William McGuire

Objective: To assess the economic consequences of initiating full milk feeds from birth compared with intravenous fluids with gradual feeding in infants born preterm. Design: Within-trial economic evaluation alongside a prospective, multicentre, randomised controlled trial (Fluids Exclusively Enteral from Day 1). A cost-consequence approach was used (revised from the planned cost-effectiveness analysis to avoid double counting length of stay within costs). Setting: 46 UK National Health Service (NHS) neonatal units. Patients: Preterm infants born at 30+0to 32+6 weeks’ gestation. Interventions: Infants were allocated to either full milk feeds or gradual feeding with intravenous support within 3 hours of birth. Main outcome measure: Resource use and costs were captured from birth to 6 weeks’ corrected age. Costs were assessed from an NHS and personal social services perspective. The primary clinical outcome was length of hospital stay. Results: 2088 infants were enrolled. There was no statistically significant difference in mean (95% CI) length of hospital stay between groups (−0.050 days (−0.638 to 0.538)). Mean total costs were £670 lower in the full milk group (95% CI: –£1562 to £223; p=0.141). Subgroup analyses suggested lower costs among infants born at 30 weeks’ gestation and those below the 10th birth weight centile; no evidence of interaction was found. Conclusions: Initiating full milk feeds from birth was associated with a modest reduction in costs compared with gradual feeding. While overall hospital stays and costs were not significantly reduced, early full feeding may offer economic advantages in selected subgroups. Further research is needed to assess long-term outcomes. Trial registration number: ISRCTN89654042 .

Background When sufficient maternal milk is not available, donor human milk or formula are the alternative forms of enteral nutrition for very preterm or very low‐birthweight (VLBW) infants. Donor human milk may retain the non‐nutritive benefits of maternal milk and has been proposed as a strategy to reduce the risk of necrotising enterocolitis (NEC) and associated mortality and morbidity in very preterm or VLBW infants. Objectives To assess the effectiveness of donor human milk compared with formula for preventing NEC and associated morbidity and mortality in very preterm or VLBW infants when sufficient maternal milk is not available. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Maternity and Infant Care (MIC) database, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), from the earliest records to February 2024. We searched clinical trials registries and examined the reference lists of included studies. Selection criteria Randomised or quasi‐randomised controlled trials comparing feeding with donor human milk versus formula in very preterm (< 32 weeks' gestation) or VLBW (< 1500 g) infants. Data collection and analysis Two review authors evaluated the risk of bias in the trials, extracted data, and synthesised effect estimates using risk ratio, risk difference, and mean difference, with associated 95% confidence intervals. The primary outcomes were NEC, late‐onset invasive infection, and all‐cause mortality before hospital discharge. The secondary outcomes were growth parameters and neurodevelopment. We used the GRADE approach to assess the certainty of the evidence for our primary outcomes. Main results Twelve trials with a total of 2296 infants fulfilled the inclusion criteria. Most trials were small (average sample size was 191 infants). All trials were performed in neonatal units in Europe or North America. Five trials were conducted more than 40 years ago; the remaining seven trials were conducted in the year 2000 or later. Some trials had methodological weaknesses, including concerns regarding masking of investigators and selective reporting. Meta‐analysis showed that donor human milk reduces the risk of NEC (risk ratio (RR) 0.53, 95% confidence interval (CI) 0.37 to 0.76; I² = 4%; risk difference (RD) −0.03, 95% CI −0.05 to −0.01; 11 trials, 2261 infants; high certainty evidence). Donor human milk probably has little or no effect on late‐onset invasive infection (RR 1.12, 0.95 to 1.31; I² = 27%; RD 0.03, 95% CI −0.01 to −0.07; 7 trials, 1611 infants; moderate certainty evidence) or all‐cause mortality (RR 1.00, 95% CI 0.76 to 1.31; I² = 0%; RD −0.00, 95% CI −0.02 to 0.02; 9 trials, 2116 infants; moderate certainty evidence). Authors' conclusions The evidence shows that donor human milk reduces the risk of NEC by about half in very preterm or VLBW infants. There is probably little or no effect on late‐onset invasive infection or all‐cause mortality before hospital discharge.

