Clinical Effect Of Bifidobacterium On Preventing Cholestasis In Preterm Infants

Background:Premature infants refer to the newborns whose gestational age is less than 37 weeks,and gastrointestinal function has not developed well.In addition,they often suffer from cholestasis,necrotizing enterocolitis of newborn(NEC),feeding intolerance(FI)because of asphyxia,infection,bleeding or other traumatic stress at birth or after birth.Therefore,they often need parenteral nutrition(PN)to replace enteral nutrition(EN)to survive.However,long-term PN can gradually increase the incidence of PN-associated cholestasis(PNAC)in premature infants.At the same time,long-term PN is easy to result in alteration of intestinal flora,damaged gastrointestinal mucosal cells,and increased cell membrane permeability,which makes the absorption of endotoxin increase,thus resulting in hepatocellular injury and more severe cholestasis.Therefore,how to take effective measures to improve the feeding tolerance of premature infants and reduce the incidence rate of cholestasis has become a hot issue in perinatal medicineObjective:To explore the clinical application effect,safety and impact on the quality of life of Bifidobacteria in the prevention and treatment of cholestasis for premature infants through meta-analysis and clinical prospective study,and provide theoretical basis for the clinical application of Bifidobacteria in premature infants.Methods:Part ?:Meta-analysis of the clinical effect of Bifidobacterium on preventing cholestasis in preterm infants and its effect on their quality of lifeThe key words "cholestasis","Bifidobacterium","premature infant" and"prevention" in English and Chinese were determined respectively,logical operators(OR,NOT,AND)were used to combine keywords and subject words,and Wanfang database,VIP,CNKI,China Biology Medicine disc,Chinese academic periodical full-text database(full selection of the general catalogue)were searched by using computer.The English literatures were searched in PubMed,EMBASE,and Web of Science using "cholestasis","Bifidobacterium","preterm infant" and "prevention",the published literatures about Bifidobacterium and cholestasis of premature infants from January 20,1980 to January 20,2019 were collectedRead through the preliminary literature,extract the relevant information(sample content,publication time,research time,research location and research content)of the article,remove the literature that does not meet the requirements of this study according to the inclusion and exclusion criteria,and include the final selected literature that meets the requirements into the analysisThe methodological quality of included literatures was evaluated by using Cochron system evaluation quality standard,and RCT quality evaluation was completed by using Revman 5.3 software.Revman 5.3 software provided by Cochrane Collaboration was used to carry out Meta-analysis for the incidence of cholestasis,NEC and sepsis before discharge,mortality before discharge,incidence of FI,recovery to birth weight of premature infants,time to full gastrointestinal feeding and length of stay.Q-test and I2 test were used to evaluate the heterogeneity of the included literature.When I2?50%and P>0.1,fixed effect model was used to merge;when I2>50%or P<0.1,random effect model was used to merge.The odds ratio(OR)and 95%confidence interval(CI)were used to express the enumeration data.The standard mean difference(SMD)and 95%CI were used to express the measurement data.SMD was used to represent the treatment effect of each clinical trial and the relative size of the observation variables of the standard trial.P<0.05 represents that the difference is statistically significant.Part ?:Preliminary study on the prevention of cholestasis by Bifidobacterium supplementation in premature infantsLow birth weight infants who were admitted in neonatology department of Children's Hospital of Soochow University from July 1 0,2017 to January 31,2020 were selected,whose gestational age was 28?34 weeks and birth weight was less than 2500g(this study conforms to the Chinese clinical research norms and the declaration of Helsinki(2013 Version),and has been reviewed and approved by the ethics committee of Children's Hospital of Soochow University,all the legal guardians of the sick children signed the informed consent the informed consent form.).According to the order of admission time,the sick children were divided into control group and study group.Routine treatment was adopted in the control group:all premature infants were treated with primary disease,kept warm,fed with formula milk,and received full-time nursing by nursing staff.Before the infants reached the full gastrointestinal feeding,they were given unified PN management,and compound glycyrrhizin was given when liver enzyme increased(produced by Xi'an Desai bio Pharmaceutical Co.,Ltd.,2ml/piece,2ml/kg,used intravenously,once a day),the sick children with cholestasis were treated with ursodeoxycholic acid(produced by Dr.FalkPharmaGmbH,250mg/grain,10?15mg/kg.d,orally,twice)combined with ademetionine1,4-butanedisulfonate for injection(produced by Abbott Laboratories,0.5g/tablet,30?50mg/kg.d,intravenously,once a day),and the average