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ORIGINAL RESEARCH |
https://doi.org/10.5005/jp-journals-11002-0094 |
A Clinical Care Bundle to Prevent Necrotizing Enterocolitis
Corresponding Author: Corresponding Author: Nitasha Bagga, Department of Neonatology, Rainbow Children’s Hospital, Hyderabad, Telangana, India; Global Newborn Society, Clarksville, Maryland, United States of America, Phone: +91 90007 64206, e-mail: nitashabagga@gmail.com
How to cite this article: Bagga N, Maheshwari A, Jha K, et al. A Clinical Care Bundle to Prevent Necrotizing Enterocolitis. Newborn 2024;3(2):70–82.
Source of support: Parts of the information in this article were obtained in studies supported by the NIH grants HL124078 and HL133022 (AM).
Conflict of interest: Dr Akhil Maheshwari is associated as the Editor-in-Chief of this journal. This manuscript was subjected to this journal’s standard review procedures, with this peer review handled independently of the Editor-in-Chief and his research group.
Received on: 12 May 2024; Accepted on: 10 June 2024; Published on: 21 June 2024
ABSTRACT
Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in very-low-birth-weight (VLBW) infants all over the world. Even thought the incidence of NEC has decreased over the past decade, it continues to affect 5–7% of premature infants born ≤ 32–33 weeks. The disconcerting part is that the incidence of NEC has not changed despite continuous efforts to understand its etiopathogenesis. Because of limited information about the cause of this disease, our group has increasingly focused on developing a clinical care bundle to treat these patients. As we know, a bundle is a structured attempt to improve the care of patients with a specific nosological entity, to improve outcomes. The team adopts a small number of, usually 3–5 evidence-based, proven practices which when performed reliably and consistently, have been shown to improve patient outcomes. In this article, we have focused on the use of human milk, including mother’s own, that from donors, and of oral colostrum; standardized feeding practices; prevention of intestinal dysbiosis with antibiotic stewardship and use of probiotics; avoiding certain medications, such as histamine receptor blockers; adequate management of anemia; and antenatal use of corticosteroids. In these efforts, we have combined information from our own peer-reviewed clinical and preclinical studies with an extensive review of the literature from the databases PubMed, EMBASE, and Scopus.
Keywords: Care bundle, Human milk oligosaccharides, Intestinal injury, Intestinal failure, Institute of Health Care Improvement, Mother’s own milk, NEC Newborn, Neonate, Preterm.
KEYPOINTS
Necrotizingenterocolitis (NEC) is a leading cause of morbidity and mortality in very-low-birth-weight (VLBW) infants all over the world.
Despite all efforts, the etiopathogenesis of NEC remains unclear. Hence, at our centers, we have focused on developing a clinical care bundle to address known risk factors.
Per accepted definitions of clinical bundles, this is a structured attempt to establish protocols to prevent/mitigate five major risk factors associated with NEC.
We have focused on efforts to promote human milk feedings, standardize feeding practices, prevent intestinal dysbiosis, manage anemia, and encourage prenatal use of corticosteroids.
This clinical care bundle is focused on risk factors seen in both temperate and the relatively disadvantaged peri-equatorial and tropical climate regions. There is a need for continued evaluation and refinement of the components of this bundle.
INTRODUCTION
Necrotizingenterocolitis (NEC) is one of the most dreaded illnesses of premature infants. Although the incidence has decreased over the past decade, it continues to affect 5–7% of premature infants born < 32–33 weeks. Even though we have had some success in reducing the incidence of NEC in the West, the absolute number of infants with NEC has increased globally with increasing survival of more premature infants all over the world.1–3 NEC is not only associated with high morbidity and mortality, but it also lengthens the hospital stay, increases the cost of care, and affects the neurodevelopmental outcomes of premature infants.4–6 Many studies have evaluated antenatal steroids, delayed cord clamping, exclusive use of mother’s own milk (MOM)/human milk (HM), oral colostrum care, standardized feeding guidelines, antibiotic stewardship, reduced use of proton pump inhibitors (PPIs) and H2-blockers, administration of probiotics, and prevention of severe anemia as strategies to prevent NEC. These interventions have traditionally been assessed as singular measures7–9 but now a combined, care bundle approach is emerging as an alternative, effective option.10–12 In this article, we have described our efforts to identify, develop, evaluate, refine, and re-implement five chosen prongs of a care bundle to prevent NEC: antenatal practices, human milk feedings, enteral feeding practices, prevention of intestinal dysbiosis, and prevention of anemia.
Besides emphasizing specific practice measures, we also need a better understanding of implementation science to focus on compliance and continuing education.13,14 The efforts to define/refine the care bundle have to be a continuous process.15 If considered from a more global perspective, these efforts will have to be tailored for different parts of the world. For instance, maternal anemia might make delayed cord clamping particularly important in some regions.16 The importance of probiotics might vary because the acquisition, spectrum, and expansion of gut microflora in the neonatal intestine might not be identical across the world.17 The effects of these bacterial genera might change with the degree of prematurity.18 Maybe even with climatic conditions.19 Donated human milk might need to be stored differently.20 There might be a genetic predisposition to many toxins and pathogens in different regions.21 In short, we will continuously need more information.
Defining NEC
NEC is an inflammatory condition of the bowel. It has been defined/assessed for severity using Bell’s criteria (1978)22 and then with the modifications proposed in this staging (Walsh and Kliegman):23
i. Stage I (suspect): non-specific signs and symptoms, non-diagnostic radiographs;
ii. Stage II (definite): definite pneumatosis or hepatic portal venous gas on X-rays or intestinal ultrasound or surgical or autopsy diagnosis of NEC:
IIa: mildly ill.
IIb: moderately ill with systemic toxicity.
iii. Stage III (advanced): definite pneumatosis or hepatic portal venous gas on X-rays or intestinal ultrasound or surgical or autopsy diagnosis of NEC.
IIIa: critically ill, Disseminated intravascular coagulation, shock, ascites, impending intestinal perforation.
IIIb: critically ill, as in IIIa, with pneumoperitoneum.
Even though Bell’s staging has been challenged and modified in the last decade with many state-of-the-art reviews,24–26 defining it is beyond the scope of this article. Also, we must be cautious while defining NEC as there is a risk of misclassification with conditions that mimic NEC (NEC associated with congenital heart disease, cow’s milk protein intolerance, transfusion-associated gut injury, and viral illness).27,28 There is a controversy if spontaneous intestinal perforation (SIP) and NEC are the two spectrums of the same illness.29,30 For all practical purposes, diagnosis of ‘NEC-mimics’ or radiographs showing pneumoperitoneum without pneumatosis or systemic signs are not considered NEC. It is always advisable to have the agreement of two neonatologists, with one involved in patient care or a neonatologist and a radiologist while confirming the diagnosis of NEC. NEC is a multifactorial pathogenesis that involves numerous pathways.31 Intestinal immaturity, highly immunoreactive intestines, disturbed intestinal microbiota and colonization of the gut with bacteria are the most common etiopathogenesis of NEC.32–34 Despite best understanding of the disease per se and many preventive interventions, NEC has got global burden of 20–30% mortality, with increased mortality in surgical cases with long-term complications being intestinal stricture, short bowel syndrome, and intestinal failure.35–37
Defining Care Bundle
Care bundles are a group of evidence-based interventions related to a disease or care process that when executed together, result in better outcomes than when these are implemented individually.38 To improve medical care and adherence to evidence-based guidelines in ICUs, the concept of “care bundles” was strategized by the Institute of Health Care Improvement (IHI).39,40 Care bundles were outlined to be a group of either evidence-based or nationally accepted guidelines consisting of 3–5 interventions to be applied to all patients unless contraindicated.39–42 For NEC, a care bundle was first implemented in the East of England due to the high incidence of NEC in 17 local units. Aiming to decrease the incidence of NEC, 15 factors associated with NEC were evaluated and eventually, three – exclusive breast milk feeding, prevention of infection, and enteral feeding strategies were found evidence-based and easy to implement.10 This care bundle became a routine practice in the region. Subsequently, many quality improvement initiatives were evaluated in the last decade for reinforcing the care bundle10,12,43–45 but these were not found as effective. In one robust study, Belal et al.11 from Canada studied the impact of bundled multidisciplinary guidelines over 10 years and noted a sustained reduction in the NEC in very preterm infants. This study showed that a multipronged approach can be important for preventing a disease with an uncertain, possibly multifactorial etiopathogenesis. Here, we have reviewed our NEC care bundle that is comprised of five prongs: exclusive HM feeds, enteral feeding practices, prevention of intestinal dysbiosis, prevention of severe anemia, and antenatal practices (Fig. 1).
