Continuation rates of two different-sized copper intrauterine devices among nulliparous women: Interim 12-month results of a single-blind, randomised, multicentre trial

David Hubacher, Courtney A Schreiber, David K Turok, Jeffrey T Jensen, Mitchell D Creinin, Kavita Nanda, Katharine O'Connell White, Ila Dayananda, Stephanie B Teal, Pai-Lien Chen, Beatrice A Chen, Alisa B Goldberg, Jennifer L Kerns, Clint Dart, Anita L Nelson, Michael A Thomas, David F Archer, Jill E Brown, Paula M Castaño, Anne E Burke, Bliss Kaneshiro, Diana L Blithe, David Hubacher, Courtney A Schreiber, David K Turok, Jeffrey T Jensen, Mitchell D Creinin, Kavita Nanda, Katharine O'Connell White, Ila Dayananda, Stephanie B Teal, Pai-Lien Chen, Beatrice A Chen, Alisa B Goldberg, Jennifer L Kerns, Clint Dart, Anita L Nelson, Michael A Thomas, David F Archer, Jill E Brown, Paula M Castaño, Anne E Burke, Bliss Kaneshiro, Diana L Blithe

Abstract

Background: The most widely used copper intrauterine device (IUD) in the world (the TCu380A), and the only product available in many countries, causes side effects and early removals for many users. These problems are exacerbated in nulliparous women, who have smaller uterine cavities compared to parous women. We compared first-year continuation rates and reasons/probabilities for early removal of the TCu380A versus a smaller Belgian copper IUD among nulliparous users.

Methods: This 12-month interim report is derived from a pre-planned interim analysis of a sub population and focused on key secondary comparative endpoints. In this participant-blinded trial at 16 centres in the USA, we randomised participants aged 17-40 in a 4:1 ratio to the NT380-Mini or the TCu380A. In the first year, participants had follow-up visits at 6-weeks and 3, 6, and 12-months, and a phone contact at 9 months; we documented continued use, expulsions, and reasons for removal. Among participants with successful IUD placement, we compared probabilities of IUD continuation and specific reasons for discontinuation using log-rank tests. This trial is registered with ClinicalTrials.gov number NCT03124160 and is closed to recruitment.

Findings: Between June 1, 2017, and February 25, 2019, we assigned 927 nulliparous women to either the NT380-Mini (n = 744) or the TCu380A (n = 183); the analysis population was 732 (NT380-Mini) and 176 (TCu380A). Participants using the NT380-Mini, compared to the TCu380A, had higher 12-month continuation rates (78·7% [95% CI: 72·9-84·5%] vs. 70·2% [95% CI: 59·7-80·7], p = 0·014), lower rates of removal for bleeding and/or pain (8·1% vs. 16·2%, p = 0·003) and lower IUD expulsion rates (4·8% vs. 8·9%, p = 0·023), respectively.

Interpretation: The NT380-Mini offers important benefits for a nulliparous population compared to the TCu380A in the first twelve months, when pivotal experiences typically occur. Higher continuation rates with the NT380-Mini may avert disruptions in contraceptive use and help users avoid unintended pregnancy.

Funding: Bill & Melinda Gates Foundation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and Mona Lisa, N.V. (Belgium).

Keywords: 12-Month; Bleeding and pain; Blinded; Comparative; Continuation rates; Copper intrauterine device; Early removal; Expulsion; IUD; Nulliparous; Randomized; Satisfaction; Trial.

