Beyond the Basics
Ksenia Zukowsky, PhD, APRN, NNP-BC ❍ Section Editor
Probiotic Guideline for Necrotizing Enterocolitis Prevention in Very Low-Birth-Weight Neonates Ruslana Parker, DNP, APRN, NNP-BC
ABSTRACT Necrotizing enterocolitis (NEC) is a gastrointestinal emergency that leads to inflammation and intestinal necrosis. Although probiotics can decrease the incidence of NEC, consistent recommendations for probiotic administration to very low-birth-weight (VLBW) neonates are lacking. Here, the best available evidence is reviewed and a practice guideline for probiotic administrations to VLBW neonates is described. A systematic review was conducted using MEDLINE and EMBASE, and the strength of evidence was classified using the Centre for Evidence-Based Medicine classification schema. Probiotics for VLBW neonates may decrease the incidence of NEC. Providers may choose to give probiotics to VLBW neonates at risk of acquiring NEC in facilities with a high NEC incidence. Clinicians must monitor infants for possible adverse effects. Contraindications for probiotic use include extremely low birth weight, clinical instability, abnormal abdominal examination, the presence of congenital abnormalities, post-NEC, stage III asphyxia, and umbilical catheters. Key Words: enterocolitis, guideline, infant, necrotizing, probiotics, very low birth weight
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ecrotizing enterocolitis (NEC) is a gastrointestinal (GI) emergency in which inflammation and death of mucosal and submucosal layers of the intestinal tissue occur. This disease mostly affects premature and compromised fullterm neonates.1,2 The lower the neonate’s gestational Author Affiliation: Neonatal Nurse Practitioner Program, University of Utah, and Evidence Based Practice Briefs, University of Utah, Salt Lake City. The author thanks dedicated mentors Janice Morse, PhD, RN, associate professor at the University of Utah; Sandra Smith, PhD, APRN, NNP-BC, associate professor at the University of Louisville; Marilyn Rigby, DNP, APRN, NNP-BC, assistant professor (clinical) at the University of Utah; Gary Chan, MD, neonatologist, associate professor at the University of Utah; and Christian Con Yost, MD, neonatologist, assistant professor at the University of Utah. The author declares no conflict of interest. Correspondence: Ruslana Parker, DNP, APRN, NNP-BC, 100 Mario Capecchi Dr, Salt Lake City, UT 84113 ([email protected]). Copyright © 2014 by The National Association of Neonatal Nurses DOI: 10.1097/ANC.0000000000000043 88
age and birth weight, the higher the risk of developing NEC.3,4 Among infants who were diagnosed with NEC, the mortality rate is 1 out of 7.5,6 According to data from 2009, the incidence of NEC increased and NEC is now the 11th leading cause of death in infants.6,7 The prolonged hospitalization of neonates because of NEC increases the costs of hospitalization by approximately $15,440 per NEC case.8 Infants who acquire NEC develop a systemic inflammatory response and may develop GI perforation and peritonitis requiring surgical intervention.3,9 Survivors of surgical NEC may suffer from short gut syndrome, growth restriction, difficulties with oral feedings, and lengthened and/or recurrent hospitalizations, and are at risk for negative developmental outcomes and chronic lung disease.3,10,11 Researchers12 hypothesize that prematurity with incomplete GI development in conjunction with an interruption in blood flow to the intestine after birth and gut colonization with pathogenic bacteria increase the risk for NEC. Premature neonates who have an immature gastrointestinal system and are cared for in the neonatal intensive care unit (NICU) have a higher risk of intestinal colonization with pathogenic bacteria and are predisposed to bacterial translocation and NEC.13,14 Advances in Neonatal Care • Vol. 14, No. 2 • pp. 88-95
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Probiotic Guideline for Necrotizing Enterocolitis Prevention in Very Low-Birth-Weight Neonates
Probiotics are living microorganisms that may promote the colonization and establishment of favorable bacterial flora in the GI tract. They enhance carbohydrate fermentation and absorption and play a role in reducing gut permeability, enhancing the production of mucus, inhibiting the colonization of pathogens in the intestines, and releasing antibacterial substances.15,16 Probiotics may decrease the incidence of NEC and improve mortality.4,17-20 Nevertheless, consistent recommendations regarding the use of probiotics to very low-birth-weight (VLBW) neonates are lacking and the current literature is complex.21-26 Despite the absence of consistent recommendations, probiotics are used in clinical trials and clinical practice in NICUs throughout the United States and worldwide.27,28 From a meta-analysis,29 randomized controlled trials (RCTs) of probiotic usage for NEC included more than 3800 neonates. The exact number of patients who receive probiotics in clinical practice is unknown. An enteral feeding survey30 was conducted among members of the National Association of Neonatal Nurses and found that probiotics were used in some NICUs in the United States. Among 68 participants from different NICUs, the answers varied from not using probiotics at all (88.6%), using them only in certain circumstances (7.1%), and using them most of the time (1.4%). Clinicians have tried routine administrations of probiotics to all neonates, including patients with congenital heart disease, GI defects, and extreme prematurity even though there is insufficient evidence regarding probiotics’ safety and efficacy in these groups of patients.4,18,27,31,32 A guideline33 was published in 2011 and the authors provided recommendations for the routine administration of probiotics to premature neonates to prevent NEC mainly in academic centers. Since the publication of that guideline, more than 9 clinical studies and case reports evaluating the effects of probiotics in premature neonates were published.23,27,29,34-38 Therefore, the purpose of this article was to review the best available evidence and develop a probiotic practice guideline for NEC prevention in VLBW neonates. Therefore, the purpose of this article was to review the best available evidence and develop a probiotic practice guideline for NEC prevention in VLBW neonates (see Table). VLBW neonates are patients with a birth weight from 1000 to 1500 g and extremely low birth weight (ELBW) are those born less than 1000 g.
METHODS To evaluate the evidence-based literature about the efficacy and safety of probiotic use in the prevention of NEC in neonates, the following key search terms were used: “preterm infant AND probiotics
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AND necrotizing enterocolitis,” “probiotics AND necrotizing enterocolitis,” “preterm neonate AND necrotizing enterocolitis AND safety and efficacy,” “neonates AND probiotics,” and “Lactobacillus OR Bifidobacterium AND necrotizing enterocolitis.” The search inclusion criteria were limited to systematic reviews, meta-analyses, RCTs, practice guidelines, and case studies. A comprehensive literature search was performed in MEDLINE from 1966 to January 2013 and EMBASE from 1980 to January 2013. The search was limited by the subject’s age and research in humans. Originally, 480 references were obtained and assessed for relevancy to the clinical question and power of evidence. The reference lists of the systematic reviews and metaanalyses were also examined for additional sources.
