Letter to the Editor. Fetal closure of myelomeningocele

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TO THE EDITOR: We read with great interest the 75th anniversary invited review of fetal surgery for spina bifida by Dewan and Wellons2 (Dewan MC, Wellons JC III: Fetal surgery for spina bifida. JNSPG 75th Anniversary Invited Review Article. J Neurosurg Pediatr 24:105–114, August 2019). Fetal closure of myelomeningocele (MMC) is a landmark advance that has revolutionized care for these children. The authors are uniquely positioned to review fetal surgery, as their center was one of the original participants in the Management of Myelomeningocele Study (MOMS) and remains one of the busiest programs in North America for intrauterine MMC closure (IUMC). The MOMS trial is one of the few randomized trials to address a topic of pediatric neurosurgical importance. We congratulate these authors, their co-investigators, and the researchers at other fetal surgery centers, and we celebrate ongoing refinement to mitigate risk and define optimal inclusion criteria for fetal surgery. We do, however, have a couple of concerns that we would like to raise and invite the authors’ commentary.

While the efficacy of IUMC was demonstrated by the randomized trial, this was a highly selected group of patients, treated at very experienced centers.1 As such, the external validity remains unproven, and the class I evidence can only be considered to apply for patients meeting inclusion criteria for the original trial. This important nuance is nearly uniformly lost in discussions pertaining to IUMC.

We must also be cautious that enthusiasm for a new technique does not lead us to overstate the potential benefits and that conclusions are closely supported by the data. For example, Dewan and Wellons discuss the rate of shunt revision in children who have undergone fetal versus postnatal surgery. These data were published in this journal by Tulipan et al. in the updated results of the entire MOMS cohort.6 In both the original publication and the current review, a statistically significant difference in shunt revision rate is reported (15.4% vs 40.2%, p < 0.001). However, these rates are obtained by dividing the number of patients who underwent shunt revision by the total in the entire cohort (14 revisions in 91 patients for fetal surgery versus 37 revisions in 92 patients in postnatal surgery). It could be questioned whether it is appropriate to include patients who do not have shunts in an analysis of shunt revision. If one considers only those patients who had shunts placed, the result is quite different (14 revisions in 40 patients for fetal surgery: 35% vs 37 revisions in 77 patients for postnatal surgery: 48%). Chi-square testing produces a p value of 0.177 for this comparison. So, should we really conclude that fetal surgery protects against shunt failure?

In the same issue of Journal of Neurosurgery: Pediatrics is a study by Mummareddy et al. regarding quality of life (QOL) in children with MMC.4 The authors administered QOL surveys to 74 children who had MMC repair between 1997 and 2003. They received 23 responses (31%): 11 with intrauterine closure and 12 with postnatal closure. Those with intrauterine closure scored significantly higher on overall and psychosocial QOL, but they observed no difference in physical QOL.

There are several limitations to that study, and the authors do an excellent job of detailing them. Possible participants were drawn from only one center, and the response rate was only 31%. The 2 groups are different in the proportion with hydrocephalus and the level of MMC, both of which have been shown to be associated with QOL in previous studies.3,5 The intrauterine closure group is highly selected by definition, since only families with financial resources, social support, and excellent healthcare access would have been eligible for this treatment in the first place. The study does not control for these factors, and, as the authors point out, the sample size is small, representing less than one-third of the eligible cohort. With this study design and these limitations, a measured conclusion with recognition that these are preliminary data would seem appropriate. Indeed, the text is measured and careful. However, the title of the paper says something quite different. “Intrauterine closure of myelomeningocele is associated with superior long-term quality of life than postnatal closure: a single-center study” strongly implies an answered question with limited room for doubt. Furthermore, the review article by Dewan and Wellons makes reference to this study without note of its limitations. The title would seem to infer a strength of evidence that the data cannot support. We anticipate that further such references to this paper from groups that lack the nuanced knowledge of the IUMC literature would similarly omit awareness or reference to the substantive limitations of the study design in the article by Mummareddy et al.

Another issue pertains to evolution of technique. As Dewan and Wellons point out, enthusiasm is high, and a large number of new centers for fetal surgery have opened across the country in the last several years. Some centers prefer open while others prefer fetoscopic technique, and there is variation in technique between individual surgeons within these broader divisions. As such, progressively larger numbers of centers are treating a limited number of patients with widely varying experience levels. With limited exceptions, each center’s cohort of patients will be underpowered to provide insight into the value or shortcomings of the techniques employed. Therefore, we would suggest that a registry of all patients undergoing IUMC might be useful in capturing and compiling this critical experience. The National Spina Bifida Patient Registry is a Centers for Disease Control and Prevention–sponsored, prospective registry that has enrolled more than 10,000 patients with spina bifida since its inception in 2004. Perhaps a parallel or extended component of the National Spina Bifida Patient Registry would provide fitting infrastructure to capture these important variables and cases. Centers such as Vanderbilt should be at the core of defining this extension of the registry and developing the critical variables.

