Risk factors of necrotizing enterocolitis in very low birth weight infants: a meta-analysis.

Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants

Background and Objective: Necrotizing enterocolitis (NEC) remains an important cause of mortality in preterm neonates. There are many risk factors for NEC; however, probably the most controversial one is red blood cell transfusions (RBCT). The data concerning the link between NEC and RBCT has been conflicting. Therefore, we aimed to analyze the association between NEC and RBCT in Neonatal Intensive Care Unit (NICU) at the Hospital of Lithuanian University of Health Sciences. Materials and Methods: We used the Very Low Birth Weight (VLBW) Infants database to match all infants with ≥2a Bell’s stage NEC admitted between 1 January 2005 and 31 December 2014 (n = 54) with a control group (n = 54) of similar gestational age and birth weight and without NEC. We analyzed the charts of these infants and performed statistical analysis on 20 clinical variables including RBCT. Results: The main clinical and demographic characteristics did not differ between the two groups. All variables associated with RBCT (receipt of any RBCT, the number of transfusions and the volume transfused in total) were significantly higher in the NEC group both before the onset of NEC and throughout the hospitalization. RBCT increased the odds of NEC even after adjustment for confounding factors. In addition, we found that congenital infection was more abundant in the NEC group and increased the odds of NEC 2.7 times (95% confidence interval CI (1.1, 6.3), p = 0.024). Conclusions: A higher number and the total volume of RBCT are associated with an increased risk of NEC in VLBW infants. The presence of congenital infection might identify the infants at risk.

We evaluated the efficacy of probiotics in reducing the incidence and severity of necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants. A prospective, masked, randomized control trial was conducted to evaluate the beneficial effects of probiotics in reducing the incidence and severity of NEC among VLBW (<1500 g) infants. VLBW infants who started to fed enterally and survived beyond the seventh day after birth were eligible for the trial. They were randomized into 2 groups after parental informed consents were obtained. The infants in the study group were fed with Infloran (Lactobacillus acidophilus and Bifidobacterium infantis) with breast milk twice daily until discharged. Infants in the control group were fed with breast milk alone. The clinicians caring for the infants were blinded to the group assignment. The primary outcome was death or NEC (>or= stage 2). Three hundred sixty-seven infants were enrolled: 180 in the study group and 187 in the control group. The demographic and clinical variables were similar in both groups. The incidence of death or NEC (>or= stage 2) was significantly lower in the study group (9 of 180 vs 24 of 187). The incidence of NEC (>or= stage 2) was also significantly lower in the study when compared with the control group (2 of 180 vs 10 of 187). There were 6 cases of severe NEC (Bell stage 3) in the control group and none in the study group. None of the positive blood culture grew Lactobacillus or Bifidobacterium species. Infloran as probiotics fed enterally with breast milk reduces the incidence and severity of NEC in VLBW infants.

The use of human milk as a sole source of nutrients for preterm infants has been the subject of debate in recent years. We studied the morbidity factors associated with hospitalization of very low birth weight (VLBW) infants fed human milk with and without fortification. One hundred VLBW infants were randomly assigned to two groups with stratification for gestation and weight. The control group (n=50; mean birth weight 1239+/-186 g and mean gestation 29.3+/-2.1 wks) was fed human milk only, and in the fortifier group (n=50; mean birth weight 1245+/-191 g and mean gestation 29.5+/-2.1 wks), human milk was enriched with a fortifier after the babies reached a volume of 140 mL/kg/day by the enteral route. Weight was measured twice weekly, biochemical indices of nutritional and bone status and serum electrolytes were obtained weekly, and clinical evidence for sepsis, necrotizing enterocolitis and feeding intolerance was assessed regularly until infants were discharged. Hospital stay was less than 45 days in the majority (94%) of the babies in the fortifier group, whereas the majority (66%) of the babies in the control group stayed for more than 45 days (P<0.01). Low serum phosphorus and raised alkaline phosphatase levels were seen more frequently in the control group without fortification (P<0.01), as well as hyponatremia (P<0.01), late metabolic acidosis of prematurity (P<0.01) and culture-proven sepsis (P<0.05). There was no significant difference in the occurrence of necrotizing enterocolitis between the two groups (P>0.05). Human milk fortification has beneficial effects on the growth of VLBW infants and decreases hospital stay and morbidity associated with prematurity and very low birth weight, with economic and psychological benefits for the parents.

