Abstract
Background and Purpose
Chlormadinone acetate (CMA) is a synthetic progestin for which cases of intracranial meningioma have been reported following prolonged exposure.
Method
An observational cohort study was conducted based on the French national health data system. Women aged 10‐70 years and who started CMA between 2007 and 2017 were included. Participants were considered to be exposed if they had received a cumulative dose >360 mg of CMA during the first 6 months and very slightly exposed (control group) when they had received a cumulative dose ≤360 mg. The outcome was surgery or radiotherapy for one or more intracranial meningioma(s). Poisson models assessed the relative risk (RR) of meningioma.
Results
In total, 828,499 women were included: 469,976 in the exposed group (mean age 39.1 years, SD 10.1) and 358,523 in the control group (38.3 years, SD 11.0). Surgery or radiotherapy for intracranial meningioma between 2007 and 2017 was recorded for 164 and 104 women in the exposed and control groups, respectively. The incidence of meningioma was 18.5 and 6.8 per 100,000 person‐years for the exposed and control groups respectively (crude RR = 2.7, 95% confidence interval [CI] 2.1–3.5; age‐adjusted RR = 3.1, 95% CI 2.4–4.0). Meningioma incidence reached almost 47 cases/100,000 person‐years in the most exposed group (>8.64 g), giving an age‐adjusted RR of 6.9, 95% CI 5.1–9.2, relative to the control group.
Conclusions
A strong dose–effect relationship was observed between prolonged use of CMA and risk of meningiomas. As with other progestogens, meningiomas associated with CMA are more likely to be found at the base of the skull.
Keywords: contraceptive, meningioma, menopause, neurosurgery, progestogen
INTRODUCTION
Chlormadinone acetate (CMA) is a synthetic progestogen used by millions of women worldwide. At low dose (2 mg), it is used in combination with oestrogen for contraception or hormonal menopause treatment in about 40 countries (except North America) and at moderate and high doses (5–10 mg) it is used in France and Japan for various gynaecological indications (including endometriosis, Data S1, Supplement A). Several cases of intracranial meningioma have been reported following prolonged exposure to CMA, as for other high‐dose progestogens (cyproterone acetate [CPA] and nomegestrol acetate [NOMAC]) [1, 2, 3]. The aim was to evaluate the risk of intracranial meningioma associated with long‐term CMA use.
METHODS
An observational cohort study was conducted based on the French national health data system (SNDS) (which provides health reimbursement information for 99.5% of individuals living in France). All women aged 10–70 living in France and beginning CMA treatment between 2007 and 2017 (at least one dispensation of 2, 5 or 10 mg) with no history of meningioma or other benign brain tumours, neurofibromatosis type 2 or intake of progestogens known to increase the risk of meningioma (CPA/NOMAC) were identified (Data S1, Supplements B–D). This method is explained in more detail in a similar article on NOMAC [3].
Participants were considered exposed if they had received a cumulative dose of >360 mg CMA in the first 6 months of treatment (exposed group) and slightly exposed (control group) if they had received a cumulative dose of ≤360 mg. The cumulative dose of 360 mg corresponds to a maximum of three standard boxes each containing 12 tablets at a dose of 10 mg. The control group therefore included women who stopped treatment prematurely (dose threshold already used in previous studies) [1, 3]. Follow‐up began 6 months after first dispensation. The outcome was identified by the association of a first hospitalization for a meningioma coded as a principal or related diagnosis according to the International Statistical Classification of Diseases (ICD‐10) code D32 ‘Benign meningeal tumour’ with at least one procedure for excision of a tumour or a procedure from a list of codes likely to be used for meningioma surgery (optic nerve decompression surgery, for example) or a stereotactic radiosurgery procedure or a fractionated radiotherapy procedure during this same hospitalization (Data S1, Supplements E and F).
All participants were followed until 31 December 2018 (end of the study) or the occurrence of one of the following events: meningioma, loss to follow‐up (defined as ≥24 months with no healthcare reimbursement), dispensation of CPA or NOMAC, pregnancy, resumption of CMA treatment in controls, discontinuation of CMA for at least 1 year for the exposed group, or death. Poisson models were used to compare meningioma occurrence rates between the exposed and control groups, with cumulative dose and age as time‐dependent variables. Meningioma characteristics, risk associated with cumulative dose in subclasses, risk after discontinuation of CMA (three‐group analysis: exposed, control and discontinuation) and risk within a subgroup of women without concomitant use of oestrogen (Data S1, Supplement G) were also assessed.
