<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/NCT03014245</url>
  </required_header>
  <id_info>
    <org_study_id>2/08/16</org_study_id>
    <nct_id>NCT03014245</nct_id>
  </id_info>
  <brief_title>Melatonin in Pregnancy Compared to Non-pregnant</brief_title>
  <acronym>MEL-P</acronym>
  <official_title>Circulating Melatonin and 6-hydroxymelatonin Levels During Pregnancy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Aberdeen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>NHS Grampian</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Aberdeen</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Melatonin is well known for its role in the sleep-wake cycle but it is less well known as an&#xD;
      effective antioxidant. It has been reported to be synthesised in the placenta and may have&#xD;
      both receptor mediated and non-receptor mediated protective functions during pregnancy.&#xD;
      Severe pre-eclampsia has been reported to be associated with low levels of melatonin in the&#xD;
      placenta although it is not known if the placental melatonin contributes to circulating&#xD;
      levels. There is little reported on the circulating levels of melatonin or oxidative stress&#xD;
      at different stages of normal pregnancy. More information on the role of melatonin and&#xD;
      metabolism of melatonin in pregnancy as well as any significant association with adverse&#xD;
      pregnancy outcomes would inform planning of larger research studies to investigate the&#xD;
      potential role for melatonin as a biomarker for obstetric disease and potentially as a&#xD;
      therapeutic agent in future.&#xD;
&#xD;
      This observational pilot study aims to measure serum melatonin levels and 6-hydroxymelatonin&#xD;
      sulphate (the major metabolite of melatonin) during each trimester of pregnancy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Melatonin, a substance produced by the pineal gland, is well known for its role in the&#xD;
      sleep-wake cycle but it is less well known as an effective antioxidant. It is able to access&#xD;
      all parts of the cell, and can cross the blood-brain and placental barrier. Melatonin has&#xD;
      been reported to be synthesised in the placenta and may have both receptor mediated and&#xD;
      non-receptor mediated protective functions during pregnancy. Severe pre-eclampsia has been&#xD;
      reported to be associated with low levels of melatonin in the placenta although it is not&#xD;
      known if the placental melatonin contributes to circulating levels. Despite this, melatonin&#xD;
      levels have been proposed as a biomarker of pre-eclampsia. A further study suggested pregnant&#xD;
      women with hypertensive or diabetic conditions had lower melatonin levels and less circadian&#xD;
      variation, again suggesting the potential protective role melatonin may have during&#xD;
      pregnancy. Due to its antioxidant effects melatonin has also been proposed as a protective&#xD;
      substance for women undergoing assisted reproduction techniques.&#xD;
&#xD;
      Rationale for study There is little reported on the circulating levels of melatonin or&#xD;
      oxidative stress at different stages of normal pregnancy. More information on the role of&#xD;
      melatonin and metabolism of melatonin in pregnancy as well as any significant association&#xD;
      with adverse pregnancy outcomes would inform planning of larger research studies to&#xD;
      investigate the potential role for melatonin as a bio-marker for obstetric disease and&#xD;
      potentially as a therapeutic agent in future.&#xD;
&#xD;
      This observational pilot study aims to measure serum melatonin levels and 6-hydroxymelatonin&#xD;
      sulphate (the major metabolite of melatonin) during each trimester of pregnancy.&#xD;
&#xD;
      STUDY OBJECTIVES Objectives Primary Objective To determine if serum melatonin and&#xD;
      6-hydroxymelatonin sulphate levels differ in each trimester of pregnancy and how these&#xD;
      compare to non-pregnant women Secondary Objectives&#xD;
&#xD;
        1. To determine level of oxidative stress at time of serum sample by measuring lipid&#xD;
           peroxide levels&#xD;
&#xD;
        2. To explore whether levels of serum melatonin and 6-hydroxymelatonin sulphate vary in&#xD;
           women who develop antenatal complications (pre-eclampsia or hypertensive diseases of&#xD;
           pregnancy, preterm labour or gestational diabetes)&#xD;
&#xD;
      OUTCOMES Primary Outcome Serum melatonin and 6-hydroxymelatonin sulphate levels Secondary&#xD;
      Outcomes&#xD;
&#xD;
        1. Level of oxidative stress at time of sampling (lipid peroxide levels)&#xD;
&#xD;
        2. Outcome of pregnancy (live birth or not, development of preeclampsia / hypertensive&#xD;
           disease of pregnancy, gestational diabetes or preterm labor.&#xD;
&#xD;
      STUDY DESIGN Study Description&#xD;
&#xD;
      Twenty healthy women in their first pregnancy will be recruited at their first antenatal&#xD;
      (scan) visit at 11-13 weeks gestation. Recruitment will continue throughout the medical&#xD;
      student's allocated project time period to allow recruitment of as many women as possible,&#xD;
      but at least twenty pregnant women. A venous blood sample to measure serum melatonin and&#xD;
      6-hydroxymelatonin sulphate levels will be obtained using aseptic technique. Sampling, when&#xD;
      possible, will be carried out at the same time as for routine clinical screening. The first&#xD;
      blood sample will be done at 11-13 weeks gestation (first trimester) and could be done along&#xD;
      with routine antenatal screening blood tests. A second blood sample will be taken when women&#xD;
      attend for their detailed ultrasound scan at approximately 20 weeks (2nd trimester). The&#xD;
      participant may not need other routine blood tests at this time, therefore this blood sample&#xD;
      would only be for the purpose of the study.&#xD;
&#xD;
      A third and final blood sample will be obtained at around 28 weeks gestation (third&#xD;
      trimester). This could be done at the routine 28 week appointment with the participant's&#xD;
      community midwife when routine pregnancy blood tests will already be undertaken. Consent will&#xD;
      be sought from the participant to contact the applicable community midwife to arrange to&#xD;
      attend the midwifery appointment at around 28 weeks. The third blood sample will be taken&#xD;
      either at Aberdeen Maternity Hospital or at the participant's GP practice depending on&#xD;
      preference and convenience of appointment location for the participant and community midwife.&#xD;
      The researchers will not contact the participant directly. If the woman is attending the&#xD;
      obstetric antenatal clinic at that gestation the blood sample could alternatively be obtained&#xD;
      there along with the routine antenatal screening blood tests.&#xD;
&#xD;
      Non-pregnant controls will be recruited by advertising using posters around the University of&#xD;
