# Descriptive analysis and outcomes of PitNETs treated surgically during pregnancy and postpartum

Cindy Odot, Mathilde Brière, Marie Laure Raffin-Sanson, Mirella Hage, Chiara Villa, Théophraste Henry, Stephan Gaillard, Bertrand Baussart, Philippe Caron, Lionel Groussin, et al.

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## To cite this version:

Cindy Odot, Mathilde Brière, Marie Laure Raffin-Sanson, Mirella Hage, Chiara Villa, et al. Descriptive analysis and outcomes of PitNETs treated surgically during pregnancy and postpartum. European Journal of Endocrinology, 2025, 192 (2), pp.150-158. 10.1093/ejendo/lvaf018. hal-05029199

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**Descriptive analysis and outcomes of PitNETs treated surgically during pregnancy and postpartum (84 characters)**

**Short Title** (29 characters): PitNETs treated during pregnancy

Cindy Odot¹, Mathilde Brière¹, Chiara Villa³, Théophraste Henry⁴, Stephan Gaillard⁵, Philippe Caron⁶, Lionel Groussin⁷, Yves Reznik⁸, Anne Rod⁸, Camille Ghorra⁹, Marie-Laure Raffin-Sanson ¹,², Bertrand Baussart ⁵,¹⁰, Mirella Hage ¹,².

1. Department of Endocrinology, Diabetology, and Nutrition, Ambroise Paré University Hospital, Assistance Publique-Hôpitaux de Paris, 92100 Boulogne Billancourt, France.

2. EA4340, University of Versailles Saint-Quentin-en-Yvelines, UFR of Health Sciences Simone Veil, 78423 Montigny-le-Bretonneux, France.

3. Department of Neuropathology, Assistance Publique-Hôpitaux de Paris, La Pitié-Salpêtrière University Hospital, 75013 Paris, France.

4. Department of Nuclear Medicine, Gustave Roussy Institute, 94800 Villejuif, France.

5. Department of Neurosurgery, Assistance Publique-Hôpitaux de Paris, La Pitié-Salpêtrière University Hospital, 75013 Paris, France.

6. Department of Endocrinology, Metabolic Diseases, and Nutrition, Hôpital Larrey, 24 chemin de Pouvourville, TSA 30030, 31059 Toulouse Cedex, France.

7. Department of Endocrinology, Cochin-Port Royal University Hospital, Assistance Publique des Hôpitaux de Paris, 75014 Paris, France.

8. Department of Endocrinology and Diabetology, Caen University Hospital, 14033 Caen, France.

9. Department of Radiology, Ambroise Paré University Hospital, Assistance Publique-Hôpitaux de Paris, 92100 Boulogne Billancourt, France.

10. University of Paris Cité, CNRS, INSERM, Cochin Institute, 75014 Paris, France.
**Corresponding author:** postal and email address

Mirella Hage, MD, PhD

Service d'Endocrinologie de Diabétologie et de Nutrition

Centre Hospitalier Universitaire Ambroise Paré

9 avenue Charles De Gaulle

92100 Boulogne Billancourt

France

ORCID ID: 0000-0002-7458-7102

**Keywords:** PitNETs, pituitary adenoma, pregnancy, neurosurgery, outcome, proliferation markers

**Word count:** 3387 3660 words in manuscript excluding references, figure legends, abstract, significance statement and acknowledgments
For Review Only
1 **Abstract (245 words)**

2

3 **Objective:** Data on pituitary neuroendocrine tumors (PitNETs) surgically treated during pregnancy is limited, and no studies have compared these cases to those treated in non-pregnant women. This study aimed to describe the clinical, radiological, and histological profiles of patients treated surgically for PitNETs during pregnancy and evaluate long-term prognosis.

7 **Design:** This study was multicentric, observational and retrospective.

8 **Methods:** We included 10 patients from 5 university hospitals who underwent surgical treatment for PitNETs during pregnancy or within 12 months postpartum, along with 30 matched non-pregnant controls treated surgically for PitNETs. Clinical and histological data, as well as progression-free survival without additional treatment, were compared between pregnant and non-pregnant patients.

13 **Results and Conclusions:** Among the 10 PitNETs, 4 were corticotropic, 2 gonadotropic, 2 lactotropic, and 2 somatotropic. The primary surgical indication (tumour syndrome with or without failure of medical treatment) was similar between the two groups: 7/10 vs 19/30 (p = 1.00). There was no statistically significant difference in volume (p = 0.072) or radiological invasion markers (optic chiasm compression, p = 0.059, and cavernous sinus invasion, p = 0.274). However, PitNETs in pregnant women showed higher mitotic activity (p = 0.038) and were more frequently classified as grade 2b (Trouillas clinicopathological classification; p = -0.010; p = 0.049). The need for second-line treatment was also more frequent (p = 0.005). PitNETs requiring surgical treatment during pregnancy are characterized by increased proliferative activity and progression after surgery. Despite this, the long-term prognosis remains favorable. These results need confirmation in a larger study.

24
25 **Significance Statement (126 words)**

26 The characteristics and prognosis of PitNETs during pregnancy are not well-documented. Our 27 case-control study provides the first comprehensive histopathological and prognostic analysis of 28 PitNETs treated surgically during pregnancy or postpartum. While tumour size and radiological 29 invasion markers did not differ statistically knwing that the sample size is limited significantly 30 compared to non-pregnant controls, our findings indicate that adenomas in pregnant patients 31 exhibit more proliferative behavior. Although tumor size and radiological invasion markers did 32 not show a statistically significant difference, with the caveat of a small sample size, our findings 33 suggest that adenomas PitNETs in pregnant patients exhibit more proliferative behavior compared 34 to non-pregnant controls. Specifically, these PitNETs tumours show higher mitotic activity, are 35 more frequently classified as grade 2b according to Trouillas clinicopathological classification, 36 and require second-line treatments more often. This underscores the importance of close 37 postoperative monitoring for pregnant patients with PitNETspituitary tumours and highlights the 38 need for further research to elucidate long-term outcomes and the pathophysiological mechanisms 39 driving this increased proliferative activity. 40
## 51 Introduction

52 Pituitary adenomas, now referred to as pituitary neuroendocrine tumours (PitNET) are a 53 heterogeneous group of intracranial tumours. The classification of PitNETspituitary tumors was 54 recently updated in the 2021 5th edition of the World Health Organization (WHO) Classification 55 of Central Nervous System Tumours (CNS5) and the 2022 5th edition of the WHO Classification 56 of Endocrine and Neuroendocrine Tumours (ENDO5). These revisions provide a more detailed 57 histological typing and subtyping of PitNETs, guided by immunohistochemistry for lineage- 58 restricted pituitary transcription factors. (1,2) According to the World Health Organization's 2017 59 2022 classification, PitNETs are categorized into 5 main histological subtypes based on the adeno- 60 hypophyseal cell lineages found in normal pituitary tissue. Morpho-functional subtypes have also 61 been defined. While most PitNETs are benign and indolent, they can occasionally exhibit 62 aggressive behavior, leading to compression of adjacent structures and resulting in visual loss, 63 ocular nerve palsy, or intracranial hypertension due to local progression or tumour apoplexy. 64 Additionally, some PitNETs may cause significant symptoms due to hormonal hypersecretion, 65 particularly of cortisol or growth hormone (3). 66

67 Some benign or malignant tumours, like adrenal or breast neoplasms, may show a more aggressive 68 course during pregnancy. Pregnancy leads to enlargement of the pituitary gland due to estrogen- 69 induced hypertrophy of lactotroph cells (4–6), causing prolactinomas to increase in size (7–9). In 70 most patients, the lesions are small, and the overall increase in size is not clinically significant 71 (7,8). The effect of pregnancy on other types of PitNETs is not well understood. However, a few 72 patients with PitNETs may experience severe symptoms that necessitate emergency treatment 73 during pregnancy (10–15).
74 The reasons why a small number of these adenomas PitNETs grow more rapidly and become 75 symptomatic during pregnancy are unclear. Guidance on the management of PitNETs during 76 pregnancy has recently been published; however, the long-term prognosis of these tumors remains 77 poorly described (16,17).

78 The occurrence of symptomatic PitNETs during pregnancy is rare, with only 38 published patients 79 cases primarily providing clinical and radiological descriptions (7,10–15,18–36). No data are 80 available on the histopathological markers or the long-term recurrence risk compared to control 81 PitNETstumours surgically treated outside of pregnancy. We thus conducted a multicentric, 82 observational retrospective study in 5 university FIRENDO centers (French National Healthcare 83 Network for Rare Endocrine Diseases) with the objective of reporting data from women with 84 symptomatic PitNETs, discovered (or diagnosed) or complicated during pregnancy, and requiring 85 surgical treatment either during pregnancy or within the first 12 months postpartum. The data were 86 compared to a control cohort of women with PitNETs requiring surgery, matched by histological 87 adenoma type. 88

89
90 **Patients and Methods**

91

92 **Methods**

93

94 The study was conducted as a multicentric, observational, and retrospective analysis across 5

95 French university hospitals in the FIRENDO network. Physicians documented the medical records

96 of patients who underwent PitNET surgery during pregnancy or postpartum. The principal

97 investigator reviewed these records to ensure patients met the inclusion criteria and consented to

98 the use of their medical data. The control group was selected from a single-center database at Pitié

99 Salpêtrière Hospital, including 3,252 patients, with 1,886 women who underwent PitNET

100 endoscopic surgery between 2008 and 2023.

