Safer Oral Contraceptives Low Clot Risk

When counseling about contraceptive pills in the clinic, there are really many people who hesitate before the word "blood clot." When you search "pill blood clot" online, scary stories show up first, so people come carrying worry even before starting the medication. But even with the same "oral contraceptive," the risk of a blood clot (venous thromboembolism, VTE) differs slightly depending on the ingredients inside. In particular, the reported level of risk varies according to which generation the progestin—which plays the role of the corpus luteum hormone—belongs to. Today, I will calmly outline why blood clot risk differs by ingredient, and how far the research on new ingredients designed to lower risk has come.

A blood clot is certainly a side effect to mind, but the absolute frequency itself tends to be low. According to material organized by the American Society for Reproductive Medicine (ASRM, 2016), the risk of venous clots in women taking combined oral contraceptives is higher than in non-pregnant non-users, but is reported to be lower than during pregnancy itself or the period right after childbirth.

As a director, there is an analogy I often offer patients. We do not say to a pregnant woman, "Let's stop the pregnancy because a clot might form." Even though pregnancy and the period right after childbirth are reported to carry higher clot risk than the pill. To that extent, the clot risk of the pill is an area you "go along with while managing," not a contraindication to be avoided unconditionally.

That said, whatever the statistics, there are people who say, "It's unsettling that the medication itself carries such a risk." For them, let us go one step deeper into how ingredients change the risk.

Combined oral contraceptives are usually made by mixing one type of estrogen and one type of progestin. To understand clot risk, you need to look separately at how these two ingredients affect the coagulation system.

Estrogen acts in the direction of increasing the synthesis of coagulation factors in the liver. Ethinylestradiol (EE), the synthetic estrogen in traditional pills, has a relatively strong such effect. By contrast, progestin, depending on its type, partly offsets this coagulation change—or offsets it less.

Looking at the mechanism organized in Frontiers in Endocrinology (2021), the levonorgestrel class, with strong androgenic activity, relatively better offsets the coagulation change created by estrogen. Conversely, progestins with weak androgenic activity or an anti-androgenic character have a weaker offsetting effect, so as a result their influence on clotting factors tends to be reported as greater. This is exactly why, even with the same "pill," risk differs depending on the ingredient combination.

Progestins are commonly divided into generations according to the time of development and chemical structure. The generation division does not mean "newer is better"; it is merely a classification indicating the order of appearance and differences in character.

In the clinic, patients ask "which generation is best?" and the correct answer is "it differs by person." For androgen-related concerns such as acne or oiliness, anti-androgenic new progestins can be helpful, while looking only at the clot aspect, the 2nd generation is sometimes reported to have relatively lower risk. So we choose by placing several conditions together, not by one single criterion.

To state the key conclusion first, 3rd- and 4th-generation progestins tend to be reported as having somewhat higher venous clot risk than 2nd-generation levonorgestrel. The UK Faculty of Sexual and Reproductive Healthcare (FSRH, 2023) combined hormonal contraception guideline and several meta-analyses consistently point in this direction.

Rather than specific percentages, it is better to focus on the "direction." Pills using ingredients such as desogestrel, gestodene, drospirenone, and cyproterone were reported to have relatively higher risk than pills using levonorgestrel (a systematic review and meta-analysis published in 2018). However, this is purely a "relative comparison," and as said earlier, the overall absolute risk itself is in a low range.

So many guidelines show a trend of recommending that people starting the pill for the first time consider a levonorgestrel-containing product first. This is because its risk is reported to be relatively low and because, having been used for a long time, data has accumulated. That does not mean other ingredients are "dangerous medications"; it means options differ according to indication and individual condition.

If you are curious about your own risk factors before starting the pill, you may also lightly ask via inquire about pill consultation through chat. What choice is appropriate when you have a coexisting condition such as high blood pressure is organized in more detail in the article addressing oral contraceptive choice when you have high blood pressure.

Let us return to the new-ingredient story introduced in the original article. Clot risk is not a matter of the progestin generation alone; it is also greatly influenced by which estrogen is used together.

