<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/NCT03023137</url>
  </required_header>
  <id_info>
    <org_study_id>HospitalSERJ</org_study_id>
    <nct_id>NCT03023137</nct_id>
  </id_info>
  <brief_title>Walking and Dietary Modification for Recurrent Early Miscarriages</brief_title>
  <acronym>W&amp;D</acronym>
  <official_title>Walking and Dietary Modification for Women With Consecutive Early Miscarriages: a Randomized Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospital dos Servidores do Estado do Rio de Janeiro</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hospital dos Servidores do Estado do Rio de Janeiro</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>
      This study is part of a big one aiming to evaluate how lifestyle interventions during&#xD;
      pregnancy affect obstetric results, neonatal metabolism and the intelligence of the offspring&#xD;
      (study not yet completed). Data regarding obstetric and neonatal results were entered in&#xD;
      NCT01409382, but we decided to split results in two for the sake of clarity.&#xD;
&#xD;
      A cohort of women with early pregnancy losses without antiphospholipid antibodies was&#xD;
      selected for two reasons. One is that these women follow strictly the recommendadtions. The&#xD;
      second is that no medication has been shown to increase the rate of take-home babies in women&#xD;
      with early miscarriages who test negative for antiphospholipid antibodies. We decided to&#xD;
      focus on the fibrinolytic system because trophoblast migration and placental vasculogenesis&#xD;
      and angiogenesis depend on plasmin-dependent extracellular matrix remodeling. Plasminogen&#xD;
      activator inhibitor (PAI)-1 inhibits the generation of plasmin. Since both glucose and&#xD;
      insulin increase PAI-1 synthesis, hyperglycemia itself, or by stimulating insulin production,&#xD;
      reduces plasmin generation, which may impair placentation.&#xD;
&#xD;
      Abnormalities in glucose metabolism may be also deleterious to embryos by causing epigenetic&#xD;
      changes. Chromosomal abnormalities are considered an important cause of early pregnancy&#xD;
      losses.&#xD;
&#xD;
      Several lines of evidence lend support to the hypothesis that carbohydrate metabolism&#xD;
      abnormalities contribute to the pathogenesis of recurrent early pregnancy losses. One is that&#xD;
      of the pregnancies of the women with polycystic ovary syndrome, around 30 and 50% end with&#xD;
      first-trimester miscarriages. Hyperinsulinemia is a prevalent feature of the syndrome, and&#xD;
      interventions proven effective in reducing insulin levels, such as metformin, have been shown&#xD;
      to reduce the rate of early miscarriages. The other is that patients with body mass index of&#xD;
      ≥25 kg/m2 have significantly higher odds of early miscarriage, regardless of the method of&#xD;
      conception.&#xD;
&#xD;
      The investigator's hypothesis was that a balanced diet combined to regular exercise, by&#xD;
      improving glucose homeostasis, would increase the take-home baby rate in women with&#xD;
      consecutive early miscarriages. Moderate exercises are usually well tolerated not only by the&#xD;
      mother, but also by the fetus, as indicated by tests of fetal well-being, including umbilical&#xD;
      artery systolic to diastolic ratio.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Women aged 18 to 40 years trying to conceive spontaneously were eligible if they had two or&#xD;
      more consecutive pregnancy losses in the first trimester, documented by pathology or&#xD;
      ultrasound-confirmed gestational sac.&#xD;
&#xD;
      All participants underwent ultrasound examination before inclusion in the study. Exclusion&#xD;
      criteria were any of the following: anatomic anomalies that may increase the risk of&#xD;
      pregnancy losses, not amenable to surgical correction during pregnancy, such as uterine&#xD;
      septum; antiphospholipid antibodies; prior second- or third-trimester losses; current&#xD;
      multiple gestation; disabilities such as hemiplegia or paraplegia; renal or liver failure;&#xD;
      conditions requiring a priori anticoagulation.&#xD;
&#xD;
      Participants were enrolled by staff at the participating center. Randomization to the&#xD;
      intervention protocol Walking and Diet (W&amp;D) or to a control group was performed before&#xD;
      pregnancy occurred by a statistician using a computer-generated random-number table. This was&#xD;
      not a double blind study, but care was taken to ensure that appointments of the patients&#xD;
      assigned to the intervention protocol did not coincide with those of controls.&#xD;
&#xD;
      The intervention was standardized by training of research staff. Women assigned to W&amp;D were&#xD;
      instructed to walk at a moderate pace (4 km/h) for at least 40 minutes, seven days a week.&#xD;
      Besides, those who remained seated most of the day were advised to walk 25 to 30 minutes&#xD;
      twice a day, avoiding hence more than 12 hours of physical inactivity. Walking could be&#xD;
      replaced by stationary bicycle rides or swimming when convenient, which often occurred near&#xD;
      term and when the mother was obese. Strenuous exercises were discouraged.&#xD;
&#xD;
      Patients assigned to protocol W&amp;D were also informed of the importance of a balanced diet and&#xD;
      recommended to avoid high-glycemic index meals (high-carbohydrate, low-fiber). Sucralose&#xD;
      could be used as a sweetener. As a strategy to promote satiety and reduce carbohydrate&#xD;
      intake, W&amp;D participants were also advised to eat at least two daily servings of protein-rich&#xD;
      food. The intervention began when participants wished to conceive, continuing until delivery.&#xD;
      Careful instructions about walking speed and diet were given to participants assigned to W&amp;D&#xD;
      at enrolment and at each consultation. During exercise, neither fetal nor maternal cardiac&#xD;
      rate were assessed.&#xD;
&#xD;
      Non-adherence to the intervention protocol was suspected when non-obese participants assigned&#xD;
      to W&amp;D gained &gt; 1 kg in 4 weeks until the 28th week of gestation, &gt; 1.5 kg from the 28th to&#xD;
      the 32nd week, and &gt; 2 kg in 4 weeks thereafter, in the absence of edema. The threshold was&#xD;
      lower for obese participants: &gt; 700 g in 4 weeks until the 28th week of gestation, &gt; 1 kg&#xD;
      from the 28th to the 32nd week, and &gt; 1.5 kg in 4 weeks thereafter21. Excessive weight gain&#xD;
      aroused the suspicion of protocol violation because high carbohydrate consumption, especially&#xD;
      when combined with physical inactivity stimulates the pancreas to overproduce insulin, a&#xD;
      hormone that promotes fat storage. To enhance adherence to the protocol, W&amp;D participants who&#xD;
      gained excessive weight were recommended to increase the frequency, duration and intensity of&#xD;
      the physical activity and to increase the protein intake. Participants of the W&amp;D group who&#xD;
      had a successful pregnancy volunteered to encourage mothers assigned to the intervention&#xD;
      protocol, especially those who gained excessive weight.&#xD;
&#xD;
      At enrollment and during first-trimester consultations, W&amp;D participants were explained that&#xD;
      antiemetics such as ondansetron should be taken before nausea became severe, in order to help&#xD;
      them tolerate balanced meals.&#xD;
&#xD;
      No recommendations regarding diet or physical activity were given to controls. Antiemetics&#xD;
      such as ondansetron were given to controls who complained of hyperemesis.&#xD;
&#xD;
      All participants were given folic acid tablets 5 mg daily until 14 weeks of gestation, as&#xD;
      prevention of neural tube defects. In both groups, participants reporting abdominal pain,&#xD;
      cramps, and vaginal bleeding during the first-trimester were medicated with vaginal&#xD;
      progesterone. Subcutaneous heparin was given to all participants whose pregnancies were&#xD;
      complicated with nephrotic range proteinuria or any evidence of placental insufficiency.&#xD;
      Antihypertensive medications included methyldopa, amlodipine and hydralazine. No patient&#xD;
      received aspirin or metformin in this study.&#xD;
&#xD;
      Appointments were scheduled according to the routine. Maternal weight and blood pressure were&#xD;
      assessed at every appointment and all mothers were screened for gestational diabetes&#xD;
      according to the American Diabetes Association recommendations.&#xD;
&#xD;
      Obstetric and neonatal outcomes were obtained from the hospital records. Neonates were&#xD;
      classified as small, appropriate or large for gestational age according to Olsen et al.&#xD;
      growth curves.&#xD;
&#xD;
      Written informed consent was obtained from each participant after a full explanation of the&#xD;
      study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>May 2011</start_date>
  <completion_date type="Actual">February 2017</completion_date>
  <primary_completion_date type="Actual">August 2016</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
    <masking_description>Participants were not blinded, but visits of the two groups were scheduled so as to not coincide..</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Take-home Baby Rate</measure>
    <time_frame>End of pregnancy</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Gestational Diabetes Mellitus</measure>
    <time_frame>Pregnancies reaching 24 weeks' gestation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Preeclampsia</measure>
