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Effect of levonorgestrel emergency contraception on implantation and fertility: A review

  • M Endler
    Correspondence
    Corresponding author. M. Endler
    Affiliations
    Department of Women´s and Children´s Health, Karolinska Institute, and the WHO Collaborating Centre for Research in Human Reproduction, Karolinska University Hospital, Stockholm, Sweden
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  • RHW Li
    Affiliations
    Department of Obstetrics and Gynaecology, The University of Hong Kong, Pokfulam, Hong Kong
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  • K Gemzell Danielsson
    Affiliations
    Department of Women´s and Children´s Health, Karolinska Institute, and the WHO Collaborating Centre for Research in Human Reproduction, Karolinska University Hospital, Stockholm, Sweden
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Open AccessPublished:January 23, 2022DOI:https://doi.org/10.1016/j.contraception.2022.01.006

      Abstract

      Purpose

      Levonorgestrel-only emergency contraception (EC) inhibits ovulation to prevent fertilization. Misconceptions regarding its mechanism of action contribute to low use in some settings. We aimed to review the mechanism of action of Levonorgestrel EC and assess the evidence for a postovulatory effect on viable pregnancy development in the exposed and subsequent cycles.

      Basic procedures

      We searched Pubmed, Embase, Web of Science, clinicaltrials.gov, the Cochrane database, and the US FDA Adverse Event Reporting System. We included studies reporting on the effect of Levonorgestrel EC exposure on (1) ovulation, (2) conception, (3) implantation, (4) ectopic pregnancy, (5) pregnancy viability, and (6) fertility in subsequent cycles. Data were extracted and tabulated from included studies by two researchers. The results were analyzed and summarized in narrative form.

      Main findings

      We included 33 studies. Women exposed to Levonorgestrel EC at or after the LH (luteinizing hormone) surge had similar rates of inhibited ovulation (3 studies) and conception rates (2 studies) as controls. Nine out of ten studies found no difference in endometrial receptivity to implantation after exposure to Levonorgestrel EC compared to controls. The evidence for an association between Levonorgestrel EC and reduced fallopian tube motility or ectopic pregnancy was conflicting. We found no evidence of increased miscarriage or teratogenicity (3 studies) or disrupted menstrual cycle (3 studies) after Levonorgestrel EC exposure compared to controls.

      Principal conclusions

      This review supports that Levonorgestrel EC taken after ovulation does not affect implantation and results in similar conception rates compared to placebo. There is no evidence that exposure to Levonorgestrel EC affects fetal development, miscarriage, stillbirth, or subsequent menstruations.

      Keywords

      1. Introduction

      The levonorgestrel-only regimen for emergency contraception (EC) acts by inhibiting ovulation [
      • Gemzell-Danielsson K
      • Berger C
      • Lalitkumar PGL.
      Emergency contraception - mechanisms of action.
      ]. It was introduced in the 1990s, and Food and Drug Administration approved based on an estimated efficiency of 84% when taken within 3 days of unprotected sex [
      • von Hertzen H
      • Piaggio G
      • Ding J
      • Chen J
      • Song S
      • Bártfai G
      • et al.
      Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial.
      ]. Systematic literature reviews and reports of controlled trials have shown that adverse events related to Levonorgestrel EC use are rare, reported side effects appear to be mild, and acceptability among women is high [
      • Halpern V
      • Raymond EG
      • Lopez LM.
      Repeated use of pre- and postcoital hormonal contraception for prevention of pregnancy.
      ,
      • Festin MP
      • Bahamondes L
      • Nguyen TMH
      • 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.
      ,
      • Leelakanok N
      • Methaneethorn J.
      A systematic review and meta-analysis of the adverse effects of levonorgestrel emergency oral contraceptive.
      ,
      • Shen J
      • Che Y
      • Showell E
      • Chen K
      • Cheng L
      Interventions for emergency contraception.
      ].
      EC is part of the WHO list of essential medicines for reproductive health and is available over the counter or without prescription in many settings [

      PATH, the World Health Organization, and the United Nations Population Fund. Essential Medicines for Reproductive Health: Guiding Principles for Their Inclusion on National Medicines Lists. Seattle: PATH; 2006.

      ]. Ever-use among women in the US is estimated at 20%. Outside of the US, use is much lower with rates ranging between 1.2 and 6.5% [

      Key statistics from the National Survey of Family Growth . Centers for disease control and prevention. Atlanta: National Center for Health Statistics; 2017.

      ,
      • Larson E
      • Morzenti A
      • Guiella G
      • Gichangi P
      • Makumbi F
      • Choi Y.
      Reconceptualizing measurement of emergency contraceptive use: Comparison of approaches to estimate the use of emergency contraception.
      ]. This is believed to be a result of patient and provider misconceptions related to the impact of EC [
      • Westley E
      • Glasier A.
      Emergency contraception: Dispelling the myths and misperceptions.
      ,
      • Ajayi AI
      • Nwokocha EE
      • Akpan W
      • Adeniyi OV.
      Use of non-emergency contraceptive pills and concoctions as emergency contraception among Nigerian University students: results of a qualitative study.
      ,
      • Moore A
      • Ryan S
      • Stamm C.
      Seeking emergency contraception in the United States: A review of access and barriers.
      ]. Studies indicate that a majority of women are concerned about adverse effects, and almost a third believe that EC causes birth defects [
      • Mackin ML
      • Clark MK
      • McCarthy AM
      • Farris K.
      Knowledge and use of emergency contraception in college women.
      ,
      • Mollen CJ
      • Miller MK
      • Hayes KL
      • Barg FK.
      Knowledge, attitudes, and beliefs about emergency contraception: A survey of female adolescents seeking care in the emergency department.
      ]. The narrative that EC affects future fertility is exemplified by a survey in which 4 in 10 women believed that repeated use of EC could make them infertile and half of them thought that it could only be used once per cycle.[

      ellaOne. Fact Not Fiction. https://www.mymorningafter.co.uk/factnotfiction. accessed January 12, 2020. 2020.

      ,

      Mawathe A. Kenya concern over pill popping. BBC News 2009. http://newsbbccouk/2/hi/africa/8145418.stm accessed January 12, 2021

      ]. It has also been proposed that Levonorgestrel EC affects pregnancy implantation if it does not inhibit ovulation and conception occurs [
      • Mozzanega B
      • Nardelli GB.
      UPA and LNG in emergency contraception: the information by EMA and the scientific evidences indicate a prevalent anti-implantation effect.
      ].
      Our aim was to review the mechanism of action of Levonorgestrel EC and assess the existing evidence for (1) the postovulatory effect of Levonorgestrel EC exposure on viable pregnancy development in the exposed cycle, and (2) the effect of Levonorgestrel EC exposure on fertility in subsequent cycles, compared to controls.

      2. Methods

      2.1 Literature search

      We performed searches in Pubmed, Embase, Web of Science, clinicaltrials.gov, the Cochrane database, and the US Food and Drug Administration Adverse Event Reporting System (FAERS) Public Dashboard up until January 15, 2021. No other limitations were made regarding language, setting, or study period. A search module relevant to each study question was designed for each database. The search model used can be seen in Supplementary Table 1.

