<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/NCT03253016</url>
  </required_header>
  <id_info>
    <org_study_id>0196-16-NHR</org_study_id>
    <nct_id>NCT03253016</nct_id>
  </id_info>
  <brief_title>The Impact of Cervical Cerclage or Vaginal Progesterone on Vaginal Microbiome Distribution</brief_title>
  <official_title>A Comparative Evaluation to Evaluate the Correlation Between Cervical Cerclage or Vaginal Progesterone and Maternal Vaginal Microbiome Distribution During Pregnancy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Western Galilee Hospital-Nahariya</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Western Galilee Hospital-Nahariya</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      A comparative evaluation to evaluate the correlation between cervical cerclage or vaginal&#xD;
      progesterone and maternal vaginal microbiome distribution during pregnancy&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cervical insufficiency is primarily a clinical diagnosis, characterized by painless cervical&#xD;
      dilation leading to recurrent second-trimester pregnancy losses/births of otherwise normal&#xD;
      pregnancies.&#xD;
&#xD;
      Adverse perinatal events associated with cervical insufficiency include prolapse of the fetal&#xD;
      membranes into the vagina, intra-amniotic infection, preterm premature rupture of membranes,&#xD;
      preterm labor and fetal loss.&#xD;
&#xD;
      Congenital and acquired cervical abnormalities increase the risk of cervical insufficiency;&#xD;
      Acquired risk factors are more common and include cervical trauma during delivery, rapid&#xD;
      mechanical cervical dilation before a gynecologic procedure or treatment of cervical&#xD;
      intraepithelial neoplasia (1). Congenital abnormalities include genetic disorders affecting&#xD;
      collagen, uterine anomalies and in the past - in utero diethylstilbestrol (DES) exposure (2,&#xD;
      3).&#xD;
&#xD;
      The diagnosis of cervical insufficiency is based on either&#xD;
&#xD;
        -  History of painless cervical dilatation with preterm (midtrimester) delivery&#xD;
&#xD;
        -  History of prior second-trimester pregnancy losses or preterm births and cervical length&#xD;
           ≤25 mm on transvaginal ultrasonography examination or advanced cervical changes on&#xD;
           physical examination before 24 weeks of gestation.&#xD;
&#xD;
      The diagnosis of cervical insufficiency is usually limited to singleton gestations. In&#xD;
      addition, preterm labor, infection, abruptio placenta, and bleeding placenta previa should be&#xD;
      excluded, as these disorders could account for biochemically mediated cervical ripening&#xD;
      leading to second-trimester pregnancy loss or preterm delivery independent of&#xD;
      structural/anatomic cervical weakness [4].&#xD;
&#xD;
      The American College of Obstetricians and Gynecologists (ACOG) defines cervical insufficiency&#xD;
      as the inability of the uterine cervix to retain a pregnancy in the second trimester in the&#xD;
      absence of clinical contractions, labor, or both [5].&#xD;
&#xD;
      Women with a history of cervical insufficiency should be considered for history-indicated&#xD;
      cerclage in future pregnancies at 12 to 14 weeks of gestation (6, 7).&#xD;
&#xD;
      Cerclage placement is considered a benign proce¬dure, the risks of such procedure include -&#xD;
      cervical lacerations at the time of delivery, the need for cesarean delivery because of the&#xD;
      inability of the cervix to dilate secondary to cervical scarring and dystocia, infection,&#xD;
      cervical cerclage displacement Nonsurgical interventions have been advocated for patients&#xD;
      with presumed cervical insufficiency. Progesterone supplementation appears to reduce the rate&#xD;
      of spontaneous singleton preterm birth in women who have had a previous spontaneous preterm&#xD;
      singleton birth and in women with a short cervix on ultrasound examination in the current&#xD;
      pregnancy (8). In women with a prior preterm birth, continuing progesterone supplementation&#xD;
      after placement of a cerclage has not been proven to be useful, but available data are&#xD;
      limited.&#xD;
&#xD;
      Most cerclages are placed via a transvaginal approach. The transabdominal approach is more&#xD;
      invasive, but allows higher placement, while transvaginal cerclages often end up distal to&#xD;
      the internal os. The two most common transvaginal techniques for cerclage are McDonald&#xD;
      procedure and Shirodkar procedure. The McDonald procedure is easier to perform and remove.&#xD;
      The bulk of data show no significant differences in pregnancy outcome between the two&#xD;
      procedures (6, 9, 10).&#xD;
&#xD;
      McDonald cerclage -&#xD;
&#xD;
        -  The procedure is begun by grasping the anterior and posterior lips of the cervix with&#xD;
           one or two ring forceps&#xD;
&#xD;
        -  A curved needle loaded with large caliber non-absorbable synthetic suture (at least&#xD;
           number 1 or 2 braided or monofilament) is inserted at 12 o'clock, at least 2 cm above&#xD;
           the external os.&#xD;
&#xD;
        -  Four to six passes of a purse-string suture are taken circumferentially around the&#xD;
           entire cervix as high as safely possible.&#xD;
&#xD;
        -  The two ends of the suture are then tied securely and cut, leaving the ends long enough&#xD;
           to grasp with a clamp when it is time to remove it (11).&#xD;
&#xD;
      During gestation, the female body undergoes hormonal, immunological, and metabolic changes to&#xD;
      support fetal growth and development. There are noticeable changes in the microbiota at&#xD;
      different body sites during pregnancy.&#xD;
&#xD;
      The human vaginal microbiota is a key component in the defense system against microbial and&#xD;
      viral infections. The vaginal microbiome is dominated by many species including Lactobacillus&#xD;
      and members of the Clostridiales, Bacteriodales, and Actinomycetales. Specifically, these&#xD;
      lactic acid producing bacteria can create a barrier against pathogen invasion by maintaining&#xD;
      a low pH (&lt; 4.5) and by secreting metabolites that play an important role in inhibition of&#xD;
      bacterial and viral infection in the urogenital tract.&#xD;
&#xD;
      The vaginal microbiome undergoes significant changes during pregnancy, including a&#xD;
      significant decrease in overall diversity, increased stability and enrichment with&#xD;