RESULTS Evidence for Probiotic Use In several RCTs, VLBW neonates who received probiotics showed a statistically significant reduction in the incidence of NEC.4,19,20,24,39,40 These authors used several strains of probiotics, but all studied VLBW infants. The sample sizes of the studies varied from 145 to 472 participants.4,19,20,24,39,40 One author41 criticized the large RCTs of 2 studies4,20 for being underpowered because of an insufficient sample size (each group was fewer than 317 participants). To calculate the power in a hypothetical scenario, this author41 used a small incidence of NEC (5%) and a large effect size (70%). A few investigators26,38,42,43 found no effect in decreasing the incidence of NEC with probiotic administration. Some authors44-48 observed trends toward NEC reduction but did not reach statistical significance. There is currently no literature on probiotics contributing to the development of NEC. There are meta-analyses on probiotic use and reducing the risk of NEC. A meta-analysis18 of 16 RCTs on probiotic use in low-birth-weight neonates and the incidence of NEC was conducted. The combined sample consisted of 2842 neonates who received different strains of probiotics. The authors18 found a significant decrease in NEC with probiotic administrations (relative risk [RR] = 0.35; 95% confidence interval [CI]: 0.24-0.52). A metaanalysis17 of 11 RCTs with enteral administrations of probiotics in VLBW neonates was performed. The authors concluded that the risk of NEC and mortality was significantly less (30% risk reduction; RR = 0.35, 95% CI: 0.23-0.55 for the decrease in incidence of NEC and RR 0.42, 95% CI: 0.29-0.62, for the reduction in mortality rate). In addition, a meta-analysis29 of 20 RCTs was directed in which the influence of probiotics on the incidence of NEC in 3816 VLBW neonates was studied. The
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TABLE. Probiotic Guideline for Necrotizing Enterocolitis (NEC) Prevention in Very Low-Birth-Weight Neonates Recommendations With LOE by CEBM50 Population
LOE
VLBW neonates
Level 1
a4,17-20,29,52
Level 3b4,19,20,23 Level 4c27 Cautious use
ELBW infants, infants with cardiac defects, clinically unstable, GI Level 118 abnormalities, other severe congenital defects, stage III Level 34,20,62 asphyxia, post-NEC, and umbilical lines Level 431,49,54
Adverse effect monitoring
Lactic acidosis, sepsis, meningitis, diarrhea, emesis, and distension of the abdomen
Probiotic strain
Combination of Bifidobacterium and Lactobacillus. The following Level 129,52 strains showed statistically significant results: Lactobacillus Level 34,19,23,24,39,40,62 rhamnosus GG, Lactobacillus acidophilus, Bifidobacteria Level 463 infantis, Bifidobacteria bifidum, Lactobacillus casei
Dose
May use range of 0.056 to 6 × 107 to 109 CFU/day
Level 432,34,35,49,54,57 Level 5d55
Level 34,19,20,23,24,39,40,62 Level 427,34,63
When to start Duration Preparation
Storage
Infant is clinically stable, able to start enteral feedings, and has a normal abdominal examination
Level 34,20 19 38
4-6 wks, up to 36 wks of adjusted gestational age or until discharge
Level 34,19,20,24,40,62
Mix with 3 mL of feedings; prepare by trained individuals with aseptic techniques to prevent crosscontamination and ensure consistency
Level 34,19,23,24,62
Refrigerate at 2°C-8°C or as the manufacturer suggests; at least 1 daily quality assessment of the refrigerator’s temperature
Level 34,20
Level 434 Level 427,34,63 Level 434 Level 561
Quality assurance Before choosing a probiotic agent, confirm content of the package using a laboratory analysis and/or check the manufacturer’s background
Level 4 34 Level 34,23,71 Level 434 Level 561
Abbreviations: CEBM, Centre for Evidence-Based Medicine; CFU, colony-forming unit; ELBW, extremely low birth weight; GI, gastrointestinal; LOE, level of evidence; VLBW, very low birth weight. Source: Author. aLevel 2a evidence according to previously known CEBM classification of 2009.50 b c
Level 2b evidence according to previously known CEBM classification of 2009.50
Level 3b to 4 evidence according to previously known CEBM classification of 2009.50
d
Level 5 evidence according to previously known CEBM classification of 2009.50
investigators found a significant risk reduction in NEC of 0.33 (95% CI: 0.24-0.46). However, neonates of various gestational ages and weights were studied and the strains of probiotics and dosing regimen differed across the clinical trials, thus limiting the findings of these meta-analyses. In addition to the RCTs and meta-analyses on probiotic use, retrospective studies demonstrate the benefits of probiotics in premature neonates. Investigators34 analyzed the incidence of NEC when Lactobacillus reuteri was introduced to neonates less than 1000 g during 2009 to 2011 compared to
previous years when probiotics were not given (2004-2009). There were significantly fewer NEC cases in those neonates who received probiotic supplementation. Other researchers27 found that the incidence of NEC was decreased in a cohort of 1130 VLBW neonates who received probiotics (Lactobacillus rhamnosus) in comparison to participants who had not received supplementation before 2008. However, the evidence from these observational studies is not strong because of the retrospective designs and absence of randomization and blinding. www.advancesinneonatalcare.org
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Although the evidence for probiotic use in VLBW neonates for NEC prevention is increasing, the safety and efficacy have not been clearly established.41 There were reports of sepsis linked with probiotic usage in ELBW neonates, infants with short gut syndrome, and cardiac and GI malformations.31,32,35,49 Therefore, probiotics should be used with caution in VLBW neonates on a case-by-case basis and preferably in clinical environments where the risk of NEC is high and the benefits of probiotic use outweigh the risks for negative consequences of probiotic administration.
Level of Evidence by Center for Evidence-Based Medicine For this clinical guideline, the levels of evidence were identified according to the hierarchy of evidence from the Centre for Evidence-Based Medicine (CEBM) 2011.50 Thus, for the development of this guideline, the author chose to use the 2009 classifications. The findings presented by meta-analyses are identified as level 1 evidence, RCTs as level 2, cohort studies as level 3, case-control studies and clinical case reports as level 4, and mechanism-based reasoning as level 5. There are methodological limitations in the RCTs and meta-analyses that support this clinical guideline and publication bias has to be considered. These RCTs and meta-analyses were rigorously criticized.41,51 One RCT24 needed 282 subjects per group to obtain a 60% reduction of NEC if the incidence of NEC before the study was 10%. However, only 231 subjects were studied. This study was stopped prematurely because of the observed significant benefits in the intervention group. The nutritional team members and research assistants were not blinded, but they did not participate in the patient care. The healthcare providers and nurses were blinded. In 3 studies,4,20,23 clinicians and nurses were not aware of the group assignments. The members of the breast milk team or feeding preparation team knew the group assignments, but they were not involved in the patient care. The sample size in the study published in 201323 was small and the study was underpowered. Another RCT of probiotic use40 was also underpowered and NEC was a secondary outcome. The weaknesses of the meta-analyses consist of the inclusion of RCTs that studied various probiotic strains, administration regimens, and patients of various birth weight and gestational age.17,18,29,52 Population for Whom Probiotics Can Be Used or Used With Caution There is a body of evidence of RCTs, meta-analyses, and observational studies supporting probiotic use for the prevention of NEC in VLBW neonates.4,17,20,29,52 However, providers should not routinely use probiotics in all VLBW neonates but must
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evaluate the risk/benefit ratio for each patient. Although ELBW neonates are at a high risk (11%)53 for acquiring NEC, there is a lack of evidence that probiotics are safe and beneficial for this group of neonates. A systematic review18 found that there is not enough evidence regarding the safety and effects of probiotics in infants weighing less than 1000 g. This group of neonates has not been studied enough in large RCTs. A report from a population study34 does not provide strong evidence for probiotic use in ELBW infants because the data were reviewed retrospectively, there was no randomization or blinding, and only 79 ELBW neonates received probiotics. In addition, there was a report35 of an occurrence of septicemia in one ELBW neonate associated with a probiotic administration. Similarly, the safety of probiotic use is not clearly defined in infants with short gut syndrome, congenital cardiovascular disease, gastrointestinal abnormalities, post-GI surgery, or post-NEC and probiotics may be harmful in these groups of neonates.31,32,49,54
Monitoring for Adverse Effects There are possible adverse effects from probiotic use that are concerning to providers such as lactic acidosis, sepsis, meningitis, diarrhea, emesis, and distension of the abdomen.55 Reports of single cases of sepsis possibly associated with probiotics have been published.32,35,54,56,57 No adverse effects from using probiotics in VLBW neonates were reported in the RCTs or retrospective cohort studies.4,19,20,34,39,58,59 No sepsis related to probiotic use or other possible adverse effects were recognized in a 6-year-followup study by reviewing the complete data on 743 patients who received Lactobacillus rhamnosus GG for 4 to 6 weeks during a NICU stay and until discharge.60 To promote patient safety, clinicians should monitor for any adverse effects of probiotic use including feeding intolerance and infection, create a surveillance system and databases in their facility, and stop the probiotic administration promptly if any adverse effects are found.61 Probiotic Strain The probiotic strains, species, and administration regimens may have an influence on the efficacy of NEC prevention. Researchers4 studied Bifidobacterium bifidum and Lactobacillus acidophilus in neonates weighing less than 1500 g versus placebo. In an RCT of 434 neonates, they found a significant decrease in the incidence of NEC in the experimental group compared with the placebo group. There were 4 cases of NEC in the experimental group and 20 cases in the control group (P = .002). In contrast, the probiotic supplementation of Saccharomyces boulardii in premature neonates was also investigated.44 The authors found no significant difference in the incidence of NEC in the experimental group
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compared with the control group. The efficacy of Lactobacillus casei subspecies rhamnosus and the incidence of NEC were studied in a small sample of 80 VLBW neonates.45 No statistically significant difference was found in the incidence of NEC between the control and treatment groups. These findings suggest that specific bacterial species are needed to prevent NEC. The use of a combination of at least 2 probiotic strains appears more effective than the administration of a single probiotic strain. According to a metaanalysis,52 the administration of Bifidobacterium spp and Lactobacillus acidophilus was more effective in reducing the incidence of NEC than the delivery of a single probiotic agent. Similarly, other investigators29 found that a combination of Lactobacillus and Bifidobacteria (P < 0.0001) was more effective than Lactobacillus (P < 0.004) or Bifidobacteria (P < 0.0003) alone in reducing the risk of NEC in VLBW neonates. A statistically significant risk reduction in the incidence of NEC was found when the following probiotic strains were used: Lactobacillus rhamnosus GG, Lactobacillus acidophilus, Bifidobacteria infantis, Bifidobacteria bifidum, and Lactobacillus casei.4,19,20,23,24,39,62,63 These probiotics have been successful, but more clinical trials are required to validate the efficacy of these agents. Thus, a clinician may use a combination of Lactobacillus and Bifidobacteria from the list of the strains described previously for the prevention of NEC in VLBW neonates.
Probiotic Dose Investigators who reported statistically significant results used probiotic doses of 0.056 to 6 × 107-109 colony-forming units (CFU)/day administered daily or divided into 2 doses.4,19,20,24,27,34,39,62,63 No adverse effects were found in the studies with these probiotic dose ranges.4,19,20,23,24,27,34,62,63 In a 2011 probiotic use guideline,33 the recommended dose was 3 × 109 CFU/ day for neonates born less than 32 weeks of gestation. The conclusion regarding this dose was drawn by looking at the probiotics studies and identifying the median dose used by researchers. According to a study,60 the use of Lactobacillus rhamnosus GG with a dose of 3 × 109 CFU/day (administered once a day) showed no adverse outcomes in a 6-year observational study of VLBW neonates.60 Therefore, the literature supports using a dosage range of 0.056 to 6 × 107 to 109 CFU/day of probiotics, which may be effective and safe for NEC prevention in VLBW neonates. Beginning the Probiotic Administration The authors of the RCTs used various initiation regimens of probiotics in VLBW neonates.4,20,24,27,40,62 The authors of 4 RCTs and 1 small observational study that obtained a statistically significant reduc-
tion in the incidence of NEC started the probiotics when the neonates were clinically stable and able to start oral feedings and had a normal abdominal examination.4,19,20,23,34 The infants with umbilical lines were excluded from one study20 and the safety of probiotics during the time when umbilical artery or venous catheters are in place is unknown. Although the evidence is not strong, the probiotic administration may be started if the patient has a normal abdominal examination and is clinically ready to start enteral feedings. Researchers38 studied the timing effectiveness of probiotic colonization of the gut. This RCT involved 36 VLBW neonates. They found only a trend toward an increased colonization rate of the GI tract with Bifidobacterium bifidum when starting the administration of this probiotic agent in the first 48 hours of life. Thus, there is no evidence regarding the safety and benefits of starting probiotics within the first 48 hours of life.
Duration of Therapy To identify the optimal duration of therapy, the duration of probiotic administrations in clinical studies was reviewed. Some investigators34 gave probiotics to ELBW neonates in 2009 after 1 to 2 weeks after birth. In 2010, participants received probiotics when they were stable enough to be fed enterally and until discharge. In other studies20,23,62 probiotics were begun shortly after birth when VLBW neonates were stable to start feedings and continued until the neonate’s discharge. Additional investigators administered probiotics shortly after birth until the neonates reached 36 weeks of adjusted gestational age,19,27 from the 2nd day of life through the 30th or until discharge,24 or used probiotics for 6 weeks or until discharge.4 Therefore, if used to prevent NEC in VLBW neonates, the literature supports continuing probiotic therapy for 4 to 6 weeks and up to 36 weeks of adjusted gestational age or until the neonate’s discharge. Preparation Probiotics may be mixed with 3 mL of breast milk or preterm infant formula.19,23,24 Although there are no clear synergistic effects of breast milk with probiotics, the researchers who achieved statistically significant results in decreasing the incidence of NEC used breast milk.4,19,20,23,24,34,62 The effects of the carbohydrates and proteins used in the formula on probiotics are not clearly understood.64 The question about the range of osmolarity for the probiotic preparation when mixing probiotics with milk or preterm formula has not been answered. In the other guideline,33 the authors recommend maintaining an osmolarity of the solution less than 600 mOsm/L. This recommendation is grounded in a principle of
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physiology, but there is no clinical trial to support which osmolarity is the most efficient and safe when probiotics are mixed with feedings. In the clinical trials where no adverse side effects occurred from probiotic use, the mixing of probiotics with breast milk or preterm infant formula was prepared by a pharmacy or specially trained individuals. In a retrospective study,34 researchers ensured that probiotics were prepared by a pharmacy following strict sterile techniques. Therefore, to protect the vulnerable population of VLBW neonates when choosing a probiotic for patients, clinicians should ensure that the preparation occurs by properly trained individuals. It is not recommended to prepare probiotics at the infant’s bedside by a caregiver as there is a potential risk of cross-contamination and lack of consistency in the preparation.61,65
Storage and Quality Assurance In 2 RCTs,4,20 probiotics were refrigerated at 2°C to 8°C, but a length of time for storage was not defined. Other researchers34 also refrigerated the probiotics and they were administered no later than 6 hours after removal from the refrigerator. The authors of this study also did at least 1 daily quality assessment of the refrigerator’s temperature. In contrast, another clinical trial23 had the probiotics stored at room temperature and no known adverse effects were detected in the study group participants. Per the manufacturer’s recommendation of Culturelle, which contains Lactobacillus GG, storage at room temperature is recommended, but not higher than 75°F.66 Therefore, because it is not completely understood if it is safe to store probiotics at room temperature, probiotics should be refrigerated at 2°C to 8°C or per the manufacturer’s recommendation. Healthcare providers have to ensure that a quality assessment of the refrigerator’s temperature occurs at least once a day. The manufacturer of Align (Bifidobacteruim infantis 35624) advises storing their probiotic product at room temperature.67,68 The manufacturer of BioGaia (Lactobacillus reiteri) recommends storage at temperatures lower than 77°F and does not specify a time range in which the product should be administered,69 but the authors of a retrospective study34 refrigerated this product and administered it within 6 hours of preparation time. Because probiotics are not approved by the Food and Drug Administration for NEC prevention, before choosing and using a product, clinicians should conduct a quality assurance review that the content of the package corresponds with the strains and amount described by the manufacturer preferably by using a laboratory analysis and/or checking the background of the probiotic manufacturer.61,70 The clinical site should have the ability to order/perform 16S rRNA sequencing and pulsed-field gel
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electrophoresis to confirm that any discovered cases of bacterial sepsis are not related to the administration of probiotics.61,71
CONCLUSION Although the meta-analyses, RCTs, and observational studies report that probiotic administration to VLBW neonates can decrease the incidence of NEC,4,17-20,23,24,27,29,34,62,63 the safety and efficacy of the treatment are not clearly established. The current guideline is intended for probiotics administration in VLBW neonates who are at high risk of acquiring NEC in facilities with a high incidence of NEC. Providers should avoid administering probiotics to ELBW neonates,18 neonates who are clinically unstable and unable to start feedings,4,20,62 and neonates with GI problems and cardiac or other genetic abnormalities31,32,49,54 because there is insufficient evidence on the safety of probiotics in these groups. With each clinical case, the clinician should weigh the benefits and risks of probiotic use and NEC and evaluate if there are resources available for a safe administration, quality assurance of the probiotic product, preparation and storage, and surveillance for the short- and long-term adverse effects.
