Abstract
Background
For persons of childbearing potential prescribed isotretinoin, the iPLEDGE program requires use of two simultaneous methods of contraception or commitment to abstinence.
Objective
To model the relative effectiveness of a variety of contraception strategies for patients taking isotretinoin including those that are acceptable according to iPLEDGE.
Methods
We performed a decision analysis modeling the estimated rate of pregnancy with various contraception strategies during a typical six-month course of isotretinoin.
Results
Tier 1 contraception options (e.g. subdermal hormonal implant, intrauterine devices) each had effectiveness of greater than 99.5% alone. When combined with a secondary form of contraception, Tier 2 contraception options (e.g. depot medroxyprogesterone injections, combined oral contraceptives) each had effectiveness greater than 99%.
Limitations
Sensitivity analyses were conducted to evaluate the impact of uncertain parameters on the results.
Conclusion
There may be opportunities to simplify iPLEDGE by recognizing the high effectiveness of Tier 1 contraception options and increasing use of secondary forms of contraception among those using Tier 2 contraception options as their primary form of contraception. Future studies are needed to understand the most effective strategies in clinical practice to prevent unintended pregnancy for patients taking isotretinoin to improve outcomes and provide patient-centered care.
Capsule Summary
• Effective contraception is essential during isotretinoin treatment and is required by iPLEDGE. Tier 1 contraceptives (e.g. intrauterine devices) alone and Tier 2 options (e.g. combined oral contraceptives) in combination with barrier methods each had estimated effectiveness of >99%.
• Tier 1 options are sufficient as monotherapy to prevent pregnancy while taking isotretinoin. Secondary forms of contraception should be emphasized among those using Tier 2 options.
Introduction
Isotretinoin is a highly effective treatment for acne that can reliably result in disease remission.1 However, it is also teratogenic, and retinoid embryopathy is a serious complication of systemic retinoid exposure during pregnancy.2 As a result of this teratogenicity, the Food and Drug Administration mandates that patients treated with isotretinoin enroll in the iPLEDGE pregnancy prevention program,3 which requires persons of childbearing potential either to use two methods of contraception simultaneously or to commit to continuous abstinence during the course of therapy.
For patients using two methods of contraception, iPLEDGE requires both a primary and secondary method. Acceptable forms of primary contraception include: the subdermal hormonal implant, permanent surgical contraception (i.e. vasectomy, tubal ligation, or salpingectomy), the hormonal or non-hormonal intrauterine device (IUD), the depot medroxyprogesterone (DMPA) injection, and the hormonal contraceptive pill, patch, or ring. Acceptable forms of secondary contraception include barrier methods (i.e. male latex condom, diaphragm, cervical cap) and the vaginal sponge. Progestin-only contraceptive pills, female condoms, fertility awareness-based methods, and withdrawal are unacceptable methods of contraception under the iPLEDGE program.
Given the potential differences in effectiveness of these contraception combinations, we undertook this study to model the relative effectiveness with typical use of different contraception strategies for patients being treated with isotretinoin.
Methods
Contraception identification
This study was conducted in accordance with the CHEERS statement.4 Contraception options were classified according to the framework outlined by the Centers for Disease Control and Prevention: Tier 1 includes the subdermal hormonal implant, permanent surgical contraception, and the hormonal and non-hormonal intrauterine device (IUD). Tier 2 includes the depot medroxyprogesterone (DMPA) injection, and the combined hormonal (including both estrogen and progestin hormones) contraceptive pill, patch, and ring. Tier 3 includes barrier methods and fertility awareness-based methods.5,6 Abstinence was included as an additional category, and typical use estimates were derived from previous literature on abstinence compliance among patients using isotretinoin.7
Effectiveness of contraceptive methods for pregnancy prevention
Rates of relative effectiveness with typical use were based on the iPLEDGE Prescriber Isotretinoin Educational Kit, which relies on United States population-based estimates of contraceptive effectiveness derived primarily from the National Survey of Family Growth.6,8 For barrier methods, the effectiveness of male condoms was used. We assumed that the effectiveness of each contraceptive method was independent. The relative effectiveness of each of these primary forms of contraception was modeled with potential secondary forms of contraception. Since the typical course of isotretinoin is approximately six months, rates of effectiveness with respect to prevention of unintended pregnancy are presented for a six-month treatment period (e.g. since the rate of failure of combined oral contraceptives with typical use is 9% annually, we used a failure rate of 4.5% for our model to reflect a typical six-month treatment period). In addition, we calculated the number needed to use a secondary form of contraception to prevent one additional unintended pregnancy compared to use of the primary form alone.