Objective To explore the diagnostic value of neutrophil-derived fecal marker fecal calprotectin (FC) in diagnosing necrotizing enterocolitis (NEC) for very low birth weight (VLBW) infants. Methods A total of 35 cases of VLBW infants with NEC symptoms who were gathered from Changzhou Children's Hospital and Changzhou Maternal and Child Health Care Hospital between July 2011 to June 2013 were selected as NEC group. NEC group were further divided into diagnosed NEC sub-group (n=15) and suspected NEC sub-group (n=20). Meanwhile, 30 VLBW infants with feeding intolerance were selected into feeding intolerance group (n=30), and 30 VLBW infants with normal milk-feeding and no gastrointestinal symptoms were selected into control group(n=30). The study protocol was approved by the Ethical Review Board of Investigation in Human Being of Changzhou Children's Hospital and Changzhou Maternal and Child Health Care Hospital. Informed consent was obtained from the parents of each participating child. The FC levels and occult blood (OB) were detected among different groups. And the FC levels and positive detection rates of OB among 4 groups were compared. Results The FC levels in the early stage and critical stage of diagnosed NEC sub-group were higher than that of control group (t=6.62, 8.44; P 0.05). Furthermore, there was significant difference in the aspect of positive detection rate of OB between critical stage in diagnosed NEC sub-group and control group (χ2=15.469, P 0.05). But there were no significant differences between suspected stage in suspected NEC sub-group and control group, recovery stage in suspected NEC sub-group and control group, feeding intolerance group and control group (χ2=2.000, 0.000, 0.185; P>0.05). Conclusions Compared with fecal OB test, the examination of FC was more sensitive in diagnosing early-stage NEC. FC level can be considered as an effective index to diagnose and evaluate VLBW infants combined with NEC. It can also be used to distinguish NEC and feeding intolerance. Key words: Infant, very low birth weight; Enterocolitis, necrotizing; Fecal calprotectin; Infant, newborn

ObjectivesWe aimed to identify the factors associated with necrotizing enterocolitis (NEC) and to assess the associations of the initial empirical antibiotic therapy (IEAT) duration and antibiotic therapy duration/hospital stay ratio (A/H ratio) before NEC with subsequent NEC in very low birth weight (VLBW) infants with gestational age less than 32 weeks without proven sepsis.MethodsA retrospective study was conducted at the NICU of the First Affiliated Hospital of Medical University of Anhui province from June 2015 to May 2022, and 567 VLBW infants with gestational age less than 32 weeks were included in the study. We divided the VLBW infants into those with and without NEC according to modified Bell’s criteria. We then used descriptive statistics to identify the factors associated with NEC and multivariate analyses to evaluate the associations of IEAT duration and A/H ratio with the occurrence of NEC.ResultsOf the 567 VLBW neonates admitted to our center, 547 survived and reached the normal discharge criteria. Fifty-one infants (8.99%) were diagnosed as showing NEC. Infants with NEC had a longer total parenteral nutrition time, total enteral nutrition time, and IEAT duration, as well as a higher A/H ratio than those without NEC. In multivariate analyses adjusted for the other factors, IEAT duration was associated with an increased odds of NEC [odds ratio (OR) = 1.267; 95% confidence interval (CI), 1.128–1.423], and the A/H ratio was also associated with increased odds of NEC (OR = 8.718; 95% CI, 2.450–31.030). For the A/H ratio, the area under the curve (AUC) was 0.767 and the ideal cutoff was 0.357, and the sensitivity and specificity were 0.843 and 0.645, respectively.ConclusionProlonged antibiotic therapy may increase the risk of NEC in VLBW infants with a gestational age of fewer than 32 weeks and should be used with caution.

