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Bossom EContraception or deception?
M. Durand, M. Seppala, M. Cravioto, H. Koistinen, R. Koistinen, José González-Macedo, F. Larrea (2005)Late follicular phase administration of levonorgestrel as an emergency contraceptive changes the secretory pattern of glycodelin in serum and endometrium during the luteal phase of the menstrual cycle.
Contraception, 71 6
K. Brito, L. Bahamondes, J. Nascimento, L. Santis, M. Munuce (2005)The in vitro effect of emergency contraception doses of levonorgestrel on the acrosome reaction of human spermatozoa.
Contraception, 72 3
Statement on the so-called “morning-after pill.”
N. Novikova, E. Weisberg, F. Stanczyk, H. Croxatto, I. Fraser (2007)Effectiveness of levonorgestrel emergency contraception given before or after ovulation--a pilot study.
Contraception, 75 2
N. Macklon, J. Geraedts, B. Fauser (2002)Conception to ongoing pregnancy: the 'black box' of early pregnancy loss.
Human reproduction update, 8 4
Felicia Stewart, James Trussell (2000)Prevention of pregnancy resulting from rape: a neglected preventive health measure.
American journal of preventive medicine, 19 4
L. Rosenstock (2006)Protecting special interests in the name of "good science".
JAMA, 295 20
N. Novikova, E. Weisberg, F. Stanczyk, H. Croxatto, I. Fraser (2007)Original research article Effectiveness of levonorgestrel emergency contraception given before or after ovulation — a pilot study B
L. Finer, S. Henshaw (2002)Perspectives on sexual and reproductive health
J. Berek (1996)Novak's Gynecology
Saletan WThe birds and the Plan B’s.
J. Trussell, A. Hedley, E. Raymond (2003)Ectopic pregnancy following use of progestin-only ECPs
Journal of Family Planning and Reproductive Health Care, 29
E. Raymond, A. Goldberg, J. Trussell, M. Hays, E. Roach, Douglas Taylor (2005)Bleeding patterns after use of levonorgestrel emergency contraceptive pills.
Contraception, 73 4
K. Gemzell‐Danielsson, L. Marions (2004)Mechanisms of action of mifepristone and levonorgestrel when used for emergency contraception.
Human reproduction update, 10 4
Finer LB, Henshaw SK (2006)Disparities in rates of unintended pregnancy in the United States, 1994 and 2001.
Perspect Sex Reprod Health, 38
Croxatto HB (2002)Emergency contraception pills: how do they work?
IPPF Medical Bulletin, 36
H. Croxatto, V. Brache, M. Pavez, L. Cochón, M. Forcelledo, F. Alvarez, R. Massai, Anibal Faúndes, A. Salvatierra (2004)Pituitary-ovarian function following the standard levonorgestrel emergency contraceptive dose or a single 0.75-mg dose given on the days preceding ovulation.
Contraception, 70 6
Plan B (levonorgestrel) for emergency contraception Rx-to-OTC switch [briefing document].
Decision process to deny initial application for over-the-counter marketing of the emergency contraceptive drug Plan B was unusual.
G. Piaggio, H. Hertzen, D. Grimes, P. Look (1999)Timing of emergency contraception with levonorgestrel or the Yuzpe regimen
The Lancet, 353
L. Marions, S. Cekan, M. Bygdeman, K. Gemzell‐Danielsson (2004)Effect of emergency contraception with levonorgestrel or mifepristone on ovarian function.
Contraception, 69 5
W. Verpoest, D. Cahill, C. Harlow, M. Hull (2000)Relationship between midcycle luteinizing hormone surge quality and oocyte fertilization.
Fertility and sterility, 73 1
J. Trussell, C. Ellertson, L. Dorflinger (2003)Effectiveness of the Yuzpe regimen of emergency contraception by cycle day of intercourse: implications for mechanism of action.
Contraception, 67 3
M. Durand, M. Cravioto, E. Raymond, Ofelia Durán-Sánchez, Ma Cruz-Hinojosa, A. Castell-Rodríguez, R. Schiavon, F. Larrea (2001)On the mechanisms of action of short-term levonorgestrel administration in emergency contraception.
