Interventions for emergency contraception

Abstract

Background: Emergency contraception (EC) is using a drug or copper intrauterine device (Cu-IUD) to prevent pregnancy shortly after unprotected intercourse. Several interventions are available for EC. Information on the comparative effectiveness, safety and convenience of these methods is crucial for reproductive healthcare providers and the women they serve. This is an update of a review previously published in 2009 and 2012.

Objectives: To determine which EC method following unprotected intercourse is the most effective, safe and convenient to prevent pregnancy.

Search methods: In February 2017 we searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, Popline and PubMed, The Chinese biomedical databases and UNDP/UNFPA/WHO/World Bank Special Programme on Human Reproduction (HRP) emergency contraception database. We also searched ICTRP and ClinicalTrials.gov as well as contacting content experts and pharmaceutical companies, and searching reference lists of appropriate papers.

Selection criteria: Randomised controlled trials including women attending services for EC following a single act of unprotected intercourse were eligible.

Data collection and analysis: We used standard methodological procedures recommended by Cochrane. The primary review outcome was observed number of pregnancies. Side effects and changes of menses were secondary outcomes.

Main results: We included 115 trials with 60,479 women in this review. The quality of the evidence for the primary outcome ranged from moderate to high, and for other outcomes ranged from very low to high. The main limitations were risk of bias (associated with poor reporting of methods), imprecision and inconsistency. Comparative effectiveness of different emergency contraceptive pills (ECP)Levonorgestrel was associated with fewer pregnancies than Yuzpe (estradiol-levonorgestrel combination) (RR 0.57, 95% CI 0.39 to 0.84, 6 RCTs, n = 4750, I2 = 23%, high-quality evidence). This suggests that if the chance of pregnancy using Yuzpe is assumed to be 29 women per 1000, the chance of pregnancy using levonorgestrel would be between 11 and 24 women per 1000.Mifepristone (all doses) was associated with fewer pregnancies than Yuzpe (RR 0.14, 95% CI 0.05 to 0.41, 3 RCTs, n = 2144, I2 = 0%, high-quality evidence). This suggests that if the chance of pregnancy following Yuzpe is assumed to be 25 women per 1000 women, the chance following mifepristone would be between 1 and 10 women per 1000.Both low-dose mifepristone (less than 25 mg) and mid-dose mifepristone (25 mg to 50 mg) were probably associated with fewer pregnancies than levonorgestrel (RR 0.72, 95% CI 0.52 to 0.99, 14 RCTs, n = 8752, I2 = 0%, high-quality evidence; RR 0.61, 95% CI 0.45 to 0.83, 27 RCTs, n = 6052, I2 = 0%, moderate-quality evidence; respectively). This suggests that if the chance of pregnancy following levonorgestrel is assumed to be 20 women per 1000, the chance of pregnancy following low-dose mifepristone would be between 10 and 20 women per 1000; and that if the chance of pregnancy following levonorgestrel is assumed to be 35 women per 1000, the chance of pregnancy following mid-dose mifepristone would be between 16 and 29 women per 1000.Ulipristal acetate (UPA) was associated with fewer pregnancies than levonorgestrel (RR 0.59; 95% CI 0.35 to 0.99, 2 RCTs, n = 3448, I2 = 0%, high-quality evidence). Comparative effectiveness of different ECP dosesIt was unclear whether there was any difference in pregnancy rate between single-dose levonorgestrel (1.5 mg) and the standard two-dose regimen (0.75 mg 12 hours apart) (RR 0.84, 95% CI 0.53 to 1.33, 3 RCTs, n = 6653, I2 = 0%, moderate-quality evidence).Mid-dose mifepristone was associated with fewer pregnancies than low-dose mifepristone (RR 0.73; 95% CI 0.55 to 0.97, 25 RCTs, n = 11,914, I2 = 0%, high-quality evidence). Comparative effectiveness of Cu-IUD versus mifepristoneThere was no conclusive evidence of a difference in the risk of pregnancy between the Cu-IUD and mifepristone (RR 0.33, 95% CI 0.04 to 2.74, 2 RCTs, n = 395, low-quality evidence). Adverse effectsNausea and vomiting were the main adverse effects associated with emergency contraception. There is probably a lower risk of nausea (RR 0.63, 95% CI 0.53 to 0.76, 3 RCTs, n = 2186 , I2 = 59%, moderate-quality evidence) or vomiting (RR 0.12, 95% CI 0.07 to 0.20, 3 RCTs, n = 2186, I2 = 0%, high-quality evidence) associated with mifepristone than with Yuzpe. levonorgestrel is probably associated with a lower risk of nausea (RR 0.40, 95% CI 0.36 to 0.44, 6 RCTs, n = 4750, I2 = 82%, moderate-quality evidence), or vomiting (RR 0.29, 95% CI 0.24 to 0.35, 5 RCTs, n = 3640, I2 = 78%, moderate-quality evidence) than Yuzpe. Levonorgestrel users were less likely to have any side effects than Yuzpe users (RR 0.80, 95% CI 0.75 to 0.86; 1 RCT, n = 1955, high-quality evidence). UPA users were more likely than levonorgestrel users to have resumption of menstruation after the expected date (RR 1.65, 95% CI 1.42 to 1.92, 2 RCTs, n = 3593, I2 = 0%, high-quality evidence). Menstrual delay was more common with mifepristone than with any other intervention and appeared to be dose-related. Cu-IUD may be associated with higher risks of abdominal pain than mifepristone (18 events in 95 women using Cu-IUD versus no events in 190 women using mifepristone, low-quality evidence).