      2.2 Population

      The study population was women using Levonorgestrel EC or cell line or cultured human tissue exposed to levonorgestrel in vitro. Our comparison group included women, human cell-lines or tissue unexposed to levonorgestrel EC.

      2.3 Intervention

      We defined the intervention as exposure to Levonorgestrel EC at doses equivalent to those used for EC, i.e., single oral or vaginal administration of 1.5 mg, or two split doses of 0.75 mg at a 12-hour interval, or either of these doses taken recurrently at any time during the menstrual cycle. We defined the control population as women not exposed to Levonorgestrel EC, or the same woman unexposed to Levonorgestrel EC in another cycle, where women acted as their own control. In the case of in vitro studies, cell line or human tissue was treated with Levonorgestrel EC at pharmacological or supra-pharmacological concentrations, with the control population defined as biological tissue not exposed to levonorgestrel.

      2.4 Outcomes

      Our outcomes of interest in relation to Levonorgestrel EC effect in the exposed cycle were: (1) ovulation, (2) conception, (3) implantation, (4) ectopic pregnancy, and (5) pregnancy viability.
      We defined inhibited ovulation as delayed or inhibited LH surge ≥5 days, or absent ovulation verified by ultrasound. As a measure of conception rate, we accepted the verification of a pregnancy by a pregnancy test or ultrasound. As measures of reduced implantation, we included measures of embryo-endometrial attachment rate or changes in biomarkers in endometrial constructs cultured in vitro. As measures of ectopic pregnancy, we accepted a clinical diagnosis of ectopic pregnancy by serial serum-hCG measurements, ultrasound, and/or surgery. We also accepted histological changes or biomarkers consistent with reduced fallopian tube motility. Tubal motility is relevant to the transport of the fertilized ovum to the uterus for implantation and reduced motility could theoretically increase the risk of ectopic pregnancy and non-viable pregnancy. We did not include data on outcomes that preceded fertilization such as sperm motility or cervical mucus changes in the exposed cycle as these precede fertilization.
      As measures of pregnancy viability, we accepted the following outcomes: increased rates of miscarriage, stillbirth, or fetal abnormalities in pregnancies conceived in the exposed cycle.
      Our outcomes of interest in relation to the impact of Levonorgestrel EC on future fertility were the following: (1) resumption of a normal menstrual cycle or ovulation in the subsequent cycle, (2) increased use of assisted reproduction treatment or reported infertility post-exposure, (3) time to conception in subsequent cycles, and (4) fertility within 12 months of exposure.

      2.5 Data extraction

      We included original research articles on the association between the use of Levonorgestrel EC and one or more of our outcomes of interest. Identified citations were uploaded into an EndNote database (EndNote X9) and duplicates were removed. Two researchers (ME and RHWL) screened citations by title and performed a full-text or abstract analysis of reports seeming to fulfill inclusion criteria. We excluded studies on other forms of EC. We excluded case reports, opinion pieces, or review articles.

      2.6 Data analysis

      To differentiate between pre- and post-ovulatory effects we presented outcome measures according to the timing of Levonorgestrel EC exposure: before the LH surge corresponding to a time that allows inhibition of ovulation, or at or after the LH surge corresponding to a time when ovulation cannot be inhibited. Outcomes were standardized for comparability if possible. We standardized the timing of levonorgestrel administration in relation to ovulation to refer to days (+/-) from the LH surge or follicle size. In vitro levonorgestrel concentrations were converted from μg/L to μM and related to serum concentrations after oral Levonorgestrel EC intake. Peak serum concentration of levonorgestrel after a single 1.5 mg oral dose is 12.3 ng/mL or 0.039 μM [
      • Johansson E
      • Brache V
      • Alvarez F
      • Faundes A
      • Cochon L
      • Ranta S
      • et al.
      Pharmacokinetic study of different dosing regimens of levonorgestrel for emergency contraception in healthy women.
      ]. Data were summarized as average incidence and/or incidence range. The data were tabulated and presented in descriptive form. The research did not require ethical approval.

      2.7 Quality of evidence

      We did not apply a systematic grading of the quality of evidence, but we assessed strengths and weaknesses of included studies based on (1) the existence of a placebo (or equivalent controlled) group, (2) power (sample size), and (3) accuracy of the timing of exposure in relation to ovulation. Placebo (or equivalent controlled) studies with adequate sample size and reliable timing of exposure in relation to ovulation, verified by ultrasound and/or serum-hormone measurement, were assessed as high-quality evidence. Placebo (or equivalent controlled), with small sample sizes but reliable timing of exposure in relation to ovulation, were assessed as moderate-quality evidence. Uncontrolled studies with unreliable or poorly described timing of exposure in relation to ovulation were assessed as low-quality evidence.

      3. Results

      Our search identified 1325 articles that were screened by title or abstract. We included 33 studies in the review that reported on one or more of the following outcomes: ovulation (n = 9), conception rate (n = 2), fallopian tube motility (n = 5), implantation (n = 10), ectopic pregnancy (n = 3), pregnancy viability post-exposure (teratogenicity, miscarriage or stillbirth, n = 3), and return to normal menstrual cycle (n = 3). We identified no studies on increased use of assisted reproduction treatment or reported infertility post-exposure, time to conception in subsequent cycles, or fertility within 12 months of Levonorgestrel EC exposure.
      A flowchart illustrating the inclusion process is shown in Figure 1.
      Fig 1
      Fig. 1Prisma Flowchart of inclusion process in a systematic review of use levonorgestrel for emergency contraception (LNG-EC) and fertility after failed use and in subsequent cycles.

