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The National Catholic Bioethics Quarterly  Winter 2013

­Gundersen Health System should reconsider he concludes, “If Rella’s hypothesis were its positions on tube feeding and ventilator true—if shortened luteal phases do in fact support and remove these documents from lead to loss—then one would circulation. expect women with shortened luteal phases to experience infertility. As the committee Ralph A. Capone, MD, FACP concludes, however, after decades of study UPMC McKeesport (luteal phase deficiency was first described Pittsburgh, Pennsylvania in 1949), there is still insufficient evidence St. Vincent College to warrant this claim.” 5 Latrobe, Pennsylvania Context is everything. The ASRM opin- ion addresses the possible linkage between infertility and luteal phase deficiency. Those terms of art must be properly understood if the ASRM opinion is to be properly eval- Mechanism of Action uated. The Mayo Clinic states, “Infertility of Levonorgestrel is defined as not being able to get pregnant despite having frequent, unprotected sex for To the Editor: Rev. Nicanor Austriaco’s latest at least a year for most people and six months contribution to the dialogue about the mech- in certain circumstances.”6 ASRM itself anism of action (MOA) of levonorgestrel clearly states that “infertility is the result when used as an emergency contraceptive of a disease.”7 Infertility is not a onetime­ ­(LNG-EC) is a reply to Walter Rella, MD, ­substance-induced failure to ­conceive or who proposed a robust postfertilization interruption of conception, which is the MOA.1 Rella correctly pointed out that raw core issue in the Plan B debate. It is an data from a study by Gabriela Noé and underlying condition. When ASRM refers colleagues establishes an extraordinarily to “infertility”­ in relation to luteal phase high rate among women who took deficiency, it is not referring to a single LNG-EC during the fertile window and, incident in which pregnancy is prevented or paradoxically, a total absence of expected interrupted by a drug such as levonorgestrel. .2 Rella hypothesized that at It addresses the relationship of a persistent,­ least 50 percent of the antifertility action is spontaneous condition and sustained absence attributable to a postfertilization MOA, and of pregnancy over a certain defined time proposed a significantly shortened luteal period. The ASRM was clear enough: phase associated with impaired function of “Although there appears to be an association the as a candidate. Austriaco’s with infertility, it has not been established reply, in which he claims that “damning” that persistent [luteal phase deficiency] is a evidence undermines Rella’s opinion, is cause of infertility. Moreover, [luteal phase deeply flawed. deficiency] is only clinically relevant if it is Austriaco cites a recent opinion on luteal consistently present in most cycles.” 8 phase deficiency from the American Society This has nothing to do with induced of .3 That opinion luteal phase deficiency, which considerable addresses the relationship, widely sus- evidence points to as the consequence of pected but still debated, between natural the intentional introduction of LNG-EC. infertility and spontaneously occurring A recent paper by Rebecca Peck, MD, and luteal phase deficiency. Austriaco seizes Rev. Juan Vélez, MD (which appears in on the following quote from the ASRM this issue of the Journal) examines some of opinion: “While is important this evidence and proposes that LNG-EC for the process of implantation and early is likely to produce an induced one-time embryonic development, [luteal phase defi- condition that mimics luteal phase defi- ciency], as an independent entity causing ciency.9 There is no question that induced infertility, has not been proven.” 4 From this significant shortening of the luteal phase has

