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Research Update: Toward a Safe Method of Minimally Invasive Myelomeningocele Repair

Since the 1930s, the first step in the treatment of newborns with myelomeningocele has been to surgically close the incompletely developed portion of the spinal cord within a few days of birth. In 2011, the Management of Myelomeningocele Study (MOMS), sponsored by the National Institutes of Health (NIH), found that infants who undergo surgery in utero had a decreased need for ventriculoperitoneal shunting and improved motor function when compared to the standard-of-care procedure performed after birth.1 After the publication of study results in March of that year, a team affiliated with The Fetal Center at Children’s Memorial Hermann Hospital was among the first in the country to perform in-utero repair – with excellent outcomes. Today, researchers at The Fetal Center and UTHealth Medical School are engaged in laboratory studies aimed at developing an approach to minimally invasive spina bifida repair that is safe for both mother and child.
 
Spina-Bifida REV“Surgeons in several countries have performed cases of minimally invasive repair, many of which have been announced in the public sector before publication in peer-reviewed journals,” says Kenneth J. Moise Jr., M.D., co-director of The Fetal Center and a professor in the division of Maternal-Fetal Medicine and department of Pediatric Surgery at UTHealth Medical School. “Our concern with minimally invasive spina bifida repair is that fetal surgeons are using techniques and materials that have not been subjected to rigorous scientific testing. We believe strongly in the bench-to-bedside process – repeated studies in animal models, followed by human pilot trials, then randomized clinical trials, analysis of data and peer review before and after publication. Based on the results of our research, we’re optimistic about the future of minimally invasive repair, but until we can show data to prove that this new approach is better, open surgical repair for spina bifida will remain the gold standard. If I were to perform a minimally invasive spina bifida repair on a fetus today, based on the data available, I’d have to tell the mother that yes, this is definitely better for you, but I can’t predict your child’s outcome.”
 
Investigators at Vanderbilt University were the first to attempt in-utero repair of myelomeningocele (MMC) in human fetuses using endoscopy. The surgeons used a maternal skin graft in an attempt to cover the defect using laparoscopic instrumentation inserted into the uterus. When the procedure resulted in high perinatal mortality, no further attempts at minimally invasive repair were made, and a new approach using an open hysterotomy was developed. After three fetuses underwent standard surgical repair and only one of the three required a ventriculoperitoneal shunt, the researchers concluded that open fetal surgery for spina bifida repair was feasible.

After the success of these cases and 79 others, four U.S. centers began offering fetal repair of myelomeningocele. In January 1999, investigators at one of the centers – the University of California, San Francisco (UCSF) – applied to the National Institutes of Health for a single-center study of in-utero MMC repair. A consensus conference on fetal myelomeningocele repair, hosted by the National Institute of Child Health and Human Development, led to a recommendation for a multicenter randomized trial.

Physicians affiliated with The Fetal Center at Children’s Memorial Hermann Hospital were moving forward aggressively with a fetal surgery program for spina bifida when the MOMS trial was announced by the NIH in early 2003. When three centers – UCSF, Vanderbilt University Medical Center and Children’s Hospital of Philadelphia – were chosen for the trial, The Fetal Center complied by stopping its program to avoid creating a “back door” that could affect enrollment in the trial. After the MOMS trial showed decreased need for shunting at 12 months and ambulation without assistance by age 2 1/2, open fetal spina bifida repair was adopted as the gold standard by which outcomes from all newer techniques would be measured.

Thomas Kohl, M.D., of the German Center for Fetal Surgery and Minimally Invasive Therapy at the University of Giessen-Marburg in Giessen, Germany, is among the few fetal surgeons who have published the results of their attempts at minimally invasive MMC repair. In a two-part article published in Ultrasound in Obstetrics and Gynecology in 2014,2,3 he and other authors reported on 51 cases in which three trocars were inserted percutaneously into the amniotic cavity using ultrasound guidance. After insertion of the trocars, the amniotic fluid was partially evacuated and replaced with carbon dioxide to allow for improved fetal visualization and manipulation. Following the procedure, the gas was removed and the amniotic cavity refilled with warmed crystalline solution.

“One of our concerns about this procedure is that the effect of carbon dioxide on the fetus remains unknown,” Dr. Moise says. “We know that the fetus lacks an enzyme that allows it to process carbon dioxide. In a sheep model, fetuses subjected to CO2 became acidotic.4 We also haven’t adequately studied the effects of the gas on fetal membranes. Will it damage their integrity? We simply don’t know.”

