University of Oulu

Kaunitz, A. M., Achilles, S. L., Zatik, J., Weyers, S., Piltonen, T., Suturina, L., Apolikhina, I., Bouchard, C., Chen, M. J., Jensen, J. T., Westhoff, C. L., Jost, M., Foidart, J. M., & Creinin, M. D. (2022). 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. Contraception, 116, 29–36.

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

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Author: Kaunitz, Andrew M.1; Achilles, Sharon L.2; Zatik, János3;
Organizations: 1Department of Obstetrics and Gynecology, University of Florida College of Medicine- Jacksonville, Jacksonville, FL, USA
2Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh/Magee-Womens Research Institute, Pittsburgh, PA, USA
3Gynecological Praxis St. Anna, Debrecen, Hungary
4Department of Obstetrics and Gynecology, University Hospital, Gent, Belgium
5Department of Obstetrics and Gynecology, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland
6Department of Reproductive Health Protection, Scientific Centre for Family Health and Human Reproduction, Irkutsk, Russia
7National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, Moscow, Russia
8Clinique de Recherche en Santé de la femme (RSF) Inc., Québec City, Québec, Canada
9Department of Obstetrics and Gynecology, University of California, Davis, Sacramento, CA, USA
10Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, USA
11Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY, USA
12Estetra SRL, an affiliate company of Mithra Pharmaceuticals, Liège, Belgium
13Department of Obstetrics and Gynecology, University of Liège, Liège, Belgium
14Department of Obstetrics and Gynecology, University of California, Davis, Sacramento, CA, US
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.7 MB)
Persistent link:
Language: English
Published: Elsevier, 2022
Publish Date: 2023-05-30


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.

Conclusions: 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.

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Series: Contraception
ISSN: 0010-7824
ISSN-E: 1879-0518
ISSN-L: 0010-7824
Volume: 116
Pages: 29 - 36
DOI: 10.1016/j.contraception.2022.07.010
Type of Publication: A1 Journal article – refereed
Field of Science: 3123 Gynaecology and paediatrics
Copyright information: © 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (