- Email: [email protected]
Simplifying Contraception Requirements for iPLEDGE: A Decision Analysis
Journal Pre-proof Simplifying Contraception Requirements for iPLEDGE: A Decision Analysis John S. Barbieri, MD, MBA, Andrea H. Roe, MD, MPH, Arash Mostaghimi, MD, MPA, MPH PII:
S0190-9622(20)30230-9
DOI:
https://doi.org/10.1016/j.jaad.2020.02.022
Reference:
YMJD 14238
To appear in:
Journal of the American Academy of Dermatology
Received Date: 11 January 2020 Revised Date:
3 February 2020
Accepted Date: 5 February 2020
Please cite this article as: Barbieri JS, Roe AH, Mostaghimi A, Simplifying Contraception Requirements for iPLEDGE: A Decision Analysis, Journal of the American Academy of Dermatology (2020), doi: https://doi.org/10.1016/j.jaad.2020.02.022. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Simplifying Contraception Requirements for iPLEDGE: A Decision Analysis John S. Barbieri MD, MBA,1 Andrea H. Roe, MD, MPH,2 Arash Mostaghimi, MD, MPA, MPH3 1) Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 2) Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 3) Department of Dermatology, Brigham and Women’s Hospital, Boston, MA Corresponding author: John Barbieri PCAM 7 South Pavilion, 3400 Civic Center Blvd Philadelphia, PA 19104, USA Phone: 215-662-2737; Fax: 215-349-8839 Email: [email protected]
18
Word count: 1,641
19
Abstract: 196/200
20
Capsule summary: 50/50
21
Number of tables: 3
22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38
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. 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 T32AR-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.
1
39
ABSTRACT
40
Background: For persons of childbearing potential prescribed isotretinoin, the iPLEDGE
41
program requires use of two simultaneous methods of contraception or commitment to
42
abstinence.
43
Objective: To model the relative effectiveness of a variety of contraception strategies for
44
patients taking isotretinoin including those that are acceptable according to iPLEDGE.
45
Methods: We performed a decision analysis modeling the estimated rate of pregnancy with
46
various contraception strategies during a typical six-month course of isotretinoin.
47
Results: Tier 1 contraception options (e.g. subdermal hormonal implant, intrauterine devices)
48
each had effectiveness of greater than 99.5% alone. When combined with a secondary form of
49
contraception, Tier 2 contraception options (e.g. depot medroxyprogesterone injections,
50
combined oral contraceptives) each had effectiveness greater than 99%.
51
Limitations: Sensitivity analyses were conducted to evaluate the impact of uncertain parameters
52
on the results.
53
Conclusion: There may be opportunities to simplify iPLEDGE by recognizing the high
54
effectiveness of Tier 1 contraception options and increasing use of secondary forms of
55
contraception among those using Tier 2 contraception options as their primary form of
56
contraception. Future studies are needed to understand the most effective strategies in clinical
57
practice to prevent unintended pregnancy for patients taking isotretinoin to improve outcomes
58
and provide patient-centered care.
2
59 60
Capsule Summary •
Effective contraception is essential during isotretinoin treatment and is required by
61
iPLEDGE. Tier 1 contraceptives (e.g. intrauterine devices) alone and Tier 2 options (e.g.
62
combined oral contraceptives) in combination with barrier methods each had estimated
63
effectiveness of >99%.
64
•
Tier 1 options are sufficient as monotherapy to prevent pregnancy while taking
65
isotretinoin. Secondary forms of contraception should be emphasized among those using
66
Tier 2 options.
67 68
3
69 70
Introduction Isotretinoin is a highly effective treatment for acne that can reliably result in disease
71
remission.1 However, it is also teratogenic, and retinoid embryopathy is a serious complication of
72
systemic retinoid exposure during pregnancy.2 As a result of this teratogenicity, the Food and
73
Drug Administration mandates that patients treated with isotretinoin enroll in the iPLEDGE
74
pregnancy prevention program,3 which requires persons of childbearing potential either to use
75
two methods of contraception simultaneously or to commit to continuous abstinence during the
76
course of therapy.
77
For patients using two methods of contraception, iPLEDGE requires both a primary and
78
secondary method. Acceptable forms of primary contraception include: the subdermal hormonal
79
implant, permanent surgical contraception (i.e. vasectomy, tubal ligation, or salpingectomy), the
80
hormonal or non-hormonal intrauterine device (IUD), the depot medroxyprogesterone (DMPA)
81
injection, and the hormonal contraceptive pill, patch, or ring. Acceptable forms of secondary
82
contraception include barrier methods (i.e. male latex condom, diaphragm, cervical cap) and the
83
vaginal sponge. Progestin-only contraceptive pills, female condoms, fertility awareness-based
84
methods, and withdrawal are unacceptable methods of contraception under the iPLEDGE
85
program.
