Brain malformations in the sheep model of myelomeningocele are similar to those found in human disease: preliminary report

Purpose  To examine if brain malformations, similar to those which account for cognitive disorders seen in human disease, are present in an ovine model of myelomeningocele (MMC). Methods  An MMC-like lesion was surgically created in 16 fetal lambs between 60 and 80 days of gestation. Ten did not undergo fetal repair (group A), 2 were repaired with an open two-layer closure (group B), 2 with open bioglue coverage (group C) and 2 with fetoscopic coverage (group D). Lambs were killed and their brains were examined. Two brains from normal unoperated lambs served as controls. Results  Thirteen lambs died in utero (81%). Two lambs in group A and 1 in group B were delivered at term. Group A brains showed hydrocephalus and extensive areas of polymicrogyria. There was also an extensive denudation of the ependymal lining under the polymicrogyric areas and the corpus callosum was thinner than normal. No hindbrain herniation was observed. Brains from group B and the control did not show any of these abnormalities. Conclusions  Some of the central nervous system abnormalities associated to MMC in human patients are also found in the uncorrected fetal lamb model of MMC but not in the only survivor to intrauterine coverage. Further studies are necessary to ascertain if these abnormalities can be prevented by coverage of the defect.     

Fetal surgery for repair of myelomeningocele allows normal development of anal sphincter muscles in sheep

One major problem for patients with myelomeningocele (MMC) is fecal incontinence. To prevent this problem, fetal surgery for repair of MMC has been recently undertaken. The strategy behind this surgery is to allow normal development of anal sphincter muscles. The purpose of this study was to determine whether fetal surgery for repair of MMC allows normal development of anal sphincter muscles. Myelomeningocele was surgically created in fetal sheep at 75 days of gestation. At 100 days of gestation, fetal surgery for repair of the MMC lesion was performed. Three repair methods were used: standard neurosurgical repair (4 fetal sheep), covering the MMC lesion with Alloderm (2 fetal sheep), and covering the MMC lesion with Gore-Tex (2 fetal sheep). After the sheep were delivered (140 days of gestation), external and internal anal sphincter muscles were analyzed histopathologically. In control fetal sheep (not repaired) anal sphincter muscles did not develop normally. In contrast, in fetal sheep that underwent repair of the MMC, the external and internal anal sphincter muscles developed normally. Histopathologically, in the external sphincter muscles, muscle fibers were dense. In the internal sphincter muscles, endomysial spaces were small, myofibrils were numerous, and fascicular units were larger than those in unrepaired fetal sheep. There was no difference in muscle development for the repair methods. Fetal surgery for repair of MMC allows normal development of anal sphincter muscles.     

Fetal surgery for myelomeningocele: After the Management of Myelomeningocele Study (MOMS)

Myelomeningocele (MMC) is the most frequently occurring congenital abnormality of the central nervous system and leads to significant physical disabilities. Historically treatment involved postnatal closure with management of the associated sequelae including ventricular shunting. The mechanism of neurologic damage that begins with abnormal neurulation followed by continued injury over the course of gestation made MMC a plausible candidate for in-utero surgical repair. Animal and early human studies demonstrated the feasibility of fetal closure. The benefit of in-utero closure was debated until the results of the prospective randomized multicenter Management of Myelomeningocele Study (MOMS trial) were published, demonstrating a decreased need for shunting, reversal of hindbrain herniation, and better neurologic function in the prenatal repair group compared to postnatal repair with maternal complications and prematurity as a trade-off. As such, fetal MMC closure has become a standard of care option for prenatally diagnosed spina bifida. This paper reviews the MOMS trial and the journey of fetal MMC closure since that time.     

