<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/NCT03008824</url>
  </required_header>
  <id_info>
    <org_study_id>MR/J000094/1</org_study_id>
    <nct_id>NCT03008824</nct_id>
  </id_info>
  <brief_title>Micronutrients in Pregnancy as a Risk Factor for Diabetes and Effects on Mother and Baby</brief_title>
  <acronym>PRiDE</acronym>
  <official_title>Micronutrients in Pregnancy as a Risk Factor for Diabetes and Effects on Mother and Baby: PRiDE Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Warwick</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>George Eliot Hospital NHS Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Warwick</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      There is a rapidly escalating epidemic of obesity and type 2 diabetes across the world, with&#xD;
      the fastest rise occurring in low- and middle-income countries. India not only has one of the&#xD;
      highest rates in the world, but the disease starts at a younger age and lower levels of body&#xD;
      weight than in UK white caucasians. Among city-dwelling Indians, approximately 8% of people&#xD;
      aged 30-40 years already have diabetes. This is creating a heavy burden of disease and&#xD;
      disability, and an intolerable economic burden through medical costs and lost earnings. Until&#xD;
      now, efforts to prevent diabetes have mainly focussed on modifying the diet, lifestyle and&#xD;
      activity of at-risk adults (for example those who are overweight, have a family history of&#xD;
      diabetes or already have high blood sugar). However, recent research has indicated that&#xD;
      factors acting in early life (during development in the womb) place an individual at risk of&#xD;
      later diabetes. These include maternal malnutrition and low birthweight, and diabetes in the&#xD;
      mother during pregnancy. Our research has shown that Indian mothers often have low vitamin&#xD;
      B12 levels, which in turn causes high blood levels of a harmful metabolite (homocysteine). We&#xD;
      have shown that these mothers get more diabetes in pregnancy. Their children are more likely&#xD;
      to born with a low birth weight, and develop more body fat and higher plasma insulin levels&#xD;
      during childhood, which are signs of higher diabetes risk in later life. The risk is&#xD;
      increased further if the mother has normal or high status for another B vitamin, folate.&#xD;
      Thus, we have shown, for the first time a link between a specific nutritional deficiency in&#xD;
      the mother and diabetes risk in the next generation. One possible mechanism for the effect of&#xD;
      maternal nutrition on risk of diabetes in her children is through epigenetic effects, whereby&#xD;
      the nutritional environment during early development affects the switches that control gene&#xD;
      expression. Since these switches are passed on via either parent, we think it is possible&#xD;
      that paternal vitamin B12 status could also be important.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
      Risk of GDM and offspring's metabolic risk:&#xD;
&#xD;
      There is an escalating epidemic of type 2 diabetes (T2D) across the world in all ethnic&#xD;
      groups, in particular, people of South Asian origin. Current strategies for preventing T2D&#xD;
      rely mainly on altering risk factors such as obesity, sedentary lifestyle and healthy eating.&#xD;
      Though this is important, it is unlikely to make a big impact on this escalating epidemic,&#xD;
      which consumes significant proportion of health care budgets, world-wide. Some of the risk of&#xD;
      developing metabolic diseases such as T2D and cardiovascular disorders (CVD) are evident even&#xD;
      at birth. Indeed, recent research suggests that factors acting during early development,&#xD;
      including foetal growth restriction and exposure to gestational diabetes (GDM) in the mother&#xD;
      increases diabetes and obesity risk in later life. The investigators recent work has shown&#xD;
      that maternal vitamin B12 insufficiency and hyper-homocysteinaemia, in combination with&#xD;
      normal/high maternal folate status, is associated with an increased risk of GDM in the&#xD;
      mothers, growth restriction in the foetus, and adiposity and insulin resistance in the&#xD;
      children.&#xD;
&#xD;
      GDM is described as glucose intolerance first recognised in pregnancy. Similar to T2D, GDM is&#xD;
      also increasing at an alarming rate, attributed partly to increasing maternal age and body&#xD;
      weight. The current estimate is around 4% of all pregnancy though this could increase to as&#xD;
      much as 17% if the new IADPSG guidelines are implemented. Women who develop GDM are at 7-8&#xD;
      times higher risk of T2D13 and the children born to them are at higher risk of developing&#xD;
      T2D, abdominal obesity and metabolic syndrome later in life thus increasing their risk of CVD&#xD;
      in adulthood. Though the exact etiological processes of such increased risk not clear, some&#xD;
      of these effects could act through epigenetic mechanisms (intra-uterine programming).&#xD;
&#xD;
      The study by Krishnaveni et al raises an intriguing possibility for a simple measure for&#xD;
      preventing GDM and future T2D. It is believed that the high prevalence of B12 insufficiency&#xD;
      in India was attributed to vegetarianism. As the majority of the UK population is&#xD;
      non-vegetarian, it is conceivable that B12 deficiency is unlikely during pregnancy. However,&#xD;
      the investigators have recently shown: a) B12 deficiency is not uncommon in women of&#xD;
      childbearing age (14%) and pregnant women (20% at 16-18 weeks of pregnancy) and b) B12&#xD;
      deficiency in GDM is associated with higher BMI and higher birth weight in a clinic&#xD;
      population.&#xD;
&#xD;
