The levonorgestrel oral emergency contraceptive is well tolerated and effective, however its use is still limited, mainly due to safety concerns.
This systematic review and meta-analysis aimed to summarize current evidence regarding the adverse events, and their prevalence, reported during the use of oral levonorgestrel emergency contraceptives.
Four electronic databases and the US FDA Adverse Event Reporting System (FAERS) Public Dashboard were searched. Studies that reported or investigated safety outcomes or adverse reactions during the use of levonorgestrel as an emergency oral contraceptive were included. Data on study design, demographics of levonorgestrel and the control cohort, and reported adverse effects were extracted.
A total of 47 articles were included in this systematic review, from which it was shown that most of the adverse reactions were common and not serious. Uncommon adverse reactions identified included anorexia, ectopic pregnancy, exanthema, chloasma, miscarriage, and weight gain. Multiple serious adverse events, including convulsion, ectopic pregnancy, febrile neutropenia, stroke, abdominal hernia, anaphylaxis, cancer, ovarian cyst rupture, serious infections, and suicidal ideation, were reported. In addition, the prevalence of adverse events after a levonorgestrel 0.75 mg two-dose regimen and a levonorgestrel 1.5 mg single-dose regimen were not statistically different (p > 0.05).
The most common adverse effects of levonorgestrel were not serious. This systematic review shows that data regarding the adverse reactions of repeated use of levonorgestrel are scarce. Studies on the multiple uses of levonorgestrel emergency contraception are still required to ensure its safety.
This is a preview of subscription content,to check access.
Access this article
Similar content being viewed by others
Black KI, Hussainy SY. Emergency contraception: oral and intrauterine options. Aust Fam Physician. 2017;46(10):722–6.
Hansen LB, Saseen JJ, Teal SB. Levonorgestrel-only dosing strategies for emergency contraception. Pharmacotherapy. 2007;27(2):278–84.
Shohel M, Rahman MM, Zaman A, Uddin MM, Al-Amin MM, Reza HM. A systematic review of effectiveness and safety of different regimens of levonorgestrel oral tablets for emergency contraception. BMC Womens Health. 2014;14:54.
Dinger JC, Cronin M, Mohner S, Schellschmidt I, Minh TD, Westhoff C. Oral contraceptive effectiveness according to body mass index, weight, age, and other factors. Am J Obstet Gynecol. 2009;201(3):263.e1–9.
Cleland K, Raymond EG, Westley E, Trussell J. Emergency contraception review: evidence-based recommendations for clinicians. Clin Obstet Gynecol. 2014;57(4):741–50.
Upadhya KK. Emergency contraception. Pediatrics. 2019;144(6):3149.
Doci F, Thaci J, Foster AM. Emergency contraception in Albania: a multimethods qualitative study of awareness, knowledge, attitudes and practices. Contraception. 2018;98(2):110–4.
Kongnyuy EJ, Ngassa P, Fomulu N, Wiysonge CS, Kouam L, Doh AS. A survey of knowledge, attitudes and practice of emergency contraception among university students in Cameroon. BMC Emerg Med. 2007;7:7.
Kgosiemang B, Blitz J. Emergency contraceptive knowledge, attitudes and practices among female students at the University of Botswana: a descriptive survey. Afr J Primary Health Care Family Med. 2018;10(1):e1–6.
Said A, Ganso M, Freudewald L, Schulz M. Trends in dispensing oral emergency contraceptives and safety issues: a survey of German community pharmacists. Int J Clin Pharm. 2019;41(6):1499–506.
Free C, Lee RM, Ogden J. Young women’s accounts of factors influencing their use and non-use of emergency contraception: in-depth interview study. BMJ. 2002;325(7377):1393.
Westley E, Glasier A. Emergency contraception: dispelling the myths and misperceptions. Bull WHO. 2010;88(4):243–4.
Zhang J, Li C, Zhao WH, Xi X, Cao SJ, Ping H, et al. Association between levonorgestrel emergency contraception and the risk of ectopic pregnancy: a multicenter case-control study. Sci Rep. 2015;5:8487.
Assouni Mindjah YA, Essiben F, Foumane P, Dohbit JS, Mboudou ET. Risk factors for ectopic pregnancy in a population of Cameroonian women: a case-control study. PLoS One. 2018;13(12):e0207699.
Kurian A, Kaushik K, Subeesh V, Maheswari E, Kunnavil R. Safety profile of levonorgestrel: a disproportionality analysis of food and drug administration adverse event reporting system (FAERS) database. J Reprod Infertil. 2018;19(3):152–6.
Jatlaoui TC, Riley H, Curtis KM. Safety data for levonorgestrel, ulipristal acetate and Yuzpe regimens for emergency contraception. Contraception. 2016;93(2):93–112.
Cleland K, Raymond E, Trussell J, Cheng L, Zhu H. Ectopic pregnancy and emergency contraceptive pills: a systematic review. Obstet Gynecol. 2010;115(6):1263–6.
van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJM, Rosendaal FR. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case–control study. BMJ. 2009;339:b2921.
Farmer RDT, Lawrenson RA. Oral contraceptives and venous thromboembolic disease: the findings from database studies in the United Kingdom and Germany. Am J Obstet Gynecol. 1998;179(3):s78–86.
Wilks JF. Hormonal birth control and pregnancy: a comparative analysis of thromboembolic risk. Ann Pharmacother. 2003;37(6):912–6.
Lidegaard O, Nielsen LH, Skovlund CW, Skjeldestad FE, Lokkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: danish cohort study, 2001–9. BMJ. 2011;343:d6423.
Combined hormonal contraception and the risk of venous thromboembolism: a guideline. Fertil Steril. 2017;107(1):43-51.
Najafi-Sharjabad F, Hajivandi A, Rayani M. Knowledge, attitude, and practice about emergency contraception among health staff in Bushehr state, south of Iran. Global J Health Sci. 2013;6(1):52–60.
Byamugisha JK, Mirembe FM, Faxelid E, Gemzell-Danielsson K. Knowledge, attitudes and prescribing pattern of emergency contraceptives by health care workers in Kampala, Uganda. Acta Obstet Gynecol Scand. 2007;86(9):1111–6.
Harrison A. Knowledge and attitude towards emergency contraception among medical doctors in Delta State. Afr J Med Health Sci. 2014;13(1):39–46.
Chung-Park M. Emergency contraception knowledge, attitudes, practices, and barriers among providers at a military treatment facility. Mil Med. 2008;173(3):305–12.
Sychareun V, Phongsavan K, Hansana V, Phengsavanh A. Policy maker and provider knowledge and attitudes regarding the provision of emergency contraceptive pills within Lao PDR. BMC Health Serv Res. 2010;10(1):212.
Reactions Reporting Adverse Drug. Definitions of terms and criteria for their use. Geneva: World Health Organization; 1999.
Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.
Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2014 [cited 25 Nov 2019]. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
Herzog R, Álvarez-Pasquin MJ, Díaz C, Del Barrio JL, Estrada JM, Gil Á. Are healthcare workers’ intentions to vaccinate related to their knowledge, beliefs and attitudes? a systematic review. BMC Public Health. 2013;13(1):154.
Zeng X, Zhang Y, Kwong JS, Zhang C, Li S, Sun F, et al. The methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review. J Evid Based Med. 2015;8(1):2–10.
Pierson DJ. How to read a case report (or teaching case of the month). Respir Care. 2009;54(10):1372–8.
Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58:295–300.
Murad MH, Sultan S, Haffar S, Bazerbachi F. Methodological quality and synthesis of case series and case reports. BMJ Evid-Based Med. 2018;23(2):60–3.
Likis FE, Andrews JC, Collins MR, Lewis RM, Seroogy JJ, Starr SA, et al. AHRQ comparative effectiveness reviews. nitrous oxide for the management of labor pain. Rockville: Agency for Healthcare Research and Quality; 2012.
Wallace BC, Schmid CH, Lau J, Trikalinos TA. Meta-analyst: software for meta-analysis of binary, continuous and diagnostic data. BMC Med Res Methodol. 2009;9(1):80.
Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60.