      Aberdeen/Aberdeen Royal Infirmary campus, aiming for 20 non pregnant women, aged between 16&#xD;
      and 45 to have blood samples taken for serum melatonin and 6-hydroxy-melatonin sulphate&#xD;
      levels. Samples will be taken at the same time of day and year as pregnant subjects to&#xD;
      account for any seasonal effects.&#xD;
&#xD;
      Serum melatonin will be measured using liquid chromatography-tandem mass spectrometry and&#xD;
      6-hydroxymelatonin sulphate will be measured using enzyme immunoassay. Lipid peroxides will&#xD;
      be measured using a colorimetric assay.&#xD;
&#xD;
      Written informed consent will be obtained from all participants. Women will be asked for&#xD;
      their age, body mass index, gestation stage, smoking status, name of their community midwife&#xD;
      and a series of screening questions to determine eligibility according to inclusion criteria.&#xD;
      Once recruited, an anonymous code will be assigned and all data will be kept separately from&#xD;
      identifiable information.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 2016</start_date>
  <completion_date type="Actual">May 18, 2017</completion_date>
  <primary_completion_date type="Actual">April 2017</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Change in melatonin and 6-hydroxymelatonin levels during pregnancy</measure>
    <time_frame>Values up to 40 weeks</time_frame>
    <description>Do serum melatonin and 6-hydroxymelatonin sulphate levels differ in each trimester of pregnancy? Levels during each trimester will be compared.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in lipid peroxide levels during pregnancy</measure>
    <time_frame>Values up to 40 weeks</time_frame>
    <description>Does oxidative stress (lipid peroxide levels) vary in each trimester. Levels during each trimester will be compared.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relationship between melatonin and 6-hydroxymelatonin levels and duration of pregnancy.</measure>
    <time_frame>Up to 40 weeks</time_frame>
    <description>What is melatonin status in women who deliver at different gestation (in weeks).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relationship between melatonin and 6-hydroxymelatonin levels with different types of delivery.</measure>
    <time_frame>Up to 40 weeks</time_frame>
    <description>What is melatonin status in women with different labours (induced, spontaneous or planned caesarean section)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relationship between melatonin and 6-hydroxymelatonin levels and pre-eclampsia</measure>
    <time_frame>Up to 40 weeks</time_frame>
    <description>What is melatonin status in women who had pre-eclampsia ( as yes/no) and those who did not.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relationship between melatonin and 6-hydroxymelatonin levels and gestational diabetes</measure>
    <time_frame>Up to 40 weeks</time_frame>
    <description>What is melatonin status in women who had gestational diabetes ( as yes/no) compared to those who did not.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Melatonin and 6-hydroxymelatonin levels in pregnancy compared to non pregnant</measure>
    <time_frame>Up to 40 weeks</time_frame>
    <description>Is melatonin status at any time during pregnancy different to that in healthy non pregnant women? :Levels of melatonin and 6-hydroxymelatonin in non-pregnant women will be compared with levels in pregnant women.</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">60</enrollment>
  <condition>Pregnancy Transient Hypertension</condition>
  <arm_group>
    <arm_group_label>Pregnant</arm_group_label>
    <description>Normal pregnant women (first baby) singleton</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <description>Non pregnant healthy women</description>
  </arm_group>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Healthy women pregnant with first baby (singleton) presenting for first trimester scan and&#xD;
        healthy non-pregnant women of child bearing age.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Pregnant subjects&#xD;
&#xD;
          -  Primigravid women (in their first pregnancy)&#xD;
&#xD;
          -  Singleton pregnancy&#xD;
&#xD;
          -  Aged 16-45&#xD;
&#xD;
          -  Taking no regular medication other than pregnancy related vitamins or supplements&#xD;
&#xD;
          -  First trimester (FVS) ultrasound scan reported as normal&#xD;
&#xD;
        Non pregnant subjects&#xD;
&#xD;
          -  Non pregnant women&#xD;
&#xD;
          -  Aged 16-45&#xD;
&#xD;
          -  No chronic health issues and not taking any medication&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Pregnant subjects&#xD;
&#xD;
          -  Pregnancy non-viable on scan&#xD;
&#xD;
          -  Twins or higher multiple pregnancies&#xD;
&#xD;
          -  Outside age range&#xD;
&#xD;
          -  Diabetes or pre-existing hypertension, chronic kidney disease or known autoimmune&#xD;
             disorder&#xD;
&#xD;
        Non pregnant subjects&#xD;
&#xD;
          -  Male&#xD;
&#xD;
          -  Outside age range&#xD;
&#xD;
          -  Chronic health complaint/taking medication&#xD;
&#xD;
          -  Recent blood donation over 1 unit&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Aberdeen Maternity Hospital (NHS Grampian)</name>
      <address>
        <city>Aberdeen</city>
        <state>Aberdeenshire</state>
        <zip>AB25 2ZB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>January 2017</verification_date>
  <study_first_submitted>December 12, 2016</study_first_submitted>
  <study_first_submitted_qc>January 6, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 9, 2017</study_first_posted>
  <last_update_submitted>May 22, 2017</last_update_submitted>
  <last_update_submitted_qc>May 22, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">May 23, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension, Pregnancy-Induced</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT03014245
org study id: 2/08/16
nct id: NCT03014245
lead sponsor: 
collaborator: 
has dmc: No
Melatonin is well known for its role in the sleep-wake cycle but it is less well known as an
      effective antioxidant. It has been reported to be synthesised in the placenta and may have
      both receptor mediated and non-receptor mediated protective functions during pregnancy.
      Severe pre-eclampsia has been reported to be associated with low levels of melatonin in the
      placenta although it is not known if the placental melatonin contributes to circulating
      levels. There is little reported on the circulating levels of melatonin or oxidative stress
      at different stages of normal pregnancy. More information on the role of melatonin and
      metabolism of melatonin in pregnancy as well as any significant association with adverse
      pregnancy outcomes would inform planning of larger research studies to investigate the
      potential role for melatonin as a biomarker for obstetric disease and potentially as a
      therapeutic agent in future.

