Stroke and myocardial infarction with contemporary hormonal contraception:  real-world, nationwide, prospective cohort study

Harman Yonis; Ellen Løkkegaard; Kristian Kragholm; Christopher B Granger; Amalie Lykkemark Møller; Lina Steinrud Mørch; Christian Torp-Pedersen; Amani Meaidi

doi:10.1136/bmj-2024-082801

Contraception Adverse Effects

Stroke and myocardial infarction with contemporary hormonal contraception: real-world, nationwide, prospective cohort study

Yonis H, Løkkegaard E, Kragholm K, Granger CB, Møller AL, Mørch LS, Torp-Pedersen C, Meaidi A

Published February 12, 2025 BMJ (Clinical Research Ed.), 388, e082801

DOI 10.1136/bmj-2024-082801 PMID 39938934 PMC PMC11816856

RRM Academy Synopsis

Combined oral contraception linked to twice the ischemic stroke rate

In a nationwide Danish cohort, combined oral contraception was associated with twice the ischemic stroke and heart attack rates compared with no use. The cohort followed more than 2 million women aged 15 to 49 without prior thrombosis. Rates were also higher with progestin-only pills. The progestin-only intrauterine device showed no association with ischemic stroke or heart attack rates.

Key Findings

Against no use, current combined oral contraception had an adjusted rate ratio of 2.0 for both ischemic stroke (95% CI 1.9 to 2.2) and myocardial infarction (1.7 to 2.2).
Versus no use, current combined oral contraception had standardized rate differences of 21 (18 to 24) additional ischemic strokes and 10 (7 to 12) additional myocardial infarctions per 100 000 person years.
Progestin-only pills had adjusted rate ratios of 1.6 for ischemic stroke (95% CI 1.3 to 2.0) and 1.5 for myocardial infarction (1.1 to 2.1).
Adjusted ischemic stroke rate ratios (95% CI): combined vaginal ring 2.4 (1.5 to 3.7), patch 3.4 (1.3 to 9.1), progestin-only implant 2.1 (1.2 to 3.8).
The progestin-only intrauterine device had adjusted rate ratios of 1.1 for ischemic stroke (95% CI 1.0 to 1.3) and 1.1 for myocardial infarction (0.9 to 1.3).

Interpretation

This cohort study followed more than 2 million Danish women through national health records. The authors found about one extra ischemic stroke for every 4760 women who took combined birth control pills for a year, compared with women who used none. The authors note that their numbers for progestin-only pills, implants, and injections were less certain, since fewer women used those methods. The findings support larger studies on stroke and heart attack risk from birth control.

RRM Context

Restorative reproductive medicine looks for the cause of a symptom first, before treating it. In that approach, birth control used for cycle symptoms counts as a suppressive medication.

Our editorial summary of this paper, not the article's abstract.

Abstract

Objective

To evaluate the association between contemporary hormonal contraceptive use and the risk of incident ischaemic stroke and myocardial infarction.

Design

Real-world, nationwide, prospective cohort study.

Setting

Denmark, by use of national registries.

Participants

All women aged 15-49 years residing in Denmark between 1996 and 2021, with no history of arterial or venous thrombosis, antipsychotics use, cancer, thrombophilia, liver disease, kidney disease, polycystic ovary syndrome, endometriosis, infertility treatment, hormone therapy use, oophorectomy, and hysterectomy.

Main Outcome Measures

First time diagnosis of ischaemic stroke or myocardial infarction at discharge.

Results

Among 2 025 691 women followed up for 22 209 697 person years, 4730 ischaemic strokes and 2072 myocardial infarctions occurred. Standardised ischaemic stroke rate per 100 000 person years were 18 (95% confidence interval 18 to 19) for no use, 39 (36 to 42) for combined oral contraception, 33 (25 to 44) for progestin-only pills, and 23 (17 to 29) for intrauterine device. Standardised myocardial infarction rate per 100 000 person years were 8 (8 to 9) for no use, 18 (16 to 20) for combined oral contraception, 13 (8 to 19) for progestin-only pills, and 11 (7 to 16) for intrauterine device. Compared with no use, current use of combined oral contraception was associated with an adjusted rate ratio of 2.0 (1.9 to 2.2) for ischaemic stroke and 2.0 (1.7 to 2.2) for myocardial infarction. These corresponded to standardised rate differences of 21 (18 to 24) extra ischaemic strokes and 10 (7 to 12) extra myocardial infarctions per 100 000 person years. Compared with no use, current use of progestin-only pills was associated with an adjusted rate ratio of 1.6 (95% CI 1.3 to 2.0) for ischaemic stroke and 1.5 (1.1 to 2.1) for myocardial infarction, equating to 15 (6 to 24) extra ischaemic strokes and four (-1 to 9) extra myocardial infarctions per 100 000 person years. Increased arterial thrombotic risk was also observed with use of the combined vaginal ring (adjusted incidence rate ratio of 2.4 (1.5 to 3.7) for ischaemic stroke and 3.8 (2.0 to 7.3) for myocardial infarction), patch (3.4 (1.3 to 9.1) and no myocardial infarctions), and progestin-only implant (2.1 (1.2 to 3.8) and ≤3 myocardial infarctions), whereas no increased risk was observed with progestin-only intrauterine device (1.1 (1.0 to 1.3) for ischaemic stroke and 1.1 (0.9 to 1.3) for myocardial infarction).

Conclusions

Use of contemporary oestrogen-progestin and progestin-only contraceptives was associated with an increased risk of ischaemic stroke and, in some cases, myocardial infarction except for the levonorgestrel-releasing intrauterine device, which was not associated with either. Although absolute risks were low, clinicians should include the potential risk of arterial thrombosis in their assessment of the benefits and risks when prescribing a hormonal contraceptive method.

Topics

Contraception › Adverse Effects › Cardiovascular Effects · Therapeutics › Hormonal Agents › Estrogen Preparations

Harman Yonis, Ellen Løkkegaard, Kristian Kragholm, Christopher B Granger, Amalie Lykkemark Møller, Lina Steinrud Mørch, Christian Torp-Pedersen, Amani Meaidi

H Yonis, E Løkkegaard, K Kragholm, Chris Granger, C Granger, A Møller, L Mørch, C Torp-Pedersen, A Meaidi

PMID 39938934 39938934 DOI 10.1136/bmj-2024-082801 10.1136/bmj-2024-082801 Yonis et al. 2025, Yonis 2025

Keywords

Progestins, Contraceptives, Oral, Combined