This study complies with the STROBE statement and was authorized by decree 2016‐1871 on 26 December 2016 [4]. As an authorized permanent user of the SNDS, the author's team was exempt from approval from the institutional review board. The study was declared before implementation in the register of studies of the EPI‐PHARE Scientific Interest Group with register reference T‐2019‐07‐165. This study was also presented to a scientific board, including representatives of the French National Agency for Medicines, patient associations and specialist medical organizations (general practitioners, gynaecologists, endocrinologists).
RESULTS
In total, 828,499 women were included: 469,976 (56.7%) in the exposed group (mean age 39.1 years, SD 10.1) and 358,523 (43.3%) in the control group (38.3 years, SD 11.0). The flowchart and the characteristics of women at inclusion are presented in Data S1, Supplements H and I. Over 97% of women in the exposed group had received high‐dose CMA (5–10 mg). Mean follow‐up in the two groups was 1.9 years for exposed women and 4.3 years for the control group. Surgery or radiotherapy for intracranial meningioma between 2007 and 2017 was recorded for 164 women in the exposed group and 104 women in the control group (Table 1). The incidence of meningioma in the two groups was 18.5 and 6.8 per 100,000 person‐years (PY), for the exposed and control groups, respectively (crude relative risk [RR] 2.7, 95% confidence interval [CI] 2.1–3.5; age‐adjusted RR [aRR] 3.1, 95% CI 2.4–4.0) (Figure 1, Data S1, Supplement J).
TABLE 1.
Description of the meningiomas treated surgically in 2007–2017 (N = 268).
| Total | Exposed group | Control group | p value | |
|---|---|---|---|---|
| N (%) | 268 (100) | 164 (100) | 104 (100) | |
| Initial treatment | ||||
| Neurosurgery | 232 (86.6) | 147 (89.6) | 85 (81.7) | ≥0.05 |
| Radiotherapy | 36 (13.4) | 17 (10.4) | 19 (18.3) | |
| Age at treatment of meningioma (years) | ||||
| Mean age (SD) | 48.9 (6.3) | 48.1 (5.6) | 50.2 (7.1) | <0.001 |
| Median age (IQR) | 49.5 (45.2–52.6) | 49.0 (45.0–51.5) | 50.4 (45.5–54.5) | |
| 10–24 | 0 (0) | 0 (0) | 0 (0) | |
| 25–34 | 5 (1.9) | 3 (1.8) | 2 (1.9) | |
| 35–44 | 59 (22.0) | 38 (23.2) | 21 (20.2) | |
| 45–54 | 161 (60.1) | 105 (64.0) | 56 (53.8) | |
| 55–64 | 39 (14.6) | 17 (10.4) | 22 (21.2) | |
| 65 and over | 4 (1.5) | 1 (0.6) | 3 (2.9) | |
| Coprescription of oestrogens | ||||
| Yes | 17 (6.3) | 9 (5.5) | 8 (7.7) | ≥0.05 |
| Duration of follow‐up | ||||
| Less than 2 years | 82 (30.6) | 56 (34.1) | 26 (25.0) | ≥0.05 |
| 2–5 years | 95 (35.4) | 53 (32.3) | 42 (40.4) | |
| At least 5 years | 91 (34.0) | 55 (33.5) | 36 (34.6) | |
| Cumulative dose | ||||
| ≤ 0.36 g | 104 (38.8) | 0 (0) | 104 (100) | <0.001 |
| [0.36–1.44 g] | 13 (4.9) | 13 (7.9) | 0 (0) | |
| [1.44–2.88 g] | 19 (7.1) | 19 (11.6) | 0 (0) | |
| [2.88–5.76 g] | 22 (8.2) | 22 (13.4) | 0 (0) | |
| [5.76–8.64 g] | 24 (9.0) | 24 (14.6) | 0 (0) | |
| ≥ 8.64 g | 86 (32.1) | 86 (52.4) | 0 (0) | |
| Anatomical site of meningioma | ||||
| Classification of anatomical site in six groups according to CCAM | ||||
| Group 1: Anterior skull base | 55 (23.8) | 37 (25.3) | 18 (21.2) | <0.001 |
| Group 2: Middle of skull base | 65 (28.1) | 47 (32.2) | 18 (21.2) | |
| Group 3: Posterior skull base | 28 (12.1) | 13 (8.9) | 15 (17.7) | |
| Group 4: Convexity | 70 (30.3) | 42 (28.8) | 28 (32.9) | |
| Group 5: Falx and tentorium | 13 (5.6) | 7 (4.8) | 6 (7.1) | |
| Missing data (no surgery, only radiotherapy) | 37 | 17 | 19 | |
| Grade of severity a | ||||
| Benign | 224 (97.0) | 144 (98.0) | 80 (94.1) | <0.0001 |
| Atypical | 7 (3.0) | 2 (1.4) | 5 (8.2) | |
| Malign | 1 (0) | 1 (0.7) | 0 (0) | |
