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Early application of caffeine improves white matter development in very preterm infants.
Liu, S, Zhang, X, Liu, Y, Yuan, X, Yang, L, Zhang, R, Zhang, X, Wang, X, Xu, F, Zhu, C
Respiratory physiology & neurobiology. 2020;:103495
Abstract
The aim of this study was to evaluate the effect of early prophylactic caffeine treatment on white matter development in very preterm infants using cerebral magnetic resonance imaging. A total of 194 preterm infants (≤32 weeks gestational age) were randomly assigned to the caffeine (n = 96) or placebo (n = 93) treatment group and administered with either caffeine or placebo within 72 h after birth. Cerebral magnetic resonance imaging, including diffuse tensor imaging examination, was performed at 34-36 weeks of corrected gestational age, and the fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were measured. In total, 160 infants were included in the final analysis, including 80 cases in the placebo group and 80 cases in the caffeine group. There were fewer instances of apnea of prematurity and shorter assisted ventilation times for infants in the caffeine group compared to the placebo group (p < 0.05). Infants in the caffeine group had significantly higher FA values in white matter, including the posterior limb of the internal capsule, the corpus callosum, the frontal, occipital, and parietal white matter, the cerebellum, and the cerebral peduncle, compared to infants in the placebo group. ADC values in the above white matter areas were significantly reduced in the caffeine group. However, there were no significant differences regarding the FA and ADC in the gray matter between the two groups. These results demonstrate that early administration of caffeine improves white matter micro-structural development in preterm infants, but with no significant effect on short-term complications related to prematurity.
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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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Acute hemodynamic effects of methylxanthine therapy in preterm neonates: Effect of variations in subgroups.
M, S, Nayak, K, Lewis, LES, Kamath, A, Purkayastha, J
Journal of tropical pediatrics. 2019;(3):264-272
Abstract
BACKGROUND Methylxanthines have cardiac stimulant effects. The current study aimed to compare acute hemodynamic changes between caffeine and aminophylline in ≤34 weeks' preterm neonates. METHODS The study was performed using information on echocardiography measurements from preterm neonates recruited for apnea of prematurity (75 of 240) and preventing extubation failure (113 of 156) studies. The neonates were randomized either to the caffeine or aminophylline groups. Neonates with no maintenance followed by loading doses with both the methylxanthines (caffeine and aminophylline) and incomplete echocardiography examination were excluded. RESULTS Cardiac parameters were found to be similar between groups. The heart rate was higher among the aminophylline-treated neonates (p < 0.001) than among the caffeine-treated ones. End-systolic volume was higher among both caffeine- (p < 0.001) and aminophylline-treated neonates (p = 0.001) when compared with pretreatment values. End-diastolic volume was statistically higher in both groups' neonates (p = 0.01). The odds of increase in cardiac output was higher; however, increase in ejection fraction was less in caffeine-treated small-for-gestation-age neonates. CONCLUSION Caffeine has similar effects on cardiac parameters as aminophylline; however, caffeine-treated small-for-gestation stratification gave rise to significant cardiac variations.
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Controlled Trial of Two Incremental Milk-Feeding Rates in Preterm Infants.
Dorling, J, Abbott, J, Berrington, J, Bosiak, B, Bowler, U, Boyle, E, Embleton, N, Hewer, O, Johnson, S, Juszczak, E, et al
The New England journal of medicine. 2019;(15):1434-1443
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Abstract
BACKGROUND Observational data have shown that slow advancement of enteral feeding volumes in preterm infants is associated with a reduced risk of necrotizing enterocolitis but an increased risk of late-onset sepsis. However, data from randomized trials are limited. METHODS We randomly assigned very preterm or very-low-birth-weight infants to daily milk increments of 30 ml per kilogram of body weight (faster increment) or 18 ml per kilogram (slower increment) until reaching full feeding volumes. The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months. Secondary outcomes included components of the primary outcome, confirmed or suspected late-onset sepsis, necrotizing enterocolitis, and cerebral palsy. RESULTS Among 2804 infants who underwent randomization, the primary outcome could be assessed in 1224 (87.4%) assigned to the faster increment and 1246 (88.7%) assigned to the slower increment. Survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 of 1224 infants (65.5%) assigned to the faster increment and 848 of 1246 (68.1%) assigned to the slower increment (adjusted risk ratio, 0.96; 95% confidence interval [CI], 0.92 to 1.01; P = 0.16). Late-onset sepsis occurred in 414 of 1389 infants (29.8%) in the faster-increment group and 434 of 1397 (31.1%) in the slower-increment group (adjusted risk ratio, 0.96; 95% CI, 0.86 to 1.07). Necrotizing enterocolitis occurred in 70 of 1394 infants (5.0%) in the faster-increment group and 78 of 1399 (5.6%) in the slower-increment group (adjusted risk ratio, 0.88; 95% CI, 0.68 to 1.16). CONCLUSIONS There was no significant difference in survival without moderate or severe neurodevelopmental disability at 24 months in very preterm or very-low-birth-weight infants with a strategy of advancing milk feeding volumes in daily increments of 30 ml per kilogram as compared with 18 ml per kilogram. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; SIFT Current Controlled Trials number, ISRCTN76463425.).
