Clinical Features and Surgical Management of Pituitary Adenoma During Pregnancy: Case Series and Literature Review


 Purpose

Although conservative treatment was recommended for pregnant patients with pituitary adenomas (PAs), surgical treatment is occasionally necessary for those with acute symptoms. However, surgical intervention among these patients is poorly studied.
Methods

Six patients with PAs who underwent surgical treatment during pregnancy at Peking Union Medical College Hospital between January 1990 and June 2021 and another 35 pregnant patients profiled in the literature were included.
Results

All the 41 enrolled patients (mean age 29.8 ± 5.3 years) had acute symptoms including visual field defects, severe headaches, or vision loss requiring emergency pituitary surgeries. Mean tumor diameter was 2.16 ± 0.9 cm, and 92.6% were macroadenomas. PA apoplexies were found in 23 patients. The average gestation time at surgery was 25.1 ± 7.1 weeks; 55.9% of these patients underwent surgery in the second trimester of pregnancy. Multidisciplinary team was involved from before surgery to after delivery. Except one patient underwent an induced abortion, and one fetus died due to a nuchal cord, thirty-nine patients delivered successfully, and 37 of fetuses were healthy till the last follow-up. One fetus died of congenital diaphragmatic hernia, and another had a low Apgar score after a cesarean section but survived.
Conclusion

PA surgery for pregnant patients with PAs is effective and safe during the second and third trimesters. Pregnant patients requiring emergency PA surgery need multidisciplinary evaluation and healthcare management. Cooperation of neurosurgery, endocrinology, obstetrics, anesthesiology, and neonatology is necessary for a successful surgical intervention for pregnant patients with PAs.


Introduction
Pituitary adenoma (PA) is the second most common primary brain tumor, accounting for 15-17% of brain tumors and a quarter of benign brain tumors [1]. Although PAs can occur at any age, those pregnant patients have unique characteristics. Pregnancy can cause the enlargement of pre-existing PAs which may compress the anterior pituitary gland contributing to some acute symptoms such as severe headache and visual defect, thus affecting maternal health and fetal development [2]. In addition, hormone-secreting PAs may also lead to high-hormone states such as ACTH and TSH hypersecretion resulting in poor prognoses [1,3].
During pregnancy, some PAs can be controlled by conservative treatment. For example, patients with prolactinomas can orally take dopamine agonists (DAs) [1,[4][5][6]. Although there is no evidence that somatostatin analogue (SSA) is safe for the fetus during pregnancy, SSA is effective in reducing tumor size, growth hormone (GH) and insulin-like growth factor 1 (IGF1) levels in acromegaly [7,8]. However, some pregnant patients with acute compression Enumeration data were expressed as percentages or ratios. Paired-sample t-tests were used for preoperative and postoperative comparisons. Statistical signi cance was set at P < 0.05.

Clinical characteristics
Forty-one patients with PAs who underwent surgery during pregnancy were included. A summary of their clinical characteristics was provided in Table 1, which included six cases from our center and 35 cases from the PubMed database. Except for three patients without an exact age, the age of the remaining 38 patients ranged from 21 to 41, with a mean age of 29.7 ± 5.3.  Figure 2. None of these patients had hypointensity on T1WI.
However, among two patients with decreased thyroid-stimulating hormone (TSH) levels postoperatively, the difference was not statistically signi cant (P = 0.308).

Perioperative conservative treatment
Perioperative conservative treatment for the 41 patients were shown in Table 2. Twenty-two patients did not receive conservative treatment. Seven patients were treated with bromocriptine alone, including six cases of prolactinoma and one case of nonfunctioning PA. One GH secreting PA was treated with cabergoline alone. Four patients (three cases of nonfunctioning PAs and one without pathological classi cation) were treated with a combination of dopamine agonist (DA) and glucocorticoid, and two patients were treated with glucocorticoid alone. One TSH secreting PA was treated with bromocriptine and propylthiouracil, and another such patient was treated with somatostatin. One nonfunctioning PA was treated with thyroxine and glucocorticoid. One ACTH secreting PA patient received alpha-methyldopa for hypertension, and one prolactinoma patient received 1-des amino-8-D-arginine

Discussion
During pregnancy, physicians may face many challenges when diagnosing and treating PAs. Although conservative treatment is recommended for some pregnant patients with PAs, such as prolactinoma, some patients may accept surgery due to visual defects, severe headaches, and high hormone secretion levels which cannot be alleviated after conservative treatment [7,[11][12][13][14]. We summarized the data of 41 patients with PAs who underwent surgery during pregnancy. To our knowledge, this is the most comprehensive report related to the surgery in pregnant patients with PAs.
The pituitary gland and pre-existing PAs may enlarge during pregnancy [2,38], and the risk is greater in patients with macroadenomas than in those with microadenomas [1]. This observation was con rmed here. In prolactinomas, the most common type of PAs, the risk of symptomatic tumor enlargement during pregnancy was 27.9% in patients with macroadenomas and only 2.2% in patients with microadenomas [39].

