Growth, Risks of Allergy and Metabolic Syndrome in 6 Year Old Children Born Preterm Compared to Postdischarge Nutrition
Condition: Infant, Very Low Birth Weight; Metabolic Syndrome, Protection Against; Allergy; Dietary Modification
MeSH terms: Metabolic Syndrome; Hypersensitivity; Syndrome; Birth Weight
Study type: Interventional

Summary: 
      This is a follow-up cohort study of 6 years old children born preterm in Denmark from
      2004-2008, and at four different neonatal units. During hospitalisation they received breast
      milk with fortification. At time of discharge there were made 3 different nutrition groups;
      if possible they were randomised into one of two groups:

        1. Breastfeeding solely

        2. Breastfeeding with fortification

           If breastfeeding was not possible they were put in group 3 and were bottle fed with:

        3. Preterm formula

      This nutrition intervention went on for 4 month. At the age of 6, the children will be
      invited to come for an ambulant control and other examinations regarding growth, allergy and
      metabolic syndrome.
    

Detailed description: 
      Project background:

      The study is based on a follow-up of a cohort of very preterm infants born before week 32, as
      at discharge from the neonatal departments were randomized to a protein supplement or not
      while breastfeeding after discharge. If the preterm child was not breastfed, it received a
      premature infant formula after discharge. Since we have three groups of prematures, which are
      fed differently after discharge, it is useful to follow up at 6 years of age and specifically
      examine the following areas:

      Metabolic syndrome:

      Unlike the past, the survival rate of very preterm infants is now high. Most is expected to
      survive. The question is the extent to which these children have increased morbidity compared
      with children born at term, and their quality of life is affected by the fact that they are
      born prematurely. There has previously been shown a link between children born SGA and later
      development of type 2 diabetes mellitus, hypertension, ischemic heart disease and
      cerebrovascular disasters. Too rapid catch-up growth also increases the possible risk of
      developing metabolic syndrome in the mature child. The question is whether this is also the
      case in children born prematurely and whether the risk is the same. The problem is just that
      you want to provide them with adequate amino acids for protein synthesis, as they approach
      the growth of peers fetuses and also ensure the development of the brain with essential fatty
      acids, but maybe they can not tolerate a too rapid "catch-up" - growth.

      A study comparing preterm born children aged 4-10 years with mature children born of the same
      age found that the group with preterm births had increased systolic and diastolic blood
      pressure and higher insulin levels. This was true regardless of whether the children were
      born SGA and AGA at birth. This concluded that there were metabolic abnormalities in preterm
      similar to those found in children born at term but SGA. The same article mentions the
      concept of "fetal programming". This covers a hypothesis which suggests that a fetus at risk
      in the uterus will adapt best to survive, and this adjustment will be permanent.

      The same team has published an article, which have found impaired insulin sensitivity in
      preterm infants (SGA and AGA) compared to mature AGA children. Insulin sensitivity is
      greatest in the mature AGA. Next comes the mature SGA and eventually the premature. To show
      the importance of this area, they point out that out of those who have diabetes mellitus type
      2, 35% has had low birth weight.

      In trying to find a way it will be interesting, and very relevant, to see if diet the first
      months of life have an impact on these metabolic complications later in life.

      Allergy:

      It is unknown whether preterms are at increased risk of developing allergic symptoms.
      Breastfeeding reduces the risk of developing allergic diseases, while cow milk-based infant
      formulas increase the risk. The preterm infants in this study completed during
      hospitalization with fortifier containing cow's milk protein, and the preterm infant formula
      is cow milk based. It is therefore interesting to see if there is an increased incidence of
      allergic symptoms in one of the groups. An article formed on the basis of a study of two
      groups of children, one group consisted of children with a birth weight less than 1500 g, and
      the second group consisted of children with a birth weight over 2500 g, describes that there
      was no difference in the incidence of atopy. Another study studied the incidence of food
      allergies in an area of 13,980 children, and found that 4.23 % were diagnosed with this at
      the age of six. There was no difference in the incidence of categorization in GA.

