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Recommendations for standardization of bleeding data analyses in contraceptive studies

      Abstract

      To address limitations that exist with existing definitions of menstrual bleeding changes that occur with contraceptive methods, we assembled a panel to develop new recommendations for standardization of bleeding data analyses associated with contraceptive use to better inform users, clinicians, investigators, pharmaceutical companies, and regulatory agencies. We propose three criteria for assessing bleeding outcomes: pattern, flow, and duration. The descriptors within each criterion depend on whether the contraceptive is designed to result in a predictable or unpredictable bleeding pattern. Predictable pattern outcomes quantify days of scheduled, unscheduled and no bleeding, while unpredictable pattern outcomes assess frequency. Flow is quantified based on patient comparisons to their typical flow when not using contraception, with spotting representing no menstrual products use. Duration of a prolonged bleeding and/or spotting episode is more than 7 days. Studies should assess bleeding characteristics for a minimum of 12 months for 21/7, 24/4, extended cycle or continuous regimens, two years for injectables, and the full duration of use for long-acting contraceptives. Describing pattern, flow and duration as independent categories allows a fuller understanding of the bleeding outcomes and better future assessments of acceptability and continuation. Standardization of outcomes permits better comparison between studies and data synthesis; standardization will also improve the ability of clinicians and patients to understand differences between products.

