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Progestin-only pills for contraception

Progestin-only pills for contraception (Review)
Grimes DA, Lopez LM, O'Brien PA, Raymond EG
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2013, Issue 11 Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

PLAIN LANGUAGE SUMMARY AUTHORS' CONCLUSIONS CHARACTERISTICS OF STUDIES Analysis 1.1. Comparison 1 Desogestrel 75 µg versus levonorgestrel 30 µg daily, Outcome 1 Pregnancy. . .
Analysis 1.2. Comparison 1 Desogestrel 75 µg versus levonorgestrel 30 µg daily, Outcome 2 Discontinuation because of adverse events.
Analysis 1.3. Comparison 1 Desogestrel 75 µg versus levonorgestrel 30 µg daily, Outcome 3 Discontinuation because of irregular bleeding.
Analysis 1.4. Comparison 1 Desogestrel 75 µg versus levonorgestrel 30 µg daily, Outcome 4 Discontinuation for all Analysis 2.1. Comparison 2 Mifepristone 5 mg versus levonorgestrel 30 µg daily, Outcome 1 Pregnancy.
Analysis 2.2. Comparison 2 Mifepristone 5 mg versus levonorgestrel 30 µg daily, Outcome 2 Amenorrhea. . .
Analysis 2.3. Comparison 2 Mifepristone 5 mg versus levonorgestrel 30 µg daily, Outcome 3 Mean endometrial thickness at 24 weeks.
Analysis 2.4. Comparison 2 Mifepristone 5 mg versus levonorgestrel 30 µg daily, Outcome 4 Endometrial biopsy to evaluate endometrial cavity >12 mm on ultrasound. . . . . . . . . . .
Analysis 3.1. Comparison 3 Ethynodiol diacetate 0.25 mg versus ethynodiol diacetate 1.0 mg plus mestranol 0.1 mg, Outcome 1 Irregular cycles. . . . . . . . . . . . . . .
Analysis 3.2. Comparison 3 Ethynodiol diacetate 0.25 mg versus ethynodiol diacetate 1.0 mg plus mestranol 0.1 mg, Outcome 2 Intercycle bleeding. . . . . . . . . . . . . . .
Analysis 3.3. Comparison 3 Ethynodiol diacetate 0.25 mg versus ethynodiol diacetate 1.0 mg plus mestranol 0.1 mg, Outcome 3 Discontinuation from trial. . . . . . . . . . . . .
Analysis 4.1. Comparison 4 Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg, Outcome 1 Pregnancy.
Analysis 4.2. Comparison 4 Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg, Outcome 2 Continuation at one Analysis 4.3. Comparison 4 Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg, Outcome 3 Discontinuation because of menstrual disturbance. . . . . . . . . . . . . . . .
Analysis 4.4. Comparison 4 Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg, Outcome 4 Discontinuation because Analysis 4.5. Comparison 4 Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg, Outcome 5 Discontinuation for reasons unconnected with treatment. . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Progestin-only pills for contraception
David A Grimes1, Laureen M Lopez2, Paul A O'Brien3, Elizabeth G. Raymond4 1Obstetrics and Gynecology, University of North Carolina, School of Medicine, Chapel Hill, North Carolina, USA. 2Clinical Sciences,FHI 360, Research Triangle Park, North Carolina, USA. 3Westside Contraceptive Services, London Community Healthcare, London,UK. 4Gynuity Health projects, New York, New York, USA Contact address: David A Grimes, Obstetrics and Gynecology, University of North Carolina, School of Medicine, CB#7570, ChapelHill, North Carolina, 27599-7570, USA.
Editorial group: Cochrane Fertility Regulation Group.
Publication status and date: Edited (no change to conclusions), published in Issue 11, 2013.
Review content assessed as up-to-date: 29 October 2013.
Citation: 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.
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
The introduction of a new progestin-only oral contraceptive in Europe has renewed interest in this class of oral contraceptives. Unlike themore widely used combined oral contraceptives containing an estrogen plus progestin, these pills contain only a progestin (progestogen)and are taken without interruption. How these pills compare to others in their class or to combined oral contraceptives is not clear.
This review examined randomized controlled trials of progestin-only pills for differences in efficacy, acceptability, and continuationrates.
Through October 2013, we searched the computerized databases MEDLINE, Cochrane Central Register of Controlled Trials (CEN-TRAL), POPLINE, and LILACS for studies of progestin-only pills. We also searched for current trials via ClinicalTrials.gov and ICTRP.
Previous searches also included EMBASE.
We included all randomized controlled trials in any language that included progestin-only pills for contraception. We incorporatedany comparison with a progestin-only pill; this could include different doses, other progestin-only pills, combined oral contraceptives,or other contraceptives.
Data collection and analysis
The first author abstracted the data and entered the information into RevMan 5. Another author performed a second, independentdata abstraction to verify the initial data entry.
We attempted to extract life-table rates (actuarial or continuous) and used the rate difference as the effect measure. Where life-tablerates were not published, we used the incidence rate ratio (ratio of Pearl rates). Where only the crude number of events was published,we calculated the Peto odds ratio with 95% confidence interval (CI) using a fixed-effect model. For continuous variables, the meandifference (MD) was computed with 95% CI. Because of disparate exposures, we were not able to combine studies in meta-analysis.
Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Main results
Six trials met the inclusion criteria. We have not found any new studies since the initial review. In the trial comparing the desogestrelversus levonorgestrel progestin-only pill, desogestrel was not associated with a significantly lower risk of accidental pregnancy; the rateratio was 0.27 (95% CI 0.06 to 1.19). However, the desogestrel progestin-only pill caused more bleeding problems, although thisdifference was not statistically significant. The trial comparing low-dose mifepristone versus a levonorgestrel progestin-only pill foundsimilar pregnancy rates. In the trial comparing ethynodiol diacetate versus a combined oral contraceptive, irregular cycles occurred inall women assigned to the progestin-only pill (odds ratio 135.96; 95% CI 7.61 to 2421.02). In a trial comparing two progestin-onlyand two combined oral contraceptives, the progestin-only pill containing levonorgestrel 30 µg had higher efficacy than did the pillcontaining norethisterone 350 µg. An early trial found megestrol acetate inferior to other progestin-only pills in terms of efficacy. Astudy of the timing of pill initiation after birth found no important differences, but high losses to follow up undermined the trial.
Evidence is insufficient to compare progestin-only pills to each other or to combined oral contraceptives.
Progestin-only pills for contraception
Progestin-only pills, as their name implies, contain just one hormone. The more common birth control pills combine two hormones.
How these one-hormone pills compare to each other or to two-hormone pills is not clear. Hence, we did this review to compareprogestin-only pills to other similar pills or to combined (two-hormone) pills. Through October 2013, we did a computer search andliterature search to find randomized trials of progestin-only pills.
We found six trials for the initial review. We have not found any more studies since then. Some studies are several decades old and notvery relevant to pills available today. A newer pill containing the progestin desogestrel may work better to prevent pregnancy than anolder pill with levonorgestrel. The newer pill caused more bleeding problems. Pills with levonorgestrel may be more effective than pillswith other progestins that are no longer used.
These studies are not adequate to tell how progestin-only pills compare to each other or to combined (two-hormone) pills. Largerstudies with currently used pills are needed to answer these questions.
B A C K G R O U N D
They may also appeal to women who want to use the lowest ef-fective dose of steroids to provide contraception. Some progestin- The introduction of a new progestin-only oral contraceptive in only pills were designed to allow ovulation and regular menses, Europe (; ) renewed interest in this although that goal has been reversed with the desogestrel pill.
class of oral contraceptives. Unlike the more widely used com- Lacking estrogen, progestin-only pills may have a lower risk of bined oral contraceptives containing an estrogen plus progestin complications. A World Health Organization case-control study (; ; these pills contain found no significant increase in the risk of stroke, myocardial only a progestin (progestogen) and are taken without interruption.
infarction, and venous thromboembolism among users of pro- Progestin-only pills (POPs) have both advantages and disadvan- gestin-only pills compared with non-users (A cohort tages when compared with combined pills. The pill-taking reg- study from Denmark also found no statistically significant associ- imen is simple and fixed; no pill color changes or days without ation between progestin-only pills and venous thromboembolism pill-taking occur. Fertility returns promptly upon discontinua- ). Although the literature is unsettled concerning tion. These pills are appropriate for women who cannot or should the potential impact of combined oral contraceptives on lactation, not take estrogen in combined oral contraceptives, for example, a no concerns exist for progestin-only pills ; woman older than 35 years who smokes cigarettes ).
Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
data are available concerning a potential effect on infant brain or Why it is important to do this review
liver. Like depot-medroxyprogesterone acetate injections for con- How different progestin-only pills compare to each other in terms traception (), progestin-only pills may reduce of efficacy and continuation is unclear. Because of the lower dose the frequency of sickle cell crises. Less restrictive screening for use of progestin than in combined oral contraceptives, the reliance may facilitate wider distribution by non-clinicians or over-the- on mechanisms other than ovulation inhibition, and the poten- counter provision.
tial importance of consistent daily pill taking, progestin-only pills Disadvantages include the recommendation for careful compli- may not be as effective as combined oral contraceptives. Stated ance and the disruption of normal menstrual patterns alternatively, progestin-only pills may be less 'forgiving' of late or ). These changes include irregular bleeding, short or long cy- missed pills. However, data to support or refute this hypothesis cles, bleeding and spotting, prolonged bleeding, or no bleeding at all. Overall, progestin-only pills are associated with more daysof bleeding and spotting than are combined oral contraceptives().
O B J E C T I V E S
The timing of ingestion of progestin-only pills may be more im-portant than with combined oral contraceptives. However, the po- This review examined randomized controlled trials of progestin- tential effect of timing on efficacy has not been adequately studied, only pills for differences in efficacy, acceptability, and continuation and, for practical reasons, likely will not be studied. Inter-indi- vidual variation in progestin metabolism rates is wide ; Progestin-only pills may not provide asmuch protection against ectopic pregnancy as do combined oral contraceptives (and they may be associated withmore functional ovarian cysts than are combined oral contracep-tives Criteria for considering studies for this review
Types of studies
Description of the intervention
We included all randomized controlled trials in any language that Commercially available progestin-only pills contain low doses of included progestin-only pills for contraception.
levonorgestrel, norethindrone (norethisterone), ethynodiol diac-etate, or desogestrel. The progestin dose is lower than that in com- Types of participants
bined oral contraceptives, hence the common name 'mini-pill'().
Women requiring contraception with data in the eligible trialswere included in the review.
Types of interventions
How the intervention might work
We included any comparison with a progestin-only pill; these Progestin-only pills prevent pregnancy through several potential could include different doses, other progestin-only pills, combined mechanisms. Ovulation is variably inhibited (), and oral contraceptives, or other contraceptives. Other interventions the cervical mucus becomes thick and relatively impenetrable to could include the timing of initiation of pills.
sperm. Ciliary action in the fallopian tubes is altered, as is the his-tology of the endometrium, potentially making implantation lesslikely ; ). The effec- Types of outcome measures
tiveness of progestin-only pills is not well-established. Reportedpregnancy rates in the first year of use range from zero to 13%(; ); some authors have estimated that typical pregnancy rates may approximate those of combined oral Pregnancy was the primary outcome of interest. Because of its contraceptives Consistent timing is considered infrequency in pill trials, we did not anticipate having sufficient important for successful use, but supporting evidence is limited.
power to compare pregnancy rates. However, we reported this In general, pregnancy rates may also be influenced by the woman's outcome when provided. We excluded data on invalid surrogate age, frequency of coitus, body mass, and lactation.
end points () for contraceptive efficacy, specifically Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ovulation. Although pregnancy cannot occur in the absence of Assessment of risk of bias in included studies
ovulation, the presence of ovulation does not predict the risk of We examined the methodological quality of trial reports according pregnancy, since other contraceptive mechanisms of action are to recommended principles (). We considered gener- involved with progestin-only pills.
ation of the random sequence, allocation concealment, blinding,and losses to follow up. Adequate methods of allocation conceal-ment included a centralized telephone system or pharmacy allo- cation, or use of sequentially numbered, sealed, opaque envelopes). Excluding participants after randomization can Side effects, including bleeding patterns, and continuation rates introduce bias and threaten trial validity were secondary outcomes.
Measures of treatment effect
Search methods for identification of studies
Oral contraception studies tend to have relatively high withdrawalrates. Time-to-event measures such as life-table or incidence rates See: Cochrane Fertility Regulation Group methods used in re- (Pearl rates) are commonly used, as they are based on actual ex- posure to the contraceptive and prevent an imbalance in with-drawals distorting the comparisons. In this review, we attemptedto extract life-table rates (actuarial or continuous) and used the rate difference as the effect measure. Where life-table rates were Through October 2013, we searched for studies of progestin-only not published, as was common, we used the incidence rate ratio pills in MEDLINE, Cochrane Central Register of Controlled Tri- (ratio of Pearl rates) as the effect measure. We used Microsoft Ex- als (CENTRAL), POPLINE, EMBASE, and LILACS. We also cel to generate the log rate ratios and their standard errors for use searched for current trials via ClinicalTrials.gov and ICTRP. The in RevMan using recommended methods (Where most recent strategies can be found in Previous search only the crude number of events was published, we calculated the strategies also included EMBASE (; Peto odds ratio with 95% confidence interval (CI). For continu-ous variables, the mean difference (MD) was computed with 95%CI using a fixed-effect model. RevMan uses the inverse varianceapproach. Fixed effect and random effects give the same result if Searching other resources
no heterogeneity exists, as when a comparison includes only one For the initial review, we examined the reference lists of relevant study. Because of disparate exposures, we were not able to combine articles. We also wrote to known investigators for information studies in meta-analysis.
about other published or unpublished trials not discovered in oursearch.
Dealing with missing data
We tried to contact authors for missing data and clarification ofissues related to methods. For , we calculated Data collection and analysis
the number of non-breast feeding women with the different bleed-ing patterns from the graph in the report. We were unable to do aformal comparison of rates in because standard errorswere not published.
Selection of studies
The first author reviewed the titles and abstracts of reports poten-tially eligible for inclusion. A second author confirmed the eligi-bility of the reports selected.
Data extraction and management
Description of studies
The first author abstracted the data and entered the informationinto RevMan. Another author performed a second, independentdata abstraction to verify the initial data entry. Any discrepancieswere resolved by discussion.
Results of the search
Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
The 2013 database searches produced 60 unduplicated references.
with 90 to be assigned to each of five treatment groups (four In addition, we obtained 44 unduplicated listings from Clinical- progestin-only pills and one combination oral contraceptive). The Trials.gov and ICTRP. We did not find any new studies to include.
planned fifth treatment group using a combined oral contraceptive For the initial review, six trials met our inclusion criteria. The trials was not implemented because of logistical problems. In addition, enrolled 2738 participants, and sample sizes ranged from 86 to 72 (16%) of those enrolled never began their pills, and the analysis 1306 women. Trial locations included European countries, United was limited to the 378 who took the drugs.
Kingdom, United States, India, China, South Africa, Nigeria, and in Eldoret, Kenya, randomized 200 women to receive Kenya. Several trials were decades old and studied pills no longer norgestrel 75 µg daily beginning either six weeks postpartum ver- commercially available; only one trial was published in the past sus beginning six months postpartum or when menses returned, whichever came first. Were and associates enrolled 200 women, aspart of a large international trial addressing the timing of startingprogestin-only pills during lactation. However, because of large losses after randomization (51% with unknown outcomes in bothgroups), the results cannot be considered valid.
was a multicenter trial sponsored by NVOrganon and conducted in 44 centers in six countries. It com-pared 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 Two randomized controlled trials studied the new progestin-only women using a desogestrel or levonorgestrel progestin-only pill, pill containing desogestrel 75 µg Both respectively, over 13 treatment periods of 28 days. The report pro- trials used ovulation as the outcome of interest, and ovulation vided woman-years of exposure, which we used as the denomina- is not a valid surrogate end point for pregnancy tor for pregnancy rates.
