<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/NCT02249624</url>
  </required_header>
  <id_info>
    <org_study_id>23854</org_study_id>
    <nct_id>NCT02249624</nct_id>
  </id_info>
  <brief_title>The Utility of MRI Scoring to Predict Neurodevelopmental Outcomes in Survivors of Twin-to-Twin Transfusion Syndrome</brief_title>
  <official_title>The Utility of MRI Scoring to Predict Neurodevelopmental Outcomes in Survivors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Catherine Cibulskis, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>St. Louis University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>St. Louis University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Twins who share a placenta but have two separate sacs of amniotic fluid&#xD;
      (monochorionic-diamniotic) are at risk of developing twin-to-twin transfusion syndrome&#xD;
      (TTTS). TTTS results from anastomoses in the placenta that lead to unequal sharing of blood,&#xD;
      causing abnormal blood flow to the twins. The donor twin may have low fluid levels, poor&#xD;
      growth, and anemia. The recipient twin can have high fluid levels, high red blood cell&#xD;
      counts, heart failure, and hydrops. Having TTTS, especially if there is demise of one twin or&#xD;
      if disease is severe enough to warrant laser photocoagulation of the anastomotic sites, puts&#xD;
      the surviving fetuses at risk for brain injury due to hypoxia, ischemia, or reperfusion&#xD;
      injuries. Magnetic Resonance Imaging (MRI) is superior to ultrasound at detecting subtle&#xD;
      cerebral injuries. An MRI scoring scale has been developed for use in very low birth weight&#xD;
      infants that has been shown to correlate with neurodevelopmental outcomes, but it has not&#xD;
      been tested in this patient population.&#xD;
&#xD;
      Our center's guidelines recommend fetal MRI prior to intervention, at 32 weeks gestational&#xD;
      age, and on the infants at term corrected gestational age. Infants who were treated for TTTS&#xD;
      in utero are seen in Nursery Follow-up Clinic at 4 months of age, 8 months of age, and for&#xD;
      Bayley Scales evaluations at 15-18 months of age and at 2-3 years of age.&#xD;
&#xD;
      The purpose of this study is to correlate brain MRI score with neurodevelopmental outcomes in&#xD;
      survivors of TTTS that have either required fetal surgical intervention or had demise of&#xD;
      their cotwin. The investigators predict that more severe white and gray matter injury as&#xD;
      determined by the Woodward/Inder grading scale will be positively associated with worse&#xD;
      neurodevelopmental outcomes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      All mothers with a pregnancy affected by twin-to-twin transfusion syndrome (TTTS) who are&#xD;
      referred to the St. Louis Fetal Care Institute (FCI) will be evaluated for enrollment over a&#xD;
      two year period. The women who have severe findings that indicate a need for fetal&#xD;
      intervention or who had demise of one fetus due to TTTS will be approached at FCI to discuss&#xD;
      the study. Once the baby(ies) is/are born, written consent for the infant's participation&#xD;
      will be obtained.&#xD;
&#xD;
      FCI and Cardinal Glennon Children's Medical Center have an established protocol for TTTS.&#xD;
      Fetuses affected by TTTS under fetal MRI and echocardiogram at the time of diagnosis (if time&#xD;
      permits before intervention) and again at 32 weeks of gestation. The infants receive a&#xD;
      postnatal MRI at term corrected gestational age (&gt;37 weeks of gestation). This may be done as&#xD;
      an inpatient if they are still hospitalized at Cardinal Glennon, or as an outpatient if their&#xD;
      birth hospitalization was at a different hospital, or if they are discharged to home prior to&#xD;
      37 weeks of age. They also receive a postnatal echocardiogram, which may be done during the&#xD;
      birth hospitalization, or at the time of their outpatient MRI appointment. All of the infants&#xD;
      are followed at 4-6 months of age for physical therapy evaluation, and if there are concerns,&#xD;
      they return 4 months later for a repeat physical therapy evaluation. Bayley Scales of Infant&#xD;
      Development (BSID-III) evaluations are performed by a child psychologist at 15-18 months&#xD;
      corrected age, and again between 2-3 years of age. At any time in this process, if there are&#xD;
      concerns about developmental progress, home therapy services are prescribed to help improve&#xD;
      outcomes.&#xD;
&#xD;
      This protocol of evaluations results in a total of 3-5 follow-up appointments for each infant&#xD;
