Anaplastic astrocytoma during pregnancy: the importance of an effective multidisciplinary approach

Abstract

A 34-year-old pregnant woman at 28 gestational weeks was diagnosed with a brain tumor after experiencing a generalised seizure. After completion of antenatal fetal lung maturation, she underwent an osteoplastic craniotomy parietal on the left side and a microsurgical partial tumor resection under general anaesthesia. With a histology of a diffuse astrocytoma and the postoperative stable amount of residual tumor on follow-up imaging, the pregnancy proceeded until 37 gestational weeks. A healthy baby boy was delivered by elective caesarean section. An awake craniotomy for removal of the residual tumor was planned two weeks later, followed by adjuvant treatment (combined radio-/chemotherapy). A multidisciplinary approach, combined with appropriate timing and a transparent and empathic communication, was able to create the most effective tailored management and optimise maternal and neonatal outcomes.

Background

The incidence of primary malignant brain tumours during pregnancy is 2.6–15.0 per 100.000,¹ and their progression may be explained by hormonal changes and increased levels of growth factors as well as angiogenic factors during pregnancy.²

Astrocytoma during pregnancy is an extremely rare event that represents a concrete diagnostic and therapeutic challenge in both neurosurgery and obstetrics. Due to the low incidence of these brain tumours during pregnancy, the management of these patients, the decision-making process and the clinical outcome are still poorly defined, and many questions remain unanswered by previous literature findings.

Case presentation

A 34-year-old woman, gravida 3, para 2 at 27+5 weeks of pregnancy, was transferred from a peripheral hospital with a newly diagnosed brain tumour after having a generalised seizure.

The patient herself was oligosymptomatic: in the weeks before the seizure, she reported slight amnesic aphasia, what she attributed to the general tiredness she had already experienced during the other two pregnancies.

A normal blood count including normal thrombocytes, normal liver and kidney enzymes, the absence of proteinuria and oedema excluded eclampsia as one of the potential causes of seizure during pregnancy. MRI revealed a T2-hyperintense mass of maximum of 5 cm in size on the left parietal side, compatible with a brain tumour (figure 1). There were no previous findings proving the safety of the administration of contrast medium in pregnant women; hence, this was not performed.

Figure 1.

Preoperative non-contrast-enhanced MRI head scan representing the hyperintense tumor mass of maximum of 5 cm in size on the left parietal side. (A) Coronal T2-weighted image, (B) axial T2-weighted image and (C) sagittal fluid-attenuated inversion recovery image.

The medical team organised a round table among obstetricians, neurosurgeons, anaesthetists, neonatologists and midwives to plan the surgery, the preoperative and postoperative management, as well as an action plan for emergency situations.

First, the antenatal fetal lung maturation with betamethasone was performed without tocolysis due to a normal cervical length of 35 mm. The neurosurgeons started a daily antiepileptic therapy with levetiracetam 500 mg two times per day and proposed the indication for a timely tumour resection under general anaesthesia. In consultation with the clinical pharmacists, the pregnant patient received preoperative administration of 5-aminolevulenic acid (5-ALA). The psychosomatic team supported the patient throughout the whole process.

Treatment

The patient underwent an osteoplastic craniotomy parietal on the left side and a microsurgical tumour resection. The operation was performed with neuronavigation and fluorescence-guided surgery (FGS) using 5-ALA. Four hours preoperatively, the patient received an oral 5-ALA solution in a weight-adapted dosing (20 mg/kg bodyweight), and the prophylactic tocolysis with Tractocile was started, first with an intravenous bolus of 6.75 mg and then with a maintenance dose of 8 mL/hour for 24 hours.

One hour before the operation, a cardiotocography (CTG) confirmed the fetal health status and the absence of contractions. The antiepileptic therapy with levetiracetam was continued on the day of surgery, and no sedative medication was given prior to the induction. Before the induction of anaesthesia, an arterial blood sample confirmed physiological respiratory alkalosis with renal compensation: pCO₂ 3.02 kPa (5.0–5.5 kPa), with a pH of 7.53 (7.38–7.42) and HCO₃ of 19.6 (21–26 mmol/L).

The patient was placed on the operating table in the lateral right decubitus position with a roll under the abdomen in order to minimise the risk for inferior vena cava compression.

The head was fixed in the Mayfield head clamp; the neuronavigation was referenced; and standard monitoring (ECG, pulseoxymetry and oscillometric blood pressure measurement) was started.