101

102 **Population**

103 **Patients with PitNets operated treated surgically during pregnancy or post-partum**

104 The inclusion criteria consisted of women over 18 years of age who underwent surgery for a

105 symptomatic PitNET during pregnancy or within 12 months of delivery. Exclusion criteria

106 included being under guardianship, refusal to provide consent, and lack of histopathological data.

107 From 5 French university hospitals of the FIRENDO network, we identified 13 potentially eligible

108 patients. One patient was excluded due to missing histological reports and samples, and 2 patients

109 presented a different brain tumour on histopathology (Rathke's Cleft cyst).

110 We thus included 10 symptomatic patients with a pituitary adenoma PitNET treated surgically

111 during pregnancy or within 12 months postpartum.

112
113 **Control patients with PitNets surgically treated outside of pregnancy**

114 The inclusion criteria for control patients consisted of women over 18 years of age who underwent
115 surgery for a PitNET. Exclusion criteria included being under guardianship, refusal to provide
116 consent, lack of histopathological data or pituitary surgical intervention during pregnancy or in the
117 12 months following childbirth.

118 For each pregnant patient, matching was done by randomly selecting 3 control females who had
119 undergone surgical treatment for the same histological type of PitNET, with the closest possible
120 age at surgery to that of the case in question.

121 For each pregnant patient, we selected the 3 control female patients with the closest possible age
122 at surgery and with the same histological type of PitNET.

123

124 **Data collection and measurements**

125 For each patient, the principal investigator gathered data from medical records, including the initial
126 clinical presentation, as well as hormonal, radiological, and histological findings, and details on
127 pituitary tumor PitNET progression. Radiological data were gathered from pituitary magnetic
128 resonance imaging (MRI) reports at diagnosis, preoperatively, and during follow-up: adenoma
129 size, optic chiasm involvement, suprasellar extension according to the SIPAP (superior, inferior,
130 parasellar, anterior, posterior) classification described below, cavernous sinus invasion or other
131 adjacent structures according to Knosp classification (37,38). Optic chiasm involvement was
132 classified as "not involved" when the adenoma did not extend into the suprasellar space or only
133 made contact with the optic chiasm without displacing it. It was described as "optic chiasm
134 compression" when the optic chiasm was displaced by the PitNETpituitary adenoma. Cavernous
135 sinus invasion was categorized as absent (Knosp 0), present unilaterally or bilaterally (Knosp 3b and 4), or doubtful (Knosp 1, 2, 3a).

137 The SIPAP classification, first introduced by Edal et al. in 1997 (39,40), categorizes the extension of PitNETspituitary adenomas beyond the sellae. One aspect evaluated in this classification is the suprasellar extension of PitNETspituitary adenomas, which is graded on a scale from 0 to 4. This scale ranges from Grade 0, which indicates no bulging into the suprasellar space, to Grade 4, where the adenoma's extension leads to obstructive hydrocephalus.

142 Hormone assessments were conducted in certified laboratories at various university hospitals using mostly automated immunological techniques. Different immunometric methods were used to measure somatotropic hormones (GH, IGF1), ACTH, and gonadotropins (FSH, LH), depending on the center and its equipment. Free T4, cortisol, and estradiol were measured using competitive or electro-chemiluminescent, chemiluminescent, immunofluorometric, or enzymatic markers. All assays were carried out in accredited clinical endocrinology laboratories (COFRAC) and followed national quality control standards for hormone testing (ProBioQual, France).

149 Histological slide readings or proofreading were conducted by the same expert anatomo-pathologist in accordance with the standardized report validated by the European Pituitary Pathology Group (41). Histological data were collected by the principal investigator from anatomo-pathological reports and reevaluation reports by the same expert anatomo-pathologist.
150
151
152
153 The data included histological type of the adenoma, immunostaining, presence of fibrosis or necrosis, transcription factors, proliferation markers (including Ki-67, number of mitoses per 10 high-power fields at 40X magnification).
154
155

156 Prognostic evaluation/recurrence risk

157 Tumour proliferation and local invasiveness were evaluated in both groups using the five-tiered
prognostic classification proposed by Trouillas et al and endorsed by the European Pituitary Pathology Group (EPPG), which ranks PitNETs into 5 severity levels grades based on tumour invasiveness, immunohistochemical type, and at least 2 of 3 proliferative markers (Ki-67 index, mitotic count, or p53 positivity) (42). Regarding the definition of invasion and proliferation, we followed the criteria outlined in the Trouillas classification. Invasion was evaluated based on MRI findings using the Knosp system or intraoperative observations, with a score of 1 indicating non-invasive and 2 indicating invasive. Proliferation was assessed by immunohistochemistry for cell proliferation marker Ki-67 and mitotic count, with scores of "a" for non-proliferative and "b" for proliferative. Since we did not have p53 expression data for all tumors, we used Ki67 positivity and mitotic activity to define proliferation. A tumor was classified as proliferative if Ki-67 index was ≥3% and mitoses were >2/10 HPF.

Hence, the tumors are classified into the following five grades: Grade 1a (non-invasive and non-proliferative), Grade 1b (non-invasive and proliferative), Grade 2a (invasive and non-proliferative), Grade 2b (invasive and proliferative), and Grade 3 (metastatic tumor).

This classification validated by Trouillas et al, has proven prognostic value in several cohorts independently (42,43).

Progression data during follow-up included the need for second-line treatments (dopaminergic or somatostatin analogues, additional surgery, or radiotherapy), as well as the timing of these treatments, the duration of follow-up, and the date of the last follow-up consultation.

## Statistical Analysis

Statistical analyses were performed using R software, employing non-parametric tests due to small cohort sizes. Mann-Whitney test compared quantitative variables, and Fisher's exact test was used
181 to assess qualitative data, with Bonferroni corrections applied when multiple tests were performed.

182 Kaplan-Meier survival curves were constructed to compare progression-free survival without a

183 new treatment between the two groups. The Kaplan-Meier method was used for progression-free

184 survival estimation, and the log-rank test was applied to compare progression-free survival curves

185 between the two groups. A probability value (p) less than 0.05 was considered statistically

186 significant, regardless of the statistical test used.

187 Ethical Considerations

188 The patients did not express any opposition to the anonymous use of their medical data and the

189 protocol was approved by the Scientific Committee of Gustave Roussy Institute on 14/08/2023

190 (registration number 2023-253). The FIRENDO registries were approved by the ethics committees

191 of each hospital and by the National Commission for Data Protection and Liberties (CNIL). This

192 study complies with the Declaration of Helsinki.
193 **Results**

194 **Clinical and hormonal presentation of patients with PitNETs treated surgically during pregnancy** (Figure 1 and table 1).

196 The median age of surgery of the cohort was 31 years [range: 25 to 45 years]. In five patients (5/10, 50%) the PitNET was diagnosed prior to pregnancy. The 10 patients had symptoms resulting from tumour volume or hypersecretion during the pregnancy. The median gestational age at symptom onset was 22 weeks of amenorrhea [range: 6 to 40 weeks]. In 8 patients, tumoral syndrome was observed. Symptoms included headaches (5/10), decreased visual acuity (5/10, ranging from 3/10 to 7/10; one with optic nerve atrophy), visual field alterations (5/10, mainly bitemporal hemianopsia), cavernous sinus syndrome (2/10; 1 with ptosis, 1 with unilateral V1 neuralgia), and ideomotor slowing (1/10). Additionally, 1 patient presented with vasopressin deficiency.diabetes insipidus.

205 In the 2 other patients (20%), the tumour was identified due to cortisol hypersecretion leading to Cushing's syndrome. One patient presented with tumoral syndrome but acromegalic symptoms were clearly present (10%, n = 1/10).

208 Among the 10 patients, immediate surgery was decided in 2 cases. The 8 remaining patients received initial medical treatment, including dopaminergic agonists (in 2 cases, for prolactin-secreting or lactotroph adenomas PitNETs and in 2 cases, for non-functional adenomasPitNETs), high-dose glucocorticoids for anti-oedematous purposes (in 1 non-functional PitNETadenoma with intracranial hypertension), and somatostatin analogues (in 1 somatotropic PitNET adenoma).

213 The 2 patients presenting with hypercortisolism received initial symptomatic treatment (lifestyle changes and antihypertensive treatments), which effectively controlled symptoms in 1 patient
215 allowing to differ surgery after delivery but was insufficient for the other, necessitating surgical
216 intervention during pregnancy.

217 Surgery was performed in 5 patients (5/10, 50%) during pregnancy, predominantly in the second
218 trimester, with a median gestational age at surgery of 27 weeks [range: 24 to 30 weeks]. The
219 remaining 5 patients underwent surgery during the postpartum period, with a median time to
220 surgery of 26 days [range: 2 to 330 days] (Figure 1).

