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ELFIN, the United Kingdom preterm lactoferrin trial: interpretation and future questions 1.
Berrington, JE, McGuire, W, Embleton, ND
Biochemistry and cell biology = Biochimie et biologie cellulaire. 2021;(1):1-6
Abstract
Results from previous studies have suggested that supplemental bovine lactoferrin (BLF) given to preterm infants (<32 weeks gestation) reduces late-onset sepsis (LOS) and necrotising enterocolitis (NEC). The Enteral Lactoferrin in Neonates (ELFIN) study, performed in the UK, aimed to further address this issue with a well powered double-blind placebo controlled trial of >2200 preterm infants. The results from ELFIN did not demonstrate a reduction in LOS or NEC, or several other clinically important measures. Of the 1093 infants, 316 (29%) in the intervention group developed late-onset sepsis versus 334 (31%) of 1089 in the control group, with an adjusted risk ratio of 0.95 (95% CI = 0.86-1.04; p = 0.233). Reasons for the differences in ELFIN trial results and other studies may include population differences, the routine use of antifungal prophylaxis in the UK, timing of administration of the lactoferrin in relation to disease onset, or specific properties of the lactoferrin used in the different trials. The UK National Institutes for Health Research funded "Mechanisms Affecting the Guts of Preterm Infants in Enteral feeding trials" (MAGPIE) study is further exploring the use of lactoferrin, and the results should be available soon.
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Challenges of a simplified opt-out consent process in a neonatal randomised controlled trial: qualitative study of parents' and health professionals' views and experiences.
McLeish, J, Alderdice, F, Robberts, H, Cole, C, Dorling, J, Gale, C, ,
Archives of disease in childhood. Fetal and neonatal edition. 2021;(3):244-250
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Abstract
BACKGROUND More effective recruitment strategies like alternative approaches to consent are needed to facilitate adequately powered trials. Witholding Enteral feeds Around Transfusion was a multicentre, randomised, pilot trial that compared withholding and continuing feeds around transfusion. The primary clinical outcome was necrotising enterocolitis. The trial used simplified opt-out consent with concise parent information and no consent form. OBJECTIVE To explore the views and experiences of parents and health professionals on the acceptability and feasibility of opt-out consent in randomised comparative effectiveness trials. METHODS A qualitative, descriptive interview-based study nested within a randomised trial. Semistructured interview transcripts were analysed using inductive thematic analysis. SETTING Eleven neonatal units in England. PARTICIPANTS Eleven parents and ten health professionals with experience of simplified consent. RESULTS Five themes emerged: 'opt-out consent operationalised as verbal opt-in consent', 'opt-out consent normalises participation while preserving parental choice', 'opt-out consent as an ongoing process of informed choice', 'consent without a consent form' and 'choosing to opt out of a comparative effectiveness trial', with two subthemes: 'wanting "normal care"' and 'a belief that feeding is better'. CONCLUSION Introducing a novel form of consent proved challenging in practice. The principle of a simplified, opt-out approach to consent was generally considered feasible and acceptable by health professionals for a neonatal comparative effectiveness trial. The priority for parents was having the right to decide about trial participation, and they did not see opt-out consent as undermining this. Describing a study as 'opt-out' can help to normalise participation and emphasise that parents can withdraw consent.
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Efficacy of Docosahexaenoic Acid for the Prevention of Necrotizing Enterocolitis in Preterm Infants: A Randomized Clinical Trial.
Bernabe-García, M, Calder, PC, Villegas-Silva, R, Rodríguez-Cruz, M, Chávez-Sánchez, L, Cruz-Reynoso, L, Mateos-Sánchez, L, Lara-Flores, G, Aguilera-Joaquín, AR, Sánchez-García, L
Nutrients. 2021;(2)
Abstract
Necrotizing enterocolitis (NEC) is an inflammatory bowel disease and a leading cause of morbidity and mortality in preterm infants. In this study, a randomized double-blind parallel-group (1:1) trial was carried out in two neonatal intensive care units of two tertiary hospitals. Two hundred and twenty-five preterm newborns with an expected functional gastrointestinal tract were recruited and received an enteral dose of 75 mg of docosahexaenoic acid (DHA)/kg body weight or high-oleic sunflower oil daily for 14 days from the first enteral feed after birth. Confirmed NEC was evaluated with Bell's scale from stage ≥ IIa. Two hundred and fourteen randomized infants were analyzed in terms of the intent-to-treat (DHA-group: n = 105; control-group: n = 109); data for two hundred infants were analysed per protocol. Confirmed NEC was lower in infants from the DHA-group compared with the control-group (0/100 vs. 7/100; p = 0.007), with RR = 0.93 (95% CI 0.881 to 0.981), risk difference = -7%, (95% CI -12.00 to -1.99), and number needed-to-treat = 15 (95% CI 8.3 to 50). Intent-to-treat analysis showed a lower level of treatment failure in the DHA-group compared with the control-group (6/105 (6%) vs. 16/109 (15%); p = 0.03, RR = 0.905, (95% CI 0.826 to 0.991)). The results after multivariate-regression analysis remained significant. Adverse events (apart from the incidence of NEC) were not different between groups. A daily dose of DHA for 14 days starting with the first enteral feed may prevent NEC in preterm infants.
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Effect of enteral erythropoietin on feeding-related complications in preterm newborns: A pilot randomized controlled study.
Omar, OM, Massoud, MN, Ghazal, H, Hassouna, H, Somaa, MF
Arab journal of gastroenterology : the official publication of the Pan-Arab Association of Gastroenterology. 2020;(1):37-42
Abstract
BACKGROUND AND STUDY AIMS To evaluate the effects of enteral administration of recombinant human erythropoietin (rhEPO) on feeding-related complications in preterm infants. PATIENTS AND METHODS This double-blind, randomized controlled pilot study enrolled 120 preterm infants born ≤ 32 weeks' gestation who were admitted to the neonatal intensive care unit in a tertiary hospital; 60 patients randomly received recombinant human erythropoietin while the other 60 received placebo. Newborns who underwent cardiopulmonary resuscitation, infants with genetic syndromes, infants with inborn errors of metabolism, infants with major congenital or acquired gastrointestinal tract malformations, infants with previous use of parenteral growth factors such as recombinant human erythropoietin and granulocyte-macrophage colony-stimuating factor (GM-CSF) and infants previously treated with intravenous immunoglobulin were excluded. Overall, 48 patients withdrew from the study because of intravenous haematopoietic growth factor intake or death before treatment was completed. A total of 72 preterm infants remained in the study: 36 preterm infants in the erythropoietin (EPO) group, and 36 preterm infants in the placebo group. The day that enteral feeding was successfully started, the time to establishing one-half, two-thirds, and full enteral feedings (reaching at least 150 mL/kg/day), the number of episodes of feeding intolerance, the time to regain birth weight and the incidence of necrotizing enterocolitis (NEC) were recorded. RESULTS Both groups showed no significant difference in the time to achieve one-half, two-thirds, or full enteral feeding, no signs of feeding intolerance, and no cases of NEC were recorded. CONCLUSION Enteral erythropoietin does not appear to affect feeding intolerance or NEC incidence.
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Does fortification of pasteurized donor human milk increase the incidence of necrotizing enterocolitis among preterm neonates? A randomized controlled trial.
