Early full enteral feeding for preterm or low birth weight infants.

BACKGROUND: The introduction and advancement of enteral feeds for preterm or low birth weight infants is often delayed because of concerns that early full enteral feeding will not be well tolerated or may increase the risk of necrotising enterocolitis. Early full enteral feeding, however, might increase nutrient intake and growth rates; accelerate intestinal physiological, metabolic, and microbiomic postnatal transition; and reduce the risk of complications associated with intravascular devices for fluid administration.  OBJECTIVES: To determine how early full enteral feeding, compared with delayed or progressive introduction of enteral feeds, affects growth and adverse events such as necrotising enterocolitis, in preterm or low birth weight infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials; MEDLINE Ovid, Embase Ovid, Maternity & Infant Care Database Ovid, the Cumulative Index to Nursing and Allied Health Literature, and clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials to October 2020. SELECTION CRITERIA: Randomised controlled trials that compared early full enteral feeding with delayed or progressive introduction of enteral feeds in preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal. Two review authors separately assessed trial eligibility, evaluated trial quality, extracted data, and synthesised effect estimates using risk ratios (RR), risk differences, and mean differences (MD) with 95% confidence intervals (CI). We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included six trials. All were undertaken in the 2010s in neonatal care facilities in India. In total, 526 infants participated. Most were very preterm infants of birth weight between 1000 g and 1500 g. Trials were of good methodological quality, but a potential source of bias was that parents, clinicians, and investigators were not masked. The trials compared early full feeding (60 mL/kg to 80 mL/kg on day one after birth) with minimal enteral feeding (typically 20 mL/kg on day one) supplemented with intravenous fluids. Feed volumes were advanced daily as tolerated by 20 mL/kg to 30 mL/kg body weight to a target steady-state volume of 150 mL/kg to 180 mL/kg/day. All participating infants were fed preferentially with maternal expressed breast milk, with two trials supplementing insufficient volumes with donor breast milk and four supplementing with preterm formula.  Few data were available to assess growth parameters. One trial (64 participants) reported a slower rate of weight gain (median difference -3.0 g/kg/day), and another (180 participants) reported a faster rate of weight gain in the early full enteral feeding group (MD 1.2 g/kg/day). We did not meta-analyse these data (very low-certainty evidence). None of the trials reported rate of head circumference growth. One trial reported that the mean z-score for weight at hospital discharge was higher in the early full enteral feeding group (MD 0.24, 95% CI 0.06 to 0.42; low-certainty evidence). Meta-analyses showed no evidence of an effect on necrotising enterocolitis (RR 0.98, 95% CI 0.38 to 2.54; 6 trials, 522 participants; I² = 51%; very low-certainty evidence). AUTHORS' CONCLUSIONS: Trials provided insufficient data to determine with any certainty how early full enteral feeding, compared with delayed or progressive introduction of enteral feeds, affects growth in preterm or low birth weight infants. We are uncertain whether early full enteral feeding affects the risk of necrotising enterocolitis because of the risk of bias in the trials (due to lack of masking), inconsistency, and imprecision.

Iodine supplementation for the prevention of mortality and adverse neurodevelopmental outcomes in preterm infants.

