Safe Dosing of Radiation Therapy for Brain Metastases During Pregnancy

In a general cancer patient population of male and female nonpregnant individuals, there is Level 1 evidence that surgery followed by WBRT is recommended as first-line treatment in all patients with single brain metastases with a favorable performance status and limited extracranial disease, as outlined in the 2019 guidelines put out by the Congress of Neurological Surgeons. ^{Reference Nahed, Alvarez-Breckenridge and Brastianos29} However, SRS to the tumor bed has recently been shown to have equivalent survival outcomes and just slightly inferior local control rates, and can thus be used as an effective alternative to WBRT (median survival of SRS = 12.2 months vs. WBRT = 11.6 months). ^{Reference McTyre, Johnson and Ruiz27} This may be an appealing treatment alternative in this setting to attenuate neurocognitive deficits associated with WBRT, especially poignant in young expectant mothers with well-controlled systemic disease. ^{Reference Brown, Ballman and Cerhan8} Modern shielding techniques can scatter radiation and shield the fetus from the adverse effects of WBRT, including mental retardation, organ malformations, and radiation-induced childhood malignancies. ^{Reference Greskovich and Macklis14,Reference Magne, Marcie, Pignol, Casagrande and Lagrange23,Reference Parsai, Nalk, Djemil and Chao37,Reference Yu, Jozsef, Apuzzo, MacPherson and Petrovich50}

Timing of Neurosurgical Intervention During Pregnancy

Of the 11 cases requiring neurosurgical intervention, only 1 case required emergent craniotomy to alleviate increased intracranial pressure due to tumor mass effect. Both the mother and her fetus survived the surgery and the fetus was subsequently delivered via cesarean section at 38 weeks GA. ^{Reference Wang, Cui, Yan, Jin and Hong49} Surgery should be delayed if possible until after the first trimester to minimize miscarriage risk, which can be as high as 10.5%. ^{Reference Cohen-Gadol, Friedman, Friedman, Tubbs, Munis and Meyer10,Reference Cohen-Kerem, Railton, Oren, Lishner and Koren11} However, it is generally considered to be safe during the second and third trimesters with recommended dosimetry guidelines for safety. ^{Reference Greskovich and Macklis14,Reference Paulsson, Braunstein and Phillips38,Reference Stovall, Blackwell and Cundiff42,Reference Yu, Jozsef, Apuzzo, MacPherson and Petrovich50}

To compare our study results to a larger patient population, we turned to a retrospective cohort study of pregnancy-related hospitalizations between 1998 and 2009 gathered from the Nationwide Inpatient Sample (NISQIP), a database of nonfederal US hospitalizations. Here, a recent study identified 19.75 million pregnancy-associated admissions, 397 associated with malignant brain tumors, including 165 associated deliveries (44%). ^{Reference Terry, Barker and Leffert45} Patients with malignant tumors had more pregnancy complications including preterm labor, intrauterine growth restriction, and stillbirths. The rate of craniotomies for malignant tumors was 31.4% although the study did not differentiate between primary or metastatic brain malignancies. This was much lower than the 50% rate of craniotomies from our systematic review, however, this may be due to a lower rate of metastatic brain tumors in the former study. There was also a higher rate of C-sections amongst pregnant women with malignant tumors compared to the normal population, similar to the 65% of cases that required C-sections in our systematic review.

Our systematic review also identified one patient who required VP shunting for hydrocephalus. ^{Reference Goutham, Kumar, Anil, Peter, Ravi and Chakravorthy13} A retrospective series of 77 pregnancies in 37 women with VP shunts showed that rates of shunt revisions were 10 times higher during pregnancy or the following 6 months ensuing likely due to raised intra-abdominal pressures causing distal shunt failure. ^{Reference Bradley, Liakos and McAllister7} This had led some neurosurgeons to consider ventriculoatrial (VA) shunts for pregnant women, but VA shunts carry significant risks of arrhythmias, infection, valvular dysfunction, and high morbidity associated with revisions. The neurosurgeon should, therefore, closely monitor the pregnant patient for signs and symptoms of shunt failure in the peripartum and postpartum periods. ^{Reference Tabouret, Chinot, Metellus, Tallet, Viens and Goncalves44}

