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The Linacre Quarterly

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Mechanism of action of levonorgestrel emergencycontraception

Chris Kahlenborn, Rebecca Peck & Walter B. Severs

To cite this article: Chris Kahlenborn, Rebecca Peck & Walter B. Severs (2015) Mechanism ofaction of levonorgestrel emergency contraception, The Linacre Quarterly, 82:1, 18-33, DOI:10.1179/2050854914Y.0000000026

To link to this article: http://dx.doi.org/10.1179/2050854914Y.0000000026

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Mechanism of action of levonorgestrelemergency contraception

CHRIS KAHLENBORN1, REBECCA PECK2 AND WALTER B. SEVERS3

1The Polycarp Research Institute, Enola, PA, USA2Florida State University College of Medicine, FL, USA3College of Medicine Penn State University; Hershey, PA, USA

Therehas been much debate regarding levonorgestrel emergency contraception’s (LNG-EC’s) method ofaction since 1999 when the Food and Drug Administration first approved its use. Proponents of LNG-EC have argued that they have moral certitude that LNG-EC works via a non-abortifacient mechan-ism of action, and claim that all the major scientific and medical data consistently support thishypothesis. However, newer medical data serve to undermine the consistency of the non-abortifacienthypothesis and instead support the hypothesis that preovulatory administration of LNG-EC has signifi-cant potential to work via abortion. The implications of the newer data have important ramificationsfor medical personnel, patients, and both Catholic and non-Catholic emergency room protocols. In thefuture, technology such as the use of early pregnancy factor may have the potential to quantify howfrequently preovulatory LNG-EC works via abortion.

Lay Summary: How Plan B (levonorgestrel emergency contraception) works has been vigorouslydebated ever since the Food and Drug Administration approved it in 1999. Many doctors andresearchers claim that it has either no—or at most—an extremely small chance of working via abortion.However, the latest scientific and medical evidence now demonstrates that levonorgestrel emergency con-traception theoretically works via abortion quite often. The implications of the newer data haveimportant ramifications for medical personnel, patients, and both Catholic and non-Catholic emergencyroom rape protocols.

Keywords: Levonorgestrel emergency contraception, Abortion, Moral certitude, Early pregnancyfactor

HISTORY

Emergency contraception (also known aspostcoital contraception or the morning-after pill) refers to the use of drugs ordevices as an emergency measure toprevent pregnancy (Zieman 2014). In1966, researchers began to use syntheticestrogens such as diethylstilbestrol andethinyl estradiol as emergency contracep-tion (EC). These formulations had bothlow efficacy and numerous side effects. In

the early 1970s, the Yuzpe regimen wasinvented. It was a combination birthcontrol pill given within a twelve-hourinterval within three days of sexualrelations. In 1999, the Food and DrugAdministration approved Plan B (levonor-gestrel emergency contraception,LNG-EC) as the first progestin-only typeof EC. Plan B had various advantagesover the Yuzpe regimen, including higherefficacy and the absence of estrogen-related side effects. Plan B is often given

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in both secular and Catholic hospitals(under certain conditions) in order toattempt to prevent pregnancy. Recently,other methods of EC have been intro-duced (e.g., ulipristal acetate, a selectiveprogesterone receptor modulator), butlevonorgestrel emergency contraceptionhas garnered the most attention as it is themost widely used EC in the world (Trus-sell and Raymond 2013).The controversy over LNG-EC focuses

mainly on whether it is an abortifacient,that is, whether it causes the loss of lifeafter fertilization. In order to answer thisquestion, researchers have conductednumerous studies over the years. A criticalelement of such studies is the ability toaccurately determine a woman’s day ofovulation. Many earlier studies1 (Arowo-jolu, Okewole, and Adekunle 2002;Creinin et al. 2006; Hamoda et al. 2004;He et al. 1991; Ho and Kwan 1993;Tirelli, Cagnacci, and Volpe 2008; VonHertzen and Van Look 1998; von Hertzenet al. 2002) have relied on a woman’s recallof the last day of her previous menstrualperiod as well as its length; this has beenshown to be inaccurate (Espinós et al.1999; Noe et al. 2011). Other studies haverelied solely on hormone levels (Hapan-gama, Glasier, and Baird 2001; Novikovaet al. 2007). To date, five studies havemeasured both recall and hormone levels(Croxatto et al. 2004; Durand et al. 2001,2010; Massai et al. 2007; Noe et al. 2011);four of these studied primarily sterilizedwomen (Croxatto et al. 2004; Durandet al. 2001, 2010; Massai et al. 2007).

