Review Article

595

In Utero Repair of Spina Bifida Julie S. Moldenhauer, MD1

Philadelphia, Philadelphia, Pennsylvania Am J Perinatol 2014;31:595–604.

Abstract

Keywords

► ► ► ►

fetal surgery myelomeningocele prenatal diagnosis spina bifida

Open spina bifida or myelomeningocele (MMC) is the most common congenital malformation of the central nervous system compatible with long-term survival and is associated with significant lifelong disabilities. Postnatal care of MMC involves covering the exposed spinal cord, infection prevention, and ventricular shunting for hydrocephalus. The aim of postnatal MMC surgery is not to reverse or prevent the neurologic injury seen in MMC, but to palliate. The neurologic defects result from primary incomplete neurulation and secondary chronic in utero damage to the exposed neural elements through mechanical and chemical trauma—the two-hit hypothesis. With the ability to accurately diagnose spina bifida prenatally and the concept of the two-hit hypothesis, in utero repair to decrease exposure and alter the antenatal course of neurologic destruction was conceived. Through animal models and human pilot studies, the feasibility of fetal spina bifida repair was demonstrated. Subsequently, the prospective randomized multicenter Management of Myelomeningocele Study (MOMS trial) revealed a decreased need for shunting, reversal of hindbrain herniation, and preservation of neurologic function, making in utero repair an accepted care alternative for select women carrying a fetus with spina bifida. This article will highlight the background and rationale for in utero repair, and the progression to becoming an alternative standard of care. The future directions of fetal spina bifida repair will also be addressed.

Scope and Impact of Spina Bifida Neural tube defects (NTDs) are a group of devastating congenital abnormalities of the central nervous system that arise as a result of failure of the neural tube to close in the first 4 weeks after conception, commonly before a woman realizes that she is pregnant. Those that involve the cranium are largely lethal. Spina bifida involves the more distal portion of the central nervous system and is compatible with longterm survival. It is the most common congenital abnormality of the central nervous system. Open spina bifida can present as a flat defect without a fluid-filled sac covering (myeloschisis), a membranous covering (meningocele), or a fluidfilled sac containing extruded cord (myelomeningocele; MMC). The underlying defect results in an alteration in

received December 31, 2013 accepted after revision February 10, 2014 published online May 12, 2014

Address for correspondence Julie S. Moldenhauer, MD, Center for Fetal Diagnosis and Treatment, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104 (e-mail: [email protected]).

development that leads to hydrocephaly, hindbrain herniation, and injury to exposed neural elements with associated long-term morbidity and mortality. Despite improved care and technology, the 1-year survival rate among infants with open spina bifida remains at 88 to 96%.1 Approximately 75% of affected individuals survive to adulthood.2 Individuals living with spina bifida typically experience lifelong disabilities. The likelihood of requiring a ventriculo–peritoneal (VP) shunt to divert cerebrospinal fluid secondary to hydrocephalus is more than 80% overall in contemporaneous reports.3 This need is associated with the level of lesion: 97% of individuals with thoracic lesions required shunts compared with 88% of those with lumbar level lesions and 68% of those with sacral level lesions. The requirement for shunts is fraught with complications

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DOI http://dx.doi.org/ 10.1055/s-0034-1372429. ISSN 0735-1631.

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1 Center for Fetal Diagnosis and Treatment, The Children’s Hospital of

