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20 µg versus >20 µg estrogen combined oral contraceptives for contraception

  1. Maria F Gallo1,*,
  2. Kavita Nanda2,
  3. David A Grimes3,
  4. Laureen M Lopez4,
  5. Kenneth F Schulz5

Editorial Group: Cochrane Fertility Regulation Group

Published Online: 1 AUG 2013

Assessed as up-to-date: 15 JUL 2013

DOI: 10.1002/14651858.CD003989.pub5


How to Cite

Gallo MF, Nanda K, Grimes DA, Lopez LM, Schulz KF. 20 µg versus >20 µg estrogen combined oral contraceptives for contraception. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD003989. DOI: 10.1002/14651858.CD003989.pub5.

Author Information

  1. 1

    The Ohio State University, Division of Epidemiology, Columbus, Ohio, USA

  2. 2

    FHI, Clinical Sciences, Research Triangle Park, North Carolina, USA

  3. 3

    University of North Carolina, School of Medicine, Obstetrics and Gynecology, Chapel Hill, North Carolina, USA

  4. 4

    FHI 360, Clinical Sciences, Research Triangle Park, North Carolina, USA

  5. 5

    FHI 360 and UNC School of Medicine, Quantitative Sciences, Research Triangle Park, North Carolina, USA

*Maria F Gallo, Division of Epidemiology, The Ohio State University, Room 324 Cunz Hall, 1841 Neil Avenue, Columbus, Ohio, 43210-1351, USA. mgallo@cdc.gov. fjr4@cdc.gov.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 1 AUG 2013

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Since the introduction of combined estrogen and progestin oral contraceptives (COCs) in the early 1960s, the dose of estrogen has been reduced progressively. COCs containing 50 μg of estrogen or more comprised over 99% of OC retail prescriptions in the United States (USA) in 1968 (Gerstman 1991). Twenty years later, less than 2% of these prescriptions were for 50-μg estrogen COCs. The reduction in the estrogen dose has been in response to two main discoveries. First, concern about estrogen-related adverse effects has driven the search for lower-dose estrogen COCs. COC use has been linked in epidemiological studies to breast cancer (CGHFBC 1996), and estrogen has been associated with a number of adverse events, including cerebrovascular complications, thromboembolic incidents, and myocardial infarction (Anonymous 2000). Low-estrogen COCs have been formulated in an attempt to reduce the risk of these rare events. Second, the discovery that estrogen and progestin act synergistically to inhibit ovulation revealed that contraceptive efficacy could be maintained with lower doses of each component. COCs with less than 50 μg estrogen contain ethinyl estradiol (EE) as the estrogenic component in combination with a progestin (Nelson 2007). Twenty-μg EE COCs ( Table 1) first became available in the 1970s and, by 1998, accounted for about 8% of COC prescriptions in the USA (Wallach 2000). COC pills with 15 μg of estrogen contain the lowest estrogen dose available ( Table 2) and have been approved for use in some countries in Europe, South America and elsewhere (IPPF 2013).

Reducing the estrogen dose to improve safety also could decrease contraceptive effectiveness and cycle control. Contraceptive effectiveness depends both on individual susceptibility and compliance. Determining the optimal estrogen dose required is complicated by high biological variation. The inter-individual variation in the blood levels of exogenous hormones has been estimated to vary tenfold (Guillebaud 1989) and intra-individual differences also occur. Consequently, the lowest estrogen dose needed to prevent pregnancy while also maintaining acceptable cycle control and minimal adverse side effects could vary substantially both among women and within an individual woman at different times. Also, the contraceptive effectiveness of low-estrogen COCs could be influenced more by missed pills or drug interactions (Elstein 1994).

Contraceptives with lower doses of estrogen also may compromise cycle control. Evaluating these concerns is difficult due to the lack of uniformity in the analyses of bleeding patterns. Recognizing the ambiguities in the interpretation of trial results and the comparison of contraceptive products, the World Health Organization (WHO) issued recommendations to standardize the collection and analysis of bleeding pattern data (Belsey 1986). Recently, Mishell 2007a reviewed methods used for collecting and analyzing bleeding data for trial reports of combined hormonal contraceptives. Mishell 2007b then developed recommendations for designing trials and for data collection and analysis of bleeding data. However, when this review was initially conducted, Belsey 1986 was considered the standard. 'Bleeding' was defined as a bloody vaginal discharge that requires sanitary protection whereas 'spotting' does not require protection. A 'bleeding or spotting episode' consists of one or more days with bleeding or spotting that is bounded by days without bleeding or spotting. The WHO advised that the woman, rather than the cycle, be used as the unit of analysis; this avoids disproportionate weight in the analysis from women who contribute more cycles and also prevents artificially precise confidence intervals (Belsey 1986). Outcomes should be measured using reference periods of at least 90 days, an amount of time that was sufficiently short to allow the identification of changes over time, while also long enough for bleeding patterns to be characterized properly. The reference period was modified to 84 days in a recent trial of COCs to correspond to the typical length of three pill cycles (Miller 2001). The WHO identified five bleeding outcomes to be included: the proportion of women with prolonged, frequent, infrequent, or irregular bleeding or spotting episodes and the proportion with amenorrhea during the reference period (Belsey 1986). They noted that the timing of bleeding is an additional issue particular to COC research and that terms for assessing bleeding associated with the pill-free interval (e.g., intermenstrual or breakthrough bleeding) should be defined and evaluated. However, the reporting of trial results often does not conform to the WHO recommendations. Instead many trials report only cyclical data for outcomes related to the control of the menstrual cycle, often without specifying precise definitions for the terms used.

Low-estrogen COCs have been attributed with more breakthrough bleeding and spotting (Nelson 2007). Although bleeding irregularities do not threaten health, sub-optimal cycle control impairs the acceptance of and adherence to the contraceptive. A large, six-month USA study found that 46% of pill users discontinued the method due to side effects or physician recommendations, and about 12% of these women identified bleeding irregularities as the primary reason for discontinuation (Rosenberg 1998). The progestin type and dosing regimen are also thought to affect cycle control. Reviews of COCs suggest that levonorgestrel results in better cycle control than norethindrone and that gestodene performs better than desogestrel and levonorgestrel (Rosenberg 1992; Maitra 2004). Given the possible relationship between progestin type and bleeding patterns, a meta-analysis of low-estrogen contraceptives should combine only trials that compare identical drugs, dosages, and regimens.

A secondary concern related to reducing the estrogenic component involves possible decreases in the non-contraceptive benefits of COCs. Combined oral contraception confers health benefits, such as the prevention of ovarian cancer and endometrial cancer and the reduction of acne (Nelson 2007), and the effect of reducing the estrogen level on these preventive benefits is unclear. Ness 2000 found that the reduction in the risk of ovarian cancer was similar for COCs containing less than 50 μg estrogen compared to those with 50 μg or more. Because 20-μg estrogen COCs were not analyzed separately from the other low-estrogen pills, the question remains as to whether this low dose is sufficient to maintain the protective effect. Contemporary low-estrogen COC pills may grant no protection against functional ovarian cysts, as was observed with COCs containing higher doses of estrogen (Holt 1992). As to acne reduction, a COC containing 20 μg estrogen and 100 μg levonorgestrel had better results than a placebo in Thiboutot 2001. However, whether the low-dose estrogen contraceptive is as effective in reducing acne as a higher-dose estrogen COC is unknown. Furthermore, low-estrogen contraceptives might vary in their ability to improve acne.

Combined contraceptives should have high contraceptive effectiveness, while maintaining cycle control and causing minimal adverse effects. The present review evaluates COCs containing 20 μg EE or less with those containing a higher dose of EE regarding these key outcomes. Rare adverse events, though, were not a focus because randomized controlled trials generally do not have sufficient power to study infrequent events, even when combined.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

To test the hypothesis that COCs containing ≤ 20 μg of EE perform similarly as those containing > 20 μg in terms of contraceptive effectiveness, bleeding patterns, discontinuation, and side effects.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Published or unpublished randomized controlled trials that compare a COC containing 20 μg of EE or less with a COC containing more than 20 μg EE were eligible. Trials were restricted to those reported in English (Higgins 2011).

 

Types of participants

Women of reproductive age without medical contraindications to COCs, irrespective of previous COC history were eligible.

 

Types of interventions

Eligible interventions included any COC containing ≤ 20 μg of EE that was compared with a COC containing > 20 μg EE. Trial interventions had to be designed to be administered for a minimum of three consecutive cycles to be eligible for inclusion. Studies were excluded if the interventions were used primarily as treatment for non-contraceptive conditions (e.g., acne, anovulation, dysmenorrhea, menorrhagia, pelvic pain, or endometriosis).

 

Types of outcome measures

To be included, trials had to report on contraceptive effectiveness, bleeding patterns, side effects, or trial discontinuation due to bleeding-related reasons or other side effects. Those that measured only biochemical changes were not eligible. The outcomes were measured as follows:

 

1) Contraceptive effectiveness

  • Cumulative life-table or Kaplan-Meier pregnancy rate
  • Pregnancy Pearl index
  • Proportion of women pregnant

 

2) Discontinuation (overall, due to bleeding-related reasons, and due to other side effects)

  • Cumulative life-table or Kaplan-Meier discontinuation rate
  • Proportion of women who did not complete the trial
  • Discontinuation Pearl index

 

3) Bleeding patterns

Cycle control during reference periods of 90 days (Belsey 1986) or 84 days (Miller 2001)

  • Proportion of women with amenorrhea
  • Proportion of women with prolonged (i.e., longer than 14 days) bleeding or spotting episodes
  • Proportion of women with frequent (i.e., more than 5) bleeding or spotting episodes
  • Proportion of women with infrequent (i.e., less than 3) bleeding or spotting episodes
  • Proportion of women with irregular bleeding (i.e., 3 to 5 bleeding or spotting episodes and less than 3 bleeding or spotting-free intervals of at least 14 days)

Proportion of women with amenorrhea or breakthrough (also known as intermenstrual) bleeding or spotting for cycle three or cycle six, or if data for these cycles were not reported, for the last cycle of follow up

 

4) Side effects

Proportion of women experiencing any side effect reported

 

Search methods for identification of studies

 

Electronic searches

We searched the computerized databases the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and POPLINE for eligible trials using a list of brand names of COCs containing 20 μg of EE or less (IPPF 2013). We also searched for trials via ClinicalTrials.gov and ICTRP. The strategies are shown in Appendix 1. Previous strategies, which also included EMBASE, can be found in Appendix 2.

