Intervention Review

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Progestin-only pills for contraception

  1. David A Grimes1,*,
  2. Laureen M Lopez2,
  3. Paul A O'Brien3,
  4. Elizabeth G. Raymond4

Editorial Group: Cochrane Fertility Regulation Group

Published Online: 13 NOV 2013

Assessed as up-to-date: 29 OCT 2013

DOI: 10.1002/14651858.CD007541.pub3


How to Cite

Grimes DA, Lopez LM, O'Brien PA, Raymond EG. Progestin-only pills for contraception. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD007541. DOI: 10.1002/14651858.CD007541.pub3.

Author Information

  1. 1

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

  2. 2

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

  3. 3

    London Community Healthcare, Westside Contraceptive Services, London, UK

  4. 4

    Gynuity Health projects, New York, New York, USA

*David A Grimes, Obstetrics and Gynecology, University of North Carolina, School of Medicine, CB#7570, Chapel Hill, North Carolina, 27599-7570, USA. david_grimes@med.unc.edu.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 13 NOV 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

The introduction of a new progestin-only oral contraceptive in Europe (FFPRHC 2003; Korver 2005) renewed interest in this class of oral contraceptives. Unlike the more widely used combined oral contraceptives containing an estrogen plus progestin (Edelman 2005; van Vliet 2011; Lopez 2012), these pills contain only a progestin (progestogen) and are taken without interruption.

Progestin-only pills (POPs) have both advantages and disadvantages when compared with combined pills. The pill-taking regimen is simple and fixed; no pill color changes or days without pill-taking occur. Fertility returns promptly upon discontinuation. These pills are appropriate for women who cannot or should not take estrogen in combined oral contraceptives, for example, a woman older than 35 years who smokes cigarettes (ACOG 2006).

They may also appeal to women who want to use the lowest effective dose of steroids to provide contraception. Some progestin-only pills were designed to allow ovulation and regular menses, although that goal has been reversed with the desogestrel pill. Lacking estrogen, progestin-only pills may have a lower risk of complications. A World Health Organization case-control study found no significant increase in the risk of stroke, myocardial infarction, and venous thromboembolism among users of progestin-only pills compared with non-users (WHO 1998). A cohort study from Denmark also found no statistically significant association between progestin-only pills and venous thromboembolism (Lidegaard 2009). Although the literature is unsettled concerning the potential impact of combined oral contraceptives on lactation, no concerns exist for progestin-only pills (Moggia 1991; Dunson 1993; McCann 1994; Bjarnadóttir 2001; FFPRHC 2004). No data are available concerning a potential effect on infant brain or liver. Like depot-medroxyprogesterone acetate injections for contraception (Manchikanti 2007), progestin-only pills may reduce the frequency of sickle cell crises. Less restrictive screening for use may facilitate wider distribution by non-clinicians or over-the-counter provision.

Disadvantages include the recommendation for careful compliance and the disruption of normal menstrual patterns (FSRH 2008). These changes include irregular bleeding, short or long cycles, bleeding and spotting, prolonged bleeding, or no bleeding at all. Overall, progestin-only pills are associated with more days of bleeding and spotting than are combined oral contraceptives (Raymond 2011).

The timing of ingestion of progestin-only pills may be more important than with combined oral contraceptives. However, the potential effect of timing on efficacy has not been adequately studied, and, for practical reasons, likely will not be studied. Inter-individual variation in progestin metabolism rates is wide (Goldzieher 1994; Wallach 2000). Progestin-only pills may not provide as much protection against ectopic pregnancy as do combined oral contraceptives (McCann 1994), and they may be associated with more functional ovarian cysts than are combined oral contraceptives (Raymond 2011).

 

Description of the intervention

Commercially available progestin-only pills contain low doses of levonorgestrel, norethindrone (norethisterone), ethynodiol diacetate, or desogestrel. The progestin dose is lower than that in combined oral contraceptives, hence the common name 'mini-pill' (Wallach 2000; Raymond 2011).

 

How the intervention might work

Progestin-only pills prevent pregnancy through several potential mechanisms. Ovulation is variably inhibited (FSRH 2008), and the cervical mucus becomes thick and relatively impenetrable to sperm. Ciliary action in the fallopian tubes is altered, as is the histology of the endometrium, potentially making implantation less likely (McCann 1994; Wallach 2000; Raymond 2011). The effectiveness of progestin-only pills is not well-established. Reported pregnancy rates in the first year of use range from zero to 13% (Raymond 2011; Trussell 2011); some authors have estimated that typical pregnancy rates may approximate those of combined oral contraceptives (Wallach 2000). Consistent timing is considered important for successful use, but supporting evidence is limited. In general, pregnancy rates may also be influenced by the woman's age, frequency of coitus, body mass, and lactation.

 

Why it is important to do this review

How different progestin-only pills compare to each other in terms of efficacy and continuation is unclear. Because of the lower dose of progestin than in combined oral contraceptives, the reliance on mechanisms other than ovulation inhibition, and the potential importance of consistent daily pill taking, progestin-only pills may not be as effective as combined oral contraceptives. Stated alternatively, progestin-only pills may be less 'forgiving' of late or missed pills. However, data to support or refute this hypothesis are sparse.

 

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

This review examined randomized controlled trials of progestin-only pills for differences in efficacy, acceptability, and continuation rates.

 

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

We included all randomized controlled trials in any language that included progestin-only pills for contraception.

 

Types of participants

Women requiring contraception with data in the eligible trials were included in the review.