Conflict of interest statement

DH, PLC, and KN's institution (FHI 360) received funding from Bill & Melinda Gates Foundation and Mona Lisa, N.V. to conduct this study. The following investigators’ institutions received contract funding from FHI 360 (with funds originating from Bill & Melinda Gates Foundation) to help conduct this study: CAS, ID, BAC, ABG, CD, ALN. The following investigators’ institutions received contract funding from Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) to help conduct this study: DKT, JTJ, MDC, KOW, SBT, JLK, CD, MAT, DFA, PMC, AEB. These two employees of the NIH were supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) to help conduct this study: DLB and JEB. No author received personal financial payments for this work. No author has financial relationships with Mona Lisa, N.V. DH reports board membership on Society of Family Planning. CAS reports contracts or grants to institution from Bayer Pharma, Sebela Pharma, and Danco Pharma; royalties to self and institution from Atheneum Pharma; payment for expert testimony from Center for Reproductive Rights, Planned Parenthood Federation and ACLU; a U.S. Provisional Patent Application No. 62/777,369; honoraria from American Board of Obstetrics & Gynecology. DKT reports contracts or grants to institution from The Laura and John Arnold Foundation, Society of Family Planning Research Fund, the William and Flora Hewlett Foundation, the Willard L. Eccles Foundation, the Intermountain Community Care Foundation, Bayer Women's Health, Organon, Cooper Surgical, Medicines360, Sebela Pharmaceuticals and anonymous foundation. MCD reports contracts to institution from Chemo Research SL, Evofem, HRA Pharma, Medicines360, Merck, Sebela; consulting fees from Estetra SRL, FHI360, Libbs, Mayne, Medicines360; speaking honorarium from Gedeon Richter, Mayne; payment/reimbursement of expenses for travel to meetings to present research from Medicines360; payment/reimbursement of expenses for travel to meetings to present research or attend Advisory Board from Estetra SRL; payment/reimbursement of expenses for travel to attend Advisory Board from TherapeuticsMD; Advisory Board meetings with honorarium from Evofem, Fuji Pharma, Mayne, Merck, Searchlight and TherapeuticsMD; honorarium for duties as Deputy Editor of the journal Contraception. KOW reports grants or contracts to institution from Bayer Pharmaceuticals and honoraria for a remote consultancy from Bayer Pharmaceuticals. SBT reports contracts to institution from Sebela, Medicines 360, Bayer Healthcare, Chemo Research, S.L., Merck & Co.; DSMB for Merck & Co.; Advisory Board for Bayer Healthcare; Society of Family Planning board member; American Board of Obstetrics & Gynecology (Complex Family Planning Division Member). BAC reports contracts or grants to institution from Medicines360, Sebela, and Mylan; member of American College of Obstetrics and Gynecology working group. ABG reports grants or contracts to institution from Merck; royalties from Uptodate; consulting fees from Society of Family Planning; board member of Society of Family Planning. ALN reports contracts or grants to institution from Merck, Mylan, Myovant, Sagami Rubber Industries, Sebela; consulting fees from Agile Therapeutics, Bayer HealthCare, Mayne Pharma, Pfizer, TherapeuticsMD; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Agile Pharma, Bayer HealthCare, Myovant Sciences, Merck, TherapeuticsMD; support for attending meetings and/or travel from Agile Pharma, Bayer HealthCare, Myovant Sciences, Merck, Pfizer, TherapeuticsMD. MAT reports Board member of American Society for Reproductive Medicine. DFA reports grants or contracts to institution from Bayer Healthcare, Dare Biosciences, Estetra, Myovant, and ObsEva; consulting fees from Bayer Healthcare, Exeltis, Mithra, Lupin, ObsEva, Mithra; honoraria for lecture from Exeltis; DSMB member; Board of directors for Diczfalusy Foundation; stock ownership in InnovaGyn, Inc.; stock options with Agile Therapeutics. PMC reports consulting fees from Bayer to provide remote IUD consultative support to clinicians; payments to institution from Bayer for clinical research. AEB reports grants or contracts to institution from Merck & Co, Inc (USA) and Scope/Chemo (Spain); honorarium and travel to meetings from TherapeuticsMD; support for related work and travel as associate editor for ACOG Clinical Updates; support for travel/honorarium from American Board of Obstetrics & Gynecology. BK reports grants or contracts to institution from Contramed Pharmaceuticals (Sebela), Evofem Biosciences, Gynuity Health Projects; royalties from Uptodate; consulting fees from Merck. The remaining authors do not have any related relationships to disclose: JTJ, KN, ID, PLC, JLK, CD, JEB, DLB.

© 2022 The Author(s).

Figures

Figure 1
Figure 1
Analysis population flow diagram for nulliparous participants.
Figure 2
Figure 2
a: 12-Month probabilities of overall product continuation. Kaplan–Meier plot of 12-month probabilities of overall continuation per 100. NT380-Mini (78.7%) versus TCu380A (70.2%), logrank test p-value=0.014. b: 12-Month probabilities of discontinuation due to bleeding and/or pain. Kaplan–Meier plot of 12-month probabilities per 100. NT380-Mini (8.1%) versus TCu380A (16.2%), logrank test p-value=0.003.
Figure 3
Figure 3
Dimensions of TCu380A and NT380-Mini.

