Thromboembolic safety of norethisterone vs levonorgestrel in combined oral contraceptive users: a pooled analysis of 4 large prospective cohort studies.

BACKGROUND: Norethisterone (acetate) and levonorgestrel are marketed globally as components of combined oral contraceptives. Although guidelines recommend both as first-line combined oral contraceptives, no direct, comparative safety studies are available. OBJECTIVE: We directly compared the thromboembolic event risk associated with the use of norethisterone acetate-containing and levonorgestrel-containing combined oral contraceptives. STUDY DESIGN: Data regarding the cohorts of interest, norethisterone/norethisterone acetate (ethinylestradiol ≤30 µg) and levonorgestrel (ethinylestradiol ≤30 µg), were retrieved from a pooled dataset comprising 4 prospective, noninterventional, active-surveillance cohort studies in 14 European countries, the United States, and Canada, with similar study design but differing medication cohorts. Baseline characteristics and parameters of reproductive, contraceptive, and medical history were summarized using descriptive statistics. Propensity score subclassification was applied to balance baseline parameters between cohorts. Time-to-event analysis of venous thromboembolic events was performed on the basis of the extended Cox model to calculate crude and adjusted hazard ratios, including 95% confidence intervals. The time of venous thromboembolic events was censored at the end of the observation period for women who did not have an event. Women who dropped out or were lost to follow-up without reported venous thromboembolic events were censored at the time they last confirmed that they did not have an event. RESULTS: The pooled dataset included 235,437 combined oral contraceptive users who were followed up for a total of 571,163 women years. Among these, 40,142 women were users of norethisterone/norethisterone acetate (ethinylestradiol ≤30 µg), and 39,098 women were users of levonorgestrel (ethinylestradiol ≤30 µg), contributing 61,976 and 84,816 women years of observation, respectively. The observed prevalence of prognostic factors at baseline showed typical features of US and European combined oral contraceptive users. Both cohorts showed a similar, low rate of thromboembolic events, and we could exclude a 1.5-fold increased venous thromboembolism risk for norethisterone/norethisterone acetate relative to levonorgestrel (adjusted hazard ratio, 0.73; 95% confidence interval, 0.48-1.11). CONCLUSION: These data confirm the similar risk profiles of norethisterone/norethisterone acetate and levonorgestrel regarding thromboembolic events in routine combined oral contraceptive use of around 80,000 women from Europe and the United States/Canada. The analysis provides reassurance for both combined oral contraceptive users and clinicians regarding the safety of oral contraceptives and potentially opens discussion on norethisterone acetate as a potential gold standard therapy in clinical and postmarket research alongside levonorgestrel-combined oral contraceptives.

Unintended pregnancy rates differ according to combined oral contraceptive - results from the INAS-SCORE study.

Objectives: To estimate the real-use contraceptive effectiveness of the combined oral contraceptive (COC) containing dienogest and oestradiol valerate (DNG/oEV) compared to other combined oral contraceptives (oCOC) and particularly, levonorgestrel-containing OCs (LNG). Methods: Prospective, non-interventional cohort study with two main exposure groups and one exposure subgroup: new users of DNG/oEV and oCOC, with the subgroup, LNG. In a planned secondary analysis, pregnancy outcomes were investigated, including contraceptive failure. The influence of age, parity and OC-type were assessed. Results: 30,098 COC users were followed for a total oral contraceptive exposure time of 68,362 woman-years (WY) and 287 unintended pregnancies were reported. The overall contraceptive failure rate in the European population was 0.4 events/100 WY (95% CI, 0.4-0.5). DNG/oEV showed lower contraceptive failure rates compared to the comparators. This difference was maintained when the study population was restricted to women aged 18-35 years; the pearl index (PI) for this demographic for DNG/oEV was 0.37 (95% CI 0.24-0.54) and 0.76 (95% CI 0.56-1.01) for LNG. The hazard ratios (HRs) adjusted for age, parity, smoking and BMI were 0.7 (95% CI, 0.5-0.98, p = .04) and 0.5 (95% CI, 0.3-0.8, p < .01) for DNG/oEV versus oCOC and LNG, respectively. The corresponding adjusted HRs in women aged 25 years or younger were 0.6 (95% CI 0.4-1.1) and 0.4 (95% CI, 0.2-0.8), respectively. Conclusions/discussion: DNG/oEV showed improved contraceptive effectiveness compared with oCOC and particularly LNG-COC when adjusted for age, parity, user status and smoking.

IUD use among parous women and risk of uterine perforation: a secondary analysis.

OBJECTIVE: The objective of the study was to determine if delivery and lactation are risk factors for complete intrauterine device perforations. STUDY DESIGN: We performed a reanalysis of the European Active Surveillance Study on Intra-Uterine Devices data set using complete penetration of the myometrium as the definition for perforation. RESULTS: Of the 61,448 women enrolled (70% levonorgestrel, 30% copper devices), we identified 58 complete perforations, 30 of which occurred in lactating women. Incidence per 1000 insertions was 4.5 (95% confidence interval [CI]: 3.0-6.4) for lactating and 0.6 (95% CI: 0.4-0.9) for nonlactating women. Time since delivery was also associated with perforation risk. CONCLUSIONS: Lactation and delivery are independent cofactors for perforation. Results do not differ when restricting the definition of perforation.

