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Prenatal myelomeningocele repair remains controversial as a non-lethal indication for maternal–fetal surgery. The rationale for fetal repair is not to prevent fetal or neonatal death, but rather to prevent or reduce the significant lifelong disabilities associated with myelomeningocele, which include various degrees of cognitive impairment, motor dysfunction in the legs, hydrocephalus, and bladder and bowel incontinence1. Previous reports on prenatal head growth in fetuses with unrepaired myelomeningocele showed disproportionately small head circumference (HC) measurements associated with a progressive enlargement of the lateral ventricular diameter (VD)2–4. Several studies have shown a negative correlation between the severity of ventriculomegaly and cognitive outcome in children born with myelomeningocele5, 6. Furthermore, indicators of the brain mass volume such as the cortical index (CI), have been shown to remain nearly constant or progressively decrease over gestation in fetuses with myelomeningocele, in contrast to the linear increase seen in normal fetuses2, 4, 7, 8.
Postnatal treatment for myelomeningocele consists of surgical closure of the spinal canal at birth and lifelong supportive care. However, the severe morbidity and significant mortality of myelomeningocele combined with promising results of research in animal models led to the consideration of prenatal intervention for this disorder. Initial clinical experience suggests that mid-gestational fetal myelomeningocele repair may reduce morbidity from hydrocephalus and Arnold Chiari II malformation by reversal of the hindbrain herniation component, arrest or slow the progressive ventriculomegaly, decrease the need for ventriculoperitoneal shunting and result in better than predicted leg function when compared with non-repaired fetuses with the same skeletal lesion9–13.
However, it is unknown whether maternal–fetal surgery for myelomeningocele changes the abnormal patterns of fetal head biometry and brain growth associated with myelomeningocele in reported historic observational case studies. The purpose of this paper was to assess the impact of in-utero myelomeningocele repair on fetal head growth as reflected by fetal head biometry measurements and CI.
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Several investigators have described the natural history of head growth based on biometry in fetuses with myelomeningocele. In a retrospective study of 70 fetuses diagnosed with myelomeningocele before 23 weeks, Nicolaides et al.14 found that 26% and 61%, respectively, had HC and BPD below the 5th centile, although 86% had already developed ventriculomegaly. Roberts and Campbell15 documented the reduction in BPD in fetuses with myelomeningocele and suggested that this was due to ‘abnormal brain development’. Van der Hof et al.2 reported the sonographic findings of 130 fetuses with open spina bifida and noted that HC measurements were significantly smaller in fetuses with myelomeningocele compared with normal fetuses. They found that 20 of 107 (19%) at 24 weeks or less and 10 of 23 (43%) at greater than 24 weeks had HC measurements below the 2.5th centile, despite enlargement of the lateral ventricles. Using the anterior and posterior ventricle-to-hemisphere ratio as an indirect indicator of brain size, they suggested progressive ‘loss of brain mass’ in fetuses with myelomeningocele and proposed that this may be due to further herniation of the cerebellum with subsequent ventriculomegaly2.
Bannister et al.4 evaluated 21 fetuses with myelomeningocele with the diagnosis of spina bifida between the 16th and 23rd weeks of gestation. On the initial scan 84.2% had a HC measurement below the 3rd centile and 86% had enlarged ventricular measurements. In five fetuses, serial sonographic biometric measurements were made. Whereas CI in the normal age-matched fetuses progressively increased throughout gestation, in fetuses with myelomeningocele, the CI remained constant or decreased as pregnancy progressed.
More recently, Babcook et al.3 studied 51 fetuses with myelomeningocele, looking at the correlation between VD and gestational age, and showed that the prevalence as well as the severity of ventriculomegaly in fetuses with myelomeningocele significantly increased with advancing gestational age. Only 44% of fetuses with myelomeningocele demonstrated ventriculomegaly before 24 weeks' gestation, while 94% had ventriculomegaly diagnosed after 24 weeks. Before 24 weeks, only 20% (3/15) had moderate ventriculomegaly and none had severe ventriculomegaly, while after 24 weeks 69% (11/16) developed moderate ventriculomegaly and 31% (5/16) progressed to severe ventriculomegaly.
