Management of glioblastoma multiforme in pregnancy

J Neurosurg 116:1187–1194, 2012

Management of glioblastoma multiforme in pregnancy A review Bodiabaduge A. P. Jayasekera, M.R.C.S.,1 Andrew D. Bacon, M.R.C.S., 2 and Peter C. Whitfield, Ph.D. 3 Department of Neurosurgery, John Radcliffe Hospital, Oxford; 2Department of Neurosurgery, Frenchay Hospital, Bristol; and 3Southwest Neurosurgical Centre, Derriford Hospital, Plymouth, United Kingdom 1

Glioblastoma multiforme presenting during pregnancy presents unique challenges to the clinician. In planning treatment, potential benefits to the mother must be balanced against the risks to the fetus. In addition, evidence relating to timing of surgery and the use of radiotherapy and chemotherapy in pregnancy is limited. Management of peritumoral edema and seizures in pregnancy is also complicated by the potential for drug-related teratogenic effects and adverse neonatal outcomes on the fetus. The general anesthetic used for surgery must factor obstetric and neurosurgical considerations. In this review article, the authors seek to examine the role, safety, and timing of therapies for glioblastoma in the context of pregnancy. This covers the use of radiotherapy and chemotherapy, timing of surgery, postoperative care, anesthetic considerations, and use of anticonvulsant medications and steroids. The authors hope that this will provide a framework for clinicians treating pregnant patients with glioblastomas. (http://thejns.org/doi/abs/10.3171/2012.2.JNS112077)

Key Words • pregnancy • glioblastoma • surgery • radiotherapy • chemotherapy • anesthesia • oncology

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annual global incidence of primary malignant brain tumors in women is 2.6/100,000.2 The incidence has been reported to be slightly lower in pregnant women, but the relative frequencies of each brain tumor type appear similar.35 In both groups, gliomas feature as the most prevalent histological type. Regardless, management of pregnant patients with gliomas presents unique challenges, with potential ramifications of treatment on outcome for the mother and her offspring. Ethical, philosophical, and religious persuasions of patients factor heavily in the decision-making process. There is little guidance or suggestion in the literature of how to manage such patients and of the peculiar considerations. This review article seeks to examine the role, safety, and timing of treatment modalities for glioblastoma in the context of pregnancy. These include neurosurgery, radiotherapy, chemotherapy, postoperative care, neuroanesthesia, and use of anticonvulsant medications and steroids. We hope that this will provide a framework in planning treatment and a stimulus for further work. he

Abbreviations used in this paper: AED = antiepileptic drug; ICP = intracranial pressure; NOAEL = no observable adverse effect level.

J Neurosurg / Volume 116 / June 2012

Radiation Exposure in Pregnancy: Radiotherapy and CT Scanning

Investigation and management of suspected and confirmed intracranial malignancies are heavily dependent on imaging modalities, such as CT scanning and MRI. Treatment of cancerous tumors often entails deliberate exposure to ionizing radiation. In the context of pregnancy, fetal exposure to ionizing radiation needs to be considered. Deleterious effects of ionizing radiation on the conceptus relate to the fetal-absorbed dose and gestational age.3 The dose absorbed by the fetus depends on the maternal site irradiated. For instance, CT scans of the abdomen and pelvis involve direct irradiation of the fetus. More remote imaging, such as of the head, entails negligible direct irradiation and is related to internal scatter. Therefore, the site irradiated, imaging modality, dose, and maternal factors such as weight determine the fetalabsorbed dose. Risks to the fetus include in utero death, malformations, retardation of growth and cognition, and oncogenesis.3 Carcinogenesis is the only stochastic phenomenon; the remaining are threshold, that is, the effect is only seen 1187

B. A. P. Jayasekera, A. D. Bacon, and P. C. Whitfield above a threshold dose.3 Evaluations of fetal toxicity on exposure to ionizing radiation have drawn on data from epidemiological and animal studies. Developing embryos pass through the following 3 stages: preimplantation, organogenesis, and fetal growth (fetogenesis), with specific sensitivities to the effects of radiation. Preimplantation exposure data are based on animal studies, as the human preimplantation embryo cannot be detected by current assays. Overexposure is lethal, and embryos that survive are generally free from any abnormalities.3 This reflects the fatal consequences of genetic change at this stage and the omnipotent capacity of remaining cells to repopulate all damaged tissue. The only exception in the literature seems related to radiation-induced genome instability in genetically susceptible rats.40 Similarities in dose-response relationships for lethality and chromosomal damage suggest radiation-induced cytogenetic damage as the cause of death. The NOAEL in rats is roughly 0.15–0.2 Gy during preimplantation and increases throughout gestation.3 Epidemiological studies of diagnostic exposure to irradiation failed to disclose a risk of congenital malformations. However, there are historical cases of malformation induction after gynecological radiotherapy.14 Current understanding and dose thresholds have been extrapolated from rodent experiments. Exposure during critical periods of organogenesis produces congenital anomalies in rodents, corresponding to the developmental phase of the organ or tissue involved. The NOAEL is 0.2 Gy in the rat during its most vulnerable stage (9 days postconception) and increases throughout gestation.3 Growth retardation, defined as a decrease in weight for gestational age, is observed in rodents with a threshold of 0.25 Gy during early organogenesis, and again increases with age postconception. Neurological and cognitive outcome of in utero irradiation has been addressed by many studies examining the cohort of patients exposed to the atomic bombings at Hiroshima and Nagasaki.27 Borne out of these studies was an observed increase in frequency of mental retardation and decreased school performance and IQ scores.32 A weaker association with seizure disorders has been reported.9 These outcomes are limited to exposure during 8–25 weeks postconception, with particular sensitivity from 8 to 15 weeks. The regenerative capacity of remaining neurons and exclusion by embryonic death during Weeks 0–7, and radioresistance from Weeks 26 to 40, is thought to account for the observed lack of effect during these periods. Limitations of the studies include crude outcomes measures such as a clinically defined mental retardation, the limited number of individuals exposed to high doses of irradiation, and reliance on a single study, the Japanese atomic bomb study. Factors such as maternal illness due to radiation exposure and higher rates of consanguinity and changes in physical environment closer to the epicenter have the potential to confound or bias the results, respectively. However, the observed severity and association with critical periods of susceptibility suggest a genuine effect. Contention surrounds the nature and dose relationship of neurobehavioral response to ionizing radiation. In Wistar rats, exposure to 0.2 Gy midgestation 1188

