Long-term Consequences of Necrotizing Enterocolitis in the Newborn Period
Condition: NEC - Necrotizing Enterocolitis; Complications
MeSH terms: Enterocolitis; Enterocolitis, Necrotizing
Study type: Observational

Summary: 
      Aim

      The aim of this study is to determine consequences at school age of the diagnosis of NEC in
      the neonatal period.

      Methods

      This is a case-control study, with case-group being children born in Denmark with a history
      of NEC and control-group being age-, gestational age- and year of birth matched children born
      in Denmark with no history of NEC.

      Primary outcome

      Abnormal or borderline 'total difficulties score' in the
      strenghts-and-difficulties-questionnaire as assessed by parents.
    

Detailed description: 
      Rationale

      Knowledge of the long-term complications related to necrotizing enterocolitis (NEC) in the
      neonatal period is essential, when clinicians are counseling parents about the risk for
      complications following NEC. When deciding upon a follow-up strategy for the infant after
      discharge, this knowledge is also crucial. If the infant has an increased risk for
      complications later in life, a closer follow up is important to assure proper handling of
      complications.

      So far, a definite conclusion regarding long-term complications of NEC has not been made. A
      systematic review including ten studies, have shown a significantly increased risk for
      neurodevelopmental impairment in NEC children. However, the median follow-up time did not
      exceed two years and may not reflect the true long-term complications. The ORACLE Children
      Study investigated neurodevelopmental impairments in children with a history of NEC at 7,5
      year follow-up and found no increased risk.

      No review has been published regarding growth impairments and so far, available studies have
      a less than three year follow-up period and are reporting conflicting results.

      Gastrointestinal morbidities are even less investigated and reports no association with NEC
      within three years follow-up. However, the ORACLE Children Study found increased risk of
      bowel problems at 7,5 years follow-up in children with a history of NEC.

      The Oracle Children Study and Roze et al reported behavioural problems in up to 30% of
      children with a history of NEC at school age, but no statistic significance was found when
      compared to a control-group.

      Further studies investigating the outcome of NEC-children at school age are needed.

      Objectives

      The investigators plan to conduct a retrospective parental-questionnare study, to determine
      the long-term complications related to the diagnosis of NEC at school age (5-15 years of
      age).

      Methods

      This is a case-control study. Case-group will include all surviving children born in Denmark
      between 1st of January 2002 and 31st of December 2011 with an international classification of
      diseases (ICD-10) diagnosis of NEC at discharge. Matching each child with a history of NEC to
      two children with no history of NEC by gestational age, year of birth and birthweight will
      form the control group. Matching criteria's have been chosen to balance prematurity and age
      at follow-up between case and control-group. Parental follow-up questionnaires regarding
      complications will be sent to all parents of cases and controls.

      Clinical data on the children, regarding birth and neonatal history, will be obtained and
      used in a mixed regression model to adjust for possible confounders.

      Primary outcome

      Abnormal or borderline 'total difficulties score' in the
      strenghts-and-difficulties-questionnaire as assessed by parents.

      Secondary outcomes

        1. Severe cerebral palsy (GMFCS III-IV)

        2. Head circumference as measured by parents

        3. Height as measured by parents

        4. Abdominal symptoms resulting in significant absence from school as reported by parents

        5. Diarrhoea within the last six months

        6. Constipation within the last six months

      Power calculation

      The sample size for the case group was estimated to include 200 children with NEC (after a
      no-response drop out of 20%) and in the control group 300 children without NEC, with a 1:2
      match ratio and the assumption that the response rate will be lower in the control group.,
      i.e. 250 parents of children with NEC and 500 parents of control children will be contacted.

      SDQ total score Assuming 30% prevalence of abnormal or borderline scores for 'total
      difficulties' in the strength-and-difficulties-questionnaire in NEC-survivors, compared to an
      assumed 20% in controls (19), this study will detect the difference with a power of 72% at a
      5% significance level.

      Severe cerebral palsy (GMFCS score III-V) Assuming a 20% prevalence (9) of severe cerebral
      palsy in NEC-survivors compared to an assumed 10% in controls (22) this study will detect the
      difference with a power of 87% at a 5% significance level.

      Head circumference The power calculation on our cohort shows that we, at a 5% significance
      level, can detect the difference in mean head circumference at 0.3 standard-deviations or
      more, with a power of 90%.

      Analysis plan

      Primary outcome: a p-value < 0.05 will be considered significant. To determine a difference
      in SDQ-scores between case- and control group, Chi-squared test or Fischer's Exact test will
      be used as appropriate.

      Secondary outcome: a p-value < 0.01 will be considered significant. Differences in 'height',
      'head circumference' and 'absence from school due to abdominal symptoms' will be investigated
      by t-test or Mann-Whitney's test as appropriate. 'Severe cerebral palsy', 'diarrhoea' and
      'constipation' will be analyzed by Chi-squared test or Fischer´s Exact test as appropriate.

      At first, an unadjusted analysis will be performed to investigate differences in primary and
      secondary outcome. Secondly, a mixed regression model will be used to adjust for possible
      confounders
    

Observational model: Case-Control
Time perspective: Retrospective
Sampling method: Probability Sample
Study population: 
        Case-group will include all surviving children born in Denmark between 1st of January 2002
        and 31st of December 2011 with an ICD-10 diagnosis of NEC (DP77.9) at discharge.

        Matching each child with a history of NEC to two children with no history of NEC by
        gestational age, year of birth and birthweight will form the control group. Matching
        criteria's have been chosen to balance prematurity and age at follow-up between case and
        control-group.
      
Keywords: Necrotizing enterocolitis; Followup; Neurodevelopmental impairments; Growth impairments; Gut function; Behavioural impairments