      Psychological impact of GDM:&#xD;
&#xD;
      Mothers who are screened for GDM have lower perceived well-being. Diagnosis of GDM during&#xD;
      pregnancy often comes as a shock and causes significant distress to expectant mothers. There&#xD;
      is some evidence that such distress improves after treatment, presumably due to education and&#xD;
      support. These limited data come from women of Caucasian origin and no such data exists in&#xD;
      women of South Asian origin.&#xD;
&#xD;
      To confirm these observations in the UK multi-ethnic population, the investigators plan to&#xD;
      carry out an adequately powered case-control study to examine: a) the influence of early&#xD;
      pregnancy B12, folate and homocysteine levels (as well as other clinical, biochemical and&#xD;
      genetic markers) on the risk of GDM and offspring's risk of future metabolic disorders by&#xD;
      measuring detailed anthropometry of the babies along with their biochemical and genetic&#xD;
      markers from the cord blood; and b) the psychological impact of diagnosis of GDM by measuring&#xD;
      the anxiety and distress by questionnaires.&#xD;
&#xD;
      Hypothesis:&#xD;
&#xD;
      Imbalance of B12, folate and homocysteine in early pregnancy predicts the risk of GDM in&#xD;
      mothers and metabolic risk of offspring&#xD;
&#xD;
      Research plan and methodology:&#xD;
&#xD;
      Population: Pregnant women attending antenatal care in the UK; Cases will be pregnant women&#xD;
      carrying singleton foetuses, without pre-gestational diabetes, who are diagnosed with GDM&#xD;
      during the pregnancy. Equal number of South Asian and Caucasian mothers with GDM will be&#xD;
      recruited.&#xD;
&#xD;
      Intervention / Exposure: Maternal vitamin B12, folate and homocysteine levels in early&#xD;
      pregnancy (&lt;16 weeks of gestation) Comparison Group: Mothers from the cohort who do not&#xD;
      develop GDM and are matched in age, parity and BMI to the cases&#xD;
&#xD;
      Study Design:&#xD;
&#xD;
      A prospective observational case-control study designed to compare early pregnancy B12,&#xD;
      folate and homocysteine levels in pregnant women who develop GDM (cases) and those who do not&#xD;
      (controls).&#xD;
&#xD;
      Sample size:&#xD;
&#xD;
      There is no published data on the rate of B12 deficiency in GDM women in the UK and limited&#xD;
      data exists in non-GDM women in Caucasians. Preliminary results from the investigators' group&#xD;
      have shown that approximately 15% insufficiency in non-GDM and around 20%-25% in GDM women of&#xD;
      Caucasian origin. To detect a 5% difference in the prevalence of B12 insufficiency with 90%&#xD;
      power at the 5% significance level, 700 GDMs will be required. We plan to identify 1400&#xD;
      controls matched for age, BMI and parity. To achieve this,4080 pregnant women will be&#xD;
      required in their first trimester over the 2.5 years (if 20% develop GDM). Allowing for a 10%&#xD;
      drop-out rate and for age, parity &amp; BMI matching 4500 pregnant mothers will be recruited.&#xD;
&#xD;
      Implementation plan:&#xD;
&#xD;
      Several study launches are planned to raise the awareness among the public, midwifes and&#xD;
      general practitioners in the region. The relevant clinical research networks (CRNs) will be&#xD;
      involved from the beginning both to raise the awareness and for direct involvement in the&#xD;
      study.&#xD;
&#xD;
      Most potential participants will be given the participant information sheet (PIS) when they&#xD;
      are seen for their booking visit by the community midwife. The midwife will assess their&#xD;
      eligibility for the study and hand out the PIS if they fit the inclusion criteria. The&#xD;
      midwife will inform the research team of the mothers' details via a Reply Slip if she has no&#xD;
      objection to be contacted. The research team will then contact the mother and if possible,&#xD;
      the recruitment visit will be planned to coincide with her booking bloods or dating scan&#xD;
      appointment (usually around 12 weeks of gestation) to minimise the study visits ('Research&#xD;
      Team Recruitment', see right-hand side of Recruitment Flow chart).&#xD;
&#xD;
      In the situation where a mother has been identified by her midwife as fitting the inclusion&#xD;
      criteria for the study (i.e. she has high-risk factors for GDM and is therefore referred for&#xD;
      a GTT), but is not given a PIS at the booking visit, the research team will send this out by&#xD;
      post to the mother with an invitation letter.&#xD;
&#xD;
      Feedback from the mothers at the recruitment visit (i.e. dating scan) suggests that the&#xD;
      mothers would have been happy to partake in the study at the same visit as receiving the PIS&#xD;
      for 4 main reasons: 1) the study (and the PIS) is simple to understand; 2) they spend a&#xD;
      significant amount of time awaiting scan and midwife appointment during this visit; 3) they&#xD;
      want to have their blood sample taken at the same visit (mothers have a blood test routinely&#xD;
      as a standard care); and 4) they prefer not to come back for a separate visit. The&#xD;
      investigators also believe this is reasonable as this is a non-interventional study and&#xD;
      provides opportunity for more mothers to participate in the study. Therefore if the mother&#xD;
      has had enough time to read and understand the PIS and provides consent, she could be&#xD;
      recruited straightaway and blood tests done together with her routine bloods on the same day.&#xD;
      However, if she prefers to take the PIS away and have more time to decide, the research team&#xD;
      will see her at a future date. Such a strategy can also be replicated in the community&#xD;
      booking visit to facilitate participation in the study.&#xD;
&#xD;
