Píldoras con progestina sola para la anticoncepción
Resumen
Antecedentes
La introducción de un nuevo anticonceptivo oral con progestina sola en Europa renovó el interés en esta clase de anticonceptivos orales. A diferencia de los anticonceptivos orales combinados utilizados ampliamente, que contienen un estrógeno más progestina, estas píldoras contienen sólo una progestina (progestágeno) y se toman sin interrupción. No está claro cómo estas píldoras se comparan con otras de su clase o con los anticonceptivos orales combinados.
Objetivos
Esta revisión examinó ensayos controlados aleatorios de píldoras con progestina sola con respecto a las diferencias en las tasas de eficacia, aceptabilidad y continuación.
Métodos de búsqueda
Hasta octubre de 2013, se realizaron búsquedas en las bases de datos electrónicas MEDLINE, Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials, CENTRAL), POPLINE y LILACS para identificar estudios sobre píldoras con progestina sola. También se hicieron búsquedas de estudios en curso vía ClinicalTrials.gov e ICTRP. Las búsquedas anteriores también incluyeron EMBASE.
Criterios de selección
Se incluyeron todos los ensayos controlados aleatorios realizados en cualquier idioma que analizaron píldoras con progestina sola para la anticoncepción. Se incorporó cualquier comparación con una píldora con progestina sola; lo que incluye dosis diferentes, otras píldoras con progestina sola, anticonceptivos orales combinados u otros anticonceptivos.
Obtención y análisis de los datos
El revisor principal extrajo los datos e introdujo la información en RevMan 5. Otro revisor realizó una segunda extracción de datos de forma independiente y verificó la introducción inicial de los datos.
Se intentaron extraer las tasas de las tablas de mortalidad (actuariales o continuas) y se utilizó la diferencia de tasas como la medida del efecto. Cuando no se publicaron las tasas de las tablas de mortalidad, se utilizó el cociente de tasas de incidencia (cociente de tasas de Pearl). Cuando solamente se publicó el número crudo de eventos, se calculó el odds ratio de Peto con intervalo de confianza (IC) del 95% mediante un modelo de efectos fijos. Para las variables continuas, se computó la diferencia de medias (DM) con el IC del 95%. Debido a las exposiciones diferentes, no fue posible combinar los estudios en un metanálisis.
Resultados principales
Seis ensayos cumplieron los criterios de inclusión. No se han encontrado estudios nuevos desde la revisión inicial. En el ensayo que comparó la píldora con progestina sola desogestrel versus la píldora con progestina sola levonorgestrel, el desogestrel no se asoció con un riesgo significativamente menor de embarazo accidental; el cociente de tasas fue 0,27 (IC del 95%: 0,06 a 1,19). Sin embargo, la píldora con progestina sola desogestrel provocó más problemas de hemorragia, aunque esta diferencia no fue estadísticamente significativa. El ensayo que comparó mifepristona a dosis bajas versus una píldora con progestina sola levonorgestrel encontró tasas similares de embarazo. En el ensayo que comparó diacetato de etinodiol versus un anticonceptivo oral combinado, ocurrieron ciclos irregulares en todas las mujeres asignadas a la píldora con progestina sola (odds ratio 135,96; IC del 95%: 7,61 a 2421,02). En un ensayo que comparó dos progestinas solas y dos anticonceptivos orales combinados, la píldora con progestina sola que contenía levonorgestrel 30 μg tuvo mayor eficacia que la píldora que contenía noretisterona 350 μg. Un ensayo anterior encontró que el acetato de megestrol es inferior a otras píldoras con progestina sola en cuanto a la eficacia. Un estudio sobre el momento de comienzo de la administración de las píldoras después del parto no encontró diferencias importantes, pero las pérdidas elevadas durante el seguimiento afectaron al ensayo.
Conclusiones de los autores
Las pruebas para comparar las píldoras con progestina sola entre ellas o con anticonceptivos orales combinados no son suficientes.
PICO
Resumen en términos sencillos
Píldoras con progestina sola para la anticoncepción
Las píldoras con progestina sola, como su nombre implica, contienen solo una hormona. Las píldoras anticonceptivas más frecuentes combinan dos hormonas. No está claro cómo estas píldoras se comparan con otras de su clase o con los anticonceptivos orales combinados. Por lo tanto, se realizó esta revisión para comparar las píldoras con progestina sola con otras píldoras similares o combinadas (dos hormonas). Se realizaron búsquedas electrónicas y bibliográficas para encontrar ensayos aleatorios de píldoras con progestina sola hasta octubre de 2013.
