The Utility of MRI Scoring to Predict Neurodevelopmental Outcomes in Survivors of Twin-to-Twin Transfusion Syndrome

The Utility of MRI Scoring to Predict Neurodevelopmental Outcomes in Survivors

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Fetofetal Transfusion

Detailed Description

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.

• Study Type: Observational
• Enrollment (Anticipated): 60

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63104
      • Cardinal Glennon Children's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 years (Child)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Pregnancies affected by TTTS will be identified through referrals from the St. Louis Fetal Care Institute. Surviving infants of those pregnancies that required fetal laser surgery, or had death of the cotwin, will be approached for enrollment.

Description

Inclusion Criteria:

• Infants who suffered from TTTS in utero that either required fetal laser photocoagulation or had death of their cotwin
• Born after implementation of our TTTS protocol in September 2013
• Complete postnatal MRI and follow-up at Cardinal Glennon Children's Medical Center, or at an outside hospital and release medical information to the study

Exclusion Criteria:

• Infants who did not have TTTS, or not severe enough to warrant fetal intervention or demise of the cotwin
• Infants who do not complete their follow-up per protocol

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Survivors of TTTS; Infants who have survived TTTS to hospital discharge, have an MRI at term, and return for nursery follow-up clinic.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite outcome of neurodevelopmental impairment - final	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.	3 years of age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Developmental delay - 4 months	Defined by delays of >1 month on physical therapy evaluation at 4 months of age	4 months of age
Developmental delay - 8 months	Defined by delays of >1 month on physical therapy evaluation at 8 months of age	8 months of age
Neurodevelopmental impairment - 15 months	Defined by mental, language, or physical developmental index < 2 standard deviations from the mean on the Bayley Scales of Infant Development III	15 months of age
MRI results	Score on MRI, and pattern of MRI findings on donor and recipient twins when they reach term corrected gestational age	Term gestational age

Collaborators and Investigators

• Sponsor: Catherine Cibulskis, MD
• Collaborators: St. Louis University

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Actual): September 30, 2020
• Study Completion (Anticipated): May 1, 2024

Study Registration Dates

• First Submitted: September 15, 2014
• First Submitted That Met QC Criteria: September 22, 2014
• First Posted (Estimate): September 25, 2014

Study Record Updates

• Last Update Posted (Estimate): May 5, 2023
• Last Update Submitted That Met QC Criteria: May 4, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Magnetic resonance imaging; Developmental disabilities; Twin to twin transfusion syndrome
• Additional Relevant MeSH Terms: Hematologic Diseases; Infant, Newborn, Diseases; Anemia; Anemia, Neonatal; Fetofetal Transfusion
• Other Study ID Numbers: 23854