In Utero Repair of Spina Bifida

Moldenhauer

including obstruction, infection, and displacement, among others.4 On average, young children required two shunt revisions and 55% of these were performed in the first year.3 The Arnold–Chiari II malformation (hindbrain herniation, brain stem abnormalities, and small posterior fossa) is radiographically seen in over 75% of patients.5 Clinical symptoms of apnea, swallowing difficulties, quadriparesis, balance and coordination difficulties that are related to the Arnold–Chiari II malformation are evident in up to one-third of patients.6 The level of the lesion correlates to the functional motor level in individuals with spina bifida. This is associated with a direct correlation in approximately 39%.3 However, in up to half of affected individuals, the functional level correlates to two levels higher or worse than anticipated. In general, 90% of patients with a thoracic level lesion used a wheelchair, while 45% of patients with a lumbar lesion and 17% with a sacral lesion used wheelchairs.7 Almost 90% of infants with spina bifida require intervention for a foot deformity to perform weight-bearing activities.8 Bladder and bowel incontinence are common among individuals with spina bifida, with many requiring intermittent self-catheterization. Additional urologic complications including urinary tract infections, vesicoureteral reflux, and upper tract dilation are also frequent.9 Individuals with spina bifida can achieve an IQ within the normal range. However, they are at risk for neurocognitive and language difficulties that might impact school performance and the ability to live independently.10,11 They are also at risk for poor psychosocial adjustment.12 Families caring for a member with spina bifida are also impacted.13 The disabilities seen in children remain into adulthood with up to one-third of adults requiring daily assistance and a high rate of unexpected death.14,15 The use and cost of health care for individuals with spina bifida is significantly higher than for those without spina bifida. Average neonatal costs for infants with spina bifida was $65,342 compared with an average of $1,844 for uncomplicated births using national data from the Agency for Healthcare Research and Quality (AHRQ) Healthcare Cost and Utilization Project (HCUP) 2003 Kids’ Inpatient Database (KID).16 During the first year of life, infants with spina bifida were hospitalized an average of 2.4 times for an average of 25.2 days in a statewide study in Florida over a 10-year period. The average estimated hospital costs per infant were $39,059.17 Healthcare expenditures seem to decrease with age. This is likely due to maintenance care after the initial surgical interventions that are performed most commonly within the first few years of life. Expenditures for infants with spina bifida and hydrocephaly were 10.4 times higher than infants without a major birth defect according to the data from the North Carolina Birth Defects Monitoring Program and Medicaid.18 Expenditures for infants with spina bifida without hydrocephaly were four times higher than infants without a major birth defect. Among the infants with spina bifida, those with hydrocephaly had expenditures 2.6 times higher than those without hydrocephaly. The increase in health care expenditure continues over the affected individual’s life span. In a privately insured population, children aged 1 to 17 had average medical expenditures American Journal of Perinatology

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13 times greater than children without spina bifida and adults with spina bifida had medical expenditures 3 to 6 times greater than adults without spina bifida.19 In a nationwide review of hospitalizations of adult patients with spina bifida, the most common diagnosis was urinary tract infection, followed by complications from devices/grafts/implants and skin wounds.20 Of the complications from devices/grafts/ implants, 53% were due to shunt complications. One-third of hospitalizations were deemed to be for primary diagnoses of potentially preventable conditions. The average length of stay was 6.9 days with an average total charge of $28,918 per admission. The impact of health care usage and cost remains over the continuum of the lifetime of an individual with spina bifida. Each year in the United States 1,460 babies are born with spina bifida.21 This translates into a newborn affected with spina bifida in every 2,858 births. Although certain risk factors are known to be associated with having a baby with spina bifida, it can affect the pregnancy of any woman in any population, at any age, or of any baseline health status. Based on recent data regarding the racial and ethnic distribution of spina bifida, the birth prevalence is 4.17 per 10,000 in Hispanic women, 2.64 per 10,000 in non-Hispanic Black or African American women, and 3.22 per 10,000 in non-Hispanic White women.22 Although, considered multifactorial in origin, certain genetic, nutritional, and environmental factors have been implicated in NTDs. Factors commonly associated with a higher risk for NTDs include family history of NTD, obesity, Hispanic ethnicity, pregestational diabetes, and anticonvulsant use. However, these known risk factors account for less than half of NTD cases.23 Therefore, preconception counseling for every reproductive age woman should include the use of folic acid supplementation: 0.4 mg daily for low risk women and 4 mg daily for women with a history of having a previous affected pregnancy at least 1 month prior to conception and throughout the first trimester.24,25 The prenatal diagnosis of NTDs has drastically improved through the use of maternal serum screening programs and advanced ultrasound technology. Since elevated maternal serum α-fetoprotein levels were correlated with pregnancies affected with spina bifida and anencephaly in the 1970s, wide-scale screening programs have been utilized in routine prenatal care.26–28 The gold standard for the prenatal diagnosis of NTDs has been amniocentesis to evaluate for elevated amniotic fluid α-fetoprotein levels and the presence of acetylcholinesterase. In a large series, amniotic fluid acetylcholinesterase identified 100% of cases of anencephaly and open spina bifida.29 Ultrasound alone in experienced hands has been reported to have a 97% sensitivity and 100% specificity for diagnosing NTDs prenatally.30 Common practice today combines maternal serum screening and ultrasound, given its significant advances, before proceeding with invasive testing. Regardless, women at high risk for NTDs should be evaluated and counseled at centers with the level of expertise and technology available to make this potentially devastating prenatal diagnosis. Because of the lifelong morbidity and the ability to accurately make a prenatal diagnosis of spina bifida, the idea of in

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utero surgery to improve outcomes was conceived. Early animal studies and ultimately human pilot studies laid the groundwork for the Management of Myelomeningocele Study (MOMS Trial)31 The results of this study have significantly changed the manner in which select women carrying a fetus with MMC are counseled and offered the additional option of in utero repair. This is a major paradigm shift in the world of fetal therapy that had typically been reserved for life-threatening conditions.

