<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03767634</url>
  </required_header>
  <id_info>
    <org_study_id>18IC4724</org_study_id>
    <nct_id>NCT03767634</nct_id>
  </id_info>
  <brief_title>Outcomes Following Early Parenteral Nutrition Use in Preterm Neonates</brief_title>
  <official_title>Outcomes Following Early Parenteral Nutrition Use in Preterm Neonates</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Imperial College London</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Imperial College London</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      BACKGROUND&#xD;
&#xD;
      An essential part of neonatal care is providing nutrition to ensure that babies grow and&#xD;
      develop. Providing this can be difficult in premature babies because their intestines are&#xD;
      underdeveloped. They often have difficulty digesting milk so feeds are introduced gradually.&#xD;
      To help babies grow and develop during this period, additional nutrition may be provided as a&#xD;
      fluid into a vein; this is called &quot;parenteral nutrition&quot; (PN). Unfortunately, PN increases&#xD;
      the risk of serious complications like bloodstream infection (also known as &quot;sepsis&quot;). For&#xD;
      babies who are moderately premature there is little evidence to guide decision making about&#xD;
      which babies will benefit from PN. This group of babies have more reserves of fat and are&#xD;
      less dependent on PN, but are still at risk of sepsis. As a consequence, some doctors use PN&#xD;
      and others do not.&#xD;
&#xD;
      AIMS&#xD;
&#xD;
      Firstly, to describe which babies are given PN during the first postnatal week in neonatal&#xD;
      units in England, Scotland and Wales.&#xD;
&#xD;
      Secondly, to determine whether in babies born 7-10 weeks preterm (moderately premature),&#xD;
      providing PN in the first week after birth, compared to not to providing PN, improves&#xD;
      survival to discharge from the neonatal unit.&#xD;
&#xD;
      Finally, to evaluate if the early use of PN in moderately preterm babies affects other&#xD;
      important outcomes in the neonatal core outcomes set.&#xD;
&#xD;
      IMPORTANCE&#xD;
&#xD;
      This work will describe the extent of PN use in England, Scotland and Wales. This is&#xD;
      currently unknown. This project will improve understanding of the balance of benefits and&#xD;
      harms of PN use in premature babies and will help doctors and parents make informed treatment&#xD;
      choices.&#xD;
&#xD;
      METHODS&#xD;
&#xD;
      The investigators will use the National Neonatal Research Database (NNRD) to study all babies&#xD;
      born in England, Scotland and Wales; they will identify which babies were given PN during the&#xD;
      first week, and which were not. The investigators will use the NNRD to identify babies born&#xD;
      7-10 weeks prematurely and compare outcomes in babies that were given and not given PN in the&#xD;
      first week after birth. The investigators will use statistical techniques to identify two&#xD;
      sets of babies in the NNRD who are very similar (in terms of how prematurely they were born,&#xD;
      their birth weight, and so on), the only difference being whether they were given PN or not.&#xD;
      As the two groups will be similar any difference in their outcomes (such as survival) is&#xD;
      likely to be due to whether or not they received PN.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Premature birth abruptly ends the transplacental transmission of nutrients that allows normal&#xD;
      foetal growth and development. Providing adequate nutrition is essential to allow premature&#xD;
      babies to continue to grow and mature. Very preterm infants often have difficulty tolerating&#xD;
      adequate volumes of milk feeds shortly after birth and so are given supplemental parenteral&#xD;
      nutrition (PN). Preterm babies are among the highest PN users of all NHS patients. It has&#xD;
      been estimated that PN is received by around 70% of neonatal unit admissions but it is not&#xD;
      known exactly which babies receive PN. In addition, how PN affects outcomes has never been&#xD;
      tested in a large scale, randomized, placebo controlled neonatal trial.&#xD;
&#xD;
      It is known that PN carries well established risks, of which the most serious and the most&#xD;
      common is sepsis with estimates of risk ratios varying from 2.2 to 14.6. In addition there is&#xD;
      a growing body of evidence that use of PN within the first seven days of admission to an&#xD;
      intensive care unit is associated with worse outcomes in critically unwell adults and&#xD;
      children. A subgroup analysis of the paediatric intensive care unit population focusing on&#xD;
      neonates showed an increase in infections with early PN use. This suggests that uncertainty&#xD;
      exists over the benefit of giving neonates PN in the early postnatal period. It is generally&#xD;
      accepted that PN is beneficial to extremely preterm neonates, but in moderately preterm&#xD;
      neonates the effect that PN use has on neonatal survival has never been conclusively&#xD;
      demonstrated.&#xD;
&#xD;
      The uncertainty over how PN use affects neonatal outcomes is reflected by the wide variety in&#xD;
      how PN is used in different units with large variation in use, timing and composition of PN.&#xD;
      This is, in part, due to the lack of clear evidence of how PN affects neonatal outcomes like&#xD;
      growth and survival. Neonates are also vulnerable to unanticipated treatment effects which&#xD;
      can occur in different organ systems and so it is important to show that PN is not&#xD;
      detrimental to important neonatal outcomes.&#xD;
&#xD;
      The postmenstrual age at which the nutritional benefits of PN outweigh the risks in&#xD;
      moderately preterm babies (30-33 weeks postmenstrual age) is unknown. It is therefore&#xD;
      unsurprising that their nutritional management is very variable. In moderately preterm&#xD;
      neonates in 2012 and 2013 across England, Scotland and Wales PN was given to 45% of neonates,&#xD;
      suggesting clinician equipoise around the balance of benefit to risk. Identifying whether&#xD;
      moderately preterm neonates benefit from PN would have important implications for practice in&#xD;
      the UK. This work will provide information to guide practice and inform future research.&#xD;
&#xD;
      In summary, PN is widely used in neonates but it is not known exactly how it is used in the&#xD;
      UK. It is known to have risks and benefits but there is insufficient evidence to guide&#xD;
      practice in moderately preterm neonates.&#xD;
&#xD;
      Study objectives:&#xD;
&#xD;
        -  To describe the use of PN in neonatal units across England, Scotland and Wales.&#xD;
&#xD;
        -  To identify if use of PN in the first seven postnatal days affects survival in neonates&#xD;
           born between 30 and 33 weeks postmenstrual age.&#xD;
&#xD;
        -  To explore how PN use in the first seven postnatal days affects other important neonatal&#xD;
           outcomes in neonates born between 30 and 33 weeks postmenstrual age.&#xD;
&#xD;
      Study design:&#xD;
&#xD;
      Project A: an epidemiological survey of practice using the National Neonatal Research&#xD;
      Database (NNRD).&#xD;
&#xD;
      Project B: a retrospective cohort study of matched groups of babies using data held in the&#xD;
      NNRD.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 1, 2019</start_date>
  <completion_date type="Actual">August 1, 2021</completion_date>
  <primary_completion_date type="Actual">September 1, 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Use of Parenteral Nutrition (Project A)</measure>
    <time_frame>From birth until discharge home, assessed up to 1 year</time_frame>
    <description>Any use of parenteral nutrition in the first seven days of postnatal life (assessed using daily data extracted from the National Neonatal Research Database as described in the project protocol)&#xD;
This outcome formed part of Project A ONLY, and in keeping with the research protocol is only analysed and reported for the babies in this research arm.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Survival to Discharge Home (Project B)</measure>
    <time_frame>From birth until discharge home, assessed up to 1 year</time_frame>
    <description>Defined as recorded alive at final neonatal unit discharge&#xD;
This outcome formed part of Project B ONLY, and in keeping with the research protocol is only analysed and reported for the babies in this research arm.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Late Onset Sepsis (Project B)</measure>