Fig. 1: NEC care bundle—an effort toward zero-NEC
NEC Care Bundle
Exclusive human milk (HM) feedings
i) Reinforcement of exclusive MOM: HM, with its complex composition of nutrients bioactive factors, and immune components has been shown to play a crucial role in protecting the immature gut of neonates against NEC. Human milk oligosaccharides (HMOs), alongside antimicrobial factors such as lactoferrin and secretory IgA antibodies, inhibit harmful bacteria and promote gut health. Moreover, breast milk provides essential nutrients and growth factors, such as epidermal growth factor, vital for intestinal development and repair, reducing inflammation risks. Its diverse composition also fosters a healthy intestinal microbiota, aiding in long-term immune health. Overall, HM’s multifunctionality makes it a vital defense against NEC. The correlation between the reduction of NEC and HM feeding has been extensively studied. Schanler et al., and later Sisk and colleagues and Meinzen Derr and co-workers confirmed that the effect of breast milk in reducing NEC is dose-dependent.46–49 These studies showed that every 100 mL/kg increase in HM feeding during the first 2 weeks after birth reduced the subsequent risk of NEC or death (hazard ratio) by 0.87. Mavis et al.45 reported focusing primarily on using exclusively HM, including HM-based fortifiers, and prioritizing MOM in infants born at less than 30 weeks’ gestation reduced the incidence of NEC from 19.5 to 6%. In a systematic review, Anantham and her colleagues50 showed that fortification with HM fortifier reduced the risk of NEC ≥ stage II and surgical NEC when compared with BM fortifier.
ii) Judicious use of donor HM: There is enough literature to support the fact that donor HM remains the second-best choice when a MOM is not available. Quigley et al.51,52 compared formula vs donor HM feedings in 1809 preterm and low-birthweight infants; the systemic review and meta-analysis showed that donor HM reduced the risk of NEC when compared with preterm formula. A meta-analysis of randomized controlled trials (RCTs) done by Altobelly et al.53 showed a risk reduction of NEC vs HM to formula to 0.62 (0.42–0.93). The OptiMoM trial by O’Connor et al.54 showed a statistically significant reduction in surgical NEC in the group receiving donor milk with HM-based fortifier group compared with those fed with formula. In another study, Lucas and Cole55 showed that confirmed NEC was 6–10 times more frequent than that in exclusively formula-fed babies than in those fed HM alone and three times more common than in those who received formula plus HM. Cristofelo et al.56 performed a RCT and showed that a higher risk of surgical NEC in extremely premature babies on formula feed vs HM feedings. Sullivan et al.57 further found a 50% reduction in NEC and surgical NEC of nearly 90% in infants fed an exclusive HM diet compared with a diet containing BM-based products. In another study, Allana et al.58 showed that donor HM in a community with restricted access to HM facilitated earlier commencement of enteral feeding with less NEC. However, some studies suggest that the benefits of HM still might be questionable, particularly for surgical NEC.59
iii)Oral colostrum care: HM colostrum is a rich source of proteins, immunoglobulins, minerals, and fat-soluble vitamins.7 However, for various reasons, the availability of colostrum in adequate volumes for feeds is unavailable for extremely premature infants. Several studies support the use of colostrum for oral care as immunotherapy. A meta-analysis of RCTs showed the efficacy of this oral colostrum therapy (OCT) in the prevention of NEC.60 A recent meta-analysis of eight RCTs showed that buccal application of colostrum increased IgA levels and reduced incidence of NEC.61 However, there was no significant difference in the incidence of NEC in 4 RCTs with 148 subjects. There is a need for further study.
Enteral feeding practices
i) Standardized enteral feeding protocol
The standardization of feeding protocols (SFP) is an effective structured approach that requires physicians to follow specified criteria to initiate, advance, fortify, or stop feeding. Standardization of feeding protocols is considered the most simple and effective method for improving nutritional care and reducing the risk of NEC in preterm neonates In 2015, a systematic review based on 15 observational studies62 concluded that SFPs significantly decreased the incidence of NEC. The results remained statistically significant even after comparing studies in two meta-analyses (1978–2003 vs 2004–2016).62 The authors also suggested that early introduction and advancement of enteral feeding do not increase the risk of NEC but helped prevent NEC. In 2017, Gephart et al.9 reviewed studies and showed lower/unchanged rates of NEC when a SFP was used. A similar retrospective observational study63 showed a decreased incidence of NEC stage II when unit-specific SFPs were used. All NICUs should adopt SFPs to ensure timely initiation and advancement of feedings even though these SFPs might vary widely; the following approaches have been used:7,9 (a) preferred and onset of feeding substance; (b) advancement of feeding; (c) time and type of fortification; (d) conditions to hold and specified indications on when to resume feeding; (e) management of feeding intolerance; and (f) initiation and duration of trophic feedings.
ii) Feeding during special circumstances
Feeding guidelines in infants with abnormal Dopplers: Umbilical Doppler flow abnormalities occur in 6% of high-risk pregnancies.64,65 Antenatal Doppler disturbances are associated with fetal hypoxia, inducing brain-sparing vascular redistribution and compromising splanchnic circulation. This may reduce the thickness of the intestinal wall, villous length and weight, and crypt depth, which leads to dysregulation of motor, secretory, and mucosal functions predisposing to stasis and dysbiosis leading to feed intolerance and NEC. The persistence of circulatory changes in the superior mesenteric artery (SMA) and celiac axis even after birth, causes further concerns.66 Neonates with AREDF (absent/reversal of end-diastolic flow) are twice at risk of NEC as infants with normal Dopplers.66 Minimal enteral nutrition (MEN) should be started in all preterm infants with abnormal Dopplers. ADEPT (abnormal Doppler enteral prescription trial) randomized 404 infants to early feeding (24–48 hours) or late feeding (120–144 h) and found no difference in the incidence of NEC or sepsis.67 Similarly, other studies suggest that delayed introduction of feeds in neonates with AREDF was associated with increased morbidities in neonates.68 While advancing feeds, the ADEPT trial demonstrated continuing MEN for 2–3 days for <1000 gm, while >1000 gm received progressive feeds from postnatal day 2. A recent systemic review with 1499 preterm infants concluded that with early feeding initiation, there was a trend toward an increase in rates of feeding intolerance; however, the incidence of NEC did not increase.69 The rate of advancement of feeds has wide variability. Evidence suggests that it is safe to increase feeds by 30–35 mL/kg/day in stable preterm neonates.70 A randomized trial from India in infants weighing 1000–1499 gms has also shown that those in the rapid feeding advancement group (30 mL/kg/day) achieved full volume feedings significantly earlier than the slow advancement group (median 7 days vs 9 days) (p < 0.001), had fewer days of intravenous fluids (median 2 days vs 3.4 days) (p < 0.001), shorter length of stay in hospital (median 9.5 vs 11 days; p = 0.003), and regained birth weight sooner (median 16 vs 22 days) (p < 0.001). There was no difference in the number of infants with apnea and feeding intolerance intolerance.71
Feeding during management of patent ductus arteriosus (PDA): The presence of hemodynamically-significant PDA (hs-PDA) poses a challenge in feeding premature infants due to the increased risk of gastrointestinal complications. In the presence of a ductal shunt, there might be a significant diminution of splanchnic perfusion and oxygenation depending on the magnitude of the left-to-right shunt volume through PDA. This “steal” phenomenon predisposes premature infants to feed intolerance and NEC. Furthermore, pharmacotherapy for the treatment of PDA with indomethacin, ibuprofen, and more recently, acetaminophen/paracetamol makes it more challenging as these pharmacological agents have been associated with gastrointestinal side effects like vasoconstriction of the SMA and consequent reduction in intestinal perfusion.65,72 Although ibuprofen does not reduce gut perfusion, its high osmolality has caused concerns for gastrointestinal bleeding, NEC, and bowel perforation. Having said this, other studies have suggested that infants receiving trophic feeds during pharmacotherapy with indomethacin and ibuprofen required less time to reach full feeds and did not increase the incidence of NEC.73,74 Again, the evidence to suggest that the hs-PDA and the benefits of continuing vs withholding feeding during pharmacological treatment of PDA are controversial. Due to a lack of sufficient data, it is difficult to standardize feeding guidelines during the pharmacological treatment of PDA in preterm infants and should be individualized as per the clinical and hemodynamic status of the infant.75 In infants who undergo surgical closure of hs-PDA, the risk of composite adverse outcomes including mortality, intraventricular hemorrhage grade 3 or 4, periventricular leukomalacia, severe retinopathy of prematurity, bronchopulmonary dysplasia, or NEC stage II or III in preterm infants may be higher.76 Studies have also highlighted that the timing of PDA ligation after 2–3 postnatal weeks may be associated with delayed in the achievement of full enteral feedings and higher incidence of NEC.77,78 Similarly, there may be a higher incidence of post-ligation cardiac syndrome (PLCS), characterized by hypotension requiring cardiovascular support, oxygenation failure, and assisted ventilation.78 However, the causal relation between PLCS and the risk of GI complications is not yet clearly defined.
Feeding during blood transfusions: Apart from various known risk factors, NEC has increasingly been associated with packed red blood cell (RBC) transfusions. Transfusion-associated NEC (TANEC) is a clinical condition characterized by the development of NEC (Bell’s stage II and above) within 48 hours of RBC transfusion.79 Despite the plausibility of the association and strong preclinical evidence between PRBC transfusion and NEC, the clinical evidence supporting a causal relationship remains uncertain.80–82 The RCT, feeding during red cell transfusion (FEEDUR),83 compared different regimens of feeding during transfusion and found no difference in the splanchnic oxygenation, when during transfusion, enteral feeds were either withheld, continued, or restricted. Another meta-analysis including RCT and quasi-randomized control trials was inconclusive in stopping feeds while blood transfusion in preterm infants to prevent TANEC.84 Another multicenter RCT, WHEAT (withholding enteral feeds around packed cell transfusion) is underway to provide new insights and clarity.85 Though retrospective studies have shown an association between transfusion of PRBC and NEC, RCT evidence is insufficient to recommend feeding guidelines during transfusion.84 Continuing MEN during RBC transfusions is recommended and needs larger studies to devise feeding strategies during red cell transfusion.