 

Types of interventions

We included any comparison with a progestin-only pill; these could include different doses, other progestin-only pills, combined oral contraceptives, or other contraceptives. Other interventions could include the timing of initiation of pills.

 

Types of outcome measures

 

Primary outcomes

Pregnancy was the primary outcome of interest. Because of its infrequency in pill trials, we did not anticipate having sufficient power to compare pregnancy rates. However, we reported this outcome when provided. We excluded data on invalid surrogate end points (Grimes 2010) for contraceptive efficacy, specifically ovulation. Although pregnancy cannot occur in the absence of ovulation, the presence of ovulation does not predict the risk of pregnancy, since other contraceptive mechanisms of action are involved with progestin-only pills.

 

Secondary outcomes

Side effects, including bleeding patterns, and continuation rates were secondary outcomes.

 

Search methods for identification of studies

See: Cochrane Fertility Regulation Group methods used in reviews.

 

Electronic searches

Through October 2013, we searched for studies of progestin-only pills in MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), POPLINE, EMBASE, and LILACS. We also searched for current trials via ClinicalTrials.gov and ICTRP. The most recent strategies can be found in Appendix 1. Previous search strategies also included EMBASE (Appendix 2; Appendix 3).

 

Searching other resources

For the initial review, we examined the reference lists of relevant articles. We also wrote to known investigators for information about other published or unpublished trials not discovered in our search.

 

Data collection and analysis

 

Selection of studies

The first author reviewed the titles and abstracts of reports potentially eligible for inclusion. A second author confirmed the eligibility of the reports selected.

 

Data extraction and management

The first author abstracted the data and entered the information into RevMan. Another author performed a second, independent data abstraction to verify the initial data entry. Any discrepancies were resolved by discussion.

 

Assessment of risk of bias in included studies

We examined the methodological quality of trial reports according to recommended principles (Higgins 2008). We considered generation of the random sequence, allocation concealment, blinding, and losses to follow up. Adequate methods of allocation concealment included a centralized telephone system or pharmacy allocation, or use of sequentially numbered, sealed, opaque envelopes (Schulz 2002a). Excluding participants after randomization can introduce bias and threaten trial validity (Schulz 2002b).

 

Measures of treatment effect

Oral contraception studies tend to have relatively high withdrawal rates. Time-to-event measures such as life-table or incidence rates (Pearl rates) are commonly used, as they are based on actual exposure to the contraceptive and prevent an imbalance in withdrawals distorting the comparisons. In this review, we attempted to extract life-table rates (actuarial or continuous) and used the rate difference as the effect measure. Where life-table rates were not published, as was common, we used the incidence rate ratio (ratio of Pearl rates) as the effect measure. We used Microsoft Excel to generate the log rate ratios and their standard errors for use in RevMan using recommended methods (Higgins 2008). Where only the crude number of events was published, we calculated the Peto odds ratio with 95% confidence interval (CI). For continuous variables, the mean difference (MD) was computed with 95% CI using a fixed-effect model. RevMan uses the inverse variance approach. Fixed effect and random effects give the same result if no heterogeneity exists, as when a comparison includes only one study. Because of disparate exposures, we were not able to combine studies in meta-analysis.

 

Dealing with missing data

We tried to contact authors for missing data and clarification of issues related to methods. For Collaborative 1998, we calculated the number of non-breast feeding women with the different bleeding patterns from the graph in the report. We were unable to do a formal comparison of rates in Sheth 1982 because standard errors were not published.

 

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 database searches produced 60 unduplicated references. In addition, we obtained 44 unduplicated listings from ClinicalTrials.gov and ICTRP. We did not find any new studies to include.

For the initial review, six trials met our inclusion criteria. The trials enrolled 2738 participants, and sample sizes ranged from 86 to 1306 women. Trial locations included European countries, United Kingdom, United States, India, China, South Africa, Nigeria, and Kenya. Several trials were decades old and studied pills no longer commercially available; only one trial was published in the past decade.

 

Included studies

Collaborative 1998 was a multicenter trial sponsored by NV Organon and conducted in 44 centers in six countries. It compared the safety, efficacy, and acceptability of a new progestin-only pill containing desogestrel 75 μg versus a progestin-only pill containing levonorgestrel 30 μg. The trial followed 979 and 327 women using a desogestrel or levonorgestrel progestin-only pill, respectively, over 13 treatment periods of 28 days. The report provided woman-years of exposure, which we used as the denominator for pregnancy rates.

Lakha 2007 compared mifepristone 5 mg versus levonorgestrel 30 μg daily for contraception. The primary outcome of interest was bleeding patterns, specifically the frequency of amenorrhea, but information on other side effects and pregnancy was gathered as well. The investigators enrolled 97 women in four cities in the UK, Hong Kong, and Africa. Seventy-four were assigned to mifepristone and 23 to the levonorgestrel progestin-only pill. Communication with the authors indicated a total of 356 and 85 cycles exposed to pregnancy, respectively.

Paulsen 1974 was a report from one site of a larger randomized controlled trial sponsored by G.D. Searle and Co. It compared a progestin-only pill containing ethynodiol diacetate 0.25 mg versus a combination oral contraceptive containing ethynodiol diacetate 1.0 mg plus mestranol 0.1 mg. The trial was conducted at a Planned Parenthood clinic in California. A total of 86 women were enrolled, with 43 assigned to each treatment.

