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REVIEW ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 1  |  Page : 5-18

Managing brain tumors in pregnancy: The oncologist's struggle with maternal-fetal conflict


1 Department of Radiotherapy, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Obstetrics and Gynecology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission12-Sep-2020
Date of Decision14-Oct-2021
Date of Acceptance15-Oct-2021
Date of Web Publication30-Mar-2022

Correspondence Address:
Shikha Goyal
Department of Radiotherapy, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1343_20

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 > Abstract 


The diagnosis of malignancy, particularly brain tumors, in pregnancy is uncommon but poses a complex dilemma for the management of both the patient and her fetus, as the interplay of disease with the physiological state of pregnancy affects both outcomes. The routine evaluations (symptomatology, imaging, and hormonal assessments) and treatments (surgery, radiation therapy, and chemotherapy) that are commonplace in brain tumor management may need to be omitted or modified keeping in mind the risk to offspring. Multidisciplinary care and extensive prenatal and perinatal counseling and monitoring are essential. In this review, we discuss the available data addressing these issues and factors which may affect considerations of therapeutic abortions, changes in surgical or medical practices, and outcomes thereof.

Keywords: Brain neoplasms, pregnancy, prenatal counseling, radiotherapy, teratogenesis


How to cite this article:
Goyal S, Yadav A, Madan R, Chitkara A, Singh R, Khosla D, Kumar N. Managing brain tumors in pregnancy: The oncologist's struggle with maternal-fetal conflict. J Can Res Ther 2022;18:5-18

How to cite this URL:
Goyal S, Yadav A, Madan R, Chitkara A, Singh R, Khosla D, Kumar N. Managing brain tumors in pregnancy: The oncologist's struggle with maternal-fetal conflict. J Can Res Ther [serial online] 2022 [cited 2022 May 26];18:5-18. Available from: https://www.cancerjournal.net/text.asp?2022/18/1/5/341134




 > Introduction Top


The association of brain tumors with pregnancy is fortunately uncommon. The first report of such an association was published in 1898.[1] The United States' Centre for Disease Control and Prevention and National Cancer Institute Database reported 31,988 central nervous system (CNS) tumors in women of reproductive age group (1999–2018, age 20–44 years, population of approximately 3 billion), with an age-adjusted incidence rate of 5.7 per lakh and an age-adjusted mortality rate of 3.6 per lakh.[2] Based on probability-based calculations, Simon estimated nearly 90 women per year in the United States with brain tumors during pregnancy.[3] According to GLOBOCAN 2020, the age-adjusted incidence and mortality rate estimates for 2020 for CNS tumors in Indian females in the same age group (3514 cases) stand at 1.3 per lakh and 1.0 per lakh, respectively, making CNS tumors the seventh most common cancer and fifth most common cause of mortality in this group.[4] No published Indian data or estimates on pregnancy in brain tumors exist. Many of these women may enter pregnancy undiagnosed, while some may have brain tumors detected as an incidental finding during the evaluation of infertility. Pregnancy does not seem to increase the incidence of brain tumors compared to the corresponding age-matched population, but the severity of symptoms such as seizures and growth rate measured on imaging may increase, especially in high-grade gliomas.[5] Despite its rarity, the said association poses a vexing problem to the treating team, especially in the context of curative management of the disease without compromising maternal and fetal outcomes.

The association of brain tumors with pregnancy may be two way. Patients may be diagnosed with an otherwise asymptomatic brain tumor during the evaluation of infertility. If the tumor is deemed aggressive or contributing to infertility, surgery before conception will resolve both issues. Others may become symptomatic with seizures, psychiatric issues, or focal neurologic deficits and may receive their diagnosis of de novo or recurrent brain tumor during any trimester of normal pregnancy. The second scenario is when a patient undergoing investigations or treatment for a brain tumor may conceive due to contraception failure. The latter situation merits stronger considerations of treatment modifications and even pregnancy termination in the event of incidental exposure to teratogenic effects of diagnostic or therapeutic radiation, drugs, or periods of hypoxia following conception but before confirmation of pregnancy. Exposure to chemotherapy during the first 2–3 weeks of pregnancy usually does not carry the risk of higher teratogenesis, but spontaneous abortions are common during this period.

This review addresses some of the concerns faced by physicians when managing a brain tumor in a pregnant patient, with a special focus on radiation oncology perspectives. The issue of pregnancy and its outcomes in cancer survivors is beyond the scope of this discussion.