does not lead to behavioral differences compared with controls.21 However, a delay in acquisition of 1 reflex at 0.2 Gy has been noted.20 While many authors argue that it is not possible to determine if the effects of radiation on neurological/behavior outcome are stochastic or deterministic, based on epidemiological studies, Brent3 argued that a stochastic phenomenon is biologically implausible, given the lack of histological changes compared with brains in control animals with low-level exposure and the lack of any neurological/behavioral sequelae in animal exposure in utero midgestation below 0.2 Gy. Contention surrounds the issue of increased postnatal incidence of malignancy after in utero radiation exposure. An increase in death due to childhood leukemia prompted a nationwide case-control study of deaths due to leukemia and other cancers in childhood.11 The authors reported 2-fold greater rates of abdominal x-ray exposure in mothers of children with leukemia and solid cancer compared with controls. Further case-control studies have reported similar associations with in utero exposure to diagnostic radiation and risk of leukemia and solid cancer.48 Whether such an association of low-level intrauterine radiation exposure and childhood cancer reflects a causal relationship is still contested.3,48 Arguments in favor of low-level intrauterine radiation-induced oncogenesis include the following: consistency of the association of low-level in utero radiation exposure and childhood solid malignancy and leukemia across many case-control studies, a dose-response relationship with higher relative risks associated with increasing number of x-ray examinations, and a dose-response relationship with a reduction in risk noted for cohorts experiencing reduced fetal doses of irradiation per x-ray examination.1 Furthermore, lack of identification of potential confounding factors, exclusion of recall bias by studies examining medical case records, and similar findings in studies of twins, suggesting selection bias does not contribute to the findings (as twin pregnancies in these studies presumably underwent x-ray imaging to determine fetal position, rather than because of maternal illness that might predispose the child to malignancy), lend credence to this contention. Grounds for uncertainty in a causal relationship are raised by the following points: larger cohort studies not demonstrating an elevated risk with low-level intrauterine radiation exposure; poor corroboration from animal studies; lack of excess cases of cancer deaths in in utero–exposed atomic bomb survivors; lower risk of cancer in twin pregnancies with more frequent x-ray imaging; and suspicious elevation in risk of solid cancers in utero compared with postnatal exposure and perplexing similarity in risk of solid cancers and leukemia given the known difference in radiosensitivity of tissues.1 Whatever the uncertainty regarding oncogenic risk of low-level irradiation on the fetus, the predicted increase in risk is small in comparison with other risk factors, for example, being the sibling of a child with leukemia.3 As Brent3 highlighted, the increased leukemia risk associated with 0.02-Gy fetal exposure would be 1 in 2000 compared with 1 in 3000 for unexposed controls. Exposure after 3–4 weeks of gestation is associated with a doubling of childhood cancer risk with 25 mGy, which equates to J Neurosurg / Volume 116 / June 2012

A review of management of glioblastoma multiforme in pregnancy an excess absolute childhood cancer risk coefficient of 1 in 13,000 per milli-Gray of exposure.49 The typical fetal dose from a head CT scan is 0.001– 0.01 Gy.49 Mazonakis et al.26 estimated fetal doses following irradiation of a “brain tumor” in a phantom pregnancy model with a linear accelerator (Philips SL 75/5). For a cumulative isocenter dose of 65 Gy, the maximum fetal absorbed dose was 80.9 mGy (0.089 Gy) in a 24week gestation unshielded phantom. Haba et al.16 estimated fetal dose after tumor exposure of 54 Gy with Varian and Asea Brown Boveri linear accelerators. The fetal absorbed dose without abdominal shielding was 22 mGy (0.022 Gy) for the Varian unit and 490–590 mGy (0.49–0.59 Gy) for the Asea Brown Boveri unit. In summary, doubt regarding safe threshold doses for deleterious effects is reflected by the reluctance to publish explicitly safe doses and conflicting quoted dosages. Brent3 quoted 0.2 Gy as the threshold for deterministic effects such as congenital malformations, pregnancy loss, and retardation of growth and cognition. The international commission for radiation protection concluded that no deterministic effect of practical significance would occur below 0.1 Gy.2 Given the fetal doses quoted in the aforementioned studies, it is likely, with an appropriate linear accelerator and use of precautionary measures such as abdominal shielding, that radiotherapy could be administered without an elevation in risk of deterministic effects. At present, it is not possible to exclude an increase in the risk of childhood cancer. Assuming this is the case, the risk associated with some linear accelerators maybe double that background risk. Misperception of the risks of fetal ionizing radiation exposure could alter the management of pregnant patients with malignant gliomas. Typical fetal doses from CT head scans are below the NOAEL; however, MRI as a safer alternative renders this modality redundant in an elective setting. This should not discourage use in the context of an emergency. Radiotherapy should be considered after formal estimation of fetal absorbed dose and discussion with the family. Conveying uncertainty in current understanding of radiation-induced fetal toxicity is a challenging but critical facet in counseling patients.