      3.1 Inhibition of ovulation

      We identified 9 studies that reported rates of inhibited ovulation after Levonorgestrel EC intake before or at the LH surge [
      • Brache V
      • Cochon L
      • Deniaud M
      • Croxatto HB.
      Ulipristal acetate prevents ovulation more effectively than levonorgestrel: analysis of pooled data from three randomized trials of emergency contraception regimens.
      ,
      • Brache V
      • Croxatto H
      • Sitruk-Ware R
      • Maguire R
      • Montero JC
      • Kumar N
      • et al.
      Effect of a single vaginal administration of levonorgestrel in Carraguard (R) gel on the ovulatory process: a potential candidate for "dual protection" emergency contraception.
      ,
      • Croxatto HB
      • Brache V
      • Pavez M
      • Cochon L
      • Forcelledo ML
      • Alvarez F
      • 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.
      ,
      • Hapangama D
      • Glasier AF
      • Baird DT.
      The effects of peri-ovulatory administration of levonorgestrel on the menstrual cycle.
      ,
      • Marions L
      • Cekan SZ
      • Bygdeman M
      • Gemzell-Danielsson K
      Effect of emergency contraception with levonorgestrel or mifepristone on ovarian function.
      ,
      • Marions L
      • Hultenby K
      • Lindell I
      • Sun X
      • Ståbi B
      • Gemzell-Danielsson K
      Emergency contraception with mifepristone and levonorgestrel: mechanism of action.
      ,
      • Natavio M
      • Nelson A
      • Segall-Gutierrez P
      • Stanczyk F.
      Ovulation rates after oral administration of the 1.5-mg levonorgestrel emergency contraception regimen among normal-weight and obese women.
      ,
      • Okewole IA
      • Arowojolu AO
      • Odusoga OL
      • Oloyede OA
      • Adeleye OA
      • Salu J
      • et al.
      Effect of single administration of levonorgestrel on the menstrual cycle.
      ,
      • Tirelli A
      • Cagnacci A
      • Volpe A.
      Levonorgestrel administration in emergency contraception: bleeding pattern and pituitary-ovarian function.
      ].
      Among studies reporting on the efficacy of Levonorgestrel EC in relation to the timing of ovulation, 5 were placebo-controlled (or equivalent) and of moderate to high-quality evidence [
      • Brache V
      • Cochon L
      • Deniaud M
      • Croxatto HB.
      Ulipristal acetate prevents ovulation more effectively than levonorgestrel: analysis of pooled data from three randomized trials of emergency contraception regimens.
      • Hapangama D
      • Glasier AF
      • Baird DT.
      The effects of peri-ovulatory administration of levonorgestrel on the menstrual cycle.
      ,
      • Marions L
      • Hultenby K
      • Lindell I
      • Sun X
      • Ståbi B
      • Gemzell-Danielsson K
      Emergency contraception with mifepristone and levonorgestrel: mechanism of action.
      ]. Three of these studies found that Levonorgestrel EC had a significant inhibitory effect on ovulation compared to placebo or controls when taken at a follicle diameter of 15 to 17 mm or 2 days prior to the LH surge. The rate of inhibited or delayed ovulation ≥5 days was 71% vs 0% (p = 0.03), 91% vs 45% (p = 0.003), and 83% vs 17%, respectively (p < 0.05) [
      • Brache V
      • Croxatto H
      • Sitruk-Ware R
      • Maguire R
      • Montero JC
      • Kumar N
      • et al.
      Effect of a single vaginal administration of levonorgestrel in Carraguard (R) gel on the ovulatory process: a potential candidate for "dual protection" emergency contraception.
      ,
      • Croxatto HB
      • Brache V
      • Pavez M
      • Cochon L
      • Forcelledo ML
      • Alvarez F
      • 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.
      ,
      • Marions L
      • Hultenby K
      • Lindell I
      • Sun X
      • Ståbi B
      • Gemzell-Danielsson K
      Emergency contraception with mifepristone and levonorgestrel: mechanism of action.
      ]. No study found any significant effect on ovulation for Levonorgestrel EC compared to placebo when taken at follicle size ≥18mm. Inhibited ovulation varied between 15% and 50% for Levonorgestrel EC compared to 4% to 13% for placebo [
      • Brache V
      • Cochon L
      • Deniaud M
      • Croxatto HB.
      Ulipristal acetate prevents ovulation more effectively than levonorgestrel: analysis of pooled data from three randomized trials of emergency contraception regimens.
      • Hapangama D
      • Glasier AF
      • Baird DT.
      The effects of peri-ovulatory administration of levonorgestrel on the menstrual cycle.
      ]. One study included a sub-analysis of the rate of inhibited ovulation at the start of the LH surge (n = 18), before the peak (n = 24), and at the peak (n = 46) and saw no significant difference compared to placebo in any of these groups [
      • Brache V
      • Cochon L
      • Deniaud M
      • Croxatto HB.
      Ulipristal acetate prevents ovulation more effectively than levonorgestrel: analysis of pooled data from three randomized trials of emergency contraception regimens.
      ].
      The limited window of action for Levonorgestrel EC on ovulation was supported by another 4 studies of lower quality of evidence (Table 1) [
      • Marions L
      • Cekan SZ
      • Bygdeman M
      • Gemzell-Danielsson K
      Effect of emergency contraception with levonorgestrel or mifepristone on ovarian function.
      ,
      • Natavio M
      • Nelson A
      • Segall-Gutierrez P
      • Stanczyk F.
      Ovulation rates after oral administration of the 1.5-mg levonorgestrel emergency contraception regimen among normal-weight and obese women.
      • Tirelli A
      • Cagnacci A
      • Volpe A.
      Levonorgestrel administration in emergency contraception: bleeding pattern and pituitary-ovarian function.
      ]
      Table 1Summary of original research studies reporting on ovulation rates or conception rates after exposure to Levonorgestrel for emergency contraception
      Study yearStudy designSample sizeTreatment timepoint and outcomes
      Treatment outcome: inhibited, delayed or afunctional ovulation
      Inhibited or delayed ovulation for ≥5 days.
      Quality of evidence
      Grading of evidence: A= Assessed as high-quality evidence. Placebo-controlled, adequate sample size, timing of exposure in relation to ovulation verified by ultrasound and/or serum-hormone measurement. B= Assessed as moderate quality evidence. Placebo-or equivalent controlled, small or moderate sample size, ovulation timing by home urine test (21), serum hormone measurements (28), or repeated data from previous cycles (27). C= Assessed as low-quality evidence. No control group, small or moderate sample size, timing of ovulation verified by ultrasound and/or serum-hormone measurement (22, 24, 26) or menstrual cycle length (25).
      Follicle size 12−14Follicle size 15−17Follicle size ≥18 mmAt LH surge startBefore LH peakAt LH peak
      Brache et al, 2013RCTs98(n = 98)LNG 14.6% vs placebo 4%, p > 0.05.(n = 18) LNG 25% vs placebo 0%(n = 24): LNG 14% vs placebo 10%(n = 46): LNG 9% vs placebo 4%A
      Croxatto et al, 2004RCT110(n = 36) LNG 94% vs placebo 61% (p > 0.05)(n = 44) LNG 91% vs placebo 45%, p = 0.003(n = 33) LNG 47% vs placebo 13% (p > 0.05)A
      Hapangama et al, 2001RCT24(n = 24) LNG 42% vs placebo 8%, p-value> 0.05B
      Marions et al, 2002Prospective cohort12(n = 12)LNG 83% vs placebo 17% (p < 0.05)B
      Marions et al, 2004Descriptive7(n = 7) LNG 100% control cycle not reportedC
      Natavio et al, 2018Descriptive24(n = 24) LNG 79% no control groupC
      Tirelli et al, 2008Descriptive8(n = 7)100%(n = 1)0%C
      Okewole et al, 2007Descriptive28(n = 8) LNG 50%, no control(n = 6) LNG 0%, no controlC
      Treatment outcome: observed