Authors' conclusions: Levonorgestrel and mid-dose mifepristone (25 mg to 50 mg) were more effective than Yuzpe regimen. Both mid-dose (25 mg to 50 mg) and low-dose mifepristone(less than 25 mg) were probably more effective than levonorgestrel (1.5 mg). Mifepristone low dose (less than 25 mg) was less effective than mid-dose mifepristone. UPA was more effective than levonorgestrel.Levonorgestrel users had fewer side effects than Yuzpe users, and appeared to be more likely to have a menstrual return before the expected date. UPA users were probably more likely to have a menstrual return after the expected date. Menstrual delay was probably the main adverse effect of mifepristone and seemed to be dose-related. Cu-IUD may be associated with higher risks of abdominal pain than ECPs.

Conflict of interest statement

JS: no conflicts of interest. YC: no conflicts of interest KC: no conflicts of interest LC: participated in emergency contraceptive trials included in this review (including Chen 2011). LC did not participate in selecting these studies, or extracting their data. LC has received travel costs and consulting fees from Regenex Pharmaceutical Corporation, China Resources Zizhu Pharmaceutical Co, and Bayer Pharma AG. ES: no conflicts of interest

Figures

Figure 1

Study flow diagram

Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

Figure 4

Forest plot of comparison 2.1: levonorgestrel versus Yuzpe, outcome 2.1.1 Observed number of pregnancies (all women)

Figure 5

Funnel plot of comparison 2.4: Low‐dose mifepristone (

Figure 6

Forest plot of comparison 2.4: Low‐dose mifepristone (

Analysis 1.1

Comparison 1 Intrauterine contraceptive device versus control (expectant management), Outcome 1 Observed number of pregnancies.

Analysis 2.1

Comparison 2 Levonorgestrel versus Yuzpe, Outcome 1 Observed number of pregnancies (all women).

Analysis 2.2

Comparison 2 Levonorgestrel versus Yuzpe, Outcome 2 Observed number of pregnancies (by risk status).

Analysis 2.3

Comparison 2 Levonorgestrel versus Yuzpe, Outcome 3 Observed number of pregnancies (time from intercourse).

Analysis 2.4

Comparison 2 Levonorgestrel versus Yuzpe, Outcome 4 Need for extra dose.

Analysis 2.5

Comparison 2 Levonorgestrel versus Yuzpe, Outcome 5 Any side effect.

Analysis 2.6

Comparison 2 Levonorgestrel versus Yuzpe, Outcome 6 Specific side effects.

Analysis 2.7

Comparison 2 Levonorgestrel versus Yuzpe, Outcome 7 Menses.

Analysis 3.1

Comparison 3 Levonorgestrel (all doses) versus anordrin (all doses), Outcome 1 Observed number of pregnancies (all women).

