Association between menopausal hormone therapy use and mortality risk: a Swedish population-based matched cohort study

Figures & data

Table 1. Descriptive characteristics of the study included women between 2005 and 2014.

	MHT ever-users (N = 290,186) Number of individuals (%)	MHT non-users (N = 870,165) Number of individuals (%)
Characteristics
All-cause mortality	33,650 (11.6)	104,740 (12.0)
Cardiovascular mortality	13,985 (4.8)	43,328 (5.0)
Cancer mortality	5608 (1.9)	23,956 (2.8)
Age at treatment initiation
<60 years	108,631 (37.4)	325,747 (37.4)
60–69 years	93,490 (32.2)	267,323 (30.7)
≥70 years	88,065 (30.4)	277,095 (31.8)
Type of MHT treatment
Oestrogen-only	117,996 (40.7)	–
Tibolone	17,992 (6.2)	–
Oestrogens combined progestins	154,198 (53.1)	–
Current or past use
Current users^a	118,154 (40.7)	–
Past users^b	172,032 (59.3)	–
Oestrogen-only formulations
Oestradiol	53,339 (45.2)	–
Oestriol	55,653 (47.2)	–
Conjugated oestrogens	1161 (1.00)	–
Other, mixed^c	7843 (6.7)	–
Progestin types and regimens
Progesterone-derived continuous regimens	30,123 (19.5)	–
Testosterone-derived continuous regimens	53,360 (34.6)	–
Progesterone-derived sequential regimens	3341 (2.2)	–
Testosterone-derived sequential regimens	21,247 (13.8)	–
Other, mixed^c	46,127 (29.9)	–
Clinical factors and comorbidities
Ever parous (in-hospital delivery)^d	117,861 (40.6)	353,282 (40.6)
Thrombotic events^d	40,316 (14.0)	120,931 (14.0)
Hysterectomy^d	51,811 (17.9)	155, 138 (17.8)
Diabetes^d	15,936 (5.5)	48,422 (5.6)
Obesity^d	5146 (1.8)	15,526 (1.8)
Alcohol-related diseases^d	7293 (2.5)	21,455 (2.5)
Smoking-related diseases^d	13,601 (4.7)	40,994 (4.7)
Osteoporosis	8256 (2.9)	22,764 (2.6)

MHT: menopausal hormone therapy.

^aWomen who received at least one dispensed prescription MHT during the last 6 months of follow-up were considered as current users of MHT.

^bAll other women were considered as past users of MHT.

^cOther, mixed includes women who received multiple different menopausal hormone therapy types during the study period.

^dIn addition to year of birth, these variables were used on the group-level matching.

Figure 1. Association between menopausal hormone therapy use and risk of mortality. OR: odds ratio. Note: These odds ratios and other information is provided in more detail in the Supplementary Table 3.

Table 2. The association of menopausal hormone therapy (MHT) use with all-cause and cause-specific mortality during the study period stratified by current versus past use of MHT.

	MHT users Number of women/Number of deaths	MHT non-users Number of women/Number of deaths	Multivariable adjusted OR (95% CI)^a
Current use of MHT
All-cause mortality		870,165/104,740
All MHT users	118,154–18,134		1.27 (1.24–1.30)
Oestrogen-only users	51,788/16,416		1.48 (1.44–1.52)
Tibolone users	5671/124		0.57 (0.47–0.68)
Oestrogen + progestin users	60,695/1594		0.76 (0.72–0.79)
Cardiovascular mortality		870,165/43,328
All MHT	118,154/ 8380		1.20 (1.16–1.23)
Oestrogen-only users	51,788/7849		1.24 (1.20–1.28)
Tibolone users	5671/39		0.83 (0.60–1.15)
Oestrogen + progestin users	60,695/492		0.92 (0.84–1.02)
Cancer mortality		870,165/23,956
All MHT users	118,154/1767		0.52 (0.49–0.54)
Oestrogen-only	51,788/1243		0.53 (0.50–0.56)
Tibolone users	5671/46		0.49 (0.36–0.65)
Oestrogen + progestin users	60,695/478		0.51 (0.46–0.56)
Past use of MHT
All-cause mortality
All MHT users	172,032/15,516		0.78 (0.77–0.80)
Oestrogen-only users	66,208/11,494		0.83 (0.80–0.86)
Tibolone users	12,321 367		0.62 (0.55–0.69)
Oestrogen + progestin users	93,503/3655		0.77 (0.74–0.79)
Cardiovascular mortality
All MHT users	172,032/5605		0.77 (0.75–0.80)
Oestrogen-only users	66,208/4765		0.86 (0.83–0.89)
Tibolone-only users	12,321/51		0.36 (0.27–0.48)
Oestrogen + progestin users	93,503/789		0.64 (0.59–0.68)
Cancer mortality
All MHT users	172,032/3841		0.84 (0.81–0.87)
Oestrogen-only users	66,208/1973		0.76 (0.73–0.80)
Tibolone users	12,321/214		0.93 (0.81–1.07)
Oestrogen + progestin users	93,503/1654		0.95 (0.90–1.00)

OR: odds ratio; 95% CI: 95% confidence interval.

^aAll analyses were adjusted for year of birth, hysterectomy, delivery, thrombotic events, smoking- and alcohol-related diseases, obesity, diabetes, and osteoporosis.

STROBE Statement—Checklist of items that should be included in reports of cohort studies.

