<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/NCT01723696</url>
  </required_header>
  <id_info>
    <org_study_id>HL105447</org_study_id>
    <secondary_id>R01HL105447</secondary_id>
    <nct_id>NCT01723696</nct_id>
  </id_info>
  <brief_title>Vitamin C to Decrease Effects of Smoking in Pregnancy on Infant Lung Function</brief_title>
  <acronym>VCSIP</acronym>
  <official_title>Vitamin C to Decrease Effects of Smoking in Pregnancy on Infant Lung Function</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Oregon Health and Science University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Office of Dietary Supplements (ODS)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Oregon Health and Science University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Vitamin C supplementation (500 mg per day) given to pregnant women who can not quit smoking&#xD;
      will improve the pulmonary function tests in their offspring measured at 3 months of age.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Smoking during pregnancy remains a major public health problem as at least 12% of pregnant&#xD;
      women cannot quit smoking during pregnancy. This addiction is the largest preventable cause&#xD;
      of childhood respiratory illness, including asthma, and children whose mothers smoked during&#xD;
      pregnancy show lifetime decreases in pulmonary function. Smoking is a unique morbidity in&#xD;
      that it is addictive, heavily advertised and recent genome studies show there are genotypes&#xD;
      that significantly increase the likelihood of being unable to quit. Teen pregnancy, low&#xD;
      income, low education, and living with another smoker are important factors increasing the&#xD;
      odds of smoking during pregnancy. Pulmonary function tests done shortly after birth in babies&#xD;
      born to mothers who smoked during pregnancy show decreased pulmonary function as measured by&#xD;
      decreased respiratory flows and respiratory compliance and altered tidal breathing patterns.&#xD;
      These changes can still be measured even after the infants have reached adulthood. Multiple&#xD;
      epidemiologic studies show that these decreases in pulmonary function lead to increased&#xD;
      respiratory disease and costs of hundreds of millions of dollars per year.&#xD;
&#xD;
      The primary aim of this double-blind, placebo controlled, randomized, multi-site study is to&#xD;
      demonstrate improved pulmonary function testing at 3 months of age, in infants delivered to&#xD;
      smoking mothers who are randomized to 500 mg/day of supplemental vitamin C versus placebo at&#xD;
      less than or equal to 22 weeks of pregnancy. We will recruit 278 smoking pregnant women into&#xD;
      the study. Patients will meet with research personnel at each prenatal visit and smoking&#xD;
      cessation will be actively encouraged. Patients will be monitored with a set of serial&#xD;
      biomarkers to assess smoking and medication compliance, including urine cotinine levels,&#xD;
      smoking questionnaires, pill counts and fasting plasma ascorbic acid levels. Pulmonary&#xD;
      function tests will be done at 3 months of age and will measure forced expiratory flows. The&#xD;
      infants will also be followed through one year of age with monthly validated respiratory&#xD;
      questionnaires and a follow-up pulmonary function test at 12 months of age. Success of this&#xD;
      study is supported by strong pilot data showing statistically significant improvements at&#xD;
      about 48 hours of age in pulmonary function tests in infants born to smoking mothers who&#xD;
      received vitamin C versus placebo, and preliminary data showing a lower incidence of wheezing&#xD;
      at 12 months of age in these infants. Key genetic polymorphisms shown to increase sensitivity&#xD;
      to in-utero smoke exposure will also be measured. The success of this study is also supported&#xD;
      by animal models showing the effectiveness of vitamin C to preserve pulmonary function and&#xD;
      genetic and epidemiologic studies linking the effects of smoking during pregnancy to oxidant&#xD;
      mechanisms. The secondary aims of the study include: 1) to demonstrate a decreased incidence&#xD;
      of wheezing through 12 months of age in infants delivered to smoking mothers who are&#xD;
      randomized to 500mg/day of supplemental vitamin C versus placebo during pregnancy; 2) to&#xD;
      demonstrate improved pulmonary function tests at 12 months of age in these infants.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>December 2012</start_date>
  <completion_date type="Actual">December 2017</completion_date>
  <primary_completion_date type="Actual">April 2016</primary_completion_date>
  <phase>Phase 2/Phase 3</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Forced Expiratory Flow at 75% of Expired Volume (FEF75)</measure>
    <time_frame>3 months of age</time_frame>
    <description>The primary outcome was the comparison of infant FEFs at 3 months of age obtained using the raised volume rapid thoracic compression (RVRTC) technique in offspring of pregnant smokers randomized to vitamin C versus placebo. The specific primary outcome parameter was the measurement of FEF at 75% of the expired volume (FEF75)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Forced Expiratory Flow at 75% of Expired Volume (FEF75)</measure>
    <time_frame>12 months of age</time_frame>
    <description>The measurement of forced expiratory flows and specifically FEF75 will be done at 12 months of age in infants born to pregnant smoking women randomized to vitamin C versus placebo during pregnancy. FEF75 will be measured with the raised volume rapid thoracic compression technique.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Wheezing Through 12 Months of Age</measure>
    <time_frame>12 months of age</time_frame>
    <description>The incidence of wheezing through 12 months of age will be compared in the infants delivered to smoking pregnant women who were randomized to vitamin C (500 mg) versus placebo during pregnancy.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">252</enrollment>
  <condition>Pulmonary Function; Newborn, Abnormal</condition>
  <condition>Infant Wheeze</condition>
  <condition>In-utero Nicotine</condition>
  <condition>Second Hand Smoke</condition>
  <arm_group>
    <arm_group_label>placebo tablet+prenatal vitamin</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>A daily placebo tablet</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Vitamin C +prenatal vitamin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>500 mg vitamin C /day</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Vitamin C +prenatal vitamin</intervention_name>
    <description>Pregnant smoking women will be randomized to daily vitamin C (500 mg) versus daily placebo</description>
    <arm_group_label>Vitamin C +prenatal vitamin</arm_group_label>
    <other_name>Ascorbic acid</other_name>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Placebo tablet+prenatal vitamin</intervention_name>
    <arm_group_label>placebo tablet+prenatal vitamin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria: At randomization:&#xD;
&#xD;
          -  Singleton gestation&#xD;
&#xD;
          -  ≥ 15 years old&#xD;
&#xD;
          -  Gestational age between 13 and 22 weeks&#xD;
&#xD;
          -  Receiving prenatal care&#xD;
&#xD;
          -  Current smoker&#xD;
&#xD;
          -  English speaking&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Gestational age ≥ 23 and 0/7 weeks&#xD;
&#xD;
          -  Multiple gestation&#xD;
&#xD;
          -  Major fetal congenital anomalies&#xD;
&#xD;
          -  Current use of illicit drugs&#xD;
&#xD;
          -  Current alcohol abuse&#xD;
&#xD;
          -  Use of vitamin C (≥ 500 mg/day)&gt;3 days per week since last menstrual period&#xD;
&#xD;
          -  Refusal to abstain from vitamin or supplements containing significant vitamin C other&#xD;
             than those provided through or approved by study staff&#xD;
&#xD;
          -  History of kidney stone in patient&#xD;
&#xD;
          -  Insulin dependent diabetes&#xD;
&#xD;
          -  Complex maternal medical conditions&#xD;
&#xD;
          -  Participation in other conflicting research projects&#xD;
&#xD;
          -  Unable to demonstrate stable method of communication&#xD;
&#xD;
          -  Pregnancy by in-vitro fertilization&#xD;
&#xD;
          -  Plan to terminate pregnancy&#xD;
&#xD;
          -  Failure of medication compliance trial&#xD;
&#xD;
          -  Failure to return in designated period during placebo run-in&#xD;
&#xD;
          -  Body mass index &gt; 50 at screening&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>15 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Cynthia T McEvoy, MD,MCR</last_name>
    <role>Principal Investigator</role>
    <affiliation>Oregon Health and Science University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Indiana University</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202-5167</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oregon Health &amp; Science University</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2019</verification_date>
  <study_first_submitted>November 6, 2012</study_first_submitted>
  <study_first_submitted_qc>November 7, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 8, 2012</study_first_posted>
  <results_first_submitted>October 15, 2018</results_first_submitted>
  <results_first_submitted_qc>March 28, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">April 17, 2019</results_first_posted>
  <last_update_submitted>March 28, 2019</last_update_submitted>
  <last_update_submitted_qc>March 28, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">April 17, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Oregon Health and Science University</investigator_affiliation>
    <investigator_full_name>Cynthia McEvoy</investigator_full_name>
    <investigator_title>Associate Professor of Pediatrics</investigator_title>
  </responsible_party>
  <keyword>In-utero smoke;</keyword>
  <keyword>Pulmonary function testing;</keyword>
  <keyword>Wheeze;</keyword>
  <keyword>Vitamin C;</keyword>
  <keyword>Forced expiratory flows</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamins</mesh_term>
    <mesh_term>Ascorbic Acid</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Study staff screened women at prenatal clinics between December, 2012 and June, 2015 in the catchment area of the three clinical sites to identify eligible women who continued to smoke cigarettes.</recruitment_details>
      <pre_assignment_details>To exclude highly non-compliant subjects, consented patients entered a medication compliance trial of 14 ± 7 days. Placebo tablets were given to participants and they were excluded if they failed to return for a post compliance visit within 14 ± 7 days of the screening visit or if they took &lt; 75% of the required tablets.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Placebo Tablet+Prenatal Vitamin</title>
          <description>Participants in this arm were to take a daily placebo tablet+prenatal vitamin. Placebo tablets contained microcrystalline cellulose and 100 mg of citric acid to mimic the taste of Vitamin C.</description>
        </group>
        <group group_id="P2">
          <title>Vitamin C +Prenatal Vitamin</title>
          <description>Vitamin C +prenatal vitamin: Pregnant smoking women will be randomized to daily vitamin C (500 mg) versus daily placebo</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="126"/>
                <participants group_id="P2" count="126"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="109"/>
                <participants group_id="P2" count="113"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
                <participants group_id="P2" count="13"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Baseline analysis population includes only 125 for the Vitamin C group because after randomization, it was discovered that one participant had violated the inclusion/exclusion criteria and the IRB required that their data be excluded from any analyses.</population>
      <group_list>
        <group group_id="B1">
          <title>Placebo Tablet+Prenatal Vitamin</title>
          <description>A daily placebo tablet&#xD;
Placebo tablet+prenatal vitamin</description>
        </group>
        <group group_id="B2">
          <title>Vitamin C +Prenatal Vitamin</title>
          <description>Vitamin C +prenatal vitamin: Pregnant smoking women will be randomized to daily vitamin C (500 mg) versus daily placebo</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="126"/>
            <count group_id="B2" value="125"/>
            <count group_id="B3" value="251"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="16"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="116"/>
                    <measurement group_id="B2" value="119"/>
                    <measurement group_id="B3" value="235"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <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="26.4" spread="5.9"/>
                    <measurement group_id="B2" value="26.6" spread="5.2"/>
                    <measurement group_id="B3" value="26.5" spread="5.6"/>
                  </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="126"/>
                    <measurement group_id="B2" value="125"/>
                    <measurement group_id="B3" value="251"/>
                  </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>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="119"/>
                    <measurement group_id="B2" value="122"/>
                    <measurement group_id="B3" value="241"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </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="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                  </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="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="35"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="100"/>
                    <measurement group_id="B2" value="97"/>
                    <measurement group_id="B3" value="197"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="15"/>
                  </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>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="126"/>
                    <measurement group_id="B2" value="125"/>
                    <measurement group_id="B3" value="251"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Marital Status</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Married</title>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="53"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Single</title>
                  <measurement_list>
                    <measurement group_id="B1" value="49"/>
                    <measurement group_id="B2" value="39"/>
                    <measurement group_id="B3" value="88"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Divorced</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Significant Other</title>
                  <measurement_list>
                    <measurement group_id="B1" value="39"/>
                    <measurement group_id="B2" value="56"/>
                    <measurement group_id="B3" value="95"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Highest Education Level Attained</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Less than High School</title>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="51"/>
                  </measurement_list>
                </category>
                <category>
                  <title>High School or GED</title>
                  <measurement_list>
                    <measurement group_id="B1" value="40"/>
                    <measurement group_id="B2" value="59"/>
                    <measurement group_id="B3" value="99"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Some College</title>
                  <measurement_list>
                    <measurement group_id="B1" value="49"/>
                    <measurement group_id="B2" value="43"/>
                    <measurement group_id="B3" value="92"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Bachelor's Degree</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Graduate School</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>Health Insurance Type</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Government Assistance</title>
                  <measurement_list>
                    <measurement group_id="B1" value="106"/>
                    <measurement group_id="B2" value="112"/>
                    <measurement group_id="B3" value="218"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Private Insurance</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="13"/>