While our preoperative results for HC, CI and VD were similar to those seen in other published studies, postoperative serial sonography was indicative of an increase in head growth after prenatal myelomeningocele closure. After myelomeningocele repair, HC growth patterns changed to become similar to those seen in normal fetuses. Ventriculomegaly was still present, but none of the fetuses developed severe ventriculomegaly as is commonly seen in postnatally treated fetuses with myelomeningocele; the majority of prenatally repaired fetuses had only mild to moderate ventriculomegaly. Other studies have shown that this is associated with a lower risk of developmental and neurocognitive delay16 compared with severe ventriculomegaly. When divided into early, intermediate and late myelomeningocele repair groups, HC increased in all three groups after fetal myelomeningocele repair, but CI only increased significantly when repair was performed before 22 weeks' gestation. VD increase in the intermediate and late groups was higher compared with the early group suggesting an advantage to early repair.
Several explanations of our results are possible. The increase of HC and CI suggests that head growth after fetal myelomeningocele repair may be due, at least in part, to an increase in cortical mass, and not an increase in ventriculomegaly alone. Alternatively, head growth may be due to reversal of the hindbrain herniation alone or in combination with an increase in cortical mass. In normal fetuses, the growth velocity of the infratentorial portion of the brain accelerates significantly during the second trimester17. We and others have shown experimentally, and later clinically, reversal of the hindbrain herniation following in-utero myelomeningocele closure10, 18, 19. The combination of increased infratentorial brain growth and increased intracranial tissue due to hindbrain ascent could have an impact on HC and CI. Additionally, pathological studies of the brains of fetses with myelomeningocele revealed abnormal cellular migration patterns in brain stem, cerebellum and cerebral cortex20. In normal fetuses, neuronal numbers and normal migration of neurons peak during the second trimester21, 22. It is possible that reversal of the hindbrain herniation and brainstem compression, decreased progression in ventriculomegaly and re-establishment of extra-axial fluid space after mid-gestational myelomeningocele repair may facilitate both an increase in neuronal number and normal migration patterns during this gestational period, contributing to the increased HC and CI.
Several studies have suggested that the level of the defect influences ventricular size in prenatally diagnosed myelomeningocele. Fetuses with thoracic lesions more often develop severe ventriculomegaly when compared with fetuses with lumbosacral lesions23, 24. Our data indicate that there is a correlation between prenatal anatomical level and postoperative head and brain growth. Fetuses with lower-lumbar lesions (L3–L5) had the highest increase in CI and the lowest degree of increase in ventriculomegaly.
This study suggests that fetal head biometry is altered following in-utero myelomeningocele repair. It is likely that a component of this increase in HC is due to progressive enlargement of the lateral ventricles and reappearance of the subarachnoid fluid space that occurs during reversal of the hindbrain herniation and re-establishment of more normal cerebrospinal fluid hydrodynamics. Although CI is not a direct measurement, it is reflective of cortical tissue mass in the absence of other brain malformations4. Our study found an increase in CI following prenatal repair (Figure 1) that was not seen in previously reported case series. While this may simply be due to less severe ventriculomegaly, it may also represent increased cortical mass. The finding that CI did not achieve the same rate of linear increase as seen in age-matched normal fetuses is most likely due to the increase in VD that occurred despite in-utero repair.
Limitations of this study include the small number of myelomeningocele patients, the unequal distribution in each of the subgroups studied, and the lack of comparable prenatal biometric parameters in the form of a large series of prenatally diagnosed but unrepaired myelomeningocele fetuses for direct comparison. Therefore, comparisons were made with data from previously published case series. Although we and others have tried to gather such information, it is difficult to study a cohort of patients who must return to referral centers to have frequent serial ultrasound evaluations, particularly when such examinations will not change their obstetric care and are not likely to be covered by their medical insurance.
We recognize that CI is an imprecise reflection of cortical mass. Cortical mantle measurements were available in many of the scans we reviewed, but these measurements were not obtained in a consistent manner at a predetermined anatomical landmark. However, present HC, VD, and CI findings are intriguing, and have led to further studies using more precise measurements at specific anatomical landmarks within the fetal brain obtained from ultrafast fetal magnetic resonance imaging studies. Such studies may lead to a better understanding of the observed biometric changes following prenatal myelomeningocele repair. A multicenter, prospective, randomized treatment trial called the Management of Myelomeningocele Study (MOMS) is presently underway to determine whether fetal neurosurgical closure may reduce infant morbidity and mortality and improve long-term neurocognitive and developmental outcome when compared with children who undergo postnatal neurosurgical repair.