Challenges of Pituitary Apoplexy in Pregnancy

Our purpose is to provide new insights concerning the challenges of pituitary apoplexy in pregnancy (PAP) and the postpartum period (PAPP). This is a narrative review of the English literature using a PubMed search. The inclusion criteria were clinically relevant original studies (January 2012–December 2022). Overall, we included 35 original studies: 7 observational studies (selected cases on PA) and 28 case reports, including 4 case series (N = 49; PAP/PAPP = 43/6). The characteristics of PAP patients (N = 43) are as follows: maternal age between 21 and 41 (mean of 27.76) years; 21/43 subjects with a presentation during the third trimester (only one case during first trimester); average weak of gestation of 26.38; most females were prim gravidae; 19 (out of 30 patients with available data on delivery) underwent a cesarean section. Headache remains the main clinical feature and is potentially associated with a heterogeneous panel (including visual anomalies, nausea, vomiting, cranial nerve palsies, diabetes insipidus, photophobia, and neck stiffness). Pre-pregnancy medication included dopamine agonists (15/43) and terguride (1/43) in addition to subsequent insulin therapy for gestational diabetes (N = 2) and type 1 diabetes mellitus (N = 1). Overall, 29/43 females received the conservative approach, and 22/43 women had trans-sphenoidal surgery (TSS) (and 10/22 had the initial approach). Furthermore, 18/43 patients had a pituitary adenoma undiagnosed before pregnancy. Most PA-associated tumors were prolactinomas (N = 26/43), with the majority of them (N = 16/26) being larger than 1 cm. A maternal–fetal deadly outcome is reported in a single case. The characteristics of PAPP patients (N = 6) are as follows: mean age at diagnosis of 33 years; 3/6 subjects had PA during their second pregnancy; the timing of PA varied between 5 min and 12 days after delivery; headache was the main clinical element; 5/6 had no underlying pituitary adenoma; 5/6 patients were managed conservatively and 1/6 underwent TSS; pituitary function recovered (N = 3) or led to persistent hypopituitarism (N = 3). In conclusion, PAP represents a rare, life-threatening condition. Headache is the most frequent presentation, and its prompt distinction from other conditions associated with headache, such as preeclampsia and meningitis, is essential. The index of suspicion should be high, especially in patients with additional risk factors such as pre-gestation treatment with dopamine agonists, diabetes mellitus, anticoagulation therapy, or large pituitary tumors. The management is conservative in most cases, and it mainly includes corticosteroid substitution and dopamine agonists. The most frequent surgical indication is neuro-ophthalmological deterioration, although the actual risk of pituitary surgery during pregnancy remains unknown. PAPP is exceptionally reported. To our knowledge, this sample–case series study is the largest of its kind that is meant to increase the awareness to the benefit of the maternal–fetal outcomes from multidisciplinary insights.

Generally, the initial approach of patients with PA is conservative, aiming to ensure fluid and electrolyte balance and to restore glucocorticoids replacement. Steroids are also indicated for the prevention of cerebral edema. The next step is the decision to either continue conservative treatment, with the possibility of administering dopamine agonists (DA) or to undergo surgery [14,19,[52][53][54]. Patients with prolactinoma taking DAs should stop the medication when pregnancy is confirmed. In particular cases, such as invasive adenoma or continuous tumor growth, DAs should be resumed [55][56][57][58].
Concerning PA in pregnancy, the conservative approach is often preferred. Due to the risk for the mother and fetus, surgical management during pregnancy is reserved for patients with deteriorating consciousness or severe neuro-ophthalmological deficits [57,[59][60][61]. When surgical management is chosen, the second trimester and early third trimester are preferred [59,62], with no preference regarding the anesthetic approach [63].

Aim
Our purpose is to provide new insights for AP in pregnancy and the PP period by covering different aspects from presentation to outcome.