course of treatment was 10 days.For children with severe abdominal distension,vomiting,hemafecia or suspected NEC during hospitalization,fasting was first given,changes in the condition were observed,and the next treatment plan was planned.In the study group,Bifidobacterium was added on the basis of the routine treatment(Live Combined Bifidobacterium and Lactobacillus Tablets was taken orally within 24 hours after birth,0.5g/time,3 times/d)until the full gastrointestinal feeding stopped.The general clinical data(mode of delivery(cesarean section,natural delivery),G1P1,multiple births,intrauterine distress,1 min Apgar score,5 min Apgar score,gestational age,gender(male,female),birth weight)of the sick children were collected,recorded and compared between the control group and the study group.The incidence of cholestasis and related complications(cholestatic hepatic injury,NEC,sepsis),antibiotic use rate,gastrointestinal function(FI,meconium emptying time,fasting ratio,mean fasting time)and nutrition management(days at the beginning of EN,duration of PN,time to full gastrointestinal feeding),growth and development(recovery to birth weight time,EUGR)and length of stay of the sick children were clinically evaluated,recorded and compared between the control group and the study group.The peripheral venous blood of the sick children was collected at the time of admission,on the 5th day of admission,on the 10th day of admission and at the time of discharge.The 7600-010 Hitachi automatic biochemical analyzer was used for detection.The main liver function indexes(alanine aminotransferase(ALT),total bilirubin,direct bilirubin,gamma glutamyl transferase(GGT),alkaline phosphatase(ALP),cholylglycine(CG),total cholesterol(TC)of the sick children were recorded and compared between the control group and the study group.SPSS25.0 statistical software was used for data entry and analysis.The measurement data were expressed as mean ± standard deviation(x±s),and if the homogeneity of variance was satisfied,independent sample t-test was used,if the variance was not homogeneous,t'test is used;n(%)was used for description and statistics of enumeration data,at the same time,test the theoretical number(T).If "T?5" and the number of samples?40,Pearson x2 test(no correction)shall be used;if "1?T<5" and the number of samples?T40,Yates x2 test(correction)shall be used for comparison,if T<1 or the number of samples<40,use Fisher exact probability method.P<0.05 represents that the difference is statistically significant.Results:Part ?:In 128 preliminarily searched literatures,the selected literatures were read thoroughly according to the inclusion and exclusion criteria,and the related information(sample content,publication time,research time,research location and research content)of the articles was extracted.1 literature with incomplete sample data and 1 literature with nonstandard diagnostic criteria,the non-random control literatures such as 40 comments and 42 conference literatures were eliminated,9 repetitive literatures and 8 unrelated literatures were excluded,and 28 literatures were selected.The results of literature quality assessment showed that there were 2 studies with mild bias and 26 studies with moderate bias,and the overall study was in moderate bias.The incidence of cholestasis,NEC and sepsis and mortality before discharge,incidence of FI,recovery to birth weight in premature infants,time to full gastrointestinal feeding and length of stay in hospital were analyzed by meta-analysis The results showed that compared with the control group,the incidence of cholestasis(OR=0.45,95%CI:0.30?0.68,Z=3.81,P<0.01),NEC(OR=0.19,95%CI:0.14-0.28,Z=8.84,P<0.05),premature mortality(OR=0.25,95%CI:0.15?0.41,Z=5.36,P<0.05)and the incidence of FI in premature infants(OR=0.1 8,95%CI:0.13?0.26,Z=9.59,P<0.05)significantly decreased,and the length of stay of premature infants(SMD=-1.04,95%CI:-1.52?-0.56,Z=4.27,P<0,05),recovery to birth weight in premature infants(SMD=-0.77,95%CI:-1.36?-0.19,Z=2.58,P<0.05),time to full gastrointestinal feeding(SMD=-0.87,95%CI:-1.25?-0.49,z=4.50,P<0.05)were significantly shortened,but the incidence of sepsis of premature infants(OR=0.78,95%Cl:0.37-1.64,Z=0.66,P>0.05)was not increased.Part ?:270 low birth weight infants admitted in our hospital whose gestational age was 28-34 weeks and birth weight was less than 2500g from July 10,2017 to January 31,2020 were selected.According to the inclusion criteria and exclusion criteria,70 premature infants did not meet the inclusion criteria(1 case with congenital defect,5 cases with severe digestive tract symptoms before feeding,4 cases with cholestasis diagnosed at the time of admission,25 cases were asked to withdraw from the study because their families were concerned that continuing to participate in the trial would be of no benefit to the children,35 cases with automatic discharge and abandonment of treatment.Finally,200 cases were included,male:female=8:5,average birth weight(1237.25 ±1 72.08)g,average gestational age(31.65±2.75)weeks,84 cases with less than gestational age(42.00%),116 cases with suitable gestational age(58.00%),88 cases with cesarean section(44.00%),112 cases with natural delivery(56.00%),53 