Depot Medroxyprogesterone Acetate and Risk of Meningioma in the US

Tianqi Xiao; Pranav Kumar; Mina Lobbous; Divya Yogi-Morren; Pranay Soni; Pablo F Recinos; Varun R Kshettry

doi:10.1001/jamaneurol.2025.3011

. 2025 Sep 2;82(11):1094–1102. doi: 10.1001/jamaneurol.2025.3011

Depot Medroxyprogesterone Acetate and Risk of Meningioma in the US

Tianqi Xiao ^1,², Pranav Kumar ^1,², Mina Lobbous ^2,³, Divya Yogi-Morren ⁴, Pranay Soni ^2,⁵, Pablo F Recinos ^2,⁵, Varun R Kshettry ^2,^5,^✉

¹Case Western Reserve University School of Medicine, Cleveland, Ohio

²Rosa Ella Burkhardt Brain Tumor & Neuro-Oncology Center, Neurological Institute, Cleveland Clinic, Ohio

³Department of Neurology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Ohio

⁴Department of Endocrinology and Metabolism, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Ohio

⁵Department of Neurological Surgery, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Ohio

Accepted for Publication: June 20, 2025.

Published Online: September 2, 2025. doi:10.1001/jamaneurol.2025.3011

^✉

Corresponding Author: Varun R. Kshettry, MD, Skull Base, Pituitary & Cerebrovascular Surgery, Rosa Ella Burkhardt Brain Tumor & Neuro-Oncology Center, Cleveland Clinic, 9500 Euclid Ave, CA5-86, Cleveland, OH 44195 (kshettv@ccf.org).

Author Contributions: Dr Xiao had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Xiao, Kumar, Lobbous, Yogi-Morren, Soni, Kshettry.

Acquisition, analysis, or interpretation of data: Xiao, Kumar, Lobbous, Soni, Recinos, Kshettry.

Drafting of the manuscript: Xiao, Kumar, Lobbous, Kshettry.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Xiao, Kumar, Kshettry.

Administrative, technical, or material support: Yogi-Morren, Recinos, Kshettry.

Supervision: Lobbous, Yogi-Morren, Soni, Recinos, Kshettry.

Conflict of Interest Disclosures: Dr Lobbous reported personal fees from Alexion Pharmaceuticals, Springwork Therapeutics, and Telix Pharmaceuticals outside the submitted work. Dr Recinos reported personal fees from Stryker and 3-D Matrix, and ownership interest from Acera Surgical outside the submitted work. Dr. Kshettry reported personal fees from Stryker and 3-D Matrix outside the submitted work. No other disclosures were reported.

Data Sharing Statement: See Supplement 2.

^✉

Corresponding author.

PMCID: PMC12406142 PMID: 40892397

This study examines the relative risk of meningioma diagnosis in women using depot medroxyprogesterone acetate and other related progestins.

Key Points

Question

What is the association between the use of injectable depot medroxyprogesterone acetate and a meningioma diagnosis for women in the US?

Findings

This population-based cohort study of a national US database demonstrated that women using depot medroxyprogesterone acetate had a statistically significant increased relative risk of developing a meningioma diagnosis when compared with women using oral medroxyprogesterone acetate, other contraceptives, and healthy controls without use of these contraceptives. No increased risk of meningioma diagnosis was found with any other contraceptive.

Meaning

In this study, women who used depot medroxyprogesterone acetate had an increased risk for developing a meningioma.

Abstract

Importance

There lacks data clarifying the meningioma risk conferred by depot medroxyprogesterone acetate in the US.

Objective

To examine the relative risk of meningioma diagnosis in women using depot medroxyprogesterone acetate and other related progestins.

Design, Setting, and Participants

This retrospective population-based cohort study used data from TriNetX, a US national database of 68 health care organizations. Data were analyzed from December 2004 to December 2024. The incidence of meningioma diagnosis was compared between treatment groups through propensity-score matched analyses. Participants included a sample of females with use of only 1 of the following progestins/contraceptives: depot medroxyprogesterone acetate, oral medroxyprogesterone acetate, combined oral contraceptives, intrauterine devices, progestin only pills, or subdermal implantable contraceptive. The control group included females without use of these hormonal treatments. Of the 118 289 082 total patients in TriNetX at the time of analysis, 61 588 239 patients were female and eligible.

Exposures

Patients were defined using diagnostic codes from the International Classification of Diseases, Current Procedural Terminology, and RxNorm codes within TriNetX.

Main Outcome and Measure

The main outcome was meningioma diagnosis. Relative risks and number needed to harm were calculated.