    <time_frame>72 hours of postnatal life to discharge home, assessed up to 1 year</time_frame>
    <description>Number of participants with diagnosed Later Onset Sepsis: defined in line with the Royal College of Paediatrics and Child Health National Neonatal Audit Programme (NNAP) definition &quot;pure growth of a pathogen from blood&quot; or &quot;pure growth of a skin commensal&quot; or a &quot;mixed growth&quot; after the first 72 hours of life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Necrotising Enterocolitis (Project B)</measure>
    <time_frame>From birth until discharge home, assessed up to 1 year</time_frame>
    <description>Number of participants with diagnosed necrotising enterocolitis: defined using the NNAP definition: NEC may be diagnosed at surgery, post-mortem or on the basis of the following clinical and radiographic signs:&#xD;
At least one clinical feature from:&#xD;
(i) Bilious gastric aspirate or emesis (ii) Abdominal distension (iii) Occult or gross blood in stool (no fissure)&#xD;
And at least one radiographic feature from:&#xD;
(i) Pneumatosis (ii) Hepato-biliary gas (iii) Pneumoperitoneum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brain Injury on Imaging (Project B)</measure>
    <time_frame>From birth until discharge home, assessed up to 1 year</time_frame>
    <description>Number of participants with diagnosed brain injury on imaging: defined as documented diagnosis of intraventricular haemorrhage (grade 3-4) or cystic periventricular leucomalacia</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Retinopathy of Prematurity (Project B)</measure>
    <time_frame>From birth until discharge home, assessed up to 1 year</time_frame>
    <description>Number of participants with diagnosed retinopathy of prematurity: defined as a record of any retinopathy of prematurity on routine screening in the National Neonatal Dataset &quot;retinopathy of prematurity ad-hoc form&quot;</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bronchopulmonary Dysplasia (Project B)</measure>
    <time_frame>From birth until discharge home, assessed up to 1 year</time_frame>
    <description>Number of participants with diagnosed bronchopulmonary dysplasia: defined using the NNAP definition of significant bronchopulmonary dysplasia: Receiving respiratory support at 36 weeks corrected gestational age.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Need for Surgical Procedures (Project B)</measure>
    <time_frame>From birth until discharge home, assessed up to 1 year</time_frame>
    <description>Defined as any record of surgical procedure during the neonatal admission</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Seizures (Project B)</measure>
    <time_frame>From birth until discharge home, assessed up to 1 year</time_frame>
    <description>Number of participants diagnosed as having a seizure: defined as any recorded diagnosis of seizures or seizure disorder</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Weight (Project B)</measure>
    <time_frame>From birth until discharge home, assessed up to 1 year</time_frame>
    <description>Weight z-score at discharge home. Weights at discharge home were converted to a z-score: a z-score of 0 represents the population mean, while score higher scores indicate a greater weight.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Head Circumference (Project B)</measure>
    <time_frame>From birth until discharge home, assessed up to 1 year</time_frame>
    <description>Head circumference in centimetres at discharge; head circumference velocity (measured as increase in head circumference in centimetres/day) from birth until discharge</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blindness (Project B)</measure>
    <time_frame>From birth until two years of age</time_frame>
    <description>Defined as an answer of Yes to the question &quot;Does this child have a visual impairment?&quot; on the NNAP follow up form</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Deafness (Project B)</measure>
    <time_frame>From birth until two years of age</time_frame>
    <description>Defined as an answer of Yes to the question &quot;Does this child have a hearing impairment?&quot; on the NNAP follow up form</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ability to Walk (Project B)</measure>
    <time_frame>From birth until two years of age</time_frame>
    <description>Defined as an answer of Yes to the question &quot;Is this child unable to walk without assistance?&quot; on the NNAP follow up form</description>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">97507</enrollment>
  <condition>Neonatal Death</condition>
  <condition>Prematurity</condition>
  <arm_group>
    <arm_group_label>Neonatal population (Project A)</arm_group_label>
    <description>Neonates born between 1st January 2012 and 31st December 2017 and admitted to a neonatal unit in England, Scotland and Wales).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>No PN use (Project B)</arm_group_label>
    <description>All neonates born between 30 and 33 weeks postmenstrual age in England, Wales and Scotland and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who did not receive any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>PN use (Project B)</arm_group_label>
    <description>All neonates born between 30 and 33 weeks postmenstrual age in England, Wales and Scotland and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who received any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Parenteral nutrition</intervention_name>
    <description>Parenteral nutrition is the administration of an intravenous solution containing amino acids (with or without lipids) to provide nutritional support.</description>
    <arm_group_label>PN use (Project B)</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Neonates born between 1st January 2012 and 31st December 2017 and admitted to a neonatal&#xD;
        unit in England, Scotland and Wales).&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Project A:&#xD;
&#xD;
          -  Must be born between 1st January 2012 and 31st December 2017&#xD;
&#xD;
          -  Must be admitted to a National Health Service (NHS) neonatal unit in England, Scotland&#xD;
             or Wales&#xD;
&#xD;
        Project B:&#xD;
&#xD;
          -  Must be born between 30 and 33 weeks postmenstrual age&#xD;
&#xD;
          -  Must be born between 1st January 2012 and 31st December 2017&#xD;
&#xD;
          -  Must be admitted to an NHS neonatal unit in England, Scotland or Wales&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Project A:&#xD;
&#xD;
        No exclusion criteria.&#xD;
&#xD;
        Project B:&#xD;
&#xD;
          -  Major congenital gastrointestinal malformations&#xD;
&#xD;
          -  Life limiting conditions&#xD;
&#xD;
          -  Congenital conditions requiring surgery in the neonatal period&#xD;
&#xD;
          -  Missing key background data (birthweight, sex or gestational age)&#xD;
&#xD;
          -  Missing data for the primary outcome&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>2 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Chris RK Gale, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Imperial College London</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Chelsea and Westminster Hospital</name>
      <address>
        <city>London</city>
        <zip>SW10 9NH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>January 2022</verification_date>
  <study_first_submitted>November 30, 2018</study_first_submitted>
  <study_first_submitted_qc>December 5, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 6, 2018</study_first_posted>
  <results_first_submitted>September 1, 2021</results_first_submitted>
  <results_first_submitted_qc>January 18, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">March 17, 2022</results_first_posted>
  <last_update_submitted>January 18, 2022</last_update_submitted>
  <last_update_submitted_qc>January 18, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 17, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Preterm neonate</keyword>
  <keyword>Parenteral nutrition</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Perinatal Death</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>June 20, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/34/NCT03767634/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>Project A: 4,196,314 neonates were born in England and Wales. 347,959 neonates were admitted to NHS neonatal units . 62,147 neonates received PN during the first postnatal week.&#xD;
Project B: 37,302 neonates were born over the study period. 36,644 were admitted to an NHS neonatal unit.&#xD;
