Publikationen

Needs and Research Priorities for Young People with Spinal Cord Lesion or Spina Bifida and Their Caregivers: A National Survey in Switzerland within the PEPSCI Collaboration

Irina Benninger 1, Patricia Lampart 1, Gabi Mueller 1, Marika Augutis 2, Inge Eriks-Hoogland 1, Sebastian Grunt 3, Erin Hayes Kelly 4, Beth Padden 5, Cordula Scherer 6, Sandra Shavit 7, Julian Taylor 8, Erich Rutz 9,10,11,12, Anke Scheel-Sailer 1,* and PEPSCI-Collaboration †

The aim of this study was to describe the needs and research priorities of Swiss children/adolescents and young adults (from here, “young people”) with spinal cord injury/disorder (SCI/D) or spina bifida (SB) and their parents in the health and life domains as part of the international Pan-European Pediatric Spinal Cord Injury (PEPSCI) collaboration. Surveys included queries about the satisfaction, importance, research priorities, quality of life (QoL), and characteristics of the young people. Fifty-three surveys with corresponding parent-proxy reports were collected between April and November 2019. The self-report QoL sum scores from young people with SCI/D and SB were 77% and 73%, respectively. Parent-proxy report QoL sum scores were lower, with 70% scores for parents of young people with SCI/D and 64% scores for parents of young people with SB. “Having fun”, “relation to family members”, and “physical functioning” were found to be highly important for all young people. “Physical functioning”, “prevention of pressure injuries”, “general health”, and “bowel management” received the highest scores for research priority in at least one of the subgroups. As parents tend to underestimate the QoL of their children and young people prioritized research topics differently, both young peoples’ and caregivers’ perspectives should be included in the selection of research topics.

Journal: Children 2022

Date: 27/02/2022

Swiss Paraplegic Center, Guido A. Zäch Strasse 1, 6207 Nottwil, Switzerland

Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Solnavägen 1, 171 77 Stockholm, Sweden

Department of Pediatrics, Division of Child Neurology, University Children’s Hospital Bern, University of Bern, Freiburgstrasse 15, 3010 Bern, Switzerland

American Academy of Pediatrics, 345 Park Boulevard, Itasca, IL 60143, USA

Pediatric Rehabilitation, Center for Spina Bifida, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zürich, Switzerland

Department of Pediatric Surgery, Children’s Hospital Bern, Freiburgstrasse 15, 3010 Bern, Switzerland

Department of Pediatric Surgery, Children's Hospital Lucerne, Spitalstrasse, 6000 Lucerne, Switzerland

National Spinal Injuries Centre and Stoke Mandeville Spinal Research, Buckinghamshire Healthcare NHS Trust, Aylesbury, Amersham HP7 0JD, UK

Department of Orthopaedics, The Royal Children’s Hospital, Melbourne 3052, Australia

10 Medical Faculty, University of Basel, 4001 Basel, Switzerland

11 Department of Paediatrics, The University of Melbourne, Melbourne 3010, Australia

12 Murdoch Children’s Research Institute, Melbourne 3052, Australia

Author to whom correspondence should be addressed.

† Membership of the PEPSCI-Collaboration is provided in the Acknowledgments.

Early childhood neurodevelopmental outcome after open prenatal spina bifida aperta repair

Zehra S Hepp 1, Verena M Haas 2, Beatrice Latal 1 3, Martin Meuli 3 4 5, Ueli Möhrlen 3 4 5, Sonja M Schauer 3 4, Robert Steinfeld 2, Beth A Padden 3 6, David A Wille 3 7

To investigate neurodevelopmental outcome of children with open prenatal spina bifida aperta (SBA) repair.

Journal: Developmental Medicine & Child Neurology

Date: 02/12/2021

Division of Child Developmental Medicine, University Children's Hospital Zurich, Zurich, Switzerland.

2 Division of Pediatric Neurology, University Children's Hospital Zurich, Zurich, Switzerland.

3 Zurich Center for Spina Bifida, University Children's Hospital Zurich, Zurich, Switzerland.

4 Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland.

5 The Zurich Center for Fetal Diagnosis and Therapy, Zurich, Switzerland.

6 Division of Pediatric Rehabilitation, University Children's Hospital Zurich, Zurich, Switzerland.

7 Department of Pediatric Neurology, Kantonsspital Baden, Baden, Switzerland.

Systematic classification of maternal and fetal intervention-related complications following open fetal myelomeningocele repair - results from a large prospective cohort

L Vonzun 1, 2, M K Kahr 1, F Noll 1, L Mazzone 2, 3, 4 ,5, U Moehrlen 2, 3, 4, 5, M Meuli 2, 3, 4, 5, M Hüsler 1, 2, F Krähenmann 1, 2, R Zimmermann 1, 2, N Ochsenbein-Kölble 1, 2

To systematically categorise all maternal and fetal intervention-related complications after open fetal myelomeningocele (fMMC) repair of the first 124 cases operated at the Zurich Centre for Fetal Diagnosis and Therapy.

Journal: BJOG An International Journal of Obstetrics and Gynaecology - published online: November 30, 2020

Date: 01/06/2021

1 Division of Obstetrics, University Hospital of Zurich, Zurich, Switzerland.

2 The Zurich Centre for Fetal Diagnosis and Therapy, University of Zurich, Zurich, Switzerland.

3 Department of Paediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland.

4 Spina Bifida Centre, University Children's Hospital Zurich, Zurich, Switzerland.

5 Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.

Association of uterine activity and maternal volatile anesthetic exposure during open fetal surgery for spina bifida: a retrospective analysis

S. Tra a, N. Ochsenbein-Kölble b, e, P. Stein c, M. Meuli d, e, U. Moehrlen d, e, L. Mazzone d, e, F. Kraehenmann b, e, R. Zimmermann b, e, P. Biro a, e

Recent warnings postulate a possible damaging effect of volatile anesthetics on the fetus. In our archive of fetal surgeries, we found wide variation in dosing of volatile anesthetics during spina bifida surgeries. We hypothesized that there was an association between volatile anesthetic exposure and uterine activity.

Journal: International Journal of Obstetric Anesthesia (Volume 46, May 2021, 102974) - published online: March 10, 2021

Date: 01/05/2021

a Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland

b Department of Obstetrics, University Hospital Zurich, Zurich, Switzerland

c Institute of Anesthesiology, Emergency Medical Service, Perioperative Medicine, Pain Therapy, Cantonal Hospital Winterthur, Switzerland

d Department of Surgery, University Childrens’ Hospital Zurich, Zurich, Switzerland

e The Zurich Center for Fetal Diagnosis and Therapy, Zurich, Switzerland

Long-term Outcomes of Children After Fetal Surgery for Spina Bifida-Toward Sustainability

Martin Meuli 1, 2, 3, Ueli Moehrlen 1, 2, 3

No abstract available

Journal: JAMA Pediatrics 2021;175(4):e205687 - published online: February 8, 2021

Date: 01/04/2021

1 Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland.

2 The Zurich Center for Fetal Diagnosis and Therapy, University of Zurich, Zurich, Switzerland.

3 Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.

Fetal surgery for spina bifida in Zurich: results from 150 cases

Ueli Moehrlen 1, 2, 3, 4, Nicole Ochsenbein 5, 6, 7, Ladina Vonzun 5, 6, Luca Mazzone 8, 5, 9, 10, Maya Horst 8, 9, 10, Sonja Schauer 8, 9, 10, David Alexander Wille 11, 9, 10, Cornelia Hagmann 12, 10, Raimund Kottke 13, 10, Patrice Grehten 13, 10, Barbara Casanova 8, 5, 10, Nele Strübing 5, 6, Theres Moehrlen 8, 5, 10, Sasha Tharakan 8, 5, 10, Beth Padden 14, 9, 10, Dirk Bassler 15, 7, Roland Zimmermann # 5, 6, 7, Martin Meuli # 8, 5, 10, 7

Over the past 10 years, over 150 fetal spina bifida surgeries were performed at the Zurich Center for Fetal Diagnosis and Therapy. This study looks at surrogates for success and failure of this approach.

Journal: Springer Pediatric Surgery International - published online: 12 January 2021

Date: 20/01/2021

1 Department of Pediatric Surgery, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032, Zurich, Switzerland. ueli.moehrlen@kispi.uzh.ch.

2 The Zurich Center for Fetal Diagnosis and Therapy, Zurich, Switzerland. ueli.moehrlen@kispi.uzh.ch.

3 Children's Research Center, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland. ueli.moehrlen@kispi.uzh.ch.

4 University of Zurich, Zurich, Switzerland. ueli.moehrlen@kispi.uzh.ch.

5 The Zurich Center for Fetal Diagnosis and Therapy, Zurich, Switzerland.

6 Department of Obstetrics, University Hospital Zurich, Zurich, Switzerland.

7 University of Zurich, Zurich, Switzerland.

8 Department of Pediatric Surgery, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032, Zurich, Switzerland.

9 Zurich Center for Spina Bifida, University Children's Hospital Zurich, Zurich, Switzerland.

10 Children's Research Center, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland.

11 Division of Pediatric Neurology, University Children's Hospital Zurich, Zurich, Switzerland.

12 Division of Intensive Care and Neonatology, University Children' Hospital Zurich, Zurich, Switzerland.

13 Division of Diagnostic Imaging, MR-Center, University Children's Hospital Zurich, Zurich, Switzerland.

14 Division of Pediatric Rehabilitation, University Children's Hospital Zurich, Zurich, Switzerland.

15 Department of Neonatology, University Hospital Zurich, Zurich, Switzerland.

# Contributed equally.

Urological Outcome after Fetal Spina Bifida Repair: Data from the Zurich Cohort

Luca Mazzone 1, 2, 3, Alice Catherine Hölscher 4, 5, Ueli Moehrlen 6, 5, 7, Rita Gobet 4, 5, Martin Meuli 6, 5, 7, Maya Horst 4, 5

Neurogenic lower urinary tract dysfunction (NLUTD) represents a severe burden for patients with open spina bifida (OSB). The effect of fetal OSB repair on the urological outcome remains unclear, as controversial data exist. The aim of this study was to further increment existing outcome data and to demonstrate that our earlier published positive preliminary results are not erratic.

