Menopausal hormone therapy: oral oestrogen raised clot risk; transdermal showed no increase

Design

Nationwide nested case-control study, Danish registries

Population

Women aged 50-69: 9,807 VTE, 18,460 stroke, 11,974 MI cases with matched controls

Primary outcome

First VTE, ischaemic stroke or MI by current hormone therapy use

Effect

Oral oestrogen VTE HR 1.6 (1.5 to 1.8), NNH 1,055 per year; transdermal no increase

A nationwide nested case-control study in the BMJ (23 September 2026) used Danish registries for women aged 50 to 69 between 2003 and 2021, excluding those with prior thrombosis, cancer, thrombophilia and other risk factors. It compared 9,807 women with venous thromboembolism, 18,460 with ischaemic stroke and 11,974 with myocardial infarction against about 200,000 matched controls.

Current oral oestrogen (alone or with a progestogen) was associated with higher rates of VTE (HR 1.6, 95% CI 1.5 to 1.8), ischaemic stroke (1.3, 1.2 to 1.4) and MI (1.2, 1.1 to 1.3). In absolute terms that is one extra VTE for about every 1,055 women treated for a year, one stroke per 1,642 and one MI per 3,846. Oral oestradiol raised VTE risk at any dose; above 1 mg a day for more than five years it was also associated with stroke (HR 1.8) and MI (1.8). Transdermal therapy showed no increase, except MI with transdermal combined cyclic therapy (HR 2.1, 1.1 to 4.1).

This is observational, and women prescribed patches may differ from those given tablets. But the direction matches earlier data, the numbers are large, and the absolute risks are small enough to reassure women for whom HRT is otherwise right.

The decision it changes is the route: for a woman with any thrombotic risk factor, start transdermal; for those on oral treatment long term, review the dose.

• Prefer transdermal oestrogen for women with obesity, a history of migraine with aura, smoking or other thrombotic risk factors
• Keep oral oestradiol at 1 mg a day or below where oral treatment is chosen, and review long-term use
• Give women the absolute numbers — about one extra clot per thousand women per year on oral therapy
• Consider continuous rather than cyclic combined regimens for transdermal users where suitable
• Review route and dose at the annual HRT check rather than repeating the prescription

Why it matters

The route of HRT, often an afterthought, was the difference between a raised clot risk and none.

Don't overread it

This is observational; women given patches may have differed from those given tablets in ways the registries could not capture.

The statistics, in plain English

A hazard ratio of 1.6 means VTE was 60% more frequent in current oral users, but because VTE is uncommon in this age group (about 16 per 10,000 women a year), that adds only about 0.09% per year. The number needed to harm — 1,055 — is how many women would need to take oral therapy for a year for one extra VTE.

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