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13. Madan JC, Salari RC, Saxena D, et al. Gut microbial colonisation in premature neonates predicts neonatal sepsis. Arch Dis Child Fetal Neonatal Ed. 2012;97(6):F456-F462. 14. Martin CR, Walker WA. Intestinal immune defences and the inflammatory response in necrotising enterocolitis. Semin Fetal Neonatal Med. 2006;11(5):369-377. 15. Ng SC, Hart AL, Kamm MA, Stagg AJ, Knight SC. Mechanisms of action of probiotics: recent advances. Inflamm Bowel Dis. 2009;15(2):300-310. 16. Sanz Y, Nadal I, Sanchez E. Probiotics as drugs against human gastrointestinal infections. Recent Pat Antiinfect Drug Discov. 2007;2(2):148156. 17. Deshpande G, Rao S, Patole S, Bulsara M. Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates. Pediatrics. 2010;125(5):921-930. 18. AlFaleh K, Anabrees J, Bassler D, Al-Kharfi T. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane DB Syst Rev. 2011(3). http://www.mrw.interscience.wiley.com/cochrane/clsysrev/ articles/CD005496/frame.html. Accessed March 23, 2013. 19. Bin-Nun A, Bromiker R, Wilschanski M, et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates. J Pediatr. 2005;147(2):192-196. 20. Lin H-C, Su B-H, Chen A-C, et al. Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants. Pediatrics. 2005;115(1):1-4. 21. Purdy IB, Melwak MA. Implementing evidence-based practice: a mantra for clinical change. J Perinat Neonatal Nurs. 2009;23(3):263269. 22. Hay MC, Weisner TS, Subramanian S, Duan N, Niedzinski EJ, Kravitz RL. Harnessing experience: exploring the gap between evidencebased medicine and clinical practice. J Eval Clin Pract. 2008;14(5):707713. 23. Fernández-Carrocera LA, Solis-Herrera A, Cabanillas-Ayón M, et al. Double-blind, randomised clinical assay to evaluate the efficacy of probiotics in preterm newborns weighing less than 1500 g in the prevention of necrotising enterocolitis. Arch Dis Child Fetal Neonatal Ed. 2013;98(1):F5-F9. 24. Braga TD, da Silva GAP, de Lira PIC, de Carvalho Lima M. Efficacy of Bifidobacterium breve and Lactobacillus casei oral supplementation on necrotizing enterocolitis in very-low-birth-weight preterm infants: a double-blind, randomized, controlled trial. Am J Clin Nutr. 2011;93(1):81-86. 25. Garland SM, Tobin JM, Pirotta M, et al. The ProPrems trial: investigating the effects of probiotics on late onset sepsis in very preterm infants. BMC Infect Dis. 2011;11:210. 26. Sari FN, Dizdar EA, Oguz S, Erdeve O, Uras N, Dilmen U. Oral probiotics: Lactobacillus sporogenes for prevention of necrotizing enterocolitis in very low-birth weight infants: a randomized, controlled trial. Eur J Clin Nutr. 2011;65(4):434-439. 27. Bonsante F, Iacobelli S, Gouyon JB. Routine probiotic use in very preterm infants: retrospective comparison of two cohorts. Am J Perinatol. 2012;6:6. 28. Walker WA. Mechanisms of action of probiotics. Clin Infect Dis. 2008;46(Suppl 2):S87-S91. 29. Wang Q, Dong J, Zhu Y. Probiotic supplement reduces risk of necrotizing enterocolitis and mortality in preterm very low-birth-weight infants: an updated meta-analysis of 20 randomized, controlled trials. J Pediatr Surg. 2012;47(1):241-248. 30. Gregory KE, Connolly TC. Enteral feeding practices in the NICU: results from a 2009 neonatal enteral feeding survey. Adv Neonatal Care. 2012;12(1):46-55. 31. Ohishi A, Takahashi S, Ito Y, et al. Bifidobacterium septicemia associated with postoperative probiotic therapy in a neonate with omphalocele. J Pediatr. 2010;156(4):679-681. 32. Land MH, Rouster-Stevens K, Woods CR, Cannon ML, Cnota J, Shetty AK. Lactobacillus sepsis associated with probiotic therapy. Pediatrics. 2005;115(1):178-181. 33. Deshpande GC, Rao SC, Keil AD, Patole SK. Evidence-based guidelines for use of probiotics in preterm neonates. BMC Med. 2011;9:92. 34. Hunter C, Dimaguila MA, Gal P, et al. Effect of routine probiotic, Lactobacillus reuteri DSM 17938, use on rates of necrotizing enterocolitis in neonates with birthweight < 1000 grams: a sequential analysis. BMC Pediatr. 2012;12(1):142. 35. Jenke A, Ruf EM, Hoppe T, Heldmann M, Wirth S. Bifidobacterium septicaemia in an extremely low-birthweight infant under probiotic therapy. Arch Dis Child Fetal Neonatal Ed. 2012;97(3):F217-F218. 36. Rojas MA, Lozano JM, Rojas MX, et al. Prophylactic probiotics to prevent death and nosocomial infection in preterm infants. Pediatrics. 2012;130(5):e1113-e1120. 37. Sari FN, Eras Z, Dizdar EA, et al. Do oral probiotics affect growth and neurodevelopmental outcomes in very low-birth-weight preterm infants? Am J Perinatol. 2012;7:7.