221

222 **Surgical procedure and outcome, histological data**

223 The surgical approach was primarily endoscopic via the endonasal route in 90% of cases (n =
224 9/10). The remaining patient, with a giant pituitary adenoma PitNET causing suprasellar extension
225 and obstructive hydrocephalus, required a sub-frontal approach.

226 The invasive nature of the adenoma was specified in the operative report for 80% of the patients
227 (8/10) with cavernous sinus invasion in 62.5% of these patients (5/8) including unilateral invasion
228 in 3 and bilateral invasion in 2 patients.

229 Resection of the adenoma was considered as incomplete in 80% of patients (8/10).

230 No severe postoperative complications were observed. Transient vasopressin deficiency diabetes
231 insipidus was noted in 40% of patients (4/10). One patient who underwent sub-frontal surgery for
232 a giant adenoma required a second surgery via the interhemispheric approach 7 days later, which
233 resulted resulting in transient memory disturbances and the development of a meningocele.

234 Postoperative visual acuity improved in all patients who experienced preoperative visual
235 disturbances.
236 Five PitNETs were non functional with different histological subtypes of PitNET were non-functional (n = 5/10, 50%, including: 2 silent corticotropic, 1 silent somatotropic and 2 gonadotropic tumours). Five were hormone-secreting PitNETS comprising 2 lactotropic (2/10, 20%), 2 corticotropic (2/10, 20%), and 1 somatotropic (1/10, 10%) tumour (Table 1).

240

241 **Pregnancy outcome**

242 The median term at delivery, either vaginal (n = 8/10) or cesarean (n = 2/10), was 38 weeks of gestation [range: 36 to 40 weeks]. We observed three moderate preterm births between 36 and 36 weeks +4 days (30%), with two cesarean deliveries performed to facilitate neurosurgical intervention shortly thereafter (at 2 and 4 days postpartum, respectively). Additionally, no morbidity or mortality were reported in the newborns, and no female patient died during delivery or cesarean section.

248
249 **Specificities of pituitary adenomas PitNETs treated surgically during pregnancy**
250
251 **Clinical and radiological presentation**
252
253 The clinical presentation of pregnant patients with PitNETs (cases) was similar to that of non-pregnant patients (controls), except for decreased visual acuity, which was significantly more frequent in pregnant patients (5/10, 50% vs. 4/30, 13.3%; p = 0.029). No significant difference was found in other clinical signs or symptoms between the two groups (Table 1).

257 On MRI, PitNETs treated surgically in pregnant patients tended to have a larger maximum diameter compared to controls patients (27 mm vs. 18 mm, p = 0.072) with a significantly higher proportion of pregnant patients showing a suprasellar extension grade 4 (3/8, 37.5% in cases vs. 1/29, 3.5% in controls; p = 0.026, Table 2). However, no statistically significant differences were
261 observed in optic chiasma compression (7/10, 70% in cases vs. 9/30, 30% in controls, p = 0.059),

262 and cavernous sinus invasion (p = 0.274, Table 2)

263 **Comparison of treatment and outcome**

264 Surgical indications were similar in both groups. The most common indication was a tumoral

265 syndrome with or without medical treatment failure: 7/10 (70%) in pregnant patients with PitNETs

266 vs. 19/30 (63.3%) in controls (p = 1.00). Less often, the indication was a secretory syndrome: 3/10

267 (30%) in pregnant patients vs. 11/30 (36.7%) in controls (p = 1.00, Table 1). Medical treatment

268 before surgical management was introduced in 5/10 (50%) of pregnant patients with PitNETs vs.

269 10/30 (33.3%) in controls (p = 0.457). The median duration between the initial diagnosis and

270 surgical management was similar in the two groups: 14 months for cases and 11.5 months for

271 controls (p = 0.851).

272 Noteworthy, the median age at diagnosis surgery was significantly higher in the control group: 31

273 vs. 41.5 years (p = 0.039).

274 Concerning surgical outcome, there was a tendency toward more frequently incomplete surgical

275 resection in patients treated surgically during pregnancy or postpartum, although this difference

276 was not statistically significant (8/10, 80% in case group vs. 13/29, 44.8% in controls, p = 0.074).

277 There were no significant differences in postoperative complications between the two groups

278 (4/10, 40% for cases vs. 6/30, 20% for controls, p = 0.232), except for a higher incidence of

279 transient vasopressin deficiency diabetes insipidus in pregnant women, which is likely attributable

280 to pregnancy rather than the surgery itself.

281

282 **Histological markers of proliferation**
283 A number of mitoses strictly higher than 2/10 were more frequently observed in PitNETs of 284 patients treated surgically during pregnancy or post-partum (3/9, 33.3% vs. 1/28, 3.6% in controls 285 patients, p = 0.038). However, there was no difference in median Ki-67 values or presence of Ki- 286 67 ≥ 3% between the two groups (Table 2).

288 Regarding the histoprognostic stage according to the Trouillas classification, a significant 289 proportion of PitNETs were classified as invasive and proliferative (grade 2b) in pregnant women 290 (3/9, 33.3%), compared to none (0/30) in control patients (p = 0.0100.049, Table 2).

291
292 Evolution after surgery

293 The prognostic outcomes following surgery for patients who underwent surgical procedures during 294 pregnancy or the postpartum period are summarized in Table 3. During follow-up, 8/9 (88.9%) 295 pregnant patients required additional treatment to control tumour progression or secretion: 5/9 296 (55.6%) received medical treatment (4 with dopaminergic agonists and 1 with a somatostatin 297 analogue), 2/9 (22.2%) underwent a second surgery, and 1/9 (11.1%) received radiotherapy. 298 Notably, in 1 patient, radiotherapy was performed after the failure of somatostatin analogues.

299 In the control group, 8/27 (29.6%) women required additional treatment, with medical treatment 300 in 5/27 (18.5%) patients (dopaminergic agonist in 3 patients, somatostatin analogue in 1 patient 301 and metyrapone in 1 patient), and radiotherapy in 3/27 (11.1%) patients.

302 The necessity of additional post-surgical treatment was more frequent in patients treated surgically 303 during pregnancy or postpartum: (8/9, 89% of cases vs. 8/27, 30% of controls, p = 0.005).

304 A statistically significant difference is observed between the two groups regarding progression-free survival without the need for additional treatment (p = 0.024) (Figure 2).
306 Noteworthy, the available follow-up is longer in patients treated surgically during pregnancy or
307 postpartum compared to controls patients, although this difference is not statistically significant
308 (median follow-up of 65 months [range: 4 to 163 months] in cases vs. 26 months [range: 0 to 127
309 months] in controls, p = 0.096).

310 **Discussion**

311 The impact of pregnancy on PitNETs remains unclear. In most cases, any increase in tumor size
312 is not clinically significant, although rare cases of rapid progression during pregnancy can occur,
313 necessitating emergency surgical intervention (7). This situation is uncommon, and the limited
314 available data make it challenging to thoroughly investigate why only a small number of these
315 adenomas PitNETs show rapid progression and symptoms during pregnancy. Furthermore,
316 although guidance to optimal management strategies has been recently published, the long-term
317 prognosis of PitNETs during pregnancy remains poorly defined (16,17).

318 Hence, in this national multicenter retrospective study, we reported data from 10 patients who
319 underwent pituitary surgery for a PitNET during pregnancy or the postpartum period, compared
320 with 30 non-pregnant controls. A comprehensive analysis of clinical, radiological,
321 histopathological findings, and long-term prognosis, was provided.

322 Our results are in agreement with those reported in the literature (7,10–15,18–36), particularly
323 regarding the mode of presentation (primarily as a tumour syndrome), median gestational age at
324 symptom onset, surgery, and delivery. Regarding surgical complications, although 4 out of 10
325 patients experienced transient vasopressin deficiency which is likely related to the pregnancy itself
326 and one required a second surgery after one week, no serious postoperative complications were
327 observed. Maternal and fetal outcomes were generally favorable, with no cases of fetal mortality
328 or extreme prematurity.

329 While the proportion of adenomas PitNETs with a Ki-67 index of 3% or higher was similar
330 between the two groups, the case group had a significantly higher percentage of patients tumours
331 with more than two mitoses per 10 high-power fields. Additionally, a notable number of invasive
332 and proliferative adenomas PitNETs (grade 2b according to the Trouillas histo-prognostic
333 classification) (42) were found in pregnant or postpartum patients, while none were observed in
334 the control group. These findings suggest that PitNETs pituitary adenomas in pregnant or
335 postpartum patients are more likely proliferative than those in non-pregnant patients. Whether
336 pregnancy-related changes contribute to the increased proliferative characteristics of these
337 PitNETs adenomas remains to be determined. Additionally, we cannot exclude the possibility that
338 younger age, as observed in the group of patients with PitNETs diagnosed during pregnancy, may
339 contribute to the increased proliferative behavior of tumors (44).

