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Hormonal contraceptive discontinuation patterns according to formulation: investigation of associations in an administrative claims database
Contraception 77 (2008) 257 – 263
Original research article
Hormonal contraceptive discontinuation patterns according to formulation: investigation of associations in an administrative claims database☆ Patricia Aikins Murphy a,⁎, Diana Brixner b a University of Utah College of Nursing, Salt Lake City, UT 84112-5880, USA University of Utah College of Pharmacy, Salt Lake City, UT 84112-5880, USA Received 13 August 2007; revised 13 November 2007; accepted 16 November 2007 b
Abstract Background: Hormonal contraceptive use is generally characterized by poor adherence and relatively high discontinuation. This study investigated whether specific hormonal contraceptive formulations and/or delivery systems might be correlated with discontinuation of contraception. Study Design: This was a retrospective descriptive analysis within a large administrative claims database. The sample included women aged 15–40 years with a pharmacy benefit and at least one new hormonal contraception prescription during the study period and no prescription in the previous 6 months. Filled contraceptive prescriptions were grouped into several categories of delivery system, dosage, progestin type and monophasic vs. triphasic formulations. In each, a baseline number of women was established who filled a first prescription for a contraceptive formulation in the specified category. Then, the percentage of these women who filled a prescription for a contraceptive in the same category within 3 months' time was determined. Continuation or change rates were compared within each group. Results: Oral contraceptives (OCs) were the least likely to be discontinued at 3 months; injectables were the most likely. OC formulations associated with increased risk of discontinuation (odds ratios above 1.3 representing a 5% or higher increased discontinuation) included verylow-dose (20–25 mcg ethinyl estradiol) pills containing norethindrone acetate or norgestimate, as compared to a preparation with the same progestin type but with a higher dose of estrogen. Desogestrel and norethindrone-containing triphasics were more likely to be discontinued than other triphasic progestins. OC formulations with desogestrel and norethindrone/norethindrone acetate were more likely than formulations with other progestins to be discontinued overall. Conclusions: This investigation in a sample of nearly 250,000 women suggests possible associations between discontinuation of hormonal contraception and factors such as estrogen dosing, progestin type and changes in dosage during the cycle. Identification of factors correlated with contraceptive discontinuation may inform management and improve adherence. © 2008 Elsevier Inc. All rights reserved. Keywords: Hormonal contraception; Compliance; Oral contraceptives; Administrative claims database; Pharmacotherapy outcomes
1. Introduction Oral contraceptives (OCs) are the most common reversible contraceptive used in the United States, with an estimated 11.6 million users in 2002 [1]. Continued use is critical for effectiveness of OCs; however, actual use is generally characterized by poor adherence and relatively high discontinuation [2]. During the first 6 months of use, at least one in five OC users discontinues use for method-related ☆ This study was funded by a grant from the Primary Care Research Center at the University of Utah. ⁎ Corresponding author. Tel.: +1 801 585 9360; fax: +1 801 587 9838. E-mail address: [email protected] (P.A. Murphy).
0010-7824/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2008.01.002
reasons. OC discontinuation rates rise steadily over time, reaching 32–60% after 12 months [3,4]. Within 24 months of starting the method, roughly half of all OC users have discontinued [5]. Adolescents, whose contraceptive use has been the most studied, have discontinuation rates of OCs estimated to be 50% in the first 3 months of use [6]. If characteristics of hormonal contraceptive formulation (such as delivery system, hormone type and dose or monophasic vs. triphasic formulations) contribute to discontinuation of hormonal contraception, clinicians might have the opportunity to improve contraceptive adherence by prescribing formulations associated with lower rates of discontinuation. However, aside from smaller clinical trials of specific formulations with limited comparison groups, or larger
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studies focused on specific outcomes, there have been no large-scale investigations of whether specific formulations influence discontinuation of hormonal contraceptive use. If formulations or delivery systems associated with higher continuation rates could be identified, it could inform contraceptive management and possibly influence prescribing, lead to decreased discontinuation and ultimately reduce rates of unintended pregnancy.
Given the cost of acquiring the database and the limited pilot funding available, the investigators could not access the full database. IHCIS programmers worked with the investigators to identify members who met the eligibility requirements (see below) and to populate data tables within specific comparison groupings to investigate whether there are trends toward difference in continuation across formulations of hormonal contraceptives. 2.2. Target sample
2. Materials and methods This was a retrospective descriptive analysis of a large administrative claims database to investigate whether specific hormonal contraceptive formulations and/or delivery systems might be positively or negatively correlated to discontinuation of contraception. The study was reviewed by the University of Utah Institutional Review Board (IRB), and it was determined that the project did not meet the definitions of Human Subjects Research according to Federal regulations. Therefore, IRB oversight was not required or necessary for this project. 2.1. Source The data source was Institute of Health Care Information Solutions (IHCIS) and its National Benchmark Database. This data resource contains the combined claims of over 35 health plans representing approximately 38 million unique members in 2004, predominantly in the North, North Central and Atlantic regions of the United States. Nearly 30% of members are from New England, 21% from the Middle Atlantic region. Data analyzed include medical claims (physician, facility and laboratory), pharmacy claims and eligibility data (from enrollment records). The database contains information from 1997 to the present and is updated monthly. The average number of member months is 22; there are 14 million covered lives with over 2 years of enrollment and 7.5 million with over 3 years of enrollment. Fifty-one percent of the total covered lives are women (N6 million in 2004). Approximately one quarter of all covered individuals are 17 years and under, 20% aged 18–30 years, 25% 31–44 and the remainder over 45 years. Eighty-four percent of members have a pharmacy benefit. The database is deidentified to protect confidentiality and is fully compliant with the privacy rules of the Health Insurance Portability and Accountability Act. The database is designed to support benchmarking projects, health care outcomes research and other research initiatives [11]. The active database represents 3 years of data and is updated regularly. Industry standards allow for a 3-month lag period for processing; over 90% of claims are processed within this period. Thus, the complete data for a specific time period cover the designated time period plus 3 months after to allow for claims processing.