 > Interaction of Pregnancy with Brain Tumor Activity Top


The brain tumors that are commonly seen in women in the reproductive age group may include benign tumors such as pituitary adenomas, schwannomas or meningiomas, or neoplasms such as gliomas (Grade 2–4), ependymomas and rarely, neuroepithelial tumors, chondrosarcomas, lymphomas, or intracranial metastases from systemic malignancies. According to the report of the Central Brain Tumor Registry of the United States based on 2014–2018 data, pituitary tumors are the most common brain tumors in age group 20–44 years followed by glial tumors and Grade 1 meningiomas; pituitary tumors, and Grade 1 meningiomas have a much higher incidence in females compared to males.[6] Since both pituitary and meningeal tumors are hormone-driven, their symptoms may become more apparent during pregnancy, leading to a higher probability of detection of pre-existing but previously asymptomatic lesions.

In their systematic review on gliomas and pregnancy, van Westrhenen et al. report on 337 gliomas during pregnancy – 120 were known previously and 217 newly diagnosed during pregnancy. The relative proportion of Grade 1, 2, 3, and 4 gliomas in their series comprised 4%, 65%, 8.6%, and 22.4%, respectively.[5]

Pregnancy may lead to worsening of neurologic symptoms such as seizures in patients with pre-existing gliomas, and these symptoms may precipitate obstetric emergencies. The increase in intracranial tension (ICT) may be related to increased vascularity of tumors such as gliomas due to hormonal changes. Hormonal changes during pregnancy may also aid growth of hormonally driven tumors such as gliomas, meningiomas, acoustic schwannomas, and brain metastases from breast cancer.[3] In addition, the immune changes in pregnancy may reduce antitumor immunity. A diagnosis of low-grade glioma during pregnancy does not adversely impact survival. However, there is a risk of tumor growth (clinical as well as on imaging), dedifferentiation, and recurrence in known glioma patients.[7]

Secretory pituitary tumors such as prolactinomas usually cause infertility, and their control is imperative before conception. Pregnancy itself is a state of hyperprolactinemia; hence disease control in this situation cannot be assessed based on prolactin levels. An increase in size of pituitary during pregnancy and involution after delivery has been reported.[8] Risk of symptomatic tumor enlargement is highest for women with previously untreated macrodenomas (18.1%), followed by macroadenomas treated before pregnancy with surgery or radiotherapy (RT) (4.7%) and microadenomas (2.5%).[9] Some patients with large tumors may experience their first visual symptoms such as field defects during pregnancy.[10]


 > Evaluation of New Central Nervous Symptoms During Pregnancy Top


Women with known epilepsy on antiepileptic drugs (AEDs) experience decrease in drug levels during pregnancy, which may return to normal in postpartum period. The physician and gynecologist should be mindful of this risk in a patient with planned pregnancy, and any seizure episode arising in this situation needs be evaluated for adequate drug levels of a safe AED. Women with no history of epilepsy experiencing their first seizure during pregnancy should be assessed with careful history to establish if the episode indeed was a seizure.[11] History of aura and possible seizure triggers such as stress and sleep deprivation should be sought. Other symptoms that prompt early investigation include severe localised headache with projectile vomiting (especially if arising in second or third trimester when hyperemesis gravidarum is uncommon), personality change, focal seizures with secondary generalization, especially in first trimester, negative symptoms including focal deficits such as unilateral motor or sensory loss, and visual field defects.

The woman should preferably be admitted for monitoring of self and fetus, and a meticulous workup is needed. The possible causes of seizure may vary depending on the duration of pregnancy. Metabolic alterations or poisoning in the first trimester, syncope in the second trimester, and preeclampsia or stroke in the third trimester may give rise to seizure-like presentations. AEDs should not be advised in the setting of a single seizure episode unless the diagnosis has been verified. A proper history should include medications, exposure to toxic agents, and risk of metabolic alterations. Examination should seek any concurrent focal neurologic deficits and mental state alterations. Investigations may include biochemistry including electrolytes and toxicology screen, electroencephalogram (EEG) or video EEG, brain magnetic resonance imaging (MRI) and lumbar puncture, as needed, based on clinical assessment. If metabolic abnormalities and eclampsia are ruled out, imaging would help identify any potential space-occupying lesion including abscess, tuberculoma, neurocysticercosis, bleed, or brain tumor. If indeed a diagnosis of a potential brain tumor is made, consultation with neurosurgeons and oncologists should be sought to decide the best course of management based on symptoms, deficits, extent and risk of progression of brain tumor depending on radiologic impression, and the gestational period.