Sheth 1982 reported on two centers, Bombay and Ljubljana, participating in a World Health Organization multicenter randomized trial comparing efficacy, discontinuation, and bleeding patterns of two progestin-only and two combination oral contraceptives. The four pills included norethisterone 350 μg (also known as norethindrone), levonorgestrel 30 μg, norethisterone 1 mg plus mestranol 50 μg, and levonorgestrel 150 μg plus ethinyl estradiol 30 μg. Of 599 women who agreed to participate, 518 qualified and started the assigned method; 81 women dropped out after randomization and before beginning treatment.

Vessey 1972 randomized women to four different progestin-only pills in Ljubljana, Yugoslavia. These included megestrol acetate 0.7 mg, norethisterone acetate 0.3 mg, chlormadinone acetate 0.5 mg, and norgestrel 0.075 mg. The investigators enrolled 450 women, with 90 to be assigned to each of five treatment groups (four progestin-only pills and one combination oral contraceptive). The planned fifth treatment group using a combined oral contraceptive was not implemented because of logistical problems. In addition, 72 (16%) of those enrolled never began their pills, and the analysis was limited to the 378 who took the drugs.

Were 1997 in Eldoret, Kenya, randomized 200 women to receive norgestrel 75 μg daily beginning either six weeks postpartum versus beginning six months postpartum or when menses returned, whichever came first. Were and associates enrolled 200 women, as part of a large international trial addressing the timing of starting progestin-only pills during lactation. However, because of large losses after randomization (51% with unknown outcomes in both groups), the results cannot be considered valid.

 

Excluded studies

Two randomized controlled trials studied the new progestin-only pill containing desogestrel 75 μg (Rice 1999; Korver 2005). Both trials used ovulation as the outcome of interest, and ovulation is not a valid surrogate end point for pregnancy (Grimes 2010). We also reviewed the full text of Bhattacharya 2012 to determine the composition of the OCs studied; all were combination oral contraceptives.

 

Risk of bias in included studies

 

Allocation

Allocation concealment was not mentioned in Collaborative 1998, and the method of randomization also was not specified. Correspondence with an author confirmed randomized permuted blocks with a block size of four, and identical-appearing blister packs were distributed sequentially. In Lakha 2007, random sequence generation was done by "blocked computer-generated randomization" by center, although the block lengths were not specified. Allocation concealment appears likely, since numbered pill bottles were opaque. Allocation concealment was not mentioned by Paulsen 1974. Sheth 1982 did not specify the method of random allocation. Vessey 1972 arranged pill cartons by an unspecified random process, after which serial numbers were assigned to the cartons and pill packs inside. Participants were given cartons in sequential order, which likely provided adequate concealment. Were 1997 randomly assigned participants using a computer-generated sequence developed at Family Health International; whether blocking was used is not specified in the protocol. Allocation concealment was maintained by use of sequentially numbered, opaque, sealed envelopes containing method indicator cards.

 

Blinding

In Collaborative 1998 the two pills studied were identical in appearance. The trial was described as "double blind," and correspondence confirmed that participants and investigators were kept unaware of the treatment assignment. In Lakha 2007 blinding was unlikely to have been achieved, because of dissimilar pill appearance and different bleeding patterns associated with the two treatments. Paulsen 1974 attempted to keep participants and clinicians unaware of the assigned treatment by using identical appearing pills provided by the study sponsor. The authors noted that because of the disparate bleeding patterns, clinicians could readily deduce the treatment assigned, although they felt most patients, new to oral contraception, would have less insight into expected bleeding patterns. Assessment of bleeding patterns was done by examining patient diaries blinded as to treatment. Sheth 1982 had pills re-packaged by the manufacturers in 28-day pack to blind both participants and investigators as to the treatment group. Whether the pills were identical in size, color, taste, etc., was not specified. Vessey 1972 had pills manufactured expressly for the trial; these were identical in appearance. Participants and investigators were thus unaware of the assignments to the four progestin-only pills groups. No blinding was attempted in Were 1997 comparing early versus late starting of progestin-only pills during lactation.

 

Incomplete outcome data

Collaborative 1998 excluded 14 randomized women from analysis who never began the study medications. In Lakha 2007, one randomized woman dropped out before taking her assigned drug. Overall, 57 of 74 assigned to mifepristone and 15 of 23 assigned to levonorgestrel, respectively, completed the trial. Investigators excluded six women after randomization because of "persistent protocol violations." Communication with the authors provided cycles of exposure. Two pregnancies occurred in months when both mifepristone and condoms were reportedly used. In Paulsen 1974 the authors arbitrarily excluded in the reporting of bleeding analysis those participants enrolled for less than two cycles; this left 29 of 43 in the progestin-only pill group and 37 of 43 in the COC group. The trial report also noted three pregnancies during the study but did not indicate in which treatment groups these occurred. Loss to follow up was low in Sheth 1982: only 11 of 518 women (2%). Vessey 1972 reported having information for all 378 participants who took their assigned pills either until one year of follow up or until discontinuation for some reason. The life-table analysis took into account the variable lengths of follow up which are a common problem in such trials. Interpretation of Were 1997 is handicapped by high losses to follow up. In both treatment groups, 51% of participants were lost to follow up over 18 months, due in part to ethnic strife in this region of Kenya during the trial.

 

Other potential sources of bias

In Lakha 2007, the analysis excluded from consideration months in which the assigned treatment was not the sole method of contraception used. This left 356 months of exposure in the mifepristone group and 85 months in the levonorgestrel progestin-only pill group. This exclusion of months at risk of pregnancy is inappropriate; indeed, two of the pregnancies that occurred with mifepristone were in months ostensibly protected by both mifepristone and condoms. The total number of woman-months of exposure is not stated so a full analysis set is not available. Paulsen 1974 featured a simplistic, dichotomous evaluation of bleeding patterns and intentionally excluded participants after randomization; losses after randomization were high. In Vessey 1972, 16% of those enrolled never took the medication and were dropped from the study at that point. Whether these losses were different between groups is unknown. High losses after randomization occurred in Were 1997 because of civil strife; hence, these results cannot be deemed credible.