Contraception, 64 4
Medical Officer's Safety Review of Supplemental NDA for Plan B
The August 24, 2006, decision by the US Food and Drug Administration (FDA) to approve over-the-counter (OTC) sales of the emergency contraceptive Plan B—1.5 mg of levonorgestrel taken after unprotected sexual intercourse—was a major development in a long and contentious regulatory process. Since the drug is more effective the sooner it is used, the delay in obtaining it imposed by its prior prescription-only status limited its effectiveness. In the interest of making Plan B available more quickly when needed, the distributor (Women's Capital Corp, Washington, DC) applied to the FDA in April 2003 for approval of OTC status. In December 2003, a joint FDA advisory committee voted 23-4 in favor of approval. It did so on the basis of evidence that the drug is both effective and safe and that it met all FDA criteria for OTC availability. The committee also took into account the likelihood that improved access could prevent at least some of the 3.1 million unintended pregnancies (including the 25 000 that result from rape)1,2—and, hence, some of the more than 1 million elective abortions—that occur in the United States every year.1 Although the FDA almost always accepts its advisory committees' recommendations, in the case of Plan B it twice refused to grant approval of OTC status; the current approval decision came nearly 3 years from the time of the committee vote. As 2 of the committee members who voted for approval, we like many others were surprised and troubled by the FDA's extended inaction. The agency justified its position primarily on the grounds that the number of women aged 14 to 16 years in the manufacturer's actual use study3 (5% of the 585 women actually enrolled in the study) was too small to allow meaningful inferences about the consequences of its use in younger women. Although that narrow statistical point may have some merit, it cannot explain the tortuous and highly irregular process of decision making, uncovered in a subsequent Government Accountability Office inquiry, that led the FDA to withhold initial approval.4 It is therefore difficult to avoid the conclusion that the Plan B regulatory process was “a story of the entanglement of politics, science and religious beliefs. At the heart of it is the question of whether emergency contraception is or could be a form of abortion.”5 Public assertions such as the recent claim that “the proven ‘anti-implantation’ action of the morning-after pill is really nothing other than a chemically induced abortion”6 certainly seem to support that interpretation. The authors of such claims have offered no supporting evidence regarding Plan B's mechanism of action. On the contrary, what has been offered are assertions that “the exact mechanism of action of Plan B is unknown”7 and that “the dirty little secret is, nobody really knows.”8 Such sweeping statements of uncertainty not only directly contradict the claim that Plan B's anti-implantation action is “proven” but also promote general misunderstanding and misuse of doubt in science. Doubt is the very core of the scientific enterprise, an essential part of the process by which scientific hypotheses are tested; on the other hand, doubt is sometimes exploited as a powerful way of subverting sound science-based public policy.9 Driven by the belief by some that interference with implantation is a form of abortion, the politics of doubt about Plan B’s contraceptive mechanism appears to have contributed not only to the delay in its OTC availability but also to the continuing refusal by some emergency services to provide the drug to rape survivors as well as refusal by some pharmacists to make it available to individual patients. In fact, a great deal is known about how Plan B prevents pregnancy. Now that the drug will be more widely available, it is more important than ever that the scientific evidence on its contraceptive mechanisms be as widely known as possible, so that decisions about its use can be fully informed. A summary of that evidence follows. Plan B's Pharmacologic and Clinical Properties When used immediately after unprotected sexual exposure, Plan B's contraceptive activity is evident within hours; delaying the first dose by 12 hours increases the odds of pregnancy by almost 50%, and its efficacy diminishes linearly with time.10 Much of the activity is gone by 72 hours, although there is some residual activity with delays in use of up to 120 hours. Users are therefore instructed to take one Plan B pill, which contains 0.75 mg of levonorgestrel, as soon as possible after unprotected sex, followed by a second pill 12 hours later. The drug is equally effective when both doses are taken together, but it is not approved by the FDA for use in that fashion. Clinical studies have provided estimates of Plan B's overall contraceptive effectiveness in the range of 59% to 94%; the figure given in the Plan B labeling is 89%. That degree of effectiveness, although substantial, is considerably less than that of traditional combined oral contraceptive regimens. When Plan B is used after pregnancy is established, it increases neither the rate of pregnancy loss nor