Methods
This is a narrative review of the English medical literature regarding PA in pregnancy and PP, using a PubMed-based search with the following keywords: "pituitary apoplexy" and "gestational" or, alternatively, "pregnancy" or "postpartum". The inclusion criteria consisted of clinically relevant original studies with a publication date between January 2012 and December 2022. We excluded other etiologies of PA.
Overall, we identified and analyzed 35 papers; among them, 30 original studies (including case reports) addressed subjects with PA in pregnancy, and 6 case reports recorded PA during PP (notably, 1 study, which includes 2 previously unreported individuals with PA in pregnancy and one during PP, is common to both sections). There was a total of 50 patients analyzed from the published data, including 44 patients with PA in pregnancy and 6 with PA during PP ( Figure 1). ing PA, MRI is an important tool for the differential diagnosis of neurologic disorders associated with pregnancy [50,51]. Generally, the initial approach of patients with PA is conservative, aiming to ensure fluid and electrolyte balance and to restore glucocorticoids replacement. Steroids are also indicated for the prevention of cerebral edema. The next step is the decision to either continue conservative treatment, with the possibility of administering dopamine agonists (DA) or to undergo surgery [14,19,[52][53][54]. Patients with prolactinoma taking DAs should stop the medication when pregnancy is confirmed. In particular cases, such as invasive adenoma or continuous tumor growth, DAs should be resumed [55][56][57][58].
Concerning PA in pregnancy, the conservative approach is often preferred. Due to the risk for the mother and fetus, surgical management during pregnancy is reserved for patients with deteriorating consciousness or severe neuro-ophthalmological deficits [57,[59][60][61]. When surgical management is chosen, the second trimester and early third trimester are preferred [59,62], with no preference regarding the anesthetic approach [63].

Aim
Our purpose is to provide new insights for AP in pregnancy and the PP period by covering different aspects from presentation to outcome.

Methods
This is a narrative review of the English medical literature regarding PA in pregnancy and PP, using a PubMed-based search with the following keywords: "pituitary apoplexy" and "gestational" or, alternatively, "pregnancy" or "postpartum". The inclusion criteria consisted of clinically relevant original studies with a publication date between January 2012 and December 2022. We excluded other etiologies of PA.
Overall, we identified and analyzed 35 papers; among them, 30 original studies (including case reports) addressed subjects with PA in pregnancy, and 6 case reports recorded PA during PP (notably, 1 study, which includes 2 previously unreported individuals with PA in pregnancy and one during PP, is common to both sections). There was a total of 50 patients analyzed from the published data, including 44 patients with PA in pregnancy and 6 with PA during PP ( Figure 1).

Sample-Case Series Study
Findings regarding PA in pregnancy are summarized in Tables 1 and 2.  Table 1. Characteristics, clinical presentation, management, and outcome of patients with PA in pregnancy. The studies are displayed starting with those from 2012 [20,. This table introduces the studied population, week of gestation, and clinical presentation, including the data on preexisting pituitary lesions.     The patient received treatment with cabergoline since 13 WG due to rapid, more than 10-fold increase in prolactin level. ## Patient was treated with cabergoline for 12 months before pregnancy. The patient suffered from an acute ischemic stroke 10 days PP. ### Patient 1: DA (cabergoline) before pregnancy (discontinued when pregnancy was confirmed). Patient 2: DA (bromocriptine) before pregnancy (discontinued when pregnancy was confirmed). Patient 3: DA (cabergoline) before and between pregnancies (discontinued when pregnancy was confirmed in all three pregnancies). Patient 4: type 1 DM, DA (cabergoline) before pregnancy (discontinued when pregnancy was confirmed). We identified three observational studies, of which two were retrospective [77,82] and one was not [78]. Galvão et al. [77] published a retrospective analysis investigating the consequences of pregnancy in patients with a previous diagnostic of a prolactinoma. Overall, 33 out of the 35 women had lactotroph PitNETs diagnosed before pregnancy. The majority of the patients stopped medical treatment within the 8th week of gestation (WG), and no cases of malformations were reported. No significant progression of the underlying disease was observed during pregnancy. In total, 2 out of the 35 patients developed PA in pregnancy (28 WG and 25 WG). The first patient was treated conservatively, and the second one was treated surgically. Both women were admitted for headaches and visual disturbances. They had no previously diagnostic of a PitNET, and, thus, they did not receive DAs before pregnancy. The surgically treated patient developed hypothyroidism and DI [77].