Prior to the propensity score analysis 843 neonates were excluded due to congenital conditions and 439 were excluded due to missing key data. This left 35,362 included in the propensity score analysis</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Neonatal Population (Project A)</title>
          <description>Neonates born between 1st January 2012 and 31st December 2017 and admitted to a neonatal unit in England and Wales).</description>
        </group>
        <group group_id="P2">
          <title>No PN Use (Project B)</title>
          <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who did not receive any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.</description>
        </group>
        <group group_id="P3">
          <title>PN Use (Project B)</title>
          <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who received any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.&#xD;
Parenteral nutrition: Parenteral nutrition is the administration of an intravenous solution containing amino acids (with or without lipids) to provide nutritional support.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="62145"/>
                <participants group_id="P2" count="19080">8,146 neonates were included in the matched propensity score analysis</participants>
                <participants group_id="P3" count="16282">8,146 neonates were included in the matched propensity score analysis</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="62145"/>
                <participants group_id="P2" count="19080">8,146 neonates were included in the matched propensity score analysis</participants>
                <participants group_id="P3" count="16282">8,146 neonates were included in the matched propensity score analysis</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Neonatal Population (Project A)</title>
          <description>Neonates born between 1st January 2012 and 31st December 2017 and admitted to a neonatal unit in England and Wales).</description>
        </group>
        <group group_id="B2">
          <title>No PN Use (Project B)</title>
          <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who did not receive any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.</description>
        </group>
        <group group_id="B3">
          <title>PN Use (Project B)</title>
          <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who received any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.&#xD;
Parenteral nutrition: Parenteral nutrition is the administration of an intravenous solution containing amino acids (with or without lipids) to provide nutritional support.</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="62145"/>
            <count group_id="B2" value="8146"/>
            <count group_id="B3" value="8146"/>
            <count group_id="B4" value="78437"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="62145"/>
                    <count group_id="B2" value="8146"/>
                    <count group_id="B3" value="8146"/>
                    <count group_id="B4" value="78437"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="62145"/>
                    <measurement group_id="B2" value="8146"/>
                    <measurement group_id="B3" value="8146"/>
                    <measurement group_id="B4" value="78437"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="62145"/>
                    <count group_id="B2" value="8146"/>
                    <count group_id="B3" value="8146"/>
                    <count group_id="B4" value="78437"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="27965"/>
                    <measurement group_id="B2" value="3664"/>
                    <measurement group_id="B3" value="3733"/>
                    <measurement group_id="B4" value="35362"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="34180"/>
                    <measurement group_id="B2" value="4482"/>
                    <measurement group_id="B3" value="4413"/>
                    <measurement group_id="B4" value="43075"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                    <count group_id="B4" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Use of Parenteral Nutrition (Project A)</title>
        <description>Any use of parenteral nutrition in the first seven days of postnatal life (assessed using daily data extracted from the National Neonatal Research Database as described in the project protocol)&#xD;
This outcome formed part of Project A ONLY, and in keeping with the research protocol is only analysed and reported for the babies in this research arm.</description>
        <time_frame>From birth until discharge home, assessed up to 1 year</time_frame>
        <population>This outcome formed part of Project A ONLY, and in keeping with the research protocol has only been collected, analysed and reported for the neonates in this research arm. In Project B 'use of parenteral nutrition' formed a key background characteristic, and so this outcome is not reported for the two arms of Project B.</population>
        <group_list>
          <group group_id="O1">
            <title>Neonatal Population (Project A)</title>
            <description>Neonates born between 1st January 2012 and 31st December 2017 and admitted to a neonatal unit in England, Scotland and Wales).</description>
          </group>
        </group_list>
        <measure>
          <title>Use of Parenteral Nutrition (Project A)</title>
          <description>Any use of parenteral nutrition in the first seven days of postnatal life (assessed using daily data extracted from the National Neonatal Research Database as described in the project protocol)&#xD;
This outcome formed part of Project A ONLY, and in keeping with the research protocol is only analysed and reported for the babies in this research arm.</description>
          <population>This outcome formed part of Project A ONLY, and in keeping with the research protocol has only been collected, analysed and reported for the neonates in this research arm. In Project B 'use of parenteral nutrition' formed a key background characteristic, and so this outcome is not reported for the two arms of Project B.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="347959"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="62145"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Survival to Discharge Home (Project B)</title>
        <description>Defined as recorded alive at final neonatal unit discharge&#xD;
This outcome formed part of Project B ONLY, and in keeping with the research protocol is only analysed and reported for the babies in this research arm.</description>
        <time_frame>From birth until discharge home, assessed up to 1 year</time_frame>
        <population>Analysis of propensity score matched cohorts as per the pre-specified analysis plan This outcome formed part of Project B ONLY, and in keeping with the research protocol is only analysed and reported for the babies in this research arm.</population>
        <group_list>
          <group group_id="O1">
            <title>No PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who did not receive any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.</description>
          </group>
          <group group_id="O2">
            <title>PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who received any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.&#xD;
Parenteral nutrition: Parenteral nutrition is the administration of an intravenous solution containing amino acids (with or without lipids) to provide nutritional support.</description>
          </group>
        </group_list>
        <measure>
          <title>Survival to Discharge Home (Project B)</title>
          <description>Defined as recorded alive at final neonatal unit discharge&#xD;
This outcome formed part of Project B ONLY, and in keeping with the research protocol is only analysed and reported for the babies in this research arm.</description>
          <population>Analysis of propensity score matched cohorts as per the pre-specified analysis plan This outcome formed part of Project B ONLY, and in keeping with the research protocol is only analysed and reported for the babies in this research arm.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8146"/>
                <count group_id="O2" value="8146"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7987"/>
                    <measurement group_id="O2" value="8057"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Late Onset Sepsis (Project B)</title>
        <description>Number of participants with diagnosed Later Onset Sepsis: defined in line with the Royal College of Paediatrics and Child Health National Neonatal Audit Programme (NNAP) definition &quot;pure growth of a pathogen from blood&quot; or &quot;pure growth of a skin commensal&quot; or a &quot;mixed growth&quot; after the first 72 hours of life</description>