                    <measurement group_id="B3" value="31"/>
                  </measurement_list>
                </category>
                <category>
                  <title>None or Self Pay</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Gestational Age at Enrollment</title>
          <units>weeks</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="16.4" spread="2.9"/>
                    <measurement group_id="B2" value="16.7" spread="3.1"/>
                    <measurement group_id="B3" value="16.5" spread="3.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Gestational Age at Randomization</title>
          <units>weeks</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="18.2" spread="2.8"/>
                    <measurement group_id="B2" value="18.4" spread="3.0"/>
                    <measurement group_id="B3" value="18.3" spread="2.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>BMI at Enrollment</title>
          <units>kg/m^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="30.0" spread="7.3"/>
                    <measurement group_id="B2" value="28.6" spread="6.5"/>
                    <measurement group_id="B3" value="29.3" spread="6.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Gravida</title>
          <units>pregnancies</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3.5" spread="2.4"/>
                    <measurement group_id="B2" value="3.3" spread="2"/>
                    <measurement group_id="B3" value="3.4" spread="2.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Cigarette Smoking at Enrollment</title>
          <description>This is the number of cigarettes mother reports smoking per day.</description>
          <units>cigarettes per day</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7.8" spread="4.9"/>
                    <measurement group_id="B2" value="8.0" spread="5.0"/>
                    <measurement group_id="B3" value="7.9" spread="4.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Cigarette Smoking 3 months prior to Pregnancy</title>
          <description>Number of cigarettes mother reported smoking per day, 3 months prior to becoming pregnant</description>
          <units>cigarettes per day</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="17.7" spread="10.8"/>
                    <measurement group_id="B2" value="15.9" spread="7.7"/>
                    <measurement group_id="B3" value="16.8" spread="9.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Maternal History of Asthma</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Yes</title>
                  <measurement_list>
                    <measurement group_id="B1" value="38"/>
                    <measurement group_id="B2" value="44"/>
                    <measurement group_id="B3" value="82"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No</title>
                  <measurement_list>
                    <measurement group_id="B1" value="88"/>
                    <measurement group_id="B2" value="81"/>
                    <measurement group_id="B3" value="169"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Maternal History of Substance Abuse</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Yes</title>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="36"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No</title>
                  <measurement_list>
                    <measurement group_id="B1" value="110"/>
                    <measurement group_id="B2" value="105"/>
                    <measurement group_id="B3" value="215"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Maternal History of Alcohol Abuse</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Yes</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No</title>
                  <measurement_list>
                    <measurement group_id="B1" value="126"/>
                    <measurement group_id="B2" value="121"/>
                    <measurement group_id="B3" value="247"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Forced Expiratory Flow at 75% of Expired Volume (FEF75)</title>
        <description>The primary outcome was the comparison of infant FEFs at 3 months of age obtained using the raised volume rapid thoracic compression (RVRTC) technique in offspring of pregnant smokers randomized to vitamin C versus placebo. The specific primary outcome parameter was the measurement of FEF at 75% of the expired volume (FEF75)</description>
        <time_frame>3 months of age</time_frame>
        <population>Population included in analysis were infants who were able to complete technically acceptable PFT/FEF measurements at 3 months of age.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo Tablet+Prenatal Vitamin</title>
            <description>A daily placebo tablet&#xD;
Placebo tablet+prenatal vitamin</description>
          </group>
          <group group_id="O2">
            <title>Vitamin C +Prenatal Vitamin</title>
            <description>Vitamin C +prenatal vitamin: Pregnant smoking women will be randomized to daily vitamin C (500 mg) versus daily placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Forced Expiratory Flow at 75% of Expired Volume (FEF75)</title>
          <description>The primary outcome was the comparison of infant FEFs at 3 months of age obtained using the raised volume rapid thoracic compression (RVRTC) technique in offspring of pregnant smokers randomized to vitamin C versus placebo. The specific primary outcome parameter was the measurement of FEF at 75% of the expired volume (FEF75)</description>