38. Yamasaki C, Totsu S, Uchiyama A, et al. Effect of Bifidobacterium administration on very-low-birthweight infants. Pediatr Int. 2012;54(5):651-656. 39. Awad H, Mokhtar H, Imam SS, Gad GI, Hafez H, Aboushady N. Comparison between killed and living probiotic usage versus placebo for the prevention of necrotizing enterocolitis and sepsis in neonates. Pak J Biol Sci. 2010;13(6):253-262. 40. Manzoni P, Rinaldi M, Cattani S, et al. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birthweight neonates: a randomized trial. JAMA. 2009;302(13): 1421-1428. 41. Mihatsch WA. What is the power of evidence recommending routine probiotics for necrotizing enterocolitis prevention in preterm infants? Curr Opin Clin Nutr Metab Care. 2011;14(3):302-306. 42. Szajewska H, Guandalini S, Morelli L, Van Goudoever JB, Walker A. Effect of Bifidobacterium animalis subsp lactis supplementation in preterm infants: a systematic review of randomized controlled trials. J Pediatr Gastroenterol Nutr. 2010;51(2):203-209. 43. Li Y, Shimizu T, Hosaka A, Kaneko N, Ohtsuka Y, Yamashiro Y. Effects of Bifidobacterium breve supplementation on intestinal flora of low birth weight infants. Pediatr Int. 2004;46(5):509-515. 44. Costalos C, Skouteri V, Gounaris A, et al. Enteral feeding of premature infants with Saccharomyces boulardii. Early Hum Dev. 2003;74(2): 89-96. 45. Manzoni P, Mostert M, Leonessa ML, et al. Oral supplementation with Lactobacillus casei subspecies rhamnosus prevents enteric colonization by Candida species in preterm neonates: a randomized study. Clin Infect Dis. 2006;42(12):1735-1742. 46. Mihatsch WA, Vossbeck S, Eikmanns B, Hoegel J, Pohlandt F. Effect of Bifidobacterium lactis on the incidence of nosocomial infections in very-low-birth-weight infants: a randomized controlled trial. Neonatology. 2010;98(2):156-163. 47. Dani C, Biadaioli R, Bertini G, Martelli E, Rubaltelli F. Probiotics feeding in prevention of urinary tract infection, bacterial sepsis and necrotizing enterocolitis in preterm infants. a prospective double-blind study. Biol Neonate. 2002;82(2):103-108. 48. Stratiki Z, Costalos C, Sevastiadou S, et al. The effect of a bifidobacter supplemented bovine milk on intestinal permeability of preterm infants. Early Hum Dev. 2007;83(9):575-579. 49. Kunz AN, Noel JM, Fairchok MP. Two cases of Lactobacillus bacteremia during probiotic treatment of short gut syndrome. J Pediatr Gastroenterol Nutr. 2004;38(4):457-458. 50. Howick J, Chalmers I, Glasziou P, et al. The 2011 Oxford CEBM levels of evidence. Oxford Centre for Evidence-Based Medicine. http:// www.cebm.net/index.aspx?o=5653. Published 2011. Accessed March 23, 2013. 51. Mihatsch WA, Braegger CP, Decsi T, et al. Critical systematic review of the level of evidence for routine use of probiotics for reduction of mortality and prevention of necrotizing enterocolitis and sepsis in preterm infants. Clin Nutr. 2012;31(1):6-15. 52. Guthmann F, Kluthe C, Buhrer C. Probiotics for prevention of necrotising enterocolitis: an updated meta-analysis. Klin Padiatr. 2010;222(5): 284-290 53. Stoll BJ, Hansen NI, Bell EF, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics. 2010;126(3):443-456. 54. Young RJ, Vanderhoof JA. Two cases of Lactobacillus bacteremia during probiotic treatment of short gut syndrome. J Pediatr Gastroenterol Nutr. 2004;39(4):436-437. 55. Snydman DR. The safety of probiotics. Clin Infect Dis. 2008;46(suppl 2): S104-S111. 56. Presterl E, Kneifel W, Mayer H, Zehetgruber M, Makristathis A, Graninger W. Endocarditis by Lactobacillus rhamnosus due to yogurt ingestion? Scand J Infect Dis. 2001;33(9):710-714. 57. Thompson C, McCarter YS, Krause PJ, Herson VC. Lactobacillus acidophilus sepsis in a neonate. J Perinatol. 2001;21(4):258260. 58. AlFaleh K, Anabrees J, Bassler D. Probiotics reduce the risk of necrotizing enterocolitis in preterm infants: a meta-analysis. Neonatology. 2010;97(2):93-99. 59. Luoto R, Isolauri E, Lehtonen L. Safety of Lactobacillus GG probiotic in infants with very low birth weight: twelve years of experience. Clin Infect Dis. 2010;50(9):1327-1328. 60. Manzoni P, Lista G, Gallo E, et al. Routine Lactobacillus rhamnosus GG administration in VLBW infants: a retrospective, 6-year cohort study. Early Hum Dev. 2011;87:S35-S38. 61. Seale JV, Millar M. Probiotics: a new frontier for infection control. J Hosp Infect. 2013;84(1):1-4. 62. Samanta M, Sarkar M, Ghosh P, Ghosh J, Sinha M, Chatterjee S. Prophylactic probiotics for prevention of necrotizing enterocolitis in very low birth weight newborns. J Trop Pediatr. 2009;55(2): 128-131.
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Probiotic Guideline for Necrotizing Enterocolitis Prevention in Very Low-Birth-Weight Neonates 63. Hoyos AB. Reduced incidence of necrotizing enterocolitis associated with enteral administration of Lactobacillus acidophilus and Bifidobacterium infantis to neonates in an intensive care unit. Int J Infect Diseas. 1999;3(4):197-202. 64. Rabot S, Rafter J, Rijkers GT, Watzl B, Antoine J-M. Guidance for substantiating the evidence for beneficial effects of probiotics: impact of probiotics on digestive system metabolism. J Nutr. 2010;140(3):677S-689S. 65. Venugopalan V, Shriner KA, Wong-Beringer A. Regulatory oversight and safety of probiotic use. Emerg Infect Dis. 2010;16(11):16611665. 66. i-Health Inc. Culturelle products. http://www.culturelle.com/about_ culturelle/product_digestive30. Accessed March 23, 2013.
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67. Procter & Gamble. About Bifantis. http://www.bifantis.com./ Accessed March 23, 2013. 68. Procter & Gamble. Align probiotic supplements. http://www.aligngi. com./ Accessed March 23, 2013. 69. BioGaia Global. BioGaia products. http://biogaia.com/consumer?field_ bg_product_countries_tid=11&field_bg_product_symptom_tid=All. Accessed March 23, 2013. 70. Vankerckhoven V, Huys G, Vancanneyt M, et al. Biosafety assessment of probiotics used for human consumption: recommendations from the EU-PROSAFE project. Trends Food Sci Technol. 2008;19(2):102-114. 71. Fasoli S, Marzotto M, Rizzotti L, Rossi F, Dellaglio F, Torriani S. Bacterial composition of commercial probiotic products as evaluated by PCRDGGE analysis. Int J Food Microbiol. 2003;82(1):59-70.