BACKGROUND: Parenteral nutrition solutions, artificial formulas, and human breast milk contain insufficient iodine to meet recommended intakes for preterm infants. Iodine deficiency may exacerbate transient hypothyroxinaemia in preterm infants and this may be associated with adverse neonatal and longer-term outcomes. OBJECTIVES: To assess the evidence from randomised controlled trials that dietary supplementation with iodine reduces mortality and morbidity in preterm infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 1), Ovid MEDLINE, Ovid Embase, Ovid Maternity & Infant Care Database, and CINAHL to February 2018. We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that compared supplementing enteral or parenteral feeds with iodine (as iodide salt) versus placebo or no supplementation in preterm infants. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias, and extracted data. We analysed treatment effects as described in the individual trials and reported risk ratios (RR) and risk differences for dichotomous data, and mean differences (MD) for continuous data, with 95% confidence intervals (CI). We used a fixed-effect model in meta-analyses and planned to explore potential causes of heterogeneity in sensitivity analyses. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: Two randomised controlled trials fulfilled the eligibility criteria. Both trials used methods to limit bias including allocation concealment and blinding of clinicians and investigators to the allocated intervention. The trials enrolled 1394 infants. One trial recruited 1273 participants. Most participants were born very preterm (less than 32 weeks' gestation) and about one-third were extremely preterm (less than 28 weeks' gestation). Analyses found no effect of iodine supplementation on mortality before hospital discharge (typical RR 1.01, 95% CI 0.72 to 1.42; 2 studies, 1380 infants) or on neurodevelopmental assessments at two years post-term (Bayley Scales of Infant and Toddler Development, Third Edition main domain composite scores: cognitive: MD -0.30, 95% CI -2.44 to 1.84; motor: MD 0.20, 95% CI -2.15 to 2.55; language: MD -0.10, 95% CI -2.50 to 2.30; 1 study, 1259 infants). There were no differences in the proportion of infants who died or had a composite score less than 85 in any main Bayley domain (RR 1.05, 95% CI 0.94 to 1.17; 1 study, 1259 infants), or had visual impairment (RR 0.63, 95% CI 0.28 to 1.45; 1 study, 1092 infants) or auditory impairment (RR 1.05, 95% CI 0.51 to 2.16; 1 study, 1093 infants). Using GRADE methods, we assessed the evidence for the effects on mortality and neurodevelopment outcomes as high-certainty. AUTHORS' CONCLUSIONS: The available trial data, predominantly from one large, high-quality multicentre study published in 2017, do not show any evidence of beneficial effects of iodine supplementation for preterm infants. Given the high certainty of these estimates of effect, further trials of this intervention in this population are unlikely to be considered research priorities.

Formula versus maternal breast milk for feeding preterm or low birth weight infants.

BACKGROUND: Artificial formula can be manipulated to contain higher amounts of macro-nutrients than maternal breast milk but breast milk confers important immuno-nutritional advantages for preterm or low birth weight (LBW) infants. OBJECTIVES: To determine the effect of feeding preterm or LBW infants with formula compared with maternal breast milk on growth and developmental outcomes. SEARCH METHODS: We used the standard strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 9), and Ovid MEDLINE, Ovid Embase, Ovid Maternity & Infant Care Database, and CINAHL to October 2018. We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that compared feeding preterm or low birth weight infants with formula versus maternal breast milk. DATA COLLECTION AND ANALYSIS: Two review authors planned independently to assess trial eligibility and risk of bias, and extract data. We planned to analyse treatment effects as described in the individual trials and report risk ratios and risk differences for dichotomous data, and mean differences for continuous data, with 95% confidence intervals. We planned to use a fixed-effect model in meta-analyses and to explore potential causes of heterogeneity in subgroup analyses. We planned to use the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We did not identify any eligible trials. AUTHORS' CONCLUSIONS: There are no trials of formula versus maternal breast milk for feeding preterm or low birth weight infants. Such trials are unlikely to be conducted because of the difficulty of allocating an alternative form of nutrition to an infant whose mother wishes to feed with her own breast milk. Maternal breast milk remains the default choice of enteral nutrition because observational studies, and meta-analyses of trials comparing feeding with formula versus donor breast milk, suggest that feeding with breast milk has major immuno-nutritional advantages for preterm or low birth weight infants.

Nutrient-enriched formula versus standard formula for preterm infants.

