CHAPTER 111 Brain Tumors during Pregnancy
In the past, the literature on brain tumors during pregnancy gave contradictory accounts of the relationship between pregnancy and the development or progression of such tumors. All types of nervous system tumors have been reported during pregnancy, but no single type is predominant.1 Many authors describe a relapsing pattern in tumors relative to pregnancy, menstruation, and menopausal status,2–7 and it has been suggested that steroid hormones may play a role in the development of brain tumors, in particular, meningiomas.7,8 However, literature reviews and population-based studies indicate that the incidence of brain tumors in pregnant women is lower than that in age-matched nonpregnant women.1,9–11
Neuroimaging in Pregnancy
As a general rule, imaging studies other than ultrasound should be avoided in pregnant women unless there is a clear indication. However, the well-being and safety of the mother should not be jeopardized because of concerns over radiation. Computed tomography (CT) of the head is relatively benign in pregnant women because the radiation exposure to the fetus is less than 0.005 mGy.12 It has been estimated that the radiation emanating from a CT scan to a fetus that is 30 cm or more from the scanner results in a dose 2 orders of magnitude below the maximal permissible dose of 0.5 mSv.13,14 Hence, the radiation resulting from CT of the mother’s head presents little risk to the fetus.14,15 Magnetic resonance imaging (MRI), which does not use ionizing radiation, is considered relatively harmless to the fetus.16,17 However, MRI is recommended only after 4 months of gestation.18 From a practical standpoint, we therefore tend to avoid follow-up MRI during the first trimester, whereas initial diagnostic MRI studies, when indicated by a new onset of symptoms suggesting an intracranial neoplasm, are regularly performed. Obtaining a timely diagnosis that can appropriately guide the medical management of the rest of the pregnancy clearly outweighs the small risks associated with the procedures.
Unfortunately, the accuracy of MRI and CT relies on intravenous contrast agents, which have as of yet unknown effects on fetal development. Neither iodine- nor gadolinium-based intravenous contrast agents have been shown to be entirely safe in pregnancy.19 Although specific teratogenic effects have yet to be identified or reported in humans, these agents, as a general rule, should be used only when absolutely necessary and only after careful evaluation of the risk-to-benefit ratio.20
Neuroanesthesia in Pregnancy
Anesthesia for Pregnant Women Requiring Craniotomy
The multiple drugs required during craniotomy can increase the risk for developmental abnormalities if administered during the first trimester. In later trimesters, drug-induced abnormalities are less likely. Surgery during pregnancy often increases the risk for a first- or second-trimester spontaneous abortion, but it does not seem to increase the incidence of congenital abnormalities,21 nor does surgery appear to induce premature labor.22 Because of the physiologic changes that occur during pregnancy, issues such as surgical positioning and the dosage of drugs administered during anesthesia must be handled carefully. Pregnancy increases plasma volume and total blood volume with a dilutional anemia. Cardiac output is increased by 50%, and typically, anesthetic requirements are decreased by 30%.23 Because lung-closing capacity is increased, a supine patient is at an increased risk for atelectasis. Gastric motility is decreased, and the patient is at an increased risk for vomiting and aspiration on induction of anesthesia.24
Maintenance of normal uterine blood flow is important to avoid uterine hypoperfusion and fetal hypoxia.25 Monitoring the fetal heart rate by Doppler ultrasonography after the 16th week of gestation provides a fair indication of the adequacy of oxygen delivery to the fetus.25 Moreover, lowered uterine perfusion may lead to premature contractions.22 Thus, judicious use of vasoconstrictors such as phenylephrine or hyperventilation is recommended. A reduction in PaCO2 from 32 mm Hg, the normal level for pregnancy, to 25 mm Hg decreases uterine artery blood flow by 25%, but the effect may be caused by mechanical ventilation rather than simple changes in PaCO2.26
Precautions must be taken in positioning the patient to avoid mechanical compression of the vena cava by the uterus.27 The supine position, which increases both intrathoracic and intra-abdominal pressure, may decrease uterine blood flow, a condition called supine hypotension syndrome. In this case, a folded sheet can be placed under the right hip of the patient to minimize vena cava compression. Both the park bench and sitting positions have little harmful effect on uterine blood flow, although the latter allows better respiratory function.28 The prone position should be avoided. Therefore, even with a posterior fossa approach, the park bench position should be preferred over the prone position.
Controlled hypotension is necessary in certain instances. Several case reports of hypotension, produced by either isoflurane or nitroprusside, indicate that a mean arterial blood pressure of 40 to 50 mm Hg for up to 40 minutes does not result in injury to the fetus.29–31 In any event, this measure should be judiciously limited to the most challenging surgical situations that dictate it; otherwise, normotensive anesthetic support is encouraged.