the frequency of fetal abnormalities.11 Biology of Hormonal Contraception Traditional combination oral contraceptives (semi-synthetic estrogen plus progestin) reduce fertility primarily by suppressing the mid-cycle leuteinizing hormone (LH) surge. Because it is the LH surge that sets in motion the complex, highly coordinated chromosomal and histologic changes that lead to release of a fertilizable ovum,12 as well as to development of a competent corpus luteum, complete suppression of the LH surge prevents ovulation and corpus luteum development altogether. In contrast, the biology of traditional progestin-only contraception is considerably more complex. In women who take the traditional daily progestin-only “mini-pill” containing 0.35 mg of norethindrone, a substantial proportion of menstrual cycles are ovulatory, and luteal dysfunction occurs in many of those women who ovulate.13 Mechanism of Action of Plan B Detailed analysis of Plan B's mechanism of action can be broken down into the following specific questions. Does Plan B Interfere With the Ability of Sperm to Reach and Fertilize Ova? Levonorgestrel does not act directly on sperm to interfere with their ability to fertilize ova.14 However, within about 3 hours after it is ingested, a single dose of levonorgestrel equal to about one half of a Plan B pill decreases the number of sperm that can be recovered from the uterine cavity; by 5 hours, that dose of the drug markedly alkalinizes uterine cavity fluid, thereby immobilizing sperm; and by about 9 hours, it produces significant thickening of cervical mucus.12,15 This levonorgestrel-induced interference with sperm entry into and migration through the uterine cavity develops too late to prevent the first wave of sperm migration, which begins in minutes15; that delay is not relevant to Plan B's contraceptive activity, however, since sperm in the first wave are not yet capacitated and hence are not capable of fertilizing ova. However, when Plan B is taken immediately after sexual intercourse, these effects on the cervical and uterine environment can prevent later waves of migration of capacitated sperm, which begin about 10 hours after intercourse and continue for several days.12 Conversely, the loss of Plan B's contraceptive effectiveness with delay in use can be explained at least in part by the arrival of capacitated sperm in the fallopian tube before the drug has had a chance to assert its effects on sperm migration. Does Plan B Interfere With Ovulation? The answer depends on timing. Plan B taken prior to the day before a woman's LH surge usually suppresses the surge completely, in which case ovulation does not occur. When Plan B is used closer to the LH surge, it can blunt or delay the surge rather than suppress it completely, or may not affect the surge at all.15,16 If ova released under those circumstances are fertilized, Plan B could at least theoretically prevent some pregnancies by interfering with postfertilization events. However, ova released after a delayed or partially suppressed LH surge are resistant to fertilization, and resistance is proportional to the degree of inadequacy of the LH surge.17 Thus, occurrence of ovulation in some women who use Plan B immediately before or during the LH surge does not necessarily mean that the drug prevents pregnancy in such cases only by interrupting postfertilization events. Does Plan B Prevent Fertilization or Interrupt Fallopian Tube Function? No data are available on whether Plan B directly interferes with fertilization itself. However, since fertilization occurs in the fallopian tube, Plan B could indirectly prevent pregnancy by interrupting the transport of fertilized ova through the fallopian tube. In that case the use of Plan B should be associated with an increased risk of ectopic pregnancy. Combined data from 5 clinical trials involving nearly 6000 women showed the actual rate of ectopic pregnancies in women who had used Plan B to be 1.02%, which is slightly lower than overall national ectopic pregnancy rates (1.24%-1.97%).18 Quite apart from providing reassurance about Plan B's safety, that finding virtually excludes the possibility that it prevents pregnancy by slowing or preventing normal movement of fertilized ova through the fallopian tube. Does Plan B Impair Endometrial Structure or Physiology? In 2 studies relevant to this question, women who took Plan B at the time of ovulation underwent endometrial biopsy 8 to 9 days later, when implantation ordinarily occurs. The endometrium revealed either minimal or no changes in microscopic appearance or biochemical markers.15,19 Another study found diminished amounts of endometrial glycodelin A in some women who had received Plan B.20 Since glycodelin A may play a role in adhesion of the nascent embryo to the endometrial surface, such an effect could be a mechanism by which Plan B interferes with implantation. However, in this study endometrial glycodelin A was affected only in those women who took Plan B before the LH surge, a circumstance in which ovulation generally does not occur. The glycodelin A effect may thus be an epiphenomenon, the result of an absent or inadequate LH surge rather than a direct link in the causal