NEW DEVELOPMENTS

The Noe Study

In 2010, Noe et al. published the mostsophisticated study to date on

levonorgestrel emergency contraception(Noe et al. 2010), which they updated in2011 (Noe et al. 2011). This is the largeststudy to date to employ serial transvaginalassessments of follicular size to determineovulation. It contains some of the key datathat support the claim that LNG-ECworks at times via abortion. Noe et al.enrolled 450 women who requestedLNG-EC at a Chilean family planningclinic; each received 1.5 mg of LNG-ECwithin 120 hours of unprotected sexualrelations, and 99 percent receivedLNG-EC within 72 hours of relations. Intheir study, 103 were determined to havehad relations within the five days prior toovulation (e.g., days -5, -4, -3, -2, or -1),that is, the preovulatory group; 45 womenhad relations on the day of ovulation (day0) or after, referred to as the postovulatorygroup. Noe et al. estimated the number ofexpected pregnancies for each group bycalculating the likelihood of pregnancybased on the work of Wilcox, Weinberg,and Baird (1995), who in 1995 generateda predictive model to estimate the prob-ability of pregnancy for each day of themenstrual cycle by measuring hormonalurine profiles in women who were tryingto become pregnant. Noe et al. found thatnone of the women who took LNG-ECin the preovulatory period became clini-cally pregnant, while they predictedsixteen women should have become preg-nant had they not received LNG-EC.They concluded that levonorgestrel ECwas 100 percent effective in stopping clini-cal pregnancy if given prior to ovulation.In the postovulatory group, they foundthat eight women who received LNG-ECbecame pregnant, while the Wilcox modelpredicted that 8.7 pregnancies should haveoccurred. They concluded that levonorges-trel had no effect in stopping pregnancy ifgiven on the day of ovulation or afterovulation.

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ARGUMENTS AGAINST AN ABORTIFACIENT

EFFECT AND REBUTTALS

Argument Number 1: Redefinition ofPregnancy

Some today advance the argument thatLNG-EC is not abortifacient because theyattempt to define pregnancy as beginningat implantation and argue that any loss oflife prior to implantation is not abortion.This definition was first promoted by theAmerican Congress of Obstetricians andGynecologists (ACOG)2 in 1965 (Ameri-can College of Obstetricians andGynecologists Terminology Bulletin 1965),who attempted to redefine life as beginningat implantation. If one accepts this defi-nition, then one may conveniently forgomentioning its abortifacient effect topatients, as any destruction of life priorto implantation would be defined as “priorto being pregnant.” This argument justifiesits conclusions by arbitrarily altering thedefinition of when life begins. We considerthis argument devoid of biological accuracy.For clarity, the terms used in this paperaccept the definition that any hormone ordevice that causes an artificial interruptionof life after fertilization is an abortifacient.

Argument Number 2: LNG-EC Stops,Delays, or Alters Ovulation

Proponents of LNG-EC have argued thatLNG-EC’s dominant mechanism ofaction is inhibition or delay of ovulation.For example, in 2008, the InternationalConsortium for Emergency Contraceptionand International Federation of Gynecol-ogy & Obstetrics stated that LNG-EC“inhibits or delays ovulation” and that“this should be its primary and possiblyonly mechanism of action” (InternationalConsortium for Emergency Contraception(ICEC), International Federation of

Gynecology & Obstetrics (FIGO) 2008).Furthermore, in August 2013, the Ameri-can Congress of Obstetricians andGynecologists noted that “Before ovu-lation, treatment with emergencycontraception is believed to disrupt follicu-lar maturation and consequently inhibit ordelay ovulation.”3 Finally, in a recentreview article, Gemzell-Danielsson,Berger, and Lalitkumar (2013) noted:

Emergency contraception with a singledose of 1.5 mg LNG … acts throughinhibition of or postponing ovulation.

This has also been one of the mainarguments used by some bishops to justifythe use of LNG-EC in rape protocolswhen given prior to ovulation.4

However, recent studies clearly demon-strate that LNG-EC does not consistentlystop or delay ovulation. Noe et al. alsonoted that 80 percent of women in the pre-ovulatory group had evidence of follicularrupture5 if LNG-EC was given on days -5to -1; this increased to 92 percent (i.e., 22out of 24) if it was given on day -2. Inaddition, they noted that if LNG-EC wasgiven on day -2 or -1, about 93 percent(i.e., 26 of 28) of women had evidence ofboth follicular rupture (via ultrasound) andelevated progesterone levels (over 12 nmol/l) (Noe et al. 2010).6 Three other studiesthat measured ovulation via both hormonelevels and ultrasound corroborate Noe et al.’s findings. Massai et al. (2007) notedthat 84 percent of women had evidence offollicular rupture if they were givenLNG-EC when the follicular diameter was18 mm or greater. Croxatto et al. (2004)noted that 74 percent (29/39) of womenwho received LNG-EC on or after day -4and 88 percent (15/17) of women whosefollicular diameter was over 18 mm (i.e.,near day -2) had evidence of both follicularrupture and progesterone levels over 12nmol/l. Durand et al. (2010) studied thirtywomen who took LNG-EC in the

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preovulatory period. All of the women whotook LNG-EC when the average folliculardiameter was 18.4 mm (i.e., estimated to beday -2) had evidence of both follicularrupture and elevated progesterone levels.Thus, the studies to date that used bothultrasound and hormone levels to measurethe day of ovulation found that whenLNG-EC was given within 5 days prior toovulation, it had limited effect upon ovu-lation (Croxatto et al. 2004; Massai et al.2007; Noe et al. 2011) and even less so ifgiven near day -2. Finally, Durand et al.(2001) noted that LNG-EC had no effectupon the day of ovulation when given onday -3, that is, it caused no delay in ovu-lation. Brache et al. (2013) also noted thatif LNG-EC was given around day -2, itcaused no delay in ovulation. We considerthese points strong evidence against theclaim that levonorgestrel EC stops or delaysovulation when given in the preovulatoryperiod. A recent paper co-authored by Dr.Croxatto seems to partially concede thispoint:

From previous studies, it has becomeclear that the ability of LNG to interferewith the ovulatory process decreases asovulation nears. (Brache et al. 2013)

Noe et al. offer an alternative explanationas to why women in the preovulatory periodwho receive LNG-EC do not become preg-nant. They claim that LNG-EC alters thenormal ovulatory process and thereforemakes it more difficult for fertilization tooccur. The basis of this claim comes fromDr. Croxatto’s 2004 paper (Croxatto et al.2004) in which he defined the term “ovula-tory dysfunction” as: “Follicular rupture notpreceded by an LH peak or preceded by ablunted LH peak (<21 IU/l), or not fol-lowed by elevation of serum P over 12nmol/l.” However, there is scant support inthe literature for the ovulatory dysfunctionhypothesis for several reasons.

First, we noted above that the studies ofboth Noe et al. and Durand et al. found thatpreovulatory administration of LNG-ECresulted in both successful follicular ruptureand progesterone levels over 12 nmol/l inabout 93–100 percent of cases when givenaround day -2. In addition, Croxatto et al.’sown paper noted that all women whoexperienced “ovulatory dysfunction”—eventhose who received LNG-EC as early as 5days prior to ovulation—experienced pro-gesterone peak levels over 36 nmol/l.Therefore, the data in the medical literatureare not consistent with the latter half of Dr.Croxatto’s own definition of ovulatory dys-function, which specifies progesterone levelsunder 12 nmol/l.Second, in 2004, Croxatto et al. noted

that

Cohlen et al. reported that the probabilityof conception in spontaneous cycles wasrelated to the pattern of LH surge. A lowLH surge (25–42 IU/l) of short duration(1 day) was associated with a reducedpregnancy rate of 5.6%, whereas a 2-daysurge exceeding 42 IU/L resulted in apregnancy rate of 23%.

However, while Croxatto et al. empha-sized the height of the LH surge, theyfailed to emphasize the duration of thesurge. For example, Cohlen et al. (1993)noted in Table 2 of their paper that inwomen who had LH surges of shorterduration, the difference in pregnancy ratesbetween low and high LH levels was only5.6 percent versus 9.9 percent. In addition,in women who had LH surges of longerduration, the difference in pregnancy ratesbetween low and high LH levels was only20 percent versus 23.4 percent. Therefore,if one compares pregnancy rates for differ-ent LH surge levels, while keeping theduration of the LH surge constant, far lessdifference is observed.In addition, Cohlen et al.’s study noted

that cycles with lower LH surge levels of

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longer duration (i.e., 25–42 IU/l) were attimes associated with higher pregnancyrates than cycles with higher LH surgelevels of short duration (e.g., 20% versus11.6%). Cohlen et al. actually emphasizedthis point: “The data in Table 2 alsosuggest that the duration of the LH surge ismore important than the height: in therather exceptional cases in which high-shortand low-long surges occur, the pregnancyrate in the cycles with the low-long surgesis almost twice as high as the one with thehigh-short surges.” Cohlen et al. concluded:

Taking into account that the durationand height of the LH surge are corre-lated, it seems that duration is moreimportant than height.

Lastly, Croxatto et al. cited Verpoestet al.’s in vitro fertilization study (Verpoestet al. 2000) in which Verpoest et al. notedthat oocytes that had higher concentrationsof LH in their follicular fluid demonstratedhigher rates of fertilization. However, Ver-poest et al.’s conclusions were based on invitro measurements of follicular LH levels,which cannot even be measured in vivo. Inaddition, Verpoest et al.’s study resultsseem to conflict with those of Cohlenet al.; Verpoest et al. noted that the medianserum LH level of the unfertilized oocytegroup was 42.5 IU/l; however, the Cohlenet al. study noted high rates of fertilizationwhen serum LH levels were above 42 IU/l.In light of the inconsistencies and medicaldata noted above, the “ovulatory dysfunc-tion” argument does not provideconvincing or consistent support in favor ofa non-abortifacient action of LNG-EC.

Argument Number 3: Progestins AlterSperm Flow and/or Function

Noe et al. cite this as a possible mechan-ism of action when LNG-EC was givenin the preovulatory period. They note:

Follicular rupture was detected in mostwomen … nevertheless, they did notbecome pregnant. One possible expla-nation is the increase in cervical mucusviscosity produced by LNG, which inter-feres with sperm passage. (Noe et al. 2011)

In an earlier paper, Croxatto (2002)referenced an older study (Kesserü et al.1974) as the basis of their claim:

Administration of 400 mcg of LNG 3–10 hours after sexual intercourse affectedsperm migration between 3 and 9 hoursafter treatment. It reduced the number ofspermatozoa recovered from the uterinecavity, increased the pH of the uterinefluid (which immobilized the spermato-zoa) and increased the viscosity of cervicalmucus (which impeded further passage ofsperm cells into the uterine cavity).

