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Susan TolivaisaEunice Kennedy Shriver National Institute of Child Health and Human Development
Evaluating Emerging Technologies: Is the Future Now?
MOMS Clinical CentersThe Children’s Hospital of PhiladelphiaUniversity of California-San FranciscoVanderbilt University Medical Center
Coordinating CenterThe 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
• Obstetrical management, especially for high-risk patients, has often adopted practices without objective evaluation.
Background
• Fetal surgery began for lethal conditions
• Risks involve two:oMomo Baby
• Long term risks: future pregnancies
Background
Fetal surgery for myelomeningocele (MMC or spina bifida) moves beyond the typical paradigm o not a lethal condition
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
Hydrocephalus
Motor & cognitive Motor & cognitive impairmentsimpairments
Bladder & bowel incontinenceBladder & bowel incontinenceSocial & emotional challengesSocial & emotional challenges
Need for ventriculoperitoneal shunting
Complications
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 discussedo Clinically available o Limited follow-upoUnknown if outcome better
Human Fetal Myelomeningocele RepairHuman Fetal Myelomeningocele Repair
Number 252 – 2001
ACOG Committee Opinion
Maternal-fetal surgery for myelomeningocele should be evaluated in a multicenter RCT.
Why we are doing a trial?• Prior to 2002, data indicated some
benefits regarding hindbrain herniation and shunting but:oNo comparison groupoPotential confoundingoPotential risks to mom & babyoShort term data onlyoIncomplete follow-up
Development of MOMS Trial
• UCSF, CHOP, Vanderbilt held meetings
• Agreed to collaborate
• Other fetal surgery sites agreed to “no back door” policyoCannot get maternal-fetal repair
outside of the trial
x
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.
Primary hypothesesMidtrimester 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
• Composite of Bayley Scales of Infant Development MDI and motor function) assessed by independent team of examiners at 30 mos.
MOMS Primary OutcomeDual Primary Outcome:
• Death, placement of or meeting criteria for ventricular shunt by age1
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
Reasons for Central Screening/Referral
• Consistent counseling
• Allows time to process information, consider options
• Consistent eligibility screening
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
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
Screening at Clinical Site (2 days)
Travel & lodging arrangedMother and support personPaid by MOMS center
Evaluation processIf requirements met, offered randomization
Fetal surgeonNeurosurgeonNurseNeonatologistSocial workerAnesthesiologistPerinatologist
Comprehensive ultrasoundMRI of fetusFetal echocardiogramPsychological testingMeetings with evaluations team
Moms and infantsreturn 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
Human Fetal Myelomeningocele Repair
MOMS Follow-up
Moms and infantsreturn to assigned center
30 months
Neurologic Exam
Developmental Testing
MRI of head & spine
12 months
Neurologic Exam
Developmental Testing
Spine x-ray
UrodynamicsUrodynamics
Primary Outcome Measure 1
• Need for ventricular decompressive shunting at 12 months defined by objective criteriaoIf shunt placed without meeting criteria,
qualifies as primary outcomeoImportant for neurosurgeons to use criteria
• Independent committee of neurosurgeons, blinded to treatment assignment, determines whether criteria have been met
Primary Outcome Measure 2
• Composite score from the Bayley Scales of Infant Development MDI and the difference between the motor level and lesion level oEvaluated by independent examiners
blinded to treatment assignmentoVideotapes of physical exams reviewed
by independent expert
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
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 trialoEvidence of benefitoEvidence of harmoFutilityoExternal influences and events
MOMS Status (9/7/2010)
• 1510 central contacts
• 1049 screened o533 met exclusion criteriao230 decided not to participateo293 eligible & referred
• 178 randomized
Exclusion: Central Screening
0%
5%
10%
15%
20%
25%
Not s
pina
bifid
aNon
-US re
siden
tLe
sion
<S1
No ACM
Feta
l ano
mal
y
BMI>
=35
prev
sPTD
Contra
ind
to s
urg
(n=533)
Reasons for Non-participation
0%
5%
10%
15%
20%
25%
30%
Risks
too
grea
tDec
ided
to te
rmin
ate
Trav
el/F
ollo
w-up/
Fina
nces
Refus
ed a
mni
oRef
used
rand
omiza
tion
Unkno
wn
(n=230)
Screening &Enrollment
First patient randomized 3/6/03
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
1st 20
03*
2nd 20
03
3rd 20
03
4th 20
03
1st 20
04
2nd 20
04
3rd 20
04
4th 20
04
1st 20
05
2nd 20
05
3rd 20
05
4th 20
05
1st 20
06
2nd 20
06
3rd 20
06
4th 20
06
1st 20
07
2nd 20
07
3rd 20
07
4th 20
07
1st 20
08
2nd 20
08
3rd 20
08
4th 20
08
1st 20
09
2nd 20
09
3rd 20
09
4th 20
09
1st 20
10
2nd 20
10
3rd 20
10 **
Quarter Screened
Nu
mb
er o
f P
arti
cip
ants
Randomized Referred, not randomized Screened
* 2 months in this quarter** 1 month in this quarter
Randomization by Month
0
25
50
75
100
125
150
175
200
Mar-
03
Jul-
03
Nov
-03
Mar-
04
Jul-
04
Nov
-04
Mar-
05
Jul-
05
Nov
-05
Mar-
06
Jul-
06
Nov
-06
Mar-
07
Jul-
07
Nov
-07
Mar-
08
Jul-
08
Nov
-08
Mar-
09
Jul-
09
Nov
-09
Mar-
10
Jul-
10
Num
ber o
f Par
ticip
ants
Month of Randomization
Expected Actual
Follow-up Visits
99% 30-month follow-up visits to date (n=129)
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
Summary
• Challenging trial
• Slow recruitment
• Excellent follow-up
• No “back door” policy crucialoNAFTnet (North American Fetal
Therapy Network) endorsed