      versus expected

      pregnancies
      All studies compared observed number of pregnancies to a global estimate of expected pregnancy rates (29)
      Before ovulationAfter ovulation
      Novikova et al, 2007Descriptive51(n = 34) LNG 0 vs 4.2 expected(n = 17) LNG 3 vs 3.5 expectedB
      Noe et al, 2011Descriptive148(n = 34) LNG 0 vs 16 expected(p < 0.001)(n = 45) LNG 8 vs 8.7 expected (p = 1.00)B
      LH, luteinizing hormone; n, number; RCT, randomized controlled trial; LNG, levonorgestrel EC (All studies used oral administration of LNG 1.5 mg, or 0.75 mg given twice orally at a 12 hours interval, except for Brache et al. 2007 where a single vaginal dose of 0.75 mg was used). Significant changes are marked in bold.
      a Inhibited or delayed ovulation for ≥5 days.
      b All studies compared observed number of pregnancies to a global estimate of expected pregnancy rates (29)
      c Grading of evidence:A= Assessed as high-quality evidence. Placebo-controlled, adequate sample size, timing of exposure in relation to ovulation verified by ultrasound and/or serum-hormone measurement.B= Assessed as moderate quality evidence. Placebo-or equivalent controlled, small or moderate sample size, ovulation timing by home urine test (21), serum hormone measurements (28), or repeated data from previous cycles (27).C= Assessed as low-quality evidence. No control group, small or moderate sample size, timing of ovulation verified by ultrasound and/or serum-hormone measurement (22, 24, 26) or menstrual cycle length (25).

      3.2 Conception rate

      We identified two studies that reported on observed versus expected pregnancy rates after Levonorgestrel EC intake before or after ovulation [
      • Noé G
      • Croxatto HB
      • Salvatierra AM
      • Reyes V
      • Villarroel C
      • Muñoz C
      • et al.
      Contraceptive efficacy of emergency contraception with levonorgestrel given before or after ovulation.
      ,
      • Novikova N
      • Weisberg E
      • Stanczyk FZ
      • Croxatto HB
      • Fraser IS
      Effectiveness of levonorgestrel emergency contraception given before or after ovulation - a pilot study.
      ].
      The studies were of moderate quality. When Levonorgestrel EC was taken prior to ovulation, one study reported 0 pregnancies vs 4 expected, and the other 0 vs 16 expected (p < 0.001) [
      • Noé G
      • Croxatto HB
      • Salvatierra AM
      • Reyes V
      • Villarroel C
      • Muñoz C
      • et al.
      Contraceptive efficacy of emergency contraception with levonorgestrel given before or after ovulation.
      ,
      • Novikova N
      • Weisberg E
      • Stanczyk FZ
      • Croxatto HB
      • Fraser IS
      Effectiveness of levonorgestrel emergency contraception given before or after ovulation - a pilot study.
      ]. Corresponding figures for both studies after intake of Levonorgestrel EC directly after ovulation were 3 recorded pregnancies vs 3.5 expected, and 8 vs 8.7 expected (p = 1.00).
      Summarized data for all studies reporting on ovulation and conception included in the review are presented in Table 1.

      3.3 Implantation

      We identified 10 studies on endometrial receptivity measures after Levonorgestrel EC exposure. Two in vitro studies showed that treatment of 3-dimensional human endometrial tissue construct with 10μM levonorgestrel did not significantly alter human blastocyst attachment rate [
      • Lalitkumar PGL
      • Lalitkumar S
      • Meng CX
      • 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.
      ] or expression of any receptivity markers [
      • Meng CX
      • Andersson KL
      • Bentin-Ley U
      • Gemzell-Danielsson K
      • Lalitkumar PGL.
      Effect of levonorgestrel and mifepristone on endometrial receptivity markers in a three-dimensional human endometrial cell culture model.
      ]. Five in vivo biomedical studies showed that Levonorgestrel EC administered either before, on the day of, or after LH surge resulted in no change in endometrial receptivity markers compared to controls [
      • Marions L
      • Hultenby K
      • Lindell I
      • Sun X
      • Ståbi B
      • Gemzell-Danielsson K
      Emergency contraception with mifepristone and levonorgestrel: mechanism of action.
      ,
      • Barrios-Hernández AE
      • Durand-Carbajal M
      • Vega CC
      • Larrea F
      Analysis of the endometrial transcriptome at the time of implantation in women receiving a single post-ovulatory dose of levonorgestrel or mifepristone.
      ,
      • do Nascimento JAA
      • Seppala M
      • Perdigao A
      • Espejo-Arce X
      • Munuce MJ
      • Hautala L
      • et al.
      In vivo assessment of the human sperm acrosome reaction and the expression of glycodelin-A in human endometrium after levonorgestrel-emergency contraceptive pill administration.
      ,
      • Meng CX
      • Cheng LN
      • Lalitkumar PG
      • Zhang L
      • Zhang HJ
      • Gemzell-Danielsson K
      Expressions of steroid receptors and Ki67 in first-trimester decidua and chorionic villi exposed to levonorgestrel used for emergency contraception.
      ,
      • Palomino WA
      • Kohen P
      • Devoto L
      A single midcycle dose of levonorgestrel similar to emergency contraceptive does not alter the expression of the L-selectin ligand or molecular markers of endometrial receptivity.
      ] and the authors concluded that levonorgestrel did not affect implantation. Two in vivo biomedical studies showed that Levonorgestrel EC taken before the LH surge induced premature rise in serum and intrauterine concentrations of glycodelin-A in the peri-ovulatory phase compared to controls, which might inhibit sperm-oocyte interaction if ovulation were to occur [
      • Durand M
      • Koistinen R
      • Chirinos M
      • Rodríguez JL
      • Zambrano E
      • Seppälä M
      • et al.
      Hormonal evaluation and midcycle detection of intrauterine glycodelin in women treated with levonorgestrel as in emergency contraception.
      ], but a weaker expression of glycodelin-A on day 9 following the LH surge (LH +9) or no significant change when taken on or after the day of LH surge, indicating lack of effect on implantation [
      • Durand M
      • Seppala M
      • Cravioto MDC
      • Koistinen H
      • Koistinen R
      • Gonzalez-Macedo J
      • et al.
      Late follicular phase administration of levonorgestrel as an emergency contraceptive changes the secretory pattern of glycodelin in serum and endometrium during the luteal phase of the menstrual cycle.
      ]. Another in vivo study showed that vaginal Levonorgestrel EC exposure after the LH surge had no effect on 14 endometrial receptivity markers, but that oral exposure affected the expression of three biomarkers: a reduction in expression of progesterone receptors (PR-A and PR-B) in the glandular epithelium, and increased expression of leukemia inhibitory factor (LIF) [
      • Meng CX
      • Marions L
      • Bystrom B
      • Gemzell-Danielsson K
      Effects of oral and vaginal administration of levonorgestrel emergency contraception on markers of endometrial receptivity.
      ]. Progesterone directly or indirectly regulates many of the endometrial cytokines involved in implantation. LIF is a cytokine whose mechanism of action in human implantation is unclear, most evidence supports that reduced, but not higher, levels, are associated with lower conception rates and higher risk of miscarriage [
      • Achache H
      • Revel A.
      Endometrial receptivity markers, the journey to successful embryo implantation.
      ].
      Data from all studies reporting on endometrial receptivity included in the review are summarised in Table 2.
      Table 2Summary of original research studies reporting on the effects of LNG-emergency contraceptive on endometrial receptivity
      Author and yearStudy design and controlsSample sizeRegimen
      All in vitro concentrations have been converted to micromoles(uM). Peak serum concentration of LNG after a single 0.75 mg or 1.5 mg oral dose are 0.02 μM and 0.039 μM respectively.
      and Timing of treatment
      OutcomesQuality of evidence
      All in vitro concentrations have been converted to micromoles(uM). Peak serum concentration of LNG after a single 0.75 mg or 1.5 mg oral dose are 0.02 μM and 0.039 μM respectively.
      Marions et al, 2002In vivo biomedical study, control and treatment cycles in same subjects6Two doses of 0.75 mg LNG taken 12H apart on LH-2 D (estimated) and LH +2 DLNG treatment produced no significant change in endometrial receptivity markers including integrin α4 and β3, cyclooxygenase-1 and -2, progesterone receptors, Dolichos biflorus agglutinin lectin binding and pinopodes in endometrial biopsy on LH +6 to 8 D.B
      Durand et al, 2005In vivo biomedical study, control and treatment cycles in same subjects30Two doses of 0.75 mg LNG taken 12 H apart on:Group 1: LH -4 or -3 DGroup 2: LH dayGroup 3: LH +2 DEndometrial biopsy on LH+9 D showed weaker endometrial glycodelin-A expression in Group 1 in the treatment cycle compared with the pre-treatment control cycle and when compared to Groups 2 and 3. No differences were found between control and treatment cycles in Groups 2 and 3.A
      Do Nascimento et al, 2007In vivo biomedical study, double-blind randomised placebo-controlled15(number contributing to endometrial study unclear)LNG 1.5 mg 24H after intrauterine inseminationNo change in endometrial glycodelin-A protein expression by immunostaining at 24 and 48H after LNG intake.B
      Lalitkumar et al, 2007In vitro blastocyst-endometrial co-culture study, in vitro control14 (LNG group) and 17 (control)Progesterone and LNG at 10μM after 5−6 D of endometrial cultureLNG treatment did not significantly alter the human blastocyst attachment rate to the in vitro 3-dimensional endometrial construct (43%) compared to control (59%).B
      Meng et al, 2009In vitro study, in vitro control9 (LNG) and 12 (control)10μM LNG in vitro treatmentLNG treatment produced no significant change in the expression of endometrial receptivity markers studied including ER-beta, PR-B, VEGF, integrin avb3 and MUC1 in 3-dimensional in vitro human endometrial tissue constructs.B
      Meng et al, 2009In vivo biomedical study, non-randomised9 (exposed to LNG-EC but got pregnant and resorting to induced abortion) and 9 (unexposed controls)LNG 1.5mg on cycle day 16−23 for emergency contraceptionWomen with LNG exposure before pregnancy did not show significant change in the immunohistochemical expressions of ER-alpha, ER-beta, PR-B, PR total, androgen receptor or proliferation index Ki67 in the first-trimester decidua and chorionic villi.B
      Meng et al, 2010In vivo biomedical study, control and treatment cycles in same subjects8 (oral group) and 7 (vaginal group)Oral LNG 0.75 mg x 4 doses at 24H intervals on LH +1 to +4 D, or vaginal LNG 1.5 mg single dose on LH +2 DIn the oral group, LNG treatment resulted in reduced immunoreactivity of PR-A and PR-B in glandular epithelium, and increased stromal immunoreactivity and mRNA expression of LIF compared with control cycle. Vaginal LNG treatment did not cause any significant change in endometrial markers.B
      Palomino et al, 2010In vivo biomedical study, randomised single-blind14 (oral group), 13 (vaginal group) and 11 (control group with no treatment)LNG 1.5 mg orally or vaginally on the day of LH surgeLNG treatment did not alter expression of receptive markers including PR, L-selectin ligand, αvβ3 integrin and glycodelin-A in endometrial biopsy taken on LH+2 and +7 D.B
      Durand et al, 2010In vivo biomedical study, control and treatment cycles in same subjects30Two doses of 0.75 mg LNG taken 12H apart on LH-2 DSerum and uterine flushing glycodelin-A on LH+1 D showed significant premature rise in the treatment cycle compared with the pre-treatment control cycle.A
      Barrios-Hernández AE et al, 2020In vivo biomedical study, control and treatment cycles in same subjects5LNG 1.5 mg on day of ovulation (follicle rupture)LNG did not alter the endometrial transcriptome studied on ovulation +6 D (the implantation window) in the treatment cycle compared with the pre-treatment cycles.B
      LH, luteinizing hormone; LNG, levonorgestrel; n, number.
      Quality of evidence
      A= Assessed as high quality of evidence. Placebo-or equivalent controlled, sample size≥20, timing of exposure in relation to ovulation verified by ultrasound and/or serum-hormone measurement.
      B = Assessed as moderate quality of evidence. Placebo-or equivalent controlled, sample size<20, timing of exposure in relation to ovulation verified by ultrasound and/or serum-hormone measurement.
      C = Assessed as low quality of evidence low. Uncontrolled, timing of exposure in relation to ovulation uncertain
      a All in vitro concentrations have been converted to micromoles(uM). Peak serum concentration of LNG after a single 0.75 mg or 1.5 mg oral dose are 0.02 μM and 0.039 μM respectively.