340 We assessed the risk of recurrence and progression in PitNETspituitary adenomas surgically
341 treated during pregnancy and postpartum. Patients in these groups had a higher and earlier risk of
342 requiring additional treatments (medical, radiotherapy, or surgery) compared to controls. Among
343 those needing further treatment, there was a greater proportion of grade 2b tumours. This is in
344 agreement with Trouillas et al.'s study, which indicated that 60% of adenomas PitNETs with
345 progression or recurrence at 8 years had a histo-prognostic grade of 2a or higher, with grade 2b
346 tumours showing a 12-fold increased risk of recurrence compared to grade 1a tumours (42). These
347 findings reinforce the relevance of the French histo-prognostic classification of 2013 and suggest
348 its applicability for PitNETsadenomas treated surgically during pregnancy.
The higher and earlier number of recurrences, requiring additional treatment, observed in our cohort may be due to less complete surgical excision during pregnancy, as neurosurgeons might be concerned about surgical complications and compromising fetal health. However, it should be noted that, although not statistically significant, the duration of follow-up was shorter in the control group, as well as an earlier loss to follow-up was observed in this group.

Due to the lack of regular MRI follow-ups or available MRI images for review by the same radiologist, we did not assess radiological recurrence or changes in residual tumour size in our study. Instead, we focused on the clinical outcome of needing additional treatment as an indicator of recurrence or progression.

Although lactotroph PitNETsadenomas are usually the most commonly reported symptomatic pituitary tumours PitNETs during pregnancy (10), our study found a higher prevalence of non-functional adenomas. This finding is not surprising, as our cohort consisted of surgical patients, given our focus on studying histological markers. To address this discrepancy and minimize potential center-related selection bias, we matched control patients with case patients based on the histological type of their PitNETspituitary adenomas. Lactotroph PitNETsadenomas are particularly expected to be more symptomatic during pregnancy due to their tendency to enlarge in response to estrogen, which can stimulate the proliferation of both normal and tumoral lactotrophs (7,8). This can lead to symptoms such as headaches and visual disturbances (45,46). While the impact of pregnancy on other pituitary tumour PitNET subtypes—such as gonadotropic, corticotropic, and thyrotropic cells—is not well established, there are reports suggesting that these macroadenomas can also grow more during pregnancy (10,47).
370 It remains unclear whether this growth is due to the general pituitary enlargement associated with 371 lactotroph-hyperplasia, which may increase overall tumour size and exacerbate mass effects, or if 372 it is a direct consequence of hormonal changes from pregnancy affecting the adenomas PitNETs 373 themselves.

374 Our study has limitations in interpreting the prognostic outcomes. Firstly, The small sample size 375 of pregnant or postpartum patients reduces the power of the study and the generalizability of the 376 results.

377 To our knowledge, our study is the first case-control analysis to characterize symptomatic 378 PitNETspituitary tumours during pregnancy and their histo-prognostic grading and prognosis. Our 379 findings indicate that symptomatic pituitary tumours PitNETs surgically treated during this period 380 are associated with increased proliferative histologic activity and a higher likelihood of 381 progression after surgery up to 5 years post-operatively. The management of symptomatic PitNETs 382 during pregnancy is more complex, and patients should be informed and closely monitored after 383 pituitary surgery. Overall, our study offers new valuable insights into this specific population of 384 pregnant patients with pituitary adenomas PitNETs. Nonetheless, further research is needed to 385 clarify the long-term prognosis of symptomatic PitNETspituitary tumours treated surgically during 386 pregnancy or postpartum and to understand the pathophysiological factors driving this increased 387 proliferative activity.

388
389 **Conflict of interest**
390 The authors declare no competing interests

391
392 **Funding**
393 This work was supported by FIRENDO and Assistance Publique Hôpitaux de Paris

394

395 Acknowledgements

396 We thank the patients and the staffs of the French National Healthcare Network for Rare Endocrine

397 Diseases (FIRENDO) and all the participating centers, especially the National Reference Center

398 for Rare Pituitary Disease (CRMR HYPO).

399

400 Contribution

401 Conceptualization; BB, CO, MB, MH, MLRS. Patients care: MH, CV, BB, SG, PC, LG, AR, CG

402 MLRS. Data collection: CO, BB. Statistical analyses and figures: CO, MH, TH. Original draft

403 preparation: CO, MB, MH, MLRS. Manuscript review and editing: all authors.

404

405 Data Availability Statement

406 The datasets generated and analyzed during the current study are not publicly available due to the

407 sensitive nature of the data and the potential high risks associated with patient confidentiality.

408 However, anonymized data may be available from the corresponding author upon reasonable

409 request and after obtaining new approval from the patients.

410

411 Figure captions:

412 Figure 1: Summary of the diagnostic and management approaches for PitNETs in 10

413 pregnant patients. GA, gestational age; PP, post-partum; SSA, somatostatin analogues; W,

414 weeks

415
Figure 2: Progression-free survival curves comparing the duration of survival without the need for additional treatment between patients undergoing surgery for PitNET during pregnancy or post-partum and matched controls.

The x-axis represents time in days weeks, ranging from 19 to 4977 days 0 to 508 weeks, while the y-axis shows the proportion of patients remaining progression-free. Patients treated surgically during pregnancy or postpartum have a significantly shorter median progression-free survival without the need for additional treatment (including second surgery, radiotherapy, or additional medical treatments; p = 0.024) compared to controls.
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**Abstract (245 words)**

2

**Objective:** Data on pituitary neuroendocrine tumors (PitNETs) surgically treated during pregnancy is limited, and no studies have compared these cases to those treated in non-pregnant women. This study aimed to describe the clinical, radiological, and histological profiles of patients treated surgically for PitNETs during pregnancy and evaluate long-term prognosis.

**Design:** This study was multicentric, observational and retrospective.

**Methods:** We included 10 patients from 5 university hospitals who underwent surgical treatment for PitNETs during pregnancy or within 12 months postpartum, along with 30 matched non-pregnant controls treated surgically for PitNETs. Clinical and histological data, as well as progression-free survival without additional treatment, were compared between pregnant and non-pregnant patients.

**Results and Conclusions:** Among the 10 PitNETs, 4 were corticotropic, 2 gonadotropic, 2 lactotropic, and 2 somatotropic. The primary surgical indication (tumour syndrome with or without failure of medical treatment) was similar between the two groups: 7/10 vs 19/30 (p = 1.00). There was no statistically significant difference in volume (p = 0.072) or radiological invasion markers (optic chiasm compression, p = 0.059, and cavernous sinus invasion, p = 0.274). However, PitNETs in pregnant women showed higher mitotic activity (p = 0.038) and were more frequently classified as grade 2b (Trouillas clinicopathological classification; p=0.049). The need for second-line treatment was also more frequent (p = 0.005). PitNETs requiring surgical treatment during pregnancy are characterized by increased proliferative activity and progression after surgery. Despite this, the long-term prognosis remains favorable. These results need confirmation in a larger study.

24
25 **Significance Statement (126 words)**

26 The characteristics and prognosis of PitNETs during pregnancy are not well-documented. Our 27 case-control study provides the first comprehensive histopathological and prognostic analysis of 28 PitNETs treated surgically during pregnancy or postpartum. Although tumor size and radiological 29 invasion markers did not show a statistically significant difference, with the caveat of a small 30 sample size, our findings suggest that PitNETs in pregnant patients exhibit more proliferative 31 behavior compared to non-pregnant controls. Specifically, these PitNETs show higher mitotic 32 activity, are more frequently classified as grade 2b according to Trouillas clinicopathological 33 classification, and require second-line treatments more often. This underscores the importance of 34 close postoperative monitoring for pregnant patients with PitNETs and highlights the need for 35 further research to elucidate long-term outcomes and the pathophysiological mechanisms driving 36 this increased proliferative activity. 37
## 51 Introduction

52 Pituitary adenomas, now referred to as pituitary neuroendocrine tumours (PitNET) are a 53 heterogeneous group of intracranial tumours. The classification of PitNETs was recently updated 54 in the 2021 5th edition of the World Health Organization (WHO) Classification of Central Nervous 55 System Tumours (CNS5) and the 2022 5th edition of the WHO Classification of Endocrine and 56 Neuroendocrine Tumours (ENDO5). These revisions provide a more detailed histological typing 57 and subtyping of PitNETs, guided by immunohistochemistry for lineage-restricted pituitary 58 transcription factors (1,2). While most PitNETs are benign and indolent, they can occasionally 59 exhibit aggressive behavior, leading to compression of adjacent structures and resulting in visual 60 loss, ocular nerve palsy, or intracranial hypertension due to local progression or tumour apoplexy. 61 Additionally, some PitNETs may cause significant symptoms due to hormonal hypersecretion, 62 particularly of cortisol or growth hormone (3). 63

64 Some benign or malignant tumours, like adrenal or breast neoplasms, may show a more aggressive 65 course during pregnancy. Pregnancy leads to enlargement of the pituitary gland due to estrogen- 66 induced hypertrophy of lactotroph cells (4–6), causing prolactinomas to increase in size (7–9). In 67 most patients, the lesions are small, and the overall increase in size is not clinically significant 68 (7,8). The effect of pregnancy on other types of PitNETs is not well understood. However, a few 69 patients with PitNETs may experience severe symptoms that necessitate emergency treatment 70 during pregnancy (10–15).