Adhisivam, B, Kohat, D, Tanigasalam, V, Bhat, V, Plakkal, N, Palanivel, C
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2019;(19):3232-3237
Abstract
Objective: To compare the effect of fortified pasteurized donor human milk (PDHM) versus unfortified PDHM on the incidence of necrotizing enterocolitis (NEC) and immediate outcome among preterm neonates. Methods: This randomized controlled trial (RCT) conducted in a tertiary care teaching hospital, south India included 80 healthy preterm neonates randomized to two groups (Group A and B). Neonates in Group A and B were fed with fortified PDHM and unfortified PDHM, respectively. Neonates in both groups were managed uniformly as per standard NICU protocol. The primary outcome was the incidence of NEC and the secondary outcomes included severity of NEC, incidence of sepsis, mortality, duration of hospital stay, number of days to reach full enteral feeds and weight gain. Neonates were followed up for 28 days or discharge whichever was earlier. Results: The baseline maternal and neonatal characteristics in both groups were comparable. There was no increase in incidence of NEC in fortified PDHM group compared to unfortified PDHM group (2.5 versus 7.5%, p = .31). Severity of NEC, incidence of sepsis, mortality, duration of hospital stay, number of days to reach full enteral feeds and weight gain were also similar in both groups. Conclusions: Standard fortification of PDHM does not increase the incidence of NEC among preterm neonates.
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Bifidobacterium breve BBG-001 in very preterm infants: a randomised controlled phase 3 trial.
Costeloe, K, Hardy, P, Juszczak, E, Wilks, M, Millar, MR, ,
Lancet (London, England). 2016;(10019):649-660
Abstract
BACKGROUND Probiotics may reduce necrotising enterocolitis and late-onset sepsis after preterm birth. However, there has been concern about the rigour and generalisability of some trials and there is no agreement about whether or not they should be used routinely. We aimed to test the effectiveness of the probiotic Bifidobacterium breve BBG-001 to reduce necrotising enterocolitis, late-onset sepsis, and death in preterm infants. METHODS In this multicentre, randomised controlled phase 3 study (the PiPS trial), we recruited infants born between 23 and 30 weeks' gestational age within 48 h of birth from 24 hospitals in southeast England. Infants were randomly assigned (1:1) to probiotic or placebo via a minimisation algorithm randomisation programme. The probiotic intervention was B breve BBG-001 suspended in dilute elemental infant formula given enterally in a daily dose of 8·2 to 9·2 log10 CFU; the placebo was dilute infant formula alone. Clinicians and families were masked to allocation. The primary outcomes were necrotising enterocolitis (Bell stage 2 or 3), blood culture positive sepsis more than 72 h after birth; and death before discharge from hospital. All primary analyses were by intention to treat. This trial is registered with ISRCTN, number 05511098 and EudraCT, number 2006-003445-17. FINDINGS Between July 1, 2010, and July 31, 2013, 1315 infants were recruited; of whom 654 were allocated to probiotic and 661 to placebo. Five infants had consent withdrawn after randomisation, thus 650 were analysed in the probiotic group and 660 in the placebo group. Rates of the primary outcomes did not differ significantly between the probiotic and placebo groups. 61 infants (9%) in the probiotic group had necrotising enterocolitis compared with 66 (10%) in the placebo group (adjusted risk ratio 0·93 (95% CI 0·68-1·27); 73 (11%) infants in the probiotics group had sepsis compared with 77 (12%) in the placebo group (0·97 (0·73-1·29); and 54 (8%) deaths occurred before discharge home in the probiotic group compared with 56 (9%) in the placebo group (0·93 [0·67-1·30]). No probiotic-associated adverse events were reported. INTERPRETATION There is no evidence of benefit for this intervention in this population; this result does not support the routine use of B breve BBG-001 for prevention of necrotising enterocolitis and late-onset sepis in very preterm infants. FUNDING UK National Institute for Health Research Health Technology Assessment programme.
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Oral lactoferrin to prevent nosocomial sepsis and necrotizing enterocolitis of premature neonates and effect on T-regulatory cells.
