Pooled analysis of two phase 3 trials evaluating the effects of a novel combined oral contraceptive containing estetrol/drospirenone on bleeding patterns in healthy women

Andrew M. Kaunitz, Sharon L. Achilles, János Zatik, Steven Weyers, Terhi Piltonen, Larisa Suturina, Inna Apolikhina, Celine Bouchard, Melissa J. Chen, Jeffrey T. Jensen, Carolyn L. Westhoff, Maud Jost, Jean Michel Foidart, Mitchell D. Creinin

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Objective: To evaluate the bleeding patterns of a new combined oral contraceptive containing estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg in a 24/4-day regimen. Study design: We pooled bleeding data from two parallel, open-label, 13-cycle phase 3 trials that enrolled participants 16 to 50 years old with body mass index (BMI) ≤35 kg/m2. Participants reported vaginal bleeding/spotting in daily diaries. For this bleeding analysis, we included participants with at least one evaluable cycle. We calculated mean frequencies of scheduled and unscheduled bleeding/spotting episodes and median duration of bleeding/spotting episodes, and assessed associations between treatment compliance, BMI and recent hormonal contraceptive use on bleeding/spotting outcomes. Results: We included 3409 participants with 33,815 cycles. Scheduled bleeding/spotting occurred in 87.2% to 90.4% of participants/cycle, with a median duration of 4 to 5 days. Unscheduled bleeding/spotting decreased from 27.1% in Cycle 1 to 20.6% in Cycle 2 to ≤17.5% from Cycle 5 onwards. Most (66.5%) unscheduled bleeding/spotting episodes were spotting-only. Between 5.8% and 7.8% of users/cycle experienced absence of any scheduled or unscheduled bleeding/spotting. Missing one or more active pills resulted in a higher occurrence of unscheduled bleeding/spotting (adjusted odds ratio [aOR] 2.13 [95% confidence interval 1.68–2.70]) and absence of scheduled bleeding/spotting (aOR 2.36 [1.82−3.07]). Participants with a BMI ≥30 kg/m2 reported more absence of scheduled bleeding/spotting (aOR 1.68 [1.37−2.05]). Switchers and starters reported similar frequencies of unscheduled bleeding/spotting (aOR 0.94 [0.83−1.07]) and absence of scheduled bleeding/spotting (aOR 1.00 [0.85−1.19]). Three percent of participants discontinued for a bleeding-related adverse event. Conclusion: E4/DRSP use results in a predictable bleeding pattern with limited unscheduled bleeding/spotting. Noncompliance and BMI affect bleeding patterns. Implications statement: Most estetrol/drospirenone users experience a predictable and regular bleeding pattern. Providers can educate patients about the expected bleeding patterns and should advise users that they may infrequently experience no scheduled bleeding/spotting. This information may improve user acceptability and continuation of this new oral contraceptive.

Original languageEnglish (US)
Pages (from-to)29-36
Number of pages8
StatePublished - Dec 2022


  • Bleeding pattern
  • Combined oral contraceptive
  • Drospirenone
  • Estetrol

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology


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