 

Searching other resources

We assessed the references of eligible trials. For the initial review, we wrote to COC manufacturers to request information about any other published or unpublished trials not discovered in our search.

 

Data collection and analysis

One author evaluated the titles and abstracts located in the literature searches to determine whether they met the inclusion criteria. Two authors independently extracted data from the studies identified for inclusion. We wrote to the researchers when clarifications or additional data were needed. Data were entered and analyzed with RevMan. For trials that included more than two intervention groups, regardless of whether the authors identified a control group, we treated the ≤ 20 μg EE contraceptive as the referent and compared it to the other study groups.

We calculated Peto odds ratios (ORs) with 95% confidence intervals (CIs) for all dichotomous outcomes and mean differences using fixed-effect models with 95% CIs for all continuous outcomes. Contraceptive effectiveness and early discontinuation also were presented as Pearl indices or survival analysis estimates when these measures were available. Pearl indices are calculated by the number of events divided by the total person-time at risk of the event (Trussell 1998). Because contraceptive failure rates typically decrease with duration of use, the Pearl index rate tends to decline as the amount of person-time contributed by each woman increases. Thus, rates from two studies will not be comparable if the studies differed in duration. Although the Pearl method is a sub-optimal measurement, it was included in the review because its use remains prevalent. Survival analyses, which include life-table and Kaplan-Meier methods, are preferred measures. Because RevMan 4.2, used for the initial review, was not designed to include Pearl indices or measures of survival analysis, these estimates were presented in  Table 3 and  Table 4. Most of the studies that included contraceptive effectiveness data simply reported the number of women who became pregnant, and we used these proportions of women to calculate ORs in RevMan. However, these measures potentially are biased in favor of OCs that result in higher discontinuation rates since women who discontinue the study treatment or study participation or who are lost to follow up were unlikely to have been followed to determine whether they became pregnant.

We included all bleeding-related outcomes reported in the eligible trials (e.g., WHO bleeding terms, breakthrough bleeding, spotting, and amenorrhea). Following WHO recommendations (Belsey 1986), we used women, rather than cycles, as the unit of analysis when possible. For studies that did not use the recommended 90- or 84-day reference period, we extracted bleeding-related data from the third and the sixth cycle, or when neither of these was available, from the last cycle of follow up. Although the choice of these cycles was arbitrary, the standardization in the data extraction facilitated comparisons across trials. Definitions of bleeding-related outcomes were described in Characteristics of included studies.

Interval estimation considers both the magnitude of the estimate and the width of the confidence intervals when assessing potential relationships (Rothman 1998). While all available data are presented in the tables, we highlighted the findings that suggest possible differences in COCs based on interval estimation as well as P values.

The review was limited to the analytic method (e.g., intent-to-treat, per-protocol, or a modification of either type) used in the trial report. We combined study results for meta-analysis only when identical drugs, dosages, and regimens were compared. Homogeneity was assessed by examining the results of both a fixed-effect model and a random-effects model. Because the chi-squared test for heterogeneity is a low-power test, the alpha-level was set at 0.10. We conducted sensitivity analyses by examining the effect of deleting each study in turn to test the robustness of any result that appeared to be based on heterogeneous combinations. We critically appraised validity of trials by assessing the potential for bias resulting from the study design, blinding, randomization method, group allocation concealment, and loss to follow up.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Description of studies

 

Results of the search

The 2013 search resulted in 201 unduplicated references: 162 from the main databases, 10 from other sources such as reference lists, and 29 ongoing or recent clinical trials. We did not find any RCTs that met our eligibility criteria for this review. One new study was excluded because it reported on pooled analysis from two uncontrolled trials (Marr 2012).

 

Included studies

The search strategy yielded 21 primary articles that were eligible for the review. Most trials recruited healthy, reproductive-age women without contraindications to COC use. Trials ranged in duration from 3 to 24 treatment cycles with most designed for 6 or 12 treatment cycles. The location was not described for 7 trials; the remaining 14 trials were conducted in North America, South America, Europe or Asia. The trials ranged from a single site (four trials) to 110 sites except for three trials with unspecified number of sites. Five trials included more than two eligible intervention arms. The trials compared 20 different COC pairs.

 

Risk of bias in included studies

The reporting of randomized clinical trials should include details on the participants, blinding, randomization method, group allocation concealment method, participant flow, and statistical methods (CONSORT 2009). One trial blinded only the study observer (Appel 1987). Three trials blinded the participants and either the clinic staff (Bounds 1979; WHO 1982) or the investigator (Endrikat 2001). Two articles described double-blinding but did not specify who was blinded (Akerlund 1993; Endrikat 1997). The remaining trials either were open (12 trials) or did not mention blinding (3 trials). Fourteen reports did not provide any details of the method of randomization. Reisman 1999 reported the use of sealed envelopes for allocation concealment; the remaining trials did not provide any details regarding attempts to conceal the allocation process. None of the articles described the person responsible for implementing the randomization process or the use of a centralized location for randomization.

The number of participants who were recruited, randomized, received treatment, lost to follow up, discontinued early, and excluded from the analysis should be reported in the details of the participant flow (CONSORT 2009). Only WHO 1982 reported the number of recruited women who were screened for trial participation. All trials reported the total number of women randomized, although these figures may have been the total numbers analyzed rather than randomized. The number of women reportedly randomized in the trials ranged from 20 to 2894. Four trials did not specify the number of women randomized to each study group (Bounds 1979; Appel 1987; Teichmann 1995; Endrikat 2001). Eleven trials reported excluding randomized women from the analysis, usually for protocol violations. Kluft 2006 used intent-to-treat analysis. Hampton 2001 reported using an intent-to-treat analysis for contraceptive effectiveness but did not specify the analytic method used for the remaining outcomes. Endrikat 2001 reported both modified intent-to-treat and per-protocol analyses without specifying which method was used for the results presented. Seven trials described using a per-protocol or modified per-protocol analysis based on the exclusion of women or treatment cycles from the analysis for failure to comply with the protocol (Akerlund 1993; Brill 1996; Winkler 1996; Chavez 1999; Kaunitz 2009; Reisman 1999; Skouby 2005). However, the decision to exclude the woman or the cycle was unclear in Chavez 1999 because different sections of the article reported conflicting procedures. Inauen 1991 had complete follow up and no early discontinuation. The remaining trials did not specify the analytic method used. Three trials did not report the proportion of women completing the study (Bounds 1979; Brill 1996; Winkler 1996), and the proportion ranged from 46% to 94% in the remaining trials.

 

Effects of interventions

 

Contraceptive effectiveness

No significant differences were found in contraceptive effectiveness for the 13 COC pairs for which this outcome was reported ( Table 3).

 

Early Discontinuation

The COC containing EE 20 μg and norethindrone acetate 1 mg had higher life-table rates of early discontinuation (overall, due to medical reasons, and due to amenorrhea) than its five comparison COCs ( Table 4), but P values were the only measure of variability provided for the estimates (WHO 1982). The remaining six comparisons with data for overall discontinuation found no significant differences between groups. Differences in bleeding-related discontinuations were apparent for three comparisons. Women in the EE 20 μg and desogestrel 150 μg group had an OR of discontinuation due to irregular bleeding 2.59 (95% CI 1.35 to 5.00) times that of the EE 30 μg and desogestrel 150 μg group (Akerlund 1993). Women assigned to use the COC with EE 20 μg and desogestrel 150 μg were 2.4 times as likely to discontinue due to metrorrhagia 2.35 (95% CI 1.16 to 4.77) than those in the EE 30 μg and gestodene 75 μg group (Kirkman 1994; Bruni 2000). In addition, women on EE 20 μg and norethindrone acetate 1 mg were more likely to discontinue due to bleeding than women on EE 30 μg and levonorgestrel 150 μg (Bounds 1979).

 

Bleeding Patterns

 

EE 20 mg and desogestrel COCs versus higher-estrogen COCs

Women in the EE 20 μg and desogestrel 150 μg group were more likely than those in the EE 30 μg and desogestrel 150 μg group to report irregular bleeding (OR 1.56; 95% CI 1.10 to 2.20) and a longer duration of irregular bleeding during the third cycle (mean difference 0.70 days; 95% CI 0.30 to 1.10) (Akerlund 1993). No significant differences in amenorrhea or the duration of irregular bleeding remained by the sixth cycle. The lower-dose estrogen group was also more likely to report the occurrence of irregular bleeding (OR 1.69; 95% CI 1.07 to 2.69) or prolonged withdrawal bleeding (OR 1.98; 95% CI 1.03 to 3.78) at least once throughout the trial than the higher-dose estrogen group. The EE 20 μg and desogestrel 150 μg group versus the EE 30 μg and gestodene 75 μg had an OR of irregular bleeding of 2.51 (95% CI 1.77 to 3.56) during the third cycle and 1.72 (95% CI 1.15 to 2.55) during the sixth cycle (Kirkman 1994). Women assigned to use EE 20 μg and desogestrel 150 μg were also more likely to report metrorrhagia (i.e., bleeding from the uterus that is not associated with menstruation) at least once during the trial than women using EE 30 μg and gestodene 75 μg (OR 1.67; 95% CI 1.05 to 2.66) (Brill 1996) or women using EE 30-40-30 μg and gestodene 50-70-100 μg (OR 2.28; 95% CI 1.39 to 3.73) (Bruni 2000).

Inauen 1991 compared a COC containing EE 20 μg and desogestrel to a second COC and also reported bleeding outcomes. However, the trial had insufficient power to detect major differences between the groups.

 

EE 20μg and gestodene COCs versus higher-estrogen COCs

Five trials compared the same gestodene dose (75 μg) but differing EE doses (20 μg versus 30 μg) with a standard (Brill 1996; Winkler 1996; Endrikat 1997; Taneepanichskul 2002) or an extended cycle length (Endrikat 2001). Limitations to assessing bleeding pattern changes included small sample sizes, insufficient data reported, and varying definitions.