Akin, IM, Atasay, B, Dogu, F, Okulu, E, Arsan, S, Karatas, HD, Ikinciogullari, A, Turmen, T
American journal of perinatology. 2014;(12):1111-20
Abstract
OBJECTIVE Lactoferrin (LF) is effective in the prevention of sepsis in very low birth weight (VLBW) neonates. T-regulatory cells (Tregs) are important subsets of T lymphocytes that control pathogen-specific immune responses and are essential for intestinal immune homoeostasis. The aim of the present study is to determine whether oral LF at a dosage of 200 mg/d reduces nosocomial sepsis episodes and necrotizing enterocolitis (NEC) in premature infants and to evaluate the possible effects of LF on Treg levels. STUDY DESIGN In this prospective, placebo-controlled, double-blind, randomized trial, infants either VLBW or born before 32 weeks were assigned to receive either placebo (n = 25), or 200 mg LF (n = 25) daily throughout hospitalization. Episodes of culture proven nosocomial sepsis and NEC were recorded. The level of FOXP3 + CD4 + CD25hi lymphocytes was studied by flow cytometry at birth and discharge. A third comparison was made with healthy term neonates (n = 16). RESULTS Fewer sepsis episodes were observed in LF-treated infants (4.4 vs. 17.3/1,000 patient days, p = 0.007) with none developing NEC, without statistical significance. Treg levels at birth and discharge were similar, while preterm infants showed significantly lower levels than term controls. However, individual increases in Treg levels were higher in the LF group. CONCLUSION LF prophylaxis reduced nosocomial sepsis episodes. Treg levels in preterm infants were lower than in term infants and an increase of Treg levels under LF prophylaxis was observed. Increase in Treg levels can be the mechanism for protective effects of LF on nosocomial sepsis.
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Effect of Bifidobacterium breve M-16V supplementation on fecal bifidobacteria in preterm neonates--a randomised double blind placebo controlled trial.
Patole, S, Keil, AD, Chang, A, Nathan, E, Doherty, D, Simmer, K, Esvaran, M, Conway, P
PloS one. 2014;(3):e89511
Abstract
BACKGROUND Probiotic supplementation significantly reduces the risk of necrotising enterocolitis (NEC) and all cause mortality in preterm neonates. Independent quality assessment is important before introducing routine probiotic supplementation in this cohort. AIM: To assess product quality, and confirm that Bifidobacterium breve (B. breve) M-16V supplementation will increase fecal B. breve counts without adverse effects. METHODS AND PARTICIPANTS Strain identity (16S rRNA gene sequencing), viability over 2 year shelf-life were confirmed, and microbial contamination of the product was ruled out. In a controlled trial preterm neonates (Gestation <33 weeks) ready to commence or on feeds for <12 hours were randomly allocated to either B. breve M-16V (3×109 cfu/day) or placebo (dextrin) supplementation until the corrected age 37 weeks. Stool samples were collected before (S1) and after 3 weeks of supplementation (S2) for studying fecal B. breve levels using quantitative PCR (Primary outcome). Secondary outcomes included total fecal bifidobacteria and NEC≥Stage II. Categorical and continuous outcomes were analysed using Chi-square and Mann-Whitney tests, and McNemar and Wilcoxon signed-rank tests for paired comparisons. RESULTS A total of 159 neonates (Probiotic: 79, Placebo: 80) were enrolled. Maternal and neonatal demographic characteristics were comparable between the groups. The proportion of neonates with detectable B. breve increased significantly post intervention: Placebo: [S1:2/66 (3%), S2: 25/66 (38%), p<0.001] Probiotic: [S1: 29/74 (40%), S2: 67/74 (91%), p<0.001]. Median S1 B. breve counts in both groups were below detection (<4.7 log cells x g(-1)), increasing significantly in S2 for the probiotic group (log 8.6) while remaining <4.7 log in the control group (p<0.001). There were no adverse effects including probiotic sepsis and no deaths. NEC≥Stage II occurred in only 1 neonate (placebo group). CONCLUSION B. breve M-16V is a suitable probiotic strain for routine use in preterm neonates. TRIAL REGISTRATION Australia New Zealand Clinical Trial Registry ACTRN 12609000374268.