      3.4 Ectopic pregnancy

      We identified five studies on fallopian tube receptivity or motility after exposure to levonorgestrel [
      • Li C
      • Wu Y
      • Zhu Q
      • Zhang H
      • Huang Z
      • Zhang D
      • et al.
      TRPV4 is involved in levonorgestrel-induced reduction in oviduct ciliary beating.
      ,
      • Li C
      • Zhang HY
      • Liang Y
      • Xia W
      • Zhu Q
      • Zhang D
      • et al.
      Effects of Levonorgestrel and progesterone on Oviductal physiology in mammals.
      ,
      • Zhao W
      • Zhu Q
      • Yan M
      • Li C
      • Yuan J
      • Qin G
      • et al.
      Levonorgestrel decreases cilia beat frequency of human fallopian tubes and rat oviducts without changing morphological structure.
      ,
      • Wånggren K
      • Stavreus-Evers A
      • Olsson C
      • Andersson E
      • Gemzell-Danielsson K.
      Regulation of muscular contractions in the human Fallopian tube through prostaglandins and progestagens.
      ,
      • Huang C
      • Zhang M
      • Meng C
      • Shi W
      • Sun L
      • Zhang J.
      Expressions of candidate molecules in the human fallopian tube and chorionic villi of tubal pregnancy exposed to levonorgestrel emergency contraception.
      ]. Two studies found no change in receptivity markers after exposure to levonorgestrel [
      • Li C
      • Zhang HY
      • Liang Y
      • Xia W
      • Zhu Q
      • Zhang D
      • et al.
      Effects of Levonorgestrel and progesterone on Oviductal physiology in mammals.
      ,
      • Huang C
      • Zhang M
      • Meng C
      • Shi W
      • Sun L
      • Zhang J.
      Expressions of candidate molecules in the human fallopian tube and chorionic villi of tubal pregnancy exposed to levonorgestrel emergency contraception.
      ]. Two studies found a dose-dependent reduction in ciliary beat frequency in human fallopian tubes exposed to levonorgestrel compared to controls. Reduced motility was only seen at supra-pharmacological concentrations [
      • Li C
      • Zhang HY
      • Liang Y
      • Xia W
      • Zhu Q
      • Zhang D
      • et al.
      Effects of Levonorgestrel and progesterone on Oviductal physiology in mammals.
      ,
      • Zhao W
      • Zhu Q
      • Yan M
      • Li C
      • Yuan J
      • Qin G
      • et al.
      Levonorgestrel decreases cilia beat frequency of human fallopian tubes and rat oviducts without changing morphological structure.
      ]. One study found that muscular contractions in the ampullo-isthmus area were reduced in a dose-dependent way after LNG exposure compared to controls (p < 0.05) [
      • Wånggren K
      • Stavreus-Evers A
      • Olsson C
      • Andersson E
      • Gemzell-Danielsson K.
      Regulation of muscular contractions in the human Fallopian tube through prostaglandins and progestagens.
      ]. The fifth study found that the expression of transient receptor potential vanilloid (TRPV) 4 channels, which regulate fallopian tube motility, were downregulated in women with ectopic pregnancy compared to women without ectopic pregnancy. TRPV4 channels were further downregulated among women with ectopic pregnancy who had taken Levonorgestrel EC (p < 0.05) [
      • Li C
      • Wu Y
      • Zhu Q
      • Zhang H
      • Huang Z
      • Zhang D
      • et al.
      TRPV4 is involved in levonorgestrel-induced reduction in oviduct ciliary beating.
      ].
      We identified 3 case-control studies that found an epidemiological association between Levonorgestrel EC use and ectopic pregnancy [
      • 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.
      ,
      • Li C
      • Zhao WH
      • Zhu Q
      • Cao SJ
      • Ping H
      • Xi X
      • et al.
      Risk factors for ectopic pregnancy: A multi-center case-control study.
      ,
      • 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.
      ]. Adjusted odds ratios in these studies were 10.5 (95% CI 2.21−46.56), 4.75 (95% CI 3.79−5.96), and 9.34 (95% CI: 3.9−16.0), respectively.
      Data from all studies reporting on measures of ectopic pregnancy, and measures of fallopian tube motility, included in the review are summarised in Table 3.
      Table 3Summary of original research studies reporting on the effects of LNG-emergency contraceptive on incidence of ectopic pregnancy or fallopian tube motility
      Author and yearStudy design and controlsSample sizeInterventions or exposureOutcomesQuality of evidence
      All in vitro concentrations have been converted to micromoles(uM). Peak serum concentration of LNG after a single 0.75 mg or 1.5 mg oral dose are 0.02 μM and 0.039 μM respectively.
      Assouni et al 2018Case control study among 88 women with EP and 176 with IUP in Cameroon264Multivariate logistic regression analysis of association between EP and potential risk factorsCurrent use of LNG-EC as contraception AOR 10.15 (95% CI 2.21−46.56).C
      Shurie et al 2018Case control study among 97 women with EP and 237 with IUP in Kenya316Multivariate logistic regression analysis of association between EP and potential risk factorsUse of LNG-EC in the cycle of conception AOR 9.34 (95% CI, 4.46−19.56).C
      Li et al 2015Case control study among 2411 women with EP and 2416 with IUP in China4827Multivariate logistic regression analysis of association between EP and potential risk factorsCurrent use of LNG-EC as contraception AOR 4.75 (95% CI 3.79−5.96).B
      Li et al 2019In vitro biomedical study on cultured fallopian tube epithelium explants and controls58Fallopian tube extract from 34 women with EP (of which 12 has taken LNG-EC and 22 had not) and 24 controls.There were significant (p < 0.05) lower protein expressions of TRPV4 (a calcium channel involved in tubal motility) in women with EP and even lower (p < 0.05) among women with EP exposed to LNG-EC compared to women without EP.A
      Li et al 2018In vitro biomedical study on cultured fallopian tube epithelium explants and controls3+3Tubal epithelium exposed to LNG concentrations ranging from 0.01 μM to 10 μMCBF dose-dependent decrease. No significant CBF decrease at pharmacological concentrations. No change in levels of fallopian tubal epithelial cell receptivity markers, including LIF, STAT3, IGFBP1, ITGB3, MUC1, and ACVR1B after LNG exposure.B
      Zhao et at 2015In vitro biomedical study on cultured fallopian tube epithelium explants and controls10 +10Tubal epithelium from the proliferative and secretory phase exposed 5. μM and 0.5μM LNG, both concentrations are suprapharmacological.CBF decreased in the secretory and proliferative cycle phase after suprapharmacological exposure to 5.0 μM of LNG. At 0.5 μM CBF decreased only in the ampulla and only during the secretory phase. Cilia morphology was unchanged by LNG at any concentration.A
      Huang et al 2013In vivo biomedical study on fallopian tube extracts5527 women exposed to LNG-EC before the EC and 28 women unexposed.No difference in mRNA or protein expressions of ER-alpha, PR, LIF, VEGF, iNOS and CB1 in fallopian tubes of women exposed to LNG-EC compared to unexposed women.A
      Wånggren et al 2008In vitro biomedical study on cultured fallopian tube epithelium explants and controls22+22Tubal epithelium exposed to supra- (0.2 μM) and pharmacological (0.02 μM) concentrations of LNG.CBF decreased in the ampullo-isthmus area in a dose-dependent way after exposure to both suprapharmacologic al and pharmacological concentrations of LNG. The decrease at a pharmacological dose was uncertain.A
      CBF, ciliary beat frequency; CI, confidence interval; EC, emergency contraception; EP, ectopic pregnancy; LNG, levonorgestrel; TRPV, Transient receptor potential vanilloid.
      Fallopian tube motility or receptivity biomarkers: LIF, leukemia inhibitory factor; STAT3, Signal transducer and activator of transcription 3; IGFBP1, insulin-like growth factor-binding protein; ITGB3, Integrin Subunit Beta 3; Muc1, Mucin 1; ACVB1R, Activin receptor type-1B; ER-alpha, estrogen alpha receptor; PR, progesterone receptor; VEGF, vascular endothelial growth factor; iNOS, inducible nitric oxide synthase; CB1, endocannabinoid receptor 1.
      Quality of evidence
      A= Assessed as high quality of evidence. Placebo-or equivalent controlled, sample size≥20, timing of exposure in relation to ovulation verified, interventions clearly described.
      B = Assessed as moderate quality of evidence. Placebo-or equivalent controlled or large epidemiological study, sample size<20, timing of exposure in relation to ovulation verified or interventions clearly described.
      C = Assessed as low quality of evidence. Uncontrolled, timing of exposure in relation to ovulation uncertain, or small epidemiological study with inadequate power as reflected by large confidence intervals.
      a All in vitro concentrations have been converted to micromoles(uM). Peak serum concentration of LNG after a single 0.75 mg or 1.5 mg oral dose are 0.02 μM and 0.039 μM respectively.