BACKGROUND: Preterm infants may accumulate nutrient deficits leading to extrauterine growth restriction. Feeding preterm infants with nutrient-enriched rather than standard formula might increase nutrient accretion and growth rates and might improve neurodevelopmental outcomes. OBJECTIVES: To compare the effects of feeding with nutrient-enriched formula versus standard formula on growth and development of preterm infants. SEARCH METHODS: We used the Cochrane Neonatal standard search strategy. This included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 11), MEDLINE, Embase, and the Cumulative Index to Nursing and Allied Health Literature (until November 2018), as well as conference proceedings, previous reviews, and clinical trials databases. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials that compared feeding preterm infants with nutrient-enriched formula (protein and energy plus minerals, vitamins, or other nutrients) versus standard formula. DATA COLLECTION AND ANALYSIS: We extracted data using the Cochrane Neonatal standard methods. Two review authors separately evaluated trial quality and extracted and synthesised data using risk ratios (RRs), risk differences, and mean differences (MDs). We assessed certainty of evidence at the outcome level using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods. MAIN RESULTS: We identified seven trials in which a total of 590 preterm infants participated. Most participants were clinically stable preterm infants of birth weight less than 1850 g. Few participants were extremely preterm, extremely low birth weight, or growth restricted at birth. Trials were conducted more than 30 years ago, were formula industry funded, and were small with methodological weaknesses (including lack of masking) that might bias effect estimates. Meta-analyses of in-hospital growth parameters were limited by statistical heterogeneity. There is no evidence of an effect on time to regain birth weight (MD -1.48 days, 95% confidence interval (CI) -4.73 to 1.77) and low-certainty evidence suggests that feeding with nutrient-enriched formula increases in-hospital rates of weight gain (MD 2.43 g/kg/d, 95% CI 1.60 to 3.26) and head circumference growth (MD 1.04 mm/week, 95% CI 0.18 to 1.89). Meta-analysis did not show an effect on the average rate of length gain (MD 0.22 mm/week, 95% CI -0.70 to 1.13). Fewer data are available for growth and developmental outcomes assessed beyond infancy, and these do not show consistent effects of nutrient-enriched formula feeding. Data from two trials did not show an effect on Bayley Mental Development Index scores at 18 months post term (MD 2.87, 95% CI -1.38 to 7.12; moderate-certainty evidence). Infants who received nutrient-enriched formula had higher Bayley Psychomotor Development Index scores at 18 months post term (MD 6.56. 95% CI 2.87 to 10.26; low-certainty evidence), but no evidence suggested an effect on cerebral palsy (typical RR 0.79, 95% CI 0.30 to 2.07; 2 studies, 377 infants). Available data did not indicate any other benefits or harms and provided low-certainty evidence about the effect of nutrient-enriched formula feeding on the risk of necrotising enterocolitis in preterm infants (typical RR 0.72, 95% CI 0.41 to 1.25; 3 studies, 489 infants). AUTHORS' CONCLUSIONS: Available trial data show that feeding preterm infants nutrient-enriched (compared with standard) formulas has only modest effects on growth rates during their initial hospital admission. No evidence suggests effects on long-term growth or development. The GRADE assessment indicates that the certainty of this evidence is low, and that these findings should be interpreted and applied with caution. Further randomised trials would be needed to resolve this uncertainty.

Evaluation of the Quality of Perinatal Trials: Making the GRADE.

BACKGROUND: Assessing the quality of clinical research is a key evidence-based practice skill. Clinicians, guideline producers, policy makers, service commissioners, and families need to have a sense of the validity, applicability, and certainty of research evidence when determining how it should inform their decision-making and practice. METHODS: We consider the various methodological and study design factors that contribute to the validity and applicability of clinical research findings. We describe the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) methodology and discuss how this approach is used to assess and report certainty of evidence and strength of recommendations. RESULTS: The randomized controlled trial (RCT) is the gold standard method for assessing interventions because randomization balances prognostic characteristics between comparison groups. The GRADE approach considers evidence from RCTs as high quality, but acknowledges that the quality and level of certainty of trial evidence may be "downgraded" based on consideration of threats across 5 domains: risk of bias in included trials, inconsistency between trials in outcome estimates, indirectness of the evidence, imprecision of estimates, and likelihood of publication bias. CONCLUSIONS: Structured critical appraisal using GRADE methods to assess risk of bias and other threats to the internal and external validity of RCTs and systematic reviews and meta-analyses of their data facilitates transparency and consistency in using evidence to inform policy and practice.

Immunonutrition for Preterm Infants.