While chronic administration of proges-tins tends to inhibit sperm via thickeningof cervical mucus (Okewole et al. 2007),this does not appear to be true for short-term administration of LNG-EC. Forexample, do Nascimento et al. (2007), in arecent and more sophisticated study thanthat of Kesserü et al. (1974), found that ifwomen were given LNG-EC 12 to 36hours after relations, viable sperm werefound in uterine flushings up to 60 hoursafter coitus and sperm acrosome reactionwas not affected. In addition, they notedthat 14.5 million and 17.3 million sperma-tozoa/ml were found respectively in womenwho took LNG-EC at 24 or 48 hours aftersexual relations. Brito et al. (2005) foundthat LNG-EC had no capacity to affectsperm’s acrosome reaction in either capaci-tated or non-capacitated sperm. Finally,when LNG was given

in a similar dose to that observed in serumfollowing oral intake for EC, LNG hadno effect on the number of motile sperma-tozoa recovered from the human fallopiantubes in vitro, on their adhesion to the

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tubal epithelium, distribution or AR rate.(Hermanny et al. 2012)

Therefore the argument that LNG-ECeffectively inhibits sperm flow or functionis clearly not supported by current medicaldata.7

Argument Number 4: ProgestinsStabilize the Endometrium

Proponents of levonorgestrel EC oftenargue that levonorgestrel EC is a proges-tin, and because progesterone, the body’snatural progestin, is often used to stabilizea pregnancy, levonorgestrel EC in turnshould have a stabilizing effect upon theendometrium. This may be true undercertain conditions. While it is true thatlevonorgestrel EC is a type of progestin, itis a synthetic hormone that is given insupraphysiological doses. For example, onedose of LNG-EC contains 1.5 mg oflevonorgestrel, the equivalent of more than75 percent of the entire month’s supply ofthe amount of levonorgestrel found incertain oral contraceptives.8

The effect of levonorgestrel appears todepend upon when in the cycle it is given.For example, the accumulation of data fromthree major studies (Arowojolu andOkewole 2004; Gainer, Mery, and Ulmann2001; von Hertzen et al. 2002) show that1,034 of 3,496 women bled within 7 days oftaking LNG-EC (i.e., 29.6% bleeding rate),and this bleeding appears to be mostcommon when LNG-EC is given prior toovulation (Gainer, Mery, and Ulmann2001). Endometrial bleeding denotes majorendometrial instability and could cause lossof the embryo that is about to be or hasrecently been implanted.However, if levonorgestrel EC is given

on the day of ovulation or after, it couldactually stabilize the endometrium andmight have the potential to increase awoman’s likelihood of pregnancy, as would

be the case if the observed number of clini-cal pregnancies were higher than theestimated number. Noe et al. (2011) notedthat in the postovulatory group, eightwomen who received levonorgestrel ECbecame pregnant while they predicted that8.7 women should have become pregnant.However, it is likely that Noe et al. overes-timated the number of women expected tobecome pregnant as they based their esti-mates on the Wilcox study (Wilcox,Weinberg, and Baird 1995). In that study,women were trying to become pregnant,and women who are trying to becomepregnant appear to have far higher spermcounts than women who take LNG-EC.For example, Espinós-Gómez et al. (1999)noted in their 2007 study that spermatozoawere detected in 63.8 percent of womenwho took EC but were present in 100percent of controls who did not take ECand were trying to get pregnant.9 They alsonoted that the controls had 3 times highersperm counts than those who took EC.Based on the work of Espinós-Gómezet al., it is very likely that the women whoreceived LNG-EC in Noe et al.’s studyhad lower sperm counts than women in theWilcox study who were trying to becomepregnant. In addition, Noe et al. notedthat 41 and 6 percent of the includedwomen said they had problems withcondom use or coitus interruptus, respect-ively; these women would theoreticallyhave lower sperm counts or even no sperm.This has been noted in the medical litera-ture: Croxatto noted in 2007 that

a large proportion of cases requesting ECin those studies correspond to “condomfailures,” and up to 36 percent of thosehave no sperm in the vagina or cervicalcanal within 6 hours after coitus. Thosecases are included in the “at-risk group”in the efficacy studies leading to an over-estimation of the efficacy of EC.(Croxatto 2007)

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In light of these data, it is highly likelythat the women who received LNG-EC inNoe et al.’s study had lower sperm counts—and some may not have had any sperm atall—compared with women who weretrying to become pregnant. Therefore, Noe et al. may have overestimated the numberof expected pregnancies, a point that Dr.Noe freely acknowledges.10 If this weretrue, that is, if the expected number of preg-nancies in the postovulatory group had beenless than 8, then LNG-EC could actuallybe stabilizing pregnancy if given on or afterthe day of ovulation. Other authors haveacknowledged this possibility. Davidoff andTrussell note:

It even raises the counter-intuitive butundocumented possibility that Plan B usedafter ovulation might actually prevent theloss of at least some of the 40 percent offertilized ova that ordinarily fail spon-taneously to implant or to survive afterimplantation. (Davidoff and Trussell 2006)

Argument Number 5: LNG-EC DoesNot Affect the Endometrium

It is argued that if LNG-EC does not affectthe endometrium it cannot be causing anabortion. There are three main reasons whythe stable endometrium theory is weak.First, while there are data, both in

animals and humans, which show thatLNG-EC has little effect upon the endo-metrium, other data do show an effect.For example, Ugocsai, Rózsa, and Ugocsai2002) noted in 2002 that when higherdoses of LNG-EC were given (i.e., about2½ times the normal dose) they causedobvious loss of ciliated cells, and pino-podes disappeared. This could haveimplications for women who have lowbody weight and might experience higherpeak concentrations of levonorgestrel.Second, Durand et al. (2005) noted that

LNG-EC changed endometrial glycodelin-A levels, which could affect implantation.

The third problem with the stable endo-metrium theory is that even though theendometrium appeared stable in somestudies on a histological level, it appearedunstable on a clinical level. We noted earlierthat women who take LNG-EC prior toovulation are those who are most likely tobleed and that studies show that 29.6percent of women who take LNG-ECdevelop menstrual bleeding within 7 days;thus, even if implantation did, or was aboutto occur, the embryo could easily bedestroyed due to substantial sloughing.Finally, even if LNG-EC had no effect

on the endometrium, it could still causeabortion via alternative mechanisms asnoted in the “Burden of Proof” section.

Argument Number 6: LNG-EC DoesNot Increase the Ratio of Ectopic

Pregnancies

Opponents of an abortifacient mechanismof LNG-EC argue that if it worked by pre-venting implantation it should decrease thenumber of intrauterine pregnancies butshould have no effect on the number ofectopic pregnancies (Davidoff and Trussell2006); therefore, the ratio of ectopic tointrauterine pregnancies should be on thehigh end of the expected ectopic pregnancyrate if LNG-EC worked via abortion andthe low end if it did not. They cite Clelandet al.’s (2010) study, whose review paperconcerning LNG-EC and ectopic preg-nancy noted a 1 percent ectopic pregnancyrate (3/307) which falls on the lower end oftheir estimated normal rate of ectopic preg-nancy (i.e., 1–1.9%). However, Clelandet al. did not include the results of twoimportant studies, both of which obtainedtheir data from retrospective chart reviews:the first, by Gainer, Mery, and Ulmann(2001) noted an ectopic pregnancy rate of4.1 percent (3/73); the second, by Lo andHo (2012) published after the Cleland

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study, noted an ectopic pregnancy rate of2.3 percent (3/128). If Cleland et al. hadincluded these studies, the new ratio wouldhave been 1.8 percent (9/508), a ratio moreconsistent with an abortifacient effect.

Argument Number 7: LNG-EC DoesNot Work Efficiently

The American Congress of Obstetriciansand Gynecologists claims that Plan B has anefficacy rate of 85 percent,3 a statistic whichis far higher than that of a more recent study(Noe et al. 2011). Researchers who haveemployed elaborate statistical models havenoted that if LNG-EC were 85 percenteffective, it would strongly imply that itworked via abortion a portion of the timeand if LNG-EC were less efficacious, itwould be less likely to be an abortifacient(Mikolajczyk and Stanford 2007; Valenzuela2007). Recent trials such as that of Noe et al. (2011) noted an efficacy rate of 68percent. However, even this estimate islikely too high, as we noted earlier, consider-ing the lower sperm counts noted in womenwho receive LNG-EC. If the latter were asignificant factor, then the efficacy ofLNG-EC could actually be less than 50percent. In addition, LNG-EC appears tohave far less effect in obese women andalmost no effect in women whose body massindex (BMI) is over 30 (Glasier et al. 2011).We agree with many researchers that

LNG-EC’s efficacy is likely much lowerthan that promulgated by the AmericanCongress of Obstetricians and Gynecolo-gists and that the lower the efficacy rate,the less likely that LNG-EC will work bycausing abortion. However, as noted inNoe et al.’s (2011) study, no women whotook LNG-EC in the preovulatory periodhad clinical pregnancies, whereas sixteenpregnancies were expected (i.e., 0/16). IfNoe et al. had had a more accurate methodof estimating expected pregnancy (e.g., by

studying only women in whom sperm werepresent and excluding women whoreported condom failure or coitus interrup-tus), they may have generated a lowerexpected pregnancy rate. However, even ifNoe et al. had generated a lower estimate,the numerator would still have been zero,so that LNG-EC still would have been 100percent effective in stopping clinical preg-nancy in the preovulatory period whilefailing to stop ovulation and sperm flowand likely fertilization. Therefore, even ifLNG-EC works less efficiently thannational sources claim, the data stillsupport an abortifacient method of actionwhen given in the preovulatory period.