      The participants will have basic demographic information collected and anthropometric&#xD;
      measurements done during the recruitment visit and be asked to fill out physical activity and&#xD;
      psychological well-being questionnaires. To facilitate the ease of filling the questionnaire,&#xD;
      where ever possible patients will be given iPads to complete them. We will then collect blood&#xD;
      samples (approximately 15-20ml in addition to their routine booking bloods), a urine and&#xD;
      stool sample (optional) from them.&#xD;
&#xD;
      Mothers will have their OGTT at 24-28 weeks gestation and further blood, urine and stool&#xD;
      (optional) samples will be taken at this time for study purposes. Modified WHO (1998) and&#xD;
      NICE criteria will be used to diagnose gestational diabetes or not(i.e. fasting plasma&#xD;
      glucose ≥ 6.1 mmol/l OR fasting plasma glucose &lt; 6.1 mmol/l and 2 hour plasma glucose &gt;&#xD;
      7.8mmol/l but &lt; 11.1 mmol/l on 75g glucose tolerance test). The criteria will be changed if&#xD;
      the new IADPSG criteria is adopted during the course of the study (or NICE updates its&#xD;
      criteria). The mothers will be asked to fill out further psychological well-being&#xD;
      questionnaires during the waiting time during the OGTT and for mothers subsequently diagnosed&#xD;
      with GDM, when they attend the antenatal-diabetes clinic.&#xD;
&#xD;
      The remainder of a participant's antenatal care will then carry on in the joint&#xD;
      antenatal-diabetes clinic (if she has been diagnosed with GDM) or in the community (for&#xD;
      non-GDM mothers, unless she has any other indication to be referred to the obstetric clinic).&#xD;
&#xD;
      All the participants will have their deliveries in one of the NHS Hospitals involved in the&#xD;
      study. Cord blood, a piece of cord and placental biopsies (around 2cm each) will be taken at&#xD;
      the time of birth as well as detailed birth and neonatal outcome data and a stool sample from&#xD;
      the baby shortly afterwards. Baby's body fat content and distribution will be measured by the&#xD;
      'PEAPOD' machine. This is a non invasive, baby friendly way of accurately measuring the fat&#xD;
      distribution in the baby. This is optional. For mothers who have Caesarean sections (for&#xD;
      medical/obstetric reasons), we will ask for separate consent to take a sample of abdominal&#xD;
      fat and subcutaneous as well as myometrial smooth muscle tissues. All the samples obtained&#xD;
      will stored for future DNA isolation.&#xD;
&#xD;
      During the post-natal OGTT for GDM mothers (6 weeks post-partum) additional blood samples&#xD;
      will be collected and stored. Also, well-being questionnaires will be given out to all&#xD;
      participants post-natally. From 3 to 12 months, breast feeding mothers will be contacted&#xD;
      either through postal questionnaire or over the telephone.&#xD;
&#xD;
      Appendices and summary of additional data collection:&#xD;
&#xD;
        1. IPAQ (Physical activity) questionnaire - baseline&#xD;
&#xD;
        2. PhQ9 questionnaire - at baseline&#xD;
&#xD;
        3. GAD7 questionnaire - at baseline&#xD;
&#xD;
        4. Warwick - Edinburgh well being questionnaire (WEMWBS) - baseline, 24-28 weeks and 6&#xD;
           weeks postpartum during OGTT&#xD;
&#xD;
        5. Euro-QoL - Quality of Life measure at baseline, 24-28 weeks and 6 weeks postpartum GTT&#xD;
&#xD;
        6. Socio-economic measure - baseline, 24-28 weeks and 6 weeks postpartum GTT&#xD;
&#xD;
        7. PSQI (Pittsburgh Sleep Quality Index questionnaire)&#xD;
&#xD;
        8. Breast feeding questionnaire (post natal)&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>September 2012</start_date>
  <completion_date type="Anticipated">June 2018</completion_date>
  <primary_completion_date type="Anticipated">June 2017</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>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Differences in B12 levels between GDM and Controls</measure>
    <time_frame>5 Years</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Differences in B12 levels in South Asians and White Caucasians</measure>
    <time_frame>5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Differences between offspring birth weight between GDM and controls</measure>
    <time_frame>5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Differences between offspring adiposity between GDM and controls</measure>
    <time_frame>5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Differences between offspring birth weight between South Asians and White Caucasians</measure>
    <time_frame>5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Differences between offspring adiposity between South Asians and White Caucasians</measure>
    <time_frame>5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical and Biochemical predictors of GDM in the first trimester</measure>
    <time_frame>5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Predictors of abnormal post-natal OGTT in the first trimester</measure>
    <time_frame>5.5 years</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Psychological impact of the diagnosis of GDM in each ethnicity</measure>
    <time_frame>5 years</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Role of sedentary behavior on incident GDM</measure>
    <time_frame>5 years</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Role of physical activity on incident GDM</measure>
    <time_frame>5 years</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Role of maternal 1-C metabolites on incident GDM</measure>
    <time_frame>5 years</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Role of maternal 1-C metabolites on metabolic risk in the offspring at birth</measure>