 

Effects of interventions

In the trial comparing the desogestrel versus levonorgestrel progestin-only pill (Collaborative 1998), desogestrel was not associated with a significantly lower risk of accidental pregnancy; the rate ratio was 0.27; 95% CI 0.06 to 1.19 ( Analysis 1.1). Adverse events were more frequent with desogestrel ( Analysis 1.2) (rate ratio 1.22; 95% CI 0.81 to 1.84, but this difference also was not statistically significant. Serious adverse events (ovarian cysts or ectopic pregnancy) were uncommon with both pills. However, the desogestrel progestin-only pill caused more bleeding problems ( Analysis 1.3). Discontinuation because of irregular bleeding was more common (rate ratio 1.32; 95% CI 0.99 to 1.78). Discontinuation for all reasons was more frequent with desogestrel as well (rate ratio 1.21; 95% CI 0.99 to 1.47) ( Analysis 1.4).

Three pregnancies occurred amongst 979 women who started treatment with desogestrel and 4 amongst 327 who started levonorgestrel. If the reduction in risk of pregnancy was real and not due to chance, then 110 women would need to be treated with desogestrel rather than levonorgestrel to prevent one pregnancy. However, 5 more of the 110 would discontinue early because of irregular bleeding.

The trial comparing low-dose mifepristone versus a levonorgestrel progestin-only pill (Lakha 2007) found a lower pregnancy rate with mifepristone (odds ratio 0.71; 95% CI 0.07 to 6.95) ( Analysis 2.1). A higher prevalence of amenorrhea occurred in the former group; about half of women assigned to mifepristone had no bleeding while taking the drug ( Analysis 2.2). No significant differences emerged in minor side effects between the regimens. The two treatments had different effects on the uterus. Women in the mifepristone group developed a thicker endometrium than did those assigned to the progestin-only pill ( Analysis 2.3). Moreover, a higher proportion of women in the mifepristone group required an endometrial biopsy to evaluate a dilated endometrial cavity (>12 mm) ( Analysis 2.4). While no biopsy indicated serious pathology, more interventions were necessitated by mifepristone. Cystic glandular dilatation of the endometrium, a condition of undetermined medical significance, was more common in the mifepristone group.

Bleeding irregularities were more common with the progestin-only pill (not currently available at this dose) than with the combined oral contraceptive in Paulsen 1974. The analysis dichotomized bleeding into "regularity of cycles" and "intercycle bleeding." Irregular cycles occurred in all women assigned to the progestin-only pill, in contrast to those assigned to the COC (odds ratio 135.96; 95% CI 7.63 to 2421.02) ( Analysis 3.1). Intercycle bleeding was significantly more common with the progestin-only pill as well (odds ratio 6.20; 95% CI 2.11 to 18.22) ( Analysis 3.2). Discontinuation from the trial was also more common with the progestin-only pill, although this difference was not statistically significant (P = 0.19) ( Analysis 3.3).

In the WHO four-pill comparison (Sheth 1982), pregnancy rates were highest with norethisterone 35 μg and lowest with the combination pill levonorgestrel 150 μg plus ethinyl estradiol 30 μg. At 360 days, the cumulative discontinuation rate for accidental pregnancy was lower with combined levonorgestrel and ethinyl estradiol (2.7%) than with the other pills: levonorgestrel alone (9.5%), combined norethisterone and mestranol (8.3%), and norethisterone alone (13.2%). Discontinuation because of bleeding disturbances was less common with the combination levonorgestrel and ethinyl estradiol pill than with the other three pills. On the other hand, the combination levonorgestrel and ethinyl estradiol pill had the highest rates of discontinuation because of gastrointestinal problems at 360 days. Overall discontinuation rates were similar for all four pills ( Table 1).

In Vessey 1972, an early small trial, accidental pregnancies were uncommon with both norethisterone acetate and norgestrel (1 in each treatment group) ( Analysis 4.1). Among pills currently used, the cumulative continuation rate with norethisterone acetate at one year was significantly higher than that with norgestrel (rate difference 28.2 per 100 women, 95% CI 12.32 to 44.08) ( Analysis 4.2). However, discontinuation because of menstrual disturbances was significantly less common with norethisterone acetate (rate ratio 0.30; 95% CI 0.15 to 0.62) ( Analysis 4.3). Discontinuation because of other side effects was also less common with norethisterone acetate, although this difference was not statistically significant ( Analysis 4.4).

Were 1997 found no pregnancies in either group. One group started the progestin-only pill six weeks postpartum, and the other group began the pill six months postpartum or when menses returned. Continuation rates were also similar ( Table 2). By 12 months, 54% of the early-start and 57% of the late-start participants were continuing their assigned method. By 18 months, these figures were 46% and 44%, respectively. The mean duration of use was similar for both groups, as were reasons for discontinuation.

 

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

Randomized controlled trials published to date are inadequate to compare progestin-only pills to each other or to combined oral contraceptives. Since progestin-only pills are commonly used during breast feeding, when fertility is low, the impact of better efficacy of any pill would be small in this setting. No trial addressed the question of consistent timing of ingestion. Likewise, a progestin-only pill may be preferred for safety reasons in older women with lower fertility who wish to continue oral contraception.

