A combined oral contraceptive with the novel estrogen, estetrol, showed high efficacy and safety and did not appear to put women at risk of blood clots, according to new research.

  • Estetrol does not affect the body the same way as other estrogens.
  • Headache was the most commonly reported adverse event.
  • The contraceptive works equally well in women with high body mass index.

Recent research has shown that a new combined oral contraceptive has high efficacy, cycle control, and safety, even among a diverse American population that included women with a body mass index of 35 kg/m2. The medication contains estetrol (a novel estrogen) and drospirenone.

Estetrol is found in high levels in fetuses. Since fetuses do not develop blood clots, investigators hoped that using estetrol in a birth control pill also would prove safer than current oral contraceptives. Phase III clinical trial data suggested the theory was correct, although a Phase IV study will be conducted to confirm the findings.1

“Estetrol doesn’t act in the body like all other estrogens,” says Mitchell D. Creinin, MD, professor, director of family planning, and director of the Complex Family Planning Fellowship, at UC Davis Health in Sacramento.

Little Effect on Breast Tissue

Researchers found the efficacy of the new combined oral contraceptive was within the range of other available contraceptives. Ethinyl estradiol (EE) is the primary estrogen used in combined oral contraceptives. It has been used since the 1960s. While it has high potency, it produces adverse events in some women, including an increased risk of cardiovascular complications, thromboembolism, and breast tenderness.1

By contrast, estetrol (E4) has little effect on breast tissue — meaning no breast tenderness for most women — and on triglycerides.

“It inhibits breast cancer, so it’s being studied for treatment of breast cancer,” Creinin says. “It’s not metabolized by the liver. All other estrogens taken as a pill go through the liver and are processed and stimulate the liver, causing changes in blood clotting, lipid factors, and triglycerides.”

The study revealed that headache was the most commonly reported adverse event and occurred in 5% of study participants. Abnormal uterine bleeding occurred in 4.6% of participants. No thromboembolic events were reported.

“In the U.S. study, we had zero blood clots,” Creinin adds. “In the European study, there was one blood clot.”

The findings suggest that at a population level, the new contraceptive would cause fewer blood clots. “It’s very promising, a highly effective combination birth control pill with excellent cycle control, and it uses a natural estrogen that has more favorable effects in the body,” Creinin says. “Also, with most products you get an increase in triglycerides, which is what we worry about with cardiovascular disease. You don’t see that with this product.”

Like other estrogens used in contraceptives, estetrol is derived from plant sources, he notes.

Could Be a ‘Game-Changer’

If the contraceptive shows an extremely low blood clot rate in Phase IV, as is expected, then it could be a great option for many women seeking a very safe oral contraceptive.

Blood clots occur in pregnancy. Two COVID-19 vaccines were briefly paused due to rare blood clots, even though they were estimated to affect one in 1 million people. Offering a new contraceptive that does not cause a significant number of blood clots is vitally important, Creinin explains.

“To me, this is a game-changer,” he says.

Although it will be a few years before Phase IV results are known, physicians in the United States, Canada, and Europe will be able to prescribe the contraceptive by fall 2021.

“It is highly effective, well controlled, has low side effects, and it works well in women of all ages, with no differences based on obesity,” Creinin explains. “It is not weight-dependent in distribution; the only differences are related to compliance and prior hormone use.”

Even with unscheduled bleeding — a common side effect with oral contraceptives — most cases reported with the combined estetrol/drospirenone pill involved spotting. “It was not the kind of bleeding that required sanitary protection,” Creinin adds.

This new birth control option is important for the majority of American women who choose to use oral contraceptives. “It’s highly effective and has low rates of side effects,” Creinin says.


  1. Creinin MD, Westhoff CL, Bouchard C, et al. Estetrol-drospirenone combination oral contraceptive: North American phase 3 efficacy and safety results. Contraception 2021;S0010-7824(21)00149-9.