Recommendations for the administration of Emergency Contraception to women after rape

Introduction

For emergency contraception (EC) two different drugs are presently available on the market:

1. Levonorgestrel (LNG) at the dose of 1.5 mg, to be taken once, or 0.75 mg to be taken twice within 12 hs.
2. Ulipristalacetate (UPA) at the dose of 30 mg (micronized), to be taken once.

LNG, known under the brand  Vikela^®, Duofem^®, Unofem^®, Plan B^® (to mention a few), is available in Austria and many other countries without prescription. UPA, known as Ella-One^® or Ella^®, on the other hand, is available with prescription only.

Recent scientific evidence holds that the primary effect (more than 50%, if there is an effect at all) of both licensed EC-preparations operates at the post-fertilization level, whereas the pre-fertilization part of activity, such as ovulation inhibition, is rather small.¹ Most of the time the EC pill is administered, when it can act neither at the pre- nor at the post-fertilization level, i.e. when there is no activity at all. Therefore, from an ethical point of view, the deliberate intake of the EC-pill may not be warranted even after rape.

In practice, the LNG-EC pill exhibits interceptive activity in about 10% of applications only, namely if it is administered from 48 hours before ovulation until 24 hours thereafter, whereas in 90% of cases its application will be either unnecessary or eventually inhibit ovulation.²

The UPA-EC pill abrogates ovulation if taken until 24 hours before ovulation. Thereafter, until the ninth day of the luteal phase, it exhibits interceptive activity preventing implantation.³ Given the fact that each EC pill acts differently, depending on when it is taken during the cycle, the question arises, if, by determining the phase of the women’s cycle, it were possible to relieve the conscience of those involved in the administration of the EC pill. Given this state of affairs, there would be no need to refuse administration of the pill in every case, but concerned women could instead be helped if, by appropriate testing, the interceptive window of the EC pill’s mode of action is identified and separated from the non-interceptive window.

Basic considerations

The undersigning persons have elaborated the following recommendations:
The fertile phase of the female cycle can be localized reliably by the combined application of four different methods, namely:

• Sonographic determination of follicle size or identification of a corpus luteum.
• Semiquantitative determination of urine LH.
• Sonographic measurement of endometrium thickness.
• Macroscopic (resp. microscopic) evaluation of cervical mucus.

1. First, the follicle size has to be determined by transvaginal sonography. Unanimous gynecological experience confirms that, even after an event of rape, this inspection does not constitute a major physical or psychical burden, if convenient small sized probes are used. After all, this examination is less troublesome than a vaginal inspection using conventional specula, which anyway has to be carried out for forensic reasons in order to safeguard the traces of rape. Moreover, it should be born in mind that this sonographic inspection can establish with certainty whether fertilization could have occurred or could take place after the act of rape, thereby procuring considerable psychical relieve to the victim at face. This aspect will ease womens compliance with this examination. It can be done even after sedative treatment, if the victim is afraid to endure the procedure in full conscience.
2. Todays state of the art holds that ovulation and fertilization after administration of the EC pill (LNG or UPA) are highly unlikely, if the follicle measures 14 mm in diameter or less.⁴ In a study by Mikolajczyk et al., however, it has been found that some follicles may rupture at a size of 17 mm or even below.⁵ The probability of fertilization is deemed within of thousandth.
3. Therefore, to be sure of the EC pills safeness, the sonographic measurement has to be supplemented by the determination of urine LH. The rise in LH (indicated by a positive test) precedes follicle rupture by 48 hours, thereby defining the period in which intake of the EC pill does not inhibit ovulation but instead might act by an interceptive mode. The LH test is preferably done from blood, but also a quicktest from urine may be employed.
4. Sonographic evaluation of the endometrium thickness procures additional security in  the case of doubt. During the preovulatory period the endometrium attains 10-12 mm in thickness and is adopting a three layered appearance quickly after ovulation. Once the endometrium has reached ≥ 9 mm in thickness, no EC pill may be given any more.⁶
5. To complete the examination, macroscopic and, whenever possible, microscopic examination of cervical mucus should be additionally employed. A positive finding would indicate ovulation to be close, whereas a negative finding is of no significance.
6. Sonography is able to ascertain if ovulation has occurred. However, to differentiate sonographically the appearance of a corpus rubrum (1-2 days after ovulation) from a corpus luteum (several days after ovulation) might not be possible in every case.⁷ The detection of liquid in the Douglas space, anyway, may be taken as evidence for a shortly past ovulation. In that case, even the LNG EC pill may not be given, because its interceptive mode of action lasts until 24 hours after ovulation.