Se encontraron seis ensayos para la revisión inicial. No se han encontrado más estudios desde entonces. Algunos estudios se hicieron hace varias décadas y no son muy relevantes para las píldoras disponibles actualmente. Una píldora más nueva que contiene la progestina desogestrel puede funcionar mejor para prevenir el embarazo que una píldora más antigua con levonorgestrel. La píldora más nueva causó más problemas de hemorragia. Las píldoras con levonorgestrel pueden ser más efectivas que las que poseen otras progestinas que ya no se utilizan.
Estos estudios no son adecuados para determinar cómo las píldoras con progestina sola se comparan entre sí o con píldoras combinadas (dos hormonas). Se necesitan estudios más grandes con píldoras utilizadas actualmente para responder estas preguntas.
Authors' conclusions
Background
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
This review examined randomized controlled trials of progestin‐only pills for differences in efficacy, acceptability, and continuation rates.
Methods
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
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).
| Outcome | Norethisterone 350 μg N = 130 | Levonorgestrel 30 μg N = 128 | Norethisterone 1 mg/mestranol 50 μg N = 123 | Levonorgestrel 150 μg/ethinyl estradiol 30 μg N = 137 | P value |
| Discontinuation at 360 days | |||||
| Accidental pregnancy | 13.2 | 9.5 | 8.3 | 2.7 | 0.077 |
| Bleeding disturbances | 24.2 | 26.0 | 23.2 | 9.7 | 0.052 |
| All gastrointestinal | 2.5 | 5.7 | 2.5 | 11.1 | 0.011 |
| All central nervous system | 5.9 | 2.7 | 13.9 | 0.9 | 0.000 |
| All causes | 57.7 | 60.9 | 61.0 | 52.6 | 0.805 |
aFrom Sheth 1982, Table II.
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.
| Cumulative proportion continuing method | ||||
| Interval (months) | Start at 6 weeks | Start at 6 months | ||
| Percent | S.E. | Percent | S.E. | |
| 0 to 6 | 85.7 | 3.8 | 85.0 | 4.0 |
| 7 to 12 | 53.6 | 7.0 | 56.7 | 7.0 |
| 13 to 18 | 46.1 | 8.9 | 43.6 | 8.3 |
bFrom Were 1997, Table 2. Although the trial was designed for 18 months of follow up, the report provided data beyond that time interval.
Discussion
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).
Comparison 1 Desogestrel 75 μg versus levonorgestrel 30 μg daily, Outcome 1 Pregnancy.
Comparison 1 Desogestrel 75 μg versus levonorgestrel 30 μg daily, Outcome 2 Discontinuation because of adverse events.
Comparison 1 Desogestrel 75 μg versus levonorgestrel 30 μg daily, Outcome 3 Discontinuation because of irregular bleeding.
Comparison 1 Desogestrel 75 μg versus levonorgestrel 30 μg daily, Outcome 4 Discontinuation for all reasons.
Comparison 2 Mifepristone 5 mg versus levonorgestrel 30 μg daily, Outcome 1 Pregnancy.
Comparison 2 Mifepristone 5 mg versus levonorgestrel 30 μg daily, Outcome 2 Amenorrhea.
Comparison 2 Mifepristone 5 mg versus levonorgestrel 30 μg daily, Outcome 3 Mean endometrial thickness at 24 weeks.
Comparison 2 Mifepristone 5 mg versus levonorgestrel 30 μg daily, Outcome 4 Endometrial biopsy to evaluate endometrial cavity >12 mm on ultrasound.
Comparison 3 Ethynodiol diacetate 0.25 mg versus ethynodiol diacetate 1.0 mg plus mestranol 0.1 mg, Outcome 1 Irregular cycles.
Comparison 3 Ethynodiol diacetate 0.25 mg versus ethynodiol diacetate 1.0 mg plus mestranol 0.1 mg, Outcome 2 Intercycle bleeding.
Comparison 3 Ethynodiol diacetate 0.25 mg versus ethynodiol diacetate 1.0 mg plus mestranol 0.1 mg, Outcome 3 Discontinuation from trial.
Comparison 4 Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg, Outcome 1 Pregnancy.
Comparison 4 Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg, Outcome 2 Continuation at one year.
Comparison 4 Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg, Outcome 3 Discontinuation because of menstrual disturbance.