 

EE 20 μg and levonorgestrel COCs versus higher-estrogen COCs

The trials comparing a low-estrogen and levonorgestrel COC to a triphasic norethindrone COC found no difference in amenorrhea between the groups at the third cycle (Chavez 1999; Reisman 1999).

 

EE 20 μg and drospirenone COC versus higher-estrogen COC

In Kaunitz 2009, the low dose group (EE 20 µg plus drospirenone) had more unscheduled bleeding days than the group with EE 25 μg and norgestimate 180-215-250 µg (mean difference 1.00; 95% CI 0.44 to 1.56).

 

EE 20 μg and norethindrone acetate COCs versus higher-estrogen COCs

The low-dose COC containing EE 20 μg and norethindrone acetate 1 mg fared worse than the COC EE 30 μg and levonorgestrel 150 μg for three bleeding outcomes during the first to third cycles: 1) frequent bleeding (OR 2.92; 95% CI 2.08 to 4.09); 2) infrequent bleeding (OR 2.84; 95% CI 1.80 to 4.46); and 3) irregular bleeding (OR 4.01; 95% CI 2.12 to 7.61) (WHO 1982). The low-dose COC also had worse bleeding outcomes during the first to third cycles when compared to a COC with the same norethindrone acetate dose (1 mg) but more estrogen (EE 50 μg): 1) frequent bleeding (OR 4.59; 95% CI 3.24 to 6.51); 2) infrequent bleeding (OR 3.08; 95% CI 1.95 to 4.86); 3) irregular bleeding (OR 5.33; 95% CI 2.74 to 10.34); and 4) prolonged bleeding (OR 3.11; 95% CI 1.83 to 5.27).

Similarly, EE 20 μg and norethindrone acetate 1 mg resulted in a longer duration of bleeding or spotting days during the third cycle when compared to three higher-dose COCs containing the same progestin type: 1) EE 30 μg and norethindrone acetate 1.5 μg (mean difference 1.10 days; 95% CI 0.37 to 1.83); 2) EE 50 μg and norethindrone acetate 1 mg (mean difference 1.20 days; 95% CI 0.43 to 1.97); and 3) EE 20-30-50 μg and norethindrone acetate 1-1.5-1 mg (mean difference 1.60 days; 95% CI 0.94 to 2.26) (Appel 1987). Women in the low-dose COC group (EE 20 μg and norethindrone acetate 1 mg) also were more likely to report frequent bleeding (OR 1.97; 95% CI 1.42 to 2.73), infrequent bleeding (OR 1.95; 95% CI 1.27 to 3.00), and irregular bleeding (OR 2.38; 95% CI 1.31 to 4.31) during the first to third cycles than those in the EE 50 μg and norethindrone acetate 1 mg group (WHO 1982). (The groups did not differ significantly in the frequency of prolonged bleeding during the first three cycles.) Likewise, women assigned to this low-dose COC reported more infrequent bleeding (OR 1.88; 95% CI 1.22 to 2.90) and irregular bleeding (OR 1.92; 95% CI 1.08 to 3.43) than those using EE 35 μg and norethindrone acetate 400 μg, but no difference in frequent or prolonged bleeding (WHO 1982).

The sole trial to compare EE 20 μg and norethindrone acetate 1 mg to mestranol 50 μg and norethindrone 1 mg found the low-dose COC group had a higher risk of frequent bleeding (OR 2.82; 95% CI 2.00 to 3.97), infrequent bleeding (OR 2.49; 95% CI 1.58 to 3.91), irregular bleeding (OR 4.85; 95% CI 2.49 to 9.43), and prolonged bleeding (OR 2.67; 95% CI 1.58 to 4.52) during the first to third cycles (WHO 1982). Finally, the COC with EE 20 μg and norethindrone acetate 1 mg resulted in more breakthrough bleeding during the third cycle (OR 2.79; 95% CI 2.09 to 3.74) and during the sixth cycle (OR 2.40; 95% CI 1.78 to 3.24) compared to the COC containing EE 25 μg and norgestimate 180-215-250 μg (Hampton 2001). When breakthrough spotting was included with the outcome breakthrough bleeding, the ORs were similar to those for breakthrough bleeding alone. The bleeding data were re-analyzed with new criteria for a secondary article; the pattern was the same. However, the percentages with unscheduled bleeding at cycle six were 33.5% for EE 20 μg and norethindrone acetate 1 mg versus 21% for EE 25 μg and norgestimate 180-215-250 μg, while the earlier estimates of breakthrough bleeding or spotting were 22.2% and 10.3%, respectively.

 

Side effects

Side effects were measured as the proportion of women experiencing the event during the study. Three of the six COC pairs with side effects reported found differences. The ORs of headache (1.71; 95% CI 0.94 to 3.11), dizziness (7.65; 95% CI 1.54 to 38.08), mood changes (1.93; 95% CI 1.05 to 3.56), and weight gain (2.46; 95% CI 1.04 to 5.84) were higher for the COC EE 20 μg and desogestrel 150 μg group than the COC EE 30 μg and desogestrel 150 μg group (Akerlund 1993). However, women in the COC EE 20 μg and desogestrel 150 μg group were less likely to report breast pain (OR 0.70; 95% CI 0.47 to 1.05) and dizziness (OR 0.40; 95% CI 0.17 to 0.93), than those in the EE 30-40-30 μg and gestodene 50-70-100 μg group (Bruni 2000). Also, compared to women in the 35 μg and norethindrone 500-750-1000 μg, group women in the 20 μg and levonorgestrel 100 μg were less likely to report breast pain (OR 0.45; 95% CI 0.22 to 0.93) or vomiting (OR 0.33; 95% CI 0.11 to 0.96) (Chavez 1999).

 

Heterogeneity

Few comparisons could be combined in meta-analysis because most studies differed in the COC pairs that were compared. Only two of the comparisons that were eligible for meta-analyses appeared to combine heterogeneous estimates with either fixed-effect or random-effects models. The risk of headache differed in the two studies that compared COCs with gestodene 75 μg but different EE doses (Brill 1996; Endrikat 1997), but neither trial found significant ORs for this outcome. The increased rate of discontinuation due to adverse events in the EE 20 μg and levonorgestrel 100 μg group versus the EE 35 μg and norethindrone 500-750-1000 μg group was the result of Reisman 1999; Chavez 1999 did not show a difference in discontinuation for this reason between the two study groups.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Summary of main results

The included trials provide insufficient evidence to determine whether the contraceptive effectiveness of COCs containing 20 μg of EE differs from those with higher estrogen doses. Most studies were underpowered to study pregnancy as a primary outcome; larger sample sizes are required because COCs are highly effective and few pregnancies occurred. Furthermore, most pregnancy estimates could not be combined in meta-analysis because the study COCs contained different progestins. Research using ultrasonography to measure the growth of follicle-like structures suggests that low-estrogen pills could have a reduced margin of safety from missed pills or drug interactions (Teichmann 1995; Spona 1996). Increased risk of pregnancy from this possible lack of 'forgiveness' for missed pills among the low-dose estrogen users might not have been detected in the present review. Also, many studies excluded women from the analysis for protocol violations, including failure to adhere to the daily pill intake, which could have biased the results.

Early discontinuation from the trial can be considered a proxy measure of method acceptability. Overall discontinuation rates did not vary substantially for most COCs compared. Four comparisons showed higher rates of discontinuation due to adverse events for EE 20 μg pills than their higher-estrogen comparison COCs, and one trial found more medical-related discontinuations for the low-dose estrogen COC than its five high-dose estrogen counterparts. However, discontinuation due to adverse events or medical reasons provides limited information because this outcome can combine disparate reasons for quitting the trial early. For example, amenorrhea is different than excessive or irregular bleeding, and studies should separate these. On the other hand, the included trials might have been underpowered to detect differences between specific reasons for discontinuation. Few trials reported data for discontinuation due to specific adverse events.

Several COCs containing 20 μg EE resulted in higher rates of outcomes related to lack of bleeding (amenorrhea and infrequent bleeding) as well as changes in bleeding (irregular, prolonged, frequent, and breakthrough bleeding) than their higher-estrogen comparison pills. Comparing bleeding data from studies is complicated by lack of uniformity in the outcomes used. Also, determining the clinical importance of changes in bleeding patterns is difficult since women in different cultures may view menstrual patterns and assess the acceptability of any changes differently. For example, amenorrhea or infrequent bleeding may be more acceptable in certain cultural settings than others. Finally, the progestin type and dose as well as the ratio of the progestin and estrogen doses could also affect bleeding patterns. Research suggests that certain progestin types could result in better cycle control than others (Rosenberg 1992). While bleeding irregularities do not pose a health risk, they reduce method acceptability and adherence by users.

 

Overall completeness and applicability of evidence

The randomized controlled trial design, generally, is not suited for evaluating the risk of rare adverse events (e.g., thromboembolic events or myocardial infarction). Studies assessing various hemostatic outcomes as markers for these rare events indicate that the effects on these intermediate variables might be less with 20 μg pills (Basdevant 1993; Norris 1996; Winkler 1996). However, usual tests of hemostasis do not predict clinical events, so these intermediate outcomes have no clinical utility.

 

Quality of the evidence

Trials often failed to report a measure of variability for outcome data (e.g., reporting dichotomous outcomes in percentages, rather than absolute numbers, not including standard deviation or confidence interval for continuous outcomes). The lack of variability estimates severely constrains the interpretation of a point estimate and, consequently, prevented their inclusion in this review. A second limitation was that none of the trials described using adequate steps to conceal the allocation process during randomization. Failure to conceal the allocation sequence can lead to biased results (Schulz 2002). Furthermore, most trials were unblinded or did not report blinding of group assignment, and the knowledge of the group assignment could have introduced bias. Losses to follow up were high in many trials, which can bias the results (Strauss 2005). Finally, all of the trials appear to have been funded by pharmaceutical companies except for WHO 1982 and two that did not specify an industry relationship (Basdevant 1993; Teichmann 1995). Pharmaceutical sponsorship represents a potential conflict of interest and can introduce bias in terms of the study design, analysis or reporting of unfavorable results (Lexchin 2003).