Fetal surgery for spina bifida: Past,present, future

Open spina bifida or myelomeningocele (MMC) is a common birth defect that is associated with significant lifelong morbidity. Little progress has been made in the postnatal surgical management of the child with spina bifida. Postnatal surgery is aimed at covering the exposed spinal cord, preventing infection, and treating hydrocephalus with a ventricular shunt. Experimental and clinical evidence suggest that the primary cause of the neurologic defects associated with MMC is not simply incomplete neurulation, but rather chronic, mechanical and amniotic-fluid induced chemical trauma that progressively damages the exposed neural tissue during gestation. The cerebrospinal fluid leak through the MMC leads to hindbrain herniation and hydrocephalus. In utero repair of open spina bifida is now performed in selected patients and presents an additional therapeutic alternative for expectant mothers carrying a fetus with MMC. In the past, studies in animal models and clinical case series laid the groundwork for a clinical trial to test the safety and efficacy of fetal MMC repair. In the present, a prospective, randomized study (the MOMS trial) has shown that fetal surgery for MMC before 26 weeks' gestation may preserve neurologic function, reverse the hindbrain herniation of the Chiari II malformation, and obviate the need for postnatal placement of a ventriculoperitoneal shunt. However, this study also demonstrates that fetal surgery is associated with significant risks related to the uterine scar and premature birth. In the future, research will expand our understanding of the pathophysiology of MMC, evaluate the long-term impact of in-utero intervention, and to refine timing and technique of fetal MMC surgery using tissue engineering technology.     

Stem cell and genetic therapies for the fetus

The prenatal diagnosis and management of congenital disease has made significant progress over the previous decade. Currently, fetal therapy (including open surgery and fetoscopic intervention) provides therapeutic options for a range of congenital anomalies; however, it is restricted to the treatment of fetal pathophysiology. Improvements in prenatal screening and the early diagnosis of genetic disease allow for preemptive treatment of anticipated postnatal disease by stem cell or genetic therapy. While currently awaiting clinical application, in utero stem cell therapy has made significant advances in overcoming the engraftment and immunologic barriers in both murine and pre-clinical large animal models. Likewise, proof in principle for fetal gene therapy has been demonstrated in rodent and large animal systems as a method to prevent the onset of inherited genetic disease; however, safety and ethical risks still need to be addressed prior to human application. In this review, we examine the current status and future direction of stem cell and genetic therapy for the fetus.     

Fetal surgery for repair of myelomeningocele allows normal development of the rectum in sheep

To determine whether fetal surgery in a fetus with myelomeningocele (MMC) allows normal development of rectal muscles and nerves, we analyzed the rectum after fetal surgery in a sheep model. An MMC lesion was surgically created in 13 fetal sheep at 75 days of gestation. One fetal sheep died after the lesion was created. Eight fetal sheep were repaired at 100 days of gestation; the others were not repaired, as a control (n=4). Three methods were used for fetal surgery of MMC: standard neurosurgical repair (4 fetal sheep), covering of the MMC lesion by Alloderm (2 fetal sheep), and covering of the MMC lesion by Gore-Tex (2 fetal sheep). At 140 days of gestation, fetal sheep were harvested and histo-pathological analysis was performed on the rectum using hematoxylin and eosin staining for muscles and S-100 protein staining for nerves. One fetal sheep treated by standard neurosurgical repair died before harvesting. The four untreated fetal sheep had hypoplastic longitudinal muscles of the rectum but well developed-circular muscles. In addition, the untreated fetuses had a hypoplastic submucosal nerve plexus but a well-developed intermuscular nerve plexus. In contrast, treated fetal sheep had well-developed longitudinal and circular muscles except for one sheep treated with standard neurosurgical repair. In addition, except for the same fetal sheep, treated fetal sheep had well-developed nerve plexuses. There was no difference in muscle and nerve development of the rectum among the three repair methods. Fetal surgery for repair of MMC allows normal development of rectal muscles and nerves.     

Experimental fetal neurosurgery: effects of in-utero manipulations on somatosensory evoked potentials

Somatosensory evoked potentials (SEP) were used to objectively evaluate sensory function in neonatal sheep after experimental fetal surgery. Posterior tibial (PTN) and ulnar (UN) nerves were stimulated electrically and averaged SEP were recorded from scalp electrodes placed over the somatosensory cortex. Animals with experimentally-created myelomeningocele (MMC) showed no SEP to PTN stimulation, but normal SEP to UN stimulation. In-utero repair of the MMC resulted in preservation of neurologic function and normal PTN SEP. In-utero thoracic spinal-cord transection resulted in no regeneration, and no SEP to PTN stimulation. In-utero unilateral transection of the sciatic nerve, even with attempted repair, resulted in little or no regeneration and absent or grossly abnormal PTN SEP from the affected side. In summary, the SEP technique provides valuable information concerning preservation of sensory function in a variety of experimentally created neurologic abnormalities and can aid in functional evaluation of experimental therapeutic fetal interventions. Accepted: 16 July 1999     