We also reviewed the full text of to determine compared mifepristone 5 mg versus levonorgestrel the composition of the OCs studied; all were combination oral 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 gath-ered as well. The investigators enrolled 97 women in four citiesin the UK, Hong Kong, and Africa. Seventy-four were assigned Risk of bias in included studies
to mifepristone and 23 to the levonorgestrel progestin-only pill.
Communication with the authors indicated a total of 356 and 85cycles exposed to pregnancy, respectively.
was a report from one site of a larger randomized controlled trial sponsored by G.D. Searle and Co. It compared aprogestin-only pill containing ethynodiol diacetate 0.25 mg ver- Allocation concealment was not mentioned in sus a combination oral contraceptive containing ethynodiol diac- and the method of randomization also was not specified. Corre- etate 1.0 mg plus mestranol 0.1 mg. The trial was conducted at spondence with an author confirmed randomized permuted blocks a Planned Parenthood clinic in California. A total of 86 women with a block size of four, and identical-appearing blister packs were were enrolled, with 43 assigned to each treatment.
distributed sequentially. In random sequence gener- reported on two centers, Bombay and Ljubljana, par- ation was done by "blocked computer-generated randomization" ticipating in a World Health Organization multicenter random- by center, although the block lengths were not specified. Alloca- ized trial comparing efficacy, discontinuation, and bleeding pat- tion concealment appears likely, since numbered pill bottles were terns of two progestin-only and two combination oral contracep- opaque. Allocation concealment was not mentioned by tives. The four pills included norethisterone 350 µg (also known did not specify the method of random alloca- as norethindrone), levonorgestrel 30 µg, norethisterone 1 mg plus tion. arranged pill cartons by an unspecified random mestranol 50 µg, and levonorgestrel 150 µg plus ethinyl estradiol process, after which serial numbers were assigned to the cartons 30 µg. Of 599 women who agreed to participate, 518 qualified and pill packs inside. Participants were given cartons in sequential and started the assigned method; 81 women dropped out after order, which likely provided adequate concealment. randomization and before beginning treatment.
randomly assigned participants using a computer-generated se- randomized women to four different progestin-only quence developed at Family Health International; whether block- pills in Ljubljana, Yugoslavia. These included megestrol acetate 0.7 ing was used is not specified in the protocol. Allocation conceal- mg, norethisterone acetate 0.3 mg, chlormadinone acetate 0.5 mg, ment was maintained by use of sequentially numbered, opaque, and norgestrel 0.075 mg. The investigators enrolled 450 women, sealed envelopes containing method indicator cards.
Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Other potential sources of bias
In the analysis excluded from consideration months In the two pills studied were identical in ap- in which the assigned treatment was not the sole method of con- pearance. The trial was described as "double blind," and corre- traception used. This left 356 months of exposure in the mifepris- spondence confirmed that participants and investigators were kept tone group and 85 months in the levonorgestrel progestin-only pill unaware of the treatment assignment. In blinding was group. This exclusion of months at risk of pregnancy is inappro- unlikely to have been achieved, because of dissimilar pill appear- priate; indeed, two of the pregnancies that occurred with mifepri- ance and different bleeding patterns associated with the two treat- stone were in months ostensibly protected by both mifepristone ments. attempted to keep participants and clinicians and condoms. The total number of woman-months of exposure unaware of the assigned treatment by using identical appearing is not stated so a full analysis set is not available. pills provided by the study sponsor. The authors noted that because featured a simplistic, dichotomous evaluation of bleeding patterns of the disparate bleeding patterns, clinicians could readily deduce and intentionally excluded participants after randomization; losses the treatment assigned, although they felt most patients, new to after randomization were high. In , 16% of those en- oral contraception, would have less insight into expected bleeding rolled never took the medication and were dropped from the study patterns. Assessment of bleeding patterns was done by examin- at that point. Whether these losses were different between groups ing patient diaries blinded as to treatment. had pills is unknown. High losses after randomization occurred in re-packaged by the manufacturers in 28-day pack to blind both because of civil strife; hence, these results cannot be deemed participants and investigators as to the treatment group. Whether the pills were identical in size, color, taste, etc., was not specified.
had pills manufactured expressly for the trial; thesewere identical in appearance. Participants and investigators were Effects of interventions
thus unaware of the assignments to the four progestin-only pillsgroups. No blinding was attempted in comparing early In the trial comparing the desogestrel versus levonorgestrel pro- versus late starting of progestin-only pills during lactation.
gestin-only pill (desogestrel was not associ-ated with a significantly lower risk of accidental pregnancy; the rateratio was 0.27; 95% CI 0.06 to 1.19 ). Adverse eventswere more frequent with desogestrel () (rate ratio 1.22; Incomplete outcome data
95% CI 0.81 to 1.84, but this difference also was not statisticallysignificant. Serious adverse events (ovarian cysts or ectopic preg- excluded 14 randomized women from analy- nancy) were uncommon with both pills. However, the desogestrel sis who never began the study medications. In , one progestin-only pill caused more bleeding problems randomized woman dropped out before taking her assigned drug.
Discontinuation because of irregular bleeding was more common Overall, 57 of 74 assigned to mifepristone and 15 of 23 assigned (rate ratio 1.32; 95% CI 0.99 to 1.78). Discontinuation for all to levonorgestrel, respectively, completed the trial. Investigators reasons was more frequent with desogestrel as well (rate ratio 1.21; excluded six women after randomization because of "persistent 95% CI 0.99 to 1.47) protocol violations." Communication with the authors provided Three pregnancies occurred amongst 979 women who started cycles of exposure. Two pregnancies occurred in months when treatment with desogestrel and 4 amongst 327 who started lev- both mifepristone and condoms were reportedly used. In onorgestrel. If the reduction in risk of pregnancy was real and not the authors arbitrarily excluded in the reporting of bleeding due to chance, then 110 women would need to be treated with analysis those participants enrolled for less than two cycles; this desogestrel rather than levonorgestrel to prevent one pregnancy.
left 29 of 43 in the progestin-only pill group and 37 of 43 in the However, 5 more of the 110 would discontinue early because of COC group. The trial report also noted three pregnancies during irregular bleeding.
the study but did not indicate in which treatment groups these The trial comparing low-dose mifepristone versus a levonorgestrel occurred. Loss to follow up was low in : only 11 of progestin-only pill ) found a lower pregnancy rate 518 women (2%). reported having information for with mifepristone (odds ratio 0.71; 95% CI 0.07 to 6.95) ( all 378 participants who took their assigned pills either until one A higher prevalence of amenorrhea occurred in the former year of follow up or until discontinuation for some reason. The group; about half of women assigned to mifepristone had no bleed- life-table analysis took into account the variable lengths of follow ing while taking the drug (No significant differ- up which are a common problem in such trials. Interpretation of ences emerged in minor side effects between the regimens. The is handicapped by high losses to follow up. In both two treatments had different effects on the uterus. Women in the treatment groups, 51% of participants were lost to follow up over mifepristone group developed a thicker endometrium than did 18 months, due in part to ethnic strife in this region of Kenya those assigned to the progestin-only pill (More- during the trial.
over, a higher proportion of women in the mifepristone group Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
required an endometrial biopsy to evaluate a dilated endometrial D I S C U S S I O N
cavity (>12 mm) (). While no biopsy indicated seri-ous pathology, more interventions were necessitated by mifepris-tone. Cystic glandular dilatation of the endometrium, a conditionof undetermined medical significance, was more common in the Summary of main results
mifepristone group.