      The first study mentioned above studied also the appearance of wheezing. This was done using
      spirometry. The result was that the lifetime risk of preterm births was 43% for developing
      wheezing, while it was only 17% in mature births. Besides wheezing low GA at birth was
      associated with decreased lung capacity, reduced forced vital capacity (FVC) and forced
      expiratory volume in 1 second (FEV1) and asthma. A relevant question is whether children
      develop these respiratory symptoms solely on the basis that they are born preterm or
      nutritional type influences the risk of its development.

      Growth and catch-up:

      Some studies have gradually studied prematurely born children's growth compared to some
      control children - especially in the first period after discharge from the neonatal units. As
      we know, human milk has the best composition in relation to children's needs. There has been
      made a study on nutrition of preterms with human milk against fortified human milk which
      states that those who get pure milk, are at greatest risk of malnutrition by discharge and
      that it is a good strategy to provide breast milk multinutrient enrichment. In the study
      mothers milked out half of their daily quantity for enrichment. Though, they request
      long-term studies to determine the long-term effects of it.

      Other studies have followed prematurely born children up to 20 years of age and 11 years of
      age and were compared with a control group of normal weight, not preterm births. Outcome was
      height, weight, BMI. In one case also head circumference. One study concludes that all very
      low birthweight children (VLBW) were smaller than the control group. In particular SGA boys
      were smaller. The second study concluded that extremely immature children have poor growth in
      early childhood, but they have catch-up until 11 years of age. All prematures remain less
      than the control group.

      A comparison of both nutrition after discharge and follow-up beyond 1 year of age will be
      very interesting to be able to optimize nutrition and growth of extremely premature infants,
      both AGA and SGA.

      A dual-energy X-ray absorptiometry (DEXA) scan is a study that reveals body composition of
      bone, muscle and fat. A study of whether the scanning can be used to detect body composition,
      concluded that DEXA is a good tool for this. It is a quick (minutes) survey that provides
      minimal radiation, and it is interesting because a scan of the 3 groups in this project will
      elucidate whether there is a difference in body composition and thus whether a nutritional
      type provides better basis for the best growth. The same study, which was built on an RCT
      (randomized controlled trial) of 33 children with GA less than 35 weeks and a birth weight
      below 1,750 grams who received either 1) standard replacement or 2) enriched compensation for
      2 months after discharge, found no difference in body composition or weight gain. It calls
      for larger studies with longer follow-up. Another study, just as this PhD project, divide the
      children into several groups depending on Nutrition (1: enriched substitute 2: standard
      replacement 3: human breast milk), found by DEXA scanning at 6 months of age, group 1 had
      lower fat mass and group 3 had lower lean (muscle) mass and higher fat mass. So, there is a
      difference in body composition depending on nutrition. It may sound logical, but will it
      affect children later in life? - and if so, in what way? From the above examples of previous
      studies, one can conclude that the optimal nutrition of preterms is under development and
      there is a continued lack of clarification of how preterm infants grow after discharge and
      whether one type of nutrition is better.

      Hypotheses:

        -  Nutrition after discharge does affect premature children's growth in the first years of
           life.

        -  Catch-up growth proceeds after 1 year of age.

        -  The growth pattern for prematures born SGA is different from prematures born AGA.

        -  There is no increase in allergies between prematures, who was fed with premature formula
           or enriched mothers milk before and after discharge compared with mothers milk without
           enrichment.

        -  Premature children fed with a preterm formula have an extended risk for developing
           metabolic syndrome on basis of excessive growth the first months of life.

        -  It is possible that premature SGA children have greater risks of developing metabolic
           syndrome on the basis of excessive growth the first month of life.

        -  Fat mass and lean mass vary among prematures depending on the nutrition the first month
           after discharge.

      Purpose of the project:

        1. Investigate whether there are long-term effect on growth after cessation of enrichment
           of breast milk in 2, 3 and 6 years of age.