71 The reasons why a small number of these PitNETs grow more rapidly and become symptomatic 72 during pregnancy are unclear. Guidance on the management of PitNETs during pregnancy has 73 recently been published; however, the long-term prognosis of these tumors remains poorly 74 described (16,17).
The occurrence of symptomatic PitNETs during pregnancy is rare, with only 38 published cases primarily providing clinical and radiological descriptions (7,10–15,18–36). No data are available on the histopathological markers or the long-term recurrence risk compared to control PitNETs surgically treated outside of pregnancy. We thus conducted a multicentric, observational retrospective study in 5 university FIRENDO (French National Healthcare Network for Rare Endocrine Diseases) centers with the objective of reporting data from women with symptomatic PitNETs, diagnosed or complicated during pregnancy, and requiring surgical treatment either during pregnancy or within the first 12 months postpartum. The data were compared to a control cohort of women with PitNETs requiring surgery, matched by histological adenoma type.

## Patients and Methods

### Methods

The study was conducted as a multicentric, observational, and retrospective analysis across 5 French university hospitals in the FIRENDO network. Physicians documented the medical records of patients who underwent PitNET surgery during pregnancy or postpartum. The principal investigator reviewed these records to ensure patients met the inclusion criteria and consented to the use of their medical data. The control group was selected from a single-center database at Pitié Salpêtrière Hospital, including 3,252 patients, with 1,886 women who underwent PitNET endoscopic surgery between 2008 and 2023.

### Population

#### Patients with PitNets treated surgically during pregnancy or post-partum
The inclusion criteria consisted of women over 18 years of age who underwent surgery for a symptomatic PitNET during pregnancy or within 12 months of delivery. Exclusion criteria included being under guardianship, refusal to provide consent, and lack of histopathological data.

From 5 French university hospitals of the FIRENDO network, we identified 13 potentially eligible patients. One patient was excluded due to missing histological reports and samples, and 2 patients presented a different brain tumour on histopathology (Rathke's Cleft cyst).

We thus included 10 symptomatic patients with a PitNET treated surgically during pregnancy or within 12 months postpartum.

107

## 108 Control patients with PitNets surgically treated outside of pregnancy

The inclusion criteria for control patients consisted of women over 18 years of age who underwent surgery for a PitNET. Exclusion criteria included being under guardianship, refusal to provide consent, lack of histopathological data or pituitary surgical intervention during pregnancy or in the 12 months following childbirth.

For each pregnant patient, we selected the 3 control female patients with the closest possible age at surgery and with the same histological type of PitNET.

115

## 116 Data collection and measurements

For each patient, the principal investigator gathered data from medical records, including the initial clinical presentation, as well as hormonal, radiological, and histological findings, and details on PitNET progression. Radiological data were gathered from pituitary magnetic resonance imaging (MRI) reports at diagnosis, preoperatively, and during follow-up: adenoma size, optic chiasm
involvement, suprasellar extension according to the SIPAP (superior, inferior, parasellar, anterior, posterior) classification described below, cavernous sinus invasion or other adjacent structures according to Knosp classification (37,38). Optic chiasm involvement was classified as "not involved" when the adenoma did not extend into the suprasellar space or only made contact with the optic chiasm without displacing it. It was described as "optic chiasm compression" when the optic chiasm was displaced by the PitNET. Cavernous sinus invasion was categorized as absent (Knosp 0), present unilaterally or bilaterally (Knosp 3b and 4), or doubtful (Knosp 1, 2, 3a).

The SIPAP classification, first introduced by Edal et al. in 1997 (39,40), categorizes the extension of PitNETs beyond the sellae. One aspect evaluated in this classification is the suprasellar extension of PitNETs, which is graded on a scale from 0 to 4. This scale ranges from Grade 0, which indicates no bulging into the suprasellar space, to Grade 4, where the adenoma's extension leads to obstructive hydrocephalus.

Hormone assessments were conducted in certified laboratories at various university hospitals using mostly automated immunological techniques. Different immunometric methods were used to measure somatotropic hormones (GH, IGF1), ACTH, and gonadotropins (FSH, LH), depending on the center and its equipment. Free T4, cortisol, and estradiol were measured using competitive or electro-chemiluminescent, chemiluminescent, immunofluorometric, or enzymatic markers. All assays were carried out in accredited clinical endocrinology laboratories (COFRAC) and followed national quality control standards for hormone testing (ProBioQual, France).

Histological slide readings or proofreading were conducted by the same expert anatomo-pathologist in accordance with the standardized report validated by the European Pituitary Pathology Group (41). Histological data were collected by the principal investigator from anatomo-pathological reports and reevaluation reports by the same expert anatomo-pathologist.
144 The data included histological type of the adenoma, immunostaining, presence of fibrosis or
145 necrosis, transcription factors, proliferation markers (including Ki-67, number of mitoses per 10
146 high-power fields at 40X magnification).

147 Prognostic evaluation/recurrence risk

148 Tumour proliferation and local invasiveness were evaluated in both groups using the five-tiered
149 prognostic classification proposed by Trouillas et al and endorsed by the European Pituitary
150 Pathology Group (EPPG), which ranks PitNETs into 5 grades based on tumour invasiveness,
151 immunohistochemical type, and at least 2 of 3 proliferative markers (Ki-67 index, mitotic count,
152 or p53 positivity) (42). Regarding the definition of invasion and proliferation, we followed the
153 criteria outlined in the Trouillas classification. Invasion was evaluated based on MRI findings
154 using the Knosp system or intraoperative observations, with a score of 1 indicating non-invasive
155 and 2 indicating invasive. Proliferation was assessed by immunohistochemistry for cell
156 proliferation marker Ki-67 and mitotic count, with scores of "a" for non-proliferative and "b" for
157 proliferative. Since we did not have p53 expression data for all tumors, we used Ki67 positivity
158 and mitotic activity to define proliferation. A tumor was classified as proliferative if Ki-67 index
159 was ≥3% and mitoses were >2/10 HPF.

160 Hence, the tumors are classified into the following five grades: Grade 1a (non-invasive and non-
161 proliferative), Grade 1b (non-invasive and proliferative), Grade 2a (invasive and non-
162 proliferative), Grade 2b (invasive and proliferative), and Grade 3 (metastatic tumor).

163 This classification validated by Trouillas et al, has proven prognostic value in several cohorts
164 independently (42,43).
Progression data during follow-up included the need for second-line treatments (dopaminergic or somatostatin analogues, additional surgery, or radiotherapy), as well as the timing of these treatments, the duration of follow-up, and the date of the last follow-up consultation.

## 169 Statistical Analysis

Statistical analyses were performed using R software, employing non-parametric tests due to small cohort sizes. Mann-Whitney test compared quantitative variables, and Fisher's exact test was used to assess qualitative data, with Bonferroni corrections applied when multiple tests were performed. Kaplan-Meier survival curves were constructed to compare progression-free survival without a new treatment between the two groups. The Kaplan-Meier method was used for progression-free survival estimation, and the log-rank test was applied to compare progression-free survival curves between the two groups. A probability value (p) less than 0.05 was considered statistically significant, regardless of the statistical test used.

## 178 Ethical Considerations

The patients did not express any opposition to the anonymous use of their medical data and the protocol was approved by the Scientific Committee of Gustave Roussy Institute on 14/08/2023 (registration number 2023-253). The FIRENDO registries were approved by the ethics committees of each hospital and by the National Commission for Data Protection and Liberties (CNIL). This study complies with the Declaration of Helsinki.
184 **Results**

185 **Clinical and hormonal presentation of patients with PitNETs treated surgically during pregnancy** (Figure 1 and table 1).

187 The median age of surgery of the cohort was 31 years [range: 25 to 45 years]. In five patients (5/10, 50%) the PitNET was diagnosed prior to pregnancy. The 10 patients had symptoms resulting from tumour volume or hypersecretion during the pregnancy. The median gestational age at symptom onset was 22 weeks of amenorrhea [range: 6 to 40 weeks]. In 8 patients, tumoural syndrome was observed. Symptoms included headaches (5/10), decreased visual acuity (5/10, ranging from 3/10 to 7/10; one with optic nerve atrophy), visual field alterations (5/10, mainly bitemporal hemianopsia), cavernous sinus syndrome (2/10; 1 with ptosis, 1 with unilateral V1 neuralgia), and ideomotor slowing (1/10). Additionally, 1 patient presented with vasopressin deficiency.

196 In the 2 other patients (20%), the tumour was identified due to cortisol hypersecretion leading to Cushing's syndrome. One patient presented with tumoural syndrome but acromegalic symptoms were clearly present (10%, n = 1/10).