Randomized controlled trials published to date are inadequate to Bleeding irregularities were more common with the progestin-only compare progestin-only pills to each other or to combined oral pill (not currently available at this dose) than with the combined contraceptives. Since progestin-only pills are commonly used dur- oral contraceptive in . The analysis dichotomized ing breast feeding, when fertility is low, the impact of better effi- bleeding into "regularity of cycles" and "intercycle bleeding." Ir- cacy of any pill would be small in this setting. No trial addressed regular cycles occurred in all women assigned to the progestin- the question of consistent timing of ingestion. Likewise, a pro- only pill, in contrast to those assigned to the COC (odds ratio gestin-only pill may be preferred for safety reasons in older women 135.96; 95% CI 7.63 to 2421.02) Intercycle bleed- with lower fertility who wish to continue oral contraception.
ing was significantly more common with the progestin-only pill Any potential benefit of better contraceptive efficacy with deso- as well (odds ratio 6.20; 95% CI 2.11 to 18.22) ().
gestrel 75 µg versus levonorgestrel 30 µg Discontinuation from the trial was also more common with the may be offset by worse bleeding patterns. These include prolonged progestin-only pill, although this difference was not statistically bleeding and absence of bleeding. For every 1 pregnancy that might significant (P = 0.19) be prevented with desogestrel, 5 women will discontinue early In the WHO four-pill comparison (pregnancy rates because of irregular bleeding. The trade-off between efficacy and were highest with norethisterone 35 µg and lowest with the com- continuation may be viewed differently in different settings, and bination pill levonorgestrel 150 µg plus ethinyl estradiol 30 µg. At amongst women in the same settings. For some women efficacy 360 days, the cumulative discontinuation rate for accidental preg- will be the chief consideration, while for others regular bleeding nancy was lower with combined levonorgestrel and ethinyl estra- will be more important.
diol (2.7%) than with the other pills: levonorgestrel alone (9.5%), These abnormal bleeding patterns may reflect the better suppres- combined norethisterone and mestranol (8.3%), and norethis- sion of ovulation with the desogestrel progestin-only pill than with terone alone (13.2%). Discontinuation because of bleeding dis- the levonorgestrel progestin-only pill (However, the turbances was less common with the combination levonorgestrel suggestion () that the desogestrel pill "is therefore ex- and ethinyl estradiol pill than with the other three pills. On the pected to have a lower failure rate than the currently available POP" other hand, the combination levonorgestrel and ethinyl estradiol [levonorgestrel 30 µg] remains unproven. While ovulation is a pill had the highest rates of discontinuation because of gastroin- prerequisite for pregnancy, it does not predict the risk of pregnancy testinal problems at 360 days. Overall discontinuation rates were Alternative mechanisms of progestin-only contra- similar for all four pills ).
ceptives are important, since ovulation is common with other pro- In , an early small trial, accidental pregnancies were gestin-only pills (; ), yet pregnancy is uncommon with both norethisterone acetate and norgestrel (1 in each treatment group) ). Among pills currently used, While daily low-dose mifepristone resulted in a higher propor- the cumulative continuation rate with norethisterone acetate at tion of women free from the nuisance bleeding and spotting, the one year was significantly higher than that with norgestrel (rate likelihood of pregnancy appeared similar among women receiving difference 28.2 per 100 women, 95% CI 12.32 to 44.08) mifepristone or levonorgestrel (Daily mifepristone ). However, discontinuation because of menstrual disturbances caused endometrial thickening and distension of the uterine cav- was significantly less common with norethisterone acetate (rate ity; these required histological evaluation more often than did the ratio 0.30; 95% CI 0.15 to 0.62) (). Discontinuation progestin-only pill. To identify those at risk of hyperplasia, the because of other side effects was also less common with norethis- investigators performed an endometrial biopsy on any participant terone acetate, although this difference was not statistically signif- if her uterine cavity measured >12 mm. Ovulation was better sup- pressed with mifepristone, but about one in five women had hor- found no pregnancies in either group. One group monal evidence of ovulation at any of three follow up visits.
started the progestin-only pill six weeks postpartum, and the other A progestin-only pill containing ethynodiol diacetate 0.25 mg group began the pill six months postpartum or when menses re- caused irregular cycles in all and intercycle bleeding in most par- turned. Continuation rates were also similar (). By 12 ticipants (). In contrast, a combined oral contracep- months, 54% of the early-start and 57% of the late-start partici- tive containing a higher dose of the same progestin (1.0 mg) plus pants were continuing their assigned method. By 18 months, these mestranol 0.1 mg resulted in more regular bleeding patterns. The figures were 46% and 44%, respectively. The mean duration of use drop-out rate was higher with the progestin-only pill than the was similar for both groups, as were reasons for discontinuation.
combination oral contraceptive in this trial.
Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
The four-group trial by the WHO found discontin- Agreements and disagreements with other
uation rates lowest with the combination levonorgestrel-ethinyl studies or reviews
estradiol pill. The combination pill with levonorgestrel and ethinyl A review concurred that the desogestrel pill had a lower failure estradiol caused fewer bleeding problems leading to discontinu- rate than the levonorgestrel pill, but that the difference was not ation than did the other three pills, although this was offset by statistically significant (). lacked more discontinuations because of gastrointestinal disturbances.
the power to differentiate between pregnancy rates. The review The progestin-only pill containing levonorgestrel had a lower preg- also noted that breastfeeding women may start progestin-only pills nancy rate than the pill with norethisterone. Poor reporting lim- at any time after delivery, since no adverse effect of these pills on ited the usefulness of this trial.
lactation has been identified ().
Another four-group trial () found megestrol acetatelower in efficacy than the other three pills; this difference was notstatistically significant, but the sample size of only 90 per grouplimited the power of the study. The other notable finding wasthe poorer bleeding patterns seen with norgestrel in the first six months of use. The authors concluded that norethisterone acetate30 µg appeared the most promising of the four drugs tested. Poor Implications for practice
reporting limited the usefulness of this trial as well.
The Kenyan trial of when to start a norgestrel progestin-only pill Desogestrel may be more effective than levonorgestrel, but this postpartum found no important differences (). Since benefit probably applies only to women not breast feeding. In most women were fully or nearly fully breastfeeding during the breast feeding women, the difference in efficacy was small. The po- trial, the likelihood of pregnancy was remote, and no pregnancies tential for better efficacy with desogestrel was offset by worse bleed- occurred over 18 months of observation. The high losses to follow ing patterns and more adverse events than with levonorgestrel.
up because of civil unrest undermined this trial.
Given the higher cost of mifepristone and its effects on the en-dometrium, the prospects for daily contraception with this an-tiprogestin appear limited. No firm conclusion is possible con-cerning the comparative efficacy of progestin-only pills or whether Overall completeness and applicability of
such pills are as effective as combined oral contraceptives. One poor-quality trial suggested no large effect of timing of initiation The age of several trials ; limited their on efficacy or continuation rates.
relevance to contemporary practice, since only two products stud-ied are currently available. Sample sizes, even in the largest trial Implications for research
(were inadequate to address relative efficacy.
Trials comparing progestin-only pills versus combination oral con- Similarly, the comparison of levonorgestrel to mifepristone was an traceptives are needed to address comparative efficacy, an unre- exploratory trial, since the latter is not used for ongoing contra- solved issue. Nuisance bleeding with progestin-only pills remains ception. Little information was available about the advice given an obstacle to wider use. Studies of ways to reduce this problem as to the timing of administration of the pills or whether back and to support women who do experience troublesome bleeding up contraception should be used in case of a late or missed pill.
might make this method more acceptable. A trial with sufficient Although accurate timing of administration is considered impor- power is needed to confirm the potentially higher efficacy of the tant for progestin-only pills, little empirical evidence supports this desogestrel progestin-only pill. Alternatively, older progestins but hypothesis, and the inter-individual variation in the metabolism with higher doses could be examined, which might allow longer of progestins is wide (; ).
half-lives and thus more time to remember the next pill. Trialsmight also encourage use of condoms as a backup to progestin-only pills. Future trials should report more fully Quality of the evidence
and should provide cumulative life-table rates and their cor-responding standard errors.
Incomplete reporting of methods was a generic problem, includinga trial ) published since the CONSORT guidelines(; were internationally adopted.
Potential biases in the review process
Carol Manion of FHI 360 developed the search strategies and ran None evident.
certain searches for the initial review.
Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
R E F E R E N C E S
References to studies included in this review
Rice 1999 {published data only}
Rice CF, Killick SR, Dieben R, Coelingh Bennink H. A Collaborative 1998 {published and unpublished data}
comparison of the inhibition of ovulation achieved by Collaborative Study Group on the Desogestrel-containing desogestrel 75µg and levonorgestrel 30 µg daily. Human Progestogen-only Pill. A double-blind study comparing the contraceptive efficacy, acceptability and safety of twoprogestogen-only pills containing desogestrel 75 µg/day or levonorgestrel 30 µg/day. European Journal of Contraception
and Reproductive Health Care
1998;3:169–78.
ACOG 2006
American College of Obstetricians and Gynecologists.
Lakha 2007 {published and unpublished data}
ACOG technical bulletin. Use of hormonal contraception Lakha F, Ho PC, Van der Spuy ZM, Dada K, Elton R, in women with coexisting medical conditions. Washington, Glasier AF, et al.A novel estrogen-free oral contraceptive D.C.: American College of Obstetricians and Gynecologists, pill for women: multicentre, double-blind, randomized controlled trial of mifepristone and progestogen-only pill
(levonorgestrel). Human Reproduction 2007;22:2428–36.
Bjarnadóttir RI, Gottfredsdóttir H, Sigurdardóttir K, Paulsen 1974 {published data only}
Geirsson RT, Dieben TOM. Comparative study of the Paulsen ML, Varaday A, Brown BW Jr, Kalman SM.
effects of a progestogen-only pill containing desogestrel and A randomized contraceptive trial comparing a daily an intrauterine contraceptive device in lactating women.
progestogen with a combined oral contraceptive steroid.
British Journal of Obstetrics and Gynaecology 2001;108:
Sheth 1982 {published data only}
CONSORT 2010
Sheth A, Jain U, Sharma S, Adatia A, Patankar S, Andolsek CONSORT group. CONSORT: Transparent reporting of L, et al.A randomized, double-blind study of two combined trials. http://www.consort-statement.org/ (accessed 04 May and two progestogen-only oral contraceptives. Contraception Dunson 1993
Vessey 1972 {published data only}
Dunson TR, McLaurin VL, Grubb GS, Rosman AW. A Vessey MP, Mears E, Andolsek L, Ogrinc-Oven M.
multicenter clinical trial of a progestin-only contraceptive in Randomised double-blind trial of four oral progestogen- lactating women. Contraception 1993;47:23–35.
only contraceptives. Lancet 1972;1:915–22.
Edelman 2005
Were 1997 {published data only}
Edelman AB, Gallo MF, Jensen JT, Nichols MD, Schulz Were EO, Kendall JZ, Nyongesa P. Randomised clinical KF, Grimes DA. Continuous or extended cycle versus cyclic trial to determine optimum initiation time of norgestrel- use of combined oral contraceptives for contraception.
progestin only contraception in Eldoret Teaching Hospital, Cochrane Database of Systematic Reviews 2005, Issue 3.
Kenya. East African Medical Journal 1997;74:103–7.
References to studies excluded from this review
Family Health International 1991
Family Health International. Time of progestin-only oralcontraceptive initiation among lactating women (protocol # Bhattacharya 2012 {published data only}
874). Internal document 1991.
Bhattacharya SM, Jha A. Comparative study of thetherapeutic effects of oral contraceptive pills containing FFPRHC 2003
desogestrel, cyproterone acetate, and drospirenone in Faculty of Family Planning and Reproductive Health Care patients with polycystic ovary syndrome. Fertility and Clinical Effectiveness Unit. New product review (April 2003) desogestrel-only pill (Cerazette). Journal of Family
Planning and Reproductive Health Care
2003;29:162–4.
Korver 2005 {published data only}
Korver T, Klipping C, Heger-Mahn D, Duijkers I, van Osta FFPRHC 2004
G, Dieben T. Maintenance of ovulation inhibition with the Faculty of Family Planning and Reproductive Health Care.
75-µg desogestrel-only contraceptive pill (Cerazette®) after FFPRHC guidance (July 2004) Contraceptive choices scheduled 12-h delays in tablet intake. Contraception 2005; for breastfeeding women. Journal of Family Planning and Reproductive Health Care 2004;30:181–9.
Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
FSRH 2008
lactating women in Buenos Aires, Argentina. Contraception Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit. Progestogen-only pills. http:// Moher 2001
www.ffprhc.org.uk/ (accessed 2 April 2009).
Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the Goldzieher JW, Fotherby K. Pharmacology of the contraceptive quality of reports of parallel-group randomised trials. Lancet steroids. New York: Raven Press, 1994.
Raymond 2011
Grimes 2010
Raymond EG. Progestin-only pills. In: Hatcher RA, Grimes DA, Schulz KF, Raymond EG. Surrogate end points Trussell J, Nelson AL, Cates W Jr, Kowal D, Policar MS in women's health research: science, protoscience, and editor(s). Contraceptive Technology. 20th Edition. New pseudoscience. Fertility and Sterility 2010;93(6):1731–4.
York: Ardent Media, Inc., 2011:237–47.
Higgins 2008
Schulz 2002a
Higgins JPT, Green S. Cochrane handbook for systematic Schulz KF, Grimes DA. Allocation concealment in reviews of interventions 5.0.0 [updated February 2008].
randomised trials: defending against deciphering. Lancet http://www.cochrane-handbook.org/ (accessed 9 July Schulz 2002b
Schulz KF, Grimes DA. Sample size slippages in randomised Lidegaard Ø, Løkkegaard, Svendsen AL, Agger C. Hormonal trials: exclusions and the lost and wayward. Lancet 2002; contraception and risk of venous thromboembolism: national follow-up study. British Medical Journal 2009;339:
Trussell J. Contraceptive failure in the United States.
Lopez 2012
Lopez LM, Newmann SJ, Grimes DA, Nanda van Vliet 2011
K, Schulz KF. Immmediate start of hormonal van Vliet HA, Grimes DA, Lopez LM, Schulz KF, contraceptives for contraception. Cochrane Database Helmerhorst FM. Triphasic versus monophasic oral of Systematic Reviews 2012, Issue 12. [DOI: 10.1002/ contraceptives for contraception. Cochrane Database of Systematic Reviews 2011, Issue 11. [DOI: 10.1002/14651858.CD003553.pub3] Gomez AM, Grimes DA, Lopez LM, Schulz KF. Steroid Wallach 2000
hormones for contraception in women with sickle cell Wallach M, Grimes DA, Chaney EJ, Connell EB, Creinin disease. Cochrane Database of Systematic Reviews 2007, Issue MD, Emans SJ, et al.Modern oral contraception. Totowa, 2. [DOI: 10.1002/14651858.CD006261.pub2] NJ: Enron, 2000.
McCann 1994
World Health Organization collaborative study of McCann MF, Potter LS. Progestin-only oral contraception: cardiovascular disease and steroid contraception.
a comprehensive review. Contraception 1994;50:S1–S198.
Cardiovascular disease and use of oral and injectable Moggia 1991
progestogen-only contraceptives and combined injectable Mogggia AV, Harris GS, Dunson TR, Dias R, Moffia contraceptives: results of an international, multicenter, case- MS, Ferrer MA, et al.A comparative study of a progestin- control study. Contraception 1998;57:315–24.
only oral contraceptive versus non-hormonal methods in ∗ Indicates the major publication for the study Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Characteristics of included studies [ordered by study ID]
Stratified randomized controlled trial; double blind. Stratification: breastfeeding, switch-ers (use of oral contraceptives within past 2 months), or starters (not a switcher or breast-feeding). Randomized 3:1 desogestrel:levonorgestrel. Allocation concealment providedby pharmacy distribution of identical pills in identical packages 1320 healthy sexually active women aged 18 to 45 years with normal cycles; 405 womenwere breast feeding. Recruited at 44 centers in Europe. Mean cycle length between 24and 35 days and intraindividual variation +/- 3 days. Willing to fill in diary card onbleeding and pill intake. Body weight between 80% and 130% of ideal. Willing to giveinformed consent. Exclusion criteria included contraindications to steroids, prior ectopicpregnancy, pelvic inflammatory disease, or symptomatic functional ovarian cysts Desogestrel 75 µg/day versus levonorgestrel 30 µg/day.
