Influence of Bovine Lactoferrin on Feeding Intolerance and Intestinal Permeability in Preterm Neonates

Feeding Intolerance in Preterm Clinical Trial

Official title:

Influence of Bovine Lactoferrin on Feeding Intolerance and Intestinal Permeability in Preterm Neonates: a Randomized Controlled Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04738058
• Other study ID #: MD.20.08.344
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: December 15, 2020
• Est. completion date: June 2022

Study information

• Verified date: January 2021
• Source: Mansoura University Children Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Preterm infants are at increased risk of developing feeding intolerance due to functional immaturity of their gastrointestinal tract and may lead to discontinuation of enterak feeding.

Lactoferrin promotes the growth of probiotic bacteria, stimulates differntiation and proliferation of enterocytes and expression of intestinal digestive enzymes , lead to improvement of feeding intolerance.

So we hypothesized that supplementation of bovine lactoferrin would be benificial on feeding intolerance and decrease intestinal permeability in preterm infants with feeding intolerance.

Description:

Preterm infants are at increased risk of developing feeding intolerance (FI) due to functional immaturity of their gastrointestinal tract. Feeding intolerance often leads to discontinuation of enteral feeds, delayed achievement of full enteral feeding, increased length of hospital stay, sub-optimal nutrition, postnatal growth restriction, prolonged parenteral feeding with an increased risk of nosocomial infections and poor neurodevelopmental outcome.1,2 Although there is no consensus on the definition of FI, a gastric residual volume of more than 50% of the previous feeding volume, gastric regurgitation, abdominal distension and/or emesis, are used as indicators for FI.1,3 Intestinal microflora plays an important role in the promotion and maintenance of intestinal functions such as mucosal trophism, gut barrier, sensori-motor function, hormone secretion, angiogenesis and immune defences.4 Many factors lead to unbalanced microflora colonization in the preterm infant as cesarean delivery, NICU stays, fasting and antibiotic use, leading to FI and necrotizing enterocolitis (NEC).5 Several strategies have been developed to improve the enteral feeding tolerance in preterm infants such as the implementation of standardized feeding protocols, the use of prokinetic agents and probiotics. The beneficial effect of probiotic supplementation on FI has been reported in several studies.6,7 Multiple mechanism of action has been proposed, including strengthening the intestinal mucosal barrier function, thereby inhibiting bacterial translocation, regulation of bacterial colonization, modulation of intestinal inflammation.8 Although probiotics may be a promising approach for the prevention of FI and NEC in preterm infants, several issues exist regarding strain specificity, schedule of supplementation, and long-term adverse effects.9 Lactoferrin (LF), a member of the transferrin family of iron-binding glycoproteins, is present in high amounts in colostrum and maternal milk.

Lactoferrin is almost completely absent from processed formulae. Lactoferrin is the major factor responsible for the protective effects of breast milk-decreased rates of infection and NEC, improved neurodevelopment and better immune responses due to its antimicrobial, anti-oxidant, anti-inflammatory and immunomodulatory properties.10 Lactoferrin stimulates gastrointestinal cell proliferation and differentiation via extracellular signal-regulated kinase, limits IL-8 secretion, prevents NF-kB and hypoxia-inducible factor-1a activation, suggesting strong anti-inflammatory effects.11 Lactoferrin also promotes the growth of probiotic bacteria, stimulates differentiation and proliferation of enterocytes and expression of intestinal digestive enzymes.12 Its bifidogenic activity in the gut may improve tolerance to feeds.13 Very preterm infants receive little or no milk during early neonatal period and have low intake of LF.14 Because human LF is expensive, bovine lactoferrin has been considered as an alternate supplement to correct this deficiency, as it is about 70% homologous with human LF but has higher antimicrobial activity.15 Bovine LF has no known toxicity and is registered as GRAS (Generally Recognised As Safe) by the US Food and Drug Administration.16 A systematic review including 6 RCTs involving almost 1100 preterm infants concluded that there is an evidence of low quality suggesting that LF supplementation to enteral feeds with or without probiotics decreases late-onset sepsis and NEC stage II or III in preterm infants without adverse effects.17 A more recent systematic review, included 9 trials that enrolled 1834 preterm infants indicated that LF supplementation in preterm neonates is safe without obvious adverse effects, could significantly reduce the incidence of NEC, and hospital-acquired infection. Moreover, LF could reduce the time to achieve full enteral feeding (the mean difference for days to achieve full enteral feeding in preterm infants was -2.19 days) and duration of hospitalization of preterm infants.18 A large RCT "The ELFIN Trial", included 2203 infants, has demonstrated that enteral LF supplementation (150 mg/kg per day until 34 weeks' postmenstrual age) does not reduce the risk of late-onset infection, other morbidity, or mortality in very preterm infants. However, this study did not rule out important potential benefits, particularly for infants who receive formula for over half of days of enteral feeds.19 The intestinal barrier provides highly selective protection of the human body against the environment. It has several facets, which include: intestinal microbiota; a protective mucus layer; intestinal epithelium cells with tight junctions (TJ); and cells of the immune system and enteric nervous system.20 Intestinal barrier maturation in preterm infants is gestational age and postnatal age-dependent and is influenced by feeding type and antibiotic exposure.21 Zonulin (ZO), is an established marker of intestinal permeability. Zonulin is one of the proteins that regulate the function of TJ between intestinal epithelial cells, which determines paracellular transport in the gut. It is one of the main factors securing the action of the "gate of the gut" mechanism by reversibly influencing TJ's tightness. Zonulin increase and disruption of TJ has been demonstrated in an animal model of NEC with intestinal TJ destruction proven by immune histochemical evaluation.22 Zonulin increases in newborns presenting symptoms of infection and/ or inflammation of the gut or being at risk of intestinal pathology.23 We hypothesized that supplementation of bovine LF would have beneficial effects on feeding tolerance and decrease intestinal permeability in preterm infants with FI.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 60
• Est. completion date: June 2022
• Est. primary completion date: December 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 26 Weeks to 34 Weeks