86
Given the potential differences in effectiveness of these contraception combinations, we
87
undertook this study to model the relative effectiveness with typical use of different
88
contraception strategies for patients being treated with isotretinoin.
89 90
4
91
Methods
92
Contraception identification
93
This study was conducted in accordance with the CHEERS statement.4 Contraception options
94
were classified according to the framework outlined by the Centers for Disease Control and
95
Prevention: Tier 1 includes the subdermal hormonal implant, permanent surgical contraception,
96
and the hormonal and non-hormonal intrauterine device (IUD). Tier 2 includes the depot
97
medroxyprogesterone (DMPA) injection, and the combined hormonal (including both estrogen
98
and progestin hormones) contraceptive pill, patch, and ring. Tier 3 includes barrier methods and
99
fertility awareness-based methods.5,6 Abstinence was included as an additional category, and
100
typical use estimates were derived from previous literature on abstinence compliance among
101
patients using isotretinoin.7
102
Effectiveness of contraceptive methods for pregnancy prevention.
103
Rates of relative effectiveness with typical use were based on the iPLEDGE Prescriber
104
Isotretinoin Educational Kit, which relies on United States population-based estimates of
105
contraceptive effectiveness derived primarily from the National Survey of Family Growth.6,8 For
106
barrier methods, the effectiveness of male condoms was used. We assumed that the effectiveness
107
of each contraceptive method was independent. The relative effectiveness of each of these
108
primary forms of contraception was modeled with potential secondary forms of contraception.
109
Since the typical course of isotretinoin is approximately six months, rates of effectiveness with
110
respect to prevention of unintended pregnancy are presented for a six-month treatment period
111
(e.g. since the rate of failure of combined oral contraceptives with typical use is 9% annually, we
112
used a failure rate of 4.5% for our model to reflect a typical six-month treatment period). In
5
113
addition, we calculated the number needed to use a secondary form of contraception to prevent
114
one additional unintended pregnancy compared to use of the primary form alone.
115
Effectiveness of abstinence for pregnancy prevention.
116
Given that approximately 20% of individuals reporting abstinence for the iPLEDGE program
117
are in fact sexually active while on the medication, we also modeled the effectiveness of
118
abstinence.7 It has been estimated that adults in the United States 18-29 years-old and 30-39
119
years-old engage in sexual activity about 1.5 times per week.9 Due to the fact that rates of sexual
120
activity among those taking isotretinoin may differ from the general population, we estimated the
121
rate of unintended pregnancy among those choosing abstinence using four different frequencies
122
of intercourse (twice per week, once per week, once per month, and once per year).10 Based on
123
prior literature on fertility, the rate of pregnancy per act of unprotected intercourse was estimated
124
to be 4.5%.11
125
In addition, since some patients who report abstinence and are sexually active may use
126
contraception, we accounted for the possibility of this contraception use in our models and
127
performed sensitivity analyses varying the percentage of patients who were sexually active and
128
the percentage who were using contraception.7 For these sensitivity analyses, the percentage
129
reporting abstinence who are sexually active and not using contraception was varied between 5%
130
and 30%. The percentage who were sexually active and using contraception was varied between
131
10% and 30%. Since combined hormonal contraceptives and condoms are the most frequently
132
chosen forms of contraception, the rate of pregnancy among those using contraception was based
133
on the estimate for combined oral contraceptives and condoms from our primary analysis.7
134 135
6
136 137
Results Without any secondary form of contraception, Tier 1 contraception options such as the
138
subdermal hormonal implant (99.98%), the hormonal IUD (99.90%), and the non-hormonal IUD
139
(99.60%) each had effectiveness of greater than 99.5% during the first six months of typical use.
140
The effectiveness of most Tier 1 contraception options increased by less than 0.1% with the
141
addition of a secondary form of contraception such as barrier methods. Without any secondary
142
form of contraception, Tier 2 contraception options such as the DMPA injection (97.0%) and
143
combined hormonal contraceptives (e.g. pill, patch, ring; 95.5%) each had a failure rate of 3% or
144
greater during the first six months of typical use. However, adding a secondary form of
145
contraception such as barrier methods increased the effectiveness to greater than 99% for DMPA
146
injections (99.5%) and combined hormonal contraceptives (99.2%). Tier 3 options such as
147
barrier methods (91.0%) and fertility awareness-based methods (88.0%) had low effectiveness
148
alone (Table 1).
149
Based on the increase in effectiveness with the addition of barrier methods to the primary
150
forms of contraception, we estimated that 4,878, 1,220, 305, and 27 patients would need to use
151
barrier methods to prevent one additional pregnancy for those using the subdermal implant,
152
hormonal IUD, non-hormonal IUD, and combined hormonal contraceptives, respectively, over a
153
6-month period (Table 2).
154
Among patients reporting abstinence, in our base case scenario the effectiveness of this
155
approach during a typical six-month course of isotretinoin would be 95.0%, 95.4%, 97.8% and
156
99.7% with twice weekly, weekly, monthly, and yearly frequency of intercourse. This rate was
157
entirely dependent on the percentage of those choosing abstinence who were sexually active
158
(Table 3).
7
159 160
Discussion In this study, we identify variation in effectiveness for contraception strategies approved by
161
iPLEDGE for reduction of fetal exposure to isotretinoin. Tier 1 contraception options, including
162
long-acting reversible contraception such as the subdermal hormonal implant and IUDs, are
163
more effective alone than other acceptable contraception options in combination. As a result, for
164
patients using Tier 1 contraception for >30 days prior to initiation of isotretinoin, it may be
165
reasonable to abandon the requirement for a secondary form of contraception and the 30-day
166
waiting period. In addition, to reduce unnecessary burdens on patients and clinicians, it may not
167
be necessary to have monthly pregnancy testing and iPLEDGE attestation for patients using Tier
168
1 contraception options, which typically require a clinical visit for removal or reversal.
169
Tier 2 contraception options such as combined oral contraceptives are expected to have
170
similar effectiveness to Tier 1 options when combined with a secondary form of contraception
171
such as barrier methods. The importance of using a secondary form of contraception in this
172
population is highlighted by the fact that the number needed to use barrier methods to prevent
173
one additional unintended pregnancy is only 27 for those using combined oral contraceptives.
174
For patients choosing Tier 2 options, reinforcing consistent use of a secondary form of
175
contraception may be particularly valuable to reduce the incidence of unintended pregnancy. In
176
addition, given the effectiveness of Tier 2 options when used in combination with a secondary
177
form of contraception (similar to that of Tier 1 options), iPLEDGE should continue to allow for
178
use of Tier 2 options as acceptable forms of contraception to ensure flexibility with respect to
179
patient preferences and autonomy.
180 181
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
8
182
crucial. In addition, future research should evaluate patient perspectives regarding use of
183
secondary forms of contraception, particularly among those using Tier 2 contraception options.
184
Given the low cost and high effectiveness of combining secondary barrier methods with Tier 2
185
contraception options, approaches to ease access to barrier methods should be explored,
186
including advance provision to patients being treated with isotretinoin. There also may be
187
opportunities to better educate patients about the role of emergency contraception in the setting
188
of contraception failure or unprotected intercourse.14 Finally, efforts should be made to identify
189
the risks and benefits of advance provision of emergency contraception, particularly as some
190
patients on isotretinoin may not have an established relationship with a gynecologist or feel
191
comfortable obtaining over-the-counter emergency contraception on their own.10,15,16
192
The results of this study should be interpreted in the context of the study design. Although
193
our models assumed that the effectiveness of each contraceptive method was independent, it is
194
possible that adherence to the primary form of contraception may be correlated with adherence to
195
the secondary form of contraception. In addition, given the contraception and pregnancy
196
counseling associated with iPLEDGE, it is possible that rates of unintended pregnancy with
197
typical use of contraception may be lower than in the general population. However, since this
198
effect should be similar across all contraception options, the relative differences in contraception
199
effectiveness would be expected to be unchanged. There is also uncertainty with respect to
200
several important parameters of our models (i.e., percentage of those choosing abstinence who
201
are sexually active, rate unprotected intercourse among those are sexually active). We have tried
202
to account for this potential variation and uncertainty through several sensitivity analyses (Table
203
3).
9
204
This study highlights opportunities to improve iPLEDGE by recognizing the high
205
effectiveness of Tier 1 contraception options and increasing use of secondary forms of
206
contraception among those using Tier 2 contraception options as their primary form of
207
contraception.17 Future studies are needed to understand the most effective strategies in clinical
208
practice to prevent unintended pregnancy for patients taking isotretinoin to improve outcomes
209
and provide patient-centered care.
210
10
211 212 213 214
References: 1.
Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74(5):945-973.e33.
215 216
2.
Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med. 1985;313(14):837-841.
217 218
3.
Prevost N, English JC. Isotretinoin: update on controversial issues. J Pediatr Adolesc Gynecol. 2013;26(5):290-293.
219 220
4.
Husereau D, Drummond M, Petrou S, et al. Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. BMJ. 2013;346:f1049. doi:10.1136/bmj.f1049
221 222 223
5.
Centers for Disease Control and Prevention. Contraception | Reproductive Health. https://www.cdc.gov/reproductivehealth/contraception/index.htm. Published August 7, 2019. Accessed August 28, 2019.
224
6.
Trussell J. Contraceptive failure in the United States. Contraception. 2011;83(5):397-404.
225 226
7.
Collins M-K, Moreau JF, Opel D, et al. Compliance with pregnancy prevention measures during isotretinoin therapy. J Am Acad Dermatol. 2014;70(1):55-59.
227 228 229
8.
Prescriber Isotretinoin Educational Kit. https://www.ipledgeprogram.com/iPledgeUI/rems/pdf/resources/Prescriber%20Isotretinoin %20Educational%20Kit.pdf. Accessed August 28, 2019.
230 231
9.
Twenge JM, Sherman RA, Wells BE. Declines in Sexual Frequency among American Adults, 1989-2014. Arch Sex Behav. 2017;46(8):2389-2401.
232 233 234 235
10. Foster DG, Raine TR, Brindis C, Rostovtseva DP, Darney PD. Should Providers Give Women Advance Provision of Emergency Contraceptive Pills? A Cost-Effectiveness Analysis. Womens Health Issues Off Publ Jacobs Inst Womens Health. 2010;20(4):242247.
236 237
11. Li D, Wilcox AJ, Dunson DB. Benchmark Pregnancy Rates and the Assessment of Postcoital Contraceptives: An Update. Contraception. 2015;91(4):344-349.
238 239 240
12. Tkachenko E, Singer S, Sharma P, Barbieri J, Mostaghimi A. US Food and Drug Administration Reports of Pregnancy and Pregnancy-Related Adverse Events Associated With Isotretinoin. JAMA Dermatol.
241 242 243
13. Shin J, Cheetham TC, Wong L, et al. The impact of the iPLEDGE program on isotretinoin fetal exposure in an integrated health care system. J Am Acad Dermatol. 2011;65(6):11171125.
244 245
14. Shen J, Che Y, Showell E, Chen K, Cheng L. Interventions for emergency contraception. Cochrane Database Syst Rev. 2017;8:CD001324. doi:10.1002/14651858.CD001324.pub5 11
246 247
15. Glasier A, Baird D. The effects of self-administering emergency contraception. N Engl J Med. 1998;339(1):1-4. doi:10.1056/NEJM199807023390101
248 249 250
16. Polis CB, Schaffer K, Blanchard K, Glasier A, Harper CC, Grimes DA. Advance provision of emergency contraception for pregnancy prevention (full review). Cochrane Database Syst Rev. 2007;(2):CD005497.
251 252 253
17. Barbieri JS, Frieden IJ, Nagler AR. Isotretinoin, Patient Safety, and Patient-Centered CareTime to Reform iPLEDGE. JAMA Dermatol. October 2019. doi:10.1001/jamadermatol.2019.3270
254
12
255 256
Table 1. Contraceptive effectiveness during within first six months of (typical) use
Abstinence Tier 3 Tier 2
Tier 1
Secondary Forms
Subdermal hormonal implant Permanent surgical contraception (i.e. vasectomy) Permanent surgical contraception (i.e. tubal ligation) Hormonal IUD Non-hormonal IUD DMPA injection Combined hormonal pill/patch/ring Barrier methods (condoms, sponge, diaphragm) Fertility awareness-based methods Abstinence (twice weekly model) Abstinence (weekly model) Abstinence (monthly model) Abstinence (yearly model)
Alone 99.975% 99.925% 99.750% 99.900% 99.600% 97.000% 95.500% 91.000% 88.000% 97.571% 97.979% 99.201% 99.891%
COC, hormonal patch/ring 99.998% 99.993% 99.978% 99.991% 99.964% 99.190% 98.920% -
Barrier methods 99.996% 99.987% 99.955% 99.982% 99.928% 99.460% 99.190% 97.840% -
Fertility awareness 99.994% 99.982% 99.940% 99.976% 99.904% 99.280% 98.920% 97.840% -
257 258
13
259 260
Table 2. Number needed to treat with secondary form to prevent one pregnancy during a typical six-month course of isotretinoin
Tier 3 Tier 2
Tier 1
Secondary Forms
261 262 263
Subdermal hormonal implant Permanent surgical contraception (i.e. vasectomy) Permanent surgical contraception (i.e. tubal ligation) Hormonal IUD Non-hormonal IUD DMPA injection Combined hormonal pill/patch/ring Barrier methods (condoms, sponge, diaphragm) Fertility awareness-based methods
Hormonal Patch/Pill/Ring 4396 1465
Barrier Methods (i.e. condoms) 4878 1626
440 1099 275
488 1220 305 41 27
12 9
Fertility awareness 5263 1754 526 1316 329 44 29 15
10
-
IUD: Intrauterine device; DMPA: depot medroxyprogesterone.
14
264 265
Table 3. Estimated effectiveness of abstinence for pregnancy prevention during typical six-month course of isotretinoin
Frequency of intercourse
Percentage Sexually Active (no contraception) Percentage Sexually Active (COCs and condoms)
266 267 268 269
10%
5% 20%
30%
10%
10% 20%
30%
10%
20% 20%
30%
10%
30% 20%
30%
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
15
S0190-9622(20)30230-9
DOI:
https://doi.org/10.1016/j.jaad.2020.02.022
Reference:
YMJD 14238
To appear in:
Journal of the American Academy of Dermatology
Received Date: 11 January 2020 Revised Date:
3 February 2020
Accepted Date: 5 February 2020
Please cite this article as: Barbieri JS, Roe AH, Mostaghimi A, Simplifying Contraception Requirements for iPLEDGE: A Decision Analysis, Journal of the American Academy of Dermatology (2020), doi: https://doi.org/10.1016/j.jaad.2020.02.022. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Simplifying Contraception Requirements for iPLEDGE: A Decision Analysis John S. Barbieri MD, MBA,1 Andrea H. Roe, MD, MPH,2 Arash Mostaghimi, MD, MPA, MPH3 1) Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 2) Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 3) Department of Dermatology, Brigham and Women’s Hospital, Boston, MA Corresponding author: John Barbieri PCAM 7 South Pavilion, 3400 Civic Center Blvd Philadelphia, PA 19104, USA Phone: 215-662-2737; Fax: 215-349-8839 Email: [email protected]
18
Word count: 1,641
19
Abstract: 196/200
20
Capsule summary: 50/50
21
Number of tables: 3
22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38
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. 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 T32AR-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.
1
39
ABSTRACT
40
Background: For persons of childbearing potential prescribed isotretinoin, the iPLEDGE
41
program requires use of two simultaneous methods of contraception or commitment to
42
abstinence.
43
Objective: To model the relative effectiveness of a variety of contraception strategies for
44
patients taking isotretinoin including those that are acceptable according to iPLEDGE.
45
Methods: We performed a decision analysis modeling the estimated rate of pregnancy with
46
various contraception strategies during a typical six-month course of isotretinoin.
47
Results: Tier 1 contraception options (e.g. subdermal hormonal implant, intrauterine devices)
48
each had effectiveness of greater than 99.5% alone. When combined with a secondary form of
49
contraception, Tier 2 contraception options (e.g. depot medroxyprogesterone injections,
50
combined oral contraceptives) each had effectiveness greater than 99%.
51
Limitations: Sensitivity analyses were conducted to evaluate the impact of uncertain parameters
52
on the results.
53
Conclusion: There may be opportunities to simplify iPLEDGE by recognizing the high
54
effectiveness of Tier 1 contraception options and increasing use of secondary forms of
55
contraception among those using Tier 2 contraception options as their primary form of
56
contraception. Future studies are needed to understand the most effective strategies in clinical
57
practice to prevent unintended pregnancy for patients taking isotretinoin to improve outcomes
58
and provide patient-centered care.
2
59 60
Capsule Summary •
Effective contraception is essential during isotretinoin treatment and is required by
61
iPLEDGE. Tier 1 contraceptives (e.g. intrauterine devices) alone and Tier 2 options (e.g.
62
combined oral contraceptives) in combination with barrier methods each had estimated
63
effectiveness of >99%.
64
•
Tier 1 options are sufficient as monotherapy to prevent pregnancy while taking
65
isotretinoin. Secondary forms of contraception should be emphasized among those using
66
Tier 2 options.
67 68
3
69 70
Introduction Isotretinoin is a highly effective treatment for acne that can reliably result in disease
71
remission.1 However, it is also teratogenic, and retinoid embryopathy is a serious complication of
72
systemic retinoid exposure during pregnancy.2 As a result of this teratogenicity, the Food and
73
Drug Administration mandates that patients treated with isotretinoin enroll in the iPLEDGE
74
pregnancy prevention program,3 which requires persons of childbearing potential either to use
75
two methods of contraception simultaneously or to commit to continuous abstinence during the
76
course of therapy.
77
For patients using two methods of contraception, iPLEDGE requires both a primary and
78
secondary method. Acceptable forms of primary contraception include: the subdermal hormonal
79
implant, permanent surgical contraception (i.e. vasectomy, tubal ligation, or salpingectomy), the
80
hormonal or non-hormonal intrauterine device (IUD), the depot medroxyprogesterone (DMPA)
81
injection, and the hormonal contraceptive pill, patch, or ring. Acceptable forms of secondary
82
contraception include barrier methods (i.e. male latex condom, diaphragm, cervical cap) and the
83
vaginal sponge. Progestin-only contraceptive pills, female condoms, fertility awareness-based
84
methods, and withdrawal are unacceptable methods of contraception under the iPLEDGE
85
program.
86
Given the potential differences in effectiveness of these contraception combinations, we
87
undertook this study to model the relative effectiveness with typical use of different
88
contraception strategies for patients being treated with isotretinoin.
