Advertisement

Adherence among a cohort taking progestin-only pills prescribed by a healthcare provider: Results of the BENCHMARK study

Open AccessPublished:April 23, 2022DOI:https://doi.org/10.1016/j.contraception.2022.04.006

      Abstract

      Objectives

      To measure adherence over six months of progestin-only pill (POP) use.

      Study Design

      Prospective observational cohort study measuring adherence to daily dosing and timing of dose in patients prescribed a POP, with up to six months of follow-up, conducted from January to October 2020. A pharmacy benefit manager identified potential participants with a newly prescribed POP and extended an invitation to participate. We enrolled qualified respondents by telephone, trained them to use an electronic diary to report daily whether they had taken their POP and at what time. We followed participants for up to six months. We calculated adherence to daily pill taking as the proportion of evaluable days in which a participant took a POP, and the proportion of participants reporting ≥85% adherence. We calculated adherence to same time each day as the proportion of doses taken no later than three hours after the previous dose time of day.

      Results

      The user population comprised 199 participants, 154 (77.4%) of whom completed six months of follow-up. The majority (n = 170, 85.4%) were taking norethindrone. Norethindrone users reported POP intake on 22,327 (96.4%) of 23,156 evaluable days, with 155 (91.2%) participants reporting ≥85% adherence; less than half (n = 73, 42.9%) reported 100% adherence. Participants reported adherence to same time each day on 21,698 of 22,157 (97.9%) evaluable days.

      Conclusions

      Among participants taking a prescribed POP, participants demonstrated high adherence for daily pill taking and the same time of day, though the majority were not 100% adherent.

      Implications

      This study reports data specific to adherence among those taking a progestin-only pill (POP) in the prescription setting. Clinicians who counsel patients about POP use should be aware that majority of patients were not 100% adherent, although most report ≥85% adherence.

      Keywords

      1. Introduction

      Progestin-only pills (POPs) contain a low dose of progestogen which is taken daily without any hormone-free interval. Clinical guidance advises taking pills at the same time every day; a POP is considered late if taken more than three hours after it should have been. However, White et al. note that this is not based on firm evidence; no clinical data are available that correlate pregnancy rates with timeliness in taking POPs [
      • White K
      • Potter JE
      • Hopkins K
      • Fernández L
      • Amastae J
      • Grossman D.
      Contraindications to progestin-only oral contraceptive pills among reproductive-aged women.
      ,
      • Raymond EG.
      • et al.
      Progestin-only pills.
      ]. POPs prevent pregnancy through multiple potential mechanisms, including variable inhibition of ovulation and thickening of cervical mucus to render it relatively impenetrable to sperm [
      • McCann MF
      • Potter LS.
      Progestin-only oral contraception: a comprehensive review.
      ]. Two small pharmacokinetic studies undertaken among users taking d-norgestrel 30 mcg or norgestrel 75 mcg suggested that peak concentrations are reached about 2 hours after ingestion, and rapid distribution and elimination result in serum steroid levels near baseline after 24 hours [
      • Weiner E
      • Victor A
      • Johansson ED.
      Plasma levels of d-norgestrel after oral administration.
      ,
      • Brenner PF
      • Mishell DR
      • Stanczyk FZ
      • Goebelsmann U.
      Serum levels of d-norgestrel, luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone in women during and following ingestion of combination oral contraceptives containing dl-norgestrel.
      ]. Cervical mucus studies suggest that the effect of a POP on cervical mucus lasts 36 to 38 hours [
      • Chretien FC
      • Sureau C
      • Neau C.
      Experimental study of cervical blockage induced by continuous low-dose oral progestogens.
      ,
      • Lebech PE
      • Svendsen PA
      • Ostergaard E.
      The effects of small doses of megestrol acetate on the cervical mucus.
      ]. While there are no direct data that define the increased pregnancy risk associated with missing a dose or taking a pill late, the available data have been interpreted to mean that POPs are more sensitive to deviations from dosing instructions than combined oral contraceptives (COCs). If that is the case, then understanding adherence among POP users may support clinicians in providing optimal counseling and care.

      2. Materials and Methods

      We conducted a 24-week prospective observational cohort study entitled Baseline Evaluation of adhereNce among Consumers with Home Management of A Prescribed POP as Representative in Kind (BENCHMARK), to evaluate adherence to recommendations to take POPs every day, at the same time of day. The Sterling Institutional Review Board (Atlanta, GA) approved this study.

