A double-blinded randomized trial on growth and feeding tolerance with Saccharomyces boulardii CNCM I-745 in formula-fed preterm infants

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in formula-fed preterm infants" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "296" "paginaFinal" => "301" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Lingfen Xu, Yun Wang, Yang Wang, Jianhua Fu, Mei Sun, Zhiqin Mao, Yvan Vandenplas" "autores" => array:7 [ 0 => array:3 [ "nombre" => "Lingfen" "apellidos" => "Xu" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Yun" "apellidos" => "Wang" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Yang" "apellidos" => "Wang" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Jianhua" "apellidos" => "Fu" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Mei" "apellidos" => "Sun" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 5 => array:4 [ "nombre" => "Zhiqin" "apellidos" => "Mao" "email" => array:1 [ 0 => "maozq@sj-hospital.org" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 6 => array:3 [ "nombre" => "Yvan" "apellidos" => "Vandenplas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Department of Pediatrics, Shengjing Hospital, China Medical University, Shenyang, China" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Pediatrics, Qingdao Women and Children's Hospital, Qingdao, China" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "UZ Brussel, Department of Pediatrics, Vrije Universiteit Brussel, Brussels, Belgium" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Ensaio duplo-cego randomizado sobre crescimento e tolerância de alimentação com a Saccharomyces boulardii CNCM I-745 em neonatos prematuros alimentados com fórmula" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1604 "Ancho" => 1670 "Tamanyo" => 113831 ] ] "descripcion" => array:1 [ "en" => "Study flow chart." ] ] ] "textoCompleto" => "IntroductionThe gastrointestinal (GI) barrier function, gut motility, mucosal immunity, and digestive/absorptive capacity are all significantly underdeveloped in the preterm neonate.<a class="elsevierStyleCrossRef" href="#bib0135">1</a> Preterm infants have an increased risk of poor growth, nosocomial infections, and necrotizing enterocolitis (NEC), and of developing a different intestinal microbiota than healthy breast fed infants.<a class="elsevierStyleCrossRefs" href="#bib0135">1,2</a> The latter is related to a higher incidence of delivery through cesarean section, decreased exposure to maternal microbiota, increased exposure to organisms that colonize neonatal intensive care units (NICUs), antibiotics (multiple courses), and delay in enteral feeding.<a class="elsevierStyleCrossRef" href="#bib0145">3</a>The role for probiotics in the care of preterm newborns is debated. Probiotics are defined as “live microorganisms which, when administered in adequate amounts, confer a health benefit to the host”.<a class="elsevierStyleCrossRef" href="#bib0150">4</a> While reports of improved growth and a decreased incidence of NEC are enticing, many aspects on the mechanisms of action are still unclear.<a class="elsevierStyleCrossRefs" href="#bib0155">5,6</a> Studies have used different strains and dosages, making it difficult to draw evidence-based conclusions.<a class="elsevierStyleCrossRefs" href="#bib0155">5–7</a>Until now, researchers often selected strains belonging to bacterial species naturally present in the intestinal flora, such as lactobacilli and bifidobacteria.<a class="elsevierStyleCrossRef" href="#bib0170">8</a>Saccharomyces boulardii CNCM I-745 (S. boulardii) is a probiotic yeast isolated from the peel of fruits such as lychees, growing in Indochina.<a class="elsevierStyleCrossRef" href="#bib0175">9</a>S. boulardii has been poorly studied in preterm and low birth weight infants. The objective of the present study was to asses if S. boulardii administered to formula-fed preterm newborns >30 weeks of gestational age would improve weight gain and clinical outcome.MethodsPatient inclusionStable formula fed preterm neonates admitted to the NICU of the Shengjing Hospital of the China Medical University in Shenyang (China) were included in this prospective randomized controlled double-blinded study, performed from April to July 2013. Informed consent was obtained from the infants’ parents/guardians. The study protocol was approved by the University Hospital Ethical Committee.The sample size was calculated prior to the start of the study for a significance level of p<0.05 (two-sided), with a power of 80% (β=0.2) to estimate the needed sample size, and with a weight gain standard deviation of 9g/day in both groups and a weight gain difference between the two groups of 5g/day. This resulted in a sample size of 125 infants, considering a 20% drop out rate.Inclusion and exclusion criteriaInclusion criteria were hospital-born formula-fed infants with a gestational age of 30–37 weeks and a birth weight between 1500 and 2500g.Exclusion criteria were severe neonatal pathologies, such as severe birth complications, GI malformations, chromosomal abnormalities, known immunodeficiency, hydrops fetalis, central venous catheter, antifungal drugs, and probiotics. All included patients received parenteral nutrition and/or preterm formula. No neonates received mother's milk. Minimal enteral nutrition or trophic feeding was started as soon as possible at 1mL/kg/day. Minimal enteral feeding is the practice of feeding small volumes of enteral feed in order to stimulate the development of the immature GI tract of the preterm infant; it improves GI enzyme activity, hormone release, blood flow, motility, and microbial flora. Clinical benefits include improved milk tolerance, greater postnatal growth, reduced systemic sepsis, and shorter hospital stay.<a class="elsevierStyleCrossRef" href="#bib0180">10</a> As soon as minimal enteral feeding was tolerated, the patient was randomly allocated to one of two groups at a 1/1 ratio (S. boulardii or control group). Randomization was conducted according to a random computer-determined allocation order considering birth weight. Feeding volume was increased when it was well tolerated according to the local protocol.InterventionThe intervention group received S. boulardii CNCM I-745, administered two times per day as separate medication, not mixed with formula, at a dosage of 50mg/kg (Bioflor®; CMS Shenzhen Kangzhe Pharmaceutical Co. Ltd., Shenzhen, China; manufactured by Biocodex, Paris, France); 50mg is approximately 109 colony forming units (CFU). The dosage of the probiotic was derived from previous studies in neonates.<a class="elsevierStyleCrossRef" href="#bib0185">11</a> Nothing was administered to the control group. The study period ended at the 28th day after birth or when the infant was discharged from the hospital, if this was possible earlier. However, the minimal duration of the intervention was at least 7 days. Observational and routine clinical data were collected from all infants. Blinding was possible because the nursing staff who administered S. boulardii to the infants was not involved in the daily care and the attending neonatal team was unaware of the randomization assignments.OutcomePrimary outcomes were short-term growth parameters: weight gain (g/kg/day) and linear growth (cm/week). Secondary outcomes included: days of parenteral nutrition needed to reach full enteral feeding, maximal enteral feeding volume tolerated (mL/kg/day), and duration of hospitalization (days). Feeding intolerance was defined when vomiting and gastric residuals were considered too important. Complications were defined as incidence of NEC (defined as suspected or confirmed positive Bell stage II or more) and sepsis (defined as positive blood culture).<a class="elsevierStyleCrossRef" href="#bib0175">9</a>Statistics-registrationThe data were collected and entered into a statistical database (SPSS, version 16.0; IBM, Armonk, USA). The data are presented as mean±standard deviation. The demographic data and procedure variables were analyzed using the t-test or the chi-squared test. A p-value of <0.05 was considered to indicate a statistically significant difference. This study did not receive external funds, and was registered at the website <a id="intr0010" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/">https://clinicaltrials.gov</a> under the number <a id="intr0015" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT02310425">NCT02310425</a>.ResultsPatient descriptionA total of 125 formula-fed preterm neonates were enrolled and randomly allocated. Sixty-three patients received S. boulardii as soon as they could tolerate minimal enteral feeding and 62 neonates were included in the control group. In total, 25 (20%) patients were considered dropouts (12 [19.1%] in the S. boulardii group and 13 [20.1%] in the control group) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Reasons for dropout were withdrawal of consent (n=9), loss to follow-up (n=11), central venous catheter (n=1), congenital syphilis (n=1), and inappropriate inclusions (congenital intestinal atresia [n=2], trisomy 21 [n=1]). Fifty-one subjects could be analyzed in the intervention group and 49 in the control group. The characteristics of all neonates at study entry are listed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>, and did not show any statistically significant difference.<elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>S. boulardii was administered for the first time at 2.63 days after birth (range: day 1 to day 6; in 46 infants within 3 days, and in only five infants between day 4 and 6). The total number of days of S. boulardii administration averaged 25.3 days (range: 9–28 days).Feeding toleranceFormula intake at maximal enteral feeding (128.4±6.7 vs. 112.3±7.2mL/kg/day, p<0.05) was higher in the S. boulardii than in the control group, and the time needed to reach full enteral feeding (0.4±0.1 vs. 1.7±0.5 day, p<0.05) was shorter in the intervention than in the control group (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Growth and hospital stayThe weight gain in the S. boulardii group was 16.14±1.96g/kg/day versus 10.73±1.77g/kg/day (p<0.05) in the control group. There was no significant difference in linear growth, head circumference growth, incidence of abdominal distension, and incidence of sepsis (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). Hospital stay in the S. boulardii group was shorter (p=0.035) (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). No infants developed NEC.Adverse effectsNo preterms developed fungemia, and no adverse reactions to S. boulardii were reported.DiscussionThis study demonstrated that S. boulardii can safely be administered to preterm infants, and that it improves oral feeding tolerance and weight gain. In term infants, formula supplemented with Lactobacillus (L.) rhamnosus GG was shown to increase weight gain, but formulas supplemented with Bifidobacterium (B.) longum, B. animalis subsp. lactis, and L. reuteri did not.<a class="elsevierStyleCrossRefs" href="#bib0185">11–13</a> In preterm infants, administration of B. breve also improved weight gain.<a class="elsevierStyleCrossRef" href="#bib0200">14</a> The mechanisms by which weight gain is affected are not yet clear.S. boulardii is effective in the treatment of a number of GI disorders related to the presence of bacterial and viral pathogens.<a class="elsevierStyleCrossRef" href="#bib0205">15</a> It competes with pathogens for binding sites and produces a wide range of antimicrobial substances.<a class="elsevierStyleCrossRef" href="#bib0210">16</a>S. boulardii has the ability to produce polyamines, which are substances essential for cell growth and differentiation and enhance intestinal maturation, what is reflected in increased levels of enzyme expression.<a class="elsevierStyleCrossRef" href="#bib0215">17</a>S. boulardii is a yeast that significantly increases the activity of metabolic enzymes in the intestinal mucosa, stimulates the secretion of disaccharide enzymes, participates in the metabolism and absorption of carbohydrates, and stimulates secretory IgA production as the result of a trophic effect on intestinal mucosa.<a class="elsevierStyleCrossRef" href="#bib0220">18</a> In addition, S. boulardii promotes the stability of the intestinal microbiome and reduces the possibility of malabsorption caused by GI disorders.<a class="elsevierStyleCrossRef" href="#bib0225">19</a> Translocation of S. boulardii has not been reported; on the contrary, S. boulardii was reported to reduce bacterial translocation.<a class="elsevierStyleCrossRef" href="#bib0230">20</a> Based on these properties, it was hypothesized that S. boulardii could improve growth and clinical outcomes in preterm or low birth weight infants.Although several clinical trials strongly suggest a place for S. boulardii in the prevention and treatment of several GI diseases in adults and children, data in preterm infants are limited.<a class="elsevierStyleCrossRef" href="#bib0220">18</a>S. boulardii supplemented formula was shown to be well tolerated by preterm infants and to have beneficial effects on the GI microbiome, bringing it closer to that of breastfed babies.<a class="elsevierStyleCrossRef" href="#bib0185">11</a> Clinical trials in preterm infants also suggested that S. boulardii improved feeding tolerance and reduced the risk of sepsis.<a class="elsevierStyleCrossRefs" href="#bib0235">21,22</a> In order to achieve optimum growth for a preterm infant, the goal is to mimic intrauterine growth while obtaining a functional outcome comparable to term infants.<a class="elsevierStyleCrossRef" href="#bib0245">23</a> A gain in weight of 15–20g/kg/day, in length of 0.7–1.0cm/week, and in head circumference of 0.7cm/week is recommended.<a class="elsevierStyleCrossRefs" href="#bib0250">24,25</a> In the S. boulardii group, the average weight gain was 16.14g/kg/day, linear growth was 0.9cm/week, and head circumference increase was 0.7cm/week. Weight gain in the control group was 10.73g/kg/day, which is below the recommendation. The number of days to reach full enteral nutrition was shorter in the S. boulardii than in the control group. The better weight gain is likely to be related to the improvement of feeding tolerance. It was observed that the incidence of vomiting, gastric residual volume, and abdominal distension (“GI symptoms”, <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>) were decreased in the intervention group in comparison to the control group, although there was no statistical significant difference. The total hospital stay in the S. boulardii group was shorter than that in the control group.No significant difference was observed in linear growth and head circumference evolution, which could be related to the relative short intervention period of 1 month. Other limitations of this study are the lack of information on postnatal clinical characteristics of the neonates that could have been factors influencing the outcome, such as the ratio of patent ductus arteriosus, intraventricular hemorrhage, and others. Information on the number of infants with predisposing factors for NEC, sepsis, or other problems such as pre-eclampsia, antenatal steroid use, premature rupture of membranes, and caesarian birth are missing. The absence of breastfeeding is another weakness of the study.A recent Cochrane review reported on 24 trials on probiotics in preterm infants and concluded that the trials were highly variable with regard to enrollment criteria (birth weight, gestational age), baseline risk of NEC, timing, dose, formulation of the probiotics, and feeding regimens.<a class="elsevierStyleCrossRef" href="#bib0170">8</a> Enteral supplementation with probiotics significantly reduced the incidence of severe NEC (stage II or more) (typical relative risk [RR] 0.43, 95% confidence interval [CI] 0.33–0.56; 20 studies, 5529 infants) and mortality (typical RR 0.65, 95% CI 0.52–0.81; 17 studies, 5112 infants).<a class="elsevierStyleCrossRef" href="#bib0170">8</a> According to this meta-analysis, there was no evidence for a significant reduction of nosocomial sepsis (typical RR 0.91, 95% CI 0.80–1.03; 19 studies, 5338 infants).<a class="elsevierStyleCrossRef" href="#bib0170">8</a> In the present trial, there were no preterms who developed NEC; this is likely to be related to the fact that gestational age for inclusion was 30–37 weeks and that NEC occurs more frequently in infants born with a lesser gestational age. Previous clinical trials showed that S. boulardii supplementation did not reduce the incidence of death or NEC in very low birth weight infants, but improved feeding tolerance and reduced the risk of clinical sepsis, while adverse effects related to the intake of S. boulardii were not observed.<a class="elsevierStyleCrossRefs" href="#bib0235">21,22</a>S. boulardii has a protective effect against various enteric pathogens by two main mechanisms: production of factors that neutralize bacterial toxins and modulation of the host cell signaling pathway implicated in proinflammatory response during bacterial infection.<a class="elsevierStyleCrossRefs" href="#bib0220">18,19</a> In addition, S. boulardii can increase the activity of regulatory T cells and secretion of IgA of intestinal epithelial and crypt cells, improving intestinal protection through immune regulation.<a class="elsevierStyleCrossRef" href="#bib0220">18</a> In this study, there was no statistically significant difference in the incidence of sepsis between the two groups (4/51 vs. 6/49). This finding is in agreement with the Cochrane analysis, showing that the included trials reported no systemic infection with the supplemental probiotics organism.<a class="elsevierStyleCrossRef" href="#bib0170">8</a>S. boulardii fungemia has been reported in patients with deep central venous access.<a class="elsevierStyleCrossRef" href="#bib0220">18</a> In this clinical trial, there were no cases of fungemia, and no side effects occurred. The authors of the recent Cochrane review concluded that the updated review of available evidence strongly supports a change in practice, meaning that probiotics should be given to preterm infants to decrease the risk for NEC and mortality.<a class="elsevierStyleCrossRef" href="#bib0170">8</a>In conclusion, the results of the present study show that prophylactic use of S. boulardii in preterm infants accelerates weight gain and improves feeding tolerance. These data confirm a recent retrospective analysis concluding that probiotics improve feeding tolerance, leading to better overall growth in preterm infants.<a class="elsevierStyleCrossRef" href="#bib0260">26</a> It is the first time that better weight gain of preterm infants provided with S. boulardii has been demonstrated. Future double-blinded placebo-controlled trials are needed to confirm these data.Conflicts of interestY. Vandenplas is a consultant for United Pharmaceuticals and Biocodex. The others authors declare no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres655703" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Method" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec665321" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres655702" "titulo" => "Resumo" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusão" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec665322" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Patient inclusion" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Inclusion and exclusion criteria" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Intervention" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Outcome" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Statistics-registration" ] ] ] 6 => array:3 [ "identificador" => "sec0040" "titulo" => "Results" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Patient description" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Feeding tolerance" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Growth and hospital stay" ] 3 => array:2 [ "identificador" => "sec0060" "titulo" => "Adverse effects" ] ] ] 7 => array:2 [ "identificador" => "sec0065" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-05-21" "fechaAceptado" => "2015-08-10" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec665321" "palabras" => array:6 [ 0 => "Feeding (in)tolerance" 1 => "Growth" 2 => "Necrotizing enterocolitis" 3 => "Preterm infant" 4 => "Probiotic" 5 => "Sepsis" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec665322" "palabras" => array:6 [ 0 => "(In)Tolerância de alimentação" 1 => "Crescimento" 2 => "Enterocolite necrosante" 3 => "Neonato prematuro" 4 => "Probiótico" 5 => "Sepse" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "ObjectiveThe use of probiotics is increasingly popular in preterm neonates, as they may prevent necrotizing enterocolitis sepsis and improve growth and feeding tolerance. There is only limited literature on Saccharomyces boulardii CNCM I-745 (S. boulardii) in preterm infants. MethodA prospective, randomized, case-controlled trial with the probiotic S. boulardii (50mg/kg twice daily) was conducted in newborns with a gestational age of 30–37 weeks and a birth weight between 1500 and 2500g. Results125 neonates were enrolled; 63 in the treatment and 62 in the control group. Weight gain (16.14±1.96 vs. 10.73±1.77g/kg/day, p<0.05) and formula intake at maximal enteral feeding (128.4±6.7 vs. 112.3±7.2mL/kg/day, p<0.05) were significantly higher in the intervention group. Once enteral feeding was started, the time needed to reach full enteral feeding was significantly shorter in the probiotic group (0.4±0.1 vs. 1.7±0.5 days, p<0.05). There was no significant difference in sepsis. Necrotizing enterocolitis did not occur. No adverse effects related to S. boulardii were observed. ConclusionProphylactic supplementation of S. boulardii at a dose of 50mg/kg twice a day improved weight gain, improved feeding tolerance, and had no adverse effects in preterm infants >30 weeks old." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Method" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "pt" => array:3 [ "titulo" => "Resumo" "resumen" => "ObjetivoO uso de probióticos está cada vez mais popular em neonatos prematuros, já que podem prevenir a enterocolite necrosante (ECN) e a sepse e aumentar o crescimento e a tolerância de alimentação. Há apenas uma literatura limitada sobre a Saccharomyces boulardii CNCM I-745 (S. boulardii) em neonatos prematuros. MétodoUm ensaio de caso-controle prospectivo randomizado com o probiótico S. boulardii (50mg/kg duas vezes por dia) foi realizado com recém-nascidos com idade gestacional de 30 a 37 semanas e peso ao nascer entre 1500 e 2500g. ResultadosForam incluídos 125 neonatos, 63 no grupo de tratamento e 62 no de controle. O ganho de peso (16,14±1,96 em comparação a 10,73±1,77g/kg/dia, p<0,05) e a ingestão de fórmula com nutrição enteral máxima (128,4±6,7 em comparação a 112,3±7,2mL/kg/dia, p<0,05) foram significativamente maiores no grupo de intervenção. Assim que a nutrição enteral foi iniciada, o tempo necessário para atingir a nutrição enteral completa foi significativamente menor no grupo probiótico (0,4±0,1 em comparação a 1,7±0,5 dia, p<0,05). Não houve nenhuma diferença significativa em sepse. Não ocorreu ECN. Não foi observado nenhum efeito colateral relacionado à S. boulardii. ConclusãoA suplementação profilática de S. boulardii a uma dose de 50mg/kg duas vezes por dia melhorou o ganho de peso, aumentou a tolerância de alimentação e não teve nenhum efeito colateral em neonatos prematuros >30 semanas de idade." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusão" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Xu L, Wang Y, Wang Y, Fu J, Sun M, Mao Z, et al. A double-blinded randomized trial on growth and feeding tolerance with Saccharomyces boulardii CNCM I-745 in formula-fed preterm infants. J Pediatr (Rio J). 2016;92:296–301." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1604 "Ancho" => 1670 "Tamanyo" => 113831 ] ] "descripcion" => array:1 [ "en" => "Study flow chart." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Respiratory difficulties: includes respiratory distress syndrome and wet lung.S, Saccharomyces; p>0.05 (all)." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">S. boulardii \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Control \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Birthweight (g) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1947±54 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1957±51 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Gestation age (weeks) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">33+0.72 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">33+1.04 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Boys/girls \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">27/24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24/25 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Respiratory difficulties \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hyperbilirubinema (n [%]) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16 (31.4%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14 (28%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Maximal total bilirubin (μmol/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18.5±2.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">19.4±2.8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Anemia (n [%]) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">23 (45.1%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25 (51.0%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Antibiotic treatment (n [%]) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 (21.6%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 (18.4%) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1077201.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Characteristics (mean+1 SD) of the included infants." ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "HC, head circumference; GI, gastrointestinal symptoms: regurgitation, vomiting, gastric residuals; S, Saccharomyces." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">S. boulardii \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Control \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Weight gain (g/day) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16.14±1.96 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.73±1.77g \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.02 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Max enteral feeding (mL/kg/day) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">128.44±6.67 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">112.29±7.24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.03 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">From start of feeding, time needed until full enteral feeding (days) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.37±0.13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.70±0.45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HC increase (cm/week) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.74±0.03 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.72±0.04 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.67 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Linear growth (cm/week) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.89±0.04 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.87±0.04 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.17 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Incidence of sepsis (n [%]) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 (7.8%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 (12.2%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.06 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Incidence GI symptoms (n [%]) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7/51 (13.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10/49 (20.4%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.05 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hospital stay (days) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">23.3±1.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">28.0±1.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.035 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1077200.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Comparison of weight gain, growth (mean+1 SD), feeding tolerance, adverse events (sepsis, gastro-intestinal symptoms), and duration of hospitalization between the S. boulardii and control group." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:26 [ 0 => array:3 [ "identificador" => "bib0135" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Factors influencing gastrointestinal tract and microbiota immune interaction in preterm infants" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M.C. 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Ensaio duplo-cego randomizado sobre crescimento e tolerância de alimentação com a Saccharomyces boulardii CNCM I-745 em neonatos prematuros alimentados com fórmula

Lingfen Xua, Yun Wangb, Yang Wanga, Jianhua Fua, Mei Suna, Zhiqin Maoa,

Corresponding author

maozq@sj-hospital.org

Corresponding author.

, Yvan Vandenplasc

a Department of Pediatrics, Shengjing Hospital, China Medical University, Shenyang, China

b Department of Pediatrics, Qingdao Women and Children's Hospital, Qingdao, China

c UZ Brussel, Department of Pediatrics, Vrije Universiteit Brussel, Brussels, Belgium

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The gastrointestinal &#40;GI&#41; barrier function&#44; gut motility&#44; mucosal immunity&#44; and digestive&#47;absorptive capacity are all significantly underdeveloped in the preterm neonate&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">1</span></a> Preterm infants have an increased risk of poor growth&#44; nosocomial infections&#44; and necrotizing enterocolitis &#40;NEC&#41;&#44; and of developing a different intestinal microbiota than healthy breast fed infants&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">1&#44;2</span></a> The latter is related to a higher incidence of delivery through cesarean section&#44; decreased exposure to maternal microbiota&#44; increased exposure to organisms that colonize neonatal intensive care units &#40;NICUs&#41;&#44; antibiotics &#40;multiple courses&#41;&#44; and delay in enteral feeding&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The role for probiotics in the care of preterm newborns is debated&#46; Probiotics are defined as &#8220;live microorganisms which&#44; when administered in adequate amounts&#44; confer a health benefit to the host&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">4</span></a> While reports of improved growth and a decreased incidence of NEC are enticing&#44; many aspects on the mechanisms of action are still unclear&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">5&#44;6</span></a> Studies have used different strains and dosages&#44; making it difficult to draw evidence-based conclusions&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">5&#8211;7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Until now&#44; researchers often selected strains belonging to bacterial species naturally present in the intestinal flora&#44; such as lactobacilli and bifidobacteria&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleItalic">Saccharomyces boulardii</span> CNCM I-745 &#40;<span class="elsevierStyleItalic">S&#46; boulardii</span>&#41; is a probiotic yeast isolated from the peel of fruits such as lychees&#44; growing in Indochina&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">9</span></a><span class="elsevierStyleItalic">S&#46; boulardii</span> has been poorly studied in preterm and low birth weight infants&#46; The objective of the present study was to asses if <span class="elsevierStyleItalic">S&#46; boulardii</span> administered to formula-fed preterm newborns &#62;30 weeks of gestational age would improve weight gain and clinical outcome&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Patient inclusion</span><p id="par0020" class="elsevierStylePara elsevierViewall">Stable formula fed preterm neonates admitted to the NICU of the Shengjing Hospital of the China Medical University in Shenyang &#40;China&#41; were included in this prospective randomized controlled double-blinded study&#44; performed from April to July 2013&#46; Informed consent was obtained from the infants&#8217; parents&#47;guardians&#46; The study protocol was approved by the University Hospital Ethical Committee&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The sample size was calculated prior to the start of the study for a significance level of <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 &#40;two-sided&#41;&#44; with a power of 80&#37; &#40;<span class="elsevierStyleItalic">&#946;</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;2&#41; to estimate the needed sample size&#44; and with a weight gain standard deviation of 9<span class="elsevierStyleHsp" style=""></span>g&#47;day in both groups and a weight gain difference between the two groups of 5<span class="elsevierStyleHsp" style=""></span>g&#47;day&#46; This resulted in a sample size of 125 infants&#44; considering a 20&#37; drop out rate&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Inclusion and exclusion criteria</span><p id="par0030" class="elsevierStylePara elsevierViewall">Inclusion criteria were hospital-born formula-fed infants with a gestational age of 30&#8211;37 weeks and a birth weight between 1500 and 2500<span class="elsevierStyleHsp" style=""></span>g&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Exclusion criteria were severe neonatal pathologies&#44; such as severe birth complications&#44; GI malformations&#44; chromosomal abnormalities&#44; known immunodeficiency&#44; hydrops fetalis&#44; central venous catheter&#44; antifungal drugs&#44; and probiotics&#46; All included patients received parenteral nutrition and&#47;or preterm formula&#46; No neonates received mother&#39;s milk&#46; Minimal enteral nutrition or trophic feeding was started as soon as possible at 1<span class="elsevierStyleHsp" style=""></span>mL&#47;kg&#47;day&#46; Minimal enteral feeding is the practice of feeding small volumes of enteral feed in order to stimulate the development of the immature GI tract of the preterm infant&#59; it improves GI enzyme activity&#44; hormone release&#44; blood flow&#44; motility&#44; and microbial flora&#46; Clinical benefits include improved milk tolerance&#44; greater postnatal growth&#44; reduced systemic sepsis&#44; and shorter hospital stay&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">10</span></a> As soon as minimal enteral feeding was tolerated&#44; the patient was randomly allocated to one of two groups at a 1&#47;1 ratio &#40;<span class="elsevierStyleItalic">S&#46; boulardii</span> or control group&#41;&#46; Randomization was conducted according to a random computer-determined allocation order considering birth weight&#46; Feeding volume was increased when it was well tolerated according to the local protocol&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Intervention</span><p id="par0040" class="elsevierStylePara elsevierViewall">The intervention group received <span class="elsevierStyleItalic">S&#46; boulardii</span> CNCM I-745&#44; administered two times per day as separate medication&#44; not mixed with formula&#44; at a dosage of 50<span class="elsevierStyleHsp" style=""></span>mg&#47;kg &#40;Bioflor<span class="elsevierStyleSup">&#174;</span>&#59; CMS Shenzhen Kangzhe Pharmaceutical Co&#46; Ltd&#46;&#44; Shenzhen&#44; China&#59; manufactured by Biocodex&#44; Paris&#44; France&#41;&#59; 50<span class="elsevierStyleHsp" style=""></span>mg is approximately 10<span class="elsevierStyleSup">9</span> colony forming units &#40;CFU&#41;&#46; The dosage of the probiotic was derived from previous studies in neonates&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">11</span></a> Nothing was administered to the control group&#46; The study period ended at the 28th day after birth or when the infant was discharged from the hospital&#44; if this was possible earlier&#46; However&#44; the minimal duration of the intervention was at least 7 days&#46; Observational and routine clinical data were collected from all infants&#46; Blinding was possible because the nursing staff who administered <span class="elsevierStyleItalic">S&#46; boulardii</span> to the infants was not involved in the daily care and the attending neonatal team was unaware of the randomization assignments&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Outcome</span><p id="par0045" class="elsevierStylePara elsevierViewall">Primary outcomes were short-term growth parameters&#58; weight gain &#40;g&#47;kg&#47;day&#41; and linear growth &#40;cm&#47;week&#41;&#46; Secondary outcomes included&#58; days of parenteral nutrition needed to reach full enteral feeding&#44; maximal enteral feeding volume tolerated &#40;mL&#47;kg&#47;day&#41;&#44; and duration of hospitalization &#40;days&#41;&#46; Feeding intolerance was defined when vomiting and gastric residuals were considered too important&#46; Complications were defined as incidence of NEC &#40;defined as suspected or confirmed positive Bell stage II or more&#41; and sepsis &#40;defined as positive blood culture&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">9</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistics-registration</span><p id="par0050" class="elsevierStylePara elsevierViewall">The data were collected and entered into a statistical database &#40;SPSS&#44; version 16&#46;0&#59; IBM&#44; Armonk&#44; USA&#41;&#46; The data are presented as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation&#46; The demographic data and procedure variables were analyzed using the <span class="elsevierStyleItalic">t</span>-test or the chi-squared test&#46; A <span class="elsevierStyleItalic">p</span>-value of &#60;0&#46;05 was considered to indicate a statistically significant difference&#46; This study did not receive external funds&#44; and was registered at the website <a id="intr0010" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/">https&#58;&#47;&#47;clinicaltrials&#46;gov</a> under the number <a id="intr0015" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT02310425">NCT02310425</a>&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Patient description</span><p id="par0055" class="elsevierStylePara elsevierViewall">A total of 125 formula-fed preterm neonates were enrolled and randomly allocated&#46; Sixty-three patients received <span class="elsevierStyleItalic">S&#46; boulardii</span> as soon as they could tolerate minimal enteral feeding and 62 neonates were included in the control group&#46; In total&#44; 25 &#40;20&#37;&#41; patients were considered dropouts &#40;12 &#91;19&#46;1&#37;&#93; in the <span class="elsevierStyleItalic">S&#46; boulardii</span> group and 13 &#91;20&#46;1&#37;&#93; in the control group&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Reasons for dropout were withdrawal of consent &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41;&#44; loss to follow-up &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>11&#41;&#44; central