 2 years corrected age among very preterm infants (APTS): a multicentre, randomised clinical trial.

BACKGROUND: Very preterm infants are at increased risk of adverse outcomes in early childhood. We assessed whether delayed clamping of the umbilical cord reduces mortality or major disability at 2 years in the APTS Childhood Follow Up Study. METHODS: In this long-term follow-up analysis of the multicentre, randomised APTS trial in 25 centres in seven countries, infants (<30 weeks gestation) were randomly assigned before birth (1:1) to have clinicians aim to delay clamping for 60 s or more or clamp within 10 s of birth, both without cord milking. The primary outcome was death or major disability (cerebral palsy, severe visual loss, deafness requiring a hearing aid or cochlear implants, major language or speech problems, or cognitive delay) at 2 years corrected age, analysed in the intention-to-treat population. This trial is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12610000633088). FINDINGS: Between Oct 21, 2009, and Jan 6, 2017, consent was obtained for follow-up for 1531 infants, of whom 767 were randomly assigned to delayed clamping and 764 to immediate clamping. 384 (25%) of 1531 infants were multiple births, 862 (56%) infants were male, and 505 (33%) were born before 27 weeks gestation. 564 (74%) of 767 infants assigned to delayed clamping and 726 (96%) of 764 infants assigned to immediate clamping received treatment that fully adhered to the protocol. Death or major disability was determined in 1419 (93%) infants and occurred in 204 (29%) of 709 infants who were assigned to delayed clamping versus 240 (34%) of 710 assigned to immediate clamping, (relative risk [RR]) 0·83, 95% CI 0·72-0·95; p=0·010). 60 (8%) of 725 infants in the delayed clamping group and 81 (11%) of 720 infants in the immediate clamping group died by 2 years of age (RR 0·70, 95% CI 0·52-0·95); among those who survived, major disability at 2 years occurred in 23% (144/627) versus 26% (159/603) of infants, respectively (RR 0·88, 0·74-1·04). INTERPRETATION: Clamping the umbilical cord at least 60 s after birth reduced the risk of death or major disability at 2 years by 17%, reflecting a 30% reduction in relative mortality with no difference in major disability. FUNDING: Australian National Health and Medical Research Council.

Higher versus Lower Oxygen Concentration during Respiratory Support in the Delivery Room in Extremely Preterm Infants: A Pilot Feasibility Study.

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.

Normalising comparative effectiveness trials as clinical practice.

There is a lack of high-quality evidence underpinning many contemporary clinical practice guidelines embedded in the healthcare systems, leading to treatment uncertainty and practice variation in most medical disciplines. Comparative effectiveness trials (CETs) represent a diverse range of research that focuses on optimising health outcomes by comparing currently approved interventions to generate high-quality evidence to inform decision makers. Yet, despite their ability to produce real-world evidence that addresses the key priorities of patients and health systems, many implementation challenges exist within the healthcare environment.This manuscript aims to highlight common barriers to conducting CETs and describes potential solutions to normalise their conduct as part of a learning healthcare system.

A Pilot Randomized Controlled Trial of a Partial Meal Replacement Preconception Weight Loss Program for Women with Overweight and Obesity.

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/m2 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.

Outcomes of delivery room resuscitation of bradycardic preterm infants: A retrospective cohort study of randomised trials of high vs low initial oxygen concentration and an individual patient data analysis.

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 <32 weeks gestational age were eligible. Individual patient level data were requested from the authors. Newborns receiving chest compressions in the DR and those with no recorded HR in the first 2 min after birth were excluded. Prolonged bradycardia (PB) was defined as HR < 100 bpm for ≥2 min. Individual patient data analysis and pooled data analysis were conducted. RESULTS: Data were collected from 720 infants in 8 RCTs. Neonates with PB had higher odds of hospital death before [OR 3.8 (95% CI 1.5, 9.3)] and after [OR 1.7 (1.2, 2.5)] adjusting for potential confounders. Bradycardia occurred in 58% infants, while 38% had PB. Infants with bradycardia were more premature and had lower birth weights. The incidence of bradycardia in infants resuscitated with low (≤30%) and high (≥60%) oxygen was similar. Neonates with both, PB and SpO2 < 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.

Evidence from systematic reviews of randomized trials on enteral lactoferrin supplementation in preterm neonates.