Ethinylestradiol, the synthetic estrogen long used as the standard, has a relatively large influence on the liver's synthesis of coagulation factors. So the question "even with the same progestin, wouldn't changing the estrogen alter the clot profile?" naturally arose, and research on natural-type estrogen classes followed.

One stream of that is estetrol (Estetrol, E4), which the original article covered. E4 is a natural female hormone made in the fetus's liver during pregnancy and found in maternal blood. Interestingly, it shows a selective character, acting on the uterus and vagina while having relatively less influence on tissues such as the liver and breast. Thanks to such properties, the expectation that its influence on coagulation factors is small and that clot risk may be evaluated as low was raised at the research stage.

The estetrol–drospirenone (E4/DRSP) combination, which was "under study" at the time the original article was written, has since accumulated more clinical data. Even here, however, rather than asserting "it is safer," the expression "the risk was reported to be relatively low" is accurate.

In a clinical study conducted in Europe and Russia (BJOG, 2022), the E4/DRSP combination showed favorable results in terms of contraceptive efficacy and bleeding patterns. In a comparative study examining coagulation and fibrinolysis markers (2024), E4/DRSP was reported in the direction of stimulating the coagulation system relatively less than ethinylestradiol-based products. In other words, the combination using natural-type estrogen was evaluated as having a smaller influence on coagulation factors than the synthetic estrogen combination.

• Contraceptive efficacy and cycle-control ability reported as similar to or favorable compared with existing products
• Evaluated in the direction of small influence on coagulation factors
• Influence on breast tissue, triglycerides, and glucose metabolism also reported as relatively small

Of course, a new ingredient has less accumulated data than a long-used one. So it is safer to understand it not as "there is no risk" but as "in research so far there is a tendency for risk to be reported as low, and long-term data continues to accumulate." Because there can be individual variation, it is best to judge through an examination which ingredient suits you.

In the end, ingredient choice is not decided by clot risk alone. In the clinic, we look at the following factors together.

In clinical experience, the first thing we check is risk factors. Smoking, age 35 or older, obesity, high blood pressure, a family history of clots, and whether migraine is present directly affect the choice of an estrogen-containing pill. If such factors are present, we also examine other options such as a progestin-only pill or an intrauterine device (Mirena) that do not contain estrogen.

Next is the purpose of taking it. The suitable ingredient differs depending on whether it is simple contraception or whether you also want control of menstrual pain, irregular periods, or acne. If you are curious about the big picture of what contraceptive methods exist, you may first read the article summarizing the types of contraceptive methods, and in an after-the-fact situation, how to wisely choose emergency contraception is also a useful reference.

Above all, I do not recommend assertions like "it's a new ingredient so it's unconditionally good" or "clots are scary so I'll avoid it unconditionally." Even for the same person, the right answer changes with timing and health condition. If you are curious about the choice that suits your situation, please feel free to inquire via the get a consultation on pill ingredients button. Costs will be provided after consultation.

To summarize today's content in one line: even with the same pill, clot risk is reported differently depending on the progestin generation and the type of estrogen, and research on new ingredients designed to lower risk continues steadily. However, since no medication has zero risk, the process of checking your own risk factors and deciding together is most important.

Written by: Lee Dong-hee Director · Obstetrics and Gynecology Specialist · View medical staff profile

First published December 23, 2023 · Last reviewed May 30, 2026

References: FSRH Combined Hormonal Contraception Guideline (2023), ASRM Combined Hormonal Contraception and Venous Thromboembolism Guideline (2016), Frontiers in Endocrinology Review of Combined Oral Contraceptives and Venous Thrombosis (2021), International Journal of Gynecology & Obstetrics Combined Oral Contraceptive Thrombosis Meta-analysis (2018), BJOG Estetrol-Drospirenone Clinical Study (2022)

This article is intended to provide general health information and does not replace individual diagnosis or treatment. If you have symptoms, please consult through an examination.