Reference
The risk of pituitary adenoma enlargement is higher during pregnancy. Barraud S et al. [82] published a retrospective study also following pregnancies in females with lactotroph PitNETs and the associated risk of tumor growth. Overall, 85 pregnancies (46/85 were macroprolactinomas), in women who were treated with DAs before pregnancy, were included. Adenoma growth and symptomatic tumor progression occurred in 19.6% of cases. In total, 3/85 women had PA in pregnancy; none was under DAs. Emergency transsphenoidal surgery (TSS) was performed in 2/3 females with PA due to vision anomalies (within the 4th month and 36th WG) [82] Lambert et al. [78] published a prospective study on 71 pregnant subjects with pituitary tumors (49/71 macroprolactinoma, 16/71 non-functioning adenomas, 3/71 somatotropinoma, and 3/71-corticotropinoma). In the study, 2/71 subjects developed PA (one with macroprolactinoma and the other with non-functioning pituitary adenoma), and they were conservatively managed [78].
The largest cohort of consecutive PAs in pregnancy contains from three to five individuals/series [20,81,88,90]. Grand'Maison et al. [20] introduced 4 PAs during pregnancy and PP (one case was excluded due to previous publication by Couture et al. [64] in 2012, and the fourth case is presented in the section regarding PA in PP and summarized in Table 3) [20,64]. The remaining 2/4 cases, two females of 33 and 30 years of age, developed PA at 39 WG and 20 WG, respectively, while being admitted for headache and visual disturbances. One of the patients had a history of prolactinoma and was treated with cabergoline before pregnancy; DA was stopped within the first trimester, but it was restarted. One sub-ject associated high blood pressure and preeclampsia. Patients were treated conservatively, and they delivered at term two healthy newborns [20].
Kato et al. [88] reported three PAs in pregnancy (median maternal age of 28 years). One of the women was known to have lactotroph PitNET before pregnancy. The median gestational age at the beginning of symptoms (headache and visual field defects) was 31 WG. The management was similar: a conservative approach amid pregnancy in 100% of cases; the babies were delivered by caesarean section; after birth, all subjects suffered TSS. The postoperative pathological examination confirmed 2/3 lactotroph PitNETs and one plurihormonal PitNET (lactotroph and gonadotroph). After 3 months of follow-up, the patients had no signs of hypopituitarism [88] Kuhn et al. [90] identified five PAs in pregnancy (median maternal age of 26 years) with a pre-gestational confirmation of lactotroph PitNETs. The median gestational age of PA was 26 WG. Initially, conservative therapy was chosen, but one female underwent TSS during pregnancy and another after delivery. As hormonal complications, we mention DI (1/3), and adrenal insufficiency (1/3) [90].
Another series of three subjects was introduced by Jemel et al. [81]. The median maternal age was 32 years, and one woman was diagnosed with a pituitary adenoma before pregnancy. The median gestational age at the beginning of symptoms was 27 WG. The management was different: while 2/3 had TSS, 1/3 had conservative therapy [81].
Overall, most data are provided from case reports rather than original studies specifically addressing pregnancies complicated with PA. The cited studies are observational and retrospective. The majority of pituitary masses, if their type is known, were prolactinomas. The enlargement of the mass is often reflected in the clinical presentation, specifically with headache (followed by a heterogeneous spectrum of visual anomalies of different degrees of severity), which is a common finding with the data we currently have on other types of PA outside gestation. The specific medication for prolactinomas, as cabergoline or bromocriptine, was stopped within the first weeks of pregnancy confirmation as generally recommended. Most studies enrolled subjects within their third decade of life [20,.
Even though most patients suffered a single episode of PA in pregnancy, Geissler et al. reported a repeated PA episode during two of her pregnancies. The patient presented with similar symptoms both times, with headache and visual disturbances at 34 WG and 32 WG, respectively. She also suffered from gestational diabetes mellitus (DM) requiring insulin therapy during both of her pregnancies. PA was conservatively approached each time. She delivered healthy babies by CS at 36 and 34 WG but was unable to breastfeed [86].
The diagnosis of PA was established starting from clinical presentation, as mentioned. A good multidisciplinary collaboration is required in this circumstance. The hormonal panel is classical for newly onset hypopituitarism. It investigates each line of pituitary hormones, mostly according to baseline blood assessment rather than using dynamic tests during pregnancy. In addition to endocrine confirmation of central hypothyroidism, adrenal insufficiency, and, in some cases, diabetes insipidus, the diagnosis also includes the imaging scans that show distinct features of apoplexy, tumor remnants or even intact areas of the pituitary gland [20,.
Another risk factor was anticoagulant therapy. For example, Watson V et al. [74] reported the case of a 30-year-old woman, with an undiagnosed pituitary adenoma, who underwent prophylactic treatment with low-molecular-weight heparin throughout pregnancy. She displayed severe headache and visual disturbance at 37 WG. A pituitary hemorrhage was confirmed by MRI. The patient received conservative treatment with hydrocortisone and delivered the baby at term by CS. On discharge, she was offered oral hydrocortisone for persistent hypocortisolism [74].