Bhattacharjee SK, Romeo J, Kononova ES, Pretnar-Darovec A, Saraya L, Shi YE, et al. Postcoital contraception with levonorgestrel during the peri-ovulatory phase of the menstrual cycle. Task force on post-ovulatory methods for fertility regulation. Contraception. 1987;36(3):275–86.
He CH, Shi YE, Xu JQ, Van Look PF. A multicenter clinical study on two types of levonorgestrel tablets administered for postcoital contraception. Int J Gynaecol Obstet. 1991;36(1):43–8.
Ho PC, Kwan MS. A prospective randomized comparison of levonorgestrel with the Yuzpe regimen in post-coital contraception. Hum Reprod. 1993;8(3):389–92.
Lerkiatbundit S, Reanmongkol W. Use of 0.75 mg Levonorgestrel for postcoital contraception in Thailand. J Clin Pharm Ther. 2000;25(3):185–90.
Efficacy and side effects of immediate postcoital levonorgestrel used repeatedly for contraception. United Nations Development Programme/United Nations Population Fund/World Health Organization/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, Task Force on Post-Ovulatory Methods of Fertility Regulation. Contraception. 2000;61(5):303-8.
von Hertzen H, Piaggio G, Ding J, Chen J, Song S, Bartfai G, et al. Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial. Lancet. 2002;360(9348):1803–10.
Hamoda H, Ashok PW, Stalder C, Flett GM, Kennedy E, Templeton A. A randomized trial of mifepristone (10 mg) and levonorgestrel for emergency contraception. Obstet Gynecol. 2004;104(6):1307–13.
Harper CC, Rocca CH, Darney PD, von Hertzen H, Raine TR. Tolerability of levonorgestrel emergency contraception in adolescents. Am J Obstet Gynecol. 2004;191(4):1158–63.
Ngai SW, Fan S, Li S, Cheng L, Ding J, Jing X, et al. A randomized trial to compare 24 h versus 12 h double dose regimen of levonorgestrel for emergency contraception. Hum Reprod. 2005;20(1):307–11.
Creinin MD, Schlaff W, Archer DF, Wan L, Frezieres R, Thomas M, et al. Progesterone receptor modulator for emergency contraception: a randomized controlled trial. Obstet Gynecol. 2006;108(5):1089–97.
Raymond EG, Goldberg A, Trussell J, Hays M, Roach E, Taylor D. Bleeding patterns after use of levonorgestrel emergency contraceptive pills. Contraception. 2006;73(4):376–81.
Tirelli A, Cagnacci A, Volpe A. Levonorgestrel administration in emergency contraception: bleeding pattern and pituitary-ovarian function. Contraception. 2008;77(5):328–32.
Farajkhoda T, Khoshbin A, Enjezab B, Bokaei M, Karimi Zarchi M. Assessment of two emergency contraceptive regimens in Iran: levonorgestrel versus the Yuzpe. Niger J Clin Pract. 2009;12(4):450–2.
Hoseini FS, Eslami M, Abbasi M, Noroozi Fashkhami F, Besharati S. A randomized, controlled trial of levonorgestrel vs. the yuzpe regimen as emergency contraception method among Iranian women. Iran J Public Health. 2013;42(10):1158–66.
Dada OA, Godfrey EM, Piaggio G, von Hertzen H. A randomized, double-blind, noninferiority study to compare two regimens of levonorgestrel for emergency contraception in Nigeria. Contraception. 2010;82(4):373–8.
Lech MM, Ostrowska L, Swiatek E. Emergency contraception in a country with restricted access to contraceptives and termination of pregnancy, a prospective follow-up study. Acta Obstet Gynecol Scand. 2013;92(10):1183–7.
Taylor DJ, Lendvay A, Halpern V, Bahamondes LG, Fine PM, Ginde SY, et al. A single-arm study to evaluate the efficacy, safety and acceptability of pericoital oral contraception with levonorgestrel. Contraception. 2014;89(3):215–21.
Arowojolu AO, Okewole IA. Vaginal bleeding following the use of a single dose of 1.5 mg levonorgestrel (LNG) for emergency contraception. West Afr J Med. 2004;23(3):191–3.