          <population>Population included in analysis were infants who were able to complete technically acceptable PFT/FEF measurements at 3 months of age.</population>
          <units>ml/s</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="109"/>
                <count group_id="O2" value="113"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="188.7" spread="66.4"/>
                    <measurement group_id="O2" value="200.7" spread="71.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Our targeted sample size of 218 infants with successful FEFs at 3 months of age was determined to detect with 90% power, at a significance level of 0.05, increases of 15% in mean FEF75 in the vitamin C group compared to the placebo group.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.19</p_value>
            <p_value_desc>P-value adjusted for design factors of site, gestational age at randomization and covariates of length, race, and sex of infant.</p_value_desc>
            <method>ANCOVA</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>12.1</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-6.1</ci_lower_limit>
            <ci_upper_limit>30.3</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Forced Expiratory Flow at 75% of Expired Volume (FEF75)</title>
        <description>The measurement of forced expiratory flows and specifically FEF75 will be done at 12 months of age in infants born to pregnant smoking women randomized to vitamin C versus placebo during pregnancy. FEF75 will be measured with the raised volume rapid thoracic compression technique.</description>
        <time_frame>12 months of age</time_frame>
        <population>These measurements were performed at the 12 month visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo Tablet+Prenatal Vitamin</title>
            <description>A daily placebo tablet&#xD;
Placebo tablet+prenatal vitamin</description>
          </group>
          <group group_id="O2">
            <title>Vitamin C +Prenatal Vitamin</title>
            <description>Vitamin C +prenatal vitamin: Pregnant smoking women will be randomized to daily vitamin C (500 mg) versus daily placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Forced Expiratory Flow at 75% of Expired Volume (FEF75)</title>
          <description>The measurement of forced expiratory flows and specifically FEF75 will be done at 12 months of age in infants born to pregnant smoking women randomized to vitamin C versus placebo during pregnancy. FEF75 will be measured with the raised volume rapid thoracic compression technique.</description>
          <population>These measurements were performed at the 12 month visit.</population>
          <units>mL/s</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="101"/>
                <count group_id="O2" value="101"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="324" spread="84.1"/>
                    <measurement group_id="O2" value="351.6" spread="71.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Incidence of Wheezing Through 12 Months of Age</title>
        <description>The incidence of wheezing through 12 months of age will be compared in the infants delivered to smoking pregnant women who were randomized to vitamin C (500 mg) versus placebo during pregnancy.</description>
        <time_frame>12 months of age</time_frame>
        <population>Population is infants who have reached 12 months of age, and whose parent/caregiver has completed at least 1 respiratory questionnaire past 122 days after birth.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo Tablet+Prenatal Vitamin</title>
            <description>A daily placebo tablet&#xD;
Placebo tablet+prenatal vitamin</description>
          </group>
          <group group_id="O2">
            <title>Vitamin C +Prenatal Vitamin</title>
            <description>Vitamin C +prenatal vitamin: Pregnant smoking women will be randomized to daily vitamin C (500 mg) versus daily placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Incidence of Wheezing Through 12 Months of Age</title>
          <description>The incidence of wheezing through 12 months of age will be compared in the infants delivered to smoking pregnant women who were randomized to vitamin C (500 mg) versus placebo during pregnancy.</description>
          <population>Population is infants who have reached 12 months of age, and whose parent/caregiver has completed at least 1 respiratory questionnaire past 122 days after birth.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="119"/>
                <count group_id="O2" value="118"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="63"/>
                    <measurement group_id="O2" value="51"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were monitored and collect from time of enrollment until 12 months post delivery.</time_frame>
      <desc>Population at risk for infants are different than population at risk for mother/fetus because we had some dropout from time of randomization to delivery</desc>
      <group_list>
        <group group_id="E1">
          <title>Maternal/Fetal (Placebo)</title>
          <description>A daily placebo tablet&#xD;
Placebo tablet+prenatal vitamin</description>
        </group>
        <group group_id="E2">
          <title>Maternal/Fetal (Vitamin C)</title>
          <description>Vitamin C +prenatal vitamin: Pregnant smoking women will be randomized to daily vitamin C (500 mg) versus daily placebo</description>
        </group>
        <group group_id="E3">
          <title>Infant (Placebo)</title>