Chemotherapy for Brain Tumors

Evidence on use of chemotherapy in pregnancy is limited, particularly with regard to primary brain neoplasms, and is based in large part on animal data. Most chemotherapeutic agents are generally smaller than 600 kD and can easily cross the placenta.33 Physiological changes including increased hepatic oxidation and renal clearance, as well as decreased serum levels of drug binding to albumin, complicate pharmacokinetic and pharmacodynamic relationships in pregnancy. This makes predictions of toxicity and efficacy difficult. In general, exposure during organogenesis can precipitate major malformations, spontaneous abortion, and intrauterine fetal death.4 Use of chemotherapy during the second and third trimesters can result in intrauterine growth retardation, low birth weight, premature delivery, and stillbirth. The CNS, J Neurosurg / Volume 116 / June 2012

hematological system, genitalia, and eyes remain susceptible to the effects of chemotherapy, with consequential neonatal myelosuppression, sterility, and neurobehavioral disorders.4 The pivotal trial by the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) demonstrated substantial survival benefits in patients treated with radiotherapy and concomitant and adjuvant temozolomide, compared with radiotherapy alone.41 No articles relating to use of temozolomide in pregnancy were found in a PubMed search. The use of carmustine (BiCNU)–containing Gliadel wafers in pregnancy has not been reported. However, given that studies suggest practically undetectable levels in the circulation, this would presumably have little effect on the conceptus.33 Given the lack of data, recommendations on the use of chemotherapy during pregnancy are difficult. Frank discussion regarding potential adverse outcome and uncertainty should take place with the patient in conjunction with an oncologist.

Timing of Surgery and Delivery in Pregnancy

No clear evidence exists on the exact timing of neurosurgical intervention in pregnant patients. Authors of case series have considered surgery and delivery in relation to severity of neurological symptoms and gestation. After reviewing the literature, Tewari et al.43 made the following recommendations. In stable patients presenting in the first or early second trimester, with no evidence of neurological deterioration, gestational advancement should be permitted to the early second trimester before neurosurgery and radiotherapy. Unstable patients with impending brain herniation require neurosurgery and should be forewarned of the risk of fetal loss. In patients in their late second trimester and third trimester, Tewari et al. recommend that surgery should be avoided because of the high risk of intracranial hemorrhage associated with increased maternal intravascular volume. Stable patients should be observed closely with gestational advancement to fetal maturity. In patients with progressive neurological deficit, radiotherapy may be considered. For patients who are clinically unstable with a risk of brain herniation, delivery of the child by cesarean section under general anesthesia with subsequent neurosurgical decompression during the same anesthetic was recommended. A vaginal delivery is possible but should be reserved for those patients who are stable. A short second stage of labor is important, given the increase in ICP with bearing down efforts.43 Lynch et al.24 advised operative intervention for all cases of malignant glioma regardless of gestation period to maximize tumor resection at presentation. Given the increased risk of miscarriage associated with surgery in the first trimester and the suggestion in the literature of an increase in risk of birth defects (although not significant), we suggest that surgery should be delayed when possible until the early second trimester. 5 Most obstetricians and neonatologists would defer delivery when possible to 32 weeks of gestation to ensure fetal maturity and survival. 1189

B. A. P. Jayasekera, A. D. Bacon, and P. C. Whitfield Postoperative Management of Pregnant Neurosurgical Patients

After craniotomy, attention should be paid to adequate analgesia, antiemesis, and thromboprophylaxis. Pain control is achieved through a combination of scalp infiltration with local anesthesia, opioids, and paracetamol. Given tramadol’s propensity to lower the seizure threshold, it should be used cautiously in neurosurgical patients. Sudheer et al.42 demonstrated better analgesia with use of a morphine patient-controlled analgesia pump compared with codeine or a tramadol patient-controlled analgesia pump, without adverse respiratory effects, excessive sedation, or vomiting. Promethazine is the most studied antiemetic in pregnancy and is safe. Metoclopramide and antihistamines such as cyclizine are also safe in pregnancy as antiemetics. In younger women, however, there is a risk of extrapyramidal side effects and oculogyric crises. Ondansetron also appears to be effective, and there have been no reports of teratogenicity.19 Pregnant patients are hypercoagulable, especially following an operation. Venous thromboembolism is the most frequent cause of direct maternal death.8 Nonpharmacological thromboprophylactic measure should always be instituted. Timing of pharmacological thromboprophylaxis should be discussed with the neurosurgical team, given the attendant risks of intracranial hemorrhage.