Journal: Karger Fetal Diagnosis and Therapie - published online: September 7, 2020

Date: 01/12/2020

1 The Zurich Center for Fetal Diagnosis and Therapy, Zurich, Switzerland, luca.mazzone@kispi.uzh.ch.

2 Division of Pediatric Urology, University Children's Hospital Zurich, Zurich, Switzerland, luca.mazzone@kispi.uzh.ch.

3 Children's Research Center, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland, luca.mazzone@kispi.uzh.ch.

4 Division of Pediatric Urology, University Children's Hospital Zurich, Zurich, Switzerland.

5 Children's Research Center, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland.

6 The Zurich Center for Fetal Diagnosis and Therapy, Zurich, Switzerland.

7 Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland.

Determination of Anatomical Levels in Spina Bifida Fetuses with Ultrasound and MRI

Ladina Vonzun 1 2, Maike Katja Kahr 1, David Wille 3 4, Raimund Kottke 5 4, Ueli Moehrlen 6 2 4, Martin Meuli 6 2 4, Nicole Ochsenbein-Kölble 1 2, Franziska Kraehenmann 1 2, Roland Zimmermann 1 2, Luca Mazzone 6 2 4

The goal of this study was to assess the accuracy of prenatal anatomical level determination by ultrasound (US) and magnetic resonance imaging (MRI) by analyzing the congruence with the "true" anatomical level identified by postnatal MRI.

Journal: Thieme Ultraschall in Med - published online: 2. Oktober 2020

Date: 02/10/2020

1Department of Obstetrics, University Hospital of Zurich, Frauenklinikstrasse 10, 8006 Zurich, Switzerland.

2The Zurich Center for Fetal Diagnosis and Therapy (www.swissfetus.ch), University of Zurich, Zurich, Switzerland.

3Department of Pediatric Neurology, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland.

4Spina Bifida Center, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland.

5Department of Diagnostic Imaging, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland.

6Department of Pediatric Surgery, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland.

Open Intrauterine Fetal Myelomeningocele Repair: Changes in the Surgical Procedure and Perinatal Complications during the First 8 Years of Experience at a Single Center

Maike K Kahr 1 2, Franziska M Winder 3 4, Ladina Vonzun 3 4, Luca Mazzone 5 4, Ueli Moehrlen 5 4, Martin Meuli 5 4, Margaret Hüsler 3 4, Franziska Krähenmann 3 4, Roland Zimmermann 3 4, Nicole Ochsenbein-Kölble 3 4

Open fetal myelomeningocele (fMMC) repair is nowadays a therapeutic option in selected cases. We aimed to evaluate changes in maternal and fetal outcome after fMMC repair during the first 8 years of experience at a tertiary referral fetal medicine center in Switzerland. -Materials and Methods: Between 2010 and 2018, fMMC repair and delivery of the neonate via planned cesarean section was performed in 67 cases. Cases were retrospectively stratified into 2 groups: a "training phase" (TP) with supervision from an external surgeon during 11 operations (2010-2014, 15 cases) followed by an "experienced phase" (EP, 2014-2018, 52 cases); each phase lasted about 4 years. Both phases were compared with regard to various maternal and fetal outcome parameters.

Journal: Karger Fetal Diagnosis and Therapie - published online: December 4, 2019

Date: 01/06/2020

1Division of Obstetrics, University Hospital of Zurich, Zurich, Switzerland, maikekatja.kahr@usz.ch.

2The Zurich Center for Fetal Diagnosis and Therapy, University of Zurich, Zurich, Switzerland, maikekatja.kahr@usz.ch.

3Division of Obstetrics, University Hospital of Zurich, Zurich, Switzerland.

4The Zurich Center for Fetal Diagnosis and Therapy, University of Zurich, Zurich, Switzerland.

5Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland.

Hindbrain Herniation and Banana and Lemon Sign After Open Fetal Myelomeningocele Repair - When Do These Signs Disappear and is Shunting Predictable?

Ladina Vonzun 1 2, Franziska Maria Winder 2, Martin Meuli 1 3, Ueli Moehrlen 1 3, Luca Mazzone 1 3, Franziska Kraehenmann 1 2, Margaret Huesler 1 2, Roland Zimmermann 1 2, Nicole Ochsenbein-Kölble 1 2

The aim was to describe the sonographic follow-up of hindbrain herniation (HH), the banana and lemon sign after fetal myelomeningocele (fMMC) repair, and the time of disappearance of these signs after the intervention, and to investigate any predictive value for the necessity of shunting during the infant's first year of life. Additionally, the sonographic evolution of the transcerebellar diameter (TCD) before and after fetal intervention was assessed.

Journal: Thieme Ultraschall in Med.

Date: 24/04/2020

1University Hospital Zurich, The Zurich Center for Fetal Diagnosis and Therapy, Zurich, Switzerland.

2Department of Obstetrics, University Hospital Zurich, Zurich, Switzerland.

3University Children's Hospital Zurich, Spina-Bifida-Center, Zurich, Switzerland.

In utero Hepatitis B Immunization during Fetal Surgery for Spina Bifida

Ueli Moehrlen 1 2 3, Julia Elrod 1 3, Nicole Ochsenbein-Kölble 2 4, Christoph Berger 3 5, Roberto F Speck 6, Luca Mazzone 1 2 3, Franziska Krähenmann 2 4, Roland Zimmermann 2 4, Martin Meuli 7 8 9

Fetal surgery for spina bifida aperta may lead to significantly better outcomes than postnatal repair, particularly regarding shunt-dependent hydrocephalus, independent ambulation, and voiding functions. The "Management of Myelomeningocele Study" (MOMS) represents the current benchmark, also in terms of eligibility criteria.

Journal: Karger Fetal Diagnosis and Therapy - published online: November 13, 2019

Date: 01/04/2020

1. Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland.
2. The Zurich Center for Fetal Diagnosis and Therapy, University of Zurich, Zurich, Switzerland.
3. Children's Research Center (CRC), University Children's Hospital Zurich, Zurich, Switzerland.
4. Department of Obstetrics, University Hospital Zurich, Zurich, Switzerland.
5. Division of Infectious Diseases and Hospital Epidemiology, University Children's Hospital Zurich, Zurich, Switzerland.
6. Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland.
7. Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland, martin.meuli@kispi.uzh.ch.
8. The Zurich Center for Fetal Diagnosis and Therapy, University of Zurich, Zurich, Switzerland, martin.meuli@kispi.uzh.ch.
9. Children's Research Center (CRC), University Children's Hospital Zurich, Zurich, Switzerland, martin.meuli@kispi.uzh.ch.

Benchmarking against the MOMS Trial: Zurich Results of Open Fetal Surgery for Spina Bifida

Ueli Moehrlen 1 2 3, Nicole Ochsenbein-Kölble 2 4, Luca Mazzone 1 2 3, Franziska Kraehenmann 2 4, Margaret Hüsler 2 4, Barbara Casanova 1 2 3, Peter Biro 1 5, David Wille 6 3, Bea Latal 7 3, Ianina Scheer 2 8 3, Vera Bernet 9 3, Theres Moehrlen 1 2 3, Leonhard Held 10, Alan W Flake 11, Roland Zimmermann 2 4, Martin Meuli 12 13 14

The Management of Myelomeningocele Study, a.k.a. the MOMS trial, was published in 2011 in the New England Journal of Medicine. This prospective randomized controlled trial proved to be a milestone publication that provided definitive evidence that fetal surgery is a novel standard of care for select fetuses with spina bifida aperta (SB). The goal of our study is to assess whether our center can match these benchmark results.

Journal: Karger Fetal Diagnosis and Therapie - published online: June 5, 2019

Date: 01/02/2020

1Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland.

2The Zurich Center for Fetal Diagnosis and Therapy, Zurich, Switzerland.

3Children's Research Center, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland.

4Department of Obstetrics, University Hospital Zurich, Zurich, Switzerland.

5Institute of Anaesthesiology, University Hospital Zurich, Zurich, Switzerland.

6Department of Pediatric Neurology, University Children's Hospital Zurich, Zurich, Switzerland.

7Child Development Center, University Children's Hospital Zurich, Zurich, Switzerland.

8Department of Diagnostic Imaging, MR-Center, University Children's Hospital Zurich, Zurich, Switzerland.

9Department of Intensive Care and Neonatology, University Children's Hospital Zurich, Zurich, Switzerland.

10Department of Biostatistics, Institute for Epidemiology, Biostatistics and Prevention, University of Zurich, Zurich, Switzerland.

11The Center for Fetal Diagnosis and Treatment, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

12Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland

13The Zurich Center for Fetal Diagnosis and Therapy, Zurich, Switzerland

14Children's Research Center, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland

Bioengineering and in utero transplantation of fetal skin in the sheep model: A crucial step towards clinical application in human fetal spina bifida repair

Luca Mazzone 1, 2, 3, 4, Ueli Moehrlen 1, 2, 4, Nicole Ochsenbein-Kölble 2, 5, Luca Pontiggia 3, 4, Thomas Biedermann 3, 4, Ernst Reichmann 3, 4, Martin Meuli 1, 2, 3, 4

An intricate problem during open human fetal surgery for spina bifida regards back skin closure, particularly in those cases where the skin defect is much too large for primary closure. We hypothesize that tissue engineering of fetal skin might provide an adequate autologous skin substitute for in utero application in such situations. Eight sheep fetuses of four time-mated ewes underwent fetoscopic skin biopsy at 65 days of gestation. Fibroblasts and keratinocytes isolated from the biopsy were used to create fetal dermo-epidermal skin substitutes. These were transplanted on the fetuses by open fetal surgery at 90 days of gestation on skin defects (excisional wounds) created during the same procedure. Pregnancy was allowed to continue until euthanasia at 120 days of gestation. The graft area was analyzed macroscopically and microscopically. The transplanted fetal dermo-epidermal skin substitutes was well discernable in situ in three of the four fetuses available for analysis. Histology confirmed healed grafts with a close to natural histological skin architecture four weeks after in utero transplantation. This experimental study generates evidence that laboratory grown autologous fetal skin analogues can successfully be transplanted in utero. These results have clinical implications as an analogous procedure might be applied in human fetuses undergoing prenatal repair to facilitate primary skin closure. Finally, this study may also fertilize the field of fetal tissue engineering in general, particularly when more interventional, minimally invasive, and open fetal surgical procedures become available.