        <time_frame>72 hours of postnatal life to discharge home, assessed up to 1 year</time_frame>
        <population>Analysis of propensity score matched cohorts as per the pre-specified analysis plan</population>
        <group_list>
          <group group_id="O1">
            <title>No PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who did not receive any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.</description>
          </group>
          <group group_id="O2">
            <title>PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who received any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.&#xD;
Parenteral nutrition: Parenteral nutrition is the administration of an intravenous solution containing amino acids (with or without lipids) to provide nutritional support.</description>
          </group>
        </group_list>
        <measure>
          <title>Late Onset Sepsis (Project B)</title>
          <description>Number of participants with diagnosed Later Onset Sepsis: defined in line with the Royal College of Paediatrics and Child Health National Neonatal Audit Programme (NNAP) definition &quot;pure growth of a pathogen from blood&quot; or &quot;pure growth of a skin commensal&quot; or a &quot;mixed growth&quot; after the first 72 hours of life</description>
          <population>Analysis of propensity score matched cohorts as per the pre-specified analysis plan</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8146"/>
                <count group_id="O2" value="8146"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="59"/>
                    <measurement group_id="O2" value="179"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Necrotising Enterocolitis (Project B)</title>
        <description>Number of participants with diagnosed necrotising enterocolitis: defined using the NNAP definition: NEC may be diagnosed at surgery, post-mortem or on the basis of the following clinical and radiographic signs:&#xD;
At least one clinical feature from:&#xD;
(i) Bilious gastric aspirate or emesis (ii) Abdominal distension (iii) Occult or gross blood in stool (no fissure)&#xD;
And at least one radiographic feature from:&#xD;
(i) Pneumatosis (ii) Hepato-biliary gas (iii) Pneumoperitoneum</description>
        <time_frame>From birth until discharge home, assessed up to 1 year</time_frame>
        <population>Analysis of propensity score matched cohorts as per the pre-specified analysis plan</population>
        <group_list>
          <group group_id="O1">
            <title>No PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who did not receive any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.</description>
          </group>
          <group group_id="O2">
            <title>PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who received any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.&#xD;
Parenteral nutrition: Parenteral nutrition is the administration of an intravenous solution containing amino acids (with or without lipids) to provide nutritional support.</description>
          </group>
        </group_list>
        <measure>
          <title>Necrotising Enterocolitis (Project B)</title>
          <description>Number of participants with diagnosed necrotising enterocolitis: defined using the NNAP definition: NEC may be diagnosed at surgery, post-mortem or on the basis of the following clinical and radiographic signs:&#xD;
At least one clinical feature from:&#xD;
(i) Bilious gastric aspirate or emesis (ii) Abdominal distension (iii) Occult or gross blood in stool (no fissure)&#xD;
And at least one radiographic feature from:&#xD;
(i) Pneumatosis (ii) Hepato-biliary gas (iii) Pneumoperitoneum</description>
          <population>Analysis of propensity score matched cohorts as per the pre-specified analysis plan</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8146"/>
                <count group_id="O2" value="8146"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="285"/>
                    <measurement group_id="O2" value="660"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Brain Injury on Imaging (Project B)</title>
        <description>Number of participants with diagnosed brain injury on imaging: defined as documented diagnosis of intraventricular haemorrhage (grade 3-4) or cystic periventricular leucomalacia</description>
        <time_frame>From birth until discharge home, assessed up to 1 year</time_frame>
        <population>Analysis of propensity score matched cohorts as per the pre-specified analysis plan</population>
        <group_list>
          <group group_id="O1">
            <title>No PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who did not receive any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.</description>
          </group>
          <group group_id="O2">
            <title>PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who received any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.&#xD;
Parenteral nutrition: Parenteral nutrition is the administration of an intravenous solution containing amino acids (with or without lipids) to provide nutritional support.</description>
          </group>
        </group_list>
        <measure>
          <title>Brain Injury on Imaging (Project B)</title>
          <description>Number of participants with diagnosed brain injury on imaging: defined as documented diagnosis of intraventricular haemorrhage (grade 3-4) or cystic periventricular leucomalacia</description>
          <population>Analysis of propensity score matched cohorts as per the pre-specified analysis plan</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8146"/>
                <count group_id="O2" value="8146"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="48"/>
                    <measurement group_id="O2" value="73"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Retinopathy of Prematurity (Project B)</title>
        <description>Number of participants with diagnosed retinopathy of prematurity: defined as a record of any retinopathy of prematurity on routine screening in the National Neonatal Dataset &quot;retinopathy of prematurity ad-hoc form&quot;</description>
        <time_frame>From birth until discharge home, assessed up to 1 year</time_frame>
        <population>Analysis of propensity score matched cohorts as per the pre-specified analysis plan</population>
        <group_list>
          <group group_id="O1">
            <title>No PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who did not receive any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.</description>
          </group>
          <group group_id="O2">
            <title>PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who received any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.&#xD;
Parenteral nutrition: Parenteral nutrition is the administration of an intravenous solution containing amino acids (with or without lipids) to provide nutritional support.</description>
          </group>
        </group_list>
        <measure>
          <title>Retinopathy of Prematurity (Project B)</title>
          <description>Number of participants with diagnosed retinopathy of prematurity: defined as a record of any retinopathy of prematurity on routine screening in the National Neonatal Dataset &quot;retinopathy of prematurity ad-hoc form&quot;</description>
          <population>Analysis of propensity score matched cohorts as per the pre-specified analysis plan</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8146"/>
                <count group_id="O2" value="8146"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="272"/>
                    <measurement group_id="O2" value="297"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Bronchopulmonary Dysplasia (Project B)</title>
        <description>Number of participants with diagnosed bronchopulmonary dysplasia: defined using the NNAP definition of significant bronchopulmonary dysplasia: Receiving respiratory support at 36 weeks corrected gestational age.</description>
        <time_frame>From birth until discharge home, assessed up to 1 year</time_frame>
        <population>Analysis of propensity score matched cohorts as per the pre-specified analysis plan</population>
        <group_list>
          <group group_id="O1">
            <title>No PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who did not receive any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.</description>
          </group>
          <group group_id="O2">