      3.5 Teratogenicity and miscarriage

      We included 3 studies on exposure to Levonorgestrel EC during conception or early pregnancy [
      • 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.
      • 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 study.
      ]. In one cohort study, researchers compared pregnancy outcomes between 332 women exposed to Levonorgestrel EC in early pregnancy and 332 unexposed women [
      • Zhang L
      • Chen J
      • Wang Y
      • Ren F
      • Yu W
      • Cheng L.
      Pregnancy outcome after levonorgestrel-only emergency contraception failure: a prospective cohort study.
      ]. There was no significant difference in rate of miscarriage (10.3 vs 8.6%, p = 0.47) or congenital malformations (1.5 vs 1.3%, RR 1.1, 95% confidence interval 0.28−4.37). A study from the same setting subsequently compared rate of congenital malformations between 195 exposed and 214 unexposed women with similar findings (2.1 vs 1.4%, p > 0.05). Two-year follow-up found no differences in height, weight, head circumference or intelligence between exposed and unexposed participants [
      • 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 study.
      ]. A third study reported on similar outcomes after exposure to Levonorgestrel EC (n = 25) compared to a non-exposed group (n = 80). There were no significant differences in the rate of miscarriage (p > 0.05) or congenital malformations, but the study was considered underpowered to assess these outcomes [
      • 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.
      ].

      3.6 Future fertility

      We identified no studies reporting on increased use of assisted reproduction treatment or reported infertility after Levonorgestrel EC exposure, time to conception in subsequent cycles, or fertility within 12 months of exposure.
      We identified three studies that reported on menstrual bleeding patterns in the cycle following Levonorgestrel EC intake (second cycle), but no studies on ovulation in this cycle. According to all studies, Levonorgestrel EC was, as expected, associated with significant change in menstrual pattern in the exposed cycle but no change in the second cycle. A prospective observational study of 232 women with normal baseline menstrual cycles (27–29 days) found that the second cycle was not significantly different from the pre-exposure cycle [
      • Gainer E
      • Kenfack B
      • Mboudou E
      • Doh AS
      • Bouyer J.
      Menstrual bleeding patterns following levonorgestrel emergency contraception.
      ]. Another study among 69 women found cycle length was normalized in the second cycle irrespective of timing of Levonorgestrel EC intake in relation to ovulation in the exposed cycle [
      • Tirelli A
      • Cagnacci A
      • Volpe A.
      Levonorgestrel administration in emergency contraception: bleeding pattern and pituitary-ovarian function.
      ]. One study among 113 women found that the median cycle length of the second and third cycle was not different from baseline [
      • Raymond EG
      • Goldberg A
      • Trussell J
      • Hays M
      • Roach E
      • Taylor D.
      Bleeding patterns after use of levonorgestrel emergency contraceptive pills.
      ].

      4. Discussion

      4.1 Main findings

      This review confirms that Levonorgestrel EC acts by postponing or inhibiting ovulation and that there is little to no post-ovulatory action. We found no evidence to support that exposure to Levonorgestrel EC affects fetal development, miscarriage, stillbirth, or subsequent menstruations.