    <time_frame>Pregnancies reaching 20 weeks' gestation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mothers Who Used Heparin for Nephrotic Range Proteinuria or Placental Insufficiency</measure>
    <time_frame>End of pregnancy</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Excessive Weight Gain</measure>
    <time_frame>End of term pregnancies</time_frame>
    <description>Weight gain &gt;13 kg for underweight, normal weight or overweight mothers and &gt; 9 kg for obese mothers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>First-trimester Losses</measure>
    <time_frame>14 weeks of gestation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Second and Third-trimester Losses</measure>
    <time_frame>28 weeks of gestation and end of gestation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Live-born Children</measure>
    <time_frame>End of pregnancy</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Babies Born at Term</measure>
    <time_frame>End of pregnancy</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Appropriate-for-gestational Age Babies</measure>
    <time_frame>End of pregnancy</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neonates With Hypoglycemia</measure>
    <time_frame>One, two and fours hours after birth</time_frame>
    <description>Hypoglycemia was defined as any blood glucose concentration ≤ 40 mg/dL.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">480</enrollment>
  <condition>Recurrent Miscarriage</condition>
  <arm_group>
    <arm_group_label>Walking &amp; dietary modification (W&amp;D)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>W&amp;D should begin when participants wish to conceive. The intervention was standardized by training of research staff. Careful instructions about walking speed and diet would be given to participants assigned to W&amp;D at enrolment and at each consultation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Controls</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>No recommendations regarding diet or physical activity were given to controls. Antiemetics such as ondansetron would be given to controls complaining of vomiting.</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Walking &amp; dietary modification</intervention_name>
    <description>Daily walking at a moderate pace (4 km/h) &gt; 40 min, 7/7. Those remaining seated most of the day should walk 25-30 min twice a day, avoiding &gt;12 h of physical inactivity. Walking may be replaced by stationary bicycle rides or swimming when convenient, which often occurred near term and when the mother was obese.&#xD;
At least two daily servings of protein-rich food (≥ 4 g/kg of meat, poultry, fish or eggs) per day. Avoidance of high-carbohydrate, low-fiber meals, such as snacks, candies, fiber-free juices, coconut water or sugar-sweetened beverages. Sucralose could be used as a sweetener. Participants are recommended to use ondansetron for nausea and vomiting prevention</description>
    <arm_group_label>Walking &amp; dietary modification (W&amp;D)</arm_group_label>
    <other_name>W&amp;D</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  ≥ 2 consecutive pregnancy losses in the first trimester;&#xD;
&#xD;
          -  losses should be documented by pathology or ultrasound-confirmed gestational sac.&#xD;
&#xD;
        Exclusion Criteria (any of the following):&#xD;
&#xD;
          -  anatomic anomalies that may increase the risk of pregnancy losses, not amenable to&#xD;
             surgical correction during pregnancy, such as uterine septum;&#xD;
&#xD;
          -  antiphospholipid antibodies;&#xD;
&#xD;
          -  prior second- or third-trimester losses;&#xD;
&#xD;
          -  current multiple gestation;&#xD;
&#xD;
          -  disabilities such as hemiplegia or paraplegia;&#xD;
&#xD;
          -  renal or liver failure;&#xD;
&#xD;
          -  conditions requiring a priori anticoagulation&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Silvia Hoirisch-Clapauch, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hospital Federal dos Servidores do Estado</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital Federal dos Servidores do Estado, Ministry of Health</name>
      <address>
        <city>Rio de Janeiro</city>
        <state>RJ</state>
        <zip>20221-903</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <verification_date>April 2017</verification_date>
  <study_first_submitted>January 13, 2017</study_first_submitted>
  <study_first_submitted_qc>January 17, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 18, 2017</study_first_posted>
  <results_first_submitted>February 2, 2017</results_first_submitted>
  <results_first_submitted_qc>February 20, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">April 6, 2017</results_first_posted>
  <last_update_submitted>April 6, 2017</last_update_submitted>
  <last_update_submitted_qc>April 6, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">April 10, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Hospital dos Servidores do Estado do Rio de Janeiro</investigator_affiliation>
    <investigator_full_name>Silvia Hoirisch Clapauch</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>prevention</keyword>
  <keyword>carbohydrate</keyword>
  <keyword>exercise</keyword>
  <keyword>neonatal hypoglycemia</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Abortion, Spontaneous</mesh_term>
    <mesh_term>Abortion, Habitual</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Recruitment started on May 2011 and was stopped on April 2015.</recruitment_details>
      <pre_assignment_details>Of 491 patients approached, 11 declined participation in the study and 480 were enrolled. Participants in the W+D arm were recommended lifestyle changes to be started when they wished to conceive. Only participants in both groups who managed to get pregnant were included in the study.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Walking &amp; Dietary Modification (W&amp;D)</title>
          <description>The intervention was standardized by training of research staff and should begin when participants wish to conceive. Careful instructions about walking speed and diet would be given to participants assigned to W&amp;D at enrollment and at each consultation.&#xD;
Walking &amp; dietary modification: 1. Daily walking at a moderate pace (4 km/h) &gt; 40 min, 7/7. Those whose jobs required them to seat for long periods should walk 25-30 min twice a day, avoiding &gt;12 h of physical inactivity. Walking may be replaced by stationary bicycle rides or swimming when convenient, such as near term.&#xD;
2. At least two daily servings of protein-rich food (≥ 4 g/kg of meat, poultry, fish or eggs) per day. Avoidance of high-carbohydrate, low-fiber meals, such as snacks, candies, fiber-free juices, coconut water, sugar-sweetened beverages or large amount of fruits. Sucralose could be used as a sweetener. Participants were recommended to use ondansetron for nausea and vomiting prevention</description>
        </group>
        <group group_id="P2">
          <title>Controls</title>
          <description>No recommendations regarding diet or physical activity were given to controls. Antiemetics such as ondansetron would be given to controls complaining of vomiting.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="178"/>
                <participants group_id="P2" count="171"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="174"/>
                <participants group_id="P2" count="162"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Multiple pregnancy</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost the baby in a car accident</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Walking &amp; Dietary Modification (W&amp;D)</title>
          <description>The intervention was standardized by training of research staff and should begin when participants wish to conceive. Careful instructions about walking speed and diet would be given to participants assigned to W&amp;D at enrolment and at each consultation.&#xD;
Walking &amp; dietary modification: 1. Daily walking at a moderate pace (4 km/h) &gt; 40 min, 7/7. Those whose jobs required them to seat for long periods should walk 25-30 min twice a day, avoiding &gt;12 h of physical inactivity. Walking may be replaced by stationary bicycle rides or swimming when convenient, such as near term.&#xD;
2. At least two daily servings of protein-rich food (≥ 4 g/kg of meat, poultry, fish or eggs) per day. Avoidance of high-carbohydrate, low-fiber meals, such as snacks, candies, fiber-free juices, coconut water or sugar-sweetened beverages. Sucralose could be used as a sweetener. Participants were recommended to use ondansetron for nausea and vomiting prevention</description>
        </group>
        <group group_id="B2">
          <title>Controls</title>
          <description>No recommendations regarding diet or physical activity were given to controls. Antiemetics such as ondansetron would be given to controls complaining of vomiting.</description>
        </group>
        <group group_id="B3">
          <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="174"/>
            <count group_id="B2" value="162"/>
            <count group_id="B3" value="336"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="31" spread="7"/>
                    <measurement group_id="B2" value="30" spread="8"/>
                    <measurement group_id="B3" value="30" spread="8"/>
                  </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>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="174"/>
                    <measurement group_id="B2" value="162"/>
