Letter to the Editor: Pregnancy, epilepsy, and glioma survival

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TO THE EDITOR: We enjoyed reading the recent paper by Rønning et al.5 (Rønning PA, Helseth E, Meling TR, et al: The effect of pregnancy on survival in a low-grade glioma cohort. J Neurosurg [epub ahead of print January 1, 2016. DOI: 10.3171/2015.6.JNS15985]). The authors are to be congratulated for this informative, population-based study including patients from 2 large, prospectively maintained registries (Cancer Registry of Norway and Medical Birth Registry of Norway). They performed the largest study to date focused on the impact of pregnancy on survival in patients with low-grade glioma (LGG; 12 WHO Grade I and 53 WHO Grade II) and proposed that pregnancy does not seem to have an impact on the survival of female patients with LGG.

Given the findings from our own clinical practice, we enthusiastically support all data allowing better counseling of women harboring a glioma and envisioning a pregnancy or women with a glioma discovered during pregnancy. Rønning et al. report encouraging results supporting the absence of a survival impact in pregnant women with LGG. However, their final statement as regards the counseling of female patients with LGG that “pregnancy does not seem to influence their overall survival” sounds overly optimistic and should be restricted to indicate simply that the present results showed no negative impact of pregnancy on overall survival in LGG, which is an important and novel finding. Indeed, the authors' population-based study contains an inevitable bias in the group definition as LGG aggressiveness and evolution possibly interact with the choice of being or not being pregnant. Thus, the pregnancies possibly occurred in “low-risk LGG” patients, a factor that the present study is unable to identify (note that there is no information regarding tumor size, location, functional status, extent of resection, molecular markers, or detailed oncological treatment). Patients who did not deliver may have had worsening of their LGG, as supported by their higher proportion of adjuvant therapies (chemotherapy 10.3% vs 1.5%, radiotherapy 24.6% vs 9.2%). In contrast, patients who gave birth were in good clinical condition and possibly maintained control of their LGG, as supported by a younger age (25.3 vs 31.4 years), by an increased overall survival, and by parity after an LGG diagnosis.

Moreover, the prognostic significance of epilepsy on LGG survival cannot be drawn from the present results as the authors apparently studied the rate of “epilepsy during pregnancy,” not the rate of “epilepsy at LGG diagnosis.” The discussion should ideally suggest that “we did not observe any statistically significant effect of epilepsy [during pregnancy] as a prognostic factor” and that “we believe the prognostic effects of epilepsy during pregnancy to be modest, if present at all.” To be more precise, a history of epileptic seizures at diagnosis has been identified as a strong, independent, protective prognostic parameter for malignant transformation and for overall survival in the largest series ever published regarding epileptic seizures in 1509 adults with supratentorial WHO Grade II gliomas.2

Finally, this quality study questions why the transient clinical and imaging deteriorations we observe during pregnancy, in both Grade I and II gliomas, do not systematically translate into worsened long-term evolution, even though malignant transformation has been reported.1,3,4,6,7

References

  • 1

    Knafo SGoutagny SPallud J: Increased growth rate of a WHO grade I ganglioglioma during pregnancy. Br J Neurosurg 27:1191212013

  • 2

    Pallud JAudureau EBlonski MSanai NBauchet LFontaine D: Epileptic seizures in diffuse low-grade gliomas in adults. Brain 137:4494622014

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  • 3

    Pallud JDuffau HRazak RABarbarino-Monnier PCapelle LFontaine D: Influence of pregnancy in the behavior of diffuse gliomas: clinical cases of a French glioma study group. J Neurol 256:201420202009

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  • 4

    Pallud JMandonnet EDeroulers CFontaine DBadoual MCapelle L: Pregnancy increases the growth rates of World Health Organization grade II gliomas. Ann Neurol 67:3984042010

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  • 5

    Rønning PAHelseth EMeling TRJohannesen TB: The effect of pregnancy on survival in a low-grade glioma cohort. J Neurosurg [epub ahead of print January 1 2016. DOI: 10.3171/20156.JNS15985]

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  • 6

    Yust-Katz Sde Groot JFLiu DWu JYuan YAnderson MD: Pregnancy and glial brain tumors. Neuro Oncol 16:128912942014

  • 7

    Zwinkels HDörr JKloet FTaphoorn MJBVecht CJ: Pregnancy in women with gliomas: a case-series and review of the literature. J Neurooncol 115:2933012013

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Disclosures

The authors report no conflict of interest.

Response

We thank Dr. Pallud and Ms. Peeters for their thoughtful comments on our article. The issue of pregnancy in patients with LGG is difficult to study given that LGG is a rare disease and that pregnancies in patients with LGG are even rarer. Hence, untangling the prognostic effect of pregnancy is challenging. Moreover, the prospect of obtaining definite proof would require a randomized controlled trial randomizing patients to either pregnancy or no pregnancy, which is untenable for obvious ethical reasons. Thus, we are left with observational data to answer and guide our patients on the topic of pregnancy.

