Pooled efficacy results of estetrol/drospirenone combined oral contraception phase 3 trials
Jeffrey T Jensen, Sharon L Achilles, Steven Weyers
Terhi Piltonen, Л. В. Сутурина, И.А. Аполихина, Céline Bouchard, Melissa J Chen, Dan Apter, Jean-Michel Foidart, Mitchell D Creinin, Maud Jost, Inna Apolikhina , Andrew M Kaunitz , Larisa Suturina , János Zatik
Scientific Center of Family Health Problems and Human ReproductionROR
National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I.Kulakov of the Ministry of Healthcare of the Russian FederationROR
National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, Moscow, Russia.
To evaluate overall and subgroup efficacy of an estetrol (E4) 15 mg drospirenone (DRSP) 3 mg oral contraceptive in a 24/4-day regimen.
Study Design
We pooled efficacy outcomes from 2 pivotal phase 3 contraceptive trials with E4/DRSP conducted in the United States/Canada and Europe/Russia. We assessed Pearl Index (PI; pregnancies per 100 participant-years) and 13-cycle life-table pregnancy rates in at-risk cycles (confirmed intercourse and no other contraceptive use) among participants 16 to 35 years. We calculated PI by age and further subcategorization (contraceptive history and body mass index [BMI]). We performed multivariable analysis using Cox regression to assess impact of potential confounding factors.
Results
Analyses included 3027 participants, of whom 451 (14.9%) had a BMI ≥30 kg/m(2). The pooled PI was 1.52 (95% confidence interval 1.04-2.16) and the 13-cycle life-table pregnancy rate was 1.28% (0.83%-1.73%). We calculated unadjusted pooled PI in participants 16 to 25 years and 26 to 35 years of 1.61 (0.94-2.57) and 1.43 (0.78-2.40), respectively; in new starters and switchers of 1.88 (1.09-3.00) and 1.24 (0.68-2.08), respectively; and by BMI <25 kg/m(2), 25 to 29.9 kg/m(2), and ≥30 kg/m(2) of 1.14 (0.64-1.88), 2.19 (1.05-4.03), and 2.27 (0.83-4.94), respectively. In multivariable analysis, we found associations of prior pregnancy (hazard ratio [HR] 3.61[1.56-8.38]), Black race (HR 4.61[1.97-10.80]), age 16 to 25 years (HR 2.37[1.09-5.15]) and compliance <99% of expected pills (HR 4.21[2.04-8.66]) with conception.
Conclusion
E4/DRSP is an effective oral contraceptive overall and across subgroups stratified by age, contraceptive history, and BMI. Other than compliance, predictors of contraceptive failure are nonmodifiable. IMPLICATIONS STATEMENT: Pooled results from two phase 3 trials demonstrate high contraceptive efficacy of the novel estetrol-drospirenone oral contraceptive. Several non-modifiable risk factors, including prior pregnancy, race, and age, are associated with higher pregnancy risk. Additional research is needed to better understand predictors of combined oral contraceptive failure.
PMID 35921870 35921870 DOI 10.1016/j.contraception.2022.07.009 10.1016/j.contraception.2022.07.009
Cite this article
Jensen, J. T., Kaunitz, A. M., Achilles, S. L., Zatik, J., Weyers, S., Piltonen, T., Suturina, L., Apolikhina, I., Bouchard, C., Chen, M. J., Apter, D., Jost, M., Foidart, J. M., & Creinin, M. D. (2022). Pooled efficacy results of estetrol/drospirenone combined oral contraception phase 3 trials. Contraception, 116, 37-43. https://doi.org/10.1016/j.contraception.2022.07.009
Jensen JT, Kaunitz AM, Achilles SL, Zatik J, Weyers S, Piltonen T, et al. Pooled efficacy results of estetrol/drospirenone combined oral contraception phase 3 trials. Contraception. 2022;116:37-43. doi:10.1016/j.contraception.2022.07.009
Jensen, J. T., et al. "Pooled efficacy results of estetrol/drospirenone combined oral contraception phase 3 trials." Contraception, vol. 116, 2022, pp. 37-43.
To examine trends in national reporting of broken intrauterine devices (IUDs). We enumerated IUD device "breakage" reports in the Food and Drug Administration Adverse Event Reporting System from inception (1998) until February 2022. We explored associations of breakage with IUD type (copper versus hormonal), year reported, reporter (consumer versus clinician), and patient characteristics (age and weight). We identified 4144 breakage reports for copper versus 2140 for hormonal IUDs. Among the 170,215 adverse events reported, breaks were disproportionately reported for copper (9.6%) versus hormonal (1.7%) IUDs. National pharmacovigilance data suggests disproportionate breakage in copper versus hormonal IUDs though the true prevalence of breaks cannot be calculated from this dataset.