Early Research on In Utero Repair of Myelomeningocele: The Pre-MOMS Period The neurologic injury that occurs with MMC is thought to be 2-fold. First, there is an anatomic abnormality of a relatively normal spinal cord that then becomes secondarily damaged by the intrauterine environment through amniotic fluid exposure, direct trauma, hydrodynamic pressure, or a combination of these; thus the “two-hit hypothesis.” Primary prevention is the only means to prevent the first hit in the development of MMC. The ability to ameloriate the secondary damage caused by exposure to the in utero environment gave rise to the concept of fetal surgery for MMC repair. Observations to support the theory of the two-hit hypothesis in human MMC have been described. Pathologic examination of the spinal cords of eight stillborn human fetuses with MMC was performed, describing the relationships of the spinal cord, meninges, and dermal–epidermal junction.32 At the site of the defect, varying degrees of neural tissue loss was noted, but normal appearing dorsal and ventral horns were seen proximal to the defect. Evaluation of an additional 10 aborted fetuses with MMC revealed the same findings.33 Sonographic evidence suggests that in utero insults occur over the course of gestation that worsen the clinical picture of fetuses with spina bifida.34,35 Korenromp demonstrated normal fetal lower extremity movement at 16 to 17 weeks to refute the contemporary theory that poor lower extremity movement was suggestive of a spinal defect if the spine was difficult to visualize by ultrasound.34 In another study, leg movements were observed in 13 fetuses with MMC.35 Prenatal ultrasound showed normal leg movement in 12 of 13, but only 2 had normal postnatal leg movement. Correlation of prenatal functional assessment to the neonatal neurologic outcome varies significantly and caution must be used when counseling patients about the implications and correlations of prenatal lower extremity movement and postnatal function. Traumatic neurologic injury to the exposed spinal cord during labor and vaginal delivery has also been demonstrated. The outcomes of 160 infants with MMC were compared based on mode of delivery: vaginal delivery, cesarean delivery before the onset of labor, and cesarean delivery after the onset of labor.36 Cesarean delivery before the onset of labor resulted in improved motor function at 2 years of age compared with vaginal delivery or cesarean delivery after the onset of labor. Cesarean delivery following rupture of membranes and labor had worse motor outcomes than those with intact amniotic membranes with or without labor.37 For those with intact

Moldenhauer

membranes, there was no difference in motor outcomes with or without labor prior to cesarean delivery. Normal amniotic fluid seems to act as a protective buffer to decrease the risk for direct traumatic injury to the defect. Observational evidence to support the two-hit hypothesis in MMC led to the development of animal models to demonstrate the feasibility of fetal surgery. The first animal model was a primate model in which a fetal L3–5 laminectomy was performed late in gestation resulting in MMC type lesions and neurologic deficits at birth.38 Immediate in utero repair of the laminectomy was performed in a similar group of primates who were neurologically normal at birth. An early rat model using a 2–3 level laminectomy was also developed.39 The experimental group did not undergo repair and the defects were exposed to the amniotic fluid. The control group underwent immediate repair and were normal at birth. This experimental model was used on fetal pigs with similar findings.40 Although these animal models gave credibility to the concept of the two-hit hypothesis in MMC and the principle of improved neurologic function with in utero repair, they could not be directly correlated to the defects seen in humans. A more fitting large animal model was developed using sheep in midgestation in which the lambs were born near term with cystic sacs containing abnormal spinal cord tissue with histologic evidence of neural tissue damage in the exposed segments.41,42 As had been demonstrated in the human pathologic evaluation, the spinal cord proximal to the defect appeared normal. These lambs had flaccid paraplegia, lack of sensation in the hind limbs, and incontinence of urine and stool. This model was then used to demonstrate the feasibility of in utero closure of MMC. After the defect was created in midgestation and exposed to the in utero environment, a second surgery was performed later in gestation to close the defect with a latissimus dorsi flap.42 The lambs were then delivered near term. Those that underwent in utero repair had near normal motor function, intact sensation, and apparent continence of stool and urine. Histologic evaluation of the spinal cord revealed preservation of the neuroarchitecture. Additional studies with the sheep model demonstrated reversal of hindbrain herniation with in utero repair.43,44 The sheep model very closely resembled the human MMC and provided evidence for preservation of neurologic function and reversal of hindbrain herniation with in utero repair. This information lent credibility to initiate pilot studies in human pregnancies. This was a major shift in the paradigm for fetal intervention. Prior to this point, fetal surgery was reserved only for life-threatening fetal anomalies. The first two reported cases of fetal myelomeningocele (fMMC) coverage used an endoscopic approach with placement of a maternal split thickness skin graft over the neural placode.45 This approach was abandoned as one fetus was soon delivered after surgery and died of severe prematurity. Shortly thereafter, reports of successful open fetal surgery for MMC repair came out of two different groups. The group from Vanderbilt reported on four open fetal surgeries for MMC repair at 28 to 30 weeks gestation.46 Reversal of hindbrain herniation was noted in all four patients. The Children’s American Journal of Perinatology

