Levonorgestrel-containing Combined Oral Contraceptives Research Articles

Unintended pregnancy in users of nomegestrol acetate and 17β-oestradiol (NOMAC-E2) compared with levonorgestrel-containing combined oral contraceptives: final results from the PRO-E2 study

Objective To assess and compare the risk of unintended pregnancy in NOMAC-E2 users with levonorgestrel-containing COC (COCLNG) users in clinical practice. Study design In this observational study, new users 1 of NOMAC-E2 and COCLNG were recruited in Europe, Australia, and Latin America and followed for up to 2 years. Unintended pregnancy was expressed by the Pearl Index (contraceptive failures per 100 women-years [WY]), crude hazard ratios (HRcrude) and adjusted hazard ratios (HRadj). Results Overall, 44,559 and 46,754 users were recruited to the NOMAC-E2 and COCLNG user cohorts, respectively. There were 64 unintended pregnancies in NOMAC-E2 users (0.15 per 100 WY; 95% CI, 0.11–0.19) and 200 in COCLNG users (0.41 per 100 WY; 95% CI, 0.35–0.47). The unintended pregnancy risk was statistically significantly lower in the NOMAC-E2 cohort (p<.0001) compared to the COCLNG user cohort. The HRadj of NOMAC-E2 vs COCLNG was 0.45 (95% CI, 0.34–0.60; adjusted for age, body mass index, gravidity, COC user status, education level). Conclusions NOMAC-E2 demonstrated superior contraceptive effectiveness compared to COCLNG, likely due to the comparatively short hormone-free interval and possibly reinforced by the long half-life of NOMAC.

Real world utilization of 91 day extended levonorgestrel-containing combined oral contraceptives in Europe: a multinational database study

Objective As part of the risk management plan in Europe, this study was conducted to characterize drug utilization patterns of Seasonique, a 91 day extended levonorgestrel-containing combined oral contraceptive (COCLNG). Methods A retrospective observational study was conducted in France, Italy and Belgium using electronic medical record databases obtained from general practitioners (GPs) in all participating countries and gynecologists in France from 2015 to 2018. The study population included women receiving ≥1 prescription of 91 day COCLNG during the study period. Prescribing patterns of 91 day COCLNG were examined including: (1) treatment duration; (2) indication; (3) use of combined oral contraceptive (COC) before 91 day COCLNG initiation; and (4) switch from and to combined hormonal contraceptives (CHCs) or other contraceptives. Results Totals of 235, 220, 207 and 659 women using 91 day COCLNG were identified in French, Italian and Belgian GP, and French gynecologist databases, respectively. Across databases, 46–76% of women were prescribed a single 91 day COCLNG prescription and median treatment duration ranged from 3 to 6 months. The most common indication was contraception (42–81%), followed by menstrual migraines (2–14%). Use of COC during the 6 months prior to 91 day COCLNG initiation was 14% across GP databases, but was lower (8%) in the French gynecologist database. The frequency of switching from 91 day COCLNG to CHCs or other contraceptives was generally low (5–12%), with the highest proportion being among patients of French gynecologists. Conclusions Findings indicate that 91 day COCLNG was prescribed for relatively short durations and predominantly as indicated for contraception. Most results were comparable across all participating countries. KEY POINTS Findings from this drug utilization study in European databases across general practitioners and French gynecologists confirmed that 91 day extended levonorgestrel-containing combined oral contraceptive (COCLNG) was prescribed for relatively short durations (median 3–6 months); predominantly for the intended indication of contraception. Combined oral contraceptive use during the 6 months prior to 91 day COCLNG initiation, and switching from 91 day COCLNG to combined hormonal contraceptives or other contraceptives, were generally low (14% or less). These findings were mostly consistent across participating countries.

Differential Effects of the Hormonal and Copper Intrauterine Device on the Endometrial Transcriptome

The contraceptive effectiveness of intrauterine devices (IUDs) has been attributed in part to a foreign body reaction in the endometrium. We performed this study to better understand mechanisms of action of contraceptives of by studying their effects on endometrial and cervical transcriptomes. We collected endometrial and cervical biopsies from women using the levonorgestrel-releasing intrauterine system (LNG-IUS, n = 11), copper intrauterine device (cu-IUD, n = 13) or levonorgestrel-containing combined oral contraceptives (COC, n = 12), and from women not using contraceptives (control group, n = 11). Transcriptional profiling was performed with Affymetrix arrays, Principal Component Analysis and the bioconductor package limma. In endometrial samples from cu-IUD users, there were no genes with statistically significant differential expression compared to controls. In LNG-IUS users, 2509 genes were differentially expressed and mapped predominantly onto immune and inflammatory pathways. The cervical samples showed no statistically significant differential gene expression compared to controls. Hormonal and copper IUDs have significantly different effects on the endometrial transcriptome, with the LNG-IUS transcriptome showing pronounced inflammation and immune activation compared to controls whereas the cu-IUD transcriptome was indistinguishable from luteal phase endometrium. These findings argue against a foreign body reaction as a common mechanism of action of IUDs.

