<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/NCT02191683</url>
  </required_header>
  <id_info>
    <org_study_id>1309-00003B</org_study_id>
    <secondary_id>Strategiske Forskningsråd</secondary_id>
    <nct_id>NCT02191683</nct_id>
  </id_info>
  <brief_title>Foetal Exposure and Epidemiological Transition: Role of Anaemia in Early Life for Non-communicable Diseases Later</brief_title>
  <acronym>FOETALforNCD</acronym>
  <official_title>Foetal Exposure and Epidemiological Transition: the Role of Anaemia in Early Life for Non-communicable Diseases in Later Life</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Copenhagen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Copenhagen University Hospital, Denmark</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Aarhus University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Lund University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute for Medical Research, Tanzania</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Department of Clinical Pathology Naestved Hospital Denmark</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Copenhagen</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Study Hypotheses:&#xD;
&#xD;
        1. Anaemia, which is frequent before conception as well as during early pregnancy, affects&#xD;
           metabolism and foetal growth trajectories, influencing the risk of NCDs in the&#xD;
           offspring.&#xD;
&#xD;
        2. Anaemia from conception till end of 2nd trimester is most detrimental for foetal and&#xD;
           newborns' health, compared to 3rd trimester anaemia.&#xD;
&#xD;
        3. Anaemia from conception till end of 2nd trimester affects foetal and newborns health&#xD;
           through poor placental development reflected in increased villous branching and changed&#xD;
           umbilical and uterine blood flow.&#xD;
&#xD;
        4. Anaemia in early pregnancy disrupts the vascular endothelial growth factor A&#xD;
           (VEGF-A)/placental growth factor (PlGF) balance and the insulin-like growth factor (IGF)&#xD;
           axis resulting in poor placental development, and poor health of newborns. This may be&#xD;
           reflected in specific methylation patterns.&#xD;
&#xD;
        5. Anaemia's impact on the risk for NCDs in the offspring may be mediated via epigenetic&#xD;
           mechanisms, including changes in DNA methylation patterns.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Specific objectives are:&#xD;
&#xD;
        1. Characterize the health of women aged 18-40 years before conception and during&#xD;
           pregnancy, focusing on prevalence of anaemia, infections, nutritional status, and&#xD;
           Non-Communicable Diseases (NCDs).&#xD;
&#xD;
        2. Describe how 1st and 2nd trimester anaemia compared to 3rd trimester anaemia alters&#xD;
           foetal growth and newborns' body composition.&#xD;
&#xD;
        3. Evaluate how 1st and 2nd trimester anaemia compared to 3rd trimester anaemia affects&#xD;
           villous branching in the placenta, as well as uterine and umbilical artery blood flow.&#xD;
&#xD;
        4. Characterize how 1st, 2nd and 3rd trimester anaemia differentially changes the vascular&#xD;
           endothelial growth factor A (VEGF-A)/placental growth factor (PlGF) balance and the&#xD;
           insulin-like growth factor axis.&#xD;
&#xD;
        5. Determine which markers for foetal programming such as methylation of regulatory genes&#xD;
           related to metabolism and haematopoiesis may be discovered early after exposure to&#xD;
           anaemia in1st and 2nd trimester compared to 3rd trimester anaemia.&#xD;
&#xD;
      Outcome parameter for the pre-pregnancy study (i.): 1) Prevalence and severity of anaemia&#xD;
      among non-pregnant Tanzanian women at fertile age and their nutritional status. 2) Incidence&#xD;
      of conception among such women.&#xD;
&#xD;
      Outcome parameter for the pregnancy study (ii.): 1) Foetal growth rate in 2nd and 3rd&#xD;
      trimester in offspring of anaemic mothers vs Foetal growth rate in non-anaemic mothers'&#xD;
      offspring, 2) Comparison of anaemic mothers' vs non-anaemic mothers' newborn's body&#xD;
      composition, placental villous branching, umbilical and uterine blood flow, VEGF-A/PlGF&#xD;
      levels, and insulin-like growth factor axis.&#xD;
&#xD;
      For all analyses main exposure variable will be anaemia (Hb&lt;5mmol/L) in 1st, 2nd and/or3rd&#xD;
      trimester of pregnancy. Confounding exposure variables will be chronic health conditions&#xD;
      (e.g. HIV), all temporary conditions mentioned above (e.g. malaria) as well as socioeconomic&#xD;
      status and paternal characteristics. Regression modelling using both multiple linear and&#xD;
      logistic regressions as well as modelling for repeated measures will be used for statistical&#xD;
      analyses. For genetic and epigenetic changes, findings in the subgroup of 180 other/newborns,&#xD;
      remaining significant after correction for multiple comparisons, will be validated in the&#xD;
      remaining cohort. This will enable us within one study to replicate initial findings in one&#xD;
      representative and distinct subgroup in another larger comparable study group from an overall&#xD;
      homogenous study. Indeed, findings surviving both corrections for multiple testing in the&#xD;
      initial hypothesis generating array approaches, as well as being replicated in the remaining&#xD;
      study group with single target validation techniques, are highly likely to be biological&#xD;
      important. Possible findings from the candidate gene approach will be corrected for multiple&#xD;
      testing and the significant results will be compared with previous findings of the same genes&#xD;
      from studies in muscle and adipose tissue conducted by Diabetes and Metabolism, Copenhagen&#xD;
      University Hospital.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 2014</start_date>