References

    1. Sivin I, Stern J. Long-acting, more effective copper T IUDs: a summary of U.S. experience, 1970-75. Stud Fam Plann. 1979;10(10):263–281.
    1. Sivin I, Greenslade F, Schmidt F, Waldman SN. The Population Council, Inc; New York: 1992. The Copper T380 Intrauterine Device: a Summary of Scientific Data. Accessed 20 April 2021.
    1. Wildemeersch D. Intrauterine contraceptives that do not fit well contribute to early discontinuation. Eur J Contraception Reprod Health Care. 2011;16(2):135–141.
    1. Committee on Adolescent Health Care Long-Acting Reversible Contraception Working Group The American College of Obstetricians Gynecologists Committee opinion no. 539: adolescents and long-acting reversible contraception: implants and intrauterine devices. Obstet Gynecol. 2012;120(4):983–988.
    1. Long-acting reversible contraception. National Institute for Health and Care Excellence; 2019. Available from: . Accessed 2 December 2021.
    1. UK Medical Eligibility for Contraceptive Use. Faculty of Sexual and Reproductive Healthcare. 2016. . Accessed 10 November 2021.
    1. Goldstuck N. Assessment of uterine cavity size and shape: a systematic review addressing relevance to intrauterine procedures and events. Afr J Reprod Health. 2012;16(3):130–139.
    1. Wildemeersch D, Hasskamp T, Nolte K, et al. A multicenter study assessing uterine cavity width in over 400 nulliparous women seeking IUD insertion using 2D and 3D sonography. Eur J Obstet Gynecol Reprod Biol. 2016;206:232–238.
    1. Shipp TD, Bromley B, Benacerraf BR. The width of the uterine cavity is narrower in patients with an embedded intrauterine device (IUD) compared to a normally positioned IUD. J Ultrasound Med. 2010;29(10):1453–1456.
    1. ParaGard® T380A INTRAUTERINE COPPER CONTRACEPTIVE US Prescribing Information, Revised: 9/2019. CooperSurgical, Inc. . Accessed 10 January 2020.
    1. Tatum HJ. Intrauterine contraception. Am J Obstet Gynecol. 1972;112(7):1000–1023.
    1. Hubacher D. Copper intrauterine device use by nulliparous women: review of side effects. Contraception. 2007;75(6 suppl):S8–11.
    1. Akintomide H, Barnes P, Brima N, Mansour D. Higher discontinuation rate with a standard-sized compared to a small-sized ‘gold standard’ copper intrauterine device: a case-control review. BMJ Sex Reprod Health. 2019;45(4):263–268.
    1. Otero-Flores JB, Guerrero-Carreno FJ, Vazquez-Estrada LA. A comparative randomized study of three different IUDs in nulliparous Mexican women. Contraception. 2003;67(4):273–276.
    1. Sivin I. Problems in the conduct and analysis of “a comparative randomized study of three different IUDs in nulliparous Mexican women”. Contraception. 2004;69(3):259–260.
    1. Kulier R, O'Brien PA, Helmerhorst FM, Usher-Patel M, D'Arcangues C. Copper containing, framed intra-uterine devices for contraception. Cochrane Database Syst Rev. 2007;(4)
    1. Stanback J, Grimes D. Can intrauterine device removals for bleeding or pain be predicted at a one-month follow-up visit? A multivariate analysis. Contraception. 1998;58(6):357–360.
    1. Mona Lisa NT Cu380 Mini NCT03124160. US National Library of Medicine, . . Accessed 25 March 2022.
    1. Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. medical eligibility criteria for contraceptive use, 2016. MMWR Recommend Rep. 2016;65(3):1–103.
    1. O'Neil-Callahan M, Peipert JF, Zhao Q, Madden T, Secura G. Twenty-four-month continuation of reversible contraception. Obstet Gynecol. 2013;122(5):1083–1091.
    1. Madden T, McNicholas C, Zhao Q, Secura GM, Eisenberg DL, Peipert JF. Association of age and parity with intrauterine device expulsion. Obstet Gynecol. 2014;124(4):718–726.
    1. Shimoni N, Davis A, Westhoff C. Can ultrasound predict IUD expulsion after medical abortion? Contraception. 2014;89(5):434–439.
    1. Tatum HJ. Intrauterine contraceptive device, United States Patent and Trademark Office, Patent 3533406. 1970. . Accessed 20 June 2021.
    1. Akintomide H, Brima N, Mansour DJ, Shawe J. Copper IUD continuation, unwanted effects and cost consequences at 1 year in users aged under 30–a secondary analysis of the EURAS-IUD study. Eur J Contraception Reprod Health Care. 2021;26(3):175–183.
    1. Gemzell-Danielsson K, Schellschmidt I, Apter D. A randomized, phase II study describing the efficacy, bleeding profile, and safety of two low-dose levonorgestrel-releasing intrauterine contraceptive systems and Mirena. Fertil Steril. 2012;97(3):616–622. e1-3.
    1. Contraceptive Use by Method 2019, Data Booklet: United Nations, Department of Economic and Social Affairs, Population Division. . Accessed 3 January 2022.
    1. Cea-Soriano L, Garcia Rodriguez LA, Machlitt A, Wallander MA. Use of prescription contraceptive methods in the UK general population: a primary care study. BJOG. 2014;121(1):53–60. discussion-1.
    1. King LA, Michels KA, Graubard BI, Trabert B. Trends in oral contraceptive and intrauterine device use among reproductive-aged women in the US from 1999 to 2017. Cancer Causes Control. 2021;32(6):587–595.
    1. PHEXXI prescribing information. Evofem Biosciences, Inc. . Accessed 3 January 2022.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner