Meningioma in Users of Medroxyprogesterone and Other Progestogen Contraceptives: A Mixed-Methods Disproportionality Analysis of the FDA Adverse Event Reporting System (FAERS) Restricted; Files Only

Abstract

Background: Recent observational studies have suggested medroxyprogesterone, a progesterone derivative commonly used for contraception, may increase the risk of intracranial meningioma tumors among exposed females. However, this potential association remains incompletely understood.

Objective: This study evaluated the association between medroxyprogesterone and meningioma reporting to the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) among adult females. Other progestogen contraceptives were also examined.

Methods: Individual case safety reports (ICSRs) submitted to FAERS (second quarter of 2016–first quarter of 2024) were analyzed. Drug-event pairs comprising these ICSRs were also separately analyzed. Eleven Medical Dictionary for Regulatory Activities (MedDRA) preferred terms classified meningioma cases. Disproportionality was measured by crude reporting odds ratios (cRORs) and 95% confidence intervals (CIs) at the drug-event pair level, with a statistically significant ROR >1.0 and ≥3 meningioma cases indicating a disproportionality signal. Logistic regression was used to estimate adjusted RORs (aRORs) at the ICSR level, adjusting for age, weight, use of medications in contraceptive indications, number of component drug-event pairs, reporter country and reporter occupation.

Results: A total of 4,560,280 ICSRs involving females were reported to FAERS during the study period, including 1,384 meningioma cases. Medroxyprogesterone was recorded in 9,438 ICSRs and 22 meningioma cases. Crude meningioma disproportionality signals were identified among drug-event pairs associated with all medroxyprogesterone-containing medications (cROR 9.99; 95% CI 6.74-14.81) and medroxyprogesterone monotherapies (cROR 10.20; 95% CI 6.57-15.84). These signals persisted in fully-adjusted logistic models (any medroxyprogesterone: aROR 4.01; 95% CI 2.10-7.66; medroxyprogesterone monotherapies: aROR 3.79; 95% CI 1.93-7.46) at the ICSR level. Sensitivity analyses using imputation for missing values and defining alternate study periods yielded similar results. Age ≥40 years and contraceptive indications were also strong predictors of meningioma reporting in adjusted models. Crude meningioma disproportionality signals (cRORs ranging from 2.08 to 22.55) were further identified for the progestogens desogestrel, dienogest, drospirenone, etonogestrel and levonorgestrel in exploratory analyses at the drug-event pair level.

Conclusion: Among females, meningioma was disproportionately reported to FAERS with medroxyprogesterone and several other progestogen contraceptives between the second quarter of 2016 and first quarter of 2024. Notwithstanding the inherent limitations of disproportionality analyses, these findings add to a growing body of literature describing a potential association between medroxyprogesterone and meningioma, and extend this possible connection to other progestogens. Screening should be recommended for females with relevant treatment histories experiencing symptoms consistent with meningioma.

Table of Contents

CHAPTER 1: BACKGROUND LITERATURE REVIEW…8

1.1 Introduction…8

1.2 Unintended Pregnancy and Contraceptive Utilization…9

1.3 Medroxyprogesterone in the United States…12

1.4 Meningioma…15

1.5 Medroxyprogesterone and Meningioma…17

1.6 Significance of Studying Meningioma Among Medroxyprogesterone Users…23

CHAPTER 2: MANUSCRIPT…24

2.1 Introduction…24

2.2 Materials and Methods…25

2.2.1 Data Source…25

2.2.2 Exposure and Outcome Definitions…26

2.2.3 Data Cleaning and Configuration…27

2.2.4 Analytical Approach…28

2.3 Results…30

2.3.1 Descriptive Statistics…30

2.3.2 Drug-Event Pair Level Disproportionality Analysis…32

2.3.3 ICSR Level Logistic Regression Analysis…32

2.3.4 ICSR Level Sensitivity Analysis…33

2.4 Discussion…34

2.5 Strengths and Limitations…39

2.6 Conclusion…42

TABLES…44

FIGURES…48

SUPPLEMENTARY APPENDIX…50

CHAPTER 3: FUTURE DIRECTIONS & PUBLIC HEALTH IMPLICATIONS…58

REFERENCES…62

CONFLICTS OF INTEREST…74

About this Master's Thesis

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School	Rollins School of Public Health
Department	Executive Masters of Public Health - MPH
Subfield / Discipline	Applied Epidemiology
Degree	M.P.H.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Obstetrics and Gynecology Health Sciences, Epidemiology Health Sciences, Oncology
Keyword	FAERS progestogens safety signal medroxyprogesterone contraception meningioma
Committee Chair / Thesis Advisor	Vijaya Kancherla, MS, PhD, Emory University Thomas J. Moore, AB, Johns Hopkins University

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