title: GRADE guidelines: 4. Rating the quality of evidence--study limitations (risk of bias). Probiotic Effects on Late-onset Sepsis in Very Preterm Infants: A Randomized Controlled Trial Oral gentamicin therapy in the prevention of neonatal necrotizing enterocolitis. A controlled double-blind trial. Prevention of Neonatal Necrotizing Enterocolitis Prevention of necrotizing enterocolitis in low-birth-weight infants by IgA-IgG feeding. Mortality of necrotizing enterocolitis expressed by birth weight categories. Breast milk and neonatal necrotising enterocolitis Prevention of necrotizing enterocolitis in neonates at risk by oral administration of monomeric IgG. Necrotizing enterocolitis prophylaxis: oral antibiotics and lyophilized enterobacteria vs oral immunoglobulins Oral Probiotics Reduce the Incidence and Severity of Necrotizing Enterocolitis in Very Low Birth Weight Infants Enteral human IgG for prevention of necrotising enterocolitis: a placebo-controlled, randomised trial
abstract: In the GRADE approach , r and omized trials start as high- quality evidence and observational studies as low- quality evidence , but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias . Well-established limitations of r and omized trials include failure to conceal allocation , failure to blind , loss to follow-up , and failure to appropriately consider the intention-to-treat principle . More recently recognized limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results . Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance . Risk of bias may vary across outcomes ( e.g. , loss to follow-up may be far less for all-cause mortality than for quality of life ) , a consideration that many systematic review s ignore . In deciding whether to rate down for risk of bias -- whether for r and omized trials or observational studies -- authors should not take an approach that averages across studies . Rather , for any individual outcome , when there are some studies with a high risk , and some with a low risk of bias , they should consider including only the studies with a lower risk of bias BACKGROUND AND OBJECTIVE : Late-onset sepsis frequently complicates prematurity , contributing to morbidity and mortality . Probiotics may reduce mortality and necrotizing enterocolitis ( NEC ) in preterm infants , with unclear effect on late-onset sepsis . This study aim ed to determine the effect of administering a specific combination of probiotics to very preterm infants on culture-proven late-onset  sepsis . METHODS : A prospect i ve multicenter , double-blinded , placebo-controlled , r and omized trial compared daily administration of a probiotic combination ( Bifidobacterium infantis , Streptococcus thermophilus , and Bifidobacterium lactis , containing 1 × 109 total organisms ) with placebo ( maltodextrin ) in infants born before 32 completed weeks ’ gestation weighing < 1500 g. The primary outcome was at least 1 episode of definite late-onset sepsis . RESULTS : Between October 2007 and November 2011 , 1099 very preterm infants from Australia and New Zeal and were r and omized . Rates of definite late-onset sepsis ( 16.2 % ) , NEC of Bell stage 2 or more ( 4.4 % ) , and mortality ( 5.1 % ) were low in controls , with high breast milk feeding rates ( 96.9 % ) . No significant difference in definite late-onset sepsis or all-cause mortality was found , but this probiotic combination reduced NEC of Bell stage 2 or more ( 2.0 % versus 4.4 % ; relative risk 0.46 , 95 % confidence interval 0.23 to 0.93 , P = .03 ; number needed to treat 43 , 95 % confidence interval 23 to 333 ) . CONCLUSIONS : The probiotics B infantis , S thermophilus , and B lactis significantly reduced NEC of Bell stage 2 or more in very preterm infants , but not definite late-onset sepsis or mortality . Treatment with this combination of probiotics appears to be safe The value of prophylactic oral gentamicin sulfate therapy in the prevention of necrotizing enterocolitis ( NEC ) was evaluated in a group of 42 high-risk neonates over a four-month period in a r and omized , double-blind controlled trial . Twenty babies in the treatment group received 2.5 mg/kg of gentamicin sulfate every six hours for one week after birth , and 22 babies received dextrose- and -water placebo in an equivalently small volume . None of the 20 gentamicin-treated babies developed NEC . Four of the control babies did . Two of these babies died , and their diagnosis was pathologically confirmed . This difference in the incidence of NEC between the treatment and control group was significant at the .05 level . These results support the prophylactic use of orally given gentamicin for selected babies at high risk for NEC  , particularly those born prematurely and those who have a history of perinatal asphyxia or umbilical artery catheterization or both . Continued surveillance for changes in antimicrobial sensitivity patterns is recommended Small premature infants are often hypochlorhydric , and frequently their stomachs are colonized by enteric , gram-negative bacteria . We tested a hypothesis that gastric pH affected the colonization of the stomach with enteric bacteria and that this colonization was causally related to the risk or severity of necrotizing enterocolitis . A prospect i ve , double-blind study was conducted that compared a group of infants supplemented with 0.01–0.02 ml of 1 N HCl/ml of milk to a group with a similar supplement of water .  