venous catheter &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&#44; congenital syphilis &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&#44; and inappropriate inclusions &#40;congenital intestinal atresia &#91;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#93;&#44; trisomy 21 &#91;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#93;&#41;&#46; Fifty-one subjects could be analyzed in the intervention group and 49 in the control group&#46; The characteristics of all neonates at study entry are listed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#44; and did not show any statistically significant difference&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">S&#46; boulardii</span> was administered for the first time at 2&#46;63 days after birth &#40;range&#58; day 1 to day 6&#59; in 46 infants within 3 days&#44; and in only five infants between day 4 and 6&#41;&#46; The total number of days of <span class="elsevierStyleItalic">S&#46; boulardii</span> administration averaged 25&#46;3 days &#40;range&#58; 9&#8211;28 days&#41;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Feeding tolerance</span><p id="par0065" class="elsevierStylePara elsevierViewall">Formula intake at maximal enteral feeding &#40;128&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;7 <span class="elsevierStyleItalic">vs&#46;</span> 112&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;2<span class="elsevierStyleHsp" style=""></span>mL&#47;kg&#47;day&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; was higher in the <span class="elsevierStyleItalic">S&#46; boulardii</span> than in the control group&#44; and the time needed to reach full enteral feeding &#40;0&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;1 <span class="elsevierStyleItalic">vs&#46;</span> 1&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;5 day&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; was shorter in the intervention than in the control group &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Growth and hospital stay</span><p id="par0070" class="elsevierStylePara elsevierViewall">The weight gain in the <span class="elsevierStyleItalic">S&#46; boulardii</span> group was 16&#46;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;96<span class="elsevierStyleHsp" style=""></span>g&#47;kg&#47;day <span class="elsevierStyleItalic">versus</span> 10&#46;73<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;77<span class="elsevierStyleHsp" style=""></span>g&#47;kg&#47;day &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; in the control group&#46; There was no significant difference in linear growth&#44; head circumference growth&#44; incidence of abdominal distension&#44; and incidence of sepsis &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Hospital stay in the <span class="elsevierStyleItalic">S&#46; boulardii</span> group was shorter &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; No infants developed NEC&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Adverse effects</span><p id="par0075" class="elsevierStylePara elsevierViewall">No preterms developed fungemia&#44; and no adverse reactions to <span class="elsevierStyleItalic">S&#46; boulardii</span> were reported&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Discussion</span><p id="par0080" class="elsevierStylePara elsevierViewall">This study demonstrated that <span class="elsevierStyleItalic">S&#46; boulardii</span> can safely be administered to preterm infants&#44; and that it improves oral feeding tolerance and weight gain&#46; In term infants&#44; formula supplemented with <span class="elsevierStyleItalic">Lactobacillus</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">rhamnosus</span> GG was shown to increase weight gain&#44; but formulas supplemented with <span class="elsevierStyleItalic">Bifidobacterium</span> &#40;<span class="elsevierStyleItalic">B&#46;</span>&#41; <span class="elsevierStyleItalic">longum</span>&#44; <span class="elsevierStyleItalic">B&#46; animalis subsp&#46; lactis</span>&#44; and <span class="elsevierStyleItalic">L&#46; reuteri</span> did not&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">11&#8211;13</span></a> In preterm infants&#44; administration of <span class="elsevierStyleItalic">B&#46; breve</span> also improved weight gain&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">14</span></a> The mechanisms by which weight gain is affected are not yet clear&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">S&#46; boulardii</span> is effective in the treatment of a number of GI disorders related to the presence of bacterial and viral pathogens&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">15</span></a> It competes with pathogens for binding sites and produces a wide range of antimicrobial substances&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">16</span></a><span class="elsevierStyleItalic">S&#46; boulardii</span> has the ability to produce polyamines&#44; which are substances essential for cell growth and differentiation and enhance intestinal maturation&#44; what is reflected in increased levels of enzyme expression&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleItalic">S&#46; boulardii</span> is a yeast that significantly increases the activity of metabolic enzymes in the intestinal mucosa&#44; stimulates the secretion of disaccharide enzymes&#44; participates in the metabolism and absorption of carbohydrates&#44; and stimulates secretory IgA production as the result of a trophic effect on intestinal mucosa&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">18</span></a> In addition&#44; <span class="elsevierStyleItalic">S&#46; boulardii</span> promotes the stability of the intestinal microbiome and reduces the possibility of malabsorption caused by GI disorders&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">19</span></a> Translocation of <span class="elsevierStyleItalic">S&#46; boulardii</span> has not been reported&#59; on the contrary&#44; <span class="elsevierStyleItalic">S&#46; boulardii</span> was reported to reduce bacterial translocation&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">20</span></a> Based on these properties&#44; it was hypothesized that <span class="elsevierStyleItalic">S&#46; boulardii</span> could improve growth and clinical outcomes in preterm or low birth weight infants&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Although several clinical trials strongly suggest a place for <span class="elsevierStyleItalic">S&#46; boulardii</span> in the prevention and treatment of several GI diseases in adults and children&#44; data in preterm infants are limited&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">18</span></a><span class="elsevierStyleItalic">S&#46; boulardii</span> supplemented formula was shown to be well tolerated by preterm infants and to have beneficial effects on the GI microbiome&#44; bringing it closer to that of breastfed babies&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">11</span></a> Clinical trials in preterm infants also suggested that <span class="elsevierStyleItalic">S&#46; boulardii</span> improved feeding tolerance and reduced the risk of sepsis&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">21&#44;22</span></a> In order to achieve optimum growth for a preterm infant&#44; the goal is to mimic intrauterine growth while obtaining a functional outcome comparable to term infants&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">23</span></a> A gain in weight of 15&#8211;20<span class="elsevierStyleHsp" style=""></span>g&#47;kg&#47;day&#44; in length of 0&#46;7&#8211;1&#46;0<span class="elsevierStyleHsp" style=""></span>cm&#47;week&#44; and in head circumference of 0&#46;7<span class="elsevierStyleHsp" style=""></span>cm&#47;week is recommended&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">24&#44;25</span></a> In the <span class="elsevierStyleItalic">S&#46; boulardii</span> group&#44; the average weight gain was 16&#46;14<span class="elsevierStyleHsp" style=""></span>g&#47;kg&#47;day&#44; linear growth was 0&#46;9<span class="elsevierStyleHsp" style=""></span>cm&#47;week&#44; and head circumference increase was 0&#46;7<span class="elsevierStyleHsp" style=""></span>cm&#47;week&#46; Weight gain in the control group was 10&#46;73<span class="elsevierStyleHsp" style=""></span>g&#47;kg&#47;day&#44; which is below the recommendation&#46; The number of days to reach full enteral nutrition was shorter in the <span class="elsevierStyleItalic">S&#46; boulardii</span> than in the control group&#46; The better weight gain is likely to be related to the improvement of feeding tolerance&#46; It was observed that the incidence of vomiting&#44; gastric residual volume&#44; and abdominal distension &#40;&#8220;GI symptoms&#8221;&#44; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; were decreased in the intervention group in comparison to the control group&#44; although there was no statistical significant difference&#46; The total hospital stay in the <span class="elsevierStyleItalic">S&#46; boulardii</span> group was shorter than that in the control group&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">No significant difference was observed in linear growth and head circumference evolution&#44; which could be related to the relative short intervention period of 1 month&#46; Other limitations of this study are the lack of information on postnatal clinical characteristics of the neonates that could have been factors influencing the outcome&#44; such as the ratio of patent ductus arteriosus&#44; intraventricular hemorrhage&#44; and others&#46; Information on the number of infants with predisposing factors for NEC&#44; sepsis&#44; or other problems such as pre-eclampsia&#44; antenatal steroid use&#44; premature rupture of membranes&#44; and caesarian birth are missing&#46; The absence of breastfeeding is another weakness of the study&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">A recent Cochrane review reported on 24 trials on probiotics in preterm infants and concluded that the trials were highly variable with regard to enrollment criteria &#40;birth weight&#44; gestational age&#41;&#44; baseline