Byamugisha JK, Mirembe FM, Faxelid E, Tumwesigye NM, Gemzell-Danielsson K. A randomized clinical trial of two emergency contraceptive pill regimens in a Ugandan population. Acta Obstet Gynecol Scand. 2010;89(5):670–6.
Chen QJ, Xiang WP, Zhang DK, Wang RP, Luo YF, Kang JZ, et al. Efficacy and safety of a levonorgestrel enteric-coated tablet as an over-the-counter drug for emergency contraception: a Phase IV clinical trial. Hum Reprod. 2011;26(9):2316–21.
Festin MP, Bahamondes L, Nguyen TM, Habib N, Thamkhantho M, Singh K, et al. A prospective, open-label, single arm, multicentre study to evaluate efficacy, safety and acceptability of pericoital oral contraception using levonorgestrel 1.5 mg. Hum Reprod. 2016;31(3):530–40.
Glasier AF, Cameron ST, Fine PM, Logan SJ, Casale W, Van Horn J, et al. Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis. Lancet. 2010;375(9714):555–62.
Mittal S, Sehgal R, Jindal VI, Sikka P, Kandpal S, Maiti L, et al. Single dose levonorgestrel and two regimens of centchroman for emergency contraception. J Turk Ger Gynecol Assoc. 2008;9:134–8.
Raine TR, Ricciotti N, Sokoloff A, Brown BA, Hummel A, Harper CC. An over-the-counter simulation study of a single-tablet emergency contraceptive in young females. Obstet Gynecol. 2012;119(4):772–9.
Shaaban OM, Hassen SG, Nour SA, Kames MA, Yones EM. Emergency contraceptive pills as a backup for lactational amenorrhea method (LAM) of contraception: a randomized controlled trial. Contraception. 2013;87(3):363–9.
Kesserü E, Larrañaga A, Parada J. Postcoital contraception with D-norgestrel. Contraception. 1973;7(5):367–79.
De Santis M, Cavaliere AF, Straface G, Carducci B, Caruso A. Failure of the emergency contraceptive levonorgestrel and the risk of adverse effects in pregnancy and on fetal development: an observational cohort study. Fertil Steril. 2005;84(2):296–9.
Polakow-Farkash S, Gilad O, Merlob P, Stahl B, Yogev Y, Klinger G. Levonorgestrel used for emergency contraception during lactation-a prospective observational cohort study on maternal and infant safety. J Matern Fetal Neonatal Med. 2013;26(3):219–21.
Zhang L, Ye W, Yu W, Cheng L, Shen L, Yang Z. Physical and mental development of children after levonorgestrel emergency contraception exposure: a follow-up prospective cohort study1. Biol Reprod. 2014;91(1):27.
Carvajal A, Sainz M, Velasco V, Garcia Ortega P, Treceno C, Martin Arias LH, et al. Emergency contraceptive pill safety profile. Comparison of the results of a follow-up study to those coming from spontaneous reporting. Pharmacoepidemiol Drug Saf. 2015;24(1):93–7.
Rodriguez de Antonio LA, Fuentes B, Aguilar-Amat MJ, Diez-Tejedor E. Emergency contraception and stroke. A new case report. Med Clin (Barc). 2011;136(14):647–8.
Lomana AV, Aznar JMF, Cuenca VH. Venous thrombosis of the upper extremity following the ingestion of levonorgestrel as an emergency contraceptive. Anales de Patologia Vascular. 2010;4(4):204–6.
Foer D, Buchheit KM, Gargiulo AR, Lynch DM, Castells M, Wickner PG. Progestogen hypersensitivity in 24 cases: diagnosis, management, and proposed renaming and classification. J Allergy Clin Immunol Pract. 2016;4(4):723–9.
Basu A, Candelier C. Ectopic pregnancy with postcoital contraception–a case report. Eur J Contracept Reprod Health Care. 2005;10(1):6–8.
Cabar FR, Pereira PP, Zugaib M. Intrauterine pregnancy after salpingectomy for tubal pregnancy due to emergency contraception: a case report. Clinics (Sao Paulo). 2007;62(5):641–2.