Myelomeningocele: prenatal diagnosis,pathophysiology and management

Myelomeningocele (MMC) is a common birth defect that is associated with significant lifelong morbidity. Little progress has been made in the postnatal surgical management of the child with spina bifida. Postnatal surgery is aimed at covering the exposed spinal cord, preventing infection, and treating hydrocephalus with a ventricular shunt. In utero repair of open spina bifida is now performed in selected patients and presents an additional therapeutic alternative for expectant mothers carrying a fetus with MMC. Early fetal intervention may improve neurologic outcome and reduce the hindbrain herniation associated with the Arnold-Chiari II malformation. These changes may improve long-term neurologic function and limit requirements for shunt placements and other surgical interventions. Further research is needed to better understand the pathophysiology of MMC, the ideal timing and technique of repair, and the long-term impact of in utero intervention. A prospective, randomized clinical trial is planned comparing prenatal MMC repair with postnatal repair.     

Psychosocial aspects in the treatment of children with myelomeningocele: An assessment after a decade

The aim of this study was to recognize the possible psychological advantages when children with a severe CNS disorder like myelomeningocele (MMC) are given very early rehabilitation treatment. One hundred and seven newborns with MMC seen between 1971–1992 were prospectively analysed with respect to two different therapeutic approaches. The children born during the period 1971–1980 did not receive very early therapeutic rehabilitation treatment, whereas those born during the period 1981–1992, received this treatment. In the latter group, special attention was paid to support an improvement in the difficult relationship between the parents and the child with MMC as well as between parents and caregivers. The following statistically significant differences between the two treatment programmes were found: (1) all children achieved independent locomotion at 5 years, in the very early intervention group, compared to only 35% (P<0.001) in the group without this programme. Orthopaedic operations in the first-mentioned group were markedly reduced; (2) urological surgery decreased drastically in the group with very early urodynamic rehabilitation. Thus, there were 0.6 operations per patient in the older group, but only 0.06 operations per patient in the younger one (P<0.001); (3) normal schooling was reached by 76% (22/29) and social continence by 80% (23/29) of the children with very early interventional therapy. In the older group only 54% reached normal schooling (P<0.05) and 29% social continence (P<0.001). The very early co-ordinated medical and physiotherapeutic rehabilitation treatment of children with MMC usually reduces the psychosocial stress and improves the quality of life of these children and of their families.Presented in part at the German Neuropediatric Congress, Stuttgart, October 1991     

Fetal surgery for myelomeningocele is effective: a critical look at the whys

Formerly, the disastrous cluster of neurologic deficits and associated neurogenic problems in patients with myelomeningocele (MMC) was generally thought to solely result from the primary malformation, i.e., failure of neurulation. Today, however, there is no doubt that a dimensional additional pathogenic mechanism exists. Most likely, it contributes much more to loss of neurologic function than non-neurulation does. Today, there is a large body of compelling experimental and clinical evidence confirming that the exposed part of the non-neurulated spinal cord is progressively destroyed during gestation, particularly so in the third trimester. These considerations gave rise to the two-hit-pathogenesis of MMC with non-neurulation being the first and consecutive in utero acquired neural tissue destruction being the second hit. This novel pathophysiologic understanding has obviously triggered the question whether the serious and irreversible functional loss caused by the second hit could not be prevented or, at least, significantly alleviated by timely protecting the exposed spinal cord segments, i.e., by early in utero repair of the MMC lesion. Based on this intriguing hypothesis and the above-mentioned data, human fetal surgery for MMC was born in the late nineties of the last century and has made its way to become a novel standard of care, particularly after the so-called “MOMS Trial”. This trial, published in the New England Journal of Medicine, has indisputably shown that overall, open prenatal repair is distinctly better than postnatal care alone. Finally, a number of important other topics deserve being mentioned, including the necessity to work on the up till now immature endoscopic fetal repair technique and the need for concentration of these extremely challenging cases to a small number of really qualified fetal surgery centers worldwide. In conclusion, despite the fact that in utero repair of MMC is not a complete cure and not free of risk for both mother and fetus, current data clearly demonstrate that open fetal–maternal surgery is to be recommended as novel standard of care when pregnancy is to be continued and when respective criteria for the intervention before birth are met. Undoubtedly, it is imperative to inform expecting mothers about the option of prenatal surgery once their fetus is diagnosed with open spina bifida.     