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Probiotic supplementation in mothers of very low birth weight infants.
Benor, S, Marom, R, Ben Tov, A, Armoni Domany, K, Zaidenberg-Israeli, G, Dollberg, S
American journal of perinatology. 2014;(6):497-504
Abstract
OBJECTIVE Oral probiotic supplementation reduces the risk of necrotizing enterocolitis (NEC) in preterm infants. Concerns about safety and purity of probiotic preparations have limited their use in preterm infants. The authors administered probiotic bacteria to mothers of preterm infants, thereby avoiding the risks of direct exposure of infants to probiotic bacteria. DESIGN This prospective, randomized, double blind, placebo-controlled trial at the Tel Aviv Medical Center (June 2007-November 2009) examined the effects of maternal oral probiotic supplementation on the incidence of NEC, death, and sepsis in very low birth weight (VLBW) infants fed with maternal breast milk. Mothers were assigned to supplementation with Lactobacillus acidophilus and Bifidobacteria lactis 2 × 10(E) [DOSAGE ERROR CORRECTED] CFU/d or to placebo starting from 1 to 3 days postpartum. The primary outcome measures were NEC, sepsis, and death. RESULTS In total 49 mothers of 58 VLBW infants were recruited. A total of 25 infants were in the probiotic group and 33 in the placebo group. The overall incidence of Bell stage II to III NEC was 12%, with an incidence of 4% in the infants of the probiotic group and 18.2% in the placebo group (p = 0.12), respectively. Sepsis and mortality rates were similar. CONCLUSION Postpartum maternal supplementation with probiotic bacteria may decrease the incidence of NEC in breastfed infants.
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Effect of oral probiotics supplementation in the prevention of necrotizing enterocolitis among very low birth weight preterm infants.
Saengtawesin, V, Tangpolkaiwalsak, R, Kanjanapattankul, W
Journal of the Medical Association of Thailand = Chotmaihet thangphaet. 2014;:S20-5
Abstract
BACKGROUND Necrotizing enterocolitis (NEC) is the most serious gastrointestinal problem in very low birth weight preterm infants. Multiple risk factors activate the inflammatory cascade leading to high expressions of pro-inflammatory mediators causing bowel injury in NEC. The anti-inflammatory effect of probiotics is due to the inhibition and reduction of inflammatory signal in intestinal epithelium. OBJECTIVE To evaluate the efficacy of probiotics supplementation in the prevention of NEC among very low birth weight preterm infants. STUDY DESIGN A prospective randomized controlled trial. MATERIAL AND METHOD All preterm infants with gestational age less than or equal to 34 weeks and birth weight less than or equal to 1,500 grams admitted in neonatal care unit, Queen Sirikit National Institute of Child Health during June 1st, 2012 and January 31th, 2013 were enrolled in this study. They were randomized into two groups, study and control group. Infants in the study group were fed Infloran (Lactobacillus acidophilus 1 x 10(9) and Bifidobacterium bifidum 1 x 10(9) organisms) dose 125 mg/kg/dose twice a day with breast milk or premature formula from the start of feeding until 6 weeks or discharge. Infants in the control group were fed with either breast milk or premature formula alone. The primary outcome was NEC stage ≥ 2. RESULTS Sixty infants completed the study, 31 infants in the study group and 29 infants in the control group. The baseline characteristic data of infants were similar except for more males in the present study group. Incidence of NEC stage ≥ 2 were similar in both the groups, 3.2 vs. 3.4% (p = 0.74). There were no deaths during the study period. Days to reach full feeding, 150 ml/kg/day, were no differences between the two groups, 12.03 ± 5.49 days vs. 13.76 ± 8.25 days (p = 0.31). No adverse effects such as sepsis, flatulence or diarrhea were noted. CONCLUSION In this study, there was no difference in incidence of NEC stage ≥ 2 between the two groups. No adverse effects of probiotics supplementation were observed.