Differentiating PA in Pregnancy from Other Entities
The differential diagnosis of PA in pregnancy first starts from headache, as is this case with, for example, eclampsia. The importance of differentiating between these conditions is highlighted by Sedai et al. [92]. In their report, a 40-year-old woman presented at 21 WG with headache, projectile vomiting, ptosis, decreased visual acuity, and altered consciousness. The patient received conservative management for eclampsia at first, but the progression of neurological deficits was consistent with further PA expansion of a previously undiagnosed PitNET. A craniotomy for tumor resection and hematoma evacuation was performed with a fatal outcome in the second postoperative day [92]. This case further emphasizes the importance of adequate management in PA. With regard to PA-associated meningism in terms of photophobia and neck stiffness, a differentiation from meningitis is necessary in these cases [20,70,75,90].
Cases with prolactinomas developing PA in pregnancy seem the most frequent with regard to the type of PitNET. Chegour et al. [68] reported PA in a 29-year-old woman with a macroprolactinoma unconfirmed before pregnancy, who received treatment with bromocriptine for hyperprolactinemia of uninvestigated etiology. At 19 WG, she presented with headache and visual disturbances due to PA, and she was conservatively managed with cabergoline leading to the complete regression of the visual symptoms [68]. Another interesting case history was reported by Couture et al. [64]: a 37-year-old female with a known lactotroph PitNET larger than 1 cm was treated with cabergoline before pregnancy. At 16 WG, she presented with headache, nausea, vomiting, and blurred vision, and MRI confirmed PA. Cabergoline treatment was resumed, resulting in regression of the pituitary mass after 5 weeks. Her pregnancy ended successfully at 38 WG with delivery by CS [64]. Annamalai et al. [76] reported a 25-year-old individual with a known macroprolactinoma treated with cabergoline; at 37 WG, she complained of headache, and MRI confirmed PA. She was offered hydrocortisone and resumed cabergoline. Two days after admission, the patient delivered a healthy baby by cesarean section. After 4 months of follow-up, the complete resolution of the pituitary adenoma was registered [76]. De Ycaza et al. [73] introduced a young female with a known macroprolactinoma treated with cabergoline that experienced headache at 28 WG confirmed with MRI as being PA. Cabergoline was resumed, and then she gave birth vaginally at term; 1 year later, the tumor was less than 1 cm, and substitution with hydrocortisone was stopped [73]. Additionally, Janssen et al. [65] reported a woman with a lactotroph PitNET larger than 1 cm who received treatment with bromocriptine until pregnancy was confirmed. At 10 WG, she developed PA, and bromocriptine was resumed in association with hydrocortisone and L-thyroxine replacement. She gave birth vaginally at 40 WG [65].
Hayes et al. [69] reported a case of pituitary hemorrhage and compression of the optic nerve and chiasma. After corticosteroid treatment, the patient underwent TSS due to visual decline. She vaginally delivered a healthy boy at term. No hormonal deficits were detected, and, at 14 months after birth, the patient remained well [69]. Oguz et al. [85] reported a 26-year-old female diagnosed with prolactinoma 2 years prior to pregnancy. She presented at 22 WG with headache, nausea, and visual disturbance. After 8 days of admission, TSS was performed due to the persistence of visual symptoms. She delivered in good condition at 37 WG. Eight months after delivery, she was still treated with levothyroxine [85]. O'Neal et al. [79] reported a case of undiagnosed pituitary microadenoma in which the female had headache and visual disturbances at 29 WG. MRI showed an expanded pituitary with compression of the optic chiasma. Two days after admission she underwent TSS. She delivered at term a healthy boy. She also developed DI after surgery [79]. Abraham et al. [75] reported a spontaneous PA in pregnancy with sensory loss. The patient, a 32-yearold, developed headache, photophobia, and right-sided numbness at 23 WG. Emergency surgery was performed with decompression of the optic nerve. She developed DI on the second postoperative day, requiring desmopressin [75]. In another case, a 27-yearold female received the first diagnosis of prolactinoma at 19 WG and bromocriptine was administrated. At 36 WG, she had headache and acute vision loss in the left eye with MRI confirmation of a hemorrhagic pituitary mass of 2.1 cm maximum diameter with optic chiasm compression. The patient underwent TSS with good postoperative course. A cesarian section was performed, and a healthy baby was born. At follow-up, MRI showed the complete resolution of tumor [71].