Effectiveness of abstinence for pregnancy prevention
Given that approximately 20% of individuals reporting abstinence for the iPLEDGE program are in fact sexually active while on the medication, we also modeled the effectiveness of abstinence.7 It has been estimated that adults in the United States 18–29 years-old and 30–39 years-old engage in sexual activity about 1.5 times per week.9 Due to the fact that rates of sexual activity among those taking isotretinoin may differ from the general population, we estimated the rate of unintended pregnancy among those choosing abstinence using four different frequencies of intercourse (twice per week, once per week, once per month, and once per year).10 Based on prior literature on fertility, the rate of pregnancy per act of unprotected intercourse was estimated to be 4.5%.11
In addition, since some patients who report abstinence and are sexually active may use contraception, we accounted for the possibility of this contraception use in our models and performed sensitivity analyses varying the percentage of patients who were sexually active and the percentage who were using contraception.7 For these sensitivity analyses, the percentage reporting abstinence who are sexually active and not using contraception was varied between 5% and 30%. The percentage who were sexually active and using contraception was varied between 10% and 30%. Since combined hormonal contraceptives and condoms are the most frequently chosen forms of contraception, the rate of pregnancy among those using contraception was based on the estimate for combined oral contraceptives and condoms from our primary analysis.7
Results
Without any secondary form of contraception, Tier 1 contraception options such as the subdermal hormonal implant (99.98%), the hormonal IUD (99.90%), and the non-hormonal IUD (99.60%) each had effectiveness of greater than 99.5% during the first six months of typical use. The effectiveness of most Tier 1 contraception options increased by less than 0.1% with the addition of a secondary form of contraception such as barrier methods. Without any secondary form of contraception, Tier 2 contraception options such as the DMPA injection (97.0%) and combined hormonal contraceptives (e.g. pill, patch, ring; 95.5%) each had a failure rate of 3% or greater during the first six months of typical use. However, adding a secondary form of contraception such as barrier methods increased the effectiveness to greater than 99% for DMPA injections (99.5%) and combined hormonal contraceptives (99.2%). Tier 3 options such as barrier methods (91.0%) and fertility awareness-based methods (88.0%) had low effectiveness alone (Table 1).
Table 1.
Contraceptive effectiveness during within first six months of (typical) use
| Secondary Forms | |||||
|---|---|---|---|---|---|
| Alone | COC, hormonal patch/ring | Barrier methods | Fertility awareness | ||
| Tier 1 | Subdermal hormonal implant | 99.975% | 99.998% | 99.996% | 99.994% |
| Permanent surgical contraception (i.e. vasectomy) | 99.925% | 99.993% | 99.987% | 99.982% | |
| Permanent surgical contraception (i.e. tubal ligation) | 99.750% | 99.978% | 99.955% | 99.940% | |
| Hormonal IUD | 99.900% | 99.991% | 99.982% | 99.976% | |
| Non-hormonal IUD | 99.600% | 99.964% | 99.928% | 99.904% | |
| Tier 2 | DMPA injection | 97.000% | - | 99.460% | 99.280% |
| Combined hormonal pill/patch/ring | 95.500% | - | 99.190% | 98.920% | |
| Tier 3 | Barrier methods (condoms, sponge, diaphragm) | 91.000% | 99.190% | - | 97.840% |
| Fertility awareness-based methods < | 88.000% | 98.920% | 97.840% | - | |
| Abstinence | Abstinence (twice weekly model) | 97.571% | - | - | - |
| Abstinence (weekly model) | 97.979% | - | - | - | |
| Abstinence (monthly model) | 99.201% | - | - | - | |
| Abstinence (yearly model) | 99.891% | - | - | - | |
Based on the increase in effectiveness with the addition of barrier methods to the primary forms of contraception, we estimated that 4,878, 1,220, 305, and 27 patients would need to use barrier methods to prevent one additional pregnancy for those using the subdermal implant, hormonal IUD, non-hormonal IUD, and combined hormonal contraceptives, respectively, over a 6-month period (Table 2).
Table 2.
Number needed to treat with secondary form to prevent one pregnancy during a typical six-month course of isotretinoin
| Secondary Forms | ||||
|---|---|---|---|---|
| Hormonal Patch/Pill/Ring | Barrier Methods (i.e. condoms) | Fertility awareness | ||
| Tier 1 | Subdermal hormonal implant | 4396 | 4878 | 5263 |
| Permanent surgical contraception (i.e. vasectomy) | 1465 | 1626 | 1754 | |
| Permanent surgical contraception (i.e. tubal ligation) | 440 | 488 | 526 | |
| Hormonal IUD | 1099 | 1220 | 1316 | |
| Non-hormonal IUD | 275 | 305 | 329 | |
| Tier 2 | DMPA injection | - | 41 | 44 |
| Combined hormonal pill/patch/ring | - | 27 | 29 | |
| Tier 3 | Barrier methods (condoms, sponge, diaphragm) | 12 | - | 15 |
| Fertility awareness-based methods | 9 | 10 | - | |
IUD: Intrauterine device; DMPA: depot medroxyprogesterone.
Among patients reporting abstinence, in our base case scenario the effectiveness of this approach during a typical six-month course of isotretinoin would be 95.0%, 95.4%, 97.8% and 99.7% with twice weekly, weekly, monthly, and yearly frequency of intercourse. This rate was entirely dependent on the percentage of those choosing abstinence who were sexually active (Table 3).
Table 3.