Recommendations

Hence, with inclusion of sufficient safeguard limits, the following significant procedures can be recommended for the treatment of women after rape.

1. Transvaginal ultrasound for valuation of follicle size or corpus luteum
2. Determination of endometrium thickness
3. Quicktest for urine LH
4. Valuation of cervical mucus

These examinations can actually be carried out by any gynecologist in his consulting room or in a hospital ambulance.

If the women presents herself in her preovulatory phase with the follicle size holding ≤ 14 mm and the endometrium thickness < 9 mm, and with the LH test and mucus score both negative, – in that case both EC preparations (LNG-EC in combination with NSAR) may be administered without moral constraints, because pre-fertilization but not post-fertilization mechanisms will operate. If available, UPA should be preferred, because no combination with NSAR is necessary and because it exhibits a greater reliability in obese women. If, in contrast, the follicle measures >14 mm and /or the endometrium thickness is >8 mm and/or either LH test or mucus score are positive – in that case neither EC pill may be administered, because both will operate most probably at the post-fertilization level.⁸

If the women presents herself in her luteal phase with sonographic evidence of an older corpus luteum , i.e. the follicle rupture past two or more days, in that case the LNG-EC pill is ineffective. It may be given without risk of an interceptive mode of action. In contrast, the UPA-EC pill may not be given during the luteal phase at all, because UPA damages the endometrium and interferes with the implantation of the embryo.⁹ If sonographic signs indicate recent follicle rupture, in that case the LNG-EC pill may not be given either, because its interceptive mode of action lasts until 24 hours after ovulation occurred.¹⁰

If these conditions are respected and if doubtful cases are handled with restriction, the administration of EC preparations is safe and will most certainly not entail early embryonal abortion.

Appraisal

If the proposed procedure is followed, women and their physicians could be helped significantly and would not be left alone in a moral dilemma. Most concerned women will be reassured by the message that the act of rape did not or could not give rise to a pregnancy or that intake of the EC-pill will prevent pregnancy by inhibiting ovulation, but not by causing early embryonal demise. Specifically:

1. If the women is found in her preovulatory phase and if the above mentioned conditions prevail, the message is: She can take the EC-pill (UPA, or LNG together with a COX-2 inhibitor) without moral constraints. The pill will act by inhibiting or postponing ovulation but not by an interceptive mode. If the above mentioned conditions do not prevail, the message is: Ovulation is imminent or has happened recently. Therefore, pregnancy may ensue with a probability of 30%. The EC pill acts most probably by an interceptive mode. Therefore, from a moral standpoint, administration of either EC preparation is not warranted.
2. If the women is found in her luteal phase, administration of the UPA-pill is not warranted, because it acts by preventing implantation.
3. If ovulation is past recently, as evidenced by ultrasound, administration of the LNG EC-pill is warranted neither. If ultrasound manifests a corpus luteum, the womens fertile phase is past, provided the act of rape had occurred within the last 24 hours. The women may be pregnant, however, from an earlier intercourse (e.g. by her husband). In that case, administration of the LNG-EC pill is possible, but not recommended in view eventual side effects of the high dosed hormonal drug.
4. Once UPA is prescribed no further act of unprotected intercourse is permitted until next menses.

Overall, the proposed procedure seems to us more affable and empathetic for women in this difficult situation.