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In Utero Repair of Spina Bifida

In Utero Repair of Spina Bifida

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Hospital of Philadelphia (CHOP) reported their first successful open fMMC repair on a 23 week fetus.47 Reversal of hindbrain herniation was also noted in this fetus. However, long-term function was impacted by spinal cord tethering. Subsequent series were reported from both groups using different selection criteria and gestational age at in utero repair. The CHOP group reported on 10 patients who underwent fMMC repair at 22 to 25 weeks gestation.48 Reversal of hindbrain herniation in utero was observed postoperatively. Leg function was better by two or more spinal segment levels in five of the nine surviving patients. One neonate delivered prematurely at 25 weeks and died from respiratory complications. The group from Vanderbilt reported on 29 patients undergoing fMMC repair between 24 and 30 weeks gestation.49 In their series, 38% of prenatally repaired infants demonstrated postoperative cerebellar herniation compared to 95% in a postnatally repaired group. Ventriculoperitoneal shunting was necessary in 59% of the prenatal repair group compared to 91% of the postnatal repair group. The results of these early series of open fMMC repair were very encouraging. The clinical implications of in utero repair included reversal of hindbrain herniation and a decreased need for ventriculoperitoneal shunting. Restoration of normal anatomic positioning of the cerebellum in the posterior fossa could negate the clinical sequelae of the Arnold–Chiari malformation. Improved motor function of the lower extremities also seemed to be of promise. Although supportive evidence was being reported, these initial series did not have control groups outside of historical controls, making fMMC repair a prime candidate for a randomized trial leading to the concept of the MOMS trial.

The Management of Myelomeningocele Study Because the results of the early series of in utero MMC repair were so encouraging, it was time to take pause. Women who presented for evaluation for in utero surgery for fMMC repair were a highly motivated, self-selected group. The initial clinical reports on fMMC repair did not include contemporaneous controls, but were compared with historical controls. Another caveat was selection criteria bias. These factors could potentially lead to bias in the reporting of fMMC repair outcomes. Clearly, a randomized trial would be needed to answer the question of whether or not a true benefit existed with in utero repair of MMC, and could additionally delineate the risks of the procedure. To this end, the National Institutes of Health (NIH) sponsored a multicenter randomized trial, known as the Management of Myelomeningocele Study (MOMS) trial, comparing outcomes between prenatal MMC repair with standard postnatal repair.31 The trial started in 2003 with a planned sample size of 200 patients. The study was performed in three fetal surgery centers—CHOP, Vanderbilt University, and University of California, San Francisco (UCSF). Initial patient referrals and data management were coordinated through the Data and Study Coordinating Center (DSCC) at George Washington University. The trial was conducted with tremendous scrutiny American Journal of Perinatology

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including local oversight and institutional review board committees; a steering committee composed of principal investigators from each fetal surgery site and the DSCC; a NICHD (The Eunice Kennedy Shriver National Institute of Child Health and Human Development) MFMU (Maternal Fetal Medicine Units) Network program scientist, and multiple subcommittees compromised of experts in their respective fields. Further input was provided from a MFMU Network Advisory Board. All potential U.S. centers outside of the trial agreed not to offer fetal surgery for MMC until the trial was completed, closing any backdoor to fMMC repair. After patients were initially referred to the DSCC, they were screened as potential candidates. If they met criteria, they were then referred to one of the three fetal surgery centers based on geographic location. Prenatal, perioperative, and postnatal patient care protocols were standardized among the three centers. Strict adherence to the inclusion and exclusion criteria (►Table 1) was maintained. If a patient met all the criteria and was willing to accept either procedure, she was then randomized at a gestational age of 19.0 to 25.9 weeks. Women who were randomized to prenatal surgery underwent the procedure no sooner than the following working day, and no later than 3 working days after randomization or 25 weeks 6 days gestation, whichever was sooner. They then remained near the fetal surgery center until cesarean delivery at 37 weeks. The women in the postnatal surgery group were able to return home with the plan to return to the same fetal surgery center where they were counseled to undergo planned cesarean delivery at 37 weeks with subsequent postnatal repair by the same neurosurgical team. Children were evaluated at 12 and 30 months of age. The study objective was to determine if prenatal repair of MMC resulted in improved outcomes compared with standard postnatal repair. There were two primary outcomes. A composite of fetal/neonatal death or the need for a cerebrospinal fluid shunt (either placement of the shunt or meeting objective criteria for its placement) at 12 months of age defined the first primary outcome. The second primary outcome was a composite score of the Mental Development Index of the Bayley Scales of Infant Development II and the child’s motor function, with adjustment for lesion level at 30 months of age. Independent clinicians reviewed the clinical and radiologic data. The secondary outcomes included maternal, fetal, and neonatal surgical and pregnancy complications as well as neonatal morbidity and mortality. The trial was powered to a sample size of 200 patients; 100 in each arm. Enrollment in the study took longer than anticipated, likely due to the significant personal commitment with prolonged relocation. However, enrollment was stopped by the data safety monitoring committee at interim analysis due to efficacy of fetal surgery in December 2010 after 183 patients were randomized. The reported data include the 12 month outcomes of 158 infants. A summary of the results are presented in ►Table 2. The first primary outcome occurred in 68% of the prenatal surgery group and 98% of the postnatal surgery group (p < 0.001). The need for cerebrospinal fluid shunt was 40% in the prenatal surgery group and 82% in the postnatal surgery group. The second