      after initial hospital discharge, and are all standard of care at the investigators hospital.&#xD;
&#xD;
      MRI provides more detailed information than ultrasound in diagnosing hypoxic ischemic brain&#xD;
      damage both prenatally and postnatally (1,2). Ultrasound has low sensitivity to detect&#xD;
      non-hemorrhagic brain injuries, and studies have shown that only 14-27% of infants with&#xD;
      cerebral injury on MRI had any abnormalities seen on head ultrasound(3,4).&#xD;
&#xD;
      Studies in premature infants have shown a correlation between MRI findings at term corrected&#xD;
      age and neurodevelopmental outcomes. A grading scale has been proposed by Woodward and Inder&#xD;
      to assess the degree of white and gray matter injury on MRI(5-7). After multivariate&#xD;
      adjustment, this scale showed that increasing severity of white matter abnormalities was&#xD;
      associated with increased risks of severe motor delay and cerebral palsy (5). The presence of&#xD;
      any white matter abnormalities was found to be more sensitive at identifying children who had&#xD;
      neurodevelopmental impairments than ultrasound findings of intraventricular hemorrhage or&#xD;
      periventricular leukomalacia(5). Furthermore, most children with a normal or only mildly&#xD;
      abnormal MRI were free of severe impairments at 2 years of age(5).&#xD;
&#xD;
      If infants at highest risk of neurodevelopmental delays could be identified earlier and more&#xD;
      accurately, these infants could be monitored more closely and earlier interventions could be&#xD;
      administered. This would potentially result in better long-term neurodevelopmental outcomes&#xD;
      for these high-risk children. However, there is currently no correlative data between MRI&#xD;
      findings and long-term neurodevelopmental outcomes in the survivors of TTTS.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date>September 2014</start_date>
  <completion_date type="Anticipated">May 2024</completion_date>
  <primary_completion_date type="Actual">September 30, 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Only</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Composite outcome of neurodevelopmental impairment - final</measure>
    <time_frame>3 years of age</time_frame>
    <description>Defined by mental, language, or physical developmental index &lt; 2 standard deviations from the mean on the Bayley Scales of Infant Development III, neurosensory impairment (hearing loss requiring aids or blindness), or the diagnosis of cerebral palsy.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Developmental delay - 4 months</measure>
    <time_frame>4 months of age</time_frame>
    <description>Defined by delays of &gt;1 month on physical therapy evaluation at 4 months of age</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Developmental delay - 8 months</measure>
    <time_frame>8 months of age</time_frame>
    <description>Defined by delays of &gt;1 month on physical therapy evaluation at 8 months of age</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurodevelopmental impairment - 15 months</measure>
    <time_frame>15 months of age</time_frame>
    <description>Defined by mental, language, or physical developmental index &lt; 2 standard deviations from the mean on the Bayley Scales of Infant Development III</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MRI results</measure>
    <time_frame>Term gestational age</time_frame>
    <description>Score on MRI, and pattern of MRI findings on donor and recipient twins when they reach term corrected gestational age</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Fetofetal Transfusion</condition>
  <arm_group>
    <arm_group_label>Survivors of TTTS</arm_group_label>
    <description>Infants who have survived TTTS to hospital discharge, have an MRI at term, and return for nursery follow-up clinic.</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Pregnancies affected by TTTS will be identified through referrals from the St. Louis Fetal&#xD;
        Care Institute. Surviving infants of those pregnancies that required fetal laser surgery,&#xD;
        or had death of the cotwin, will be approached for enrollment.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Infants who suffered from TTTS in utero that either required fetal laser&#xD;
             photocoagulation or had death of their cotwin&#xD;
&#xD;
          -  Born after implementation of our TTTS protocol in September 2013&#xD;
&#xD;
          -  Complete postnatal MRI and follow-up at Cardinal Glennon Children's Medical Center, or&#xD;
             at an outside hospital and release medical information to the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Infants who did not have TTTS, or not severe enough to warrant fetal intervention or&#xD;