Fetal echocardiography

Since the first report of fetal echocardiography in 1972 by Winsberg, several advances in ultrasound technology have occurred allowing datailed evaluation of cardiac anatomy in the second trimester fetus. Fetal echo is indicated in high risk pregnancies where the chances of fetus having a congenital heart disease (CHD) are likely to be high e.g., in fetus with extracardiac anomalies picked up on obstetric ultrasound, those with a history of CHD in family, maternal diabetes (especially insulin dependent), maternal connective tissue disorder etc. The reported sensitivity of fetal echo has ranged from 4–96% in various series depending upon the equipment, level of training, study design and examination technique. Although many CHD can be detected in four chamber view, an important group malformations that would need early intervention are likely to be missed. Hence a detailed echocardiographic examination including the outflow views must be done. Defects like atrial septal defect and patent ductus arteriosus cannot be diagnosed in fetal echo, as these are part of normal fetal physiology. Other CHD like coarctation of aorta, small ventricular septal defects, mild valvular stenosis, partial anomalous pulmonary venous drainage are also difficult to diagnose. Ultrasound assessment of fetus, however, has a clear role in the diagnosis, monitoring and management of fetuses with sustained arrhythmias. Prenatal diagnosis of CHD helps in planning the optimal management of the baby e.g. a fetus with a ductus dependent lesion can be planned to be delivered in a tertialy care centre for stabilisation and early initiation of prostaglandin therapy to avoid acidosis and organ damage. Future of fetal medicine lies in fetal cardiac surgery for which echocardiography will play a very important role.     

The effect of prenatal treatment with steroids and preterm delivery in a model of myelomeningocele on the rabbit foetus

Damage of neural elements (spinal cord and encephalus) in myelomeningocele (MMC) seems to be progressive during gestation because of amniotic fluid chemical contact and continuous leakage of CSF. We studied the effect of preterm delivery and steroid treatment in a model of MMC in the rabbit foetus. Twelve New Zealand White rabbits underwent laparotomy and hysterotomy at 23 days of gestation. Fifty-nine out of 107 foetuses underwent lumbar laminectomy (three to four levels). Dura was opened to expose the neural elements to the amniotic fluid. Six rabbits underwent caesarean section on gestational day 31 for fetal harvest; three of them had no treatment (group T) and three received corticosteroid treatment (group TC). The other six rabbits underwent caesarean section on gestational day 29 for fetal harvest (preterm delivery); three of them had no treatment (group P) and three received corticosteroid treatment (group PC). Alive newborns were clinically, neurophysiologically and histologically analysed. None of mothers died during the procedure. After birth, animals in group preterm showed statistically significant less deformity than animals in group at term. Lower kyphosis was observed in group PC (preterm and steroids). Pain related and spontaneous mobility of lower extremities was higher in groups treated with corticosteroids (TC and PC). Only newborns at term (T and TC groups) showed response to evoked potentials (CMEPs). The response was earlier and higher in group treated with steroids (TC). Histologically, we observed progressive lesion of the spinal cord. Groups treated with steroids (TC and PC) show less inflammatory response. Arnold–Chiari malformation was present in all groups. Animals in group preterm with steroids show statistically significant less herniation than those group at term. Preterm delivery and prenatal steroid therapy seem to be an effective treatment to get less neural injury (spinal cord and encephalus) in myelomeningocele foetuses.     

胎儿先天性心脏病介入治疗进展

既往观点认为,一旦胎儿患有左心发育不良综合征(HLHS)等严重心血管畸形,结局就只能是出生后功能性单心室循环、心脏移植或中止妊娠.到目前为止,开放性胎儿心脏外科技术尚不成熟,而通过胎儿心脏介入治疗技术可以在很大程度上阻止因先天性心脏病引起的胎儿水肿、自发性流产或胎儿死亡,促进发育不良的心室重新发育,形成生后的双心室循环,重塑右室流出道梗阻胎儿的肺血管床等,改善了胎儿严重心血管畸形的预后.这些进步在很大程度上依赖于对胎儿先天性心脏病病理生理学特点的准确判断.超声技术的发展以及其他评价手段的进步可促进目前还比较有限的胎儿先天性心脏病介入治疗进一步发展.     