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Ksenia Zukowsky, PhD, APRN, NNP-BC ❍ Section Editor
Probiotic Guideline for Necrotizing Enterocolitis Prevention in Very Low-Birth-Weight Neonates Ruslana Parker, DNP, APRN, NNP-BC
ABSTRACT Necrotizing enterocolitis (NEC) is a gastrointestinal emergency that leads to inflammation and intestinal necrosis. Although probiotics can decrease the incidence of NEC, consistent recommendations for probiotic administration to very low-birth-weight (VLBW) neonates are lacking. Here, the best available evidence is reviewed and a practice guideline for probiotic administrations to VLBW neonates is described. A systematic review was conducted using MEDLINE and EMBASE, and the strength of evidence was classified using the Centre for Evidence-Based Medicine classification schema. Probiotics for VLBW neonates may decrease the incidence of NEC. Providers may choose to give probiotics to VLBW neonates at risk of acquiring NEC in facilities with a high NEC incidence. Clinicians must monitor infants for possible adverse effects. Contraindications for probiotic use include extremely low birth weight, clinical instability, abnormal abdominal examination, the presence of congenital abnormalities, post-NEC, stage III asphyxia, and umbilical catheters. Key Words: enterocolitis, guideline, infant, necrotizing, probiotics, very low birth weight
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ecrotizing enterocolitis (NEC) is a gastrointestinal (GI) emergency in which inflammation and death of mucosal and submucosal layers of the intestinal tissue occur. This disease mostly affects premature and compromised fullterm neonates.1,2 The lower the neonate’s gestational Author Affiliation: Neonatal Nurse Practitioner Program, University of Utah, and Evidence Based Practice Briefs, University of Utah, Salt Lake City. The author thanks dedicated mentors Janice Morse, PhD, RN, associate professor at the University of Utah; Sandra Smith, PhD, APRN, NNP-BC, associate professor at the University of Louisville; Marilyn Rigby, DNP, APRN, NNP-BC, assistant professor (clinical) at the University of Utah; Gary Chan, MD, neonatologist, associate professor at the University of Utah; and Christian Con Yost, MD, neonatologist, assistant professor at the University of Utah. The author declares no conflict of interest. Correspondence: Ruslana Parker, DNP, APRN, NNP-BC, 100 Mario Capecchi Dr, Salt Lake City, UT 84113 ([email protected]). Copyright © 2014 by The National Association of Neonatal Nurses DOI: 10.1097/ANC.0000000000000043 88
age and birth weight, the higher the risk of developing NEC.3,4 Among infants who were diagnosed with NEC, the mortality rate is 1 out of 7.5,6 According to data from 2009, the incidence of NEC increased and NEC is now the 11th leading cause of death in infants.6,7 The prolonged hospitalization of neonates because of NEC increases the costs of hospitalization by approximately $15,440 per NEC case.8 Infants who acquire NEC develop a systemic inflammatory response and may develop GI perforation and peritonitis requiring surgical intervention.3,9 Survivors of surgical NEC may suffer from short gut syndrome, growth restriction, difficulties with oral feedings, and lengthened and/or recurrent hospitalizations, and are at risk for negative developmental outcomes and chronic lung disease.3,10,11 Researchers12 hypothesize that prematurity with incomplete GI development in conjunction with an interruption in blood flow to the intestine after birth and gut colonization with pathogenic bacteria increase the risk for NEC. Premature neonates who have an immature gastrointestinal system and are cared for in the neonatal intensive care unit (NICU) have a higher risk of intestinal colonization with pathogenic bacteria and are predisposed to bacterial translocation and NEC.13,14 Advances in Neonatal Care • Vol. 14, No. 2 • pp. 88-95
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Probiotic Guideline for Necrotizing Enterocolitis Prevention in Very Low-Birth-Weight Neonates
Probiotics are living microorganisms that may promote the colonization and establishment of favorable bacterial flora in the GI tract. They enhance carbohydrate fermentation and absorption and play a role in reducing gut permeability, enhancing the production of mucus, inhibiting the colonization of pathogens in the intestines, and releasing antibacterial substances.15,16 Probiotics may decrease the incidence of NEC and improve mortality.4,17-20 Nevertheless, consistent recommendations regarding the use of probiotics to very low-birth-weight (VLBW) neonates are lacking and the current literature is complex.21-26 Despite the absence of consistent recommendations, probiotics are used in clinical trials and clinical practice in NICUs throughout the United States and worldwide.27,28 From a meta-analysis,29 randomized controlled trials (RCTs) of probiotic usage for NEC included more than 3800 neonates. The exact number of patients who receive probiotics in clinical practice is unknown. An enteral feeding survey30 was conducted among members of the National Association of Neonatal Nurses and found that probiotics were used in some NICUs in the United States. Among 68 participants from different NICUs, the answers varied from not using probiotics at all (88.6%), using them only in certain circumstances (7.1%), and using them most of the time (1.4%). Clinicians have tried routine administrations of probiotics to all neonates, including patients with congenital heart disease, GI defects, and extreme prematurity even though there is insufficient evidence regarding probiotics’ safety and efficacy in these groups of patients.4,18,27,31,32 A guideline33 was published in 2011 and the authors provided recommendations for the routine administration of probiotics to premature neonates to prevent NEC mainly in academic centers. Since the publication of that guideline, more than 9 clinical studies and case reports evaluating the effects of probiotics in premature neonates were published.23,27,29,34-38 Therefore, the purpose of this article was to review the best available evidence and develop a probiotic practice guideline for NEC prevention in VLBW neonates. Therefore, the purpose of this article was to review the best available evidence and develop a probiotic practice guideline for NEC prevention in VLBW neonates (see Table). VLBW neonates are patients with a birth weight from 1000 to 1500 g and extremely low birth weight (ELBW) are those born less than 1000 g.
METHODS To evaluate the evidence-based literature about the efficacy and safety of probiotic use in the prevention of NEC in neonates, the following key search terms were used: “preterm infant AND probiotics
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AND necrotizing enterocolitis,” “probiotics AND necrotizing enterocolitis,” “preterm neonate AND necrotizing enterocolitis AND safety and efficacy,” “neonates AND probiotics,” and “Lactobacillus OR Bifidobacterium AND necrotizing enterocolitis.” The search inclusion criteria were limited to systematic reviews, meta-analyses, RCTs, practice guidelines, and case studies. A comprehensive literature search was performed in MEDLINE from 1966 to January 2013 and EMBASE from 1980 to January 2013. The search was limited by the subject’s age and research in humans. Originally, 480 references were obtained and assessed for relevancy to the clinical question and power of evidence. The reference lists of the systematic reviews and metaanalyses were also examined for additional sources.
RESULTS Evidence for Probiotic Use In several RCTs, VLBW neonates who received probiotics showed a statistically significant reduction in the incidence of NEC.4,19,20,24,39,40 These authors used several strains of probiotics, but all studied VLBW infants. The sample sizes of the studies varied from 145 to 472 participants.4,19,20,24,39,40 One author41 criticized the large RCTs of 2 studies4,20 for being underpowered because of an insufficient sample size (each group was fewer than 317 participants). To calculate the power in a hypothetical scenario, this author41 used a small incidence of NEC (5%) and a large effect size (70%). A few investigators26,38,42,43 found no effect in decreasing the incidence of NEC with probiotic administration. Some authors44-48 observed trends toward NEC reduction but did not reach statistical significance. There is currently no literature on probiotics contributing to the development of NEC. There are meta-analyses on probiotic use and reducing the risk of NEC. A meta-analysis18 of 16 RCTs on probiotic use in low-birth-weight neonates and the incidence of NEC was conducted. The combined sample consisted of 2842 neonates who received different strains of probiotics. The authors18 found a significant decrease in NEC with probiotic administrations (relative risk [RR] = 0.35; 95% confidence interval [CI]: 0.24-0.52). A metaanalysis17 of 11 RCTs with enteral administrations of probiotics in VLBW neonates was performed. The authors concluded that the risk of NEC and mortality was significantly less (30% risk reduction; RR = 0.35, 95% CI: 0.23-0.55 for the decrease in incidence of NEC and RR 0.42, 95% CI: 0.29-0.62, for the reduction in mortality rate). In addition, a meta-analysis29 of 20 RCTs was directed in which the influence of probiotics on the incidence of NEC in 3816 VLBW neonates was studied. The
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TABLE. Probiotic Guideline for Necrotizing Enterocolitis (NEC) Prevention in Very Low-Birth-Weight Neonates Recommendations With LOE by CEBM50 Population
LOE
VLBW neonates
Level 1
a4,17-20,29,52
Level 3b4,19,20,23 Level 4c27 Cautious use
ELBW infants, infants with cardiac defects, clinically unstable, GI Level 118 abnormalities, other severe congenital defects, stage III Level 34,20,62 asphyxia, post-NEC, and umbilical lines Level 431,49,54
Adverse effect monitoring
Lactic acidosis, sepsis, meningitis, diarrhea, emesis, and distension of the abdomen
Probiotic strain
