Fetal Surgery for MMC

MOMS TrialHanmin Lee, MD

Professor of Surgery, Pediatrics, Obstetrics, Gynecology and Reproductive Sciences

Chief, Division of Pediatric Surgery

Director, Fetal Treatment Center

University of California, San Francisco

Fetal Surgery: Guiding Principles

Minimal Harm to Pregnant Woman

Severe Disease in Fetus

High Probability for Prevention and Reversal of Fetal Injury

Specific ChallengesEthical– Pregnant Woman– FetusTechnical– Uterus – FetusLogistic– Who, What , WhereScientific– Proof of Principle– Validation

Keys to Success of Fetal Treatment

Multidisciplinary

BenchBedsideBenchBedside

Accelerated but judicious incorporation of novel technologies/techniques into clinical medicine

Human Fetal Myelomeningocele Repair

• 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 • Primary outcomes:

1) Infant death or need for ventricular shunt by 1 year of life; 2) A composite of Bayley Scales of Infant Development Mental Development Index and difference between functional and anatomic level of lesion at 30 months corrected age

• Screening and randomization: Central preliminary screening and central randomization to MOMS center

• Outcome evaluation by blinded independent investigators

Primary Hypotheses

Midtrimester repair of fetal myelomeningocele compared with standard postnatal repair:

Reduces the risk of death or ventricular decompression shunting

Results in an improvement in neurologic and neuromotor function

ComplicationsHydrocephalus

Motor and cognitive impairments

Bladder and bowel incontinenceSocial and emotional challenges

Need for ventriculoperitoneal shunting

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

Gestational age 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 preterm birth (short cervix, prior preterm birth)

Placental abruption

BMI >35

Contraindication to prenatal surgery

Central Screening• Patients centrally screened at the

Coordinating Center

• Via telephone

• Review of medical records

• Those eligible and still interested are assigned to one of the three MOMS centers

• Patient and support person travel to assigned center for evaluation, screening and if consenting, randomization

Screening at Clinical Center (2 days)

Travel & lodging arrangedMother and support personPaid by MOMS center

Evaluation processIf requirements met, offered randomization

Fetal surgeonNeurosurgeonNurseNeonatologist

Social workerAnesthesiologistPerinatologist

Comprehensive ultrasoundMRI of fetusFetal echocardiogramPsychological testingMeetings with evaluations team

Randomization to Neonatal Discharge

Moms and infantsgo to assigned center

Postnatal group

Return home

Return at 37wks to MOMS center for delivery by Cesarean

Remains near center until delivery

Prenatal group

Admitted to MOMS center

In utero repair

Postnatal closure within 48h

Deliver by Cesarean @ 37wks if undelivered

First 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

Second 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

Online Feb 9, 2011 5pm NEJM.org

Results• The trial was stopped for efficacy of prenatal

surgery after the recruitment of 183 of a planned 200 patients

• This presentation is based on results in 158 patients whose children were evaluated at 12 months (randomized before July 1, 2009)

• For 30 month outcomes 134 women are included (randomized before December 1, 2007)

Demographics

Prenataln=78

Postnatal 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

Prenataln=78

Postnatal 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)

Demographics (cont’d)

First Primary Outcome (12 months)

Two perinatal deaths in each group:Prenatal: IUFD at 26wks, NND at 23 wksPostnatal: NND with severe symptoms of Chiari II

PrenatalN=78

PostnatalN=80

RR(95% CI)

P

Primary outcome 53 (68) 78 (98)0.70

(0.58–0.84)<0.001

Components of primary outcome<0.001

Death before shunt placement 2 (3) 0

Shunt criteria met 51 (65) 74 (92)

Shunt placed not met criteria 0 4 (5)

Placement of shunt 31 (40) 66 (82)0.48

(0.36–0.64)<0.001

Second Primary Outcome (30 months)

PrenatalN=64

PostnatalN=70

P

Primary outcome score 148.6 ± 57.5 122.6 ± 57.2 0.007

Components of primary outcome

Bayley mental developmental index

89.7 ± 14.0 87.3 ± 18.4 0.53

Difference between motor function and anatomic levels

0.58 ± 1.94 -0.69 ± 1.99 0.001

Secondary Outcome: Hindbrain Herniation (12 months)

PrenatalN=70

PostnatalN=69

RR(95% CI)

P

Any hindbrain herniation 45 (64) 66 (96)0.67

(0.56–0.81)<0.001

Degree of hindbrain herniation<0.001

None 25 (36) 3 ( 4)

Mild 28 (40) 20 (29)

Moderate 13 (19) 31 (45)

Severe 4 ( 6) 15 (22)

Secondary Outcome: Difference between motor function and anatomic

levels (30 months)

PrenatalN=62

PostnatalN=67

≥ Two levels better 20 (32) 8 (12)

One level better 7 (11) 6 (9)

No difference 14 (23) 17 (25)

One level worse 13 (21) 17 (25)

≥ Two levels worse 8 (13) 19 (28)

P=0.002

Secondary Outcome: Ambulation

PrenatalN=62

PostnatalN=67

RR(95% CI)

P

Walking independently on exam

26 (42) 14 (21)2.01

(1.16–3.48)0.01

Walking status 0.03

No 18 (29) 29 (43)

Walking with orthotics or devices

18 (29) 24 (36)

Walking without orthotics 26 (42) 14 (21)

Maternal OutcomesPrenatal

N=78Postnatal

N=80RR

(95% CI)P

Chorioamniotic membrane separation

20 (25.6) 0 (0.0) — <0.001

Pulmonary edema 5 (6.4) 0 (0.0) — 0.03

Modified biophysical profile < 8

13 (16.7) 6(7.5)2.22

(0.89– 5.55)0.08

Oligohydramnios 16 (20.5) 3 (3.8)5.47

(1.66-18.04)0.001

Placental abruption 5 (6.4) 0(0.0) — 0.03

Chorioamnionitis 2 (2.6) 0 (0.0) — 0.24

Blood transf. at delivery 7(9.0) 1 (1.3)7.18

(0.90-57.01)0.03

Maternal Outcome: Hysterotomy Site

Prenataln=76

Intact, well-healed 49 (64.5)

Very thin 19 (25.0)

Area of dehiscence 7 (9.2)

Complete dehiscence 1 (1.3)

35.5%

PrenatalN=78

PostnatalN=80

RR(95% CI)

P

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 weeks 26 (33.3) 4 (5.0)

35-36 weeks 26 (33.3) 8 (10.0)

>=37 weeks 16 (20.5) 68 (85.0)

80% 15%

Fetal and Neonatal Outcomes

Neonatal Outcomes (cont’d)

PrenatalN=78

PostnatalN=80

RR(95% CI)

P

Birth weight (g) 2383±688 3039 ±469 <0.001

Dehiscence at repair site 10 (12.8) 5 (6.3)2.05

(0.73-5.73)0.16

RDS 16 (20.8) 5 (6.3)3.32

(1.28-8.63)0.008

Sepsis — no. % 4 (5.2) 1 (1.3)4.16

(0.48-36.36)0.20

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

SummaryPrenatal 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%)

Thanks to: •The women, their children and families who have taken part and continue to take part in the MOMS trial

•The Society for Maternal Fetal Medicine

•The fetal therapy community

•The perinatal community

• 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

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.

Questions answeredMore questions uncovered

What is cost/value of relatively risks/benefits

Who should perform– Training

– Volume

How to collect data(transplant registry?)

How to innovate