Intrauterine closure of MMC is a great advance in neurosurgery. It has been shown with class I evidence to be beneficial for families who meet strict criteria.1 The power and the promise of this work require that we ensure that studies of this treatment are rigorously conducted and reported.

Disclosures

The authors report no conflict of interest.

References

  • 1

    Adzick NSThom EASpong CYBrock JW IIIBurrows PKJohnson MP: A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med 364:99310042011

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  • 2

    Dewan MCWellons JC III: Fetal surgery for spina bifida. JNSPG 75th Anniversary invited review article. J Neurosurg Pediatr 24:1051142019

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    • Export Citation
  • 3

    Flanagan AGorzkowski MAltiok HHassani SAhn KW: Activity level, functional health, and quality of life of children with myelomeningocele as perceived by parents. Clin Orthop Relat Res 469:123012352011

    • Search Google Scholar
    • Export Citation
  • 4

    Mummareddy NDewan MCHuang ABasem JBennett KAShannon CN: Intrauterine closure of myelomeningocele is associated with superior long-term quality of life than postnatal closure: a single-center study. J Neurosurg Pediatr 24:1151192019

    • Search Google Scholar
    • Export Citation
  • 5

    Rocque BGBishop ERScogin MAHopson BDArynchyna AABoddiford CJ: Assessing health-related quality of life in children with spina bifida. J Neurosurg Pediatr 15:1441492015

    • Search Google Scholar
    • Export Citation
  • 6

    Tulipan NWellons JC IIIThom EAGupta NSutton LNBurrows PK: Prenatal surgery for myelomeningocele and the need for cerebrospinal fluid shunt placement. J Neurosurg Pediatr 16:6136202015

    • Search Google Scholar
    • Export Citation
Keywords:

Response

We read with interest the letter to the editor by Dr. Rocque, Ms. Hopson, and Dr. Blount regarding the invited article on fetal surgery for spina bifida that was written in celebration of the Journal of Neurosurgery’s 75th anniversary. These concerns spill over to the original MOMS published in the New England Journal of Medicine in 2011, the follow-up study specific to hydrocephalus from that same cohort published in 2015, and the report on the results of a long-term study by our group in the same issue.1–3 We address these concerns below.

Issue 1 is that of the external validity of MOMS due to the study inclusion criteria. We are not well versed on a study without some sort of inclusion or exclusion criteria. A quick check of an early surgical trial, the Asymptomatic Carotid Atherosclerosis Study published in 1995, shows that even with its limited exclusion criteria, more than 42,000 patients were screened and only 1662 were enrolled. Unless we were to randomize all patients with said disease process, we have to bear the validity issues raised with inclusion criteria. One can state that a given study seems accurate for the studied population, but how valid, or generalizable, it is depends on those criteria. The MOMS inclusion criteria, as detailed in both the original paper and our review, were defined by the original investigators and based on expertise, data, and consensus in the time leading up to the trial. We, the readers and recipients of the results, are left to decide if we then keep the parameters steady in our implementation of the results or push the envelope closer to the edge of safety. Prior placental abruption, age younger than 18 years, and twin pregnancy all seem appropriate exclusions considering the risk entailed with the actual surgery itself.

The main issue that we should be discussing in regard to exclusion criteria is the BMI cutoff and the socioeconomic and racial exclusion that may or may not result from an interaction between those variables. The relationship of obesity to surgical morbidity is well known. At risk, that outside the safety envelope, is death of the fetus, or worse, that of the mother. What onboarding center is willing to risk that? What experienced center is? Yet, certainly there is indeed room to expand the BMI threshold with focused studies, as we do call for in the final paragraph of our review.

One additional point relevant to this issue of access to care is that of public versus private insurance and reimbursement for the procedure. How the reimbursement source lines up on socioeconomic status and racial lines can have a profound effect on what procedure is available to what population. TennCare, for example, has a mechanism in place to reimburse for fetal spina bifida repair. Alabama Medicaid does not. Reimbursement is a key facet of access to care; hence, advocacy at the level of state government by spina bifida experts, such as our colleagues at University of Alabama at Birmingham (UAB), would be key to improving access to the benefits noted in the initial study population for everyone.

So, on the issue of expanding the indications, we agree with our colleagues. On devaluing a well-executed study because of the time-tested necessity of study criteria, we do not. We would suggest that all of us agree on the issue of reducing disparity of healthcare access.

Issue 2 is that of overstatement of the reduction in shunt burden to those in the intrauterine surgery group. This appears to be a simple issue of how one elects to interpret the concept of shunt revision. The authors of that article, which included the majority of the MOMS investigators, chose to conceptualize that a reduction in shunt revision in the intrauterine surgery cohort was due in part to a reduction in shunt burden.3 The letter authors are correct in their interpretation as well. Over the years, we have come to feel that the best way to reduce shunt infection, for example, is to reduce the need for shunt revision. The best way to reduce the need for shunt revision is to reduce the number of shunts placed, either by relaxing criteria or finding alternate operations, such as ETV or ETV/CPC. We would imagine that our colleagues at UAB find the reduction in the pool of patients in need of shunt revision to be a benefit, indeed a justification, of both.