risk of NEC&#44; timing&#44; dose&#44; formulation of the probiotics&#44; and feeding regimens&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">8</span></a> Enteral supplementation with probiotics significantly reduced the incidence of severe NEC &#40;stage II or more&#41; &#40;typical relative risk &#91;RR&#93; 0&#46;43&#44; 95&#37; confidence interval &#91;CI&#93; 0&#46;33&#8211;0&#46;56&#59; 20 studies&#44; 5529 infants&#41; and mortality &#40;typical RR 0&#46;65&#44; 95&#37; CI 0&#46;52&#8211;0&#46;81&#59; 17 studies&#44; 5112 infants&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">8</span></a> According to this meta-analysis&#44; there was no evidence for a significant reduction of nosocomial sepsis &#40;typical RR 0&#46;91&#44; 95&#37; CI 0&#46;80&#8211;1&#46;03&#59; 19 studies&#44; 5338 infants&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">8</span></a> In the present trial&#44; there were no preterms who developed NEC&#59; this is likely to be related to the fact that gestational age for inclusion was 30&#8211;37 weeks and that NEC occurs more frequently in infants born with a lesser gestational age&#46; Previous clinical trials showed that <span class="elsevierStyleItalic">S&#46; boulardii</span> supplementation did not reduce the incidence of death or NEC in very low birth weight infants&#44; but improved feeding tolerance and reduced the risk of clinical sepsis&#44; while adverse effects related to the intake of <span class="elsevierStyleItalic">S&#46; boulardii</span> were not observed&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">21&#44;22</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">S&#46; boulardii</span> has a protective effect against various enteric pathogens by two main mechanisms&#58; production of factors that neutralize bacterial toxins and modulation of the host cell signaling pathway implicated in proinflammatory response during bacterial infection&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">18&#44;19</span></a> In addition&#44; <span class="elsevierStyleItalic">S&#46; boulardii</span> can increase the activity of regulatory T cells and secretion of IgA of intestinal epithelial and crypt cells&#44; improving intestinal protection through immune regulation&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">18</span></a> In this study&#44; there was no statistically significant difference in the incidence of sepsis between the two groups &#40;4&#47;51 <span class="elsevierStyleItalic">vs&#46;</span> 6&#47;49&#41;&#46; This finding is in agreement with the Cochrane analysis&#44; showing that the included trials reported no systemic infection with the supplemental probiotics organism&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleItalic">S&#46; boulardii</span> fungemia has been reported in patients with deep central venous access&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">18</span></a> In this clinical trial&#44; there were no cases of fungemia&#44; and no side effects occurred&#46; The authors of the recent Cochrane review concluded that the updated review of available evidence strongly supports a change in practice&#44; meaning that probiotics should be given to preterm infants to decrease the risk for NEC and mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">8</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">In conclusion&#44; the results of the present study show that prophylactic use of <span class="elsevierStyleItalic">S&#46; boulardii</span> in preterm infants accelerates weight gain and improves feeding tolerance&#46; These data confirm a recent retrospective analysis concluding that probiotics improve feeding tolerance&#44; leading to better overall growth in preterm infants&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">26</span></a> It is the first time that better weight gain of preterm infants provided with <span class="elsevierStyleItalic">S&#46; boulardii</span> has been demonstrated&#46; Future double-blinded placebo-controlled trials are needed to confirm these data&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conflicts of interest</span><p id="par0115" class="elsevierStylePara elsevierViewall">Y&#46; Vandenplas is a consultant for United Pharmaceuticals and Biocodex&#46; The others authors declare no conflicts of interest&#46;</p></span></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The use of probiotics is increasingly popular in preterm neonates&#44; as they may prevent necrotizing enterocolitis sepsis and improve growth and feeding tolerance&#46; There is only limited literature on <span class="elsevierStyleItalic">Saccharomyces boulardii</span> CNCM I-745 &#40;<span class="elsevierStyleItalic">S&#46; boulardii</span>&#41; in preterm infants&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Method</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A prospective&#44; randomized&#44; case-controlled trial with the probiotic <span class="elsevierStyleItalic">S&#46; boulardii</span> &#40;50<span class="elsevierStyleHsp" style=""></span>mg&#47;kg twice daily&#41; was conducted in newborns with a gestational age of 30&#8211;37 weeks and a birth weight between 1500 and 2500<span class="elsevierStyleHsp" style=""></span>g&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">125 neonates were enrolled&#59; 63 in the treatment and 62 in the control group&#46; Weight gain &#40;16&#46;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;96 <span class="elsevierStyleItalic">vs&#46;</span> 10&#46;73<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;77<span class="elsevierStyleHsp" style=""></span>g&#47;kg&#47;day&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; and formula intake at maximal enteral feeding &#40;128&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;7 <span class="elsevierStyleItalic">vs&#46;</span> 112&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;2<span class="elsevierStyleHsp" style=""></span>mL&#47;kg&#47;day&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; were significantly higher in the intervention group&#46; Once enteral feeding was started&#44; the time needed to reach full enteral feeding was significantly shorter in the probiotic group &#40;0&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;1 <span class="elsevierStyleItalic">vs&#46;</span> 1&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;5 days&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; There was no significant difference in sepsis&#46; Necrotizing enterocolitis did not occur&#46; No adverse effects related to <span class="elsevierStyleItalic">S&#46; boulardii</span> were observed&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Prophylactic supplementation of <span class="elsevierStyleItalic">S&#46; boulardii</span> at a dose of 50<span class="elsevierStyleHsp" style=""></span>mg&#47;kg twice a day improved weight gain&#44; improved feeding tolerance&#44; and had no adverse effects in preterm infants &#62;30 weeks old&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">O uso de probi&#243;ticos est&#225; cada vez mais popular em neonatos prematuros&#44; j&#225; que podem prevenir a enterocolite necrosante &#40;ECN&#41; e a sepse e aumentar o crescimento e a toler&#226;ncia de alimenta&#231;&#227;o&#46; H&#225; apenas uma literatura limitada sobre a <span class="elsevierStyleItalic">Saccharomyces boulardii</span> CNCM I-745 &#40;<span class="elsevierStyleItalic">S&#46; boulardii</span>&#41; em neonatos prematuros&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todo</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Um ensaio de caso-controle prospectivo randomizado com o probi&#243;tico <span class="elsevierStyleItalic">S&#46; boulardii</span> &#40;50<span class="elsevierStyleHsp" style=""></span>mg&#47;kg duas vezes por dia&#41; foi realizado com rec&#233;m-nascidos com idade gestacional de 30 a 37 semanas e peso ao nascer entre 1500 e 2500<span class="elsevierStyleHsp" style=""></span>g&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Foram inclu&#237;dos 125 neonatos&#44; 63 no grupo de tratamento e 62 no de controle&#46; O ganho de peso &#40;16&#44;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#44;96 em compara&#231;&#227;o a 10&#44;73<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#44;77<span class="elsevierStyleHsp" style=""></span>g&#47;kg&#47;dia&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41; e a ingest&#227;o de f&#243;rmula com nutri&#231;&#227;o enteral m&#225;xima &#40;128&#44;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#44;7 em compara&#231;&#227;o a 112&#44;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#44;2<span class="elsevierStyleHsp" style=""></span>mL&#47;kg&#47;dia&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41; foram significativamente maiores no grupo de interven&#231;&#227;o&#46; Assim que a nutri&#231;&#227;o enteral foi iniciada&#44; o tempo necess&#225;rio para atingir a nutri&#231;&#227;o enteral completa foi significativamente menor no grupo probi&#243;tico &#40;0&#44;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;1 em compara&#231;&#227;o a 1&#44;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;5 dia&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41;&#46; N&#227;o houve nenhuma diferen&#231;a significativa em sepse&#46; N&#227;o ocorreu ECN&#46; N&#227;o foi observado nenhum efeito colateral relacionado &#224; <span class="elsevierStyleItalic">S&#46; boulardii</span>&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclus&#227;o</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A suplementa&#231;&#227;o profil&#225;tica de <span class="elsevierStyleItalic">S&#46; boulardii</span> a uma dose de 50<span class="elsevierStyleHsp" style=""></span>mg&#47;kg duas vezes por dia melhorou o ganho de peso&#44; aumentou a toler&#226;ncia de alimenta&#231;&#227;o e n&#227;o teve nenhum efeito colateral em neonatos prematuros &#62;30 semanas de idade&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Xu L&#44; Wang Y&#44; Wang Y&#44; Fu J&#44; Sun M&#44; Mao Z&#44; et al&#46; A double-blinded randomized trial on growth and feeding tolerance with <span class="elsevierStyleItalic">Saccharomyces boulardii</span> CNCM I-745 in formula-fed preterm infants&#46; J Pediatr &#40;Rio J&#41;&#46; 2016&#59;92&#58;296&#8211;301&#46;</p>"