Fertility AwarenessApp ComparisonFertile Window IdentificationBBT and Cervical Mucus
The Natural Cycles app employs daily basal body temperature to define the fertile window via a proprietary algorithm and is clinically established effective in preventing pregnancy. We sought to (1) compare the app-defined fertile window of Natural Cycles to that of CycleProGo, an app that uses BBT and cervical mucus to define the fertile window and (2) compare the app-defined fertile windows to the estimated physiologic fertile window. Daily BBT were entered into Natural Cycles from 20 randomly selected regularly cycling women with at least 12 complete cycles from the CycleProGo database. The proportion of cycles with equivalent (±1 cycle day) fertile-window starts and fertile-window ends was determined. The app-defined fertile windows were then compared to the estimated physiologic fertile window using Peak mucus to estimate ovulation. Fifty seven percent of cycles (136/238) had equivalent fertile-window starts and 36% (72/181) had equivalent fertile-window end days. The mean overall fertile-window length from Natural Cycles was 12.8 days compared to 15.1 days for CycleProGo (p < 0.001). The Natural Cycles algorithm declared 12% to 30% of cycles with a fertile-window start and 13% to 38% of cycles with a fertile-window end within the estimated physiologic fertile window. The CycleProGo algorithm declared 4% to 14% of cycles with a fertile-window start and no cycles with a fertile-window end within the estimated physiologic fertile window. Natural Cycles designated a higher proportion of cycles days as infertile within the estimated physiologic fertile window than CycleProGo.
Use of cervical mucus in addition to BBT may improve the accuracy of identifying the fertile window. Additional studies with other markers of ovulation and the fertile window would give additional insight into the clinical implications of app-defined fertile window differences.
To summarize the evidence on typical and perfect-use effectiveness of fertility awareness-based methods for avoiding pregnancy during the postpartum period, whether breastfeeding or not. We conducted a systematic review of studies published in English, Spanish, French, or German by November 2021 in MEDLINE, EMBASE, CINAHL, Web of Science, and ClinicalTrials.gov. Abstract and full text reviews were completed by 2 independent reviewers. at least 50 subjects who enrolled prior to experiencing 3 cycles after childbirth and were using a specific fertility awareness-based method to avoid pregnancy; unintended pregnancy rate or probability calculated; postpartum amenorrheic and postpartum cycling individuals analyzed separately; and prospectively measured pregnancy intentions and outcomes. Outcomes were abstracted and study quality was systematically assessed by 2 independent investigators. Four studies provided effectiveness data for 1 specific fertility awareness-based method among postpartum individuals. Of these, there were zero high quality, 1 moderate quality, and 3 low quality for our question of interest. Typical-use pregnancy probability for the first 6 cycles postpartum for Marquette Method users was 12.0 per 100 women years (standard error [SE] not reported) and for Billings Ovulation Method users ranged from 9.1 (SE 3.9) for non-lactating women <30 years old to 26.8 (SE 4.6) for lactating women <30 years old. Typical-use pregnancy probabilities for the first 6 months post-first menses for the Postpartum Bridge to Standard Days Method users was 11.8 (95% confidence interval 6.01-17.16) and for Billings Ovulation Method users was 8.5 per 100 women (SE 1.7). The current evidence on the effectiveness of each fertility awareness-based method for postpartum persons is very limited and of mostly low quality. More high quality studies on the effectiveness of fertility awareness-based method in postpartum persons are needed to inform clinical counseling and patient-centered decision-making.
Although postpartum individuals may desire to use fertility awareness-based methods to avoid pregnancy, the evidence of the effectiveness of fertility awareness-based methods in this population is limited. More high-quality studies are needed to inform shared decision-making.
tudies on the effect of long-term use of combined oral contraceptives (COCs) on cervical dysplasia and/or cancer risk have been inconsistent. Less is known about the effects of other forms of hormonal contraception (HC). We examine whether HC use increases the risk of incident cervical intraepithelial neoplasia (CIN) 2, 3 and/or cancer after accounting for preexisting human papillomavirus (HPV) infection. Systematic review of prospective studies on HC use as risk factor for cervical dysplasia with HPV infection documented prior to outcome assessment including PubMed and EMBASE records between January 2000 and February 2020 (Prospero #CRD42019130725). Among nine eligible studies, seven described recency and type of HC use and therefore comprise the primary analysis; two studies limit comparisons to ever versus never use and are summarized separately. All seven studies explored the relationship between oral contraceptive (OC) use and cervical two found increased risk (adjusted odds ratio, aOR = 1.5-2.7), one found no association but decreased risk when restricted to women with persistent HPV (adjusted hazard ratio = 0.5), and four found no association. None of the seven studies differentiated between COC and progestin-only pills (POPs) by use recency or duration. The only study that included injectable progestin-only contraception (DMPA) found increased CIN3 incidence among current versus never users (aOR = 1.6). The one study that included Norplant found no association. Two studies included intrauterine device (IUD) use, but did not differentiate between hormonal and copper IUDs, and found no association. We found no consistent evidence that OC use is associated with increased risk for cervical dysplasia/cancer after controlling for HPV infection. There were too few studies of progestin-only injectables, implants or IUDs to assess their effect on cervical dysplasia/cancer risk. Use of single self-reported HC measures and insufficient distinction by hormonal constituent cloud our understanding of whether some HCs increase risk for cervical cancer. Methodologically rigorous studies with distinct HCs measured as time-varying exposures are needed to inform cervical cancer prevention efforts and improve our understanding of cervical cancer etiology.