             demise of the cotwin&#xD;
&#xD;
          -  Infants who do not complete their follow-up per protocol&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>3 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Catherine Cibulskis, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>St. Louis University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cardinal Glennon Children's Medical Center</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Simonazzi G, Segata M, Ghi T, Sandri F, Ancora G, Bernardi B, Tani G, Rizzo N, Santini D, Bonasoni P, Pilu G. Accurate neurosonographic prediction of brain injury in the surviving fetus after the death of a monochorionic cotwin. Ultrasound Obstet Gynecol. 2006 May;27(5):517-21. doi: 10.1002/uog.2701.</citation>
    <PMID>16586472</PMID>
  </reference>
  <reference>
    <citation>Righini A, Kustermann A, Parazzini C, Fogliani R, Ceriani F, Triulzi F. Diffusion-weighted magnetic resonance imaging of acute hypoxic-ischemic cerebral lesions in the survivor of a monochorionic twin pregnancy: case report. Ultrasound Obstet Gynecol. 2007 Apr;29(4):453-6. doi: 10.1002/uog.3967.</citation>
    <PMID>17390325</PMID>
  </reference>
  <reference>
    <citation>Merhar SL, Kline-Fath BM, Meinzen-Derr J, Schibler KR, Leach JL. Fetal and postnatal brain MRI in premature infants with twin-twin transfusion syndrome. J Perinatol. 2013 Feb;33(2):112-8. doi: 10.1038/jp.2012.87. Epub 2012 Jun 28.</citation>
    <PMID>22743408</PMID>
  </reference>
  <reference>
    <citation>Inder TE, Anderson NJ, Spencer C, Wells S, Volpe JJ. White matter injury in the premature infant: a comparison between serial cranial sonographic and MR findings at term. AJNR Am J Neuroradiol. 2003 May;24(5):805-9.</citation>
    <PMID>12748075</PMID>
  </reference>
  <reference>
    <citation>Woodward LJ, Anderson PJ, Austin NC, Howard K, Inder TE. Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N Engl J Med. 2006 Aug 17;355(7):685-94. doi: 10.1056/NEJMoa053792.</citation>
    <PMID>16914704</PMID>
  </reference>
  <reference>
    <citation>Inder TE, Wells SJ, Mogridge NB, Spencer C, Volpe JJ. Defining the nature of the cerebral abnormalities in the premature infant: a qualitative magnetic resonance imaging study. J Pediatr. 2003 Aug;143(2):171-9. doi: 10.1067/S0022-3476(03)00357-3.</citation>
    <PMID>12970628</PMID>
  </reference>
  <reference>
    <citation>Woodward LJ, Mogridge N, Wells SW, Inder TE. Can neurobehavioral examination predict the presence of cerebral injury in the very low birth weight infant? J Dev Behav Pediatr. 2004 Oct;25(5):326-34. doi: 10.1097/00004703-200410000-00004.</citation>
    <PMID>15502549</PMID>
  </reference>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>September 15, 2014</study_first_submitted>
  <study_first_submitted_qc>September 22, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 25, 2014</study_first_posted>
  <last_update_submitted>May 4, 2023</last_update_submitted>
  <last_update_submitted_qc>May 4, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>St. Louis University</investigator_affiliation>
    <investigator_full_name>Catherine Cibulskis, MD</investigator_full_name>
    <investigator_title>Assistant Professor of Pediatrics</investigator_title>
  </responsible_party>
  <keyword>Twin to twin transfusion syndrome</keyword>
  <keyword>Developmental disabilities</keyword>
  <keyword>Magnetic resonance imaging</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fetofetal Transfusion</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/NCT02249624
org study id: 23854
nct id: NCT02249624
lead sponsor: 
collaborator: 
has dmc: No
Twins who share a placenta but have two separate sacs of amniotic fluid
      (monochorionic-diamniotic) are at risk of developing twin-to-twin transfusion syndrome
      (TTTS). TTTS results from anastomoses in the placenta that lead to unequal sharing of blood,
      causing abnormal blood flow to the twins. The donor twin may have low fluid levels, poor
      growth, and anemia. The recipient twin can have high fluid levels, high red blood cell
      counts, heart failure, and hydrops. Having TTTS, especially if there is demise of one twin or
      if disease is severe enough to warrant laser photocoagulation of the anastomotic sites, puts
      the surviving fetuses at risk for brain injury due to hypoxia, ischemia, or reperfusion
      injuries. Magnetic Resonance Imaging (MRI) is superior to ultrasound at detecting subtle
      cerebral injuries. An MRI scoring scale has been developed for use in very low birth weight
      infants that has been shown to correlate with neurodevelopmental outcomes, but it has not
      been tested in this patient population.