Conservative treatment during pregnancy
Conservative treatment during pregnancy mainly includes treatment of PAs and supplementation to hormone de ciency. DAs have been recommended for prolactinomas [1], and GH secreting PAs may be treated with SSAs [1,7]. Although there is no evidence that SSAs increase the risk of fetal malformation [6, [40][41][42], discontinuation of all medication except DAs during pregnancy is recommended to ensure fetal health to the maximum extent possible [7,8,43]. Resumption is recommended only when symptoms leading to poor prognoses such as visual defects or severe headaches occur. In some patients with prolactinomas, symptoms can be controlled by DAs; however, in cases without signi cant remission, clinicians should consider surgical treatment as soon as possible, following a multidisciplinary evaluation [8, 11,43]. Additionally, to ensure maternal health and fetal development, hormone de ciencies such as glucocorticoid or thyroxine should be supplemented in time [44].

Indications for surgery during pregnancy
Patients with macroadenomas have a higher risk of symptomatic progression during pregnancy [1]. However, the size of PA is not the criterion. The severity of visual defects and headaches should be used as surgical indications for PAs during pregnancy [11,12]. Some microadenomas are also associated with adverse effects on maternal and fetal health due to high hormone levels [45]. Based on our results, the surgical indications during pregnancy are summarized as follows: Visual defects PAs are more likely to compress the optic chiasm during pregnancy than outside of pregnancy, leading to visual defects [2]. When conservative treatment cannot relieve visual impairment, clinicians should conduct a multidisciplinary evaluation to balance visual defects with pregnancy safety and decide whether to treat surgically as soon as possible. Although the recovery rate of visual eld can be as high as 80% [46] or even 95.7% [47], the severity and duration of visual impairment are essential factors for postoperative visual prognosis, and irreversible adverse effects caused by severe visual impairment during pregnancy should be avoided [47].

Severe headache
Sudden, severe headache is the most common symptom of PAs with apoplexy, primarily due to the enlargement of PAs during pregnancy, increased pressure on the sella turcica, and dural pressure [44]. Headache is often accompanied by nausea, vomiting, eye muscle paralysis, and impairment of consciousness. Because severe headache can induce contractions, the surgery is indicated if the multidisciplinary evaluation considers that the headache is due to mass effect and that pain medication would affect fetal health [48].
Hormonal abnormalities ACTH secreting PAs and TSH secreting PAs can cause ovulation disorders in women of reproductive age [49]. This type of patient should be treated before pregnancy as early as possible. Nevertheless, a few patients have unintended pregnancies after diagnosis [36, 50,51] or are diagnosed during pregnancy [52][53][54][55]. High hormone secretion during pregnancy, such as ACTH and TSH hypersecretion, is closely related to several complications and poor prognoses [45,49]. Surgical treatment in appropriate timing is the most effective method for reducing hormone levels in such patients [11,16,43].
Operative timing during pregnancy The timing of transsphenoidal surgery depends on the potential risks and bene ts, including maternal symptoms, fetal safety, and gestational weeks, which is the most critical indicator. The spontaneous abortion rate in the rst trimester is approximately 12% versus only 5% in the second and third trimesters [12]. The overall malformation incidence in pregnancy is 2%, compared with 3.9% in the rst trimester, and the incidence of neural tube defects and preterm delivery is highest in the third trimester [56]. In our study, most patients also underwent surgery in the second trimester [16,18,19,23,24,27,29,33,[35][36][37][51][52][53][54][55]. Therefore, the second trimester is the best time for PA surgery [11-13, 57, 58].
For patients in the rst trimester, the surgery should be postponed to the second trimester to the extent possible [13,14]. For patients in the third trimester, considering that fetal survival can reach 90% after 27 weeks of gestation, Lynch et al. [59] recommended delaying surgery to 30 weeks of gestation if possible. In comparison, Priddy et al. [13] suggested that induced labor or cesarean section should be delayed until 34 weeks of gestation, if possible, followed by surgical treatment. However, among the 13 patients in this study who underwent surgeries in the third trimester, 12 patients and fetuses were healthy; one fetus survived with a low Apgar score, but the mother was healthy [17, 20-22, 25, 26, 31, 34]. In this regard, we suggest that the balance of symptom severity and gestational weeks should be considered in the third trimester, when glucocorticoids can be administered to promote fetal lung maturation. If symptoms do not worsen signi cantly, a cesarean section should be performed rst. However, surgical treatment should then be performed promptly if symptoms progress signi cantly (Fig. 3).

