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					   Maternal-Fetal Surgery for
         Myelomeningocele




                   Catherine Y Spong, MD
Pregnancy and Perinatology Branch, NICHD
              National Institutes of Health
• MOMS Centers
   – The Children’s Hospital of
     Philadelphia
   – University of California-
     San Francisco
   – Vanderbilt University
     Medical Center
• Coordinating Center
   – The George Washington
     University Biostatistics
     Center
• NICHD
   – Pregnancy & Perinatology
     Branch
                        Management of
                    Myelomeningocele Study
                          (MOMS)
• Aim: To compare the safety and efficacy of in
  utero repair of open neural tube defects with
  standard postnatal repair
• Intervention: Unmasked randomized clinical
  trial
• Outcome evaluation by blinded independent
  investigators
Myelomeningocele

 • Most common & severe CNS
   congenital anomaly
 • Affecting ~ 1500 fetuses in US annually
 • Significant morbidity and mortality
 • Life-long disabilities
 • Severity correlated with levels of the spinal
   cord lesion
                                    Complications
          Hydrocephalus
          Need for ventriculoperitoneal shunting


                             Motor and cognitive
                             impairments




Bladder and bowel incontinence
Social and emotional challenges
        Myelomeningocele: Fetal Sheep Model

    In utero coverage of MMC




Rescues neurologic function at birth


     Without prenatal coverage         With prenatal coverage
Human Fetal Myelomeningocele Repair
         Goal of the Trial
To compare the safety and efficacy of in
utero repair of myelomeningocele (MMC)
with that of the standard postnatal repair
Inclusion criteria
•   Singleton
•   Upper MMC boundary at T1-S1
•   Evidence of hindbrain herniation
•   GA 19.0-25.9 weeks at randomization
•   Normal karyotype
•   US residency
•   Maternal age >18 years
Major exclusion criteria
•   Fetal anomaly unrelated to MMC
•   Severe kyphosis
•   Risk of PTB (short cervix, prior PTB)
•   Placental abruption
•   BMI >35
•   Contraindication to prenatal surgery
Central Screening at Coordinating Center
 Screening at Clinical Site (2 days)
  Travel & lodging arranged                            If requirements met,
  Mother and support person   Evaluation process       offered randomization
  Paid by MOMS center

                      Comprehensive ultrasound
                      MRI of fetus
                      Fetal echocardiogram
                      Psychological testing
                      Meetings with evaluations team

                                 Fetal surgeon
                                 Neurosurgeon
                                 Nurse
                                 Neonatologist
                                 Social worker
                                 Anesthesiologist
                                 Perinatologist
Randomization to Neonatal Discharge

                      Moms and infants
                     go to assigned center

                                   Postnatal group
               Prenatal group
                                   Return home
     Admitted to MOMS center
                                   Return at 37wks to MOMS
               In utero repair     center for delivery by CD
          Remain near center       Postnatal closure within 48h
            until delivery

         Deliver by CD
      @ 37wks if undelivered
     Primary Outcome (12 months)
• Death or need for ventricular decompressive shunting
  at 12 months defined by objective criteria
   – If shunt placed without meeting criteria – qualifies as
     primary outcome
• Independent committee of neurosurgeons, blinded to
  treatment assignment, determines whether criteria
  have been met
  Primary Outcome (30 months)
• A 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
    Secondary Outcomes
•   Gestational age at delivery
•   Hindbrain herniation
•   Difference between motor function and anatomic levels
•   Ambulation
•   Oligohydramnios
•   Blood transfusion at delivery
•   Placental abruption
•   Pulmonary edema
•   Hysterotomy site
•   Bradycardia at fetal repair
L2–S4 Myelomeningocele




                         T12 L1
                                  L2
                                   L3
Motor Impairment: Level of Spinal Cord Injury
Secondary Outcome:
Difference between motor function and anatomic levels


           (Observed motor function) – (anatomic level)

         (obs S1) – (anatomic L4) = + 2 levels


         (obs L2) – (anatomic L4) = - 2 levels
Demographics
                                  Prenatal     Postnatal
                                   n=78          n=80
Fetal gender female — no. (%)     35 (44.9)    51 (63.8)
Gest. age at randomization (wk)   23.6 ± 1.4   23.9 ± 1.3
Maternal age (yr)                 29.3 ± 5.3   28.8 ± 4.9
Black or African American         1   (1.3)     1   (1.3)
White                             73 (93.6)    74 (92.5)
Married— no. (%)                  73 (93.6)    74 (92.5)
Years of schooling — no. (%)      14.8 ± 1.7   15.0 ± 1.6
Body mass index at trial entry    26.2 ± 3.7   25.9 ± 3.9
Current smoker — no. (%)          6   (7.7)     4   (5.0)
Nullipara — no.(%)                33 (42.3)    36 (45.0)
Cervical length — mm              38.9 ± 7.3   39.7 ± 5.7
Demographics (cont’d)
                           Prenatal    Postnatal
                            n=78         n=80
Lesion level by sonogram
 Thoracic                   4 (5.1)     3 (3.8)
 L1-L2                     21 (26.9)   10 (12.5)
 L3-L4                     30 (38.5)   45 (56.3)
 L5-S1                     23 (29.5)   22 (27.5)
Lesion level L3 or lower   53 (67.9)   67 (83.8)
Clubfoot by ultrasound     20 (25.6)   15 (18.8)
MOMS: Primary Outcome (12 mo)
                                    death or need for shunt
                             Prenatal        Postnatal         P value
                               n=78            n=80            RR (95%CI)
Primary outcome                 53(68%)            78(98%)         <0.001
                                                             0.70(0.58-0.84)
Death before shunt            2( 3%)                0
Shunt criteria met           51(65%)               74(92%)
Shunt placed without criteria 0                     4( 5%)