                    <measurement group_id="B3" value="336"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                    <measurement group_id="B2" value="13"/>
                    <measurement group_id="B3" value="34"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="72"/>
                    <measurement group_id="B2" value="62"/>
                    <measurement group_id="B3" value="134"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="81"/>
                    <measurement group_id="B2" value="87"/>
                    <measurement group_id="B3" value="168"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Brazil</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="174"/>
                    <measurement group_id="B2" value="162"/>
                    <measurement group_id="B3" value="336"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Normal or underweight (BMI &lt;25 kg/m2)</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="105"/>
                    <measurement group_id="B2" value="95"/>
                    <measurement group_id="B3" value="200"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Owerweight (BMI 25-30 kg/m2)</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="53"/>
                    <measurement group_id="B2" value="48"/>
                    <measurement group_id="B3" value="101"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Obese (BMI &gt; 30 kg/m2)</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                    <measurement group_id="B2" value="19"/>
                    <measurement group_id="B3" value="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Type 1 diabetes mellitus</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Chronic hypertension</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Women with live offspring</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="36"/>
                    <measurement group_id="B2" value="28"/>
                    <measurement group_id="B3" value="64"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Take-home Baby Rate</title>
        <time_frame>End of pregnancy</time_frame>
        <population>Since we excluded multiple gestations, there were 174 single pregnancies in group W&amp;D and 162 in the control group.</population>
        <group_list>
          <group group_id="O1">
            <title>Walking &amp; Dietary Modification (W&amp;D)</title>
            <description>The intervention was standardized by training of research staff and should begin when participants wish to conceive. Careful instructions about walking speed and diet would be given to participants assigned to W&amp;D at enrollment and at each consultation.&#xD;
Walking &amp; dietary modification: 1. Daily walking at a moderate pace (4 km/h) &gt; 40 min, 7/7. Those whose jobs required them to seat for long periods should walk 25-30 min twice a day, avoiding &gt;12 h of physical inactivity. Walking may be replaced by stationary bicycle rides or swimming when convenient, such as near term.&#xD;
2. At least two daily servings of protein-rich food (≥ 4 g/kg of meat, poultry, fish or eggs) per day. Avoidance of high-carbohydrate, low-fiber meals, such as snacks, candies, fiber-free juices, coconut water, sugar-sweetened beverages and large amount of fruits. Sucralose could be used as a sweetener. Participants were recommended to use ondansetron for nausea and vomiting prevention</description>
          </group>
          <group group_id="O2">
            <title>Controls</title>
            <description>No recommendations regarding diet or physical activity were given to controls. Antiemetics such as ondansetron would be given to controls complaining of vomiting.</description>
          </group>
        </group_list>
        <measure>
          <title>Take-home Baby Rate</title>
          <population>Since we excluded multiple gestations, there were 174 single pregnancies in group W&amp;D and 162 in the control group.</population>
          <units>babies</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="174"/>
                <count group_id="O2" value="162"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="152"/>
                    <measurement group_id="O2" value="83"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Gestational Diabetes Mellitus</title>
        <time_frame>Pregnancies reaching 24 weeks' gestation</time_frame>
        <population>A total of 154 pregnancies in group W&amp;D and 98 pregnancies in the control group reached 24 weeks of gestation.</population>
        <group_list>
          <group group_id="O1">
            <title>Walking &amp; Dietary Modification (W&amp;D)</title>
            <description>The intervention was standardized by training of research staff and should begin when participants wish to conceive. Careful instructions about walking speed and diet would be given to participants assigned to W&amp;D at enrollment and at each consultation.&#xD;
Walking &amp; dietary modification: 1. Daily walking at a moderate pace (4 km/h) &gt; 40 min, 7/7. Those whose jobs required them to seat for long periods should walk 25-30 min twice a day, avoiding &gt;12 h of physical inactivity. Walking may be replaced by stationary bicycle rides or swimming when convenient, such as near term.&#xD;
2. At least two daily servings of protein-rich food (≥ 4 g/kg of meat, poultry, fish or eggs) per day. Avoidance of high-carbohydrate, low-fiber meals, such as snacks, candies, fiber-free juices, coconut water, sugar-sweetened beverages or large amount of fruits. Sucralose could be used as a sweetener. Participants were recommended to use ondansetron for nausea and vomiting prevention</description>
          </group>
          <group group_id="O2">
            <title>Controls</title>
            <description>No recommendations regarding diet or physical activity were given to controls. Antiemetics such as ondansetron would be given to controls complaining of vomiting.</description>
          </group>
        </group_list>
        <measure>
          <title>Gestational Diabetes Mellitus</title>
          <population>A total of 154 pregnancies in group W&amp;D and 98 pregnancies in the control group reached 24 weeks of gestation.</population>
          <units>mothers</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="154"/>
                <count group_id="O2" value="98"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Preeclampsia</title>
        <time_frame>Pregnancies reaching 20 weeks' gestation</time_frame>
        <population>A total of 154 pregnancies reached 20 weeks in group W&amp;D and 98 in the control group.</population>
        <group_list>
          <group group_id="O1">
            <title>Walking &amp; Dietary Modification (W&amp;D)</title>
            <description>The intervention was standardized by training of research staff and should begin when participants wish to conceive. Careful instructions about walking speed and diet would be given to participants assigned to W&amp;D at enrollment and at each consultation.&#xD;
Walking &amp; dietary modification: 1. Daily walking at a moderate pace (4 km/h) &gt; 40 min, 7/7. Those whose jobs required them to seat for long periods should walk 25-30 min twice a day, avoiding &gt;12 h of physical inactivity. Walking may be replaced by stationary bicycle rides or swimming when convenient, such as near term.&#xD;
2. At least two daily servings of protein-rich food (≥ 4 g/kg of meat, poultry, fish or eggs) per day. Avoidance of high-carbohydrate, low-fiber meals, such as snacks, candies, fiber-free juices, coconut water, sugar-sweetened beverages or large amount of fruits. Sucralose could be used as a sweetener. Participants were recommended to use ondansetron for nausea and vomiting prevention</description>
          </group>
          <group group_id="O2">
            <title>Controls</title>
            <description>No recommendations regarding diet or physical activity were given to controls. Antiemetics such as ondansetron would be given to controls complaining of vomiting.</description>
          </group>
        </group_list>
        <measure>
          <title>Preeclampsia</title>
          <population>A total of 154 pregnancies reached 20 weeks in group W&amp;D and 98 in the control group.</population>
          <units>mothers</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="154"/>
                <count group_id="O2" value="98"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                    <measurement group_id="O2" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mothers Who Used Heparin for Nephrotic Range Proteinuria or Placental Insufficiency</title>
        <time_frame>End of pregnancy</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Walking &amp; Dietary Modification (W&amp;D)</title>
            <description>The intervention was standardized by training of research staff and should begin when participants wish to conceive. Careful instructions about walking speed and diet would be given to participants assigned to W&amp;D at enrollment and at each consultation.&#xD;
Walking &amp; dietary modification: 1. Daily walking at a moderate pace (4 km/h) &gt; 40 min, 7/7. Those whose jobs required them to seat for long periods should walk 25-30 min twice a day, avoiding &gt;12 h of physical inactivity. Walking may be replaced by stationary bicycle rides or swimming when convenient, such as near term.&#xD;
2. At least two daily servings of protein-rich food (≥ 4 g/kg of meat, poultry, fish or eggs) per day. Avoidance of high-carbohydrate, low-fiber meals, such as snacks, candies, fiber-free juices, coconut water, sugar-sweetened beverages or large amount of fruits. Sucralose could be used as a sweetener. Participants were recommended to use ondansetron for nausea and vomiting prevention</description>