PitNET Analysis
Overall, 18/44 patients had a pituitary adenoma undiagnosed before pregnancy, and 21 patients had a known pituitary adenoma (please see Tables 1 and 2). However, three studies included only patients with known pituitary adenomas, and some of them further developed PA [77,78,82]. Notably, one female was diagnosed during pregnancy with a pituitary adenoma and developed PA later during pregnancy [71]. Even though almost all patients had pituitary adenomas, one patient developed PA due to pituitary hyperplasia, without adenoma [20], and in another case, no pituitary adenoma was found at all [75]. Most pituitary adenomas were lactotroph PitNETs (N = 26), while one patient had a lacto-gonadotroph PitNET [88], and a non-functional adenoma was present in three subjects [66,78,81]. Out of lactotroph tumors, the majority (N = 16) were larger than 1 cm, while one prolactinoma was giant, measuring 4.5 cm maximum diameter [89].
Moreover, Ye et al. [91] published a case of PA associated with extra-pontine myelinolysis in pregnancy at 32 WG with no previously known pituitary adenoma and that presented with vomiting. The laboratory analysis showed hyponatremia, so the patient received sodium repletion. She developed aphasia and hemiplegia the next day. MRI showed PA and abnormal signals in some areas that suggested extra-pontine myelinolysis.
The patient received treatment with hydrocortisone and levothyroxine. She gave birth at 38 WG (CS) to a healthy baby [91].
A fatal outcome of the newborn was reported by Khaldi et al. on a case of a giant prolactinoma complicated with PA in pregnancy. The subject was treated with cabergoline and surgery and presented at 22 WG with symptoms of PA. She received treatment with bromocriptine and hydrocortisone. She developed corticotropic and thyrotrophic insufficiency. Unfortunately, she gave birth prematurely at 28 WG to twins who died on the 7th day of life [89]. In another study, a fatal maternal outcome was reported following a craniotomy for PA at 21 WG [92].
Regarding breastfeeding in females who experienced PA in pregnancy, we have the data on three patients who were unable to breastfeed [86,90,91], while one patient was able to breastfeed for only 2 weeks [69]. Two patients were able to have an uneventful second pregnancy following PA amid previous gestation [20,73].
All patients presented headache as the main symptom, which was described as severe (2/6); throbbing/pulsatile (2/6); either frontal (1/6), frontotemporal (1/6), or occipital (1/6); and accompanied by eye pain (1/6), nausea (3/6), and vomiting (1/6). In the case of Mathur et al.'s patient, headache persisted over the course of 48 h without remission after treatment with paracetamol [93]. Visual symptoms (N = 3) included a decrease in visual acuity, diplopia, ptosis, and anisocoria. Photophobia (N = 1), fever (N = 1), polyuria