Analysis 3.2

Comparison 3 Levonorgestrel (all doses) versus anordrin (all doses), Outcome 2 Any side effect.

Analysis 4.1

Comparison 4 Mifepristone mid‐dose (25 mg‐50 mg) versus levonorgestrel 1.5 mg, Outcome 1 Observed number of pregnancies (all women).

Analysis 4.2

Comparison 4 Mifepristone mid‐dose (25 mg‐50 mg) versus levonorgestrel 1.5 mg, Outcome 2 Observed number of pregnancies (by risk status).

Analysis 4.3

Comparison 4 Mifepristone mid‐dose (25 mg‐50 mg) versus levonorgestrel 1.5 mg, Outcome 3 Any side effect.

Analysis 4.4

Comparison 4 Mifepristone mid‐dose (25 mg‐50 mg) versus levonorgestrel 1.5 mg, Outcome 4 Specific side effect.

Analysis 4.5

Comparison 4 Mifepristone mid‐dose (25 mg‐50 mg) versus levonorgestrel 1.5 mg, Outcome 5 Menses.

Analysis 4.6

Comparison 4 Mifepristone mid‐dose (25 mg‐50 mg) versus levonorgestrel 1.5 mg, Outcome 6 ITT (all loss follow‐up as pregnancy in LNG, and no preg in Mife).

Analysis 4.7

Comparison 4 Mifepristone mid‐dose (25 mg‐50 mg) versus levonorgestrel 1.5 mg, Outcome 7 ITT (all loss follow‐up as no pregnancy in LNG, and preg in Mife).

Analysis 5.1

Comparison 5 Mifepristone low dose (

Analysis 5.2

Comparison 5 Mifepristone low dose (

Analysis 5.3

Comparison 5 Mifepristone low dose (

Analysis 5.4

Comparison 5 Mifepristone low dose (

Analysis 5.5

Comparison 5 Mifepristone low dose (

Analysis 5.6

Comparison 5 Mifepristone low dose (

Analysis 5.7

Comparison 5 Mifepristone low dose (

Analysis 5.8

Comparison 5 Mifepristone low dose (

Analysis 6.1

Comparison 6 Mifepristone (all doses) versus Yuzpe, Outcome 1 Observed number of pregnancies (all women).

Analysis 6.2

Comparison 6 Mifepristone (all doses) versus Yuzpe, Outcome 2 Observed number of pregnancies (by risk status).

Analysis 6.3

Comparison 6 Mifepristone (all doses) versus Yuzpe, Outcome 3 Observed number of pregnancies (time from intercourse).

Analysis 6.4

Comparison 6 Mifepristone (all doses) versus Yuzpe, Outcome 4 Need for extra dose.

Analysis 6.5

Comparison 6 Mifepristone (all doses) versus Yuzpe, Outcome 5 Any side effect.

Analysis 6.6

Comparison 6 Mifepristone (all doses) versus Yuzpe, Outcome 6 Specific side effects.

Analysis 6.7

Comparison 6 Mifepristone (all doses) versus Yuzpe, Outcome 7 Menses.

Analysis 7.1

Comparison 7 Mifepristone (all doses) versus anordrin (all doses), Outcome 1 Observed number of pregnancies (all women).

Analysis 7.2

Comparison 7 Mifepristone (all doses) versus anordrin (all doses), Outcome 2 Any side effect.

Analysis 7.3

Comparison 7 Mifepristone (all doses) versus anordrin (all doses), Outcome 3 Specific side effects.

Analysis 7.4

Comparison 7 Mifepristone (all doses) versus anordrin (all doses), Outcome 4 Menses.

Analysis 8.1

Comparison 8 Mifepristone alone (low or mid dose) versus mifepristone + anordrin (all doses), Outcome 1 Observed number of pregnancies (all women).

Analysis 8.2

Comparison 8 Mifepristone alone (low or mid dose) versus mifepristone + anordrin (all doses), Outcome 2 Any side effect.

Analysis 8.3

Comparison 8 Mifepristone alone (low or mid dose) versus mifepristone + anordrin (all doses), Outcome 3 Specific side effects.