In this commentary, we summarize the current evidence from randomized controlled trials on enteral lactoferrin supplementation in preterm neonates. Our recently completed systematic review includes 12 randomized controlled trials performed all over the world. Our meta-analysis suggests clinical benefit in decreasing late-onset sepsis, late-onset fungal sepsis, length of stay in the hospital and urinary tract infections. There were no adverse effects. There was no statistically significant decrease in necrotizing enterocolitis, mortality or neurodevelopmental impairment in lactoferrin supplemented preterm infants. There was significant statistical heterogeneity in the effects of lactoferrin on late-onset sepsis between larger and smaller studies, which may reflect either small study biases, differences in the effectiveness, dose or duration of supplemental lactoferrin products, or differences in underlying population risk, or any or all of these.

The effect of lactoferrin supplementation on death or major morbidity in very low birthweight infants (LIFT): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Very low birthweight or preterm infants are at increased risk of adverse outcomes including sepsis, necrotising enterocolitis, and death. We assessed whether supplementing the enteral diet of very low-birthweight infants with lactoferrin, an antimicrobial protein, reduces all-cause mortality or major morbidity. METHODS: We did a multicentre, double-blind, pragmatic, randomised superiority trial in 14 Australian and two New Zealand neonatal intensive care units. Infants born weighing less than 1500 g and aged less than 8 days, were eligible and randomly assigned (1:1) using minimising web-based randomisation to receive once daily 200 mg/kg pasteurised bovine lactoferrin supplements or no lactoferrin supplement added to breast or formula milk until 34 weeks' post-menstrual age (or for 2 weeks, if longer), or until discharge from the study hospital if that occurred first. Designated nurses preparing the daily feeds were not masked to group assignment, but other nurses, doctors, parents, caregivers, and investigators were unaware. The primary outcome was survival to hospital discharge or major morbidity (defined as brain injury, necrotising enterocolitis, late-onset sepsis at 36 weeks' post-menstrual age, or retinopathy treated before discharge) assessed in the intention-to-treat population. Safety analyses were by treatment received. We also did a prespecified, PRISMA-compliant meta-analysis, which included this study and other relevant randomised controlled trials, to estimate more precisely the effects of lactoferrin supplementation on late-onset sepsis, necrotising enterocolitis, and survival. This trial is registered with the Australian and New Zealand Clinical Trials Registry, ACTRN12611000247976. FINDINGS: Between June 27, 2014, and Sept 1, 2017, we recruited 1542 infants; 771 were assigned to the intervention group and 771 to the control group. One infant who had consent withdrawn before beginning lactoferrin treatment was excluded from analysis. In-hospital death or major morbidity occurred in 162 (21%) of 770 infants in the intervention group and in 170 (22%) of 771 infants in the control group (relative risk [RR] 0·95, 95% CI 0·79-1·14; p=0·60). Three suspected unexpected serious adverse reactions occurred; two in the lactoferrin group, namely unexplained late jaundice and inspissated milk syndrome, but were not attributed to the intervention and one in the control group had fatal inspissated milk syndrome. Our meta-analysis identified 13 trials completed before Feb 18, 2020, including this Article, in 5609 preterm infants. Lactoferrin supplements significantly reduced late-onset sepsis (RR 0·79, 95% CI 0·71-0·88; p<0·0001; I2=58%), but not necrotising enterocolitis or all-cause mortality. INTERPRETATION: Lactoferrin supplementation did not improve death or major morbidity in this trial, but might reduce late-onset sepsis, as found in our meta-analysis of over 5000 infants. Future collaborative studies should use products with demonstrated biological activity, be large enough to detect moderate and clinically important effects reliably, and assess greater doses of lactoferrin in infants at increased risk, such as those not exclusively receiving breastmilk or infants of extremely low birthweight. FUNDING: Australian National Health and Medical Research Council.

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. REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ANZCTR) (ACTRN12619001305112) and International Prospective Register of Systematic Reviews (PROSPERO, CRD42019136640).

Lactoferrin infant feeding trial_Canada (LIFT_Canada): protocol for a randomized trial of adding lactoferrin to feeds of very-low-birth-weight preterm infants.

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_Canada (LIFT_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_Australia/New Zealand (LIFT_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_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.

Safety and efficacy of sildenafil citrate to reduce operative birth for intrapartum fetal compromise at term: a phase 2 randomized controlled trial.

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.

Improving incidence trends of severe intraventricular haemorrhages in preterm infants <32 weeks gestation: a cohort study.

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.