Reduction In Necrotizing Enterocolitis Research Articles

Is choline deficiency an unrecognized factor in necrotizing enterocolitis of preterm infants?

We undertook this review to determine if it is plausible that choline or phosphatidylcholine (PC) deficiency is a factor in necrotizing enterocolitis (NEC) after two clinical trials found a dramatic and unexpected reduction in NEC in an experimental group provided higher PC compared to a control group. Sources and amounts of choline/PC for preterm infants are compared to the choline status of preterm infants at birth and following conventional nutritional management. The roles of choline/PC in intestinal structure, mucus, mesenteric blood flow, and the cholinergic anti-inflammatory system are summarized. Low choline/PC status is linked to prematurity/immaturity, parenteral and enteral feeding, microbial dysbiosis and hypoxia/ischemia, factors long associated with the risk of developing NEC. We conclude that low choline status exists in preterm infants provided conventional parenteral and enteral nutritional management, and that it is plausible low choline/PC status adversely affects intestinal function to set up the vicious cycle of inflammation, loss of intestinal barrier function and worsening tissue hypoxia that occurs with NEC. In conclusion, this review supports the need for randomized clinical trials to test the hypothesis that additional choline or PC provided parenterally or enterally can reduce the incidence of NEC in preterm infants. IMPACT STATEMENT: Low choline status in preterm infants who are managed by conventional nutrition is plausibly linked to the risk of developing necrotizing enterocolitis.

Utilization of a High Potency Probiotic Product for Prevention of Necrotizing Enterocolitis in Preterm Infants at a Level IV NICU.

Necrotizing enterocolitis (NEC) is a serious gastrointestinal disease that can be seen in premature infants with high risk for morbidity and mortality. There is currently no US Food and Drug Administration (FDA) medication approved for the prevention of NEC. Despite great heterogeneity among available studies, large meta-analyses of clinical trials have demonstrated the efficacy of multiple-strain probiotics in reducing NEC and all-cause mortality. In 2020, Medical City Dallas's Level IV neonatal intensive care unit (NICU) implemented a probiotic protocol for NEC prevention. As a result, a reduction in NEC was observed, with no occurrence of probiotic-related sepsis.

Enteral long-chain polyunsaturated fatty acids and necrotizing enterocolitis: A systematic review and meta-analysis

BackgroundPreterm infants are at risk of long-chain polyunsaturated fatty acid (LCPUFA) deficiency. Recent studies on high-dose DHA; n-3 LCPUFA in preterm infants suggested potential positive effects on cognitive outcomes but raised concerns about some increased neonatal morbidities. These studies and recent recommendations for DHA supplementation generated controversy owing to the lack of balance between DHA and arachidonic acid (ARA; n-6 LCPUFA). ObjectivesTo identify the effect of enteral supplementation of DHA, with and without ARA, on necrotizing enterocolitis (NEC) in very preterm infants. MethodsA systematic review of randomized and controlled trials compared enteral LCPUFAs with placebo or no supplementation in very preterm infants. We searched PubMed, Ovid-MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and CINHAL databases from inception to July 2022. Data were extracted in duplicate using a structured proforma. A meta-analysis and metaregression with random-effects models were used. The interventions evaluated were DHA alone vs. that combined with ARA, source of DHA, dose, and supplement delivery methods. Methodological qualities and risk of bias were assessed using the Cochrane risk-of-bias tool. ResultsFifteen randomized clinical trials (RCTs) included 3963 very preterm infants with 217 cases of NEC. Supplementation with DHA alone increased NEC (2620 infants; RR: 1.56; 95% CI: 1.02, 2.39) with no evidence of heterogeneity (I2 = 0.0%, P = 0.46). Multiple metaregression revealed significant reduction in NEC when ARA was supplemented with DHA (aRR 0.42; 95% CI: 0.21, 0.88). The source of DHA, dose, and feeding type revealed no associations with NEC. Two RCTs supplemented high-dose DHA to lactating mothers. There was a significant increase in risk of NEC with this approach (1148 infants; RR: 1.92; 95% CI: 1.02, 3.61) with no evidence of heterogeneity (I2 = 0.0, P = 0.81). ConclusionsSupplementation with DHA alone may increase risk of NEC. Concurrent supplementation with ARA needs to be considered when adding DHA to preterm infants’ diet.