and polydipsia (N = 2), and the inability to lactate (N = 1) were also identified. Raina S et al. [94] presented a case of PA in PP associated with isolated third cranial nerve palsy; the patient had a history of PP hemorrhage following a full-term home-conducted vaginal delivery. On the second day of admission, she complained of blurred vision, headache, and diplopia. Ptosis on the right side was also noted. MRI established the diagnosis of PA. She started thyroid hormone replacement therapy along with oral hydrocortisone. During follow-up, the subject had a full recovery with the normalization of thyroid function [94].
In one study, 5/6 subjects had no underlying pituitary adenoma [20,[93][94][95][96]. Pop et al. reported a non-functioning large pituitary adenoma of 3.3 × 1.05 × 1.55 cm that was undiagnosed before pregnancy [97].   Two patients associated additional risk factors: type 1 diabetes [20] and postpartum hemorrhage [94]. A co-morbidity in terms of subdural hematoma is reported by Hoang et al. [96], in which a 34-year-old subject experienced PA in PP and subdural hematoma following epidural anesthesia. She delivered by CS at 38 WG, and 2 days after delivery, she showed signs of right facial paralysis, which was associated with headaches, eye pain, and blurred vision. MRI confirmed PA and a left frontal subdural hematoma. PA was conservatively approached followed by a full recovery within 1 year [96]. Another incidental event is reversible cerebral vasoconstrictive syndrome (RCVS). Mathur et al. [93] reported a 34-year-old female who developed PA after an emergency CS under spinal anesthesia. She had severe PP headache and neurologic deficits. MRI showed PA. DI developed after 48 h. She was managed conservatively with oral hydrocortisone in order to prevent secondary adrenal insufficiency. Ten days following PA, the persistent headache led to the identification of a new subarachnoid hemorrhage on MRI; she was further confirmed with reversible cerebral vasoconstrictive syndrome. Twenty months after the event, she did not require any hormone replacement therapy, but the MRI showed the enlargement of the pituitary bordering the optic chiasm [93].
Pituitary function recovered and remained normal at the latest follow-up in three of the six patients [93,94,96], while the other three subjects required therapy for hypopituitarism [20,95,97].
In the case of Mathur et al.'s patient, a differential diagnosis of headache included multiple conditions: this is a 34-year-old female who underwent CS under spinal anesthesia and received a bolus of oxytocin at delivery. The patient complained of persistent headache over the course of 48 h after delivery. MRI scans were performed and showed pituitary hemorrhage. Both spinal anesthesia and oxytocin bolus may cause headache in PP, therefore complicating the differential diagnosis of PA [93].