          <description>Infants of mothers in the Placebo group, who took a daily placebo + prenatal vitamin.</description>
        </group>
        <group group_id="E4">
          <title>Infant (Vitamin C)</title>
          <description>Infants of mothers in the Vitamin C group, who took daily vitamin C (500 mg) and a prenatal vitamin</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (10.0)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="125"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="123"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="30" subjects_at_risk="126"/>
                <counts group_id="E2" subjects_affected="20" subjects_at_risk="125"/>
                <counts group_id="E3" subjects_affected="31" subjects_at_risk="123"/>
                <counts group_id="E4" subjects_affected="33" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Jaundice neonatal</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Foetal heart rate deceleration</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Pulmonary valve stenosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Cardiac tamponade</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Cardio-respiratory arrest neonatal</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Congenital, familial and genetic disorders</title>
            <event_list>
              <event>
                <sub_title>Syndactyly</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Talipes</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Pyloric stenosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Congenital cystic kidney disease</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Congenital ureteric anomaly</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Congenital hydronephrosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Skeletal dysplasia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Optic nerve hypoplasia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Appendicitis perforated</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Gastric ulcer perforation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Intussusception</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Duodenal atresia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Ileus</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Fever neonatal</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Lethargy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Cholelithiasis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>HELLP syndrome</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Colitis ulcerative</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Pyelonephritis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Postpartum sepsis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Wound infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Periorbital cellulitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Candida infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Sepsis neonatal</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Viral infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Anastomotic complication</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Convulsions</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="126"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Dysaesthesia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Convulsions</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Hyperbilirubinaemia neonatal</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Pregnancy, puerperium and perinatal conditions</title>
            <event_list>
              <event>
                <sub_title>Foetal growth restriction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Gestational hypertension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Oligohydramnios</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Placenta previa</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Postpartum haemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Pre-eclampsia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="126"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Premature delivery</sub_title>
                <counts group_id="E1" events="10" subjects_affected="10" subjects_at_risk="126"/>
                <counts group_id="E2" events="14" subjects_affected="14" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Premature labour</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Premature rupture of membranes</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="126"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Premature separation of placenta</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Threatened labour</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Foetal exposure timing unspecified</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Necrotising enterocolititis neonatal</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Premature baby</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="8" subjects_affected="8" subjects_at_risk="123"/>
                <counts group_id="E4" events="9" subjects_affected="9" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Shoulder dystocia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Drug withdrawal syndrome</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Sleep apnoea syndrome</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Drug withdrawal syndrome neonatal</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="6" subjects_affected="6" subjects_at_risk="123"/>