Background Intestinal dysbiosis may contribute to the pathogenesis of necrotising enterocolitis (NEC) in very preterm or very low birth weight (VLBW) infants. Dietary supplementation with probiotics to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of NEC and associated mortality and morbidity in very preterm or VLBW infants. Objectives To determine the effect of supplemental probiotics on the risk of NEC and associated mortality and morbidity in very preterm or very low birth weight infants. Search methods We searched CENTRAL, MEDLINE, Embase, the Maternity and Infant Care database, and CINAHL from inception to July 2022. We searched clinical trials databases and conference proceedings, and examined the reference lists of retrieved articles. Selection criteria We included randomised controlled trials (RCTs) and quasi‐RCTs comparing probiotics with placebo or no probiotics in very preterm infants (born before 32 weeks' gestation) and VLBW infants (weighing less than 1500 g at birth). Data collection and analysis Two review authors independently evaluated risk of bias of the trials, extracted data, and synthesised effect estimates using risk ratios (RRs), risk differences (RDs), and mean differences (MDs), with associated 95% confidence intervals (CIs). The primary outcomes were NEC and all‐cause mortality; secondary outcome measures were late‐onset invasive infection (more than 48 hours after birth), duration of hospitalisation from birth, and neurodevelopmental impairment. We used the GRADE approach to assess the certainty of the evidence. Main results We included 60 trials with 11,156 infants. Most trials were small (median sample size 145 infants). The main potential sources of bias were unclear reporting of methods for concealing allocation and masking caregivers or investigators in about half of the trials. The formulation of the probiotics varied across trials. The most common preparations contained Bifidobacterium spp., Lactobacillus spp., Saccharomyces spp., andStreptococcus spp., alone or in combination. Very preterm or very low birth weight infants Probiotics may reduce the risk of NEC (RR 0.54, 95% CI 0.46 to 0.65; I² = 17%; 57 trials, 10,918 infants; low certainty). The number needed to treat for an additional beneficial outcome (NNTB) was 33 (95% CI 25 to 50). Probiotics probably reduce mortality slightly (RR 0.77, 95% CI 0.66 to 0.90; I² = 0%; 54 trials, 10,484 infants; moderate certainty); the NNTB was 50 (95% CI 50 to 100). Probiotics probably have little or no effect on the risk of late‐onset invasive infection (RR 0.89, 95% CI 0.82 to 0.97; I² = 22%; 49 trials, 9876 infants; moderate certainty). Probiotics may have little or no effect on neurodevelopmental impairment (RR 1.03, 95% CI 0.84 to 1.26; I² = 0%; 5 trials, 1518 infants; low certainty). Extremely preterm or extremely low birth weight infants Few data were available for extremely preterm or extremely low birth weight (ELBW) infants. In this population, probiotics may have little or no effect on NEC (RR 0.92, 95% CI 0.69 to 1.22, I² = 0%; 10 trials, 1836 infants; low certainty), all‐cause mortality (RR 0.92, 95% CI 0.72 to 1.18; I² = 0%; 7 trials, 1723 infants; low certainty), or late‐onset invasive infection (RR 0.93, 95% CI 0.78 to 1.09; I² = 0%; 7 trials, 1533 infants; low certainty). No trials provided data for measures of neurodevelopmental impairment in extremely preterm or ELBW infants. Authors' conclusions Given the low to moderate certainty of evidence for the effects of probiotic supplements on the risk of NEC and associated morbidity and mortality for very preterm or VLBW infants, and particularly for extremely preterm or ELBW infants, there is a need for further large, high‐quality trials to provide evidence of sufficient validity and applicability to inform policy and practice.