Placement of shunt              31(40%)            66(82%)         <0.001
                                                             0.48(0.36-0.64)
Two perinatal deaths in each group:
Prenatal: IUFD at 26wks, NND at 23 wks
Postnatal: NND with severe symptoms of Chiari II
MOMS: Primary Outcome (30 mo)
                           Prenatal    Postnatal    P value
                             n=64        n=70
Primary outcome           148.6+57.5   122.6+57.2   0.007

Bayley MDI                 89.7+14.0   87.3+18.4    0.53
Difference between         0.58+1.94   -0.69+1.99   0.001
 motor function & anatomic level
Secondary Outcome: Hindbrain Herniation
                             (12 months)
Secondary Outcome:
 Difference between motor function and
 anatomic levels
                                   P=0.002


          better
        better


        worse
         worse
     Secondary Outcome: Ambulation
                         Prenatal       Postnatal      P value
                           n=64           n=70         RR (95%CI)
Walking independently      26/62(42%)     14/67(21%) 0.01
                                                  2.01(1.16-3.48)

Walking status                                           0.03
 None                      18/62(29%)     29/67(43%)
 Orthotics/devices         18/62(29%)     24/67(36%)
 Walking independently     26/62(42%)     14/67(21%)
Maternal Outcomes
                         Prenatal    Postnatal       RR
                                                                  P
                          n=78         n=80       (95% CI)
Chorioamniotic
                         20 (25.6)    0 (0.0)        —          <0.001
  membrane separation
Pulmonary edema           5 (6.4)     0 (0.0)        —           0.03
Modified biophysical                                 2.22
                         13 (16.7)    6(7.5)                     0.08
  profile < 8                                    (0.89– 5.55)
                                                     5.47
Oligohydramnios          16 (20.5)    3 (3.8)                   0.001
                                                 (1.66-18.04)
Placental abruption       5 (6.4)     0(0.0)         —           0.03
Chorioamnionitis          2 (2.6)     0 (0.0)        —           0.24
                                                     7.18
Blood transf. at deliv    7(9.0)      1 (1.3)                    0.03
                                                 (0.90-57.01)
Maternal Outcome:
 Hysterotomy site
                      Prenatal
                       n=76
Intact, well-healed   49 (64.5)

Very thin             19 (25.0)
Area of dehiscence    7   (9.2)   35.5%
Complete dehiscence   1   (1.3)
Fetal and Neonatal Outcomes
                        Prenatal    Postnatal
                                                 RR (95% CI)         P
                         N=78         N=80