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Control&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Birthweight &#40;g&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1947<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>54&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1957<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>51&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Gestation age &#40;weeks&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">33<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>0&#46;72&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">33<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1&#46;04&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Boys&#47;girls&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">27&#47;24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24&#47;25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Respiratory difficulties&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hyperbilirubinema &#40;<span class="elsevierStyleItalic">n</span> &#91;&#37;&#93;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14 &#40;28&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Maximal total bilirubin &#40;&#956;mol&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">19&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Anemia &#40;<span class="elsevierStyleItalic">n</span> &#91;&#37;&#93;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25 &#40;51&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Antibiotic treatment &#40;<span class="elsevierStyleItalic">n</span> &#91;&#37;&#93;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11 &#40;21&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9 &#40;18&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Characteristics &#40;mean<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1 SD&#41; of the included infants&#46;</p>"
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">HC&#44; head circumference&#59; GI&#44; gastrointestinal symptoms&#58; regurgitation&#44; vomiting&#44; gastric residuals&#59; <span class="elsevierStyleItalic">S</span>&#44; <span class="elsevierStyleItalic">Saccharomyce</span>s&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">S&#46; boulardii</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16&#46;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;96&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#46;73<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;77<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;02&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Max enteral feeding &#40;mL&#47;kg&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">112&#46;29<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;03&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">From start of feeding&#44; time needed until full enteral feeding &#40;days&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;70<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;0&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HC increase &#40;cm&#47;week&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;74<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;03&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;67&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Linear growth &#40;cm&#47;week&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;89<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;04&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Incidence of sepsis &#40;<span class="elsevierStyleItalic">n</span> &#91;&#37;&#93;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 &#40;7&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 &#40;12&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;06&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Incidence GI symptoms &#40;<span class="elsevierStyleItalic">n</span> &#91;&#37;&#93;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#47;51 &#40;13&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#47;49 &#40;20&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;05&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hospital stay &#40;days&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">23&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">28&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;035&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Comparison of weight gain&#44; growth &#40;mean<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1 SD&#41;&#44; feeding tolerance&#44; adverse events &#40;sepsis&#44; gastro-intestinal symptoms&#41;&#44; and duration of hospitalization between the <span class="elsevierStyleItalic">S&#46; boulardii</span> and control group&#46;</p>"
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      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:26 [
            0 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "1"
              "referencia" => array:1 [
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                  "contribucion" => array:1 [
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                      "titulo" => "Factors influencing gastrointestinal tract and microbiota immune interaction in preterm infants"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "M&#46;C&#46; Collado"
                            1 => "M&#46; Cernada"
                            2 => "J&#46; Neu"
                            3 => "G&#46; P&#233;rez-Mart&#237;nez"
                            4 => "M&#46; Gormaz"
                            5 => "M&#46; Vento"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/pr.2015.54"
                      "Revista" => array:6 [
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                        "fecha" => "2015"
                        "volumen" => "77"
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              ]
            ]
            1 => array:3 [
              "identificador" => "bib0140"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Development of the intestinal bacterial composition in hospitalized preterm infants in comparison with breast-fed&#44; full-term infants"
                      "autores" => array:1 [
                        0 => array:2 [
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                            0 => "A&#46; Schwiertz"
                            1 => "B&#46; Gruhl"
                            2 => "M&#46; L&#246;bnitz"
                            3 => "P&#46; Michel"
                            4 => "M&#46; Radke"
                            5 => "M&#46; Blaut"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1203/01.PDR.0000078274.74607.7A"
                      "Revista" => array:6 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12788986"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Enteral feeding for very low birth weight infants&#58; reducing the risk of necrotising enterocolitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                            0 => "M&#46; Chauhan"
                            1 => "G&#46; Henderson"
                            2 => "W&#46; McGuire"
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                  "host" => array:1 [
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                      "Revista" => array:6 [
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18006565"
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              ]
            ]
            3 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Guidelines for the evaluation of probiotics in food&#46; Report of a Joint FAO&#47;WHO Working Group on drafting guidelines for the evaluation of probiotics in food"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Food and Agriculture Organization of the United Nations &#40;FAO&#41;"
                            1 => "World Health Organization &#40;WHO&#41;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:3 [
                        "fecha" => "2002"
                        "editorial" => "FAO&#44; WHO"
                        "editorialLocalizacion" => "London&#44; Ontario&#44; Canada"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Probiotics for prevention of necrotising enterocolitis in preterm neonates with very low birthweight&#58; a systematic review of randomised controlled trials"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "G&#46; Deshpande"
                            1 => "S&#46; Rao"
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                          ]
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(07)60748-X"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2007"
                        "volumen" => "369"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17499603"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Probiotic supplement reduces risk of necrotizing enterocolitis and mortality in preterm very low-birth-weight infants&#58; an updated meta-analysis of 20 randomized&#44; controlled trials"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Q&#46; Wang"
                            1 => "J&#46; Dong"
                            2 => "Y&#46; Zhu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jpedsurg.2011.09.064"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr Surg"
                        "fecha" => "2012"
                        "volumen" => "47"
                        "paginaInicial" => "241"
                        "paginaFinal" => "248"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22244424"
                            "web" => "Medline"
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              "identificador" => "bib0165"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evidence-based guidelines for use of probiotics in preterm neonates"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
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                      "titulo" => "Nutritional outcomes with implementation of probiotics in preterm infants"
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]