Background Dietary supplementation with prebiotic oligosaccharides to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of necrotising enterocolitis (NEC) and associated mortality and morbidity in very preterm or very low birth weight (VLBW) infants. Objectives To assess the benefits and harms of enteral supplementation with prebiotics (versus placebo or no treatment) for preventing NEC and associated morbidity and mortality in very preterm or VLBW infants. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Maternity and Infant Care database and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), from the earliest records to July 2022. We searched clinical trials databases and conference proceedings, and examined the reference lists of retrieved articles. Selection criteria We included randomised controlled trials (RCTs) and quasi‐RCTs comparing prebiotics with placebo or no prebiotics in very preterm (< 32 weeks' gestation) or VLBW (< 1500 g) infants. The primary outcomes were NEC and all‐cause mortality, and the secondary outcomes were late‐onset invasive infection, duration of hospitalisation since birth, and neurodevelopmental impairment. Data collection and analysis Two review authors separately evaluated risk of bias of the trials, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference (MD), with associated 95% confidence intervals (CIs). The primary outcomes of interest were NEC and all‐cause mortality; our secondary outcome measures were late‐onset (> 48 hours after birth) invasive infection, duration of hospitalisation, and neurodevelopmental impairment. We used the GRADE approach to assess the level of certainty of the evidence. Main results We included seven trials in which a total of 705 infants participated. All the trials were small (mean sample size 100). Lack of clarity on methods to conceal allocation and mask caregivers or investigators were potential sources of bias in three of the trials. The studied prebiotics were fructo‐ and galacto‐oligosaccharides, inulin, and lactulose, typically administered daily with enteral feeds during birth hospitalisation. Meta‐analyses of data from seven trials (686 infants) suggest that prebiotics may result in little or no difference in NEC (RR 0.97, 95% CI 0.60 to 1.56; RD none fewer per 1000, 95% CI 50 fewer to 40 more; low‐certainty evidence), all‐cause mortality (RR 0.43, 95% CI 0.20 to 0.92; 40 per 1000 fewer, 95% CI 70 fewer to none fewer; low‐certainty evidence), or late‐onset invasive infection (RR 0.79, 95% CI 0.60 to 1.06; 50 per 1000 fewer, 95% CI 100 fewer to 10 more; low‐certainty evidence) prior to hospital discharge. The certainty of this evidence is low because of concerns about the risk of bias in some trials and the imprecision of the effect size estimates. The data available from one trial provided only very low‐certainty evidence about the effect of prebiotics on measures of neurodevelopmental impairment (Bayley Scales of Infant Development (BSID) Mental Development Index score < 85: RR 0.84, 95% CI 0.25 to 2.90; very low‐certainty evidence; BSID Psychomotor Development Index score < 85: RR 0.24, 95% 0.03 to 2.00; very low‐certainty evidence; cerebral palsy: RR 0.35, 95% CI 0.01 to 8.35; very low‐certainty evidence). Authors' conclusions The available trial data provide low‐certainty evidence about the effects of prebiotics on the risk of NEC, all‐cause mortality before discharge, and invasive infection, and very low‐certainty evidence about the effect on neurodevelopmental impairment for very preterm or VLBW infants. Our confidence in the effect estimates is limited; the true effects may be substantially different. Large, high‐quality trials are needed to provide evidence of sufficient validity to inform policy and practice decisions.

Background Several types of pressure sources, including underwater bubble devices, mechanical ventilators, and the Infant Flow Driver, are used for providing continuous positive airway pressure (CPAP) to preterm infants with respiratory distress. It is unclear whether the use of bubble CPAP versus other pressure sources is associated with lower rates of CPAP treatment failure, or mortality and other morbidity. Objectives To assess the benefits and harms of bubble CPAP versus other pressure sources (mechanical ventilators or Infant Flow Driver) for reducing treatment failure and associated morbidity and mortality in newborn preterm infants with or at risk of respiratory distress. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2023, Issue 1); MEDLINE (1946 to 6 January 2023), Embase (1974 to 6 January 2023), Maternity & Infant Care Database (1971 to 6 January 2023), and the Cumulative Index to Nursing and Allied Health Literature (1982 to 6 January 2023). We searched clinical trials databases and the reference lists of retrieved articles. Selection criteria We included randomised controlled trials comparing bubble CPAP with other pressure sources (mechanical ventilators or Infant Flow Driver) for the delivery of nasal CPAP to preterm infants. Data collection and analysis We used standard Cochrane methods. Two review authors separately evaluated trial quality, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference. We used the GRADE approach to assess the certainty of the evidence for effects on treatment failure, all‐cause mortality, neurodevelopmental impairment, pneumothorax, moderate‐severe nasal trauma, and bronchopulmonary dysplasia. Main results We included 15 trials involving a total of 1437 infants. All trials were small (median number of participants 88). The methods used to generate the randomisation sequence and ensure allocation concealment were unclear in about half of the trial reports. Lack of measures to blind caregivers or investigators was a potential source of bias in all of the included trials. The trials took place during the past 25 years in care facilities internationally, predominantly in India (five trials) and Iran (four trials). The studied pressure sources were commercially available bubble CPAP devices versus a variety of mechanical ventilator (11 trials) or Infant Flow Driver (4 trials) devices. Meta‐analyses suggest that the use of bubble CPAP compared with mechanical ventilator or Infant Flow Driver CPAP may reduce the rate of treatment failure (RR 0.76, 95% confidence interval (CI) 0.60 to 0.95; (I² = 31%); RD −0.05, 95% CI −0.10 to −0.01; number needed to treat for an additional beneficial outcome 20, 95% CI 10 to 100; 13 trials, 1230 infants; low certainty evidence). The type of pressure source may not affect mortality prior to hospital discharge (RR 0.93, 95% CI 0.64 to 1.36 (I² = 0%); RD −0.01, 95% CI −0.04 to 0.02; 10 trials, 1189 infants; low certainty evidence). No data were available on neurodevelopmental impairment. Meta‐analysis suggests that the pressure source may not affect the risk of pneumothorax (RR 0.73, 95% CI 0.40 to 1.34 (I² = 0%); RD −0.01, 95% CI −0.03 to 0.01; 14 trials, 1340 infants; low certainty evidence). Bubble CPAP likely increases the risk of moderate‐severe nasal injury (RR 2.29, 95% CI 1.37 to 3.82 (I² = 17%); RD 0.07, 95% CI 0.03 to 0.11; number needed to treat for an additional harmful outcome 14, 95% CI 9 to 33; 8 trials, 753 infants; moderate certainty evidence). The pressure source may not affect the risk of bronchopulmonary dysplasia (RR 0.76, 95% CI 0.53 to 1.10 (I² = 0%); RD −0.04, 95% CI −0.09 to 0.01; 7 trials, 603 infants; low certainty evidence). Authors' conclusions Given the low level of certainty about the effects of bubble CPAP versus other pressure sources on the risk of treatment failure and most associated morbidity and mortality for preterm infants, further large, high‐quality trials are needed to provide evidence of sufficient validity and applicability to inform context‐ and setting‐relevant policy and practice.