      Lactobacillus species (12). These correlate with a decrease in the vaginal pH and an increase&#xD;
      in vaginal secretions. Vaginal microbial compositions were found to differ according to&#xD;
      gestational age, while the communities at the later stages of pregnancy resembled those of&#xD;
      the non-pregnant state. The dominant Lactobacillus species in pregnancy varies according to&#xD;
      ethnic group. In women whose vaginal microbiota is not lactobacilli-dominated anti-bacterial&#xD;
      defense mechanisms are reduced. The enhanced proliferation of pathogenic bacteria plus&#xD;
      degradation of the cervical barrier increase bacterial passage into the endometrium and&#xD;
      amniotic cavity and trigger preterm myometrial contractions (13).&#xD;
&#xD;
      About 2 million cervical cerclages are performed annually to prevent preterm birth. Two types&#xD;
      of suture material are used for cerclage: monofilament or multifilament braided. Braided&#xD;
      sutures are most frequently used, although no evidence exists to favor them over monofilament&#xD;
      sutures. Birth outcomes in a retrospective cohort of 678 women receiving cervical cerclage in&#xD;
      five UK university hospitals showed that braided cerclage was associated with increased&#xD;
      intrauterine death (15% versus 5%; P = 0.0001) and preterm birth (28% versus 17%; P = 0.0006)&#xD;
      compared to monofilament suture. A prospective study explored the vaginal microbiome in women&#xD;
      at risk of preterm birth because of short cervical length (≤25 mm) who received braided (n =&#xD;
      25) or monofilament (n = 24) cerclage under comparable circumstances (14). Braided suture&#xD;
      induced a persistent shift toward vaginal microbiome dysbiosis characterized by reduced&#xD;
      Lactobacillus spp. and enrichment of pathobionts. Vaginal dysbiosis was associated with&#xD;
      inflammatory cytokine and interstitial collagenase excretion into cervicovaginal fluid and&#xD;
      premature cervical remodeling. Monofilament suture had comparatively minimal impact upon the&#xD;
      vaginal microbiome and its interactions with the host. The shift of the human vaginal&#xD;
      microbiome toward dysbiosis correlated with preterm birth (14).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">March 26, 2017</start_date>
  <completion_date type="Anticipated">January 2021</completion_date>
  <primary_completion_date type="Anticipated">January 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>vaginal microbiome distribution between the arms</measure>
    <time_frame>5 years</time_frame>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Preterm Labor</condition>
  <arm_group>
    <arm_group_label>cervicall cerclage</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>to test vaginal microbiome distribution in women with cervical cerclage due to cervical incompetence in weeks: 12 14 18 26 32</description>
  </arm_group>
  <arm_group>
    <arm_group_label>vaginal progesterone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>to test vaginal microbiome distribution in women treated with vaginal progesterone due to cervical shortening in weeks: 12 14 18 26 32</description>
  </arm_group>
  <arm_group>
    <arm_group_label>contol</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>to test vaginal microbiome during pregnancies without cerclage or progesterone</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>vaginal swab -microbiome test and blood test for cytokines</intervention_name>
    <description>vaginal microbiome test and blood test for cytokines repeated during pregnancy in the 3 arms</description>
    <arm_group_label>cervicall cerclage</arm_group_label>
    <arm_group_label>vaginal progesterone</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  G- roup 1 - Pregnant women with a singleton gestation and cervical cerclage at 12-14&#xD;
             weeks of gestation due to obstetrical history characteristic of cervical insufficiency&#xD;
             G- roup 2 - Pregnant women with a singleton gestation at 12-14 weeks of gestation&#xD;
             without a history of cervical insufficiency&#xD;
&#xD;
          -  Group 3 - Pregnant women treated with progesterone due to previous preterm labor&#xD;
             without cerclage&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  A- cute cervical insufficiency P- roven or suspected chorioamnionitis P- remature&#xD;
             rupture of membranes F- etal structural abnormality G- estation beyond 15 weeks A-&#xD;
             ntibiotic usage in the past month P- robiotic use in the past month R- eported&#xD;
             autoimmune disease or immunosuppressive disorder&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Female</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Maya Wolf, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Western Galilee Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Maya Wolf, MD</last_name>
    <phone>972-507887800</phone>
    <email>Mayaf@gmc.gov.il</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Maya Wolf, MD</last_name>
    <phone>972-507887800</phone>
    <email>homesickid@yahoo.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Galil Medical Center</name>
      <address>
        <city>Nahariyya</city>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Maya Wolf, MD</last_name>
      <phone>972-507887800</phone>
      <email>homesickid@yahoo.com</email>
    </contact>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <verification_date>March 2017</verification_date>
  <study_first_submitted>August 14, 2017</study_first_submitted>
  <study_first_submitted_qc>August 14, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 17, 2017</study_first_posted>
  <last_update_submitted>August 14, 2017</last_update_submitted>
  <last_update_submitted_qc>August 14, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">August 17, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Obstetric Labor, Premature</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03253016
org study id: 0196-16-NHR
nct id: NCT03253016
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
A comparative evaluation to evaluate the correlation between cervical cerclage or vaginal
      progesterone and maternal vaginal microbiome distribution during pregnancy
Cervical insufficiency is primarily a clinical diagnosis, characterized by painless cervical
      dilation leading to recurrent second-trimester pregnancy losses/births of otherwise normal
      pregnancies.