  <completion_date type="Actual">October 2018</completion_date>
  <primary_completion_date type="Actual">December 2017</primary_completion_date>
  <study_type>Observational [Patient Registry]</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Other</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <target_duration>21 Months</target_duration>
  <primary_outcome>
    <measure>Outcome parameter for the pre-pregnancy study (i.):</measure>
    <time_frame>12 months from start</time_frame>
    <description>Prevalence and severity of anaemia among non-pregnant Tanzanian women at fertile age and their nutritional status.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Outcome parameter for the pregnancy study (ii.):</measure>
    <time_frame>31 months</time_frame>
    <description>Anemia's effect on foetal growth rate in 2nd and 3rd trimester measured as a) discrepancy in estimated and predicted gestational age (GA) between inclusion and antenatal visit at GA 20 weeks &amp; 30, b) change in z-score for foetal weight/body weight and c) gain in g/week26 at GA of 26, 32 and 37 and delivery. Newborn's body composition, placental villous branching, umbilical and uterine blood flow, VEGF-A/PlGF levels, and GFaxis. For all analyses main exposure variable are anaemia in 1st, 2nd and/or3rd trimester of pregnancy. Confounding exposure variables are chronic health conditions, temporary conditions mentioned above (e.g. malaria) and socioeconomic status and paternal characteristics. Regression modelling using multiple linear and logistic regressions and modelling for repeated measures are used for statistical analyses. Genetic and epigenetic significant changes in subgroup of 180 mother/newborns, after correction for multiple comparisons, will be validated in remaining cohort.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of conception among non-pregnant Tanzanian women.</measure>
    <time_frame>12 months</time_frame>
    <description>Number of women screened, with and without anaemia, respectively, who actually become pregnant within the observation period</description>
  </primary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">1748</enrollment>
  <condition>Anemia and Pregnancy</condition>
  <condition>Metabolism and Foetal Growth</condition>
  <condition>Epigenetics</condition>
  <arm_group>
    <arm_group_label>Health of women before conception</arm_group_label>
    <description>Tanzanian women aged 18-40 years focusing on prevalence of anaemia, infections, nutritional status, and NCDs.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>480 women during pregnancy</arm_group_label>
    <description>Describe how 1st and 2nd trimester anaemia compared to 3rd trimester anaemia alters foetal growth and newborns' body composition.&#xD;
Evaluate anaemia's effect on villous branching in placenta, and uterine and umbilical artery blood flow.&#xD;
Evaluate effect on vascular endothelial growth factor A/placental growth factor balance and insulin-like growth factor axis.&#xD;
Determine which markers for foetal programming such as methylation of regulatory genes related to metabolism and haematopoiesis may be discovered early after exposure to anaemia.</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Periperal vein blood, umbilical cord blood, placentas&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Amendment October 2014: replacement of two-phase case-control study by two sub-projects,&#xD;
        running in parallel, and following two distinct groups of women, 1) a cohort of 1500&#xD;
        non-pregnant women, disregarding Hb level, of whom 270 followed throughout pregnancy&#xD;
        disregarding Hb level and gestational age at first contact, and 2) a case control study of&#xD;
        480 pregnant women followed from 1st trimester with a 160:160:160 ratio of women with&#xD;
        Hb≤8g/dL: 8.1-10.9g/dL: ≥11g/dL.&#xD;
&#xD;
        The Danish Council for Strategic Research notified and accepted in November 2014.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  wishing to get pregnant&#xD;
&#xD;
          -  negative pregnancy test&#xD;
&#xD;
          -  not using family planning&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  not wishing to get pregnant&#xD;
&#xD;
          -  being pregnant&#xD;
&#xD;
          -  using family planning&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mwelecele N Malecela, PHd</last_name>
    <role>Study Chair</role>
    <affiliation>National Institute for Medical Research, Tanzania</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institute for Medical research</name>
      <address>
        <city>Korogwe</city>
        <state>Tanga Region</state>
        <country>Tanzania</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Tanzania</country>
  </location_countries>
  <verification_date>September 2019</verification_date>
  <study_first_submitted>July 2, 2014</study_first_submitted>
  <study_first_submitted_qc>July 13, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 16, 2014</study_first_posted>
  <last_update_submitted>September 26, 2019</last_update_submitted>
  <last_update_submitted_qc>September 26, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">September 30, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Copenhagen</investigator_affiliation>
    <investigator_full_name>Ib Christian Bygbjerg</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Anaemia</keyword>
  <keyword>Pregnancy</keyword>
  <keyword>Foetal programming</keyword>
  <keyword>Epigenetics</keyword>
  <keyword>Non-communicable diseases</keyword>
  <keyword>Tanzania</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anemia</mesh_term>
    <mesh_term>Noncommunicable Diseases</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT02191683
org study id: 1309-00003B
secondary id: Strategiske Forskningsråd
nct id: NCT02191683
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
Study Hypotheses:

        1. Anaemia, which is frequent before conception as well as during early pregnancy, affects
           metabolism and foetal growth trajectories, influencing the risk of NCDs in the
           offspring.

        2. Anaemia from conception till end of 2nd trimester is most detrimental for foetal and
           newborns' health, compared to 3rd trimester anaemia.

        3. Anaemia from conception till end of 2nd trimester affects foetal and newborns health
           through poor placental development reflected in increased villous branching and changed
           umbilical and uterine blood flow.

        4. Anaemia in early pregnancy disrupts the vascular endothelial growth factor A
           (VEGF-A)/placental growth factor (PlGF) balance and the insulin-like growth factor (IGF)
           axis resulting in poor placental development, and poor health of newborns. This may be
           reflected in specific methylation patterns.

        5. Anaemia's impact on the risk for NCDs in the offspring may be mediated via epigenetic
           mechanisms, including changes in DNA methylation patterns.
Specific objectives are:

        1. Characterize the health of women aged 18-40 years before conception and during
           pregnancy, focusing on prevalence of anaemia, infections, nutritional status, and
           Non-Communicable Diseases (NCDs).

        2. Describe how 1st and 2nd trimester anaemia compared to 3rd trimester anaemia alters
           foetal growth and newborns' body composition.

        3. Evaluate how 1st and 2nd trimester anaemia compared to 3rd trimester anaemia affects
           villous branching in the placenta, as well as uterine and umbilical artery blood flow.

        4. Characterize how 1st, 2nd and 3rd trimester anaemia differentially changes the vascular
           endothelial growth factor A (VEGF-A)/placental growth factor (PlGF) balance and the
           insulin-like growth factor axis.

        5. Determine which markers for foetal programming such as methylation of regulatory genes
           related to metabolism and haematopoiesis may be discovered early after exposure to
           anaemia in1st and 2nd trimester compared to 3rd trimester anaemia.

      Outcome parameter for the pre-pregnancy study (i.): 1) Prevalence and severity of anaemia
      among non-pregnant Tanzanian women at fertile age and their nutritional status. 2) Incidence
      of conception among such women.