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      References

        • Rosenberg MJ
        • Waugh MS.
        Oral contraceptive discontinuation: a prospective evaluation of frequency and reasons.
        Am J Obstet Gynecol. 1998; 179 (Pt 1): 577-582https://doi.org/10.1016/s0002-9378(98)70047-x
        • Kaunitz AM.
        Long-acting injectable contraception with depot medroxyprogesterone acetate.
        Am J Obstet Gynecol. 1994; 170 (Pt 2PMID: 8178904): 1543-1549
        • Grunloh DS
        • Casner T
        • Secura GM
        • Peipert JF
        • Madden T.
        Characteristics associated with discontinuation of long-acting reversible contraception within the first 6 months of use.
        Obstet Gynecol. 2013; 122: 1214-1221https://doi.org/10.1097/01.AOG.0000435452.86108.59
        • Polis CB
        • Hussain R
        • Berry A.
        There might be blood: a scoping review on women's responses to contraceptive-induced menstrual bleeding changes.
        Reprod Health. 2018 26; 15: 114https://doi.org/10.1186/s12978-018-0561-0
        • Cohen R
        • Sheeder J
        • Teal SB.
        Predictors of discontinuation of long-acting reversible contraception before 30 months of use by adolescents and young women.
        J Adolesc Health. 2019; 65 (2019.02.020): 295-302https://doi.org/10.1016/j.jadohealth
        • Kaunitz AM
        • Bissonnette F
        • Monteiro I
        • Lukkari-Lax E
        • Muysers C
        • Jensen JT.
        Levonorgestrel-releasing intrauterine system or medroxyprogesterone for heavy menstrual bleeding: a randomized controlled trial.
        Obstet Gynecol. 2010; 116: 625-632https://doi.org/10.1097/AOG.0b013e3181ec622b
        • Mawet M
        • Nollevaux F
        • Nizet D
        • Nizet D
        • Wijzen F
        • Gordenne V
        • et al.
        Impact of a new levonorgestrel intrauterine system, Levosert(®), on heavy menstrual bleeding: results of a one-year randomised controlled trial.
        Eur J Contracept Reprod Health Care. 2014; 19: 169-179https://doi.org/10.3109/13625187.2014.894184
        • Sivin I
        • el Mahgoub S
        • McCarthy T
        • Mishell Jr, DR
        • Shoupe D
        • Alvarez F
        • et al.
        Long-term contraception with the levonorgestrel 20 mcg/day (LNg 20) and the copper T 380Ag intrauterine devices: a five-year randomized study.
        Contraception. 1990; 42: 361-378https://doi.org/10.1016/0010-7824(90)90046-x
        • Rowe P
        • Farley T
        • Peregoudov A
        • Piaggio G
        • Boccard S
        • Landoulsi S
        • et al.
        Safety and efficacy in parous women of a 52-mg levonorgestrel-medicated intrauterine device: a 7-year randomized comparative study with the TCu380A.
        Contraception. 2016; 93: 498-506https://doi.org/10.1016/j.contraception.2016.02.024
        • Belsey EM
        • Machin D
        • d'Arcangues C.
        The analysis of vaginal bleeding patterns induced by fertility regulating methods. World Health Organization Special Programme of Research, Development and Research Training in Human Reproduction.
        Contraception. 1986; 34: 253-260https://doi.org/10.1016/0010-7824(86)90006-5
        • Rodriguez G
        • Faundes-Latham A
        • Atkinson LE.
        An approach to the analysis of menstrual patterns in the critical evaluation of contraceptives.
        Stud Fam Plann. 1976; 7: 42-51
        • Belsey EM
        • Farley TM.
        The analysis of menstrual bleeding patterns: a review.
        Contraception. 1988; 38: 129-156https://doi.org/10.1016/0010-7824(88)90035-2
        • Mishell Jr, DR
        • Guillebaud J
        • Westhoff C
        • Nelson AL
        • Kaunitz AM
        • Trussell J
        • et al.
        Combined hormonal contraceptive trials: variable data collection and bleeding assessment methodologies influence study outcomes and physician perception.
        Contraception. 2007; 75: 4-10https://doi.org/10.1016/j.contraception.2006.08.008
        • Mishell Jr, DR
        • Guillebaud J
        • Westhoff C
        • Nelson AL
        • Kaunitz AM
        • Trussell J
        • et al.
        Recommendations for standardization of data collection and analysis of bleeding in combined hormone contraceptive trials.
        Contraception. 2007; 75: 11-15https://doi.org/10.1016/j.contraception.2006.08.012
        • Baldaszti E
        • Wimmer-Puchinger B
        • Löschke K.
        Acceptability of the long-term contraceptive levonorgestrel-releasing intrauterine system (Mirena): a 3-year follow-up study.
        Contraception. 2003; 67: 87-91https://doi.org/10.1016/s0010-7824(02)00482-1
        • Bastianelli C
        • Farris M
        • Mirena Rapiti S.
        An Italian experience.
        Minerva Ginecol. 2011; 63: 343-349
        • Modesto W
        • Bahamondes MV
        • Bahamondes L.
        A randomized clinical trial of the effect of intensive versus non-intensive counselling on discontinuation rates due to bleeding disturbances of three long-acting reversible contraceptives.
        Hum Reprod. 2014; 29: 1393-1399https://doi.org/10.1093/humrep/deu089
        • Williamson PR
        • Altman DG
        • Blazeby JM
        • Clarke M
        • Gargon E.
        The COMET (Core Outcome Measures in Effectiveness Trials) Initiative.
        Trials. 2011; 12: A70
      1. Williamson P, Clarke M. The COMET (Core Outcome Measures in Effectiveness Trials) Initiative: Its Role in Improving Cochrane Reviews. Cochrane Database Syst Rev. 2012;(5):ED000041. doi: 10.1002/14651858.ED000041.