      This observational pilot study aims to measure serum melatonin levels and 6-hydroxymelatonin
      sulphate (the major metabolite of melatonin) during each trimester of pregnancy.
Melatonin, a substance produced by the pineal gland, is well known for its role in the
      sleep-wake cycle but it is less well known as an effective antioxidant. It is able to access
      all parts of the cell, and can cross the blood-brain and placental barrier. Melatonin has
      been reported to be synthesised in the placenta and may have both receptor mediated and
      non-receptor mediated protective functions during pregnancy. Severe pre-eclampsia has been
      reported to be associated with low levels of melatonin in the placenta although it is not
      known if the placental melatonin contributes to circulating levels. Despite this, melatonin
      levels have been proposed as a biomarker of pre-eclampsia. A further study suggested pregnant
      women with hypertensive or diabetic conditions had lower melatonin levels and less circadian
      variation, again suggesting the potential protective role melatonin may have during
      pregnancy. Due to its antioxidant effects melatonin has also been proposed as a protective
      substance for women undergoing assisted reproduction techniques.

      Rationale for study There is little reported on the circulating levels of melatonin or
      oxidative stress at different stages of normal pregnancy. More information on the role of
      melatonin and metabolism of melatonin in pregnancy as well as any significant association
      with adverse pregnancy outcomes would inform planning of larger research studies to
      investigate the potential role for melatonin as a bio-marker for obstetric disease and
      potentially as a therapeutic agent in future.