                <counts group_id="E4" events="3" subjects_affected="3" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Hydronephrosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Renal failure acute</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Vaginal haemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Ovarian cyst</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Cervical incompetence</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Endometritis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Chordee</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Acute respiratory failure</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Asthma</sub_title>
                <counts group_id="E1" events="6" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="2" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Bronchitis viral</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Apparent life threatening event</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Bronchial hyperreactivity</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Bronchiolitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="123"/>
                <counts group_id="E4" events="4" subjects_affected="3" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Cheyne-Stokes respiration</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Metapneumovirus infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Neonatal hypoxia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Neonatal respiratory distress syndrome</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="123"/>
                <counts group_id="E4" events="5" subjects_affected="5" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Neonatal respiratory failure</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Respiratory syncytial virus bronchiolitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="123"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Gastrectomy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Endotracheal intubation</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Nephrectomy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Haemorrhoids</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Congenital aortic stenosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="125"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (10.0)</default_vocab>
        <default_assessment>Non-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="54" subjects_at_risk="126"/>
                <counts group_id="E2" subjects_affected="59" subjects_at_risk="125"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" events="9" subjects_affected="9" subjects_at_risk="126"/>
                <counts group_id="E2" events="9" subjects_affected="9" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="126"/>
                <counts group_id="E2" events="16" subjects_affected="16" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Pregnancy, puerperium and perinatal conditions</title>
            <event_list>
              <event>
                <sub_title>Gestational diabetes</sub_title>
                <counts group_id="E1" events="17" subjects_affected="16" subjects_at_risk="126"/>
                <counts group_id="E2" events="11" subjects_affected="9" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Foetal hypokinesia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="126"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Vulvovaginal mycotic infection</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="126"/>
                <counts group_id="E2" events="12" subjects_affected="12" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Vaginitis bacterial</sub_title>
                <counts group_id="E1" events="9" subjects_affected="9" subjects_at_risk="126"/>
                <counts group_id="E2" events="10" subjects_affected="10" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="15" subjects_affected="15" subjects_at_risk="126"/>
                <counts group_id="E2" events="21" subjects_affected="19" subjects_at_risk="125"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </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>
    <point_of_contact>
      <name_or_title>Cindy McEvoy, MD</name_or_title>
      <organization>OHSU</organization>
      <phone>503-494-0223</phone>
      <email>mcevoyc@ohsu.edu</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/NCT01723696
org study id: HL105447
secondary id: R01HL105447
nct id: NCT01723696
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
Vitamin C supplementation (500 mg per day) given to pregnant women who can not quit smoking
      will improve the pulmonary function tests in their offspring measured at 3 months of age.
Smoking during pregnancy remains a major public health problem as at least 12% of pregnant
      women cannot quit smoking during pregnancy. This addiction is the largest preventable cause
      of childhood respiratory illness, including asthma, and children whose mothers smoked during
      pregnancy show lifetime decreases in pulmonary function. Smoking is a unique morbidity in
      that it is addictive, heavily advertised and recent genome studies show there are genotypes
      that significantly increase the likelihood of being unable to quit. Teen pregnancy, low
      income, low education, and living with another smoker are important factors increasing the
      odds of smoking during pregnancy. Pulmonary function tests done shortly after birth in babies
      born to mothers who smoked during pregnancy show decreased pulmonary function as measured by
      decreased respiratory flows and respiratory compliance and altered tidal breathing patterns.