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

 

Implications for practice

While COCs containing 20 μg EE may be theoretically safer, this review did not focus on the rare events required to assess this hypothesis. Data from existing randomized controlled trials are inadequate to detect possible differences in contraceptive effectiveness. Twenty μg EE COCs resulted in higher rates of bleeding pattern disruptions. However, most trials compared oral contraceptives containing different progestin types, and changes in bleeding patterns could be related to progestin type as well as estrogen dose.

 
Implications for research

Large randomized controlled trials comparing regimens with the same progestin type are needed to determine whether the contraceptive effectiveness of 20-μg EE COCs is similar to that of their higher-estrogen counterparts. Likewise, studies of bleeding patterns should compare pills containing the same progestin type but different estrogen doses. Trials should use standardized methods for collecting and analyzing bleeding data (Mishell 2007b). Trials should also employ better research methods, e.g., adequate allocation concealment (Schulz 2002), and follow CONSORT guidelines for reporting the results (CONSORT 2009). Higher follow-up rates are essential for meaningful interpretation of the results.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Carol Manion of FHI 360 helped develop and execute the literature searches.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
Download statistical data

 
Comparison 1. EE 20 µg and desogestrel 150 µg versus EE 30 µg and desogestrel 150 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman1982Peto Odds Ratio (Peto, Fixed, 95% CI)0.69 [0.12, 3.97]

 2 Discontinuation - overall11000Peto Odds Ratio (Peto, Fixed, 95% CI)1.20 [0.92, 1.56]

 3 Discontinuation - mood changes11000Peto Odds Ratio (Peto, Fixed, 95% CI)1.51 [0.68, 3.33]

 4 Discontinuation - irregular bleeding11000Peto Odds Ratio (Peto, Fixed, 95% CI)2.59 [1.35, 5.00]

 5 Discontinuation - nausea158Peto Odds Ratio (Peto, Fixed, 95% CI)0.75 [0.04, 12.64]

 6 Amenorrhea - cycle 31778Peto Odds Ratio (Peto, Fixed, 95% CI)1.49 [0.75, 2.97]

 7 Amenorrhea - cycle 61721Peto Odds Ratio (Peto, Fixed, 95% CI)1.43 [0.65, 3.12]

 8 Irregular bleeding - cycle 31778Peto Odds Ratio (Peto, Fixed, 95% CI)1.56 [1.10, 2.20]

 9 Duration of irregular bleeding in days - cycle 31778Mean Difference (IV, Fixed, 95% CI)0.70 [0.30, 1.10]

 10 Duration of irregular bleeding in days - cycle 61721Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.46, 0.26]

 11 Dizziness1982Peto Odds Ratio (Peto, Fixed, 95% CI)7.65 [1.54, 38.08]

 12 Dysmenorrhea1982Peto Odds Ratio (Peto, Fixed, 95% CI)1.46 [0.70, 3.06]

 13 Headache1982Peto Odds Ratio (Peto, Fixed, 95% CI)1.71 [0.94, 3.11]

 14 Increased weight1982Peto Odds Ratio (Peto, Fixed, 95% CI)2.46 [1.04, 5.84]

 15 Irregular bleeding1982Peto Odds Ratio (Peto, Fixed, 95% CI)1.69 [1.07, 2.69]

 16 Mood change1982Peto Odds Ratio (Peto, Fixed, 95% CI)1.93 [1.05, 3.56]

 17 Nausea, diarrhea, vomiting1982Peto Odds Ratio (Peto, Fixed, 95% CI)1.42 [0.74, 2.72]

 18 Prolonged withdrawal bleeding1982Peto Odds Ratio (Peto, Fixed, 95% CI)1.98 [1.03, 3.78]

 
Comparison 2. EE 20 µg and desogestrel 150 µg versus EE 50 µg and desogestrel 125 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Breakthough bleeding - cycles 1 to 3140Peto Odds Ratio (Peto, Fixed, 95% CI)8.23 [0.81, 84.07]

 2 Breakthrough spotting - cycles 1 to 3140Peto Odds Ratio (Peto, Fixed, 95% CI)7.79 [0.47, 129.11]

 3 Acne140Peto Odds Ratio (Peto, Fixed, 95% CI)0.13 [0.01, 2.13]

 4 Breast tenderness140Peto Odds Ratio (Peto, Fixed, 95% CI)1.0 [0.13, 7.69]

 5 Headache140Peto Odds Ratio (Peto, Fixed, 95% CI)0.14 [0.00, 6.82]

 6 Weight gain140Peto Odds Ratio (Peto, Fixed, 95% CI)0.13 [0.01, 2.13]

 
Comparison 3. EE 20 µg and desogestrel 150 µg versus EE 30 µg and gestodene 75 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman22027Peto Odds Ratio (Peto, Fixed, 95% CI)1.00 [0.20, 4.96]

 2 Discontinuation - overall33033Peto Odds Ratio (Peto, Fixed, 95% CI)1.03 [0.85, 1.26]

 3 Discontinuation - abdominal pain1416Peto Odds Ratio (Peto, Fixed, 95% CI)1.49 [0.43, 5.22]

 4 Discontinuation - adverse event33033Peto Odds Ratio (Peto, Fixed, 95% CI)1.28 [0.98, 1.68]

 5 Discontinuation - breast tension1416Peto Odds Ratio (Peto, Fixed, 95% CI)0.51 [0.05, 4.90]

 6 Discontinuation - colpitis1416Peto Odds Ratio (Peto, Fixed, 95% CI)0.99 [0.06, 15.89]

 7 Discontinuation - depressive mood1416Peto Odds Ratio (Peto, Fixed, 95% CI)0.51 [0.05, 4.90]

 8 Discontinuation - dizziness1416Peto Odds Ratio (Peto, Fixed, 95% CI)7.43 [1.04, 53.09]

 9 Discontinuation - headache1416Peto Odds Ratio (Peto, Fixed, 95% CI)1.24 [0.33, 4.65]

 10 Discontinuation - hypertension1416Peto Odds Ratio (Peto, Fixed, 95% CI)7.32 [0.15, 368.86]

 11 Discontinuation - hypomenorrhea11006Peto Odds Ratio (Peto, Fixed, 95% CI)7.46 [0.47, 119.49]

 12 Discontinuation - intermenstrual bleeding1416Peto Odds Ratio (Peto, Fixed, 95% CI)0.74 [0.17, 3.30]

 13 Discontinuation - menorrhagia11006Peto Odds Ratio (Peto, Fixed, 95% CI)1.01 [0.14, 7.18]

 14 Discontinuation - menstrual disorder11006Peto Odds Ratio (Peto, Fixed, 95% CI)0.52 [0.05, 4.98]

 15 Discontinuation - metrorrhagia22617Peto Odds Ratio (Peto, Fixed, 95% CI)2.35 [1.16, 4.77]

 16 Discontinuation - nausea1416Peto Odds Ratio (Peto, Fixed, 95% CI)0.99 [0.24, 4.01]

 17 Discontinuation - nervousness1416Peto Odds Ratio (Peto, Fixed, 95% CI)7.39 [0.76, 71.43]

 18 Discontinuation - pruritus1416Peto Odds Ratio (Peto, Fixed, 95% CI)7.32 [0.15, 368.86]

 19 Discontinuation - vomiting1416Peto Odds Ratio (Peto, Fixed, 95% CI)3.82 [0.76, 19.10]

 20 Irregular bleeding - cycle 31910Peto Odds Ratio (Peto, Fixed, 95% CI)2.51 [1.77, 3.56]

 21 Irregular bleeding - cycle 61823Peto Odds Ratio (Peto, Fixed, 95% CI)1.72 [1.15, 2.55]

 22 Amenorrhea - cycle 31910Peto Odds Ratio (Peto, Fixed, 95% CI)2.38 [0.83, 6.82]

 23 Amenorrhea - cycle 61823Peto Odds Ratio (Peto, Fixed, 95% CI)0.37 [0.09, 1.47]

 24 Abdominal pain11611Peto Odds Ratio (Peto, Fixed, 95% CI)1.19 [0.71, 2.01]

 25 Acne11611Peto Odds Ratio (Peto, Fixed, 95% CI)0.94 [0.46, 1.91]

 26 Breast pain11611Peto Odds Ratio (Peto, Fixed, 95% CI)0.85 [0.56, 1.30]

 27 Decreased libido11611Peto Odds Ratio (Peto, Fixed, 95% CI)0.64 [0.25, 1.62]

 28 Depression11611Peto Odds Ratio (Peto, Fixed, 95% CI)0.76 [0.40, 1.46]

 29 Dizziness11611Peto Odds Ratio (Peto, Fixed, 95% CI)0.60 [0.23, 1.62]

 30 Dysmenorrhea11611Peto Odds Ratio (Peto, Fixed, 95% CI)0.94 [0.48, 1.85]

 31 Emotional lability11611Peto Odds Ratio (Peto, Fixed, 95% CI)0.72 [0.38, 1.38]

 32 Flatulence11611Peto Odds Ratio (Peto, Fixed, 95% CI)0.59 [0.24, 1.45]

 33 Headache11611Peto Odds Ratio (Peto, Fixed, 95% CI)1.08 [0.81, 1.42]

 34 Menstrual disorder11611Peto Odds Ratio (Peto, Fixed, 95% CI)1.00 [0.41, 2.42]

 35 Metrorrhagia11611Peto Odds Ratio (Peto, Fixed, 95% CI)1.67 [1.05, 2.66]

 36 Migraine11611Peto Odds Ratio (Peto, Fixed, 95% CI)2.38 [0.83, 6.80]

 37 Nausea11611Peto Odds Ratio (Peto, Fixed, 95% CI)1.16 [0.68, 1.95]

 38 Pain11611Peto Odds Ratio (Peto, Fixed, 95% CI)1.37 [0.63, 2.97]

 39 Vaginal moniliasis11611Peto Odds Ratio (Peto, Fixed, 95% CI)1.45 [0.62, 3.36]

 40 Vomiting11611Peto Odds Ratio (Peto, Fixed, 95% CI)0.48 [0.19, 1.17]

 41 Weight gain11611Peto Odds Ratio (Peto, Fixed, 95% CI)0.68 [0.34, 1.38]

 42 Weight gain in kg1805Mean Difference (IV, Fixed, 95% CI)-0.20 [-0.40, -0.00]

 
Comparison 4. EE 20 µg and desogestrel 150 µg versus EE 30-40-30 µg and gestodene 50-70-100 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman11613Peto Odds Ratio (Peto, Fixed, 95% CI)1.00 [0.14, 7.14]