 > Risk to Mother and Foetus with Diagnostic Imaging Top


Computed tomography (CT) scan of brain or head-and-neck region renders a fetal dose of 0.0001–0.001 centigray (cGy).[12] Although CT scan is not recommended for a patient with known pregnancy, considerations for termination of pregnancy may need to be made for an inadvertent CT exposure for evaluation of brain tumor. Intravenous (IV) contrast during CT or MRI of the brain adds considerably to the diagnostic yield. For the general population, iodinated contrast used in CT scanning carries the potential to cause nephrotoxicity and allergy-related side effects; however, it has not been shown to directly cause birth defects. Based on reports of rare instances of iodinated IV contrast causing hypothyroidism in the fetus, neonatal thyroid function testing during the 1st week of life is recommended when their mothers underwent such imaging during pregnancy.[13] MRI contrast is gadolinium based has a better side effect profile than CT contrast, carries a lower propensity to cause an allergic reaction, and has no nephrotoxic potential. Although MRI contrast can cross the placenta, no birth defects in the fetus have been reported.[14] Despite these reports, imaging still has a controversial role, and wherever possible, a noncontrast MRI is preferred, if omission of MRI contrast does not compromise a diagnostic study, to keep fetal risk at a minimum.

Technetium 99 m may occasionally be used for brain single-photon emission CT studies or during ventilation-perfusion in pregnant women with suspected venous thromboembolism. It has a short half-life of 6 hours and emits gamma rays only. Fetal exposure from a single study is under 0.5 cGy, which is considered safe during pregnancy. Iodine-131, on the other hand, has a long half-life of 8 days, readily crosses the placenta and may affect fetal thyroid if given after 10–12 weeks of gestation; its use is, therefore, contraindicated during pregnancy.[15]


 > Surgery/Anesthesia Top


Most brain tumors, especially large, high grade or aggressive tumors, would require surgical resection as the first treatment modality to take care of the mass effect and establish a histopathologic diagnosis to guide need for further treatment. Craniotomy, if necessary due to expected histology, symptoms, or mass effect, is not predicated by timing of gestation. No adverse outcomes related to surgery have been reported. There is a slightly higher risk of miscarriage in the first trimester, and patients with low-grade malignancies or benign diseases may be followed up for progression; if the patient is asymptomatic and stable, surgery may be postponed till delivery.[5],[16] Stable high-grade gliomas diagnosed during pregnancy may be operated at presentation, but attempts should be made to delay surgery and delivery till fetal maturity in the early third trimester. However, there is a risk to maternal life due to raised ICT. In presence of moderately controlled symptoms in a brain tumor diagnosed in first or second trimester where a long delay of surgical resection till fetal maturity seems improbable, surgery is safer to carry out in the second trimester with the continuation of pregnancy, due to vulnerability of fetus during first trimester and higher risk of intraoperative bleeding during third trimester.[8] Induction of labor may be considered as early as 34 weeks in asymptomatic patients followed by surgery for brain tumor.[17],[18]

In certain instances, surgery may be possible under local or regional anesthesia and IV sedation, without any increased risk of teratogenesis and lesser risk of maternal breathing complications. General anesthesia (GA) is also acceptable and considered safer than spinal or epidural anesthesia due to the risk of higher neurologic morbidity with a cerebrospinal fluid leak in the latter. Tracheal intubation allows the mother to hyperventilate, and this helps to control raised ICT.[19] Stereotactic biopsy under local anesthesia, to obtain a tissue diagnosis in lesions that are deep seated or in close contact with eloquent areas of the brain is a reasonable option. Involvement of maternal-fetal medicine service for the surgical procedure is recommended, with intraoperative fetal monitoring, especially after week 25 of gestation. Patient positioning may need modification, such as a sitting or lateral position instead of prone position, depending on tumor location as well as to maintain vena caval blood flow to reduce fetal risk. Intermittent but increased fetal monitoring may be necessary in the postoperative period as well. Pain management may involve avoidance of drugs with potential for fetal harm depending on the period of gestation; imaging, if necessary, should minimize the use of ionizing radiation and contrast agents.


 > Drug Therapy (Including Antiepileptics and Chemotherapy) Top


Corticosteroids are safe and recommended in pregnant patients with brain tumors to reduce intracranial edema and promote fetal lung maturity. Long-term steroid use, however, may induce adrenal insufficiency in the fetus, and hence judicious use is recommended. Mannitol is not advisable as it may lead to fetal dehydration.[20]

Propofol is considered safe during GA and has not shown any adverse effects on the fetus. Isoflurane, desflurane, and sevoflurane have shown fetal neurotoxic effects and are not recommended.[20],[21] Anesthesia for any procedure during pregnancy should be of shortest duration, safest dose, and with minimum interval between induction and start of resection to minimise exposure. Remifentanil, with its opioid properties and short duration of action, helps control intraoperative stress response and is the preferred agent for emergency cesarean section (CS) for patients with neurologic risk factors. Dexmedetomidine is another anesthetic considered safe in pregnancy.

Nearly 25%–30% of brain tumor patients may experience new seizures or increase in seizure frequency during pregnancy. Uncontrolled seizures and status epilepticus may threaten the maternal and fetal life, while AEDs may have a negative impact on the newborn.[7],[22],[23] AEDs are commonly used to treat patients with cortical brain tumors, but their use is somewhat controversial in pregnancy. Many AEDs such as phenytoin and valproic acid are known teratogens.[11] All AEDs cross placenta, and patients with epilepsy on AEDs during pregnancy show a slightly higher congenital malformation rate (4%–8%) than the general population (2%–3%). However, it is widely accepted that, in a patient presenting with seizures, the risk of harm from repeated seizures outweighs the potential side effects from AEDs including potential teratogenicity. They are not recommended for seizure prophylaxis in the absence of symptoms. A neurologist may help guide the choice of appropriate AEDs. Lamotrigine, levetiracetam, and carbamazepine monotherapy are safe and first choice among AEDs, while valproate causes developmental delay and is contraindicated.[5]

In prolactin-secreting pituitary tumors, drugs such as bromocriptine and dopamine analogs have acceptable safety profiles with no increase in the risk of spontaneous abortion, premature labor, multiple births, or congenital malformations and may also delay or obviate the need for surgical resection. They should, however, be used sparingly in breastfeeding mothers.[24] Octreotide is acceptable and safe in pregnant patients with acromegaly.

Glioma patients undergoing resection may benefit from local chemotherapy using carmustine-impregnated wafers with acceptable safety profile.[25] Vascular endothelial growth factor receptor inhibitors such as bevacizumab are generally not administered during pregnancy.

European Society of Medical Oncology clinical practice guidelines on systemic therapy in pregnancy recommend avoiding chemotherapy during the first trimester due to the high risk of congenital malformations of nearly 20% of patients.[16] Those with aggressive malignancies needing chemotherapy in the first trimester should consider termination of pregnancy. Most, but not all, chemotherapeutic agents may be safe to administer in subsequent trimesters, but need and risk, however miniscule, should be individually assessed for each situation. Vinblastine is safe even during first trimester, antimetabolites cytarabine and 5-fluorouracil are safe during second or third trimester, so are alkylating agents cyclophosphamide and dararbazine, anthracyclines doxorubicin and epirubicin, vinca alkaloids vinblastine, vincristine and vinorelbine, taxanes paclitaxel and docetaxel, and platinum agents cisplatin and carboplatin. Agents such as busulfan, idarubicin, daunorubicin, and oxaliplatin should be avoided.[26] Methotrexate should not be administered in any trimester, and carboplatin should be preferred over cisplatin due to lower risk of fetal adverse events. Considerations of dose modifications and allowances for change in pharmacokinetics of some cytotoxic agents during pregnancy should be made. If chemotherapy is administered during the third trimester, efforts should be made to ensure a 3-week gap between last chemotherapy and delivery to avoid delivery during the nadir period of blood counts. For this objective, chemotherapy should be avoided beyond week 33 to account for the possibility of preterm or spontaneous delivery at any point after week 34. If chemotherapy after this gestational period is desirable, weekly schedules (doxorubicin, epirubicin, and paclitaxel) may be safer due to lower hematological toxicity and shorter nadir duration.[27] Chemotherapy beyond first trimester may cause intrauterine growth retardation, low birth weight, premature birth, stillbirth, myocardial toxicity, impaired functional development, and myelosuppression.[28] There is no evidence of impairment in cognition, academic performance, or behavioral competence in children exposed to chemotherapy in utero.[29] Maggen et al. have elucidated on the transplacental passage of cytotoxic agents with highest concentrations with platinum compounds (>60%) and lowest with taxanes (2%). They recommend postnatal auditory test following cisplatin exposure and postnatal echocardiography following anthracycline exposure.[30]

