In recent weeks, there has been much controversy surrounding the possible abortifacient effect of some contraceptives given the Bush administration’s proposal to redefine some forms of hormonal contraception as abortion. A year ago, I authored an essay published in the National Catholic Bioethics Quarterly, which summarized the scientific evidence that suggested that Plan B is not an abortifacient.  I would like to update my analysis and conclusions to date.
I open with a brief overview of the menstrual cycle because knowledge of the cycle is important to properly understand the debate over the mode of action of Plan B. A typical cycle lasts about twenty-eight days counting from the first day of menstrual flow. A woman’s period, which typically lasts about four days (days 1–4), is followed by the follicular or proliferative phase, which lasts about eight days (days 5–13). During this phase, a single egg matures in the ovary in a structure called the follicle. The follicular phase is followed by the peri-ovulatory phase, the period flanking ovulation. Ovulation takes place on day 14 when the mature egg is released from the ovary. It is preceded by a surge of lutenizing hormone (LH) in the woman’s blood that triggers the release of the egg. Ovulation is followed by the luteal or secretory phase, which lasts thirteen days or so (days 15–28). During this phase, the woman’s uterus matures so that it would be ready to nourish an embryo if conception occurs. The development of the uterus is supported by hormones secreted by the remnant of the ovarian follicle called the corpus luteum. If an egg is not fertilized, the cycle ends and begins again with the onset of menses. In contrast, if an egg is fertilized, the embryo implants into his mother’s uterus and the pregnancy continues.
If Plan B is taken during the follicular phase of a woman’s cycle, it prevents ovulation. This is not controversial. Clearly, the drug is a contraceptive. However, if Plan B is taken during the periovulatory or the luteal phase, some have suggested that it can act as an abortifacient. In support of this claim, proponents have appealed to statistical studies that report an effectiveness rate for Plan B between 58 percent and 95 percent, depending upon the delay in administration after intercourse. They have argued that the high effectiveness rates for LNG point to a post-fertilization effect: If ovulation disruption is taken to be the only significant mechanism of action of Plan B, the total effectiveness should not be much higher than 50 percent if it is administered immediately after intercourse.  Similarly, without post-fertilization effects, if Plan B is administered with a twenty-four-hour delay, the highest possible effectiveness would be about 60 percent.
In response, critics have criticized the studies that report a high effectiveness rate for Plan B because they relied on a flawed methodology that was based on a woman’s self-report of her ovulation date. A recent paper has shown that only 40 percent of women can accurately determine their correct stage in the menstrual cycle.  Because of their flawed methodology, it is likely that the earlier studies noted above may have overestimated the effectiveness of Plan B. This critique has now been supported by a recent systematic review of twenty-three different studies that evaluated various strategies designed to enhance women’s access to emergency contraceptive pills. This review revealed that increased access to emergency contraception including the levonorgestrel-only regimen has not reduced the rates of unintended pregnancy. To explain this unexpected finding, the authors believe that earlier studies that had estimated the efficacy rates for emergency contraception, including Plan B, were probably overstated, possibly quite substantially. They conclude: “Clearly, if the method [of emergency contraception] is weakly efficacious, it is unlikely to produce a major reduction in unintended pregnancy rates no matter how often women use it.”  A substantially lower effectiveness rate that could account for the unexpected absence of reductions in the pregnancy rates seen in these population studies of emergency contraception would undermine the validity of the argument that Plan B is an abortifacient. At the very least, these studies cast serious doubt on the statistical claim that Plan B has a post-fertilization effect: If the drug is an abortifacient with a high effectiveness rate, how could these population studies—despite their poor design in some cases—be systematically erroneous?
Next, I turn to reports that more directly determine the mode of action of Plan B. In theory, these studies should be more informative than the statistical studies described above since they are investigating particular biological mechanisms for LNG’s mode of action.
If Plan B is an abortifacient, it could be an abortifacient in three primary ways: First, it could be an abortifacient by increasing the risk of ectopic pregnancies. In support of this possibility, isolated case studies had linked the drug to ectopic pregnancies. However, combined data from five clinical trials with nearly six thousand women showed that the rate of ectopic pregnancies in women who have used Plan B is 1.02 percent as compared to the overall national ectopic pregnancy rate between 1.24 percent and 1.97 percent. In light of this finding, it is unlikely that Plan B increases the ectopic pregnancy rate, suggesting that the isolated case studies in the literature are atypical. This conclusion is supported by a study that has shown that the standard dose of Plan B as an emergency contraceptive does not affect the biology of the fallopian tube.  In contrast, the same study showed that RU-486 or mifepristone—a bona fide abortifacient—taken as emergency contraception did change the biology of that tissue.
Next, Plan B could be an abortifacient by preventing the implantation of an embryo into the uterine wall. It could do this in at least three different ways. First, it could prevent implantation by undermining the development of the endometrium making it inhospitable for embryo implantation. However, morphological and biochemical analyses of endometrial biopsies of women who had taken Plan B eight or nine days prior to the biopsy have revealed that the drug does not dramatically alter the structure of this tissue. This suggests that the drug does not compromise endometrial development. In contrast, there is clear evidence that the abortifacient RU-486 or mifepristone does alter the structure of the endometrium in ways that could be detrimental to an embryo. 