12 Colloquy been repeatedly observed in studies where LH and follicular fluid LH concentrations fell LNG-EC was ­administered in the late follic- within the ranges associated with that ular fertile phase.10 Several of these studies, were fertilized and sustained cleavage (spe- ­systematically unpacked by Peck and Vélez, cifically, serum LH levels were 43–58 IU/L also show impaired luteal phase progesterone for fertilized oocytes and 36.5–47 IU/L for following LNG-EC intake in the late follic- “unfertilized” oocytes, while follicular fluid ular phase, a significant indicator of corpus concentrations of LH were 13.2–16.4 IU/L luteum ­dysfunction.11 Austriaco also ques- for fertilized oocytes and 7.9–13.9 IU/L for tions whether Rella correctly points to short- “unfertilized” oocytes).16 ened luteal phase at all, debating the length of Assuming for the sake of argument that impairment sufficient to meet the criteria for this MOA actually occurs in vivo, it would that diagnosis. While Rella touches on data constitute something monstrous—the pre- concerning shortened luteal phase associated destined, preprogrammed early demise of with LNG-EC intake during the follicular human beings. But whether such events phase, the body of data is more extensively occur is unclear. In a recent article by Viv- presented by Peck and Vélez. ian Brache et al., the authors search for a Of course, the length of the luteal phase is prefertilization MOA to explain the absence not the only biological datum critically asso- of expected pregnancies despite follicular ciated with progesterone levels. In addition rupture reported in the 2011 study by Noé to its nexus with shortened luteal phase and and others and the 2007 study by Natalia inadequate endometrial development, defi- Novikova et al.17 They plainly admit that cient luteal progesterone points to vulnera- whether “the abnormal blunted or absent bility of the to immunological attack. LH peak preceding follicular rupture in the Adequate progesterone regulates maternal LNG-treated cycles in which rupture occurs immune response to the embryo, thereby contributes to the alteration of the ovulatory making successful pregnancy possible.12 process and has any clinical consequence is To explain the absence of pregnancies unknown.” The most they can offer is that it despite a high ovulation rate among women is “biologically plausible.” 18 who took LNG-EC during the follicular That is a rather tepid assertion and one phase, Austriaco proposes that a blunted LH that does not reference the Verpoest find- (luteinizing ) surge results in ings. This is doubly significant. One of that are “hard to fertilize.” This is the same the authors of the Brache study is Horacio theory he suggested in the Winter 2011 issue Croxatto, who previously cited the Verpoest of the NCBQ after other proposed prefer- study for the hard-to-fertilize- theory.19 tilization MOAs collapsed under scrutiny.13 Moreover, the authority cited by Brache et But the hard-to-fertilize egg theory is merely al. to support biological plausibility is a 1993 conjecture, and its reliance on findings by study that reports merely a higher successful Willem Verpoest et al. is misplaced.14 The pregnancy rate associated with normal LH.20 Verpoest group reported that eggs resisted Finally, additional research suggests that a fertilization in IVF procedures when they synthetic progestin, such as levonorgestrel, were conditioned by inadequate LH. How- administered before ovulation may actually ever, their definition of fertilization required trigger the resumption of egg maturation and two pronuclei and continued cleavage for up meiosis in the presence of blunted LH.21 That to seventy-two hours.15 This means oocytes is an area warranting further study, but the that were actually fertilized but failed to sus- hard-to-fertilize-egg theory is an extraordi- tain cleavage for the specified duration were narily weak explanation for the absence of deemed “unfertilized.” The fact that “unfer- expected pregnancies in the 2011 Noé study tilized” oocytes included actual on and, even if true, would almost certainly a path to early demise is further evidenced by entail a postfertilization MOA. reported LH levels. Some of the “unfertilized” Good evidence also suggests that LNG oocytes were from women whose peak serum may affect embryo transport through the

13 The National Catholic Bioethics Quarterly  Winter 2013

­fallopian tube by inhibiting muscular contrac- traception. The evidence plainly shows that tions or reducing tubal epithelial ciliary beat the burden has not been met. frequency, essential mechanisms enabling Rev. Deacon Thomas J. Davis Jr., timely zygote migration to the uterus.22 If JD, LLM, MA slowed beyond the implantation window, Pope John Paul II Bioethics Center the embryo would be unable to nest in the Holy Apostles College and Seminary .23 Delayed tubal transport is Cromwell, Connecticut but one of several possible postfertilization MOAs requiring further inquiry. Sister Hanna Klaus, MD The discussion about LNG-EC and its Center MOA is properly about moral certitude. And of Washington, DC, the burden of establishing moral certitude and Teen STAR Program should properly rest on the proponents of Bethesda, Maryland LNG-EC.24 Moral certitude that LNG-EC Judith M. Mascolo, MD is not abortifacient requires resolution of Connecticut Guild of the reasonable doubts to the contrary. That Catholic Medical Association is the standard long accepted in Catholic West Hartford, Connecticut teaching on moral certitude.25 It is clear that claims of that level of clarity by propo- Bruno Mozzanega, MD nents of LNG-EC are and always have been University of Padua unwarranted. Although several proponents Padua, Italy claim that the data satisfy that standard, their Dominic M. Pedulla, MD representations do not withstand rigorous Oklahoma Vein and Endovascular Center scrutiny.26 Peck and Vélez show that the Oklahoma City weight of the data, properly understood and freed from excessive opinion, conjecture, Julio Tudela, PhD and bias, makes a considerably stronger case Life Sciences Institute for a predominant postfertilization MOA Catholic University of Valencia than for an MOA that occurs principally Valencia, Spain before fertilization. Their analysis includes Patrick Yeung Jr., MD a powerful refutation of MOAs associated Saint Louis University School of Medicine­ with impaired migration, survivabil- St. Louis, Missouri ity, and capacitance, sperm–egg binding, suppression of ovulation, and ovulatory dysfunction. In 2011, Bruno Mozzanega 1 Walter Rella, letter, National Catholic Bio- and Erich Cosmi similarly demonstrated in ethics Quarterly 13.1 (Spring 2013): 7–10; and National a concise fashion the weakness of propo- Nicanor Pier Giorgio Austriaco, letter, 27 Catholic Bioethics Quarterly 13.3 (Autumn nents’ claims. Peck and Vélez provide an 2013): 398–399. evidence-based argument for the reasonable- 2 G. Noé et al., “Contraceptive Efficacy of ness of post­fertilization MOAs, including with Levonorgestrel impaired function­ of the corpus luteum as Given Before or After Ovulation,” Contraception well as impaired endometrial receptivity 84.5 (November 2011): 491. and embryo implantation. Their superb work 3 Practice Committee of the American Society will be essential reading for all interested in for Reproductive Medicine, “The Clinical Rele- this topic. vance of Luteal Phase Deficiency: A Committee Opinion,” and Sterility 98.5 (November The final verdict on LNG-EC awaits its 2012): 1113. day, and perhaps further study will resolve 4 ASRM Practice Committee, “Clinical Rele- all reasonable doubt. On the path to that day vance,” 1115. the burden of proof rests on proponents of 5 Austriaco, letter, 398. the use of levonorgestrel as emergency con- 6 Mayo Clinic staff, “Infertility: Definition,”Pa -

14 Colloquy tient Care and Health Information, July 19, 2013, 391–397. While this article addresses ulipristal http://www.mayoclinic.org/diseases-conditions/ acetate as emergency contraception, it shows the infertility/basics/definition/CON-20034770. critical role of progesterone as a regulator of the 7 ASRM, “Infertility,” ReproductiveFacts.org, mother’s immune system in successful pregnancy: 2013, http://www.reproductivefacts.org/topics/ “For a pregnancy to be successful, one of the many detail.aspx?id=36. vital actions of progesterone is its ability to induce 8 ASRM Practice Committee, “Clinical Rele- selective immune tolerance of the [maternal innate vance,” 1112. immune system] toward the paternal allogeneic 9 Rebecca