Journal: Journal of tissue engineering and regenerative medicine - published online: November 29, 2019

Date: 01/01/2020

1 Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland.

2 Zurich Center for Fetal Diagnosis and Treatment, Zurich, Switzerland.

3 Tissue Biology Research Unit, Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland.

4 Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.

5 Department of Obstetrics, University Hospital Zurich, Zurich, Switzerland.

Risk Factors for Preterm Birth following Open Fetal Myelomeningocele Repair: Results from a Prospective Cohort

Maike Katja Kahr 1 2, Franziska Winder 3 4, Ladina Vonzun 3 4, Martin Meuli 5 4, Luca Mazzone 5 4, Ueli Moehrlen 5 4, Franziska Krähenmann 3 4, Margaret Hüsler 3 4, Roland Zimmermann 3 4, Nicole Ochsenbein-Kölble 3 4

etal myelomeningocele (fMMC) repair is a therapeutic option in selected cases. This study aimed to identify risk factors for preterm birth (PTB) following open fMMC repair.

Journal: Karger Fetal Diagnosis and Therapie - published online: May 17, 2019

Date: 01/01/2020

1Division of Obstetrics, University Hospital of Zürich, Zurich, Switzerland, maikekatja.kahr@usz.ch.

2Zurich Center for Fetal Diagnosis and Therapy, University of Zurich, Zurich, Switzerland, maikekatja.kahr@usz.ch.

3Division of Obstetrics, University Hospital of Zürich, Zurich, Switzerland.

4Zurich Center for Fetal Diagnosis and Therapy, University of Zurich, Zurich, Switzerland.

5Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland.

Inclusion Cysts after Fetal Spina Bifida Repair: A Third Hit?

Pascal Heye 1 2, Ueli Moehrlen 3 4 5 6, Luca Mazzone 3 4 5 6, Robert Weil 3 4 7, Stefan Altermatt 3 4 7, David-Alexander Wille 4 8, Ianina Scheer 4 9, Martin Meuli 3 4 5 6, Maya Horst 3 4 10

Fetal spina bifida repair (fSBR) has proven effective in the reversibility of hindbrain herniation, lower rate of shunt-dependent hydrocephalus, and independent ambulation. Besides distinct advantages, there are also concerns related to fSBR. One of these is the postnatal occurrence of inclusion cysts (IC).

Journal: Karger Fetal Diagnosis and Therapie - published online September 10, 2018

Date: 01/07/2019

1Department of Pediatric Surgery, University Children's Hospital Zurich, Zürich, Switzerland, pascalheye@gmail.com.

2Children's Research Center, University Children's Hospital Zurich, Zürich, Switzerland, pascalheye@gmail.com.

3Department of Pediatric Surgery, University Children's Hospital Zurich, Zürich, Switzerland.

4Children's Research Center, University Children's Hospital Zurich, Zürich, Switzerland.

5Division of Fetal Surgery, University Children's Hospital Zurich, Zürich, Switzerland.

6The Zurich Center for Fetal Diagnosis and Therapy, University of Zurich, Zürich, Switzerland.

7Division of Pediatric Neurosurgery, University Children's Hospital Zurich, Zürich, Switzerland.

8Division of Pediatric Neurology, University Children's Hospital Zurich, Zürich, Switzerland.

9Division of Diagnostic Imaging, University Children's Hospital Zurich, Zürich, Switzerland.

10Division of Pediatric Urology, University Children's Hospital Zurich, Zürich, Switzerland.

Open Spina Bifida: Why Not Fetal Surgery?

Luca Mazzone 1, 2, 3, Ueli Moehrlen 4, 5, 6, Barbara Casanova 4, 5, 6, Samira Ryf 4, Nicole Ochsenbein-Kölble 7, 5, Roland Zimmermann 7, 5, Franziska Kraehenmann 7, 5, Martin Meuli 4, 5, 6

The majority of patients counseled for prenatal open spina bifida repair (SBR) do not undergo fetal surgery. The aim of this study was to analyze the reasons for this phenomenon

Journal: Karger Fetal Diagnosis and Therapie - published online: September 11, 2018

Date: 01/06/2019

1 Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland, luca.mazzone@kispi.uzh.ch.

2 The Zurich Center for Fetal Diagnosis and Therapy, Zurich, Switzerland, luca.mazzone@kispi.uzh.ch.

3 Children's Research Center (CRC), Zurich, Switzerland, luca.mazzone@kispi.uzh.ch.

4 Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland.

5 The Zurich Center for Fetal Diagnosis and Therapy, Zurich, Switzerland.

6 Children's Research Center (CRC), Zurich, Switzerland.

7 Department of Obstetrics, University Hospital Zurich, Zurich, Switzerland.

In utero Plastic Surgery in Zurich: Successful Use of Distally Pedicled Random Pattern Transposition Flaps for Definitive Skin Closure during Open Fetal Spina Bifida Repair

Martin Meuli  1 , Claudia Meuli-Simmen, Luca Mazzone, Sasha J Tharakan, Roland Zimmermann, Nicole Ochsenbein, Ueli Moehrlen

One of the intraoperative challenges of fetal spina bifida repair is skin closure when there is an extended skin defect. Thus, we examined whether distally pedicled random pattern transposition flaps (TFs) are a valid option to overcome this problem.

Journal: Karger Fetal Diagnosis and Therapie - published online: December 20, 2017

Date: 01/10/2018

1 Zurich Center for Fetal Diagnosis and Therapy, University Children's Hospital Zurich, Zurich, Switzerland.

Maternal Complications following Open Fetal Myelomeningocele Repair at the Zurich Center for Fetal Diagnosis and Therapy

Franziska M Winder 1, Ladina Vonzun 2, Martin Meuli 3, Ueli Moehrlen 3, Luca Mazzone 3, Franziska Krähenmann 4, Margret Hüsler 4, Roland Zimmermann 4, Nicole Ochsenbein-Kölble 4

Despite undoubtable benefits of open fetal myelomeningocele (fMMC) repair, there are considerable maternal risks. The aim of this study was to evaluate and systematically categorize maternal complications after open fMMC repair.

Journal: Karger Fetal Diagnosis and Therapie - published online: November 14, 2018

Date: 01/09/2018

1Department of Obstetrics, University Hospital Zurich, Zurich, Switzerland, Franziska.Winder@usz.ch.

2Department of Obstetrics, University Hospital Zurich, Zurich, Switzerland.

3Department of Pediatric Surgery, Zurich Center for Fetal Diagnosis and Therapy, University Children's Hospital Zurich, Zurich, Switzerland.

4Department of Obstetrics, Zurich Center for Fetal Diagnosis and Therapy, University Hospital Zurich, Zurich, Switzerland.

Fetale Chirurgie bei Spina bifida (in: Spina bifida: Interdisziplinäre Diagnostik, Therapie und Beratung. 2. Auflage, Kapitel 2.4:38-48. Herausgegeben von: Theodor Michael, Arpad von Moers, Elisabeth Strehl, Hannes Haberl und Susanne Lebek. De Gruyter, 2018)

Möhrlen U., Meuli M.

Über dieses Buch:
Die grundlegend aktualisierte 2. Auflage bietet einen einzigartigen und fachübergreifenden Überblick zu den Grundlagen der Spina bifida, urologischen und orthopädischen Details sowie psychosozialen und juristischen Aspekten. Fallbeispiele machen das Buch besonders für Studenten, praxisnah arbeitende Ärzte und Physiotherapeuten attraktiv.
• Komplett überarbeitete und ergänzte 2. Auflage
• Praxisnah und aktuell mit Fallbeispielen
• Neu gestaltete Abbildungen

Journal: Spina bifida: Interdisziplinäre Diagnostik, Therapie und Beratung (ISBN 978-3-11-020953-2)

Date: 09/07/2018

Tocolysis for in utero Surgery: Atosiban Performs Distinctly Better than Magnesium Sulfate

Nicole Ochsenbein-Kölble  1 , Franziska Krähenmann, Margret Hüsler, Martin Meuli, Ueli Moehrlen, Lucca Mazzone, Peter Biro, Roland Zimmermann  

To compare tocolysis with magnesium sulfate versus atosiban regarding the occurrence of short-term preterm labor and maternal side effects during and after open fetal myelomeningocele (MMC) repair.

Journal: Karger Fetal Diagnosis and Therapie - published online: August 1, 2017

Date: 01/07/2018

1 Zurich Center for Fetal Diagnosis and Therapy, Zurich, Switzerland.

Fetale Chirurgie (in: Kinderchirurgie. Viszerale und allgemeine Chirurgie des Kindesalters. 2. Auflage 2013, Kapitel 11:125-134. Herausgeber: Dietrich von Schweinitz, Benno Ure. ISBN 978-3-662-58202-2)

Böttcher S., Meuli M.