Menstrual cycle-dependent alterations in glycosylation: a roadmap for defining biomarkers of favorable and unfavorable mucus.

To understand glycosylation of endocervical proteins at different times throughout the menstrual cycle in naturally cycling women and in women using hormonal or non-hormonal contraceptive methods, in order to characterize biochemical fingerprints of favorable and unfavorable cervical mucus. Lectin/antibody-probed protein blot analysis of endocervical mucus samples collected onto ophthalmologic sponges (wicks) from two groups: a longitudinal cohort of naturally cycling women at three time points in their menstrual cycles (discovery cohort), and a cross-sectional cohort of women on hormonal or non-hormonal contraceptive methods (validation cohort). Participants were recruited from the San Francisco Bay Area from 2010 to 2016. Women with regular cycles not using hormonal or intrauterine device (IUD) contraceptives were recruited for the longitudinal cohort (n= 8). Samples from women using levonorgestrel-containing combined oral contraceptives (n= 16), levonorgestrel containing IUDs (n= 14), copper IUDs (n= 17), depo-medroxyprogesterone acetate (DMPA) (n= 15), and controls (n= 13) were used for validation. None. Detection of specific glycosylation patterns on lectin/antibody probed protein blots. Two lectins (Lens culinaris agglutinin and Lycopersicon esculentum [tomato lectin]), and the antibody MECA-79 demonstrated consistent cycle-dependent changes in protein binding. The glycan-binding patterns of the levonorgestrel-containing contraceptives were generally similar to each other and to those from women in the luteal phase. The DMPA samples showed slightly different binding patterns. We identified molecular signatures of unfavorable mucus from women in the luteal phase and on hormonal contraceptives. Further characterization of these biomarkers may be useful in contraceptive development and in evaluation of infertility.

Drospirenone-Containing Oral Contraceptive Pills and the Risk of Venous Thromboembolism: An Assessment of Risk in First-Time Users and Restarters.

The effects of drospirenone-containing combined oral contraceptives (COCs) on the risk of venous thromboembolism (VTE) remain controversial due to the challenge in distinguishing between first-time users and restarters, and their different underlying VTE risks, in healthcare databases. The aim of this study was to describe the challenge of studying the risk of VTE among first-time users of drospirenone-containing COCs in a healthcare database and assess the risk among first-time users and restarters. We used data from the Clinical Practice Research Datalink to construct two cohorts. The first-time user cohort included all women aged 16-45years who received a first ever prescription of drospirenone- or levonorgestrel-containing COCs between May 2002 and March 2015. The restarter cohort included those who were restarting a COC after a period of non-use of ≥6months. Cox proportional hazards models adjusted for high dimensional propensity scores were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). The final cohorts included 55,139 first-time users (3582 drospirenone and 51,557 levonorgestrel) and 162,959 restarters (23,191 drospirenone and 139,768 levonorgestrel). The adjusted HR of VTE associated with drospirenone versus levonorgestrel was 3.19 (95% CI 1.12-9.08) for first-time users and 1.96 (95% CI 1.12-3.41) for restarters. We found an elevated risk of VTE associated with drospirenone-containing COCs in comparison with levonorgestrel-containing COCs in both cohorts. While left truncation of healthcare databases is a concern for the identification of first-time users, the use of a more explicit cohort of restarters suggests a doubling of VTE risk with drospirenone-containing COCs.

Impact of estrogen type on cardiovascular safety of combined oral contraceptives

ObjectivesThe International Active Surveillance study “Safety of Contraceptives: Role of Estrogens” (INAS-SCORE) investigated the cardiovascular risks associated with the use of a combined oral contraceptive (COC) containing dienogest and estradiol valerate (DNG/EV) compared to established COCs in a routine clinical setting. Study DesignTransatlantic, prospective, noninterventional cohort study conducted in the United States and seven European countries with two main exposure groups and one exposure subgroup: new users of DNG/EV and other COC (oCOC), particularly levonorgestrel-containing COCs (LNG). All self-reported clinical outcomes of interest (OoI) were validated via attending physicians and relevant source documents. Main OoI were serious cardiovascular events (SCE), particularly venous thromboembolic (VTEs) events. Comprehensive follow-up procedures were implemented. Statistical analyses were based on Cox regression models. ResultsA total of 50,203 new COC users were followed up for up to 5.5years (mean value, 2.1years). Overall 20.3% and 79.7% of these women used DNG/EV and oCOC (including 11.5% LNG users), respectively. A low loss to follow-up of 3.1% was achieved. Based on 47 (VTE) and 233 (SCE) events, the primary analysis (European data set) yielded adjusted hazard ratios for DNG/EV vs. oCOC of 0.4 and 0.5, respectively. The upper bounds of the 95% confidence intervals were 0.98 (VTE) and 0.96 (SCE). The corresponding hazard ratios for DNG/EV vs. LNG showed similar point estimates but the confidence intervals included unity. ConclusionDNG/EV is associated with similar or even lower cardiovascular risk compared to oCOC and LNG. Implication StatementA COC containing DNG and EV is associated with similar or even lower cardiovascular risk compared to COCs containing levonorgestrel or other progestogens.