            <title>PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who received any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.&#xD;
Parenteral nutrition: Parenteral nutrition is the administration of an intravenous solution containing amino acids (with or without lipids) to provide nutritional support.</description>
          </group>
        </group_list>
        <measure>
          <title>Bronchopulmonary Dysplasia (Project B)</title>
          <description>Number of participants with diagnosed bronchopulmonary dysplasia: defined using the NNAP definition of significant bronchopulmonary dysplasia: Receiving respiratory support at 36 weeks corrected gestational age.</description>
          <population>Analysis of propensity score matched cohorts as per the pre-specified analysis plan</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8146"/>
                <count group_id="O2" value="8146"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="302"/>
                    <measurement group_id="O2" value="619"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Need for Surgical Procedures (Project B)</title>
        <description>Defined as any record of surgical procedure during the neonatal admission</description>
        <time_frame>From birth until discharge home, assessed up to 1 year</time_frame>
        <population>Analysis of propensity score matched cohorts as per the pre-specified analysis plan</population>
        <group_list>
          <group group_id="O1">
            <title>No PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who did not receive any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.</description>
          </group>
          <group group_id="O2">
            <title>PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who received any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.&#xD;
Parenteral nutrition: Parenteral nutrition is the administration of an intravenous solution containing amino acids (with or without lipids) to provide nutritional support.</description>
          </group>
        </group_list>
        <measure>
          <title>Need for Surgical Procedures (Project B)</title>
          <description>Defined as any record of surgical procedure during the neonatal admission</description>
          <population>Analysis of propensity score matched cohorts as per the pre-specified analysis plan</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8146"/>
                <count group_id="O2" value="8146"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="69"/>
                    <measurement group_id="O2" value="147"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Seizures (Project B)</title>
        <description>Number of participants diagnosed as having a seizure: defined as any recorded diagnosis of seizures or seizure disorder</description>
        <time_frame>From birth until discharge home, assessed up to 1 year</time_frame>
        <population>Analysis of propensity score matched cohorts as per the pre-specified analysis plan</population>
        <group_list>
          <group group_id="O1">
            <title>No PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who did not receive any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.</description>
          </group>
          <group group_id="O2">
            <title>PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who received any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.&#xD;
Parenteral nutrition: Parenteral nutrition is the administration of an intravenous solution containing amino acids (with or without lipids) to provide nutritional support.</description>
          </group>
        </group_list>
        <measure>
          <title>Seizures (Project B)</title>
          <description>Number of participants diagnosed as having a seizure: defined as any recorded diagnosis of seizures or seizure disorder</description>
          <population>Analysis of propensity score matched cohorts as per the pre-specified analysis plan</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8146"/>
                <count group_id="O2" value="8146"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="81"/>
                    <measurement group_id="O2" value="114"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Weight (Project B)</title>
        <description>Weight z-score at discharge home. Weights at discharge home were converted to a z-score: a z-score of 0 represents the population mean, while score higher scores indicate a greater weight.</description>
        <time_frame>From birth until discharge home, assessed up to 1 year</time_frame>
        <population>Analysis of propensity score matched cohorts as per the pre-specified analysis plan</population>
        <group_list>
          <group group_id="O1">
            <title>No PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who did not receive any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.</description>
          </group>
          <group group_id="O2">
            <title>PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who received any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.&#xD;
Parenteral nutrition: Parenteral nutrition is the administration of an intravenous solution containing amino acids (with or without lipids) to provide nutritional support.</description>
          </group>
        </group_list>
        <measure>
          <title>Weight (Project B)</title>
          <description>Weight z-score at discharge home. Weights at discharge home were converted to a z-score: a z-score of 0 represents the population mean, while score higher scores indicate a greater weight.</description>
          <population>Analysis of propensity score matched cohorts as per the pre-specified analysis plan</population>
          <units>Z-score</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8146"/>
                <count group_id="O2" value="8146"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.073" spread="0.98"/>
                    <measurement group_id="O2" value="-0.024" spread="0.96"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Head Circumference (Project B)</title>
        <description>Head circumference in centimetres at discharge; head circumference velocity (measured as increase in head circumference in centimetres/day) from birth until discharge</description>
        <time_frame>From birth until discharge home, assessed up to 1 year</time_frame>
        <population>Initial analyses revealed considerable amounts of missing data (&gt;90% missing): as the data represented under 10% of the true population it would not be possible to meaningfully summarise this data and it was highly unreliable (due to the high risk of systematic bias in this unrepresentative sample). For this reason full data relating to this outcome was not extracted from the National Neonatal Research Database as it was not in any way informative, and any further analysis was unjustified.</population>
        <group_list>
          <group group_id="O1">
            <title>No PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who did not receive any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.</description>
          </group>
          <group group_id="O2">
            <title>PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who received any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.&#xD;
Parenteral nutrition: Parenteral nutrition is the administration of an intravenous solution containing amino acids (with or without lipids) to provide nutritional support.</description>
          </group>
        </group_list>
        <measure>
          <title>Head Circumference (Project B)</title>
          <description>Head circumference in centimetres at discharge; head circumference velocity (measured as increase in head circumference in centimetres/day) from birth until discharge</description>
          <population>Initial analyses revealed considerable amounts of missing data (&gt;90% missing): as the data represented under 10% of the true population it would not be possible to meaningfully summarise this data and it was highly unreliable (due to the high risk of systematic bias in this unrepresentative sample). For this reason full data relating to this outcome was not extracted from the National Neonatal Research Database as it was not in any way informative, and any further analysis was unjustified.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Blindness (Project B)</title>
        <description>Defined as an answer of Yes to the question &quot;Does this child have a visual impairment?&quot; on the NNAP follow up form</description>
        <time_frame>From birth until two years of age</time_frame>