Ghosh B, Dadhwal V, Deka D, Ramesan CK, Mittal S. Ectopic pregnancy following levonorgestrel emergency contraception: a case report. Contraception. 2009;79(2):155–7.
Jian Z, Linan C. Ectopic gestation following emergency contraception with levonorgestrel. Eur J Contracept Reprod Health Care. 2003;8(4):225–8.
Kaymak O, Simşek Y, Doğanay M, Yıldız Y, Mollamahmutoğlu L. Ectopic pregnancy following levonorgestrel emergency contraception: a case report. J Turk German Gynecol Assoc. 2010;11(3):168–9.
Kitani Y, Ishiguro T, Kobayashi A, Tamura R, Ueda H, Adachi S, et al. Ectopic pregnancy following oral levonorgestrel emergency contraception use. J Obstet Gynaecol Res. 2019;45(2):473–6.
Kozinszky Z, Bakken RT, Lieng M. Ectopic pregnancy after levonorgestrel emergency contraception. Contraception. 2011;83(3):281–3.
Pereira PP, Cabar FR, Raiza LC, Roncaglia MT, Zugaib M. Emergency contraception and ectopic pregnancy: report of 2 cases. Clinics (Sao Paulo). 2005;60(6):497–500.
Sheffer-Mimouni G, Pauzner D, Maslovitch S, Lessing JB, Gamzu R. Ectopic pregnancies following emergency levonorgestrel contraception. Contraception. 2003;67(4):267–9.
Steele BJ, Layman K. Ectopic pregnancy after plan b emergency contraceptive use. J Emerg Med. 2016;50(4):663–6.
Tan S, Bourke R, Roberts M, Chew M, Beilby R, Roach V. Heterotopic pregnancy after Postinor-2. Aust N Z J Obstet Gynaecol. 2004;44(5):460–1.
Sehgal A, Rani S, Singh A. Ectopic pregnancy following levonorgestrel postcoital contraceptive. J South Asian Feder Obst Gynae. 2017;9(2):131–2.
Cameron S, Li H, Gemzell-Danielsson K. Current controversies with oral emergency contraception. BJOG. 2017;124(13):1948–56.
Puig Borràs C, Álvarez Álvarez BI. The history of universal access to emergency contraception in Peru: a case of politics deepening inequalities. Reprod Health Matters. 2018;26(54):47–50.
Plan B One-Step (levonorgestrel) tablet, 1.5 mg, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021998lbl.pdf.
Motta E, Golba A, Ostrowska Z, Steposz A, Huc M, Kotas-Rusnak J, et al. Progesterone therapy in women with epilepsy. Pharmacol Rep. 2013;65(1):89–98.
Moran MH, Smith SS. Progesterone withdrawal I: pro-convulsant effects. Brain Res. 1998;807(1–2):84–90.
Shiono S, Williamson J, Kapur J, Joshi S. Progesterone receptor activation regulates seizure susceptibility. Ann Clin Transl Neurol. 2019;6(7):1302–10.
Shurie S, Were E, Orang’o O, Keter A. Levonorgestrel only emergency contraceptive use and risk of ectopic pregnancy in Eldoret Kenya: a case-control study. Pan Afr Med J. 2018;31:214.
Li C, Zhang H-Y, Liang Y, Xia W, Zhu Q, Zhang D, et al. Effects of levonorgestrel and progesterone on oviductal physiology in mammals. Reprod Biol Endocrinol. 2018;16(1):59.
Chakhtoura Z, Canonico M, Gompel A, Thalabard JC, Scarabin PY, Plu-Bureau G. Progestogen-only contraceptives and the risk of stroke: a meta-analysis. Stroke. 2009;40(4):1059–62.
van Hylckama Vlieg A, Helmerhorst FM, Rosendaal FR. The risk of deep venous thrombosis associated with injectable depot-medroxyprogesterone acetate contraceptives or a levonorgestrel intrauterine device. Arterioscler Thromb Vasc Biol. 2010;30(11):2297–300.
de Bastos M, Stegeman BH, Rosendaal FR, Van Hylckama Vlieg A, Helmerhorst FM, Stijnen T, et al. Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev. 2014;(3):CD010813.