 2 Discontinuation - overall11613Peto Odds Ratio (Peto, Fixed, 95% CI)1.07 [0.82, 1.40]

 3 Discontinuation - adverse reaction11613Peto Odds Ratio (Peto, Fixed, 95% CI)1.35 [0.91, 1.99]

 4 Discontinuation - metrorrhagia11613Peto Odds Ratio (Peto, Fixed, 95% CI)2.97 [1.00, 8.85]

 5 Abdominal pain11613Peto Odds Ratio (Peto, Fixed, 95% CI)1.20 [0.71, 2.01]

 6 Acne11613Peto Odds Ratio (Peto, Fixed, 95% CI)0.75 [0.38, 1.46]

 7 Breast pain11613Peto Odds Ratio (Peto, Fixed, 95% CI)0.70 [0.47, 1.05]

 8 Decreased libido11613Peto Odds Ratio (Peto, Fixed, 95% CI)1.00 [0.35, 2.87]

 9 Depression11613Peto Odds Ratio (Peto, Fixed, 95% CI)1.07 [0.53, 2.18]

 10 Dizziness11613Peto Odds Ratio (Peto, Fixed, 95% CI)0.40 [0.17, 0.93]

 11 Dysmenorrhea11613Peto Odds Ratio (Peto, Fixed, 95% CI)1.22 [0.60, 2.49]

 12 Emotional lability11613Peto Odds Ratio (Peto, Fixed, 95% CI)0.89 [0.45, 1.76]

 13 Flatulence11613Peto Odds Ratio (Peto, Fixed, 95% CI)1.17 [0.39, 3.49]

 14 Headache11613Peto Odds Ratio (Peto, Fixed, 95% CI)1.04 [0.78, 1.37]

 15 Menstrual disorder11613Peto Odds Ratio (Peto, Fixed, 95% CI)1.43 [0.55, 3.73]

 16 Metrorrhagia11613Peto Odds Ratio (Peto, Fixed, 95% CI)2.28 [1.39, 3.73]

 17 Migraine11613Peto Odds Ratio (Peto, Fixed, 95% CI)0.83 [0.36, 1.94]

 18 Nausea11613Peto Odds Ratio (Peto, Fixed, 95% CI)0.73 [0.46, 1.17]

 19 Pain11613Peto Odds Ratio (Peto, Fixed, 95% CI)2.10 [0.90, 4.86]

 20 Vaginal moniliasis11613Peto Odds Ratio (Peto, Fixed, 95% CI)2.11 [0.86, 5.22]

 21 Vomiting11613Peto Odds Ratio (Peto, Fixed, 95% CI)0.86 [0.29, 2.56]

 22 Weight gain11613Peto Odds Ratio (Peto, Fixed, 95% CI)0.62 [0.31, 1.22]

 
Comparison 5. EE 20 µg and desogestrel 150 µg versus EE 35 µg and norgestimate 180-215-250 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman1309Peto Odds Ratio (Peto, Fixed, 95% CI)0.13 [0.01, 1.30]

 
Comparison 6. EE 20 µg and gestodene 75 µg versus EE 30 µg and gestodene 75 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman2799Peto Odds Ratio (Peto, Fixed, 95% CI)0.23 [0.02, 2.55]

 2 Discontinuation - overall2799Peto Odds Ratio (Peto, Fixed, 95% CI)1.14 [0.80, 1.63]

 3 Discontinuation - adverse event3753Peto Odds Ratio (Peto, Fixed, 95% CI)1.46 [0.86, 2.46]

 4 Discontinuation - intermenstrual bleeding164Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Discontinuation - metrorrhagia140Peto Odds Ratio (Peto, Fixed, 95% CI)0.14 [0.00, 6.82]

 6 Breakthrough bleeding - cycle 31114Peto Odds Ratio (Peto, Fixed, 95% CI)6.90 [0.14, 348.82]

 7 Breakthrough bleeding - cycle 61114Peto Odds Ratio (Peto, Fixed, 95% CI)0.13 [0.00, 6.36]

 8 Spotting - cycle 31114Peto Odds Ratio (Peto, Fixed, 95% CI)0.61 [0.10, 3.66]

 9 Spotting - cycle 61114Peto Odds Ratio (Peto, Fixed, 95% CI)0.93 [0.06, 15.10]

 10 Acne2707Peto Odds Ratio (Peto, Fixed, 95% CI)1.35 [0.60, 3.08]

 11 Breast tension or tenderness3821Peto Odds Ratio (Peto, Fixed, 95% CI)1.18 [0.68, 2.05]

 12 Change in libido1649Peto Odds Ratio (Peto, Fixed, 95% CI)1.72 [0.64, 4.61]

 13 Chloasma1114Peto Odds Ratio (Peto, Fixed, 95% CI)0.93 [0.13, 6.79]

 14 Depressive moods2707Peto Odds Ratio (Peto, Fixed, 95% CI)2.12 [0.80, 5.66]

 15 Diarrhea1114Peto Odds Ratio (Peto, Fixed, 95% CI)0.33 [0.05, 2.43]

 16 Dizziness2763Peto Odds Ratio (Peto, Fixed, 95% CI)1.52 [0.57, 4.02]

 17 Edema1649Peto Odds Ratio (Peto, Fixed, 95% CI)0.49 [0.09, 2.66]

 18 Headache2707Peto Odds Ratio (Peto, Fixed, 95% CI)0.98 [0.60, 1.59]

 19 Nausea2707Peto Odds Ratio (Peto, Fixed, 95% CI)1.27 [0.66, 2.45]

 20 Nausea and vomiting1114Peto Odds Ratio (Peto, Fixed, 95% CI)1.84 [0.19, 18.04]

 21 Nervousness1649Peto Odds Ratio (Peto, Fixed, 95% CI)1.51 [0.59, 3.87]

 22 Varicose conditions1649Peto Odds Ratio (Peto, Fixed, 95% CI)0.86 [0.20, 3.72]

 23 Vomiting2707Peto Odds Ratio (Peto, Fixed, 95% CI)0.68 [0.20, 2.25]

 24 Weight gain >2 kg1452Peto Odds Ratio (Peto, Fixed, 95% CI)1.06 [0.63, 1.81]

 25 Weight gain in kg1114Mean Difference (IV, Fixed, 95% CI)-1.5 [-4.23, 1.23]

 
Comparison 7. EE 20 µg and gestodene 75 µg (23-day) versus EE 30 µg and gestodene 75 µg (21-day)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman169Peto Odds Ratio (Peto, Fixed, 95% CI)0.13 [0.00, 6.63]

 2 Intracyclic bleeding - cycle 1 and at least once during cycles 2 to 6166Peto Odds Ratio (Peto, Fixed, 95% CI)0.11 [0.02, 0.46]

 
Comparison 8. EE 20 µg and levonorgestrel 100 µg versus EE 35 µg and norethindrone 500-750-1000 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman2729Peto Odds Ratio (Peto, Fixed, 95% CI)0.52 [0.10, 2.60]

 2 Discontinuation - overall2729Peto Odds Ratio (Peto, Fixed, 95% CI)1.16 [0.78, 1.73]

 3 Discontinuation - adverse events2729Peto Odds Ratio (Peto, Fixed, 95% CI)1.44 [0.86, 2.41]

 4 Discontinuation - breakthrough bleeding1387Peto Odds Ratio (Peto, Fixed, 95% CI)2.78 [0.39, 19.91]

 5 Discontinuation - headache1387Peto Odds Ratio (Peto, Fixed, 95% CI)3.42 [0.59, 19.90]

 6 Discontinuation - nausea or vomiting1387Peto Odds Ratio (Peto, Fixed, 95% CI)1.27 [0.34, 4.77]

 7 Intermenstrual bleeding - cycle 32420Peto Odds Ratio (Peto, Fixed, 95% CI)0.85 [0.57, 1.26]

 8 Amenorrhea - cycle 32420Peto Odds Ratio (Peto, Fixed, 95% CI)1.43 [0.32, 6.34]

 9 Breast pain1289Peto Odds Ratio (Peto, Fixed, 95% CI)0.45 [0.22, 0.93]

 10 Dysmenorrhea1289Peto Odds Ratio (Peto, Fixed, 95% CI)0.82 [0.49, 1.36]

 11 Headache1289Peto Odds Ratio (Peto, Fixed, 95% CI)0.94 [0.57, 1.56]

 12 Nausea1289Peto Odds Ratio (Peto, Fixed, 95% CI)0.74 [0.40, 1.36]

 13 Vomiting1289Peto Odds Ratio (Peto, Fixed, 95% CI)0.33 [0.11, 0.96]

 
Comparison 9. EE 20 µg and levonorgestrel 100 µg versus EE 35 µg and norgestimate 180-215-250 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman1309Peto Odds Ratio (Peto, Fixed, 95% CI)0.37 [0.05, 2.63]

 
Comparison 10. EE 20 µg and norethindrone acetate 1 mg versus EE 30 µg and levonorgestrel 150 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman1110Peto Odds Ratio (Peto, Fixed, 95% CI)2.80 [0.38, 20.41]