Prevention of intestinal dysbiosis
i) Antibiotic stewardship: Premature infants and infants with co-morbidities are highly susceptible to infections; antibiotics are a cornerstone for neonatal care. However, non-specific presentation and lack of sensitivity and specificity value make unnecessary overuse of antibiotics, which is linked to adverse outcomes like NEC, sepsis, fungal infection, and mortality.86,87 As prior bacterial infections are a known risk factor for NEC, there have been two schools of thought-prophylactic antibiotic usage for prevention of NEC and restrictive use of antibiotics to prevent intestinal dysbiosis and NEC.88 A few RCTs such as the ones conducted by Tagare et al.,89 Kenyon et al.,90 and Owen et al.91 concluded that there is no role of routine antibiotic use in the prevention of NEC. Moreover, a meta-analysis by Fan et al.92 included 9 RCTs and retrospective cohort studies; they analyzed 5207 preterm infants but found no role of prophylactic antibiotics in the prevention of NEC in high-risk preterm infants. Other studies, actually show some evidence to suggest that prolonged use of empirical antibiotics might increase risk of NEC. Cotton et al.93 showed that empirical use of antibiotics for more than 4 days in culture-negative sepsis increased the risk of NEC or death in extremely low birth weight infants. Implementing antimicrobial stewardship programs is a core element outlined by the Centers for Disease Control and Prevention (CDC) to promote thoughtful antibiotic use in NICUs. These programs advocate for targeted therapy with reduced duration and unnecessary consequences of antibiotic misuse. A multicenter study has demonstrated a 34% reduction in antibiotic use with implementation of antimicrobial stewardship guidelines.94
ii) Avoid using histamine-2 receptor antagonists (H2-receptor blockers) and PPIs: Use of H2-receptor blockers and PPIs can alter the intestinal flora and consequently, increase the risk of NEC.95–99 H2-blockers and PPIs make the gastric pH alkaline, increase the risk of gastrointestinal infections, especially with Gram-negative bacteria,100 and also increase intestinal motility and contractility, which could all increase the risk of NEC.101 Guillet et al. concluded in their case-control study that there is an increased risk of NEC (>Bell’s stage II) with the use of H2 blockers.95 In a multicenter trial, Terrin et al.102 showed a 6.6-fold increase in the risk of NEC with the use of H2-blockers. A systematic review and meta-analysis of three observational studies further supported this association.103
iii) Probiotics: These are live microorganisms that can confer health benefits to the host when administered in adequate amounts.104 Probiotic bacteria prevent gut dysbiosis, an imbalance between pathogenic and commensal microbes, which is a predisposing factor for both NEC and late-onset sepsis (LOS) in VLBW infants.105–108 Dysbiosis can predispose the premature gut to a pro-inflammatory state, with increased cytokine production and altered immunomodulation.109 The administration of probiotics has been evaluated with >50 RCTs and >10,000 participants.110 In a systematic review and meta-analysis of preclinical studies, Athalye-Jape et al.111 included a total of 29 RCTs (Rats: 16, Mice: 7, Piglets: 3, Quail: 2, Rabbit: 1; N~2,310), and concluded that probiotics significantly reduced NEC via beneficial effects on immunity, inflammation, tissue injury, gut barrier, and intestinal dysbiosis. The 2023 Cochrane review by Sharif et al. included 60 randomized control trials with 11,156 preterm infants. They showed that probiotics may reduce the risk of NEC in preterm VLBW infants (RR: 0.54, 95% CI: 0.46 – 0.65; I² = 17%; 57 trials, 10,918 infants; Certainty of evidence/CoE: low). The number needed to treat for an additional beneficial outcome (NNTB) was 33 (95% CI: 25–50). In the ELBW population, limited data show that probiotics may have little or no effect on NEC (RR; 0.92, 95% CI: 0.69–1.22, I² = 0%; 10 trials, 1836 infants; CoE: low). Given the low to moderate CoE for probiotic supplementation effects on the risk of NEC and associated morbidity and mortality, the authors recommended further large, high-quality trials to provide evidence of sufficient validity and applicability to inform policy and practice.112 Deshmukh et al.113 included 30 good-quality non-RCTs (n = 77,018) from 18 countries. The meta-analysis showed that routine probiotic supplementation was associated with reduced NEC ≥ Stage II. Subgroup analysis showed decreased NEC ≥ Stage II (4.5% compared with 7.9%) in ELBW infants supplemented with probiotics. Multi-strain probiotics (MSP) were more effective than single strains.113
Wang et al.114 assessed the comparative effectiveness of alternative prophylactic strategies (including probiotics) for preventing mortality and morbidity in preterm infants through an NMA (network meta-analysis) of RCTs. A total of 106 trials involving 25,840 preterm infants were included. Only MSP were associated with reduced all-cause mortality compared with placebo or in combination with oligosaccharides; these were effective interventions to reduce severe NEC (NEC ≥ stage II). Combination products, including single- and MSP combined with prebiotics or lactoferrin, were associated with reduced morbidity and mortality.114
Morgan et al.115 performed another NMA and noted that the combination of one or more Lactobacillus spp. and Bifidobacterium spp. was associated with decreased all-cause mortality. In another such study, Beghetti et al.116 examined 51 RCTs (10,664 infants, 29 probiotic interventions). Thirty-one studies (19 different probiotic regimens) were suitable for subgroup analysis according to type of feeding. In the overall analysis, L. acidophilus LB was the most promising strain for reducing NEC risk. Subgroup analysis showed that B. lactis Bb-12/B94 reduced the risk of NEC stage ≥ 2 in both feeding type populations, with a discrepancy in the relative effect size in favor of exclusively HM-fed infants.
Thomas et al.117 identified probiotic strains with maximum benefit in preventing neonatal mortality, sepsis, and NEC using Bayesian NMA. Twenty-nine RCTs enrolling 4,906 neonates and evaluating 24 probiotics were included. All studies compared probiotics with a placebo; none had a head-to-head comparison of different probiotic species. Compared with placebo, the combination of B. longum, B. bifidum, B. infantis, and L. acidophilus may reduce the risk of NEC (RR: 0.31; 95% CI: 0.10–0.78; CoE: uncertain). A single probiotic species, B lactis, may reduce the risk of mortality (RR 0.21; 0.05–0.66) and NEC (RR 0.09; 0.01–0.32; CoE: low). However, given the low to very low certainty of evidence, no firm conclusions were made on the most optimal probiotics for use in preterm neonates in low- and middle-income countries.117
In the most recent systematic review in the Cochrane library, Sharif and co-workers112 presented current evidence on the protective effects of probiotics against NEC in very preterm (born at ≤32 weeks’ gestation) and very low-birthweight infants. They found 60 trials with 11,156 infants; most of these studies were small (median sample size 145 infants) with some design flaws that might have biased their findings. The most common preparations contained Bifidobacterium spp., Lactobacillus spp., Saccharomyces spp., and Streptococcus spp., alone or in combination. Probiotics were generally seen as safe. However, the authors were very cautious in drawing inferences about benefit. Probiotics may reduce the risk of NEC (RR 0.54, 95% CI: 0.46–0.65; I² = 17%; 57 trials, 10,918 infants; low certainty). The number needed to treat for an additional beneficial outcome (NNTB) was 33 (95% CI: 25–50). Probiotics probably reduce mortality slightly (RR 0.77, 95% CI: 0.66–0.90; I² = 0%; 54 trials, 10,484 infants; moderate certainty); the NNTB was 50 (95% CI: 50–100). Probiotics probably have little or no effect on the risk of late‐onset sepsis (RR 0.89, 95% CI: 0.82–0.97; I² = 22%; 49 trials, 9876 infants; moderate certainty). Probiotics may have little or no effect on neurodevelopmental impairment (RR 1.03, 95% CI: 0.84–1.26; I² = 0%; 5 trials, 1518 infants; low certainty).
The data from extremely preterm or ELBW infants were limited. In this population, probiotics may have little or no effect on NEC (RR 0.92, 95% CI: 0.69–1.22, I² = 0%; 10 trials, 1836 infants; low certainty), all‐cause mortality (RR 0.92, 95% CI: 0.72–1.18; I² = 0%; 7 trials, 1723 infants; low certainty), or late‐onset invasive infection (RR 0.93, 95% CI: 0.78–1.09; I² = 0%; 7 trials, 1533 infants; low certainty). No trials provided data for measures of neurodevelopmental impairment in extremely preterm or ELBW infants.
The authors opined that the methods used in the included trials may have exaggerated the benefits of giving probiotics to very preterm and VLBW infants. The effects could have been biased by a small number of subjects in these trials and unreliable methods. They suggested a need for caution; further evidence is needed before drawing firm conclusions about the benefits of altering the natural temporal changes in gut microbial flora.
Instead of extrapolating information from the West, we might need specific evaluation of probiotics in tropical/peri-equatorial climates. Increasing information suggests that the bacterial strains causing neonatal sepsis/inflammatory illnesses in these warmer regions might differ from those in the temperate zones.118 In tropical regions, Gram-negative bacteria seem to be a notable component of the vaginal flora and the patterns of bacterial colonization in the neonatal intestine might differ from those in the West. Padhi et al.119 evaluated 15 studies in a random-effects meta-analysis; Gram-negative bacteria constituted 23.2% (95% CI: 11.77–37.08, I2 = 99.79%) of the flora in the birth canal. In a systematic review, Zelellw et al.120 have shown that in the warmer regions, early-onset neonatal sepsis is often caused by Gram-negative pathogens such as E. coli and Klebsiella, whereas late-onset neonatal sepsis is frequently caused by Gram-positive organisms like Staphylococcus spp. and S. pneumoniae. We hence, we need to be cautious when drawing inferences about the impact of probiotics across different climatic regions.
Position Statements of Committees
In 2023, the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Special Interest Group on Gut Microbiota and Modifications provided updated recommendations for the use of probiotics for the management of NEC. Clinicians may recommend L. rhamnosus alone at a dose of 1–6 × 109 colony-forming units (CFU) or a combination of B. infantis, B. lactis, and S. thermophilus (dose: 3–3.5 × 108 CFU of each strain) while citing the importance of product quality control for safety (CoE: low).121
In 2020, the American Gastroenterological Association recommended a combination of Lactobacillus spp. and Bifidobacterium spp. for NEC prevention in preterm infants. They compared this regimen with another with no or other probiotics in preterm infants (CoE: moderate).122 In 2012, the American Pediatric Surgical Association Committee review recommended probiotics to decrease the incidence of NEC in preterm LBW infants.123
4. Adequate management of anemia
Anemia is the most common hematopathological condition seen in preterm infants. It is observed that almost 100% of extremely preterm and 94.6% of very preterm infants developed anemia.124 Neonatal anemia relates to intestinal injury in preterm infants.125 In a murine model, RBC transfusions caused NEC-like intestinal damage in severely-anemic, but not in non-anemic controls; the severity of bowel injury was proportional to the degree and duration of anemia.126 Many human studies have shown a similar association between the severity of anemia and the risk of NEC following transfusions.127,128 Even though the activation of inflammatory macrophages by free circulating hemoglobin is the best-supported mechanism, many other possibilities have been considered: (i) activated T-crypt antigen, which results in the use of washed blood components;129 (ii) hypoperfusion-reperfusion injury and chronic anemia; (iii) enteral nutrition resulting in splanchnic ischemia during RBC transfusions; and (iv) extended RBC storage that may enhance RBC adhesion and reduce nitric oxide in these cells.79
RBC transfusions are very frequently administered in severely anemic infants; around 40% of VLBW infants and 80% of extremely low-birthweight infants require at least one blood transfusion before discharge.79 Despite these transfusions being a life-saving intervention, it was found to be associated with a higher incidence of complications such as NEC. Transfusion-associated NEC (TANEC) is a clinical condition characterized by the development of NEC (Bell’s stage II and above) within 48 hours of RBC transfusion.130 Around 20–35% of all NEC cases are associated with transfusions.126 TANEC typically occurred at a later age when compared with NEC which is unrelated to blood transfusions.81 Transfusion-related immune triggers, impaired intestinal blood flow from severe anemia, and ischemia-reperfusion injury are some factors that might increase the risk of TANEC.