Bradycardia at repair   8 (10.3)       0                            0.003

Perinatal death          2 (2.6)     2 (2.5)    1.03 (0.14-7.10)     1.00

GA at birth             34.1±3.1    37.3±1.1                       <0.001
   < 30 wks             10 (12.8)    0 (0.0)
   30-34 weeks80%       26 (33.3)    4 (5.0)    15%
   35-36 weeks          26 (33.3)    8 (10.0)
   >=37 weeks           16 (20.5)   68 (85.0)
Neonatal Outcomes (cont’d)
                            Prenatal    Postnatal       RR
                                                                     P
                             N=78         N=80       (95% CI)
Birth weight (g)            2383±688    3039 ±469                  <0.001
                                                        2.05
Dehiscence at repair site   10 (12.8)    5 (6.3)                     0.16
                                                    (0.73-5.73)
                                                        3.32
RDS                         16 (20.8)    5 (6.3)                    0.008
                                                    (1.28-8.63)
                                                        4.16
Sepsis — no. %               4 (5.2)     1 (1.3)                   0.20
                                                    (0.48-36.36)
Summary
• Prenatal surgery for myelomeningocele
  reduces the need for a shunt or death and
  improves motor outcomes at 30 months but
  is associated with maternal and fetal risks
Summary
• Prenatal surgery is associated with other
  favorable secondary outcomes:
  – Reduces hindbrain herniation at 12 months
           No evidence of herniation in 36% vs 4%
  – Doubles ability to walk without orthotics
           42% vs 21%
  – More likely to have a level of function that was two
    or more levels better than expected according to
    anatomic levels
           32% vs 12%
Summary
• Prenatal surgery associated with maternal and
  fetal risks
  – Preterm birth: 80% vs 15%
       • RDS in 21% vs 6%
  –   Bradycardia
  –   Oligohydramnios
  –   Placental abruption
  –   Transfusion at delivery
  –   Uterine dehiscence at surgical site (35%)
Many thanks to:
• Radiology Review committee: Dorothy Bulas, M.D.,
  Charles Fitz, M.D. and Gilbert Vezina, M.D.
• Shunt Outcome Review Committee: D. Douglas Cochrane, M.D., James
  Drake, M.D., John Kestle, M.D. and Jerry Oakes, M.D.
• Pediatrician and psychologist examiners: Alex Espinosa, M.D., Julia
  Hayes, M.D., Elizabeth Higley, Ph.D., Rita Jeremy, Ph.D., Rowena
  Korobkin, M.D., David Kube, M.D., Leanne Pollard, Jonathan Rowland,
  Elizabeth Saslow, Ph.D. and Toni Whitaker, M.D.
• Training and QA monitoring: Mario Petersen, M.D., Melissa Fallone,
  Ph.D., Theresa Leach, M.Ed. and Susan Anderson,M.D.
• The Data and Safety Monitoring Committee: George Macones, M.D.,
  Michael Ross, M.D., Donald Stablein, Ph.D., Alessandro Ghidini, M.D.,
  Michele Prince, MS, C.G.C., Barbara Schmidt, M.D., Antoine Khoury,
  M.D., Sonya Oppenheimer, M.D., John McLaughlin, M.D., Reverend
  Phillip Cato, Ph.D., Kellie Murphy, M.D., M.Sc., Dale Phelps, M.D.,
  Keith Aronyk, M.D., William Hay, Jr., M.D., Mary E. Hannah, M.D.,
  M.Sc., Jeremy Sugarman, M.D.
And at the sites, many thanks to
• The Children’s Hospital of Philadelphia, Philadelphia, PA – Alan Flake, M.D.,
  Holly Hedrick, M.D., Jamie Koh, R.N., M.S.N., Jack Rychik, M.D., David Cohen,
  M.D., Natalie Rintoul, M.D., Beverly Coleman, M.D., Patrick Pasquariello, M.D.,
  Enrico Danzer, M.D., Larissa Bilaniuk, M.D., Martha Hudson, M.S.W., Michael
  Carr, M.D., Ph.D., Michael Bebbington, M.D., M.H.Sc., Julie Moldenhauer, M.D.,
  and R. Douglas Wilson, M.D.
• University of California San Francisco, San Francisco, CA – Michael Harrison,
  M.D., Hanmin Lee, M.D., Larry Rand, M.D., Tamara Ryan, R.N., Cindy Lazzaretti,
  R.N., Rachel Perry, R.N., Stephanie Berman, L.C.S.W., Vicki Feldstein, M.D., Ruth
  Goldstein, M.D., Peter Callen, M.D., Orit Glenn, M.D., Larry Baskin, M.D., Mark
  Rosen, M.D., Charles Cauldwell, Ph.D., M.D., and Vilma Zarate, Ph.D.
• Vanderbilt University Medical Center, Nashville, TN – Katharine Wenstrom, M.D.,
  Lisa Trusler, R.N., M.S.N., Joseph Bruner, M.D., Bill Walsh, M.D., Edmund Yang,
  M.D., Ph.D., Ann Kavanaugh-McHugh, M.D., Tracy Perry, Jennifer Anderson,
  R.N., Mark Bliton, Ph.D. and Denise Pepin, M.S.W., L.C.S.W.
• The George Washington University Biostatistics Center, Washington, DC – Jessica
  Ratay, M.S., C.G.C., Erin Greenbaum Musok, M.A., Kristen Holloway, Catherine
  Shaer, M.D., Shanika Gregory, Julia Zachary, Lucy Leuchtenburg, Jeremy Drehmer,
  M.P.H. and Megan Mitchell, M.P.H.
• The Eunice Kennedy Shriver National Institute of Child Health and Human
  Development, Bethesda, MD – Susan Tolivaisa, Nancy Chescheir, M.D. and Marian
  Willinger, Ph.D.
                                  Thanks to:
                                  • The women, their children and
• MOMS Centers
                                    families who have taken part
   – The Children’s Hospital Of     and continue to take part in
     Philadelphia                   the MOMS trial
   – University Of California-    • The fetal therapy community
     San Francisco
   – Vanderbilt University        • The perinatal community
     Medical Center               • The Society for Maternal Fetal
• Coordinating Center               Medicine
   – The George Washington
     University Biostatistics
     Center
• NICHD
   – Pregnancy and
     Perinatology Branch

				
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