Pituitary Apoplexy in Pregnancy: What do We Know?

Pituitary apoplexy refers to a rare clinical syndrome consisting of signs and symptoms that occur due to rapid expansion of the contents of the sella turcica . It can occur spontaneously or associated with pituitary tumors. It can have a broad clinical spectrum, but usually presents with severe headache, visual impairment and hypopituitarism. Sudden onset of symptoms associated to imagiologic confirmation makes the diagnosis. Surgical treatment is advised when there is important compression of the optic tract. We present a case report and a review of the literature on pituitary apoplexy in pregnancy. The cases were reviewed to obtain information on maternal characteristics, clinical presentation, diagnostic studies, therapeutic modalities and maternal and fetal outcomes. Our review found 36 cases of pituitary apoplexy in pregnancy. Most of the cases occurred in the second trimester of pregnancy and headache was the most frequent symptom at presentation. Surgical therapy was required in more than half of the patients. In what respect maternal and fetal outcomes, there were 3 cases of preterm delivery and one case of maternal death. Our clinical case and literature review reinforces the importance of an early diagnosis to avoid potential adverse consequences.

with conservative management and also to present a review of the literature on this subject.

Methods
We report a case of pituitary apoplexy during pregnancy and present a review of the published cases in the literature on this subject. To identify these cases, we performed a research using PubMed/MEDLINE, using the MeSH terms ''pituitary apoplexy" and ''pregnancy." We included all studies published until January 2021. Our search was limited to studies published as full-text articles in English or in Portuguese. All the articles without pituitary imaging were excluded. Written informed consent was obtained from the patient described in our case report. The selected cases were reviewed to obtain information on maternal characteristics, clinical presentation, diagnostic studies, therapeutic modalities and maternal and fetal outcomes. The collected data was analyzed and summarized in a table along with the author's name and respective reference (►Chart 1). 1-37

Case Report
A 36-year-old women, 30 weeks pregnant was admitted to the emergency service with severe holocranial headache, blurred vision, photophobia and vomiting for the last 4 days. In the day before she had been discharged from another hospital with the diagnosis of migraine. She had type 1 Diabetes Mellitus for 18 years, without known micro or macrovascular complications. She was on insulin (detemir and lispro), acetylsalicylic acid, folic acid, ferrous sulfate and potassium iodine. At admission, physical examination, blood pressure and neurologic examination were normal. Hemoglobin, platelets, renal and hepatic function were in the normal range and sFLT-1 /PLGF ratio was negative (<38), excluding pre-eclampsia as the cause of this clinical picture. Brain MRI was suggestive of pituitary apoplexy with compression and swelling of the optic tract: "Enlarged pituitary gland 12 mm in height, with heterogeneous sign. There is an evident suprasellar extension and shaping of the optic chiasm." (►Fig. 1) After neuro-ophthalmological examination, optic chiasm compression was excluded and surgery was postponed. Blood levels of ACTH, FT4, TSH and cortisol were unremarkable. She was started on intravenous hydrocortisone 100 mg every 8 hours, with progressive improvement of symptoms. At 35 weeks of gestation, an urgent c-section was performed because of a non-reassuring fetal heart rate tracing (►Fig. 1) associated with absence fetal movements. A baby girl was born with 4080 g and an apgar index of 7/9. She was asymptomatic on discharge (►Fig. 2). In the post-partum period she remained clinically stable, asymptomatic and she was diagnosed with a non-functioning macroadenoma. She suspended corticotherapy without relapse.

Discussion
Pituitary apoplexy is a rare event and far less frequent in pregnancy. In the absence of more robust studies, the experience provided by case reports establishes an important guidance for managing these patients. The estimated  prevalence of pituitary apoplexy is 1:10000 pregnancies at term, with a mean gestational age of diagnose of 24 weeks' gestation and 10% of cases occurring in puerperium. In many cases, as in our case report, it constitutes the first presentation of a pituitary tumor, especially macroadenomas as they tend to be more hemorrhagic. 3,14,15 Pituitary apoplexy can occur spontaneously or associated with pituitary tumors. The etiology is multifactorial, but several precipitating factors have been described: pregnancy (as in our clinical case), hemorrhagic disturbances, anticoagulation therapy, hypertension, diabetes mellitus, radiation or head trauma, cerebral aneurysm, major surgery, especially coronary artery bypass grafting, estrogen therapy, lumbar punction, upper respiratory tract infection, endocrine stimulation tests, initiation, or withdrawal of dopaminergic therapy. 1,[4][5][6][7] The typical presentation of pituitary apoplexy is the one described in our case, with sudden onset of severe bilateral headache, visual disturbances, nausea and vomiting and secondary symptoms to the involvement of cranial nerves (the oculomotor is the most frequently affected). The absence of classic symptoms can delay the diagnosis. In $80% of the cases, patients will develop deficiency of one or more anterior pituitary hormones, depending on the percentage of pituitary tissue destroyed. Gonadotrophins are the most affected, followed by ACTH and TSH and less frequently prolactin. In this case, gonadotrophins are difficult to value since they are physiologically braked in pregnancy. [1][2][3][4] Acute secondary adrenal insufficiency is seen in approximately two-thirds of patients with pituitary tumor apoplexy and it's the major source of mortality associated with the condition, requiring prompt corticosteroid replacement in anticipation.
The diagnosis is done in the presence of the clinical syndrome associated with sella turcica imaging. Magnetic resonance (MRI) is the most sensitive method to confirm the diagnosis and usually reveals a pituitary tumor with hemorrhagic and/or necrotic components. 4,6 In the pregnancy context the treatment of choice is conservative. Medical therapy includes corticotherapy, dopamine agonists, such as cabergoline and bromocriptine and reposition of hormonal deficits. Surgery might be required during pregnancy, when there are important visual disturbances due to compression, endocrinal hypersecretion (especially Cushing disease) or for life-threatening apoplexy. 4,7,14 As a result of a literature research on Pubmed we found 36 case reports. From their analysis, we found that the average age of the pregnant women was 29 years old (AE4 years), with an average gestational age of 25 weeks (AE8 weeks) at diagnose. Most cases occurred in the second trimester. Regarding previously diagnosed lesions, it was present in 47% of patients. There were 7 cases of macroadenomas, 4 cases of microadenomas and 6 cases of adenomas without size specification. Therefore, pituitary apoplexy during pregnancy can be the first manifestation of an unrecognized pituitary adenoma in a large portion of this series. Headache was the most frequent symptom, being present in 86% of cases. Corticotherapy was used in 11% of cases and surgery was required in 61%. Most deliveries were uneventful. Csection was the mode of delivery in 15 cases, there were 6 cases of vaginal delivery and the route of delivery was unknown in 48% of the cases. There were 3 cases of preterm delivery and 28 term deliveries. There was one case of maternal death.

Conclusion
We consider our case report an example of successful management with conservative therapy, since our patient had sustained remission of symptoms without surgery and has already suspended medical treatment without relapse. We would like to reinforce that a precocious diagnosis is essential to a timely approach, avoiding the morbimortality potentially related to this condition.

Conflicts to Interest
The authos have no conflicts of interest to declare.