In Utero Fetoscopic Repair Program for Sacral Myelomeningoceles and Mye-LDM (PRIUM2)

The purpose of the study is to evaluate the feasibility and the maternal, fetal and postnatal outcomes of sacral myelomeningocele (MMC) and Myelic Limited Dorsal Myeloschisis (MyeLDM) fetoscopic repair at Trousseau Hospital (Paris, France).

Study Overview

• Status: Recruiting
• Conditions: Neural Tube Defects; Spina Bifida; Sacral Myelomeningocele
• Intervention / Treatment: Procedure: Fetoscopy

Detailed Description

Myelomeningocele and Myelic limited dorsal myeloschisis (MyeLDM) correspond to neural tube defects which lead to lifelong disabilities including lower extremity paralysis, sphincters deficiency, and cerebral complications (Chiari 2 malformation and hydrocephalus). It is demonstrated that fetal surgery repair of MMC with upper limit between the first thoracic vertebra (T1) and the first sacral vertebra (S1) improves motor and cerebral prognosis. Nowadays, this fetal surgery is performed either after maternal laparotomy and hysterotomy (open fetal surgery) or using fetoscopy. the investigators, at Trousseau Hospital (APHP, Paris), initiated an open fetal surgery of MMC program called PRIUM1 and 16 fetuses has been currently operated.

Fetoscopic repair of MMC is proposed by several international groups in order to prevent from maternal and obstetric morbidity related to the hysterotomy and improve the mother's obstetrical prognosis by allowing vaginal delivery. Results of fetoscopic MMC repair are very satisfying, both in terms of repair surgery efficacy and in terms of obstetrical prognosis. The research team believe that it is justified to propose this minimally invasive repair technique using fetoscopy, for represented by sacral MMC (level S1 and lower) as well as for intermediate forms between open and closed dysgraphisms, represented by MyeLDM. Indeed, these dysraphism are associated with the same cerebral complications than MMC with upper limit between T1 and S1 which could be corrected with prenatal repair. In addition, the spinal cord protection offered by prenatal surgery could prevent from the neuroepithelium destruction observed during pregnancy, with a potential motor benefit for the children.

The main objective of PRIUM 2 is to evaluate the success of fetoscopic surgical repair of sacral MMC or MyeLDM with a birth after 32 weeks of gestation and without severe perinatal morbidity and mortality.

The secondary objectives of PRIUM 2 are to evaluate the complications of pregnancy related to fetoscopic surgery as well as to evaluate the prenatal and postnatal evolution of the cerebral complications (Chiari 2 malformation and hydrocephalus) after fetoscopic repair surgery of the dysraphism (up to 12 months of age).

In this protocol, fetal sacral MMC/ MyeLDM repair surgery will be performed using gas fetoscopy before 26 weeks. After an exteriorization of the uterus through a laparotomy, humidified and warmed gas will be insufflated with low pressure (6 to 8mmHg mmHg). Fetoscopic repair surgery will be performed by a multidisciplinary team (maternal fetal medicine specialists, pediatric neurosurgeons, pediatric surgeons).

After discharge, patients will be followed weekly by a midwife and every two weeks by a referring obstetrician who will perform a clinical examination and a fetal ultrasound.A post procedure MRI will be performed 4 weeks after the surgery. If there is no obstetrical contraindication, vaginal delivery will be authorized.

The children will be followed according to the conventional management of children with dysraphisms and consultations at 8 weeks of life and 12 months of life will be scheduled at Trousseau Hospital, with the multidisciplinary team (pediatric neurosurgeons, physical medicine and rehabilitation specialists, pediatric orthopedic surgeons). During these two consultations, the children will have a complete clinical examination, a cerebral and spinal MRI and an ultrasound of the urinary tract.