        • Hallberg L
        • Högdahl AM
        • Nilsson L
        • Rybo G.
        Menstrual blood loss–a population study. Variation at different ages and attempts to define normality.
        Acta Obstet Gynecol Scand. 1966; 45: 320-351https://doi.org/10.3109/00016346609158455
        • Mansour D
        • Fraser IS
        • Edelman A
        • Vieira CS
        • Kaunitz AM
        • Korver T
        • et al.
        Can initial vaginal bleeding patterns in etonogestrel implant users predict subsequent bleeding in the first 2 years of use?.
        Contraception. 2019; 100: 264-268https://doi.org/10.1016/j.contraception.2019.05.017
        • Munro MG
        • Critchley HO
        • Broder MS
        • Fraser IS
        FIGO Working Group on Menstrual Disorders. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age.
        Int J Gynaecol Obstet. 2011; 113: 3-13https://doi.org/10.1016/j.ijgo.2010.11.011
        • Munro MG
        • Critchley HOD
        • Fraser IS
        FIGO Menstrual Disorders Committee. The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions.
        Int J Gynaecol Obstet. 2018; 143: 393-408https://doi.org/10.1002/ijgo.12666
        • Mansour D
        • Korver T
        • Marintcheva-Petrova M
        • Fraser IS.
        The effects of Implanon on menstrual bleeding patterns.
        Eur J Contracept Reprod Health Care. 2008; 13 (Suppl 1): 13-28https://doi.org/10.1080/13625180801959931
        • Fraser IS
        • Critchley HO
        • Munro MG
        • Broder M.
        Can we achieve international agreement on terminologies and definitions used to describe abnormalities of menstrual bleeding?.
        Hum Reprod. 2007; 22: 635-643https://doi.org/10.1093/humrep/del478
        • Creinin MD
        • Keverline S
        • Meyn LA.
        How regular is regular? An analysis of menstrual cycle regularity.
        Contraception. 2004; 70: 289-292https://doi.org/10.1016/j.contraception.2004.04.012
        • Masson S
        • Franssen E
        • Hilditch JR
        • Powell MG.
        A clinical comparison of two triphasic oral contraceptives with levonorgestrel or norethindrone: a prospective, randomized, single-blind study.
        Contraception. 1993; 47: 43-54https://doi.org/10.1016/0010-7824(93)90108-j
        • Creinin MD
        • Westhoff CL
        • Bouchard C
        • Chen MJ
        • Jensen JT
        • Kaunitz AM
        • et al.
        Estetrol-drospirenone combination oral contraceptive: North American phase 3 efficacy and safety results.
        Contraception. 2021; 104: 222-228https://doi.org/10.1016/j.contraception.2021.05.002
        • Zakherah MS
        • Sayed GH
        • El-Nashar SA
        • Shaaban MM.
        Pictorial blood loss assessment chart in the evaluation of heavy menstrual bleeding: diagnostic accuracy compared to alkaline hematin.
        Gynecol Obstet Invest. 2011; 71: 281-284https://doi.org/10.1159/000320336
        • Magnay JL
        • O'Brien S
        • Gerlinger C
        • Seitz C.
        A systematic review of methods to measure menstrual blood loss.
        BMC Womens Health. 2018; 18 (22): 142https://doi.org/10.1186/s12905-018-0627-8
        • Wouters OJ
        • McKee M
        • Luyten J.
        Estimated research and development investment needed to bring a new medicine to market.
        JAMA. 2020; 323 (2009-2018): 844-853https://doi.org/10.1001/jama.2020.1166
        • Hubacher D
        • Lopez L
        • Steiner MJ
        • Dorflinger L.
        Menstrual pattern changes from levonorgestrel subdermal implants and DMPA: systematic review and evidence-based comparisons.
        Contraception. 2009; 80: 113-118https://doi.org/10.1016/j.contraception.2009.02.008
      2. Depo-Provera CI package insert: Pfizer. Depo-Provera prescribing information (10/2010).

        • Jacobson AE
        • Vesely SK
        • Haamid F
        • Christian-Rancy M
        • O'Brien SH
        Mobile application vs paper pictorial blood assessment chart to track menses in young women: a randomized cross-over design.
        J Pediatr Adolesc Gynecol. 2018; 31: 84-88https://doi.org/10.1016/j.jpag.2017.09.009
        • Huber LR
        • Broel EC
        • Mitchelides AN
        • Dmochowski J
        • Dulin M
        • Scholes D.
        Comparison of prospective daily diaries and retrospective recall to measure oral contraceptive adherence.
        Contraception. 2013; 88: 492-497https://doi.org/10.1016/j.contraception.2013.02.007
        • Nelson AL
        • Cohen S
        • Galitsky A
        • Hathaway M
        • Kappus D
        • Kerolous M
        • et al.
        Women's perceptions and treatment patterns related to contraception: results of a survey of US women.
        Contraception. 2018; 97: 256-273https://doi.org/10.1016/j.contraception.2017.09.010