A series of six patients with malignant gliomas who were unintentionally exposed to chemotherapy (procarbazine, lomustine, vincristine, and temozolomide) during the 1st month of pregnancy where drugs were discontinued immediately at diagnosis of pregnancy did not experience any fetal adverse events till a median follow-up of 25 months.[31] Case reports of fetal exposure to temozolomide (considered a category D drug for pregnancy) during the 1st month of gestation in a patient with glioblastoma did not compromise fetal outcome, with normal neonatal development till 6 months of follow up.[32],[33] Another report described favorable maternal and child outcomes in a lady diagnosed in the second trimester with glioblastoma and treated with surgery, adjuvant RT (6000 cGy) and concurrent temozolomide.[34] After a planned CS at 36+5 weeks, adjuvant temozolomide was given for 6 cycles (delay of 3 months between adjuvant RT and adjuvant temozolomide). Some authors have used the approach of close follow-up and resurgery in favorable category glioblastoma initially detected at 20 weeks of gestation and managed with surgery alone, although this approach cannot be generalized.[35] All these anecdotal reports indicate that the risk of fetal harm and maternal gain with chemotherapeutic agents in high-grade gliomas need to be considered on a case-by-case basis in a multidisciplinary board factoring disease type, extent, symptomatic and quality of life impact, performance status of mother, period of gestation at diagnosis, and available treatment options. If curative intent treatment can be offered, surgery and cranial RT with appropriate precautions can be considered more easily than systemic therapy in any trimester. No definite recommendations can be made, and it appears best to avoid alkylating agents such as temozolomide and antiangiogenic agents such as bevacizumab during any trimester of pregnancy as well as during lactation. For those who may have taken the drug inadvertently before detection of pregnancy in the first trimester, perhaps termination of pregnancy may not be justifiable without discussing the pros and cons with the patient and family.


 > Radiation Therapy Top


RT, especially if given in the first trimester, with fetal doses of 10–20 cGy may potentially produce deterministic effects such as fetal death, mental retardation, congenital defects, and growth retardation.[36],[37] Radiation dose of 100 cGy is associated with up to 40% risk of several mental retardation. The risk of deterministic effects is lower in subsequent trimesters. Data from atomic bomb survivors by Otake and Miller suggest that exposure during week 3–11 to doses of 20 cGy or above may result in skeletal, genital, and other malformations. Exposure between weeks 8–15 to doses as low as 10 cGy may result in reduced intelligence quotient, while microcephaly results from exposure to high doses exceeding 2000 cGy in the same period. For mental retardation, exposure may range from 6 cGy to >50 cGy during weeks 8–15 or 25–28 cGy between weeks 16–25.[38],[39] The stochastic effect of developing childhood malignancy or sterility is possible at all absorbed dose levels. Whenever possible, RT should be postponed to the postpartum period unless there is an urgent clinical need. When fetal dose estimates exceed 10 cGy especially in 1st trimester, it may be justifiable to terminate pregnancy.[40]

In indications where RT is considered imperative to disease control and maternal survival, appropriate measures may be taken to decrease effects on the fetus such as dose reduction, alteration in patient position during treatment, pretreatment simulations of exposure using anthropometric phantom studies, lead screens near neck below field edge, lead shield over abdomen, treatment plan modifications to minimize fetal exposure to acceptable doses below 10 cGy and prevent unwanted side effects, as well as the measurement of actual dose delivered using thermoluminescent dosimeters (TLDs) at surrogate positions such as abdominal wall and symphysis pubis during treatment delivery.[41],[42] Leakage from machine head, scatter from collimator, and internal scatter from irradiated volume during treatment may contribute to fetal dose. An Indian report on three dimensional conformal RT (3DCRT) using 4 fields and 6 megavolt (MV) photons in a pregnant patient with pituitary adenoma used TLD measurements to assess the contribution to fetal dose from head relative leakage (52%), wedge scatter (31%), collimator scatter (14%), and internal scatter (13%). Multileaf collimator use decreased peripheral dose by 10%.[43] The various factors which determine the fetal exposure include beam energy, use of beam modifying devices such as wedges, field size, distance of fetus from field isocenter (distance decreases with advancing gestational age), and the use of abdominal shielding.

Cobalt machine and linear accelerators with photon energies over 10 MV should be avoided, use of beam modifying devices minimized, 3DCRT preferred over intensity-modulated radiation therapy (IMRT), and shielding with borated polyethylene in addition to lead should be added to reduce peripheral dose from neutrons.[44],[45] Dosimetric modeling plan for the same target in a patient with Grade 3 glioma showed maximum fetal dose estimates with Tomotherapy and minimum with 3DCRT. IMRT with flattening filter contributed more dose than a similar plan with flattening filter free beam.[46] Stereotactic radiosurgery (SRS) with due quality assurance is considered safe with negligible fetal radiation exposure.

RT delivery during pregnancy requires meticulous considerations of all alternative options before proceeding. A special high-risk informed consent is mandatory, and should include discussion on anticipated fetal dose from planned RT, comparison with background natural radiation exposure, inability to distinguish radiation-induced anomalies from those caused by natural causes, rate of natural occurrence of abnormalities and change in this rate with radiation, reports on recommendations for or against therapeutic abortion in specific situations; this should be signed by patient as well as a credible witness after affirming that they have understood the imparted information clearly. It is important to document the indication of treatment, risk of fetal harm with RT, along with fetal dose estimates measured in phantom as well as in patient during actual treatment delivery.[44]

For high-grade gliomas, adjuvant RT improves survival and should not be delayed. If malignancy is diagnosed in the early first trimester, option of therapeutic abortion should be considered to enable the entire treatment course including RT and chemotherapy. Else, adjuvant RT (starting within 4 weeks of surgery) can be offered in any trimester with all measures noted above to minimize fetal dose.

[Table 1] cites studies with fetal dose estimates from therapeutic radiation in pregnant women.[42],[43],[44],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55]
Table 1: Fetal dose measurements for various indications for brain tumors planned for radiotherapy during pregnancy[42],[43],[44],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55]

Click here to view


[Table 2] lists the available clinical outcomes (maternal and fetal) for patients who received RT for brain tumors during pregnancy.[7],[48],[49],[51],[53],[56],[57],[58],[59],[60],[61],[62]
Table 2: Available clinical outcomes (maternal and fetal) for patients who received radiotherapy for brain tumors during pregnancy[7],[48],[49],[51],[53],[56],[57],[58],[59],[60],[61],[62]

Click here to view


Data from [Table 1] and [Table 2] show that brain tumors may be given appropriate curative doses while maintaining fetal exposure under 10 cGy, respecting the deterministic threshold for fetal adverse effects.

A registry of cancer in pregnancy was started by The International Network on Cancer, Infertility, and Pregnancy in 2005, and nearly 2000 patients have been registered till date. A 20-year report of 1170 patients from 16 participating countries showed only 2% patients with brain tumors in the cohort. Among brain tumors, 11% of pregnancy terminations and 11% of maternal deaths were reported. Nearly 47% had live births after 37 weeks, while 32% had life births earlier. Surgery was performed in 48%, while RT and chemotherapy each in 5% of patients. In the entire cohort of pregnant patients with malignancy, most malignancies were diagnosed in the second trimester. Over the period of study stratified every 5 years, the use of antenatal treatment, especially chemotherapy increased, the pregnancy outcomes of live births increased, and iatrogenic preterm deliveries decreased. Platinum-based chemotherapy was associated most commonly with small for gestational age babies, and taxane chemotherapy with neonatal intensive care unit admissions.[63]


 > Recommendations for Specific Tumor Types Top


Pituitary tumors

Although women with known pituitary tumors are less likely to conceive spontaneously due to hormonal imbalances, pregnancy may still post a challenge in management after spontaneous or assisted conception. The European Society of Endocrinology, in their guidelines, recommends that multidisciplinary team should discuss possibility and problems with pregnancy in large or functioning adenomas in preconception phase itself, and any preexisting hypopituitarism should be corrected before pregnancy.[64] Patients with prolactinomas or acromegaly can be continued on the lowest possible doses of cabergoline before pregnancy and the drug discontinued during pregnancy unless there is symptomatic progression. Patients with active Cushing's disease should, on the other hand, be discouraged from considering pregnancy, with due explanation of risks to both mother and infant. During pregnancy, regular endocrinology follow-up should include hormonal profile, neuro-ophthalmology examination and MRI if symptomatic for progression or apoplexy, education on adrenal crisis and its management, consideration of surgery for symptomatic disease preferably in the second trimester if medical management is ineffective or not feasible. RT can usually be avoided or delayed till the completion of pregnancy. Disease status can be reassessed after delivery and breastfeeding is usually not contraindicated.

Meningioma

Pre-existing indolent meningiomas may become symptomatic and diagnosed for the first time during pregnancy. Most tumors in this age group are low grade and may be followed up till completion of pregnancy without affecting maternal outcomes, but large tumors with risk of herniation, pressure effects over optic apparatus, or symptoms such as persistent seizures or loss of consciousness, may need consideration for early surgery, preferably during late second trimester.[65] Steroids in perioperative period may help reduce edema. Fetal monitoring with ultrasound and cardiotocography is recommended. It is usually possible to postpone RT (irrespective of grade if surgical debulking has been done) till after delivery, else it may be planned with due precautions and risk discussion, as noted earlier.