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lucie GUILBAUD, MD; Phone Number: +33 (0) 1 44 73 52 28; Email: lucie.guilbaud@aphp.fr
• Study Contact Backup: Name: Jean-Marie JOUANNIC, MD; Phone Number: +33 (0) 1 71 73 84 51; Email: jean-marie.jouannic@aphp.fr

Study Locations

• France
  • Paris, France, 75012
    • Recruiting
    • Service médecine foetale-Hôpital Trousseau
    • Contact: Lucie GUILBAUD, MD; Phone Number: +33 (0) 1 44 73 52 28; Email: lucie.guilbaud@aphp.fr
    • Contact: Jean-Marie JOUANNIC, PU-PH; Phone Number: +33 (0) 1 71 73 84 51; Email: jean-marie.jouannic@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

Inclusion Criteria :

• Pregnant women age 18 years and older who are able to consent
• Singleton pregnancy before 26 weeks of gestation,
• Sacral MMC (upper level S1 or below) or MyeLDM diagnosed on ultrasound and MRI, 4. Absence of associated malformation apart from the anomalies usually observed in cases of open dysraphisms (i.e. feet malpositions, associated cerebral signs) or chromosomal anomaly if verification of the karyotype was desired by the couple
• Affiliated to health insurance, understanding and speaking French
• Written consent of the patient for the surgery and representatives of the parental authority for the postnatal follow-up of the child
• Patient who made the choice to continue the pregnancy

Exclusion Criteria:

• Abnormal angulation of the fetal spine,
• risk factors for prematurity: cervical length less < 15mm, history of late miscarriage before 22 weeks, pre-existing rupture of the membranes at inclusion,
• Placenta praevia,
• BMI greater than 35 kg / m2,
• Abnormality of the uterus: large fibroid, uterine malformation, history of uterine body surgery
• Maternal infection at risk of maternal-fetal transmission: HIV, HBV, HCV,
• Surgical or anesthetic contraindication.
• Participation in another interventional research protocol,
• Patients under legal protection (guardianship, curatorship).
• Allergies to drugs used in the research

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Fetoscopic repair; Sacral Myelomeningocele and Mye-LDM Fetoscopic repair