Any potential benefit of better contraceptive efficacy with desogestrel 75 μg versus levonorgestrel 30 μg (Collaborative 1998) may be offset by worse bleeding patterns. These include prolonged bleeding and absence of bleeding. For every 1 pregnancy that might be prevented with desogestrel, 5 women will discontinue early because of irregular bleeding. The trade-off between efficacy and continuation may be viewed differently in different settings, and amongst women in the same settings. For some women efficacy will be the chief consideration, while for others regular bleeding will be more important.

These abnormal bleeding patterns may reflect the better suppression of ovulation with the desogestrel progestin-only pill than with the levonorgestrel progestin-only pill (Rice 1999). However, the suggestion (Rice 1999) that the desogestrel pill "is therefore expected to have a lower failure rate than the currently available POP" [levonorgestrel 30 μg] remains unproven. While ovulation is a prerequisite for pregnancy, it does not predict the risk of pregnancy (Grimes 2010). Alternative mechanisms of progestin-only contraceptives are important, since ovulation is common with other progestin-only pills (FSRH 2008; Raymond 2011), yet pregnancy is infrequent.

While daily low-dose mifepristone resulted in a higher proportion of women free from the nuisance bleeding and spotting, the likelihood of pregnancy appeared similar among women receiving mifepristone or levonorgestrel (Lakha 2007). Daily mifepristone caused endometrial thickening and distension of the uterine cavity; these required histological evaluation more often than did the progestin-only pill. To identify those at risk of hyperplasia, the investigators performed an endometrial biopsy on any participant if her uterine cavity measured >12 mm. Ovulation was better suppressed with mifepristone, but about one in five women had hormonal evidence of ovulation at any of three follow up visits.

A progestin-only pill containing ethynodiol diacetate 0.25 mg caused irregular cycles in all and intercycle bleeding in most participants (Paulsen 1974). In contrast, a combined oral contraceptive containing a higher dose of the same progestin (1.0 mg) plus mestranol 0.1 mg resulted in more regular bleeding patterns. The drop-out rate was higher with the progestin-only pill than the combination oral contraceptive in this trial.

The four-group trial by the WHO (Sheth 1982) found discontinuation rates lowest with the combination levonorgestrel-ethinyl estradiol pill. The combination pill with levonorgestrel and ethinyl estradiol caused fewer bleeding problems leading to discontinuation than did the other three pills, although this was offset by more discontinuations because of gastrointestinal disturbances. The progestin-only pill containing levonorgestrel had a lower pregnancy rate than the pill with norethisterone. Poor reporting limited the usefulness of this trial.

Another four-group trial (Vessey 1972) found megestrol acetate lower in efficacy than the other three pills; this difference was not statistically significant, but the sample size of only 90 per group limited the power of the study. The other notable finding was the poorer bleeding patterns seen with norgestrel in the first six months of use. The authors concluded that norethisterone acetate 30 μg appeared the most promising of the four drugs tested. Poor reporting limited the usefulness of this trial as well.

The Kenyan trial of when to start a norgestrel progestin-only pill postpartum found no important differences (Were 1997). Since most women were fully or nearly fully breastfeeding during the trial, the likelihood of pregnancy was remote, and no pregnancies occurred over 18 months of observation. The high losses to follow up because of civil unrest undermined this trial.

 

Overall completeness and applicability of evidence

The age of several trials (Vessey 1972; Paulsen 1974) limited their relevance to contemporary practice, since only two products studied are currently available. Sample sizes, even in the largest trial (Collaborative 1998), were inadequate to address relative efficacy. Similarly, the comparison of levonorgestrel to mifepristone was an exploratory trial, since the latter is not used for ongoing contraception. Little information was available about the advice given as to the timing of administration of the pills or whether back up contraception should be used in case of a late or missed pill. Although accurate timing of administration is considered important for progestin-only pills, little empirical evidence supports this hypothesis, and the inter-individual variation in the metabolism of progestins is wide (Goldzieher 1994; Wallach 2000).

 

Quality of the evidence

Incomplete reporting of methods was a generic problem, including a trial (Lakha 2007) published since the CONSORT guidelines (Moher 2001; CONSORT 2010) were internationally adopted.

 

Potential biases in the review process

None evident.

 

Agreements and disagreements with other studies or reviews

A review concurred that the desogestrel pill had a lower failure rate than the levonorgestrel pill, but that the difference was not statistically significant (FSRH 2008). Collaborative 1998 lacked the power to differentiate between pregnancy rates. The review also noted that breastfeeding women may start progestin-only pills at any time after delivery, since no adverse effect of these pills on lactation has been identified (FSRH 2008).

 

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

Desogestrel may be more effective than levonorgestrel, but this benefit probably applies only to women not breast feeding. In breast feeding women, the difference in efficacy was small. The potential for better efficacy with desogestrel was offset by worse bleeding patterns and more adverse events than with levonorgestrel. Given the higher cost of mifepristone and its effects on the endometrium, the prospects for daily contraception with this antiprogestin appear limited. No firm conclusion is possible concerning the comparative efficacy of progestin-only pills or whether such pills are as effective as combined oral contraceptives. One poor-quality trial suggested no large effect of timing of initiation on efficacy or continuation rates.