      Our center's guidelines recommend fetal MRI prior to intervention, at 32 weeks gestational
      age, and on the infants at term corrected gestational age. Infants who were treated for TTTS
      in utero are seen in Nursery Follow-up Clinic at 4 months of age, 8 months of age, and for
      Bayley Scales evaluations at 15-18 months of age and at 2-3 years of age.

      The purpose of this study is to correlate brain MRI score with neurodevelopmental outcomes in
      survivors of TTTS that have either required fetal surgical intervention or had demise of
      their cotwin. The investigators predict that more severe white and gray matter injury as
      determined by the Woodward/Inder grading scale will be positively associated with worse
      neurodevelopmental outcomes.
All mothers with a pregnancy affected by twin-to-twin transfusion syndrome (TTTS) who are
      referred to the St. Louis Fetal Care Institute (FCI) will be evaluated for enrollment over a
      two year period. The women who have severe findings that indicate a need for fetal
      intervention or who had demise of one fetus due to TTTS will be approached at FCI to discuss
      the study. Once the baby(ies) is/are born, written consent for the infant's participation
      will be obtained.

      FCI and Cardinal Glennon Children's Medical Center have an established protocol for TTTS.
      Fetuses affected by TTTS under fetal MRI and echocardiogram at the time of diagnosis (if time
      permits before intervention) and again at 32 weeks of gestation. The infants receive a
      postnatal MRI at term corrected gestational age (>37 weeks of gestation). This may be done as
      an inpatient if they are still hospitalized at Cardinal Glennon, or as an outpatient if their
      birth hospitalization was at a different hospital, or if they are discharged to home prior to
      37 weeks of age. They also receive a postnatal echocardiogram, which may be done during the
      birth hospitalization, or at the time of their outpatient MRI appointment. All of the infants
      are followed at 4-6 months of age for physical therapy evaluation, and if there are concerns,
      they return 4 months later for a repeat physical therapy evaluation. Bayley Scales of Infant
      Development (BSID-III) evaluations are performed by a child psychologist at 15-18 months
      corrected age, and again between 2-3 years of age. At any time in this process, if there are
      concerns about developmental progress, home therapy services are prescribed to help improve
      outcomes.

      This protocol of evaluations results in a total of 3-5 follow-up appointments for each infant
      after initial hospital discharge, and are all standard of care at the investigators hospital.

      MRI provides more detailed information than ultrasound in diagnosing hypoxic ischemic brain
      damage both prenatally and postnatally (1,2). Ultrasound has low sensitivity to detect
      non-hemorrhagic brain injuries, and studies have shown that only 14-27% of infants with
      cerebral injury on MRI had any abnormalities seen on head ultrasound(3,4).

      Studies in premature infants have shown a correlation between MRI findings at term corrected
      age and neurodevelopmental outcomes. A grading scale has been proposed by Woodward and Inder
      to assess the degree of white and gray matter injury on MRI(5-7). After multivariate
      adjustment, this scale showed that increasing severity of white matter abnormalities was
      associated with increased risks of severe motor delay and cerebral palsy (5). The presence of
      any white matter abnormalities was found to be more sensitive at identifying children who had
      neurodevelopmental impairments than ultrasound findings of intraventricular hemorrhage or
      periventricular leukomalacia(5). Furthermore, most children with a normal or only mildly
      abnormal MRI were free of severe impairments at 2 years of age(5).

