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 natura...»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 repor...»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 natura...»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 repor...»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 natura...»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 repor...»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.