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, 11–14]. 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.
Clinical characteristics
Here, the three most common clinical symptoms of these patients were visual field defects (68.3%) [15–34], headaches (65.9%) [15, 16, 18–24, 26–36], and vision loss (48.8%) [17–23, 25, 26, 28, 29, 31, 32, 35, 37]. Previous studies showed that the two most common clinical symptoms of PA patients with apoplexy during pregnancy were headaches and visual impairment [18, 33], which is similar to our study.
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 confirmed 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 deficiency. 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, 40–42], 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 significant 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 deficiencies 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 field 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 [52–55]. 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 benefits, including maternal symptoms, fetal safety, and gestational weeks, which is the most critical indicator. The spontaneous abortion rate in the first 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 first 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, 35–37, 51–55]. Therefore, the second trimester is the best time for PA surgery [11–13, 57, 58].
For patients in the first 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 significantly, a cesarean section should be performed first. However, surgical treatment should then be performed promptly if symptoms progress significantly (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 sufficient to make a definitive 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 field, fundus, retinal nerve fiber 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-field defects, and severe degeneration of the retinal nerve fiber 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]. The endocrine examination can assess pituitary function, and, if necessary, relevant deficient hormones should be supplemented. Preoperative operations such as enemas that can induce contractions should be avoided. After evaluation, patients and their families should be fully informed of the risks and benefits of surgery. And written informed consent should be obtained after weighing the advantages and disadvantages and making a careful choice.
During the surgery
Inhaled anesthetics can reduce uterine tension, increase bleeding risk and cerebral perfusion pressure in a concentration-dependent manner [61]. Total intravenous anesthesia, which is preferred during pregnancy, does not affect uterine tension and can constrict the cerebrovascular system and maintain cerebral perfusion pressure [62]. FDA Class B drugs such as propofol are recommended. However, Class C drugs, which have potential risks but can be used given sufficient expected benefit, 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 insufficiency, and cerebral insufficiency. 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 significant 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.