    <time_frame>5 years</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Role of maternal metabolic risk factors on offspring adiposity measured by PEAPOD</measure>
    <time_frame>8 years</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Validation of newborn adiposity measured by skin-fold thickness and objective measurement by PEAPOD</measure>
    <time_frame>8 years</time_frame>
  </other_outcome>
  <enrollment type="Anticipated">4500</enrollment>
  <condition>Gestational Diabetes</condition>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Plasma, serum and whole blood for isolating DNA&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        All pregnant women between 18-75 years of age who satisfy NICE criteria for GDM screening&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Pregnant women &lt;16 years of age&#xD;
&#xD;
          -  High risk for GDM (at least 1 of the risk factors) - BMI &gt;30&#xD;
&#xD;
          -  Previous GDM&#xD;
&#xD;
          -  First degree relatives with GDM&#xD;
&#xD;
          -  Previous unexplained still birth&#xD;
&#xD;
          -  Previous baby &gt;4.5kg&#xD;
&#xD;
          -  PCOS&#xD;
&#xD;
          -  Ethnic minority groups&#xD;
&#xD;
          -  Age &gt;35years&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregestational Type 1 or Type 2 Diabetes&#xD;
&#xD;
          -  Diagnosis of B12 or folate deficiency in the current pregnancy&#xD;
&#xD;
          -  Previous pregnancies with NTDs&#xD;
&#xD;
          -  Diagnosis of severe aneamia (&lt;10g/dL)&#xD;
&#xD;
          -  Vitamin B12 injections in the previous 6 months&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ponnusamy Saravanan, FRCP PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Warwick</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Ponnusamy Saravanan, FRCP PhD</last_name>
    <phone>00442476865329</phone>
    <email>p.saravanan@warwick.ac.uk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Amitha Gopinath, MBA</last_name>
    <phone>00442476153592</phone>
    <email>amitha.gopinath@geh.nhs.uk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University of Warwick</name>
      <address>
        <city>Coventry</city>
        <zip>CV47AL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ponnusamy Saravanan, FRCP PhD</last_name>
      <phone>00442476865329</phone>
      <email>p.saravanan@warwick.ac.uk</email>
    </contact>
    <contact_backup>
      <last_name>Amitha Gopinath, MBA</last_name>
      <phone>00442476153592</phone>
      <email>amitha.gopinath@geh.nhs.uk</email>
    </contact_backup>
    <investigator>
      <last_name>Ponnusamy Saravanan, FRCP PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Nigel Stallard, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>December 2016</verification_date>
  <study_first_submitted>December 22, 2016</study_first_submitted>
  <study_first_submitted_qc>December 29, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 4, 2017</study_first_posted>
  <last_update_submitted>December 29, 2016</last_update_submitted>
  <last_update_submitted_qc>December 29, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 4, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Warwick</investigator_affiliation>
    <investigator_full_name>Dr P Saravanan</investigator_full_name>
    <investigator_title>Associate Clinical Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes, Gestational</mesh_term>
    <mesh_term>Diabetes Mellitus</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>A core dataset and the metatdata that is funded by MRC will be archived</ipd_description>
  </patient_data>
  <!-- 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/NCT03008824
org study id: MR/J000094/1
nct id: NCT03008824
lead sponsor: 
collaborator: 
has dmc: No
There is a rapidly escalating epidemic of obesity and type 2 diabetes across the world, with
      the fastest rise occurring in low- and middle-income countries. India not only has one of the
      highest rates in the world, but the disease starts at a younger age and lower levels of body
      weight than in UK white caucasians. Among city-dwelling Indians, approximately 8% of people
      aged 30-40 years already have diabetes. This is creating a heavy burden of disease and
      disability, and an intolerable economic burden through medical costs and lost earnings. Until
      now, efforts to prevent diabetes have mainly focussed on modifying the diet, lifestyle and
      activity of at-risk adults (for example those who are overweight, have a family history of
      diabetes or already have high blood sugar). However, recent research has indicated that
      factors acting in early life (during development in the womb) place an individual at risk of
      later diabetes. These include maternal malnutrition and low birthweight, and diabetes in the
      mother during pregnancy. Our research has shown that Indian mothers often have low vitamin
      B12 levels, which in turn causes high blood levels of a harmful metabolite (homocysteine). We
      have shown that these mothers get more diabetes in pregnancy. Their children are more likely
      to born with a low birth weight, and develop more body fat and higher plasma insulin levels
      during childhood, which are signs of higher diabetes risk in later life. The risk is
      increased further if the mother has normal or high status for another B vitamin, folate.
      Thus, we have shown, for the first time a link between a specific nutritional deficiency in
      the mother and diabetes risk in the next generation. One possible mechanism for the effect of
      maternal nutrition on risk of diabetes in her children is through epigenetic effects, whereby
      the nutritional environment during early development affects the switches that control gene
      expression. Since these switches are passed on via either parent, we think it is possible
      that paternal vitamin B12 status could also be important.
Background:

      Risk of GDM and offspring's metabolic risk:

      There is an escalating epidemic of type 2 diabetes (T2D) across the world in all ethnic
      groups, in particular, people of South Asian origin. Current strategies for preventing T2D
      rely mainly on altering risk factors such as obesity, sedentary lifestyle and healthy eating.
      Though this is important, it is unlikely to make a big impact on this escalating epidemic,
      which consumes significant proportion of health care budgets, world-wide. Some of the risk of
      developing metabolic diseases such as T2D and cardiovascular disorders (CVD) are evident even
      at birth. Indeed, recent research suggests that factors acting during early development,
      including foetal growth restriction and exposure to gestational diabetes (GDM) in the mother
      increases diabetes and obesity risk in later life. The investigators recent work has shown
      that maternal vitamin B12 insufficiency and hyper-homocysteinaemia, in combination with
      normal/high maternal folate status, is associated with an increased risk of GDM in the
      mothers, growth restriction in the foetus, and adiposity and insulin resistance in the
      children.

      GDM is described as glucose intolerance first recognised in pregnancy. Similar to T2D, GDM is
      also increasing at an alarming rate, attributed partly to increasing maternal age and body
      weight. The current estimate is around 4% of all pregnancy though this could increase to as
      much as 17% if the new IADPSG guidelines are implemented. Women who develop GDM are at 7-8
      times higher risk of T2D13 and the children born to them are at higher risk of developing
      T2D, abdominal obesity and metabolic syndrome later in life thus increasing their risk of CVD
      in adulthood. Though the exact etiological processes of such increased risk not clear, some
      of these effects could act through epigenetic mechanisms (intra-uterine programming).