Results

There were 10 425 438 patients that met inclusion criteria with a mean age of 33.4 years at inclusion. After propensity score matching, 88 667 patients with mean age of 26.2 years at inclusion were in the depot medroxyprogesterone acetate group. Use of depot medroxyprogesterone acetate had a relative risk of 2.43 (95% CI, 1.77-3.33) for meningioma diagnosis compared with controls. Notably, this risk was confined for patients with longer than 4 years of exposure or starting the prescription at ages older than 31 years. Oral medroxyprogesterone acetate had increased relative risk of 1.18 (95% CI, 1.10-1.27) compared with controls. No increased risk of meningioma diagnosis was found with any other contraceptive. The number needed to harm for the depot medroxyprogesterone acetate was 1152 patients and 3020 patients for oral medroxyprogesterone acetate.

Conclusions and Relevance

In this study, women receiving depot medroxyprogesterone acetate had a greater relative risk of subsequent meningioma diagnosis, especially with prolonged exposures and starting the medication at older ages. The high number needed to harm suggests low clinical risk overall.

Introduction

Meningiomas are the most common primary brain tumor and comprise about 40% of all primary brain tumors in the US. Meningiomas have a female to male prevalence of approximately 2:1 across all ages and a peak difference of over 3:1 in patients in the third to fifth decade of life.^1,2,3 One popular hypothesis is that this female predilection is attributable to female sex hormone exposure.⁴ Evidence for hormonal contribution includes increased meningioma diagnoses associated with breast cancer, hormone replacement therapy, the peripartum periods, and exposure to exogenous progestins.^{5,6,7,8,9,10,11,12,13,14,15,16,17} Studies indicate that 72.2% of meningiomas express progesterone receptors and 11.3% express estrogen receptors, which indicates potential biological mechanisms for hormonal-tumor interactions.^{18,19,20,21,22}

A recent publication in the French population demonstrated a statistically significant increased odds ratios of patients who underwent meningioma resection being exposed to prior depot medroxyprogesterone acetate (dMPA), an exogenous progesterone commonly marketed as a long-acting injectable contraceptive.^23,24 dMPA is used in the US by approximately 2% of women aged 15 to 49 years and approximately 68 million women across 114 countries.^25,26 The only US population-based study published to date on dMPA used a large insurance database with a case-control study design, mirroring the French study and their results support a similar relationship.²⁷ This association between dMPA usage and meningioma incidence has led to concern about the risk of dMPA in the US and internationally. However, there is a paucity of data, as these studies only examined patients who required meningioma resections and the overall number of patients with prior dMPA use in those undergoing resection were small: 9 patients with dMPA exposure of 18 061 undergoing resection (0.05%) in the French study by Roland.²⁴ In addition, these studies used case-control designs, which limits the ability to accurately identify clinical and absolute risks.

In the present study, we use the US national database TriNetX to examine the association between contraceptive use and the incidence of meningioma using a forward-looking cohort study and control for potential confounders via propensity-score matched (PSM) analyses.²⁸ We aim to examine the incidence of meningioma diagnosis among women using dMPA, oral medroxyprogesterone acetate (oMPA), combined oral contraceptives (COCs), intrauterine devices (IUDs), progestin only pills (POP), subdermal implantable contraceptives (SDI), as well as healthy women without use of these progestins/contraceptives.

Methods

Study Design

This is a retrospective population-based cohort study adhering to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines. We compared groups using a PSM model to control for confounding variables. The groups were patients exposed to dMPA, oMPA, COC, IUD, POP, SDI, and control patients without any documented use of the treatment group progestins/contraceptives. The IUD group was also examined as 3 subgroups: copper IUD (Cu IUD), 52 mg levonorgestrel-releasing IUD (52 LGN IUD), and 13.5/19.5 mg levonorgestrel-releasing IUD (low LGN IUD). Our main outcome was a diagnosis of meningioma any time after initial exposure to the treatment progestin/contraceptive. Patients were followed up with until their most recent record in the database.

Data Source

We used the TriNetX platform, a federated database for health research. This platform integrates real-time deidentified patient information from electronic health records obtained from affiliated health care organizations (HCOs). Patient data were extracted through structured queries using standardized medical coding systems, including the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10), Healthcare Common Procedure Coding System (HCPCS), Current Procedural Terminology (CPT), and RxNorm. The exact query codes for group selection are shown in eTable 1 in Supplement 1. The TriNetX US Collaborative Network of 68 US HCOs across various geographical and population centers was used at the time of analysis. As our study used deidentified patient data, it met exemption criteria from Western institutional review board approval, as outlined in Section §164.514(b)(1) of the Health Insurance Portability and Accountability Act Privacy Rule, and informed consent was waived.