          </group>
          <group group_id="O2">
            <title>Controls</title>
            <description>No recommendations regarding diet or physical activity were given to controls. Antiemetics such as ondansetron would be given to controls complaining of vomiting.</description>
          </group>
        </group_list>
        <measure>
          <title>Mothers Who Used Heparin for Nephrotic Range Proteinuria or Placental Insufficiency</title>
          <units>mothers</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="174"/>
                <count group_id="O2" value="162"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10"/>
                    <measurement group_id="O2" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Excessive Weight Gain</title>
        <description>Weight gain &gt;13 kg for underweight, normal weight or overweight mothers and &gt; 9 kg for obese mothers</description>
        <time_frame>End of term pregnancies</time_frame>
        <population>A total of 148 pregnancies in group W&amp;D and 57 pregnancies in the control group reached term.</population>
        <group_list>
          <group group_id="O1">
            <title>Walking &amp; Dietary Modification (W&amp;D)</title>
            <description>The intervention was standardized by training of research staff and should begin when participants wish to conceive. Careful instructions about walking speed and diet would be given to participants assigned to W&amp;D at enrollment and at each consultation.&#xD;
Walking &amp; dietary modification: 1. Daily walking at a moderate pace (4 km/h) &gt; 40 min, 7/7. Those whose jobs required them to seat for long periods should walk 25-30 min twice a day, avoiding &gt;12 h of physical inactivity. Walking may be replaced by stationary bicycle rides or swimming when convenient, such as near term.&#xD;
2. At least two daily servings of protein-rich food (≥ 4 g/kg of meat, poultry, fish or eggs) per day. Avoidance of high-carbohydrate, low-fiber meals, such as snacks, candies, fiber-free juices, coconut water, sugar-sweetened beverages or large amount of fruits. Sucralose could be used as a sweetener. Participants were recommended to use ondansetron for nausea and vomiting prevention</description>
          </group>
          <group group_id="O2">
            <title>Controls</title>
            <description>No recommendations regarding diet or physical activity were given to controls. Antiemetics such as ondansetron would be given to controls complaining of vomiting.</description>
          </group>
        </group_list>
        <measure>
          <title>Excessive Weight Gain</title>
          <description>Weight gain &gt;13 kg for underweight, normal weight or overweight mothers and &gt; 9 kg for obese mothers</description>
          <population>A total of 148 pregnancies in group W&amp;D and 57 pregnancies in the control group reached term.</population>
          <units>mothers</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="148"/>
                <count group_id="O2" value="57"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12"/>
                    <measurement group_id="O2" value="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>First-trimester Losses</title>
        <time_frame>14 weeks of gestation</time_frame>
        <population>Since we excluded multiple gestations, there were 174 single pregnancies in group W&amp;D and 162 in the control group.</population>
        <group_list>
          <group group_id="O1">
            <title>Walking &amp; Dietary Modification (W&amp;D)</title>
            <description>The intervention was standardized by training of research staff and should begin when participants wish to conceive. Careful instructions about walking speed and diet would be given to participants assigned to W&amp;D at enrollment and at each consultation.&#xD;
Walking &amp; dietary modification: 1. Daily walking at a moderate pace (4 km/h) &gt; 40 min, 7/7. Those whose jobs required them to seat for long periods should walk 25-30 min twice a day, avoiding &gt;12 h of physical inactivity. Walking may be replaced by stationary bicycle rides or swimming when convenient, such as near term.&#xD;
2. At least two daily servings of protein-rich food (≥ 4 g/kg of meat, poultry, fish or eggs) per day. Avoidance of high-carbohydrate, low-fiber meals, such as snacks, candies, fiber-free juices, coconut water, sugar-sweetened beverages or large amount of fruits. Sucralose could be used as a sweetener. Participants were recommended to use ondansetron for nausea and vomiting prevention</description>
          </group>
          <group group_id="O2">
            <title>Controls</title>
            <description>No recommendations regarding diet or physical activity were given to controls. Antiemetics such as ondansetron would be given to controls complaining of vomiting.</description>
          </group>
        </group_list>
        <measure>
          <title>First-trimester Losses</title>
          <population>Since we excluded multiple gestations, there were 174 single pregnancies in group W&amp;D and 162 in the control group.</population>
          <units>embryos</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="174"/>
                <count group_id="O2" value="162"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21"/>
                    <measurement group_id="O2" value="63"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Second and Third-trimester Losses</title>
        <time_frame>28 weeks of gestation and end of gestation</time_frame>
        <population>Since we excluded multiple gestations, there were 174 single pregnancies in group W&amp;D and 162 in the control group.</population>
        <group_list>
          <group group_id="O1">
            <title>Walking &amp; Dietary Modification (W&amp;D)</title>
            <description>The intervention was standardized by training of research staff and should begin when participants wish to conceive. Careful instructions about walking speed and diet would be given to participants assigned to W&amp;D at enrollment and at each consultation.&#xD;
Walking &amp; dietary modification: 1. Daily walking at a moderate pace (4 km/h) &gt; 40 min, 7/7. Those whose jobs required them to seat for long periods should walk 25-30 min twice a day, avoiding &gt;12 h of physical inactivity. Walking may be replaced by stationary bicycle rides or swimming when convenient, such as near term.&#xD;
2. At least two daily servings of protein-rich food (≥ 4 g/kg of meat, poultry, fish or eggs) per day. Avoidance of high-carbohydrate, low-fiber meals, such as snacks, candies, fiber-free juices, coconut water, sugar-sweetened beverages or large amount of fruits. Sucralose could be used as a sweetener. Participants were recommended to use ondansetron for nausea and vomiting prevention</description>
          </group>
          <group group_id="O2">
            <title>Controls</title>
            <description>No recommendations regarding diet or physical activity were given to controls. Antiemetics such as ondansetron would be given to controls complaining of vomiting.</description>
          </group>
        </group_list>
        <measure>
          <title>Second and Third-trimester Losses</title>
          <population>Since we excluded multiple gestations, there were 174 single pregnancies in group W&amp;D and 162 in the control group.</population>
          <units>fetuses</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="174"/>
                <count group_id="O2" value="162"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Live-born Children</title>
        <time_frame>End of pregnancy</time_frame>
        <population>A total of 153 babies were born alive in group W&amp;D and 91 in the control group.</population>
        <group_list>
          <group group_id="O1">
            <title>Walking &amp; Dietary Modification (W&amp;D)</title>
            <description>The intervention was standardized by training of research staff and should begin when participants wish to conceive. Careful instructions about walking speed and diet would be given to participants assigned to W&amp;D at enrollment and at each consultation.&#xD;
Walking &amp; dietary modification: 1. Daily walking at a moderate pace (4 km/h) &gt; 40 min, 7/7. Those whose jobs required them to seat for long periods should walk 25-30 min twice a day, avoiding &gt;12 h of physical inactivity. Walking may be replaced by stationary bicycle rides or swimming when convenient, such as near term.&#xD;
2. At least two daily servings of protein-rich food (≥ 4 g/kg of meat, poultry, fish or eggs) per day. Avoidance of high-carbohydrate, low-fiber meals, such as snacks, candies, fiber-free juices, coconut water, sugar-sweetened beverages or large amount of fruits. Sucralose could be used as a sweetener. Participants were recommended to use ondansetron for nausea and vomiting prevention</description>
          </group>
          <group group_id="O2">
            <title>Controls</title>
            <description>No recommendations regarding diet or physical activity were given to controls. Antiemetics such as ondansetron would be given to controls complaining of vomiting.</description>
          </group>
        </group_list>
        <measure>
          <title>Live-born Children</title>
          <population>A total of 153 babies were born alive in group W&amp;D and 91 in the control group.</population>
          <units>babies</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="174"/>
                <count group_id="O2" value="162"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="153"/>