Discussions
Our case-sample-based analysis followed 35 original publications: 7 studies (selected cases on PA from larger cohorts that included 22 women), and 28 case reports (1 patient/article, N = 28); thus, a total of 50 subjects were considered (44 with PA in pregnancy and 6 with PA diagnosed after delivery). We noticed that the original studies were of small sample sizes (the highest number of females with the actual diagnosis of PA was 5), and the studies addressed different issues of PitNETs outside PA (the largest cohorts consisted of 35, 46, and 71 patients with PitNETs). Notably, we used the terms of "case series" or "study" in a table according to the original publication, but our final report, as introduced below, takes into consideration 28 case reports (1 female/paper) and 7 non-case reports (2-5 females/paper) that specifically refer to PA (Figure 2). of small sample sizes (the highest number of females with the actual diagnosis of PA was 5), and the studies addressed different issues of PitNETs outside PA (the largest cohorts consisted of 35, 46, and 71 patients with PitNETs). Notably, we used the terms of "case series" or "study" in a table according to the original publication, but our final report, as introduced below, takes into consideration 28 case reports (1 female/paper) and 7 non-case reports (2-5 females/paper) that specifically refer to PA (Figure 2).

Integrating PA in Pregnancy and PP to the Larger Frame of PAs
The growth of pituitary tumors, especially lactotroph tumors, during pregnancy, as well as pituitary hypertrophy, increases the risk of PA in gestation. The low number of cases found between 2012 and 2022, however, suggests the rarity of the disease. The clinical presentation of patients with PA in pregnancy and PP is similar to the clinical presentation of non-pregnant patients with PA with sudden and severe headache; nausea and vomiting; visual disturbances including a decrease in visual acuity; and signs and

Integrating PA in Pregnancy and PP to the Larger Frame of PAs
The growth of pituitary tumors, especially lactotroph tumors, during pregnancy, as well as pituitary hypertrophy, increases the risk of PA in gestation. The low number of cases found between 2012 and 2022, however, suggests the rarity of the disease. The clinical presentation of patients with PA in pregnancy and PP is similar to the clinical presentation of non-pregnant patients with PA with sudden and severe headache; nausea and vomiting; visual disturbances including a decrease in visual acuity; and signs and symptoms of cranial nerve palsies such as visual field defects, ptosis, anisocoria, and diplopia [14,39,[98][99][100][101][102]. Presentation with hypocortisolism occurred in one of the patients with PA in pregnancy [91].
We also observed DI as an initial presentation in patients with PA during pregnancy and PP [83,93,97]. The manifestation of DI during pregnancy ranges from the exacerbation of pre-existing central or nephrogenic DI to pregnancy-induced transient DI due to the increased metabolism of the antidiuretic hormone vasopressin (AVP) by placental vasopressinase [12,99,[103][104][105].
We mentioned that many patients present during pregnancy or PP with PA as the initial symptom of a previously undiagnosed PitNET. In patients with known pituitary tumors, the most frequent type was lactotroph PitNET. Additional risk factors are gestational and type 1 DM, while pre-gestation treatment with DA was discontinued at the moment of pregnancy confirmation. The majority of prolactinomas were macroadenomas; thus, it could be hypothesized that the tumor size may increase the risk of PA in pregnancy.
The management of PA is similar to that of non-pregnant patients. Most patients were treated conservatively, while surgery was reserved for cases with persistent and evolving visual disturbances or altered consciousness. The TSS was preferred in all postpartum cases except for one [92].
Generally, the maternal-fetal outcomes are favorable. Hormonal deficits are relatively frequent, and they include hypocortisolism, hypothyroidism, and sometimes hypogonadism or growth hormone deficits. One noticeable postoperative complication observed in patients with PA in pregnancy that underwent surgery was DI, either transient or persistent [66,71,77,79]. No case of neonatal abnormalities and congenital malformation were observed. We still do not have long-term surveillance studies of children born from mothers who experienced PA in pregnancy or PP.
As seen outside pregnancy, the differential diagnosis of headache is crucial in establishing an adequate diagnosis. PA in pregnancy may mimic a series of conditions including eclampsia [92], meningitis due to photophobia [70,75,90], and nuchal rigidity [20]. In the PP, a differential diagnosis includes anesthesia and ocytocin bolus [93]. Another condition associated with headache was RCVS (N = 1) [93]. RCVS is a condition accompanied by the constriction of cerebral arteries, manifesting with headaches and possible neurological deficits. Its frequency is higher during PP. Its resolution is spontaneous, but it may lead to subarachnoid hemorrhage and even hemorrhagic or ischemic strokes [98,[106][107][108].
Due to the gravity of the aforementioned conditions, differential diagnoses and prompt and proper treatment are essential, as illustrated by one case with an initial misdiagnosis that led to a delay in identifying and treating PA and, finally, to exitus [92].