(i) Prevention and management strategies for anemia
Optimizing hemoglobin thresholds for transfusions: Studies are needed to determine the optimal hemoglobin thresholds for transfusion in preterm infants to balance the benefits of correcting anemia with the risks of transfusion-related complications, including NEC;131
Delayed cord clamping: Delayed cord clamping (DCC), a practice that allows placenta-to-neonate transfusion at birth, allows the passive transfer of blood from the placenta to the newborn infant. DCC can help prevent severity of anemia during the neonatal period and the need for RBC transfusions.132 Such interventions might be particularly important in regions with higher frequency of nutritional anemia, such as due to iron deficiency, in pregnant mothers.133
Minimizing losses from phlebotomy: Blood loss due to repeated phlebotomy is considered one of the major causes of anemia in preterm infants. In critically ill neonates, the blood volumes removed during the 1st few weeks of life may be as much as 58% of the total blood volume.134 In one study, the blood draws for laboratory testing in the NICU were 19% higher than what the hospital laboratory had requested; the authors suggested that using tubes with explicit markings could help prevent these overdraws.135 In ELBW infants, point-of-care analyzers can reduce the mean volume of RBC transfusions by 43%.136
(ii) Characteristics of blood products
To minimize the transmission of the cytomegalovirus and to prevent transfusion-associated graft vs host disease in infants weighing less than 1200 gms, RBC transfusions for premature infants should be leukocyte-depleted and irradiated, respectively.137
(iii) Iron supplementation
Enteral iron supplementation is recommended once infants are on full enteral feedings to prevent iron deficiency anemia and reduce the need for blood transfusions. Preterm newborns should begin receiving 2–3 mg/kg of elemental iron per day starting at the age of 2 weeks, and newborns receiving exogenous erythropoietin should receive up to 6 mg/kg of iron according to ESPHGAN guidelines on enteral nutrition in preterm neonates 2022.138
5. Antenatal practices
(i) Antenatal Steroid–Antenatal corticosteroids (ACS): These are an effective intervention for improving outcomes for preterm neonates. Steroids confer benefits by crossing the placenta and accelerating the structural maturation of many vital organs.139 The administration of ACS to a woman at risk of imminent preterm birth is strongly associated with decreased neonatal morbidity and mortality. A recent Cochrane review showed that ACS can significantly lower the incidence of respiratory distress syndrome (relative risk [RR], 0.85; 95% confidence interval [CI], 0.77–0.93), intracranial hemorrhage (RR, 0.58; 95% CI, 0.45–0.75), neonatal death (RR, 0.78; 95% CI, 0.70–0.87), and NEC (RR, 0.50; 95% CI, 0.32–0.78) in the newborn infant.140 In NEC, ACS can reduce both the incidence and morbidity; the mechanisms are unclear. One possibility is accelerated maturation of the intestinal mucosa;141,142 Israel et al.143 have shown in an animal model that ACS accelerated the maturation of the git mucosal barrier with lower intestinal permeability, reduced uptake of macromolecules, and consequently, decreased bacteria translocation.
(ii) Delayed cord clamping (DCC): Delayed cord clamping is defined as umbilical cord clamping delayed for at least 30–60 seconds after birth.144 It allows the placental transfusion of oxygenated blood into newborns. In preterm infants, DCC can reduce the need for blood transfusion, the severity of respiratory distress syndrome, NEC, and intraventricular hemorrhage.145 During the early postpartum period, DCC can prevent transitional phase hypovolemia and fluctuations in cardiac output and promote hemodynamic stability.146,147 DCC may reduce the risk of NEC by preventing severe anemia and the need for transfusions.127 These effects were also seen in a systematic review (RR 0.59, 95% CI: 0.37), although the findings might be less important as the age of onset of NEC becomes progressively more delayed in premature infants.148 There is a need for large high-quality trials, with sufficient power to reliably assess the role of DCC in the prevention of NEC. As mentioned above, DCC might be very important in the less-advantaged parts of the world.133
Implementation Science
To improve the clinical outcomes in ICUs, the bundle approach can be an effective strategy.149–151 However, a high level of compliance with the care bundles is essential. We still do not know the most optimum timing and sequence in which these bundles can be implemented in NICUs. Implementation science focuses on various strategies that might be recommended to improve standardization of care bundles across multiple ICUs, with an eventual goal of consistent application of best practices and reduction in variation. A number of ways have been described in the literature to improve the compliance of care bundles.152,153 Both single and multifaceted strategies have been used.150,154 One of the most important interventions to improve the implementation of care bundles was an improvement of the organizational culture,150 including senior leaders, team leaders, and frontline staff. This model facilitated change in the management to execute the planned intervention. Following this, a systematic review including 47 studies was done by Borgert et al.155 and concluded that education, reminders, audits, and feedback are important strategies to implement successful care bundles. Further work is needed to develop protocols and optimize the implementation.
CONCLUSION
The care of premature and critically ill infants requires the implementation of multiple interventions in a timely fashion. As has been seen in multiple RCTs, many interventions have statistically significant benefits, but the effect size is often small. There is a risk that the benefits accrued from a few appropriately-applied interventions could be nullified if some others are not. Hence, the strategy of developing care bundles might be useful. In the following Tables 1 to 3, we have summarized the information provided to standardize the five interventions to reduce the incidence and severity of NEC.
| 1. Exclusive human milk feeds | Antenatal and postnatal lactation counseling Breastfeeding education, training, handouts, video-based learning Maintaining daily records and frequent reminders of milk expression Encouraging expression of MOM during nights as these milk samples contain more fats and hence, caloric content Early and frequent pumping, educating about hands-on pumping, manual and electrical pumps Mother and nurse champions supporting MOM Colostrum collection kits in the labor room for OCT |
| 2. Standard enteral feeding practices | Formatting an evidence-based standardized enteral feeding guidelines of the unit Adherence to the feeding protocol in general and specific circumstances like PDA, blood transfusion, and Doppler abnormalities Standardized protocols for holding feedings in infants with feeding intolerance |
| 3. Prevention of intestinal dysbiosis | Antibiotic Stewardship – Prevention of prolonged use of empiric antibiotics, limiting empirical use of antibiotics only to infants with risk factors for sepsis, treatment guided by antibiotic susceptibility in culture reports Avoid using proton pump inhibitors and H2 blockers Judicious use of probiotics Involving a nurse and a pharmacist in maintaining daily logs and feedback loops |
| 4. Adequate management of anemia | Optimizing hemoglobin thresholds for transfusion Delayed cord clamping Minimizing phlebotomies in NICU Preference for leukodepleted and irradiated blood products Enteral iron supplementation Observation for transfusion-associated organ injury |
| 5. Antenatal practices | Antenatal steroids Delayed cord clamping |
| Grade | Description for evidence | Certainty of evidence* |
|---|---|---|
| A | Strong – Consists of studies from strong research | High |
| B | Moderate – Consists of studies of strong research design but there are inconsistencies in results, generalizability, and/or risk/bias | Moderate |
| C | Weak – Studies show inconsistent results and there are serious concerns with conclusions, generalizability, and/or risk/bias | Low |
| D | A conclusion is either not possible or limited:evidence is unavailable and/or is of poor quality and/or is contradictory | Very low |
| Recommendation | Description | Grade | Quality of evidence |
|---|---|---|---|
| Exclusive mother’s own milk (MOM) | Providing exclusive MOM as first choice of milk for all the preterm infants | A | Ia |
| Donor human milk | To be used as second-best source of milk for preterm infants if MOM is unavailable | A | Ia |
| Antenatal corticosteroids | Administration of antenatal corticosteroids to all the mothers expectant of delivery ≤34+6/7 weeks of gestation | A | Ia |
| Oral colostrum care | Use of colostrum for oral care as immunotherapy | B | IIb |
| Probiotics | Lactobacillus – Bifidobacterium combination | B | Ib |
| Standardized feeding guidelines | Implementation of evidence-based guidelines in the neonatal unit | B | IIIa |
| Prevention of severe anemia | Using antenatal and postnatal precautions and standardized blood transfusion protocols to prevent anemia | C | IIIa |
| Avoid H2 blockers and proton pump inhibitors | Histamine blockers and proton pump inhibitors increase the risk of NEC | C | IIIb |
| Antibiotic stewardship | Avoid prolonged use of empirical antibiotics (>36 hours in full-term and >48 hours in preterm infants) | C | IIIa |
| Avoid use of cow’s milk protein fortifiers | Use of human milk fortifier is preferred over cow’s milk fortifier | C | IIb |
| Holding feeds during blood transfusion | Holding plain and/or hyperosmolar (fortified) feedings during/around the time of transfusions | D | IIIb |
| Delayed cord clamping | Prevention of anemia and the need for transfusions | D | IIIb |
Summary of Recommendations with Evidence
The Neonatal Gut Health group utilized the grading of recommendations, assessment, development and evaluation (GRADE) system156 to explain the level of evidence of various risk factors of NEC.157
ACKNOWLEDGMENTS
The authors would like to express their gratitude to Drs E. Bernard Cartaya (USA), Alejandro Diego (USA), Melissa Halpern (USA), Michel Mikhael (USA), Brian Sims (USA), Benjamin Torres (USA), and Amit Upadhyay (India) for continuous discussions; and their leadership at the Global Newborn Society, Drs Waldemar Carlo, Kei Lui, and Horacio Osiovich, for guidance.