Delivery in Patients with Cranial Lesions
The time of delivery is of prime significance to infant viability. In the past, delivery was postponed until after 36 to 38 weeks of pregnancy to decrease the likelihood of respiratory distress syndrome. Improvements in the use of surfactant have demonstrated that safe delivery at 32 weeks of pregnancy may be a reasonable option.32
The anesthetic plan for delivery is greatly affected by the intracranial pathology of the patient. If delivery and craniotomy are to be accomplished concurrently, the anesthetic management plan should be that required for a craniotomy. Rapid initiation of general anesthesia with intravenous agents, endotracheal intubation, and mild hyperventilation do not seem to have an adverse effect on the fetus. If delivery is to be accomplished before neurosurgical treatment, the presence of an intracranial lesion causing a mass effect requires a different strategy. Patients with such lesions who are ready to deliver are best anesthetized with general endotracheal anesthesia. The effect of active labor on the central nervous system of such patients is little understood, but it is unlikely to produce a positive effect. A cesarean section under general anesthesia is preferable because it is quick and safe and has minimal disadvantages to the fetus. Respiratory depression in the newborn, which is a potential problem associated with such delivery, is easily treated. Regional anesthesia should be avoided in patients with a demonstrated significant intracranial mass effect and possible shift because of the risk of loss of cerebrospinal fluid and the consequent potential risk of herniation through the foramen magnum. Regional anesthesia, specifically epidural anesthesia, is sufficient for lesions that do not exert a mass effect. In such instances, instrumented delivery should be encouraged. In general, we tend to discourage, unless rigorously dictated by a deteriorating clinical/neurological condition, craniotomies at the time of or shortly after the delivery because of the transient coagulopathy that is known to frequently develop during the immediate postpartum period.32a
Pituitary Brain Tumors
Conversely, pregnancy may affect the evolution of a pituitary adenoma (Fig. 111-1). Since the late 18th century, it has been noted that the pituitary gland enlarges during pregnancy as a physiologic consequence of gestation.33–36 This is due to an increase in the size and number of lactotroph cells.35,37,38 The increased levels of estrogens during pregnancy have been associated with hypertrophic and hyperplastic changes in lactotroph cells.37,38 This hypothesis is also supported by the observation that exogenous administration of estrogens induces enlargement of the pituitary gland in rats.39 MRI studies conducted in pregnant women have shown that the volume of the pituitary gland may increase by 45%40 at a growth rate of 0.08 mm/wk.41 Theoretically, the stimulatory effect of peripheral hormone surges during gestation could result in enlargement of a pituitary adenoma as well. Indeed, it has been reported that pituitary adenomas may grow more rapidly in pregnant women.42 As a result, tumors are at risk for hemorrhage because of enhanced pituitary vascularity and edema, in addition to estrogen-mediated pituitary hyperplasia.35 Studies show that tumor enlargement during pregnancy occurs more frequently with macroadenomas than with microadenomas—5% to 20% of cases versus 1% of cases, respectively—and that the effect is more pronounced in the second and third trimesters.42,43 A recent review of the literature also revealed that pregnancy exacerbated acromegaly in 4 of 24 patients (17%), with therapeutic abortion being necessary in 1 patient.44 Oral contraceptives have not been implicated in the development of prolactinomas.45,46
Although pregnancy may cause enlargement of an existing adenoma (directly or indirectly through enlargement of the gland), there is no evidence that it increases the incidence of adenomas per se. One study showed that among 69 women who died during pregnancy, after abortion, or during the postpartum period, 12% had noninvasive microadenomas, an incidence rate similar to that found in studies conducted on a general sampling of adult autopsies.36,47
In the clinical setting, endocrinopathy and local compression are symptomatic of pituitary tumors. Functional adenomas secrete excessive amounts of pituitary hormones and can frequently be diagnosed when they are small—less than 5 mm in diameter. Nonfunctional adenomas are larger at the time of diagnosis and can be discerned by their direct compression of surrounding structures. Compression of surrounding structures by pituitary tumors may lead to three major consequences: pituitary insufficiency, caused by compression of the pituitary gland; compromise of the hypothalamic-hypophysial axis, caused by compression of the pituitary stalk; or visual problems such as bitemporal hemianopia, caused by compression of the optic pathways. In addition, such tumors may cause oculomotor problems and sometimes stroke by compressing the cavernous sinuses and the neurovascular structures contained in them. Headaches are commonly associated with these tumors as well because the surrounding dura mater is stretched. Patients harboring microadenomas have been shown to have a significantly smaller risk for the development of visual loss than do patients affected by adenomas greater than 1.2 cm.48
Pituitary apoplexy is a rare event that can occur in a patient with a pituitary adenoma. It involves a sudden hemorrhage or ischemic or hemorrhagic infarction of the pituitary adenoma, which causes a rapid increase in intrasellar pressure. Common symptoms are sudden or violent headaches frequently accompanied by vomiting and rapid deterioration of vision or ocular motility. Emergency treatment with a decompressive surgical procedure is needed to avoid progression of the syndrome and potential death.49
Diagnosis
Imaging studies for evaluation of patients with pituitary tumors have improved significantly. Skull radiographs and polytomography, which identify indirect signs of pituitary tumors in the form of bony erosion of the sella turcica and clinoids, have been replaced by high-resolution CT and MRI. CT and MRI can usually outline even the smallest tumors and their effects on surrounding neurovascular structures.50–52 MRI is the preferred diagnostic procedure for pituitary adenomas because it allows visualization of the details of vascular structures, thereby virtually eliminating the need for an angiogram, and it offers the advantage of multiplanar views, which are essential for a complete evaluation. CT, however, provides detailed definition of the sella and surrounding bony structures. This information is of particular importance in the preoperative evaluation of the sphenoidal bones when transsphenoidal resection is being planned.
