Advertisement

Does ulipristal acetate emergency contraception (ella®) interfere with implantation?

      Abstract

      Background

      Ulipristal acetate (UPA) 30 mg (ella®, HRA-Pharma, Paris, France) acts as an emergency contraceptive (EC) by delaying ovulation. Because it is a selective progesterone receptor modulator, an additional effect on interfering with implantation has been suggested.

      Objective

      This review discusses the evidence for, and against, an anti-implantation effect of UPA-EC.

      Sources of evidence

      Primary research on the effect of UPA, at a relevant dose, on endometrium, implantation, efficacy and pregnancy outcome.

      Results

      UPA-EC does not appear to have a direct effect on the embryo. Changes in endometrial histology are small and not consistent, varying among studies. While UPA-EC affects the profile of gene expression in human endometrium, the findings vary between studies, and it is not clear that these changes affect endometrial receptivity or prevent implantation. UPA at pharmacological concentrations does not appear to have any inhibitory effect on embryo attachment in in vitro systems of human endometrium. UPA-EC is not more effective at preventing pregnancy than chance alone if used after ovulation and does not increase miscarriage rates.

      Conclusions

      An anti-implantation effect of UPA is highly unlikely at the dose used for EC. Maintaining the warning on the FDA-approved label that “it may also work by preventing implantation to the uterus” might deter some women from using EC, leaving them no option to prevent unwanted pregnancy after unprotected sexual intercourse.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Contraception
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Brache V.
        • Cochon L.
        • Jesam C.
        • Maldonado R.
        • Salvatierra A.M.
        • Levy D.P.
        • et al.
        Immediate pre-ovulatory administration of 30 mg ulipristal acetate significantly delays follicular rupture.
        Hum Reprod. 2010; 25: 2256-2263
        • Brache V.
        • Cochon L.
        • Deniaud M.
        • Croxatto H.B.
        Ulipristal acetate prevents ovulation more effectively than levonorgestrel: analysis of pooled data from three randomized trials of emergency contraception regimens.
        Contraception. 2013; 88: 611-618
        • Rosato E.
        • Farris M.
        • Bastianelli C.
        Mechanism of action of ulipristal acetate for emergency contraception: A systematic review.
        Front Pharmacol. 2016; 6: 315
        • Leo J.C.
        • Lin V.C.
        The activities of progesterone receptor isoform A and B are differentially modulated by their ligands in a gene-selective manner.
        Int J Cancer. 2008; 122: 230-243
        • Su R.W.
        • Fazleabas A.T.
        Implantation and establishment of pregnancy in human and nonhuman primates.
        Adv Anat Embryol Cell Biol. 2015; 216: 189-213
        • Gómez-Elías M.D.
        • Munuce M.J.
        • Bahamondes L.
        • Cuasnicú P.S.
        • Cohen D.J.
        In vitro and in vivo effects of ulipristal acetate on fertilization and early embryo development in mice.
        Hum Reprod. 2016; 31: 53-59
        • Levy D.P.
        • Jager M.
        • Kapp N.
        • Abitbol J.L.
        Ulipristal acetate for emergency contraception: post-marketing experience after use by more than 1 million women.
        Contraception. 2014; 89: 431-433
        • Glasier A.F.
        • Cameron S.T.
        • Fine P.M.
        • Logan S.J.
        • Casale W.
        • Van Horn J.
        • et al.
        Ulipristal acetate versus levonorgestrel for emergency contraception: a randomized non-inferiority trial and meta-analysis.
        Lancet. 2010; 375: 555-562
        • Stratton P.
        • Hartog B.
        • Hajizadeh N.
        • Piquion J.
        • Sutherland D.
        • Merino M.
        • et al.
        Nieman LK. A single mid-follicular dose of CDB-2914, a new antiprogestin, inhibits folliculogenesis and endometrial differentiation in normally cycling women.
        Hum Reprod. 2000; 15: 1092-1099
        • Noyes R.W.
        • Hertig A.T.
        • Rock J.
        Dating the endometrial biopsy.
        Fertil Steril. 1950; 1: 3-17
        • Passaro M.D.
        • Piquion J.
        • Mullen N.
        • Sutherland D.
        • Zhai S.
        • Figg W.D.
        • et al.
        Luteal phase dose–response relationships of the antiprogestin CDB-2914 in normally cycling women.
        Hum Reprod. 2003; 18: 1820-1827
        • Stratton P.
        • Levens E.
        • Harto B.
        • Piquion J.
        • Wei Q.
        • Merino M.
        • et al.
        Endometrial effects of a single early-luteal dose of the selective progesterone receptor modulator CDB-2914.
        Fertil Steril. 2010; 93: 2035-2041
        • Foulk R.A.
        • Zdravkovic T.
        • Genbacev O.
        • Prakobphol A.
        Expression of L-selectin ligand MECA-79 as a predictive marker of human uterine receptivity.
        J Assisted Reprodutcion and Geneteics. 2007; 24: 316-321
        • Horne F.M.
        • Blithe D.L.
        Progesterone receptor modulators and the endometrium: changes and consequences.
        Hum Reprod Update. 2007; 13: 567-580
        • Coutifaris C.
        • Myers E.R.
        • Guzick D.S.
        • Diamond M.P.
        • Carson S.A.
        • Legro R.S.
        • et al.