cases with G1P1(76.50%),42 cases with multiple births(21.00%),15 cases with intrauterine distress(7.50%),average 1 min Apgar score(8.85 ± 1.04),average 5 min Apgar score(9.48 ± 0.45)(1)Comparison on general clinical data of sick children between two groupsThe general clinical data of sick children in the two groups showed that:delivery mode(cesarean section,natural delivery),multiple births,intrauterine distress,1 min Apgar score,5 min Apgar score,gestational age,small for gestation age,suitable for gestational age,gender(male,female),birth weight had no significant difference between the two groups(P>0.05)(2)Comparison on cholestasis,related complications and antibiotic use of sick children between two groupsThe results showed that the incidence of cholestasis,the incidence of cholestatic hepatic injury,the incidence of NEC,the utilization rate of antibiotics in the study group were significantly lower than that in the control group,and the difference was statistically significant(P<0.05);however,there was no significant difference in incidence of sepsis between the two groups(P>0.05)(3)Comparison on main liver function indexes of sick children between the two groups during hospitalizationThere was no significant difference in the initial ALT,total bilirubin,direct bilirubin,GGT,ALP,CG and TC between the two groups(P>0.05);The ALT in the study group was lower than that in the control group on the 5th day of admission,on the 10th day of admission and at the time of discharge,and the difference was statistically significant(P<0.05);The total bilirubin in the study group was lower than that in the control group on the 5th day of admission,on the 10th day of admission and at the time of discharge,and the difference was statistically significant(P<0.05);In the study group,the direct bilirubin was lower than that in the control group on the 5th day of admission,on the 10th day of admission and at the time of discharge,and the difference was statistically significant(P<0.05);In the study group,GGT in the study group was lower than that in the control group on the 5th day of admission,on the 10th day of admission and at the time of discharge,and the difference was statistically significant(P<0.05);In the study group,ALP was lower than that in the control group on the 5th day of admission,on the 10th day of admission and at the time of discharge,and the difference was statistically significant(P<0.05);In the study group,CG lower than that in the control group on the 5th day of admission,on the 10th day of admission and at the time of discharge,and the difference was statistically significant(P<0.05);In the study group,TC was lower than that in the control group on the 5th day of admission,on the 10th day of admission and at the time of discharge,and the difference was statistically significant(P<0.05);(4)Comparison on gastrointestinal function and nutrition management between the two groupsThe results showed that the incidence of FI,the fasting rate in the study group were lower than that in the control group,and the difference was statistically significant(P<0.05);the emptying time of meconium,the mean fasting time in the study group were shorter than that in the control group,and the difference was statistically significant(P<0.05);there was no statistically significant difference in the age of the beginning of EN between the two groups(P>0.05);the age of PN at the beginning of the two groups was less than 28 days,and the duration of PN in the two groups was greater than 7 days,but the duration of PN,the feeding time of the total gastrointestinal tract in the study group were significantly shorter than that in the control group,and the difference was statistically significant(P<0.05).(5)Comparison on growth and development status and length of stay between the two groupsThe analysis results of the two groups showed that the time of recovery to birth weight,the length of stay in the study group were significantly shorter than that in the control group,and the difference was statistically significant(P<0.05);the incidence of EUGR in the study group was lower than that in the control group,and the difference was statistically significant(P<0.05)Conclusions:Part ?:(1)Preventive applicationn of Bifidobacterium can reduce the incidence of cholestasis,NEC,FI and mortality of premature infants(2)Preventive applicationn Bifidobacteria can shorten the time for premature infants to achieve full gastrointestinal feeding,the time to return to birth weight and the length of stay.(3)Although Bifidobacteria did not increase the incidence of sepsis in this study,its safety still remainss to be further explored.Part ?:(1)Preventive applicationn of Bifidobacterium can reduce the incidence of cholestasis,cholestatic hepatic injury and NEC,and the use of antibiotics,and not increase the incidence of sepsis in premature infants.(2)Preventive applicationn of Bifidobacteria can promote the recovery of liver function,improve gastrointestinal function,promote growth and development,and improve the quality of life(3)Preventive applicationn of Bifidobacterium in premature infants is safe and reliable,but its long-term safety still remains to be further studied and verified.