Patient Selection Criteria

Inclusion Criteria

Patient data across a 20-year span from December 1, 2004, to December 1, 2024, were analyzed. Only female patients were included and all ages were included to account for early initiation of contraceptives. Nine mutually exclusive experimental cohorts were created for patients with prescription and encounter for dMPA, oMPA, COC, IUD, 52 LGN IUD, low LGN IUD, Cu IUD, POP, or SDI. All groups excluded the inclusion criteria of all other experimental groups. A control cohort was created with patients who presented for a general examination without any complaints or suspected diagnosis and without exposure to any experimental group treatment. Patients were only included in each cohort once they met all respective query codes listed in eTable 1 in Supplement 1.

Exclusion Criteria

All patients with prior meningiomas to the initiation of the treatment were excluded. If patients were missing any data from the query, they were excluded completely from the analysis automatically via the TriNetX platform.

Outcomes Measured

The primary outcome was any meningioma diagnosis defined by the presence of ICD-10 code CM:D32 determined at the discretion of the individual practitioners/institutions, regardless of whether patients received surgery, radiation, or observation.

PSM Analysis

We performed 2 main sets of PSM analyses. The first set compared all experimental groups with the control group. This analysis contained 9 covariates due to the limited computing ability for the PSM model and due to the large sample size of the control group. The covariates were age at inclusion, race, ethnicity, history of pregnancy, history of breast cancer, neurofibromatosis, history of radiation exposure, and body mass index (BMI) (Table 1). A second set of PSM analyses were performed with these same covariates and 18 additional covariates examining dMPA against all other experimental groups. The covariates used in the second set of PSM analyses are displayed in Table 2. Two additional subgroup analyses were performed comparing dMPA with controls, while stratifying for dMPA length of exposure (Table 3) and patient age at initiation of dMPA (eTable 2 in Supplement 1). All additional PSM analyses can be found in eTables 3 through 24 in Supplement 1. Per TriNetX, any outcomes with 10 or more instances after PSM were rounded up to 10 instances exactly to protect patient identity.

Table 1. Propensity-Matched Analysis Covariates: Depot Medroxyprogesterone Acetate (dMPA) vs Control.

Characteristic	No. (%)
	Before PSM			After PSM
	dMPA (n = 88 668)	Control (n = 8 186 531)	Standard difference	dMPA (n = 88 667)	Control (n = 88 667)	Standard difference
Demographics
Age, y, mean (SD)	26.2 (9.4)	36.4 (25.8)	0.524	26.2 (9.4)	26.4 (9.9)	0.018
Race and ethnicity^a
African American	30 859 (34.8)	1 286 126 (15.8)	0.449	30 858 (34.8)	31 137 (35.1)	0.007
Hispanic or Latino	15 429 (17.4)	935 077 (11.5)	0.170	15 429 (17.4)	15 606 (17.6)	0.005
White	45 338 (51.1)	5 083 654 (62.3)	0.524	45 338 (51.1)	45 335 (51.1)	0.018
Diagnosis
Pregnancy, childbirth, and puerperium	31 011 (35.0)	354 242 (4.3)	0.835	31 010 (35.0)	30 509 (34.4)	0.012
Malignant neoplasm of breast	48 (0.1)	142 080 (1.7)	0.180	48 (0.1)	40 (<0.1)	0.004
Neurofibromatosis	61 (0.1)	2509 (<0.1)	0.017	61 (0.1)	31 (<0.1)	0.015
Radiology procedures	49 235 (55.5)	2 224 859 (27.3)	0.599	49 234 (55.5)	48 901 (55.2)	0.008
BMI,^b mean (SD)	28.4 (8.2)	28.4 (8.2)	0.007	28.4 (8.2)	28.7 (8.5)	0.034

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Abbreviations: BMI, body mass index; PSM, propensity score match.

^{^a}

Race and ethnicity were self-reported in the database.

^{^b}

Calculated as weight in kilograms divided by height in meters squared.

Table 2. Propensity-Matched Analysis: Depot Medroxyprogesterone Acetate (dMPA) vs Intrauterine Device (IUD).

Characteristic	No. (%)
	Before PSM			After PSM
	dMPA (n = 88 668)	IUD (n = 614 666)	Standard difference	dMPA (n = 86 064)	IUD (n = 86 064)	Standard difference
Demographics
Age, y, mean (SD)	26.2 (9.4)	32.0 (9.5)	0.608	26.5 (9.4)	27.0 (8.8)	0.051
Race^a
African American	30 859 (34.8)	75 357 (12.3)	0.551	28 343 (32.9)	29 307 (34.1)	0.024
Asian	1916 (2.2)	25 572 (4.2)	0.115	1916 (2.2)	1885 (2.2)	0.002
Hawaiian/Pacific Islander	1019 (1.1)	3644 (0.6)	0.060	995 (1.2)	924 (1.1)	0.008
Native American	643 (0.7)	3104 (0.5)	0.028	631 (0.7)	564 (0.7)	0.009
White	45 338 (51.1)	426 641 (69.5)	0.382	45 295 (52.6)	44 748 (52.0)	0.013
Other^b	2972 (3.4)	27 866 (4.5)	0.061	2971 (3.5)	2875 (3.3)	0.006
Unknown	5921 (6.7)	51 912 (8.5)	0.067	5913 (6.9)	5761 (6.7)	0.007
Ethnicity^a
Hispanic or Latino	15 429 (17.4)	82 034 (13.4)	0.112	15 221 (17.7)	15 579 (18.1)	0.011
Not Hispanic or Latino	54 579 (61.6)	383 988 (62.5)	0.020	52 571 (61.1)	51 713 (60.1)	0.020
Unknown	18 660 (21.0)	148 074 (24.1)	0.073	18 272 (21.2)	18 772 (21.8)	0.014
Diagnosis
Pregnancy, childbirth, and puerperium	31 011 (35.0)	198 986 (32.4)	0.054	30 486 (35.4)	32 200 (37.4)	0.041
Obesity/overweight	17 452 (19.7)	90 899 (14.8)	0.129	16 694 (19.4)	17 816 (20.7)	0.033
Hyperlipidemia	4349 (4.9)	38 803 (6.3)	0.061	4246 (4.9)	4490 (5.2)	0.013
Diabetes	3509 (4.0)	21 222 (3.5)	0.027	3402 (4.0)	3416 (4.0)	0.001
Leiomyoma of uterus	2374 (2.7)	20 875 (3.4)	0.042	2353 (2.7)	2357 (2.7)	<0.001
Other benign neoplasm of uterus	100 (0.1)	786 (0.1)	0.004	99 (0.1)	79 (0.1)	0.007
Malignant neoplasm of uterus	10 (<0.1)	183 (<0.1)	0.013	10 (<0.1)	10 (<0.1)	<0.001
Benign neoplasm of ovary	252 (0.3)	1987 (0.3)	0.007	249 (0.3)	218 (0.3)	0.007
Malignant neoplasm of ovary	27 (<0.1)	324 (0.1)	0.011	27 (<0.1)	30 (<0.1)	0.002
Benign neoplasm of breast	459 (0.5)	4472 (0.7)	0.027	446 (0.5)	370 (0.4)	0.013
Malignant neoplasm of breast	48 (0.1)	2872 (0.5)	0.081	48 (0.1)	42 (<0.1)	0.003
Malignant neoplasm of lymphoid or blood	198 (0.2)	1482 (0.2)	0.004	193 (0.2)	168 (0.2)	0.006
Neurofibromatosis	61 (0.1)	208 (<0.1)	0.015	57 (0.1)	33 (<0.1)	0.012
Tobacco use	3872 (4.4)	11 696 (1.9)	0.142	3585 (4.2)	3848 (4.5)	0.015
Radiology procedures	49 235 (55.5)	308 292 (50.2)	0.107	47 712 (55.4)	49 666 (57.7)	0.046
BMI,^c mean (SD)	28.4 (8.2)	29.6 (8.0)	0.150	28.5 (8.2)	30.2 (8.5)	0.212

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Abbreviations: BMI, body mass index; PSM, propensity score match.

^{^a}

Race and ethnicity were self-reported in the database.

^{^b}

This category includes all people who self-reported having a specific race, but were not one of the following: Asian, American Indian or Alaska Native, Black or African American, Native Hawaiian or Pacific Islander, or White. This could include multiracial individuals.

^{^c}

Calculated as weight in kilograms divided by height in meters squared.

Table 3. Meningioma Incidence Risk of Depot Medroxyprogesterone Acetate (dMPA) vs Control, Given Different Time Lengths of Exposure.