Article information

ISSN: 00217557
Original language: English

DOI:10.1016/j.jped.2015.08.013

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Year/Month	Html	Pdf	Total

2024 November	3	2	5
2024 October	21	29	50
2024 September	30	25	55
2024 August	35	42	77
2024 July	44	26	70
2024 June	28	13	41
2024 May	23	13	36
2024 April	22	19	41
2024 March	20	16	36
2024 February	26	20	46
2024 January	19	21	40
2023 December	15	24	39
2023 November	25	35	60
2023 October	28	38	66
2023 September	30	39	69
2023 August	19	14	33
2023 July	14	12	26
2023 June	18	9	27
2023 May	30	15	45
2023 April	21	6	27
2023 March	31	21	52
2023 February	21	14	35
2023 January	18	21	39
2022 December	44	22	66
2022 November	23	26	49
2022 October	30	26	56
2022 September	21	33	54
2022 August	31	28	59
2022 July	27	27	54
2022 June	35	28	63
2022 May	58	34	92
2022 April	70	29	99
2022 March	20	26	46
2022 February	21	22	43
2022 January	15	19	34
2021 December	16	27	43
2021 November	8	31	39
2021 October	15	33	48
2021 September	4	11	15
2021 August	15	11	26
2021 July	6	11	17
2021 June	10	19	29
2021 May	12	34	46
2021 April	31	57	88
2021 March	12	16	28
2021 February	12	5	17
2021 January	13	20	33
2020 December	10	9	19
2020 November	10	14	24
2020 October	13	6	19
2020 September	25	15	40
2020 August	9	7	16
2020 July	17	4	21
2020 June	12	5	17
2020 May	15	3	18
2020 April	14	15	29
2020 March	7	6	13
2020 February	15	10	25
2020 January	20	17	37
2019 December	22	8	30
2019 November	13	4	17
2019 October	12	8	20
2019 September	6	9	15
2019 August	14	10	24
2019 July	20	11	31
2019 June	37	14	51
2019 May	14	8	22
2019 April	20	16	36
2019 March	13	8	21
2019 February	15	8	23
2019 January	15	7	22
2018 December	19	8	27
2018 November	49	6	55
2018 October	155	17	172
2018 September	58	7	65
2018 August	5	14	19
2018 July	11	9	20
2018 June	8	26	34
2018 May	14	54	68
2018 April	9	6	15
2018 March	11	3	14
2018 February	6	3	9
2018 January	6	3	9
2017 December	10	2	12
2017 November	4	3	7
2017 October	13	6	19
2017 September	8	4	12
2017 August	3	0	3
2017 July	1	0	1
2017 June	6	2	8
2017 May	14	2	16
2017 April	26	17	43
2017 March	11	1	12
2017 February	4	3	7
2017 January	10	4	14
2016 December	6	5	11
2016 November	5	5	10
2016 October	19	14	33
2016 September	23	2	25
2016 August	25	5	30
2016 July	53	15	68
2016 June	52	12	64
2016 May	54	73	127
2016 April	15	16	31
2016 March	5	3	8

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