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Susan Tolivaisa Eunice Kennedy Shriver National Institute of Child Health and Human Development

Evaluating Emerging Technologies: Is the Future Now?. Susan Tolivaisa Eunice Kennedy Shriver National Institute of Child Health and Human Development. The MOMS Trial and Its Development. MOMS Clinical Centers The Children’s Hospital of Philadelphia University of California-San Francisco

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Susan Tolivaisa Eunice Kennedy Shriver National Institute of Child Health and Human Development

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  1. Evaluating Emerging Technologies: Is the Future Now? Susan Tolivaisa Eunice Kennedy Shriver National Institute of Child Health and Human Development

  2. The MOMS Trial and Its Development • MOMS Clinical Centers • The Children’s Hospital of Philadelphia • University of California-San Francisco • Vanderbilt University Medical Center • Coordinating Center • The George Washington University Biostatistics Center • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Pregnancy and Perinatology Branch

  3. Background • Obstetrical management, especially for high-risk patients, has often adopted practices without objective evaluation.

  4. Background • Fetal surgery began for lethal conditions • Risks involve two: • Mom • Baby • Long term risks: future pregnancies

  5. Fetal surgery for myelomeningocele (MMC or spina bifida) moves beyond the typical paradigm • not a lethal condition

  6. Myelomeningocele (MMC) Open neural tube defect • Most common & severe CNS congenital anomaly • Affects ~ 1500 fetuses in U.S. annually • Severity varies depending on level of lesion • Significant morbidity and mortality • Life-long disabilities

  7. Complications Hydrocephalus Need for ventriculoperitoneal shunting Motor & cognitive impairments Bladder & bowel incontinence Social & emotional challenges

  8. History of Trial“NICHD Workshop: Current Scientific, Ethical & Clinical Considerations of Maternal-Fetal Surgery” • Multidisciplinary workshop in July, 2000 • Examined the relevant issues • Encouraged name of “maternal-fetal surgery” • Myelomeningocele discussed • Clinically available • Limited follow-up • Unknown if outcome better

  9. Human Fetal Myelomeningocele Repair

  10. Number 252 – 2001 ACOG Committee Opinion Maternal-fetal surgery for myelomeningocele should be evaluated in a multicenter RCT.

  11. Why we are doing a trial? • Prior to 2002, data indicated some benefits regarding hindbrain herniation and shunting but: • No comparison group • Potential confounding • Potential risks to mom & baby • Short term data only • Incomplete follow-up

  12. Development of MOMS Trial • UCSF, CHOP, Vanderbilt held meetings • Agreed to collaborate • Other fetal surgery sites agreed to “no back door” policy • Cannot get maternal-fetal repairoutside of the trial x

  13. Goal of the Trial • To compare the safety and efficacy of in utero repair of open neural tube defects with that of the standard postnatal repair.

  14. Primary hypotheses Midtrimester repair of fetal MMC compared with standard postnatal repair • Reduces the risk of death • or ventricular decompression • shunting • Results in an improvement • in neurologic and • neuromotor function

  15. MOMS Primary Outcome • Dual Primary Outcome: • Death, placement of or meeting criteria for ventricular shunt by age1 • Composite of Bayley Scales of Infant Development MDI and motor function) assessed by independent team of examiners at 30 mos.

  16. Basic Study Design • Unmasked randomized trial • Sample size 200 • Central screening • Eligible and interested are assigned to a MOMS center • Evaluated at MOMS center and if consenting, randomized • Prenatal, postnatal repair & delivery at MOMS center • 12 and 30 month follow-up

  17. Reasons for Central Screening/Referral • Consistent counseling • Allows time to process information, consider options • Consistent eligibility screening

  18. Inclusion Criteria • MMC starting at T1-S1 with evidence of hindbrain herniation • Singleton pregnancy 190 to 256 weeks, normal karyotype • U.S. resident • Minimum 18 years old

  19. Major Exclusion Criteria • Increased risk for preterm delivery, e.g. prior spontaneous PTD • Contraindication to surgery, e.g. previous classical cesarean or fetal surgery • BMI > 35

  20. Screening at Clinical Site (2 days) Travel & lodging arranged Mother and support person Paid by MOMS center If requirements met, offered randomization Evaluation process Comprehensive ultrasound MRI of fetus Fetal echocardiogram Psychological testing Meetings with evaluations team Fetal surgeon Neurosurgeon Nurse Neonatologist Social worker Anesthesiologist Perinatologist

  21. Randomization to Neonatal Discharge Moms and infants return to assigned center Postnatal group Prenatal group Return home Admitted to MOMS center Return at 37wks to MOMS center for delivery by CD In utero repair Remains near center until delivery Postnatal closure within 48h Deliver by CD @ 37wks if undelivered

  22. Human Fetal Myelomeningocele Repair

  23. MOMS Follow-up Moms and infants return to assigned center 12 months 30 months Neurologic Exam Neurologic Exam Developmental Testing Developmental Testing Urodynamics Urodynamics MRI of head & spine Spine x-ray

  24. PrimaryOutcome Measure 1 • Need for ventricular decompressive shunting at 12 months defined by objective criteria • If shunt placed without meeting criteria, qualifies as primary outcome • Important for neurosurgeons to use criteria • Independent committee of neurosurgeons, blinded to treatment assignment, determines whether criteria have been met

  25. PrimaryOutcome Measure 2 • Composite score from the Bayley Scales of Infant Development MDI and the difference between the motor level and lesion level • Evaluated by independent examiners blinded to treatment assignment • Videotapes of physical exams reviewed by independent expert

  26. Why independent review committees/examiners? • Primary outcome 1 and urology both practice dependent • Unmasked trial; therefore susceptible to bias (investigator, ascertainment) • Ensure consistent outcome determination across centers

  27. Data and Safety Monitoring Committee (DSMC) • Appointed by NIH; no conflict of interest • Multidisciplinary (Biostatistics, Epidemiology, Maternal-Fetal Medicine, Neonatology, Pediatrics, Neurosurgery, Urology, Ethics, Layperson) • Reviews interim data and has the authority to recommend stopping trial • Evidence of benefit • Evidence of harm • Futility • External influences and events

  28. MOMS Status (9/7/2010) • 1510 central contacts • 1049 screened • 533 met exclusion criteria • 230 decided not to participate • 293 eligible & referred • 178 randomized

  29. Exclusion: Central Screening (n=533)

  30. Reasons for Non-participation (n=230)

  31. Screening &Enrollment * 2 months in this quarter ** 1 month in this quarter First patient randomized 3/6/03

  32. Randomization by Month

  33. Follow-up Visits 99% 30-month follow-up visits to date (n=129)

  34. MOMS Publicity 2010 • Mass mailings – 1,500 pieces • Mass emails – 4 (SMFM,NSGC,SBA Parents & Providers) • Advertisements – 2 (Green journal, Google) • Meetings/Speaking engagements – 21 • Association newsletters – 16 • Links to website – 10

  35. Summary • Challenging trial • Slow recruitment • Excellent follow-up • No “back door” policy crucial • NAFTnet (North American Fetal Therapy Network) endorsed

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