                    <measurement group_id="O2" value="91"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Babies Born at Term</title>
        <time_frame>End of pregnancy</time_frame>
        <population>A total of 153 babies were born alive in group W&amp;D and 91 in the control group.</population>
        <group_list>
          <group group_id="O1">
            <title>Walking &amp; Dietary Modification (W&amp;D)</title>
            <description>The intervention was standardized by training of research staff and should begin when participants wish to conceive. Careful instructions about walking speed and diet would be given to participants assigned to W&amp;D at enrollment and at each consultation.&#xD;
Walking &amp; dietary modification: 1. Daily walking at a moderate pace (4 km/h) &gt; 40 min, 7/7. Those whose jobs required them to seat for long periods should walk 25-30 min twice a day, avoiding &gt;12 h of physical inactivity. Walking may be replaced by stationary bicycle rides or swimming when convenient, such as near term.&#xD;
2. At least two daily servings of protein-rich food (≥ 4 g/kg of meat, poultry, fish or eggs) per day. Avoidance of high-carbohydrate, low-fiber meals, such as snacks, candies, fiber-free juices, coconut water, sugar-sweetened beverages or large amount of fruits. Sucralose could be used as a sweetener. Participants were recommended to use ondansetron for nausea and vomiting prevention</description>
          </group>
          <group group_id="O2">
            <title>Controls</title>
            <description>No recommendations regarding diet or physical activity were given to controls. Antiemetics such as ondansetron would be given to controls complaining of vomiting.</description>
          </group>
        </group_list>
        <measure>
          <title>Babies Born at Term</title>
          <population>A total of 153 babies were born alive in group W&amp;D and 91 in the control group.</population>
          <units>babies</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="153"/>
                <count group_id="O2" value="91"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="138"/>
                    <measurement group_id="O2" value="57"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Appropriate-for-gestational Age Babies</title>
        <time_frame>End of pregnancy</time_frame>
        <population>A total of 153 babies were born alive in group W&amp;D and 91 in the control group.</population>
        <group_list>
          <group group_id="O1">
            <title>Walking &amp; Dietary Modification (W&amp;D)</title>
            <description>The intervention was standardized by training of research staff and should begin when participants wish to conceive. Careful instructions about walking speed and diet would be given to participants assigned to W&amp;D at enrollment and at each consultation.&#xD;
Walking &amp; dietary modification: 1. Daily walking at a moderate pace (4 km/h) &gt; 40 min, 7/7. Those whose jobs required them to seat for long periods should walk 25-30 min twice a day, avoiding &gt;12 h of physical inactivity. Walking may be replaced by stationary bicycle rides or swimming when convenient, such as near term.&#xD;
2. At least two daily servings of protein-rich food (≥ 4 g/kg of meat, poultry, fish or eggs) per day. Avoidance of high-carbohydrate, low-fiber meals, such as snacks, candies, fiber-free juices, coconut water, sugar-sweetened beverages or large amount of fruits. Sucralose could be used as a sweetener. Participants were recommended to use ondansetron for nausea and vomiting prevention</description>
          </group>
          <group group_id="O2">
            <title>Controls</title>
            <description>No recommendations regarding diet or physical activity were given to controls. Antiemetics such as ondansetron would be given to controls complaining of vomiting.</description>
          </group>
        </group_list>
        <measure>
          <title>Appropriate-for-gestational Age Babies</title>
          <population>A total of 153 babies were born alive in group W&amp;D and 91 in the control group.</population>
          <units>babies</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="153"/>
                <count group_id="O2" value="91"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="141"/>
                    <measurement group_id="O2" value="56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Neonates With Hypoglycemia</title>
        <description>Hypoglycemia was defined as any blood glucose concentration ≤ 40 mg/dL.</description>
        <time_frame>One, two and fours hours after birth</time_frame>
        <population>A total of 153 babies were born alive in group W&amp;D and 91 in the control group.</population>
        <group_list>
          <group group_id="O1">
            <title>Walking &amp; Dietary Modification (W&amp;D)</title>
            <description>The intervention was standardized by training of research staff and should begin when participants wish to conceive. Careful instructions about walking speed and diet would be given to participants assigned to W&amp;D at enrollment and at each consultation.&#xD;
Walking &amp; dietary modification: 1. Daily walking at a moderate pace (4 km/h) &gt; 40 min, 7/7. Those whose jobs required them to seat for long periods should walk 25-30 min twice a day, avoiding &gt;12 h of physical inactivity. Walking may be replaced by stationary bicycle rides or swimming when convenient, such as near term.&#xD;
2. At least two daily servings of protein-rich food (≥ 4 g/kg of meat, poultry, fish or eggs) per day. Avoidance of high-carbohydrate, low-fiber meals, such as snacks, candies, fiber-free juices, coconut water, sugar-sweetened beverages or large amount of fruits. Sucralose could be used as a sweetener. Participants were recommended to use ondansetron for nausea and vomiting prevention</description>
          </group>
          <group group_id="O2">
            <title>Controls</title>
            <description>No recommendations regarding diet or physical activity were given to controls. Antiemetics such as ondansetron would be given to controls complaining of vomiting.</description>
          </group>
        </group_list>
        <measure>
          <title>Neonates With Hypoglycemia</title>
          <description>Hypoglycemia was defined as any blood glucose concentration ≤ 40 mg/dL.</description>
          <population>A total of 153 babies were born alive in group W&amp;D and 91 in the control group.</population>
          <units>babies</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="153"/>
                <count group_id="O2" value="91"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Throughout pregnancy</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Walking &amp; Dietary Modification (W&amp;D)</title>
          <description>The intervention was standardized by training of research staff and should begin when participants wish to conceive. Careful instructions about walking speed and diet will be given to participants assigned to W&amp;D at enrollment and at each consultation.&#xD;
Walking &amp; dietary modification: 1. Daily walking at a moderate pace (4 km/h) &gt; 40 min, 7/7. Those whose jobs required them to seat for long periods should walk 25-30 min twice a day, avoiding &gt;12 h of physical inactivity. Walking may be replaced by stationary bicycle rides or swimming when convenient, such as near term.&#xD;
2. At least two daily servings of protein-rich food (≥ 4 g/kg of meat, poultry, fish or eggs) per day. Avoidance of high-carbohydrate, low-fiber meals, such as snacks, candies, fiber-free juices, coconut water, sugar-sweetened beverages or large amount of fruits. Sucralose could be used as a sweetener. Participants were recommended to use ondansetron for nausea and vomiting prevention</description>
        </group>
        <group group_id="E2">
          <title>Controls</title>
          <description>No recommendations regarding diet or physical activity were given to controls. Antiemetics such as ondansetron would be given to controls complaining of vomiting.</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="0" subjects_at_risk="245"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="255"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="245"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="255"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="245"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="255"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Bone and joint injury</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="245"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="255"/>
              </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>An important limitation of this study is that it did not assess the exact composition of the participants' diet.&#xD;
Another limitation is that the use of heparin use was not controlled in this study.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. Silvia Hoirisch-Clapauch</name_or_title>
      <organization>Hospital Federal dos Servidores do Estado</organization>
      <phone>5521999737500</phone>
      <email>sclapauch@gmail.com</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/NCT03023137
org study id: HospitalSERJ
nct id: NCT03023137
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This study is part of a big one aiming to evaluate how lifestyle interventions during
      pregnancy affect obstetric results, neonatal metabolism and the intelligence of the offspring
      (study not yet completed). Data regarding obstetric and neonatal results were entered in
      NCT01409382, but we decided to split results in two for the sake of clarity.