Prenatal Diagnosis and Treatment of Steroid 21-Hydroxylase Deficiency

Steroid 21-hydroxylase deficiency (21-OHD) accounts for 90–95% of congenital adrenal hyperplasia (CAH) cases. It is classified into three distinct clinical phenotypes: the salt-wasting (SW), simple virilizing (SV) and nonclassical forms (NC). As girls with the SW and SV forms of 21-OHD are exposed to high systemic levels of adrenal androgens during fetal life, they show genital ambiguity. To ameliorate the degree of genital virilization, prenatal dexamethasone treatment has been performed for more than two decades, although mainly in the USA and Europe. This treatment has proven to be effective in preventing or reducing genital virilization. Some data also show that prenatal diagnosis and treatment are safe for the mother and fetus. However, prenatal treatment is still controversial for the following reasons. First, the risk of having an affected female fetus is only one in eight when both parents are known carriers of the autosomal recessive trait. Therefore, seven of eight fetuses will receive dexamethasone unnecessarily, and this raises ethical questions. Furthermore, maternal side effects such as excessive weight gain and hypertension have been observed. Finally, the long-term safety and outcome for dexamethasone-exposed children have not been established. In Japan, prenatal diagnosis and treatment has rarely been reported because of these reasons. Therefore, we must be cautious, and this treatment should be carried out in special centers with the approval of their ethical committees, that are capable of performing chorionic villus sampling (CVS) and subsequently determining the karyotype and genotype of 21-OHD.     

Arm span, serum IGF-1 and IGFBP-3 levels as screening parameters for the diagnosis of growth hormone deficiency in patients with myelomeningocele – preliminary data

Short stature is a common problem in patients with myelomeningocele (MMC) and hydrocephalus. We evaluated auxological and laboratory parameters to differentiate short stature due to neurological defect from short stature additionally caused by growth hormone deficiency (GHD). In a group of 38 prepubertal patients with MMC and hydrocephalus aged 3.8–11.0 years, auxological parameters, including arm span and bone age, and serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) levels were measured. Patients with normal supine length (n = 15) had normal arm span. Serum IGF-1 and IGFBP-3 levels were normal (≥ 10th percentile) in 14/15 patients. Twenty-three MMC patients had short stature (height SDS < −2), 11/23 patients had reduced arm span (SDS < −2), and 12/23 had normal arm span. Serum IGF-1 and IGFBP-3 levels were normal in 10/12 of short statured patients with normal arm span, but low (<10th percentile) in those patients with reduced arm span (IGF-1: 8/11 patients, P<0.05; IGFBP-3: 9/11 patients, P<0.005). In 7/11 short statured MMC patients with reduced arm span and low serum IGF-1 and IGFBP-3 levels, growth hormone secretion was investigated. All had a disturbed growth hormone secretion (GHD: n = 4; neurosecretory dysfunction: n = 3). Conclusion Arm span, serum IGF-1 and IGFBP-3 levels are estimated to be appropriate screening parameters for GHD in patients with MMC. Initiating growth hormone therapy should be considered not only according to endocrine findings but also with respect to neurological and orthopaedic anomalies. Received: 27 March 1997 / Accepted: revised form 18 September 1997     

How Do Carriers of Hemophilia Experience Prenatal Diagnosis (PND)?Carriers’Immediate and Later Reactions to Amniocentesis and Fetal Blood Sampling

ABSTRACT. A semistructured personal interview was performed with 29 carriers of hemophilia A or B, 1–5 years after a pregnancy in which prenatal diagnosis (PND) was performed by fetal blood sampling. Fetal blood sampling by fetoscopy was significantly more often reported by the women to be more trying than expected than was ultrasound-guided heart puncture. Of 29 women 13 were classified as having experienced the PND process (amniocentesis and fetal blood sampling) as distressing, having had mental or psychosomatic symptoms associated with it. All of the women who had abortion/miscarriage after PND reported a very high frequency of psychological sequelae during the 6 months that followed PND. Of 22 women who continued their pregnancy with a healthy fetus after PND 8 experienced the period until delivery as trying and felt that their emotional and somatic status influenced their daily life activities. This was particularly common among women who after fetoscopy received routine profylactic terbutalin treatment and had continuous sickleave until the 36th gestational week. 17/29 would consider going through PND in the future. Qualified psychological assistance must be offered both before and after PND.     

