The objective of the review was to compare the various currently available low dose OCs containing different progestogens and assess their acceptability according to the following indicators:

1. Effectiveness (pregnancy rates)

2. Discontinuation rates

3. Reasons for discontinuation

4. Cycle control

5. Side-effects

Trials had to report clinical outcomes to be eligible for inclusion. Trials focusing on biochemical changes only were not eligible for the review. The primary outcome of interest in this review is acceptability.

1. Any monophasic low-dose estrogen (<50 mcg) combined OC containing a third-generation progestogen versus any monophasic low-dose estrogen combined OC containing a second-generation progestogen (same for multiphasic preparations)

2. Any monophasic low-dose estrogen combined OC containing a third generation progestogen versus any monophasic low-dose estrogen combined OC containing a first-generation progestogen (same for multiphasic preparations)

3. Any monophasic low-dose estrogen combined OC containing a second-generation progestogen versus any monophasic low-dose estrogen combined OC containing a first-generation progestogen (same for multiphasic preparations)

4. Comparisons between low-dose estrogen OCs containing a certain type of progestogen.

1. We searched the Cochrane Controlled Trials Register, MEDLINE and EMBASE with the following search strategy:

CONTRACEPTIVES-ORAL*:ME

LEVONORGESTREL

NORETHISTERONE

norethyndrone

NORETHINDRONE

NORGESTIMATE

DESOGESTREL

GESTODENE

(((((((#1 or #2) or #3) or #4) or #5) or #6) or #7) or #8)

MENOPAUS*

NORPLANT

REPLACEMENT

ANIMAL

INJECT*

CANCER

IUD

INTRAUTERINE

PROSTAT*

((((((((#10 or #11) or #12) or #13) or #14) or #15) or #16) or #17) or #18)

(#9 not #19)

2. Letters requesting information from pharmaceutical companies who have combined low-dose estrogen OCs containing different progestogens were sent.

3. Informal contacts with researchers in the field were made to identify any trials.

The reports identified with the electronic search were checked initially for two characteristics:

1. Random allocation to comparison groups

2. Clinical outcomes reported

If these characteristics were not clear from the title or the abstract the full report was retrieved. Reports that have met above criteria were assessed for other inclusion criteria, methodological quality and validity of the data. Both application of inclusion criteria and the data extraction were made by the reviewers independently and differences were resolved by discussion.

Randomized controlled trials comparing low-dose estrogen (<50 mcg) combined oral contraceptive (OC) formulations were eligible. Cross-over studies were not considered. Trials had to include women of reproductive age, using OCs for contraception, irrespective of the duration of past OC use, or being new starters or switchers. Trials enrolling volunteers for biochemical change assessments or women receiving OCs for non-contraceptive purposes (such as acne vulgaris) were not eligible. Comparisons between same phasic dosages were eligible. A trial comparing a monophasic OC with a multiphasic OC was not eligible even if the progestogens were within the scope of the review.

Interventions had to be applied for a minimum of six months for a trial to be considered for inclusion.

In addition to the clinical outcomes, systematic data extraction was carried out for each trial for the following variables:

The trials were conducted in many diverse settings and some were multicenter trials including centers from several countries (table 2). The participants were usually described as women seeking contraception excluding those with medical conditions not suitable for OC use. Some trials reported selected outcomes such as cycle control but not other components of acceptability 89. Thirteen studies clearly stated the inclusion and exclusion criteria. Both starters and switchers were included. Only one study 10 mentions a washout period of one cycle amongst the switchers prior to starting the study medication. In the study by Rossmanith 8, 40% of the switchers received the same OC before as after the randomization. The Zichella 11 trial recruited only starters, defined as women who had not used hormonal contraception for three months prior to study. Eleven trials were conducted in Europe, six in the United States and Canada, two in Latin America and two in South East Asia. The study by Dunson 12 was set across all major continents.

Eighteen trials used OCs distributed as 28-day cycles with 21 active pills and 7 days of no tablet taking. One trial 13 distributed one OC as a 24-day formulation with all active pills compared to a 21-day cycle. Another trial used 28-day packages for both groups, with 21 active hormone tablets and 7 iron tablets for one group and 7 inactive tablets for the other group 12. We were unable to find information on the duration of OC dosing used for two trials 914.

The day of pill start varied within and between studies to either a first-day start, first-Sunday start or fifth-day start. Thirteen trials had no information on the day of pill start. Shoupe used first-Sunday start for both OCs 15. Day-1 start for both pill types was used in six trials 131617181920. First Sunday and day 1 start for the two OC formulations was used in one trial 21. Fifth day start for both OC types was advocated in the study by Ramos 22.