Comparison 4 Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg, Outcome 4 Discontinuation because of other side effects.
Comparison 4 Norethisterone acetate 0.3 mg versus norgestrel 0.075 mg, Outcome 5 Discontinuation for reasons unconnected with treatment.
| Outcome | Norethisterone 350 μg N = 130 | Levonorgestrel 30 μg N = 128 | Norethisterone 1 mg/mestranol 50 μg N = 123 | Levonorgestrel 150 μg/ethinyl estradiol 30 μg N = 137 | P value |
| Discontinuation at 360 days | |||||
| Accidental pregnancy | 13.2 | 9.5 | 8.3 | 2.7 | 0.077 |
| Bleeding disturbances | 24.2 | 26.0 | 23.2 | 9.7 | 0.052 |
| All gastrointestinal | 2.5 | 5.7 | 2.5 | 11.1 | 0.011 |
| All central nervous system | 5.9 | 2.7 | 13.9 | 0.9 | 0.000 |
| All causes | 57.7 | 60.9 | 61.0 | 52.6 | 0.805 |
| aFrom Sheth 1982, Table II. | |||||
| Cumulative proportion continuing method | ||||
| Interval (months) | Start at 6 weeks | Start at 6 months | ||
| Percent | S.E. | Percent | S.E. | |
| 0 to 6 | 85.7 | 3.8 | 85.0 | 4.0 |
| 7 to 12 | 53.6 | 7.0 | 56.7 | 7.0 |
| 13 to 18 | 46.1 | 8.9 | 43.6 | 8.3 |
| bFrom Were 1997, Table 2. Although the trial was designed for 18 months of follow up, the report provided data beyond that time interval. | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Pregnancy Show forest plot | 1 | 1320 | Rate Ratio (Fixed, 95% CI) | 0.27 [0.06, 1.19] |
| 2 Discontinuation because of adverse events Show forest plot | 1 | 1320 | Rate Ratio (Fixed, 95% CI) | 1.22 [0.81, 1.84] |
| 3 Discontinuation because of irregular bleeding Show forest plot | 1 | 1320 | Rate Ratio (Fixed, 95% CI) | 1.32 [0.99, 1.78] |
| 4 Discontinuation for all reasons Show forest plot | 1 | 1320 | Rate Ratio (Fixed, 95% CI) | 1.21 [0.99, 1.47] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Pregnancy Show forest plot | 1 | 441 | Odds Ratio (Peto, Fixed, 95% CI) | 0.71 [0.07, 6.95] |
| 2 Amenorrhea Show forest plot | 1 | 96 | Odds Ratio (Peto, Fixed, 95% CI) | 0.02 [0.00, 0.37] |
| 3 Mean endometrial thickness at 24 weeks Show forest plot | 1 | 73 | Mean Difference (IV, Fixed, 95% CI) | 6.30 [4.28, 8.32] |
| 4 Endometrial biopsy to evaluate endometrial cavity >12 mm on ultrasound Show forest plot | 1 | 96 | Odds Ratio (Peto, Fixed, 95% CI) | 7.74 [0.98, 61.41] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Irregular cycles Show forest plot | 1 | 66 | Odds Ratio (Peto, Fixed, 95% CI) | 135.96 [7.63, 2421.02] |
| 2 Intercycle bleeding Show forest plot | 1 | 66 | Odds Ratio (Peto, Fixed, 95% CI) | 6.20 [2.11, 18.22] |
| 3 Discontinuation from trial Show forest plot | 1 | 86 | Odds Ratio (Peto, Fixed, 95% CI) | 1.78 [0.75, 4.24] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Pregnancy Show forest plot | 1 | 150 | Rate Ratio (Fixed, 95% CI) | 0.78 [0.05, 12.35] |
| 2 Continuation at one year Show forest plot | 1 | Risk Difference (Fixed, 95% CI) | 28.2 [12.32, 44.08] | |
| 3 Discontinuation because of menstrual disturbance Show forest plot | 1 | 150 | Rate Ratio (Fixed, 95% CI) | 0.30 [0.15, 0.62] |
| 4 Discontinuation because of other side effects Show forest plot | 1 | 150 | Rate Ratio (Fixed, 95% CI) | 0.52 [0.15, 1.87] |
| 5 Discontinuation for reasons unconnected with treatment Show forest plot | 1 | 150 | Rate Ratio (Fixed, 95% CI) | 1.06 [0.57, 1.99] |