89 90
4
91
Methods
92
Contraception identification
93
This study was conducted in accordance with the CHEERS statement.4 Contraception options
94
were classified according to the framework outlined by the Centers for Disease Control and
95
Prevention: Tier 1 includes the subdermal hormonal implant, permanent surgical contraception,
96
and the hormonal and non-hormonal intrauterine device (IUD). Tier 2 includes the depot
97
medroxyprogesterone (DMPA) injection, and the combined hormonal (including both estrogen
98
and progestin hormones) contraceptive pill, patch, and ring. Tier 3 includes barrier methods and
99
fertility awareness-based methods.5,6 Abstinence was included as an additional category, and
100
typical use estimates were derived from previous literature on abstinence compliance among
101
patients using isotretinoin.7
102
Effectiveness of contraceptive methods for pregnancy prevention.
103
Rates of relative effectiveness with typical use were based on the iPLEDGE Prescriber
104
Isotretinoin Educational Kit, which relies on United States population-based estimates of
105
contraceptive effectiveness derived primarily from the National Survey of Family Growth.6,8 For
106
barrier methods, the effectiveness of male condoms was used. We assumed that the effectiveness
107
of each contraceptive method was independent. The relative effectiveness of each of these
108
primary forms of contraception was modeled with potential secondary forms of contraception.
109
Since the typical course of isotretinoin is approximately six months, rates of effectiveness with
110
respect to prevention of unintended pregnancy are presented for a six-month treatment period
111
(e.g. since the rate of failure of combined oral contraceptives with typical use is 9% annually, we
112
used a failure rate of 4.5% for our model to reflect a typical six-month treatment period). In
5
113
addition, we calculated the number needed to use a secondary form of contraception to prevent
114
one additional unintended pregnancy compared to use of the primary form alone.
115
Effectiveness of abstinence for pregnancy prevention.
116
Given that approximately 20% of individuals reporting abstinence for the iPLEDGE program
117
are in fact sexually active while on the medication, we also modeled the effectiveness of
118
abstinence.7 It has been estimated that adults in the United States 18-29 years-old and 30-39
119
years-old engage in sexual activity about 1.5 times per week.9 Due to the fact that rates of sexual
120
activity among those taking isotretinoin may differ from the general population, we estimated the
121
rate of unintended pregnancy among those choosing abstinence using four different frequencies
122
of intercourse (twice per week, once per week, once per month, and once per year).10 Based on
123
prior literature on fertility, the rate of pregnancy per act of unprotected intercourse was estimated
124
to be 4.5%.11
125
In addition, since some patients who report abstinence and are sexually active may use
126
contraception, we accounted for the possibility of this contraception use in our models and
127
performed sensitivity analyses varying the percentage of patients who were sexually active and
128
the percentage who were using contraception.7 For these sensitivity analyses, the percentage
129
reporting abstinence who are sexually active and not using contraception was varied between 5%
130
and 30%. The percentage who were sexually active and using contraception was varied between
131
10% and 30%. Since combined hormonal contraceptives and condoms are the most frequently
132
chosen forms of contraception, the rate of pregnancy among those using contraception was based
133
on the estimate for combined oral contraceptives and condoms from our primary analysis.7
134 135
6
136 137
Results Without any secondary form of contraception, Tier 1 contraception options such as the
138
subdermal hormonal implant (99.98%), the hormonal IUD (99.90%), and the non-hormonal IUD
139
(99.60%) each had effectiveness of greater than 99.5% during the first six months of typical use.
140
The effectiveness of most Tier 1 contraception options increased by less than 0.1% with the
141
addition of a secondary form of contraception such as barrier methods. Without any secondary
142
form of contraception, Tier 2 contraception options such as the DMPA injection (97.0%) and
143
combined hormonal contraceptives (e.g. pill, patch, ring; 95.5%) each had a failure rate of 3% or
144
greater during the first six months of typical use. However, adding a secondary form of
145
contraception such as barrier methods increased the effectiveness to greater than 99% for DMPA
146
injections (99.5%) and combined hormonal contraceptives (99.2%). Tier 3 options such as
147
barrier methods (91.0%) and fertility awareness-based methods (88.0%) had low effectiveness
148
alone (Table 1).
149
Based on the increase in effectiveness with the addition of barrier methods to the primary
150
forms of contraception, we estimated that 4,878, 1,220, 305, and 27 patients would need to use
151
barrier methods to prevent one additional pregnancy for those using the subdermal implant,
152
hormonal IUD, non-hormonal IUD, and combined hormonal contraceptives, respectively, over a
153
6-month period (Table 2).