Perforation risk and intra-uterine devices: results of the EURAS-IUD 5-year extension study.

OBJECTIVES: The objective of this analysis was to identify intra-uterine devices (IUD) perforations detected from 12 to 60 months following IUD insertion, and to combine this information with (our previously published) data about perforations detected in the first 12 months to calculate cumulative perforation rates. METHODS AND MATERIALS: Prospective, non-interventional cohort study with new users of levonorgestrel-releasing intra-uterine systems (LNG-IUS) and copper-IUD. The original cohort included 61,448 women followed for 12 months. Of these, we had sufficient resources to perform an additional follow-up and analysis at 60 months in 39,009 women. Inclusion criteria for this analysis was insertion prior to 31 July 2010. All potential cases were validated via the health care professional or medical records. Crude and adjusted relative risks were calculated using a logistic regression model. RESULTS: We identified 23 additional perforations (19 LNG-IUS and 4 copper-IUD) more than 12 months after insertion. Added to perforations detected at 12 months, the overall perforation rate was 2.1 per 1000 insertions (95% CI: 1.6-2.8) for LNG-IUS users (40 + 19 perforations/27,630 insertions) and 1.6 per 1000 insertions (95% CI: 0.9-2.5) for copper-IUD users (14 + 4 perforations/11,379 insertions). LNG-IUS users had a borderline higher risk of perforation compared with copper-IUD users (ORadj 1.7; 95% CI: 1.0-2.8). Forty-five (58%) of the 77 perforations were associated with suspected risk factors. Breastfeeding (RR 4.9, 95% CI: 3.0-7.8) and time since delivery (RR 3.0, CI: 1.5-5.4) remained significant risk factors in perforations detected after 12 months. No perforations resulted in serious injury to intra-abdominal or pelvic structures. CONCLUSIONS: The incidence of uterine perforations in this study was low, although higher than the commonly reported rate. Approximately one third of perforations are detected 12 months after insertion. Clinical sequalae of perforations are generally mild and associated with a very low risk of injury to intra-abdominal and pelvic structures. Implications Uterine perforation is a rare risk associated with intra-uterine device use. Late diagnosed perforations can occur, although women can be reassured that the morbidity associated with detection and removal is low.

Fertility and combined oral contraceptives - unintended pregnancies and planned pregnancies following oral contraceptive use - results from the INAS-SCORE study.

OBJECTIVES: To estimate the real-use contraceptive effectiveness of the combined oral contraceptive containing dienogest and estradiol valerate (DNG/EV) and whether DNG/EV compared to other combined oral contraceptives (oCOC) has a negative effect on return to fertility. METHODS: Transatlantic, prospective, non-interventional cohort study conducted in the USA 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). In a planned secondary analysis, pregnancy outcomes were investigated including contraceptive effectiveness and pregnancy following contraceptive cessation. The influence of age, parity and OC-type were assessed. RESULTS: 50,203 COC users were followed for 105,761 woman-years (WY). There were 677 unintended pregnancies reported: 451 in the USA and 226 in Europe. The contraceptive failure rate in Europe was 0.5 events/100 WY (95% CI: 0.4-0.5) and in the USA 1.9 events/100 WY (95% CI: 1.7-2.1). Differences in compliance (1.3 pregnancies/100 WY) accounted for 90% of the geographical difference seen between Europe and the USA. DNG/EV showed lower contraceptive failure rates compared to the comparators; 0.9% DNG/EV, 2.1% oCOC and 2.8% LNG after 4 years. Overall, 1167 (2.3%) of women stopped contraceptive use with the intention of becoming pregnant with 89% conceiving within 2 years. No significant differences were seen between groups after adjusting for age. CONCLUSION/DISCUSSION: DNG/EV is associated with similar contraceptive effectiveness in typical-use settings when compared to oCOC and LNG. There was no difference observed between cohorts in fertility following OC use.

Delphi survey of international pharmacology experts: an attempt to derive international recommendations for use of medicine in breastfeeding women.

INTRODUCTION: There are currently no common guidelines used by health professionals to aid decision-making around the use of medicines during breastfeeding. Several specialized books, Web sites, and drug information services exist; however, all use slightly different criteria to derive their "safety hierarchy." The aim of this study was to build consensus among international experts in pharmacology and breastfeeding to develop an agreed-upon classification system for safety of medicine use in breastfeeding women. STUDY METHOD: A three-round Web-based Delphi qualitative research design was used. RESULTS: Seventeen experts in pharmacy/pharmacology and breastfeeding identified 15 key parameters that are used to inform decisions about medicines and breastfeeding. The most important parameters about the infant were the age and health of the child, and those of the medicine were the safety profile and experience of use in infants. The experts had a clear understanding of the complexity of decision-making when prescribing for breastfeeding women. Although the current number or letter classification systems do not incorporate important considerations such as infant age, a longer "descriptive text" incorporating all considerations may be impractical in busy clinical practice. CONCLUSIONS: Although clinicians and lay people would appreciate a simple classification scheme, in practice, decision-making about the safety of medicines for breastfeeding women is complex.