The LAYA Group of the Global Newborn Society – Authors
Nitasha Bagga1,2, Akhil Maheshwari2,3,4, Kamlesh Jha2,5, Gayatri Athalye-Jape2,6,7, Jenisha Jain2,8, Aimen E Ben Ayad2,9, Kallem V Reddy10, Pradeep Reddy1, Roya Huseynova2,11, Md Mozibur Rahman2,12, Niraj Vora13, Gangajal Kasniya14, and Aftab Ahmed2,15
1Department of Neonatology, Rainbow Children’s Hospital, Hyderabad, Telangana, India
2Global Newborn Society, Clarksville, Maryland, United States of America
3Department of Neonatology/Pediatrics, Louisiana State University Health Sciences Center – Shreveport, Louisiana, United States of America
4Banaras Hindu University Institute of Eminence, Varanasi, India
5Neonatology/Pediatrics, University of Chicago, Chicago, Illinois, United States of America
6Neonatal Directorate, King Edward Memorial Hospital for Women, Subiaco, Western Australia
7School of Medicine, University of Western Australia, Perth, Australia
8Choithram Hospital and Research Centre, Indore, Madhya Pradesh, India
9Tawam Hospital, Al Ain, United Arab Emirates
10Paramitha Children’s Hospital, Hyderabad, Telangana, India
11Department of Neonatal Intensive Care, King Saud Medical City, Riyadh, Saudi Arabia
12Department of Neonatology, Institute of Child and Mother Health, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
13Neonatology, Texas A&M College of Medicine, Temple, Texas, United States of America
14Department of Neonatology, Ochsner-Baptist Hospital, New Orleans, Louisiana, United States of America
15Pediatrics, National Institute of Child Health, Jinnah Sindh Medical University, Pakistan
ORCID
Roya A Huseynova https://orcid.org/0000-0002-8914-5892
REFERENCES
1. Maheshwari A, Corbin L, Schelonka RL. Neonatal necrotizing enterocolitis. Res Reps Neonatol 2011;1(39):53. DOI: 10.2147/RRN.S23459.
2. Alsaied A, Islam N, Thalib L. Global incidence of Necrotizing Enterocolitis: A systematic review and Meta-analysis. BMC Pediatr 2020;20(1):344. DOI: 10.1186/s12887-020-02231-5.
3. Yee WH, Soraisham AS, Shah VS, et al. Incidence and timing of presentation of necrotizing enterocolitis in preterm infants. Pediatrics 2012;129(2):e298–304. DOI: 10.1542/peds.2011-2022.
4. Stey A, Barnert ES, Tseng CH, et al. Outcomes and costs of surgical treatments of necrotizing enterocolitis. Pediatrics 2015;135(5):e1190–e1197. DOI: 10.1542/peds.2014-1058.
5. Jones IH, Hall NJ. Contemporary Outcomes for Infants with Necrotizing Enterocolitis-A Systematic Review. J Pediatr 2020;220:86–92 e3. DOI: 10.1016/j.jpeds.2019.11.011.
6. Ganapathy V, Hay JW, Kim JH, et al. Long term healthcare costs of infants who survived neonatal necrotizing enterocolitis: A retrospective longitudinal study among infants enrolled in Texas Medicaid. BMC Pediatr 2013;13:127. DOI: 10.1186/1471-2431-13-127.
7. Jin YT, Duan Y, Deng XK, et al. Prevention of necrotizing enterocolitis in premature infants - an updated review. World J Clin Pediatr 2019;8(2):23–32. DOI: 10.5409/wjcp.v8.i2.23.
8. Nathan AT, Ward L, Schibler K, et al. A quality improvement initiative to reduce necrotizing enterocolitis across hospital systems. J Perinatol 2018;38(6):742–750. DOI: 10.1038/s41372-018-0104-0.
9. Gephart SM, Hanson C, Wetzel CM, et al. NEC-zero recommendations from scoping review of evidence to prevent and foster timely recognition of necrotizing enterocolitis. Matern Health Neonatol Perinatol 2017;3:23. DOI: 10.1186/s40748-017-0062-0.
10. Radbone L, Birch J, Upton M. The development and implementation of a care bundle aimed at reducing the incidence of NEC. 2013 [14–19]. Available from: https://www.infantjournal.co.uk/pdf/inf_049_ime.pdf.
11. Alshaikh BN, Sproat TDR, Wood C, et al. A Quality Improvement Initiative to Reduce Necrotizing Enterocolitis in Very Preterm Infants. Pediatrics 2023;152(6). DOI: 10.1542/peds.2023-061273.
12. Villosis M-Fe, Ambat MAT, Rezaie K, et al. A bundle of care that led to sustained low incidence of necrotizing enterocolitis in very low birth weight infants: A 10-year quality improvement project. Pediatrics 2021;147:759–760. DOI: 10.1542/peds.147.3MA8.759b.
13. Bauer MS, Damschroder L, Hagedorn H, et al. An introduction to implementation science for the non-specialist. BMC Psychol 2015;3(1):32. DOI: 10.1186/s40359-015-0089-9.
14. Davis D. Continuing education, guideline implementation, and the emerging transdisciplinary field of knowledge translation. J Contin Educ Health Prof 2006;26(1):5–12. DOI: 10.1002/chp.46.
15. Team I. What Is a Bundle?: Institute for Healthcare Improvement; 2012.
16. Guner S, Saydam BK. The Impact of Umbilical Cord Clamping Time on the Infant Anemia: A Randomized Controlled Trial. Iran J Public Health 2021;50(5):990–998. DOI: 10.18502/ijph.v50i5.6116.
17. Borrello K, Lim U, Park SY, et al. Dietary Intake Mediates Ethnic Differences in Gut Microbial Composition. Nutrients 2022; 14 (3). DOI: 10.3390/nu14030660.
18. Jia Q, Yu X, Chang Y, et al. Dynamic Changes of the Gut Microbiota in Preterm Infants With Different Gestational Age. Front Microbiol 2022;13:923273. DOI: 10.3389/fmicb.2022.923273.
19. Cheng Y, Selma-Royo M, Cao X, et al. Influence of Geographical Location on Maternal-Infant Microbiota: Study in Two Populations From Asia and Europe. Front Cell Infect Microbiol 2021;11:663513. DOI: 10.3389/fcimb.2021.663513.
20. Kaech C, Kilgour C, Fischer Fumeaux CJ, et al. Factors that influence the sustainability of human milk donation to milk banks: A systematic review. Nutrients 2022;14(24). DOI: 10.3390/nu14245253.
21. Flores J, Okhuysen PC. Genetics of susceptibility to infection with enteric pathogens. Curr Opin Infect Dis 2009;22(5):471–476. DOI: 10.1097/QCO.0b013e3283304eb6.
22. Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg. 1978;187(1):1–7. DOI: 10.1097/00000658-197801000-00001.
23. Walsh MC, Kliegman RM. Necrotizing enterocolitis: Treatment based on staging criteria. Pediatr Clin North Am. 1986;33(1):179–201. DOI: 10.1016/s0031-3955(16)34975-6.
24. Gephart SM, Gordon PV, Penn AH, et al. Changing the paradigm of defining, detecting, and diagnosing NEC: Perspectives on Bell’s stages and biomarkers for NEC. Semin Pediatr Surg 2018;27(1):3–10. DOI: 10.1053/j.sempedsurg.2017.11.002.
25. Gordon PV, Swanson JR, MacQueen BC, et al. A critical question for NEC researchers: Can we create a consensus definition of NEC that facilitates research progress? Semin Perinatol 2017;41(1):7–14. DOI: 10.1053/j.semperi.2016.09.013.
26. Gordon PV, Swanson JR. Necrotizing enterocolitis is one disease with many origins and potential means of prevention. Pathophysiology 2014;21(1):13–19. DOI: 10.1016/j.pathophys.2013.11.015.
27. Christensen RD, Lambert DK, Gordon PV, et al. Neonates presenting with bloody stools and eosinophilia can progress to two different types of necrotizing enterocolitis. J Perinatol 2012;32(11):874–879. DOI: 10.1038/jp.2011.163.
28. Gordon PV, Swanson JR, Attridge JT, et al. Emerging trends in acquired neonatal intestinal disease: Is it time to abandon Bell’s criteria? J Perinatol 2007;27(11):661–671. DOI: 10.1038/sj.jp.7211782.
29. Garg PM, Garg PP, Shenberger JS. Is necrotizing enterocolitis and spontaneous intestinal perforation part of same disease spectrum - new insights? Curr Pediatr Rev 2024. DOI: 10.2174/0115733963298717240404032451.
30. Skerritt C, Modi N, and Clarke S. Reply to state of the art article ‘Bell’s is broken’. J Perinatol 2008;28. DOI: 10.1038/sj.jp.7211907.
31. Neu J, Modi N, Caplan M. Necrotizing enterocolitis comes in different forms: Historical perspectives and defining the disease. Semin Fetal Neonatal Med 2018;23(6):370–373. DOI: 10.1016/j.siny.2018.07.004.
32. Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011;364(3):255–264. DOI: 10.1056/NEJMra1005408.
33. Gibbs K, Lin J, Holzman IR. Necrotising enterocolitis: The state of the science. Indian J Pediatr 2007;74(1):67–72. DOI: 10.1007/s12098-007-0031-0.
34. Warner BB, Deych E, Zhou Y, Hall-Moore C, et al. Gut bacteria dysbiosis and necrotising enterocolitis in very low birthweight infants: A prospective case-control study. Lancet 2016;387(10031):1928–1936. DOI: 10.1016/S0140-6736(16)00081-7.