      4.2 Interpretation

      It has been argued that Levonorgestrel EC inhibits implantation since the rate of ovulatory inhibition is too small to account for the overall effectiveness of the treatment and that Levonorgestrel EC may therefore be a form of “emergency abortion”. Original research articles in support of a postovulatory effect are lacking [
      • Mozzanega B
      • Nardelli GB.
      UPA and LNG in emergency contraception: the information by EMA and the scientific evidences indicate a prevalent anti-implantation effect.
      ,
      • Kahlenborn C
      • Peck R
      • Severs WB.
      Mechanism of action of levonorgestrel emergency contraception.
      ,
      • Peck R
      • Rella W
      • Tudela J
      • Aznar J
      • Mozzanega B.
      Does levonorgestrel emergency contraceptive have a post-fertilization effect? A review of its mechanism of action.
      ]. The synthesized data in this review finds no evidence that Levonorgestrel EC taken after ovulation prevents implantation. If Levonorgestrel EC does not inhibit ovulation, the resulting conception rates are similar to those expected after unprotected intercourse in the high-fertile period. This is supported by a Cochrane meta-analysis in which women with further acts of unprotected intercourse in the same cycle after use of hormonal EC (including levonorgestrel) had significantly higher risk of pregnancy compared to those without further unprotected intercourse. This implies that when ovulation is postponed, fertility is still preserved in the later part of the same cycle after EC use [
      • Shen J
      • Che Y
      • Showell E
      • Chen K
      • Cheng L
      Interventions for emergency contraception.
      ].
      Some studies have suggested that the efficacy of Levonorgestrel EC has been overestimated in clinical studies and that its real-life efficacy is between 50 and 75% [
      • Leung VWY
      • Soon JA
      • Levine M.
      Measuring and reporting of the treatment effect of hormonal emergency contraceptives.
      ,
      • Westley E
      • Bigrigg A
      • Webb A
      • Haskell S
      • Blanchard K
      • Loftus-Granberg B
      • et al.
      Risk of pregnancy and external validity in clinical trials of emergency contraception.
      ,
      • Stanford J.
      Emergency contraception: Overestimated effectiveness and questionable expectations.
      ,
      • Sarkar NN.
      The emergency contraceptive drug, levonorgestrel: A review of post-coital oral and peri-coital vaginal administration for prevention of pregnancy.
      ]. According to these researchers, this overestimation has lent unfounded support to the theories of “missing mechanism of action” of Levonorgestrel EC [
      • Noé G
      • Croxatto HB
      • Salvatierra AM
      • Reyes V
      • Villarroel C
      • Muñoz C
      • et al.
      Contraceptive efficacy of emergency contraception with levonorgestrel given before or after ovulation.
      ]. Another explanation for the discrepancy between levonorgestrel´s inhibitory effect on ovulation and its total efficacy in preventing pregnancy, is that the standard definition of inhibited ovulation underestimates Levonorgestrel EC´s inhibitory effect. A 5-day delay is the standard definition of inhibited ovulation, based on the concept of 5-day sperm viability. Depending on when intercourse occurs however, a 2-to-3-day delay could be sufficient to avoid fertilization. Most reviewed studies indicate a statistically non-significant difference between placebo and Levonorgestrel EC when given close to the LH surge or at follicle size ≥18mm. Most studies were small, and these differences may have been significant in a larger study. Levonorgestrel EC could therefore have a window of action that extends to, or even includes, the LH surge that explains that its overall effect in practice exceeds the rate of inhibited ovulation reported in these studies.
      In our review, 9 of 10 studies supported that although levonorgestrel sometimes affects endometrial receptivity if taken before the LH surge, it has no effect on receptivity or blastocyst attachment after ovulation. The effect seen after pre-ovulatory intake is likely secondary to the lack of luteal activity following inhibited ovulation. One study found that 3 of 14 receptivity biomarkers were reduced after LNG administration after the LH surge with oral but not vaginal administration. Overall, the evidence is overwhelmingly in support of a lack of postovulatory implantation effect. Furthermore, there is no evidence to demonstrate that changes in endometrial receptivity biomarkers translate into clinical effects on embryo implantation. In vivo animal studies have convincingly shown that Levonorgestrel EC has no postfertilization effect and that conception rates are not different from those after placebo [
      • Müller AL
      • Llados CM
      • Croxatto HB.
      Postcoital treatment with levonorgestrel does not disrupt postfertilization events in the rat.
      ,
      • Ortiz ME
      • Ortiz RE
      • Fuentes MA
      • Parraguez VH
      • Croxatto HB.
      Post-coital administration of levonorgestrel does not interfere with post-fertilization events in the new-world monkey Cebus apella.
      ].
      With one exception, in vitro studies included in our review support that Levonorgestrel EC, at doses equivalent to those used for EC, does not affect the receptivity in the fallopian tubes in a way to increase the risk of extrauterine implantation. Several in vitro studies indicate that exposure at concentrations tenfold those seen in serum after oral intake of Levonorgestrel EC, reduces fallopian tube motility. According to all these studies the effect is dose-dependent and ceases or is minimal at pharmacological concentration. We found one vivo study that reported that ion channels involved in fallopian tube motility were downregulated in women with ectopic pregnancy exposed to Levonorgestrel EC. Channels were downregulated also in women with ectopic pregnancy compared to those without, so the role of Levonorgestrel EC, as well as how the finding translates to clinical tubal motility, was uncertain. We found 3 epidemiological studies that found an increased risk of ectopic pregnancy after Levonorgestrel EC use of which only one was large enough to address the proposed outcomes. Other known potential confounders for ectopic pregnancy were adjusted for but residual confounding may explain the association seen. Post-marketing surveillance data have found no association between ectopic pregnancy and Levonorgestrel EC use [
      • Gainer E
      • Méry C
      • Ulmann A.
      Letter to the editor.
      ,]. Similarly, a systematic review in 2011 that collated safety data, including ectopic pregnancy, from 25 studies on Levonorgestrel EC found a cumulative incidence of ectopic pregnancy of 1% after EC use which is not higher than expected baseline rates [
      • Cleland K
      • Raymond E
      • Trussell J
      • Cheng L
      • Zhu H.
      Ectopic pregnancy and emergency contraceptive pills: A systematic review.
      ]. The in vitro and epidemiological results synthesized in the review are conflicting, however, any increased relative risk of ectopic pregnancy after Levonorgestrel EC use must be viewed in the context of the small risk in absolute terms of the combined occurrence of contraceptive failure, conception, and baseline risk of ectopic pregnancy.
      We found no increased risk of miscarriage, fetal abnormality or child development problems in pregnancies occurring after Levonorgestrel EC exposure which is supported by previous systematic reviews on the safety of Levonorgestrel EC use [
      • Leelakanok N
      • Methaneethorn J.
      A systematic review and meta-analysis of the adverse effects of levonorgestrel emergency oral contraceptive.
      ,
      • Jatlaoui TC
      • Riley H
      • Curtis KM.
      Safety data for levonorgestrel, ulipristal acetate and Yuzpe regimens for emergency contraception.
      ]. We found no indication that Levonorgestrel EC disrupts the return of a normal menstrual cycle in the cycle following exposure. Although we found no studies on long-term fertility after Levonorgestrel EC use, there is substantial evidence that other levonorgestrel-only contraceptives do not impair future fertility, even after prolonged use. The half-life of levonorgestrel after discontinuation of the levonorgestrel-implant is estimated at 42 +/- 16 hours, with only trace amounts remaining after 96 hours and clearance is not influenced by duration of use [
      • Croxatto HB
      • Díaz S
      • Pavez M
      • Cárdenas H
      • Larsson M
      • Johansson EDB.
      Clearance of levonorgestrel from the circulation following removal of NORPLANTR subdermal implants.
      ]. Against this background repeated use of Levonorgestrel EC is unlikely to affect future fertility. Three systematic reviews on future fertility after contraceptive use have all concluded that Levonorgestrel containing contraceptives, irrespective of parity, gravidity or duration of use, have no detrimental effect on time to pregnancy or fecundity compared to non-hormonal methods and that conception rates are similar to those expected in the general population [
      • Dinehart E
      • Lathi RB
      • Aghajanova L.
      Levonorgestrel IUD: Is there a long-lasting effect on return to fertility?.
      ,
      • Girum T
      • Wasie A.
      Return of fertility after discontinuation of contraception: A systematic review and meta-analysis.
      ,
      • Hassan MA
      • Killick SR.
      Is previous use of hormonal contraception associated with a detrimental effect on subsequent fecundity?.
      ].
      Levonorgestrel EC is a safe method that reduces the risk of an unplanned pregnancy by inhibiting ovulation. Our review supports that, women can use this medication without risking adverse effects in a pregnancy exposed to Levonorgestrel EC effect and that concerns about "abortifacient" effects are unfounded. While there is no definitive evidence regarding the impact of Levonorgestrel EC on future fertility, the body of evidence for other Levonorgestrel contraceptives suggests there should be minimal effect.

      4.3 Strengths and limitations

      This review encompassed a wide range of outcomes relating to pregnancy viability and future fertility after exposure to Levonorgestrel EC. The search was systematic to retrieve all available data, data were screened by two independent researchers using standardized criteria to assess quality of evidence. Results are presented in descriptive form so as not to dissimulate the heterogeneity of study designs and outcome measures. Many of the clinical studies were small which lends uncertainty to the results. A further limitation to the data relates to the uncertainty of time of ovulation. Time of ovulation in relation to exposure was central to most outcomes reviewed in the study. This measure is however challenged by the fact that it is difficult to pinpoint the exact timing of LH surge, follicle size, and serum hormone levels in relation to ovulation. We included an assessment of the reliability of this measure in our quality assessment.

      5. Conclusion

      Based on the current available evidence, Levonorgestrel EC acts by inhibiting or postponing ovulation, but has no significant post-ovulatory action. There is no evidence that exposure to Levonorgestrel EC affects fetal development, miscarriage, stillbirth, or subsequent menstruations.

      Author contributions

      ME and KGD designed the study. ME designed and performed the systematic search. ME and RHWL performed the review of selected studies and analysis of data. All authors contributed to the finalization of the manuscript.

      Funding

      The research was funded in part by the Foundation Consumer Healthcare.

      Role of the funding source

      The funder played no role in the study design, data collection, analysis, or presentation of the findings in this article.

      Declaration of Competing Interest

      ME received a partial salary for the research involved in performing the systematic review from Foundation Consumer Healthcare. She has no other conflicts of interest to report. KGD has served as ad hoc invited speaker or on advisory meetings for Gedeon Richter, Bayer AG, MSD, Exelgyn, Exeltis, Azanta, HRA Pharma, and Ferring. RHWL has received research support from HRA Pharma and Ferring and served as an ad hoc invited speaker for Ferring.

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