Der Band liefert umfassendes Wissen und praxisorientierte Entscheidungshilfen zu Operationsverfahren, diagnostischen Möglichkeiten, Krankheitsverlauf und Krankheitsfolgen sowie operativen und konservativen Therapieoptionen bei Kindern. Neben der ausführlich behandelten Chirurgie der Thorax- und Abdominalorgane werden auch die wichtigsten Themen der allgemeinen Chirurgie des Kindesalters dargestellt. Die Neuauflage enthält ein zusätzliches Kapitel zur bariatrischen Chirurgie bei Kindern. Mit Beiträgen renommierte Kinderchirurgen und Pädiater.

Journal: Springer

Date: 22/06/2018

Prenatal myelomeningocele repair: Do bladders better?

Maya Horst  1 , Luca Mazzone  2 , Thomas Schraner  3 , Christine Bodmer  1 , Ueli Möhrlen  4 , Martin Meuli  4 , Rita Gobet  1               

Prenatal myelomeningocele (MMC) repair has been proven to significantly reduce the need for hydrocephalus shunting and improve lower-extremity motor outcomes. The aim of this study was to evaluate the effect of prenatal MMC repair on the urological outcome.

Journal: WILEY Neurourology and Urodynamics - first published: 15 November 2016

Date: 01/08/2017

1 Division of Pediatric Urology, University Children's Hospital, Zurich, Switzerland.

2 Department of Pediatric Surgery, University Children's Hospital, Zurich, Switzerland.

3 Diagnostic Imaging, University Children's Hospital, Zurich, Switzerland.

4 The Zurich Center for Fetal Diagnosis and Therapy, University of Zurich, Zurich, Switzerland.

Evolution of posterior fossa and brain morphology after in utero repair of open neural tube defects assessed by MRI

Christin Rethmann  1   2   3 , Ianina Scheer  4   5   6 , Martin Meuli  5   6   7 , Luca Mazzone  5   6   7 , Ueli Moehrlen  5   6   7 , Christian Johannes Kellenberger  4   5   6               

To describe characteristics of foetuses undergoing in utero repair of open neural tube defects (ONTD) and assess postoperative evolution of posterior fossa and brain morphology.

Journal: Springer European Radiology

Date: 12/05/2017

1 Department of Diagnostic Imaging, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032, Zurich, Switzerland. Christin.Rethmann@web.de.

2 The Zurich Center for Fetal Diagnosis and Therapy, University of Zurich, Zurich, Switzerland. Christin.Rethmann@web.de.

3 Children's Research Center (CRC), Zurich, Switzerland. Christin.Rethmann@web.de.

4 Department of Diagnostic Imaging, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032, Zurich, Switzerland.

5 The Zurich Center for Fetal Diagnosis and Therapy, University of Zurich, Zurich, Switzerland.

6 Children's Research Center (CRC), Zurich, Switzerland.

7 Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland.

Preliminary Results in Children with Myelomeningocele after Fetal Surgery: Data from the Zurich Cohort

D. A. Wille 1, A. Klein 1, 2, L. Mazzone 3, U. Moehrlen 3, M. Meuli 3, B. Latal 4, C. Rethmann 5, B. Plecko 1

The purpose of this study was to investigate the neurological outcome of patients with meningomyelocele treated with fetal closure.

Journal: Thieme Neuropediatrics 2016; 47 - FV01-09

Date: 01/01/2016

1 Department of Pediatric Neurology, University Children`s Hospital Zurich, Zurich, Switzerland

2 Department of Pediatric Neurology, University Children`s Hospital Basel, Basel, Switzerland

3 Department of Pediatric Surgery, University Children’s Hospital Zurich, Zurich, Switzerland

4 University Childrens Hospital Zurich, Child Development Center Zurich, Switzerland

5 Department of Neuroradiology, University Childrens Hospital Zurich, Zurich, Switzerland

Rückendeckung für das Ungeborene - Fetale Chirurgie hilft bei Spina bifida

M. Meuli, U. Möhrlen

Vor etwa 20 Jahren haben tierexperimentelle Studien gezeigt, dass die Myelomeningozele (MMC) eine kongenitale Malformation ist, die mit hoher Wahrscheinlichkeit von einer frühest möglichen operativen Versorgung, d. h. in utero, profitieren würde. Im Gefolge dieser Studien wurde der vorgeburtliche Verschluss der MMC vorerst in Einzelfällen, später in größeren Serien und schließlich in einer prospektiv randomisierten Studie untersucht und auch mit der bis anhin üblichen postnatalen Versorgung verglichen. Letztere Studie hat eine eindeutige Evidenz dafür generiert, dass die fetale Versorgung der postnatalen Versorgung in wesentlichen Aspekten überlegen ist und damit einen neuen Therapiestandard darstellt.

Journal: chirurgische praxis 2016, Band 81/2 (259-270), Mediengruppe Oberfranken - Fachverlage GmbH & Co. KG (Printausgabe ISSN 0009–4846, Digitalausgabe ISSN 2198-1671))

Date: 01/01/2016

Klinik für Kinderchirurgie (Direktor: Prof. Dr. M. Meuli) des Universitäts-Kinderspitals Zürich

Anesthesia for and analgesia after in-utero repair of myelomeningocele

Biro P

Journal: Nesa Days 2015

Date: 01/09/2015

Institute of Anesthesiology, University Hospital Zurich, CHF 8091 Zurich, Switzerland

Perinatal outcome of our first 20 cases after open fetal myelomeningocele repair at the Zurich Center for Fetal Diagnosis and Therapy

U Moehrlen 1, 2, N Ochsenbein 2, 3, M Huesler 2, 3, P Biro 2, 4, I Scheer 2, 5, L Mazzone 1, 2, R Zimmermann 2, 3, M Meuli 1, 2

After the MOMS trial was published in 2010, open fetal surgery is considered the standard treatment for selected fetuses with Myelomeningocele (MMC) in experienced hands. We report our data on perinatal outcome of the first 20 in utero operated fetuses.

Journal: Thieme Zeitschrift für Geburtshilfe und Neonatologie 2015; 219 - FV09_6

Date: 01/01/2015

1 Universitäts Kinderspital Zürich, Chirurgische Klinik, Zürich, Switzerland

2 Zentrum für fetale Diagnostik und Therapie Zürich, Zürich, Switzerland

3 UniversitätsSpital Zürich, Klinik für Geburtshilfe, Zürich, Switzerland

4 UniversitätsSpital Zürich, Klinik für Anästhesiologie, Zurich, Switzerland

5 Universitäts Kinderspital Zürich, Radiologie, Zürich, Switzerland

Experimental tissue engineering of fetal skin

L Mazzone  1 , L Pontiggia, E Reichmann, N Ochsenbein-Kölble, U Moehrlen, M Meuli

In some human fetuses undergoing prenatal spina bifida repair, the skin defect is too large for primary closure. The aim of this study was to engineer an autologous fetal skin analogue suitable for in utero skin reconstruction during spina bifida repair.

Journal: Pediatric Surgery International (2014) 30:1241-1247 - published online: 22 October 2014

Date: 22/10/2014

1 Department of Surgery, University Children's Hospital Zurich, Zurich, Switzerland, luca.mazzone@kispi.uzh.ch.

Assessment of long-term donor-site morbidity after harvesting the latissimus dorsi flap for neonatal myelomeningocele repair

R Osinga  1 , L Mazzone  2 , M Meuli  2 , C Meuli-Simmen  3 , A von Campe  3               

The latissimus dorsi flap (LDF) has been employed very successfully over decades to cover large soft-tissue defects. Its donor-site morbidity has been extensively investigated in adults - but not in children - and is considered to be nonrestrictive. The aim of this long-term study was to assess donor-site morbidity with the modified Constant score more than 8 years after coverage of large myelomeningocele (MMC) defects with a reverse latissimus dorsi flap.

Journal: Journal of Plastic, Reconstructive and Aesthetic Surgery - published online May 2, 2014

Date: 01/08/2014

1 Clinic of Hand, Reconstructive and Plastic Surgery, Kantonsspital Aarau, Aarau, Switzerland. Electronic address: Rikthedutch@mac.com.

2 Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland.

3 Clinic of Hand, Reconstructive and Plastic Surgery, Kantonsspital Aarau, Aarau, Switzerland.

Fetal surgery for myelomeningocele is effective: a critical look at the whys

Martin Meuli 1, Ueli Moehrlen

Formerly, the disastrous cluster of neurologic deficits and associated neurogenic problems in patients with myelomeningocele (MMC) was generally thought to solely result from the primary malformation, i.e., failure of neurulation.

Journal: Springer Pedicatric Surgery International - Published online: 8 June 2014

Date: 01/07/2014

1. Department of Pediatric Surgery, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032, Zurich, Switzerland, martin.meuli@kispi.uzh.ch.

Kinderchirurgie: Fötale Chirurgie bei Spina bifida

Martin Meuli a c, Roland Zimmermann b c, Nicole Ochsenbein b c, Ueli Möhrlen a c

Neues Verständnis der Pathogenese als Grundstein für die intrauterine Chirurgie

Journal: Swiss Medical Forum, (14):976-978

Date: 01/04/2014

a Universitäts-Kinderspital Zürich, Chirurgische Klinik, Steinwiesstrasse 75, 8032 Zürich, Schweiz;
b Klinik für Geburtshilfe, UniversitätsSpital Zürich, Frauenklinikstrasse 10, 8091 Zürich, Schweiz;
c Zentrum für Fetale Diagnostik und Therapie, Frauenklinikstrstrasse 10, 8091 Zürich, Schweiz

Premiere use of Integra™ artificial skin to close an extensive fetal skin defect during open in utero repair of myelomeningocele

Martin Meuli  1 , Claudia Meuli-Simmen, Alan W Flake, Roland Zimmermann, Nicole Ochsenbein, Ianina Scheer, Luca Mazzone, Ueli Moehrlen

There are fetuses demonstrating very large myelomeningocele lesion which can not be covered with autochothonous skin.