Combination of Bifidobacterium and Lactobacillus. The following Level 129,52 strains showed statistically significant results: Lactobacillus Level 34,19,23,24,39,40,62 rhamnosus GG, Lactobacillus acidophilus, Bifidobacteria Level 463 infantis, Bifidobacteria bifidum, Lactobacillus casei
Dose
May use range of 0.056 to 6 × 107 to 109 CFU/day
Level 432,34,35,49,54,57 Level 5d55
Level 34,19,20,23,24,39,40,62 Level 427,34,63
When to start Duration Preparation
Storage
Infant is clinically stable, able to start enteral feedings, and has a normal abdominal examination
Level 34,20 19 38
4-6 wks, up to 36 wks of adjusted gestational age or until discharge
Level 34,19,20,24,40,62
Mix with 3 mL of feedings; prepare by trained individuals with aseptic techniques to prevent crosscontamination and ensure consistency
Level 34,19,23,24,62
Refrigerate at 2°C-8°C or as the manufacturer suggests; at least 1 daily quality assessment of the refrigerator’s temperature
Level 34,20
Level 434 Level 427,34,63 Level 434 Level 561
Quality assurance Before choosing a probiotic agent, confirm content of the package using a laboratory analysis and/or check the manufacturer’s background
Level 4 34 Level 34,23,71 Level 434 Level 561
Abbreviations: CEBM, Centre for Evidence-Based Medicine; CFU, colony-forming unit; ELBW, extremely low birth weight; GI, gastrointestinal; LOE, level of evidence; VLBW, very low birth weight. Source: Author. aLevel 2a evidence according to previously known CEBM classification of 2009.50 b c
Level 2b evidence according to previously known CEBM classification of 2009.50
Level 3b to 4 evidence according to previously known CEBM classification of 2009.50
d
Level 5 evidence according to previously known CEBM classification of 2009.50
investigators found a significant risk reduction in NEC of 0.33 (95% CI: 0.24-0.46). However, neonates of various gestational ages and weights were studied and the strains of probiotics and dosing regimen differed across the clinical trials, thus limiting the findings of these meta-analyses. In addition to the RCTs and meta-analyses on probiotic use, retrospective studies demonstrate the benefits of probiotics in premature neonates. Investigators34 analyzed the incidence of NEC when Lactobacillus reuteri was introduced to neonates less than 1000 g during 2009 to 2011 compared to
previous years when probiotics were not given (2004-2009). There were significantly fewer NEC cases in those neonates who received probiotic supplementation. Other researchers27 found that the incidence of NEC was decreased in a cohort of 1130 VLBW neonates who received probiotics (Lactobacillus rhamnosus) in comparison to participants who had not received supplementation before 2008. However, the evidence from these observational studies is not strong because of the retrospective designs and absence of randomization and blinding. www.advancesinneonatalcare.org
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Probiotic Guideline for Necrotizing Enterocolitis Prevention in Very Low-Birth-Weight Neonates
Although the evidence for probiotic use in VLBW neonates for NEC prevention is increasing, the safety and efficacy have not been clearly established.41 There were reports of sepsis linked with probiotic usage in ELBW neonates, infants with short gut syndrome, and cardiac and GI malformations.31,32,35,49 Therefore, probiotics should be used with caution in VLBW neonates on a case-by-case basis and preferably in clinical environments where the risk of NEC is high and the benefits of probiotic use outweigh the risks for negative consequences of probiotic administration.
Level of Evidence by Center for Evidence-Based Medicine For this clinical guideline, the levels of evidence were identified according to the hierarchy of evidence from the Centre for Evidence-Based Medicine (CEBM) 2011.50 Thus, for the development of this guideline, the author chose to use the 2009 classifications. The findings presented by meta-analyses are identified as level 1 evidence, RCTs as level 2, cohort studies as level 3, case-control studies and clinical case reports as level 4, and mechanism-based reasoning as level 5. There are methodological limitations in the RCTs and meta-analyses that support this clinical guideline and publication bias has to be considered. These RCTs and meta-analyses were rigorously criticized.41,51 One RCT24 needed 282 subjects per group to obtain a 60% reduction of NEC if the incidence of NEC before the study was 10%. However, only 231 subjects were studied. This study was stopped prematurely because of the observed significant benefits in the intervention group. The nutritional team members and research assistants were not blinded, but they did not participate in the patient care. The healthcare providers and nurses were blinded. In 3 studies,4,20,23 clinicians and nurses were not aware of the group assignments. The members of the breast milk team or feeding preparation team knew the group assignments, but they were not involved in the patient care. The sample size in the study published in 201323 was small and the study was underpowered. Another RCT of probiotic use40 was also underpowered and NEC was a secondary outcome. The weaknesses of the meta-analyses consist of the inclusion of RCTs that studied various probiotic strains, administration regimens, and patients of various birth weight and gestational age.17,18,29,52 Population for Whom Probiotics Can Be Used or Used With Caution There is a body of evidence of RCTs, meta-analyses, and observational studies supporting probiotic use for the prevention of NEC in VLBW neonates.4,17,20,29,52 However, providers should not routinely use probiotics in all VLBW neonates but must
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evaluate the risk/benefit ratio for each patient. Although ELBW neonates are at a high risk (11%)53 for acquiring NEC, there is a lack of evidence that probiotics are safe and beneficial for this group of neonates. A systematic review18 found that there is not enough evidence regarding the safety and effects of probiotics in infants weighing less than 1000 g. This group of neonates has not been studied enough in large RCTs. A report from a population study34 does not provide strong evidence for probiotic use in ELBW infants because the data were reviewed retrospectively, there was no randomization or blinding, and only 79 ELBW neonates received probiotics. In addition, there was a report35 of an occurrence of septicemia in one ELBW neonate associated with a probiotic administration. Similarly, the safety of probiotic use is not clearly defined in infants with short gut syndrome, congenital cardiovascular disease, gastrointestinal abnormalities, post-GI surgery, or post-NEC and probiotics may be harmful in these groups of neonates.31,32,49,54
Monitoring for Adverse Effects There are possible adverse effects from probiotic use that are concerning to providers such as lactic acidosis, sepsis, meningitis, diarrhea, emesis, and distension of the abdomen.55 Reports of single cases of sepsis possibly associated with probiotics have been published.32,35,54,56,57 No adverse effects from using probiotics in VLBW neonates were reported in the RCTs or retrospective cohort studies.4,19,20,34,39,58,59 No sepsis related to probiotic use or other possible adverse effects were recognized in a 6-year-followup study by reviewing the complete data on 743 patients who received Lactobacillus rhamnosus GG for 4 to 6 weeks during a NICU stay and until discharge.60 To promote patient safety, clinicians should monitor for any adverse effects of probiotic use including feeding intolerance and infection, create a surveillance system and databases in their facility, and stop the probiotic administration promptly if any adverse effects are found.61 Probiotic Strain The probiotic strains, species, and administration regimens may have an influence on the efficacy of NEC prevention. Researchers4 studied Bifidobacterium bifidum and Lactobacillus acidophilus in neonates weighing less than 1500 g versus placebo. In an RCT of 434 neonates, they found a significant decrease in the incidence of NEC in the experimental group compared with the placebo group. There were 4 cases of NEC in the experimental group and 20 cases in the control group (P = .002). In contrast, the probiotic supplementation of Saccharomyces boulardii in premature neonates was also investigated.44 The authors found no significant difference in the incidence of NEC in the experimental group
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compared with the control group. The efficacy of Lactobacillus casei subspecies rhamnosus and the incidence of NEC were studied in a small sample of 80 VLBW neonates.45 No statistically significant difference was found in the incidence of NEC between the control and treatment groups. These findings suggest that specific bacterial species are needed to prevent NEC. The use of a combination of at least 2 probiotic strains appears more effective than the administration of a single probiotic strain. According to a metaanalysis,52 the administration of Bifidobacterium spp and Lactobacillus acidophilus was more effective in reducing the incidence of NEC than the delivery of a single probiotic agent. Similarly, other investigators29 found that a combination of Lactobacillus and Bifidobacteria (P < 0.0001) was more effective than Lactobacillus (P < 0.004) or Bifidobacteria (P < 0.0003) alone in reducing the risk of NEC in VLBW neonates. A statistically significant risk reduction in the incidence of NEC was found when the following probiotic strains were used: Lactobacillus rhamnosus GG, Lactobacillus acidophilus, Bifidobacteria infantis, Bifidobacteria bifidum, and Lactobacillus casei.4,19,20,23,24,39,62,63 These probiotics have been successful, but more clinical trials are required to validate the efficacy of these agents. Thus, a clinician may use a combination of Lactobacillus and Bifidobacteria from the list of the strains described previously for the prevention of NEC in VLBW neonates.