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Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial.
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Lancet (London, England). 2019;(10170):423-433
Abstract
BACKGROUND Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. METHODS In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002. FINDINGS We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86-1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention. INTERPRETATION Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants. FUNDING UK National Institute for Health Research Health Technology Assessment programme (10/57/49).
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Adverse Maternal and Neonatal Outcomes in Indicated Compared with Spontaneous Preterm Birth in Healthy Nulliparas: A Secondary Analysis of a Randomized Trial.
Tita, AT, Doherty, L, Roberts, JM, Myatt, L, Leveno, KJ, Varner, MW, Wapner, RJ, Thorp, JM, Mercer, BM, Peaceman, A, et al
American journal of perinatology. 2018;(7):624-631
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OBJECTIVE To compare the risks of adverse maternal and neonatal outcomes associated with spontaneous (SPTB) versus indicated preterm births (IPTB). METHODS A secondary analysis of a multicenter trial of vitamin C and E supplementation in healthy low-risk nulliparous women. Outcomes were compared between women with SPTB (due to spontaneous membrane rupture or labor) and those with IPTB (due to medical or obstetric complications). A primary maternal composite outcome included: death, pulmonary edema, blood transfusion, adult respiratory distress syndrome (RDS), cerebrovascular accident, acute tubular necrosis, disseminated intravascular coagulopathy, or liver rupture. A neonatal composite outcome included: neonatal death, RDS, grades III or IV intraventricular hemorrhage (IVH), sepsis, necrotizing enterocolitis (NEC), or retinopathy of prematurity. RESULTS Of 9,867 women, 10.4% (N = 1,038) were PTBs; 32.7% (n = 340) IPTBs and 67.3% (n = 698) SPTBs. Compared with SPTB, the composite maternal outcome was more frequent in IPTB-4.4% versus 0.9% (adjusted odds ratio [aOR], 4.0; 95% confidence interval [CI], 1.4-11.8), as were blood transfusion and prolonged hospital stay (3.2 and 3.7 times, respectively). The frequency of composite neonatal outcome was higher in IPTBs (aOR, 1.8; 95% CI, 1.1-3.0), as were RDS (1.7 times), small for gestational age (SGA) < 5th percentile (7.9 times), and neonatal intensive care unit (NICU) admission (1.8 times). CONCLUSION Adverse maternal and neonatal outcomes were significantly more likely with IPTB than with SPTB.
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Dose-Response Effects of Early Vitamin D Supplementation on Neurodevelopmental and Respiratory Outcomes of Extremely Preterm Infants at 2 Years of Age: A Randomized Trial.
Salas, AA, Woodfin, T, Phillips, V, Peralta-Carcelen, M, Carlo, WA, Ambalavanan, N
Neonatology. 2018;(3):256-262
Abstract
BACKGROUND Many extremely preterm infants have low vitamin D concentrations at birth, but early childhood outcomes after vitamin D supplementation have not been reported. OBJECTIVE To determine a dose-response relationship between increasing doses of enteral vitamin D in the first 28 days after birth and cognitive scores at 2 years of age. METHODS In this phase II double-blind dose-response randomized trial, infants with gestational ages between 23 and 27 weeks were randomly assigned to receive placebo or a vitamin D dose of 200 or 800 IU/day from day 1 of enteral feeding to postnatal day 28. The primary outcome of this follow-up study was Bayley III cognitive score at 22-26 months of age. RESULTS Seventy of 80 survivors had a follow-up evaluation at 2 years of age (88%). There were no significant differences in cognitive scores between supplementation groups (p = 0.47). Cognitive scores did not differ between the higher vitamin D dose group and the placebo group (median difference favoring the 800 IU group: +5 points; 95% CI: -5 to 15; p = 0.23). The linear trend between increasing doses of vitamin D and reduction of neurodevelopmental impairment (placebo group: 54%; 200 IU group: 43%; 800 IU group: 30%; p = 0.08) or language impairment (placebo group: 64%; 200 IU group: 57%; 800 IU group: 45%; p = 0.15) was not statistically significant. Respiratory outcomes at 2 years of age (need for supplemental oxygen or asthma medications) did not differ between groups. CONCLUSION In extremely preterm infants, early vitamin D supplementation did not significantly improve cognitive scores. Though underpowered for clinically meaningful differences in early childhood outcomes, this trial may help determine dosing for further investigation of vitamin D supplementation.