        2. Examine the relationship between protein intake to 4 months of age (corrected) and blood
           pressure, HbA1c and serum cholesterol by 6 years of age.

        3. Uncover the incidence of allergy symptoms from the eyes and nose, skin, stomach /
           intestinal and respiratory tract incl affected lung function in children born
           prematurely.

        4. Elucidate whether there is an increased risk of metabolic syndrome in children born
           prematurely and nourished in different ways.

        5. Investigate whether preterms have different fat distribution and nutrition up to 4
           months corrected age affect them.

        6. Illuminate catch-up growth in children born prematurely and up to 6 years of age.

      Planned studies:

        1. Weight, height, head circumference, blood pressure

        2. Registration of any allergy symptoms and airway symptoms.

        3. Blood tests for diabetes, screening for metabolic syndrome and allergies.

        4. Questionaires to investigate allergy symptoms.

        5. A dexa scan to see the body composition of fat, muscle and bone.

      Randomization:

      The children were randomized when they could eat (breast or bottle) at gestational age 34-42.
      Twins and triplets were randomly assigned to the same group.

      At randomization an impartial person in the department the child was hospitalized in, pulled
      an envelope with information on what kind of nutrition, the child should have after discharge
      and up to 4 months of corrected age.

      Statistics:

      Originally, there were strength calculations prior to randomization in the project. This
      showed that there were needed 85 children in each feeding group. A total of 320 children in
      the original project were enrolled. However, there has been a waiver until 1 year of age, and
      there are 278 children remaining to follow-up.

      Wilcoxon rank-sum test or t-test for continuous variables, and if categorical variables
      chi2test will be used to compare the nutritional groups.

      Multiple logistic regression models will be used to compare the clinical relevant variables
      that have possible influence on the growth of various dietary groups.

      Growth will be analyzed from Z-score and delta z-score and will be calculated from a relevant
      reference for comparing nutritional groups growth.

      Allergy risks and metabolic syndrome will be calculated using the above methods and odds
      ratio.

      Project Period:

      From 2004 - 2008 there were formed three groups of preterm children at clinical
      randomization. A Ph.D. dissertation was made subsequently dealing with preterm growth up to 1
      year of age, nutrition and composition of breast milk of mothers of preterm babies.

      Between the ages of 2 and 3 years, children have come to control for a follow-up Ph.D. The
      children become 6 years from July 2010 - 2014, where they also will be invited to a follow-up
      check on the current Ph.D. project.

      The children will be followed up in their respective departments / hospitals in Kolding,
      Skejby, Holbæk and Odense.

      Ethical considerations:

      For inclusion in the randomized controlled study parents signed an acceptance which included
      follow-up at 6 years of age.

      The initial randomized controlled study was approved by the Ethics Committee 1 July 2004 (J.
      Nr.VF20030208). As part of the 6-year follow-up, there is added and approved Protocol 1-8.

      In addition, permission from the Data Inspectorate of the original project with change in
      2007 (J. No 2007-41-1349) is extended until 2016.
    

Intervention name(s): Enfamil HM fortifier, Mead Johnson; Enfalac Premature Formula, Mead Johnson Nutritionals; Mothers own milk
Intervention type(s): Dietary Supplement; Dietary Supplement; Dietary Supplement
Intervention description(s): Enfamil was added to a small amount of mothers expressed milk and given in a bottle or with a small cup every day. Group 2 (HMF) received 5 packets each day for 4 month containing; 17.5 kcal, 1.375 g protein/ 5 packets; Group 3 received Enfalac containing:
68 kcal, 2 g protein, 7.4 g carbohydrate, 3.5 g fat/ 100 ml; Group 1 received mothers own milk without fortification
Other intervention name(s): Enfamil HM fortifier, Mead Johnson, Njimegen, Netherlands; Enfalac PF, Mead Johnson Nutritionals, Njimegen, Netherlands
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: very preterm; nutrition; 6 year follow-up; growth; metabolic syndrome; allergy; dexa