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

Abstract

Objective

To assess and compare the risk of unintended pregnancy in NOMAC-E2 users with levonorgestrel-containing COC (COC_LNG) users in clinical practice.

Study design

In this observational study, new users¹ of NOMAC-E2 and COC_LNG 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 (HR_crude) and adjusted hazard ratios (HR_adj).

Results

Overall, 44,559 and 46,754 users were recruited to the NOMAC-E2 and COC_LNG 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 COC_LNG 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 COC_LNG user cohort. The HR_adj of NOMAC-E2 vs COC_LNG 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 COC_LNG, likely due to the comparatively short hormone-free interval and possibly reinforced by the long half-life of NOMAC.

与含左炔诺孕酮的复方口服避孕药相比, 诺美孕酮和17β-雌二醇（NOMAC-E2）的使用者意外怀孕：PRO-E2研究的最终结果 摘要

目的: 评估和比较在临床中服用NOMAC-E2妇女与服用含有左炔诺孕酮的避孕药物 （COC_LNG）妇女的意外怀孕的风险。

方法: 在这项观察性研究在欧洲、澳大利亚和拉丁美洲招募使用NOMAC-E2和COC_LNG的新患者并随访长达2年。Pearl指数（每100名妇女每年年避孕失败[WY]）、粗风险比率（HR_crude）和调整后的风险比率（HR_adj）用来描述意外怀孕。

结果: 总体来说, 研究分别招募了44559名使用NOMAC-E2妇女和 46,754 名使用COC_LNG 队列妇女。 NOMAC-E2 妇女中有64例意外怀孕（0.15/100 WY；95% CI, 0.11–0.19）, COC_LNG妇女中有200例意外怀孕（0.41/100 WY；95% CI, 0.35–0.47）。 与 服用COC_LNG 妇女队列相比, NOMAC-E2 队列的意外怀孕风险在统计学上显著降低 (p<.0001)。 NOMAC-E2 与 COC_LNG 的 调整后风险比为 0.45（95% CI, 0.34-0.60；根据年龄、体重指数、妊娠、COC 使用者状态、教育水平进行调整）。

结论: 与 COC_LNG 相比, NOMAC-E2 表现出更好的避孕效果, 这可能是由于相对较短的无激素间隔时间, 加上NOMAC 的较长的半衰期。

Keywords:

• NOMAC-E2
• nomegestrol acetate
• oestradiol
• levonorgestrel
• unintended pregnancy
• contraceptive failure
• contraceptive effectiveness

Acknowledgements

The authors acknowledge the valuable scientific contribution of the SMAC. Their critical review of the data and challenging discussions substantially enhanced the overall quality of the study and the interpretation of the results. SMAC members included David Grimes, Michael Lewis, Robert Reid, Samuel Shapiro⁷, Carolyn Westhoff, Ulrich Winkler and Stephanie Teal. Advisors to the SMAC included Jochen Albrecht and Fritz von Weizsäcker⁸. The authors also thank the colleagues in the local field organisations who conducted the day-to-day field work. Their remarkable dedication and flexibility despite the challenging circumstances caused by the pandemic ensured the success of the study. The authors also thank the ZEG Berlin staff members (statisticians, data managers, event validation staff, medical advisers) whose contribution to the study was invaluable.

Disclosure statement

Carol Koro and Julia DiBello are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and hold stock/stock options in Merck & Co., Inc., Kenilworth, NJ, USA. Merck Sharp & Dohme Corp. was exclusively licenced by Theramex to sell Zoely in certain territories (other than the U.S. and Canada) until January 2020, and held Marketing Authorisations for the product in the non-EU markets of such territory. In January 2020, these rights were transferred back to Theramex. The rights to sell the product in the U.S. and Canada pursuant to a licence from Teva remained with Merck until spin-off of Organon on June 2, 2021.

Notes

1 First-ever users of an eligible COC or restarting with an eligible COC (same COC as before or a new COC) after a break of at least 2 months.

2 Due to non-compliance with study procedures, data contributed by 625 study participants in Mexico were excluded from these analyses as advised by the SMAC. The local field organisation deviated from the required storage requirements and destroyed 545 of the informed consent forms. After recontacting the women, proof of consent was available for 235 women.

3 1) NOMAC-E2, 2) COC_LNG monophasic preparation containing 20-30mcg of ethinylestradiol, 3) COC_LNG multiphasic preparation containing up to 40mcg of ethinylestradiol.

4 If there was ambiguity concerning the date of conception or COC use, the woman and/or her HCP were contacted for clarification. The consent form included permission to contact any treating physician to follow up on specific outcomes.

5 Study participants reported their reason(s) for COC use only at study entry; their reason(s) for use may have changed during follow-up (e.g., a woman who began using a COC for contraceptive only reasons may have experienced a relationship change and continued using the COC for non-contraceptive reasons).

6 If there was ambiguity concerning the date of conception or COC use, the woman and/or her HCP were contacted for clarification.

7 Died 19 April 2016.

8 Died 19 November 2019.

Additional information

Funding

Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Theramex Ireland Limited, Dublin, Ireland provided funding for this research.