Timing of Use of Antileptic Drugs During Pregnancy

Important to the neurosurgical management of patients with supratentorial tumors is the use of antiepileptic drugs (AEDs) to manage symptomatic lesions presenting with seizures. Older generation AEDs such as valproic acid and phenobarbital have been associated with increased rates of teratogenicity and congenital malformations (up to 9.3% and 5.5%, respectively) such as cardiac defects, cleft lip/palate, neural tube defects, and dysmorphic syndromes. ^{Reference Hernandez-Diaz, Smith and Shen16} However, newer agents such as lamotrigine and levetiracetam (currently, the most commonly used AED in neurosurgery) have improved safety profiles for use in pregnancy with much lower reported rates of congenital malformations between 0.7% and 2.4%. ^{Reference Hernandez-Diaz, Smith and Shen16,Reference Mawhinney, Craig and Morrow25} Doses of AEDs should be tapered to the minimally effective dose to achieve seizure control and used for the shortest period of time possible during pregnancy. ^{Reference Hernandez-Diaz, Smith and Shen16}

Surgical Considerations of the Pregnant Patient During Neurosurgical Procedures

Unique challenges exist during the positioning of the patient for non-obstetric surgeries during pregnancy. Prevention of positioning injuries to mother and fetus needs to be observed and the operating table should be centered and parallel to the longest wall in the room to minimize the need for relocation prior to the patient entering the operating room. ^{Reference Barnett, Bartalot, Nezhat, Nezhat, Kavic, Lanzafame, Lindsay and Polk4} When possible, the patient should be maintained in the left lateral recumbent position using a positioning wedge to avoid a flat supine position once transferred onto the operating table with attention to the application of non-constricting safety straps to not harm, yet prevent the patient from falling off the table. ² A uterine displacing wedge or chests rolls should be used to reduce pressure from the pregnant uterus on the vena cava and straps across the chest are discouraged to avoid restricting respiratory effectiveness. ^{Reference Carzo, Viveiro, Rothrock and McEwen9} Pressure points on the mother’s body should be well padded to prevent ulcers and peripheral neuropathies during surgery. Hypothermia should be carefully avoided (e.g. with the use of a warming blanket). Intraoperative electronic fetal monitoring past 26 weeks GA may be applied if the fetus is viable, if the monitor does not physically interfere with the procedure, if an obstetrician is available with prior consent obtained to perform an emergency C-section for fetal distress, and if the type of surgery is safe for the interruption to perform an emergency delivery if warranted. ^{Reference Barnett, Bartalot, Nezhat, Nezhat, Kavic, Lanzafame, Lindsay and Polk4,Reference Reitman and Flood40}

Anesthetic Considerations for the Pregnant Patient

Special anesthetic considerations are also required for non-obstetric procedures during pregnancy in order to avoid the complications of fetal loss, premature labor, and delivery. Cardiopulmonary changes in maternal physiology during pregnancy can lead to unintended general hypotension, difficult laryngeal intubation with potential airway edema, hypoxemia, and increased uterine irritability leading to preterm labor. ^{Reference Nejdlova and Johnson32} The mother should be informed regarding the low risk of teratogenicity associated with anesthetic agents and a neonatal team should be available and present should premature labor be anticipated. Regional anesthesia is preferred over general anesthesia where it is feasible to minimize drug exposure to the fetal and allow the mother to maintain her own airway, however, there is a lack of evidence supporting these claims in the form of randomized clinical trials.

In the case of neurosurgical procedures, general anesthesia can rarely be avoided. ^{Reference Ni Mhuireachtaigh and O’Gorman33} Maintenance of P_CO2 during the surgery can also be challenging as ventilation should be aimed to keep levels within the normal range of pregnancy, however, hyperventilation may be required to decrease central vasodilation as a means of lowering intracranial pressures during tumor resection. Extubation should be performed with a full anesthetic reversal and preferably in the lateral position to avoid aspiration. ^{Reference Sharma, Nguyen, Lozen and Mueller41}