154
Among patients reporting abstinence, in our base case scenario the effectiveness of this
155
approach during a typical six-month course of isotretinoin would be 95.0%, 95.4%, 97.8% and
156
99.7% with twice weekly, weekly, monthly, and yearly frequency of intercourse. This rate was
157
entirely dependent on the percentage of those choosing abstinence who were sexually active
158
(Table 3).
7
159 160
Discussion In this study, we identify variation in effectiveness for contraception strategies approved by
161
iPLEDGE for reduction of fetal exposure to isotretinoin. Tier 1 contraception options, including
162
long-acting reversible contraception such as the subdermal hormonal implant and IUDs, are
163
more effective alone than other acceptable contraception options in combination. As a result, for
164
patients using Tier 1 contraception for >30 days prior to initiation of isotretinoin, it may be
165
reasonable to abandon the requirement for a secondary form of contraception and the 30-day
166
waiting period. In addition, to reduce unnecessary burdens on patients and clinicians, it may not
167
be necessary to have monthly pregnancy testing and iPLEDGE attestation for patients using Tier
168
1 contraception options, which typically require a clinical visit for removal or reversal.
169
Tier 2 contraception options such as combined oral contraceptives are expected to have
170
similar effectiveness to Tier 1 options when combined with a secondary form of contraception
171
such as barrier methods. The importance of using a secondary form of contraception in this
172
population is highlighted by the fact that the number needed to use barrier methods to prevent
173
one additional unintended pregnancy is only 27 for those using combined oral contraceptives.
174
For patients choosing Tier 2 options, reinforcing consistent use of a secondary form of
175
contraception may be particularly valuable to reduce the incidence of unintended pregnancy. In
176
addition, given the effectiveness of Tier 2 options when used in combination with a secondary
177
form of contraception (similar to that of Tier 1 options), iPLEDGE should continue to allow for
178
use of Tier 2 options as acceptable forms of contraception to ensure flexibility with respect to
179
patient preferences and autonomy.
180 181
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
8
182
crucial. In addition, future research should evaluate patient perspectives regarding use of
183
secondary forms of contraception, particularly among those using Tier 2 contraception options.
184
Given the low cost and high effectiveness of combining secondary barrier methods with Tier 2
185
contraception options, approaches to ease access to barrier methods should be explored,
186
including advance provision to patients being treated with isotretinoin. There also may be
187
opportunities to better educate patients about the role of emergency contraception in the setting
188
of contraception failure or unprotected intercourse.14 Finally, efforts should be made to identify
189
the risks and benefits of advance provision of emergency contraception, particularly as some
190
patients on isotretinoin may not have an established relationship with a gynecologist or feel
191
comfortable obtaining over-the-counter emergency contraception on their own.10,15,16
192
The results of this study should be interpreted in the context of the study design. Although
193
our models assumed that the effectiveness of each contraceptive method was independent, it is
194
possible that adherence to the primary form of contraception may be correlated with adherence to
195
the secondary form of contraception. In addition, given the contraception and pregnancy
196
counseling associated with iPLEDGE, it is possible that rates of unintended pregnancy with
197
typical use of contraception may be lower than in the general population. However, since this
198
effect should be similar across all contraception options, the relative differences in contraception
199
effectiveness would be expected to be unchanged. There is also uncertainty with respect to
200
several important parameters of our models (i.e., percentage of those choosing abstinence who
201
are sexually active, rate unprotected intercourse among those are sexually active). We have tried
202
to account for this potential variation and uncertainty through several sensitivity analyses (Table
203
3).
9
204
This study highlights opportunities to improve iPLEDGE by recognizing the high
205
effectiveness of Tier 1 contraception options and increasing use of secondary forms of
206
contraception among those using Tier 2 contraception options as their primary form of
207
contraception.17 Future studies are needed to understand the most effective strategies in clinical
208
practice to prevent unintended pregnancy for patients taking isotretinoin to improve outcomes
209
and provide patient-centered care.
210
10
211 212 213 214
References: 1.
Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74(5):945-973.e33.
215 216
2.
Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med. 1985;313(14):837-841.
217 218
3.
Prevost N, English JC. Isotretinoin: update on controversial issues. J Pediatr Adolesc Gynecol. 2013;26(5):290-293.
219 220
4.
Husereau D, Drummond M, Petrou S, et al. Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. BMJ. 2013;346:f1049. doi:10.1136/bmj.f1049
221 222 223
5.
Centers for Disease Control and Prevention. Contraception | Reproductive Health. https://www.cdc.gov/reproductivehealth/contraception/index.htm. Published August 7, 2019. Accessed August 28, 2019.
224
6.
Trussell J. Contraceptive failure in the United States. Contraception. 2011;83(5):397-404.
225 226
7.
Collins M-K, Moreau JF, Opel D, et al. Compliance with pregnancy prevention measures during isotretinoin therapy. J Am Acad Dermatol. 2014;70(1):55-59.