The sample was identified as all women aged 15–40 years in the administrative claims database as of January 1, 1999, with the following characteristics: 1. With a pharmacy benefit; 2. At least one hormonal contraception prescription during period January 1, 1999, to March 31, 2004; 3. No hormonal contraception prescription within 6 months prior to the identified first contraception prescription and 4. Continuously enrolled in the health plan from at least 6 months prior to the first contraception prescription to at least 1 year after the first contraception prescription. Hormonal contraceptive use was defined as filling a prescription for any OC containing ethinyl estradiol (EE) and a progestin, for a transdermal contraceptive, for a vaginal ring contraceptive or for depomedroxyprogesterone acetate injection as identified by the National Drug Code (NDC) number in the database. Progestin-only pills were not included. Given that the use of these preparations is largely confined to breastfeeding women and women with medical conditions that contraindicate the use of estrogen, the use and discontinuation of these pills would likely differ fundamentally from combined contraceptives. 2.3. Comparison tables For the purposes of a preliminary assessment, formulations were grouped broadly among four categories. One grouping was according to delivery method for the hormonal contraceptive products: oral vs. transdermal vs. intravaginal vs. intramuscular injection. A second grouping was OCs among levels of EE (30–35 vs. 20 mcg) in monophasic OC preparations. A third grouping compared a monophasic vs. a triphasic preparation. Finally, we grouped OC products according to the progestin type. In a second-level assessment, additional data were obtained from the programmers at IHCIS in order to calculate discontinuation rates across strata grouped more specifically by steroid hormone and dosage. 2.4. Analysis Contraceptive prescriptions filled were grouped into the above categories. In each category, programmers identified the number of women who filled a first prescription for a
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259
Table 1 ORs for discontinuation of specific hormonal contraceptive formulations at 3 months from initial prescription Comparison
Stratum
Baseline eligible members
Refill at 3 months [n (%)]
OR for discontinuation at 3 months
95% CI
237,242
130,415 (55.0%)
Oral Transdermal Vaginal Injectable
220,785 12,263 1402 314
140,163 (63.5%) 66,377 (52.0%) 709 (50.6%) 130 (41.4%)
Referent 1.6 1.7 2.5
– 1.5–1.7 1.5–1.9 2.0–3.0
30–35 mcg 20–25 mcg
77,898 29,506
46,346 (59.5%) 16,875 (57.2%)
Referent 1.1
– 1.1–1.1
Monophasic Triphasic
107,404 85,338
64,696 (60.2%) 54,705 (64.1%)
Referent 0.9
– 0.8–0.9
Norgestrel/levonorgestrel Ethynodiol diacetate Norethindrone/norethindrone acetate Desogestrel Norgestimate Drosperinone
54,329 4223 61,495
31,839 (58.6%) 2608 (61.8%) 34,690 (56.4%)
1.2 1.1 1.3
1.2–1.2 1.0–1.1 1.3–1.4
26,930 65,225 11,061
15,517 (57.6%) 41,227 (63.2%) 6588 (59.6%)
1.3 Referent 1.2
1.2–1.3 – 1.2–1.2
Total Route
Monophasic; by EE dose
Monophasic vs. triphasic
Progestin
contraceptive formulation in the specified category. Then the percentage of these women who filled a prescription for a contraceptive in the same category within 3 months' time was determined. In general, within the pharmacy plans represented by this database, prescriptions of contraceptives could be filled with up to a 3-month supply. A window of 3 weeks allowed for initiation of the prescription after the date it was originally filled. Continuation or change rates were compared within each grouping. Refills were identified as a pharmacy record for the same NDC number at a later service date for a member. Tables were populated by stratum of interest with the appropriate numbers and percentages of members who initiated and continued use. Logistic regression was used to calculate odds ratios (ORs) and 95% CIs for discontinuation. Analysis was for descriptive purposes only. The categories in the table were not mutually exclusive. Individual women could not be followed in order to control for factors such as age, given the data available to us.
3. Results A population of 237,242 eligible women were identified, of whom 130,415 refilled their prescription at three months (55% continuation rate). Table 1 describes results by the strata of 1: route of delivery, 2: monophasic preparations by EE dose, 3: monophasic vs. triphasic formulation and 4: progestin type. OCs in general were the least likely to be discontinued at 3 months (63.5% of prescriptions were refilled at 3 months); injectables were 2.5 times more likely to be discontinued (95% CI 2.0–3.0); only 41.4% of prescriptions were refilled at 3 months. The transdermal patch and vaginal ring were 1.6 and 1.7 times more likely to be discontinued at 3 months than OC pills (95% CI 1.5–1.7 and 1.5–1.9, respectively). There was little difference in continuation rates of monophasic preparations in general. Overall, triphasic preparations were less likely to be discontinued than monophasics (OR, 0.85; 95% CI, 0.8– 0.9]; discontinuation rates at 3 months were 35.9% for
Table 2 OR for discontinuation of 20–25-mcg EE preparations by progestin type Comparison/subgroup
20-mcg EE pills by progestin Desogestrel Norethindrone acetate Norgestimate Levonorgestrel a
Example branded product a
Baseline prescriptions
Refill at 3 months [n (%)]
OR for discontinuation at 3 months
95% CI
Mircette Loestrin 1/20 Ortho TriCyclen Lo Alesse
11,446 9585 4970 19,921
6520 (57%) 5116 (53.4%) 2836 (57.1%) 11,645 (58.5%)
1.1 1.2 1.1 Referent
1.0–1.1 1.2–1.3 1.0–1.1
One example product is given, but the various strata include other branded products and generic versions with the same hormone and dosing as the example brand.
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Table 3 OR for discontinuation of 30–35-mcg EE preparations by progestin type Comparison/subgroup
30–35-mcg EE pills by progestin Desogestrel Drosperinone Ethynodiol diacetate Norgestimate Norethindrone acetate Levonorgestrel
Example branded product a
Baseline prescriptions
Refill at 3 months [n (%)]
OR for discontinuation at 3 months
95% CI
Desogen Yasmin Demulen OrthoCyclen Loestrin 1.5/30 Nordette
14,471 11,061 4223 9900 6292 5827
8270 (57.1%) 6588 (59.6%) 2608 (61.8%) 6002 (60.6%) 3846 (61.1%) 3599 (61.8%)
1.2 1.1 1.0 1.1 1.0 Referent
1.1–1.3 1.0–1.2 0.9–1.1 1.0–1.1 1.0–1.1
a One example product is given, but the various strata include other branded products and generic versions with the same hormone and dosing as the example brand.