We concede that a possible explanation for our findings and our conclusion of a negligible effect of pregnancy is a selection bias toward pregnancies only in patients with “low-risk LGG.” Unfortunately, the data in the Norwegian cancer registry (CRN) are insufficiently detailed with regard to currently well-established prognostic factors (tumor size, location, extent of resection, molecular markers, and so forth), and we are unable to access these data in retrospect.

Historically, however, many of these prognostic factors for LGG were not identified and universally accepted at the time of diagnosis; consequently, we doubt whether any clinician at the time of diagnosis would have classified them as low-risk or high-risk LGG. From a theoretical standpoint, since the data are observational and not randomized, one could also hypothesize that pregnancy itself could impede the growth and/or transformation of the LGG and thus explain the lower rates of chemotherapy and radiotherapy utilized.

Pallud and Peeters claim that we studied the rate of “epilepsy during pregnancy” and not the rate of “epilepsy at LGG diagnosis.” We respectfully disagree. In Norway, upon confirmation of pregnancy, the general practitioner or midwife completes a primary notification of pregnancy. This notification includes a tick mark for prior epilepsy including specification of any antiepileptic medication. Upon delivery of a child, the midwife completes a new notification based on the primary notification that also includes information on any new health issues arising during pregnancy (http://www.fhi.no/eway/default.aspx?pid=240&trg=Main_6664&Main_6664=6898:0:25,7840:1:0:0:::0:0). Our analysis was based on information regarding prior epilepsy. Thus, we maintain that we studied the rate of epilepsy at diagnosis. We are well aware that this is at odds with the findings by Pallud et al.2 However, corresponding to our findings are data in a cohort of 379 Norwegian LGG patients in whom epilepsy was not found to be a significant prognostic factor.1

We admit that our data do not tell the whole story, but given the dearth of pregnant LGG patients we must base our patient recommendations on the best available evidence. To our knowledge, this is the largest cohort of pregnant LGG patients described, and we failed to identify pregnancy as a detrimental prognostic factor. Thus, in the future, we will counsel our female LGG patients that pregnancy in itself has not been documented to worsen prognosis. However, the patient will also be informed about the uncertainties pertaining to this issue and that she must be cognizant of the overall reduced expected survival from the LGG.

We welcome all international collaboration on the issue of pregnancy in LGG patients because it can only be resolved with a larger number of observations due to the ethical concerns prohibiting definitive certainty.

References

  • 1

    Lote KEgeland THager BStenwig BSkullerud KBerg-Johnsen J: Survival, prognostic factors, and therapeutic efficacy in low-grade glioma: a retrospective study in 379 patients. J Clin Oncol 15:312931401997

    • Search Google Scholar
    • Export Citation
  • 2

    Pallud JAudureau EBlonski MSanai NBauchet LFontaine D: Epileptic seizures in diffuse low-grade gliomas in adults. Brain 137:4494622014

    • Search Google Scholar
    • Export Citation

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Article Information

INCLUDE WHEN CITING Published online May 13, 2016; DOI: 10.3171/2016.1.JNS16119.

© AANS, except where prohibited by US copyright law.

Headings

References

  • 1

    Knafo SGoutagny SPallud J: Increased growth rate of a WHO grade I ganglioglioma during pregnancy. Br J Neurosurg 27:1191212013

  • 2

    Pallud JAudureau EBlonski MSanai NBauchet LFontaine D: Epileptic seizures in diffuse low-grade gliomas in adults. Brain 137:4494622014

    • Search Google Scholar
    • Export Citation
  • 3

    Pallud JDuffau HRazak RABarbarino-Monnier PCapelle LFontaine D: Influence of pregnancy in the behavior of diffuse gliomas: clinical cases of a French glioma study group. J Neurol 256:201420202009

    • Search Google Scholar
    • Export Citation
  • 4

    Pallud JMandonnet EDeroulers CFontaine DBadoual MCapelle L: Pregnancy increases the growth rates of World Health Organization grade II gliomas. Ann Neurol 67:3984042010

    • Search Google Scholar
    • Export Citation
  • 5

    Rønning PAHelseth EMeling TRJohannesen TB: The effect of pregnancy on survival in a low-grade glioma cohort. J Neurosurg [epub ahead of print January 1 2016. DOI: 10.3171/20156.JNS15985]

    • Search Google Scholar
    • Export Citation
  • 6

    Yust-Katz Sde Groot JFLiu DWu JYuan YAnderson MD: Pregnancy and glial brain tumors. Neuro Oncol 16:128912942014

  • 7

    Zwinkels HDörr JKloet FTaphoorn MJBVecht CJ: Pregnancy in women with gliomas: a case-series and review of the literature. J Neurooncol 115:2933012013

    • Search Google Scholar
    • Export Citation
  • 1

    Lote KEgeland THager BStenwig BSkullerud KBerg-Johnsen J: Survival, prognostic factors, and therapeutic efficacy in low-grade glioma: a retrospective study in 379 patients. J Clin Oncol 15:312931401997

    • Search Google Scholar
    • Export Citation
  • 2

    Pallud JAudureau EBlonski MSanai NBauchet LFontaine D: Epileptic seizures in diffuse low-grade gliomas in adults. Brain 137:4494622014

    • Search Google Scholar
    • Export Citation

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