Gastric pH , gastric enteric bacteria counts , and the incidence and severity of necrotizing enterocolitis were monitored . The median gastric pH of the HCl-supplemented group was lower ( 3.0 ) than controls ( 4.0 ) throughout the study ( p < 0.001 ) . The gastric enteric bacterial colonization rate and the quantitative bacterial counts were strongly correlated with gastric pH over 4 ( p < 0.001 ) . Somatic growth rates in infants in the HCl-supplemented group were equal to , or exceeded , those in the control group . There was 1 case of necrotizing entero-colitis among the 34 infants in the HCl-supplemented group and 8 cases among the 34 in the control group ( p = 0.02 ) . It appears that acidifying the feedings of small premature infants to a pH low enough to inhibit bacterial proliferation in the stomach significantly lowers the risk of necrotizing enterocolitis In a r and omized clinical trial , we evaluated the efficacy of an oral immunoglobulin preparation ( 73 percent IgA and 26 percent IgG ) in reducing the incidence of necrotizing enterocolitis in infants of low birth weight for whom breast milk from their mothers was not available . A total of 434 infants weighing between 800 and 2000 g were eligible for entry in the study . Of these , 255 were withdrawn - 234 during the first week of the study because breast milk from their mothers became available ( 123 in the treatment group and 111 in the control group ) , and 21 because of violations of protocol or because breast milk became available after the first week . The duration of follow-up was 28 days . Among the infants for whom breast milk did not become available during the study , there were no cases of necrotizing enterocolitis among the 88 receiving oral IgA-IgG , as compared with six cases among the 91 control infants ( P = 0.0143 ) . Of the infants withdrawn from the study , two assigned to the control group had necrotizing enterocolitis . We conclude that the oral administration of IgA-IgG may prevent the development of necrotizing enterocolitis in low-birth-weight infants PURPOSE Low birth weight is the most important risk factor for developing necrotizing enterocolitis ( NEC ) . We aim ed to establish birth weight-based benchmarks for in-hospital mortality in neonates with NEC . METHODS Five hundred eleven centers belonging to the Vermont Oxford Network prospect ively evaluated 71,808 neonates with birth weight of 501 to 1500 g between January 2005 and December 2006 . The primary outcome variable was in-hospital mortality . RESULTS Birth weight was divided into 4 categories by 250-g increments . The NEC risk ( P < .001 ) and mortality ( P < .001 ) decreased with higher birth weight category . Necrotizing enterocolitis was associated with a significant odds ratio for death for each category ( P < .001 ) . Across groups , the odds ratio for NEC mortality increased with higher birth weight category ( category 1 = 1.6 vs category 4 = 9.9 ; P < .001 ) . CONCLUSION The in-hospital mortality rate of neonates with NEC remains high and is significantly related to birth weight category . Although the risk and absolute mortality of NEC decrease with higher birth weight , the odds ratios indicate that NEC has a relatively greater impact upon mortality at higher birth weight . These data afford birth weight-based mortality benchmarks that may be useful in assessing single center NEC outcomes and facilitating comparisons between centers In a prospect i ve multicentre study on 926 preterm infants formally assigned to their early diet , necrotising enterocolitis developed in 51 ( 5.5 % ) .  Mortality was 26 % in stringently confirmed cases . In exclusively  formula-fed  babies confirmed disease was 6 - 10 times more common than in those fed breast milk alone and 3 times more common than in those who received formula plus breast milk . Pasteurised donor milk seemed to be as protective as raw maternal milk . Among babies born at more than 30 weeks ' gestation confirmed necrotising enterocolitis was rare in those whose diet included breast milk ; it was 20 times more common in those fed formula only . Other risk factors included very low  gestational age , respiratory disease , umbilical artery catheterisation , and polycythaemia . In formula-fed but not breast-milk-fed infants , delayed enteral feeding was associated with a lower frequency of necrotising enterocolitis . With the fall in the use of breast milk in British neonatal units , exclusive formula feeding could account for an estimated 500 extra cases of necrotising enterocolitis each year . About 100 of these infants would die Necrotizing enterocolitis ( NEC ) represents one of the major causes of morbidity in low-birth-weight ( LBW ) preterm infants . This r and omized clinical trial evaluated the efficacy of an oral immunoglobulin preparation ( containing monomeric IgG in a concentration of 90 % ) in reducing the incidence of NEC in infants of LBW for whom maternal