Weill A, Dalichampt M, Raguideau F, Ricordeau P, Blotière P-O, Rudant J, et al. Low dose oestrogen combined oral contraception and risk of pulmonary embolism, stroke, and myocardial infarction in five million French women: cohort study. BMJ. 2016;353:i2002.
Dragoman MV, Tepper NK, Fu R, Curtis KM, Chou R, Gaffield ME. A systematic review and meta-analysis of venous thrombosis risk among users of combined oral contraception. Int J Gynaecol Obstet. 2018;141(3):287–94.
Cardiovascular disease and use of oral and injectable progestogen-only contraceptives and combined injectable contraceptives. Results of an international, multicenter, case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Contraception. 1998;57(5):315–24.
Lidegaard O, Kreiner S. Contraceptives and cerebral thrombosis: a five-year national case-control study. Contraception. 2002;65(3):197–205.
Shaaban MM, Elwan SI, El-Kabsh MY, Farghaly SA, Thabet N. Effect of levonorgestrel contraceptive implants, Norplant, on blood coagulation. Contraception. 1984;30(5):421–30.
Middeldorp S, Meijers JC, van den Ende AE, van Enk A, Bouma BN, Tans G, et al. Effects on coagulation of levonorgestrel- and desogestrel-containing low dose oral contraceptives: a cross-over study. Thromb Haemost. 2000;84(1):4–8.
Ruan X, Neubauer H, Yang Y, Schneck H, Schultz S, Fehm T, et al. Progestogens and membrane-initiated effects on the proliferation of human breast cancer cells. Climacteric. 2012;15(5):467–72.
Sivik T, Jansson A. Progesterone and levonorgestrel regulate expression of 17betaHSD-enzymes in progesterone receptor positive breast cancer cell line T47D. Biochem Biophys Res Commun. 2012;422(1):109–13.
Neubauer H, Ma Q, Zhou J, Yu Q, Ruan X, Seeger H, et al. Possible role of PGRMC1 in breast cancer development. Climacteric. 2013;16(5):509–13.
Soini T, Hurskainen R, Grenman S, Maenpaa J, Paavonen J, Pukkala E. Cancer risk in women using the levonorgestrel-releasing intrauterine system in Finland. Obstet Gynecol. 2014;124(2 Pt 1):292–9.
Jareid M, Thalabard JC, Aarflot M, Bovelstad HM, Lund E, Braaten T. Levonorgestrel-releasing intrauterine system use is associated with a decreased risk of ovarian and endometrial cancer, without increased risk of breast cancer. Results from the NOWAC Study. Gynecol Oncol. 2018;149(1):127–32.
Averbach S, Silverberg MJ, Leyden W, Smith-McCune K, Raine-Bennett T, Sawaya GF. Recent intrauterine device use and the risk of precancerous cervical lesions and cervical cancer. Contraception. Epub 17 Apr 2018. https://doi.org/10.1016/j.contraception.2018.04.008.
Misra JS, Engineer AD, Tandon P. Cervical cytology associated with levonorgestrel contraception. Acta Cytol. 1995;39(1):45–9.
Yoo YA, Son J, Mehta FF, DeMayo FJ, Lydon JP, Chung S-H. Progesterone signaling inhibits cervical carcinogenesis in mice. Am J Pathol. 2013;183(5):1679–87.
Chung S-H. Targeting female hormone receptors as cervical cancer therapy. Trends Endocrinol Metab. 2015;26(8):399–401.
Mehta FF, Baik S, Chung S-H. Recurrence of cervical cancer and its resistance to progestin therapy in a mouse model. Oncotarget. 2017;8(2):2372–80.
Polis CB, Schaffer K, Blanchard K, Glasier A, Harper CC, Grimes DA. Advance provision of emergency contraception for pregnancy prevention (full review). Cochrane Database Syst Rev. 2007;2:CD005497.
Sander PM, Raymond EG, Weaver MA. Emergency contraceptive use as a marker of future risky sex, pregnancy, and sexually transmitted infection. Am J Obstet Gynecol. 2009;201(2):146.
Hall OJ, Klein SL. Progesterone-based compounds affect immune responses and susceptibility to infections at diverse mucosal sites. Mucosal Immunol. 2017;10(5):1097–107.