      2.1 Recruitment

      Two research companies (United Biosource Corporation, Blue Bell, PA and Healthcore, Wilmington, DE) with access to pharmacy benefits manager data (Express Scripts, St. Louis, MO and Humana Pharmacy Solutions, Lexington, KY) identified patients across the U.S. with a new prescription within the past two months for any POP available in the U.S., and no other within the past year. They sent invitations in four waves from January 16, 2020, to April 7, 2020, during which norethindrone and drospirenone were available by prescription only. Respondents either called in for telephone screening or completed an on-line questionnaire. We enrolled participants able to read, speak and understand English, assigned female at birth, aged 18 years or older, who had internet access and a smartphone or tablet, who did not work in healthcare, and who had started taking a POP within the previous two months.

      2.2 Study procedures

      In a standardized enrollment telephone interview, participants provided explicit verbal consent and reported brief medical history, current medication use, and demographic information. At the end of the enrollment interview we trained participants to use an app-based electronic diary (e-diary). We asked participants to record each day whether, on the day before, they had taken their POP and at what time, whether they had sexual intercourse, and whether they used any additional form(s) of contraception. When participants recorded that they missed a POP dose, the e-diary application prompted them to indicate from a list of options the reason(s) why. To avoid influencing adherence, we sent reminders to complete the e-diary every four days. The e-diary allowed participants to enter data up to 10 days in arrears and recorded the date and time of each entry.
      Trained nurse interviewers collected data via up to seven telephone interviews at weeks two, four, eight, 12, 16, 20, and 24 documenting if and when participants took the POP, any adverse events (AEs), concomitant medications, and other actions related to the use of the POP. To further assess the possible impact of missing diary entries, we inquired about POP use on the missing days during scheduled telephone interviews and collected clarifications to be analyzed separately. Participants could discontinue the POP at their discretion or in consultation with their provider, which we considered distinct from nonadherence to dosing directions. If a participant elected to discontinue use of the POP, we conducted the scheduled interview and end-of-study interview and ended their participation. At the end of the study, participants performed a self-administered urine pregnancy test. The first participant was enrolled on January 23, 2020, with enrollment continuing until April 13, 2020. The final participant concluded participation on October 29, 2020.

      2.3 Measures

      We defined “adherence evaluation days” as the days between each participant's first reported use of the POP through their discontinuation of the POP or study completion. We designated the primary measure of adherence as the proportion of adherence evaluation days where a diary report was available on which participants reported taking the POP. Additional analyses took into consideration whether participants took actions to mitigate pregnancy risk associated with missing a pill by using a barrier method of contraception or not having intercourse during the following 48 hours. We calculated adherence to daily use at the participant level as the proportion of participants who took their POP on at least 85% of their adherence evaluation days, representing no more than one missed pill per week on average, consistent with adherence to COCs under typical use conditions based on literature reports [
      • Hou MY
      • Hurwitz S
      • Kavanagh E
      • Fortin J
      • Goldberg AB.
      Using daily text-message reminders to improve adherence with oral contraceptives.
      ,
      • Potter L
      • Oakley D
      • de Leon-Wong E
      • Canamar R.
      Measuring compliance among oral contraceptive users.
      ,
      • Huber LRB
      • Broel EC
      • Mitchelides AN
      • Dmochowski J
      • Dulin M
      • Scholes D.
      Comparison of prospective daily diaries and retrospective recall to measure oral contraceptive adherence.
      ,
      • Oakley D
      • Sereika S
      • Bogue EL.
      Oral contraceptive pill use after an initial visit to a family planning clinic.
      ].
      We measured participants’ use of their POP at the same time of day among all adherence evaluation days in which participants reported a dosing time. We considered dosing within three hours after the immediately previous pill's dosing time as correct for “same-time” dosing.
      For all measures we calculated simple proportions with 95% confidence interval (Exact method), excluding missing data for the primary analyses. To assess the impact of missing data, we performed best-case and worst-case sensitivity analyses in which each day with missing diary data the POP was either assumed to have been taken (best-case) or not been taken (worst-case).
      We determined the target sample size of approximately 200 based on the number needed to obtain a margin of error of 5% at a proportion of 85% with a confidence level of 95%.

      3. Results

      3.1 Participant Characteristics

      We extended 8,830 invitations, to which 354 respondents initiated screening, of whom 146 (41.2%) did not qualify, most (n = 115, 78.8%) because they had started POP use more than 2 months prior. The study flow chart (Fig. 1) documents participant screening, disposition, and participation throughout the study. Of 203 enrollees, 199 (98.0%) reported use of their POP at least once (user population), of whom 85.4% (n = 170) were taking norethindrone and comprised the adherence analysis population. About two-thirds of all enrollees (n = 141, 69.5%; 70.9% of users) completed all follow-up assessments.
      Fig 1
      Fig. 1Study flow diagram: Prospective cohort study of pill adherence to progestin-only pills (POP) in the U.S. from January to October 2020
      [
      • White K
      • Potter JE
      • Hopkins K
      • Fernández L
      • Amastae J
      • Grossman D.
      Contraindications to progestin-only oral contraceptive pills among reproductive-aged women.
      ]
      Not necessarily unique individuals
      [
      • Raymond EG.
      • et al.
      Progestin-only pills.
      ]
      Participants who missed an interim interview allowed to continue
      [
      • McCann MF
      • Potter LS.
      Progestin-only oral contraception: a comprehensive review.
      ]
      End-of-study (EOS) interview conducted at the time of withdrawal if participant willing, data provided up to time of withdrawal included in analyses
      [
      • Weiner E
      • Victor A
      • Johansson ED.
      Plasma levels of d-norgestrel after oral administration.
      ]
      Data provided prior to loss to follow-up included in analyses
      [
      • Brenner PF
      • Mishell DR
      • Stanczyk FZ
      • Goebelsmann U.
      Serum levels of d-norgestrel, luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone in women during and following ingestion of combination oral contraceptives containing dl-norgestrel.
      ]
      End-of-study data collection done at end of participation, whenever that occurred.
      Table 1 presents characteristics of the user population. Table 2 outlines the distribution of health conditions of interest, many of which included possible contraindications to estrogen [
      • Curtis KM
      • Tepper NK
      • Jatlaoui TC
      • Berry-Bibee E
      • Horton LG
      • Zapata LB
      • et al.
      U.S. Medical eligibility criteria for contraceptive use, 2016.
      ]. Over three-quarters of participants reported at least one of the conditions of interest (n = 155, 77.9%); almost half (n = 92, 46.2%) reported current breastfeeding. Over a quarter (n = 54, 27.1%) reported having migraine headaches, more than half of whom (n = 33, 16.6%) reported migraine with aura. There were 59 participants (29.6%) with a contraindication for estrogen and 145 (72.9%) who were breastfeeding and/or had a contraindication for estrogen. Based on BMI, 52 (26.1%) were obese.
      Table 1Demographics of new users of progestin-only pills (POP)
      Progestin-only pill.
      participating in a prospective cohort study on pill adherence in the U.S. from January to October 2020
      User population
      (N = 199)
      Age category
       18–19 years9 (4.5%)
       20–30 years64 (32.2%)
       31–40 years97 (48.7%)
       41–50 years23 (11.6%)
       51 years or older6 (3.0%)
      Age (years)32 (18-53)
      Education Level
       Some high school2 (1.0%)
       High school graduate, GED, or certificate8 (4.0%)
       Some college or technical school35 (17.6%)
       College graduate109 (54.8%)
       Postgraduate degree45 (22.6%)
      Ethnicity
       Hispanic or Latino/Latina14 (7.0%)
       Not Hispanic or Latino/Latina185 (93.0%)
      Race
       Asian8 (4.0%)
       Black or African American21 (10.6%)
       White173 (86.9%)
       Other9 (4.5%)
      Estimated Household Income
       Less than $25,000 per year8 (4.0%)
       $25,001 - $50,00028 (14.1%)
       $50,001 - $75,00035 (17.6%)
       $75,001 - $100,00047 (23.6%)
       $100,001 - $150,00042 (21.1%)
       More than $150,00038 (19.1%)
       Don't know / Not sure1 (0.5%)
      Body Mass Index (kg/m2)
      BMI calculated from self-reported height and weight.
       <2595 (47.7%)
       25–29.952 (26.1%)
       30–34.931 (15.6%)
       ≥3521 (10.6%)
      Prior HBC
      Hormonal birth control.
      Experience
      History of any HBC use173 (86.9%)
       History of oral contraceptive use163 (81.9%)
       No history of oral contraceptive use10 (5.0%)
       No history of HBC use26 (13.1%)
      Current POP
      Progestin-only pill.
      type
       Norethindrone170 (85.4%)
       Drospirenone22 (11.1%)
       Other/Don't Know7 (3.5%)
      Geographic Region
       Northeast34 (17.1%)
       Southeast62 (31.2%)
       Midwest43 (21.6%)
       West35 (17.6%)
      Southwest25 (12.6%)
      a Progestin-only pill.
      b BMI calculated from self-reported height and weight.
      c Hormonal birth control.
      Table 2Health conditions of interest among new users of progestin-only pills participating in a prospective cohort study on pill adherence in the U.S. from January to October 2020
      All users
      (N = 199)
      Self-reported health conditions of interest
      Ever been diagnosed with cancer1 (0.5%)
      Liver problems1 (0.5%)
      High blood pressure20 (10.1%)
      Gallbladder disease0 (0.0%)
      High cholesterol7 (3.5%)
      Diabetes0 (0.0%)
      Migraines with aura33 (16.6%)
      Migraines without aura21 (10.6%)
      Blood clot history0 (0.0%)
      Heart disease2 (1.0%)
      History of heart attack or stroke0 (0.0%)
      Current smoker11 (5.5%)
      Currently breastfeeding92 (46.2%)
      Total Number of Participants Who Report Having at Least one of the Health Conditions of Interest155 (77.9%)
      Total Number of Participants Contraindicated for Use of an estrogen-containing contraceptive
      Participants who reported at least one of the following: migraine with aura, smokers age 35 and older, breast cancer, hypertension, heart disease, liver problems, or history of blood clots, stroke, or heart attack.
      59 (29.6%)
      Total Number of Participants Contraindicated for Use of an estrogen-containing contraceptive
      Participants who reported at least one of the following: migraine with aura, smokers age 35 and older, breast cancer, hypertension, heart disease, liver problems, or history of blood clots, stroke, or heart attack.
      and/or Breastfeeding
      145 (72.9%)
      a Participants who reported at least one of the following: migraine with aura, smokers age 35 and older, breast cancer, hypertension, heart disease, liver problems, or history of blood clots, stroke, or heart attack.
      While we did not design the study to evaluate efficacy, no pregnancies were reported.

      3.2 Adherence

      Among the user population, participants completed their e-diary entries within four days in 90% of instances (n = 24,979 of 27,552 evaluable e-diary entries); most (n = 20,837; 75.6%) reported on the first (n = 16,018; 58.1%) or second (n = 4,819; 17.5%) day. Participants taking norethindrone reported taking the POP on 22,327 (93.7%) of 23,838 adherence evaluation days; participants reported not taking the POP on 829 (3.5%) days and e-diary data were missing for 682 (2.9%) days, yielding 96.4% (95% CI 96.3–96.7, n = 22,327 of 23,156) adherence to daily dosing. Sensitivity analyses showed worst-case adherence to be 93.7% (95% CI 93.3–94.0; n = 22,327 of 23,838) and best-case adherence to be 96.5% (95% CI 96.3–96.8; n = 23,009 of 23,838). Among 368 missing days that we were able to clarify during telephone interviews, participants reported having taken their POP on most such days (n = 350, 95.1%). Some missing days were not clarified because of missing interim interviews or time elapsed since the missing entry.
      For the 829 days without POP intake, 189 (22.8%) participants reported having sex at least once that day or the following two days without using a barrier method, 71 (8.6%) reported sex with a barrier method, and 550 (66.3%) reported no sex.
      When evaluated by participant, 155 (91.2%, 95% CI 85.9–95.0) were adherent to daily use of their POP on at least 85% of adherence evaluation days. Sensitivity analyses for missing days yielded estimates of 87.1% (95% CI 81.1–91.7; n = 148 of 170) under worst-case assumptions, and 91.8% (95% CI 86.6–95.4; n = 156 of 170) under best-case assumptions. As shown in Fig. 2, individual adherence ranged from 58.9% to 100%, with less than half (n = 73, 42.9%) reporting 100% adherence.
      Fig 2
      Fig. 2Participant level adherence among new users of progestin-only pills participating in a prospective cohort study on pill adherence in the U.S. from January to October 2020.
      Of the 22,157 (92.9%) adherence evaluation days evaluable for time of dose, reported dosing was no more than three hours after the time of day of the previous dose on 21,698 (97.9%, 95% CI 97.7–98.1) days, with 20,695 (93.4%, 95% CI 93.1-93.7) within no more than one hour.
      We performed adherence analyses for participants taking drospirenone (n = 22, 11.1%) and for those taking an unknown POP (n = 7, 3.5%) and observed no clinically meaningful differences in adherence (data not shown).
      Among 959 missed doses for the entire user population, the most common reason selected was “Forgot” (n = 635, 66.2%). Reasons related to access to pills were common: “Ran out of pills – but plan to continue” was cited for 116 (12.1%) missed doses, and “Didn't have pills with me” for 68 (7.1%). “Other reason” (no further information) was cited for 127 (13.2%).

      4. Discussion

      This study provides data on adherence to daily pill taking and timeliness of dosing among people taking a prescribed POP. Adherence with all types of daily medication is far from perfect, especially for preventive medications including oral contraceptives (OC) [
      • Hou MY
      • Hurwitz S
      • Kavanagh E
      • Fortin J
      • Goldberg AB.
      Using daily text-message reminders to improve adherence with oral contraceptives.
      ,
      • Potter L
      • Oakley D
      • de Leon-Wong E
      • Canamar R.
      Measuring compliance among oral contraceptive users.
      ,
      • Durand H
      • Hayes P
      • Morrissey EC
      • Newell J
      • Casey M
      • Murphy AW
      • et al.
      Medication adherence among patients with apparent treatment-resistant hypertension.
      ,
      • Fox MC
      • Creinin MD
      • Murthy AS
      • Harwood B
      • Reid LM.
      Feasibility study of the use of a daily electronic mail reminder to improve oral contraceptive compliance.
      ]. Published data on adherence to COCs from studies with a range of methodologies suggests that most users are not fully adherent to daily dosing and that there is significant variability in adherence behaviors between users and between cycles within the same users [
      • Hou MY
      • Hurwitz S
      • Kavanagh E
      • Fortin J
      • Goldberg AB.
      Using daily text-message reminders to improve adherence with oral contraceptives.
      ,
      • Potter L
      • Oakley D
      • de Leon-Wong E
      • Canamar R.
      Measuring compliance among oral contraceptive users.
      ,
      • Huber LRB
      • Broel EC
      • Mitchelides AN
      • Dmochowski J
      • Dulin M
      • Scholes D.
      Comparison of prospective daily diaries and retrospective recall to measure oral contraceptive adherence.
      ,
      • Oakley D
      • Sereika S
      • Bogue EL.
      Oral contraceptive pill use after an initial visit to a family planning clinic.
      ,
      • Fox MC
      • Creinin MD
      • Murthy AS
      • Harwood B
      • Reid LM.
      Feasibility study of the use of a daily electronic mail reminder to improve oral contraceptive compliance.
      ,
      • Woods JL
      • Shew ML
      • Tu W
      • Ofner S
      • Ott MA
      • Fortenberry JD.
      Patterns of oral contraceptive pill-taking and condom use among adolescent contraceptive pill users.
      ,
      • Hughey AB
      • Neustadt AB
      • Mistretta SQ
      • Tilmon SJ
      • Gilliam ML.
      Daily context matters: predictors of missed oral contraceptive pills among college and graduate students.
      ,
      • Aubeny E
      • Buhler M
      • Colau JC
      • Vicaut E
      • Zadikian M
      • Childs M.
      The Coraliance study: non-compliant behavior. Results after a 6-month follow-up of patients on oral contraceptives.
      ,
      • Wiegratz I
      • Elliesen J
      • Paoletti AM
      • Walzer A
      • Kirsch B.
      Adherence with ethinylestradiol 20 μg/drospirenone 3 mg in a flexible extended regimen supported by the use of a digital tablet dispenser with or without acoustic alarm: an open-label, randomized, multicenter study.
      ]. Two adherence studies for COC users with daily diaries, each with 3 months of participation, demonstrated that up to 18% of users reported missing three or more active pills per cycle [
      • Potter L
      • Oakley D
      • de Leon-Wong E
      • Canamar R.
      Measuring compliance among oral contraceptive users.
      ,
      • Fox MC
      • Creinin MD
      • Murthy AS
      • Harwood B
      • Reid LM.
      Feasibility study of the use of a daily electronic mail reminder to improve oral contraceptive compliance.
      ].
      We found that POP users are generally adherent to daily pill taking, though as with COC users, they do sometimes miss taking their pills. There is inter- and intra-participant variability in adherence behavior. The participant-level analysis demonstrates that while most participants reported high levels of adherence, the range in overall adherence level is wide.
      The potential outcome of nonadherence is pregnancy. No study has directly quantified pregnancy risk or occurrence after one or more missed POPs, and while it is presumed that an extended period of nonadherence is likely to increase pregnancy risk, there are no data to suggest how episodic nonadherence relates to pregnancy risk.
      According to prescribing information, norgestrel should be taken at the same time each day, within a three-hour window. The literature on OC adherence suggests that adherence to “same time” directions is limited. In two studies evaluating dose timing in COC users, the majority of pills were not taken within two hours of the time of day of the previous dose [
      • Oakley D
      • Sereika S
      • Bogue EL.
      Oral contraceptive pill use after an initial visit to a family planning clinic.
      ,
      • Wiegratz I
      • Elliesen J
      • Paoletti AM
      • Walzer A
      • Kirsch B.
      Adherence with ethinylestradiol 20 μg/drospirenone 3 mg in a flexible extended regimen supported by the use of a digital tablet dispenser with or without acoustic alarm: an open-label, randomized, multicenter study.
      ]. Participants in our study reported a high degree of adherence to the recommendation to take the pill at the same time each day, doing so on 97.9% of evaluable days. The expected impact of departures from “same-time” directions on pregnancy risk in POP users is difficult to evaluate, especially as the three-hour window recommendation is based on limited pharmacokinetic data [
      • Weiner E
      • Victor A
      • Johansson ED.
      Plasma levels of d-norgestrel after oral administration.
      ,
      • Brenner PF
      • Mishell DR
      • Stanczyk FZ
      • Goebelsmann U.
      Serum levels of d-norgestrel, luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone in women during and following ingestion of combination oral contraceptives containing dl-norgestrel.
      ].
      There is considerable interest and support from the medical community in expanding access to oral contraceptives by making them available over-the-counter [

      OCs OTC Working Group. Statement of Purpose 2016. https://ocsotc.org/statement-of-purpose/(accessed February 1, 2022).

      ,
      Over-the-Counter Access to Hormonal Contraception: ACOG Committee Opinion, Number 788.
      ]. The favorable safety profile of POPs make them prime candidates for a first over-the-counter oral contraceptive in the U.S.[

      OCs OTC Working Group. Statement of Purpose 2016. https://ocsotc.org/statement-of-purpose/(accessed February 1, 2022).

      ,

      OCs OTC Working Group. Over-the-counter birth control: background on progestin-only pills n.d. https://ocsotc.org/wp-content/uploads/2016/09/Increasing-OC-access-with-the-POP_9-16-2016-FINAL.pdf (accessed February 1, 2022).

      ]. We found that some nonadherence was attributable to limitations in access to the medication; in one out of five instances of nonadherence, participants reported that they had run out of pills but planned to continue, or that they did not have their pill with them. Over-the-counter access to an oral contraceptive would reduce such barriers. Participants in our study may have been given directions on daily same-time dosing. Of course, carrying out those directions still rests with the user. Review of available studies suggests that provider counseling may not improve adherence [
      • Mack N
      • Crawford TJ
      • Guise J-M
      • Chen M
      • Grey TW
      • Feldblum PJ
      • et al.
      Strategies to improve adherence and continuation of shorter-term hormonal methods of contraception.
      ].
      Strengths of this study include a sample comprising patients who were prescribed a POP in the context of a natural interaction with a healthcare provider. We collected adherence data prospectively using a daily electronic diary on the participants’ own devices. Contemporaneous reporting of sexual activity and any use of additional methods of contraception inform pregnancy risk associated with missing doses. We collected up to 24 weeks of daily use data from participants. Missing data were minimal, and sensitivity analyses outline best- and worst-case adherence measures, and diary clarification efforts provided context for understanding missing diary entries. The large number of adherence evaluation days allows for a relatively precise estimate of overall adherence.
      Our study was limited by omission of uninsured participants. While we did not collect data on the nature of insurance coverage, the pharmacy benefits managers we used included both private and public plans. The number of participants taking drospirenone, a newer POP, is small. While the dosing instructions for drospirenone advise users to take it at the same time every day, they do not include the three-hour window instruction. We began collecting data up to two months into use, which may bias overall measures of adherence by either missing the adherence in the first weeks of use, or by omitting those who stopped use within two months. Study measurement procedures may have influenced participants’ adherence.
      Sample characteristics may limit generalizability to contraception-seeking women in general. Our sample was older and more educated than the general population of oral contraceptive users in the U.S.[
      • Emans SJ
      • Grace E
      • Woods ER
      • Smith DE
      • Klein K
      • Merola J.
      Adolescents’ compliance with the use of oral contraceptives.
      ] In the US, POPs are typically used in those who are breastfeeding or who have a medical contraindication to estrogen, which may also be influenced by age. Oral contraceptive users that are older, have more years of education, higher levels of health literacy, and/or better socioeconomic status have comparatively greater odds of adherence and oral contraceptive continuation, so this study may represent a best-case sample for adherence, and over-estimate adherence for a more general population of OC users [
      • Emans SJ
      • Grace E
      • Woods ER
      • Smith DE
      • Klein K
      • Merola J.
      Adolescents’ compliance with the use of oral contraceptives.
      ,
      • Rosenberg MJ
      • Burnhill MS
      • Waugh MS
      • Grimes DA
      • Hillard PJA.
      Compliance and oral contraceptives: a review.
      ,
      • Hall KS
      • Castaño PM
      • Westhoff CL.
      The influence of oral contraceptive knowledge on oral contraceptive continuation among young women.
      ,
      • Liddelow C
      • Mullan B
      • Boyes M.
      Adherence to the oral contraceptive pill: the roles of health literacy and knowledge.
      ]. Nearly half of the study participants reported breastfeeding, with another quarter reporting a history of migraine headaches. This contrasts with the expected characteristics of a general oral contraceptive user population, which might be expected to be younger and healthier, with a much smaller proportion of those who are recently postpartum.
      In summary, participants were largely adherent to daily pill taking, though missed pills were not uncommon. They were also highly adherent to the recommendation to take the product at the same time every day.

      Acknowledgments

      The authors would like to offer a very special thanks to all those participants who agreed to enroll in this study, sharing with us their personal experiences and contributing to our collective understanding of how POPs are used. We also thank all of those at PEGUS Research, Pinney Associates and HRA Pharma who contributed to the conduct of this study and this manuscript. We especially appreciate Lucy Owen's skilled editorial review.

      References

        • White K
        • Potter JE
        • Hopkins K
        • Fernández L
        • Amastae J
        • Grossman D.
        Contraindications to progestin-only oral contraceptive pills among reproductive-aged women.
        Contraception. 2012; 86: 199-203https://doi.org/10.1016/J.CONTRACEPTION.2012.01.008
        • Raymond EG.
        • et al.
        Progestin-only pills.
        (editor)in: Hatcher RA Trussell J Nelson AL Contracept Technol. 20th ed. Ardent Media, Inc, New York2011: 237-247
        • McCann MF
        • Potter LS.
        Progestin-only oral contraception: a comprehensive review.
        Contraception. 1994; 50: S13-S21https://doi.org/10.1016/0010-7824(94)90114-7
        • Weiner E
        • Victor A
        • Johansson ED.
        Plasma levels of d-norgestrel after oral administration.
        Contraception. 1976; 14: 563-570https://doi.org/10.1016/0010-7824(76)90007-x
        • Brenner PF
        • Mishell DR
        • Stanczyk FZ
        • Goebelsmann U.
        Serum levels of d-norgestrel, luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone in women during and following ingestion of combination oral contraceptives containing dl-norgestrel.
        Am J Obstet Gynecol. 1977; 129: 133-140https://doi.org/10.1016/0002-9378(77)90733-5
        • Chretien FC
        • Sureau C
        • Neau C.
        Experimental study of cervical blockage induced by continuous low-dose oral progestogens.
        Contraception. 1980; 22: 445-456https://doi.org/10.1016/0010-7824(80)90098-0
        • Lebech PE
        • Svendsen PA
        • Ostergaard E.
        The effects of small doses of megestrol acetate on the cervical mucus.
        Int J Fertil. 1970; 15: 65-76
        • Hou MY
        • Hurwitz S
        • Kavanagh E
        • Fortin J
        • Goldberg AB.
        Using daily text-message reminders to improve adherence with oral contraceptives.
        Obstetrics & Gynecology. 2010; 116: 633-640https://doi.org/10.1097/AOG.0b013e3181eb6b0f
        • Potter L
        • Oakley D
        • de Leon-Wong E
        • Canamar R.
        Measuring compliance among oral contraceptive users.
        Family Planning Perspectives. 1996; 28: 154-158https://doi.org/10.2307/2136191
        • Huber LRB
        • 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
        • Oakley D
        • Sereika S
        • Bogue EL.
        Oral contraceptive pill use after an initial visit to a family planning clinic.
        Family Plann Perspect. 1991; 23: 150-154https://doi.org/10.2307/2135737
        • Curtis KM
        • Tepper NK
        • Jatlaoui TC
        • Berry-Bibee E
        • Horton LG
        • Zapata LB
        • et al.
        U.S. Medical eligibility criteria for contraceptive use, 2016.
        MMWR Recommend Rep. 2016; 65: 1-103https://doi.org/10.15585/mmwr.rr6503a1
        • Durand H
        • Hayes P
        • Morrissey EC
        • Newell J
        • Casey M
        • Murphy AW
        • et al.
        Medication adherence among patients with apparent treatment-resistant hypertension.
        J Hypertension. 2017; 35: 2346-2357https://doi.org/10.1097/hjh.0000000000001502
        • Fox MC
        • Creinin MD
        • Murthy AS
        • Harwood B
        • Reid LM.
        Feasibility study of the use of a daily electronic mail reminder to improve oral contraceptive compliance.
        Contraception. 2003; 68: 365-371https://doi.org/10.1016/j.contraception.2003.08.013
        • Woods JL
        • Shew ML
        • Tu W
        • Ofner S
        • Ott MA
        • Fortenberry JD.
        Patterns of oral contraceptive pill-taking and condom use among adolescent contraceptive pill users.
        J Adolescent Health. 2006; 39: 381-387https://doi.org/10.1016/j.jadohealth.2005.12.014
        • Hughey AB
        • Neustadt AB
        • Mistretta SQ
        • Tilmon SJ
        • Gilliam ML.
        Daily context matters: predictors of missed oral contraceptive pills among college and graduate students.
        Am J Obstetr Gynecol. 2010; 203: 323.e1-323.e7https://doi.org/10.1016/j.ajog.2010.05.039
        • Aubeny E
        • Buhler M
        • Colau JC
        • Vicaut E
        • Zadikian M
        • Childs M.
        The Coraliance study: non-compliant behavior. Results after a 6-month follow-up of patients on oral contraceptives.
        Eur J Contraception Reprod Health Care. 2004; 9: 267-277https://doi.org/10.1080/13625180400017776
        • Wiegratz I
        • Elliesen J
        • Paoletti AM
        • Walzer A
        • Kirsch B.
        Adherence with ethinylestradiol 20 μg/drospirenone 3 mg in a flexible extended regimen supported by the use of a digital tablet dispenser with or without acoustic alarm: an open-label, randomized, multicenter study.
        Int J Womens Health. 2015; 7: 19-29https://doi.org/10.2147/IJWH.S71906
      1. OCs OTC Working Group. Statement of Purpose 2016. https://ocsotc.org/statement-of-purpose/(accessed February 1, 2022).

      2. Over-the-Counter Access to Hormonal Contraception: ACOG Committee Opinion, Number 788.
        Obstet Gynecol. 2019; 134: E96-105https://doi.org/10.1097/AOG.0000000000003473
      3. OCs OTC Working Group. Over-the-counter birth control: background on progestin-only pills n.d. https://ocsotc.org/wp-content/uploads/2016/09/Increasing-OC-access-with-the-POP_9-16-2016-FINAL.pdf (accessed February 1, 2022).

        • Mack N
        • Crawford TJ
        • Guise J-M
        • Chen M
        • Grey TW
        • Feldblum PJ
        • et al.
        Strategies to improve adherence and continuation of shorter-term hormonal methods of contraception.
        Cochrane Database Systematic Rev. 2019; 2019https://doi.org/10.1002/14651858.CD004317.pub5
        • Emans SJ
        • Grace E
        • Woods ER
        • Smith DE
        • Klein K
        • Merola J.
        Adolescents’ compliance with the use of oral contraceptives.
        JAMA. 1987; 257: 3377-3381https://doi.org/10.1001/jama.1987.03390240083028
        • Rosenberg MJ
        • Burnhill MS
        • Waugh MS
        • Grimes DA
        • Hillard PJA.
        Compliance and oral contraceptives: a review.
        Contraception. 1995; 52: 137-141https://doi.org/10.1016/0010-7824(95)00161-3
        • Hall KS
        • Castaño PM
        • Westhoff CL.
        The influence of oral contraceptive knowledge on oral contraceptive continuation among young women.
        J Women's Health. 2014; 23: 596-601https://doi.org/10.1089/jwh.2013.4574
        • Liddelow C
        • Mullan B
        • Boyes M.
        Adherence to the oral contraceptive pill: the roles of health literacy and knowledge.
        Health Psychol Behav Med. 2020; 8: 587-600https://doi.org/10.1080/21642850.2020.1850288