35. Fitzgibbons SC, Ching Y, Yu D, et al. Mortality of necrotizing enterocolitis expressed by birth weight categories. J Pediatr Surg 2009;44(6):1072–1075; discussion 5–6. DOI: 10.1016/j.jpedsurg.2009.02.013.
36. Hull MA, Fisher JG, Gutierrez IM, et al. Mortality and management of surgical necrotizing enterocolitis in very low birth weight neonates: A prospective cohort study. J Am Coll Surg 2014;218(6):1148–1155. DOI: 10.1016/j.jamcollsurg.2013.11.015.
37. Thyoka M, de Coppi P, Eaton S, et al. Advanced necrotizing enterocolitis part 1: Mortality. Eur J Pediatr Surg 2012;22(1):8–12. DOI: 10.1055/s-0032-1306263.
38. Haraden C. What is a bundle?: Institute for Healthcare Improvement; 2011.
39. Resar R, Griffin FA, Haraden C, et al. Using Care Bundles to Improve Health Care Quality. IHI Innovation Series white paper. Cambridge, MA2012. Available from: https://www.ihi.org/resources/white-papers/using-care-bundles-improve-health-care-quality.
40. IHI-Team. What Is a Bundle?: Institute for Healthcare Improvement; 2012.
41. Fulbrook P. Developing best practice in critical care nursing: knowledge, evidence and practice. Nurs Crit Care 2003;8(3):96–102. DOI: 10.1046/j.1478-5153.2003.00010.x.
42. Fulbrook P, Mooney S. Care bundles in critical care: A practical approach to evidence-based practice. Nurs Crit Care 2003;8(6):249–255. DOI: 10.1111/j.1362-1017.2003.00039.x.
43. Sekhon MK, Grubb PH, Newman M, et al. Implementation of a probiotic protocol to reduce rates of necrotizing enterocolitis. J Perinatol 2019;39(9):1315–1322. DOI: 10.1038/s41372-019-0443-5.
44. Alshaikh B, Kostecky L, Blachly N, et al. Effect of a Quality Improvement Project to Use Exclusive Mother’s Own Milk on Rate of Necrotizing Enterocolitis in Preterm Infants. Breastfeed Med 2015;10(7):355–361. DOI: 10.1089/bfm.2015.0042.
45. Mavis SC, Gallup MC, Meyer M, et al. A quality improvement initiative to reduce necrotizing enterocolitis in high-risk neonates. J Perinatol 2023;43(1):97–102. DOI: 10.1038/s41372-022-01476-5.
46. Schanler RJ, Shulman RJ, Lau C, et al. Feeding strategies for premature infants: Randomized trial of gastrointestinal priming and tube-feeding method. Pediatrics. 1999;103(2):434–439. DOI: 10.1542/peds.103.2.434.
47. Schanler RJ, Shulman RJ, Lau C. Feeding strategies for premature infants: Beneficial outcomes of feeding fortified human milk versus preterm formula. Pediatrics. 1999;103(6 Pt 1):1150–1157. DOI: 10.1542/peds.103.6.1150.
48. Sisk PM, Lovelady CA, Dillard RG, et al. Early human milk feeding is associated with a lower risk of necrotizing enterocolitis in very low birth weight infants. J Perinatol 2007;27(7):428–433. DOI: 10.1038/sj.jp.7211758.
49. Meinzen-Derr J, Poindexter B, Wrage L, et al. Role of human milk in extremely low birth weight infants’ risk of necrotizing enterocolitis or death. J Perinatol 2009;29(1):57–62. DOI: 10.1038/jp.2008.117.
50. Ananthan A, Balasubramanian H, Rao S, et al. Human Milk-Derived Fortifiers Compared with Bovine Milk-Derived Fortifiers in Preterm Infants: A Systematic Review and Meta-Analysis. Adv Nutr 2020;11(5):1325–1333. DOI: 10.1093/advances/nmaa039.
51. Quigley M, Embleton ND, McGuire W. Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev 2018;6(6):CD002971. DOI: 10.1002/14651858.CD002971.pub4.
52. Quigley JD, Deikun L, Hill TM, et al. Effects of colostrum and milk replacer feeding rates on intake, growth, and digestibility in calves. J Dairy Sci 2019;102(12):11016–11025. DOI: 10.3168/jds.2019-16682.
53. Altobelli E, Angeletti PM, Verrotti A, et al. The impact of human milk on necrotizing enterocolitis: A systematic review and meta-analysis. Nutrients 2020; 12 (5). DOI: 10.3390/nu12051322.
54. O’Connor DL, Kiss A, Tomlinson C, et al. Nutrient enrichment of human milk with human and bovine milk-based fortifiers for infants born weighing <1250 g: A randomized clinical trial. Am J Clin Nutr 2018;108(1):108–116. DOI: 10.1093/ajcn/nqy067.
55. Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet. 1990;336(8730):1519–1523. DOI: 10.1016/0140-6736(90)93304-8.
56. Cristofalo EA, Schanler RJ, Blanco CL, et al. Randomized trial of exclusive human milk versus preterm formula diets in extremely premature infants. J Pediatr 2013;163(6):1592–1595 e1. DOI: 10.1016/j.jpeds.2013.07.011.
57. Sullivan S, Schanler RJ, Kim JH, et al. An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 2010;156(4):562–567 e1. DOI: 10.1016/j.jpeds.2009.10.040.
58. Allana A, Lo K, Batool M, et al. Impact of donor human milk in an urban NICU population. Children (Basel) 2022;9(11). DOI: 10.3390/children9111639.
59. Silano M, Milani GP, Fattore G, et al. Donor human milk and risk of surgical necrotizing enterocolitis: A meta-analysis. Clin Nutr 2019;38(3):1061–1066. DOI: 10.1016/j.clnu.2018.03.004.
60. Garg BD, Balasubramanian H, Kabra NS, et al. Effect of oropharyngeal colostrum therapy in the prevention of necrotising enterocolitis among very low birthweight neonates: A meta-analysis of randomised controlled trials. J Hum Nutr Diet 2018;31(5):612–624. DOI: 10.1111/jhn.12585.
61. Ma A, Yang J, Li Y, et al. Oropharyngeal colostrum therapy reduces the incidence of ventilator-associated pneumonia in very low birth weight infants: A systematic review and meta-analysis. Pediatr Res 2021;89(1):54–62. DOI: 10.1038/s41390-020-0854-1.
62. Jasani B, Patole S. Standardized feeding regimen for reducing necrotizing enterocolitis in preterm infants: An updated systematic review. J Perinatol 2017;37(7):827–833. DOI: 10.1038/jp.2017.37.
63. Patel S, Chaudhari M, Kadam S, et al. Standardized feeding and probiotic supplementation for reducing necrotizing enterocolitis in preterm infants in a resource limited set up. Eur J Clin Nutr 2018;72(2):281–287. DOI: 10.1038/s41430-017-0040-7.
64. Barone G, Maggio L, Saracino A, et al. How to feed small for gestational age newborns. Ital J Pediatr 2013;39:28. DOI: 10.1186/1824-7288-39-28.
65. Christmann V, Liem KD, Semmekrot BA, et al. Changes in cerebral, renal and mesenteric blood flow velocity during continuous and bolus infusion of indomethacin. Acta Paediatr 2002;91(4):440–446. DOI: 10.1080/080352502317371698.
66. Dorling J, Kempley S, Leaf A. Feeding growth restricted preterm infants with abnormal antenatal Doppler results. Arch Dis Child Fetal Neonatal Ed 2005;90(5):F359–F363. DOI: 10.1136/adc.2004.060350.
67. Leaf A, Dorling J, Kempley S, et al. ADEPT - Abnormal Doppler Enteral Prescription Trial. BMC Pediatr 2009;9:63. DOI: 10.1186/1471-2431-9-63.
68. Martini S, Annunziata M, Della Gatta AN, et al. Association between abnormal antenatal Doppler characteristics and gastrointestinal outcomes in preterm infants. Nutrients 2022;14(23). DOI: 10.3390/nu14235121.
69. Anne RP, Aradhya AS, Murki S. Feeding in preterm neonates with antenatal Doppler abnormalities: A systematic review and meta-analysis. J Pediatr Gastroenterol Nutr 2022;75(2):202–209. DOI: 10.1097/MPG.0000000000003487.
70. Abbott J, Berrington J, Bowler U, et al. The speed of increasing milk feeds: A randomised controlled trial. BMC Pediatr 2017;17(1):39. DOI: 10.1186/s12887-017-0794-z.
71. Jain S, Mukhopadhyay K, Jain V, et al. Slow versus rapid enteral feed in preterm neonates with antenatal absent end diastolic flow. J Matern Fetal Neonatal Med 2016;29(17):2828–2833. DOI: 10.3109/14767058.2015.1105954.
72. Coombs RC, Morgan ME, Durbin GM, et al. Gut blood flow velocities in the newborn: Effects of patent ductus arteriosus and parenteral indomethacin. Arch Dis Child. 1990;65(10 Spec No):1067–1071. DOI: 10.1136/adc.65.10_spec_no.1067.
73. Clyman R, Wickremasinghe A, Jhaveri N, et al. Enteral feeding during indomethacin and ibuprofen treatment of a patent ductus arteriosus. J Pediatr 2013;163(2):406–411. DOI: 10.1016/j.jpeds.2013.01.057.
74. Louis D, Torgalkar R, Shah J, et al. Enteral feeding during indomethacin treatment for patent ductus arteriosus: Association with gastrointestinal outcomes. J Perinatol 2016;36(7):544–548. DOI: 10.1038/jp.2016.11.
75. Martini S, Aceti A, Galletti S, et al. To feed or not to feed: A critical overview of enteral feeding management and gastrointestinal complications in preterm neonates with a patent ductus arteriosus. Nutrients 2019; 12 (1). DOI: 10.3390/nu12010083.
76. Mirea L, Sankaran K, Seshia M, et al. Treatment of patent ductus arteriosus and neonatal mortality/morbidities: Adjustment for treatment selection bias. J Pediatr 2012;161(4):689–694 e1. DOI: 10.1016/j.jpeds.2012.05.007.
