Before 1995, we considered only fetuses with life-threatening anomalies and very poor predicted outcomes to be candidates for fetal surgery.[39
] However, the promising results of animal research, and the development of diagnostic fetal magnetic resonance imaging (MRI) techniques at CHOP led to increased consideration of prenatal intervention. Beginning in Philadelphia in 1995, expectant mothers considering in utero
therapy for myelomeningocele underwent extensive prenatal evaluation to include obstetrical evaluation, genetic screening, ultrasonography, and ultrafast MRI. Although most cases of MMC are isolated abnormalities, genetic screening permits identification of some of the genetic and chromosomal syndromes associated with spinal dysraphism. Ultrasonography assesses lower extremity function, identifies club foot anomalies, and determines the spinal level of the defect by localizing vertebral arch defects. As a rule, fetuses with thoracolumbar defects have the worst functional outcomes, while those with progressively lower lesions tend to do better.[40
] Using ultrafast MR sequencing techniques developed by Anne Hubbard and her colleagues at CHOP, we were able to define the presence or absence of the Arnold-Chiari malformation, hydrocephalus, and any other brain abnormalities.[41
] We were able to enhance prenatal counseling of parents and planning for possible fetal surgery by careful correlation of imaging results with known clinical outcomes.
Fetal surgery has significant risks; so it was initially offered only to those mothers in which the fetus had a large thoracolumbar defect, the Arnold-Chiari malformation, mild or moderate ventriculomegaly, normal leg movements, no apparent clubbing of the feet, normal karyotype, and absence of other anomalies. Encouraging results with the first few patients led to surgical repair of smaller spinal defects provided the other criteria were met. It is mandatory that fetal surgery candidates exhibit hindbrain herniation, since those fetuses are most likely to suffer from hydrocephalus or life-threatening brainstem symptoms, both of which require frequent postnatal surgery.
We speculated that the surgical procedure was ideally performed between 19 and 25 weeks gestation based upon our experience with other fetal surgical interventions and our animal models. Repair at this age minimizes the length of time during which neuronal damage to the exposed cord may occur as before this age fetal tissues are quite gelatinous making the procedure technically difficult. We also believed early repair might limit progression of hydrocephalus, since increasing ventricular size over the course of gestation is characteristic of fetal MMC.[42
The first successful open fetal MMC surgery in an early gestation human fetus was performed at CHOP and reported in The Lancet
] A 23-week gestation fetus with a T11-S1 lesion, hindbrain herniation, and normal lower extremity movement underwent open surgical coverage of the dysraphic defect. Fetal surgery and recovery were uneventful, and the fetus was subsequently delivered by cesarean section at 30 weeks of gestation after the onset of preterm labor. The baby had a right clubfoot deformity, and neuromotor function at the L4 level on the right and L5 level on the left. Whereas hindbrain herniation was found preoperatively, postnatal MRI documented hindbrain herniation reversal and absence of ventriculomegaly, so shunting has never been required. Unfortunately, this first patient developed severe tethering of the spinal cord at the repair site after 6 months of age leading to loss of lower extremity function and requiring operative release. In this first case, the MMC defect had been covered only with skin flaps, and the neural placode became adherent to the overlying skin. This late decline in function due to tethering motivated us to investigate better repair techniques and coverage materials for fetal MMC repair. Subsequent studies reported by neurosurgeons Leslie Sutton from CHOP and Noel Tulipan from Vanderbilt University showed that infants treated prenatally had improvement in hindbrain herniation after fetal MMC surgery and had a diminished need for shunting relative to infants that underwent standard postnatal neurosurgical repair.[44
] Compared to historical controls it was estimated that fetal MMC surgery reduced the need for VP shunt placement from 80-90% to 40%.[46
The intraoperative and postoperative management algorithm for fetal MMC surgery has been extensively described in the recent MOMS trial publication in the New England Journal of Medicine
] After maternal laparotomy followed by hysterotomy using a uterine stapling device, the fetus is positioned with the MMC lesion visible through the uterine incision. We have shown that intraoperative fetal echocardiographic monitoring is imperative.[48
] The cystic membrane of the MMC is excised and the attachments of the meninges to the skin and soft tissues are detached. If possible, native dura is closed over the spinal cord as a first layer, followed by closure of paraspinal myofascial flaps, and then the skin surrounding the lesion is mobilized and closed to complete the repair (). When the skin cannot be closed primarily, an acellular human dermis graft is used to complete the closure.
Fig. 2a. Exposure of 22 week gestation fetus through hysterotomy showing the MMC.