199 Among the 10 patients, immediate surgery was decided in 2 cases. The 8 remaining patients received initial medical treatment, including dopaminergic agonists (in 2 cases, for prolactin-secreting PitNETs and in 2 cases, for non-functional PitNETs), high-dose glucocorticoids for anti-oedematous purposes (in 1 non-functional PitNET with intracranial hypertension), and somatostatin analogues (in 1 somatotropic PitNET).

204 The 2 patients presenting with hypercortisolism received initial symptomatic treatment (lifestyle changes and antihypertensive treatments), which effectively controlled symptoms in 1 patient
206 allowing to differ surgery after delivery but was insufficient for the other, necessitating surgical
207 intervention during pregnancy.

208 Surgery was performed in 5 patients (5/10, 50%) during pregnancy, predominantly in the second
209 trimester, with a median gestational age at surgery of 27 weeks [range: 24 to 30 weeks]. The
210 remaining 5 patients underwent surgery during the postpartum period, with a median time to
211 surgery of 26 days [range: 2 to 330 days] (Figure 1).

212

213 **Surgical procedure and outcome, histological data**

214 The surgical approach was primarily endoscopic via the endonasal route in 90% of cases (n =
215 9/10). The remaining patient, with a giant PitNET causing suprasellar extension and obstructive
216 hydrocephalus, required a sub-frontal approach.

217 The invasive nature of the adenoma was specified in the operative report for 80% of the patients
218 (8/10) with cavernous sinus invasion in 62.5% of these patients (5/8) including unilateral invasion
219 in 3 and bilateral invasion in 2 patients.

220 Resection of the adenoma was considered as incomplete in 80% of patients (8/10).

221 No severe postoperative complications were observed. Transient vasopressin deficiency was noted
222 in 40% of patients (4/10). One patient who underwent sub-frontal surgery for a giant adenoma
223 required a second surgery via the interhemispheric approach 7 days later, which resulted in
224 transient memory disturbances and the development of a meningocele. Postoperative visual acuity
225 improved in all patients who experienced preoperative visual disturbances.

226 Five PitNETs were nonfunctional with different histological subtypes (n = 5/10, 50%, including 2
227 corticotropic, 1 somatotropic and 2 gonadotropic tumours). Five were hormone-secreting PitNETS
228 comprising 2 lactotropic (2/10, 20%), 2 corticotropic (2/10, 20%), and 1 somatotropic (1/10, 10%)

229 tumour (Table 1).

230
231 **Pregnancy outcome**
232 The median term at delivery, either vaginal (n = 8/10) or cesarean (n = 2/10), was 38 weeks of gestation [range: 36 to 40 weeks]. We observed 3 moderate preterm births between 36 and 36 weeks +4 days (30%), with two cesarean deliveries performed to facilitate neurosurgical intervention shortly thereafter (at 2 and 4 days postpartum, respectively). Additionally, no morbidity or mortality were reported in the newborns, and no female patient died during delivery or cesarean section.

238
239 **Specificities of PitNETs treated surgically during pregnancy**

240
241 **Clinical and radiological presentation**
242
243 The clinical presentation of pregnant patients with PitNETs (cases) was similar to that of non-pregnant patients (controls), except for decreased visual acuity, which was significantly more frequent in pregnant patients (5/10, 50% vs. 4/30, 13.3%; p = 0.029). No significant difference was found in other clinical signs or symptoms between the two groups (Table 1).

247 On MRI, PitNETs treated surgically in pregnant patients tended to have a larger maximum diameter compared to controls patients (27 mm vs. 18 mm, p = 0.072) with a significantly higher proportion of pregnant patients showing a suprasellar extension grade 4 (3/8, 37.5% in cases vs. 1/29, 3.5% in controls; p = 0.026, Table 2). However, no statistically significant differences were observed in optic chiasma compression (7/10, 70% in cases vs. 9/30, 30% in controls, p = 0.059), and cavernous sinus invasion (p = 0.274, Table 2)
253 **Comparison of treatment and outcome**

254 Surgical indications were similar in both groups. The most common indication was a tumoural
255 syndrome with or without medical treatment failure: 7/10 (70%) in pregnant patients with PitNETs
256 vs. 19/30 (63.3%) in controls (p = 1.00). Less often, the indication was a secretory syndrome: 3/10
257 (30%) in pregnant patients vs. 11/30 (36.7%) in controls (p = 1.00, Table 1). Medical treatment
258 before surgical management was introduced in 5/10 (50%) of pregnant patients with PitNETs vs.
259 10/30 (33.3%) in controls (p = 0.457). The median duration between the initial diagnosis and
260 surgical management was similar in the two groups: 14 months for cases and 11.5 months for
261 controls (p = 0.851).

262 Noteworthy, the median age at surgery was significantly higher in the control group: 31 vs. 41.5
263 years (p = 0.039).

264 Concerning surgical outcome, there was a tendency toward more frequently incomplete surgical
265 resection in patients treated surgically during pregnancy or postpartum, although this difference
266 was not statistically significant (8/10, 80% in case group vs. 13/29, 44.8% in controls, p = 0.074).
267 There were no significant differences in postoperative complications between the two groups
268 (4/10, 40% for cases vs. 6/30, 20% for controls, p = 0.232), except for a higher incidence of
269 transient vasopressin deficiency in pregnant women, which is likely attributable to pregnancy
270 rather than the surgery itself.

271

272 **Histological markers of proliferation**

273
274 A number of mitoses strictly higher than 2/10 were more frequently observed in PitNETs of
275 patients treated surgically during pregnancy or post-partum (3/9, 33.3% vs.1/28, 3.6% in controls
276 patients, p = 0.038). However, there was no difference in median Ki-67 values or presence of Ki-67 ≥ 3% between the two groups (Table 2).

278 Regarding the histoprognostic stage according to the Trouillas classification, a significant
279 proportion of PitNETs were classified as invasive and proliferative (grade 2b) in pregnant women
280 (3/9, 33.3%), compared to none (0/30) in control patients (p =0.049, Table 2).

281
282 **Evolution after surgery**

283 The prognostic outcomes following surgery for patients who underwent surgical procedures during
284 pregnancy or the postpartum period are summarized in Table 3. During follow-up, 8/9 (88.9%)
285 pregnant patients required additional treatment to control tumour progression or secretion: 5/9
286 (55.6%) received medical treatment (4 with dopaminergic agonists and 1 with a somatostatin
287 analogue), 2/9 (22.2%) underwent a second surgery, and 1/9 (11.1%) received radiotherapy.
288 Notably, in 1 patient, radiotherapy was performed after the failure of somatostatin analogues.

289 In the control group, 8/27 (29.6%) women required additional treatment, with medical treatment
290 in 5/27 (18.5%) patients (dopaminergic agonist in 3 patients, somatostatin analogue in 1 patient
291 and metyrapone in 1 patient), and radiotherapy in 3/27 (11.1%) patients.

292 The necessity of additional post-surgical treatment was more frequent in patients treated surgically
293 during pregnancy or postpartum: (8/9, 89% of cases vs. 8/27, 30% of controls, p = 0.005).

294 A statistically significant difference is observed between the two groups regarding progression-
295 free survival without the need for additional treatment (p = 0.024) (Figure 2).

296 Noteworthy, the available follow-up is longer in patients treated surgically during pregnancy or
297 postpartum compared to controls patients, although this difference is not statistically significant
298 (median follow-up of 65 months [range: 4 to 163 months] in cases vs. 26 months [range: 0 to 127
299 months] in controls, p = 0.096).
300 **Discussion**

301 The impact of pregnancy on PitNETs remains unclear. In most cases, any increase in tumor size
302 is not clinically significant, although rare cases of rapid progression during pregnancy can occur,
303 necessitating emergency surgical intervention (7). This situation is uncommon, and the limited
304 available data make it challenging to thoroughly investigate why only a small number of these
305 PitNETs show rapid progression and symptoms during pregnancy. Furthermore, although
306 guidance to optimal management strategies has been recently published, the long-term prognosis
307 of PitNETs during pregnancy remains poorly defined (16,17).

308 Hence, in this national multicenter retrospective study, we reported data from 10 patients who
309 underwent pituitary surgery for a PitNET during pregnancy or the postpartum period, compared
310 with 30 non-pregnant controls. A comprehensive analysis of clinical, radiological,
311 histopathological findings, and long-term prognosis, was provided.

312 Our results are in agreement with those reported in the literature (7,10–15,18–36), particularly
313 regarding the mode of presentation (primarily as a tumour syndrome), median gestational age at
314 symptom onset, surgery, and delivery. Regarding surgical complications, although 4 out of 10
315 patients experienced transient vasopressin deficiency which is likely related to the pregnancy itself
316 and one required a second surgery after one week, no serious postoperative complications were
317 observed. Maternal and fetal outcomes were generally favorable, with no cases of fetal mortality
318 or extreme prematurity.