Preliminary hormonal evaluations to determine the functioning of the anterior and posterior pituitary involve the following measurements: urine volume; serum electrolytes and osmolarity; serum prolactin; early-morning cortisol level; serum gonadotropins; and thyroxine, triiodothyronine, and thyroid-stimulating hormone levels. If the clinical examination and laboratory testing reveal a specific endocrinopathy, more targeted tests should be conducted. For instance, urinary free cortisol, dexamethasone suppression tests, and adrenocorticotropic hormone levels help diagnose Cushing’s syndrome. Serum levels of antidiuretic hormone help diagnose diabetes insipidus. Growth hormone (GH), insulin-like growth factor-I levels, and glucose suppression tests help diagnose acromegaly53; however, such a diagnosis may be difficult to make during pregnancy because of placental secretion of GH. Thus, to diagnose acromegaly during pregnancy, one should measure GH levels by radioimmunoassay with monoclonal antibodies that recognize specific epitopes of pituitary and placental GH. Sometimes, loss of physiologic pulsatile secretion of pituitary GH helps determine the diagnosis.43,44 Insulin-like growth factor-I levels are less useful because they are elevated in normal as well as in acromegalic pregnancies.44,54
Treatment
Bromocriptine is highly effective in the treatment of hyperprolactinemic patients. Bromocriptine can significantly slow or even arrest the growth of a prolactin-secreting tumor and often results in restoration of normal endocrine function and a concurrent reduction in the size of the adenoma.55 As already indicated, patients with prolactinomas and the classic amenorrhea-galactorrhea syndrome who receive bromocriptine therapy may resume regular ovulatory cycles and eventually become pregnant. Hyperprolactinemia also occurs in 30% to 40% of acromegalic patients,56 and bromocriptine has been shown to be effective in restoring normal ovulatory cycles in these patients as well.57–60 Several reports have shown that bromocriptine is safe when administered through the first weeks of gestation in hyperprolactinemic patients.56,61–63 After 9 years’ follow-up of children of mothers treated with bromocriptine during the first weeks of pregnancy, teratogenicity rates were no higher than those expected in an untreated population.64 The only reported fetal malformation secondary to bromocriptine use is talipes, and it was the sole complication in 114 pregnancies in the study.65 In other studies, continuation of bromocriptine treatment throughout pregnancy resulted in uncomplicated deliveries of normal infants.58,59 Because bromocriptine crosses the placenta, it is recommended that women discontinue taking the drug while they are trying to conceive to minimize any possible effects on the developing fetus.44,66 Also, hypertension, stroke, and seizures have been reported in the puerperium after suppression of lactation with bromocriptine.67 In addition to bromocriptine, cabergoline has recently gained popularity in the treatment of prolactinomas in the general population; however, at this time, data on its side effect profile in pregnant patients are limited.
There are multiple reported cases of pregnancy after successful treatment of acromegaly with the somatostatin analogue octreotide.44,68,69 In all cases, treatment was discontinued within the first month of gestation, and in no instance did exposure to the drug cause adverse events in either the fetus or the mother.44,68,69 Of the 14 reports of pregnant patients treated with octreotide, no malformations were reported in their children.70 Nevertheless, until more safety data are available, use of this drug should be discontinued during pregnancy.44
The metabolic and cardiovascular complications of acromegaly require special consideration in the management of pregnant women affected by GH-secreting adenomas. In particular, GH antagonizes the action of insulin and results in carbohydrate intolerance or diabetes mellitus.71 Because pregnancy itself is an insulin-resistant state, pregnant patients harboring GH-secreting adenomas are at greater risk for hyperglycemia.44
Medical therapies available for the treatment of hyperfunctional pituitary adenomas are less effective for Cushing’s disease.72–74 Ketoconazole has been associated with intrauterine growth retardation in two cases.75,76 Aminoglutethimide and mitotane are contraindicated in pregnancy. In these cases, operative intervention appears to be the safer option.
To summarize, most pregnant women with pituitary adenomas can be safely observed with frequent ophthalmic evaluations and MRI. The safety of continuous bromocriptine or octreotide therapy has not been fully assessed, and women should be advised to discontinue such treatment after pregnancy is confirmed.43,44 This approach has been shown to be safe and carries only a small risk of tumor enlargement in cases of microprolactinomas and nonsecreting or GH-secreting adenomas. However, there is a greater than 15% risk of symptomatic enlargement of a macroprolactinoma during pregnancy, thus mandating close surveillance. Periodic assessment of visual fields every 3 months in women with microadenomas and every 6 weeks in those with macroadenomas has been recommended.44
