20 mcg versus over 20 mcg estrogen combined oral contraceptives for contraception

Evidence Summaries

Level of Evidence = B
Combined oral contraceptives with 20 mcg estrogen appear to have similar efficacy as those with >20 mcg estrogen. Bleeding pattern disruption are more common with low-dose estrogen. Venous and arterial thromboembolism may be higher with over 20 mcg of oestrogen compared with 20mcg of oestrogen preparations.

A Cochrane review 1 included 21 studies. English-language reports of randomized controlled trials that compare a COC containing 20 mcg EE with a COC containing >20 mcg EE were eligible. No differences were found in contraceptive effectiveness for the 13 COC pairs for which this outcome was reported. Several COCs containing 20 mcg EE resulted in higher rates of early trial discontinuation (overall and due to adverse events such as irregular bleeding) as well as increased risk of bleeding disturbances (both amenorrhea/infrequent bleeding and irregular, prolonged, frequent bleeding, or breakthrough bleeding or spotting) than their higher-estrogen comparison pills.

A database cohort study 2 included 4,945,088 women aged 15-49 years. 1800 pulmonary embolisms (33 per 100,000 women years), 1046 ischaemic strokes (19 per 100,000 women years), and 407 myocardial infarctions (7 per 100,000 women years) were observed. After adjustment for progestogen and risk factors, the relative risks for women using low dose oestrogen (20 µg vs 30-40 µg) were 0.75 (95% CI 0.67 to 0.85) for pulmonary embolism, 0.82 (0.70 to 0.96) for ischaemic stroke, and 0.56 (0.39 to 0.79) for myocardial infarction. After adjustment for oestrogen dose and risk factors, desogestrel and gestodene were associated with statistically significantly higher relative risks for pulmonary embolism (2.16, 1.93 to 2.41 and 1.63, 1.34 to 1.97, respectively) compared with levonorgestrel.

In a nationwide cohort study (Danish national registries) 2 million women were followed for 21 million person years, 8710 VTEs occurred. Contraceptives were defined for risk groups. High risk: combined oestrogen and progestin patch, vaginal ring, and tablets containing 50 µg ethinyl oestradiol, or the progestins desogestrel, gestodene, drospirenone, or cyproterone. Medium risk: all other COCs and the medroxyprogesterone injection. Low/no risk progestin-only tablets, implants, and LNG-IUD. Compared with non-use of NSAIDs, use of NSAIDs was associated with an adjusted incidence rate ratio of VTE of 7.2 (95% CI 6.0 to 8.5) in women not using hormonal contraception, 11.0 (9.6 to 12.6) in women using high risk hormonal contraception, 7.9 (5.9 to 10.6) in those using medium risk hormonal contraception, and 4.5 (2.6 to 8.1) in users of low/no risk hormonal contraception.

Comment: The quality of evidence is downgraded by study quality (unclear allocation concealment, lack of blinding, and more than 20% loss to follow up).


1. Gallo MF, Nanda K, Grimes DA et al. 20 µg versus >20 µg estrogen combined oral contraceptives for contraception. Cochrane Database Syst Rev 2013;(8):CD003989.  [PMID:23904209]
2. Weill A, Dalichampt M, Raguideau F et al. Low dose oestrogen combined oral contraception and risk of pulmonary embolism, stroke, and myocardial infarction in five million French women: cohort study. BMJ 2016;353():i2002.  [PMID:27164970]
3. Meaidi A, Mascolo A, Sessa M, et al. Venous thromboembolism with use of hormonal contraception and non-steroidal anti-inflammatory drugs: nationwide cohort study. BMJ 2023;382():e074450  [PMID:37673431]
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