      Adverse perinatal events associated with cervical insufficiency include prolapse of the fetal
      membranes into the vagina, intra-amniotic infection, preterm premature rupture of membranes,
      preterm labor and fetal loss.

      Congenital and acquired cervical abnormalities increase the risk of cervical insufficiency;
      Acquired risk factors are more common and include cervical trauma during delivery, rapid
      mechanical cervical dilation before a gynecologic procedure or treatment of cervical
      intraepithelial neoplasia (1). Congenital abnormalities include genetic disorders affecting
      collagen, uterine anomalies and in the past - in utero diethylstilbestrol (DES) exposure (2,
      3).

      The diagnosis of cervical insufficiency is based on either

        -  History of painless cervical dilatation with preterm (midtrimester) delivery

        -  History of prior second-trimester pregnancy losses or preterm births and cervical length
           ≤25 mm on transvaginal ultrasonography examination or advanced cervical changes on
           physical examination before 24 weeks of gestation.

      The diagnosis of cervical insufficiency is usually limited to singleton gestations. In
      addition, preterm labor, infection, abruptio placenta, and bleeding placenta previa should be
      excluded, as these disorders could account for biochemically mediated cervical ripening
      leading to second-trimester pregnancy loss or preterm delivery independent of
      structural/anatomic cervical weakness [4].

      The American College of Obstetricians and Gynecologists (ACOG) defines cervical insufficiency
      as the inability of the uterine cervix to retain a pregnancy in the second trimester in the
      absence of clinical contractions, labor, or both [5].

      Women with a history of cervical insufficiency should be considered for history-indicated
      cerclage in future pregnancies at 12 to 14 weeks of gestation (6, 7).

      Cerclage placement is considered a benign proce¬dure, the risks of such procedure include -
      cervical lacerations at the time of delivery, the need for cesarean delivery because of the
      inability of the cervix to dilate secondary to cervical scarring and dystocia, infection,
      cervical cerclage displacement Nonsurgical interventions have been advocated for patients
      with presumed cervical insufficiency. Progesterone supplementation appears to reduce the rate
      of spontaneous singleton preterm birth in women who have had a previous spontaneous preterm
      singleton birth and in women with a short cervix on ultrasound examination in the current
      pregnancy (8). In women with a prior preterm birth, continuing progesterone supplementation
      after placement of a cerclage has not been proven to be useful, but available data are
      limited.

      Most cerclages are placed via a transvaginal approach. The transabdominal approach is more
      invasive, but allows higher placement, while transvaginal cerclages often end up distal to
      the internal os. The two most common transvaginal techniques for cerclage are McDonald
      procedure and Shirodkar procedure. The McDonald procedure is easier to perform and remove.
      The bulk of data show no significant differences in pregnancy outcome between the two
      procedures (6, 9, 10).