Monitoring was completed with invasive blood pressure measurement and processed electroencephalogram (Bispectral Index).

Rapid sequence induction and intubation was performed with propofol (target controlled infusion (TCI)), fentanyl (2 µg/kg) and succinylcholine (1 mg/kg).

Anaesthesia was maintained with TCI of propofol (Schnider model, effect site concentration) and remifentanil (Minto model, effect site concentration). Blood pressure was maintained with an infusion of norepinephrine at 2–5 µg/min. Dexamethasone (8 mg) and ondansetron (4 mg) were given as prophylaxis of postoperative nausea and vomiting, while cefuroxime (3 mg) was given as an antibiotic shield.

The parietal glioma was approached through a tumor-centred craniotomy, and superficial tumour parts were removed. Because the patient was under general anaesthesia, the resection was terminated before diving into the critical language areas.

The patient remained stable while under anaesthesia with steady blood pressure without phases of hypotension.

The patient was extubated immediately following termination of surgery and was transferred to the surgical intensive care unit, and a CTG was repeated without any abnormalities.

Outcome and follow-up

Postoperatively, the patient reacted well without any neurological deficit. The physiotherapy team started mobilisation on the first postoperative day. An MRI scan 1 day postoperatively without contrast medium administration revealed persisting tumour parts at the posterior edge of the resection cavity and at the anteroinferior aspect (figure 2).

Figure 2.

Postoperative non-contrast-enhanced MRI scan showing residual tumour at the cranial and caudal borders of the resection cavity after the first surgery (red circles). (A) Axial T2-weighted image; (B) axial T2-weighted image, cranial plane; (C) axial T2-weighted image, caudal plane.

The patient was transferred to the prenatal department on her second postoperative day, and the antiepileptic therapy with levetiracetam 500 mg two times per day was continued until delivery.

She received iron infusion (500 mg inravenously) on the third postoperative day due to haemoglobin of 102 g/L. She was discharged in good general condition after 1 week.

The histopathology report revealed a diffuse anaplastic astrocytoma with isocitrate dehydrogenase (IDH) mutation.

Due to the residual tumour parts reaching to critical language and motor areas, there was an indication for a re-resection performed with an awake craniotomy, with the aim of removing the tumour as comprehensively as possible under preservation of neurological function.

An MRI without contrast medium was performed 1 month after the operation. Due to stable residual tumour proportions and favourable histological prognostic markers, it was decided during a second round table to continue the pregnancy. At 37+6 weeks of pregnancy, a healthy eutrophic baby boy (3070 g) was delivered by elective caesarean section (C-section) with normal Apgar, pH and an uncomplicated neonatal adaptation. Two days after the C-section, an MRI with gadolinium was performed, showing only very faint contrast enhancement in one small tumour part. Two weeks after the C-section, an awake craniotomy for resection of residual tumour was performed. The tumour resection was conducted under continuous neuropsychological testing of speech and right-sided motor function and with the use of electrophysiology for cortical and subcortical motor stimulation and mapping. Small amounts of tumour were left behind due to positive function mapping in these areas. Postoperatively, the patient was treated with combined radiotherapy and chemotherapy with temozolomide for a duration of 6 weeks. She was able to breast feed until the start of the adjuvant therapy.

At the latest neurological exam, 4 months after the second tumour resection, she was under maintenance therapy with temozolomide. She was in a slightly reduced general condition due to a mild postoperative motor aphasia and structural epilepsy under daily treatment with levetiracetam 3 g and lacosamide 200 mg.

Discussion

Although no increased risk of glioma development during pregnancy has been stated so far, an increase in tumour progression, onset of symptoms as seizures and change in histopathological grade during pregnancy have been reported.¹

Specifically, an increased tumour growth and dedifferentiation of low-grade glioma (LGG) during pregnancy have been observed.³

There is no evidence that overall survival in LGG is affected by pregnancy,⁴ but hormonal changes and increases in the levels of growth factors as well as angiogenic factors during pregnancy could probably explain the progression of brain tumours during pregnancy.²

Due to the increased tumour growth rate, seizures are a frequent symptom in pregnant patients with brain tumours, but during pregnancy, eclampsia might be presumed first. Eclampsia is more common during pregnancy but it is normally accompanied by hypertension and proteinuria, or abnormal blood account, hyperreflexia and oedema, which are usually absent in patients with brain tumours.⁵

The generalised seizure was crucial for the underlying diagnosis of the tumour but also for the decision to operate on the patient in the shortest time possible to avoid other attacks that could have increased maternal and fetal morbidity and mortality. The increase in blood pressure, oxygenation and electrolyte changes during a seizure are harmful to the fetus. Seizure-related traumas, spontaneous miscarriages and intrauterine deaths are possible fatal events. Teramo et al showed in CTG follow-ups that during term pregnancy, generalised tonic–clonic seizures lead to temporary fetal asphyxia. Fetal bradycardia, decelerations and a decrease in variability may be observed for 15 min following a seizure.⁶

Furthermore, other indications for surgery were the mass effect, unclear histology and amnesic aphasia. It was decided to perform the operation under general anaesthesia to remove the superficial tumour mass, aware that a second operation would be necessary under awake conditions afterwards.

Surgery took place once the patient completed the fetal pulmonary maturation to increase the probability of survival of the fetus in case of premature birth.

An anticonvulsant therapy was started directly after the diagnosis to decrease the probability of new seizures. Among anticonvulsants, levetiracetam was chosen because of its low teratogenic risk.¹

The FGS using 5-ALA permits the intraoperative visualisation of malignant glioma tissue and discrimination from normal brain and supports the neurosurgeon to reach a complete resection of the contrast-enhancing tumour. Some studies show a potential risk for the fetus if 5-ALA has been given together with irradiation in the first trimester.⁷

To this date, there is no evidence of a possible teratogenic effect of 5-ALA in the third trimester.^8–10

The use of gadolinium-based contrast enhancement increases the specificity of MRI, and ahead of a brain tumour surgery it can alter the surgical strategy. However, its administration during pregnancy is controversial. Gadolinium is a water-soluble substance and can cross the placenta into the fetal circulation and amniotic fluid. Since free gadolinium is toxic, a possible dissociation from the chelation agent could be harmful or even fatal for the fetus. Animal studies revealed that intravenous gadolinium is teratogenic when used in high and repeated doses. However, this teratogenic effect was not recorded in a small number of human studies where gadolinium was administered during pregnancy. Due to the lack of complete safety data, it is still not recommended to use gadolinium during pregnancy unless there is an essential clinical indication.¹¹

We discussed this issue with the patient, but she decided against it. Regarding the mode of delivery, no benefits of caesarean section over vaginal delivery have been reported in stable women at term after brain surgery.^{1 12}

The decision whether to proceed with vaginal delivery or C-section is influenced by the tumour burden, parity and patient’s condition.^{12 13}

C-section under general anaesthesia has to be encouraged in cases of increased intracranial pressure at the time of delivery.¹³

Our patient already had two previous vaginal deliveries. However, after a thorough individual discussion with her, she opted for an elective C-section to avoid further psychological stress.

Histology did show diffuse IDH mutant astrocytoma classified between WHO grade II and III. The tumour exhibits methylation of the O-6 methylguanine DNA methyltransferase (MGMT) promotor and no complete deletion of cyclin-dependent kinase inhibitor 2a/b (CDKN2a/b). IDH mutation, MGMT methylation and no complete deletion of CDKN2a/b locus are positive prognostic and IDH mutation and MGMT methylation positive predictive molecular markers. The median overall survival of diffuse IDH mutant astrocytomas is around 10 years.¹⁴

Patient’s perspective.

Receiving a cancer diagnosis is difficult for anyone. From the beginning, my priority was the safety of my baby. From the earliest stages of the process, I wanted to discuss all the choices with all possible risks for me and the fetus. The most difficult moment was to say goodbye to my two kids and my husband before the first surgery; I was aware of the risks I was facing and I did not know whether I would still be the same after the operation. In this journey, there were many desperate and hopeless moments, and the care of the psychosomatic support group helped me to carry on. In addition, having the same team of neurosurgeons, anaesthetists and gynaecologists at my side throughout the whole experience created a relationship of complete trust. I am not wondering why this is happening to me, but I have the desire that the description of this experience of mine can help in the diagnosis and treatment of other women in the same situation.

Learning points.

• A multidisciplinary approach helps obstetricians and neurosurgeons in the challenge of preserving both the life of the mother and the fetus without losing the opportunity to act timely to start the therapy and, at the same time, to avoid fetal problems due to prematurity.

• Good timing and a transparent and empathic communication with patients are two other very important factors in all-round patient care to achieve an effective tailored management.

• The use of gadolinium-based contrast enhancement during pregnancy is still controversial, and further research is needed to prove its safety.