227 228 229
8.
Prescriber Isotretinoin Educational Kit. https://www.ipledgeprogram.com/iPledgeUI/rems/pdf/resources/Prescriber%20Isotretinoin %20Educational%20Kit.pdf. Accessed August 28, 2019.
230 231
9.
Twenge JM, Sherman RA, Wells BE. Declines in Sexual Frequency among American Adults, 1989-2014. Arch Sex Behav. 2017;46(8):2389-2401.
232 233 234 235
10. Foster DG, Raine TR, Brindis C, Rostovtseva DP, Darney PD. Should Providers Give Women Advance Provision of Emergency Contraceptive Pills? A Cost-Effectiveness Analysis. Womens Health Issues Off Publ Jacobs Inst Womens Health. 2010;20(4):242247.
236 237
11. Li D, Wilcox AJ, Dunson DB. Benchmark Pregnancy Rates and the Assessment of Postcoital Contraceptives: An Update. Contraception. 2015;91(4):344-349.
238 239 240
12. Tkachenko E, Singer S, Sharma P, Barbieri J, Mostaghimi A. US Food and Drug Administration Reports of Pregnancy and Pregnancy-Related Adverse Events Associated With Isotretinoin. JAMA Dermatol.
241 242 243
13. Shin J, Cheetham TC, Wong L, et al. The impact of the iPLEDGE program on isotretinoin fetal exposure in an integrated health care system. J Am Acad Dermatol. 2011;65(6):11171125.
244 245
14. Shen J, Che Y, Showell E, Chen K, Cheng L. Interventions for emergency contraception. Cochrane Database Syst Rev. 2017;8:CD001324. doi:10.1002/14651858.CD001324.pub5 11
246 247
15. Glasier A, Baird D. The effects of self-administering emergency contraception. N Engl J Med. 1998;339(1):1-4. doi:10.1056/NEJM199807023390101
248 249 250
16. Polis CB, Schaffer K, Blanchard K, Glasier A, Harper CC, Grimes DA. Advance provision of emergency contraception for pregnancy prevention (full review). Cochrane Database Syst Rev. 2007;(2):CD005497.
251 252 253
17. Barbieri JS, Frieden IJ, Nagler AR. Isotretinoin, Patient Safety, and Patient-Centered CareTime to Reform iPLEDGE. JAMA Dermatol. October 2019. doi:10.1001/jamadermatol.2019.3270
254
12
255 256
Table 1. Contraceptive effectiveness during within first six months of (typical) use
Abstinence Tier 3 Tier 2
Tier 1
Secondary Forms
Subdermal hormonal implant Permanent surgical contraception (i.e. vasectomy) Permanent surgical contraception (i.e. tubal ligation) Hormonal IUD Non-hormonal IUD DMPA injection Combined hormonal pill/patch/ring Barrier methods (condoms, sponge, diaphragm) Fertility awareness-based methods Abstinence (twice weekly model) Abstinence (weekly model) Abstinence (monthly model) Abstinence (yearly model)
Alone 99.975% 99.925% 99.750% 99.900% 99.600% 97.000% 95.500% 91.000% 88.000% 97.571% 97.979% 99.201% 99.891%
COC, hormonal patch/ring 99.998% 99.993% 99.978% 99.991% 99.964% 99.190% 98.920% -
Barrier methods 99.996% 99.987% 99.955% 99.982% 99.928% 99.460% 99.190% 97.840% -
Fertility awareness 99.994% 99.982% 99.940% 99.976% 99.904% 99.280% 98.920% 97.840% -
257 258
13
259 260
Table 2. Number needed to treat with secondary form to prevent one pregnancy during a typical six-month course of isotretinoin
Tier 3 Tier 2
Tier 1
Secondary Forms
261 262 263
Subdermal hormonal implant Permanent surgical contraception (i.e. vasectomy) Permanent surgical contraception (i.e. tubal ligation) Hormonal IUD Non-hormonal IUD DMPA injection Combined hormonal pill/patch/ring Barrier methods (condoms, sponge, diaphragm) Fertility awareness-based methods
Hormonal Patch/Pill/Ring 4396 1465
Barrier Methods (i.e. condoms) 4878 1626
440 1099 275
488 1220 305 41 27
12 9
Fertility awareness 5263 1754 526 1316 329 44 29 15
10
-
IUD: Intrauterine device; DMPA: depot medroxyprogesterone.
14
264 265
Table 3. Estimated effectiveness of abstinence for pregnancy prevention during typical six-month course of isotretinoin
Frequency of intercourse
Percentage Sexually Active (no contraception) Percentage Sexually Active (COCs and condoms)
266 267 268 269
10%
5% 20%
30%
10%
10% 20%
30%
10%
20% 20%
30%
10%
30% 20%
30%
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
15