| Multiple locations a | 12 (5.2) | 8 (5.4) | 4 (4.7) | 1 |
| Length of hospital stay for initial treatment | ||||
| Mean duration (SD) in days | 9.0 (10.8) | 8.6 (7.3) | 9.7 (14.7) | ≥0.05 |
| Median duration (IQR) in days | 7 (5–9) | 7 (6–9) | 7 (5–10) | |
| Less than 7 days | 111 (41.4) | 67 (40.9) | 44 (42.3) | |
| 7–9 days | 92 (34.3) | 59 (36.0) | 33 (31.7) | |
| At least 10 days | 65 (24.3) | 38 (23.2) | 27 (26.0) | |
| Death | ||||
| Deaths within 30 days | 2 (0.7) | 1 (0.6) | 1 (1.0) | ≥0.05 |
| Deaths within 1 year | 2 (0.7) | 1 (0.6) | 1 (1.0) | |
| Antiepileptic drug treatment b | ||||
| From discharge to 1 year | 103/187 (55.1) | 65/115 (56.5) | 38/72 (52.8) | ≥0.05 |
| 1–2 years after discharge | 69/187 (36.9) | 50/115 (43.5) | 19/72 (26.4) | <0.05 |
| Hospitalization for seizures b | ||||
| From discharge to 1 year | 2/187 (1.1) | 2/115 (1.7) | 0/72 (0) | ≥0.05 |
| 1–2 years after initial discharge | 1/187 (0.5) | 1/115 (0.9) | 0/72 (0) | ≥0.05 |
| Neurosurgical reoperation b , c | ||||
| From discharge to 1 year | 2/187 (1.1) | 2/115 (1.7) | 0/72 (0) | ≥0.05 |
| 1–2 years after initial operation | 6/187 (3.2) | 5/115 (4.3) | 1/72 (1.4) | ≥0.05 |
Abbreviations: CCAM, Classification Commune des Actes Médicaux (common classification for medical acts); IQR, Interquartile range; SD, standard deviation.
On all operated meningiomas for which information is available (N = 232).
Only operated meningiomas occurring in 2007–2016 were considered to have a sufficient look‐back period.
Neurosurgical reoperation designates a new occurrence or the recurrence of a meningioma.
FIGURE 1.
Associations between chlormadinone acetate use and the risk of intracranial meningioma, by cumulative dose, discontinuation and meningioma location. Poisson models: *adjustment for age; cumulative dose and age considered as time‐dependent variables; **discontinuation of CMA for at least 1 year, depending on prior cumulative CMA dose; ***location was known for a total of 231 meningiomas, remaining unknown for tumours not treated by surgery (radiotherapy only). CI, confidence interval; CMA, chlormadinone acetate; g, grammes; PY, person‐years; aRR, adjusted risk ratio.
A strong dose–response relationship was observed in the analysis by cumulative dose of CMA: the higher the cumulative dose, the greater the risk of meningioma. Meningioma incidence reached almost 47 cases per 100,000 PY in the most exposed group (>8.64 g), giving an aRR of 6.9 (95% CI 5.1–9.2) relative to the control group. The aRR was not significantly different from 1 below a cumulative exposure of 1.44 g. In the three‐group sensitivity analysis, the risk of meningioma decreased to 1.3 (95% CI 1.0–1.7) in the group that discontinued CMA use for at least 1 year, provided that the previous cumulative dose was below 2.88 g. CMA exposure seemed to be associated with a preferential location of meningiomas in the anterior or middle part of the skull base (aRR of 3.6 [95% CI 2.0–6.2] and 4.5 [95% CI 2.6–7.8], respectively). Analyses in a subgroup of women without oestrogen coprescription yielded similar results (Data S1, Supplement K).
DISCUSSION
Under optimal epidemiological conditions (i.e., cohort of new incident users with known cumulative doses over time), the hypothesis of an association between CMA exposure and meningioma risk in a very large population‐based cohort was tested. A strong, dose‐dependent association was observed between prolonged CMA use and the risk of intracranial meningioma. The risk of meningioma requiring surgery or radiotherapy decreased significantly if treatment was discontinued for at least 1 year. Indeed, in some published cases, a decrease in tumour volume was observed when CMA treatment was stopped [5].