Journal: Springer Link Pediatric Surgery International 29, 1321-1326 (2013)

Date: 22/09/2013

1 The Zurich Center for Fetal Diagnosis and Therapy, Zurich, Switzerland, martin.meuli@kispi.uzh.ch.

Fetal Surgery for Myelomeningocele: A Critical Appraisal

Martin Meuli  1 , Ueli Moehrlen

This article narrates the thrilling story of how the pathogenetic understanding of myelomeningocele was fundamentally revised during the last decades and how these new insights, in particular the "two-hit hypothesis," have prepared the terrain for human fetal surgery. Formerly, the devastating cluster of neurologic and neurogenic problems was mainly attributed to the primary malformation, that is, failure of neurulation. At present, there is solid evidence that in early gestation the nonneurulated spinal cord functions well, but suffers from progressive traumatic and degenerative damage in later gestation because it is openly exposed to the amniotic cavity. There is no doubt that the secondary, in utero acquired spinal cord destruction is mainly responsible for the disastrous and irreversible peripheral neurologic deficit present at birth, and there is no doubt either that timely prenatal protective coverage can potentially arrest these deleterious dynamics and preserve neurologic function. Also, tethering of the cord within and constant outflow of cerebrospinal fluid from the lesion are seen as the driving forces behind the Chiari II malformation and consequent ventriculomegaly. Untethering and watertight sealing of the lesion reverses hindbrain herniation and lowers the risk for a relevant hydrocephalus. This article then details how human fetal surgery started in the late 1990s and follows the evolution from the pioneer case studies via the first case series providing encouraging results to the ground breaking Management of Myelomeningocele Study Trial, published in The New England Journal of Medicine in February 2011 by Adzick et al, that has, for the first time, generated unequivocal evidence that patients with prenatal repair do significantly better than those with postnatal care only. Finally, this review looks at several other critical issues, including the hitherto immature endoscopic approach to fetal repair, some future directions of research and clinical practice, and also utters a plea for concentration of these equally rare and complex cases to a few truly qualified centers worldwide. The conclusion derived from all data existing today is that maternal-fetal surgery, although not a cure and not free of risks, represents a novel standard of care for select mothers and their fetuses suffering from one of the most ruinous nonlethal congenital malformations.

Journal: Georg Thieme Verlag KG European Journal of Pediatric Surgery

Date: 09/04/2013

1 Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland. martin.meuli@kispi.uzh.ch

Fetal surgery in Zurich: key features of our first open in utero repair of myelomeningocele

Martin Meuli  1 , Ueli Moehrlen  1 , Alan Flake  2 , Nicole Ochsenbein  3 , Margaret Huesler  3 , Peter Biro  4 , Ianina Scheer  5 , Sasha Tharakan  1 , Peter Dürig  6 , Roland Zimmermann  3               

The first description of apparently secondary, that is, in utero acquired, damage to the pathologically exposed spinal cord within the myelomeningocele (MMC) lesion dates back to 1956. For obvious reasons, the significance of this observation regarding therapeutic consequences was not recognized until fetal surgery became a reality in the 1980s. Only then was the hypothesis born that early in utero intervention might stop the ongoing neural tissue destruction and so reduce the neurologic deficit otherwise seen at birth.

Journal: Thieme European Journal of Pediatric Surgery 2013; 23(06): 494-498

Date: 01/01/2013

1 Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland.

2 The Center for Fetal Diagnosis and Treatment, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States.

3 Department of Obstetrics, University Hospital Zurich, Zurich, Switzerland.

4 Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.

5 Department of Radiology, University Children's Hospital Zurich, Zurich, Switzerland.

6 Effinger Center for Obstetrics and Gynecology, Zurich, Switzerland.

The dysraphic levels of skin and vertebrae are different in mouse fetuses and neonates with myelomeningocele

Dorothea Stiefel  1 , Martin Meuli

Mouse fetuses with spontaneous myelomeningocele (MMC) were investigated, determining the various levels of dysraphism in soft tissue, spinal cord, and vertebrae. Morphology was correlated with hind limb function.

Journal: Journal of Pediatric Surgery (Volume 43, Issue 4, April 2008, Pages 683-690)

Date: 08/04/2008

1 Department of Pediatric Surgery, University Children's Hospital Zürich, 8032 Zürich, Switzerland. stiefel_d@yahoo.co.uk

Scanning electron microscopy of fetal murine myelomeningocele reveals growth and development of the spinal cord in early gestation and neural tissue destruction around birth

Dorothea Stiefel  1 , Martin Meuli

Previous studies demonstrated that the spinal cord within a fetal myelomeningocele (MMC) lesion suffers progressive destruction during gestation. This study aims at elucidating this pathophysiologic feature on a cellular and ultrastructural level in a model of genetically determined MMC.

Journal: Journal of Pediatric Surgery (Volume 42, Issue 9, September 2007, Pages 1561-1565)

Date: 01/09/2007

1 Neural Development Unit, Institute of Child Health, University College London, London, WC1N 1EH United Kingdom.

Fetal spina bifida in a mouse model: loss of neural function in utero

Dorothea Stiefel  1 , Andrew J Copp, Martin Meuli

The devastating neurological deficit associated with myelomeningocele has previously been assumed to be a direct and inevitable consequence of the primary malformation-failure of neural tube closure. An alternative view is that secondary damage to the pathologically exposed spinal cord tissue in utero is responsible for the neurological deficiency. If the latter mechanism were shown to be correct, it would provide an objective rationale for the performance of in utero surgery for myelomeningocele, because coverage of the exposed spinal cord could be expected to alleviate or perhaps prevent neurodegeneration. To examine this question, the authors studied the development of neuronal connections and neurological function of mice during fetal and neonatal stages in a genetic model of exposed lumbosacral spina bifida.

Journal: JNS Journal of Neurosurgery (Volume 106: Issue 3, March 2007)

Date: 01/03/2007

1 Department of Pediatric Surgery, University Children's Hospital Zurich, Switzerland. stiefel_d@yahoo.co.uk

Tethering of the spinal cord in mouse fetuses and neonates with spina bifida

Dorothea Stiefel  1 , Takashi Shibata, Martin Meuli, Patrick G Duffy, Andrew J Copp

Tethering of the spinal cord is a well-known complication in humans with spina bifida aperta or occulta. Its pathogenesis consists of a pathological fixation of the spinal cord resulting in traction on the neural tissue which, in turn, leads to ischemia and progressive neurological deterioration. Although well established in humans, this phenomenon has not been described in animal models of spina bifida.

Journal: JNS Journal of Neurosurgery: Spine (Volume 99: Issue 2, Sep. 2003)

Date: 01/09/2003

1 Neural Development Unit, Institute of Child Health, University College London, United Kingdom.

Physiologically low oxygen concentrations in fetal skin regulate hypoxia-inducible factor 1 and transforming growth factor-beta3.

Annette Scheid1, Roland H Wenger1,Leonhard Schäffer1,Isabelle Camenisch1,Oliver Distler1, Andrej Ferenc1, Heidi Cristina1, Heather E Ryan1, Randall S Johnson1, Klaus F Wagner1, Urs G Stauffer1, Christian Bauer1, Max Gassmann1, Martin Meuli1

In the first-trimester mammalian fetus, skin wounds heal with perfect reconstitution of the dermal architecture without scar formation. Understanding environmental molecular regulation in fetal wound healing may reveal scar-limiting therapeutical strategies for the prevention of postnatal scarring wound repair. Therefore, we performed studies on fetal skin oxygenation and skin and wound expression of hypoxia-inducible factor 1alpha (HIF-1alpha) in the sheep model in vivo and performed studies on the potential relevance of HIF-1alpha during wound healing in vitro. Skin oxygen partial pressure levels were hypoxic throughout normal development. In nonscarring fetal skin at gestation day (GD)60, HIF-1alpha could be detected neither in healthy nor in wounded tissue. At GD100, in wounds with minimal scar formation, HIF-1alpha was expressed in fibroblasts and was markedly up-regulated at the wound edge. In scarring fetal wounds at GD120, HIF-1alpha was predominantly expressed in inflammatory cells. Expression of transforming growth factor beta3 (TGF-beta3), a potent antiscarring cytokine, overlapped with HIF-1a expression at GD100. HIF-1alpha-deficient mouse embryonic fibroblasts showed impaired migratory capabilities and demonstrated that TGF-beta3, but not proscarring TGF-beta1, manifests hypoxia- and HIF-1alpha-dependent regulation. In conclusion, HIF-1alpha-dependent regulation of a potent antiscarring cytokine may provide new strategies for antiscarring manipulation of wound healing.

Journal: PubMed

Date: 20/02/2003

Department of Surgery, University Children's Hospital of Zürich, Switzerland. ascheid@physiol.unizh.ch

Fetal Surgery for Myelomeningocele: Panacea or Peril?

Shinjiro Hirose  1 , Claudia Meuli-Simmen, Martin Meuli

Myelomeningocele affects thousands of children worldwide with devastating consequences. In an effort to improve neurologic outcome, fetal surgery has been performed for myelomeningocele for the past 5 years. Sensorimotor function is not appreciably improved, although there may be a reduction in hindbrain herniation and a decreased need for ventriculoperitoneal shunting. The long-term clinical consequences of these findings are not clear. What is clear, however, is that further study in the form of a prospective, randomized trial is mandatory.

Journal: World Journal of Surgery - published online: December 19, 2002

Date: 06/01/2003

1 The Fetal Treatment Center, Department of Surgery, Division of Pediatric Surgery, University of California, San Francisco, 513 Parnassus Avenue, Room HSW 1601, San Francisco, California 94143-0570, USA.

Hypoxia-regulated gene expression in fetal wound regeneration and adult wound repair

A Scheid1, R H Wenger1, H Christina1, I Camenisch1, A Ferenc1, U G Stauffer1, M Gassmann1, M Meuli1

Journal: PubMed

Date: 01/05/2002

1Department of Surgery, University Children's Hospital Zurich, Switzerland.