Analysis 8.4

Comparison 8 Mifepristone alone (low or mid dose) versus mifepristone + anordrin (all doses), Outcome 4 Delay in menses.

Analysis 9.1

Comparison 9 Mifepristone versus mifepristone + misoprostol (all doses), Outcome 1 Observed number of pregnancies (all women).

Analysis 9.2

Comparison 9 Mifepristone versus mifepristone + misoprostol (all doses), Outcome 2 Specific side effect.

Analysis 10.1

Comparison 10 Mifepristone alone (all doses) versus mifepristone + tamoxifen (all doses), Outcome 1 Observed number of pregnancies (all women).

Analysis 10.2

Comparison 10 Mifepristone alone (all doses) versus mifepristone + tamoxifen (all doses), Outcome 2 Specific side effect.

Analysis 10.3

Comparison 10 Mifepristone alone (all doses) versus mifepristone + tamoxifen (all doses), Outcome 3 Menses.

Analysis 11.1

Comparison 11 Mifepristone alone (all doses) versus mifepristone + methotrexate (all doses), Outcome 1 Observed number of pregnancy (all women).

Analysis 11.2

Comparison 11 Mifepristone alone (all doses) versus mifepristone + methotrexate (all doses), Outcome 2 Any side effect.

Analysis 11.3

Comparison 11 Mifepristone alone (all doses) versus mifepristone + methotrexate (all doses), Outcome 3 Menses.

Analysis 12.1

Comparison 12 Mifepristone (all doses) versus danazol (all doses), Outcome 1 Observed number of pregnancies (all women).

Analysis 12.2

Comparison 12 Mifepristone (all doses) versus danazol (all doses), Outcome 2 Any side effect.

Analysis 12.3

Comparison 12 Mifepristone (all doses) versus danazol (all doses), Outcome 3 Specific side effect.

Analysis 12.4

Comparison 12 Mifepristone (all doses) versus danazol (all doses), Outcome 4 Menses.

Analysis 13.1

Comparison 13 Mifepristone versus gestrinone, Outcome 1 Observed number of pregnancies (all women).

Analysis 13.2

Comparison 13 Mifepristone versus gestrinone, Outcome 2 Side effects.

Analysis 13.3

Comparison 13 Mifepristone versus gestrinone, Outcome 3 Menses.

Analysis 14.1

Comparison 14 High‐dose oestrogens versus Yuzpe, Outcome 1 Observed number of pregnancies (all women).

Analysis 15.1

Comparison 15 Danazol (all doses) versus Yuzpe, Outcome 1 Observed number of pregnancies (all women).

Analysis 15.2

Comparison 15 Danazol (all doses) versus Yuzpe, Outcome 2 Specific side effects.

Analysis 15.3

Comparison 15 Danazol (all doses) versus Yuzpe, Outcome 3 Menses.

Analysis 16.1

Comparison 16 Ulipristal acetate (all doses) versus levonorgestrel, Outcome 1 Observed number of pregnancies (all women).

Analysis 16.2

Comparison 16 Ulipristal acetate (all doses) versus levonorgestrel, Outcome 2 Observed number of pregnancies (by risk status).

Analysis 16.3

Comparison 16 Ulipristal acetate (all doses) versus levonorgestrel, Outcome 3 Observed number of pregnancies (time from intercourse).

Analysis 16.4

Comparison 16 Ulipristal acetate (all doses) versus levonorgestrel, Outcome 4 Observed number of pregnancies within 0‐72 h.

Analysis 16.5

Comparison 16 Ulipristal acetate (all doses) versus levonorgestrel, Outcome 5 Specific side effects.

Analysis 16.6

Comparison 16 Ulipristal acetate (all doses) versus levonorgestrel, Outcome 6 Menses.

Analysis 17.1

Comparison 17 Levonorgestrel split dose, 24 hours versus 12 hours, Outcome 1 Observed number of pregnancy (all women).

Analysis 17.2

Comparison 17 Levonorgestrel split dose, 24 hours versus 12 hours, Outcome 2 Observed number of pregnancies (by risk status).

