Spina Bifida: Fetal Surgery

*** TO ENSURE ACCURACY ON THE SUBJECT, THE FOLLOWING INFORMATION WAS TAKEN DIRECTLY FROM WIKIPEDIA. ***

Fetal surgery research

1980 - Fetal surgical techniques using animal models were first developed at the University of California, San Francisco by Dr. Michael R. Harrison, Dr. N. Scott Adzick and research colleagues.

1994 - A surgical model that simulates the human disease is the fetal lamb model of myelomeningocele (MMC) introduced by Meuli and Adzick in 1994. The MMC-like defect was surgically created at 75 days of gestation (term 145 to 150 days) by a lumbo-sacral laminectomy. Approximately 3 weeks after creation of the defect a reversed latissimus dorsi flap was used to cover the exposed neural placode and the animals were delivered by cesarean section just prior term. Human MMC-like lesions with similar neurological deficit were found in the control newborn lambs. In contrast, animals that underwent closure had near-normal neurological function and well-preserved cytoarchitecture of the covered spinal cord on histopathological examination. Despite mild paraparesis, they were able to stand, walk, perform demanding motor test and demonstrated no signs of incontinence. Furthermore, sensory function of the hind limbs was present clinically and confirmed electrophysiologically. Further studies showed that this model, when combined with a lumbar spinal cord myelotomy leads to the hindbrain herniation characteristic of the Chiari II malformation and that in utero surgery restores normal hindbrain anatomy by stopping the leak of cerebrospinal fluid through the myelomeningocele lesion.

Surgeons at Vanderbilt University, led by Dr. Joseph Bruner, attempted to close spina bifida in 4 human fetuses using a skin graft from the mother using a laparoscope. Four cases were performed before stopping the procedure - two of the four fetuses died.

1998 - Dr. N. Scott Adzick and team at The Children's Hospital of Philadelphia performed open fetal surgery for spina bifida in an early gestation fetus (22 week gestation fetus) with a successful outcome.

Surgeons at Vanderbilt University, led by Dr. Noel Tulipan, made an incision in the mother's uterus to obtain better exposure to fetuses of 28 to 30 weeks' gestation. All 4 fetuses were born premature but with evidence of reversal of their Chiari II malformation. Only 2 of the 4 required ventricular shunts after birth. Fetal surgery after 25 weeks has not shown benefit in subsequent studies.

Subsequently, 4 medical centers conducted 253 open spina bifida repairs prior to the MOMs trial. The outcomes were mixed, and the only comparison groups were other children who had not undergone repair after birth in the past.

MOMS trial

Management of Myelomeningocele Study (MOMS) is a phase III clinical trial to evaluate the safety and efficacy of fetal surgery to close a myelomeningocele. This involves surgically opening the pregnant mother's abdomen anduterus to operate on the fetus. This route of access to the fetus is called open fetal surgery. The exposed fetal spinal cord is covered in layers with surrounding fetal tissue at mid-gestation (19–25 weeks) to protect it from further damage caused by prolonged exposure to amniotic fluid. The fetal surgery may decrease some of the damaging effects of the spina bifida, but at some risk to both the fetus and the pregnant woman.

The MOMS trial was closed for efficacy in December 2010 based on comparing outcomes after prenatal and postnatal repair in 183 patients - 77 patients were treated at The Children’s Hospital of Philadelphia, 54 at Vanderbilt University and 52 at The University of California San Francisco. Unfortunately the study failed to address the possibility that some of the benefit of surgery to central nervous system function in the intervention group may have been caused by early delivery from the intrauterine environment. This issue casts some doubt on the studies findings. A case controlled comparison of intervention vs conservative management would have been unethical because of the exposure of infants within a control group to the adversity of premature delivery.

The trial concluded that the outcomes after prenatal spina bifida treatment are improved to the degree that the benefits of the surgery outweigh the maternal risks. This conclusion requires a value judgment on the relative value of fetal and maternal outcomes on which opinion is still divided. Results were reported in the New England Journal of Medicine by Adzick et al.

To be specific, the study found that prenatal repair resulted in:

• Reversal of the hindbrain herniation component of the Chiari II malformation
• Reduced need for ventricular shunting (a procedure in which a thin tube is introduced into the brain’s ventricles to drain fluid and relieve hydrocephalus)
• Reduced incidence or severity of potentially devastating neurologic effects caused by the spine’s exposure to amniotic fluid, such as impaired motor function

In Europe, open fetal surgery for spina bifida was introduced in 2003 by the Polish pediatric surgeon Janusz Bohosiewicz in Katowice. Through the end of 2011, more than 40 fetuses with spina bifida were operated at this center.