Pregnancy, adverse events, and bleeding patterns assessed after 3, 7, and 13 treatmentcycles of 28 days Both pills were identical in appearance. Sample size chosen to allow detection of adifference in incidence of 7% between the two groups for the primary bleeding patternvariables with a power of 80% and alpha of 0.05. Intended sample size was 1200, inpart to meet regulatory requirement for cycles of exposure. As a result of 10% over-recruitment, 1320 women were enrolled Risk of bias
Support for judgement
Allocation concealment (selection bias) No mention of allocation concealment.
Intentional exclusion of participants afterrandomization Blinding (performance bias and detection Low risk Tablets described as "identical-looking." bias)All outcomes Incomplete outcome data (attrition bias) Small numbers of participants excluded from analysis because of missing informa-tion or protocol violations Selective reporting (reporting bias) Uniform determination of outcomes forboth groups.
Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Lakha 2007
Randomized controlled trial in four centers; blocked computer-generated randomizationscheme developed in Edinburgh and stratified by center. Block size and whether sizevaried was not stated 97 healthy women in Nigeria, South Africa, Hong Kong, and Edinburgh. Aged 18to 40 years, regular menstrual cycles (21 to 42 days). Negative pregnancy test uponadmission. Excluded women with hormonal contraception use in past 3 months exceptin Edinburgh, where 9 women using progestin-only pill and having regular cycles wereincluded. Randomized in 3:1 ratio of mifepristone to levonorgestrel Mifepristone 5 mg versus levonorgestrel 30 µg per day. Participants were studied for onepretreatment cycle, six cycles of therapy, and one cycle after stopping therapy Frequency of amenorrhea, bleeding patterns, side effects, and efficacy Provided baseline characteristics as recommended but performed statistical testing onthese, which is improper Risk of bias
Support for judgement
Allocation concealment (selection bias) Participants were given coded opaque pillbottles.
Blinding (performance bias and detection Low risk Double dummy approach; participants re- ceived either mifepristone (half tablet) with placebo or levonorgestrel with a placebo(half tablet). Mifepristone and placebotablets both white but of different size Incomplete outcome data (attrition bias) Six participants excluded from analysis be- cause of protocol violations Selective reporting (reporting bias) Similar determination of outcomes forboth groups.
Paulsen 1974
Randomized controlled trial in one clinic; double blinding attempted. Randomizationsequence developed by study sponsor (Searle) 86 healthy women in a Planned Parenthood clinic in San Jose, California. Aged 18 to39 years and without medical contraindications to oral contraception Progestin-only pill containing ethynodiol diacetate 0.25 mg versus combined oral con-traceptive containing ethynodiol diacetate 1.0 mg plus mestranol 0.1 mg; followed for12 months Progestin-only pills for contraception (Review)
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Paulsen 1974
Bleeding patterns, discontinuation from study.
Part of a larger trial sponsored by G.D. Searle and Co.
Risk of bias
Support for judgement
Allocation concealment (selection bias) No mention of allocation concealment.
Blinding (performance bias and detection Unclear risk Pills were prepared by the manufacturer so that participants could not distinguish be- tween the two types of pills. Whether pack-aging was identical was not stated Incomplete outcome data (attrition bias) Differential discontinuation rates.
Selective reporting (reporting bias) Differential exclusion of participants frombleeding pattern analysis Sheth 1982
Randomized controlled trial in two centers as part of a World Health Organization study;double-blind 518 women who were healthy and had no contraindications to oral contraception, aged18 to 38 years, if post-partum greater than 28 and days and menstruating, if lactatingto have breast fed at least 165 days and be menstruating, no oral contraceptive use in 28days or injectable hormonal contraceptive use in 90 days, regular menstrual cycles of 21to 35 days. Participants came from Bombay and Ljubljana, Yugoslavia Four oral contraceptives, two progestin-only and two combination pills: norethisterone(norethindrone) 350 µg, levonorgestrel 30 µg, norethisterone 1 mg plus mestranol 50µg, and levonorgestrel 150 µg plus ethinyl estradiol 30 µg Pregnancy, discontinuation, and bleeding disturbances.
Two of the planned four international sites were dropped from the study because ofrecruitment problems. The remaining sites provided about half the intended sample size(1200 women) Risk of bias
Support for judgement
Allocation concealment (selection bias) Randomization technique not specified.
Progestin-only pills for contraception (Review)
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Sheth 1982
Blinding (performance bias and detection High risk Pills produced by manufacturers as usual.
All pills were repackaged in 28-day packs.
Pill packs were identified only by a randomnumber. Although uniform packaging wasprovided, pills could be identified Incomplete outcome data (attrition bias) Investigators excluded participants from analysis for noncompliance Selective reporting (reporting bias) Low losses to follow up.
Vessey 1972
Randomized controlled trial in one center in Ljubljana, Yugoslavia; double-blind 360 women aged 18 to 44 years, of proven fertility but with no more spontaneousabortions than live born children, no hormone preparation in past two months, normalgynecological examination, and healthy Four treatment groups randomized to progestin-only pills: megestrol acetate 700 µg,norethisterone acetate 300 µg, chlormadinone acetate 500 µg, or norgestrel 75 µg.
Participants were followed at 4, 7, 10, and 13 months after starting the trial. Observationplanned for a year Discontinuation because of pregnancy, menstrual disturbances, other side effects, otherreasons A fifth concurrent group of 90 women was assigned in non-random fashion to a com-bination contraceptive, ethinyl estradiol 100 µg plus megestrol acetate 2 mg Risk of bias
Support for judgement
Allocation concealment (selection bias) Pill cartons were "arranged in random or-der" and then given a serial number. Eachwomen enrolled was given the next cartonas her assignment Blinding (performance bias and detection Low risk All progestin-only pills were manufactured to be identical in appearance and consis- tency. These were packaged in bubble packsof 42 tablets; nine packs were placed in acarton Incomplete outcome data (attrition bias) All participants successfully followed for one year or until discontinuation Progestin-only pills for contraception (Review)
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Vessey 1972
Selective reporting (reporting bias) Sixteen percent of participants excluded af-ter randomization for noncompliance Were 1997
Randomized controlled trial in one academic center in Eldoret, Kenya; open label 200 women aged 18 to 35 years, had delivered a health term infant with plans to breastfeed for at least six months, planned to be sexually active, agreed to randomization, agreedto rely exclusively on the assigned contraceptive, and planned to remain available forfollow up for 18 months. Exclusion criteria included separation from the infant for morethan six hours per day, diastolic blood pressure > 90 Torr, or other contraindications toprogestin-only pills Participants were randomized to begin norgestrel 75 µg daily either at six weeks post-partum (group 1) versus at six months postpartum or after return of menses (group 2),whichever occurred first Pregnancy and discontinuation rates by reason.
This report is from one center of a planned multicenter trial, designed to have 2000participants ). The outcome of the overall trial isunknown. Although the trial planned for 18 months of follow up, some data beyondthat time interval are reported Risk of bias
Support for judgement
Allocation concealment (selection bias) Method indicator cards inside sequentiallynumbered, opaque, sealed envelopes Blinding (performance bias and detection High risk Not feasible.
bias)All outcomes Incomplete outcome data (attrition bias) Large number of participants lost after ran- domization due to ethnic strife in region Selective reporting (reporting bias) Small minority of participants in bothgroups completed trial as planned Progestin-only pills for contraception (Review)
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Characteristics of excluded studies [ordered by study ID]
Reason for exclusion Bhattacharya 2012 All three study arms received combination oral contraceptives Although this was a randomized controlled trial, the outcome of interest was ovulation, not pregnancy Although this was a randomized controlled trial, the outcome of interest was ovulation, not pregnancy Progestin-only pills for contraception (Review)
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Comparison 1. Desogestrel 75 µg versus levonorgestrel 30 µg daily
Outcome or subgroup title
Effect size
Rate Ratio (Fixed, 95% CI) 0.27 [0.06, 1.19] Rate Ratio (Fixed, 95% CI) 1.22 [0.81, 1.84] Rate Ratio (Fixed, 95% CI) 1.32 [0.99, 1.78] Rate Ratio (Fixed, 95% CI) 1.21 [0.99, 1.47] Comparison 2. Mifepristone 5 mg versus levonorgestrel 30 µg daily
Outcome or subgroup title
Effect size
Odds Ratio (Peto, Fixed, 95% CI) 0.71 [0.07, 6.95] Odds Ratio (Peto, Fixed, 95% CI) 0.02 [0.00, 0.37] Mean Difference (IV, Fixed, 95% CI) 6.30 [4.28, 8.32] Odds 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 title
Effect size
Odds Ratio (Peto, Fixed, 95% CI) 135.96 [7.63, 2421.