Timing of Caffeine Therapy in Very Low Birth Weight Infants

The identification of probiotic species involved in gut homeostasis and their potential therapeutic benefits have led to an interest in their use for preventing necrotizing enterocolitis (NEC). Although bifidobacterium and lactobacilli sp. have been used to reduce the incidence of NEC in clinical trials. Lactobacillus sporogenes has not been used in the prevention of NEC in very low-birth weight infants yet. The objective of this study was to evaluate the efficacy of orally administered L sporogenes in reducing the incidence and severity of NEC in very low-birth weight (VLBW) infants. A prospective, blinded, randomized controlled trial was conducted in preterm infants with a gestational age of <33 weeks or birth weight of <1500 g. VLBW infants who survived to start enteral feeding were randomized into two groups The infants in the study group were given L. sporogenes with a dose of 350,000,000 c.f.u. added to breast milk or formula, once a day, starting with the first feed until discharged. The infants in the control group were fed without L. sporogenes supplementation. The primary outcome measurement was death or NEC (Bell's stage ≥2). A total of 221 infants were studied: 110 in the study group and 111 in the control group. There was no significant difference in the incidence of death or NEC between the groups. Feeding intolerance was significantly lower in the probiotics group than in the control group (44.5% (n: 49) vs 63.1% (n: 70), respectively; P=0.006). L. sporogenes supplementation at the dose of 350,000,000 c.f.u/day is not effective in reducing the incidence of death or NEC in VLBW infants, however, it could improve the feeding tolerance.

To evaluate the association between red blood cell (RBC) transfusion leading to necrotizing enterocolitis (NEC) within 48h, known as transfusion-associated necrotizing enterocolitis (TANEC). A nested case-control study using historical data was conducted in the neonatal intensive care unit of Songklanagarind Hospital, Thailand. All very low birth weight (VLBW) infants delivered between November 2009 and July 2016 were enrolled. The infants were identified as RBC transfusion received and NEC developed. Logistic regression was used to evaluate risk factors for transfusion and the association between RBC transfusion and NEC. Four hundred and forty-four VLBW infants were enrolled in the study. The median (interquartile range) gestational age was 29 (27, 31) wk. The overall incidence of NEC was 13%. Three (5.2%) of the NEC infants had TANEC. The infants who received RBC transfusion had a lower gestational age [odds ratio, OR 0.64; 95% confidence interval (95%CI) 0.57, 0.73, p <0.001] and were more likely to have pneumonia (OR 9.86; 95%CI 5.02, 19.35, p < 0.001) or to have received H2 blocker (OR 2.92; 95%CI 1.73, 4.93, p <0.001). The ORs (95% CI) after adjusting for confounders, the association between RBC transfusion and NEC for transfusions ≤2 d, >2 to 4 d, and > 4 to 6 d prior to NEC were 1.83 (0.41, 8.16; p = 0.43), 1.7 (0.26, 11.16; p =0.58) and 1.19 (0.31, 4.62; p = 0.80) respectively. After controlling of confounders, no evidence of association was found between RBC transfusion and TANEC.

Our objective was to compare survival and neonatal morbidity rates between very low birth weight (VLBW) infants with Down syndrome (DS) and VLBW infants with non-DS chromosomal anomalies, nonchromosomal birth defects (BDs), and no chromosomal anomaly or major BD. Data were collected prospectively for infants weighing 401 to 1500 g who were born and/or cared for at one of the study centers participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network in 1994-2008. Risk of death and morbidities, including patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), late-onset sepsis (LOS), retinopathy of prematurity, and bronchopulmonary dysplasia (BPD), were compared between VLBW infants with DS and infants in the other groups. Infants with DS were at increased risk of death (adjusted relative risk: 2.47 [95% confidence interval: 2.00-3.07]), PDA, NEC, LOS, and BPD, relative to infants with no BDs. Decreased risk of death (relative risk: 0.40 [95% confidence interval: 0.31-0.52]) and increased risks of NEC and LOS were observed when infants with DS were compared with infants with other non-DS chromosomal anomalies. Relative to infants with nonchromosomal BDs, infants with DS were at increased risk of PDA and NEC. The increased risk of morbidities among VLBW infants with DS provides useful information for counseling parents and for anticipating the need for enhanced surveillance for prevention of these morbidities.