triphasics vs. 39.8% monophasics (pb.05). There was some variation in discontinuation rates across progestin types. Norgestimate-containing preparations were the least likely to be discontinued at 3 months (36.8% discontinuation rate). Compared to this, OCs containing other progestin types were 20–30% more likely to be discontinued (pb.05) (see Table 1). Formulations were then compared by EE dosage and progestin type. Table 2 describes these comparisons by the 20–25-mcg EE dosing. Levonorgestrel-containing preparations were the least likely to be discontinued and used as the referent (58.5% refill rate), but there were few differences across progestin types. Only norethindrone acetate-containing preparations were statistically significantly more likely to be discontinued (53.4% refill rate; OR for discontinuation, 1.2; pb.05). Table 3 describes discontinuation of monophasic preparations containing 30–35 mcg EE according to progestin type. Levonorgestrel-containing preparations were again the least likely to be discontinued and used as the referent (61.8% refill rate), but differences among most of the preparations were minimal. Only desogestrel-containing preparations were statistically significantly more likely to be discontinued than the referent (57.1% refill rate; OR for discontinuation, 1.2, pb.05). Triphasic preparations were also compared across progestin type (Table 4). Levonorgestrel-containing preparations were again the referent (66.2% refill rate), although there were minimal differences in discontinuation between this progestin and a triphasic with norethindrone (65.2% refill rate, nonsignificant). Desoges-
trel-containing preparations were 70% more likely to be discontinued (53.7% refill rate; OR for discontinuation, 1.7; 95% CI, 1.5–1.9). Finally, the 20–25-mcg EE formulations were compared with 30–35-mcg EE formulations within the same progestin groupings. The 20–25-mcg formulations were more likely to be discontinued in all of the progestin groups. Table 5 describes these comparisons: 61% of prescriptions for 30mcg EE pills with norethindrone acetate were refilled at 3 months, compared to 53.4% of the 20-mcg EE prescriptions (OR, 1.4; 95% CI, 1.3–1.5; pb.05), and 63% of prescriptions for the higher EE dose triphasic with norgestimate were refilled, compared to 57% of the lower EE dose with norgestimate (OR, 1.3; 95% CI, 1.2–1.4; pb.05). Table 6 describes comparisons of monophasic vs. triphasic formulations with the same progestin type. Levonorgestrel-containing monophasics were slightly more likely to be discontinued that levonorgestrel-containing triphasics. Sixty-six percent of prescriptions for a levonorgestrelcontaining triphasic were refilled at 3 months, compared to 62% of monophasic formulations with the same progestin (OR, 1.2; 95% CI, 1.1–1.2; pb.05).
4. Discussion This investigation of contraceptive discontinuation is unique in approach, using an administrative database of
Table 4 ORs for discontinuation of different triphasic preparations across progestin types Comparison/subgroup
Example branded product a
Triphasic formulations by progestin Desogestrel Cyclessa Norethindrone acetate Estrostep Norgestimate OrthoTri-Cyclen Norethindrone Ortho Novum 7/7/7 Levonorgestrel Triphasil
Baseline prescriptions
Refill at 3 months [n (%)]
OR for discontinuation at 3 months
95% CI
1013 5370 50,355 8750 14,880
544 (53.7%) 3117 (58%) 31,717 (63%) 5701 (65.2%) 9853 (66.2%)
1.7 1.4 1.2 1.1 Referent
1.5–1.9 1.3–1.5 1.1–1.2 1.0–1.1
a One example product is given, but the various strata include other branded products and generic versions with the same hormone and dosing as the example brand.
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Table 5 ORs for discontinuation of different dose formulations of EE across progestin types Comparison/subgroup
Example branded product
20–25- vs. 30–35-mcg EE pills with same progestin type Norethindrone acetate Triphasic EE Estrostep Very low dose Loestrin 1/20 Low dose Loestrin 1.5/30 Levonorgestrel Very low dose Alesse Low dose Nordette Norgestimate Very low dose Ortho TriCyclen Lo Low dose Ortho TriCyclen
Baseline prescriptions
Refill at 3 months [n (%)]
OR for discontinuation at 3 months
95% CI
3117 (58%) 5116 (53.4%) 3846 (61.1%)
1.1 1.4 Referent
1–1.2 1.3–1.5
19,921 5827
11,645 (58.5%) 3599 (61.8%)
1.2 Referent
1.1–1.2
4970 50,355
2836 (57.1%) 31,717 (63%)
1.3 Referent
1.2–1.4
5370 9585 6292
insurance claims to track trends in nearly one quarter of a million women. Among contraceptive products grouped by delivery route, OCs were the least likely to be discontinued. Injectables (depot medroxyprogesterone acetate was the only injectable in the database) were 2.5 times more likely to be discontinued at the 3-month mark (refill rate 63.5% vs. 41.4%, respectively, pb.05). Transdermal and vaginal contraceptive products were also less likely than OCs to be refilled at the 3-month mark (52% and 50.6%, respectively, pb.05). Across OC subgroups, most comparisons show little difference in continuation rates. However, some trends suggest the potential for clinically important effects of formulation on discontinuation (ORs ranging from 1.3–1.7 or higher, consistent with a statistically significant difference of 5% or more in discontinuation rates). Examples include very-low-dose (20–25 mcg EE) pills containing norethindrone acetate or norgestimate, as compared to a preparation with the same progestin type but with a higher dose. Desogestrel and norethindrone-containing triphasics were more likely to be discontinued than other triphasic progestins. Formulations with desogestrel and norethindrone/norethindrone acetate were more likely to be discontinued overall. Given the nature of the data available for the analyses in this brief report, these findings can only be considered suggestive. We were unable to identify the discontinuation patterns of individual women, nor did we have information on reasons for discontinuation or potentially confounding factors. In addition, the large numbers of OC users in each analytic stratum attributed statistical
significance to small differences in discontinuation that may be clinically insignificant. However, some trends (30% or more likelihood of discontinuation) suggest that further evaluation, if it can be coupled with an ability to control for certain potentially confounding factors, could uncover useful information about associations between formulation and discontinuation. Poor adherence to contraceptive use can be driven by various factors, including side effects, method of delivery and hormone levels. These aspects have been studied in small clinical trials and in prospective observational studies in somewhat larger patient groups. In one study [3], 1657 women beginning a new contraceptive prescription and receiving care in private offices, planned parenthood affiliates and a health maintenance organization were enrolled in a prospective study; there was a 65% response to the 2-month follow-up. Side effects, such as perceived cycle disruption, weight gain, nausea, breast tenderness and headaches while taking OCs, were the most frequent reasons given by women for discontinuing use (37% of discontinuers gave these reasons). Another 15% discontinued because the method was too hard to use, too expensive or the user had concerns about hormones. There were no differences in discontinuation according to type of OC used, which, in this study, were a variety of 30- and 35-mcg EE formulations, and approximately 1% received prescriptions for 50-mcg preparations. Many contemporary OCs contain 20 and 25 mcg of EE, with 50-mcg preparations rarely prescribed. In addition, there have been newer progestins developed for use
