Näytönastekatsaukset

Risk of venous thromboembolism in women using combined contraceptives containing natural estrogens estradiol/estetrol (E2/E4) compared to ethinylestradiol (EE)

Näytönastekatsaukset

21.1.2025

Bianca Arrhenius

Level of evidence: B

The use of combined oral contraceptives containing estradiol or etsetrol (E2/E4) appears to carry a lower risk for venous thromboembolism compared to the use of ethinylestradiol (EE) containing oral contraceptives in adult women.

Level of evidence is upgraded due to biologically plausible effect demonstrated in several observational studies and supported by indirect evidence from coagulation biomarker studies.

Description of the included studies

Reference	Study type	Population	Intervention and comparison	Outcomes	Risk of bias
«Douxfils J, Raskin L, Didembourg M, ym. Are natural estrogens used in contraception at lower risk of venous thromboembolism than synthetic ones? A systematic literature review and meta-analysis. Front»1	Meta-analysis based on five observational studies (three cohort and two case-control studies)	Women aged over 18 years	Intervention: COCs with natural estrogens E2 or E4 (estradiol, estradiol valerate, estetrol) Comparator: COCs with synthetic estrogens (ethinylestradiol (EE) combined with any progestin)	Risk of thrombosis Any type of venous thrombosis (suspected, confirmed, idiopathic)	Low
«Didembourg M, Locquet M, Raskin L, ym. Lower reporting of venous thromboembolisms events with natural estrogen-based combined oral contraceptives compared to ethinylestradiol-containing pills: A dispr»2	Disproportionality reporting rate analysis (registerbased observational study)	Not reported	Reporting rates of thrombotic and other adverse events in natural estrogen-based COC use (E2 and E4) and conventional synthetic estrogen-based COC use (EE).	Number of extracted thrombotic and other adverse events from the EudraVigilance database. Comparison of the proportionality of reporting rates of thrombotic vs other adverse events for different COCs.	Moderate

COC = combined oral contraceptive; E2 = estradiol or estradiol valerate; E4 = etsetrol; EE = ethinylestradiol

Additional comments for included studies

Reference	Comments
«Douxfils J, Raskin L, Didembourg M, ym. Are natural estrogens used in contraception at lower risk of venous thromboembolism than synthetic ones? A systematic literature review and meta-analysis. Front»1	The meta-analysis was based on observational studies, and it used GRADE criteria for rating the quality of the studies. The literature search was comprehensive, and the PICO question clearly formulated. Three authors went through the literature and two extracted the data, but it was not reported how many authors performed the quality assessment. Publication bias could not be assessed due to low number of studies. Moderate risk of bias was present in some of the included studies, but the meta-analysis found robust results and low heterogeneity across studies and in sensitivity analyses.
«Didembourg M, Locquet M, Raskin L, ym. Lower reporting of venous thromboembolisms events with natural estrogen-based combined oral contraceptives compared to ethinylestradiol-containing pills: A dispr»2	The report consists of “real life” based data from pharmacovigilance databases. The reporting system is spontaneous and limited by potential underreporting and other reporting biases. Furthermore, no defined population at risk can be defined, which may result in an incomplete or skewed estimate of the true incidence of the events.

Reference

Comments

«Douxfils J, Raskin L, Didembourg M, ym. Are natural estrogens used in contraception at lower risk of venous thromboembolism than synthetic ones? A systematic literature review and meta-analysis. Front»1

The meta-analysis was based on observational studies, and it used GRADE criteria for rating the quality of the studies. The literature search was comprehensive, and the PICO question clearly formulated. Three authors went through the literature and two extracted the data, but it was not reported how many authors performed the quality assessment. Publication bias could not be assessed due to low number of studies. Moderate risk of bias was present in some of the included studies, but the meta-analysis found robust results and low heterogeneity across studies and in sensitivity analyses.

«Didembourg M, Locquet M, Raskin L, ym. Lower reporting of venous thromboembolisms events with natural estrogen-based combined oral contraceptives compared to ethinylestradiol-containing pills: A dispr»2

The report consists of “real life” based data from pharmacovigilance databases. The reporting system is spontaneous and limited by potential underreporting and other reporting biases. Furthermore, no defined population at risk can be defined, which may result in an incomplete or skewed estimate of the true incidence of the events.

Results

Outcome 1: Confirmed venous thromboembolism events per person-time for prospective studies or event per number of participants for case-control studies. I= use of E2 based preparations, C= used of ethinylestradiol based preparations

Reference	Number of studies and number of patients (I/C)	Follow-up time	Absolute number of events, I	Absolute number of events, C	Relative effect (95% CI)
Level of evidence: moderate Level of evidence is upgraded due to biologically plausible effect demonstrated in several observational studies.
«Douxfils J, Raskin L, Didembourg M, ym. Are natural estrogens used in contraception at lower risk of venous thromboembolism than synthetic ones? A systematic literature review and meta-analysis. Front»1	5 studies I=72 210 C=487 942	Not reported (only that the longest follow-up time was used if an article reported on several time points)	59	1607	0.67 (0.51-0.87) Heterogeneity: I2=0%, p=0.46

I=intervention; C=comparison; CI=confidence interval

Outcome 2: Number of thrombotic and other adverse events in I=natural estrogen-based COC use (E2 and E4) and C= conventional synthetic estrogen-based COC use (EE).

Reference	Number of patients	Follow-up time	Absolute number of events, I	Absolute number of events, C	Proportionality reporting rate (95% CI)
Level of evidence: low
«Didembourg M, Locquet M, Raskin L, ym. Lower reporting of venous thromboembolisms events with natural estrogen-based combined oral contraceptives compared to ethinylestradiol-containing pills: A dispr»2	No defined population at risk	Data from registers was gathered 2004-2024	E2/NOMAC: 158 thrombotic events; 1256 other adverse events E4/DRSP: 34 158 thrombotic events; 507 others adverse events	EE/LNG (gold standard): 3869 thrombotic events; 13583 other adverse events	E2/NOMAC vs EE/LNG 0.44 (0.38−0.51) E4/DRSP vs EE/LNG 0.24 (0.17−0.33)

I=intervention; C=comparison; CI=confidence interval; COC = combined oral contraceptive; E2/NOMAC = COC containing estradiol and nomegestrol acetate; E4/DRSP = COC containing etsetrol and drospirenone; EE/LNG = COC containing ethinylestradiol and levonorgestrel.

References

Douxfils J, Raskin L, Didembourg M, ym. Are natural estrogens used in contraception at lower risk of venous thromboembolism than synthetic ones? A systematic literature review and meta-analysis. Front Endocrinol (Lausanne) 2024;15():1428597 «PMID: 39220361»PubMed
Didembourg M, Locquet M, Raskin L, ym. Lower reporting of venous thromboembolisms events with natural estrogen-based combined oral contraceptives compared to ethinylestradiol-containing pills: A disproportionality analysis of the Eudravigilance database. Contraception 2025;142():110727 «PMID: 39424122»PubMed