Analysis 17.3

Comparison 17 Levonorgestrel split dose, 24 hours versus 12 hours, Outcome 3 Specific side effects.

Analysis 17.4

Comparison 17 Levonorgestrel split dose, 24 hours versus 12 hours, Outcome 4 Menses.

Analysis 18.1

Comparison 18 Levonorgestrel single dose versus split dose, Outcome 1 Observed number of pregnancies (all women).

Analysis 18.2

Comparison 18 Levonorgestrel single dose versus split dose, Outcome 2 Observed number of pregnancies (by risk status).

Analysis 18.3

Comparison 18 Levonorgestrel single dose versus split dose, Outcome 3 Observed number of pregnancies (time from intercourse).

Analysis 18.4

Comparison 18 Levonorgestrel single dose versus split dose, Outcome 4 Specific side effects.

Analysis 18.5

Comparison 18 Levonorgestrel single dose versus split dose, Outcome 5 Menses.

Analysis 19.1

Comparison 19 Mifepristone low dose (10 mg) versus low dose (5 mg), Outcome 1 Observed number of pregnancies (all women).

Analysis 19.2

Comparison 19 Mifepristone low dose (10 mg) versus low dose (5 mg), Outcome 2 Specific side effects.

Analysis 19.3

Comparison 19 Mifepristone low dose (10 mg) versus low dose (5 mg), Outcome 3 Delay of menses.

Analysis 20.1

Comparison 20 Low dose mifepristone (10 mg) versus split low dose mifepristone (10 mg x2), Outcome 1 Observed number of pregnancies (all women).

Analysis 20.2

Comparison 20 Low dose mifepristone (10 mg) versus split low dose mifepristone (10 mg x2), Outcome 2 Any side effect.

Analysis 20.3

Comparison 20 Low dose mifepristone (10 mg) versus split low dose mifepristone (10 mg x2), Outcome 3 Menses.

Analysis 21.1

Comparison 21 Mifepristone mid dose (25‐50 mg) versus mifepristone low dose (

Analysis 21.2

Comparison 21 Mifepristone mid dose (25‐50 mg) versus mifepristone low dose (

Analysis 21.3

Comparison 21 Mifepristone mid dose (25‐50 mg) versus mifepristone low dose (

Analysis 21.4

Comparison 21 Mifepristone mid dose (25‐50 mg) versus mifepristone low dose (

Analysis 21.5

Comparison 21 Mifepristone mid dose (25‐50 mg) versus mifepristone low dose (

Analysis 22.1

Comparison 22 Mifepristone mid dose (50 mg) versus mifepristone mid dose (25 mg), Outcome 1 Observed number of pregnancies (all women).

Analysis 22.2

Comparison 22 Mifepristone mid dose (50 mg) versus mifepristone mid dose (25 mg), Outcome 2 Any side effect.

Analysis 22.3

Comparison 22 Mifepristone mid dose (50 mg) versus mifepristone mid dose (25 mg), Outcome 3 Specific side effects.

Analysis 22.4

Comparison 22 Mifepristone mid dose (50 mg) versus mifepristone mid dose (25 mg), Outcome 4 Delay in menses.

Analysis 23.1

Comparison 23 Mid dose mifepristone split dose comparisons, Outcome 1 Observed number of pregnancies (all women).

Analysis 23.2

Comparison 23 Mid dose mifepristone split dose comparisons, Outcome 2 Any side effect.

Analysis 23.3

Comparison 23 Mid dose mifepristone split dose comparisons, Outcome 3 Early menses.

Analysis 23.4

Comparison 23 Mid dose mifepristone split dose comparisons, Outcome 4 Delay menses.

Analysis 24.1

Comparison 24 Mifepristone high dose (> 50 mg) versus mifepristone low dose (

Analysis 24.2

Comparison 24 Mifepristone high dose (> 50 mg) versus mifepristone low dose (

Analysis 24.3

Comparison 24 Mifepristone high dose (> 50 mg) versus mifepristone low dose (

Analysis 24.4

Comparison 24 Mifepristone high dose (> 50 mg) versus mifepristone low dose (

Analysis 24.5

Comparison 24 Mifepristone high dose (> 50 mg) versus mifepristone low dose (

Analysis 25.1

Comparison 25 Mifepristone high dose (> 50 mg) versus mifepristone mid dose (25‐50 mg), Outcome 1 Observed number of pregnancies (all women).