Table 6 ORs for discontinuation of monophasic vs. triphasic preparations within the same progestin type Comparison/subgroup
Example branded product
Monophasic vs. triphasic formulations with same progestin Monophasic with levonorgestrel Nordette Triphasic with levonorgestrel Triphasil Monophasic with norgestimate OrthoCyclen Triphasic with norgestimate Ortho TriCyclen
Baseline prescriptions
Refill at 3 months [n (%)]
OR for discontinuation at 3 months
95% CI
5827 14,880 9900 50,355
3599 (61.8%) 9853 (66.2%) 6002 (60.6%) 31,717 (63%)
1.2 Referent 1.1 Referent
1.1–1.3 1.1–1.2
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in OCs in the 10 years since these data were collected, and nonoral delivery systems are now available. In a trial directly comparing discontinuation among 463 OC starters or switchers randomized to one of three groups (two receiving 20-mcg EE formulations and one group receiving a 35-mcg formulation), discontinuation rates were similar, comparing users of the lowest dose to those using 35-mcg preparations [7]. Among starters, discontinuation was highest during the first cycle of use with all preparations. At the end of six cycles, discontinuation rates for starters were 20% for one 20-mcg preparation (with 0.15 mg desogestrel), 29% for a second 20-mcg preparation (with 0.1 mg levonorgestrel) and 33% for the 35-mcg preparation (with a tricyclic dosing of norgestimate) (p=.28). In contrast, discontinuation rates among switchers were uniform over the study period. By the end of the sixth cycle, discontinuation rates for switchers in all three treatment groups were nearly identical at 9% for Alesse and Mircette and 6% for TriCyclen (p=0.72). Of interest in another study [8], women using monophasic preparations (with the same dose of hormone throughout the 21-day active pill cycle) were 1.3 times more likely to discontinue than women using triphasic preparations (where dosage changes, and the color and/or shape of the pill change to mark the different dosages). Women using 28-day pill packs (that contain 7 days of placebo pills in addition to the 21 active days) were 4 times more likely to discontinue than women using 21-day packages (without placebo pills), despite the clinical belief that the 28-day packs should simplify use. This study suggests that certain characteristics of formulation, packaging or appearance may also contribute to hormonal contraceptive discontinuation. Reasons for discontinuation vary. A common reason for discontinuing OCs is, of course, to become pregnant. Nearly one in four women in a prospective study discontinued for this reason [3], and it is cited as the most common reason for discontinuation by a European workgroup that reviewed the literature on continuation rates for contraceptives [9]. Another smaller group of women are advised to discontinue because they develop medical conditions that are contraindications of hormonal contraceptive use. These are primarily related to the use of estrogen-containing contraceptives and include deep vein thrombosis or other thrombotic events such as pulmonary embolism, stroke or myocardial infarction. However, many women discontinue hormonal contraceptives who do not desire pregnancy or develop complications but simply stop. Frequently, they either fail to adopt another contraceptive method or use one that is less effective than hormonal contraception [3]. Identifying factors associated with discontinuation has been a subject of considerable research in order to reduce the risk of unintended pregnancy. However, these observations come largely from smaller clinical trials of specific formulations with limited comparison groups, from synthesis of smaller studies and from a few larger prospective studies done
before lower dose formulations and newer progestins were commonly prescribed. Although outcomes research in large databases can provide valuable information on the health care utilization and costs for different treatment options, there are unique methodological issues. Clinical information is generally not available in claims databases, and certain variables commonly used to assess confounding factors and interactions (race-ethnicity, socioeconomic status, parity) are not available. However, using the commercial database approach and “real-world” data, defined as data used for decision making that are not collected in randomized controlled trials [10], offers a major benefit over smaller and more limited trials — the ability to describe trends and patterns in a larger number of women than would be possible in any other type of study. Given the format of the data available to us, we were unable to assess for confounding and potential bias. However, uncontrolled confounding or bias due to random misclassification is generally thought to reduce the ability to observe an effect; thus, if small effects are seen in such a sample, they would likely be larger in further targeted study that is able to control for such variables. The likelihood of systematic bias, such as regional or provider differences in prescription or counseling patterns, would be diminished by the size and scope of the database. This investigation in a sample of nearly 250,000 women suggests associations between the likelihood of discontinuing or switching hormonal contraceptives and factors such as estrogen dosing and progestin type. A contemporary large population-based investigation of this population allowing for the control of covariates could provide further evidence as to whether specific formulations influence discontinuation of hormonal contraceptives. Acknowledgments The authors acknowledge the assistance of Dr. William Dudley and Adrian Musters of the Center for Applied Statistics at the University of Utah College of Nursing. References [1] Mosher WD, Martinez GM, Chandra A, Abma JC, Willson SJ. Use of contraception and use of family planning services in the United States: 1982–2002. Adv Data 2004;350:1–36. [2] Halpern V, Grimes DA, Lopez L, Gallo MF. Strategies to improve adherence and acceptability of hormonal methods for contraception. Cochrane Database Syst Rev 2006:CD004317. [3] Rosenberg MJ, Waugh MS. Oral contraceptive discontinuation: a prospective evaluation of frequency and reasons. Am J Obstet Gynecol 1998;179:577–82. [4] Trussell J, Leveque JA, Koenig JD, London R, Borden S, Henneberry J, et al. The economic value of contraception: a comparison of 15 methods. Am J Public Health 1995;85:494–503. [5] Potter L. Oral contraceptive compliance and its role in the effectiveness of the method. In: Cramer J, Spilker B, editors. Patient compliance in medical practice and clinical trials. New York: Raven Press; 1991. p. 195–207.
P.A. Murphy, D. Brixner / Contraception 77 (2008) 257–263 [6] Balassone ML. Risk of contraceptive discontinuation among adolescents. J Adolesc Health Care 1989;10:527–33. [7] Rosenberg MJ, Meyers A, Roy V. Efficacy, cycle control, and side effects of low- and lower-dose oral contraceptives: a randomized trial of 20 micrograms and 35 micrograms estrogen preparations. Contraception 1999;60:321–9. [8] Rosenberg MJ, Waugh MS, Meehan TE. Use and misuse of oral contraceptives: risk indicators for poor pill taking and discontinuation. Contraception 1995;51:283–8.
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[9] ESHRE. Continuation rates for oral contraceptives and hormone replacement therapy. The ESHRE Capri Workshop Group. Hum Reprod 2000;15:1865–71. [10] Garrison L, Neumann P, Erickson P, MArshall D, Mullins C. Using real-world data for coverage and payment decisions: the ISPOR real-world data task force report. Value Health 2007; 10:326–35. [11] IHCIS National Managed Care Benchmark Database User Manual, 2005.
Original research article
Hormonal contraceptive discontinuation patterns according to formulation: investigation of associations in an administrative claims database☆ Patricia Aikins Murphy a,⁎, Diana Brixner b a University of Utah College of Nursing, Salt Lake City, UT 84112-5880, USA University of Utah College of Pharmacy, Salt Lake City, UT 84112-5880, USA Received 13 August 2007; revised 13 November 2007; accepted 16 November 2007 b
Abstract Background: Hormonal contraceptive use is generally characterized by poor adherence and relatively high discontinuation. This study investigated whether specific hormonal contraceptive formulations and/or delivery systems might be correlated with discontinuation of contraception. Study Design: This was a retrospective descriptive analysis within a large administrative claims database. The sample included women aged 15–40 years with a pharmacy benefit and at least one new hormonal contraception prescription during the study period and no prescription in the previous 6 months. Filled contraceptive prescriptions were grouped into several categories of delivery system, dosage, progestin type and monophasic vs. triphasic formulations. In each, a baseline number of women was established who filled a first prescription for a contraceptive formulation in the specified category. Then, the percentage of these women who filled a prescription for a contraceptive in the same category within 3 months' time was determined. Continuation or change rates were compared within each group. Results: Oral contraceptives (OCs) were the least likely to be discontinued at 3 months; injectables were the most likely. OC formulations associated with increased risk of discontinuation (odds ratios above 1.3 representing a 5% or higher increased discontinuation) included verylow-dose (20–25 mcg ethinyl estradiol) pills containing norethindrone acetate or norgestimate, as compared to a preparation with the same progestin type but with a higher dose of estrogen. Desogestrel and norethindrone-containing triphasics were more likely to be discontinued than other triphasic progestins. OC formulations with desogestrel and norethindrone/norethindrone acetate were more likely than formulations with other progestins to be discontinued overall. Conclusions: This investigation in a sample of nearly 250,000 women suggests possible associations between discontinuation of hormonal contraception and factors such as estrogen dosing, progestin type and changes in dosage during the cycle. Identification of factors correlated with contraceptive discontinuation may inform management and improve adherence. © 2008 Elsevier Inc. All rights reserved. Keywords: Hormonal contraception; Compliance; Oral contraceptives; Administrative claims database; Pharmacotherapy outcomes
1. Introduction Oral contraceptives (OCs) are the most common reversible contraceptive used in the United States, with an estimated 11.6 million users in 2002 [1]. Continued use is critical for effectiveness of OCs; however, actual use is generally characterized by poor adherence and relatively high discontinuation [2]. During the first 6 months of use, at least one in five OC users discontinues use for method-related ☆ This study was funded by a grant from the Primary Care Research Center at the University of Utah. ⁎ Corresponding author. Tel.: +1 801 585 9360; fax: +1 801 587 9838. E-mail address: [email protected] (P.A. Murphy).
0010-7824/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2008.01.002
reasons. OC discontinuation rates rise steadily over time, reaching 32–60% after 12 months [3,4]. Within 24 months of starting the method, roughly half of all OC users have discontinued [5]. Adolescents, whose contraceptive use has been the most studied, have discontinuation rates of OCs estimated to be 50% in the first 3 months of use [6]. If characteristics of hormonal contraceptive formulation (such as delivery system, hormone type and dose or monophasic vs. triphasic formulations) contribute to discontinuation of hormonal contraception, clinicians might have the opportunity to improve contraceptive adherence by prescribing formulations associated with lower rates of discontinuation. However, aside from smaller clinical trials of specific formulations with limited comparison groups, or larger
258
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studies focused on specific outcomes, there have been no large-scale investigations of whether specific formulations influence discontinuation of hormonal contraceptive use. If formulations or delivery systems associated with higher continuation rates could be identified, it could inform contraceptive management and possibly influence prescribing, lead to decreased discontinuation and ultimately reduce rates of unintended pregnancy.
Given the cost of acquiring the database and the limited pilot funding available, the investigators could not access the full database. IHCIS programmers worked with the investigators to identify members who met the eligibility requirements (see below) and to populate data tables within specific comparison groupings to investigate whether there are trends toward difference in continuation across formulations of hormonal contraceptives. 2.2. Target sample
2. Materials and methods This was a retrospective descriptive analysis of a large administrative claims database to investigate whether specific hormonal contraceptive formulations and/or delivery systems might be positively or negatively correlated to discontinuation of contraception. The study was reviewed by the University of Utah Institutional Review Board (IRB), and it was determined that the project did not meet the definitions of Human Subjects Research according to Federal regulations. Therefore, IRB oversight was not required or necessary for this project. 2.1. Source The data source was Institute of Health Care Information Solutions (IHCIS) and its National Benchmark Database. This data resource contains the combined claims of over 35 health plans representing approximately 38 million unique members in 2004, predominantly in the North, North Central and Atlantic regions of the United States. Nearly 30% of members are from New England, 21% from the Middle Atlantic region. Data analyzed include medical claims (physician, facility and laboratory), pharmacy claims and eligibility data (from enrollment records). The database contains information from 1997 to the present and is updated monthly. The average number of member months is 22; there are 14 million covered lives with over 2 years of enrollment and 7.5 million with over 3 years of enrollment. Fifty-one percent of the total covered lives are women (N6 million in 2004). Approximately one quarter of all covered individuals are 17 years and under, 20% aged 18–30 years, 25% 31–44 and the remainder over 45 years. Eighty-four percent of members have a pharmacy benefit. The database is deidentified to protect confidentiality and is fully compliant with the privacy rules of the Health Insurance Portability and Accountability Act. The database is designed to support benchmarking projects, health care outcomes research and other research initiatives [11]. The active database represents 3 years of data and is updated regularly. Industry standards allow for a 3-month lag period for processing; over 90% of claims are processed within this period. Thus, the complete data for a specific time period cover the designated time period plus 3 months after to allow for claims processing.
The sample was identified as all women aged 15–40 years in the administrative claims database as of January 1, 1999, with the following characteristics: 1. With a pharmacy benefit; 2. At least one hormonal contraception prescription during period January 1, 1999, to March 31, 2004; 3. No hormonal contraception prescription within 6 months prior to the identified first contraception prescription and 4. Continuously enrolled in the health plan from at least 6 months prior to the first contraception prescription to at least 1 year after the first contraception prescription. Hormonal contraceptive use was defined as filling a prescription for any OC containing ethinyl estradiol (EE) and a progestin, for a transdermal contraceptive, for a vaginal ring contraceptive or for depomedroxyprogesterone acetate injection as identified by the National Drug Code (NDC) number in the database. Progestin-only pills were not included. Given that the use of these preparations is largely confined to breastfeeding women and women with medical conditions that contraindicate the use of estrogen, the use and discontinuation of these pills would likely differ fundamentally from combined contraceptives. 2.3. Comparison tables For the purposes of a preliminary assessment, formulations were grouped broadly among four categories. One grouping was according to delivery method for the hormonal contraceptive products: oral vs. transdermal vs. intravaginal vs. intramuscular injection. A second grouping was OCs among levels of EE (30–35 vs. 20 mcg) in monophasic OC preparations. A third grouping compared a monophasic vs. a triphasic preparation. Finally, we grouped OC products according to the progestin type. In a second-level assessment, additional data were obtained from the programmers at IHCIS in order to calculate discontinuation rates across strata grouped more specifically by steroid hormone and dosage. 2.4. Analysis Contraceptive prescriptions filled were grouped into the above categories. In each category, programmers identified the number of women who filled a first prescription for a
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Table 1 ORs for discontinuation of specific hormonal contraceptive formulations at 3 months from initial prescription Comparison
Stratum
Baseline eligible members
Refill at 3 months [n (%)]
OR for discontinuation at 3 months
95% CI
237,242
130,415 (55.0%)
Oral Transdermal Vaginal Injectable
220,785 12,263 1402 314
140,163 (63.5%) 66,377 (52.0%) 709 (50.6%) 130 (41.4%)
Referent 1.6 1.7 2.5
– 1.5–1.7 1.5–1.9 2.0–3.0
30–35 mcg 20–25 mcg
77,898 29,506
46,346 (59.5%) 16,875 (57.2%)
Referent 1.1
– 1.1–1.1
Monophasic Triphasic
107,404 85,338
64,696 (60.2%) 54,705 (64.1%)
Referent 0.9
– 0.8–0.9
Norgestrel/levonorgestrel Ethynodiol diacetate Norethindrone/norethindrone acetate Desogestrel Norgestimate Drosperinone
54,329 4223 61,495
31,839 (58.6%) 2608 (61.8%) 34,690 (56.4%)
1.2 1.1 1.3
1.2–1.2 1.0–1.1 1.3–1.4
26,930 65,225 11,061
15,517 (57.6%) 41,227 (63.2%) 6588 (59.6%)
1.3 Referent 1.2
1.2–1.3 – 1.2–1.2
Total Route
Monophasic; by EE dose
Monophasic vs. triphasic
Progestin
contraceptive formulation in the specified category. Then the percentage of these women who filled a prescription for a contraceptive in the same category within 3 months' time was determined. In general, within the pharmacy plans represented by this database, prescriptions of contraceptives could be filled with up to a 3-month supply. A window of 3 weeks allowed for initiation of the prescription after the date it was originally filled. Continuation or change rates were compared within each grouping. Refills were identified as a pharmacy record for the same NDC number at a later service date for a member. Tables were populated by stratum of interest with the appropriate numbers and percentages of members who initiated and continued use. Logistic regression was used to calculate odds ratios (ORs) and 95% CIs for discontinuation. Analysis was for descriptive purposes only. The categories in the table were not mutually exclusive. Individual women could not be followed in order to control for factors such as age, given the data available to us.
3. Results A population of 237,242 eligible women were identified, of whom 130,415 refilled their prescription at three months (55% continuation rate). Table 1 describes results by the strata of 1: route of delivery, 2: monophasic preparations by EE dose, 3: monophasic vs. triphasic formulation and 4: progestin type. OCs in general were the least likely to be discontinued at 3 months (63.5% of prescriptions were refilled at 3 months); injectables were 2.5 times more likely to be discontinued (95% CI 2.0–3.0); only 41.4% of prescriptions were refilled at 3 months. The transdermal patch and vaginal ring were 1.6 and 1.7 times more likely to be discontinued at 3 months than OC pills (95% CI 1.5–1.7 and 1.5–1.9, respectively). There was little difference in continuation rates of monophasic preparations in general. Overall, triphasic preparations were less likely to be discontinued than monophasics (OR, 0.85; 95% CI, 0.8– 0.9]; discontinuation rates at 3 months were 35.9% for
Table 2 OR for discontinuation of 20–25-mcg EE preparations by progestin type Comparison/subgroup
20-mcg EE pills by progestin Desogestrel Norethindrone acetate Norgestimate Levonorgestrel a
Example branded product a
Baseline prescriptions
Refill at 3 months [n (%)]
OR for discontinuation at 3 months
95% CI
Mircette Loestrin 1/20 Ortho TriCyclen Lo Alesse
11,446 9585 4970 19,921
6520 (57%) 5116 (53.4%) 2836 (57.1%) 11,645 (58.5%)
1.1 1.2 1.1 Referent
1.0–1.1 1.2–1.3 1.0–1.1
One example product is given, but the various strata include other branded products and generic versions with the same hormone and dosing as the example brand.
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Table 3 OR for discontinuation of 30–35-mcg EE preparations by progestin type Comparison/subgroup
30–35-mcg EE pills by progestin Desogestrel Drosperinone Ethynodiol diacetate Norgestimate Norethindrone acetate Levonorgestrel
Example branded product a
Baseline prescriptions
Refill at 3 months [n (%)]
OR for discontinuation at 3 months
95% CI
Desogen Yasmin Demulen OrthoCyclen Loestrin 1.5/30 Nordette
14,471 11,061 4223 9900 6292 5827
8270 (57.1%) 6588 (59.6%) 2608 (61.8%) 6002 (60.6%) 3846 (61.1%) 3599 (61.8%)
1.2 1.1 1.0 1.1 1.0 Referent
1.1–1.3 1.0–1.2 0.9–1.1 1.0–1.1 1.0–1.1
a One example product is given, but the various strata include other branded products and generic versions with the same hormone and dosing as the example brand.
triphasics vs. 39.8% monophasics (pb.05). There was some variation in discontinuation rates across progestin types. Norgestimate-containing preparations were the least likely to be discontinued at 3 months (36.8% discontinuation rate). Compared to this, OCs containing other progestin types were 20–30% more likely to be discontinued (pb.05) (see Table 1). Formulations were then compared by EE dosage and progestin type. Table 2 describes these comparisons by the 20–25-mcg EE dosing. Levonorgestrel-containing preparations were the least likely to be discontinued and used as the referent (58.5% refill rate), but there were few differences across progestin types. Only norethindrone acetate-containing preparations were statistically significantly more likely to be discontinued (53.4% refill rate; OR for discontinuation, 1.2; pb.05). Table 3 describes discontinuation of monophasic preparations containing 30–35 mcg EE according to progestin type. Levonorgestrel-containing preparations were again the least likely to be discontinued and used as the referent (61.8% refill rate), but differences among most of the preparations were minimal. Only desogestrel-containing preparations were statistically significantly more likely to be discontinued than the referent (57.1% refill rate; OR for discontinuation, 1.2, pb.05). Triphasic preparations were also compared across progestin type (Table 4). Levonorgestrel-containing preparations were again the referent (66.2% refill rate), although there were minimal differences in discontinuation between this progestin and a triphasic with norethindrone (65.2% refill rate, nonsignificant). Desoges-
trel-containing preparations were 70% more likely to be discontinued (53.7% refill rate; OR for discontinuation, 1.7; 95% CI, 1.5–1.9). Finally, the 20–25-mcg EE formulations were compared with 30–35-mcg EE formulations within the same progestin groupings. The 20–25-mcg formulations were more likely to be discontinued in all of the progestin groups. Table 5 describes these comparisons: 61% of prescriptions for 30mcg EE pills with norethindrone acetate were refilled at 3 months, compared to 53.4% of the 20-mcg EE prescriptions (OR, 1.4; 95% CI, 1.3–1.5; pb.05), and 63% of prescriptions for the higher EE dose triphasic with norgestimate were refilled, compared to 57% of the lower EE dose with norgestimate (OR, 1.3; 95% CI, 1.2–1.4; pb.05). Table 6 describes comparisons of monophasic vs. triphasic formulations with the same progestin type. Levonorgestrel-containing monophasics were slightly more likely to be discontinued that levonorgestrel-containing triphasics. Sixty-six percent of prescriptions for a levonorgestrelcontaining triphasic were refilled at 3 months, compared to 62% of monophasic formulations with the same progestin (OR, 1.2; 95% CI, 1.1–1.2; pb.05).
4. Discussion This investigation of contraceptive discontinuation is unique in approach, using an administrative database of
Table 4 ORs for discontinuation of different triphasic preparations across progestin types Comparison/subgroup
Example branded product a
Triphasic formulations by progestin Desogestrel Cyclessa Norethindrone acetate Estrostep Norgestimate OrthoTri-Cyclen Norethindrone Ortho Novum 7/7/7 Levonorgestrel Triphasil
Baseline prescriptions
Refill at 3 months [n (%)]
OR for discontinuation at 3 months
95% CI
1013 5370 50,355 8750 14,880
544 (53.7%) 3117 (58%) 31,717 (63%) 5701 (65.2%) 9853 (66.2%)
1.7 1.4 1.2 1.1 Referent
1.5–1.9 1.3–1.5 1.1–1.2 1.0–1.1
a One example product is given, but the various strata include other branded products and generic versions with the same hormone and dosing as the example brand.
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Table 5 ORs for discontinuation of different dose formulations of EE across progestin types Comparison/subgroup
Example branded product
20–25- vs. 30–35-mcg EE pills with same progestin type Norethindrone acetate Triphasic EE Estrostep Very low dose Loestrin 1/20 Low dose Loestrin 1.5/30 Levonorgestrel Very low dose Alesse Low dose Nordette Norgestimate Very low dose Ortho TriCyclen Lo Low dose Ortho TriCyclen
Baseline prescriptions
Refill at 3 months [n (%)]
OR for discontinuation at 3 months
95% CI
3117 (58%) 5116 (53.4%) 3846 (61.1%)
1.1 1.4 Referent
1–1.2 1.3–1.5
19,921 5827
11,645 (58.5%) 3599 (61.8%)
1.2 Referent
1.1–1.2
4970 50,355
2836 (57.1%) 31,717 (63%)
1.3 Referent
1.2–1.4
5370 9585 6292
insurance claims to track trends in nearly one quarter of a million women. Among contraceptive products grouped by delivery route, OCs were the least likely to be discontinued. Injectables (depot medroxyprogesterone acetate was the only injectable in the database) were 2.5 times more likely to be discontinued at the 3-month mark (refill rate 63.5% vs. 41.4%, respectively, pb.05). Transdermal and vaginal contraceptive products were also less likely than OCs to be refilled at the 3-month mark (52% and 50.6%, respectively, pb.05). Across OC subgroups, most comparisons show little difference in continuation rates. However, some trends suggest the potential for clinically important effects of formulation on discontinuation (ORs ranging from 1.3–1.7 or higher, consistent with a statistically significant difference of 5% or more in discontinuation rates). Examples include very-low-dose (20–25 mcg EE) pills containing norethindrone acetate or norgestimate, as compared to a preparation with the same progestin type but with a higher dose. Desogestrel and norethindrone-containing triphasics were more likely to be discontinued than other triphasic progestins. Formulations with desogestrel and norethindrone/norethindrone acetate were more likely to be discontinued overall. Given the nature of the data available for the analyses in this brief report, these findings can only be considered suggestive. We were unable to identify the discontinuation patterns of individual women, nor did we have information on reasons for discontinuation or potentially confounding factors. In addition, the large numbers of OC users in each analytic stratum attributed statistical
significance to small differences in discontinuation that may be clinically insignificant. However, some trends (30% or more likelihood of discontinuation) suggest that further evaluation, if it can be coupled with an ability to control for certain potentially confounding factors, could uncover useful information about associations between formulation and discontinuation. Poor adherence to contraceptive use can be driven by various factors, including side effects, method of delivery and hormone levels. These aspects have been studied in small clinical trials and in prospective observational studies in somewhat larger patient groups. In one study [3], 1657 women beginning a new contraceptive prescription and receiving care in private offices, planned parenthood affiliates and a health maintenance organization were enrolled in a prospective study; there was a 65% response to the 2-month follow-up. Side effects, such as perceived cycle disruption, weight gain, nausea, breast tenderness and headaches while taking OCs, were the most frequent reasons given by women for discontinuing use (37% of discontinuers gave these reasons). Another 15% discontinued because the method was too hard to use, too expensive or the user had concerns about hormones. There were no differences in discontinuation according to type of OC used, which, in this study, were a variety of 30- and 35-mcg EE formulations, and approximately 1% received prescriptions for 50-mcg preparations. Many contemporary OCs contain 20 and 25 mcg of EE, with 50-mcg preparations rarely prescribed. In addition, there have been newer progestins developed for use