Second, the drug could prevent implantation by disrupting the function of the corpus luteum, indirectly interfering with endometrial function. Recall that the corpus luteum is the remnant of the ovarian follicle that gave rise to the egg. During the luteal phase, the corpus luteum releases hormones that are required for the maintainence of the endometrium so that it will remain hospitable for implantation for several days. If Plan B impaired corpus luteum function, the endometrium would fail, leading to the onset of an earlier menstrual period. Failure of the endometrium would prevent embryo implantation and thus lead to death. In support of this possible mode of action for Plan B, there are studies that have shown that menstrual bleeding begins earlier than usual in some women who use Plan B at the time of expected ovulation. One particular study by Durand et al. has shown that taking Plan B during the LH surge one or two days prior to ovulation would blunt the surge but not prevent ovulation.  According to this study and a subsequent paper from the same group using the same data set, this would impair corpus luteum function leading to diminished levels of endometrial glycodelin A.  Since glycodelin A may play a role in adhesion of the embryo to the endometrium, this could potentially disrupt embryo implantation.
In response, a recent paper by Tirelli et al. has clarified the findings of these earlier studies.  It reported that shortened menstrual cycles are only seen in women who had not ovulated. In fact, in the one case when Plan B was taken during the LH surge, the woman showed a regular ovulatory cycle characterized by normal levels of hormones during the luteal phase. This one subject, whose response to Plan B is at odds with the findings of the Durand et al. study noted above, demonstrates that the use of the drug does not necessarily impair luteal function even if it is taken prior to ovulation during the LH surge. At most, if it does, it only does so in some women and only some of the time. Significantly, it is important to note that eggs released after a delayed or a partially suppressed LH surge—the conditions presupposed by the studies described above—are resistant to fertilization with a resistance proportional to the degree that the LH surge was blunted.  Together, this data suggests that the risk of a post-fertilization effect from this mode of action for any particular individual woman, if it is real, would be vanishingly small.
Third, the drug could prevent implantation by directly interfering with the implantation process itself. As I discussed in detail in my earlier writings on this subject, one study that directly tested the ability of human embryos to implant on endometrial tissue exposed to LNG—though grossly immoral—does not support this mode of action for Plan B.  Incidentally, a more recent study from this same group has shown that Plan B, unlike RU-486, did not affect the expression of endometrial receptivity markers on their cell culture model of the human endometrium, a finding consonant with their earlier work.  Finally, this mode of action for LNG is also unlikely, given one small clinical study with an improved methodology in comparison to the earlier studies noted above that showed that the rate of pregnancy of women who had taken Plan B after ovulation was not reduced. 
Finally, Plan B could be an abortifacient by killing an already implanted embryo. Clearly, RU-486 has this post-implantation effect. It is routinely used to terminate established pregnancies in so-called medical abortions. However, a report from the FDA shows that Plan B does not increase the rate of pregnancy loss nor the frequency of fetal abnormalities once a pregnancy has been established. 
In sum, recent population-based studies with Plan B suggest that its effectiveness rate was probably overstated. A substantially lower effectiveness rate would undermine the statistical argument that Plan B is an abortifacient. Moreover, all the mode of action studies show that it is unlikely that Plan B increases the risk of ectopic pregnancies, prevents the implantation of the embryo into the uterine wall, or kills an already implanted embryo. At most, if the finding of the Durand et al. study is real, one could say that it could increase the risk of a miscarriage in some women some of the time only if they take the drug during the brief interval of the LH surge prior to ovulation, and only if this blunting of the LH surge leads to the ovulation of an egg that is amenable to fertilization, and only if this egg is fertilized. As already noted above, fulfilling these conditions is very unlikely, given that eggs that are released after a blunting of the LH surge are themselves refractory to fertilization. In light of the available scientific evidence and given the inherent limitations of the studies, it is unlikely that Plan B is an abortifacient.
Fr. Nicanor Austriaco, O.P., Ph.D., S.T.L. is assistant professor of biology and instructor of theology at Providence College in Providence, RI.
 N.P.G. Austriaco, O.P., “Is Plan B an Abortifacient? A Critical Look at the Scientific Evidence,” National Catholic Bioethics Quarterly 7.4 (Winter 2007): 703-707.
 For data analysis and discussion, see the following studies, among others: L. Marions et al., “Emergency Contraception with Levonorgestrel and Mifepristone: Mechanism of Action,” Obstetrics and Gynecology 100.1 (July 2002): 65–71; L. Marions et al., “Effect of Emergency Contraception with Levonorgestrel or Mifepristone on Ovarian Function,” Contraception 69.5 (May 2004): 373–377.
 For data analysis and discussion, see the following studies, among others: A. O. Arowojolu, I. A. Okewole, A. O. Adekunle, “Comparative Evaluation of the Effectiveness and Safety of Two Regimens of Levonorgestrel for Emergency Contraception in Nigerians,” Contraception 66.4 (October 2002): 269–273; and S. W. Ngai et al., “A Randomized Trial to Compare 24 h versus 12 h Double Dose Regimen of Levonorgestrel for Emergency Contraception,” Human Reproduction 20.1 (January 2005): 307–311.
