Probiotics in the Management of Necrotizing Enterocolitis in HIV-exposed Premature Infants
Condition: Necrotizing Enterocolitis
MeSH terms: Enterocolitis; Enterocolitis, Necrotizing; Premature Birth
Study type: Interventional
Phase: Phase 3

Summary: 
      A randomized, double blind, placebo controlled clinical trial was conducted in the neonatal
      high care unit of Tygerberg Children's Hospital (TBCH) Cape Town, South Africa for the period
      July 2011 to August 2012. The primary objective of the study was to assess the effect of
      probiotics on the incidence of NEC in high risk infants born to HIV-positive and HIV-negative
      women.

      Throughout the study period, the standard of care protocol consisted of one dose (5 drops)
      probiotic/placebo daily for 4 weeks (28 days). This provided the study group with L.
      rhamnosus GG (0.35 x 109 colony-forming units [CFU]) and B. infantis (0.35 x 109 CFU) daily.
      The control group received placebo consisting of medium chain triglyceride (MCT) oil.
      Supplementation of the probiotic/placebo was initiated when enteral feeds started. Probiotic/
      placebo supplementation was delayed/ halted in the event of: the infants being nill per os
      (NPO); when a query Necrotizing Enterocolitis (NEC) was suspected the infant continued with
      treatment until a confirmed a positive diagnosis of NEC I was made through abdominal X-ray;
      if the infant remained a query NEC and was NPO the infant did not receive probiotics/ placebo
      until the enteral feeds were commenced again. Supplementation was discontinued when
      HIV-exposed infants had a positive polymerase chain reaction (PCR) result on day 14 of life.

      All study participants received human breast milk. Both the probiotics and placebo were mixed
      with the mothers own breast milk or donor breast milk before administration via the
      orogastric tube or orally. The probiotic/ placebo was added to the breast milk by the
      researcher and two research assistants who were blinded and not involved in the routine care
      of the infants. Participants exited the study on day 28 after birth or upon discharge from
      the hospital.
    

Detailed description: 
      A randomized, double blind, placebo controlled clinical trial was conducted in the neonatal
      high care unit of Tygerberg Children's Hospital (TBCH) Cape Town, South Africa for the period
      July 2011 to August 2012. The primary objective of the study was to assess the effect of
      probiotics on the incidence of NEC in high risk infants born to HIV-positive and HIV-negative
      women. All mothers and infants pairs that conformed to the inclusion criteria and provided
      written informed consent were included into the study. Premature (<34 weeks' gestation) and
      very-low birth weight (<1 250g) HIV-exposed and unexposed infants were randomized into the
      study or control groups by a random-number table sequence assigned by a statistician. Sample
      size was determined by a statistician according to the life birth statistics form the
      institution. Participants were enrolled and assigned to the respective groups by the
      researcher and two research assistants. Inclusion criteria for the mothers included: (1)
      HIV-positive or-negative mothers who gave birth to a premature and low birth weight baby at
      TBCH and consented to participate in the study; (2) Only breastfeeding mothers, regardless of
      their HIV status and (3) HIV-positive mothers that were on the prevention of mother to child
      transmission (PMTCT) treatment schedule and received nevirapine and zidovudine (AZT) as well
      as those that received highly active antiretroviral (HAART) medication were included in the
      study Babies were included if they were (1) born prematurely with a birth weight of of ≥500g
      and ≤1250g; (2) were HIV exposed or unexposed; (3) HIV-exposed infants and received
      antiretroviral (ARV) medication and (4) received breast milk (either from their mothers or
      donor breast milk). Breast milk of HIV-positive mothers was pasteurized (according to ward
      protocol) before it was administered to the infants. Infants were excluded if they had major
      abnormalities such as gastroschisis, a large omphalocele or congenital diaphragmatic hernia
      Throughout the study period, the standard of care protocol consisted of one dose (5 drops)
      probiotic/placebo daily for 4 weeks (28 days). This provided the study group with L.
      rhamnosus GG (0.35 x 109 colony-forming units [CFU]) and B. infantis (0.35 x 109 CFU) daily.
      The control group received placebo consisting of medium chain triglyceride (MCT) oil.
      Supplementation of the probiotic/placebo was initiated when enteral feeds started. Probiotic/
      placebo supplementation was delayed/ halted in the event of: the infants being nill per os
      (NPO); when a query NEC was suspected the infant continued with treatment until a confirmed a
      positive diagnosis of NEC I was made through abdominal X-ray; if the infant remained a query
      NEC and was NPO the infant did not receive probiotics/ placebo until the enteral feeds were
      commenced again. Supplementation was discontinued when HIV-exposed infants had a positive
      polymerase chain reaction (PCR) result on day 14 of life.

      All study participants received human breast milk. Both the probiotics and placebo were mixed
      with the mothers own breast milk or donor breast milk before administration via the
      orogastric tube or orally. The probiotic/ placebo was added to the breast milk by the
      researcher and two research assistants who were blinded and not involved in the routine care
      of the infants. Participants exited the study on day 28 after birth or upon discharge from
      the hospital.

      Data on birth weight, estimated gestational age, gender, type of delivery, and Apgar scores
      were collected. Gestational age was determined by the best estimate of the neonatal and
      obstetrical care providers based upon physical examination of the infants. Anthropometrical
      measurements (weight, length and head circumference), intake and output and daily clinical
      progress notes were reviewed. Infants were evaluated daily for the development of NEC by the
      attending neonatologists. Whenever a study infant was suspected to have NEC the infant was
      evaluated by the attending neonatologists in conjunction with the pediatric radiologist and
      categorized by modified Bell's classification. Infants who developed Stage I of Bell's
      criteria and required surgery were exited from the study. Ethical approval was granted by the
      Human Research Ethics Committee of the Faculty of Health Sciences, Stellenbosch University
      and Tygerberg Academic Hospital. The clinical trial registration number: DOH-27-0413-4277.
      Data analyses were performed with Statistica Software (version 11). Frequencies between
      groups were compared using the likelihood ratio chi-square test and means between groups
      using t-tests. Statistical significance was defined as a p-value less than 0.05.
    

Intervention name(s): Probiotic; Placebo
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Lactobacillus rhamnosus GG and Bifidobacterium infantis'; MCT oil
Other intervention name(s): Brand name: Pro-B2; Lactobacillus rhamnosus GG and Bifidobacterium infantis'
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Human Immunodeficiency Virus; Necrotizing Enterocolitis; Premature infant; Probiotic; Very Low Birth Weight