Gliomas

Clinical course of women with known low-grade gliomas is usually unaffected by pregnancy, though symptoms may be more apparent in nearly a third of them.[66] Women with asymptomatic or minimally symptomatic low gliomas may be followed up with serial plain MRI to observe the rate of progression, with possibly delay of all interventions till after fetal maturity and delivery, without compromising the survival of the mother.[67] Decisions of high-grade gliomas have to be individualized. In those diagnosed within first trimester, a weighted decision to terminate pregnancy after discussion with family may have to be taken so that delay of treatment does not compromise maternal health. If termination is not agreed upon, surgical management may be carried out preferably in the second trimester. Adjuvant RT may be offered with appropriate technique and fetal shielding. Recommendations on chemotherapy are less well defined as most effective agents such as temozolomide and procarbazine are alkylating agents with a potential of long-term harm, and chemotherapy should be delayed as long as feasible, especially if there is no or minimal postoperative residual. In nonglial tumors where platinum and taxane-based drugs are effective, they may be offered as discussed previously in the section on drug therapy.

Brain metastases

Brain metastases perhaps represent the most concerning tumor type in pregnancy. Interruption of effective therapy for known malignancy during pregnancy may trigger tumor growth and dissemination and lead to a higher risk of brain metastases. The most common primary sites include breast, skin, and lung as reported in a neurosurgical review.[68] Management decisions would be guided by the symptoms, volume of intracranial as well as extracranial disease, performance status of mother, prognosis of malignancy based on type and extent, period of gestation, and fetal health. It is usually not advisable or possible to postpone specific management. Surgical interventions such as resection of solitary or limited volume intracranial disease or ventriculoperitoneal shunt for hydrocephalus may be needed at any time but carry lesser risk of fetal loss if carried out in the second or early third trimester. AEDs and steroids may be needed in the presence of seizures and raised ICT. Case reports of whole-brain RT or SRS have demonstrated successful fetal outcomes, while abdominal RT should be avoided to reduce risk of fetal loss. Systemic therapies such as hormone therapy (tamoxifen, aromatase inhibitors) are contraindicated due to the high risk of fetal malformations, while no data exist on CDK4/6 inhibitors.[26] Some chemotherapeutic agents may be safe to deliver usually in the second or third trimester, as detailed earlier. Specifically, brain metastases from gestational trophoblastic neoplasia carry a good prognosis after excluding early deaths related to disease volume with 5-year maternal survival exceeding 80%.[69] Standard chemotherapy with the omission of methotrexate and if possible, delay or omission of whole-brain RT yields good maternal and fetal outcomes with no increased risk of fetal loss or malformations.


 > Prenatal counseling Top


Treatment of cancers during pregnancy poses many management and ethical dilemmas. Evidence-based guidelines are elusive due to the rarity of pregnancy-associated cancers and ethical challenges in planning prospective trials for studying management outcomes in this group. A conflict of interest may exist between the mother and child since the recommended treatment type and timeline for mother's disease may put the fetus at risk. Treatments need to strike a balance between the impact of timing and aggressiveness of treatment on maternal health and survival, and the risk of fetal effects such as congenital developmental anomalies, miscarriage, stillbirth, and growth retardation. There are no specific recommendations in the setting of maternal cancer and risks from unintentional or potential fetal exposure to teratogenic chemotherapeutic agents or RT, and the available data is sporadic and limited to case reports and short series reporting fetal and maternal outcomes. Patients in whom unintentional exposure to chemotherapy or RT has happened in first trimester but disease category mandates early or immediate therapy should be counseled to strongly consider termination of pregnancy. Those desirous of continuing pregnancy need to be made aware of the maternal and fetal risks. During the second trimester, fetal risks are lower but treatment decisions may need to be individualised. Chances of preterm labor, intrauterine growth restriction, and stillbirth still remain. Besides treatment, the malignancy itself may alter the course and outcome of pregnancy. Seizures may increase the possibility of maternal and fetal hypoxia, while psychiatric, personality and neurologic changes may affect self-care and maternal/fetal nutrition. Patients with rapidly progressive malignancies in early pregnancy may warrant lesser considerations of the impact of therapy on fetal outcome.[28]

Patients and families should be informed regarding available data and associated uncertainties, and their autonomy and decision should be respected. The Centre for Disease Control and Prevention has published data on the effect of various doses of RT to fetus at various gestational periods and stages of development. These data may help guide the physicians to counsel patients regarding possible effects on the fetus, prenatal testing, and possible need of termination of pregnancy if exposures exceed acceptable levels.[70] Multidisciplinary approach should include a psychologist, psychiatrist, and geneticist in addition to routine health-care providers (oncologist, obstetrician, pediatrician, pathologist, radiologist, nursing, endocrinologist, and anesthesiologist). Counseling should also guide on the possibility of future fertility in the background of individual disease prognosis and any available fertility preservation options. The common options of embryo or oocyte preservation, and gonadotropin-releasing hormones during chemotherapy to preserve ovarian function have not been tested in brain tumors, but decisions may be individualized based on disease site, histology, prognosis, and proposed treatment.[16]