        Histological dating of timed endometrial biopsy tissue is not related to fertility status.
        Fertil Steril. 2004; 82: 1264-1272
        • Myers E.R.
        • Silva S.
        • Barnhart K.
        • Groben P.A.
        • Richardson M.S.
        • Robboy S.L.
        • et al.
        Interobserver and intraobserver variability in the histological dating of the endometrium in fertile and infertile women.
        Fertil Steril. 2004; 82: 1278-1282
        • Murray M.J.
        • Meyer W.R.
        • Zaino R.J.
        • Lessey B.A.
        • Novotny D.B.
        • Ireland K.
        • et al.
        A critical analysis of the accuracy, reproducibility, and clinical utility of histologic endometrial dating in fertile women.
        Fertil Steril. 2004; 81: 1333-1343
        • Altmäe S.
        • Koel M.
        • Võsa U.
        • Adler P.
        • Suhorutšenko M.
        • Laisk-Podar T.
        • et al.
        Meta-signature of human endometrial receptivity: a meta-analysis and validation study of transcriptome biomarkers.
        Sci Rep. 2017; 30: 10088
        • Lira-Albarrán S.
        • Durand M.
        • Larrea-Schiavon M.F.
        • González L.
        • Barrera D.
        • Vega C.
        • et al.
        Ulipristal acetate administration at mid-cycle changes gene expression profiling of endometrial biopsies taken during the receptive period of the human menstrual cycle.
        Mol Cell Endocrinol. 2017; 447: 1-11
        • Rosario G.X.
        • Stewart C.L.
        The multifaceted actions of leukaemia inhibitory factor in mediating uterine receptivity and embryo implantation.
        Am J Reprod Immunol. 2016; 75: 246-255
        • Uchida H.
        • Maruyama T.
        • Ohta K.
        • Ono M.
        • Arase T.
        • Kagami M.
        • et al.
        Histone deacetylase inhibitor-induced glycodelin enhances the initial step of implantation.
        Hum Reprod. 2007; 22: 2615-2622
        • Lira-Albarrán S.
        • Durand M.
        • Barrera D.
        • Vega C.
        • Becerra R.G.
        • Díaz L.
        • et al.
        A single preovulatory administration of ulipristal acetate affects the decidualization process of the human endometrium during the receptive period of the menstrual cycle.
        Mol Cell Endocrinol. 2018; 476: 70-78
        • Lessey B.A.
        Assessment of endometrial receptivity.
        Fertil Steril. 2011; 96: 522-529
        • Berger C.
        • Boggavarapu N.R.
        • Menezes J.
        • Lalitkumar P.G.
        • Gemzell-Danielsson K.
        Effects of ulipristal acetate on human embryo attachment and endometrial cell gene expression in an in vitro co-culture system.
        Hum Reprod. 2015; 30: 800-811
        • Lalitkumar P.G.L.
        • Lalitkumar S.
        • Meng C.X.
        • Stavreus-Evers A.
        • Hambiliki F.
        • Bentin-Ley U.
        • et al.
        Mifepristone, but not levonorgestrel, inhibits human blastocyst attachment to an in vitro endometrial three-dimensional cell culture model.
        Hum Reprod. 2007; 11: 3031-3037
        • Ortiz M.E.
        • Ortiz R.E.
        • Fuentes M.A.
        • Parraguez V.H.
        • Croxatto H.B.
        Post-coital administration of levonorgestrel does not interfere with post-fertilization events in the new-world monkey Cebus apella.
        Hum Reprod. 2004; 19: 1352-1356
        • Vargas M.F.
        • Tapia-Pizarro A.A.
        • Henríquez S.P.
        • Quezada M.
        • Salvatierra A.M.
        • Noe G.
        • et al.
        Effect of single post-ovulatory administration of levonorgestrel on gene expression profile during the receptive period of the human endometrium.
        J Mol Endocrinol. 2012; 48: 25-36
        • Boggavarapua N.R.
        • Bergera C.
        • von Grothusena C.
        • Menezesb J.
        • Gemzell-Danielsson K.
        • Lalitkumar P.G.L.
        Effects of low doses of mifepristone on human embryo implantation process in a three-dimensional human endometrial in vitro co-culture system.
        Contraception. 2016; 94: 143-151
        • Li H.W.R.
        • Li Y.X.
        • Li T.T.
        • Fan H.
        • Ng E.H.
        • Yeung W.S.
        • et al.
        Effect of ulipristal acetate and mifepristone at emergency contraception dose on the embryo-endometrial attachment using an in vitro human trophoblastic spheroid and endometrial cell co-culture model.
        Hum Reprod. 2017; 32: 2414-2422
        • Li H.W.R.
        • Lo S.S.T.
        • Ng E.H.Y.
        • Ho P.C.
        Efficacy of ulipristal acetate for emergency contraception and its effect on the subsequent bleeding pattern when administered before or after ovulation.
        Hum Reprod. 2016; 31: 1200-1207
        • Trussell J.
        • Ellertson C.
        • Dorflinger L.
        Effectiveness of the Yuzpe regimen of emergency contraception by cycle day of intercourse: implications for mechanism of action.
        Contraception. 2003; 67: 167-171
        • Lee K.Y.
        • DeMayo F.J.
        Animal models of implantation.
        Reproduction. 2004; 128: 679-695
        • Uygun S.
        • Peng C.
        • Lehti-Shiu M.D.
        • Last R.L.
        • Shiu S.-H.
        Utility and limitations of using gene expression to identify functional associations.
        PLoS Comput Biol. 2016; 12e1005244
      1. FDA. Prescribing information for Ella (ulipristal acetate), https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022474s000lbl.pdf; 2019a [accessed 1 February 2019].