Issue 3 is that the authors take issue with the title of the manuscript at hand.2 “Association” refers to a relationship between variables. This has less strong implications than the term “causation,” which refers to direct cause and effect. These are well-known epidemiological terms, and one would hope the difference between the two is understood to the readers (and writers) of the medical literature. As written, the title plainly describes the association identified—no more, and no less. We reject the implication of a lack of rigor on our part. We have reported on those who answered the survey and the association noted and put stock in the integrity of the editorial process and scientific community in its evaluation of this body of work in the future.

Issue 4 is that of technique evolution. A degree of evolution is only expected as a procedure is adopted across a field, particularly as instruments and techniques advance. As a response to this occurring during the implementation phase since MOMS, we are on record several times calling for a “phase 4–type study” on both intrauterine and postnatal surgery, suggesting variables and outcomes of interest at several national talks and lectures on this topic over the past 3 years. We are encouraged to see that our colleagues at UAB agree and welcome their ideas of incorporating this effort into the National Spina Bifida Patient Registry.

Lastly, and with a final commentary: As we are joined in volume levels and expertise by other centers, we should indeed be sharing our learning, our outcomes, and our data. There may very well be further advances to be made, including BMI, reimbursement, and others, that result in no excluded patients in the future. This will depend on how we move forward as a field. Do we as the corpus of pediatric neurosurgery, with our deep engagement in the spina bifida community, lead this effort, by defining the next steps, designing the studies, and directly affecting the outcomes in the children that we treat? Or do we cede it to alternative subspecialists who operate and walk away, leaving others to care for the short- and long-term effects? We believe the answer is clear. Our colleagues at UAB represent a strong voice of advocacy for this population. Their comments overall should be taken as intended, to further along the conversation and stoke action.

References

  • 1

    Adzick NSThom EASpong CYBrock JW IIIBurrows PKJohnson MP: A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med 364:99310042011

    • Search Google Scholar
    • Export Citation
  • 2

    Mummareddy NDewan MCHuang ABasem JBennett KAShannon CN: Intrauterine closure of myelomeningocele is associated with superior long-term quality of life than postnatal closure: a single-center study. J Neurosurg Pediatr 24:1151192019

    • Search Google Scholar
    • Export Citation
  • 3

    Tulipan NWellons JC IIIThom EAGupta NSutton LNBurrows PK: Prenatal surgery for myelomeningocele and the need for cerebrospinal fluid shunt placement. J Neurosurg Pediatr 16:6136202015

    • Search Google Scholar
    • Export Citation

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Article Information

Contributor Notes

Correspondence Brandon G. Rocque: brandon.rocque@childrensal.org.INCLUDE WHEN CITING Published online November 29, 2019; DOI: 10.3171/2019.8.PEDS19498.Disclosures The authors report no conflict of interest.
Headings
References
  • 1

    Adzick NSThom EASpong CYBrock JW IIIBurrows PKJohnson MP: A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med 364:99310042011

    • Search Google Scholar
    • Export Citation
  • 2

    Dewan MCWellons JC III: Fetal surgery for spina bifida. JNSPG 75th Anniversary invited review article. J Neurosurg Pediatr 24:1051142019

    • Search Google Scholar
    • Export Citation
  • 3

    Flanagan AGorzkowski MAltiok HHassani SAhn KW: Activity level, functional health, and quality of life of children with myelomeningocele as perceived by parents. Clin Orthop Relat Res 469:123012352011

    • Search Google Scholar
    • Export Citation
  • 4

    Mummareddy NDewan MCHuang ABasem JBennett KAShannon CN: Intrauterine closure of myelomeningocele is associated with superior long-term quality of life than postnatal closure: a single-center study. J Neurosurg Pediatr 24:1151192019

    • Search Google Scholar
    • Export Citation
  • 5

    Rocque BGBishop ERScogin MAHopson BDArynchyna AABoddiford CJ: Assessing health-related quality of life in children with spina bifida. J Neurosurg Pediatr 15:1441492015

    • Search Google Scholar
    • Export Citation
  • 6

    Tulipan NWellons JC IIIThom EAGupta NSutton LNBurrows PK: Prenatal surgery for myelomeningocele and the need for cerebrospinal fluid shunt placement. J Neurosurg Pediatr 16:6136202015

    • Search Google Scholar
    • Export Citation
  • 1

    Adzick NSThom EASpong CYBrock JW IIIBurrows PKJohnson MP: A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med 364:99310042011

    • Search Google Scholar
    • Export Citation
  • 2

    Mummareddy NDewan MCHuang ABasem JBennett KAShannon CN: Intrauterine closure of myelomeningocele is associated with superior long-term quality of life than postnatal closure: a single-center study. J Neurosurg Pediatr 24:1151192019

    • Search Google Scholar
    • Export Citation
  • 3

    Tulipan NWellons JC IIIThom EAGupta NSutton LNBurrows PK: Prenatal surgery for myelomeningocele and the need for cerebrospinal fluid shunt placement. J Neurosurg Pediatr 16:6136202015

    • Search Google Scholar
    • Export Citation
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