 For data analysis and discussion in support of this claim for a generic emergency contraceptive, see J. Trussell and E. G. Raymond, “Statistical Evidence about the Mechanism of Action of the Yuzpe Regimen of Emergency Contraception,” Obstetrics and Gynecology 93.5, part 2 (May 1999): 872–876.
 N. Novikova et al., “Effectiveness of Levonorgestrel Emergency Contraception Given Before or After Ovulation—A Pilot Study,” Contraception 75.2 (February 2007): 112–118.
 E. G. Raymond et al., “Population Effect of Increased Access to Emergency Contraceptive Pills: A Systematic Review,” Obstetrics and Gynecology 109.1 (January 2007): 181–188.
 Ibid., 187.
 For one example, see H. Matsushita, T. Takayanagi, and H. Ikarashi, “Ectopic Pregnancy Following Emergency Contraception with Ethinyloestradiol-Levonorgestrel: A Case Report,” European Journal of Contraception and Reproductive Health Care 12.2 (June 2007): 184–186.
 J. Trussell, A. Hedley, and E. Raymond, “Ectopic Pregnancy Following Use of Progestin-Only ECPs,” Journal of Family Planning and Reproductive Health Care 29.4 (October 2003): 249.
 A. Christow, X. Sun, and K. Gemzell-Danielsson, “Effect of Mifepristone and Levonorgestrel on Expression of Steroid Receptors in the Human Fallopian Tube,”Molecular Human Reproduction 8.4 (April 2002): 333–340.
 K. Gemzell-Danielsson and L. Marions, “Mechanisms of Action of Mifepristone and Levonorgestrel when Used for Emergency Contraception,” Human Reproduction Update 10.4 (July–August 2004): 341–348; and M. Durand et al., “On the Mechanisms of Action of Short-Term Levonorgestrel Administration in Emergency Contraception,” Contraception 64.4 (October 2001): 227–234. Also see B. M . Landgren et al., “The Effect of Levonorgestrel in Large Doses at Different Stages of the Cycle on Ovarian Function and Endometrial Morphology,” Contraception 39.3 (March 1989): 275–289; and Marions et al., “Emergency Contraception.”
 For data analysis and further references to the literature, see R. D. Catalano et al., “Mifepristone Induced Progesterone Withdrawal Reveals Novel Regulatory Pathways in Human Endometrium,” Molecular Human Reproduction 13.9 (September 2007): 641–654.
 E. Gainer et al., “Menstrual Bleeding Patterns Following Levonorgestrel Emergency Contraception,” Contraception 74.2 (August 2006): 118–124; E.G. Raymond et al., “Bleeding Patterns after Use of Levonorgestrel Emergency Contraceptive Pills,” Contraception 73.4 (April 2006): 376–381; and D. Hapangama, A.F. Glasier, and D.T. Baird, “The Effects of Peri-Ovulatory Administration of Levonorgestrel on the Menstrual Cycle,” Contraception 63.3 (March 2001): 123–129.
 Durand et al., “On the Mechanism of Action.” Also see Gemzell-Danielsson and Marions, “Mechanisms of Action”; and Croxatto et al., “Pituitary-Ovarian Function Following the Standard Levonorgestrel Contraceptive Dose or a Single 0.75 mg Dose Given on the Days Preceding Ovulation,” Contraception 70.6 (December 2004): 442–450.
 M. Durand 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 71.6 (June 2005): 451–457.
 A. Tirelli, A. Cagnacci, A. Volpe, “Levonorgestrel Administration in Emergency Contraception: Bleeding Pattern and Pituitary-Ovarian Function,” Contraception77.5 (May 2008): 328–332.
 W. M. Verpoest et al., “Relationship between Midcycle Luteinizing Hormone Surge Quality and Oocyte Fertilization,” Fertility and Sterility. 73.1 (January 2000): 75–77.
 P. G. L. Lalitkumar et al., “Mifepristone, but not Levonorgestrel, Inhibits Human Blastocyst Attachment to an In Vitro Endometrial Three-Dimensional Cell Culture Model,” Human Reproduction 22.11 (November 2007): 3031–3037.
 C. X. Meng et al., “Effect of Levonorgestrel and Mifepristone on Endometrial Receptivity Markers in a Three-Dimensional Human Endometrial Cell Culture Model,” Fertility and Sterility, published online January 16, 2008.
 Novikova et al., “Effectiveness of Levonorgestrel.”
 H. Hamoda and G. M. Flett, “Medical Termination of Pregnancy in the Early First Trimester,” Journal of Family Planning and Reproductive Health Care 31.1 (January 2005): 10–14.
 Medical Officer’s Safety Review of Supplemental NDA for Plan B: Division of Reproductive and Urologic Products, Food and Drug Administration.
Available at www.fda.gov/OHRMS/DOCKETS/AC/03/briefing/4015B1_
12_FDA-Tab 5-1-Medical Officer Review.doc. Last accessed on July 26, 2008.