319 While the proportion of PitNETs with a Ki-67 index of 3% or higher was similar between the two
320 groups, the case group had a significantly higher percentage of tumours with more than two
321 mitoses per 10 high-power fields. Additionally, a notable number of invasive and proliferative
PitNETs (grade 2b according to the Trouillas histo-prognostic classification) (42) were found in 322 pregnant or postpartum patients, while none were observed in the control group. These findings 323 suggest that PitNETs in pregnant or postpartum patients are more likely proliferative than those in 324 non-pregnant patients. Whether pregnancy-related changes contribute to the increased 325 proliferative characteristics of these PitNETs remains to be determined. Additionally, we cannot 326 exclude the possibility that younger age, as observed in the group of patients with PitNETs 327 diagnosed during pregnancy, may contribute to the increased proliferative behavior of tumors (44). 328

We assessed the risk of recurrence and progression in PitNETs surgically treated during pregnancy 329 and postpartum. Patients in these groups had a higher and earlier risk of requiring additional 330 treatments (medical, radiotherapy, or surgery) compared to controls. Among those needing further 331 treatment, there was a greater proportion of grade 2b tumours. This is in agreement with Trouillas 332 et al.'s study, which indicated that 60% of PitNETs with progression or recurrence at 8 years had 333 a histo-prognostic grade of 2a or higher, with grade 2b tumours showing a 12-fold increased risk 334 of recurrence compared to grade 1a tumours (42). These findings reinforce the relevance of the 335 French histo-prognostic classification of 2013 and suggest its applicability for PitNETs treated 336 surgically during pregnancy. 337

The higher and earlier number of recurrences, requiring additional treatment, observed in our 338 cohort may be due to less complete surgical excision during pregnancy, as neurosurgeons might 339 be concerned about surgical complications and compromising fetal health. However, it should be 340 noted that, although not statistically significant, the duration of follow-up was shorter in the control 341 group, as well as an earlier loss to follow-up was observed in this group. 342
343 Due to the lack of regular MRI follow-ups or available MRI images for review by the same radiologist, we did not assess radiological recurrence or changes in residual tumour size in our study. Instead, we focused on the clinical outcome of needing additional treatment as an indicator of recurrence or progression.
344
345
346

347 Although lactotroph PitNETs are usually the most commonly reported symptomatic PitNETs during pregnancy (10), our study found a higher prevalence of non-functional adenomas. This finding is not surprising, as our cohort consisted of surgical patients, given our focus on studying histological markers. To address this discrepancy and minimize potential center-related selection bias, we matched control patients with case patients based on the histological type of their PitNETs. Lactotroph PitNETs are particularly expected to be more symptomatic during pregnancy due to their tendency to enlarge in response to estrogen, which can stimulate the proliferation of both normal and tumoral lactotrophs (7,8). This can lead to symptoms such as headaches and visual disturbances (45,46). While the impact of pregnancy on other PitNET subtypes—such as gonadotropic, corticotropic, and thyrotropic cells—is not well established, there are reports suggesting that these macroadenomas can also grow more during pregnancy (10,47).
348
349
350
351
352
353
354
355
356
357

358 It remains unclear whether this growth is due to the general pituitary enlargement associated with lactotroph-hyperplasia, which may increase overall tumour size and exacerbate mass effects, or if it is a direct consequence of hormonal changes from pregnancy affecting the PitNETs themselves.
359
360

361 Our study has limitations in interpreting the prognostic outcomes. The small sample size of pregnant or postpartum patients reduces the power of the study and the generalizability of the results.
362
363
364 To our knowledge, our study is the first case-control analysis to characterize symptomatic PitNETs during pregnancy and their histo-prognostic grading and prognosis. Our findings indicate that 365 symptomatic PitNETs surgically treated during this period are associated with increased 366 proliferative histologic activity and a higher likelihood of progression after surgery up to 5 years 367 post-operatively. The management of symptomatic PitNETs during pregnancy is more complex, 368 and patients should be informed and closely monitored after pituitary surgery. Overall, our study 369 offers new valuable insights into this specific population of pregnant patients with PitNETs. 370

371 Nonetheless, further research is needed to clarify the long-term prognosis of symptomatic PitNETs 372 treated surgically during pregnancy or postpartum and to understand the pathophysiological factors 373 driving this increased proliferative activity. 374

375 **Conflict of interest**

376 The authors declare no competing interests

377
378 **Funding**

379 This work was supported by FIRENDO and Assistance Publique Hôpitaux de Paris

380
381 **Acknowledgements**

382 We thank the patients and the staffs of the French National Healthcare Network for Rare Endocrine 383 Diseases (FIRENDO) and all the participating centers, especially the National Reference Center 384 for Rare Pituitary Disease (CRMR HYPO).

385
386 **Contribution**
387 Conceptualization; BB, CO, MB, MH, MLRS. Patients care: MH, CV, BB, SG, PC, LG, AR, CG

388 MLRS. Data collection: CO, BB. Statistical analyses and figures: CO, MH, TH. Original draft

389 preparation: CO, MB, MH, MLRS. Manuscript review and editing: all authors.

390

391 **Data Availability Statement**

392 The datasets generated and analyzed during the current study are not publicly available due to the

393 sensitive nature of the data and the potential high risks associated with patient confidentiality.

394 However, anonymized data may be available from the corresponding author upon reasonable

395 request and after obtaining new approval from the patients.

396

397 **Figure captions:**

398 **Figure 1: Summary of the diagnostic and management approaches for PitNETs in 10**

399 **pregnant patients.** GA, gestational age; PP, post-partum; SSA, somatostatin analogues; W,

400 weeks

401

402 **Figure 2: Progression-free survival curves comparing the duration of survival without the**

403 **need for additional treatment between patients undergoing surgery for PitNET during**

404 **pregnancy or post-partum and matched controls.**

405 The x-axis represents time in weeks, ranging from 0 to 508 weeks, while the y-axis shows the

406 proportion of patients remaining progression-free. Patients treated surgically during pregnancy or

407 postpartum have a significantly shorter median progression-free survival without the need for

408 additional treatment (including second surgery, radiotherapy, or additional medical treatments; p

409 = 0.024) compared to controls.
410

411

412

413

414

415
416 References

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<table><caption>Table 1: Demographic, clinical and histological characteristics of patients undergoing surgery for PitNET during pregnancy or post-partum and matched controls</caption><thead><tr><th></th><th>Cases (n=10)</th><th>Controls (n=30)</th><th>p-value</th></tr></thead><tbody><tr><td>Age at surgery in years, median (min-max)</td><td>31 (25-45)</td><td>41.5 (20-67)</td><td>0.04</td></tr><tr><td>Main symptoms, %</td><td></td><td></td><td></td></tr><tr><td>Headache, %</td><td>50 (5/10)</td><td>43.3 (13/30)</td><td>0.73</td></tr><tr><td>Visual field impairment %</td><td>50 (5/10)</td><td>20 (6/30)</td><td>0.10</td></tr><tr><td>Decrease visual acuity, %</td><td>50 (5/10)</td><td>13.3 (4/30)</td><td>0.03</td></tr><tr><td>Optic nerve atrophy, %</td><td>16.7 (1/6)</td><td>0 (0/11)</td><td>0.35</td></tr><tr><td>Papillary edema, %</td><td>0 (0/6)</td><td>9.1 (1/11)</td><td>1.00</td></tr><tr><td>Cavernous sinus syndrome %</td><td>20 (2/10)</td><td>6.7 (2/30)</td><td>0.26</td></tr><tr><td>Cushing syndrome, %</td><td>20 (2/10)</td><td>20 (6/30)</td><td>1.00</td></tr><tr><td>Galactorrhea, %</td><td>0 (0)</td><td>13.3 (4/30)</td><td>0.56</td></tr><tr><td>Acromegalic syndrome, %</td><td>10 (1/10)</td><td>10 (3/30)</td><td>1.00</td></tr><tr><td>Diabetes insipidus, %</td><td>10 (1/10)</td><td>0 (0)</td><td>0.25</td></tr><tr><td>Ideomotor slowing, memory disorder %</td><td>10 (1/10)</td><td>3.3 (1/30)</td><td>0.44</td></tr><tr><td>Type of PitNET</td><td></td><td></td><td></td></tr><tr><td>Corticotropic microadenoma, %</td><td>20 (2/10)</td><td>20 (6/30)</td><td>1.00</td></tr><tr><td>Lactotropic macroadenoma, %</td><td>20 (2/10)</td><td>20 (6/30)</td><td>1.00</td></tr><tr><td>Somatotropic macroadenoma, %</td><td>10 (1/10)</td><td>10 (3/30)</td><td>1.00</td></tr><tr><td>Silent corticotropic macroadenoma, %</td><td>20 (2/10)</td><td>20 (6/30)</td><td>1.00</td></tr><tr><td>Non-functional gonadotropic macroadenoma, %</td><td>20 (2/10)</td><td>20 (6/30)</td><td>1.00</td></tr><tr><td>Silent somatotropic macroadenoma, %</td><td>10 (1/10)</td><td>10 (3/30)</td><td>1.00</td></tr><tr><td>Surgical indications</td><td></td><td></td><td></td></tr><tr><td>Tumoral syndrome with or without failure of medical treatment, %</td><td>70 (7/10)</td><td>63.3 (19/30)</td><td>1.00</td></tr><tr><td>Hormonal hypersecretion, %</td><td>30 (3/10)</td><td>36.7 (11/30)</td><td>1.00</td></tr><tr><td>Duration from diagnosis to surgery, median in months (min-max)</td><td>14 (0-97)</td><td>11.5 (1-186)</td><td>0.85</td></tr></tbody></table>