      A cohort of women with early pregnancy losses without antiphospholipid antibodies was
      selected for two reasons. One is that these women follow strictly the recommendadtions. The
      second is that no medication has been shown to increase the rate of take-home babies in women
      with early miscarriages who test negative for antiphospholipid antibodies. We decided to
      focus on the fibrinolytic system because trophoblast migration and placental vasculogenesis
      and angiogenesis depend on plasmin-dependent extracellular matrix remodeling. Plasminogen
      activator inhibitor (PAI)-1 inhibits the generation of plasmin. Since both glucose and
      insulin increase PAI-1 synthesis, hyperglycemia itself, or by stimulating insulin production,
      reduces plasmin generation, which may impair placentation.

      Abnormalities in glucose metabolism may be also deleterious to embryos by causing epigenetic
      changes. Chromosomal abnormalities are considered an important cause of early pregnancy
      losses.

      Several lines of evidence lend support to the hypothesis that carbohydrate metabolism
      abnormalities contribute to the pathogenesis of recurrent early pregnancy losses. One is that
      of the pregnancies of the women with polycystic ovary syndrome, around 30 and 50% end with
      first-trimester miscarriages. Hyperinsulinemia is a prevalent feature of the syndrome, and
      interventions proven effective in reducing insulin levels, such as metformin, have been shown
      to reduce the rate of early miscarriages. The other is that patients with body mass index of
      ≥25 kg/m2 have significantly higher odds of early miscarriage, regardless of the method of
      conception.