Fetal surgery: for what purpose?]

Widespread use of prenatal ultrasonography allows accurate diagnosis of many fetal malformations. The natural history and pathophysiology of some fetal diseases will undoubtedly induce lethal issue. Prenatal ultrasounds allow to determine prognosis during the second trimester of pregnancy. Experimental model and clinical practice have shown that prenatal surgery could be proposed for some correctable malformations: congenital diaphragmatic hernia, cystic adenomatoid lung disease, sacrococcygeal teratoma, lower urinary tract obstruction. To purpose this fetal therapy, great attention has to be paid to maternal risk and her future fertility, keeping in mind the aim of such fetal surgery: a new hope for improved management of the fetus with life-threatening defect.     

Intrauterine surgery in myelomeningocele

Intrauterine surgery for repair of fetal myelomeningocele has been performed since 1994. Open repair through a hysterotomy has been performed since 1997. Although much has been published about diagnosis, counseling, case selection, pre-, intra-, and postoperative management, delivery and long-term sequelae for both mother and baby, and associated ethical issues, several questions have yet to be openly discussed in a public forum.     

Diagnostic prénatal non invasif de la mucoviscidose

Cystic fibrosis (CF) is a frequently fatal autosomal recessive inherited disease affecting around one in 3000 newborns in France, the carrier frequency varying from one in 20 to one in 40 subjects depending on the geographical area. The disease is caused by a chloride channel defect that is attributable to mutations in the gene that encodes the CF transmembrane conductance regulator (CFTR). Approximately, 1200 different mutations have been discovered. Among them, the F508del mutation accounts for 70% of mutated alleles worldwide. Prenatal diagnosis (PND) of inherited monogenic disorders such as CF currently relies on invasive procedures-amniocentesis, chorionic villus sampling (CVS) - which carry a significant risk of miscarriage (from 0.5 to 3%). Several methods have been proposed to enrich circulating fetal cells (CFCs) from blood and use them in PND. However, up to now, no assay has been shown to be reliable enough for routine application in place of the invasive protocols. When combined with laser microdissection, isolation by size of epithelial tumor/trophoblastic cells (ISET) allows mutation analysis of DNA from single cells demonstrated to be fetal (circulating fetal trophoblastic cells [CFTC]) by short tandem repeat (STR) genotyping and uncontaminated with maternal DNA. Application of this protocol to 12 couples at risk of having a child affected by CF has shown, in a blind study, that the new method affords a reliable and safe PND of affected fetus, healthy carrier or normal non carrier fetus. A following prospective blind study has then been performed on 32 couples at risk of having an affected child. For each mother, five or 10 CFTCs have been analyzed with an individual genetic diagnosis performed per CFTC. Results have been obtained in 240 CFTC showing that seven mothers were carrying an affected foetus, with 100% sensitivity and 100% specificity. These results open the way to a multicenter clinical validation trial and to the potential future application of the ISET non invasive approach as a reliable alternative to the invasive PND procedures.     

How do carriers of hemophilia experience prenatal diagnosis (PND)? Carriers' Immediate and later reactions to amniocentesis and fetal blood sampling

A semistructured personal interview was performed with 29 carriers of hemophilia A or B, 1-5 years after a pregnancy in which prenatal diagnosis (PND) was performed by fetal blood sampling. Fetal blood sampling by fetoscopy was significantly more often reported by the women to the more trying than expected than was ultrasound-guided heart puncture. Of 29 women 13 was classified as having experienced the PND process (amniocentesis and fetal blood sampling) as distressing, having had mental or psychosomatic symptoms associated with it. All of the women who had abortion/miscarriage after PND reported a very high frequency of psychological sequelae during the 6 months that followed PND. Of 22 women who continued their pregnancy with a healthy fetus after PND 8 experienced the period until delivery as trying and felt that their emotional and somatic status influenced their daily life activities. This was particularly common among women who after fetoscopy received routine profylactic terbutalin treatment and had continuous sickleave until the 36th gestational week, 17/29 would consider going through PND in the future. Qualified psychological assistance must be offered both before and after PND.