Years exposed (No. after PSM vs control)	Overall meningioma risk
Years exposed (No. after PSM vs control)	Meningioma instances	Meningioma relative risk (95% CI)	P value
0-2 y (n = 62 855)	40 (vs 27)	1.48 (0.91-2.41)	.11
2-4 y (n = 13 681)	22 (vs 14)	1.57 (0.80-3.07)	.18
4-6 y (n = 6922)	30 (vs 10)	3.00 (1.47-6.13)	.002
>6 y (n = 6168)	39 (vs 10)	3.90 (1.95-7.81)	<.001

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Abbreviation: PSM, propensity score match.

Statistical Analysis

We performed a PSM analysis to control for confounding variables and limit bias. TriNetX uses a 1:1 greedy nearest-neighbor PSM technique that uses logistic regression to generate same-sized cohorts. Well-matched covariates were those with a standard mean difference (SMD) less than 0.060. Built-in analytic tools were used to calculate incidence rates, P values (significance <.05), odds ratios, and relative risk (RR) with 95% CI. Number needed to harm (NNH), attributable risk (AR), and attributable risk percentage (ARP) were calculated for the dMPA and oMPA vs control PSM analyses. Frequency counts and statistical calculations not included in TriNetX were performed using Excel (Microsoft Corp).

Results

Demographics Description

There were 118 289 082 patients in the US Collaborative Network of TriNetX at the time of analysis and 61 588 239 were female. A total of 10 425 438 patients were included across all groups with a mean age of 33.4 years old at inclusion. The queries yielded the following group sizes: control (n = 8 186 531), dMPA (n = 88 668), oMPA (n = 736 443), COC (n = 388 192), IUD (n = 614 666), Cu IUD (n = 29 666), 52 LGN IUD (n = 180 035), low LGN IUD (n = 22 643), POP (n = 39 406), and SDI (n = 172 188). After PSM, group samples sizes were well matched with low standard differences (Tables 1-2; eTables 3 through 24 in Supplement 1).

Meningioma Risk After dMPA

dMPA vs Control

The dMPA vs control PSM analysis showed significantly increased risk of having a meningioma diagnosis in the dMPA group (RR, 2.43; 95% CI, 1.77-3.33). The incidence of meningioma diagnosis for the dMPA group in the PSM was 7.39 per 100 000 patient-years (131 of 88 667). The meningioma incidence of the control in the PSM analysis was 3.05 per 100 000 patient-years (54 of 88 667) (Table 4). The number needed to harm between the dMPA vs control was 1152 patients. The attributable risk was 0.00087 with attributable risk percentage of 59%.

Table 4. Meningioma Incidence Risk Following Propensity-Matched Analysis of Contraceptive Use.

Groups	Overall meningioma risk
Groups	Meningioma instances	Meningioma relative risk (95% CI)	P value
dMPA vs control (n = 88 667)	131 (vs 54)	2.43 (1.77-3.33)	<.001
oMPA vs control (n = 715 711)	1568 (vs 1331)	1.18 (1.10-1.27)	<.001
COC vs control (n = 387 240)	158 (vs 215)	0.74 (0.60-0.90)	.003
IUD vs control (n = 611 868)	530 (vs 613)	0.87 (0.77-0.97)	.01
POP vs control (n = 39 385)	22 (vs 22)	1.00 (0.55-1.81)	1.00
SDI vs control (n = 171 687)	42 (vs 59)	0.71 (0.50-1.06)	.09
Cu IUD vs control (n = 29 652)	17 (vs 17)	1.00 (0.51-1.96)	1.00
52 LGN IUD vs control (n = 180 035)	144 (vs 183)	0.79 (0.63-0.98)	.03
Low LGN IUD vs control (n = 22 643)	10 (vs 10)	1.00 (0.42-2.40)	1.00
dMPA vs IUD (n = 86 064)	131 (vs 41)	3.20 (2.25-4.54)	<.001
dMPA vs COC (n = 84 763)	127 (vs 34)	3.74 (2.56-5.45)	<.001
dMPA vs POP (n = 35 506)	65 (vs 20)	3.25 (1.97-5.36)	<.001
dMPA vs oMPA (n = 88 651)	131 (vs 58)	2.26 (1.66-3.08)	<.001
dMPA vs SDI (n = 84 175)	113 (vs 29)	3.90 (2.59-5.86)	<.001

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Abbreviations: COC, combined oral contraceptives; Cu, copper; dMPA, depot medroxyprogesterone acetate; IUD, intrauterine device; LGN, levonorgestrel; oMPA, oral medroxyprogesterone acetate; POP, progesterone only pill; SDI, subdermal implant.