Precautions for surgery during pregnancy
Before the surgery A professional multidisciplinary team should be established to conduct individualized evaluations prior to surgery for pregnant patients with PAs indicated for surgical treatment. The team should include neurosurgeons, endocrinologists, obstetricians, gynecologists, pediatricians, and anesthesiologists [19,58]. MRI must be acquired before the surgery. Although fetal toxicity of gadolinium is not established, MRI without gadolinium enhancement is preferred and is su cient to make a de nitive diagnosis and plan the surgery. Given the teratogenicity of X-rays, computed tomography should be avoided [60].
Preoperative ophthalmic examination is also essential, including examinations of visual acuity, visual eld, fundus, retinal nerve ber layer, and optical coherence tomography of the ganglion cell complex [11]. The ophthalmic examination can roughly predict the postoperative recovery rates for visual impairment [47]. The possible visual sequelae include severe visual impairment, severe visual-eld defects, and severe degeneration of the retinal nerve ber layer/ganglion cell complex [11].
Preoperative fetal ultrasonography should be performed routinely to evaluate fetal health. Continuous fetal heart rate monitoring is feasible under the proper conditions [11]. FDA Class B drugs such as propofol are recommended. However, Class C drugs, which have potential risks but can be used given su cient expected bene t, should be carefully used after weighing the pros and cons [57].
Intraoperative reduction of cardiac return can lead to severe complications such as hypotension, placental insu ciency, and cerebral insu ciency. Therefore, surgeons should lower the left side of the patient below the right side to avoid compression of the inferior vena cava [11,12]. Although there is no optimal cerebral perfusion pressure target, it seems reasonable to control the mean arterial pressure 20% above the baseline [12]. During surgery, the use of diuretics and anticonvulsants should be avoided. If necessary, contractions should be suppressed to protect the fetus [11].
After the surgery Fetal heart rate variation is an essential indicator of fetal health and can indicate fetal distress; therefore, continuous fetal heart rate monitoring should be performed after the surgery [12]. If postoperative reactions such as nausea, vomiting, and headache occur, Class B drugs such as pethidine can be used for symptomatic treatment. Routine ophthalmic examinations should be conducted postoperatively to evaluate visual defect recovery. If no signi cant improvement is observed, differential diagnoses with other diseases leading to visual impairment, such as optic neuritis, should be considered [20]. Hormone stoss therapy, neurotrophic drugs, and other treatments can also be administered.

Conclusions
The surgical treatment and perioperative management of PAs during pregnancy is complex. And the surgical indications and timing issues must be well understood and carefully considered with the cooperation of neurosurgery, endocrinology, obstetrics, anesthesiology, neonatology, and other related specialties. In the second and third trimesters, transsphenoidal surgery is a safe and effective approach for emergency treatment during pregnancy after evaluation by a multi-disciplinary team. Additionally, for patients with irregular menstrual cycles, pituitary screening is necessary. Women of reproductive age who have been diagnosed with PAs should follow the advice of their endocrinologists and neurosurgeons before pregnancy.

Declarations Data availability
All data generated or analyzed here are included in this article or in public repositories.  Figure 1 Shown is a comparison of the preoperative and postoperative visual elds for Case 6. Preoperative visual eld examination shows bitemporal hemianopsia, which is more severe in the left eye. Three days after surgery, examination reveals a partial temporal visual eld defect in the left eye and a standard visual eld in the right eye Figure 2 Three typical images of PA apoplexy are shown. Sagittal T1WI shows isointensity and hyperintensity with a visible liquid level (Fig. 2a, Case 15) or mixed, mainly hyperintensity (Fig 2b, Case 40). Coronal T1WI of another PA apoplexy shows isointensity (Fig 2c,