      The study by Krishnaveni et al raises an intriguing possibility for a simple measure for
      preventing GDM and future T2D. It is believed that the high prevalence of B12 insufficiency
      in India was attributed to vegetarianism. As the majority of the UK population is
      non-vegetarian, it is conceivable that B12 deficiency is unlikely during pregnancy. However,
      the investigators have recently shown: a) B12 deficiency is not uncommon in women of
      childbearing age (14%) and pregnant women (20% at 16-18 weeks of pregnancy) and b) B12
      deficiency in GDM is associated with higher BMI and higher birth weight in a clinic
      population.

      Psychological impact of GDM:

      Mothers who are screened for GDM have lower perceived well-being. Diagnosis of GDM during
      pregnancy often comes as a shock and causes significant distress to expectant mothers. There
      is some evidence that such distress improves after treatment, presumably due to education and
      support. These limited data come from women of Caucasian origin and no such data exists in
      women of South Asian origin.

      To confirm these observations in the UK multi-ethnic population, the investigators plan to
      carry out an adequately powered case-control study to examine: a) the influence of early
      pregnancy B12, folate and homocysteine levels (as well as other clinical, biochemical and
      genetic markers) on the risk of GDM and offspring's risk of future metabolic disorders by
      measuring detailed anthropometry of the babies along with their biochemical and genetic
      markers from the cord blood; and b) the psychological impact of diagnosis of GDM by measuring
      the anxiety and distress by questionnaires.

      Hypothesis:

      Imbalance of B12, folate and homocysteine in early pregnancy predicts the risk of GDM in
      mothers and metabolic risk of offspring

      Research plan and methodology:

      Population: Pregnant women attending antenatal care in the UK; Cases will be pregnant women
      carrying singleton foetuses, without pre-gestational diabetes, who are diagnosed with GDM
      during the pregnancy. Equal number of South Asian and Caucasian mothers with GDM will be
      recruited.