dMPA Subgroup Analyses

Compared with PSM control patients, length of dMPA exposure showed significantly increased RR of meningioma diagnosis for exposures of 4 to 6 years (RR, 3.00; 95% CI, 1.47-6.13) and more than 6 years (RR, 3.90; 95% CI, 1.95-7.81) (Table 3). Patient age at the initiation of dMPA showed significantly increased RR of meningioma diagnosis for age brackets 31 to 40 years (RR, 3.77; 95% CI; 2.05-6.95), 41 to 50 years (RR, 2.75; 95% CI, 1.55-4.87), and older than 50 years (RR, 3.20; 95% CI, 1.58-6.49) compared with propensity score age-matched controls (eTable 2 in Supplement 1).

oMPA vs Control

The oMPA vs control PSM showed statistically significant increased RR of having a meningioma diagnosis in the oMPA group (RR, 1.18; 95% CI; 1.10-1.27). The NNH was 3020 patients with AR of 0.00033 and ARP of 15%.

dMPA vs Other Experimental Groups

Injection dMPA showed increased risk of having a meningioma diagnosis compared with oMPA and every other contraceptive (Table 4) (Figure).

Meningioma Risk After Other Contraceptives

There was no significant increase in risk for overall meningioma diagnosis in any of the nonmedroxyprogesterone acetate PSM analyses (COC, IUD, POP, SDI, Cu IUD, 52 LGN IUD, low LGN IUD) vs controls. Compared with controls, there was a statistically decreased RR of meningioma diagnosis among the COC (RR, 0.74; 95% CI, 0.60-0.90), IUD (RR, 0.87; 95% CI, 0.77-0.97), and 52 LGN IUD (RR, 0.79; 95% CI, 0.63-0.98) PSM analyses.

Discussion

In this study, we found that injection dMPA use was associated with a 2.43 increased RR for a meningioma diagnosis compared with controls without contraceptive use. Use of dMPA also had increased RR compared with oMPA and all other contraceptives. Notably, this risk was confined for patients with longer than 4 years of exposure or started dMPA at ages older than 31 years. Our study offers additional evidence of dMPA risks as the first population based PSM cohort study.

Progesterone Interactions With Meningiomas

Exogenous progesterone use has been linked to an increased risk of meningioma development. Three main progestins have been widely studied: cyproterone acetate (CPA), chlormadinone acetate, and nomegestrol acetate, none are available in the US.²⁹ Among these, CPA has the strongest documented association with meningioma development following a positive dose-dependent relationship.^30,31 Meningiomas additionally appear to regress with CPA cessation. One French case series demonstrated spontaneous meningioma reduction in 11 of 12 patients after CPA cessation.⁵ This growth and shrinkage pattern with progestin cessation has been reported extensively but little for dMPA.^{6,8,10,11,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46} CPA is not available in the US; however, dMPA is widely used in the US and internationally.^47,48,49,50

Roland et al²⁴ reported an increased OR of 5.55 (95% CI, 2.27-13.56) of French patients using dMPA and undergoing meningioma surgery. This was the second highest OR after CPA use. In the US population, Griffin²⁷ reported a smaller yet still significant OR of 1.53 (95% CI, 1.40-1.67). These pharmacoepidemiology case-control studies are useful for identifying associations considering multiple risk factors, but cohort studies provide additional validity by estimating absolute risk and incidence rates.⁵¹ Our study used a cohort design and performed PSM analyses, which is beneficial in balancing groups with multiple covariates and for treatments with marginal effects.²⁸ Previous studies only matched cases to controls with 1 to 2 covariates.^24,27 In contrast, our PSM controlled for many cofounding variables (Table 1-2). Uniquely, we controlled for race and BMI, as Black and obese populations are more prevalent in the US vs France.^52,53 Additionally, previous studies have found that Black non-Hispanic women and women with obesity are at a higher risk for meningiomas.^1,54,55 Furthermore, Black women and women with obesity were found to less likely use prescription contraceptives. However, when using prescription contraceptives, patients with obesity are specifically more likely to receive or request long-acting reversible contraception, such as dMPA, IUD, or SDI.^56,57,58 These nuances underscore the importance of accounting for race and BMI when assessing contraceptive risks in the US population.

