Appreciation for analysis of how levonorgestrel works and reservations with the use of meloxicam as emergency contraception

Abstract

This paper is a response to Dr. Kathleen Raviele's recent article on her critical analysis of the use of levonorgestrel given to women postsexual assault and her suggestion that the use of Meloxicam may be an ethical alternative.

Keywords:

• The use of levonorgestrel post sexual assault
• The use of Meloxicam post sexual assault
• Mobic for women
• Progesterone
• Breakthrough ovulation
• Prostaglandins
• NSAID
• Medically induced abortions
• Abortifacient

Acknowledgements

With deepest gratitude for his courageous witness to the sanctity of life, this paper is dedicated to St. John Paul II. The writing and editing assistance of Deborah A. Burton, M.A., Ph.D. (cand.), is gratefully acknowledged.

The authors also wish to express their deep appreciation to the following manuscript reviewers for their interest, comments, and suggestions: Nancy K. Mullen, M.D., University of Kentucky; Otto R. Piechowski, M.A. (theology), M.A. (philosophy), Catholic University of America; and Amberly K. Windisch, M.D.

Notes

1 Strong ethical solidarity with Raviele's primary conclusion of the ethical impermissibility of Plan B does not equate to support for every point made in her paper. Reservations include, but are not limited to, her reference to performing a “pregnancy test to make sure the woman is not pregnant from an act of intercourse two weeks or more before the assault” (Raviele 2014, 118, last paragraph). While we agree that no pregnancy test can detect pregnancy within 72 hours of coitus, and that testing at 3 weeks after midcycle coitus, not 3 days, is standard, she herself quotes on p. 117 the Ethical and Religious Directives for Catholic Health Care Services that specifically refer to “a potential conception from the assault. If, after appropriate testing, there is no evidence that conception has already occurred.” Is the pregnancy test before EC sound science and how is a negative result customarily explained to the patient?

 Additionally, she states, “Any drug which could disrupt a previous implanted embryo would be abortifacient” (Raviele 2014, 120). As explained in note 3 below baboon researches established decades ago that Plan B (levonorgestrel) is an interceptive. We trust that Dr. Raviele agrees that life and pregnancy begin with conception (fertilization), and that whether the mechanism of action is interceptive (before implantation) or contragestive (after implantation) the agent is an abortifacient.

 Similarly, and pertinent to this point, she quotes extensively from Dignitas personae on p. 125 of her paper (including the critical sentence—who ever “prescribes such a pharmaceutical, generally intends an abortion”), but omits the relevant quote in footnote 43, “The interceptive methods which are best known are the IUD (intrauterine device) and the so-called ‘morning after pills’” (CDF 2008).

 Likewise, Raviele states, “Secondly, he [Sulmasy] proposes that that the administration of contraceptive hormones is not intrinsically evil because they are given for other disorders in women” (Raviele 2014, 126). This statement is partially correct, but the prescription of the birth control pill, a known WHO Group 1 carcinogen —same category as asbestos and arsenic —to a child or a young girl for a non-lethal condition such as acne, and without informed consent to her and a parent/guardian is indefensible medically, ethically and legally (Schneider et al. 2014).

 Raviele properly takes further issue with Sulmasy's assertion that contraceptives are given for other disorders in women, “This is an incorrect conclusion as the dosage of LNG-EC is equivalent to 50 ‘mini-pills’ of a progesterone-only oral contraceptive and is not physiologic.” Raviele is right that Plan B is equivalent to 50 mini-pills, but levonorgestrel is not progesterone (the hormone critical to embryo implantation and maintenance of pregnancy). It is a progestin, an anti-fertility agent. A review succinctly summarizes, “Progestins have been used for contraception for more than 30 years” (Erkkola and Landgren 2005). Similarly, Speroff and Darney's contraception text notes that when LNG is administered as the progestin-only Minipill, “Approximately, 40% of patients ovulate normally,” and, rather than becoming more receptive, “the endometrium involutes and becomes hostile to implantation” (Speroff and Darney 2006). Plan B is a massive hormonal dose of a sex steroid (the equivalent of 50 mini-pills whose anti-fertility hormone, levonorgestrel, is 200 times as potent at progesterone). The action of Plan B is not that of progesterone, but the opposite of progesterone in action and risk (Schneider et al. 2014). Progesterone is used for luteal supplementation and the reversal of the first step of RU-486 (the administration of mifepristone) (Delgado and Davenport 2012). Plan B is a potent anti-fertility drug that is available to children.