Specific Anesthetic Considerations in Pregnant Patients Undergoing Neurosurgery

Anesthesiology in pregnancy must take into account that any change in maternal physiology will have an impact on uteroplacental perfusion and fetal gas exchange. In addition, the anesthetist must be cognizant of the myriad of physiological changes in pregnancy. Close liaison between the obstetrician and neuroanesthetist is required. Most agents used for induction and maintenance of general anesthesia are not known to be teratogenic. General considerations for anesthesia in pregnant patients undergoing nonobstetric operations have already been covered in several review articles.31,46 During labor, blood pressure and ICP may increase during contractions. First-stage contractions can increase ICP by 31 cm H2O, and second-stage contractions can increase ICP by 71 cm H2O in patients with no intracranial masses.25 Pregnant patients with intracranial neoplasms may experience greater increases in ICP. Such increases in ICP and blood pressure may be ameliorated to some extent by adequate analgesia, in addition to suppressing maternal hyperventilation and improving oxygenation.10 Epidural blocks are consistent in providing good analgesia; however, in a patient with an intracranial mass and increased ICP, dural puncture could prove catastrophic. Therefore, epidural administration is best performed by an experienced anesthetist. A short second stage of labor is advised with expedition by assisted delivery if necessary. An ideal agent for induction of anesthesia in neurosurgical patients would avoid any precipitous change in ICP, blood pressure, or cerebral blood flow.31 Anesthetic 1190

agent–induced hypotension or an increase in blood pressure and ICP with laryngoscopy is undesirable. A rapid sequence induction is preferred in pregnant patients from early in the second trimester onward to limit the risk of aspiration. Thiopental is commonly used in pregnant patients for a rapid sequence induction due to the high incidence of difficult intubation. Both propofol and thiopental have favorable effects in terms of preservation of cerebral autoregulation and reduction in cerebral metabolic rate and ICP.31 However, Gin et al.12 demonstrated significantly smaller increases in systolic arterial pressure in response to laryngoscopy and intubation in propofol versus thiopental in patients undergoing cesarean section. Similarly, for maintenance of general anesthesia, isoflurane and sevoflurane are favored in obstetric anesthesia and neuroanesthesia, the latter for the reduction in cerebral metabolic rate that it produces and the minimal effect on ICP. General anesthesia may consist of induction with either propofol or thiopental plus a volatile anesthetic for maintenance or induction and maintenance with intravenous propofol.50 Gregory et al.15 reported low neurological adaptive capacity scores in mothers on a maintenance infusion of propofol at 2 hours, but this had completely abated by 24 hours. There should be sufficient left lateral tilt while the patient is on the operating table to avoid aortocaval compression. Noxious stimulation associated with operative and perioperative preparation of the patient for neurosurgery (for example, intubation, head pinning, and scalp incision) can elicit hypertensive responses. Consideration should be given to use of a short-acting opioid, such as remifentanil, as a bolus or infusion to limit such changes.10,42 Scalp infiltration with local anesthetics may similarly blunt such responses. Principles of fluid therapy are similar in pregnant and nonpregnant patients undergoing neurosurgery (that is, the avoidance of hypoosmolar dextrose-containing solutions with use of isotonic or marginally hypertonic solutions). Mannitol used in doses of 25–50 mg/kg has been used safely in pregnancy,10 although one should be cognizant of the potential deleterious effects on fetal lung maturation and urinary blood flow.31 Temporary correction of ICP with hyperventilation is still occasionally used. However, hyperventilation has the potential to impair fetal oxygenation by inducing uterine vasospasm and shifting the maternal oxyhemoglobin dissociation curve leftward. Wang and Paech50 suggested maintaining a PaCO2 between 25 and 30 mm Hg. Discussions should take place among the anesthetist, obstetrician, and neurosurgeon regarding transfer to the ICU, although in general this would be preferable for postoperative observation.

Use of Anticonvulsants

Epilepsy is a common feature of patients with brain tumors. First presentation with seizures is seen in 30%– 50% of patients.45,47 Electrical quiescence of the primary lesion suggests epileptogenesis in the adjacent cortex. Seizure incidence relates to tumor type and location. Primary brain tumors manifest with seizures more freJ Neurosurg / Volume 116 / June 2012

A review of management of glioblastoma multiforme in pregnancy quently than metastases. Cortical location is predictive of epilepsy, and frontal and temporal lobe tumors have the highest risk of epilepsy. Van Breemen et al.45 highlighted the difficulties in managing epilepsy in the context of brain tumors. These include the refractory nature of the seizures, adverse cognitive outcomes to the patient, and interactions between AEDs, chemotherapeutic agents, and corticosteroids. The choice of anticonvulsant in the context of brain tumors during pregnancy is difficult. Few studies have compared AED efficacy in patients with brain tumors, let alone in the context of pregnancy. Wick et al.52 examined seizure recurrence in 104 patients with low- and highgrade gliomas. Seizures recurred less frequently with valproate (44%) than lamotrigine (51%) or carbamazepine (70%). Optimal treatment may not differ from other causes of simple or complex partial seizures. However, drug interactions with chemotherapeutic agents and fetal toxicity need to be considered. Carbamazepine and valproate have a higher propensity to interact with chemotherapeutic agents and corticosteroids than lamotrigine. Villanueva et al.47 recommend the use of newer AEDs such as levetiracetam, gabapentin, and pregabalin as first-line agents, given their favorable pharmacokinetic characteristics, that is, they are not enzyme inducers or inhibitors. However, evidence on use in pregnancy is less extensive for these agents. Lamotrigine, oxcarbazepine, topiramate, and zonisamide do not influence, but are influenced by, chemotherapeutic agents. Altered metabolism during pregnancy should also be kept in mind with close monitoring of therapeutic levels of anticonvulsants. The choice of AED in women of childbearing age is very important. Deleterious effects to offspring, in the form of teratogenesis and poor perinatal and long-term cognitive outcomes, warrant consideration in pregnant patients with brain tumors. It is now well established that there is an increased risk of major congenital malformations in the babies of women with epilepsy who take AEDs.17,28,44 Polytherapy confers a greater risk than monotherapy. Sodium valproate confers the greatest risk and in particular increases the risk of neural tube defects. Carbamazepine, lamotrigine, and levetiracetam are associated with the lowest risk. Phenytoin, phenobarbitone, and topiramate also infer an increased risk.17,18,28,44 The risk of major congenital malformations is influenced not only by the type of AED but also by dose, which should be taken into account in the management of epilepsy in women of childbearing potential,44 and, therefore, limiting the dose of AEDs, if possible, is advised. There is now also evidence that AED use during pregnancy may increase the risk of cognitive impairment in the baby. Valproate exposure increases the risk of poor cognitive outcome, while phenytoin and phenobarbital likely also increase the risk.17 Carbamazepine is probably not associated with increased risk. Levetiracetam and lamotrigine have not been found to be associated with an increased risk of poor cognitive outcome.7,38 Again, polytherapy likely increases the risk compared with monotherapy. In their special report, Harden et al.17 reported a probJ Neurosurg / Volume 116 / June 2012

able increase in the risk of being small for gestational age in women taking AEDs and a possible risk of a 1-minute Apgar score of less than 7. They concluded that perinatal death was not likely increased with AEDs. Decisions regarding AEDs in pregnant patients with brain tumors should be multidisciplinary, involving oncologists and neurologists with an interest in epilepsy, and should factor in the use of chemotherapy and other medications. Lamotrigine, levetiracetam, and carbamazepine are the safest agents for the developing baby and should be used as first-line therapy, if possible. Moreover, polytherapy should be avoided if possible. Prophylaxis with anticonvulsants in patients with brain tumors has been suggested, given the high incidence of seizures. The Quality Standards Subcommittee of the American Academy of Neurology made the following point:13 the incidence and severity of anticonvulsant side effects are greater in the population of patients with brain tumors. Antiepileptic drugs can interact with corticosteroids and chemotherapeutic agents, reducing their efficacy. Conversely, corticosteroids and chemotherapeutic agents can alter the pharmacokinetics of AEDs, increasing the likelihood of over- and underdosing. Adverse effects are not offset by benefit in terms of seizure reduction. On this basis, the committee did not recommend routine use of anticonvulsant medication for prophylaxis in patients with brain tumors. In the context of pregnancy, one should also be cognizant of potential adverse fetal outcome. Evidence on the use of prophylactic AEDs in patients undergoing craniotomy is conflicting. In their meta-analyses, Sirven et al.39 found no benefit of AEDs in the 1st postoperative week with regard to seizure reduction. The aforementioned committee highlighted the lack of evidence in perioperative use of anticonvulsants. The quality of evidence available prompted the committee to limit its recommendation to the withdrawal of therapy after 1 week postprocedure. However, once commenced for seizures, AEDs should be continued, depending on life expectancy, frequent recurrence despite medication, and inadequate evidence regarding withdrawal of anticonvulsants in brain tumor patients.

Steroids in Pregnant Patients

Steroids are commonly used in patients with gliomas to reduce peritumoral edema. They also permit expedited delivery in preterm pregnant patients by promoting fetal lung maturation, reducing the risk of intraventricular hemorrhage, and decreasing mortality in preterm infants.30 A Cochrane review reported that in women at risk for preterm birth treated with a single course of corticosteroids, there was a significant reduction in neonatal death, respiratory distress syndrome, and intraventricular hemorrhage.34 The Royal College of Obstetricians and Gynaecologists’ green top guideline number 7 suggests offering a single course of antenatal corticosteroids in women at risk for spontaneous or iatrogenic preterm birth between 24 weeks and 34 weeks and 6 days.36 The guideline also advises administering antenatal corticosteroids in an elective cesarean section prior to 38 weeks 1191