Our dMPA vs control PSM yielded an absolute risk of 0.00148 (131 of 88 667) compared with an absolute risk of 0.00061 (54 of 88 667) in the control group (RR, 2.43; 95% CI, 1.77-3.33). Our RR of 2.43 is lower than the OR of 5.55 reported by Roland et al.²⁴ This discrepancy may be due to the greater number of covariates controlled in our study, the low number of meningioma cases with dMPA exposure in the French study or differences between the French and American populations. Additionally, oMPA also had an increased RR of 1.18 (95% CI, 1.10-1.27) compared with control group. However, the NNH was 3020 patients, so this relationship may not be clinically significant. No other experimental group had increased RR of meningioma diagnosis compared with controls, suggesting that the MPA progestins may act differently on meninges/meningiomas than other contraceptive progestins. Comparing dMPA vs oMPA, dMPA had a significantly increased RR of 2.26 (95% CI, 1.66-3.08) for a meningioma diagnosis. oMPA is most often used for amenorrhea and not contraception, so this population potentially has a different clinical profile. The increased risk with dMPA vs oMPA may be due to the different routes of administration, dosages, or patient populations.

Definitive length of exposure or dosage of dMPA was not available in TriNetX, so we used bracketed years of exposure as a proxy. Patients with more than 4 years of exposure had statistically significant increased risks of meningioma diagnosis, while those with less than 4 years did not (Table 3). This risk peaks for patients who had over 6 years of dMPA exposure (RR, 3.90; 95% CI, 1.95-7.81). Our results mirror the increased odds of having a meningioma resection with prolonged dMPA use in prior studies.^24,27 Our results, in combination with previous studies, suggest that dMPA could have a cumulative effect in which longer exposure or dosage confer greater risk. We also stratified our dMPA group by age at initiation of dMPA. Compared with age-matched controls after PSM, there was increased risk for patients who started dMPA after the age of 31 years (eTable 2 in Supplement 1). The greatest risk is among patients in the 31- to 40-year old group (RR, 3.77; 95% CI, 2.05-6.95). This association was not seen in patients starting dMPA younger than 30 years. It is known that meningioma incidence increases with age.^1,2 Incidence rises from 5 to 12 per 100 000 patient-years among ages 25 to 30 years, up to 50 per 100 000 patient-years for those older than 85 years old.⁵⁹ Thus, older patients may have increased susceptible to dMPA associated meningiomas. However, it is important to consider that older patients and patients with longer exposures may have more follow up which allows for greater detection of meningiomas and could confound this relationship.⁶⁰

Clinical Significance

The findings of our study must be considered for individual patient risk. Our cohort design allows precise calculations of number needed to harm and attributable risk. The NNH with dMPA use compared with controls is 1152 people (AR, 0.00087; ARP, 59%). So, although dMPA use is statistically associated with meningioma risk, the high NNH indicates that this association may not be as clinically significant. However, among those who used dMPA and developed meningiomas, around 59% of cases might be attributable to dMPA. The clinical risk is even less with oMPA with a NNH of 3020 and ARP of 15%.

Although the evidence is limited, there is 1 case report of meningioma regression after dMPA cessation in 5 of 10 patients.⁶¹ Similar to the meningioma reduction reported with CPA cessation, dMPA cessation may lead to meningioma shrinkage. However, injectable dMPA is used for contraception, abnormal uterine bleeding, endometriosis, and other indications, and the complications of discontinuing this medication must be weighed against the risks for meningioma development.²⁶ Therefore, patients must be counseled on these potential complications if considering dMPA cessation or alternatives.

Contraceptive Options Besides dMPA

We also compared patients using dMPA with other common contraceptives to account for selection bias. All other contraceptive options examined (COC, IUD, POP, SDI) showed statistically significant lower risks for meningioma diagnosis compared with dMPA and no significantly increased RR when compared with controls. Interestingly, we found a decreased risk of meningioma diagnosis with COC, IUD, and 52 LGN IUD (Table 4). This may be due to the pharmacological suppression of endogenous estrogen and progesterone due to these low doses of exogenous hormones or differences in the mechanism of these progestins vs MPA.^62,63 Roland et al²⁴ also found a decreased OR of meningioma resections with their oral and intravaginal progesterone group (OR, 0.88; 95% CI, 0.78-0.99) and near significance with their 52 mg LGN IUD group (OR, 0.94; 95% CI, 0.86-1.04). Our findings align with those of previous studies.^24,64 As such, these contraceptives may be alternatives when considering cessation of dMPA.