BackgroundRed blood cell (RBC) transfusion improves cardiorespiratory status of preterm infants by increasing circulating hemoglobin, improving tissue oxygenation, and reducing cardiac output. However, RBC transfusion itself has also been suggested to negatively affect short-term outcomes such as intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), and necrotizing enterocolitis (NEC) in premature infants.PurposeThis study aimed to analyze the relationship between RBC transfusion and short-term outcomes in very low birth weight (VLBW) infants (birth weight, <1,500 g).MethodsWe retrospectively reviewed the medical records of VLBW infants admitted to the Soonchunhyang University Bucheon Hospital between October 2010 and December 2017. Infants who died during hospitalization were excluded. The infants were divided into 2 groups according to RBC transfusion status. We investigated the relationship between RBC transfusion and short-term outcomes including BPD, ROP, NEC, and IVH.ResultsOf the 250 enrolled VLBW infants, 109 (43.6%) underwent transfusion. Univariate analysis revealed that all short-term outcomes except early-onset sepsis and patent ductus arteriosus were associated with RBC transfusion. In multivariate analysis adjusted for gestational age, birth weight and Apgar score at 1 minute, RBC transfusion was significantly correlated with BPD (odds ratio [OR], 5.42; P<0.001) and NEC (OR, 3.40; P= 0.009).ConclusionRBC transfusion is significantly associated with adverse clinical outcomes such as NEC and BPD in VLBW infants. Careful consideration of the patient’s clinical condition and appropriate guidelines is required before administration of RBC transfusions.

This study aimed to investigate the relationship between ABO blood group and the incidence of necrotizing enterocolitis (NEC) or mortality in very low birth weight (VLBW) infants. A retrospective single-center cohort study was conducted on VLBW infants admitted to Shengjing Hospital of China Medical University from 2014 to 2023. Bell's staging system was used to define NEC severity, and deaths were recorded. Confirmed NEC with Bell's stage ≥2 and mortality were defined as primary outcomes and compared among the four ABO blood groups. The primary composite outcome occurred in 14.7% (847/5774). Among the 5774 VLBW infants enrolled, the overall mortality was 11.0% (635/5774). Confirmed NEC (Bell's stage ≥2) occurred in 5.0% (288/5774) of the cohort, with NEC-related mortality of 21.2% (61/288). ABO blood groups were not associated with mortality and the incidence of NEC in VLBW infants. These findings remained consistent after adjusting for perinatal factors, maternal factors, and admission year. This study suggests no significant association between ABO blood group and NEC incidence, severity, or mortality in VLBW infants, contrasting with previous reports. Variations in study populations, definition of primary outcomes, statistical methods, and transfusion strategies may explain the differing findings. ABO blood groups have no influence on the incidence of confirmed NEC or mortality in VLBW infants. Variations in study populations, definitions of primary outcomes, and statistical methods may explain discrepancies between our findings and previous reports. Transfusion strategies may also confound the relationship between ABO blood group and NEC.

To examine the cost-effectiveness of prophylactic probiotics on necrotizing enterocolitis (NEC) prevention in very low birth weight (VLBW) infants. We built a decision-analytic model using TreeAge. Effectiveness was assessed using quality-adjusted life-years (QALY). Primary outcome was an incremental cost-effectiveness ratio (ICER) expressed as cost per QALY gained. Costs were expressed in 2017 US dollars. Deterministic and probabilistic sensitivity analyses (SA) were performed. For the base case analysis, the ICER of probiotics versus no probiotics for the prevention of NEC in VLBW infants was $1868/QALY. SA revealed that probiotics became cost-saving at a NEC rate of 6.5% and higher or with incremental NEC cost of $37,500 or higher. Our model demonstrated that prophylactic probiotics were a cost-effective strategy in NEC reduction. SA confirmed that the model is customizable to various clinical settings and thus, can aid in understanding the economic impact of this intervention.