02] Odds Ratio (Peto, Fixed, 95% CI) 6.20 [2.11, 18.22] Odds Ratio (Peto, Fixed, 95% CI) 1.78 [0.75, 4.24] Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Comparison 4. Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg
Outcome or subgroup title
Effect size
Rate Ratio (Fixed, 95% CI) 0.78 [0.05, 12.35] Risk Difference (Fixed, 95% CI) 28.2 [12.32, 44.08] Rate Ratio (Fixed, 95% CI) 0.30 [0.15, 0.62] Rate Ratio (Fixed, 95% CI) 0.52 [0.15, 1.87] Rate Ratio (Fixed, 95% CI) 1.06 [0.57, 1.99] Analysis 1.1. Comparison 1 Desogestrel 75 µg versus levonorgestrel 30 µg daily, Outcome 1 Pregnancy.
Progestin-only pills for contraception g versus levonorgestrel 30 Study or subgroup Collaborative 1998 0.27 [ 0.06, 1.19 ] Total (95% CI)
0.27 [ 0.06, 1.19 ]
Heterogeneity: not applicable Test for overall effect: Z = 1.73 (P = 0.084) Test for subgroup differences: Not applicable Favours desogestrel Favours levonorgestrel Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.2. Comparison 1 Desogestrel 75 µg versus levonorgestrel 30 µg daily, Outcome 2
Discontinuation because of adverse events.
Progestin-only pills for contraception g versus levonorgestrel 30 2 Discontinuation because of adverse events Study or subgroup Collaborative 1998 1.22 [ 0.81, 1.84 ] Total (95% CI)
1.22 [ 0.81, 1.84 ]
Heterogeneity: not applicable Test for overall effect: Z = 0.95 (P = 0.34) Test for subgroup differences: Not applicable Favours desogestrel Favours levonorgestrel Analysis 1.3. Comparison 1 Desogestrel 75 µg versus levonorgestrel 30 µg daily, Outcome 3
Discontinuation because of irregular bleeding.
Progestin-only pills for contraception g versus levonorgestrel 30 3 Discontinuation because of irregular bleeding Study or subgroup Collaborative 1998 1.32 [ 0.99, 1.78 ] Total (95% CI)
1.32 [ 0.99, 1.78 ]
Heterogeneity: not applicable Test for overall effect: Z = 1.87 (P = 0.062) Test for subgroup differences: Not applicable Favours desogestrel Favours levonorgestrel Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.4. Comparison 1 Desogestrel 75 µg versus levonorgestrel 30 µg daily, Outcome 4
Discontinuation for all reasons.
Progestin-only pills for contraception g versus levonorgestrel 30 4 Discontinuation for all reasons Study or subgroup Collaborative 1998 1.21 [ 0.99, 1.47 ] Total (95% CI)
1.21 [ 0.99, 1.47 ]
Heterogeneity: not applicable Test for overall effect: Z = 1.90 (P = 0.057) Test for subgroup differences: Not applicable Favours desogestrel Favours levonorgestrel Analysis 2.1. Comparison 2 Mifepristone 5 mg versus levonorgestrel 30 µg daily, Outcome 1 Pregnancy.
Progestin-only pills for contraception 2 Mifepristone 5 mg versus levonorgestrel 30 Study or subgroup Peto,Fixed,95% CI Peto,Fixed,95% CI 0.71 [ 0.07, 6.95 ] Total (95% CI)
0.71 [ 0.07, 6.95 ]
Total events: 3 (Mifepristone), 1 (Levonorgestrel) Heterogeneity: not applicable Test for overall effect: Z = 0.29 (P = 0.77) Test for subgroup differences: Not applicable Favours mifepristone Favours levonorgestrel Progestin-only pills for contraception (Review)
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Analysis 2.2. Comparison 2 Mifepristone 5 mg versus levonorgestrel 30 µg daily, Outcome 2 Amenorrhea.
Progestin-only pills for contraception 2 Mifepristone 5 mg versus levonorgestrel 30 Study or subgroup Peto,Fixed,95% CI Peto,Fixed,95% CI 0.02 [ 0.00, 0.37 ] Total (95% CI)
0.02 [ 0.00, 0.37 ]
Total events: 36 (Mifepristone), 0 (Levonorgestrel) Heterogeneity: not applicable Test for overall effect: Z = 2.64 (P = 0.0083) Test for subgroup differences: Not applicable Favours levonorgestrel Favours mifepristone Analysis 2.3. Comparison 2 Mifepristone 5 mg versus levonorgestrel 30 µg daily, Outcome 3 Mean
endometrial thickness at 24 weeks.
Progestin-only pills for contraception 2 Mifepristone 5 mg versus levonorgestrel 30 3 Mean endometrial thickness at 24 weeks Study or subgroup 6.30 [ 4.28, 8.32 ] Total (95% CI)
6.30 [ 4.28, 8.32 ]
Heterogeneity: not applicable Test for overall effect: Z = 6.11 (P < 0.00001) Test for subgroup differences: Not applicable Favours mifepristone Favours levonorgestrel Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.4. Comparison 2 Mifepristone 5 mg versus levonorgestrel 30 µg daily, Outcome 4 Endometrial
biopsy to evaluate endometrial cavity >12 mm on ultrasound.
Progestin-only pills for contraception 2 Mifepristone 5 mg versus levonorgestrel 30 4 Endometrial biopsy to evaluate endometrial cavity >12 mm on ultrasound Study or subgroup Peto,Fixed,95% CI Peto,Fixed,95% CI 7.74 [ 0.98, 61.41 ] Total (95% CI)
7.74 [ 0.98, 61.41 ]
Total events: 19 (Mifepristone), 1 (Levonorgestrel) Heterogeneity: not applicable Test for overall effect: Z = 1.94 (P = 0.053) Test for subgroup differences: Not applicable Favours mifepristone Favours levonorgestrel Analysis 3.1. Comparison 3 Ethynodiol diacetate 0.25 mg versus ethynodiol diacetate 1.0 mg plus mestranol
0.1 mg, Outcome 1 Irregular cycles.
Progestin-only pills for contraception 3 Ethynodiol diacetate 0.25 mg versus ethynodiol diacetate 1.0 mg plus mestranol 0.1 mg 1 Irregular cycles Study or subgroup Peto,Fixed,95% CI Peto,Fixed,95% CI 135.96 [ 7.63, 2421.02 ] Total (95% CI)
135.96 [ 7.63, 2421.02 ]
Total events: 29 (POP), 11 (COC) Heterogeneity: not applicable Test for overall effect: Z = 3.34 (P = 0.00083) Test for subgroup differences: Not applicable Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 3.2. Comparison 3 Ethynodiol diacetate 0.25 mg versus ethynodiol diacetate 1.0 mg plus mestranol
0.1 mg, Outcome 2 Intercycle bleeding.
Progestin-only pills for contraception 3 Ethynodiol diacetate 0.25 mg versus ethynodiol diacetate 1.0 mg plus mestranol 0.1 mg 2 Intercycle bleeding Study or subgroup Peto,Fixed,95% CI Peto,Fixed,95% CI 6.20 [ 2.11, 18.22 ] Total (95% CI)
6.20 [ 2.11, 18.22 ]
Total events: 21 (POP), 11 (COC) Heterogeneity: not applicable Test for overall effect: Z = 3.32 (P = 0.00090) Test for subgroup differences: Not applicable Analysis 3.3. Comparison 3 Ethynodiol diacetate 0.25 mg versus ethynodiol diacetate 1.0 mg plus mestranol
0.1 mg, Outcome 3 Discontinuation from trial.