Yao Y, Li H, Ding J, Xia Y, Wang L. Progesterone impairs antigen-non-specific immune protection by CD8 T memory cells via interferon-gamma gene hypermethylation. PLoS Pathog. 2017;13(11):e1006736.
Levonorgestrel-containing IUDs: psychiatric adverse events. React Week. 2018;1704(1):9.
Gingnell M, Engman J, Frick A, Moby L, Wikstrom J, Fredrikson M, et al. Oral contraceptive use changes brain activity and mood in women with previous negative affect on the pill–a double-blinded, placebo-controlled randomized trial of a levonorgestrel-containing combined oral contraceptive. Psychoneuroendocrinology. 2013;38(7):1133–44.
Skovlund CW, Mørch LS, Kessing LV, Lidegaard Ø. Association of Hormonal Contraception With Depression. JAMA Psychiatry. 2016;73(11):1154–62.
Glick ID, Bennett SE. Psychiatric complications of progesterone and oral contraceptives. J Clin Psychopharmacol. 1981;1(6):350–67.
Skovlund CW, Morch LS, Kessing LV, Lange T, Lidegaard O. Association of hormonal contraception with suicide attempts and suicides. Am J Psychiatry. 2018;175(4):336–42.
Brinton RD, Thompson RF, Foy MR, Baudry M, Wang J, Finch CE, et al. Progesterone receptors: form and function in brain. Front Neuroendocrinol. 2008;29(2):313–39.
Jin J, Maren S. Prefrontal–hippocampal interactions in memory and emotion. Front Syst Neurosci. 2015;9:170.
Sigurdsson T, Duvarci S. hippocampal–prefrontal interactions in cognition, behavior and psychiatric disease. Front Syst Neurosci. 2016;9:190.
Xiong X, Buekens P, Wollast E. IUD use and the risk of ectopic pregnancy: a meta-analysis of case–control studies. Contraception. 1995;52(1):23–34.
Romita P, Foti C, Calogiuri G, Cantore S, Ballini A, Dipalma G, et al. Contact dermatitis due to transdermal therapeutic systems: a clinical update. Acta bio-medica. 2018;90(1):5–10.
Bondon-Guitton E, Bagheri H, Montastruc JL. Drug-induced gingival overgrowth: a study in the French Pharmacovigilance Database. J Clin Periodontol. 2012;39(6):513–8.
Brinker A, Beitz J. Use of a spontaneous adverse drug events database for identification of unanticipated drug benefits. Clin Pharmacol Ther. 2002;71(1):99–102.
Buccellato E, Biagi C, Vaccheri A, Melis M, Montanaro N, Motola D. Possible occurrence of paraesthesia in patients taking norethisterone: an analysis on the WHO Global Individual Case Reports database (VigiBase). Expert Opin Drug Saf. 2013;12(5):615–9.
Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet. 1995;346(8990):1589–93.
Etminan M, Delaney JA, Bressler B, Brophy JM. Oral contraceptives and the risk of gallbladder disease: a comparative safety study. CMAJ. 2011;183(8):899–904.
Manzouri L, Parhizkar S, Mohammadi N. Comparison the effectiveness and side effects of two methods of emergency contraception: levonorgestrel versus LD, HD. Maturitas. 2015;81(1):194–5.
van Rooijen M, Silveira A, Thomassen S, Hansson LO, Rosing J, Hamsten A, et al. Rapid activation of haemostasis after hormonal emergency contraception. Thromb Haemost. 2007;97(1):15–20.
Task Force on Post-Ovulatory Methods for Fertility Regulation. Efficacy and side effects of immediate postcoital levonorgestrel used repeatedly for contraception. Contraception. 2000;61(5):303–8.
This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest
Nattawut Leelakanok and Janthima Methaneethorn declare they have no conflicts of interest.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
Leelakanok, N., Methaneethorn, J. A Systematic Review and Meta-analysis of the Adverse Effects of Levonorgestrel Emergency Oral Contraceptive. Clin Drug Investig 40, 395–420 (2020). https://doi.org/10.1007/s40261-020-00901-x