      These changes can still be measured even after the infants have reached adulthood. Multiple
      epidemiologic studies show that these decreases in pulmonary function lead to increased
      respiratory disease and costs of hundreds of millions of dollars per year.

      The primary aim of this double-blind, placebo controlled, randomized, multi-site study is to
      demonstrate improved pulmonary function testing at 3 months of age, in infants delivered to
      smoking mothers who are randomized to 500 mg/day of supplemental vitamin C versus placebo at
      less than or equal to 22 weeks of pregnancy. We will recruit 278 smoking pregnant women into
      the study. Patients will meet with research personnel at each prenatal visit and smoking
      cessation will be actively encouraged. Patients will be monitored with a set of serial
      biomarkers to assess smoking and medication compliance, including urine cotinine levels,
      smoking questionnaires, pill counts and fasting plasma ascorbic acid levels. Pulmonary
      function tests will be done at 3 months of age and will measure forced expiratory flows. The
      infants will also be followed through one year of age with monthly validated respiratory
      questionnaires and a follow-up pulmonary function test at 12 months of age. Success of this
      study is supported by strong pilot data showing statistically significant improvements at
      about 48 hours of age in pulmonary function tests in infants born to smoking mothers who
      received vitamin C versus placebo, and preliminary data showing a lower incidence of wheezing
      at 12 months of age in these infants. Key genetic polymorphisms shown to increase sensitivity
      to in-utero smoke exposure will also be measured. The success of this study is also supported
      by animal models showing the effectiveness of vitamin C to preserve pulmonary function and
      genetic and epidemiologic studies linking the effects of smoking during pregnancy to oxidant
      mechanisms. The secondary aims of the study include: 1) to demonstrate a decreased incidence
      of wheezing through 12 months of age in infants delivered to smoking mothers who are
      randomized to 500mg/day of supplemental vitamin C versus placebo during pregnancy; 2) to
      demonstrate improved pulmonary function tests at 12 months of age in these infants.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Forced Expiratory Flow at 75% of Expired Volume (FEF75)
time frame: 3 months of age
description: The primary outcome was the comparison of infant FEFs at 3 months of age obtained using the raised volume rapid thoracic compression (RVRTC) technique in offspring of pregnant smokers randomized to vitamin C versus placebo. The specific primary outcome parameter was the measurement of FEF at 75% of the expired volume (FEF75)
measure: Forced Expiratory Flow at 75% of Expired Volume (FEF75)
time frame: 12 months of age
description: The measurement of forced expiratory flows and specifically FEF75 will be done at 12 months of age in infants born to pregnant smoking women randomized to vitamin C versus placebo during pregnancy. FEF75 will be measured with the raised volume rapid thoracic compression technique.
measure: Incidence of Wheezing Through 12 Months of Age
time frame: 12 months of age
description: The incidence of wheezing through 12 months of age will be compared in the infants delivered to smoking pregnant women who were randomized to vitamin C (500 mg) versus placebo during pregnancy.
arm group label: placebo tablet+prenatal vitamin
arm group type: Placebo Comparator
description: A daily placebo tablet
arm group label: Vitamin C +prenatal vitamin
arm group type: Active Comparator
description: 500 mg vitamin C /day
intervention type: Dietary Supplement
intervention name: Vitamin C +prenatal vitamin
description: Pregnant smoking women will be randomized to daily vitamin C (500 mg) versus daily placebo
arm group label: Vitamin C +prenatal vitamin
other name: Ascorbic acid
intervention type: Dietary Supplement
intervention name: Placebo tablet+prenatal vitamin
arm group label: placebo tablet+prenatal vitamin
criteria: 
gender: Female
minimum age: 15 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Cynthia T McEvoy, MD,MCR
role: Principal Investigator
affiliation: Oregon Health and Science University
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Oregon Health and Science University
investigator full name: Cynthia McEvoy
investigator title: Associate Professor of Pediatrics
mesh term: Vitamins
mesh term: Ascorbic Acid
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 