Quadriphasic versus monophasic oral contraceptives for contraception.

BACKGROUND: Quadriphasic oral contraceptives have been developed to reduce the adverse effects of oral contraceptives and are presented as more physiological since they mimic the natural cycle. However, suggested disadvantages of quadriphasic oral contraceptives include a possible increased risk of pill-taking errors caused by the array of different color pills, complicated directions for catching up when a pill is missed, the higher price and potential inferiority in terms of side effects. OBJECTIVES: To compare the contraceptive effectiveness, bleeding pattern, minor side effects and acceptability of quadriphasic contraceptive pills versus monophasic contraceptive pills. SEARCH METHODS: We searched CENTRAL, MEDLINE, EMBASE, POPLINE, ClinicalTrials.gov and ICTRP for trials comparing quadriphasic pills with monophasic pills. We contacted researchers and manufacturers of quadriphasic oral contraceptives to identify additional studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing quadriphasic with monophasic oral contraceptives . Trials had to report on contraceptive effectiveness, bleeding patterns, minor side effects, ease of use or trial discontinuation. We excluded studies where the intervention was primarily used as a treatment for disorders or was administered for fewer than three consecutive cycles. DATA COLLECTION AND ANALYSIS: T wo authors abstracted and entered data into RevMan. We critically appraised the methodological quality of the included trials. For continuous variables, we computed the mean difference with 95% confidence interval (CI) using the random-effects model. For dichotomous variables, we calculated the risk ratio with 95% CI using the random-effects model. MAIN RESULTS: We included one double-blind, double-dummy RCT comparing a quadriphasic oral contraceptive composed of dienogest and estradiol valerate with a monophasic oral contraceptive composed of levonorgestrel and ethinylestradiol. Contraceptive effectiveness, intracyclic bleeding and discontinuation due to side effects were similar for quadriphasic and monophasic pills. The number of women experiencing withdrawal bleeding was higher in the monophasic group compared to the quadriphasic group. Users of quadriphasic pills reported fewer bleeding/spotting days and fewer bleeding/spotting episodes than users of monophasic pills but the report did not specify whether the bleeding/spotting was scheduled or unscheduled. More women using quadriphasic oral contraceptives reported breast pain compared to women using monophasic oral contraceptives. AUTHORS' CONCLUSIONS: The available evidence is insufficient to determine whether quadriphasic differ from monophasic oral contraceptives in contraceptive effectiveness, bleeding pattern, minor side effects and acceptability. Studies that compare quadriphasic and monophasic oral contraceptives with an identical progestogen and estrogen type are needed to determine whether the quadriphasic approach differs from the monophasic approach. Studies that compare quadriphasic pills with monophasic pills containing 30 µg ethinylestradiol are indicated to determine whether quadriphasic oral contraceptives have an advantage over the current, first choice oral contraceptive . Until then, we recommend monophasic pills containing 30 µg estrogen as the first choice for women starting oral contraceptive use.

The effect of different hormonal contraceptives on plasma levels of free protein S and free TFPI.

Use of combined oral contraceptives is associated with a three- to six-fold increased risk of venous thrombosis. Hormonal contraceptives induce acquired resistance to activated protein C (APC), which predicts the risk of venous thrombosis. The biological basis of the acquired APC resistance is unknown. Free protein S (PS) and free tissue factor pathway inhibitor (TFPI) are the two main determinants of APC. Our objective was to assess the effect of both hormonal and non-hormonal contraceptives with different routes of administration on free TFPI and free PS levels. We conducted an observational study in 243 users of different contraceptives and measured APC sensitivity ratios (nAPCsr), free TFPI and free PS levels. Users of contraceptives with the highest risk of venous thrombosis as reported in recent literature, had the lowest free TFPI and free PS levels, and vice versa, women who used contraceptives with the lowest risk of venous thrombosis had the highest free TFPI and free PS levels. An association was observed between levels of free TFPI and nAPCsr, and between free PS and nAPCsr. The effect of oral contraceptives on TFPI and PS is a possible explanation for the increased risk of venous thrombosis associated with oral contraceptives.