Oral contraceptive use changes brain activity and mood in women with previous negative affect on the pill—A double-blinded, placebo-controlled randomized trial of a levonorgestrel-containing combined oral contraceptive

Most women on combined oral contraceptives (COC) report high levels of satisfaction, but 4-10% complain of adverse mood effects. The aim of this randomized, double-blinded, placebo-controlled trial was to investigate if COC use would induce more pronounced mood symptoms than placebo in women with previous history of COC-induced adverse mood. A second aim was to determine if COC use is associated with changes in brain reactivity in regions previously associated with emotion processing. Thirty-four women with previous experience of mood deterioration during COC use were randomized to one treatment cycle with a levonorgestrel-containing COC or placebo. An emotional face matching task (vs. geometrical shapes) was administered during functional magnetic resonance imaging (fMRI) prior to and during the COC treatment cycle. Throughout the trial, women recorded daily symptom ratings on the Cyclicity Diagnoser (CD) scale. During the last week of the treatment cycle COC users had higher scores of depressed mood, mood swings, and fatigue than placebo users. COC users also had lower emotion-induced reactivity in the left insula, left middle frontal gyrus, and bilateral inferior frontal gyri as compared to placebo users. In comparison with their pretreatment cycle, the COC group had decreased emotion-induced reactivity in the bilateral inferior frontal gyri, whereas placebo users had decreased reactivity in the right amygdala. COC use in women who previously had experienced emotional side effects resulted in mood deterioration, and COC use was also accompanied by changes in emotional brain reactivity. These findings are of relevance for the understanding of how combined oral contraceptives may influence mood. Placebo-controlled fMRI studies in COC sensitive women could be of relevance for future testing of adverse mood effects in new oral contraceptives.

Fatal Venous Thromboembolism Associated with Different Combined Oral Contraceptives

Fatal venous thromboembolism (VTE) is a rare complication of combined oral contraceptive (COC) treatment. This study aims to determine incidences of fatal VTE in relation to the type of COC and the percentage of cases reported to the Swedish Adverse Drug Reactions Advisory Committee (SADRAC). A further aim is to compare the characteristics of reported and not reported cases. This retrospective study is a separate analysis using data from a larger study that included women aged 15-44 years between 1990 and 1999 with VTE coded as the underlying or contributory cause of death in the Swedish Cause of Death Register. COC use within 2 months of the date of symptom onset or death was identified in 28 cases. Sales data were obtained from the National Corporation of Swedish Pharmacies. Reported cases were identified in the SADRAC database. After excluding two cases where the type of COC was unknown, the crude incidences of fatal VTE were 5.1 (95% CI 2.3, 9.6), 8.6 (95% CI 4.3, 15.4) and 9.1 (95% CI 3.3, 19.8) cases per million women per year for levonorgestrel-, desogestrel- and norethisterone-containing COCs, respectively. Age-adjusted incidences were approximately twice as high for desogestrel- and norethisterone-containing COCs compared with levonorgestrel-containing COCs, although differences were not statistically significant. Thirty-six percent of cases were reported. Reporting was positively associated with information in medical records relevant to the VTE diagnosis that the patient was a COC user and was significantly higher in northern Sweden. Results from this study support a higher incidence of fatal VTE with desogestrel-containing COCs than with levonorgestrel-containing COCs.

Absolute and Attributable Risk of Venous Thromboembolism in Women on Combined Cyproterone Acetate and Ethinylestradiol

Objective: To achieve absolute risk estimates of venous thromboembolism (YTE) among women on cyproterone acetate plus ethinylestradiol (CPA/EE), and among women on combined oral contraceptives (COCs).Methods: From the Danish National Register of Patients (NRP), 1996 to 1998, the records of 1.1 million Danish women, ages 15 to 44 years, were searched for evidence of VTE. COC use was ascertained through mailed questionnaires. Sales statistics of COCs and CPA/EE were provided through Danish Drug Statistics.Results: During the time frame of the study, 330 women were found to have had VTE while on COCs. Of these women, 67 were on levonorgestrel-containing COCs. Eleven were on CPA/EE. The corresponding absolute risk of VTE was 3.4 (range, 3.1-3.8) per 10 000 women years among the women on COCs, 4.2 (range, 3.2-5.2) per 10 000 women years among women on levonorgestrel-containing COCs, and 3.1 (range, 1.3-4.9) per 10 000 women years among the women on CPA/EE.Conclusion: Our Results suggest the absolute risk of VTE among Danish women on COCs is similar to that among women taking CPA/EE.