      The investigator's hypothesis was that a balanced diet combined to regular exercise, by
      improving glucose homeostasis, would increase the take-home baby rate in women with
      consecutive early miscarriages. Moderate exercises are usually well tolerated not only by the
      mother, but also by the fetus, as indicated by tests of fetal well-being, including umbilical
      artery systolic to diastolic ratio.
Women aged 18 to 40 years trying to conceive spontaneously were eligible if they had two or
      more consecutive pregnancy losses in the first trimester, documented by pathology or
      ultrasound-confirmed gestational sac.

      All participants underwent ultrasound examination before inclusion in the study. Exclusion
      criteria were any of the following: anatomic anomalies that may increase the risk of
      pregnancy losses, not amenable to surgical correction during pregnancy, such as uterine
      septum; antiphospholipid antibodies; prior second- or third-trimester losses; current
      multiple gestation; disabilities such as hemiplegia or paraplegia; renal or liver failure;
      conditions requiring a priori anticoagulation.

      Participants were enrolled by staff at the participating center. Randomization to the
      intervention protocol Walking and Diet (W&D) or to a control group was performed before
      pregnancy occurred by a statistician using a computer-generated random-number table. This was
      not a double blind study, but care was taken to ensure that appointments of the patients
      assigned to the intervention protocol did not coincide with those of controls.

      The intervention was standardized by training of research staff. Women assigned to W&D were
      instructed to walk at a moderate pace (4 km/h) for at least 40 minutes, seven days a week.
      Besides, those who remained seated most of the day were advised to walk 25 to 30 minutes
      twice a day, avoiding hence more than 12 hours of physical inactivity. Walking could be
      replaced by stationary bicycle rides or swimming when convenient, which often occurred near
      term and when the mother was obese. Strenuous exercises were discouraged.