Effects of prophylactic probiotics supplementation on infants born very preterm or very low birth weight.

To evaluate the effects of guideline-driven prophylactic supplementation of a multi-strain neonatal intensive care unit-specific probiotic product on infants born very preterm (VP) or very low birth weight (VLBW). A prospective cohort of 125 infants born in one year after implementation who received probiotics were compared to a retrospective cohort of eligible 126 VP or VLBW infants who did not receive probiotics. The primary outcome of interest was necrotizing enterocolitis (NEC). The incidence of NEC decreased from 6.3 to 1.6%. After adjusting for multiple variables, there were no significant differences in primary or other outcomes of interest; odds ratio (95% confidence interval) NEC 0.27 (0.05-1.33), death 0.76 (0.26-2.21) and late-onset sepsis 0.54 (0.18-1.63). No adverse effects related to probiotics supplementation were observed. Although nonsignificant, prophylactic probiotics supplementation in infants born VP or VLBW was associated with reduction of NEC.

The impact of a multifaceted quality improvement program on the incidence of necrotizing enterocolitis in very low birth weight infants

Necrotizing enterocolitis (NEC) is a multifactorial gastrointestinal disease which mostly occurs in very low birth weight (VLBW) infants. In addition to decreasing gestational age (GA) or birth weight (BW), artificial formula, delayed initiation or rapidly advanced feeding, severe anemia and systemic infections were associated with NEC. Several studies demonstrated that breast milk, standardized feeding advancement regimens and treatment of anemia are associated with less incidence of NEC. It is not known if including all these interventions in one multifaceted program will lead to significant reduction in NEC. The NICU team at The George Washington University Hospital created a multifaceted interdisciplinary quality improvement project to tackle several aspects of NEC prevention that addressed researched risk factors for NEC. The program was made of four quality improvement protocols: 1) Standardized Structured Feeding Program, 2) Feeding Intolerance Management Algorithm, 3) Enteral Osmolality Control Tool, and 4) Packed Red Blood Cell (RBC) Standardized Transfusion Protocol. This time-series, quasi experimental study design examined the differences in the incidence of NEC between infants with BW < 1500g who were admitted to the GW Hospital NICU before and after the program implementation. Data from 408 VLBW infants were included in the study. Although not statistically significant, there was a decreasing trend of NEC incidence in the post-implementation group (n=199) compared to the pre-implementation group (n=209), (3.5% vs. 5.3%, p=0.88). The trend in the incidence of NEC declined further after the introduction of RBC transfusion protocol which was introduced ten month after starting the other elements of the program. Integration of the multifaceted quality improvement program may be associated with a decline in the occurrence of NEC. Further analysis with a larger sample size is required to determine if the changes seen are statistically significant.

Incidence of spontaneous intestinal perforations exceeds necrotizing enterocolitis in extremely low birth weight infants fed an exclusive human milk-based diet: A single center experience

BackgroundSpontaneous intestinal perforation (SIP) and necrotizing enterocolitis (NEC) are complications of extremely low birth weight (ELBW, ≤1000 g) infants. ELBW infants at Texas Children's Hospital receive an exclusive human milk-based diet, which has been associated with a reduction of NEC. Objectives1) Assess incidence of SIP and NEC (Stage II or greater) in ELBW infants receiving 100% human milk-based diet, 2) Describe mortality rates of ELBW infants with SIP and NEC. MethodsProspective single-center observational cohort study of ELBW infants born between 2010 and 2014 with SIP or NEC (exclusion: congenital anomalies and death within 48 h). ResultsOf 379 ELBW infants, 345 were eligible. Of these, 28 (8.1%) had SIP and 8 (2.3%) had NEC (medical n = 1, surgical n = 7). SIP infant mortality was 32% (n = 9) compared to 63% (n = 5) for NEC patients. Of SIP infants with PD (n = 25), 52% required subsequent exploratory laparotomy (LAP). Of NEC infants with peritoneal drainage (PD) (n = 2), both required subsequent LAP. ConclusionUsing an exclusive human milk-based diet, the incidence of SIP exceeds NEC in ELBW infants at our institution. This shows a changing trend in the incidence of these two diagnoses in the era of human milk, as NEC had previously been more prevalent in ELBW infants. More than half of infants who initially received PD later required LAP. There were no differences in survival outcomes in both SIP and NEC groups based on surgical management.