 Finally, Raviele states, in a discussion of the Peoria protocol, that if the “serum progesterone level is between 1.5 and 5.9 ng/ml, then she is near ovulation and LNG-EC should not be given” (Raviele 2014, 119). A full discussion of the Peoria protocol deserves a separate paper, but a few comments are perhaps needed here. The protocol has been neither standardized nor validated. A PubMed search located no citations other than Raviele's report. The use of meloxicam with the protocol in women would be a novel application.

 Even if a stat progesterone level could be obtained rapidly in the ED, its interpretation is uncertain. The 2012–2015 LabCorp manual states that the progesterone level during the follicular phase is (0.2–1.4 ng/ml)—outside of Raviele's range for “near ovulation” (1.5–5.9 ng/ml). Moreover, the phases in the Labcorp manual are not defined by cycle day and there is overlap in the ranges between the follicular and ovulation phases (0.2–1.5 vs. 0.8–3.0 ng/ml), as well as the ovulation and luteal phases (0.8–3.0 vs. 1.7–27.0 ng/ml) (Labcorp 2012, 686). A single progesterone level, even if obtained rapidly, does not allow the ED physician to know precisely the day of the menstrual cycle and even the menstrual phase.

 The 23rd edition of the Williams textbook of Obstetrics is 1385 pages in length, but contains only a single paragraph on progesterone and no cycle day information (Cunningham et al. 2010, 41). Similarly, the six volume Gynecology and Obstetrics contains a chart on plasma progesterone by week of pregnancy that provides no data prior to the fifth week (Pepe and Albrecht 2003, no. 38, chart on p. 15).

 Moreover, Baird et al. studied progesterone levels in early pregnancy as reflected in its major urinary metabolite, pregnanediol-3-glucuronide (PdG). When PdG data are analyzed by day of implantation, the average PdG concentration “increased significantly on the day after implantation (P, 0.001)” and “continued to increase gradually during the first week after implantation. The gradual increase in mean PdG concentration after implantation suggests that humans do not exhibit the abrupt rise in progesterone described for nonhuman primates” (Baird et al. 2002). EC researchers, even when armed with multi-day and multi-modality testing including ultra-sound are often in error in their determination of the coital cycle date (Durand et al. 2001). Given the rudimentary tools available late at night in the ED, precise timing of the cycle date is challenging and probably impossible.

 The Pill was approved in 1957 for menstrual irregularities, as fertility was not yet viewed as a disease, but evidence of health. By 1960, the Pill (“Enovid”) was FDA approved for “contraception,” a stretch of the FDA mandate and authority, as fertility was not yet viewed as a disease. The developers knew that there was an implantation prevention (“interceptive” or abortifacient) effect, so in 1965 ACOG attempted to re-define life and pregnancy as beginning with implantation.

 Thus, the phrase “emergency contraception” is actually a double (and expanding) lie. It is not a pregnancy that is being prevented, but the birth of a baby, by his or her elimination at the pre-implantation embryo stage with traditional strategies such as DES, Yuzpe or Plan B via interceptive abortions (Oettel et al. 1980). Later, EC was expanded to include contragestive abortions via RU-486 or ella taken in the middle to even late embryonic period, or the insertion of an IUD on day 28 (or beyond). Surgical abortions may legally be performed at any time for EC “failures.” These expansions stretch the meaning of EC beyond any semblance of coherence. Is there any other clinical situation in which a medical remedy given 3–5 days after diagnosis (and beyond) is referred to (and properly coded) as “emergency” treatment?