Care and outcomes for very preterm infants continue to improve, but important causes of mortality and acute and long-term morbidity associated with prolonged hospitalisation remain. Necrotising enterocolitis (NEC) and late-onset infection have emerged as the major causes of death beyond the early neonatal period and of neurodisability in very preterm infants. Although the pathogenesis of these conditions is incompletely understood, it appears to be related to the content and mode of delivery of the enteral diet, particularly the impact of immunonutrients from human breast milk on the microbial and metabolic balance within the immature intestine. Evidence exists to support investment in measures to help mothers to express breast milk as the primary source of nutrition for their very preterm infants. In the absence of maternal milk, pasteurised donor breast milk provides protection against NEC, but its nutritive adequacy is not clear and its cost-effectiveness is uncertain. Supplementation with individual immunonutrients, including immunoglobulins and lactoferrin, has not been shown to be effective in preventing NEC or infection in randomised controlled trials. The evidence base for prebiotics and probiotics is stronger, but concerns exist about the choice, safety and availability of formulations. Other strategies - including avoidance of drugs such as gastric acid suppressants that compromise innate immunity, as well as evidence-based progressive feeding strategies that reduce exposure to invasive interventions - are emerging as key components of care packages to reduce the burden of NEC, infection and associated growth and developmental faltering for very preterm infants.

Mind the (support) gap: supporting academic trainees through peer networks.

Academic Foundation Programme (AFP) trainees face challenges in making the most of the research opportunities available to them. Improved support for trainees throughout the AFP may result in improved outcomes and increase retention of clinical academic trainees. Peer support may address some of the challenges faced by AFP trainees at this early stage of their careers. A Plan-Do-Study-Act (PDSA) approach was used to design and implement a peer support programme for AFP trainees in paediatrics. Feedback from recent AFP graduates was used to identify challenges and possible solutions, which were then incorporated into the programme. Trainee views informed the format of the support offered, especially the role of trainee coordinator and importance of regular meetings. The PDSA approach facilitated constant re-evaluation of the programme, which continued to evolve over several years. Peer support is highly valued by AFP trainees, who use the network to obtain information, as well as concrete assistance, and emotional support from their peers. Such networks are not self-perpetuating, and a significant commitment is required from fellow trainees to ensure the success of the network.

Ethical Issues in Perinatal Clinical Research.

BACKGROUND: Perinatal clinical research to improve the quality of care and outcomes for newborn infants relies on transparency, trust, and respect for the autonomy and well-being of study participants and their families. METHODS: Here we consider the underpinning principles of ethical research with a focus on perinatal clinical research in the acute care or emergency setting where particular challenges to parental engagement and informed consent exist. RESULTS: Several approaches to improving the validity of the consent process for perinatal research have been proposed and evaluated. These include consent waiver, antenatal consent, deferred consent preceded by verbal assent, and continuous consent. These have strengths and weaknesses and uncertainty remains about their validity and acceptability in certain research contexts. Prior exploration with parents and parent-advocacy groups of approaches to engagement and consent, and independent evaluation and ongoing monitoring of research studies, can enhance adherence to the ethical principles of justice and autonomy, and ensure that benefits to participants and their families exceed harm. CONCLUSIONS: High-quality research and ethics are interdependent. Only research that meets ethical standards can be regarded as valid and applicable, and only research designs that are methodologically rigorous and appropriate can be regarded as ethical.

Extreme warfarin hypersensitivity after oophorectomy.

We report the case of a woman who developed unexplained warfarin hypersensitivity after undergoing surgery to remove her ovaries. Presurgery, the patient's international normalised ratios (INR) control was stable and uneventful but 11 days after her operation she presented with extremely high (frequently ≥10) INR. Warfarin was discontinued on day 24 postoperation but 11 days later the plasma warfarin concentration was high at 4.8 mg/l (therapeutic range 0.7-2.3 mg/l). After cessation of warfarin, she required frequent doses of oral and intravenous vitamin K1 (totalling 48 mg) as well as two doses of prothrombin complex concentrate to normalise the INR. The patient was switched from warfarin to heparin, then to dabigatran with no further thrombosis or bleeding. While on heparin, the kinetics of warfarin elimination and vitamin K status were found to be normal and the reason for the onset of the extreme sensitivity to warfarin remains unknown.