B. A. P. Jayasekera, A. D. Bacon, and P. C. Whitfield and 6 days. The corticosteroids of choice are 2 doses of betamethasone 12 mg intramuscularly or 4 doses of dexamethasone 6 mg intramuscularly. While dexamethasone is commonly used for neurosurgical patients, observational data suggest that betamethasone may be preferable in reducing neonatal mortality.23 Evidence on repeated antenatal steroid administration and outcome in pregnant glioma patients is lacking. However, repeated antenatal steroid administration in nonneurosurgical pregnant patients is discouraged based on a body of evidence of adverse short- and long-term outcomes to the child. Animal studies have suggested that steroids cause decreased birth weight, decreased brain weight and myelination, and hypothalamopituitary adrenal axis suppression with repeated administration of antenatal corticosteroids.30 However, these findings have not been corroborated in human studies. There is evidence from randomized trials of reduced birth weight, length, and head circumference in infants delivered from mothers receiving multiple doses of antenatal corticosteroids compared with those receiving a single dose.29 These findings have not been consistently reproduced in other trials.23 However, Schatz et al.37 reported significantly higher frequencies of preterm birth and low birth weight in mothers treated with oral corticosteroids for asthma, even after adjusting for relevant covariables. In addition, long-term follow-up in one trial reported no difference in body size between repeated- and single-dose treatment arms.6 Studies on long-term neurodevelopmental outcome and possible hypothalamopituitary axis suppression are conflicting and incomplete.23 The Royal College of Obstetricians and Gynaecologists advises against a repeat course of antenatal corticosteroids for obstetric indications, unless the first course was administered prior to 26 weeks of gestation, in which case senior advice should be sought.36 Outcomes with steroid use in early pregnancy or preconception are less clear. Other adverse effects of steroids, including myopathy, osteoporosis, peptic ulceration, weight gain, increased risk of thromboembolism, glaucoma, skin changes, immunosuppression and exogenous Cushing’s syndrome are well described and covered in other reviews.22,51 All patients should be covered with pharmacological gastric protection. Clear communication of potential risks to mother and offspring, the uncertainty in current understanding, and poor outcome to mother and unborn child by avoidance of steroids should be made before commencing steroids for peritumoral edema. This should be done in conjunction with or following discussion with an obstetrician and neonatologist.

Conclusions

The literature on treatment of glioblastoma multiforme in pregnancy is limited to case reports and case series. Risks and benefits of treatment are largely extrapolated from animal studies, or epidemiological and observation studies of pregnant patients without glioblastoma multiforme. However, based on the discussion above, we make the following recommendations regarding the 1192

management of pregnant patients who present with a suspected glioblastoma. We emphasize that this advice represents Level 3 evidence, that is, expert opinion. Initial investigation of the stable patient should entail an MRI scan when facilities permit. In unstable patients for whom MRI facilities are not easily accessible, a head CT scan would not place the fetus at increased risk of deterministic effects (for example, in utero death, malformations, and retardation of growth and cognition), although patients must be counseled on the potentially increased risk of childhood cancer. In stable patients in their first trimester, delaying biopsy or debulking until the second trimester should be considered. For patients in their late second and third trimesters who are clinically stable, gestational advancement until fetal maturity should be considered when possible, with delivery prior to neurosurgical treatment. Stable patients who are at term can deliver prior to neurosurgery. Vaginal delivery with special attention to adequate pain relief and a shortened second stage can be attempted in selected cases. Steroids can be used to control peritumoral edema; however, the future parents must be forewarned of the risks reported in some studies of low birth weight and body size, highlighting the uncertainty regarding this in the literature. Anticonvulsants for seizure prophylaxis should not be routinely prescribed perioperatively. In patients who do suffer seizures, lamotrigine, levetiracetam, or carbamazepine would be appropriate first-line agents. The decision regarding the use of anticonvulsant medication should be made in conjunction with neurologists and oncologists, and factor in use of other potentially interactive medications and chemotherapeutic agents. Future parents should be counseled on the benefits and risks of radiotherapy. In communicating risks, the lack of data in pregnant women with glioblastoma should be clarified, along with the fact that current recommendations are based on animal studies and epidemiological studies. However, current evidence and recommendations would suggest that with suitable equipment the fetal-absorbed dose may be kept below the NOAEL for deterministic effects. There is uncertainty in the risk of childhood cancer and leukemia; however, in comparison with other risk factors for childhood cancer and leukemia, this would seem small. Consideration should be given to attempting calculation of the potential fetal-absorbed dose for the patient. There is limited evidence to make recommendations on the use of chemotherapeutic agents such as temozolomide in pregnancy. In patients with neurological deterioration, further radiological investigation should be considered, and the use of radiotherapy should be discussed, if necessary. At all gestational periods, unstable patients should undergo neurosurgery if clinically appropriate for the mother. In patients with a fetus at a viable age, a combined cesarean section followed by craniotomy should be considered. Decisions regarding management of the pregnant patient with glioblastoma should involve neurosurgeons, neurologists, oncologists, obstetricians, and anesthetists with experience in obstetrics and neurosurgery. The adJ Neurosurg / Volume 116 / June 2012