Argument Number 8: Time-delayArgument

Two trials conducted via the World HealthOrganization have shown that the efficacyof LNG-EC decreases when the intervalbetween intercourse and LNG-EC admin-istration increases (Von Hertzen and VanLook 1998; von Hertzen et al. 2002). Noe et al. (2011) noted that if an endometrialeffect were present, then theoretically theefficacy of LNG-EC should not decreaseas the time period between administrationof LNG-EC and unprotected intercourselengthens as noted in the WHO trials.This argument appears weak mainlybecause in both of the World HealthOrganization trials the authors relied solelyon recall to predict the expected day of ovu-lation. Noe et al.’s (2011) own studyshowed that this method is inaccurate andlimits any firm conclusions from the trials.In addition, it is certainly possible thatLNG-EC could be causing abortion via anon-endometrial (e.g., fallopian-based)effect. For example, there is evidence thatLNG-EC may slow the transport of thenewly fertilized ovum in the fallopian tube,which could cause it to arrive at the

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endometrium outside of the implantationwindow and lead to a failure to implant.Mahmood et al. (1998) noted that higherprogesterone concentrations inhibitedciliary beat frequency in the fallopian tube.It is conceivable that high-dose levonorges-trel levels could have a similar effect.In addition, Wånggren et al. noted thatlevonorgestrel markedly decreased muscularcontractions in the fallopian tube in vitro(Wånggren et al. 2008). If LNG-ECslowed the kinetics of sperm/ova transportin the fallopian tube, it could explain whyearly administration might result in ahigher efficacy than delayed administration,since the effects of LNG-EC on the fallo-pian tube could be time-sensitive.

THE BURDEN OF PROOF

Those who advocate a non-abortifacientaction of LNG-EC must have moral certi-tude that it will not risk the loss of humanlife. We have noted significant weaknessesin all of the major arguments that havebeen used by those who claim thatLNG-EC works via a non-abortifacientaction. Two recent review papers havereached similar conclusions (Peck andVelez 2013; Raviele 2014). In light of themost recent scientific and medical datanoted in this paper, the claim of moralcertitude in regard to a non-abortifacientaction of LNG-EC is not justifiable.We noted earlier that the data support

the hypothesis that functional sperm andova are not inhibited from flowing freely tothe fallopian tube and there is no obviousreason why fertilization could not occur.11

However, Noe et al. (2011) found no evi-dence of clinical pregnancy whenLNG-EC was given prior to ovulation.The absence of any evidence of clinicalpregnancy in instances when fertilizationoccurs is, by definition, abortion. At thispoint, one cannot determine how

frequently fertilization occurs whenLNG-EC is given prior to ovulation,however, if future testing shows that fertili-zation occurs normally in the setting ofpreovulatory administration of LNG-EC,it would mean that prevoulatoryLNG-EC’s dominant method of action isvia abortion.Although the burden of proof lies on

proponents who advocate a non-abortifacient action of LNG-EC, there aremultiple theoretical explanations as to howLNG-EC could cause abortion whengiven prior to ovulation. First, as we notedearlier, LNG-EC has the potential tocause endometrial bleeding within 7 daysof its consumption 29.6 percent of thetime, especially when taken in the preovu-latory period. This could cause abortion iffertilization had occurred via endometrialsloughing. Second, LNG-EC may cause aluteal phase defect phenomenon whengiven in the follicular phase. For example,Tirelli, Cagnacci, and Volpe (2008) notedthat women who take LNG-EC in thepreovulatory period experienced nearly aneleven-day shortening of their menstrualcycle, although this phenomenon occurredless frequently when LNG-EC was givencloser to the day of ovulation. Third, wenoted previously that LNG-EC may slowthe transport of the newly fertilized ovumin the fallopian tube, which could cause itto arrive at the endometrium outside ofthe implantation window and lead to afailure to implant. Finally, it is possiblethat in the future LNG-EC might befound to cause changes in the fallopiantube or in the implantation process inways that we are unaware of today. Forexample integrins and glycodelins, bothdiscovered in the past 30 years, are criticalto the implantation process; and it is likelythat newer molecular proteins that couldaffect the fallopian tube and/or theimplantation process will be discovered inthe future. We conclude that based on

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current scientific and medical data, thereis significant potential that the clinicalefficacy of preovulatory administration ofLNG-EC is due to an abortifacienteffect, with the death of the embryo inthe fallopian tube, in utero, or afterimplantation.