Probiotics for Prevention of Severe Necrotizing Enterocolitis: Experience of New Zealand Neonatal Intensive Care Units.

Introduction: Necrotizing enterocolitis (NEC) affects mainly preterm infants, has a multifactorial etiology and is associated with intestinal dysbiosis and disordered immunity. Use of probiotics for prophylaxis is beneficial with studies indicating reduction in NEC ≥ stage 2, late onset sepsis (LOS) and mortality. However, not all studies have shown a reduction, there are questions regarding which probiotic to use, whether infants <1,000 g benefit and the risk of probiotic sepsis. All neonatal intensive care units in New Zealand (NZ) use probiotics and contribute to an international database (Australian and New Zealand Neonatal Network or ANZNN).Objective: To use ANZNN data to investigate the experience of NZ neonatal units with probiotics for NEC prevention in a setting where the baseline incidence of severe NEC was low, to compare results of 2 commonly used probiotic regimes and report on the extremely low birth weight subgroup.Method: Outcomes before (Pre group 2007–2010) and after (Probiotic group 2013–2015) starting routine probiotics for preterm infants <1,500 g or <32 weeks were compared. Clinicians reviewed cases to ensure they met database criteria. Five units used Infloran (Bifidobacterium bifidum and Lactobacillus acidophilus) and 1 unit used Lactobacillus GG (LGG) and bovine lactoferrin (bLF).Results: Four thousand five hundred and twenty nine infants were included and Pre and Probiotic groups were well-balanced with regard to gestation, birth weight and gender. The incidence of NEC in the Probiotic group was 1.6 and 2.7% in the pre group (corrected OR 0.62 CI 0.41–0.94). There was one case of probiotic sepsis. There was no significant difference between the Infloran and LGG/bLF combinations in regard to observed NEC rates. Late onset sepsis rates were significantly lower in the Probiotic group (p < 0.01).Conclusions: Introduction of probiotics for preterm infants in NZ has been associated with significant reductions in NEC and late onset sepsis.

Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants.