        <population>Initial analyses revealed considerable amounts of missing data (&gt;90% missing): as the data represented under 10% of the true population it would not be possible to meaningfully summarise this data and it was highly unreliable (due to the high risk of systematic bias in this unrepresentative sample). For this reason full data relating to this outcome was not extracted from the National Neonatal Research Database as it was not in any way informative, and any further analysis was unjustified.</population>
        <group_list>
          <group group_id="O1">
            <title>No PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who did not receive any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.</description>
          </group>
          <group group_id="O2">
            <title>PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who received any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.&#xD;
Parenteral nutrition: Parenteral nutrition is the administration of an intravenous solution containing amino acids (with or without lipids) to provide nutritional support.</description>
          </group>
        </group_list>
        <measure>
          <title>Blindness (Project B)</title>
          <description>Defined as an answer of Yes to the question &quot;Does this child have a visual impairment?&quot; on the NNAP follow up form</description>
          <population>Initial analyses revealed considerable amounts of missing data (&gt;90% missing): as the data represented under 10% of the true population it would not be possible to meaningfully summarise this data and it was highly unreliable (due to the high risk of systematic bias in this unrepresentative sample). For this reason full data relating to this outcome was not extracted from the National Neonatal Research Database as it was not in any way informative, and any further analysis was unjustified.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Deafness (Project B)</title>
        <description>Defined as an answer of Yes to the question &quot;Does this child have a hearing impairment?&quot; on the NNAP follow up form</description>
        <time_frame>From birth until two years of age</time_frame>
        <population>Initial analyses revealed considerable amounts of missing data (&gt;90% missing): as the data represented under 10% of the true population it would not be possible to meaningfully summarise this data and it was highly unreliable (due to the high risk of systematic bias in this unrepresentative sample). For this reason full data relating to this outcome was not extracted from the National Neonatal Research Database as it was not in any way informative, and any further analysis was unjustified.</population>
        <group_list>
          <group group_id="O1">
            <title>No PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who did not receive any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.</description>
          </group>
          <group group_id="O2">
            <title>PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who received any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.&#xD;
Parenteral nutrition: Parenteral nutrition is the administration of an intravenous solution containing amino acids (with or without lipids) to provide nutritional support.</description>
          </group>
        </group_list>
        <measure>
          <title>Deafness (Project B)</title>
          <description>Defined as an answer of Yes to the question &quot;Does this child have a hearing impairment?&quot; on the NNAP follow up form</description>
          <population>Initial analyses revealed considerable amounts of missing data (&gt;90% missing): as the data represented under 10% of the true population it would not be possible to meaningfully summarise this data and it was highly unreliable (due to the high risk of systematic bias in this unrepresentative sample). For this reason full data relating to this outcome was not extracted from the National Neonatal Research Database as it was not in any way informative, and any further analysis was unjustified.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Ability to Walk (Project B)</title>
        <description>Defined as an answer of Yes to the question &quot;Is this child unable to walk without assistance?&quot; on the NNAP follow up form</description>
        <time_frame>From birth until two years of age</time_frame>
        <population>Initial analyses revealed considerable amounts of missing data (&gt;90% missing): as the data represented under 10% of the true population it would not be possible to meaningfully summarise this data and it was highly unreliable (due to the high risk of systematic bias in this unrepresentative sample). For this reason full data relating to this outcome was not extracted from the National Neonatal Research Database as it was not in any way informative, and any further analysis was unjustified.</population>
        <group_list>
          <group group_id="O1">
            <title>No PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who did not receive any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.</description>
          </group>
          <group group_id="O2">
            <title>PN Use (Project B)</title>
            <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who received any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.&#xD;
Parenteral nutrition: Parenteral nutrition is the administration of an intravenous solution containing amino acids (with or without lipids) to provide nutritional support.</description>
          </group>
        </group_list>
        <measure>
          <title>Ability to Walk (Project B)</title>
          <description>Defined as an answer of Yes to the question &quot;Is this child unable to walk without assistance?&quot; on the NNAP follow up form</description>
          <population>Initial analyses revealed considerable amounts of missing data (&gt;90% missing): as the data represented under 10% of the true population it would not be possible to meaningfully summarise this data and it was highly unreliable (due to the high risk of systematic bias in this unrepresentative sample). For this reason full data relating to this outcome was not extracted from the National Neonatal Research Database as it was not in any way informative, and any further analysis was unjustified.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Project A: Adverse event data was not collected in this epidemiological study Project B: Adverse event data collected from birth until discharge home from hospital, assessed up to 1 year of age</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Neonatal Population (Project A)</title>
          <description>Neonates born between 1st January 2012 and 31st December 2017 and admitted to a neonatal unit in England and Wales).</description>
        </group>
        <group group_id="E2">
          <title>No PN Use (Project B)</title>
          <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who did not receive any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.</description>
        </group>
        <group group_id="E3">
          <title>PN Use (Project B)</title>
          <description>All neonates born between 30 and 33 weeks postmenstrual age in England and Wales and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who received any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.&#xD;
Parenteral nutrition: Parenteral nutrition is the administration of an intravenous solution containing amino acids (with or without lipids) to provide nutritional support.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="5725" subjects_at_risk="62145"/>
                <counts group_id="E2" subjects_affected="163" subjects_at_risk="8146"/>
                <counts group_id="E3" subjects_affected="90" subjects_at_risk="8146"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="62145"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8146"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8146"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="62145"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8146"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8146"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>This study was a retrospective, observational study using data held within the National Neonatal Research Database.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr Chris Gale</name_or_title>
      <organization>Imperial College London</organization>
      <phone>+44 (0)20 3315 3519</phone>
      <email>christopher.gale@imperial.ac.uk</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03767634
org study id: 18IC4724
nct id: NCT03767634
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
BACKGROUND