There’s also the matter of the patch used to repair the defect. In research led by UTHealth Medical School maternal-fetal medicine specialist Ramesha Papanna, M.D., and presented at the 33rd Annual Meeting of the International Fetal Medicine and Surgery Society in Chatham, Massachusetts, Dr. Moise and his collaborators analyzed two materials that could be employed in a patch technique for minimally invasive fetal MMC repair.5 Using a sheep model, they compared a biocellose patch (Dermafill®) attached by an underwater adhesive and a human umbilical cord graft (Amniogard®) secured to the defect with a continuous suture. When necropsy showed that the Amniogard patch remained in place in all fetuses, they concluded that the umbilical cord graft showed promise as an optimal material for minimally invasive correction of fetal MMC.

“This is a first step toward a safe minimally invasive repair. Our next step will be to apply the patch using a fetoscope in the sheep model,” Dr. Moise says. “When we’re comfortable with our results, we’ll move to a human pilot study.”

Pediatric neurosurgeon Stephen Fletcher, D.O., an associate professor in the department of Pediatric Surgery with 31 years of experience performing postnatal spina bifida repair, believes the human umbilical cord graft may also be a suitable patch material for neonatal repair. “We currently use bovine pericardium lining for the patch in postnatal repair,” he says. “We’re discovering that Amniogard is a tremendous patch that almost replicates the normal anatomy.”

The researchers are working with Russell Stewart, Ph.D., of the University of Utah department of Bioengineering to develop a waterproof patch sealant derived from the sandcastle worm. “We think we’ll be able to use the sealant while operating inside the amniotic sac, eliminating the need to evacuate the amniotic fluid and replace it with carbon dioxide,” Dr. Moise says. “This is an exciting development for the future, but we’re not there yet. We need more data to ensure its safety. Our upcoming series of sheep studies has never been done before; we’ll place the patch fetoscopically and deliver the lambs to determine if they can walk.”

The researchers’ long-term goal is to reduce the risks associated with open spina bifida repair. “We know open repair presents all the risks to the mother involved with a uterine incision, including preterm delivery,” Dr. Moise says. “Although no data equivalent to the MOMS trial outcomes has been presented showing that the minimally invasive approach produces equivalent results, in my heart I believe it will. The challenge lies in how to get there. We’re pushing the envelope but doing it in a scientific fashion. I’m as cautious as I was when we first started doing open fetal myelomeningocele repair. We’re still working on the next chapter in the story.”

1Adzick NS, Thom EA, Spong CY, Brock JW III, Burrows PK, Johnson MP, Howell LJ, Farrell JA, Dabrowiak ME, Sutton LN, Gupta N, Tulipan NB, D’Alton ME and Farmer DL for the MOMS Investigators. A Randomized Trial of Prenatal versus Postnatal Repair of Myelomeningocele. N Engl J Med. 2011 Mar 17;364;993-1004.
2Kohl T. Percutaneous minimally invasive fetoscopic surgery for spina bifida aperta. Part I: surgical technique and perioperative outcome. Ultrasound Obstet
Gynecol. 2014;44:515-24.
3Degenhardt J, Schürg R, Winarno A, Oehmke F, Khaleeva A, Kawecki A, Enzensberger C, Tinneberg H-R, Faas D, Ehrhardt H, Axt-Fliedner R, Kohl T. Percutaneous minimal-access fetoscopic surgery for spina bifida aperta. Part II: maternal management and outcome. Ultrasound Obstet Gynecol. 2014;44:525-31.
4Gratacos E, Wu J, Devlieger R, Van de Velde M, Deprest JA. Effects of amniodistention with carbon dioxide on fetal acid-base status during fetoscopic surgery in a sheep model. Surg Endosc. 2001;15:368-72.
5Moise KJ, Papanna R, Mann LM, Fletcher S, Tsao K, Argoti P, Snowise S, Schniederjan R, Bhattacharjee M, Stewart RJ, Tseng SCG. Evaluation of different patch materials for in-utero repair of myelomeningocele. Presented at the 33rd Annual Meeting of the International Fetal Medicine and Surgery Society, Chatham, Massachusetts, Sept. 2014.