Background Indomethacin is used as standard therapy to close a patent ductus arteriosus (PDA) but is associated with reduced blood flow to several organs. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective as indomethacin with fewer adverse effects. Objectives To determine the effectiveness and safety of ibuprofen compared with indomethacin, other cyclo-oxygenase inhibitor, placebo or no intervention for closing a patent ductus arteriosus in preterm, low birth weight, or preterm and low birth weight infants. Search methods We searched The Cochrane Library, MEDLINE, EMBASE, Clincialtrials.gov, Controlled-trials.com, and www.abstracts2view.com/pas in May 2014. Selection criteria Randomised or quasi-randomised controlled trials of ibuprofen for the treatment of a PDA in newborn infants. Data collection and analysis Data collection and analysis conformed to the methods of the Cochrane Neonatal Review Group. Main results We included 33 studies enrolling 2190 infants. Two studies compared intravenous (iv) ibuprofen versus placebo (270 infants). In one study (134 infants) ibuprofen reduced the incidence of failure to close a PDA (risk ratio (RR) 0.71, 95% confidence interval (CI) 0.51 to 0.99; risk difference (RD) -0.18, 95% CI -0.35 to -0.01; number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 3 to 100). In one study (136 infants), ibuprofen reduced the composite outcome of infant mortality, infants who dropped out, or infants who required rescue treatment (RR 0.58, 95% CI 0.38 to 0.89; RD -0.22, 95% CI -0.38 to -0.06; NNTB 5, 95% CI 3 to 17). One study (64 infants) compared oral ibuprofen with placebo and noted a significant reduction in failure to close a PDA (RR 0.26, 95% CI 0.11 to 0.62; RD -0.44, 95% CI -0.65 to -0.23; NNTB 2, 95% CI 2 to 4). Twenty-one studies (1102 infants) reported failure rates for PDA closure with ibuprofen (oral or iv) compared with indomethacin (oral or iv). There was no significant difference between the groups (typical RR 1.00, 95% CI 0.84 to 1.20; I2 = 0%; typical RD 0.00, 95% CI -0.05 to 0.05; I2 = 0%). The risk of developing necrotising enterocolitis (NEC) was reduced for ibuprofen (16 studies, 948 infants; typical RR 0.64, 95% CI 0.45 to 0.93; typical RD -0.05, 95% CI -0.08 to -0.01; NNTB 20, 95% CI 13 to 100; I2 = 0% for both RR and RD). The duration of ventilatory support was reduced with ibuprofen (oral or iv) compared with iv or oral indomethacin (six studies, 471 infants; mean difference (MD) -2.4 days, 95% CI -3.7 to -1.0; I2 = 19%). Eight studies (272 infants) reported on failure rates for PDA closure in a subgroup of the above studies comparing oral ibuprofen with indomethacin (oral or iv). There was no significant difference between the groups (typical RR 0.96, 95% CI 0.73 to 1.27; typical RD -0.01, 95% CI -0.12 to 0.09). The risk of NEC was reduced with oral ibuprofen compared with indomethacin (oral or iv) (seven studies, 249 infants; typical RR 0.41, 95% CI 0.23 to 0.73; typical RD -0.13, 95% CI -0.22 to -0.05; NNTB 8, 95% CI 5 to 20; I2 = 0% for both RR and RD). There was a decreased risk of failure to close a PDA with oral ibuprofen compared with iv ibuprofen (four studies, 304 infants; typical RR 0.41, 95% CI 0.27 to 0.64; typical RD -0.21, 95% CI -0.31 to -0.12; NNTB 5, 95% CI 3 to 8). Transient renal insufficiency was less common in infants who received ibuprofen compared with indomethacin. High dose versus standard dose of iv ibuprofen, early versus expectant administration of iv ibuprofen, echocardiographically guided iv ibuprofen treatment vs. standard iv ibuprofen treatment and continuous infusion of ibuprofen vs. intermittent boluses of ibuprofen and long-term follow-up were studied in too few trials to draw any conclusions. Authors' conclusions Ibuprofen is as effective as indomethacin in closing a PDA and currently appears to be the drug of choice. Ibuprofen reduces the risk of NEC and transient renal insufficiency. Oro-gastric administration of ibuprofen appears as effective as iv administration. To make further recommendations, studies are needed to assess the effectiveness of high-dose versus standard-dose ibuprofen, early versus expectant administration of ibuprofen, echocardiographically guided versus standard iv ibuprofen, and continuous infusion versus intermittent boluses of ibuprofen. Studies are lacking evaluating the effect of ibuprofen on longer-term outcomes in infants with PDA.

Probiotics for preterm infants: A National Retrospective Cohort Study.

To evaluate the effect of prophylactic probiotic (PP) administration on rates of necrotizing enterocolitis (NEC), late-onset sepsis (LOS), and mortality in preterm infants. We conducted a retrospective cohort study of infants < 29 weeks' gestation, admitted to neonatal intensive care units participating in the Canadian Neonatal Network between 1 January 2014 and 31 December 2015. Infants in the exposure group received PP. A multiple logistic regression model with generalized estimation equation was used. A total of 3093 infants were included, 652 infants (21%) received PP. The adjusted odds ratios (aOR) of NEC (aOR 0.64, 95% confidence interval [CI] 0.410, 0.996), mortality (aOR 0.41, 95% CI 0.26, 0.63), and a composite of NEC or mortality were significantly lower in the PP group. There was no significant difference in the aOR of LOS. Prophylactic probiotic administration is associated with a reduction in NEC and mortality in preterm infants.

Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants.

Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants.