 
Implications for research

Trials comparing progestin-only pills versus combination oral contraceptives are needed to address comparative efficacy, an unresolved issue. Nuisance bleeding with progestin-only pills remains an obstacle to wider use. Studies of ways to reduce this problem and to support women who do experience troublesome bleeding might make this method more acceptable. A trial with sufficient power is needed to confirm the potentially higher efficacy of the desogestrel progestin-only pill. Alternatively, older progestins but with higher doses could be examined, which might allow longer half-lives and thus more time to remember the next pill. Trials might also encourage use of condoms as a backup to progestin-only pills. Future trials should report more fully (CONSORT 2010) and should provide cumulative life-table rates and their corresponding standard errors.

 

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 developed the search strategies and ran certain searches for the initial review.

 

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. Desogestrel 75 μg versus levonorgestrel 30 μg daily

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

 1 Pregnancy11320Rate Ratio (Fixed, 95% CI)0.27 [0.06, 1.19]

 2 Discontinuation because of adverse events11320Rate Ratio (Fixed, 95% CI)1.22 [0.81, 1.84]

 3 Discontinuation because of irregular bleeding11320Rate Ratio (Fixed, 95% CI)1.32 [0.99, 1.78]

 4 Discontinuation for all reasons11320Rate Ratio (Fixed, 95% CI)1.21 [0.99, 1.47]

 
Comparison 2. Mifepristone 5 mg versus levonorgestrel 30 μg daily

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

 1 Pregnancy1441Odds Ratio (Peto, Fixed, 95% CI)0.71 [0.07, 6.95]

 2 Amenorrhea196Odds Ratio (Peto, Fixed, 95% CI)0.02 [0.00, 0.37]

 3 Mean endometrial thickness at 24 weeks173Mean Difference (IV, Fixed, 95% CI)6.30 [4.28, 8.32]

 4 Endometrial biopsy to evaluate endometrial cavity >12 mm on ultrasound196Odds Ratio (Peto, Fixed, 95% CI)7.74 [0.98, 61.41]

 
Comparison 3. Ethynodiol diacetate 0.25 mg versus ethynodiol diacetate 1.0 mg plus mestranol 0.1 mg

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

 1 Irregular cycles166Odds Ratio (Peto, Fixed, 95% CI)135.96 [7.63, 2421.02]

 2 Intercycle bleeding166Odds Ratio (Peto, Fixed, 95% CI)6.20 [2.11, 18.22]

 3 Discontinuation from trial186Odds Ratio (Peto, Fixed, 95% CI)1.78 [0.75, 4.24]

 
Comparison 4. Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg

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

 1 Pregnancy1150Rate Ratio (Fixed, 95% CI)0.78 [0.05, 12.35]

 2 Continuation at one year1Risk Difference (Fixed, 95% CI)28.2 [12.32, 44.08]

 3 Discontinuation because of menstrual disturbance1150Rate Ratio (Fixed, 95% CI)0.30 [0.15, 0.62]

 4 Discontinuation because of other side effects1150Rate Ratio (Fixed, 95% CI)0.52 [0.15, 1.87]

 5 Discontinuation for reasons unconnected with treatment1150Rate Ratio (Fixed, 95% CI)1.06 [0.57, 1.99]

 

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 2013

 

MEDLINE via PubMed (01 Jan 2011 to 28 Oct 2013)

(contraceptives, oral OR ((contraception OR contracept*) AND pill)) AND (progestin* OR progestational, hormones, synthetic OR progestogen* OR progesterone OR gestagen OR "progestin only" OR "progestogen only") NOT contraceptives, oral combined NOT estrogens NOT contraceptives, oral/DT NOT drug therapy NOT treat* NOT (intrauterine device OR intrauterine devices OR intrauterine contraceptive device OR intrauterine contraceptive devices OR intrauterine system OR intrauterine systems OR IUD* OR IUCD OR IUS) AND (Clinical Trial[ptyp])

 

POPLINE (2011 to 28 Oct 2013)

Keywords: low-dose progestins OR contraceptive agents, progestin
Filter by keywords: oral contraceptives, research report

 

CENTRAL (01 Jan 2011 to 18 Sep 2013)

oral AND contracept* in Title, Abstract, or Key words
AND progestin in Title, Abstract, or Key words

 

LILACS (10 Sep 2013)

anticoncepcionais orais OR anticonceptivos orales OR contraceptives, oral [Words]
AND progestin OR progestogen OR progestinas OR POP [Words]

 

ClinicalTrials.gov (01 Jan 2011 to 13 Sep 2013)

Search terms: (contraception OR contraceptive) AND (oral AND progestin)
Study type: Interventional Studies
Condition: NOT (endometriosis OR endometrial OR HIV OR cancer)
Gender: Studies with Female Participants
First received: 01 Jan 2011 to 13 Sep 2013

 

ICTRP (01 Jan 2011 to 18 Sep 2013)

oral contraceptives AND (progestin-only OR progestin only)

 

Appendix 2. Search 2011

 

MEDLINE via PubMed (2008 to 04 May 2011)

(contraceptives, oral OR ((contraception OR contracept*) AND pill)) AND (progestin* OR progestational, hormones, synthetic OR progestogen* OR progesterone OR gestagen OR "progestin only" OR "progestogen only") NOT contraceptives, oral combined NOT estrogens NOT contraceptives, oral/DT NOT drug therapy NOT treat* NOT (intrauterine device OR intrauterine devices OR intrauterine contraceptive device OR intrauterine contraceptive devices OR intrauterine system OR intrauterine systems OR IUD* OR IUCD OR IUS) AND (randomized controlled trial [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 OR ("clinical trial" ) OR ((singl* OR doubl* OR trebl* OR tripl* ) AND (mask* OR blind* )) OR "latin square" OR placebos [mh] OR placebo* OR random* OR research design [mh:noexp] OR comparative study OR evaluation studies OR follow-up studies [mh] )
Limited to human, female