        • Larimore W.L.
        • Stanford J.B.
        • Kahlenborn C.
        Does pregnancy begin at fertilization?.
        Fam Med. 2004; 36: 690-691
        • Willets S.
        • Mac Dougall M.
        • Cameron S.T.
        A survey regarding acceptability of oral emergency contraception according to the posited mechanism of action.
        Contraception. 2017; 96: 81-88
      2. FDA. Prescribing information for Plan B One-Step, https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021998lbl.pdf; 2019b [accessed 1 February 2019]

        • Stanford J.B.
        • Mikolajczyk R.T.
        Mechanisms of action of intrauterine devices: update and estimation of post-fertilization effects.
        Am J Obstet Gynecol. 2002; 187: 1699-1708
        • Rabe T.
        • Albring C.
        • Ahrendt H.J.
        • Merkle E.
        • König K.
        • Merki G.
        Joint statement of German Society of Gynecological Endocrinology and Reproductive Medicine (DGGEF) and the Professional Association of Gynaecologists (BVF).
        J Reprod Endokrinol. 2013; 10: 59-64
        • Glasier A.
        • Gemzell-Danielsson K.
        • Bouchard P.
        • Genazzani A.R.
        • Al-Azzawi F.
        • Berga S.
        • et al.
        ISGE statement on oral emergency contraception.
        Gynecol Endocrinol. 2014; 30: 681-682
        • American College of Obstetricians
        Emergency contraception: practice bulletin no. 152.
        Obstet Gynecol. 2015; 126: e1-e11
        • European Consortium for Emergency Contraception (ECEC)
        Emergency contraception: a guideline for service provision in Europe.
        second edition. ECEC, 2016
        • Faculty of Sexual and Reproductive Health
        FSRH guideline: emergency contraception.
        Faculty of Sexual and Reproductive Health, London2017
        • International Consortium for Emergency Contraception (ICEC)
        Emergency contraceptive pills: medical & service delivery guidance.
        4th edition. ICEC, 2018