EARLY PREGNANCY FACTOR AND

LNG-EC

Studies to determine the frequency ofabortion due to preovulatory LNG-ECmight benefit if early pregnancy factor(EPF) technology was utilized. EPF is animmunosuppressive protein secreted by theovary shortly after fertilization. It was discov-ered in 1974 by Morton, Hegh, and Clunie(1974) and has been described as the “mostsensitive parameter for the surveillance ofearly pregnancy” (Straube et al. 1989). SinceEPFs discovery, almost every study has cor-roborated its sensitivity and specificity excepttwo (Cooper and Aitken 1981; Thomsonet al. 1980). Both of these studies, however,deviated from Morton’s original method ofmeasuring EPF (Smart et al. 1982b). EPFhas been described in detail in multiplepapers from the 1970s through early 2000.We believe it could be a tool for settling thecontroversy regarding LNG-EC’s mechan-ism of action for several reasons.12

First, both animals (e.g., mice, rats,pigs, sheep, and cattle) and humansexhibit EPF early in pregnancy (Fan andZheng 1997; Shahani and Moniz 1992).It is detectable within 48 hours after ferti-lization (Rolfe 1982; Smart et al. 1981).Second, EPF levels fall to normal

within 2–5 days after induced abortion(Cheng et al. 2000; Hübel et al. 1989).This supports EPF’s role as a marker forpregnancy as well as non-pregnancy.Third, EPF levels correlate well with B

hcg (Gerhard, Katzer, and Runnebaum1991).

Fourth, historically, EPF has been citedas strong evidence to show that the intrau-terine device (IUD) works by causing earlyabortions (Smart et al. 1982a); this findingwas later corroborated by research thatmeasured early pregnancy in IUD users viaB hcg (Landesman, Coutinho, and Saxena1976).Fifth, EPF has been cited as giving evi-

dence in favor of Clomid’s potentialabortifacient effect. Shahani et al. (1995)noted that Clomid resulted in an 80percent loss of embryonic life, higher thanthe standard calculated rate of about 48percent13 (Mesrogli, Maas, and Schneider1988).Sixth, a review of the studies regarding

very early pregnancy (i.e., within sevendays after fertilization) showed that EPFwas positive 93.6 percent of the time (i.e.,44/47) (Chen 1985; Fan and Zheng 1997;Koh and Jones 1982). A review of thestudies of women who were pregnant intheir first trimester showed that EPF was91 percent accurate (i.e., 172/189) (Mehtaet al. 1987; Morton, Rolfe, and Clunie1977; Shu-Xin and Zhen-Qun 1993;Wang and Zheng 1990). Therefore, EPFhas a good ability to detect early preg-nancy (i.e., true positives), that is, it hashigh sensitivity.Seventh, EPF has good specificity (the

ability to measure true negatives). Twostudies (Koh and Jones 1982; Qin andZheng 1987) showed that EPF was negativein the serum of ninety of ninety-four (i.e.,95.7%) non-pregnant women or men.14

Given the fairly strong data about EPFand early pregnancy, the question shouldbe asked: can EPF be used to confirm ordeny the presence of human life whenLNG-EC is given prior to ovulation? Wenoted earlier that EPF was found to bepositive in six of 23 cases in which anIUD was present, which historically, hasbeen cited as strong evidence in favor anabortifacient effect (Smart et al. 1982a).

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However, using EPF to measure abortionrates with LNG-EC would be technicallychallenging. One would have to followMorton’s original protocol, which wouldrequire time and a sophisticated labora-tory. One would have to confirm EPF’ssensitivity and specificity for that particularstudy by simultaneously studying a side-control group containing early pregnancyand non-pregnancy cohorts. One wouldhave to measure EPF several times atone-day intervals starting with the secondday after fertilization to avoid missing veryearly pregnancies that might expire beforehaving the opportunity to test for them.Finally, one would have to measure EPFwhen LNG-EC is given both prior toovulation and after ovulation.Would detection of EPF under these

conditions prove the case? It would seemthat even a low rate of detection (e.g., 3–4%) would be very strong evidence of anearly abortion effect, because the rate offertilization in women who seek LNG-ECis likely far lower than women who aretrying to conceive, as previously noted.

CONCLUSIONS AND IMPLICATIONS

The arguments used to justify use ofLNG-EC as a non-abortifacient drugcarry substantial weaknesses; in addition,the preovulatory administration ofLNG-EC does not consistently altersperm or ova flow and function, yet thereis absence of clinical pregnancy in caseswhere fertilization is likely, which suggeststhat abortion is a likely mechanism ofaction. Therefore, the claim that moralcertitude exists via LNG-EC’s non-abortifacient action is currentlyindefensible.LNG-EC is not as efficacious as is cur-

rently being promoted by nationalorganizations such as the American Con-gress of Obstetricians and Gynecologists.