      An essential part of neonatal care is providing nutrition to ensure that babies grow and
      develop. Providing this can be difficult in premature babies because their intestines are
      underdeveloped. They often have difficulty digesting milk so feeds are introduced gradually.
      To help babies grow and develop during this period, additional nutrition may be provided as a
      fluid into a vein; this is called "parenteral nutrition" (PN). Unfortunately, PN increases
      the risk of serious complications like bloodstream infection (also known as "sepsis"). For
      babies who are moderately premature there is little evidence to guide decision making about
      which babies will benefit from PN. This group of babies have more reserves of fat and are
      less dependent on PN, but are still at risk of sepsis. As a consequence, some doctors use PN
      and others do not.

      AIMS

      Firstly, to describe which babies are given PN during the first postnatal week in neonatal
      units in England, Scotland and Wales.

      Secondly, to determine whether in babies born 7-10 weeks preterm (moderately premature),
      providing PN in the first week after birth, compared to not to providing PN, improves
      survival to discharge from the neonatal unit.

      Finally, to evaluate if the early use of PN in moderately preterm babies affects other
      important outcomes in the neonatal core outcomes set.

      IMPORTANCE

      This work will describe the extent of PN use in England, Scotland and Wales. This is
      currently unknown. This project will improve understanding of the balance of benefits and
      harms of PN use in premature babies and will help doctors and parents make informed treatment
      choices.

      METHODS

      The investigators will use the National Neonatal Research Database (NNRD) to study all babies
      born in England, Scotland and Wales; they will identify which babies were given PN during the
      first week, and which were not. The investigators will use the NNRD to identify babies born
      7-10 weeks prematurely and compare outcomes in babies that were given and not given PN in the
      first week after birth. The investigators will use statistical techniques to identify two
      sets of babies in the NNRD who are very similar (in terms of how prematurely they were born,
      their birth weight, and so on), the only difference being whether they were given PN or not.
      As the two groups will be similar any difference in their outcomes (such as survival) is
      likely to be due to whether or not they received PN.
Premature birth abruptly ends the transplacental transmission of nutrients that allows normal
      foetal growth and development. Providing adequate nutrition is essential to allow premature
      babies to continue to grow and mature. Very preterm infants often have difficulty tolerating
      adequate volumes of milk feeds shortly after birth and so are given supplemental parenteral
      nutrition (PN). Preterm babies are among the highest PN users of all NHS patients. It has
      been estimated that PN is received by around 70% of neonatal unit admissions but it is not
      known exactly which babies receive PN. In addition, how PN affects outcomes has never been
      tested in a large scale, randomized, placebo controlled neonatal trial.

      It is known that PN carries well established risks, of which the most serious and the most
      common is sepsis with estimates of risk ratios varying from 2.2 to 14.6. In addition there is
      a growing body of evidence that use of PN within the first seven days of admission to an
      intensive care unit is associated with worse outcomes in critically unwell adults and
      children. A subgroup analysis of the paediatric intensive care unit population focusing on
      neonates showed an increase in infections with early PN use. This suggests that uncertainty
      exists over the benefit of giving neonates PN in the early postnatal period. It is generally
      accepted that PN is beneficial to extremely preterm neonates, but in moderately preterm
      neonates the effect that PN use has on neonatal survival has never been conclusively
      demonstrated.

      The uncertainty over how PN use affects neonatal outcomes is reflected by the wide variety in
      how PN is used in different units with large variation in use, timing and composition of PN.
      This is, in part, due to the lack of clear evidence of how PN affects neonatal outcomes like
      growth and survival. Neonates are also vulnerable to unanticipated treatment effects which
      can occur in different organ systems and so it is important to show that PN is not
      detrimental to important neonatal outcomes.

      The postmenstrual age at which the nutritional benefits of PN outweigh the risks in
      moderately preterm babies (30-33 weeks postmenstrual age) is unknown. It is therefore
      unsurprising that their nutritional management is very variable. In moderately preterm
      neonates in 2012 and 2013 across England, Scotland and Wales PN was given to 45% of neonates,
      suggesting clinician equipoise around the balance of benefit to risk. Identifying whether
      moderately preterm neonates benefit from PN would have important implications for practice in
      the UK. This work will provide information to guide practice and inform future research.

