iPLEDGE Allegiance to the Pill: Evaluation of Year 1 of a Birth Defect Prevention and Monitoring System

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Thalidomide has been reintroduced to the market as a chemotherapeutic agent, but retains its Category X standing. This demonstrates that the categorization is not simply an incremental list of risks; instead it is a weighing of both risks to the fetus and benefit to the mother. Doering P. L. Boothby L. A. Cheok M. , “Review of Pregnancy Labeling of Prescription Drugs: Is the Current System Adequate to Inform of Risks?” American Journal of Obstetrics and Gynecology 187, no. 2 (2002): 333–339.

Food and Drug Administration, Briefing Document for iPLEDGE Year One Update , United States Department of Health and Human Services, available at <http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007–4311b1–02-ipledge.pdf> (last visited December 16, 2008).

According to reports, greater than 35% of fetuses exposed to isotretinoin will have some measure of “isotretinoin embryopathy.” Of those fetuses that are affected, approximately 70% will have significant ear abnormalities, 25% will have jaw abnormalities, 10% will have cleft palate, 40% will have heart defects, 30% will have thymic defects, and 20% will have eye abnormalities. In addition, central nervous system deficiencies are common (∼80% of affected cases), which may lead to poor cognitive performance and learning disabilities, even in those children who have no other structural defects. Finally, the risk of miscarriage or stillbirth is 40% in women taking isotretinoin, and the risk for delivering a baby prematurely is doubled in isotretinoin-exposed pregnancies. Robertson J. Polifka J. D. Avner M. Chambers C. Delevan G. Koren G. Lavigne D. V. Martinez L. P. Miller R. K. Carey J. C. , “A Survey of Pregnant Women Using Isotretinoin,” Birth Defects Research (Part A) 73 (2005): 881–887.

See FDA, supra note 4, at 5.

Abroms L. Maibach E. Lyon-Daniel K. Feldman S. R. , “What Is the Best Approach to Reducing Birth Defects Associated with Isotretinoin?” PLoS Medicine 3, no. 11 (2006): 1978–1983, at 1979.

Ellison R. H. Leach E. E. , “Isotretinoin and Pregnancy,” JAMA 285, no. 16 (April 25, 2001): 2080–2081.

Brinker A. Kornegay C. Nourjah P. , “Trends in Adherence to a Revised Risk Management Program Designed to Decrease or Eliminate Isotretinoin-Exposed Pregnancies: Evaluation of the Accutane SMART program,” Archives of Dermatology 141, no. 5 (May 2005): 563–569.

Id., at 564.

Honein M. A. Moore C. A. Erickson J. D. , “Can We Ensure the Safe Use of Known Human Teratogens? Introduction of Generic Isotretinoin in the US as an Example,” Drug Safety 27, no. 14 (2004): 1069–1080, at 1075.

Id., at 1078.

See FDA, supra note 4.

Hatcher R. A. Trussell J. Stewart F. , Contraceptive Technology, 18th rev. ed. (New York: Ardent Media, 2004).

Cheetham T. C. Wagner R. A. Chiu G. Day J. M. Yoshinaga M. S. Wong L. , “A Risk Management Program Aimed at Preventing Fetal Exposure to Isotretinoin: Retrospective Cohort Study,” Journal of the American Academy of Dermatology 55, no. 3 (September 2006): 442–448.

See FDA, supra note 4.

Berard A. Azoulay L. Koren G. Blais L. Perreault S. Oraichi D. , “Isotretinoin, Pregnancies, Abortions and Birth Defects: A Population-Based Perspective,” British Journal of Clinical Pharmacology 63, no. 2 (2007): 195–205.

See Hatcher , supra note 15.

Chandra A. Martinez G. M. Mosher W. D. Abma J. C. Jones J. , and National Center for Health Statistics, “Fertility, Family Planning, and Reproductive Health of US Women: Data from the 2002 National Survey of Family Growth,” Vital Health Statistics 23, no. 25 (2005).

See Hatcher , supra note 15.

Finer L. B. Henshaw S. K. , “Disparities in Rates of Unintended Pregnancy in the United States 1994–2001,” Perspectives on Sexual and Reproductive Health 38, no. 2 (2006): 90–96.

Alan Guttmacher Institute, Into a New World: Young Women's Sexual and Reproductive Lives, New York, 1998.

Id. See also Finer Henshaw , supra note 22.

Farley T. M. , “Life-Table Methods for Contraceptive Research,” Statistics in Medicine 5, no. 5 (September-October 1986): 475–489; Helmerhorst F. M. Belfield T. Kulier R. Maitra N. O'Brien P. Grimes D. A. , “The Cochrane Fertility Regulation Group: Synthesizing the Best Evidence about Family Planning,” Contraception 74, no. 4 (October 2006): 280–286; Trussell J. , “Methodological Pitfalls in the Analysis of Contraceptive Failure,” Statistics in Medicine 10, no. 2 (February 1991): 201–220.