77. Ibrahim MH, Azab AA, Kamal NM, et al. Outcomes of early ligation of patent ductus arteriosus in preterms, multicenter experience. Medicine (Baltimore) 2015;94(25):e915. DOI: 10.1097/MD.0000000000000915.
78. Bravo MC, Ybarra M, Madero R, et al. Childhood neurodevelopmental outcome in low birth weight infants with post-ligation cardiac syndrome after ductus arteriosus closure. Front Physiol 2019;10:718. DOI: 10.3389/fphys.2019.00718.
79. Ghirardello S, Dusi E, Cortinovis I, et al. Effects of red blood cell transfusions on the risk of developing complications or death: An observational study of a cohort of very low birth weight infants. Am J Perinatol 2017;34(1):88–95. DOI: 10.1055/s-0036-1584300.
80. Hay S, Zupancic JA, Flannery DD, et al. Should we believe in transfusion-associated enterocolitis? Applying a GRADE to the literature. Semin Perinatol 2017;41(1):80–91. DOI: 10.1053/j.semperi.2016.09.021.
81. Khashu M, Dame C, Lavoie PM, et al. Current understanding of transfusion-associated necrotizing enterocolitis: Review of clinical and experimental studies and a call for more definitive evidence. Newborn (Clarksville) 2022;1(1):201–208. DOI: 10.5005/jp-journals-11002-0005.
82. Kirpalani H, Zupancic JA. Do transfusions cause necrotizing enterocolitis? The complementary role of randomized trials and observational studies. Semin Perinatol 2012;36(4):269–276. DOI: 10.1053/j.semperi.2012.04.007.
83. Schindler T, Yeo KT, Bolisetty S, et al. FEEding DURing red cell transfusion (FEEDUR RCT): A multi-arm randomised controlled trial. BMC Pediatr 2020;20(1):346. DOI: 10.1186/s12887-020-02233-3.
84. Yeo KT, Kong JY, Sasi A, et al. Stopping enteral feeds for prevention of transfusion-associated necrotising enterocolitis in preterm infants. Cochrane Database Syst Rev 2019;2019(10). DOI: 10.1002/14651858.CD012888.pub2.
85. Gale C, Modi N, Jawad S, et al. The WHEAT pilot trial-WithHolding Enteral feeds Around packed red cell transfusion to prevent necrotising enterocolitis in preterm neonates: A multicentre, electronic patient record (EPR), randomised controlled point-of-care pilot trial. BMJ Open 2019;9(9):e033543. DOI: 10.1136/bmjopen-2019-033543.
86. Tsai MH, Chu SM, Hsu JF, et al. Risk factors and outcomes for multidrug-resistant Gram-negative bacteremia in the NICU. Pediatrics 2014;133(2):e322–e329. DOI: 10.1542/peds.2013-1248.
87. Bizzarro MJ, Gallagher PG. Antibiotic-resistant organisms in the neonatal intensive care unit. Semin Perinatol 2007;31(1):26–32. DOI: 10.1053/j.semperi.2007.01.004.
88. Huang XZ, Zhu LB, Li ZR, et al. Bacterial colonization and intestinal mucosal barrier development. World J Clin Pediatr 2013;2(4):46–53. DOI: 10.5409/wjcp.v2.i4.46.
89. Tagare A, Kadam S, Vaidya U, et al. Routine antibiotic use in preterm neonates: A randomised controlled trial. J Hosp Infect 2010;74(4):332–336. DOI: 10.1016/j.jhin.2009.09.010.
90. Kenyon S, Taylor DJ, Tarnow-Mordi WO, et al. ORACLE–antibiotics for preterm prelabour rupture of the membranes: Short-term and long-term outcomes. Acta Paediatr Suppl 2002;91(437):12–15. DOI: 10.1111/j.1651-2227.2002.tb00153.x.
91. Owen J, Groome LJ, Hauth JC. Randomized trial of prophylactic antibiotic therapy after preterm amnion rupture. Am J Obstet Gynecol. 1993;169(4):976–981. DOI: 10.1016/0002-9378(93)90038-k.
92. Fan X, Zhang L, Tang J, et al. The initial prophylactic antibiotic usage and subsequent necrotizing enterocolitis in high-risk premature infants: A systematic review and meta-analysis. Pediatr Surg Int 2018;34(1):35–45. DOI: 10.1007/s00383-017-4207-z.
93. Cotten CM, Taylor S, Stoll B, et al. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants. Pediatrics 2009;123(1):58–66. DOI: 10.1542/peds.2007-3423.
94. Dukhovny D, Buus-Frank ME, Edwards EM, et al. A Collaborative Multicenter QI Initiative to Improve Antibiotic Stewardship in Newborns. Pediatrics 2019; 144 (6). DOI: 10.1542/peds.2019-0589.
95. Guillet R, Stoll BJ, Cotten CM, et al. Association of H2-blocker therapy and higher incidence of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2006;117(2):e137–142. DOI: 10.1542/peds.2005-1543.
96. Patole S. Association of H2-blocker therapy and higher incidence of necrotizing enterocolitis: A case of excessive collateral damage? Pediatrics 2006;117(2):531–532. DOI: 10.1542/peds.2005-2230.
97. Lin HC, Su BH, Chen AC. H2-blocker therapy and necrotizing enterocolitis for very low birth weight preterm infants. Pediatrics 2006;118(4):1794–1795; author reply 5–6. DOI: 10.1542/peds.2006-1607.
98. More K, Athalye-Jape G, Rao S, et al. Association of inhibitors of gastric acid secretion and higher incidence of necrotizing enterocolitis in preterm very low-birth-weight infants. Am J Perinatol 2013;30(10):849–856. DOI: 10.1055/s-0033-1333671.
99. Bilali A, Galanis P, Bartsocas C, et al. H2-blocker therapy and incidence of necrotizing enterocolitis in preterm infants: A case-control study. Pediatr Neonatol 2013;54(2):141–142. DOI: 10.1016/j.pedneo.2013.01.011.
100. Malcolm WF, Cotten CM. Metoclopramide, H2 blockers, and proton pump inhibitors: Pharmacotherapy for gastroesophageal reflux in neonates. Clin Perinatol 2012;39(1):99–109. DOI: 10.1016/j.clp.2011.12.015.
101. Parkman HP, Urbain JL, Knight LC, et al. Effect of gastric acid suppressants on human gastric motility. Gut. 1998;42(2):243–250. DOI: 10.1136/gut.42.2.243.
102. Terrin G, Passariello A, De Curtis M, et al. Ranitidine is associated with infections, necrotizing enterocolitis, and fatal outcome in newborns. Pediatrics 2012;129(1):e40–e45. DOI: 10.1542/peds.2011-0796.
103. Santos VS, Freire MS, Santana RNS, et al. Association between histamine-2 receptor antagonists and adverse outcomes in neonates: A systematic review and meta-analysis. PLoS One 2019;14(4):e0214135. DOI: 10.1371/journal.pone.0214135.
104. Food-and-Agriculture-Organization. Probiotics in food: Health adbn nutritional properties and guidelines for evaluation 2006.
105. Mercer EM, Arrieta MC. Probiotics to improve the gut microbiome in premature infants: Are we there yet? Gut Microbes 2023;15(1):2201160. DOI: 10.1080/19490976.2023.2201160.
106. Pammi M, Cope J, Tarr PI, et al. Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: A systematic review and meta-analysis. Microbiome 2017;5(1):31. DOI: 10.1186/s40168-017-0248-8.
107. Samara J, Moossavi S, Alshaikh B, et al. Supplementation with a probiotic mixture accelerates gut microbiome maturation and reduces intestinal inflammation in extremely preterm infants. Cell Host Microbe 2022;30(5):696–711 e5. DOI: 10.1016/j.chom.2022.04.005.
108. Verma J, Sankar MJ, Atmakuri K, et al. Gut microbiome dysbiosis in neonatal sepsis. Prog Mol Biol Transl Sci 2022;192(1):125–147. DOI: 10.1016/bs.pmbts.2022.07.010.
109. Cuna A, Morowitz MJ, Ahmed I, et al. Dynamics of the preterm gut microbiome in health and disease. Am J Physiol Gastrointest Liver Physiol 2021;320(4):G411–G419. DOI: 10.1152/ajpgi.00399.2020.
110. Pammi M, Warner BB, Patel RM. Probiotics, prebiotics, and lactoferrin-implications for preterm mortality and morbidity. JAMA Pediatr 2023;177(11):1129–1131. DOI: 10.1001/jamapediatrics.2023.3856.
111. Athalye-Jape G, Rao S, Patole S. Effects of probiotics on experimental necrotizing enterocolitis: A systematic review and meta-analysis. Pediatr Res 2018;83(1-1):16–22. DOI: 10.1038/pr.2017.218.
112. Sharif S, Meader N, Oddie SJ, et al. Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants. Cochrane Database Syst Rev 2023;7(7):CD005496. DOI: 10.1002/14651858.CD005496.pub6.
113. Deshmukh M, Patole S. Prophylactic probiotic supplementation for preterm neonates-a systematic review and meta-analysis of nonrandomized studies. Adv Nutr 2021;12(4):1411–1423. DOI: 10.1093/advances/nmaa164.
114. Wang Y, Florez ID, Morgan RL, et al. Probiotics, prebiotics, lactoferrin, and combination products for prevention of mortality and morbidity in preterm infants: A systematic review and network meta-analysis. JAMA Pediatr 2023;177(11):1158–1167. DOI: 10.1001/jamapediatrics.2023.3849.
115. Morgan RL, Preidis GA, Kashyap PC, et al. Probiotics reduce mortality and morbidity in preterm, low-birth-weight infants: A systematic review and network meta-analysis of randomized trials. Gastroenterology 2020;159(2):467–480. DOI: 10.1053/j.gastro.2020.05.096.
116. Beghetti I, Panizza D, Lenzi J, et al. Probiotics for Preventing Necrotizing Enterocolitis in Preterm Infants: A Network Meta-Analysis. Nutrients 2021; 13 (1). DOI: 10.3390/nu13010192.