Background The aim of this study was to evaluate the association between red blood cell (RBC) transfusions on the risk of death, retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), and necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants. Study Design and Methods This is an observational study. Data were entered prospectively into the study database at the time of the first transfusion. Clinical characteristics, adverse events, and outcomes of the patients transfused in the first 28 days of life were compared with the population of VLBW infants not transfused during the same period. The association among birth weight, gestational age, comorbidities, and the number of transfusions was estimated with a Poisson regression model. The association between the composite outcome and the occurrence of death, ROP, or BPD separately considered and a set of covariates was estimated with a logistic regression model. Results We enrolled 641 VLBW infants, 42% of whom were transfused. Transfusions were associated with the risk of developing the composite outcome, independently from other conditions; this risk correlated with several transfusions ≥ 3 (odds ratio: 5.88, 95% confidence interval: 2.74-12.6). ROP and BPD were associated with several transfusions ≥ 3. Conclusion We observed an association between RBC transfusions and the composite risk of death or ROP, BPD, and NEC.

Intestinal dysbiosis may contribute to the pathogenesis of necrotising enterocolitis (NEC) in very preterm or very low birth weight (VLBW) infants. Dietary supplementation with synbiotics (probiotic micro-organisms combined with prebiotic oligosaccharides) to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of NEC and associated mortality and morbidity. To assess the effect of enteral supplementation with synbiotics (versus placebo or no treatment, or versus probiotics or prebiotics alone) for preventing NEC and associated morbidity and mortality in very preterm or VLBW infants. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, the Maternity and Infant Care database and CINAHL, from earliest records to 17 June 2021. We searched clinical trials databases and conference proceedings, and examined the reference lists of retrieved articles. We included randomised controlled trials (RCTs) and quasi-RCTs comparing prophylactic synbiotics supplementation with placebo or no synbiotics in very preterm (< 32 weeks' gestation) or very low birth weight (< 1500 g) infants. Two review authors separately performed the screening and selection process, evaluated risk of bias of the trials, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference, with associated 95% confidence intervals (CIs). We used the GRADE approach to assess the level of certainty for effects on NEC, all-cause mortality, late-onset invasive infection, and neurodevelopmental impairment. We included six trials in which a total of 925 infants participated. Most trials were small (median sample size 200). Lack of clarity on methods used to conceal allocation and mask caregivers or investigators were potential sources of bias in four of the trials. The studied synbiotics preparations contained lactobacilli or bifidobacteria (or both) combined with fructo- or galacto-oligosaccharides (or both). Meta-analyses suggested that synbiotics may reduce the risk of NEC (RR 0.18, 95% CI 0.09 to 0.40; RD 70 fewer per 1000, 95% CI 100 fewer to 40 fewer; number needed to treat for an additional beneficial outcome (NNTB) 14, 95% CI 10 to 25; six trials (907 infants); low certainty evidence); and all-cause mortality prior to hospital discharge (RR 0.53, 95% CI 0.33 to 0.85; RD 50 fewer per 1000, 95% CI 120 fewer to 100 fewer; NNTB 20, 95% CI 8 to 100; six trials (925 infants);low-certainty evidence). Synbiotics may have little or no effect on late-onset invasive infection, but the evidence is very uncertain (RR 0.84, 95% CI 0.58 to 1.21; RD 20 fewer per 1000, 95% CI 70 fewer to 30 more; five trials (707 infants);very low-certainty evidence). None of the trials assessed neurodevelopmental outcomes. In the absence ofhigh levels of heterogeneity, we did not undertake any subgroup analysis (including the type of feeding). The available trial data provide only low-certainty evidence about the effects of synbiotics on the risk of NEC and associated morbidity and mortality for very preterm or very low birth weight infants. Our confidence in the effect estimates is limited; the true effects may be substantially different from these estimates. Large, high-quality trials would be needed to provide evidence of sufficient validity and applicability to inform policy and practice.