Endoscopic fetal surgery

In contrast to the open fetal operative approach performed in the MOMS trial, a minimally-invasive fetoscopic approach has been developed by the German pediatrician Thomas Kohl of the German Center for Fetal Surgery & Minimally-Invasive Therapy at the University of Giessen, Germany.

This approach under general materno-fetal anesthesia uses three trocars (small tubes) with an external diameter of 5 mm that are directly placed through the maternal abdominal wall into the uterine cavity under ultrasound guidance. Following intrauterine access, part of the amniotic fluid is removed and the uterus is insufflated with carbon dioxide (this technique provides superior visualization of fetoscopic spina bifida closure, is called PACI (partial amniotic fluid insufflation), and has been safe for mothers and fetuses alike in over 70 procedures on human fetuses). After fetal posturing, the neural cord is freed from pathological adhesions and covered with patch material. Watertight closure is demonstrated by intraoperative bulging of the patch. Accordingly, reversal of hindbrain herniation can be documented within days after most procedures.

The observations in mothers and their fetuses that were operated over the past two and a half years by the matured minimally-invasive approach showed the following results: Compared to the open fetal surgery technique, fetoscopic repair of myelomeningocele results in far less surgical trauma to the mother, as large incisions of her abdomen and uterus are not required. In contrast, the initial punctures have a diameter of 1.2 mm only. As a result, thinning of the uterine wall or dehisscence which have been among the most worrisome and criticized complications after the open operative approach do not occur following minimally-invasive fetoscopic closure of spina bifida aperta. The risks of maternal chorioamniotis or fetal death as a result of the fetoscopic procedure run below 5%. Operated women are discharged home from hospital one week after the procedure. There is no need for chronic administration oftocolytic agents since postoperative uterine contractions are barely ever observed. The current cost of the entire fetoscopic procedure including hospital stay, drugs, perioperative clinical, ECG, ultrasound and MRI-examinations is approximately €6,000.

In a cohort of 20 infants that underwent fetoscopic surgery on the lesion between July 2010 and December 2011 and were studied during the first six months of life, reversal of hindbrain herniation was observed in 18 (90%) and shunt insertion was required in only eight (40%). Normal to near normal leg function was observed in about two thirds of the infants. An abnormal foot position at birth was observed in only two. The fetuses that were operated at a mean of 24 weeks of gestation were born at a mean gestational age at delivery of about 33 weeks of gestation. In contrast to open fetal surgery, leukomalacia has not been observed in neonates following the fetoscopic approach. Moreover, following the fetoscopic approach, postnatal spina bifida surgery can now be avoided in most patients.

In 2012, these encouraging results of the fetoscopic approach were presented at various national and international meetings, among them at the 1st European Symposium “Fetal Surgery for Spina bifida“ in April 2012 in Giessen, at the 15th Congress of the German Society for Prenatal Medicine and Obstetrics in May 2012 in Bonn, at the World Congress of the Fetal Medicine Foundation in June 2012 and at the World Congress of the International Society of Obstetrics and Gynecology (ISUOG) in Copenhagen in September 2012, and published in abstract form. In contrast to the low maternal and fetal complication rates that can be achieved by the current fetoscopic approach, its clinical introduction was affected by technical difficulties and a number of adverse fetal outcomes: Three of the first 19 procedures could not be completed, three fetuses died, and the mean gestational age at delivery was 29 weeks of gestation. As a result, the approach was heavily criticized by the independent authors of a controlled study about this cohort and deemed unethical by others. Yet, even in these earliest cases statistically significant better motor and sensory function of the lower extremities as well as a statistically significantly lower shunt rate could be demonstrated in contrast to the control patients that underwent standard postnatal procedures.

In conclusion, both the open and minimally-invasive fetoscopic fetal surgical procedures offer the chance to improve the postnatal prognosis and quality of life of patients affected by spina bifida. Fetuses that benefit the most seem those with higher lesions, normally appearing leg movements and foot position, and only a mild dilation of the lateral ventricles despite signs of hindbrain herniation. Vice versa, it seems unlikely that leg, bladder or bowel functions that were lost prior to the procedure can be regained by either approach Furthermore, fetuses that already exhibit a moderate degree of hydrocephalus at the time of fetal surgery will require postnatal cerebrospinal fluid shunting anyway. Further studies are required in order to assess the value of fetal surgery on postnatal bladder-, bowel- and sexual function.

As in patients who undergo standard postnatal spina bifida closure, deterioration of neurological function from tethered cord, surgical re-interventions, complications of hydrocephalus and Chiari II-treatment must be expected in some patients after open and minimally-invasive fetal surgery, regardless of the quality of their neurological status in the first years of life.