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 pregnancy 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 ovulation 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. pregnancies.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 corpus luteum 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 Reproductive Medicine.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 progesterone 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 oocytes 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 embryo 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 hormone) surge results in eggs 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-egg 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 embryos 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 endometrium.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 Natural Family Planning 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.