      In summary, PN is widely used in neonates but it is not known exactly how it is used in the
      UK. It is known to have risks and benefits but there is insufficient evidence to guide
      practice in moderately preterm neonates.

      Study objectives:

        -  To describe the use of PN in neonatal units across England, Scotland and Wales.

        -  To identify if use of PN in the first seven postnatal days affects survival in neonates
           born between 30 and 33 weeks postmenstrual age.

        -  To explore how PN use in the first seven postnatal days affects other important neonatal
           outcomes in neonates born between 30 and 33 weeks postmenstrual age.

      Study design:

      Project A: an epidemiological survey of practice using the National Neonatal Research
      Database (NNRD).

      Project B: a retrospective cohort study of matched groups of babies using data held in the
      NNRD.
observational model: Cohort
time perspective: Retrospective
measure: Use of Parenteral Nutrition (Project A)
time frame: From birth until discharge home, assessed up to 1 year
description: Any use of parenteral nutrition in the first seven days of postnatal life (assessed using daily data extracted from the National Neonatal Research Database as described in the project protocol)
This outcome formed part of Project A ONLY, and in keeping with the research protocol is only analysed and reported for the babies in this research arm.
measure: Survival to Discharge Home (Project B)
time frame: From birth until discharge home, assessed up to 1 year
description: Defined as recorded alive at final neonatal unit discharge
This outcome formed part of Project B ONLY, and in keeping with the research protocol is only analysed and reported for the babies in this research arm.
measure: Late Onset Sepsis (Project B)
time frame: 72 hours of postnatal life to discharge home, assessed up to 1 year
description: Number of participants with diagnosed Later Onset Sepsis: defined in line with the Royal College of Paediatrics and Child Health National Neonatal Audit Programme (NNAP) definition "pure growth of a pathogen from blood" or "pure growth of a skin commensal" or a "mixed growth" after the first 72 hours of life
measure: Necrotising Enterocolitis (Project B)
time frame: From birth until discharge home, assessed up to 1 year
description: Number of participants with diagnosed necrotising enterocolitis: defined using the NNAP definition: NEC may be diagnosed at surgery, post-mortem or on the basis of the following clinical and radiographic signs:
At least one clinical feature from:
(i) Bilious gastric aspirate or emesis (ii) Abdominal distension (iii) Occult or gross blood in stool (no fissure)
And at least one radiographic feature from:
(i) Pneumatosis (ii) Hepato-biliary gas (iii) Pneumoperitoneum
measure: Brain Injury on Imaging (Project B)
time frame: From birth until discharge home, assessed up to 1 year
description: Number of participants with diagnosed brain injury on imaging: defined as documented diagnosis of intraventricular haemorrhage (grade 3-4) or cystic periventricular leucomalacia
measure: Retinopathy of Prematurity (Project B)
time frame: From birth until discharge home, assessed up to 1 year
description: Number of participants with diagnosed retinopathy of prematurity: defined as a record of any retinopathy of prematurity on routine screening in the National Neonatal Dataset "retinopathy of prematurity ad-hoc form"
measure: Bronchopulmonary Dysplasia (Project B)
time frame: From birth until discharge home, assessed up to 1 year
description: Number of participants with diagnosed bronchopulmonary dysplasia: defined using the NNAP definition of significant bronchopulmonary dysplasia: Receiving respiratory support at 36 weeks corrected gestational age.
measure: Need for Surgical Procedures (Project B)
time frame: From birth until discharge home, assessed up to 1 year
description: Defined as any record of surgical procedure during the neonatal admission
measure: Seizures (Project B)
time frame: From birth until discharge home, assessed up to 1 year
description: Number of participants diagnosed as having a seizure: defined as any recorded diagnosis of seizures or seizure disorder
measure: Weight (Project B)
time frame: From birth until discharge home, assessed up to 1 year
description: Weight z-score at discharge home. Weights at discharge home were converted to a z-score: a z-score of 0 represents the population mean, while score higher scores indicate a greater weight.
measure: Head Circumference (Project B)
time frame: From birth until discharge home, assessed up to 1 year
description: Head circumference in centimetres at discharge; head circumference velocity (measured as increase in head circumference in centimetres/day) from birth until discharge
measure: Blindness (Project B)
time frame: From birth until two years of age
description: Defined as an answer of Yes to the question "Does this child have a visual impairment?" on the NNAP follow up form
measure: Deafness (Project B)
time frame: From birth until two years of age
description: Defined as an answer of Yes to the question "Does this child have a hearing impairment?" on the NNAP follow up form
measure: Ability to Walk (Project B)
time frame: From birth until two years of age
description: Defined as an answer of Yes to the question "Is this child unable to walk without assistance?" on the NNAP follow up form
arm group label: Neonatal population (Project A)
description: Neonates born between 1st January 2012 and 31st December 2017 and admitted to a neonatal unit in England, Scotland and Wales).
arm group label: No PN use (Project B)
description: All neonates born between 30 and 33 weeks postmenstrual age in England, Wales and Scotland and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who did not receive any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.
arm group label: PN use (Project B)
description: All neonates born between 30 and 33 weeks postmenstrual age in England, Wales and Scotland and admitted to a NHS neonatal unit between 1st January 2012 and 31st December 2017 who received any parenteral nutrition (for any duration, by any intravenous route) in the first seven postnatal days.
intervention type: Other
intervention name: Parenteral nutrition
description: Parenteral nutrition is the administration of an intravenous solution containing amino acids (with or without lipids) to provide nutritional support.
arm group label: PN use (Project B)
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: 2 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Chris RK Gale, PhD
role: Principal Investigator
affiliation: Imperial College London
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Perinatal Death
sharing ipd: Undecided
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: This study was a retrospective, observational study using data held within the National Neonatal Research Database.
point of contact: 