      If infants at highest risk of neurodevelopmental delays could be identified earlier and more
      accurately, these infants could be monitored more closely and earlier interventions could be
      administered. This would potentially result in better long-term neurodevelopmental outcomes
      for these high-risk children. However, there is currently no correlative data between MRI
      findings and long-term neurodevelopmental outcomes in the survivors of TTTS.
observational model: Case-Only
time perspective: Prospective
measure: Composite outcome of neurodevelopmental impairment - final
time frame: 3 years of age
description: Defined by mental, language, or physical developmental index < 2 standard deviations from the mean on the Bayley Scales of Infant Development III, neurosensory impairment (hearing loss requiring aids or blindness), or the diagnosis of cerebral palsy.
measure: Developmental delay - 4 months
time frame: 4 months of age
description: Defined by delays of >1 month on physical therapy evaluation at 4 months of age
measure: Developmental delay - 8 months
time frame: 8 months of age
description: Defined by delays of >1 month on physical therapy evaluation at 8 months of age
measure: Neurodevelopmental impairment - 15 months
time frame: 15 months of age
description: Defined by mental, language, or physical developmental index < 2 standard deviations from the mean on the Bayley Scales of Infant Development III
measure: MRI results
time frame: Term gestational age
description: Score on MRI, and pattern of MRI findings on donor and recipient twins when they reach term corrected gestational age
arm group label: Survivors of TTTS
description: Infants who have survived TTTS to hospital discharge, have an MRI at term, and return for nursery follow-up clinic.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: 3 Years
healthy volunteers: No
last name: Catherine Cibulskis, MD
role: Principal Investigator
affiliation: St. Louis University
facility: 
country: United States
citation: Simonazzi G, Segata M, Ghi T, Sandri F, Ancora G, Bernardi B, Tani G, Rizzo N, Santini D, Bonasoni P, Pilu G. Accurate neurosonographic prediction of brain injury in the surviving fetus after the death of a monochorionic cotwin. Ultrasound Obstet Gynecol. 2006 May;27(5):517-21. doi: 10.1002/uog.2701.
PMID: 16586472
citation: Righini A, Kustermann A, Parazzini C, Fogliani R, Ceriani F, Triulzi F. Diffusion-weighted magnetic resonance imaging of acute hypoxic-ischemic cerebral lesions in the survivor of a monochorionic twin pregnancy: case report. Ultrasound Obstet Gynecol. 2007 Apr;29(4):453-6. doi: 10.1002/uog.3967.
PMID: 17390325
citation: Merhar SL, Kline-Fath BM, Meinzen-Derr J, Schibler KR, Leach JL. Fetal and postnatal brain MRI in premature infants with twin-twin transfusion syndrome. J Perinatol. 2013 Feb;33(2):112-8. doi: 10.1038/jp.2012.87. Epub 2012 Jun 28.
PMID: 22743408
citation: Inder TE, Anderson NJ, Spencer C, Wells S, Volpe JJ. White matter injury in the premature infant: a comparison between serial cranial sonographic and MR findings at term. AJNR Am J Neuroradiol. 2003 May;24(5):805-9.
PMID: 12748075
citation: Woodward LJ, Anderson PJ, Austin NC, Howard K, Inder TE. Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N Engl J Med. 2006 Aug 17;355(7):685-94. doi: 10.1056/NEJMoa053792.
PMID: 16914704
citation: Inder TE, Wells SJ, Mogridge NB, Spencer C, Volpe JJ. Defining the nature of the cerebral abnormalities in the premature infant: a qualitative magnetic resonance imaging study. J Pediatr. 2003 Aug;143(2):171-9. doi: 10.1067/S0022-3476(03)00357-3.
PMID: 12970628
citation: Woodward LJ, Mogridge N, Wells SW, Inder TE. Can neurobehavioral examination predict the presence of cerebral injury in the very low birth weight infant? J Dev Behav Pediatr. 2004 Oct;25(5):326-34. doi: 10.1097/00004703-200410000-00004.
PMID: 15502549
responsible party type: Sponsor-Investigator
investigator affiliation: St. Louis University
investigator full name: Catherine Cibulskis, MD
investigator title: Assistant Professor of Pediatrics
mesh term: Fetofetal Transfusion