 

CENTRAL (2008 to 04 May 2011)

oral AND contracept* in Title, Abstract, or Key words
AND (progestin) in Title, Abstract, or Key words

 

POPLINE (5 years to 04 May 2011)

((progestins low dose & contracept*)/(oral contraceptives low dose & (progestin*/progestogen*))) !implant !inject* !male !treat*

 

EMBASE (2008 to 15 May 2011)

(oral contraceptive agent or ((contraception or contracept?) and pill) or contraceptive()pill)
and
(gestgen or progestin? or progestogen? or progesterone or progestin()only or progestagen()only)
not
(estrogen or drug therapy or treat? or intrauterine device? or intrauterine()contraceptive()device? or intrauterine()system? or IUD? or IUCD? or IUS?
or injectable contraceptive agent or inject? or male contraceptive agent or male)
and
(clinical trial or randomized controlled trial or comparative study or controlled clinical trial
or evaluation study or follow()up study)

 

LILACS (04 May 2011)

(anticoncepcionais orais or anticonceptivos orales or contraceptives, oral [Words])
and (progestin or progestogen or progestinas or POP) [Words]

 

ClinicalTrials.gov (04 May 2011)

Search terms: (contraception OR contraceptive) AND (oral AND progestin)
Study type: Interventional Studies
Condition: NOT (endometriosis OR endometrial OR HIV OR cancer)
Intervention: NOT (estrogen OR estradiol)
Gender: Studies with Female Participants
First received: 01 Jan 2008 or later

 

ICTRP (04 May 2011)

oral contraceptives AND progestin-only OR progestin only

 

Appendix 3. Search 2008

 

MEDLINE via PubMed

(contraceptives, oral OR ((contraception OR contracept*) AND pill)) AND (progestin* OR progestational, hormones, synthetic OR progestogen* OR progesterone OR gestagen OR "progestin only" OR "progestogen only") NOT contraceptives, oral combined NOT estrogens NOT contraceptives, oral/DT NOT drug therapy NOT treat* NOT (intrauterine device OR intrauterine devices OR intrauterine contraceptive device OR intrauterine contraceptive devices OR intrauterine system OR intrauterine systems OR IUD* OR IUCD OR IUS) AND (randomized controlled trial [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 OR ("clinical trial" ) OR ((singl* OR doubl* OR trebl* OR tripl* ) AND (mask* OR blind* )) OR "latin square" OR placebos [mh] OR placebo* OR random* OR research design [mh:noexp] OR comparative study OR evaluation studies OR follow-up studies [mh] )
Limited to human, female

 

CENTRAL

oral contracept* AND (progestin-only OR progestin only) in Title, Abstract, or Key words

 

POPLINE

((progestins low dose & contracept*)/(oral contraceptives low dose & (progestin*/progestogen*))) !implant !inject* !male !treat* & clinical trial*

 

EMBASE

(oral contraceptive agent or ((contraception or contracept?) and pill) or contraceptive()pill)
and
(gestagen or progestin? or progestogen? or progesterone or progestin()only or progestagen()only)
not
(estrogen or drug therapy or treat? or intrauterine device? or intrauterine()contraceptive()device? or intrauterine()system? or IUD? or IUCD? or IUS?
or injectable contraceptive agent or inject? or male contraceptive agent or male)
and
(clinical trial or randomized controlled trial or comparative study or controlled clinical trial or randomized controlled trial or comparative study
or evaluation study or follow()up study)

 

LILACS

(anticoncepcionais orais or anticonceptivos orales or contraceptives, oral [Words] ) and (progestin or progestogen or progestinas or POP) [Words]

 

ClinicalTrials.gov

oral contraceptives AND progestin-only OR progest

 

International Clinical Trials Registry Platform (ICTRP)

oral contraceptives AND progestin-only OR progestin only

 

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: 29 October 2013.


DateEventDescription

28 October 2013New citation required but conclusions have not changedSearches updated; no new trials were eligible. One new study was excluded (Bhattacharya 2012).



 

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, 2009
Review first published: Issue 1, 2010


DateEventDescription

4 May 2011New search has been performedSearches updated; no new trials found.

23 September 2008AmendedProtocol revised to incorporate comments



 

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

EG Raymond developed the idea, and DA Grimes registered the topic. DA Grimes identified the eligible reports and performed the primary data abstraction. LM Lopez confirmed the report eligibility and performed the second data abstraction. EG Raymond and PA O'Brien provided analytical and editorial input. For the 2011 and 2013 updates, L Lopez conducted the searches and reviewed the search results.

 

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

  • US Agency for International Development, USA.
    Support for conducting and updating the review at FHI 360 (through 2011)
  • National Institute of Child Health and Human Development, USA.
    Support for conducting and updating the review at FHI 360 (through 2013)

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
Collaborative 1998 {published and unpublished data}
  • Collaborative Study Group on the Desogestrel-containing Progestogen-only Pill. A double-blind study comparing the contraceptive efficacy, acceptability and safety of two progestogen-only pills containing desogestrel 75 μg/day or levonorgestrel 30 μg/day. European Journal of Contraception and Reproductive Health Care 1998;3:169-78.
Lakha 2007 {published and unpublished data}
  • Lakha F, Ho PC, Van der Spuy ZM, Dada K, Elton R, Glasier AF, et al. A novel estrogen-free oral contraceptive pill for women: multicentre, double-blind, randomized controlled trial of mifepristone and progestogen-only pill (levonorgestrel). Human Reproduction 2007;22:2428-36.
Paulsen 1974 {published data only}
Sheth 1982 {published data only}
  • Sheth A, Jain U, Sharma S, Adatia A, Patankar S, Andolsek L, et al. A randomized, double-blind study of two combined and two progestogen-only oral contraceptives. Contraception 1982;25:243-52.
Vessey 1972 {published data only}
Were 1997 {published data only}
  • Were EO, Kendall JZ, Nyongesa P. Randomised clinical trial to determine optimum initiation time of norgestrel-progestin only contraception in Eldoret Teaching Hospital, Kenya. East African Medical Journal 1997;74:103-7.