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Effect of Differential Enteral Protein on Growth and Neurodevelopment in Infants <1500 g: A Randomized Controlled Trial.
Dogra, S, Thakur, A, Garg, P, Kler, N
Journal of pediatric gastroenterology and nutrition. 2017;(5):e126-e132
Abstract
OBJECTIVE The aim of the study was to determine whether higher enteral protein intake leads to improved head growth at 40 weeks postmenstrual age (PMA) in preterm infants <32 weeks or 1500 g. METHODS Randomized controlled trial in which 120 infants were assigned to either group A with higher enteral protein intake achieved by fortification with higher protein containing fortifier (1 g/100 mL expressed breast milk) or to group B with lower enteral protein intake where fortification was done with standard available protein fortifier (0.4 g /100 mL expressed breast milk). RESULTS The mean (standard deviation) protein intake was higher in group A as compared to group B; 4.2 (0.47) compared with 3.6 (0.37) g · kg · day, P < 0.001. At 40 weeks PMA, the mean (standard deviation) weekly occipitofrontal circumference gain was significantly higher in group A as compared to group B; 0.66 (0.16) compared with 0.60 (0.15) cm/week (mean difference 0.064, 95% confidence interval [0.004-0.123], [P = 0.04]). Weight growth velocity in group A was 11.95 (2.2) g · kg · day as compared to 10.78 (2.6) g · kg · day in group B (mean difference 1.10, 95% confidence interval [0.25-2.07], [P = 0.01]). No difference was observed in the length between the 2 groups. There was no difference in growth indices and neurodevelopmental outcomes at 12 to 18 months corrected age in the 2 groups. CONCLUSIONS Fortification of expressed human milk with fortifier containing higher protein results in better head growth and weight gain at 40 weeks PMA in preterm infants <32 weeks or 1500 g without any benefits on long-term growth and neurodevelopment at 12 to 18 months corrected age (CTRI/2014/06/004661).
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The Speed of Increasing milk Feeds: a randomised controlled trial.
Abbott, J, Berrington, J, Bowler, U, Boyle, E, Dorling, J, Embleton, N, Juszczak, E, Leaf, A, Linsell, L, Johnson, S, et al
BMC pediatrics. 2017;(1):39
Abstract
BACKGROUND In the UK, 1-2% of infants are born very preterm (<32 weeks of gestation) or have very low birth weight (<1500 g). Very preterm infants are initially unable to be fed nutritional volumes of milk and therefore require intravenous nutrition. Milk feeding strategies influence several long and short term health outcomes including growth, survival, infection (associated with intravenous nutrition) and necrotising enterocolitis (NEC); with both infection and NEC being key predictive factors of long term disability. Currently there is no consistent strategy for feeding preterm infants across the UK. The SIFT trial will test two speeds of increasing milk feeds with the primary aim of determining effects on survival without moderate or severe neurodevelopmental disability at 24 months of age, corrected for prematurity. The trial will also examine many secondary outcomes including infection, NEC, time taken to reach full feeds and growth. METHODS/DESIGN Two thousand eight hundred very preterm or very low birth weight infants will be recruited from approximately 30 hospitals across the UK to a randomised controlled trial. Infants with severe congenital anomaly or no realistic chance of survival will be excluded. Infants will be randomly allocated to either a faster (30 ml/kg/day) or slower (18 ml/kg/day) rate of increase in milk feeds. Data will be collected during the neonatal hospital stay on weight, infection rates, episodes of NEC, length of stay and time to reach full milk feeds. Long term health outcomes comprising vision, hearing, motor and cognitive impairment will be assessed at 24 months of age (corrected for prematurity) using a parent report questionnaire. DISCUSSION Extensive searches have found no active or proposed studies investigating the rate of increasing milk feeds. The results of this trial will have importance for optimising incremental milk feeding for very preterm and/or very low birth weight infants. No additional resources will be required to implement an optimal feeding strategy, and therefore if successful, the trial results could rapidly be adopted across the NHS at low cost. TRIAL REGISTRATION ISRCTN Registry; ISRCTN76463425 on 5 March, 2013.