Probiotic Dose Investigators who reported statistically significant results used probiotic doses of 0.056 to 6 × 107-109 colony-forming units (CFU)/day administered daily or divided into 2 doses.4,19,20,24,27,34,39,62,63 No adverse effects were found in the studies with these probiotic dose ranges.4,19,20,23,24,27,34,62,63 In a 2011 probiotic use guideline,33 the recommended dose was 3 × 109 CFU/ day for neonates born less than 32 weeks of gestation. The conclusion regarding this dose was drawn by looking at the probiotics studies and identifying the median dose used by researchers. According to a study,60 the use of Lactobacillus rhamnosus GG with a dose of 3 × 109 CFU/day (administered once a day) showed no adverse outcomes in a 6-year observational study of VLBW neonates.60 Therefore, the literature supports using a dosage range of 0.056 to 6 × 107 to 109 CFU/day of probiotics, which may be effective and safe for NEC prevention in VLBW neonates. Beginning the Probiotic Administration The authors of the RCTs used various initiation regimens of probiotics in VLBW neonates.4,20,24,27,40,62 The authors of 4 RCTs and 1 small observational study that obtained a statistically significant reduc-
tion in the incidence of NEC started the probiotics when the neonates were clinically stable and able to start oral feedings and had a normal abdominal examination.4,19,20,23,34 The infants with umbilical lines were excluded from one study20 and the safety of probiotics during the time when umbilical artery or venous catheters are in place is unknown. Although the evidence is not strong, the probiotic administration may be started if the patient has a normal abdominal examination and is clinically ready to start enteral feedings. Researchers38 studied the timing effectiveness of probiotic colonization of the gut. This RCT involved 36 VLBW neonates. They found only a trend toward an increased colonization rate of the GI tract with Bifidobacterium bifidum when starting the administration of this probiotic agent in the first 48 hours of life. Thus, there is no evidence regarding the safety and benefits of starting probiotics within the first 48 hours of life.
Duration of Therapy To identify the optimal duration of therapy, the duration of probiotic administrations in clinical studies was reviewed. Some investigators34 gave probiotics to ELBW neonates in 2009 after 1 to 2 weeks after birth. In 2010, participants received probiotics when they were stable enough to be fed enterally and until discharge. In other studies20,23,62 probiotics were begun shortly after birth when VLBW neonates were stable to start feedings and continued until the neonate’s discharge. Additional investigators administered probiotics shortly after birth until the neonates reached 36 weeks of adjusted gestational age,19,27 from the 2nd day of life through the 30th or until discharge,24 or used probiotics for 6 weeks or until discharge.4 Therefore, if used to prevent NEC in VLBW neonates, the literature supports continuing probiotic therapy for 4 to 6 weeks and up to 36 weeks of adjusted gestational age or until the neonate’s discharge. Preparation Probiotics may be mixed with 3 mL of breast milk or preterm infant formula.19,23,24 Although there are no clear synergistic effects of breast milk with probiotics, the researchers who achieved statistically significant results in decreasing the incidence of NEC used breast milk.4,19,20,23,24,34,62 The effects of the carbohydrates and proteins used in the formula on probiotics are not clearly understood.64 The question about the range of osmolarity for the probiotic preparation when mixing probiotics with milk or preterm formula has not been answered. In the other guideline,33 the authors recommend maintaining an osmolarity of the solution less than 600 mOsm/L. This recommendation is grounded in a principle of
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physiology, but there is no clinical trial to support which osmolarity is the most efficient and safe when probiotics are mixed with feedings. In the clinical trials where no adverse side effects occurred from probiotic use, the mixing of probiotics with breast milk or preterm infant formula was prepared by a pharmacy or specially trained individuals. In a retrospective study,34 researchers ensured that probiotics were prepared by a pharmacy following strict sterile techniques. Therefore, to protect the vulnerable population of VLBW neonates when choosing a probiotic for patients, clinicians should ensure that the preparation occurs by properly trained individuals. It is not recommended to prepare probiotics at the infant’s bedside by a caregiver as there is a potential risk of cross-contamination and lack of consistency in the preparation.61,65
Storage and Quality Assurance In 2 RCTs,4,20 probiotics were refrigerated at 2°C to 8°C, but a length of time for storage was not defined. Other researchers34 also refrigerated the probiotics and they were administered no later than 6 hours after removal from the refrigerator. The authors of this study also did at least 1 daily quality assessment of the refrigerator’s temperature. In contrast, another clinical trial23 had the probiotics stored at room temperature and no known adverse effects were detected in the study group participants. Per the manufacturer’s recommendation of Culturelle, which contains Lactobacillus GG, storage at room temperature is recommended, but not higher than 75°F.66 Therefore, because it is not completely understood if it is safe to store probiotics at room temperature, probiotics should be refrigerated at 2°C to 8°C or per the manufacturer’s recommendation. Healthcare providers have to ensure that a quality assessment of the refrigerator’s temperature occurs at least once a day. The manufacturer of Align (Bifidobacteruim infantis 35624) advises storing their probiotic product at room temperature.67,68 The manufacturer of BioGaia (Lactobacillus reiteri) recommends storage at temperatures lower than 77°F and does not specify a time range in which the product should be administered,69 but the authors of a retrospective study34 refrigerated this product and administered it within 6 hours of preparation time. Because probiotics are not approved by the Food and Drug Administration for NEC prevention, before choosing and using a product, clinicians should conduct a quality assurance review that the content of the package corresponds with the strains and amount described by the manufacturer preferably by using a laboratory analysis and/or checking the background of the probiotic manufacturer.61,70 The clinical site should have the ability to order/perform 16S rRNA sequencing and pulsed-field gel
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electrophoresis to confirm that any discovered cases of bacterial sepsis are not related to the administration of probiotics.61,71
CONCLUSION Although the meta-analyses, RCTs, and observational studies report that probiotic administration to VLBW neonates can decrease the incidence of NEC,4,17-20,23,24,27,29,34,62,63 the safety and efficacy of the treatment are not clearly established. The current guideline is intended for probiotics administration in VLBW neonates who are at high risk of acquiring NEC in facilities with a high incidence of NEC. Providers should avoid administering probiotics to ELBW neonates,18 neonates who are clinically unstable and unable to start feedings,4,20,62 and neonates with GI problems and cardiac or other genetic abnormalities31,32,49,54 because there is insufficient evidence on the safety of probiotics in these groups. With each clinical case, the clinician should weigh the benefits and risks of probiotic use and NEC and evaluate if there are resources available for a safe administration, quality assurance of the probiotic product, preparation and storage, and surveillance for the short- and long-term adverse effects.
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