See FDA, supra note 4, at 5.

Jordan A. Y. Parks L. Chen S. Higgins K. Fleischer A. B. Feldman S. R. , “Does the Teratogenicity of Isotretinoin Outweigh Its Benefits?” Journal of Dermatological Treatment 16, no. 4 (2005): 190–192; Mitchell A. A. Van Bennekom C. Louik C. , “An Assessment of the Accutane (Isotreinoin) Pregnancy Prevention Program,” presentation, September 18–19 2000, available at <http://www.fda.gov/ohrms/dockets/ac/00/slides/3639s1.htm> (last visited December 16, 2008).

See Cheetham , supra note 16.

Goldsmith L. A. Bolognia J. L. Callen J. P. Chen S. C. Feldman S. R. Lim H. W. Lucky A. W. , “American Academy of Dermatology Consensus Conference on the Safe and Optimal Use of Isotretinoin: Summary and Recommendations,” Journal of the American Academy of Dermatology 50, no. 6 (2004): 900–906.

See Cheetham , supra note 16, at 446.

See Berard , supra note 18.

See Finer , supra note 22.

Nava-Ocampo A. A. Koren G. , “Human Teratogens and Evidence-Based Teratogen Risk Counseling: The Motherisk Approach,” Clinical Obstetrics and Gynecology 50, no. 1 (March 2007): 123–131, at 125.

Koren G. Levichek Z. , “The Teratogenicity of Drugs for Nausea and Vomiting of Pregnancy: Perceived Versus True Risk,” American Journal of Obstetrics and Gynecology 186, no. 5, Supplement (May 2002): S248–S252; Pole M. Einarson A. Pairaudeau N. Einarson T. Koren G. , “Drug Labeling and Risk Perceptions of Teratogenicity: A Survey of Pregnant Canadian Women and Their Health Professionals,” Journal of Clinical Pharmacology 40, no. 6 (June 2000): 573–577; Williams J. Myson V. Steward S. Jones G. Wilson J. F. Kerr M. P. Smith P. E. , “Self-discontinuation of Antiepileptic Medication in Pregnancy: Detection by Hair Analysis,” Epilepsia 43, no. 8 (August 2002): 824–831; Williams J. Lawthom C. Dunstan F. D. Dawson T. P. Kerr M. P. Wilson J. F. Smith P. E. , “Variability of Antiepileptic Medication Taking Behaviour in Sudden Unexplained Death in Epilepsy: Hair Analysis at Autopsy,” Journal of Neurology, Neurosurgery, and Psychiatry 77, no. 4 (April 2006): 481–484.

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See Honein , supra note 11, at 1070.

Anderson J. R. Schonfeld T. L. Kelso T. K. Prentice E. D. , “An IRB's Deliberations Regarding Restrictions on Women of Child-Bearing Potential as Subjects for an Early Phase Clinical Trial,” IRB: Ethics and Human Research 25, no. 4 (July-August 2003): 7–11.

Newport D. J. Viguera A. C. Beach A. J. Ritchie J. C. Cohen L. S. Stowe Z. N. , “Lithium Placental Passage and Obstetrical Outcome: Implications for Clinical Management during Late Pregnancy,” American Journal of Psychiatry 162, no. 11 (November 2005): 2162–2170; Yonkers K. A. Wisner K. L. Stowe Z. Leibenluft E. Cohen L. Miller L. Manber R. Viguera A. Suppes T. Altshuler L. , “Management of Bipolar Disorder during Pregnancy and the Postpartum Period,” American Journal of Psychiatry 161, no. 4 (April 2003): 608–620.

Azoulay L. Oraichi D. Berard A. , “Patterns and Utilization of Isotretinoin for Acne from 1984 to 2003: Is There Need for Concern?” European Journal of Clinical Pharmacology 62, no. 8 (2006): 667–674; also see Robertson , supra note 5. There are data to suggest that isotretinoin is being used in some contexts inappropriately: As a first-line agent, for those with less-severe forms of disease, or for longer than the recommended course of treatment. There is a sex difference in prescription use as well, which suggests that men may be underutilizing this therapy or women may be overutilizing it. See Honein , supra note 11. One reasonable way to reduce the overall risk of fetal exposure is to ensure that only those patients whose disease meets the clinical indications for isotretinoin (broadly considered to include not just physical indications) begin isotretinoin therapy. See Jones K. L. Adams J. Chambers C. D. Erickson J. D. Lammer E. Polifka J. , “Isotretinoin and Pregnancy,” JAMA 285, no. 16 (April 25, 2001): 2079–2080.

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See Goldsmith , supra note 29.

See Jordan , supra note 27.

Doshi A. E. , “The Cost of Clear Skin: Balancing the Social and Safety Costs of iPLEDGE with the Efficacy of Accutane (Isotretinoin),” Seton Hall Law Review 37, no. 2 (2007): 625–660, at 647.