Mark Johnson reported our experience at CHOP with 58 patients treated with fetal surgery from 1998-2003 prior to the beginning of the MOMS Trial.[49
] There were 4 deaths due to preterm delivery, and the average age at delivery was 34 weeks, 4 days. Comprehensive follow-up examinations were performed at 1, 2, 3 and 5 years of age. There was resolution of hindbrain herniation in nearly all patients treated in utero
, and the ascent of hindbrain structures could be shown within 3 weeks of the fetal closure using serial MRI. Hindbrain herniation reversal was significant in three ways for improved outcomes. First, the VP shunt rate was 46%, which is much lower that the predicted overall shunt rate of 84% shown by CHOP neonatologist Natalie Rintoul based upon 297 historical controls followed at the CHOP Spina Bifida Clinic between 1983 and 2000.[50
] Second, the overall head size is very small in MMC fetuses, but it increased towards normal after fetal surgery due to the restoration of extra-axial CSF spaces and increase in cortical indices.[51
] Third, the vast majority of children demonstrated no or minimal brainstem dysfunction symptoms at follow-up.[52
In assessing motor skills, fetal surgery usually resulted in better than predicted lower extremity function at birth: 57% had lower extremity neuromotor function that was better than predicted by a median of 2 functional levels, 24% had neuromotor function as predicted, while 19% had worse than predicted function by a median of 1 functional level. Sixty-nine percent of children who underwent fetal MMC repair at CHOP were independent walkers at a mean follow-up age of 66 months.[53
] Despite these promising findings, a few of the patients developed clinically symptomatic spinal cord tethering in association with dermoid inclusion cysts at the fetal closure site and required repeat surgery. A possible late decline in neurological function due to tethering ± dermoid inclusion cysts underscores the importance of careful long-term neurologic surveillance of these children.[54
Neurodevelopmental evaluation was performed at 2 years and 5 years of age in studies lead by Mark Johnson, Marsha Gerdes, and Enrico Danzer at CHOP.[55
] By 5 years of age, the majority (83%) of children had overall cognitive functioning in the average to high range. There was a pattern of consistently higher scores in verbal areas compared to scores for visual-motor or non-verbal reasoning, which suggests the possibility of later learning difficulties.
These preliminary observations and outcomes are significant. After fetal MMC repair, ascent of the hindbrain and improved CSF hydrodynamics reduces hydrocephalus and averts the need and morbidity of ventricular shunts. With a more normal anatomic location of the hindbrain, the symptomatic sequelae of the Arnold-Chiari malformation and need for subsequent surgery should be reduced. In the case of lower lumbar and sacral lesions where less impairment in lower extremity function may be predicted, normalizing hindbrain position and minimizing the need for postnatal VP shunt placement may be the primary indication for surgery. Persistence of improved lower extremity function, especially in patients with lesions at higher spinal levels, should permit greater independence and potentially improved quality of life. A reduction risk of club feet and other orthopedic anomalies should limit the need for surgical intervention and enhance the possibility of future ambulation. Two follow-up studies of women who underwent open fetal surgery at CHOP demonstrated no impairment of future reproductive capacity, and the hysterotomy risks were comparable to those of a classic cesarean section.[57
] The latter finding mandates cesarean delivery for the fetal surgery pregnancy and all subsequent pregnancies.
Although fetoscopic techniques that involve making multiple puncture wounds in the uterus are theoretically appealing to potentially mitigate maternal morbidity, clinical reports on their use are limited and the results have been disappointing, primarily because of uterine membrane problems leading to premature birth 3 to 6 weeks after the procedure and delivery before 30 weeks gestation. The first cases of fetal MMC surgery using an endoscopic approach were reported in 1997 at Vanderbilt University. This technique proved disastrous (two of four fetuses died) and was abandoned.[59
] In 2003, Farmer and colleagues from UCSF reported three patients that underwent fetoscopic MMC surgery.[60
] Fetoscopic coverage was successfully completed in one, but the patch partially detached after fetal intervention and the infant required standard repair and shunt placement postnatally. Due to technical difficulties, the MMC defect in the second fetus was never completely covered and the fetus was delivered prematurely at 31 weeks of gestation. Postnatally the newborn required neurosurgical repair of the lesion and VP shunt placement and subsequently died of urosepsis at one month of age. The third fetus required conversion to an open approach secondary to an anterior placenta and difficulties in appropriately positioning the fetus. Fetoscopic patch coverage has also been tried in Europe in a small series of patients, and has also proven very problematic.[61
] Complete coverage of the defect was only achieved in 11 of 16 (69%) fetuses. In four fetuses the surgery was terminated prior to completion of the procedure secondary to bleeding at the trocar sites. Mean age at delivery was 28 weeks which is considerably earlier than the reported mean gestational age at delivery of 34-35 weeks for the open approach.[47
] Oligohydramnios developed in 9(56%) pregnancies. Overall survival was only 81% (the 3 deaths were due to severe prematurity, intraoperative demise, and termination of pregnancy after fetal surgery). As compared with the open fetal surgery technique, fetoscopic repair of MMC has resulted in higher rates of fetal death, premature rupture of the membranes, chorioamnionitis, premature delivery, and persistent hindbrain herniation. If the problems of membrane rupture associated with multiple-port fetoscopy can be solved, this minimally invasive approach to repairing MMC before birth should be tested clinically.