PitNET, pituitary neuroendocrine tumour
<table><caption>**Table 2: Radiological invasiveness, histologic proliferation markers, and clinicopathological histoprognostic grades in patients undergoing surgery for PitNET during pregnancy or post-partum and matched controls**</caption><thead><tr><th></th><th>Cases (n=10)</th><th>Controls (n=30)</th><th>p-value</th></tr></thead><tbody><tr><td><strong>Radiological characteristics</strong></td><td></td><td></td><td></td></tr><tr><td>Median maximal adenoma diameter, mm (min-max)</td><td>27 (7-58)</td><td>18 (4-33)</td><td>0.07</td></tr><tr><td>Compression of the optic chiasm, %</td><td>70 (7/10)</td><td>30 (9/30)</td><td>0.06</td></tr><tr><td>Score ESS = 4, Suprasellar extension grade 4, %</td><td>37.5 (3/8)</td><td>3.5 (1/29)</td><td>0.03</td></tr><tr><td>Cavernous sinus invasion, %</td><td>60 (6/10)</td><td>36.7 (11/30)</td><td>0.27</td></tr><tr><td>Bilateral invasion, %</td><td>66.6 (4/6)</td><td>18.2 (2/11)</td><td>0.11</td></tr><tr><td>Score Knosp ≥ 3, %</td><td>57.1 (4/7)</td><td>20 (4/20)</td><td>0.15</td></tr><tr><td><strong>Histological proliferation markers</strong></td><td></td><td></td><td></td></tr><tr><td>Ki67, median (min-max)</td><td>4 (0-15)</td><td>3 (1-6)</td><td>0.32</td></tr><tr><td>PitNETs with Ki67 ≥ 3%, %</td><td>55.6 (5/9)</td><td>56.7 (17/30)</td><td>1.00</td></tr><tr><td>Number of mitoses *, median (min-max)</td><td>1/10 (&lt;1 - 5)</td><td>1/10 (1 - 4)</td><td>0.78</td></tr><tr><td>PitNETs with number of mitoses &gt; 2 *, %</td><td>33.3 (3/9)</td><td>3.6 (1/28)</td><td>0.04</td></tr><tr><td><strong>Trouillas' clinicopathological classification Histo-prognostic grade according to European Pituitary Pathology Group (EPPG) classification **</strong></td><td></td><td></td><td></td></tr><tr><td>Grade 1a, %</td><td>22.2 (2/9)</td><td>52 (15/29)</td><td>0.74</td></tr><tr><td>Grade 1b, %</td><td>0 (0)</td><td>3.5 (1/29)</td><td>1.00</td></tr><tr><td>Grade 2a, %</td><td>44.4 (4/9)</td><td>44.8 (13/29)</td><td>1.00</td></tr><tr><td>Grade 2b, %</td><td>33.3 (3/9)</td><td>0 (0/29)</td><td>0.049</td></tr><tr><td>Grade 3, %</td><td>0 (0)</td><td>0 (0/29)</td><td>1.00</td></tr><tr><td>Grade ≥ 2a, %</td><td>77.8 (7/9)</td><td>44.8 (13/29)</td><td>0.13</td></tr></tbody></table>

PitNET, pituitary neuroendocrine tumour

<footnote>* per 10 high-power fields at 40X magnification</footnote>

<footnote>**available in 9/10 pregnant patients and 29/30 controls</footnote>
<table><caption>Table 2: Radiological invasiveness, histologic proliferation markers, and clinicopathological grades in patients undergoing surgery for PitNETs during pregnancy or postpartum and matched controls</caption><thead><tr><th></th><th>Cases (n=10)</th><th>Controls (n=30)</th><th>p-value</th></tr></thead><tbody><tr><td><strong>Radiological characteristics</strong></td><td></td><td></td><td></td></tr><tr><td>Median maximal adenoma diameter, mm (min-max)</td><td>27 (7-58)</td><td>18 (4-33)</td><td>0.07</td></tr><tr><td>Compression of the optic chiasm, %</td><td>70 (7/10)</td><td>30 (9/30)</td><td>0.06</td></tr><tr><td>Suprasellar extension grade 4, %</td><td>37.5 (3/8)</td><td>3.5 (1/29)</td><td>0.03</td></tr><tr><td>Cavernous sinus invasion, %</td><td>60 (6/10)</td><td>36.7 (11/30)</td><td>0.27</td></tr><tr><td>Bilateral invasion, %</td><td>66.6 (4/6)</td><td>18.2 (2/11)</td><td>0.11</td></tr><tr><td>Score Knosp ≥ 3, %</td><td>57.1 (4/7)</td><td>20 (4/20)</td><td>0.15</td></tr><tr><td><strong>Histological proliferation markers</strong></td><td></td><td></td><td></td></tr><tr><td>Ki67, median (min-max)</td><td>4 (0-15)</td><td>3 (1-6)</td><td>0.32</td></tr><tr><td>PitNETs with Ki67 ≥ 3%, %</td><td>55.6 (5/9)</td><td>56.7 (17/30)</td><td>1.00</td></tr><tr><td>Number of mitoses *, median (min-max)</td><td>1/10 (&lt;1 - 5)</td><td>1/10 (1 - 4)</td><td>0.78</td></tr><tr><td>PitNETs with number of mitoses &gt; 2 *, %</td><td>33.3 (3/9)</td><td>3.6 (1/28)</td><td>0.04</td></tr><tr><td><strong>Trouillas' clinicopathological classification**</strong></td><td></td><td></td><td></td></tr><tr><td>Grade 1a, %</td><td>22.2 (2/9)</td><td>52 (15/29)</td><td>0.74</td></tr><tr><td>Grade 1b, %</td><td>0 (0)</td><td>3.5 (1/29)</td><td>1.00</td></tr><tr><td>Grade 2a, %</td><td>44.4 (4/9)</td><td>44.8 (13/29)</td><td>1.00</td></tr><tr><td>Grade 2b, %</td><td>33.3 (3/9)</td><td>0 (0/29)</td><td>0.049</td></tr><tr><td>Grade 3, %</td><td>0 (0)</td><td>0 (0/29)</td><td>1.00</td></tr><tr><td>Grade ≥ 2a, %</td><td>77.8 (7/9)</td><td>44.8 (13/29)</td><td>0.13</td></tr></tbody><tfoot><tr><td colspan="4">* per 10 high-power fields at 40X magnification</td></tr><tr><td colspan="4">**available in 9/10 pregnant patients and 29/30 controls</td></tr></tfoot></table>

PitNET, pituitary neuroendocrine tumour
<table><caption>Table 3: Prognostic outcomes following pituitary surgery in patients with PitNET treated surgically during pregnancy or postpartum</caption><thead><tr><td>Patient</td><td>Histological type of PitNETs</td><td>Trouillas' clinicopathological classification</td><td>Second line treatment</td><td>Timing after surgery</td><td>Follow-up duration</td></tr></thead><tbody><tr><td>Patient 1</td><td>non-functional gonadotropic</td><td>grade 2b</td><td>surgical reintervention</td><td>24 months</td><td>36 months</td></tr><tr><td>Patient 2</td><td>lactotropic</td><td>grade 2b</td><td>Dopamine agonist</td><td>2 months</td><td>66 months</td></tr><tr><td>Patient 3</td><td>non-functional gonadotropic</td><td>grade 2a</td><td>radiotherapy</td><td>46 months</td><td>78 months</td></tr><tr><td>Patient 4</td><td>silent corticotropic</td><td>grade 2a</td><td>Dopamine agonist</td><td>7 months</td><td>65 months</td></tr><tr><td>Patient 5</td><td>somatotropic</td><td>grade 2a</td><td>Somatostatin analogue</td><td>3 months</td><td>78 months</td></tr><tr><td>Patient 6</td><td>silent corticotropic</td><td>grade 2a</td><td>Radiotherapy</td><td>32 months</td><td>4 months</td></tr><tr><td>Patient 7</td><td>silent somatotropic</td><td>grade 2b</td><td>Dopamine agonist</td><td>4 months</td><td>34 months</td></tr><tr><td>Patient 8</td><td>corticotropic</td><td>grade 1a</td><td>Dopamine agonist</td><td>103 months</td><td>163 months</td></tr><tr><td>Patient 9</td><td>corticotropic</td><td>NA</td><td>None</td><td>NA</td><td>24 months</td></tr><tr><td>Patient 10</td><td>lactotropic</td><td>grade 1a</td><td>NA</td><td>NA</td><td>NA</td></tr></tbody></table>

NA, not available or not applicable; PitNET, pituitary neuroendocrine tumour
<figure><img src="image_3.png" /></figure>

338x190mm (96 x 96 DPI)
<figure><img src="image_4.png" /></figure>

254x142mm (96 x 96 DPI)