      Intervention / Exposure: Maternal vitamin B12, folate and homocysteine levels in early
      pregnancy (<16 weeks of gestation) Comparison Group: Mothers from the cohort who do not
      develop GDM and are matched in age, parity and BMI to the cases

      Study Design:

      A prospective observational case-control study designed to compare early pregnancy B12,
      folate and homocysteine levels in pregnant women who develop GDM (cases) and those who do not
      (controls).

      Sample size:

      There is no published data on the rate of B12 deficiency in GDM women in the UK and limited
      data exists in non-GDM women in Caucasians. Preliminary results from the investigators' group
      have shown that approximately 15% insufficiency in non-GDM and around 20%-25% in GDM women of
      Caucasian origin. To detect a 5% difference in the prevalence of B12 insufficiency with 90%
      power at the 5% significance level, 700 GDMs will be required. We plan to identify 1400
      controls matched for age, BMI and parity. To achieve this,4080 pregnant women will be
      required in their first trimester over the 2.5 years (if 20% develop GDM). Allowing for a 10%
      drop-out rate and for age, parity & BMI matching 4500 pregnant mothers will be recruited.

      Implementation plan:

      Several study launches are planned to raise the awareness among the public, midwifes and
      general practitioners in the region. The relevant clinical research networks (CRNs) will be
      involved from the beginning both to raise the awareness and for direct involvement in the
      study.

      Most potential participants will be given the participant information sheet (PIS) when they
      are seen for their booking visit by the community midwife. The midwife will assess their
      eligibility for the study and hand out the PIS if they fit the inclusion criteria. The
      midwife will inform the research team of the mothers' details via a Reply Slip if she has no
      objection to be contacted. The research team will then contact the mother and if possible,
      the recruitment visit will be planned to coincide with her booking bloods or dating scan
      appointment (usually around 12 weeks of gestation) to minimise the study visits ('Research
      Team Recruitment', see right-hand side of Recruitment Flow chart).

      In the situation where a mother has been identified by her midwife as fitting the inclusion
      criteria for the study (i.e. she has high-risk factors for GDM and is therefore referred for
      a GTT), but is not given a PIS at the booking visit, the research team will send this out by
      post to the mother with an invitation letter.

      Feedback from the mothers at the recruitment visit (i.e. dating scan) suggests that the
      mothers would have been happy to partake in the study at the same visit as receiving the PIS
      for 4 main reasons: 1) the study (and the PIS) is simple to understand; 2) they spend a
      significant amount of time awaiting scan and midwife appointment during this visit; 3) they
      want to have their blood sample taken at the same visit (mothers have a blood test routinely
      as a standard care); and 4) they prefer not to come back for a separate visit. The
      investigators also believe this is reasonable as this is a non-interventional study and
      provides opportunity for more mothers to participate in the study. Therefore if the mother
      has had enough time to read and understand the PIS and provides consent, she could be
      recruited straightaway and blood tests done together with her routine bloods on the same day.
      However, if she prefers to take the PIS away and have more time to decide, the research team
      will see her at a future date. Such a strategy can also be replicated in the community
      booking visit to facilitate participation in the study.

      The participants will have basic demographic information collected and anthropometric
      measurements done during the recruitment visit and be asked to fill out physical activity and
      psychological well-being questionnaires. To facilitate the ease of filling the questionnaire,
      where ever possible patients will be given iPads to complete them. We will then collect blood
      samples (approximately 15-20ml in addition to their routine booking bloods), a urine and
      stool sample (optional) from them.

      Mothers will have their OGTT at 24-28 weeks gestation and further blood, urine and stool
      (optional) samples will be taken at this time for study purposes. Modified WHO (1998) and
      NICE criteria will be used to diagnose gestational diabetes or not(i.e. fasting plasma
      glucose ≥ 6.1 mmol/l OR fasting plasma glucose < 6.1 mmol/l and 2 hour plasma glucose >
      7.8mmol/l but < 11.1 mmol/l on 75g glucose tolerance test). The criteria will be changed if
      the new IADPSG criteria is adopted during the course of the study (or NICE updates its
      criteria). The mothers will be asked to fill out further psychological well-being
      questionnaires during the waiting time during the OGTT and for mothers subsequently diagnosed
      with GDM, when they attend the antenatal-diabetes clinic.