A review of management of glioblastoma multiforme in pregnancy vice of pediatricians and neonatologists should also be sought when delivery is considered. Each case should be coordinated in a multidisciplinary fashion with a teambased approach. Early involvement of palliative care teams may be beneficial. Counseling patients and conveying risks of therapy with the inherent uncertainty in the literature are challenging but critical in permitting patients to make informed decisions regarding their treatment. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: Jayasekera, Whitfield. Drafting the article: Jayasekera. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Jayasekera. Acknowledgments The authors would like to thank Dr. Jayne Adcock (consultant neurologist), Dr. Nicola Warner (consultant oncologist), Dr. Mhairi Speirs (consultant neuroanesthetist), and Dr. Rebecca Black (consultant obstetrician) for reviewing the relevant sections of the article and making suggestions based on their experience and knowledge. References 1. Boice JD Jr, Miller RW: Childhood and adult cancer after intrauterine exposure to ionizing radiation. Teratology 59:227– 233, 1999 2. Bondy ML, Scheurer ME, Malmer B, Barnholtz-Sloan JS, Davis FG, Il’yasova D, et al: Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium. Cancer 113 (7 Suppl):1953–1968, 2008 3. Brent RL: Saving lives and changing family histories: appropriate counseling of pregnant women and men and women of reproductive age, concerning the risk of diagnostic radiation exposures during and before pregnancy. Am J Obstet Gynecol 200:4–24, 2009 4. Cardonick E, Iacobucci A: Use of chemotherapy during human pregnancy. Lancet Oncol 5:283–291, 2004 5. Cohen-Kerem R, Railton C, Oren D, Lishner M, Koren G: Pregnancy outcome following non-obstetric surgical intervention. Am J Surg 190:467–473, 2005 6. Crowther CA, Doyle LW, Haslam RR, Hiller JE, Harding JE, Robinson JS: Outcomes at 2 years of age after repeat doses of antenatal corticosteroids. N Engl J Med 357:1179–1189, 2007 7. Cummings C, Stewart M, Stevenson M, Morrow J, Nelson J: Neurodevelopment of children exposed in utero to lamotrigine, sodium valproate and carbamazepine. Arch Dis Child 96: 643–647, 2011 8. Dresang LT, Fontaine P, Leeman L, King VJ: Venous thromboembolism during pregnancy. Am Fam Physician 77:1709– 1716, 2008 9. Dunn K, Yoshimaru H, Otake M, Annegers JF, Schull WJ: Prenatal exposure to ionizing radiation and subsequent development of seizures. Am J Epidemiol 131:114–123, 1990 10. Finfer SR: Management of labour and delivery in patients with intracranial neoplasms. Br J Anaesth 67:784–787, 1991 11. Giles D, Hewitt D, Stewart A, Webb J: Malignant disease in childhood and diagnostic irradiation in utero. Lancet 271: 447, 1956 12. Gin T, Gregory MA, Oh TE: The haemodynamic effects of


propofol and thiopentone for induction of caesarean section. Anaesth Intensive Care 18:175–179, 1990 13. Glantz MJ, Cole BF, Forsyth PA, Recht LD, Wen PY, Chamberlain MC, et al: Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Neurology 54:1886–1893, 2000 14. Goldstein L, Murphy DPL: Etiology of ill health in children born after maternal pelvic irradiation. II. Defective children born after post-conceptional maternal irradiation. AJR Am J Roentgenol 22:322–331, 1929 15. Gregory MA, Gin T, Yau G, Leung RK, Chan K, Oh TE: Propofol infusion anaesthesia for caesarean section. Can J Anaesth 37:514–520, 1990 16. Haba Y, Twyman N, Thomas SJ, Overton C, Dendy P, Burnet NG: Radiotherapy for glioma during pregnancy: fetal dose estimates, risk assessment and clinical management. Clin Oncol (R Coll Radiol) 16:210–214, 2004 17. Harden CL, Meador KJ, Pennell PB, Hauser WA, Gronseth GS, French JA, et al: Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal outcomes: Report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 50:1237–1246, 2009 18. Hunt S, Russell A, Smithson WH, Parsons L, Robertson I, Waddell R, et al: Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology 71:272–276, 2008 19. Jarvis S, Nelson-Piercy C: Management of nausea and vomiting in pregnancy. BMJ 342:d3606, 2011 20. Jensh RP, Brent RL: The effects of prenatal X irradiation on the appearance of reflexes and physiologic markers in the neonatal rat. Radiat Res 116:416–426, 1988 21. Jensh RP, Brent RL, Vogel WH: Studies concerning the effects of low level prenatal X-irradiation on postnatal growth and adult behaviour in the Wistar rat. Int J Radiat Biol Relat Stud Phys Chem Med 50:1069–1081, 1986 22. Kaal EC, Vecht CJ: The management of brain edema in brain tumors. Curr Opin Oncol 16:593–600, 2004 23. Lee BH, Stoll BJ, McDonald SA, Higgins RD: Adverse neonatal outcomes associated with antenatal dexamethasone versus antenatal betamethasone. Pediatrics 117:1503–1510, 2006 24. Lynch JC, Gouvêa F, Emmerich JC, Kokinovrachos G, Pereira C, Welling L, et al: Management strategy for brain tumour diagnosed during pregnancy. Br J Neurosurg 25:225–230, 2011 25. Marx GF, Zemaitis MT, Orkin LR: Cerebrospinal fluid pressures during labor and obstetrical anesthesia. Anesthesiology 22:348–354, 1961 26. Mazonakis M, Damilakis J, Theoharopoulos N, Varveris H, Gourtsoyiannis N: Brain radiotherapy during pregnancy: an analysis of conceptus dose using anthropomorphic phantoms. Br J Radiol 72:274–278, 1999 27. Miller RW: Discussion: severe mental retardation and cancer among atomic bomb survivors exposed in utero. Teratology 59:234–235, 1999 28. Morrow J, Russell A, Guthrie E, Parsons L, Robertson I, Waddell R, et al: Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 77:193–198, 2006 29. Murphy KE, Hannah ME, Willan AR, Hewson SA, Ohlsson A, Kelly EN, et al: Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial. Lancet 372:2143–2151, 2008 30. Newnham JP, Jobe AH: Should we be prescribing repeated courses of antenatal corticosteroids? Semin Fetal Neonatal Med 14:157–163, 2009