Analysis 25.2

Comparison 25 Mifepristone high dose (> 50 mg) versus mifepristone mid dose (25‐50 mg), Outcome 2 Any side effect.

Analysis 25.3

Comparison 25 Mifepristone high dose (> 50 mg) versus mifepristone mid dose (25‐50 mg), Outcome 3 Specific side effects.

Analysis 25.4

Comparison 25 Mifepristone high dose (> 50 mg) versus mifepristone mid dose (25‐50 mg), Outcome 4 Menses.

Analysis 26.1

Comparison 26 Half‐dose Yuzpe versus standard Yuzpe, Outcome 1 Observed number of pregnancies (all women).

Analysis 26.2

Comparison 26 Half‐dose Yuzpe versus standard Yuzpe, Outcome 2 Any side effect.

Analysis 26.3

Comparison 26 Half‐dose Yuzpe versus standard Yuzpe, Outcome 3 Specific side effects.

Analysis 27.1

Comparison 27 Copper intrauterine device versus mifepristone (all doses), Outcome 1 Observed number of pregnancies (all women).

Analysis 27.2

Comparison 27 Copper intrauterine device versus mifepristone (all doses), Outcome 2 Any side effect.

Analysis 27.3

Comparison 27 Copper intrauterine device versus mifepristone (all doses), Outcome 3 Specific side effects.

Analysis 27.4

Comparison 27 Copper intrauterine device versus mifepristone (all doses), Outcome 4 Menses.

Analysis 28.1

Comparison 28 Time elapsed since intercourse in levonorgestrel, Outcome 1 ≤ 24 h vs > 24‐48 h.

Analysis 28.2

Comparison 28 Time elapsed since intercourse in levonorgestrel, Outcome 2 ≤ 24 h vs > 48‐72 h.

Analysis 28.3

Comparison 28 Time elapsed since intercourse in levonorgestrel, Outcome 3 > 24‐48 h vs > 48‐72 h.

Analysis 28.4

Comparison 28 Time elapsed since intercourse in levonorgestrel, Outcome 4 72 h.

Analysis 29.1

Comparison 29 Time elapsed since intercourse (coitus‐treatment interval) in mifepristone, Outcome 1 ≤ 24 h vs > 24‐48 h.

Analysis 29.2

Comparison 29 Time elapsed since intercourse (coitus‐treatment interval) in mifepristone, Outcome 2 ≤ 24 h vs > 48‐72 h.

Analysis 29.3

Comparison 29 Time elapsed since intercourse (coitus‐treatment interval) in mifepristone, Outcome 3 > 24‐48 h vs > 48‐72 h.

Analysis 29.4

Comparison 29 Time elapsed since intercourse (coitus‐treatment interval) in mifepristone, Outcome 4 72 h.

Analysis 30.1

Comparison 30 Time elapsed since intercourse in Yuzpe, Outcome 1 ≤ 24 h vs > 24‐48 h.

Analysis 30.2

Comparison 30 Time elapsed since intercourse in Yuzpe, Outcome 2 ≤ 24 h vs > 48‐72 h.

Analysis 30.3

Comparison 30 Time elapsed since intercourse in Yuzpe, Outcome 3 > 24‐48 h vs > 48‐72 h.

Analysis 31.1

Comparison 31 Time elapsed since intercourse in ulipristal acetate, Outcome 1 ≤ 24 h vs > 24‐48 h.

Analysis 31.2

Comparison 31 Time elapsed since intercourse in ulipristal acetate, Outcome 2 ≤ 24 h vs > 48‐72 h.

Analysis 31.3

Comparison 31 Time elapsed since intercourse in ulipristal acetate, Outcome 3 > 24‐48 h vs > 48‐72 h.

Analysis 31.4

Comparison 31 Time elapsed since intercourse in ulipristal acetate, Outcome 4 72 h.

Analysis 32.1

Comparison 32 High‐risk women versus low‐risk women (all hormonal methods), Outcome 1 Observed number of pregnancies.