      The remainder of a participant's antenatal care will then carry on in the joint
      antenatal-diabetes clinic (if she has been diagnosed with GDM) or in the community (for
      non-GDM mothers, unless she has any other indication to be referred to the obstetric clinic).

      All the participants will have their deliveries in one of the NHS Hospitals involved in the
      study. Cord blood, a piece of cord and placental biopsies (around 2cm each) will be taken at
      the time of birth as well as detailed birth and neonatal outcome data and a stool sample from
      the baby shortly afterwards. Baby's body fat content and distribution will be measured by the
      'PEAPOD' machine. This is a non invasive, baby friendly way of accurately measuring the fat
      distribution in the baby. This is optional. For mothers who have Caesarean sections (for
      medical/obstetric reasons), we will ask for separate consent to take a sample of abdominal
      fat and subcutaneous as well as myometrial smooth muscle tissues. All the samples obtained
      will stored for future DNA isolation.

      During the post-natal OGTT for GDM mothers (6 weeks post-partum) additional blood samples
      will be collected and stored. Also, well-being questionnaires will be given out to all
      participants post-natally. From 3 to 12 months, breast feeding mothers will be contacted
      either through postal questionnaire or over the telephone.

      Appendices and summary of additional data collection:

        1. IPAQ (Physical activity) questionnaire - baseline

        2. PhQ9 questionnaire - at baseline

        3. GAD7 questionnaire - at baseline

        4. Warwick - Edinburgh well being questionnaire (WEMWBS) - baseline, 24-28 weeks and 6
           weeks postpartum during OGTT

        5. Euro-QoL - Quality of Life measure at baseline, 24-28 weeks and 6 weeks postpartum GTT

        6. Socio-economic measure - baseline, 24-28 weeks and 6 weeks postpartum GTT

        7. PSQI (Pittsburgh Sleep Quality Index questionnaire)

        8. Breast feeding questionnaire (post natal)
observational model: Cohort
time perspective: Prospective
measure: Differences in B12 levels between GDM and Controls
time frame: 5 Years
measure: Differences in B12 levels in South Asians and White Caucasians
time frame: 5 years
measure: Differences between offspring birth weight between GDM and controls
time frame: 5 years
measure: Differences between offspring adiposity between GDM and controls
time frame: 5 years
measure: Differences between offspring birth weight between South Asians and White Caucasians
time frame: 5 years
measure: Differences between offspring adiposity between South Asians and White Caucasians
time frame: 5 years
measure: Clinical and Biochemical predictors of GDM in the first trimester
time frame: 5 years
measure: Predictors of abnormal post-natal OGTT in the first trimester
time frame: 5.5 years
measure: Psychological impact of the diagnosis of GDM in each ethnicity
time frame: 5 years
measure: Role of sedentary behavior on incident GDM
time frame: 5 years
measure: Role of physical activity on incident GDM
time frame: 5 years
measure: Role of maternal 1-C metabolites on incident GDM
time frame: 5 years
measure: Role of maternal 1-C metabolites on metabolic risk in the offspring at birth
time frame: 5 years
measure: Role of maternal metabolic risk factors on offspring adiposity measured by PEAPOD
time frame: 8 years
measure: Validation of newborn adiposity measured by skin-fold thickness and objective measurement by PEAPOD
time frame: 8 years
Plasma, serum and whole blood for isolating DNA
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Ponnusamy Saravanan, FRCP PhD
role: Principal Investigator
affiliation: University of Warwick
last name: Ponnusamy Saravanan, FRCP PhD
phone: 00442476865329
email: p.saravanan@warwick.ac.uk
last name: Amitha Gopinath, MBA
phone: 00442476153592
email: amitha.gopinath@geh.nhs.uk
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
country: United Kingdom
responsible party type: Principal Investigator
investigator affiliation: University of Warwick
investigator full name: Dr P Saravanan
investigator title: Associate Clinical Professor
mesh term: Diabetes, Gestational
mesh term: Diabetes Mellitus
sharing ipd: Undecided
ipd description: A core dataset and the metatdata that is funded by MRC will be archived