 2 Discontinuation - bleeding1110Peto Odds Ratio (Peto, Fixed, 95% CI)5.38 [1.82, 15.91]

 3 Frequent bleeding - cycles 1 to 31629Peto Odds Ratio (Peto, Fixed, 95% CI)2.92 [2.08, 4.09]

 4 Infrequent bleeding - cycles 1 to 31629Peto Odds Ratio (Peto, Fixed, 95% CI)2.84 [1.80, 4.46]

 5 Irregular bleeding - cycles 1 to 31629Peto Odds Ratio (Peto, Fixed, 95% CI)4.01 [2.12, 7.61]

 6 Prolonged bleeding - cycles 1 to 31629Peto Odds Ratio (Peto, Fixed, 95% CI)1.51 [0.94, 2.43]

 
Comparison 11. EE 20 µg and norethindrone acetate 1 mg versus EE 50 µg and levonorgestrel 150 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Frequent bleeding - cycles 1 to 31631Peto Odds Ratio (Peto, Fixed, 95% CI)4.59 [3.24, 6.51]

 2 Infrequent bleeding - cycles 1 to 31631Peto Odds Ratio (Peto, Fixed, 95% CI)3.08 [1.95, 4.86]

 3 Irregular bleeding - cycles 1 to 31631Peto Odds Ratio (Peto, Fixed, 95% CI)5.33 [2.74, 10.34]

 4 Prolonged bleeding - cycles 1 to 31631Peto Odds Ratio (Peto, Fixed, 95% CI)3.11 [1.83, 5.27]

 
Comparison 12. EE 20 µg and norethindrone acetate 1 mg versus EE 30 µg and norethindrone acetate 1.5 mg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Duration of breakthrough bleeding or spotting in days - cycle 31228Mean Difference (IV, Fixed, 95% CI)1.1 [0.37, 1.83]

 2 Amenorrhea - cycle 31228Peto Odds Ratio (Peto, Fixed, 95% CI)2.17 [0.68, 6.93]

 
Comparison 13. EE 20 µg and norethindrone acetate 1 mg versus EE 50 µg and norethindrone acetate 1 mg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Duration of breakthrough bleeding or spotting in days - cycle 31214Mean Difference (IV, Fixed, 95% CI)1.20 [0.43, 1.97]

 2 Amenorrhea - cycle 31215Peto Odds Ratio (Peto, Fixed, 95% CI)3.34 [0.94, 11.84]

 3 Frequent bleeding - cycles 1 to 31626Peto Odds Ratio (Peto, Fixed, 95% CI)1.97 [1.42, 2.73]

 4 Infrequent bleeding - cycles 1 to 31626Peto Odds Ratio (Peto, Fixed, 95% CI)1.95 [1.27, 3.00]

 5 Irregular bleeding - cycles 1 to 31626Peto Odds Ratio (Peto, Fixed, 95% CI)2.38 [1.31, 4.31]

 6 Prolonged bleeding - cycles 1 to 31626Peto Odds Ratio (Peto, Fixed, 95% CI)1.27 [0.80, 2.02]

 
Comparison 14. EE 20 µg and norethindrone acetate 1 mg versus EE 20-30-50 µg and norethindrone acetate 1-1.5-1 mg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Duration of bleeding or spotting in days - cycle 31219Mean Difference (IV, Fixed, 95% CI)1.6 [0.94, 2.26]

 2 Amenorrhea - cycle 31221Peto Odds Ratio (Peto, Fixed, 95% CI)2.04 [0.64, 6.50]

 
Comparison 15. EE 20 µg and norethindrone acetate 1 mg versus EE 35 µg and norethindrone acetate 400 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Frequent bleeding - cycles 1 to 31616Peto Odds Ratio (Peto, Fixed, 95% CI)0.87 [0.64, 1.20]

 2 Infrequent bleeding - cycles 1 to 31616Peto Odds Ratio (Peto, Fixed, 95% CI)1.88 [1.22, 2.90]

 3 Irregular bleeding - cycles 1 to 31616Peto Odds Ratio (Peto, Fixed, 95% CI)1.92 [1.08, 3.43]

 4 Prolonged bleeding - cycles 1 to 31616Peto Odds Ratio (Peto, Fixed, 95% CI)0.91 [0.59, 1.41]

 
Comparison 16. EE 20 µg and norethindrone acetate 1 mg versus mestranol 50 µg and norethindrone 1 mg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Frequent bleeding - cycles 1 to 31602Peto Odds Ratio (Peto, Fixed, 95% CI)2.82 [2.00, 3.97]

 2 Infrequent bleeding - cycles 1 to 31602Peto Odds Ratio (Peto, Fixed, 95% CI)2.49 [1.58, 3.91]

 3 Irregular bleeding - cycles 1 to 31602Peto Odds Ratio (Peto, Fixed, 95% CI)4.85 [2.49, 9.43]

 4 Prolonged bleeding - cycles 1 to 31602Peto Odds Ratio (Peto, Fixed, 95% CI)2.67 [1.58, 4.52]

 
Comparison 17. EE 20 µg and norethindrone acetate 1 mg versus EE 25 µg and norgestimate 180-215-250 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman12814Peto Odds Ratio (Peto, Fixed, 95% CI)1.41 [0.74, 2.68]

 2 Discontinuation - overall12894Peto Odds Ratio (Peto, Fixed, 95% CI)0.98 [0.81, 1.18]

 3 Discontinuation - adverse events12894Peto Odds Ratio (Peto, Fixed, 95% CI)0.79 [0.54, 1.16]

 4 Breakthrough bleeding - cycle 312330Peto Odds Ratio (Peto, Fixed, 95% CI)2.79 [2.09, 3.74]

 5 Breakthrough bleeding - cycle 612118Peto Odds Ratio (Peto, Fixed, 95% CI)2.40 [1.78, 3.24]

 6 Breakthrough bleeding or spotting - cycle 312330Peto Odds Ratio (Peto, Fixed, 95% CI)2.32 [1.85, 2.90]

 7 Breakthrough bleeding or spotting - cycle 612118Peto Odds Ratio (Peto, Fixed, 95% CI)2.51 [1.97, 3.20]

 8 Unscheduled bleeding - cycle 312478Peto Odds Ratio (Peto, Fixed, 95% CI)1.92 [1.61, 2.29]

 9 Unscheduled bleeding - cycle 612222Peto Odds Ratio (Peto, Fixed, 95% CI)1.91 [1.58, 2.32]

 10 Weight loss, maintenance, or gain <5% - cycle 612157Peto Odds Ratio (Peto, Fixed, 95% CI)1.16 [0.92, 1.46]

 
Comparison 18. EE 20 µg and drospirenone 3 mg versus EE 30 µg and drospirenone 3 mg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman150Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 19. EE 20 µg and drospirenone 3 mg versus EE 25 µg and norgestimate 180-215-250 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Unscheduled bleeding days - cycle 31332Mean Difference (IV, Fixed, 95% CI)1.0 [0.44, 1.56]

 
Comparison 20. EE 20 µg and levonorgestrel 100 µg versus EE 30 µg and levonorgestrel 150 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman170Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Adverse events170Peto Odds Ratio (Peto, Fixed, 95% CI)1.57 [0.62, 3.98]

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Appendix 1. Search strategies 2013

OC BRAND LIST (used within MEDLINE and CENTRAL searches)
Adoless OR Alesse OR Aliane OR Allestra OR Anulette 20 OR April OR Arianna OR Beyaz OR Careza OR Ciclidon OR Ciclomex OR Ciclotab OR Cycleane-20 OR Dal OR Desmin OR Desorelle OR Desoren OR Diminut OR Diva OR Dschess OR Dzhess OR Eloine OR Elyfem OR Estinette OR Eve OR Fedra OR Femadiol-Mepha OR Femexin OR Femiane OR Femilon OR Femina OR Feminet OR Feminol-20 OR Femodette OR Gedarel OR Ginelea OR Ginesse OR Gynera OR Gynostat-20 OR Gynovin OR Gyselle OR Harmonet OR Jasminelle OR Jasminellecontinu OR Leois OR Lerogin OR Levlite OR Lindynette OR Liofora OR Loestrin OR Loette OR Logest OR Lovelle OR Lovette OR Lowette OR Marvelon OR Meliane OR Meloden OR Melodene OR Melodia OR Mercilon OR Microgen OR Microgynon OR Microlevlen OR Microlite OR Midalet OR Millinette OR Minesse OR Minestril-20 OR Minestrin OR Minian OR Minima OR Minifem OR Minigeste OR Minisiston OR Miranova OR Mirelle OR Myralon OR Neolette OR Norvetal OR Novinet OR Novynette OR Ortho Tri-cyclen Lo OR Primera OR Secret OR Securgin OR Siblima OR Suavuret OR Sunya OR Tamisa OR Vivelle OR Yasmin OR Yasminelle OR Yaz

 

MEDLINE via PubMed (01 Mar 2010 to 10 Jul 2013)

contraceptives, oral[MeSH] AND ("low dose" OR "low-dose"[title/abstract word] OR "ultra low dose" OR "ultra-low-dose"[title/abstract word] OR [OC BRAND LIST])
AND (Clinical Trial[ptyp])

 

CENTRAL (2010 to 10 Jul 2013)

Title, abstract, keywords: oral AND contracept*
AND Title, abstract, keywords: low dose OR low-dose OR ultra low dose OR ultra-low-dose OR [OC BRAND LIST]

 

POPLINE (2010 to 11 Jul 2013)

oral contraceptives, low-dose OR (contraceptive agents, female)
Filter by keywords: clinical trials, oral contraceptives combined

 

ClinicalTrials.gov (01 Sep 2010 to 08 Jul 2013)

Search terms: 20 μg OR 15 μg
Study type: Interventional studies
Condition: NOT (HIV OR acne OR PMDD OR post-menopausal OR postmenopausal OR polycystic OR PCOS OR dysmenorrhea OR cancer OR anorexia)
Intervention: oral AND (contraceptive OR contraception)
Gender: Studies with female participants

 

ICTRP (01 Sep 2010 to 08 Jul 2013)

Condition: contraceptive OR contraception
Intervention: 20 μg OR 15 μg

 