	Item no	Recommendation	Page no
Title and abstract	1	(a) Indicate the study’s design with a commonly used term in the title or the abstract	1
		(b) Provide in the abstract an informative and balanced summary of what was done and what was found	5–6
Introduction
Background/rationale	2	Explain the scientific background and rationale for the investigation being reported	7-8
Objectives	3	State specific objectives, including any prespecified hypotheses	7–8
Methods
Study design	4	Present key elements of study design early in the paper	8
Setting	5	Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection	8–9
Participants	6	(a) Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up	8–9
		(b) For matched studies, give matching criteria and number of exposed and unexposed	8,11
Variables	7	Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if applicable	8–11
Data sources/measurement	8^a	For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group	8–11
Bias	9	Describe any efforts to address potential sources of bias	8–11
Study size	10	Explain how the study size was arrived at	8
Quantitative variables	11	Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why	10–11
Statistical methods	12	(a) Describe all statistical methods, including those used to control for confounding	10–11
		(b) Describe any methods used to examine subgroups and interactions	10–11
		(c) Explain how missing data were addressed	10–11
		(d) If applicable, explain how loss to follow-up was addressed
		(e) Describe any sensitivity analyses	10–11
Results
Participants	13^a	(a) Report numbers of individuals at each stage of study—e.g. numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed	11–15
		(b) Give reasons for non-participation at each stage	11–15
		(c) Consider use of a flow diagram
Descriptive data	14^a	(a) Give characteristics of study participants (e.g., demographic, clinical, social) and information on exposures and potential confounders	11–15
		(b) Indicate number of participants with missing data for each variable of interest	10
		(c) Summarise follow-up time (e.g., average and total amount)	10
Outcome data	15^a	Report numbers of outcome events or summary measures over time	11–15
Main results	16	(a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (e.g., 95% confidence interval). Make clear which confounders were adjusted for and why they were included	11–15
		(b) Report category boundaries when continuous variables were categorised	11–15
		(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period	11–15
Other analyses	17	Report other analyses done—e.g., analyses of subgroups and interactions, and sensitivity analyses	15
Discussion
Key results	18	Summarise key results with reference to study objectives	15–16
Limitations	19	Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias	16–18
Interpretation	20	Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence	18–19
Generalisability	21	Discuss the generalisability (external validity) of the study results	16
Other information
Funding	22	Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based	1,8

^aGive information separately for exposed and unexposed groups.

Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at http://www.strobe-statement.org.

Data availability statement

The dataset for this study is held securely in a coded form at Karolinska Institutet, yet it belongs to the National Board of Health and Welfare (Socialstyrelsen). Data sharing agreements prohibit publicly making the dataset available, but the data will be made available upon reasonable request to the corresponding author (JS) after obtaining relevant ethical and data-sharing approval. The underlying analysis plan is available from the corresponding author (JS) upon request.

STROBE Statement—Checklist of items that should be included in reports of cohort studies.

	Item no	Recommendation	Page no
Title and abstract	1	(a) Indicate the study’s design with a commonly used term in the title or the abstract	1
		(b) Provide in the abstract an informative and balanced summary of what was done and what was found	5–6
Introduction
Background/rationale	2	Explain the scientific background and rationale for the investigation being reported	7-8
Objectives	3	State specific objectives, including any prespecified hypotheses	7–8
Methods
Study design	4	Present key elements of study design early in the paper	8
Setting	5	Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection	8–9
Participants	6	(a) Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up	8–9
		(b) For matched studies, give matching criteria and number of exposed and unexposed	8,11
Variables	7	Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if applicable	8–11
Data sources/measurement	8^a	For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group	8–11
Bias	9	Describe any efforts to address potential sources of bias	8–11
Study size	10	Explain how the study size was arrived at	8
Quantitative variables	11	Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why	10–11
Statistical methods	12	(a) Describe all statistical methods, including those used to control for confounding	10–11
		(b) Describe any methods used to examine subgroups and interactions	10–11
		(c) Explain how missing data were addressed	10–11
		(d) If applicable, explain how loss to follow-up was addressed
		(e) Describe any sensitivity analyses	10–11
Results
Participants	13^a	(a) Report numbers of individuals at each stage of study—e.g. numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed	11–15
		(b) Give reasons for non-participation at each stage	11–15
		(c) Consider use of a flow diagram
Descriptive data	14^a	(a) Give characteristics of study participants (e.g., demographic, clinical, social) and information on exposures and potential confounders	11–15
		(b) Indicate number of participants with missing data for each variable of interest	10
		(c) Summarise follow-up time (e.g., average and total amount)	10
Outcome data	15^a	Report numbers of outcome events or summary measures over time	11–15
Main results	16	(a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (e.g., 95% confidence interval). Make clear which confounders were adjusted for and why they were included	11–15
		(b) Report category boundaries when continuous variables were categorised	11–15
		(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period	11–15
Other analyses	17	Report other analyses done—e.g., analyses of subgroups and interactions, and sensitivity analyses	15
Discussion
Key results	18	Summarise key results with reference to study objectives	15–16
Limitations	19	Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias	16–18
Interpretation	20	Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence	18–19
Generalisability	21	Discuss the generalisability (external validity) of the study results	16
Other information
Funding	22	Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based	1,8

^aGive information separately for exposed and unexposed groups.

Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at http://www.strobe-statement.org.