ENTERAL SUPPLEMENTATION WITH PROBIOTICS IN PREMATURE INFANTS: A RETROSPECTIVE COHORT STUDY

BACKGROUND: Necrotizing Enterocolitis (NEC) is the most devastating gastrointestinal emergency in preterm and very low birth weight infants. Despite preferential use of breastmilk, donor human milk, early treatment of sepsis, and a cautious approach to enteral feeding, the overall incidence of NEC remains high in Canada (1.5% to 9.3%) (2015 Canadian Neonatal Network). Probiotics, which are thought to prevent NEC by promoting colonization of the gut with beneficial organisms, have been drawing increasing attention worldwide. Expert bodies, including The Cochrane Collaboration, have indicated that a change in practice is warranted. OBJECTIVES: To assess the impact of an evidence-based practice change on multiple outcomes of an affected population; specifically, the impact of an enteral probiotic protocol on the rate of NEC in neonates born less than 33 weeks gestational age and/or less than 1500gm. DESIGN/METHODS: We conducted a retrospective cohort study with historical controls. Our NICU underwent an evidence-based change of practice in September 2014 with the implementation of a protocol for enteral administration of probiotics to infants born less than 33 weeks gestational age and/or less than 1500gm. The infants were provided with 0.5g of Florababy™, PO/NG/OG daily, starting with the first feed, and continued until discharge/transfer from hospital. We compared outcomes among infants admitted during the first 12 months of the practice change, to infants admitted 24 months prior. RESULTS: A total of 1018 infants were admitted to the NICU during the study period; 224 infants received probiotics. 390 infants formed the comparison group. All results are listed in the table below. Clinical outcomes of infants in the 2 cohorts: *N=363 for pre-probiotics cohort and 218 for post-probiotics cohort ** N=322 for pre-probiotics cohort and 188 for post-probiotics cohort *N=363 for pre-probiotics cohort and 218 for post-probiotics cohort ** N=322 for pre-probiotics cohort and 188 for post-probiotics cohort CONCLUSION: Daily, enteral supplementation with probiotics (Florababy™) to eligible infants showed a reduction in NEC. Although this finding did not reach statistical significance due to power, this result remains clinically significant considering the devastating effects of NEC.

Standardized slow enteral feeding protocol reduces necrotizing enterocolitis in micropremies.

Compared to early enteral feeds, delayed introduction and slow enteral feeding advancement to reduce necrotizing enterocolitis (NEC) is not well studied in micropremies (<750g birth weight). Pre-post case control study. Micropremies who followed a standardized slow enteral feeding (SSEF) protocol (September 2009 to March 2015) were compared with a similar group of historical controls (PreSSEF, January 2003 to July 2009). Enteral feeding withheld for first 10-14 days and advanced at <10 ml/kg/day in the SSEF group. Ninety-two infants in the SSEF group were compared with 129 PreSSEF group. Birth weight and gestational age in SSEF and PreSSEF were similar. Breast milk initiation rate was higher in SSEF (87.0 vs. 72.0%, p = 0.01) compared to PreSSEF, but were similar at full enteral feeds. Compared with PreSSEF, feeding initiation day, full enteral feeding day, parenteral nutrition days, and total central line days were longer in SSEF. There was significant reduction in NEC (1.1 vs. 16.2%, p < 0.01), surgical NEC (0.0 vs. 7.8%, p < 0.01) and NEC/death (7.6 vs. 29.5%, p < 0.01), in SSEF compared to PreSSEF. SSEF, compared to PreSSEF, had more cholestasis (41.8 vs 28.8%, p = 0.04), higher peak serum alkaline phosphatase (638 vs. 534 IU/dL, p < 0.01), but similar rates of late-onset sepsis (39.1 vs 43.4%, p = 0.53). In infants who survived to discharge, SSEF had higher discharge weight, lower extra-uterine growth restriction, and similar length of stay, compared to PreSSEF. A SSEF protocol significantly reduces the incidence of NEC and combined NEC/death in micropremies.

Reduced Necrotizing Enterocolitis after an Initiative to Promote Breastfeeding and Early Human Milk Administration.

Introduction:We sought to reduce the incidence of necrotizing enterocolitis (NEC) in premature infants (PI) by fostering the postnatal establishment of protective intestinal bacteria through early administration of human milk (HM) and probiotics.Methods:A multidisciplinary team implemented an initiative to support breastfeeding (BF) and provide early postnatal supplemental donor human milk (DHM) and probiotics to PI. Interventions included process improvements in milk preparation, storage, and fortification. PI admitted to our NICU between 2006 and 2015 were monitored for feeding of HM, DHM, and preterm formula (PF), frequency of early feedings, and incidence of NEC.Results:Retrospective review of 2557 cases revealed post-initiative increases in the percentage of PI receiving HM (91.5% to 96.1%), HM within 48 hours of birth (75% to 90.6%), and DHM (17.7% to 71.9%). The percentage of infants receiving feedings on day one increased from 23.9% to 44.6% while the percentage receiving PF within the first 72 hours declined (31.2% to 10.3%). The NEC rate declined from 4.1% to 0.4%. Reduction in NEC occurred despite a simultaneous increase in perinatal antibiotic exposure and the universal but late administration of bovine HM fortifier. The improvement associated with the decrease in NEC included initiation of probiotic administration, a reduction in PF feeding, and improvements in milk preparation, storage, and fortification processes.Conclusions:Early exclusive feedings of HM and avoidance of PF together with probiotics and milkhygiene may decrease NEC in PI. Neither brief perinatal antibiotic exposure nor late introduction of bovine fortifiers appears detrimental in this context.