Eighteen out of 22 trials were supported by pharmaceutical companies, one trial was jointly supported by a pharmaceutical company and an international organization (UNFPA) 22, whereas 2 studies were supported or conducted by international organizations, NGOs or university departments 1221. There is no information on funding for 2 trials 817.

Twenty-two trials were included in the review. The order in which the comparisons are arranged is based on the type of formulation (monophasic or triphasic) and type of progestogen (newer progestogens versus older progestogens) following the criteria given by Henzl 1. Trials were only included if the difference of the total ethinylestradiol content did not exceed 105 mcg. Sixteen trials compared monophasic OCs and 6 compared triphasic OCs 81521232425. Except for two trials using drospirenone 1026 all other trials included progestogens categorised as first-, second- or third-generation. No trials included other progestogens such as ethynodiol diacetate, lynestrenol, norethynodrel, cyproterone acetate and dienogest.

Methodological quality assessment was based on random allocation technique used, blinding, post-randomization exclusions and loss to follow-up. Each criterion was rated as met, unmet or unclear (table 2).

A clinically relevant difference in effectiveness among the different progestogens was not observed. Generally, trials with a follow-up period of up to one year or longer showed a failure rate ranging from 0.2 to 1.8% 12.

The overall discontinuation rate amongst different trials varied from 8.2% 27 to 17.9% 16 for trials using monophasic pills and had a follow-up of 6 cycles; and from 25.5% 12 to 28.7% 20 for trials conducted over a follow-up period of 12 cycles. Second-generation progestogens had higher discontinuation rates compared to third- and lower compared to first-generation preparations; which may be the reflection of a similar pattern seen with cycle disturbances.

The association between cycle disturbances and continuation has been demonstrated before. Data from longitudinal studies suggest that most of the women discontinuing OCs in the first year of use do so within the first two months and new starters are more likely to discontinue than switchers. Most of the women who discontinued did not want to fall pregnant but continued with less effective contraceptive methods 5. Apart from a Chlamydia trachomatis infection, uterine/cervical abnormalities, smoking and missing pills, low estrogenic efficacy on the endometrium might have a causal relationship with prolonged spotting and breakthrough bleeding 30. Is the estradiol dose the sole important factor or should we consider the estradiol dose in combination with the progestogen type? Each progestogen steroid differs in its estrogenic, progestogenic and androgenic properties 31. Spotting was reported in about 30% of women using a combination pill with an EE content of less than 30 mcg, as compared to about 7.5% in women using a pill with 30 mcg EE, regardless of the progestogen (GSD or DSG) content. Therefore, variation in estrogenic potential among progestogens may explain some clinical phenomena such as spotting and breakthrough bleeding. We were interested in the efficacy of preventing spotting and breakthrough bleeding by the combination of the estrogen/progestogen components, thus the progestogen together with the dose of ethinylestradiol.

One trial included in this review 13 used EE 15 mcg in one and EE 20 mcg in the other group. There was a trend that more women in the 15 mcg group reported breakthrough bleeding (RR 1.67, 95% CI 1.00–2.95), which may be related to the lower EE dose in that group. We were not able to lump data on spotting and breakthrough bleeding per cycle since a woman can experience the spotting during several cycles, but also several events of spotting per cycle. Clustering of these data might overestimate the outcome and distort the results.

1) There is a shortage of appropriately powered and independently conducted randomized trials. The majority of the trials were supported in full or partially by pharmaceutical companies. The methods of allocation concealment are unclear in most studies. 2) There is little information in all trials on other indicators of acceptability such as libido or sexual satisfaction scores: only one trial measured women's satisfaction with the treatment 21. 3) Effectiveness: Failure rate – measured as pregnancies – was a rare outcome in all trials reporting on it. Therefore, trials with adequate sample sizes are required to determine the superiority of one method over the other. The included trials in this review did not have large enough sample sizes to detect rare outcomes. 4) Application: Assessment of user or method failures was unlikely to be blinded and could be biased. Most studies define user failure as two or more missed pills in a cycle.

Also, the day of pill start, recruitment of both starters and switchers, use of a washout period for the switchers and the OC type received by switchers, particularly in double blind trials, all influence cycle control data and contraceptive outcomes.

Unfortunately, most of these factors do not appear to have been taken into account in these trials.