Progestin-only pills for contraception 3 Ethynodiol diacetate 0.25 mg versus ethynodiol diacetate 1.0 mg plus mestranol 0.1 mg 3 Discontinuation from trial Study or subgroup Peto,Fixed,95% CI Peto,Fixed,95% CI 1.78 [ 0.75, 4.24 ] Total (95% CI)
1.78 [ 0.75, 4.24 ]
Total events: 28 (POP), 22 (COC) Heterogeneity: not applicable Test for overall effect: Z = 1.31 (P = 0.19) Test for subgroup differences: Not applicable Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 4.1. Comparison 4 Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg, Outcome 1
Progestin-only pills for contraception 4 Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg Study or subgroup 0.78 [ 0.05, 12.35 ] Total (95% CI)
0.78 [ 0.05, 12.35 ]
Heterogeneity: not applicable Test for overall effect: Z = 0.18 (P = 0.86) Test for subgroup differences: Not applicable Favours norethisterone Favours norgestrel Analysis 4.2. Comparison 4 Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg, Outcome 2
Continuation at one year.
Progestin-only pills for contraception 4 Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg 2 Continuation at one year Study or subgroup Risk Difference (SE) 28.20 [ 12.32, 44.08 ] Total (95% CI)
28.20 [ 12.32, 44.08 ]
Heterogeneity: not applicable Test for overall effect: Z = 3.48 (P = 0.00050) Test for subgroup differences: Not applicable Favours norgestrel Favours norethisterone Progestin-only pills for contraception (Review)
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Analysis 4.3. Comparison 4 Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg, Outcome 3
Discontinuation because of menstrual disturbance.
Progestin-only pills for contraception 4 Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg 3 Discontinuation because of menstrual disturbance Study or subgroup 0.30 [ 0.15, 0.62 ] Total (95% CI)
0.30 [ 0.15, 0.62 ]
Heterogeneity: not applicable Test for overall effect: Z = 3.24 (P = 0.0012) Test for subgroup differences: Not applicable Favours norethisterone Favours norgestrel Analysis 4.4. Comparison 4 Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg, Outcome 4
Discontinuation because of other side effects.
Progestin-only pills for contraception 4 Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg 4 Discontinuation because of other side effects Study or subgroup 0.52 [ 0.15, 1.87 ] Total (95% CI)
0.52 [ 0.15, 1.87 ]
Heterogeneity: not applicable Test for overall effect: Z = 1.00 (P = 0.32) Test for subgroup differences: Not applicable Favours norethisterone Favours norgestrel Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 4.5. Comparison 4 Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg, Outcome 5
Discontinuation for reasons unconnected with treatment.
Progestin-only pills for contraception 4 Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg 5 Discontinuation for reasons unconnected with treatment Study or subgroup 1.06 [ 0.57, 1.99 ] Total (95% CI)
1.06 [ 0.57, 1.99 ]
Heterogeneity: not applicable Test for overall effect: Z = 0.19 (P = 0.85) Test for subgroup differences: Not applicable Favours norethisterone Favours norgestrel Table 1. Cumulative net life-table discontinuation rates at 360 daysa
Levonorgestrel 30 Norethisterone
1 mg/mestranol 50 150
estradiol 30 µg
Discontinuation at 360 days
All gastrointestinal All central nervous 5.9 a From , Table II.
Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 2. Life-table continuation rates over 18 months by treatment groupb
Cumulative proportion continuing method
Interval (months) Start at 6 monthsor with first menses b From , Table 2. Although the trial was designed for 18 months of follow up, the report provided data beyond that time A P P E N D I C E S
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, syntheticOR progestogen* OR progesterone OR gestagen OR "progestin only" OR "progestogen only") NOT contraceptives, oral combinedNOT estrogens NOT contraceptives, oral/DT NOT drug therapy NOT treat* NOT (intrauterine device OR intrauterine devices ORintrauterine 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, progestinFilter by keywords: oral contraceptives, research report CENTRAL (01 Jan 2011 to 18 Sep 2013)
oral AND contracept* in Title, Abstract, or Key wordsAND 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] Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ClinicalTrials.gov (01 Jan 2011 to 13 Sep 2013)
Search terms: (contraception OR contraceptive) AND (oral AND progestin)Study type: Interventional StudiesCondition: NOT (endometriosis OR endometrial OR HIV OR cancer)Gender: Studies with Female ParticipantsFirst 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, syntheticOR progestogen* OR progesterone OR gestagen OR "progestin only" OR "progestogen only") NOT contraceptives, oral combinedNOT estrogens NOT contraceptives, oral/DT NOT drug therapy NOT treat* NOT (intrauterine device OR intrauterine devices ORintrauterine 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] ORplacebo* 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 wordsAND (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? orIUCD? 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 trialor 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] Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ClinicalTrials.gov (04 May 2011)
Search terms: (contraception OR contraceptive) AND (oral AND progestin)Study type: Interventional StudiesCondition: NOT (endometriosis OR endometrial OR HIV OR cancer)Intervention: NOT (estrogen OR estradiol)Gender: Studies with Female ParticipantsFirst 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, syntheticOR progestogen* OR progesterone OR gestagen OR "progestin only" OR "progestogen only") NOT contraceptives, oral combinedNOT estrogens NOT contraceptives, oral/DT NOT drug therapy NOT treat* NOT (intrauterine device OR intrauterine devices ORintrauterine 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] ORplacebo* OR random* OR research design [mh:noexp] OR comparative study OR evaluation studies OR follow-up studies [mh] )Limited to human, female oral contracept* AND (progestin-only OR progestin only) in Title, Abstract, or Key words ((progestins low dose & contracept*)/(oral contraceptives low dose & (progestin*/progestogen*))) !implant !inject* !male !treat* &clinical trial* (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? orIUCD? 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 comparativestudyor evaluation study or follow()up study) Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(anticoncepcionais orais or anticonceptivos orales or contraceptives, oral [Words] ) and (progestin or progestogen or progestinas orPOP) [Words] oral contraceptives AND progestin-only OR progest International Clinical Trials Registry Platform (ICTRP)
oral contraceptives AND progestin-only OR progestin only W H A T ' S N E W
Last assessed as up-to-date: 29 October 2013.
New citation required but conclusions have not Searches updated; no new trials were eligible. One newchanged study was excluded ().
Protocol first published: Issue 1, 2009 Review first published: Issue 1, 2010 New search has been performed Searches updated; no new trials found.
23 September 2008 Protocol revised to incorporate comments EG Raymond developed the idea, and DA Grimes registered the topic. DA Grimes identified the eligible reports and performed theprimary data abstraction. LM Lopez confirmed the report eligibility and performed the second data abstraction. EG Raymond and PAO'Brien provided analytical and editorial input. For the 2011 and 2013 updates, L Lopez conducted the searches and reviewed thesearch results.
Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DA Grimes has consulted with the pharmaceutical companies Bayer Healthcare Pharmaceuticals and Merck & Co, Inc.
• No sources of support supplied • 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) I N D E X T E R M S
Medical Subject Headings (MeSH)
Contraceptives, Oral, Combined [administration & dosage]; Contraceptives, Oral, Hormonal [∗administration & dosage; adverseeffects]; Desogestrel [administration & dosage; adverse effects]; Ethynodiol Diacetate [administration & dosage]; Levonorgestrel [ad-ministration & dosage]; Progestins [∗administration & dosage; adverse effects]; Randomized Controlled Trials as Topic; Uterine Hem-orrhage [chemically induced] MeSH check words
Progestin-only pills for contraception (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Source: http://www.metaxis.com/BCP/PDF/CD007541.pdf

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Università degli Studi di Firenze – Dipartimento di Scienze dell'Educazione Mapping of policies affecting female migrants and policy analysis: the Italian case Giovanna Campani, Tiziana Chiappelli, Ilundi Cabral, Alessandra Working Paper No. 6 – WP1 December 2006