      McDonald cerclage -

        -  The procedure is begun by grasping the anterior and posterior lips of the cervix with
           one or two ring forceps

        -  A curved needle loaded with large caliber non-absorbable synthetic suture (at least
           number 1 or 2 braided or monofilament) is inserted at 12 o'clock, at least 2 cm above
           the external os.

        -  Four to six passes of a purse-string suture are taken circumferentially around the
           entire cervix as high as safely possible.

        -  The two ends of the suture are then tied securely and cut, leaving the ends long enough
           to grasp with a clamp when it is time to remove it (11).

      During gestation, the female body undergoes hormonal, immunological, and metabolic changes to
      support fetal growth and development. There are noticeable changes in the microbiota at
      different body sites during pregnancy.

      The human vaginal microbiota is a key component in the defense system against microbial and
      viral infections. The vaginal microbiome is dominated by many species including Lactobacillus
      and members of the Clostridiales, Bacteriodales, and Actinomycetales. Specifically, these
      lactic acid producing bacteria can create a barrier against pathogen invasion by maintaining
      a low pH (< 4.5) and by secreting metabolites that play an important role in inhibition of
      bacterial and viral infection in the urogenital tract.

      The vaginal microbiome undergoes significant changes during pregnancy, including a
      significant decrease in overall diversity, increased stability and enrichment with
      Lactobacillus species (12). These correlate with a decrease in the vaginal pH and an increase
      in vaginal secretions. Vaginal microbial compositions were found to differ according to
      gestational age, while the communities at the later stages of pregnancy resembled those of
      the non-pregnant state. The dominant Lactobacillus species in pregnancy varies according to
      ethnic group. In women whose vaginal microbiota is not lactobacilli-dominated anti-bacterial
      defense mechanisms are reduced. The enhanced proliferation of pathogenic bacteria plus
      degradation of the cervical barrier increase bacterial passage into the endometrium and
      amniotic cavity and trigger preterm myometrial contractions (13).

      About 2 million cervical cerclages are performed annually to prevent preterm birth. Two types
      of suture material are used for cerclage: monofilament or multifilament braided. Braided
      sutures are most frequently used, although no evidence exists to favor them over monofilament
      sutures. Birth outcomes in a retrospective cohort of 678 women receiving cervical cerclage in
      five UK university hospitals showed that braided cerclage was associated with increased
      intrauterine death (15% versus 5%; P = 0.0001) and preterm birth (28% versus 17%; P = 0.0006)
      compared to monofilament suture. A prospective study explored the vaginal microbiome in women
      at risk of preterm birth because of short cervical length (≤25 mm) who received braided (n =
      25) or monofilament (n = 24) cerclage under comparable circumstances (14). Braided suture
      induced a persistent shift toward vaginal microbiome dysbiosis characterized by reduced
      Lactobacillus spp. and enrichment of pathobionts. Vaginal dysbiosis was associated with
      inflammatory cytokine and interstitial collagenase excretion into cervicovaginal fluid and
      premature cervical remodeling. Monofilament suture had comparatively minimal impact upon the
      vaginal microbiome and its interactions with the host. The shift of the human vaginal
      microbiome toward dysbiosis correlated with preterm birth (14).
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: vaginal microbiome distribution between the arms
time frame: 5 years
arm group label: cervicall cerclage
arm group type: Experimental
description: to test vaginal microbiome distribution in women with cervical cerclage due to cervical incompetence in weeks: 12 14 18 26 32
arm group label: vaginal progesterone
arm group type: Experimental
description: to test vaginal microbiome distribution in women treated with vaginal progesterone due to cervical shortening in weeks: 12 14 18 26 32
arm group label: contol
arm group type: No Intervention
description: to test vaginal microbiome during pregnancies without cerclage or progesterone
intervention type: Diagnostic Test
intervention name: vaginal swab -microbiome test and blood test for cytokines
description: vaginal microbiome test and blood test for cytokines repeated during pregnancy in the 3 arms
arm group label: cervicall cerclage
arm group label: vaginal progesterone
criteria: 
gender: Female
gender based: Yes
gender description: Female
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: No
last name: Maya Wolf, MD
role: Principal Investigator
affiliation: Western Galilee Hospital
last name: Maya Wolf, MD
phone: 972-507887800
email: Mayaf@gmc.gov.il
last name: Maya Wolf, MD
phone: 972-507887800
email: homesickid@yahoo.com
facility: 
status: Recruiting
contact: 
country: Israel
responsible party type: Sponsor
mesh term: Obstetric Labor, Premature