Eligibility

Inclusion Criteria:

• preterm infants delivered at gestational age 26 to 34 weeks admitted to NICU OF mansoura university children hospital Diagnosed as feeding intolerance defined as gastric volume residual of more than 50% of the previous feeding volume, gastric regurgitation, abdominal distention and or emesis Receive premature cow's protein based formula enteral feeding

Exclusion Criteria:

Major congenital malformations Anatomical gastrointestinal anomalies Birth asphyxia Presence of NEC Neonate receiving Expressed breast milk Infant with history of cow's milk allergy

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Related Conditions & MeSH terms

• Feeding Intolerance in Preterm
• Intestinal Permeability in Preterm
• Premature Birth

Intervention

Drug:
• Bovine Lactoferrin Supplement
Bovine lactoferrin or placebo will be given to both arms with each feed for 30 days or till discharge from NICU the Lactoferrin dose 100mg/day Then determin is effect by serum zonulin level
• placebo
placebo

Locations

Country	Name	City	State
Egypt	Mansoura University Children Hospital	Mansoura

Sponsors (1)

Lead Sponsor	Collaborator
Mansoura University Children Hospital

Country where clinical trial is conducted

Egypt, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Duration required by the infant to achieve full enteral feeding	Full enteral feed reached when infant tolerated 150ml/kg/day	4 weeks or till discharge from NICU, whichever came first
Primary	Serum zonulin concentrations at day 7 and 4 weeks after enrollment or discharge	serum zonulin is an indicator for intestinal permeability	4 weeks or till discharge from NICU, whichever came first
Secondary	Number of episodes of gastric residual more than 50% of the previous feed	Number of episodes of gastric residual more than 50% of the previous feed	4 weeks or till discharge from NICU, whichever came first
Secondary	Weight gain	weight gain during admission	4 weeks or till discharge from NICU, whichever came first
Secondary	Late onset sepsis	by sighs and Lab. investigation of sepsis	4 weeks or till discharge from NICU, whichever came first
Secondary	Total numbers of days of antimicrobial administration	Total numbers of days of antimicrobial administration	4 weeks or till discharge from NICU, whichever came first
Secondary	Duration of parenteral nutrition	during NICU stay	4 weeks or till discharge from NICU, whichever came first
Secondary	Necrotizing enterocolitis	Bell stage 2 or 3	4 weeks or till discharge from NICU, whichever came first
Secondary	Duration of hospital stay	Duration of hospital stay	4 weeks or till discharge from NICU, whichever came first
Secondary	Iron status after 4 week of enrollment	serum iron , serum ferritin, TIBC	4 weeks or till discharge from NICU, whichever came first
Secondary	Side effect from the drug	vomiting , rash	4 weeks or till discharge from NICU, whichever came first

External Links

•   Feeding intolerance in the preterm infant. Early Human development
•   Feeding intolerance, inflammation, and neurobehaviors in preterm infants.
•   Lactoferrin as a Natural Immune Modulator
•   Prophylactic lactoferrin for preventing late-onset sepsis and necrotizing enterocolitis in preterm infants