Benefits of Bifidobacterium breve M-16V Supplementation in Preterm Neonates - A Retrospective Cohort Study.

BackgroundSystematic reviews of randomised controlled trials report that probiotics reduce the risk of necrotising enterocolitis (NEC) in preterm neonates.AimTo determine whether routine probiotic supplementation (RPS) to preterm neonates would reduce the incidence of NEC.MethodsThe incidence of NEC ≥ Stage II and all-cause mortality was compared for an equal period of 24 months ‘before’ (Epoch 1) and ‘after’ (Epoch 2) RPS with Bifidobacterium breve M-16V in neonates <34 weeks. Multivariate logistic regression analysis was conducted to adjust for relevant confounders.ResultsA total of 1755 neonates (Epoch I vs. II: 835 vs. 920) with comparable gestation and birth weights were admitted. There was a significant reduction in NEC ≥ Stage II: 3% vs. 1%, adjusted odds ratio (aOR) = 0.43 (95%CI: 0.21–0.87); ‘NEC ≥ Stage II or all-cause mortality’: 9% vs. 5%, aOR = 0.53 (95%CI: 0.32–0.88); but not all-cause mortality alone: 7% vs. 4%, aOR = 0.58 (95% CI: 0.31–1.06) in Epoch II. The benefits in neonates <28 weeks did not reach statistical significance: NEC ≥ Stage II: 6% vs. 3%, aOR 0.51 (95%CI: 0.20–1.27), ‘NEC ≥ Stage II or all-cause mortality’, 21% vs. 14%, aOR = 0.59 (95%CI: 0.29–1.18); all-cause mortality: 17% vs. 11%, aOR = 0.63 (95%CI: 0.28–1.41). There was no probiotic sepsis.ConclusionRPS with Bifidobacterium breve M-16V was associated with decreased NEC≥ Stage II and ‘NEC≥ Stage II or all-cause mortality’ in neonates <34 weeks. Large sample size is required to assess the potential benefits of RPS in neonates <28 weeks.

Harvesting the benefits of biofilms: A novel probiotic delivery system for the prevention of necrotizing enterocolitis

Background/purposeProbiotics reduce the incidence of necrotizing enterocolitis (NEC) albeit only when administered at high frequency (at least daily). We have developed a novel probiotic delivery system in which probiotics are grown as a biofilm on microspheres, allowing enhanced efficacy with only a single treatment. MethodsNeonatal rats were subjected to experimental NEC. Pups received a single enteral dose of: (1) vehicle only, (2) unloaded microspheres, (3) MRS (broth)-loaded microspheres, (4) Lactobacillus reuteri, (5) L. reuteri grown on unloaded microspheres, or (6) L. reuteri grown on MRS-loaded microspheres. Intestinal injury was graded histologically and intestinal permeability determined by serum levels of enterally administered fluorescein isothiocyanate-labeled dextran. Results69% of untreated pups developed NEC, whereas 32% of pups treated with L. reuteri grown as a biofilm on unloaded microspheres (p=0.009) and 33% of pups treated with L. reuteri grown as a biofilm on MRS-loaded microspheres (p=0.005) developed NEC. No other group had a significant reduction in NEC. Furthermore, pups treated with L. reuteri grown as a biofilm had significantly reduced intestinal permeability. ConclusionsA single dose of Lactobacillus biofilm grown on biocompatible microspheres significantly reduces NEC incidence and severity. This novel probiotic delivery system may be beneficial in the prevention of NEC in the future.