      This observational pilot study aims to measure serum melatonin levels and 6-hydroxymelatonin
      sulphate (the major metabolite of melatonin) during each trimester of pregnancy.

      STUDY OBJECTIVES Objectives Primary Objective To determine if serum melatonin and
      6-hydroxymelatonin sulphate levels differ in each trimester of pregnancy and how these
      compare to non-pregnant women Secondary Objectives

        1. To determine level of oxidative stress at time of serum sample by measuring lipid
           peroxide levels

        2. To explore whether levels of serum melatonin and 6-hydroxymelatonin sulphate vary in
           women who develop antenatal complications (pre-eclampsia or hypertensive diseases of
           pregnancy, preterm labour or gestational diabetes)

      OUTCOMES Primary Outcome Serum melatonin and 6-hydroxymelatonin sulphate levels Secondary
      Outcomes

        1. Level of oxidative stress at time of sampling (lipid peroxide levels)

        2. Outcome of pregnancy (live birth or not, development of preeclampsia / hypertensive
           disease of pregnancy, gestational diabetes or preterm labor.

      STUDY DESIGN Study Description

      Twenty healthy women in their first pregnancy will be recruited at their first antenatal
      (scan) visit at 11-13 weeks gestation. Recruitment will continue throughout the medical
      student's allocated project time period to allow recruitment of as many women as possible,
      but at least twenty pregnant women. A venous blood sample to measure serum melatonin and
      6-hydroxymelatonin sulphate levels will be obtained using aseptic technique. Sampling, when
      possible, will be carried out at the same time as for routine clinical screening. The first
      blood sample will be done at 11-13 weeks gestation (first trimester) and could be done along
      with routine antenatal screening blood tests. A second blood sample will be taken when women
      attend for their detailed ultrasound scan at approximately 20 weeks (2nd trimester). The
      participant may not need other routine blood tests at this time, therefore this blood sample
      would only be for the purpose of the study.