In addition, LNG-EC does not appear toprevent pregnancy in women with highBMIs.Physicians who dispense LNG-EC to

rape victims in the preovulatory period—especially if given within two days of pro-jected ovulation—are giving LNG-EC ata time in a woman’s menstrual cycle whenit has significant potential to work via thedeath of the embryo. Physicians who dis-pense LNG-EC in the postovulatoryperiod may be increasing a woman’s riskof becoming clinically pregnant. Physicianswho give LNG-EC in either of theseperiods who fail to inform their patient ofthese effects are not allowing their patientsto receive fully informed consent.Catholic hospitals that allow the dis-

pensing of LNG-EC prior to ovulation—especially when given within 48 hours ofovulation—are permitting the use of adrug which has a significant potential ofworking via abortion.In light of this, current Catholic rape

protocols that allow for the dispensation ofLNG-EC if the woman is determined tobe in the preovulatory period, appear to befaulty and should be revised. Since themost recent medical data clearly note thatLNG-EC does not effectively stop ovu-lation and has high potential to work viaabortion when given prior to ovulation,these protocols would no longer be incompliance with Catholic teaching.Given that the updated information

presented in the Noe et al. paper stronglyaffirms LNG-EC’s failure to inhibit ovu-lation and sperm flow, it is not accurate tolabel LNG-EC as simply a contraceptive.The nomenclature regarding LNG-ECshould be updated. If given prior to ovu-lation, LNG-EC should be labeled asemergency abortion/contraception.EPF may have the potential to more

clearly define and quantify LNG-EC’smechanism of action. If and until such atrial is done, unless proven otherwise, the

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medical literature supports the assertionthat LNG-EC has significant potential tocause an abortion, especially when givenwithin 48 hours of projected ovulation.

ENDNOTES

1. Tirelli, Cagnacci, and Volpe (2008) diduse ultrasound and hormonal evaluation ina small subset analysis in eight women.

2. ACOG was formerly the AmericanCollege of Obstetricians and Gynecologists.This is still their official position today.http://www.acog.org/About_ACOG/News_Room/News_Releases/2012/April_20_Letter_to_the_ Editor.

3. http://www.acog.org/About_ACOG/ACOG_Departments/Health_Care_for_Underserved_Women/Frequently_Asked_Questions_about_Hormonal_Approaches_to_Emergency_Contraception.

4. The most common protocol, called theovulation approach, based on the PeoriaProtocol is described in detail by Hameland Panicola (2012). This protocol allowsdispensing emergency contraception if awoman’s progesterone level is under 1.5ng/ml and her urine LH (LuteinizingHormone) test is negative, that is, if she isdetermined to be in the preovulatoryperiod. This method is based upon theassumption that emergency contraceptionefficiently inhibits ovulation when given inthe preovulatory phase and thereforetheoretically should not work via abortion.

5. Follicular rupture is the abrupt disappear-ance or a reduction in size of at least 50percent of the echo-image of a leading fol-licle that had at least attained 15 mm indiameter (Massai et al. 2007).

6. Email correspondence with Dr. GabrielaNoe, January 19, 2013.

7. To the best of this author’s knowledge, noone has adequately studied the effect ofLNG-EC when given 0–12 hours aftersexual relations. Kesserü et al. used oldertechnology and employed a dose of LNGthat was 27 percent of today’s LNG-ECdose. Extrapolating retrospectively via doNascimento et al.’s study might lead oneto hypothesize that LNG-EC would havelittle effect upon sperm migration if givenwithin 12 hours of sexual relations.

8. The following contraceptives contain atotal of 1.925 mg of levonorgestrel in eachmonth’s supply: Tri-levlen 21, Tri-levlen28 and Trivora.

9. Email correspondence with Dr. Espinós:January 18, 2013.

10. Email correspondence with Dr. GabrieleNoe: April 25, 2013.

11. One could argue that LNG-EC has anindependent direct effect upon sperm or ovawhich might be expected to be present inboth the pre- and postovulatory phasesand would theoretically inhibit fertilizationin both phases. Since this clearly does notoccur, this hypothesis does not appear tobe valid.

12. EPF might also be used to test whetheroral contraceptives work at times bycausing the destruction of the embryo, asis implied by several papers (Larimore andStanford 2000; Pierson et al. 2003).

13. The rate of pregnancy loss in womenwho have newly conceived has beendebated at length with markedly differentestimates. In their overview, Mesrogli,Maas, and Schneider (1988) quoted fourstudies. One of them (Hertig, Rock, andAdams 1956) simply measured congeni-tal abnormalities in fertilized ovum takenfrom women’s uteri during hysterectomy;the second study (Roberts and Lowe1975), based the estimate on multipleassumptions and admitted that thisamounted to “speculative arithmetic.”The only two studies that had concreteways of measuring early pregnancy losswere those of Miller et al. (1980) andRolfe (1982). If we sum their findings,we note that from 170 conceptions theyfound 81 losses, for a total pregnancy lossrate of 48 percent.

14. Note: Men were used as controls becausethey cannot become pregnant.

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BIOGRAPHICAL NOTE

Chris Kahlenborn, M.D. Dr. Kahlenbornis president of The Polycarp ResearchInstitute and a board certified internist.His email address is drchrisk@polycarp.org.

Rebecca Peck, M.D., C.C.D., ClinicalAssistant Professor, Florida State Univer-sity College of Medicine. Her emailaddress is rbamer2@yahoo.com.

Walter B. Severs, Ph.D., F.C.P. Pro-fessor Emeritus of Pharmacology &Neuroscience; College of Medicine PennState University, Hershey, PA. His emailaddress is wbs2@psu.edu.

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