Cohort Study of Probiotics in a North American Neonatal Intensive Care Unit

To determine whether routine probiotic administration to very preterm infants would reduce the incidence of necrotizing enterocolitis (NEC) without adverse consequences. Since the end of July 2011, we have administered a probiotic mixture to all admitted infants of <32 weeks' gestation. We give 0.5 g of a mixture of 4 bifidobacteria (Bifidobacterium breve, bifidum, infantis, and longum) and Lactobacillus rhamnosus HA-111 [corrected] (2 × 10(9) colony-forming units) per day, starting with the first feed, until the infant reaches 34 weeks. We compared complications among infants admitted during the first 17 months of routine use with those admitted during the previous 17 months. Two hundred ninety-four infants received probiotics, and 317 infants formed the comparison group. Introduction of probiotics was associated with a reduction in NEC (from 9.8% to 5.4%, P < .02), a nonsignificant decrease in death (9.8% to 6.8%), and a significant reduction in the combined outcome of death or NEC (from 17% to 10.5%, P < .05). After adjustment for gestational age, intrauterine growth restriction, and sex, the improvements remained significant (OR for NEC, 0.51; 95% CI, 0.26-0.98; OR for death or NEC, 0.56; 95% CI, 0.33-0.93). There was no effect of probiotics on health care-associated infection. A product that is readily available in North America, that has excellent quality control, and that contains strains similar to those that have been shown effective in randomized controlled trials substantially reduced the frequency of NEC in our neonatal intensive care unit.

Increasing the Global Supply and Affordability of Donor Milk

Human milk banking was virtually discontinued at the start of the human immunodeficiency virus era amid fears that the virus might be transmitted to preterm infants receiving donor milk. However, the demand for donor breastmilk has continued to be driven by decades of research that have increasingly demonstrated the benefits of breastmilk in neonatal care regarding the reduction of lifethreatening necrotizing enterocolitis (NEC) and infection, as well as improving long-term outcomes, notably neurodevelopment and bone health. Despite the progressive return of milk banking during the past two decades, the demand for breastmilk has not been met. Now, this problem has been greatly compounded by a recent, radical increase in demand for human donor milk resulting from compelling new research that is changing the standards for how preterm infants are fed. This new research is rooted in the concept of ‘‘lactoengineering,’’ using human milk components to produce formulations and fortifiers designed to meet the special nutritional needs of preterm infants. This concept was introduced by Lucas et al. in 1980 and more recently commercialized to produce a human milk-based fortifier designed for use in the neonatal intensive care unit. The production and use of such ‘‘lactoengineered’’ products in the United States have facilitated randomized clinical trial comparisons to be made between extremely premature infants fed on human milk plus cows’ milk-based fortifier or cows’ milk-based products alone, compared with a diet that is solely based on human milk, completely excluding exposure to cows’ milk. Published clinical trial evidence has shown that such an exclusively human milk-based diet results in a major reduction in NEC, a dramatic reduction in surgical NEC, a significant reduction in mortality, and a reduction in the duration of potentially hazardous parenteral nutrition. Apart from the demonstration of such important health benefits of an exclusively human milk-based diet, the estimated health economic benefits are large, with potential savings of billions of dollars in the United States each year. But, these benefits are only possible if the supply of donor milk increases to the level required to provide a higher protein density that forms the basis for the new lactoengineered products. The availability of donor milk has diminished to the point that milk banks cannot even serve the demands of the small percentage of hospitals using donor milk. Lack of awareness, low breastfeeding rates, and the diversion of donor milk to informal milk sharing programs have been cited as the root cause of the donor milk shortage. It has also been suggested that the responsibility for increasing the supply of donor milk rests with healthcare professionals who should compel their patients to donate breastmilk. No credible evidence has been presented to support that case, and, surprisingly, there seems to be no clear plan to solve the current shortage. General statements about encouraging breastfeeding, increasing breastfeeding rates, and the societal responsibility to ensure that nursing mothers donate milk have been put forth as a solution for years, yet the current milk banking systems continue to provide only a small percentage of the donor milk needed for the most vulnerable infants. It is time for a radically different approach if we are to see this problem solved in our lifetimes. More importantly, how many lives must be lost in neonatal units before a different approach is supported? A global perspective on the availability of donor milk is even more sobering. A recent report on global prematurity states that there are 15 million preterm infants born each year. If we can’t provide an adequate supply of donor milk in the United States for a mere 67,000 preterm babies, how can we expect countries with significant constraints on resources to do so?