Appendix 2. Previous search strategies

OC BRAND LIST (used within database searches below)
Alesse OR Allestra OR Anulette OR April OR Arianna OR Careza OR Ciclidon OR Ciclomex OR Ciclotab OR Cycleane-20 OR Dal OR Desmin OR Desorelle OR Desoren OR Diminut OR Estrostep Eve OR Fedra OR Femexin OR Femiane OR Femilon OR Femina OR Feminet OR Feminol-20 OR Femodette OR Ginelea OR Ginesse OR Gynera OR Gynostat-20 OR Gynovin OR Harmonet OR Lamuna OR Leois OR Lerogin OR Levlite OR Lindynette OR Loestrin OR Leotte OR Logest OR Lovelle OR Lovette OR Lowette OR Lovina OR Marvelon OR Meliane OR Meloden OR Melodene OR Melodia OR Mercilon OR Microdosis OR Microgen OR Microgynon OR Microlevlen OR Microlite OR Midalet OR Minesse OR Minestril-20 OR Minestrin OR Minian OR Minima OR Minifem OR Minigeste OR Miranova OR Mircette OR Mirelle OR Myralon OR Neolette OR Norvetal OR Novinet OR Novynette OR Primera OR Secret OR Securgin OR Segurin OR Siblima OR Suavuret OR Tamisa OR YAZ

 

MEDLINE via PubMed (to 21 Sep 2010)

((randomized controlled trials [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR double-blind method [mh] OR single-blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR ("clinical trial" [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR ("latin square" [tw]) OR placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh:noexp] OR comparative study [mh] OR evaluation studies [mh] OR follow-up studies [mh] OR prospective studies [mh] OR cross-over studies [mh] OR control* [tw] OR prospectiv* [tw] OR volunteer* [tw]) NOT (animal [mh] NOT human [mh])) AND (eng [la] AND contraceptives, oral[MeSH] AND ("low dose" OR "low-dose"[title/abstract word] OR "ultra low dose" OR "ultra-low-dose"[title/abstract word] OR [OC BRAND LIST])

 

CENTRAL (to 21 Sep 2010)

(oral AND (contracept*) in Title, Abstract or Keywords AND (low dose OR low-dose OR ultra low dose OR ultra-low-dose OR [OC BRAND LIST]) in Title, Abstract or Keywords

 

EMBASE (to 03 Nov 2010)

((low dose oral contraceptive OR (oral contraceptive agent AND low(W)dose)) OR (oral contraceptive agent AND [OC BRAND LIST])) AND (clinical trial OR controlled study OR randomized controlled trial OR (controlled(W)clinical(W)trial) OR (random(W)allocation) OR multicenter study OR (comparative(W)study) OR (evidence(W)based(W)medicine) OR (research(W)design) OR (double(W)blind(W)procedure) OR (single(W)blind(W)procedure) OR random) AND human

 

POPLINE (to 01 Nov 2010)

(oral contraceptives, low-dose) / (contraceptive agents, female & [OC BRAND LIST])

 

ClinicalTrials.gov (to 28 Sep 2010)

Search terms: 20 μg OR 15 μg
Condition: NOT (HIV OR acne OR PMDD OR post-menopausal OR postmenopausal OR polycystic OR PCOS OR dysmenorrhea OR cancer OR anorexia)
Intervention: oral AND (contraceptive OR contraception)
Study type: Interventional studies
Gender: Studies with female participants

 

ICTRP (to 28 Sep 2010)

Condition: contraceptive OR contraception
Intervention: 20 μg OR 15 μg

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Last assessed as up-to-date: 15 July 2013.


DateEventDescription

15 July 2013New citation required but conclusions have not changedSearches updated. No new trials were eligible for inclusion.



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Protocol first published: Issue 1, 2003
Review first published: Issue 2, 2005


DateEventDescription

3 November 2010New citation required but conclusions have not changedOne new trial was included (Kaunitz 2009). A secondary report (Hampton 2009) from Hampton 2001 was also added.

3 November 2010New search has been performedSearches were updated; searches were added for ClinicalTrials.gov and ICTRP.
In the original review, 37 studies did not have eligible outcomes and were listed as 'excluded.' Under our current procedures, we would consider them 'discarded' and not list them. Hence, we removed them for brevity.

14 April 2008AmendedConverted to new review format.

6 February 2008New citation required and conclusions have changedSubstantive amendment

6 February 2008New citation required but conclusions have not changedTwo new trials were found (Skouby 2005; Kluft 2006. A secondary report was identified (Burkman 2007) from an earlier trial (Hampton 2001) and the relevant data were added.

31 January 2008New search has been performedSearches were updated in Dec 2007 and Jan 2008.



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

M Gallo extracted data for the initial review and drafted the original review. K Nanda developed the idea and extracted data for the initial review. K Nanda, D Grimes and K Schulz revised and approved the initial review. L Lopez conducted the updates from 2008 to 2013, extracted new data, and revised the review accordingly. D Grimes did the second data extraction for the 2008 and 2010 updates.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

DA Grimes has consulted with the pharmaceutical companies Bayer Healthcare Pharmaceuticals and Merck & Co, Inc.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Internal sources

  • No sources of support supplied

 

External sources

  • National Institute of Child Health and Human Development, USA.
    Support for conducting the review at FHI 360
  • US Agency for International Development, USA.
    Support for conducting the review at FHI 360

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
  21. References to other published versions of this review
Akerlund 1993 {published data only}
  • Akerlund M. Clinical experience of a combined oral contraceptive with very low dose ethinyl estradiol. Acta Obstetricia et Gynecologica Scandinavica 1997;164(Suppl):63-5.
  • Akerlund M, Rode A, Westergaard J. Comparative profiles of reliability, cycle control and side effects of two oral contraceptive formulations containing 150 µg desogestrel and either 30 µg or 20 µg ethinyl oestradiol. British Journal of Obstetrics and Gynaecology 1993;100(9):832-8.
Appel 1987 {published data only}
  • Appel TB, Kambi AA, Birdsall C, Christenson DA, Clark DO, DeKoning JR, et al. A comparison of a new graduated estrogen formulation with three constant-dosed oral contraceptives. Contraception 1987;35(6):523-32.
Basdevant 1993 {published data only}
  • Basdevant A, Conard J, Pelissier C, Guyene TT, Lapousterle C, Mayer M, et al. Hemostatic and metabolic effects of lowering the ethinyl-estradiol dose from 30 mcg to 20 mcg in oral contraceptives containing desogestrel. Contraception 1993;48(3):193-204.
Bounds 1979 {published data only}
Brill 1996 {published data only}
  • Brill K, Then A, Beisiegel U, Jene A, Wunsch C, Leidenberger F. Investigation of the influence of two low-dose monophasic oral contraceptives containing 20 µg ethinylestradiol/75 µg gestodene and 30 µg ethinylestradiol/75 µg gestodene, on lipid metabolism in an open randomized trial. Contraception 1996;54(5):291-7.
Bruni 2000 {published data only}
  • Bruni V, Croxatto H, De La Cruz J, Dhont M, Durlot F, Fernandes MT, et al. A comparison of cycle control and effect on well-being of monophasic gestodene-, triphasic gestodene- and monophasic desogestrel-containing oral contraceptives. Gestodene Study Group. Gynecological Endocrinology 2000;14(2):90-8.
Chavez 1999 {published data only}
  • Chavez A, DelConte A. A comparison of cycle control with monophasic levonorgestrel/ethinylestradiol 100 µg/20 µg versus triphasic norethindrone/ethinylestradiol 500-750-1000 µg/35 µg: a multicenter, randomized, open-label study. The European Journal of Contraception and Reproductive Health Care 1999;4(2):75-83.
Endrikat 1997 {published data only}
  • Endrikat J, Müller U, Düsterberg B. A twelve-month comparative clinical investigation of two low-dose oral contraceptives containing 20 µg ethinylestradiol/75 µg gestodene and 30 µg ethinylestradiol/75 µg gestodene, with respect to efficacy, cycle control, and tolerance. Contraception 1997;55(3):131-7.
Endrikat 2001 {published data only}
  • Endrikat J, Klipping C, Gerlinger C, Ruebig A, Schmidt W, Holler T, et al. A double-blind comparative study of the effects of a 23-day oral contraceptive regimen with 20 µg ethinyl estradiol and 75 µg gestodene and a 21-day regimen with 30 µg ethinyl estradiol and 75 µg gestodene on hemostatic variables, lipids, and carbohydrate metabolism. Contraception 2001;64(4):235-41.
Hampton 2001 {published data only}
  • Burkman RT, Fisher AC, LaGuardia KD. Effects of low-dose oral contraceptives on body weight. Journal of Reproductive Medicine 2007;52(11):1030-4.
  • Hampton RM, Fisher AC, Pagano S, LaGuardia KD. Scheduled and unscheduled bleeding patterns with two combined hormonal contraceptives: application of new recommendations for standardization. Fertility and Sterility 2009;92(2):434-40.
  • Hampton RM, Short M, Bieber E, Bouchard C, Ayotte N, Shangold G, et al. Comparison of a novel norgestimate/ethinyl estradiol oral contraceptive (Ortho Tri-Cyclen Lo) with the oral contraceptive Loestrin Fe 1/20. Contraception 2001;63(6):289-95.
Inauen 1991 {published data only}
  • Inauen W, Stocker G, Haeberli A, Straub PW. Effects of low and high dose oral contraceptives on blood coagulation and thrombogenesis induced by vascular subendothelium exposed to flowing human blood. Contraception 1991;43(5):435-46.
Kaunitz 2009 {published data only}
  • Kaunitz AM, Burkman RT, Fisher AC, LaGuardia KD. Cycle control with a 21-day compared with a 24-day oral contraceptive pill: a randomized controlled trial. Obstetrics & Gynecology. 2009/11/26 2009; Vol. 114, issue 6:1205-12.
Kirkman 1994 {published data only}
  • Kirkman RJ. Clinical comparison of two low dose oral contraceptives in women over 30 years of age [abstract]. Advances in Contraception 1992; Vol. 8, issue 3:170-1.
  • Kirkman RJ. Clinical comparison of two low-dose oral contraceptives in women older than 30 years. Advances in Contraception 1991;7(Suppl 2):63-76.
  • Kirkman RJ, Pedersen JH, Fioretti P, Roberts HE. Clinical comparison of two low-dose oral contraceptives, Minulet® and Mercilon®, in women over 30 years of age. Contraception 1994;49(1):33-46.
  • Kirkman RJ, Pedersen JH, Fioretti P, Roberts HG. Comparison of acceptability and efficacy of low dose oral contraceptives containing gestodene or desogestrel [abstract]. Advances in Contraception 1995;11(1):36-7.
Kluft 2006 {published data only}
  • Kluft C, Endrikat J, Mulder SM, Gerlinger C, Heithecker R. A prospective study on the effects on hemostasis of two oral contraceptives containing drospirenone in combination with either 30 or 20 µg ethinyl estradiol and a reference containing desogestrel and 30 µg ethinyl estradiol. Contraception 2006;73(4):336-43.
Reisman 1999 {published data only}
  • Reisman H, Martin D, Gast MJ. A multicenter randomized comparison of cycle control and laboratory findings with oral contraceptive agents containing 100 µg levonorgestrel with 20 µg ethinyl estradiol or triphasic norethindrone with ethinyl estradiol. American Journal of Obstetrics and Gynecology 1999;181(5 Pt 1):45-52.
Rosenberg 1999 {published data only}
  • Rosenberg MJ, Meyers A, Roy V. Efficacy, cycle control, and side effects of low- and lower-dose oral contraceptives: a randomized trial of 20 µg and 35 µg estrogen preparations. Contraception 1999;60(6):321-9.
Skouby 2005 {published data only}
  • Jespersen J, Endrikat J, Dusterberg B, Schmidt W, Gerlinger C, Wessel J, et al. A 1-year study to compare the hemostatic effects of oral contraceptive containing 20 µg of ethinylestradiol and 100 µg of levonorgestrel with 30 µg of ethinylestradiol and 100 µg of levonorgestrel. Contraception 2005;72(2):98-104.
  • Skouby SO, Endrikat J, Dusterberg B, Schmidt W, Gerlinger C, Wessel J, et al. A 1-yr randomized study to evaluate the effects of a dose reduction in oral contraceptives on lipids and carbohydrate metabolism: 20 µg ethinyl estradiol combined with 100 µg levonorgesterel. Contraception 2005;71(2):111-7.
Taneepanichskul 2002 {published data only}
  • Taneepanichskul S, Kriengsinyot R, Jaisamrarn U. A comparison of cycle control, efficacy, and side effects among healthy Thai women between two low-dose oral contraceptives containing 20 µg ethinylestradiol/75 µg gestodene (Meliane) and 30 µg ethinylestradiol/75 µg gestodene (Gynera). Contraception 2002;66(6):407-9.
Teichmann 1995 {published data only}
  • Teichmann AT, Brill K, Albring M, Schnitker J, Wojtynek P, Kustra E. The influence of the dose of ethinylestradiol in oral contraceptives on follicle growth. Gynecological Endocrinology 1995;9(4):299-305.
WHO 1982 {published data only}
  • Task Force on Oral Contraceptives, WHO Special Programme of Research, Development and Research Training in Human Reproduction. A randomized, double-blind study of six combined oral contraceptives. Contraception 1982;25(3):231-41.
Winkler 1996 {published data only}
  • Winkler UH, Schindler AE, Endrikat J, Dusterberg B. A comparative study of the effects of the hemostatic system of two monophasic gestodene oral contraceptives containing 20 µg and 30 µg ethinylestradiol. Contraception 1996;53(2):75-84.