PA in Pregnancy versus Postpartum
As expected, we found more cases of PA in pregnancy than postpartum (44 versus 6 individuals). PA during pregnancy and PP share a similar clinical presentation with headaches of similar patterns and localizations accompanied by not only nausea and vomiting but also visual symptoms including a decrease in visual acuity, visual field defects, diplopia, and anisocoria. Ptosis was observed only in one patient suffering from PA during PP [97], and it was observed in pregnancy-associated PA. Further clinical similarities include photophobia, polyuria, and polydipsia and lack/difficulties of lactation [20,86,90,91]. In terms of underlying conditions, prolactinomas are most important for PA in pregnancy, while 5/6 patients suffering from PA during PP had no pituitary adenoma; however, the analysis remains at case report levels [20,[93][94][95][96]. Similar risk factors such as type 1 diabetes are commonly listed too [20,90]. Most patients received conservative treatment both in pregnancy and PP. During pregnancy, TSS was performed due to the persistence or worsening of visual symptoms [69,71,75,77,79,81,82,85,90], while in PP, TSS (N = 1) was performed due to a decrease in consciousness [97]. Outcomes in these cases were similar. Notably, DI was reported only in relation to PA during gestation [66,71,77,79]. (Table 4).

Integrating PA Amid Other Endocrine Complications of Pregnancy
Generally, despite a low level of statistical evidence, PA in pregnancy remains a key element of the endocrine conditions that require particular intervention amid gestation, which involve the thyroid, adrenal, and pituitary glands [57,[109][110][111]. Moreover, PA in pregnancy is one of the causes of acquired hypopituitarism in females during gestation [112]. For instance, Bichard et al. [83] reported the case of a 29-year-old woman developing headache, nausea, vomiting, and polyuria at 30 WG. MRI confirmed PA. She experienced panhypopituitarism, requiring hydrocortisone, levothyroxine, and desmopressin [83]. Another example was published by Pop et al. [97]: A 26-year-old female underwent CS. Forty-eight hours later, she complained of headache, photophobia, and nausea, and MRI confirmed a pituitary tumor of more than 3 cm, the largest diameter without compression, on the optic chiasma. On the 8th day after giving birth, she developed panhypopituitarism. Initially, she received conservative treatment, but due to deteriorating consciousness, surgical decompression was performed. At the 2-year follow-up, the patient remained on levothyroxine, prednisone, and estrogen-progestin replacement therapy [97]. Pregnancy-related hypophysitis is another cause of gestation-related pituitary insufficiency, and a recent retrospective analysis identified 148 of such published cases [112]. Additionally, Sheehan syndrome leads to hypopituitarism after a post-partum dramatic event, such as a hemorrhage, due to an obstetric event, and it should be differentiated from PA in PP [34,[113][114][115]. Notably, PA in PP and Sheehan syndrome might be found in women who were otherwise healthy, thus displaying a low index of clinical suspicion [34,[113][114][115].

COVID-19 Infection Associated with PA
Chan JL et al. [84] reported a case of a pregnant woman with PA suffering from SARS-CoV-2 infection. The patient presented at 38 WG with visual disturbance and headache. MRI showed a previously undiagnosed pituitary tumor with acute hemorrhage. She received conservative treatment with dexamethasone and gave birth to a healthy baby at 39 WG by VD. Two days later, TSS was performed. Two months further on, she still had hypothyroidism, hypogonadism, and hypocortisolism requiring hormonal substitution. It remains unclear whether the SARS-CoV-2 infection was a factor leading to PA or a mere coincidence [84]. However, we already know that COVID-19 infection is a new trigger for many conditions, during pregnancy or not, which are located at different organs and systems, and further evidence on coronavirus-associated PA is expected to be published [116][117][118][119][120].

Conclusions
PA in pregnancy is a rare, life-threatening condition. Most patients presenting with PA are primigravidae in the second or third trimester. Headache is the most frequent presentation, and its prompt distinction from other conditions associated with headache, such as preeclampsia and meningitis, is essential. The index of suspicion should be high, especially in patients with additional risk factors such as pre-gestation treatment with dopamine agonists, diabetes mellitus, anticoagulation therapy or large pituitary tumors. PA management is conservative in most cases, and it mainly includes corticosteroid substitution and dopamine agonists. The most frequent surgical indication is neuro-ophthalmological deterioration, although the actual risk of pituitary surgery during pregnancy remains unknown. PA in PP is exceptionally reported. To our knowledge, this sample-case series study is the largest of its kind that is meant to increase the awareness to the benefit of the maternal-fetal outcomes.