pathway of contraception. More generally, it is not known whether any of the alterations in endometrial biology sought in these studies is actually capable of interfering with implantation. Does Plan B Induce Luteal Dysfunction? The use of Plan B decreases circulating levels of progesterone and, possibly, estrogen during the luteal phase.19-21 These decreases probably explain why menstrual bleeding begins earlier than usual in some women who use Plan B. It has also been observed, however, that premature onset of menstrual bleeding is greatest when Plan B is used early in the cycle, that is, well before ovulation; premature bleeding does not occur when the drug is taken during the fourth week of the cycle.22 Since the LH surge is most effectively suppressed when Plan B is taken early in the cycle, and since luteal function and ovulation both depend on the LH surge, luteal dysfunction may also be an epiphenomenon rather than a direct participant in the mechanism of Plan B–induced contraception. What Does the Timing of Plan B's Effectiveness Reveal About Possible Interference With Postfertilization Events? If Plan B interferes with implantation, it should be capable of preventing pregnancy when it is used after fertilization. In a recent clinical study23 in which timing of ovulation was determined quite precisely using hormonal criteria, no pregnancies occurred in the 34 women who had unprotected intercourse on days –5 to –2 (day 0 being the day of ovulation) and took Plan B (1.5 mg as a single dose) before or around the time of ovulation; 4 or 5 pregnancies would have been expected in this group if they had not used the drug. In contrast, 3 pregnancies occurred among the 17 women who had intercourse around days –1 to 0 and took Plan B on day +2; 3 or 4 pregnancies would have been expected had they not used the drug. Although the results of this study need to be confirmed and extended, they are consistent with epidemiological evidence on the efficacy of emergency contraception in relation to the timing of ovulation24 and are directly contrary to what would be expected if Plan B interferes with implantation. If Plan B interferes with implantation, its efficacy should not decrease with short-term delay in use as long as it is taken just before or during implantation. In fact, delay in use causes Plan B to lose its effectiveness progressively in the 72 hours after unprotected intercourse even when use is adjusted for cycle day of unprotected sex.10 That finding is again consistent with a contraceptive mechanism that is independent of effects on implantation. Conclusions Published evidence clearly indicates that Plan B can interfere with sperm migration by altering the cervical and uterine environment, and that preovulatory use of Plan B usually suppresses the LH surge either completely or partially, which in turn either prevents ovulation or leads to the release of ova that are resistant to fertilization. Epidemiological evidence rules strongly against interruption of fallopian tube function by Plan B. Evidence that would support direct involvement of endometrial damage or luteal dysfunction in Plan B's contraceptive mechanism is either weak or lacking altogether. Both epidemiologic and clinical studies of Plan B's efficacy in relation to the timing of ovulation are inconsistent with the hypothesis that Plan B acts to prevent implantation. Progestational drugs, including levonorgestrel, are used therapeutically in assisted reproduction because they increase the rate of successful implantation and pregnancy.13 That observation a priori reduces the likelihood that Plan B interferes with implantation; it even raises the counterintuitive but undocumented possibility that Plan B used after ovulation might actually prevent the loss of at least some of the 40% of fertilized ova that ordinarily fail spontaneously to implant or to survive after implantation.25 The most obvious approach to knowing definitively whether Plan B prevents implantation would be to develop a completely reliable method for detecting fertilization prior to the time when implantation has occurred. Such a method is unfortunately not currently available. Beyond that lack of information lies the more subtle logical difficulty—some would say the impossibility—of proving the lack of existence of any particular mechanism. In the absence of absolute proof about Plan B's mechanisms of action, the right to make personal decisions about whether its use is morally acceptable must be respected and for that reason women should continue to be informed, as they are now in the Plan B labeling, that its use may affect postfertilization events. At the same time, however, all women should be informed that the ability of Plan B to interfere with implantation remains speculative, since virtually no evidence supports that mechanism and some evidence contradicts it. Women should also be informed that the best available evidence indicates that Plan B's ability to prevent pregnancy can be fully accounted for by mechanisms that do not involve interference with postfertilization events. Back to top Article Information Corresponding Author: Frank Davidoff, MD, 143 Garden St, Wethersfield, CT 06109 (email@example.com). Financial Disclosures: None reported. Disclaimer: Drs Davidoff and Trussell were members of the joint FDA advisory committee that voted to approve the OTC marketing of Plan B in the United States. Dr Davidoff is chair of the JAMA Journal Oversight Committee. References 1. Finer LB, Henshaw SK. Disparities in rates of unintended pregnancy in the United States, 1994 and 2001. Perspect Sex Reprod Health. 