Procedure: Fetoscopy; After an exteriorization of the uterus through a laparotomy, humidified and warmed gas will be insufflated with low pressure (6 to 8mmHg mmHg). Fetoscopic repair surgery will consist in a dissection of the placode, its reintegration into the spinal canal and the closure of the lesion, through a three ports access. After fetal surgery, the gas will be exsufflated and the trocar ports will be closed. The uterus will be reintegrated before suturing the maternal abdominal wall.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ability to perform fetoscopic sacral MMC/MyeLDM repair without severe perinatal morbidity and mortality	Successful complete closure of the defect using the fetoscopic technique AND birth after 32 weeks without severe perinatal morbidity and mortality including grade III-IV intra ventricular hemorrhage, severe, cerebral parenchyma hemorrhage, periventricular leukomalacia, grade III ulcero-necrotizing enterocolitis, severe bronchodysplasia)	From time of surgery to 8 weeks of life (up to 28 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Maternal outcome	diagnosis of maternal gas embolism, hemorrhage, thromboembolic complication, death	during the surgery
Maternal obstetric outcome as evidenced by preterm labor leading to delivery at less than 37 weeks of gestation	Preterm labor occuring at any time from surgery leading to delivery before 37 weeks of gestation	From time of surgery until 37 weeks of gestation
Maternal obstetric outcome as evidenced by preterm premature rupture of membranes	Preterm premature rupture of membranes occuring at any time from surgery until 37 weeks of gestation	From time of surgery until 37 weeks of gestation
Maternal obstetric outcome as evidenced by chorioamnionitis	chorioamnionitis occuring at any time from surgery until 37 weeks of gestation	From time of surgery until 37 weeks of gestation
Maternal obstetric outcome as evidenced by antenatal betamethasone treatment	indication for a betamethasone course occuring at any time from surgery until 34 weeks of gestation	From time of surgery until 34 weeks of gestation
Other Maternal obstetric outcome as evidenced by hypertensive disorders, preeclampsia, gestational diabetes	hypertensive disorders, preeclampsia, gestational diabetes occuring any time from surgery until 37 weeks of gestation	From time of surgery until 37 weeks of gestation
Prenatal evolution of brain abnormalities associated with open dysraphism, after fetoscopic repair	Difference in the growth of the cephalic perimeter measured on an axial ultrasound section	From time of surgery until birth
Prenatal evolution of brain abnormalities associated with open dysraphism, after fetoscopic repair (1)	Difference in measurement of the ventricles on an axial ultrasound section	From time of surgery until birth
Prenatal evolution of brain abnormalities associated with open dysraphism, after fetoscopic repair (2)	Difference in the measurement of the large retro-cerebellar cistern on an axial section of the posterior fossa	From time of surgery until birth
Prenatal evolution of brain abnormalities associated with open dysraphism, after fetoscopic repair (3)	Proportion of patients with reversal of hindbrain herniation (i.e. lower limit of the vermis located above the foramen magnum on ultrasound and/or fetal MRI)	From time of surgery until birth
Maternal obstetric outcome as evidenced by gestational age at delivery (1)	Gestational age of delivery regardless of indication	From time of surgery until delivery
Maternal obstetric outcome as evidenced by gestational age at delivery (2)	Proportion of deliveries before 37 weeks of gestation	From time of surgery until delivery
Maternal obstetric outcome as evidenced by the ability to deliver vaginally	Mode of delivery - either vaginal or cesarean section	From time of surgery until delivery
Proportion of postpartum hemorrhages	Maternal obstetric outcome as evidenced by postpartum hemorrhage Proportion of postpartum hemorrhages defined by blood loss of more than 500mL for vaginal delivery, and 800mL for cesarean delivery	From time of surgery until delivery
Need for maternal transfusion (number of blood cells transfused)	Maternal obstetric outcome as evidenced by postpartum hemorrhage Need for maternal transfusion (number of blood cells transfused)	From time of surgery until delivery
Adverse neonatal outcome at birth (1)	Normal or abnormal birth parameters at birth depending on the term	at birth
Adverse neonatal outcome at birth (2)	Proportion of fetal asphyxia (arterial pH at the umbilical cord <7.00)	at birth
Adverse early childhood outcome as evidenced by need for a neurosurgical intervention	need for one of the following neurosurgery; Type 1: Superficial skin recovery surgery due to scar dehiscence; Type 2: Need for surgical correction involving all aspects, without reopening the dura; Type 3: Need for complete surgical correction with repair of the dural plane	From the time of birth until 8 weeks of life
Postnatal evolution of brain abnormalities associated with open dysraphism	Difference in the growth of the cephalic perimeter by measuring the cranial perimeter between birth and the age of 12 months	From the time of birth until 12 months of life
Postnatal evolution of brain abnormalities associated with open dysraphism (1)	Difference in the measurement of the cerebral lateral ventricles measured during postnatal transfrontanellar ultrasound followed by cerebral MRI ,	From the time of birth until 12 months of life
Postnatal evolution of brain abnormalities associated with open dysraphism (2)	Proportion of patients with reversal of hindbrain herniation (i.e. lower limit of the vermis located above the foramen magnum on cerebral MRI)	From the time of birth until 12 months of life
Postnatal evolution of brain abnormalities associated with open dysraphism (3)	Proportion of patients requiring a cerebrospinal fluid shunt within the first 12 months of life	From the time of birth until 12 months of life

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Lucie GUILBAUD, MD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): April 16, 2021
• Primary Completion (Anticipated): March 1, 2024
• Study Completion (Anticipated): August 1, 2024

Study Registration Dates

• First Submitted: January 24, 2021
• First Submitted That Met QC Criteria: February 24, 2021
• First Posted (Actual): February 25, 2021

Study Record Updates

• Last Update Posted (Actual): October 18, 2021
• Last Update Submitted That Met QC Criteria: October 15, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Spina bifida; Sacral Myelomeningocele; MyeLDM; Fetal surgery; Fetoscopic Repair Program; Neural Tube Defect
• Additional Relevant MeSH Terms: Nervous System Diseases; Congenital Abnormalities; Nervous System Malformations; Meningomyelocele; Spina Bifida Cystica; Neural Tube Defects; Spinal Dysraphism
• Other Study ID Numbers: APHP191101; N° IDRCB: 2020-A01413-36 (Other Identifier: ANSM)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No