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Table 1 Inclusion and exclusion criteria for the MOMS trial Inclusion • Singleton pregnancy • Lesion level T1–S1 • Evidence of hindbrain herniation • Gestational age of 19.0–25.9 wks • Normal karyotype • U.S. residency • Maternal age 18 y or older • Fetal anomaly unrelated to myelomeningocele • Severe kyphosis greater than or equal to 30 degrees • Multiple gestation • Previous spontaneous preterm birth < 37 wks • Short cervix < 20 mm • Placental abruption or abnormal placentation (placenta previa) • Obesity defined as BMI  35 • Maternal medical condition that would place an additional risk to maternal health/surgical risk or the pregnancy (insulin-dependent diabetes, poorly controlled hypertension) • Documented history of incompetent cervix or planned/current cerclage • Maternal-fetal Rh isoimmunization, Kell sensitization, or a history of neonatal alloimmune thrombocytopenia • Maternal HIV, hepatitis B or hepatitis C positivity • Uterine anomaly such as multiple fibroids or Mullerian duct abnormality; previous hysterotomy in the active segment of the uterus • Patient does not have a support person • Inability to comply with the travel and follow-up requirements • Patient does not meet other psychosocial criteria to handle the implications of the trial • Participation in another study that influences maternal and fetal morbidity and mortality or participation in this trial in a previous pregnancy Abbreviations: BMI, body mass index; HIV, human immunodeficiency virus; MOMS, Management of Myelomeningocele Study.

primary outcome was significantly better in the prenatal surgery group compared with the postnatal surgery group (p ¼ 0.007). Motor function and ability to walk without orthotics or devices was better in the prenatal surgery group compared with the postnatal surgery group. In the prenatal surgery group, functional motor level was better by two or more levels from anatomic level in 32% and better by one level

in 11% compared with 12% and 9%, respectively, in the postnatal surgery group. Around 42% of the prenatal surgery group was walking independently as compared with 21% of the postnatal surgery group. Despite the evidence for improved outcomes with prenatal surgery for MMC repair, there were considerable risks associated with fetal surgery. Chorioamniotic membrane

Table 2 Summary of MOMS trial outcomes Outcome

Prenatal surgery

Postnatal surgery

p-Value

Primary outcome, no. (%)

53 (68)

79 (98)

< 0.001

Shunt placement, no. (%)

31 (40)

66 (82)

< 0.001

Any hindbrain herniation, no. (%)

45/70 (64)

66/69 (96)

< 0.001

Primary outcome score at 30 mo (mental development and motor function)

148.6  57.5

122.6  57.2

0.007

Walking independently on examination, no./total no. (%)

26/62 (42)

14/67 (21)

0.01

Abbreviations: MOMS, Management of Myelomeningocele Study; no., number. American Journal of Perinatology

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Exclusion

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separation (prenatal surgery: 26% vs. postnatal surgery: 0%, p ¼ < 0.001), spontaneous rupture of membranes (46 vs. 8%, p < 0.001), and spontaneous preterm labor (38 vs. 14%, p < 0.001) are all major risk factors for preterm delivery and all occurred more frequently in the prenatal surgery group. This led to the lower gestational age at delivery in the prenatal surgery group of 34.1  3.1 weeks compared with 37.3  1.1 weeks in the postnatal surgery group (p < 0.001). Within the prenatal surgery group, 13% delivered at a severely premature gestation of < 30 weeks, 33% at 30 to 34 weeks, 33% at 35 to 36 weeks, and 21% at 37 weeks or more. Maternal risks included pulmonary edema (prenatal surgery: 6% vs. postnatal surgery: 0%, p ¼ 0.03) and blood transfusion at delivery (9 vs. 1%, p ¼ 0.03). Overall the hysterotomy was intact and well healed in two-third of patients at the time of delivery. The hysterotomy was thin in 25%, and 9% had an area of dehiscence with only one woman (1%) having complete dehiscence. The complete 12 and 30 month outcomes for the entire study cohort are anticipated soon. An analysis of the full delivery cohort from the MOMS trial evaluated risk factors for preterm delivery before 34 weeks after fMMC repair.50 Short fetal surgical time may serve as a proxy for technical expertise of the operative team as longer fetal surgical time was associated with spontaneous rupture of membranes, oligohydramnios, and preterm delivery. Chorioamniotic membrane separation in the first postoperative month also proved to be a risk factor for delivery less than 34 weeks. Oligohydramnios in the postoperative period was also associated with preterm delivery.