Prenatal diagnosis of a fetus with lumbar myelocystocele

N Kölble  1 , T A Huisman, T Stallmach, M Meuli, F Zen Ruffinen Imahorn, R Zimmermann

We present a case of a fetal lumbar myelocystocele, a rare congenital malformation, characterized by herniation of the central canal through a bony spina bifida. Routine ultrasound examination at 11 weeks' gestation by the primary obstetrician showed a suspicious cyst on the fetal back. Initially, the suspected diagnosis was a meningocele. After sonographic detection of newly developed fetal brain anomalies at 22 weeks' gestation the patient was referred to us. The enlarged cyst, which floated freely in the amniotic fluid, had a funnel-like appearance and was covered by a very thin layer of skin. With the help of ultrafast fetal magnetic resonance imaging the diagnosis of a fetal myelocystocele was made.

Journal: Ultrasound in Obstetrics & Gynecology (Volume 18, Issue 5, Pages 536-539)

Date: 01/11/2001

1 Unit of Perinatal Physiology, Department of Obstetrics, University Hospital, Zurich, Switzerland. nicole.koelble@fhk.usz.ch

The Fetus with a Myelomeningocele (in: The Unborn Patient: The Art and Science of Fetal Therapy. 3rd ed. 2001, chapter 28:443-452. Authors: Michael R. Harrison, Mark I. Evans, N. Sc. Adzick. ISBN: 0-7216-8446-7)

Meuli M.

This popular reference returns in the 3rd Edition with an exciting new focus entirely committed to fetal therapy. Leading authorities from around the world provide comprehensive management strategies for several dozen diseases that can now be detected in utero. Each disease is covered in its own chapter providing all of the exciting new options in prenatal and postnatal treatment. Coverage includes updated information on pathophysiology and the technical aspects of treatment. This content also provides excellent teaching material for families considering or undergoing treatment.

Journal: Saunders: The Unborn Patient

Date: 01/01/2001

Assessment of sensory function in neonatal sheep with somatosensory evoked potentials: methodology and normative data

C D Yingling  1 , C Meuli-Simmen, M Meuli, G B Timmel, N S Adzick, M Harrison

Fetal sheep are increasingly used as animal models for fetal surgical interventions such as repair of myelomeningocele. Since behavioral observations cannot provide objective information about preservation of sensory function, we have developed a technique for reliably recording somatosensory evoked potentials in neonatal sheep. We determined anatomic criteria for placement of recording electrodes over the somatosensory cortex using external landmarks, and recorded normative data for both ulnar and posterior tibial nerve stimulation in a series of normal neonatal sheep. The methodology and normative data are presented in this report; a companion paper demonstrates the utilization of this technique in a variety of experimental fetal interventions.

Journal: Pediatric Surgery International 15, 530-534 (1999)

Date: 01/11/1999

1 Department of Neurological Surgery, University of California, San Francisco, USA.

Experimental fetal neurosurgery: effects of in-utero manipulations on somatosensory evoked potentials

C D Yingling  1 , C Meuli-Simmen, M Meuli, G B Timmel, M Harrison, N S Adzick

Somatosensory evoked potentials (SEP) were used to objectively evaluate sensory function in neonatal sheep after experimental fetal surgery. Posterior tibial (PTN) and ulnar (UN) nerves were stimulated electrically and averaged SEP were recorded from scalp electrodes placed over the somatosensory cortex. Animals with experimentally-created myelomeningocele (MMC) showed no SEP to PTN stimulation, but normal SEP to UN stimulation. In-utero repair of the MMC resulted in preservation of neurologic function and normal PTN SEP. In-utero thoracic spinal-cord transection resulted in no regeneration, and no SEP to PTN stimulation. In-utero unilateral transection of the sciatic nerve, even with attempted repair, resulted in little or no regeneration and absent or grossly abnormal PTN SEP from the affected side. In summary, the SEP technique provides valuable information concerning preservation of sensory function in a variety of experimentally created neurologic abnormalities and can aid in functional evaluation of experimental therapeutic fetal interventions.

Journal: Pediatric Surgery International 15, 535-539 (1999)

Date: 01/11/1999

1 Department of Neurological Surgery, University of California, San Francisco, USA.

Altered smooth muscle development and innervation in the lower genitourinary and gastrointestinal tract of the male human fetus with myelomeningocele

E Shapiro  1 , M J Seller, H Lepor, D K Kalousek, G M Hutchins, E J Perlman, M Meuli

Purpose: We determine whether smooth and skeletal muscle or nerve density is altered in the lower genitourinary or gastrointestinal tract of male human fetuses with myelomeningocele at 20 weeks of gestation.

Journal: The Journal of Urology: 1998 Sep;160(3 Pt 2):1047-53; discussion 1079

Date: 01/09/1998

1 Department of Urology, New York University School of Medicine, New York, USA.

Spontaneous repair of superficial defects in articular cartilage in a fetal lamb model

R S Namba  1 , M Meuli, K M Sullivan, A X Le, N S Adzick

A fetal lamb model was developed to investigate the capacity of fetal articular cartilage for repair after the creation of a superficial defect. Superficial defects, 100 micrometers deep, were made in the articular cartilage of the trochlear groove in the distal aspect of the femur in eighteen fetal lambs that were halfway through the 145-day gestational period; the contralateral limb was used as a sham control. The wounds were allowed to heal in utero for three, seven, fourteen, twenty-one, or twenty-eight days. Seven days after the injury, the defects were filled with a hypocellular matrix, which stained lightly with safranin O. At twenty-eight days, the staining of the matrix was similar to that of the sham controls and the chondrocyte density and the architectural arrangement of the cell layers had been restored. An inflammatory response was not elicited, and no fibrous scar tissue was observed.

Journal: The Journal of Bone & Joint Surgery, American Volume: 1998 Jan;80(1):4-10

Date: 01/01/1998

1 Department of Orthopaedic Surgery, University of California at San Francisco, 94143-0728, USA.

Latissimus dorsi flap procedures to cover myelomeningocele in utero: a feasibility study in human fetuses

Claudia Meuli-Simmen a, b, c, d Martin Meuli a, b, c, d N. Scott Adzick a, b, c, d Michael R Harrison a, b, c, d

There is experimental and clinical evidence that in utero repair of myelomeningocele (MMC) may preserve neurological function. In five aborted human fetuses (gestational age, 18 to 29 weeks), the authors tested whether proximally and distally based latissimus dorsi flaps (LDF) can be used to cover MMC lesions. Fetal soft tissues were developed enough to allow surgical handling, preparation of both flap types was technically easy, and the vascular pedicles could be preserved. The proximally pedicled LDF was suitable to cover the upper spine from lower cervical to lower thoracic levels, whereas the distally pedicled LDF was suitable to cover the spine between lower thoracic and lower sacral levels. These results suggest that various LDF procedures are technically feasible in early gestational human fetuses and could be used for in utero repair of MMC.

Journal: Journal of Pediatric Surgery (Volume 32, Issue 8, Pages 1154-1156)

Date: 01/08/1997

a Division of Hand, Plastic, and Reconstructive Surgery, University Children's Hospital, Zurich, Switzerland.

b the Department of Surgery, University Children's Hospital, Zurich, Switzerland.

c The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA

d The Fetal Treatment Center, University of California, San Francisco, CA, USA

 

The spinal cord lesion in human fetuses with myelomeningocele: Implications for fetal surgery

Martin Meuli a, b, c, d, e, f Claudia Meuli-Simmen a, b, c, d, e, f Grover M Hutchins a, b, c, d, e, f Mary J Seller a, b, c, d, e, f Michael R Harrison a, b, c, d, e, f N. Scott Adzick a, b, c, d, e, f

Recently produced experimental evidence suggests that secondary traumatic injury and degenerative changes, acquired in utero, to the openly exposed neural tissue may be primarily responsible for the massive neurological deficit associated with myelomeningocele (MMC). The goal of this study was to examine the morphology of human fetuses with MMC to determine if acquired trauma to the spinal cord could be identified. The MMC lesions with surrounding tissues from 10 human fetuses ranging in gestational age between 19 and 23 weeks were prepared with serial histological sections. The MMC lesions were characterized by an open vertebral arch, an open dura mater fused laterally to the dermis, and an open pia mater fused laterally to the epidermis. The spinal cord was exposed, without any meningeal, bony, or cutaneous covering, and was resting on the dorsal aspect of the abnormal arachnoid sac created by the fusion of the meninges to the cutaneous tissues. The exposed neural tissue had undergone varying degrees of recent traumatic injury as a result of its exposed position, ranging from nearly complete preservation of neural elements in four cases to nearly complete loss in two cases. The neural tissue remaining in the MMC with partial loss contained hemorrhages and abrasions from recent injury, suggesting that injury occurred during passage through the birth canal. The presence of dorsal and ventral parts of the cord with nerve roots and ganglia demonstrated that these structures had formed during development and that the loss of tissue by injury was a secondary change. The results support the concept that performing in utero surgery could protect the exposed but initially well-developed and uninjured cord, prevent secondary neural injury, and preserve neural function in the human fetus with myelomeningocele.

Journal: Journal of Pediatric Surgery (Volume 32, Issue 3, Pages 448-452)

Date: 01/03/1997

a Department of Surgery, University Children's Hospital, Zurich, Switzerland

b the Division of Hand, Plastic, and Reconstructive Surgery, University Hospital, Zurich, Switzerland

c the Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

d the Division of Medical and Molecular Genetics, Guy's Hospital, London, England

e The Fetal Treatment Center, University of California, San Francisco, CA, USA

f the Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA

Midgestational sciatic nerve transection in fetal sheep results in absent nerve regeneration and neurogenic muscle atrophy

C Meuli-Simmen  1 , M Meuli, C D Yingling, T Eiman, G B Timmel, H J Buncke, W Lineaweaver, M R Harrison, N S Adzick  

In order to test whether fetal nerve healing and regeneration result in complete functional recovery, we transected the sciatic nerve at trunk level in 13 midgestational sheep fetuses. In 10 fetuses immediate microsurgical nerve coaptation was performed. The neonatal lambs were evaluated clinically, electrophysiologically, and histologically. On the transected side, the 10 surviving lambs showed a sensorimotor sciatic nerve paralysis and atrophy of the muscles innervated by the sciatic nerve. Somatosensory evoked potentials were weakly present in 5 animals and absent in 5 animals. Histologically, minimal signs of axonal regeneration, massive degeneration of the entire nerve, and a marked neurogenic muscle atrophy were found. These unexpected results differ from the findings after peripheral nerve transections in late gestational sheep fetuses and also from the classic wallerian degeneration-regeneration pattern that follows adult nerve injury. We speculate that the almost absent regenerative potential at midgestation is related to axotomy-induced neurotrophic factor deprivation during a developmental phase where the neurons are critically dependent on growth factor for survival.