      A third and final blood sample will be obtained at around 28 weeks gestation (third
      trimester). This could be done at the routine 28 week appointment with the participant's
      community midwife when routine pregnancy blood tests will already be undertaken. Consent will
      be sought from the participant to contact the applicable community midwife to arrange to
      attend the midwifery appointment at around 28 weeks. The third blood sample will be taken
      either at Aberdeen Maternity Hospital or at the participant's GP practice depending on
      preference and convenience of appointment location for the participant and community midwife.
      The researchers will not contact the participant directly. If the woman is attending the
      obstetric antenatal clinic at that gestation the blood sample could alternatively be obtained
      there along with the routine antenatal screening blood tests.

      Non-pregnant controls will be recruited by advertising using posters around the University of
      Aberdeen/Aberdeen Royal Infirmary campus, aiming for 20 non pregnant women, aged between 16
      and 45 to have blood samples taken for serum melatonin and 6-hydroxy-melatonin sulphate
      levels. Samples will be taken at the same time of day and year as pregnant subjects to
      account for any seasonal effects.

      Serum melatonin will be measured using liquid chromatography-tandem mass spectrometry and
      6-hydroxymelatonin sulphate will be measured using enzyme immunoassay. Lipid peroxides will
      be measured using a colorimetric assay.

      Written informed consent will be obtained from all participants. Women will be asked for
      their age, body mass index, gestation stage, smoking status, name of their community midwife
      and a series of screening questions to determine eligibility according to inclusion criteria.
      Once recruited, an anonymous code will be assigned and all data will be kept separately from
      identifiable information.
observational model: Case-Control
time perspective: Prospective
measure: Change in melatonin and 6-hydroxymelatonin levels during pregnancy
time frame: Values up to 40 weeks
description: Do serum melatonin and 6-hydroxymelatonin sulphate levels differ in each trimester of pregnancy? Levels during each trimester will be compared.
measure: Change in lipid peroxide levels during pregnancy
time frame: Values up to 40 weeks
description: Does oxidative stress (lipid peroxide levels) vary in each trimester. Levels during each trimester will be compared.
measure: Relationship between melatonin and 6-hydroxymelatonin levels and duration of pregnancy.
time frame: Up to 40 weeks
description: What is melatonin status in women who deliver at different gestation (in weeks).
measure: Relationship between melatonin and 6-hydroxymelatonin levels with different types of delivery.
time frame: Up to 40 weeks
description: What is melatonin status in women with different labours (induced, spontaneous or planned caesarean section)
measure: Relationship between melatonin and 6-hydroxymelatonin levels and pre-eclampsia
time frame: Up to 40 weeks
description: What is melatonin status in women who had pre-eclampsia ( as yes/no) and those who did not.
measure: Relationship between melatonin and 6-hydroxymelatonin levels and gestational diabetes
time frame: Up to 40 weeks
description: What is melatonin status in women who had gestational diabetes ( as yes/no) compared to those who did not.
measure: Melatonin and 6-hydroxymelatonin levels in pregnancy compared to non pregnant
time frame: Up to 40 weeks
description: Is melatonin status at any time during pregnancy different to that in healthy non pregnant women? :Levels of melatonin and 6-hydroxymelatonin in non-pregnant women will be compared with levels in pregnant women.
arm group label: Pregnant
description: Normal pregnant women (first baby) singleton
arm group label: Control
description: Non pregnant healthy women
Blood
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
minimum age: 16 Years
maximum age: 45 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Hypertension, Pregnancy-Induced
sharing ipd: No