2006;38:90-9616772190Google ScholarCrossref 2. Stewart FH, Trussell J. Prevention of pregnancy resulting from rape: a neglected preventive health measure. Am J Prev Med. 2000;19:228-22911064225Google ScholarCrossref 3. Women's Capital Corporation. Plan B (levonorgestrel) for emergency contraception Rx-to-OTC switch [briefing document]. Nonprescription Drugs and Reproductive Health Drugs Advisory Committee Meeting. December 16, 2003:63 4. US Government Accountability Office. Decision process to deny initial application for over-the-counter marketing of the emergency contraceptive drug Plan B was unusual. Report GAO-06-109. http://www.gao.gov/cgi-bin/getrpt?GAP-06-109. Accessed November 14, 2005 5. Shorto R. Contra-contraception. New York Times Sunday Magazine. May 7, 2006:49 6. Pontifical Academy for Life. Statement on the so-called “morning-after pill.” http://www.vatican.va/roman_curia/pontifical_academies/acdlife/documents/rc_pa_acdlife_doc_20001031_pillola-giorno-dopo_en.html. Accessed July 10, 2006 7. Bossom E. Contraception or deception? http://www.cwfa.org/articledisplay.asp?id=1559&department=CWA&categoryid=life. Accessed July 10, 2006 8. Saletan W. The birds and the Plan B’s. Washington Post. April 2, 2006:B2 9. Rosenstock L. Protecting special interests in the name of “good science.” JAMA. 2006;295:2407-241016720826Google ScholarCrossref 10. Piaggio G, von Hertzen H, Grimes DA. et al. Timing of emergency contraception with levonorgestrel or the Yuzpe regimen. Lancet. 1999;353:72110073517Google ScholarCrossref 11. Medical Officer's Safety Review of Supplemental NDA for Plan B; Division of Reproductive and Urologic Products, Food and Drug Administration. Sections 220.127.116.11 (p 19) and 7.3.4 (p 24). http://www.fda.gov/cder/foi/nda/2006/021045s011_Plan_B__MedR.pdf. Accessed August 29, 2006 12. Croxatto HB. Emergency contraception pills: how do they work? IPPF Medical Bulletin. 2002;36:Appendix 1-1,2Google Scholar 13. Berek JS. Novak's Gynecology. 13th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2002:249 14. Brito KS, Bahamondes L, Nascimento JA, de Santis L, Munuce MJ. The in vitro effect of emergency contraception doses of levonorgestrel on the acrosome reaction of human spermatozoa. Contraception. 2005;72:225-22816102561Google ScholarCrossref 15. Gemzell-Danielsson K, Marions L. Mechanisms of action of mifepristone and levonorgestrel when used for emergency contraception. Hum Reprod Update. 2004;10:341-34815192056Google ScholarCrossref 16. Croxatto HB, Brache V, Pavez M. et al. Pituitary-ovarian function following the standard levonorestrel emergency contraceptive dose or a single 0.75 mg dose given on the days preceding ovulation. Contraception. 2004;70:442-45015541405Google ScholarCrossref 17. Verpoest WMJA, Cahill DH. et al. Relationship between midcycle luteinizing hormone surge quality and oocyte fertilization. Fertil Steril. 2000;73:75-7710632416Google ScholarCrossref 18. Trussell J, Hedley A, Raymond E. Ectopic pregnancy following use of progestin-only ECPs. J Fam Plann Reprod Health Care. 2003;29:24914662065Google ScholarCrossref 19. Durand M, delCarmen Cravioto M, Raymond EG. et al. On the mechanisms of action of short-term levonorgestrel administration in emergency contraception. Contraception. 2001;64:227-23411747872Google ScholarCrossref 20. Durand M, Seppala M, Cravioto Mdel C. et al. Late follicular phase administration of levonorgestrel as an emergency contraceptive changes the secretory pattern of glycodelin in serum and endometrium during the luteal phase of the menstrual cycle. Contraception. 2005;71:451-45715914136Google ScholarCrossref 21. Marions L, Cekan SZ, Bygdeman M, Gemzell-Denielsson K. Effect of emergency contraception with levonorgestrel or mifepristone on ovarian function. Contraception. 2004;69:373-37715105059Google ScholarCrossref 22. Raymond EG, Goldberg A, Trussell J. et al. Bleeding patterns after use of levonorgestrel emergency contraceptive pills. Contraception. 2006;73:376-38116531171Google ScholarCrossref 23. Novikova N, Weisberg E, Stanczyk FZ, Croxatto HB, Fraser IS. Effectiveness of levonorgestrel emergency contraception given before or after ovulation: a pilot study. ContraceptionIn pressGoogle Scholar 24. Trussell J, Ellertson C, Dorflinger L. Effectiveness of the Yuzpe regimen of emergency contraception by cycle day of intercourse: implications for mechanism of action. Contraception. 2003;67:167-17112618250Google ScholarCrossref 25. Macklon NS, Geraedts JP, Fauser BC. Conception to ongoing pregnancy: the “black box” of early pregnancy loss. Hum Reprod Update. 2002;8:333-34312206468Google ScholarCrossref
JAMA – American Medical Association
Published: Oct 11, 2006
Keywords: levonorgestrel,contraception, postcoital
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