Journal: Plastic and Reconstructive Surgery 1997 Feb;99(2):486-92.

Date: 01/02/1997

1 Fetal Treatment Center, University of California, San Francisco, USA.

The fetal spinal cord does not regenerate after in utero transection in a large mammalian model

C Meuli-Simmen  1 , M Meuli, G M Hutchins, C D Yingling, G B Timmel, M R Harrison, N S Adzick

Regeneration and functional recovery after spinal cord transection do not occur in mammalian animals and humans postnatally. The goal of this study was to test whether in utero transection of the fetal spinal cord is succeeded by anatomic healing and functional recovery.

Journal: Neurosurgery (Volume 39, Issue 3, Pages 555-560)

Date: 01/09/1996

1 Fetal Treatment Center, University of California San Francisco, USA.

Acquired spinal cord injury in human fetuses with myelomeningocele

G M Hutchins  1 , M Meuli, C Meuli-Simmen, M A Jordan, D S Heffez, K J Blakemore

Experimental studies have shown that there is a potential to attempt in utero repair of myelomeningocele in human fetuses. To provide a better understanding of the pathology of these lesions we prospectively studied eight stillborn human fetuses with myelomeningocele autopsied at The Johns Hopkins Hospital. The intact vertebral column with surrounding structures was removed, processed as a single block, and prepared as serial histologic sections. Study of the slides showed in all cases that in the center of the myelomeningocele the vertebral arch was open, the arrangement of meninges was such that the dura mater was open and in continuity with the deep layers of the dermis, and the pia mater was open and in continuity with a layer consisting of the superficial dermis and the epidermis. These meningeal relationships created an abnormally configured arachnoid space containing cerebrospinal fluid ventral to the spinal cord, which rested on the open pia mater and was exposed on the dorsal aspect of the sac. At the level of the myelomeningocele the naked cord had undergone varying degrees of injury up to complete loss of neural tissue. Where ventral remnants of the cord remained it was evident that a large degree of normal development of the cord had occurred. In most instances it appeared that the injury or destruction of the dorsal spinal cord was recent and consistent with occurrence during delivery. The results of this study support the concept that in utero surgery could preserve and protect the exposed spinal cord in a myelomeningocele of a human fetus and thus could reduce the severity of the neurologic deficit at birth.

Journal: Pediatric pathology & laboratory medicine: Journal of the Society for Pediatric Pathology, affiliated with the International Paediatric Pathology association (Sep-Oct 1996;16(5):701-12)

Date: 01/09/1996

1 Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.

Experimental fetal transesophageal and intracardiac echocardiography utilizing intravascular ultrasound technology

T Kohl  1 , Z Szabo, K J VanderWall, S J Hutchinson, E J Stelnicki, M Meuli, M R Harrison, N H Silverman, T M Chou

Fetal transesophageal and intracardiac echocardiography by utilizing ultrasound technology permits accurate definition of cardiac anatomy in fetal sheep. Because fetal transesophageal echocardiography is less invasive than intracardiac echocardiography, it has the potential to serve as a monitoring tool for currently developed open and fetoscopic fetal cardiac interventions.

Journal: The American Journal of Cardiology (Volume 77, Issue 10, Pages 899-903)

Date: 01/04/1996

1 Division of Pediatric Cardiology, University of California, San Francisco 94143, USA.

Percutaneous access to the uterus for fetal surgery

K J VanderWall  1 , M Meuli, Z Szabo, S W Bruch, T Kohl, W Y Hoffman, N S Adzick, M R Harrison

In utero repair of selected life-threatening malformations in the human fetus is now a clinical reality, yet fetal surgery continues to pose significant risks to both the mother and the unborn child. Preterm labor is a major problem directly related to the large uterine incision required for fetal exposure. Using technology developed for laparoscopic surgery, we have devised instruments and techniques to perform fetal endoscopic surgery. We now report a percutaneous technique for direct endoscopic access to the uterus. Minimally invasive fetoscopic surgery may expand the indications for fetal surgery by decreasing fetal risks, facilitating intervention earlier in gestation, and reducing preterm labor. This technique was developed in 4 fetal lambs who underwent endoscopic intervention at 105-110 days gestation (term = 145 days). Under ultrasound guidance, a 20-gauge spinal needle was advanced through the maternal abdomen, uterus, and directly into the amniotic cavity. Warmed saline was infused through the needle to expand the amniotic cavity. Next, a 5-mm balloon-tipped trocar was placed percutaneously with ultrasound guidance into the amniotic cavity. A 5-mm laparoscope was introduced and under endoamniotic vision two more 5-mm trocars were percutaneously placed. In all four sheep a 5-mm trocar was placed percutaneously into the gravid uterus. The most difficult step was puncturing through the amniotic membranes, but the sharp tip of the trocar facilitated getting into the amniotic cavity. Excellent visualization of the fetus was obtained with minimal uterine trauma. We have developed a fetoscopic technique in sheep for percutaneous placement of trocars into the uterus using ultrasound guidance. This approach allowed excellent visualization of the fetus with significantly less uterine trauma than open fetal surgery and is an essential prerequisite for future fetal endoscopic interventions.

Journal: Journal of Laparoendoscopic Surgery (1996 Mar;6 Suppl 1:S65-7.)

Date: 01/03/1996

1 Fetal Treatment Center, Department of Surgery, University of California, San Francisco, USA.

In utero repair of experimental myelomeningocele saves neurological function at birth

M Meuli  1 , C Meuli-Simmen, C D Yingling, G M Hutchins, G B Timmel, M R Harrison, N S Adzick

In a previous series of fetal sheep experiments, the authors demonstrated that midgestational exposure of the normal spinal cord to the amniotic space leads to a myelomeningocele (MMC) at birth that closely resembles human MMC phenotypes in terms of morphology and functional deficit. The present study tested whether delayed in utero repair of such evolving experimental MMC lesions spares neurological function. In 12 sheep fetuses, a spina bifida-type lesion with exposure of the lumbar spinal cord was created at 75 days' gestation (full term, 150 days). Four weeks later, the developing MMC lesions were repaired in utero for seven fetuses (five fetuses died before this time). Of those that had repair, three were delivered near term by cesarean section, and four died in utero or were aborted. All survivors had healed skin wounds and near-normal neurological function. Despite mild paraparesis, they were able to stand, walk, and perform demanding motor tests. Sensory function of the hindlimbs was present clinically and confirmed electrophysiologically. No signs of incontinence were detected. Histologically, the exposed and then covered spinal cord showed significant deformation, but the anatomic hallmarks as well as the cytoarchitecture of the spinal cord essentially were preserved. These findings show that timely in utero repair of developing experimental MMC stops the otherwise ongoing process of spinal cord destruction and “rescues” neurological function by the time of birth. Because there is evidence that a similar secondary damage to the exposed neural tissue also occurs in human MMC, we propose that in utero repair of selected human fetuses might reduce the neurological disaster commonly encountered after birth.

Journal: Journal of Pediatric Surgery (Volume 31, Issue 3, Pages 397-402)

Date: 01/03/1996

1 Department of Anesthesia, University of California, San Francisco, USA.

Experimental fetal neurosurgery: the normal neurology of neonatal lambs and abnormal findings after in utero manipulation

K M Hoffman  1 , G B Timmel, C Meuli-Simmen, M Meuli, C D Yingling, N S Adzick

No abstract available

Journal: Contemporary Topics in Laboratory Animal Science 1996 Jan;35(1):53-6

Date: 01/01/1996

1 Animal Care Facility, University of California, San Francisco, CA 94143, USA.

Fetal reconstructive surgery: experimental use of the latissimus dorsi flap to correct myelomeningocele in utero

C Meuli-Simmen  1 , M Meuli, G M Hutchins, M R Harrison, H J Buncke, K M Sullivan, N S Adzick

A recent study in human fetuses with myelomeningocele produced evidence that nonclosure of the spine leads to progressive damage of the exposed spinal cord during pregnancy. Thus in utero coverage might spare function. We tested the use of the latissimus dorsi flap for fetal myelomeningocele repair. In seven sheep fetuses, a lumbar myelomeningocele type of lesion was created at 75 days' gestation and was covered with a "reversed" latissimus dorsi flap at 100 days. At term, the three survivors had healed cutaneous wounds and normal hindlimb function. The vascular pedicle of the latissimus dorsi flap was patent, the viable flap covered the entire lesion, and the underlying spinal cord was grossly intact. We conclude that the latissimus dorsi flap repair is suitable for fetal surgery and provides efficient coverage of the lesion. These results have clinical implications, since fetal myelomeningocele repair may be a compelling way to reduce the severe neurologic deficit in humans.

Journal: Plastic and reconstructive surgery 1995 Oct;96(5):1007-11

Date: 01/10/1995

1 Fetal Treatment Center, University of California, San Francisco, USA.

Exogenous transforming growth factor-beta amplifies its own expression and induces scar formation in a model of human fetal skin repair.