Table 6 ORs for discontinuation of monophasic vs. triphasic preparations within the same progestin type Comparison/subgroup
Example branded product
Monophasic vs. triphasic formulations with same progestin Monophasic with levonorgestrel Nordette Triphasic with levonorgestrel Triphasil Monophasic with norgestimate OrthoCyclen Triphasic with norgestimate Ortho TriCyclen
Baseline prescriptions
Refill at 3 months [n (%)]
OR for discontinuation at 3 months
95% CI
5827 14,880 9900 50,355
3599 (61.8%) 9853 (66.2%) 6002 (60.6%) 31,717 (63%)
1.2 Referent 1.1 Referent
1.1–1.3 1.1–1.2
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in OCs in the 10 years since these data were collected, and nonoral delivery systems are now available. In a trial directly comparing discontinuation among 463 OC starters or switchers randomized to one of three groups (two receiving 20-mcg EE formulations and one group receiving a 35-mcg formulation), discontinuation rates were similar, comparing users of the lowest dose to those using 35-mcg preparations [7]. Among starters, discontinuation was highest during the first cycle of use with all preparations. At the end of six cycles, discontinuation rates for starters were 20% for one 20-mcg preparation (with 0.15 mg desogestrel), 29% for a second 20-mcg preparation (with 0.1 mg levonorgestrel) and 33% for the 35-mcg preparation (with a tricyclic dosing of norgestimate) (p=.28). In contrast, discontinuation rates among switchers were uniform over the study period. By the end of the sixth cycle, discontinuation rates for switchers in all three treatment groups were nearly identical at 9% for Alesse and Mircette and 6% for TriCyclen (p=0.72). Of interest in another study [8], women using monophasic preparations (with the same dose of hormone throughout the 21-day active pill cycle) were 1.3 times more likely to discontinue than women using triphasic preparations (where dosage changes, and the color and/or shape of the pill change to mark the different dosages). Women using 28-day pill packs (that contain 7 days of placebo pills in addition to the 21 active days) were 4 times more likely to discontinue than women using 21-day packages (without placebo pills), despite the clinical belief that the 28-day packs should simplify use. This study suggests that certain characteristics of formulation, packaging or appearance may also contribute to hormonal contraceptive discontinuation. Reasons for discontinuation vary. A common reason for discontinuing OCs is, of course, to become pregnant. Nearly one in four women in a prospective study discontinued for this reason [3], and it is cited as the most common reason for discontinuation by a European workgroup that reviewed the literature on continuation rates for contraceptives [9]. Another smaller group of women are advised to discontinue because they develop medical conditions that are contraindications of hormonal contraceptive use. These are primarily related to the use of estrogen-containing contraceptives and include deep vein thrombosis or other thrombotic events such as pulmonary embolism, stroke or myocardial infarction. However, many women discontinue hormonal contraceptives who do not desire pregnancy or develop complications but simply stop. Frequently, they either fail to adopt another contraceptive method or use one that is less effective than hormonal contraception [3]. Identifying factors associated with discontinuation has been a subject of considerable research in order to reduce the risk of unintended pregnancy. However, these observations come largely from smaller clinical trials of specific formulations with limited comparison groups, from synthesis of smaller studies and from a few larger prospective studies done
before lower dose formulations and newer progestins were commonly prescribed. Although outcomes research in large databases can provide valuable information on the health care utilization and costs for different treatment options, there are unique methodological issues. Clinical information is generally not available in claims databases, and certain variables commonly used to assess confounding factors and interactions (race-ethnicity, socioeconomic status, parity) are not available. However, using the commercial database approach and “real-world” data, defined as data used for decision making that are not collected in randomized controlled trials [10], offers a major benefit over smaller and more limited trials — the ability to describe trends and patterns in a larger number of women than would be possible in any other type of study. Given the format of the data available to us, we were unable to assess for confounding and potential bias. However, uncontrolled confounding or bias due to random misclassification is generally thought to reduce the ability to observe an effect; thus, if small effects are seen in such a sample, they would likely be larger in further targeted study that is able to control for such variables. The likelihood of systematic bias, such as regional or provider differences in prescription or counseling patterns, would be diminished by the size and scope of the database. This investigation in a sample of nearly 250,000 women suggests associations between the likelihood of discontinuing or switching hormonal contraceptives and factors such as estrogen dosing and progestin type. A contemporary large population-based investigation of this population allowing for the control of covariates could provide further evidence as to whether specific formulations influence discontinuation of hormonal contraceptives. Acknowledgments The authors acknowledge the assistance of Dr. William Dudley and Adrian Musters of the Center for Applied Statistics at the University of Utah College of Nursing. References [1] Mosher WD, Martinez GM, Chandra A, Abma JC, Willson SJ. Use of contraception and use of family planning services in the United States: 1982–2002. Adv Data 2004;350:1–36. [2] Halpern V, Grimes DA, Lopez L, Gallo MF. Strategies to improve adherence and acceptability of hormonal methods for contraception. Cochrane Database Syst Rev 2006:CD004317. [3] Rosenberg MJ, Waugh MS. Oral contraceptive discontinuation: a prospective evaluation of frequency and reasons. Am J Obstet Gynecol 1998;179:577–82. [4] Trussell J, Leveque JA, Koenig JD, London R, Borden S, Henneberry J, et al. The economic value of contraception: a comparison of 15 methods. Am J Public Health 1995;85:494–503. [5] Potter L. Oral contraceptive compliance and its role in the effectiveness of the method. In: Cramer J, Spilker B, editors. Patient compliance in medical practice and clinical trials. New York: Raven Press; 1991. p. 195–207.
P.A. Murphy, D. Brixner / Contraception 77 (2008) 257–263 [6] Balassone ML. Risk of contraceptive discontinuation among adolescents. J Adolesc Health Care 1989;10:527–33. [7] Rosenberg MJ, Meyers A, Roy V. Efficacy, cycle control, and side effects of low- and lower-dose oral contraceptives: a randomized trial of 20 micrograms and 35 micrograms estrogen preparations. Contraception 1999;60:321–9. [8] Rosenberg MJ, Waugh MS, Meehan TE. Use and misuse of oral contraceptives: risk indicators for poor pill taking and discontinuation. Contraception 1995;51:283–8.
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[9] ESHRE. Continuation rates for oral contraceptives and hormone replacement therapy. The ESHRE Capri Workshop Group. Hum Reprod 2000;15:1865–71. [10] Garrison L, Neumann P, Erickson P, MArshall D, Mullins C. Using real-world data for coverage and payment decisions: the ISPOR real-world data task force report. Value Health 2007; 10:326–35. [11] IHCIS National Managed Care Benchmark Database User Manual, 2005.