2 Durand et al.’s Table 2 says that follicular rupture occurred on day 18 in group A. If this is considered day 0 and one counts back to “day 10” (i.e., 0, −1, −2, …, −8), one concludes that Durand's “day 10” is eight days before ovulation or day –8 (Durand et al. 2001).

3 Logically it is, of course, impossible to prevent something after it already exists. The Russian baboon researchers were much more forthcoming (and scientifically precise) about the LNG mechanism of action. They noted, “Among primates the baboon is one of the best available species as a model for human implantation.…It has been demonstrated that post-coital levonorgestrel has a good interceptive effect in women” (Oettel et al. 1980).

4 See note 3 above.

5 The major justifications for over-the-counter (OTC) EC were the multiple predictions that easy EC availability would greatly reduce abortions. For instance, Anna Glasier wrote in the New England Journal of Medicine that, “each year the widespread use of EC in the United States could prevent over 1 million abortions and 2 million unintended pregnancies” (Glasier 1997).

 Although the claim was demonstrably impossible, as there were a total of 848,163 reported U.S. abortions in 2003 (Strauss et al. 2006), the claim went unopposed. It was repeated with increasing frequency and was simply assumed to be true. Nonetheless, after multiple studies failed to find the anticipated benefit of reduced abortions, two meta-analyses were conducted. Both reached the same conclusion that ease of access to LNG, the sole ingredient of Plan B, did not reduce pregnancy rates (Raymond, Trussell, and Polis 2007; Polis et al. 2007). One included report in these meta-analyses, coauthored by the very same Anna Glasier who had predicted an enormous reduction in abortions with OTC EC, provided a quite revealing title, “Advanced provision of emergency contraception to postnatal women in China makes no difference in abortion rates: a randomized control trial” (Hu et al. 2005). Zero (“no”) is certainly less than a million.

 In contrast to the Plan B “as soon as possible” efficacy recommendation in a prominent Journal of the American Medical Association commentary (Davidoff and Trussell 2006), one of these meta-analyses found advanced provision of EC was associated with “increased use,” “multiple use,” and “faster use,” but did not result in a change of pregnancy rate (Polis et al. 2007). In early 2006, Anna Glasier herself co-authored an editorial in the journal Contraception that provided the rather blunt concession, “randomized trials of advanced provision of EC in a variety of settings have all demonstrated increased use of EC, but none has shown a reduction in unintended pregnancies” (emphasis added) (Glasier and Shields 2006).

6 “All the patients requested termination of pregnancies, which were confirmed histologically” (Ho and Kwan 1993).

7 An 80% efficacy rate equals 100%* (expected pregnancies - actual pregnancies)/(expected pregnancies) = 100%* (15.18–3)/(15.18) = 80%.

8 Stedman's Medical Dictionary defines the term abortion as the “1. Expulsion from the uterus of an embryo or fetus before viability (20 weeks gestation [18 weeks after fertilization] or fetal weight less than 500 g).” Thus, a termination of pregnancy before viability, whether via an interceptive, contragestive, or surgical means, does result in an abortion. Moreover, Stedman's defines termination as an “induced ending of a pregnancy” (Stedman 2006).

9 This Croxatto group report, cited by Raviele, also contains an important admission by these EC researchers/promoters that directly contradicts the position of those promoting the ethical permissibility of Plan B. This report admits that LNG (Plan B) does “suppress the luteal phase,” a clear, and authoritatively acknowledged, postfertilization effect (Jesam et al. 2010, postfertilization example 6).

10 As the heart begins to beat on gestational age day 22, it is plausible that on day 20 “the heart, brain, spinal column and nervous system are almost complete and the eyes begin to form” (American Life League 2005). Serious facial and other birth defects have been associated with NSAIDs.

 Raviele herself quotes the National Birth Defects Prevention Study (Correa et al. 2012; Hernandez et al. 2012), which found that women exposed to NSAIDs in the first trimester had a “moderate association with anophthalmia/microphthalmia, amniotic bands/limb body wall defects, which had not been reported before, as well as oral clefts” (Raviele 2014, 127).