Limitations

The findings of this study must account for its limitations. The TriNetX database is a live database that updates in real time. Even though this ensures the most recent data are captured, the various HCOs are constantly refreshing their patient data, leading to variations in patient counts across various analyses. Additionally, this study relied on insurance codes to identify patients. As a result, any patients who were not coded correctly may have been excluded from the analysis. Furthermore, we only accounted for some covariates of meningioma risk in our PSM and, thus, other confounders may still be present. Follow-up time and time to meningioma diagnosis were not readily available in the database, so the temporal association of meningioma diagnosis after exposure could not be accurately assessed. Beyond observational findings, future studies are needed to better elucidate the biological mechanism underlying progesterone exposure and meningioma growth especially for patients already at higher risks, such as patients with neurofibromatosis-2, older age, or childhood brain radiation.^65,66

Conclusions

In this US population cohort study, we demonstrated that patients using injection dMPA had a greater RR of developing a meningioma diagnosis compared with matched patients using oMPA, other contraceptives, or controls. Notably, this risk appears to be confined to patients with more than 4 years of dMPA exposure or older than 31 years at initiation. The number needed to harm with dMPA use was high at 1152 patients and the attributable risk percentage was 59% suggesting dMPA may have low clinical risks for meningioma diagnosis but could be attributable for those who do develop meningiomas. Oral MPA had a much lower, but statistically significant increased risk of meningioma diagnosis. No increased risk of meningioma diagnosis was found with any other contraceptive.

Supplement 1.

eTable 1. Query Codes for Groups of Interest

eTable 2. Meningioma Risk of Depot Medroxyprogesterone Acetate vs Control Given Different Ages Initiating Exposure

eTable 3. Propensity Matched Analysis Covariates: Oral Medroxyprogesterone Acetate vs Control

eTable 4. Propensity Matched Analysis Covariates: Combined Oral Contraceptives vs Control

eTable 5. Propensity Matched Analysis Covariates: Intrauterine Device vs Control

eTable 6. Propensity Matched Analysis Covariates: Progesterone Only Pill vs Control

eTable 7. Propensity Matched Analysis Covariates: Subdermal Implant Contraceptive vs Control

eTable 8. Propensity Matched Analysis Covariates: Copper Intrauterine Device vs Control

eTable 9. Propensity Matched Analysis Covariates: 52mg Levonorgestrel Intrauterine Device vs Control

eTable 10. Propensity Matched Analysis Covariates: Low* Levonorgestrel Intrauterine Device vs Control

eTable 11. Propensity Matched Analysis: Depot Medroxyprogesterone vs Oral Medroxyprogesterone

eTable 12. Propensity Matched Analysis: Depot Medroxyprogesterone vs Combined Oral Contraceptives

eTable 13. Propensity Matched Analysis: Depot Medroxyprogesterone vs Progesterone Only Pill

eTable 14. Propensity Matched Analysis: Depot Medroxyprogesterone vs Subdermal Implant Contraceptive

eTable 15. Propensity Matched Analysis Covariates: Depot Medroxyprogesterone Acetate 0-2 Years Exposure vs Control

eTable 16. Propensity Matched Analysis Covariates: Depot Medroxyprogesterone Acetate 2-4 Years Exposure vs Control

eTable 17. Propensity Matched Analysis Covariates: Depot Medroxyprogesterone Acetate 4-6 Years Exposure vs Control

eTable 18. Propensity Matched Analysis Covariates: Depot Medroxyprogesterone Acetate >6 Years Exposure vs Control

eTable 19. Propensity Matched Analysis Covariates: Depot Medroxyprogesterone Acetate Age of Initiation 0-10 Years Old vs Control

eTable 20. Propensity Matched Analysis Covariates: Depot Medroxyprogesterone Acetate Age of Initiation 11-20 Years Old vs Control

eTable 21. Propensity Matched Analysis Covariates: Depot Medroxyprogesterone Acetate Age of Initiation 21-30 Years Old vs Control

eTable 22. Propensity Matched Analysis Covariates: Depot Medroxyprogesterone Acetate Age of Initiation 31-40 Years Old vs Control

eTable 23. Propensity Matched Analysis Covariates: Depot Medroxyprogesterone Acetate Age of Initiation 41-50 Years Old vs Control

eTable 24. Propensity Matched Analysis Covariates: Depot Medroxyprogesterone Acetate Age of Initiation >50 Years Old vs Control

eTable 25. Meningioma Incidence Risk Following Propensity Matched Analysis of dMPA Use vs Control: With and Without Tobacco Use as a Covariate

eTable 26. Propensity Matched Analysis Covariates: Depot Medroxyprogesterone Acetate vs Control Including Tobacco Use Covariate

jamaneurol-e253011-s001.pdf^{(474.8KB, pdf)}

Supplement 2.

Data sharing statement

jamaneurol-e253011-s002.pdf^{(11.8KB, pdf)}

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