R Y Lin1, K M Sullivan1, P A Argenta1, M Meuli1, H P Lorenz1, N S Adzick1

etal skin wounds heal without scarring. To determine the role of TGF-beta 1 in fetal wound healing, mRNA expression of TGF-beta 1 was analyzed in human fetal and adult skin wounds.

Journal: PubMed

Date: 01/08/1995

Department of Surgery, University of California-San Francisco, USA.

Exogenous transforming growth factor-beta amplifies its own expression and induces scar formation in a model of human fetal skin repair

R Y Lin  1 , K M Sullivan, P A Argenta, M Meuli, H P Lorenz, N S Adzick

Fetal skin wounds heal without scarring. To determine the role of TGF-beta 1 in fetal wound healing, mRNA expression of TGF-beta 1 was analyzed in human fetal and adult skin wounds.

Journal: Annals of Surgery (Vol. 222, No. 2, 146-154)

Date: 01/08/1995

1 Department of Surgery, University of California-San Francisco, USA.

Fetal endoscopic ('Fetendo') surgery: the relationship between insufflating pressure and the fetoplacental circulation

E D Skarsgard  1 , J F Bealer, M Meuli, N S Adzick, M R Harrison

Application of video-endoscopic surgery to the gravid uterus provides a new treatment option for the fetus with a correctable congenital anomaly. “Fetendo” surgery requires temporary enlargement of the uterine cavity to create a working space. Volume expansion of the amniotic space raises intrauterine pressure, which could increase placental vascular resistance and thereby reduce placental blood flow. To test this hypothesis, the authors developed a fetal sheep model to examine the relationship between insufflating pressure and flow in the placental circulation. Fetoplacental blood flow was measured via ultrasonic flow probes placed around the fetal common umbilical artery and the maternal uterine artery in five anesthetized 120-day-gestation ewes. Invasive feto-maternal monitoring permitted synchronous measurement of fetal mean arterial pressure, fetal central venous pressure, maternal mean arterial pressure, amniotic pressure, and fetal oxygen saturation, with calculated values for fetal and maternal placental vascular resistance. Amniotic pressure was raised from 10 mm Hg to 40 mm Hg in 5-mm Hg increments by a combination of saline amnioinfusion and external uterine compression. At amniotic pressures of 20 mm Hg or less, placental blood flow was preserved; however, elevation of amniotic pressure above 20 mm Hg resulted in a significant decrease in placental flow, with concomitant fetal hypoxia. The authors conclude that the relationship between intrauterine pressure, flow in the placental circulation, and fetal oxygen delivery must be considered when selecting intrauterine insufflation pressures for hysteroscopic intervention.

Journal: Journal of Pediatric Surgery (Volume 30, Issue 8, Pages 1165-1168)

Date: 01/08/1995

1 Fetal Treatment Center, University of California, San Francisco 94143-0570, USA.

An adult-fetal skin interface heals without scar formation in sheep

K M Sullivan  1 , M Meuli, T E MacGillivray, N S Adzick

Fetal skin heals by regeneration rather than by adult-type scarring. Prior studies indicate that scarless healing is an intrinsic property of fetal tissue.

Journal: Surgery (Volume 118, Issue 1, Pages 82-86)

Date: 01/07/1995

1 Fetal Treatment Center, University of California, San Francisco 94143-0570, USA.

Creation of myelomeningocele in utero: a model of functional damage from spinal cord exposure in fetal sheep

Martin Meuli a, b, c, d, e Claudia Meuli-Simmen a, b, c, d, e Charles D Yingling a, b, c, d, e Grover M Hutchins a, b, c, d, e Kathleen McBiles Hoffman a, b, c, d, e Michael R Harrison a, b, c, d, e N. Scott Adzick a, b, c, d, e

 

A recent study in human fetuses with myelomeningocele (MMC) suggested that the primary malformation is not neural but a failed closure of the posterior vertebral column and paraspinal soft tissue, which leads to exposure and secondary destruction of the spinal cord. The goal of this study was to test whether chronic exposure of the normal spinal cord to the amniotic space produces a lesion similar to human MMC. In fetal sheep at 75 days' gestation (group A) and 60 days' gestation (group B) (term = 150 days), the lumbar spinal cord was exposed to the amniotic cavity by excising skin and paraspinal soft tissues, and by performing a laminectomy. Some animals from both groups were fetectomized and assessed morphologically at 100 days' gestation. The remainder were delivered near term and assessed clinically, electrophysiologically, and morphologically. In group A, all animals showed MMC-type pathology. The exposed spinal cord was herniated out of the spinal canal and rested on the dorsal membranes of a cystic sac. The neural tissue was stretched and flattened out. Histologically, the hallmarks of the spinal cord were not discernable and the cytoarchitecture was lost. These changes were less severe at 100 days than at term. The three survivors in group A were paraplegic. In group B, the two survivors and two fetuses harvested at 100 days had healed skin wounds and near normal spinal cord histology. The other animal harvested at 100 days had a MMC-type lesion with less severe histological changes. The two survivors had a mild paraparesis. In conclusion, surgical exposure of the normal spinal cord to the amniotic space in a 75-day sheep fetus results in a MMC-type pathology at birth, which clinically and morphologically resembles human MMC. The creation of a spina bifida-type lesion in a 60-day-old fetus may result in spontaneous healing and minimal neurological deficit at birth. This “healing experiment of nature” suggests that in utero repair of MMC might prevent spinal cord damage and spare neurological function.

Journal: Journal of Pediatric Surgery (Volume 30, Issue 7, Pages 1028-1033)

Date: 01/07/1995

a Fetal Treatment Center, University of California San Francisco, CA, USA

b the Department of Anesthesia, University of California San Francisco, CA, USA

c the Animal Care Facility, University of California, San Francisco, CA, USA

d Microsurgical Laboratory, Davies Medical Center, San Francisco, CA, USA

e the Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

In utero surgery rescues neurological function at birth in sheep with spina bifida

M Meuli  1 , C Meuli-Simmen, G M Hutchins, C D Yingling, K M Hoffman, M R Harrison, N S Adzick

We hypothesize that the neurologic deficit associated with open spina bifida is not directly caused by the primary defect but rather is due to chronic mechanical and chemical trauma since the unprotected neural tissue is exposed to the intrauterine environment. We report here that exposure of the normal spinal cord to the amniotic cavity in midgestational sheep fetuses leads to a human-like open spina bifida with paraplegia at birth, indicating that the exposed neural tissue is progressively destroyed during pregnancy. When open spina bifida was repaired in utero at an intermediate stage, the animals had near-normal neurologic function. The spinal cord was deformed but largely preserved. These findings suggest that secondary neural tissue destruction during pregnancy is primarily responsible for the functional loss and that timely in utero repair of open spina bifida might rescue neurologic function.

Journal: Nature Medicine 1, 342-347 (1995)

Date: 01/04/1995

1 Fetal Treatment Center, University of California, San Francisco 94143-0570, USA.

Scar formation in the fetal alimentary tract

M Meuli  1 , H P Lorenz, M H Hedrick, K M Sullivan, M R Harrison, N S Adzick

The aim of this study was to determine whether the fetal alimentary tract shares the unique scarless healing properties of fetal skin. Full-thickness incisional gastric wounds were created and sutured closed in fetal lambs at 60, 75, and 120 days' gestation (full term, 145 days), and in adult control sheep. At the time of harvest, 14 days postwounding, dense fibrous adhesions were found intraperitoneally in all fetal and adult animals. Histologically, all fetal and adult gastric wounds healed with pronounced scar formation. In contrast to the adult wound, there was no significant inflammatory response in the fetal wounds. Because scar formed in the absence of inflammation in fetal gastric wounds, there is no obvious relation between scarring and the inflammatory response at this location. This study shows that not all fetal tissues exhibit scarless repair properties.

Journal: Journal of Pediatric Surgery (Volume 30, Issue 3, Pages 392-395)

Date: 01/03/1995

1 Fetal Treatment Center, University of California, San Francisco 94143, USA.

A model of scarless human fetal wound repair is deficient in transforming growth factor beta

K M Sullivan  1 , H P Lorenz, M Meuli, R Y Lin, N S Adzick

Human fetal skin heals via scarless regeneration, whereas adult skin heals with scar. Scarless repair may reflect a distinct cytokine milieu. We studied the role of the cytokine transforming growth factor beta (TGFβ) using an established model of scarless human fetal skin repair in which human fetal skin is transplanted into a subcutaneous pocket on the flank of an adult nude mouse. In this model, wounded 16-week-gestation human fetal skin heals without scar, whereas wounded adult skin heals with scar. Seven days after transplantation, incisional wounds were made in the skin grafts. In the first phase of the study, wounds were harvested from 1 hour to 4 weeks postwounding, and immunohistochemistry was performed for TGFβ (isoform nonspecific), TGFβ1, and TGFβ2. Scarfree wounds in the fetal skin grafts did not show TGFβ staining. In contrast, wounds in adult grafts that heal with scar demonstrated isoform nonspecific TGFβ staining from 6 hours through 21 days, TGFβ1 from 6 hours through 21 days, and TGFβ2 from 12 hours through 7 days. In the second phase of the study, a slow-release disk with 0.01, 0.1, 1.0, or 10 μg of TGFβ1 was placed beneath the fetal skin graft at the time of wounding. Fourteen days postwounding, there was marked scarring in the fetal grafts treated with TGFβ1, and the size of the scar was proportional to the amount of TGFβ1 applied. The relative lack of TGFβ, a cytokine known to promote fibrosis, may be one reason why the fetus heals by regeneration rather than scarring. In contrast, the fibrosis characteristic of postnatal wound repair may be associated with an excess of TGFβ. These findings suggest that anti-TGFβ therapeutic strategies may ameliorate scar formation in children and adults.

Journal: Jourlan of Pediatric Surgery (Volume 30, Issue 2, Pages 198-203)

Date: 01/02/1995

1 Fetal Treatment Center, University of California, San Francisco 94143-0570, USA.