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
  21. References to other published versions of this review
Bassol 2000 {published data only}
  • Bassol S, Alvarado A, Celis C, Cravioto MC, Peralta O, Montano R, et al. Latin American experience with two low-dose oral contraceptives containing 30 µg ethinylestradiol/75 µg gestodene and 20 µg ethinylestradiol/150 µg desogestrel. Contraception 2000;62(3):131-5.
Lawson 1979 {published data only}
Marr 2012 {published data only}
  • Bachmann G, Sulak PJ, Sampson-Landers C, Benda N, Marr J. Efficacy and safety of a low-dose 24-day combined oral contraceptive containing 20 micrograms ethinylestradiol and 3 mg drospirenone. Contraception. 2004/08/25 2004; Vol. 70, issue 3:191-8.
  • Marr J, Gerlinger C, Kunz M. A historical cycle control comparison of two drospirenone-containing combined oral contraceptives: ethinylestradiol 30 µg/drospirenone 3 mg administered in a 21/7 regimen versus ethinylestradiol 20 µg/drospirenone 3 mg administered in a 24/4 regimen. European Journal of Obstetrics & Gynecology and Reproductive Biology 2012;162(1):91-5.
  • Parsey KS, Pong A. An open-label, multicenter study to evaluate Yasmin, a low-dose combination oral contraceptive containing drospirenone, a new progestogen. Contraception. 2000/05/10 2000; Vol. 61, issue 2:105-11.
Rosenberg 1996 {published data only}
  • Benagiano G. Comparison of two monophasic oral contraceptives: gestodene/ethinyl estradiol versus desogestrel/ethinyl estradiol. International Journal of Fertility 1989;34(Suppl):31-9.
  • Rosenberg MJ, Waugh MS, Higgins JE. The effect of desogestrel, gestodene, and other factors on spotting and bleeding. Contraception 1996;53(2):85-90.
Westhoff 2005 {published data only}
  • Westhoff C, Osborne LM, Schafer JE, Morroni C. Bleeding patterns after immediate initiation of an oral compared with a vaginal hormonal contraceptive. Obstetrics and Gynecology 2005;106(1):89-96.
Wiegratz 2003 {published data only}
  • Wiegratz I, Kutschera E, Lee JH, Moore C, Mellinger U, Winkler UH, et al. Effect of four different oral contraceptives on various sex hormones and serum-binding globulins. Contraception 2003;67(1):25-32.

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
  21. References to other published versions of this review
Anonymous 2000
  • Anonymous 2000. Oral contraceptives and cardiovascular risk. Drug and Therapeutics Bulletin 2000;38(1):1-5.
Belsey 1986
CGHFBC 1996
  • Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996;347(9017):1713-27.
CONSORT 2009
  • CONSORT group. CONSORT: Transparent reporting of trials. http://www.consort-statement.org/ (accessed 15 Jul 2009).
Elstein 1994
Gerstman 1991
  • Gerstman BB, Gross TP, Kennedy DL, Bennett RC, Tomita DK, Stadel BV. Trends in the content and use of oral contraceptives in the United States, 1964-88. American Journal of Public Health 1991;81(1):90-6.
Guillebaud 1989
  • Guillebaud J. Practical prescribing of the combined oral contraceptive pill. In: Filshie M, Guillebaud J Filshie, John Guillebaud editor(s). Contraception: science and practice. London: Butterworth & Co., 1989:69-93.
Higgins 2011
  • Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. John Wiley & Sons, Ltd, (accessed 08 Jul 2013).
Holt 1992
  • Holt VL, Daling JR, McKnight B, Moore D, Stergachis A, Weiss NS. Functional ovarian cysts in relation to the use of monophasic and triphasic oral contraceptives. Obstetrics and Gynecology 1992;79(4):529-33.
IPPF 2013
  • International Planned Parenthood Federation. Directory of Hormonal Contraceptives. http://contraceptive.ippf.org/search (accessed 10 Jul 2013).
Lexchin 2003
Maitra 2004
  • Maitra N, Kulier R, Bloemenkamp KWM, Helmerhorst FM, Gülmezoglu AM. Progestogens in combined oral contraceptives for contraception. Cochrane Database of Systematic Reviews 2004, Issue 3. [DOI: 10.1002/14651858.CD004861]
Miller 2001
Mishell 2007a
  • Mishell DR, Guillebaud J, Westhoff C, Nelson AL, Kaunitz AM, Trussell J, et al. Combined hormonal contraceptive trials: variable data collection and bleeding assessment methodologies influence study outcomes and physician perception. Contraception 2007;75(1):4-10.
Mishell 2007b
  • Mishell DR, Guillebaud J, Westhoff C, Nelson AL, Kaunitz AM, Trussell J, et al. Recommendations for standardization of data collection and analysis of bleeding in combined hormone contraceptive trials. Contraception 2007;75(1):11-5.
Nelson 2007
  • Nelson AL. Combined oral contraceptives. In: Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D editor(s). Contraceptive Technology. 19th Edition. New York: Ardent Media, Inc., 2007:193-270.
Ness 2000
  • Ness RB, Grisso JA, Klapper J, Schlesselman JJ, Silberzweig S, Vergona R, et al. Risk of ovarian cancer in relation to estrogen and progestin dose and use characteristics of oral contraceptives. American Journal of Epidemiology 2000;152(3):233-41.
Norris 1996
Rosenberg 1992
  • Rosenberg MJ, Long SC. Oral contraceptives and cycle control: a critical review of the literature. Advances in Contraception 1992;8(Suppl 1):35-45.
Rosenberg 1998
Rothman 1998
  • Rothman KJ, Greenland S. Approaches to statistical analysis. In: Rothman KJ, Greenland S editor(s). Modern epidemiology. 2nd Edition. New York: Lippincott Williams and Wilkins, 1998:183-99.
Schulz 2002
Spona 1996
  • Spona J, Elstein M, Feichtinger W, Sullivan H, Ludicke F, Muller U, et al. Shorter pill-free interval in combined oral contraceptives decreases follicular development. Contraception 1996;54(2):71-7.
Strauss 2005
  • Strauss SE, Richardson WS, Glasziou P, Haynes RB. Evidence-based Medicine: How to Practice and Teach EBM. Third Edition. New York: Churchill Livingstone, 2005.
Thiboutot 2001
  • Thiboutot D, Archer DF, Lemay A, Washenik K, Roberts J, Harrison DD. A randomized, controlled trial of a low-dose contraceptive containing 20 µg of ethinyl estradiol and 100 µg of levonorgestrel for acne treatment. Fertility and Sterility 2001;76(3):461-8.
Trussell 1998
  • Trussell J. Dynamics of reproductive behavior and population change. In: Hatcher RA, Trussell J, Stewart F, Cates W Jr, Stewart GK, Guest F, et al. editor(s). Contraceptive technology. 17th Edition. New York: Ardent Media Inc., 1998:745-77.
Wallach 2000
  • Wallach M, Grimes DA. Modern oral contraception. 1st Edition. Totowa, NJ: Emron, 2000.