For patients with known gliomas desirous of pregnancy, pre-pregnancy counseling should address the possibility of tumor growth, dedifferentiation and recurrence, need for AEDs and neuroimaging during pregnancy, and need to postpone pregnancy till completion of all adjuvant therapy. Patients with aggressive, untreated, or residual gliomas awaiting or on therapy, clinical deterioration, uncontrolled seizures or gliomas with unfavourable molecular profile should be counselled against pregnancy due to grave risk to maternal health. For those considering in vitro fertilization, hormonal stimulation is not recommended.[5]

In summary, the following issues for discussion have been recommended by Del Pup et al.[28]:

  • Oncologic: Type and timing of treatment, prognosis of mother, need for surveillance and effects of treatment on mother
  • Obstetric: Effects of treatment on fetus, risk of metastases to placenta and fetus, need for fetal surveillance during pregnancy, risk of preterm delivery and associated morbidity and mortality, need for corticosteroids for fetal lung maturation, timing, and modality of delivery considered safe
  • Ethical, psychosocial, and medicolegal: Patient's fears and desires, termination of pregnancy, risk to mother, fetal viability, and future pregnancies.



 > Prenatal Genetic Testing Top


All pregnant patients, irrespective of fetal risk, are recommended to undergo prenatal screening tests in the first and second trimester (ultrasound, blood tests) to detect for neural tube defects, some structural abnormalities, trisomy 18 or trisomy 21. Noninvasive prenatal testing (NIPT) is a recent tool that can test for fetal defects at 10 weeks and beyond. However, NIPT for fetal aneuploidy screening is not recommended for women with confirmed malignancy due to doubtful accuracy in this situation.[71]

In suspected fetal genetic disorders, karyotyping and chromosomal microarray analysis on chorionic villus sampling (late first trimester) or amniocentesis (second trimester) may be diagnostic, albeit only in 10% of cases. Newer techniques of whole-genome sequencing or whole exome sequencing may improve diagnostic yield, though yet to be standardized.[72],[73]


 > Obstetric Management Top


Epidural anesthesia and CS have been recommended over normal delivery to keep ICT risk low, though evidence is inconclusive and opinions variable.[5] There is no evidence to suggest any difference in maternal or neonatal outcomes between the two modes of delivery. Individual risks of pregnancy on tumor and benefits of fetal maturity decide the timing of delivery. Term delivery (>37 weeks) is preferred since subtle cognitive impairment has been seen in preterm children exposed to chemotherapy, unless this delay endangers maternal or fetal health.[16] Ideally, it should not be attempted before weeks 34–36 in stable patients. An earlier CS under GA may be needed for patients with high ICT and viable fetus. Some surgeons have successfully conducted CS and tumor resection in the same GA setting, especially in case of obstetric emergencies.[17],[74]


 > Postdelivery Monitoring and Care Top


Following delivery, the patient should be treated on the same lines as a nonpregnant patient, and breastfeeding, contraceptive and AED modification should be discussed.[56],[75] Some brain tumors expressing progesterone receptors may cause dilemmas regarding breastfeeding. A meta-analysis of 27 studies found longer duration of breastfeeding decreased future meningioma risk while increasing glioma risk.[76] Patients would often require periodic neuroimaging during the postpartum period when they are breastfeeding. Lactating women needing CT with iodinated contrast are usually recommended to discontinue breastfeeding for 24 hours, although risk of harm to the infant is minuscule.[13] Within 24 hours following contrast MRI, <0.04% of gadolinium is excreted into breast milk; of this, the infant absorbs under 1% from its gastrointestinal tract. There are no documented reports of harm to neonate or infant from gadolinium and hence it is not recommended to interrupt breastfeeding for contrast MRI.[77]

Need for counseling or monitoring extends through pregnancy to beyond treatment completion or any fetal outcome, to follow long-term impact on mother (disease and symptom control, mental health, future pregnancies) as well as offspring (structural and neurocognitive development, second cancers, fertility).


 > Conclusion Top


The association of brain tumors with pregnancy poses a vexing problem for the managing team since no clear management guidelines exist; the situation is complicated by various ethical and medical dilemmas. Available literature is limited to small retrospective series only. Multidisciplinary plan formulation and individualized management with detailed counselling of patient and family at all steps is necessary. Only large centres equipped to comprehensively manage all obstetric, neonatal, and oncologic aspects of therapy should undertake this task. Formulation of central registries may help better collection and interpretation of data for guiding future approaches.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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