      Patients assigned to protocol W&D were also informed of the importance of a balanced diet and
      recommended to avoid high-glycemic index meals (high-carbohydrate, low-fiber). Sucralose
      could be used as a sweetener. As a strategy to promote satiety and reduce carbohydrate
      intake, W&D participants were also advised to eat at least two daily servings of protein-rich
      food. The intervention began when participants wished to conceive, continuing until delivery.
      Careful instructions about walking speed and diet were given to participants assigned to W&D
      at enrolment and at each consultation. During exercise, neither fetal nor maternal cardiac
      rate were assessed.

      Non-adherence to the intervention protocol was suspected when non-obese participants assigned
      to W&D gained > 1 kg in 4 weeks until the 28th week of gestation, > 1.5 kg from the 28th to
      the 32nd week, and > 2 kg in 4 weeks thereafter, in the absence of edema. The threshold was
      lower for obese participants: > 700 g in 4 weeks until the 28th week of gestation, > 1 kg
      from the 28th to the 32nd week, and > 1.5 kg in 4 weeks thereafter21. Excessive weight gain
      aroused the suspicion of protocol violation because high carbohydrate consumption, especially
      when combined with physical inactivity stimulates the pancreas to overproduce insulin, a
      hormone that promotes fat storage. To enhance adherence to the protocol, W&D participants who
      gained excessive weight were recommended to increase the frequency, duration and intensity of
      the physical activity and to increase the protein intake. Participants of the W&D group who
      had a successful pregnancy volunteered to encourage mothers assigned to the intervention
      protocol, especially those who gained excessive weight.

      At enrollment and during first-trimester consultations, W&D participants were explained that
      antiemetics such as ondansetron should be taken before nausea became severe, in order to help
      them tolerate balanced meals.

      No recommendations regarding diet or physical activity were given to controls. Antiemetics
      such as ondansetron were given to controls who complained of hyperemesis.

      All participants were given folic acid tablets 5 mg daily until 14 weeks of gestation, as
      prevention of neural tube defects. In both groups, participants reporting abdominal pain,
      cramps, and vaginal bleeding during the first-trimester were medicated with vaginal
      progesterone. Subcutaneous heparin was given to all participants whose pregnancies were
      complicated with nephrotic range proteinuria or any evidence of placental insufficiency.
      Antihypertensive medications included methyldopa, amlodipine and hydralazine. No patient
      received aspirin or metformin in this study.

      Appointments were scheduled according to the routine. Maternal weight and blood pressure were
      assessed at every appointment and all mothers were screened for gestational diabetes
      according to the American Diabetes Association recommendations.

      Obstetric and neonatal outcomes were obtained from the hospital records. Neonates were
      classified as small, appropriate or large for gestational age according to Olsen et al.
      growth curves.

      Written informed consent was obtained from each participant after a full explanation of the
      study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Single (Outcomes Assessor)
masking description: Participants were not blinded, but visits of the two groups were scheduled so as to not coincide..
measure: Take-home Baby Rate
time frame: End of pregnancy
measure: Gestational Diabetes Mellitus
time frame: Pregnancies reaching 24 weeks' gestation
measure: Preeclampsia
time frame: Pregnancies reaching 20 weeks' gestation
measure: Mothers Who Used Heparin for Nephrotic Range Proteinuria or Placental Insufficiency
time frame: End of pregnancy
measure: Excessive Weight Gain
time frame: End of term pregnancies
description: Weight gain >13 kg for underweight, normal weight or overweight mothers and > 9 kg for obese mothers
measure: First-trimester Losses
time frame: 14 weeks of gestation
measure: Second and Third-trimester Losses
time frame: 28 weeks of gestation and end of gestation
measure: Live-born Children
time frame: End of pregnancy
measure: Babies Born at Term
time frame: End of pregnancy
measure: Appropriate-for-gestational Age Babies
time frame: End of pregnancy
measure: Neonates With Hypoglycemia
time frame: One, two and fours hours after birth
description: Hypoglycemia was defined as any blood glucose concentration ≤ 40 mg/dL.
arm group label: Walking & dietary modification (W&D)
arm group type: Active Comparator
description: W&D should begin when participants wish to conceive. The intervention was standardized by training of research staff. Careful instructions about walking speed and diet would be given to participants assigned to W&D at enrolment and at each consultation.
arm group label: Controls
arm group type: No Intervention
description: No recommendations regarding diet or physical activity were given to controls. Antiemetics such as ondansetron would be given to controls complaining of vomiting.
intervention type: Behavioral
intervention name: Walking & dietary modification
description: Daily walking at a moderate pace (4 km/h) > 40 min, 7/7. Those remaining seated most of the day should walk 25-30 min twice a day, avoiding >12 h of physical inactivity. Walking may be replaced by stationary bicycle rides or swimming when convenient, which often occurred near term and when the mother was obese.
At least two daily servings of protein-rich food (≥ 4 g/kg of meat, poultry, fish or eggs) per day. Avoidance of high-carbohydrate, low-fiber meals, such as snacks, candies, fiber-free juices, coconut water or sugar-sweetened beverages. Sucralose could be used as a sweetener. Participants are recommended to use ondansetron for nausea and vomiting prevention
arm group label: Walking & dietary modification (W&D)
other name: W&D
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 40 Years
healthy volunteers: No
last name: Silvia Hoirisch-Clapauch, MD, PhD
role: Principal Investigator
affiliation: Hospital Federal dos Servidores do Estado
facility: 
country: Brazil
responsible party type: Principal Investigator
investigator affiliation: Hospital dos Servidores do Estado do Rio de Janeiro
investigator full name: Silvia Hoirisch Clapauch
investigator title: Principal Investigator
mesh term: Abortion, Spontaneous
mesh term: Abortion, Habitual
sharing ipd: Yes
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: An important limitation of this study is that it did not assess the exact composition of the participants' diet.
Another limitation is that the use of heparin use was not controlled in this study.
point of contact: 