Open Fetal Surgery and Perioperative Management Centers performing in utero MMC repair continue to utilize the surgical technique and perioperative management or a modified version of that used in the MOMS trial. Anesthesia involves a combination of general and epidural anesthesia. The epidural is then also used for postoperative pain management. A low transverse laparotomy is performed, exposing the gravid uterus. Depending on placental location, the uterus may be exteriorized to facilitate posterior hysterotomy. Ultrasound is performed to map the location and margins of the placenta and the position of the fetus. As the hysterotomy is made in the fundal region, a cephalic presentation is necessary to optimally expose the fetal defect and cephalic version is sometimes required. After mapping is performed, two stay sutures are placed under ultrasound guidance in a placenta free portion of the uterus void of fetal parts and umbilical cord, and the uterus is entered between the stay sutures using electrocautery, creating a 1 to 2 cm incision. This is then extended using a uterine stapling device with absorbable staples to create a bloodless hysterotomy. The fetus is further positioned to place the spinal defect directly under the 6 to 8 cm hysterotomy (►Fig. 1). An irrigation tube is placed into the amniotic cavity to continuously bathe the fetus in warmed Ringer lactate to maintain uterine volume and buoyancy. American Journal of Perinatology

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Fig. 1 The spinal defect is positioned directly in the hysterotomy. Note the hemostasis of the hysterotomy cut surfaces with the absorbable staples in place.

Once positioned, a weight-based intramuscular injection of fentanyl and vecuronium is administered to the fetus. The fetal repair involves a two-to-three layer closure similar to neonatal surgery. The neural placode is sharply dissected from the surrounding tissue. The dura and/or myofascial flaps are then reapproximated over the neural placode. A running suture is then used to close the skin (►Fig. 2). In situations where the skin cannot be primarily reapproximated, an Alloderm graft (LifeCell Corporation, Bridgewater, NJ) is used for closure. The uterus is closed in two layers (running closure and interrupted stay sutures) and covered with an omental flap. Prior the placement of the final sutures, the amniotic volume is reestablished with warmed Ringer lactate through the irrigation tube and antibiotics are infused into the amniotic cavity. The laparotomy is closed in layers in a routine fashion. Fetal heart rate and function are

Fig. 2 Completed fetal repair with the running suture visualized. The absorbable staples are seen in the hysterotomy, as well as the irrigation tube.

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continuously monitored throughout the procedure by fetal echocardiography. Maintaining uterine quiescence is a key to the success of the surgery and perioperative care. Patients receive preoperative indomethacin, as well as prophylactic perioperative antibiotics. The indomethacin is continued for 48 hours postoperatively. At the conclusion of the hysterotomy closure, a bolus of magnesium sulfate is initiated and maintenance infusion is continued for up to 24 hours postoperatively. Once the magnesium sulfate is discontinued, oral nifedipine is initiated and continued up until delivery. Activity levels are significantly modified postoperatively, even after hospital discharge. Women are then followed weekly with prenatal visits and ultrasound to monitor for any evidence of membrane separation, oligohydramnios, premature rupture of membranes, and preterm labor. Cesarean delivery is planned at 37 weeks. At the time of delivery, the omental flap is also taken down.