Estimated effectiveness of abstinence for pregnancy prevention during typical six-month course of isotretinoin
| Percentage Sexually Active (no contraception) | 5% | 10% | 20% | 30% | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Percentage Sexually Active (COCs and condoms) | 10% | 20% | 30% | 10% | 20% | 30% | 10% | 20% | 30% | 10% | 20% | 30% | |
| Frequency of intercourse | Twice weekly | 97.4% | 97.4% | 97.3% | 95.0% | 94.9% | 94.8% | 90.0% | 89.9% | 89.8% | 85.0% | 85.0% | 84.9% |
| Weekly | 97.6% | 97.6% | 97.5% | 95.4% | 95.3% | 95.2% | 90.8% | 90.8% | 90.7% | 86.3% | 86.2% | 86.1% | |
| Monthly | 98.9% | 98.8% | 98.7% | 97.8% | 97.7% | 97.6% | 95.7% | 95.6% | 95.5% | 93.6% | 93.5% | 93.4% | |
| Yearly | 99.8% | 99.7% | 99.6% | 99.7% | 99.6% | 99.5% | 99.5% | 99.4% | 99.3% | 99.2% | 99.2% | 99.1% | |
COCs: Combined oral contraceptives
Bolded values are base case scenario
Discussion
In this study, we identify variation in effectiveness for contraception strategies approved by iPLEDGE for reduction of fetal exposure to isotretinoin. Tier 1 contraception options, including long-acting reversible contraception such as the subdermal hormonal implant and IUDs, are more effective alone than other acceptable contraception options in combination. As a result, for patients using Tier 1 contraception for >30 days prior to initiation of isotretinoin, it may be reasonable to abandon the requirement for a secondary form of contraception and the 30-day waiting period. In addition, to reduce unnecessary burdens on patients and clinicians, it may not be necessary to have monthly pregnancy testing and iPLEDGE attestation for patients using Tier 1 contraception options, which typically require a clinical visit for removal or reversal.
Tier 2 contraception options such as combined oral contraceptives are expected to have similar effectiveness to Tier 1 options when combined with a secondary form of contraception such as barrier methods. The importance of using a secondary form of contraception in this population is highlighted by the fact that the number needed to use barrier methods to prevent one additional unintended pregnancy is only 27 for those using combined oral contraceptives. For patients choosing Tier 2 options, reinforcing consistent use of a secondary form of contraception may be particularly valuable to reduce the incidence of unintended pregnancy. In addition, given the effectiveness of Tier 2 options when used in combination with a secondary form of contraception (similar to that of Tier 1 options), iPLEDGE should continue to allow for use of Tier 2 options as acceptable forms of contraception to ensure flexibility with respect to patient preferences and autonomy.
Despite the implementation of iPLEDGE, fetal exposures to isotretinoin continue to occur.12,13 Emphasis on transparency and risk reduction around patients declaring abstinence is crucial. In addition, future research should evaluate patient perspectives regarding use of secondary forms of contraception, particularly among those using Tier 2 contraception options. Given the low cost and high effectiveness of combining secondary barrier methods with Tier 2 contraception options, approaches to ease access to barrier methods should be explored, including advance provision to patients being treated with isotretinoin. There also may be opportunities to better educate patients about the role of emergency contraception in the setting of contraception failure or unprotected intercourse.14 Finally, efforts should be made to identify the risks and benefits of advance provision of emergency contraception, particularly as some patients on isotretinoin may not have an established relationship with a gynecologist or feel comfortable obtaining over-the-counter emergency contraception on their own.10,15,16
The results of this study should be interpreted in the context of the study design. Although our models assumed that the effectiveness of each contraceptive method was independent, it is possible that adherence to the primary form of contraception may be correlated with adherence to the secondary form of contraception. In addition, given the contraception and pregnancy counseling associated with iPLEDGE, it is possible that rates of unintended pregnancy with typical use of contraception may be lower than in the general population. However, since this effect should be similar across all contraception options, the relative differences in contraception effectiveness would be expected to be unchanged. There is also uncertainty with respect to several important parameters of our models (i.e., percentage of those choosing abstinence who are sexually active, rate unprotected intercourse among those are sexually active). We have tried to account for this potential variation and uncertainty through several sensitivity analyses (Table 3).
This study highlights opportunities to improve iPLEDGE by recognizing the high effectiveness of Tier 1 contraception options and increasing use of secondary forms of contraception among those using Tier 2 contraception options as their primary form of contraception.17 Future studies are needed to understand the most effective strategies in clinical practice to prevent unintended pregnancy for patients taking isotretinoin to improve outcomes and provide patient-centered care.
Acknowledgments
Funding/Support: Dr. Barbieri is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award number T32-AR-007465 and receives partial salary support through a Pfizer Fellowship in Dermatology Patient Oriented Research grant to the Trustees of the University of Pennsylvania.
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Footnotes
Conflict of Interests Disclosures: Dr. Roe serves as a Nexplanon trainer for Merck and as a site principal investigator for an investigational contraceptive device developed by Sebela Pharmaceuticals. Dr. Mostaghimi receives consulting fees from Pfizer, hims, and 3derm. He has equity in Lucid and hims and receives licensing fees from Pfizer. He is on the medical advisory board for hims. He is a clinical trial investigator for Incyte, Lilly, Aclaris, and Concert. The authors have no other conflicts to declare.
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