Id., at 651.

Pseudotumor cerebri: Increased intracranial pressure, often unknown etiology, that may cause headaches, visual changes, or even vision loss.

See Goldsmith , supra note 29. Studies investigating a causal link between isotretinoin and psychological risks are just beginning to appear in the literature. It remains unclear how much of the psychological risk is attributable to isotretinoin, and how much relates to the underlying disease and/or age group. See Magin P. Pond D. Smith W. , “Isotretinoin, Depression and Suicide: A Review of the Evidence,” British Journal of General Practice: The Journal of the Royal College of General Practitioners 55, no. 511 (February 2005): 134–138; Marqueling A. L. Zane L. T. , “Depression and Suicidal Behavior in Acne Patients Treated with Isotretinoin: A Systematic Review,” Seminars in Cutaneous Medicine and Surgery 24, no. 2 (June 2005): 92–102; Strahanand J. E. Raimer S. , “Isotretinoin and the Controversy of Psychiatric Adverse Effects,” International Journal of Dermatology 45, no. 7 (July 2006): 789–799.

See Berard , supra note 18.

Assuming, of course, that the program achieves this goal satisfactorily.

See Cheetham , supra note 16; also Doshi , supra note 45.

See Doshi , supra note 45, at 659.

Potter L. , “Measuring Compliance among Oral Contraceptive Users,” Family Planning Perspectives 28, no. 4 (1996): 154–158.

See Berard , supra note 18.

Id., at 203.

Glei D. A. , “Measuring Contraceptive Use Patterns among Teenage and Adult Women,” Family Planning Perspectives 31, no. 2 (March-April 1999): 73–80; Severy L. J. Silver S. E. , “Two Reasonable People: Joint Decision Making in Contraceptive Choice and Use,” Advances in Population: Psychosocial Perspectives 1, no. 3 (1993): 207–227.

Johnsen D. , “From Driving to Drugs: Governmental Regulation of Pregnant Women's Lives after Webster,” University of Pennsylvania Law Review 138, no. 179 (1989): 179–215, at 192.

Note that this is different once women become mothers. Child Protective Services will take custody of children who test positive for illegal substance after birth. Yet a woman with a positive drug screen during pregnancy receives no sanction other than counseling (scolding?) by her health care provider.

The State of Michigan does provide a set of “Driving Safety Tips for Pregnant Women,” which include how to wear a safety belt, how to position the steering wheel, and when to avoid driving (“When possible, ride as a passenger rather than drive to avoid potential contact with the steering wheel.”) (See www.michigan.gov).

Id., at 205.

Consider, for example, that the U.S. Supreme Court struck down policies that enabled employers to discriminate against hiring women of childbearing potential for well-paying jobs because of concerns about environmental toxins affecting future pregnancies ( Minkoff Paltrow 2006), or the firestorm that was raised from the South Carolina action to jail pregnant recreational drug users.

Id., at 196.

Bottrell M. M. Alpert H. Fischbach R. L. Emanuel L. L. , “Hospital Informed Consent for Procedure Forms: Facilitating Quality Patient-Physician Interaction,” Archives of Surgery 135, no. 1 (January 2000): 26–33; Paasche-Orlow M. K. Taylor H. A. Brancati F. L. , “Readability Standards for Informed-Consent Forms as Compared with Actual Readability,” New England Journal of Medicine 348, no. 8 (February 20, 2003): 721–726.

See Abroms , supra note 7, at 1981.

However, it is important to remember the statistics reported earlier: The highest rates of pregnancy are in the 25–39-year-old age group, not with adolescents.

Bearinger L. H. Sieving R. E. Ferguson J. Sharma V. , “Global Perspectives on the Sexual and Reproductive Health of Adolescents: Patterns, Prevention, and Potential,” The Lancet 369, no. 9568 (April 7, 2007): 1220–1231; Tylee A. Haller D. M. Graham T. Churchill R. Sanci L. A. , “Youth-Friendly Primary Care Services: How Are We Doing and What More Needs to Be Done?” The Lancet 369, no. 9572 (May 5, 2007): 1565–1573.

See Alan Guttmacher Institute, supra note 23.

Mahowald M. , Women and Children in Health Care: An Unequal Majority (New York: Oxford University Press, 1996); Sherwin S. , No Longer Patient: Feminist Ethics and Health Care (Philadelphia: Temple University Press, 1992).

See Cheetham , supra note 16, at 447.

See Doshi , supra note 45, at 251.

Brent R. L. Beckman D. A. , “Prescribed Drugs, Therapeutic Agents, and Fetal Teratogenesis,” in Medicine of the Fetus and Mother, Reece E. A. Hobbins J. C. , eds., 2nd ed. (Philadelphia: Lippincott-Raven Publishers, 1999): At 289–313.