11 See note 6 above.

12 Holmes et al., as does Raviele, report a rape-related pregnancy risk of 5%, and that “32% of women who became pregnant as a result of a rape were not aware of the pregnancy until the second trimester” (Holmes et al. 1996). A DNA paternity study by Holly Hammond et al. of pregnancies alleged to be rape-associated, found that in 60% of cases (6/10), the consensual partner (or even a second consensual partner) was, in fact, the father, rather than the accused rapist (Hammond, Redman, and Caskey 1995).

13 Additional personal communication with laboratory director, J. Wilhelmus, May 15, 2014.

14 An on-line CV states that Dr. H.B. Croxatto is a physician, president of the Chilean Institute for Reproductive Medicine Society since 1985, past recipient (2002) of the Grand Lodge Masonry of Chile nomination for outstanding contribution to freedom of conscience and thinking, and past faculty member of the Pontifical Catholic University of Chile (1961–1998) (Croxatto 2008).

 Croxatto was also the first editor for a 2005 symposium/monograph in Berlin, Germany, on new methods of contraception. He alone authored the lead paper on progesterone receptors and “opportunities for contraception.” He notes that, “The aim of this workshop is to explore new avenues in contraception based upon direct pharmacological interventions on PR (progesterone receptor).” Croxatto summarized that progesterone “is required for the production of a viable pregnancy” and “is essential for the establishment and maintenance of pregnancy.” The best-known PR blocking agent is the abortion pill, RU-486. In his overview, he offers no ethical hesitation with this or any of a total of twelve listed “contraceptives,” including RU-486 (Croxatto 2005).

15 A recent review of endometrium-embryo cross talk (Banerjee and Fazleabas 2010) refers to this “delicate interaction” as “one of the most elegant and fascinating interactions in human physiology” that “initiates and maintains the process of implantation.” The “discourse” is initiated by the pre-implantation blastocyst. Chorionic gonadotropin (CG) signals the corpus luteum, and thus prevents luteal involution and loss of progesterone, that maintains a receptive endometrial lining that is critical to implantation. Moreover, CG signals the endometrium for implantation, and it “rescues stromal fibroblasts from their apoptotic demise and also differentiates them into the decidualized phenotype” (Banerjee and Fazleabas 2010).

16 “Human life must be respected and protected absolutely from the moment of conception” (emphasis added) (Catechism 1997, n. 2270).

17 This document (CDF 2008) must have had special relevance to the pope, because at the historic July 10, 2009, meeting between the Supreme Pontiff, now Pope-Emeritus Benedict XVI, and President Barack Obama, there was an unnamed gift. In a surprise gesture, as the president was departing, Pope Benedict gave the American leader a copy of Dignitas personae (Moynihan 2009).

Additional information

Notes on contributors

A. Patrick Schneider II

Biographical Note

A. Patrick Schneider II, M.D., M.P.H., is on the active medical staff of Saint Joseph Hospital, Lexington, Kentucky, and practiced obstetrics for ten years. He is a past president of the SS. Luke and Gianna Guild (Lexington) of the Catholic Medical Association, is board-certified in Family (ABFP) and Geriatric (CAQ) Medicine, and has an M.P.H. (epidemiology) from the Harvard School of Public Health. Dr. Schneider prescribed EC in the ED thirty-nine years ago.

Rev. Christopher Kubat

Rev. Christopher Kubat, M.D., has received an M.Div and an M.A. from Mount St. Mary's Seminary, Emmetsburg, Maryland, a B.S. and an M.D. from Creighton University, and has completed a residency in urology at the University of Iowa Hospital and Clinics. He is currently executive director of Catholic Social Services of Southern Nebraska.

Christine M. Zainer

Christine M. Zainer, M.D., is a board-certified anesthesiologist (ABA) and Assistant Clinical Professor of Anesthesiology at the Medical College of Wisconsin (retired). She is a past president of the Milwaukee Guild of the CMA and a former regional director for the Catholic Medical Association.