Monophasic versus multiphasic oral contraceptives

There is no evidence that multiphasic oral contraceptives (OCs) are safer or more effective than monophasic OCs. In most developing countries, low-dose monophasic OCs are widely available and acceptable. There is no justification at present to recommend multiphasic OCs in preference to monophasic OCs

RHL Commentary by Shah DS

1. EVIDENCE SUMMARY

This commentary analyses data from three reviews which compared: (i) monophasic with biphasic oral contraceptives (OCs) (1); (ii) monophasic with triphasic OCs (2); and (iii) biphasic with triphasic OCs (3).

The first review (monophasic versus biphasic OCs) included one trial that analysed 481 user-cycles of monophasic OCs (1500 µg norethindrone acetate plus 30 µg ethinyl estradiol daily) with 533 user-cycles of a biphasic OC (500 µg norethindrone plus 35 µg ethinyl estradiol for 10 days, followed by 1000 µg norethindrone plus 35 µg ethinyl estradiol for 11 days). The authors concluded that there is no evidence to suggest significant advantage of biphasic pills over monophasic pills.

The second review (monophasic versus triphasic OCs) included of 21 trials. The trials differed in terms of the progestogen component of the pills and steroid hormone dosages, which rendered meta-analysis impossible. Most trials had methodological weaknesses such as unblinded and unclear outcome assessments. Although there was an indication of better cycle control with triphasic OCs the authors concluded that because of the weaknesses in the trials mentioned above there is no evident advantage of triphasic OCs.

The third review (biphasic versus triphasic OCs) included of two trials involving 849 women. Both trials had examined different types of pills: one trial had analysed 1269 and 1163 user-cycles, respectively, of two biphasic preparations and 1154 user-cycles of a triphasic preparation. In this trial, follow-up had been carried out for 12 cycles. The second trial examined 533 user-cycles of a biphasic preparation and 506 and 524 user-cycles, respectively, of two different triphasic preparations. The outcome measures compared were pregnancy, cycle control, side-effects and number and reasons for discontinuation. There were large losses to follow-up in both trials.

Overall, it can be safely concluded that neither triphasic nor biphasic OCs have any significant advantage over monophasic pills.

For all three reviews, the trials were retrieved through searches of Cochrane Controlled Trials Register, MEDLINE, Embase and Popline. The trials in the first (monophasic versus biphasic OCs) and third (biphasic and triphasic OCs) reviews had small sample sizes and a modest number of user-cycles. Moreover, the steroid hormone content of the pills used in these trials was variable. The sociodemographic characteristics of the women in these trials were not comparable and there were large losses to follow-up, all of which rendered the internal validity of these trials questionable. With regard to the outcome measures, the authors of the reviews could not arrive at a meaningful conclusion regarding contraceptive efficacy because of the small sample sizes in the trials.

2. RELEVANCE TO UNDER-RESOURCED SETTINGS

2.1. Magnitude of the problem

OCs is one of the best methods of contraception with a failure rate of 01.–0.4 per 100 woman–years of use. Early combined OCs contained very high doses of steroid hormones (estrogen and progestogen) that remained constant in all daily pills to be taken during the cycle. To reduce the steroid load on the body and to make OCs safer, the steroid hormone levels in OCs were gradually reduced to the minimum amounts needed for contraception. Then, in a bid to improve further the safety of the method, a phasic approach was developed, which involved altering the dose of the estrogen or progestogen, or both, during the cycle. This led to the development of biphasic pills (in which the doses varied in two phases) and later triphasic pills (in which the doses varied in three phases). Both biphasic and triphasic pills are considerably more expensive than monophasic pills.

2.2. Applicability of the results

The trials included in the reviews were conducted in diverse settings internationally that included both developing and developed countries. However, the main problem with the trials included in the three reviews is the questionable internal validity. Some of the trials in the review on monophasic versus triphasic OCs were funded by pharmaceutical companies. Hence, they are more likely to show outcomes favourable to triphasic OCs than monophasic OCs. Moreover, since the progestogen content of the pills was variable the outcomes related to cycle control and discontinuation of the pills because of dissatisfaction arising from bleeding patterns are not comparable.

OCs containing levonorgestrel were associated with better cycle control than norethindrone, suggesting that the choice of the progestogen may be more important that the phasic regimen in determining bleeding patterns.

Since all the reviews failed to provide enough evidence regarding benefit of phasic pills over the monophasic pill in terms of contraceptive efficacy, accidental pregnancy rates, decontamination rates and bleeding terms, it seems only right that monophasic pills should be the choice as an oral contraceptive till further studies show any advantage related to longer term complications.

2.3. Implementation of the intervention

In India, low-dose monophasic pills are preferred because of their wide availability and considerable evidence of safety, efficacy and compliance. With low literacy rates in India, especially among women, there is always the risk that the user may not take the phasic OCs in the required sequential order, which may result in contraceptive failure or breakthrough bleeding. This is likely to be true for most under-resourced settings. Since the consequences of unintended pregnancy are generally quite serious for women in under-resourced settings, programme managers in under-resourced settings are unlikely to risk providing a method that may fail owing to poor compliance.

In most developing countries, low-dose monophasic OCs are widely accessible and acceptable and there is considerable evidence of their safety. Therefore, there is no justification at present to recommend the use of multiphasic OCs in preference to monophasic OCs.

3. RESEARCH

Given the limited use of biphasic and triphasic OCs in most of the world and lack of evidence of any advantage of using them compared with monophasic OCs, further comparative trails are probably not justified. If at all any trials are to be conducted, it may be useful to compare OCs with identical type and dosage of progestogen with strict adherence to the recommendation on recording menstrual bleeding patterns made by the World Health Organization (4). Also, any further trials, if conducted, should include evaluation of long-term complications related to OCs use.

References

  • van Vliet HAAM, Grimes DA, Helmerhorst FM, Schulz KF. Biphasic versus monophasic oral contraceptives for contraception. Cochrane Database of Systematic Reviews;Issue 3, 2006.
  • van Vliet HAAM, Grimes DA, Lopez LM, Schulz KF, Helmerhorst FM. Triphasic versus monophasic oral contraceptives for contraception. Cochrane Database of Systematic Reviews;Issue 3, 2006.
  • van Vliet HAAM, Grimes DA, Helmerhorst FM, Schulz KF. Biphasic versus triphasic oral contraceptives for contraception. Cochrane Database of Systematic Reviews;Issue 3, 2006.
  • Belsey EM, Farley TMM. The analysis of menstrual bleeding patterns: a review. Contraception 1988;38:129-156.

This document should be cited as: Shah DS. Monophasic versus multiphasic oral contraceptives: RHL commentary (last revised: 23 June 2009). The WHO Reproductive Health Library; Geneva: World Health Organization.