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
Bhattacharya 2012 {published data only}
  • Bhattacharya SM, Jha A. Comparative study of the therapeutic effects of oral contraceptive pills containing desogestrel, cyproterone acetate, and drospirenone in patients with polycystic ovary syndrome. Fertility and Sterility 2012;98(4):1053-9.
Korver 2005 {published data only}
  • Korver T, Klipping C, Heger-Mahn D, Duijkers I, van Osta G, Dieben T. Maintenance of ovulation inhibition with the 75-μg desogestrel-only contraceptive pill (Cerazette®) after scheduled 12-h delays in tablet intake. Contraception 2005;71:8-13.
Rice 1999 {published data only}
  • Rice CF, Killick SR, Dieben R, Coelingh Bennink H. A comparison of the inhibition of ovulation achieved by desogestrel 75μg and levonorgestrel 30 μg daily. Human Reproduction 1999;14:982-5.

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
ACOG 2006
  • American College of Obstetricians and Gynecologists. ACOG technical bulletin. Use of hormonal contraception in women with coexisting medical conditions. Washington, D.C.: American College of Obstetricians and Gynecologists, 2006.
Bjarnadóttir 2001
  • Bjarnadóttir RI, Gottfredsdóttir H, Sigurdardóttir K, Geirsson RT, Dieben TOM. Comparative study of the effects of a progestogen-only pill containing desogestrel and an intrauterine contraceptive device in lactating women. British Journal of Obstetrics and Gynaecology 2001;108:1174-80.
CONSORT 2010
  • CONSORT group. CONSORT: Transparent reporting of trials. http://www.consort-statement.org/ (accessed 04 May 2011).
Dunson 1993
Edelman 2005
  • Edelman AB, Gallo MF, Jensen JT, Nichols MD, Schulz KF, Grimes DA. Continuous or extended cycle versus cyclic use of combined oral contraceptives for contraception. Cochrane Database of Systematic Reviews 2005, Issue 3. [DOI: 10.1002/14651858.CD004695.pub2]
Family Health International 1991
  • Family Health International. Time of progestin-only oral contraceptive initiation among lactating women (protocol #874). Internal document 1991.
FFPRHC 2003
  • Faculty of Family Planning and Reproductive Health Care Clinical Effectiveness Unit. New product review (April 2003) desogestrel-only pill (Cerazette). Journal of Family Planning and Reproductive Health Care 2003;29:162-4.
FFPRHC 2004
  • Faculty of Family Planning and Reproductive Health Care. FFPRHC guidance (July 2004) Contraceptive choices for breastfeeding women. Journal of Family Planning and Reproductive Health Care 2004;30:181-9.
FSRH 2008
  • Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit. Progestogen-only pills. http://www.ffprhc.org.uk/ (accessed 2 April 2009).
Goldzieher 1994
  • Goldzieher JW, Fotherby K. Pharmacology of the contraceptive steroids. New York: Raven Press, 1994.
Grimes 2010
  • Grimes DA, Schulz KF, Raymond EG. Surrogate end points in women's health research: science, protoscience, and pseudoscience. Fertility and Sterility 2010;93(6):1731-4.
Higgins 2008
  • Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions 5.0.0 [updated February 2008]. http://www.cochrane-handbook.org/ (accessed 9 July 2008).
Lidegaard 2009
  • Lidegaard Ø, Løkkegaard, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. British Medical Journal 2009;339:b2890.
Lopez 2012
Manchikanti 2007
McCann 1994
  • McCann MF, Potter LS. Progestin-only oral contraception: a comprehensive review. Contraception 1994;50:S1-S198.
Moggia 1991
  • Mogggia AV, Harris GS, Dunson TR, Dias R, Moffia MS, Ferrer MA, et al. A comparative study of a progestin-only oral contraceptive versus non-hormonal methods in lactating women in Buenos Aires, Argentina. Contraception 1991;44:31-43.
Moher 2001
Raymond 2011
  • Raymond EG. Progestin-only pills. In: Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Kowal D, Policar MS editor(s). Contraceptive Technology. 20th Edition. New York: Ardent Media, Inc., 2011:237-47.
Schulz 2002a
Schulz 2002b
Trussell 2011
van Vliet 2011
  • van Vliet HA, Grimes DA, Lopez LM, Schulz KF, Helmerhorst FM. Triphasic versus monophasic oral contraceptives for contraception. Cochrane Database of Systematic Reviews 2011, Issue 11. [DOI: 10.1002/14651858.CD003553.pub3]
Wallach 2000
  • Wallach M, Grimes DA, Chaney EJ, Connell EB, Creinin MD, Emans SJ, et al. Modern oral contraception. Totowa, NJ: Enron, 2000.
WHO 1998
  • World Health Organization collaborative study of cardiovascular disease and steroid contraception. Cardiovascular disease and use of oral and injectable progestogen-only contraceptives and combined injectable contraceptives: results of an international, multicenter, case-control study. Contraception 1998;57:315-24.