      Outcome parameter for the pregnancy study (ii.): 1) Foetal growth rate in 2nd and 3rd
      trimester in offspring of anaemic mothers vs Foetal growth rate in non-anaemic mothers'
      offspring, 2) Comparison of anaemic mothers' vs non-anaemic mothers' newborn's body
      composition, placental villous branching, umbilical and uterine blood flow, VEGF-A/PlGF
      levels, and insulin-like growth factor axis.

      For all analyses main exposure variable will be anaemia (Hb<5mmol/L) in 1st, 2nd and/or3rd
      trimester of pregnancy. Confounding exposure variables will be chronic health conditions
      (e.g. HIV), all temporary conditions mentioned above (e.g. malaria) as well as socioeconomic
      status and paternal characteristics. Regression modelling using both multiple linear and
      logistic regressions as well as modelling for repeated measures will be used for statistical
      analyses. For genetic and epigenetic changes, findings in the subgroup of 180 other/newborns,
      remaining significant after correction for multiple comparisons, will be validated in the
      remaining cohort. This will enable us within one study to replicate initial findings in one
      representative and distinct subgroup in another larger comparable study group from an overall
      homogenous study. Indeed, findings surviving both corrections for multiple testing in the
      initial hypothesis generating array approaches, as well as being replicated in the remaining
      study group with single target validation techniques, are highly likely to be biological
      important. Possible findings from the candidate gene approach will be corrected for multiple
      testing and the significant results will be compared with previous findings of the same genes
      from studies in muscle and adipose tissue conducted by Diabetes and Metabolism, Copenhagen
      University Hospital.
observational model: Other
time perspective: Prospective
measure: Outcome parameter for the pre-pregnancy study (i.):
time frame: 12 months from start
description: Prevalence and severity of anaemia among non-pregnant Tanzanian women at fertile age and their nutritional status.
measure: Outcome parameter for the pregnancy study (ii.):
time frame: 31 months
description: Anemia's effect on foetal growth rate in 2nd and 3rd trimester measured as a) discrepancy in estimated and predicted gestational age (GA) between inclusion and antenatal visit at GA 20 weeks & 30, b) change in z-score for foetal weight/body weight and c) gain in g/week26 at GA of 26, 32 and 37 and delivery. Newborn's body composition, placental villous branching, umbilical and uterine blood flow, VEGF-A/PlGF levels, and GFaxis. For all analyses main exposure variable are anaemia in 1st, 2nd and/or3rd trimester of pregnancy. Confounding exposure variables are chronic health conditions, temporary conditions mentioned above (e.g. malaria) and socioeconomic status and paternal characteristics. Regression modelling using multiple linear and logistic regressions and modelling for repeated measures are used for statistical analyses. Genetic and epigenetic significant changes in subgroup of 180 mother/newborns, after correction for multiple comparisons, will be validated in remaining cohort.
measure: Incidence of conception among non-pregnant Tanzanian women.
time frame: 12 months
description: Number of women screened, with and without anaemia, respectively, who actually become pregnant within the observation period
arm group label: Health of women before conception
description: Tanzanian women aged 18-40 years focusing on prevalence of anaemia, infections, nutritional status, and NCDs.
arm group label: 480 women during pregnancy
description: Describe how 1st and 2nd trimester anaemia compared to 3rd trimester anaemia alters foetal growth and newborns' body composition.
Evaluate anaemia's effect on villous branching in placenta, and uterine and umbilical artery blood flow.
Evaluate effect on vascular endothelial growth factor A/placental growth factor balance and insulin-like growth factor axis.
Determine which markers for foetal programming such as methylation of regulatory genes related to metabolism and haematopoiesis may be discovered early after exposure to anaemia.
Periperal vein blood, umbilical cord blood, placentas
study pop: 
sampling method: Probability Sample
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 40 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Mwelecele N Malecela, PHd
role: Study Chair
affiliation: National Institute for Medical Research, Tanzania
facility: 
country: Tanzania
responsible party type: Principal Investigator
investigator affiliation: University of Copenhagen
investigator full name: Ib Christian Bygbjerg
investigator title: Professor
mesh term: Anemia
mesh term: Noncommunicable Diseases