breast milk was not available . One hundred and thirty-two formula-fed newborns with a birth weight less than or equal to 1,500 g or a gestational age less than or equal to 34 weeks were r and omly studied . Five hundred mg of IgG pro die , subdivided into 5 doses , were given orally to the test group of 65 neonates during the first 2 weeks of life . Although the number of infants included in this group is limited , the results of this study are encouraging : during the first 15 days after birth , none of the subjects developed NEC , while 4 cases were confirmed in the untreated control group . It , therefore , seems possible that oral monomeric IgG administration may prevent the development of NEC in LBW infants We conducted a prospect i ve r and omized trial to compare the efficacy of oral gentamicin versus oral IgA‐IgG for the prophylaxis of necrotizing enterocolitis ( NEC ) ;  200 newborns considered at high risk for NEC were assigned to group A ( oral IgA‐IgG , n= 100 ) or group B ( oral Gentamicin , n= 100 ) . NEC was diagnosed in 13 cases in group A and in 1 case in group B between the 3rd and 16th days of life . Surgical treatment was necessary in 3 cases ( 2 in group A ) . All infants survived . We conclude that oral gentamicin is more effective than oral IgA‐IgG in the prevention of NEC in infants at high risk Objective . We evaluated the efficacy of probiotics in reducing the incidence and severity of necrotizing enterocolitis ( NEC ) in very low birth weight ( VLBW ) infants . Patients and Methods . A prospect i ve , masked , r and omized control trial was conducted to evaluate the beneficial effects of probiotics in reducing the incidence and severity of NEC among VLBW ( < 1500 g ) infants . VLBW infants who started to fed enterally and survived beyond the seventh day after birth were eligible for the trial . They were r and omized into 2 groups after parental informed consents were obtained . The infants in the study group were fed with Infloran ( Lactobacillus acidophilus and Bifidobacterium infantis ) with breast milk twice daily until discharged . Infants in the control group were fed with breast milk alone . The clinicians caring for the infants were blinded to the group assignment . The primary outcome was death or NEC ( ≥ stage 2 ) . Results . Three hundred sixty-seven infants were enrolled : 180 in the study group and 187 in the control group . The demographic and clinical variables were similar in both groups . The incidence of death or NEC ( ≥ stage 2 ) was significantly lower in the study group ( 9 of 180 vs 24 of 187 ) . The incidence of NEC ( ≥ stage 2 ) was also significantly lower in the study when compared with the control group ( 2 of 180 vs 10 of 187 ) . There were 6 cases of severe NEC ( Bell stage 3 ) in the control group and none in the study group . None of the positive blood culture grew Lactobacillus or Bifidobacterium species . Conclusion . Infloran as probiotics fed enterally with breast milk reduces the incidence and severity of NEC in VLBW infants BACKGROUND Neonatal necrotising enterocolitis is a serious , commonly fatal disease in premature neonates . Although feeding with expressed breast milk and other good nursery practice s are partly protective , preventive measures are needed . Treating neonates enterally with a mixture of human IgA and IgG , prepared from donated blood , has been cl aim ed to protect against necrotising enterocolitis . However , no IgA preparation is available in Australia . Our aim , therefore , was to identify whether or not enteral IgG could prevent the disorder . METHODS We did a multicentre , double-blind , placebo- controlled trial . We r and omly assigned 768 infants to receive human IgG 1200 mg/kg daily , and 761 to receive placebo , for up to 28 days . Treatment began at the same time as enteral feeding . The primary outcome measure was the proportion of infants who developed definite necrotising enterocolitis during the trial , and any deaths that result ed from the disorder in the treatment and placebo groups . Analysis was on an intention-to-treat basis . FINDINGS 43 infants developed definite necrotising enterocolitis  in the IgG group , ten of whom died . In the placebo group , 41 infants contracted the disorder and six died ( p=0.47 ) . 25 infants on IgG and 36 on placebo had suspect necrotising enterocolitis ( p=0.14 ) . INTERPRETATION Supplementation of enteral feeds with human IgG does not reduce necrotising enterocolitis
target: Based on the available trials , the evidence does not support the administration of oral immunoglobulin for the prevention of NEC .
  There are no r and omized controlled trials of oral IgA alone for the prevention of NEC
background: BACKGROUND Necrotizing enterocolitis ( NEC ) is the most common emergency involving the gastrointestinal tract occurring in the neonatal period .
  There have been published reports that suggest that oral immunoglobulins (Ig)A and IgG produce an immunoprotective effect in the gastrointestinal mucosa .
  OBJECTIVES To determine the effect of oral immunoglobulin on the incidence of necrotizing enterocolitis and other complications in preterm or low birth weight ( or both ) neonates .