Peck and Juan Vélez, “The Post- embryo, beginning with fertilization and exten- ovulatory Mechanism of Action of Plan B: A ding through implantation” (392). Review of the Scientific Literature,” National 13 Nicanor Pier Giorgio Austriaco, letter, Catholic Bioethics Quarterly 13.4 (Winter 2013): ­National Catholic Bioethics Quarterly 11.4 000–000. (Winter 2011): 623–627. The proposed MOAs 10 Peck and Vélez point to findings of LNG- included impairment of sperm migration or EC-induced shortened luteal phase in the survival, suppression of ovulation, and inhibi- ­following studies: D. Hapangama, A. F. Glasier, ted sperm–egg binding secondary to elevated and D. T. Baird, “The Effects of Peri-ovulatory intrauterine glycodelin-A levels. Peck and Vélez Administration of Levonorgestrel on the Men- convincingly dismantle those claims. See also strual Cycle,” Contraception 63.3 (March 2001): Thomas J. Davis Jr., letter, National Catholic 123–129; M. Durand et al., “On the Mechani- Bioethics Quarterly 13.1 (Spring 2013): 10–14, sms of Action of Short-Term Levonorgestrel and the correspondence cited there. Administration in Emergency Contraception,” 14 W. M. Verpoest et al., “Relationship between Contraception 64.4 (October 2001): 227–234 Midcycle Surge Quality (Durand 2001); M. Durand et al., “Late Folli- and Fertilization,” Fertility and Sterility cular Phase Administration of Levonorgestrel 73.1 (January 2000): 75–77. as an Emergency Contraceptive Changes the 15 Ibid., 76. Secretory Pattern of Glycodelin in Serum and 16 Ibid., 76, table 1. Endometrium during the Luteal Phase of the 17 V. Brache et al., “Ulipristal Acetate Prevents ,” Contraception 71.6 (June Ovulation More Effectively than Levonorgestrel: 2005): 451–457 (Durand 2005); M. Durand et al., Analysis of Pooled Data from Three Randomized “Hormonal Evaluation and Midcycle Detection Trials of Emergency Contraception Regimens,” of Intrauterine Glycodelin in Women Treated Contraception 88.5 (November 2013): 611–618. with Levonorgestrel as in Emergency Contracep- The authors report that levonorgestrel inhibited tion,” Contraception 82.6 (December 2010): 532; or delayed ovulation only 14 percent of the time H. B. Croxatto et al., “Pituitary–Ovarian Function when administered in the advanced follicular following the Standard Levonorgestrel Emer- phase, the highly fertile two to three days pre- gency Contraceptive Dose or a Single 0.75-mg ceding ovulation, a rate effectively no better than Dose Given on the Days Preceding Ovulation,” placebo. Significantly, Brache was one of the Contraception 70 (2004): 442–450 (Croxatto experts who produced a statement for the Interna- 2004); I. A. Okewole et al., “Effect of Single Ad- tional Consortium for Emergency Contraception ministration of Levonorgestrel on the Menstrual and International Federation of Gynecology and Cycle,” Contraception 75.5 (May 2007): 372–377 Obstetrics (ICEC/FIGO) in 2011 (prior and sub- (Okewole 2007); and A. Tirelli, A. Cagnacci, sequent versions were issued in 2008 and 2012) and A. Volpe, “Levonorgestrel Administration that claimed inhibition or delay of ovulation as the in Emergency Contraception: Bleeding Pattern principal and possibly only MOA of levonorge- and Pituitary-Ovarian Function,” Contraception strel. But that claim, on which Austriaco relied in 77.5 (May 2008): 328–332. See Peck and Velez, a letter in 2011 (NCBQ 11.4, 623–627) and which “Post-ovulatory Mechanism,” 12, 14–16, 18, 20, was repeated in all the ICEC/FIGO statements on 23–24, and 28. LNG-EC, never warranted moral certitude, as 11 Peck and Vélez describe these findings from those critically examining the objective data had the data reported in Durand 2001 (group D), long maintained. In the 2013 study, Brache et al. Durand 2005, Croxatto 2004, and Okewole 2007 implicitly acknowledge that suppression or delay (groups A and B). Ibid., 14–16, 18, and 28. of ovulation is probably an insignificant player in 12 Ralph P. Miech, “Immunopharmacology the LNG-EC mechanism related to prevention of of Ulipristal as an Emergency Contraceptive,” clinical pregnancy. International Journal of Women’s Health 3 (2011): 18 Ibid., 617.

15 The National Catholic Bioethics Quarterly  Winter 2013

19 H. B. Croxatto et al., “Pituitary–Ovarian be judged to be the commission of an abortion Function following the Standard Levonorgestrel because of . . . doubt about how Plan B pills and Emergency Contraceptive Dose or a Single similar drugs work” and expressed “serious 0.75-mg Dose Given on the Days Preceding doubt about how Plan B pills work.” Given those Ovulation,” Contraception 70 (2004): 442–450. doubts, they opted for reluctant compliance with 20 B. J. Cohlen et al., “The Pattern of the Lu- the law. However, they went further and stated, teinizing Hormone Surge in Spontaneous Cycles “If it becomes clear that Plan B pills would lead Is Related to the Probablilty of Conception,” to an early chemical abortion in some instances, Fertility and Sterility 60.3 (September 1993): this matter would have to be reopened.” By that 413–417. statement they shifted the burden of proof to those 21 S. M. Borman et al., “Progesterone Promotes raising serious doubts about the liceity of LNG- Oocyte Maturation, but Not Ovulation, in Hu- EC, and set a high bar: “if it becomes clear” that man Primate Follicles without a Gonadotropin Plan B is an abortifacient. That burden shift and Surge,” Biology of Reproduction 71.1 (July 2004): its standard are plainly erroneous and should be 366–373. abandoned. The 2007 statement is available at 22 K. Wånggren et al., “Regulation of Muscu- http://www.catholicculture.org/culture/library/ lar Contractions in the Human Fallopian Tube view.cfm?recnum=7836. For further discus- sion of the events in Connecticut in 2007, see through Prostaglandins and Progestagens,” Thomas J. Davis Jr., “Emergency Contraception ­ 23.10 (October 2008): 2366: Mandates in Connecticut: A Case History,” pre- “Levonorgestrel markedly inhibited muscular sented at the 2009 NCBC Workshop for Bishops contractions. This could be an additional con- in Dallas, Texas, and available at http://www. traceptive function of levonorgestrel as it may holyapostles.edu/sites/default/files/bioethics/ affect the transport of the pre-embryo through EMERGENCY CONTRACEPTION MAN- the Fallopian tube.” T. Mahmood et al., “The DATES IN CONNECTICUT.pdf. Effect of Ovarian Steroids on Epithelial Ciliary 25 The standard is well formulated by Rev. Beat Frequency in the Human Fallopian Tube,” Thomas Slater, SJ, in volume 1 of his Manual of Human Reproduction 13.11 (November 1998): Moral Theology (New York: Benzinger Broth- 2991–2994: “Progesterone at concentrations of ers, 1925), a classic treatment of the morality of 10 umol/l and higher causes a significant reduc- human acts: “We have to be content with what is tion in [ciliary beat frequency] in all anatomical called moral certainty. . . . I may be conscious that regions of the Fallopian tube.” mistake is possible but not probable, as when a 23 A good discussion of the MOA of LNG-EC, man has been condemned on evidence which has including reference to slowed tubal transport, is satisfied a jury of intelligent men” (31). Even Ron offered by Justo Aznar and Julio Tudela in “Com- Hamel, a LNG-EC proponent and ethicist for the ment on the Decision of the German Bishops Catholic Health Association, has acknowledged ­Regarding the Use of Emergency Contraception that moral certitude requires “that the agent has in Rape Victims,” Civica, website of the Asoci- excluded all reasonable possibility of error.” ación de Investigadores y Professionales por la Hamel, “Thinking Ethically about Emergency Vida, April 3, 2013, http://www.investigadoresy- Contraception,” Health Progress 91.1 (January– profesionales.org/drupal/content/comment-deci- February 2010): 65. sion-german-bishops-regarding-use-emergency- 26 For a discussion of the moral certitude stan- contraception-rape-victims. dard and its application to LNG-EC, see Thomas 24 The question of who carries the burden J. Davis Jr., “Plan B Agonistics: Doubt, Debate of proof was muddled by a statement from the and Denial,” National Catholic Bioethics Quar- Connecticut Catholic bishops in September terly 10.4 (Winter 2010): 760–770. 2007, when they reversed ground from stead- 27 B. Mozzanega and E. Cosmi, “How Do fastly opposing a legislative mandate to provide Levonorgestrel-Only Emergency Contraceptive prescription emergency contraception to sexual Pills Prevent Pregnancy? Some Considerations,” assault victims. Their statement noted that Gynecological Endocrinology 27.6 (June 2011): provision of LNG-EC to rape victims “cannot 439–442.

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