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

2. 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 The MOMS Trial and Its Development

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

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

5. Fetal surgery for myelomeningocele (MMC or spina bifida) moves beyond the typical paradigm o 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. Hydrocephalus Motor & cognitive impairments Bladder & bowel incontinence Social & emotional challenges Need for ventriculoperitoneal shunting Complications

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 o Clinically available o Limited follow-up o 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: o No comparison group o Potential confounding o Potential risks to mom & baby o Short term data only o 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 o Cannot get maternal-fetal repair outside 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. Composite of Bayley Scales of Infant Development MDI and motor function) assessed by independent team of examiners at 30 mos. MOMS Primary Outcome Dual Primary Outcome: Death, placement of or meeting criteria for ventricular shunt by age1

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 19 0 to 25 6 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 Evaluation process If requirements met, offered randomization Fetal surgeon Neurosurgeon Nurse Neonatologist Social worker Anesthesiologist Perinatologist Comprehensive ultrasound MRI of fetus Fetal echocardiogram Psychological testing Meetings with evaluations team

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

22. Human Fetal Myelomeningocele Repair

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

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

25. Primary Outcome Measure 2 Composite score from the Bayley Scales of Infant Development MDI and the difference between the motor level and lesion level o Evaluated by independent examiners blinded to treatment assignment o 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 o Evidence of benefit o Evidence of harm o Futility o External influences and events

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

29. Exclusion: Central Screening (n=533)

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

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

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 o NAFTnet (North American Fetal Therapy Network) endorsed