117. Thomas D, Sharma A, Sankar MJ. Probiotics for the prevention of mortality and sepsis in preterm very low birth weight neonates from low- and middle-income countries: A Bayesian network meta-analysis. Front Nutr 2023;10:1133293. DOI: 10.3389/fnut.2023.1133293.
118. Donati L, Di Vico A, Nucci M, et al. Vaginal microbial flora and outcome of pregnancy. Arch Gynecol Obstet 2010;281(4):589–600. DOI: 10.1007/s00404-009-1318-3.
119. Padhi BK, Manna S, Pallepogula DR, et al. Prevalence of Gram-negative bacteria in maternal cervical secretions: A systematic review and meta-analysis. Newborn (Clarksville) 2022;1(4):397–407. DOI: 10.5005/jp-journals-11002-0051.
120. Zelellw DA, Dessie G, Worku Mengesha E, et al. A Systemic Review and Meta-analysis of the Leading Pathogens Causing Neonatal Sepsis in Developing Countries. Biomed Res Int 2021;2021:6626983. DOI: 10.1155/2021/6626983.
121. Szajewska H, Berni Canani R, Domellof M, et al. Probiotics for the management of pediatric gastrointestinal disorders: Position paper of the ESPGHAN special interest group on gut microbiota and modifications. J Pediatr Gastroenterol Nutr 2023;76(2):232–247. DOI: 10.1097/MPG.0000000000003633.
122. Su GL, Ko CW, Bercik P, et al. AGA clinical practice guidelines on the role of probiotics in the management of gastrointestinal disorders. Gastroenterology 2020;159(2):697–705. DOI: 10.1053/j.gastro.2020.05.059.
123. Downard CD, Renaud E, St Peter SD, et al. Treatment of necrotizing enterocolitis: An American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review. J Pediatr Surg 2012;47(11):2111–2122. DOI: 10.1016/j.jpedsurg.2012.08.011.
124. Kocherova V, Popova N. Features of anemia in extremely preterm children in neonatal period. Russian Ped J 2022;2:81–87. DOI: 10.15690/rpj.v2i2.2337.
125. Kalteren WS, Bos AF, van Oeveren W, et al. Neonatal anemia relates to intestinal injury in preterm infants. Pediatr Res 2022;91(6):1452–1458. DOI: 10.1038/s41390-021-01903-x.
126. MohanKumar K, Namachivayam K, Song T, et al. A murine neonatal model of necrotizing enterocolitis caused by anemia and red blood cell transfusions. Nat Commun 2019;10(1):3494. DOI: 10.1038/s41467-019-11199-5.
127. Patel RM, Knezevic A, Shenvi N, et al. Association of red blood cell transfusion, anemia, and necrotizing enterocolitis in very low-birth-weight infants. JAMA 2016;315(9):889–897. DOI: 10.1001/jama.2016.1204.
128. Singh R, Visintainer PF, Frantz ID, et al. Association of necrotizing enterocolitis with anemia and packed red blood cell transfusions in preterm infants. J Perinatol 2011;31(3):176–182. DOI: 10.1038/jp.2010.145.
129. Hall N, Ong EG, Ade-Ajayi N, et al. T cryptantigen activation is associated with advanced necrotizing enterocolitis. J Pediatr Surg 2002;37(5):791–793. DOI: 10.1053/jpsu.2002.32289.
130. Stritzke AI, Smyth J, Synnes A, et al. Transfusion-associated necrotising enterocolitis in neonates. Arch Dis Child Fetal Neonatal Ed 2013;98(1):F10–F14. DOI: 10.1136/fetalneonatal-2011-301282.
131. Iijima S. Clinical dilemma involving treatments for very low-birth-weight infants and the potential risk of necrotizing enterocolitis: A narrative literature review. J Clin Med 2023; 13 (1). DOI: 10.3390/jcm13010062.
132. Mercer JS, Erickson-Owens DA, Deoni SCL, et al. Effects of delayed cord clamping on 4-month ferritin levels, brain myelin content, and neurodevelopment: A randomized controlled trial. J Pediatr 2018;203:266–272 e2. DOI: 10.1016/j.jpeds.2018.06.006.
133. World-Health-Organization. Optimal timing of cord clamping for the prevention of iron deficiency anaemia in infants: WHO e-Library of Evidence for Nutrition Actions (eLENA); 2023. Available from: https://www.who.int/tools/elena/interventions/cord-clamping.
134. Puia-Dumitrescu M, Tanaka DT, Spears TG, et al. Patterns of phlebotomy blood loss and transfusions in extremely low birth weight infants. J Perinatol 2019;39(12):1670–1675. DOI: 10.1038/s41372-019-0515-6.
135. Lin JC, Strauss RG, Kulhavy JC, et al. Phlebotomy overdraw in the neonatal intensive care nursery. Pediatrics 2000;106(2):E19. DOI: 10.1542/peds.106.2.e19.
136. Madan A, Kumar R, Adams MM, et al. Reduction in red blood cell transfusions using a bedside analyzer in extremely low birth weight infants. J Perinatol 2005;25(1):21–25. DOI: 10.1038/sj.jp.7211201.
137. Sloan SR. Blood products used in the newborn. In: Cloherty JP, Eichenwald EC, Hansen AR, Stark AR, editors. Manual of neonatal care Philadelphia: Lippincott Williams & Wilkins; 2012. pp. 529–537.
138. Embleton ND, Jennifer Moltu S, Lapillonne A, et al. Enteral nutrition in preterm infants (2022): A position paper from the ESPGHAN Committee on Nutrition and Invited Experts. J Pediatr Gastroenterol Nutr 2023;76(2):248–268. DOI: 10.1097/MPG.0000000000003642.
139. Bird AD, McDougall AR, Seow B, et al. Glucocorticoid regulation of lung development: Lessons learned from conditional GR knockout mice. Mol Endocrinol 2015;29(2):158–171. DOI: 10.1210/me.2014-1362.
140. Roberts D, Brown J, Medley N, et al. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2017;3(3):CD004454. DOI: 10.1002/14651858.CD004454.pub3.
141. Bailey MT, Lubach GR, Coe CL. Prenatal stress alters bacterial colonization of the gut in infant monkeys. J Pediatr Gastroenterol Nutr 2004;38(4):414–421. DOI: 10.1097/00005176-200404000-00009.
142. Buchmiller TL, Shaw KS, Lam ML, et al. Effect of prenatal dexamethasone administration: Fetal rabbit intestinal nutrient uptake and disaccharidase development. J Surg Res. 1994;57(2):274–279. DOI: 10.1006/jsre.1994.1144.
143. Israel EJ, Schiffrin EJ, Carter EA, et al. Prevention of necrotizing enterocolitis in the rat with prenatal cortisone. Gastroenterology. 1990;99(5):1333–1338. DOI: 10.1016/0016-5085(90)91158-3.
144. American College of O, Gynecologists’ Committee on Obstetric P. Delayed Umbilical Cord Clamping After Birth: ACOG Committee Opinion, Number 814. Obstet Gynecol 2020;136(6):e100–e6. DOI: 10.1097/AOG.0000000000004167.
145. Chiruvolu A, Qin H, Nguyen ET, et al. The effect of delayed cord clamping on moderate and early late-preterm infants. Am J Perinatol 2018;35(3):286–291. DOI: 10.1055/s-0037-1607222.
146. Hooper SB, Te Pas AB, Lang J, et al. Cardiovascular transition at birth: a physiological sequence. Pediatr Res 2015;77(5):608–614. DOI: 10.1038/pr.2015.21.
147. Lin PW, Nasr TR, Stoll BJ. Necrotizing enterocolitis: recent scientific advances in pathophysiology and prevention. Semin Perinatol 2008;32(2):70–82. DOI: 10.1053/j.semperi.2008.01.004.
148. Garg BD, Kabra NS, Bansal A. Role of delayed cord clamping in prevention of necrotizing enterocolitis in preterm neonates: A systematic review. J Matern Fetal Neonatal Med 2019;32(1):164–172. DOI: 10.1080/14767058.2017.1370704.
149. Berenholtz SM, Pronovost PJ, Lipsett PA, et al. Eliminating catheter-related bloodstream infections in the intensive care unit. Crit Care Med 2004;32(10):2014–2020. DOI: 10.1097/01.ccm.0000142399.70913.2f.
150. Pronovost PJ, Berenholtz SM, Goeschel CA, et al. Creating high reliability in health care organizations. Health Serv Res 2006;41(4 Pt 2):1599–1617. DOI: 10.1111/j.1475-6773.2006.00567.x.
151. Youngquist P, Carroll M, Farber M, et al. Implementing a ventilator bundle in a community hospital. Jt Comm J Qual Patient Saf 2007;33(4):219–225. DOI: 10.1016/s1553-7250(07)33026-2.
152. Aboelela SW, Stone PW, Larson EL. Effectiveness of bundled behavioural interventions to control healthcare-associated infections: A systematic review of the literature. J Hosp Infect 2007;66(2):101–108. DOI: 10.1016/j.jhin.2006.10.019.
153. Lawrence P, Fulbrook P. The ventilator care bundle and its impact on ventilator-associated pneumonia: a review of the evidence. Nurs Crit Care 2011;16(5):222–234. DOI: 10.1111/j.1478-5153.2010.00430.x.
154. Lawrence P, Fulbrook P. Effect of feedback on ventilator care bundle compliance: before and after study. Nurs Crit Care 2012;17(6):293–301. DOI: 10.1111/j.1478-5153.2012.00519.x.
155. Borgert MJ, Goossens A, Dongelmans DA. What are effective strategies for the implementation of care bundles on ICUs: A systematic review. Implement Sci 2015;10:119. DOI: 10.1186/s13012-015-0306-1.
156. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: An emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336(7650):924–926. DOI: 10.1136/bmj.39489.470347.AD.
157. Quality EE-bPfI. Gut Health Bundle - Toward a NEC-Free Canada: The Canadian Neonatal Network; 2023.
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