fMMC Repair in the Post-MOMS Era After the conclusion of the MOMS trial, the demand for fMMC repair grew rapidly. This was associated with a rapid increase in the number of centers performing fMMC repair. Three experienced fetal centers performed all of the fMMC surgeries during the MOMS trial. Since the conclusion of the MOMS trial, more than 10 centers in the United States are performing fMMC repair. fMMC repair has received acceptance as an alternative standard of care for prenatally diagnosed cases. In January 2013, The American College of Obstetricians and Gynecologists (ACOG) issued a Committee Opinion on MaternalFetal Surgery for Myelomeningocele based on the results of the MOMS trial.51 “Based on the criteria set from this trial, the Committee on Obstetric Practice recommends that women who meet these criteria should be made aware of these findings and counseled regarding the option of maternal– fetal surgery, including both the risks and benefits to the woman and the baby.” Options for women carrying a pregnancy affected with open spina bifida now include standard postnatal repair, in utero repair, or termination. Of course, this is dependent upon meeting the appropriate criteria to be considered a candidate for fetal repair. The ACOG Committee opinion also highlighted that the discussion of maternal–fetal surgery for MMC should also include the implications of fetal surgery for future pregnancies.51 As the full-thickness uterine incision is made in the fundal region, this is associated with an inherent risk for uterine dehiscence in the index pregnancy as well as any subsequent pregnancies. Women should be counseled that they require cesarean delivery for all future pregnancies. Reproductive outcomes in subsequent pregnancies of 93 women who underwent open maternal fetal surgery from 1996 to 2007 were investigated through a questionnaire study. The questionnaire return rate was 57.3%.52 Fertility did not seem to be impacted by open fetal surgery, as 98% had a normal conception in subsequent pregnancies. The clinical implication for subsequent pregnancies based on this study

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seems to be the risk for uterine dehiscence (14%) and uterine rupture (14%). Abnormal placentation, such as accreta, in future pregnancies is an additional theoretical risk. A model to evaluate the cost-effectiveness of prenatal surgery for MMC took maternal factors and the impact on subsequent pregnancies into account.53 The conclusion of the study stated that prenatal MMC repair is cost-effective and frequently cost saving, despite the increased likelihood of maternal and future pregnancy complications. The decision analysis modeling in this study associated prenatal MMC repair with savings of $2,066,778 for every 100 cases performed. Because of the rapid expansion of fMMC repair across the country, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) convened a meeting among representatives from multiple professional societies, third party payors, and experts in the various fields related to fMMC repair to discuss these issues. Many of the concerns addressed at the meeting were similar to those expressed in the New England Journal of Medicine editorial that accompanied the publication of the MOMS trial results, such as the reproducibility of outcomes at centers outside the trial.54 Out of this initial meeting, the MMC Maternal-Fetal Management Task Force was created.55 The Task Force consisted of representatives from professional societies and organizations that were directly involved on some level with the process of fMMC repair from a maternal or neonatal aspect (►Table 3). The Task Force developed optimal care recommendations to address issues of rapid expansion of centers performing the procedure, increased patient demand for fetal surgery for MMC repair, and the reproducibility of the MOMS trial outcomes. The Position Statement on fMMC addressed six key aspects of fMMC repair, including defining a fetal therapy center, the perioperative management for fMMC repair, long-term care, counseling, reporting and

Table 3 Members of the MMC Maternal-Fetal Management Task Force American Academy of Pediatrics American College of Obstetricians and Gynecologists American Institute of Ultrasound in Medicine American Pediatric Surgical Association American Society of Anesthesiologists American Society of Pediatric Neurosurgeons International Fetal Medicine and Surgery Society American Association of Neurological Surgeons/Congress of Neurological Surgeons Section on Pediatric Neurological Surgery North American Fetal Therapy Network Society for Maternal-Fetal Medicine Society of Pediatric Anesthesia Spina Bifida Association Abbreviation: MMC, myelomeningocele. American Journal of Perinatology

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In Utero Repair of Spina Bifida

In Utero Repair of Spina Bifida

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monitoring, and access and regionalization. The Position Statement highlights the need for technical expertise of the multidisciplinary care team, adherence to the MOMS trial protocol to validate reproducibility of the outcomes, and development of a national registry to track outcomes and foster future research. In response to the Position Statement, The North American Fetal Therapy Network (NAFTNet) took a leadership role in addressing the need for outcomes reporting and collaborative research. NAFTNet (available at: https://naftnet.org/default. aspx) is a voluntary collaborative organization of 25 fetal care centers across the United States and Canada that perform advanced prenatal diagnostic and therapeutic interventions. The mission of the organization is to “foster collaborative research between active fetal diagnosis and treatment centers in both the United States and Canada, develop a peer review mechanism for study proposals, explore ways to centralize data collection and study development, and establish an educational agenda for medical professionals and the public as well as training of future leaders in the field.”56 Through NAFTNet a registry of all cases of fMMC repair has been developed. The fMMC Registry is a NAFTNet endeavor that was accepted as Study Protocol 01–12, after having gone through a peer review process and accepted as a new proposal according to the organization’s scientific review mechanism. Participation in the registry is open not only to members of NAFTNet, but to any center that is performing fMMC repair. Furthermore, to promote true collaboration among centers and establish a leadership role with the expansion of fMMC repair, NAFTNet sponsors the Fetal Myelomeningocele Repair Consortium. The Fetal Myelomeningocele Repair Consortium held their original meeting in October 2012 and has met semiannually each spring and fall. All centers performing fMMC repair are invited to attend, both within and outside of NAFTNet. The development of a multicenter registry has been the focus of the meeting. All centers present were supportive of the development of a registry and reporting mechanism for fMMC repair outcomes. To continue to stimulate communication and move the research agenda forward, these meetings are anticipated to continue on a semiannual basis. In addition to the development and implementation of the fMMC Registry, the Fetal Myelomeningocele Repair Consortium is also a platform for discussion of clinical issues related to fMMC repair, outcomes monitoring, alterations in the MOMS protocol, and the conceptualization of future research.