Univ.-Prof. Dr. Johannes Bonelli (Clinical Pharmacology)
Mag. Susanne Kummer (Ethics)
Prof. Dr. Enrique H. Prat (Ethics)
MR Dr. Karl Radner (Gynecology)
MR Dr. Romeo Reichel (Gynecology)
Dr. Walter Rella (Reproduction Medicine)

1. IMABE, Aktualisierung der Erkenntnisse zur Wirkweise der „Pille danach“, issued on 2013-02-19. http://www.imabe.org/index.php?id=1861; Rella W., How does Levonorgestrel prevent pregnancy?; Davis J. T., A Judge’s Flawed Understanding of How Levonorgestrel Works; both in: NCBQ (Colloquy); (2013); 13(1):7-14; Rella W., Neue Erkenntnisse über die Wirkweise der „Pille danach“, Imago Hominis (2008); 15(2): 121-129. Furthermore: IMABE Info 2/10 and: Aznar J., Tudela J., Ulipristal acetat. An emergency contraceptive? Medicina e Morale (2011); 2: 233-245
2. see as well ref. 4
3. The UPA-pill needs not be combined with a COX-2 inhibitor.
4. Croxatto H. B. et al., Pituitary-ovarian function following the standard levonorgestrel emergency contraceptive dose or a single 0.75-mg dose given on the days preceding ovulation, Contraception (2004); 70: 442-450; Brache V. et al., Immediate preovulatory administration of 30 mg ulipristal acetate significantly delays follicular rupture, Human Reprod. (2010); 25: 2256-2263.
   Croxatto hypothesizes that the LNG-EC pill, if administered before the onset of the LH peak (i.e. 72 to 48 hours before follicle rupture) might give rise to so-called dysfunctional ovulations. Such ovulations should occur after a blunted LH peak and were characterized by the extrusion of an egg that could not be fertilized, because meiosis was not completed. Recent research however suggests that LNG (i.e. high dose gestagen) is able by itself to induce the resumption of meiosis which otherwise is brought about by the LH peak. Therefore, to prevent follicle rupture still, LNG has to be combined with a non-steroidal antirheumatic drug (a COX-2 inhibitor) which is able to abrogate the last step in the ovulatory process, namely, the prostaglandin-mediated disintegration of the follicle wall. For details, see:: Siqueira L. C. et al., Angiotensin II, progesterone, and prostaglandins are sequential steps in the pathway to bovine oocyte nuclear maturation, Theriogenology (2012); 77: 1779-1787; Massai M. R. et al., Does meloxicam increase the incidence of anovulation induced by single administration of levonorgestrel in emergency contraception? A pilot study. Human Reproduction (2007); 22 (2): 434-439. As a COX-2 inhibtor, e.g. indomethacin 50-100 mg or meloxicam 15-30 mg may be employed.
5. Mikolajczyk R. T. et al., Multilevel model to assess sources of variation in follicular growth close to the time of ovulation in women with normal fertility: a multicenter observational study, Reproductive Biology and Endocrinology (2008); 6: 61
6. Fleischer A. C., Kalemeris G. C., Entman S. S., Sonographic depiction of the endometrium during normal cycles, Ultrasound Med Biol (1984); 12: 271; Delisle M. F., Villeneuve M., Boulvain M., Measurement of endometrial thickness with transvaginal ultrasonography: is it reproducible?, JUM (1998); 17: 481-4
7. Stratton P. et al., Endometrial effects of a single early luteal dose oft the selective progesterone receptor modulator CDB-2914, Fertility and Sterility (2010); 93 (6): 2035-2041. This paper demonstrates that UPA (= CDB-2914) causes damage to the endometrium if administered during the luteal phase. This is not the case with LNG. Therefore, UPA may not be administered to women who had intercourse (were raped) before ovulation but request post-coital contraception after ovulation. See also IMABE Info 2/10.
8. Rella W., Neue Erkenntnisse über die Wirkweise der „Pille danach“, see ref. 1
9. Stratton P et al., see ref. 7
10. IMABE, Aktualisierung der Erkenntnisse zur Wirkweise der „Pille danach“ see ref. 1; Rella W., Neue Erkenntnisse über die Wirkweise der
    „Pille danach“, see ref. 1