iPLEDGE Has Not Significantly Reduced Fetal Exposures to Isotretinoin
Despite the implementation of iPLEDGE and its stringent requirements, fetal exposure to isotretinoin has not significantly decreased, with approximately 150 isotretinoin-exposed pregnancies still occurring annually in the United States. 1
Evidence of Program Ineffectiveness
Direct Comparison Studies
The most rigorous evaluation of iPLEDGE compared to its predecessor program (SMART) found no significant reduction in fetal exposures:
In a managed care cohort of 8,344 females of childbearing potential, the rate of fetal exposure decreased only from 3.11 to 2.67 per 1,000 treatment courses after iPLEDGE implementation (P = 0.69), which was not statistically significant. 2
The hazard ratio for fetal exposures under iPLEDGE compared to SMART was 0.76 (95% CI 0.36-1.61), indicating no meaningful difference between the two programs. 2
FDA Adverse Event Data
Analysis of FDA reports from 1997-2017 reveals persistent pregnancy exposures despite iPLEDGE:
A total of 6,740 pregnancies among women taking isotretinoin were reported to the FDA over this 20-year period. 3
Pregnancy reports peaked in 2006 (768 pregnancies) at iPLEDGE initiation, then stabilized to 218-310 annual reports after 2011—still representing substantial ongoing fetal exposures. 3
The rate of pregnancy for females of childbearing potential ranged between 0.33% and 0.65%, with the peak occurring in 2006 when iPLEDGE was implemented. 3
Why iPLEDGE Fails
Patient Non-Compliance with Contraception
The fundamental problem is not pregnancy testing frequency but contraceptive failure and non-compliance:
Nearly one-third of all women of childbearing potential in a recent US study admitted noncompliance with iPLEDGE pregnancy prevention requirements. 1
Of sexually active women, 29% did not comply with the iPLEDGE requirement to use two contraceptive methods or abstain from sex. 1
Patient failure to use two contraceptive methods was the most common reason for fetal exposure, even when pregnancy testing was linked to every isotretinoin dispense. 4
Program Design Limitations
Stringent risk management programs like iPLEDGE may increase fear of teratogenic risks without translating into reduced pregnancy rates: 5
Linking negative pregnancy tests to isotretinoin dispensing did not reduce fetal exposures in controlled studies. 4
The rate of fetal exposure remained essentially unchanged (0.21% before vs 0.23% after) when mandatory pregnancy testing was implemented at Kaiser Permanente. 4
Evidence suggests that strenuous regulation alone, without effective contraceptive education and access, does not prevent pregnancies. 5
Clinical Implications
The Persistent Risk
All prescribers and patients must understand that approximately 150 isotretinoin-exposed pregnancies continue to occur annually in the United States despite iPLEDGE. 1 This represents a critical failure of the current system that prioritizes administrative burden over effective contraceptive counseling and access.
Contraceptive Education Over Administrative Requirements
The evidence clearly demonstrates that:
Programs must prioritize education about effective contraception while minimizing extraneous requirements to ensure women are not inadvertently undertreated for acne. 5
Shared decision-making in contraceptive counseling and education about long-acting reversible contraceptives (LARCs) should be emphasized. 6
Prescribers can utilize the reimbursed iPLEDGE contraceptive counseling sessions by referring patients to contraceptive specialists. 6
Potential Improvements
iPLEDGE should recognize variation in contraceptive efficacy—specifically, LARCs and permanent surgical sterilization should be exempt from monthly pregnancy testing and attestations given their superior effectiveness. 6 This would reduce administrative burden while focusing resources on patients using less reliable contraceptive methods.
Common Pitfalls
Assuming that more frequent pregnancy testing prevents pregnancies—the evidence shows it does not. 4
Believing iPLEDGE has solved the teratogenicity problem—150 annual exposures demonstrate ongoing failure. 1
Focusing on administrative compliance rather than effective contraceptive counseling—patient contraceptive non-compliance is the primary cause of fetal exposures. 1, 4
Undertreating severe acne due to iPLEDGE burdens—some physicians avoid prescribing isotretinoin entirely due to program requirements, potentially causing harm through inadequate treatment. 6