Future Studies on fMMC Repair Despite the benefits that have been demonstrated with fMMC repair, there are tremendous risks associated with the fetal surgery and many unknowns. Because the study was closed early, the MOMS trial results did not include the 30-month assessment on all patients. The 30-month assessments of the remaining MOMS cohort have just been completed and the full study analysis should be available soon, answering many questions. The impact on the long-term outcomes of children who underwent fetal surgery for spina bifida requires further American Journal of Perinatology

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study past the 30-month outcomes reported in the MOMS trial. This will be studied in the ongoing NIH-funded MOMS II study, which will involve follow-up assessment of the original trial patients at 5 to 9 years of age. With the significant maternal and fetal risk associated with open fetal surgery, can we improve on the technical aspects of the surgery or even the candidacy criteria? For example, is there a measurable level of ventriculomegaly on prenatal ultrasound above which there is no beneficial reduction by prenatal surgery in the need for VP shunting? Assessment of muscle ultrasound density and leg function is being investigated in fetuses with spina bifida.57,58 Perhaps muscle density can be used in future assessment of MMC repair candidates to determine the impact of surgery on function. Alternatively, the prenatal presence or absence of talipes may be the most accurate assessment of postnatal motor function. The impact of fMMC surgery on bladder and bowel function is not yet known, and is being studied as part of a urology supplement to the MOMS trial. The Fetal Myelomeningocele Repair Consortium and the NAFTNet fMMC Registry will help to answer questions regarding the reproducibility of the MOMS trial results and the learning curve associated with fMMC repair for centers beginning to perform the procedure. The registry will also provide a robust dataset to analyze for trends in outcomes related to gestational age at performance of fetal surgery, improvements or complications associated with nuances in technical differences between centers, and outcome trends related to fetal and maternal factors, such as BMI. Collaborative data sharing and ongoing scrutiny of fMMC repair will help to optimize the techniques used and subsequently improve outcomes. This collaborative forum can also be the platform to launch future research studies. Open fetal surgery is a major maternal commitment and is associated with preterm labor, preterm premature rupture of membranes, prematurity, and uterine scar complications. As such, minimally invasive approaches to fMMC repair continue to be investigated to decrease the risk of these complications. The fetoscopic approach was abandoned due to poor outcomes in the early attempts. Refinement of technique and use of sheep models are being used to modify the surgical approach to make this a feasible alternative to open fetal surgery.59–61 The Achilles heel of fetoscopy is the associated preterm premature rupture of membranes that is often the result of chorion–amnion separation. This is less likely to be the case when the membranes are fixed to the uterine wall by staples at the hysterotomy site. If the problems of membrane rupture associated with multiple-port fetoscopy can be solved, this minimally invasive approach to repairing MMC before birth should undergo clinical investigation. Another minimally invasive approach is tissue engineering. Using this method, ultrasound-guided injection of gelatin sponge, microsphere scaffolds, and bioactive protein coatings to cover the MMC defect have proven successful in rat models.62,63 These studies support the therapeutic potential of a tissue engineering approach for prenatal MMC coverage, perhaps by introducing these tissue engineered components through a single fetoscopic port or through an amniocentesis

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needle under ultrasound guidance. Such coverage must be completely “water tight” to prevent the leakage of cerebrospinal fluid through the MMC defect that leads to hindbrain herniation, and to prevent amniotic fluid exposure which damages the neural tissues in the MMC defect. In theory, this approach could be used earlier in gestation than current open fetal surgery procedures. Rigorous experimental testing and comparisons with open fMMC surgery techniques will be required in an effort to decrease the risks to the mother and fetus and to improve outcomes. In the wake of a gold standard randomized controlled trial for fMMC repair, there are many unanswered questions and opportunities available for collaboration and optimization of outcomes. What does remain significant in clinical practice is that women now have another option available to them when they hear the devastating news that they are carrying a fetus with MMC. Although not a cure, fMMC repair may provide hope for improved outcomes in children affected with spina bifida. Ongoing research, outcomes data reporting, and refinement of technique will allow continuous improvement for our patients while maintaining safety and quality.

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