Background Nasal masks and nasal prongs are used as interfaces for providing continuous positive airway pressure (CPAP) for preterm infants with or at risk of respiratory distress, either as primary support after birth or as ongoing support after endotracheal extubation from mechanical ventilation. It is unclear which type of interface is associated with lower rates of CPAP treatment failure, nasal trauma, or mortality and other morbidity. Objectives To assess the benefits and harms of nasal masks versus nasal prongs for reducing CPAP treatment failure, nasal trauma, or mortality and other morbidity in newborn preterm infants with or at risk of respiratory distress. Search methods We used standard, extensive Cochrane search methods. The latest search date was October 2021. Selection criteria We included randomised controlled trials comparing masks versus prongs as interfaces for delivery of nasal CPAP in newborn preterm infants (less than 37 weeks' gestation) with or at risk of respiratory distress. Data collection and analysis We used standard Cochrane methods. Our primary outcomes were 1. treatment failure, 2. all‐cause mortality, and 3. neurodevelopmental impairment. Our secondary outcomes were 4. pneumothorax, 5. moderate–severe nasal trauma, 6. bronchopulmonary dysplasia, 7. duration of CPAP use, 8. duration of oxygen supplementation, 9. duration of hospitalisation, 10. patent ductus arteriosus receiving medical or surgical treatment, 11. necrotising enterocolitis, 12. severe intraventricular haemorrhage, and 13. severe retinopathy of prematurity. We used the GRADE approach to assess the certainty of the evidence. Main results We included 12 trials with 1604 infants. All trials were small (median number of participants 118). The trials occurred after 2001 in care facilities internationally, predominantly in India (eight trials). Most participants were preterm infants of 26 to 34 weeks' gestation who received nasal CPAP as the primary form of respiratory support after birth. The studied interfaces included commonly used commercially available masks and prongs. Lack of measures to blind caregivers or investigators was a potential source of performance and detection bias in all the trials. Meta‐analyses suggested that use of masks compared with prongs may reduce CPAP treatment failure (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.58 to 0.90; 8 trials, 919 infants; low certainty). The type of interface may not affect mortality prior to hospital discharge (RR 0.83, 95% CI 0.56 to 1.22; 7 trials, 814 infants; low certainty). There are no data on neurodevelopmental impairment. Meta‐analyses suggest that the choice of interface may result in little or no difference in the risk of pneumothorax (RR 0.93, 95% CI 0.45 to 1.93; 5 trials, 625 infants; low certainty). Use of masks rather than prongs may reduce the risk of moderate–severe nasal injury (RR 0.55, 95% CI 0.44 to 0.71; 10 trials, 1058 infants; low certainty). The evidence is very uncertain about the effect on bronchopulmonary dysplasia (RR 0.69, 95% CI 0.46 to 1.03; 7 trials, 843 infants; very low certainty). Authors' conclusions The available trial data provide low‐certainty evidence that use of masks compared with prongs as the nasal CPAP interface may reduce treatment failure and nasal injury, and may have little or no effect on mortality or the risk of pneumothorax in newborn preterm infants with or at risk of respiratory distress. The effect on bronchopulmonary dysplasia is very uncertain. Large, high‐quality trials would be needed to provide evidence of sufficient validity and applicability to inform policy and practice.

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