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B. A. P. Jayasekera, A. D. Bacon, and P. C. Whitfield 31. Ní Mhuireachtaigh R, O’Gorman DA: Anesthesia in pregnant patients for nonobstetric surgery. J Clin Anesth 18:60–66, 2006 32. Otake M, Schull WJ, Yoshimaru H: A review of forty-five years study of Hiroshima and Nagasaki atomic bomb survivors. Brain damage among the prenatally exposed. J Radiat Res (Tokyo) 32 (Suppl):249–264, 1991 33. Pentheroudakis G, Pavlidis N: Cancer and pregnancy: poena magna, not anymore. Eur J Cancer 42:126–140, 2006 34. Roberts D, Dalziel S: Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 3:CD004454, 2006 35. Roelvink NC, Kamphorst W, van Alphen HA, Rao BR: Pregnancy-related primary brain and spinal tumors. Arch Neurol 44:209–215, 1987 36. Royal College of Obstetricians and Gynaecologists: Greentop Guideline No. 7. October 2010. Antenatal Corticosteroids to Reduce Neonatal Morbidity and Mortality. (http:// www.rcog.org.uk/files/rcog-corp/GTG%207.pdf) [Accessed February 13, 2012] 37. Schatz M, Dombrowski MP, Wise R, Momirova V, Landon M, Mabie W, et al: The relationship of asthma medication use to perinatal outcomes. J Allergy Clin Immunol 113:1040– 1045, 2004 38. Shallcross R, Bromley RL, Irwin B, Bonnett LJ, Morrow J, Baker GA: Child development following in utero exposure: levetiracetam vs sodium valproate. Neurology 76:383–389, 2011 39. Sirven JI, Wingerchuk DM, Drazkowski JF, Lyons MK, Zimmerman RS: Seizure prophylaxis in patients with brain tumors: a meta-analysis. Mayo Clin Proc 79:1489–1494, 2004 40. Streffer C: [Radiation effects of exposure during prenatal development.] Radiologe 35:141–147, 1995 (Ger) 41. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al: Radiotherapy plus concomitant and adjuvant temozolamide for glioblastoma. N Engl J Med 352:987–996, 2005 42. Sudheer PS, Logan SW, Terblanche C, Ateleanu B, Hall JE: Comparison of the analgesic efficacy and respiratory effects of morphine, tramadol and codeine after craniotomy. Anaesthesia 62:555–560, 2007 43. Tewari KS, Cappuccini F, Asrat T, Flamm BL, Carpenter SE, Disaia PJ, et al: Obstetric emergencies precipitated by malig-

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nant brain tumors. Am J Obstet Gynecol 182:1215–1221, 2000 44. Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Sabers A, et al: Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol 10:609–617, 2011 45. van Breemen MS, Wilms EB, Vecht CJ: Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management. Lancet Neurol 6:421–430, 2007 46. Van De Velde M, De Buck F: Anesthesia for non-obstetric surgery in the pregnant patient. Minerva Anestesiol 73:235– 240, 2007 47. Villanueva V, Codina M, Elices E: Management of epilepsy in oncological patients. Neurologist 14 (6 Suppl 1):S44–S54, 2008 48. Wakeford R: Childhood leukaemia following medical diagnostic exposure to ionizing radiation in utero or after birth. Radiat Prot Dosimetry 132:166–174, 2008 49. Wall BF, Meara JR, Muirhead CR, Bury RF, Murray M: Protection of Pregnant Patients During Diagnostic Medical Exposures to Ionising Radiation. Chilton, UK: Health Protection Agency, 2009 (http://www.hpa.org.uk/webc/ HPAwebFile/HPAweb_C/1238230848746) [Accessed February 13, 2012] 50. Wang LP, Paech MJ: Neuroanesthesia for the pregnant woman. Anesth Analg 107:193–200, 2008 51. Wick W, Küker W: Brain edema in neurooncology: radiological assessment and management. Onkologie 27:261–266, 2004 52. Wick W, Menn O, Meisner C, Steinbach J, Hermisson M, Tatagiba M, et al: Pharmacotherapy of epileptic seizures in glioma patients: who, when, why and how long? Onkologie 28:391–396, 2005 Manuscript submitted November 28, 2011. Accepted February 8, 2012. Please include this information when citing this paper: published online March 9, 2012; DOI: 10.3171/2012.2.JNS112077. Address correspondence to: Bodiabaduge A. P. Jayasekera, M.R.C.S., Department of Neurosurgery, John Radcliffe Hospital, Oxford, United Kingdom OX3 9DU. email: ashanoncall@gmail. com.