Pharmacoeconomic impact of use of the probiotic Lactobacillus reuteri DSM 17938 for prevention of necrotizing enterocolitis in extremely low-birth-weight infants

Pharmacoeconomic impact of use of the probiotic Lactobacillus reuteri DSM 17938 for prevention of necrotizing enterocolitis in extremely low-birth-weight infants Mary Ann VT Dimaguila,1,2 Peter Gal,1,3,4 Tiffany Wilson,1 John E Wimmer Jr,1,2 McCrae Smith,1,2 Rita Q Carlos,1,2 Christie C Davanzo,1,2 J Laurence Ransom1,2 1Women&#39;s Hospital of Greensboro, Cone Health, Greensboro, NC, USA; 2Piedmont Neonatology, Greensboro, NC, USA; 3Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 4Greensboro Area Health Education Center, Greensboro, NC, USA Background: A recent study showed that use of Lactobacillus reuteri as probiotic prophylaxis decreased the necrotizing enterocolitis (NEC) rate from 15.1% to 2.5% in neonates with birth weight below 1000 g. Given the controversies surrounding use of probiotics in neonatal intensive care units, we address one additional aspect of routine implementation of probiotics for NEC prophylaxis &ndash; the pharmacoeconomic impact. Methods: Using data from our initial published experience, and continuing data collection after instituting a higher dose of L. reuteri, we measured the reduction in NEC in neonates with birth weight below 1000 g. Cost savings from prior studies examining the cost and outcomes of medical and surgical NEC were used to calculate the financial impact of routine L. reuteri DSM 17938 prophylaxis. Results: Medical records for 354 neonates were reviewed, 232 in the years before introduction of L. reuteri prophylaxis and 79 who received L. reuteri prophylaxis dosed at 0.1 mL daily and 43 neonates given a total daily dose of 0.2 mL as one or two doses. The incidence of NEC was significantly lower in the neonates who received L. reuteri (two of 122 neonates [1.6%] versus 35 of 232 neonates [15.1%]). The expected benefits for our neonatal intensive care unit per 100 extremely low-birth-weight neonates treated were four fewer deaths, five fewer cases of medical NEC, eight fewer cases of surgical NEC, one less patient with short-bowel syndrome, and a cost saving of approximately $2.2 million. Conclusion: Prophylactic initiation of L. reuteri as a probiotic for prevention of NEC in neonates with birth weight &le; 1000 g is a cost-effective strategy during their stay in neonatal intensive care. Keywords: necrotizing enterocolitis, probiotic, extremely low birth weight, Lactobacillus reuteri, pharmacoeconomics

Results of a two-center, before and after study of piperacillin–tazobactam versus ampicillin and gentamicin as empiric therapy for suspected sepsis at birth in neonates ⩽1500 g

We changed from ampicillin and gentamicin (AG) to piperacillin-tazobactam (PT) for routine treatment of suspected early-onset sepsis. The rationale for this change included ototoxic and renal toxic effects of gentamicin, resistance to gentamicin in late-onset infections and emergence of ampicillin resistant Escherichia coli. A before and after study was designed before the start of PT administration to monitor whether PT was associated with altered outcomes within the 501 to 1500 g birth weight (Very Low Birth Weight) population. Both unmatched and matched comparisons of AG (2007 to 2009) and PT (2010 to 2011) exposed infants are reported. Cohorts were evaluated for initial effectiveness for congenital infections, subsequent morbidities and mortality. Data from 714 patients were collected (499 AG and 215 PT in the unmatched and 301 AG and 183 PT in the matched cohorts). No significant differences in demographics or initial Apgar scores were noted in the unmatched or matched comparisons. There were significant differences in many of the outcomes of interest in both the matched and unmatched comparisons including less necrotizing enterocolitis (NEC) and less diaper rash with PT versus AG. The only adverse finding with PT was a small, but statistically significant elevation in alkaline phosphatase. Use of PT as the initial empiric antibiotic for very low birth weight infants was not associated with adverse microbiological outcomes. There was no increase in major morbidities. Although outcomes were superior in ≤ 1500 g infants treated with PT when compared with AG, the study design does not allow us to conclude that others will see a reduction in NEC or diaper rash if they implement this alternative.