These results are similar to those obtained for CPA and NOMAC [1, 3], although the magnitude of the risk is lower. As with these progestogens, meningiomas located in the anterior and middle part of the skull base were particularly associated with prolonged exposure to CMA [1, 6]. This result is consistent with previous studies indicating a preferential location of meningiomas containing progesterone receptors in the skull base. Furthermore, meningiomas that express progesterone receptors on their surface are more frequent in women of childbearing age, during pregnancy and the post‐partum period, and on hormonal treatment. This location complicates the surgical approach and resection, increasing the risk of postoperative morbidity and recurrence.
This study focused exclusively on the moderate and high doses of CMA used in France, but it highlights the importance of considering cumulative dose even in other countries in which lower daily doses are used. Contraception based on CMA and oestrogen taken over many years may also carry a risk of meningioma that should be investigated. The SNDS lacks information about magnetic resonance imaging and histology outcomes, including whether meningiomas are long‐standing or recent. The lack of clinical, radiological (difficulties identifying meningiomatosis in our data) and histomolecular details is a key limitation of our study. Indication bias was limited by using a control group of patients who stopped using CMA early but otherwise closely resembled the exposed group [1, 3]. The effect of differences in follow‐up time between groups was also minimized by treating age as a time‐dependent variable.
Our study is in line with international research into the link between progestogens and meningiomas [7, 8, 9]. All the evidence obtained points to a causal relationship, even if the underlying biological mechanism connecting progestogens and meningioma is not yet fully understood. The benefit–risk balance of CMA use must be assessed for each woman, taking into account the cumulative dose of CMA consumed and any switches to other progestogens also associated with a risk of meningioma. Previous studies have evaluated the decrease in tumour volume at 30%–90% after the cessation of progestogen treatment, the precise decrease depending on the progestogen involved [5, 10, 11, 12, 13, 14, 15]. Neurological monitoring and a dedicated radiological screening programme [15] should be implemented if CMA treatment is continued [16], bearing in mind that stopping CMA treatment may result in tumour regression, avoiding the need for surgery [10].
AUTHOR CONTRIBUTIONS
Noémie Roland: Writing – original draft; methodology; validation; visualization; writing – review and editing. Pierre Nguyen: Conceptualization; investigation; methodology; validation; software; data curation; formal analysis. Anke Neumann: Conceptualization; investigation; methodology; software; formal analysis; data curation. Léa Hoisnard: Conceptualization; methodology; formal analysis. Thibault Passeri: Writing – review and editing; resources. Lise Duranteau: Writing – review and editing; supervision; resources. Joël Coste: Writing – review and editing. Sébastien Froelich: Writing – review and editing; resources. Mahmoud Zureik: Resources; supervision; project administration; writing – review and editing; conceptualization; methodology; validation; funding acquisition. Alain Weill: Conceptualization; investigation; methodology; project administration; resources; supervision; funding acquisition; writing – review and editing; validation.
FUNDING INFORMATION
This research was funded by the French National Health Insurance Fund (CNAM) and the French National Agency for Medicines and Health Products Safety (ANSM) via the Health Product Epidemiology Scientific Interest Group EPI‐PHARE.
CONFLICT OF INTEREST STATEMENT
The authors declare no financial relationships with any organizations that might have an interest in the submitted work over the last 3 years and no other relationships or activities that could appear to have influenced the submitted work.
Supporting information
Data S1.
ACKNOWLEDGEMENTS
The authors would like to thank Alex Edelman and Associates for English proofreading of the manuscript, and Bérangère Baricault and Pauline Dayani for their help.
Roland N, Nguyen P, Neumann A, et al. Prolonged use of chlormadinone acetate and risk of intracranial meningioma: A population‐based cohort study. Eur J Neurol. 2025;32:e16505. doi: 10.1111/ene.16505
DATA AVAILABILITY STATEMENT
Under the terms of the SNDS data use agreement, the complete study data cannot be shared with other investigators (https://www.snds.gouv.fr). However, the authors try to share publication‐related data as much as possible: algorithms and other additional information are provided in the supplemental data; aggregated data can be supplied upon request by contacting the authors at alain.weill@assurance-maladie.fr.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1.
Data Availability Statement
Under the terms of the SNDS data use agreement, the complete study data cannot be shared with other investigators (https://www.snds.gouv.fr). However, the authors try to share publication‐related data as much as possible: algorithms and other additional information are provided in the supplemental data; aggregated data can be supplied upon request by contacting the authors at alain.weill@assurance-maladie.fr.