Contraceptive failure and pregnancy rates

There have been few RCTs of COCs with pregnancy as an endpoint and they have been underpowered,4 due to the high efficacy of all COC regimens in research volunteers who are, in general, correct and consistent users. Exceptionally, there is one RCT of a 50 µg EE/250 µg levonorgestrel (LNG) COC, administered vaginally, comparing a 21/7 regimen (n=454) with continuous use (n=446), which reported four pregnancies (1.04%) in the cyclical group and none in the continuous use group (OR 0.1, 95% CI 0.02 to 0.97).4 5

Observational studies are more representative of ‘typical’ users. They concur that non-compliance risks pregnancy,6–8 yet no study has obtained the data to link that risk to the timing of tablet omissions in relation to the 7-day CFI. Moreover, there are no reports to date that confirm, or refute, that the risk due to non-compliance is any lower with 84/7 extended regimens. In the one open-label parallel RCT comparing the efficacy and safety of 30 EE/150 LNG, the Pearl Index based on method failure for the 84/7 regimen (n=456) was 0.60, which was lower than the Pearl Index of 1.78 for the 21/7 regimen (n=226), but the authors did not include tests for statistical significance.6 Prospective observational studies of conception rates for the standard 21/7 regimen versus the 365/0 continuous flexible regimen described below are likewise still awaited.

With respect to regimens with a shorter (4-day) CFI, contraceptive effectiveness comparing progestogens and regimens in ‘typical’ users was specifically addressed in a subgroup analysis of outcome data from a prospective cohort study of 52 218 US women who were using 24/4 and 21/7 regimens of COCs containing differing doses and types of progestogens and differing doses of EE.9 During 73 269 woman-years there were 1634 pregnancies of which 1405 (86%) were associated with non-compliance. The analysis specifically focused on the effect of the 24/4 versus 21/7 regimen, particularly comparing drospirenone (DRSP) with other progestogens, on the basis that drospirenone has a longer half-life. The overall Pearl Index was 1.6 (95%CI 1.4 to 1.9) for a 20 EE/3000 DRSP 24/4 regimen, 2.2 (95%CI 1.8 to 2.6) for a 30 EE/3000 DRSP 21/7 regimen, and 2.6 (95%CI 2.4 to 2.7) for all other pills. Direct comparisons within the DRSP and norethisterone acetate (NETA) groups (excluding pills with other progestogens) showed significantly lower contraceptive failure rates for 24/4 versus 21/7 regimens, and significantly lower contraceptive failure rates for DRSP versus NETA: life-table estimates of the rates of contraceptive failure for the first year of pill use were 2.1% for the 20 EE/3000 DSRP 24/4 regimen, 2.8% for the 30 EE/3000 DRSP 21/7 regimen, 3.5% for an EE/NETA 24/4 regimen, and 4.7% for an EE/NETA 21/7 regimen. While interpretation of these results is subject to the limitations of observational research, the trend is in line with the greater efficacy associated with the 24/4 regimen versus 21/7, despite the lower EE dose. The benefits of the 24/4 regimen were more pronounced and statistically significant in adolescents. In a subgroup analysis of 228 unintended pregnancies in adolescent participants using any 20 EE pills in the same study, the Pearl Index was 2.5 (95%CI 2.1 to 2.9) for the 24/4 regimen and 5.1 (95%CI 3.7 to 6.8) for the 21/7 regimen.10

Ovarian activity and risk of escape ovulation

Smith et al 11 showed that ovarian estradiol levels are routinely suppressed once seven COC tablets have been taken. Yet in their Group 1 subjects, who discontinued for 7 days after taking seven daily tablets, one woman out of 12 showed luteinisation, with a rise in plasma progesterone level to 6.8 nmol/L. This would suggest that the risk of ovulation would only arise in mid-packet by omission of seven tablets. Indeed, after prior ingestion of seven pills there appear to be no documented ovulations in the literature, nor pill-failure conceptions established as occurring through omissions of fewer than seven tablets. In the systematic review by Zapata et al,12 missing up to four consecutive pills on days not adjacent to the pill-free interval resulted in little follicular activity and low risk of ovulation.

A review of 29 studies evaluated pituitary-ovarian activity in women using 20–40 µg EE COCs.13 In 20 studies, follicles ≥10 mm diameter were identified by Day 7 of the CFI on ultrasound, the cut-off during natural menstrual cycles for selection for preferential growth and ovulation. Although most dominant follicles regress when COC are restarted, 10 studies reported ovulation. In two RCTs of 21/7 regimens, one pregnancy was reported as method failure in a woman taking 20 EE/150 DSG14 and another in a woman taking 30 EE/1500 NETA.15

The size of follicles appears to be inversely related to the dose of EE.12 13 However if the CFI is shortened, ovulation must be less likely to occur if tablets are subsequently missed. In an open-label comparative study of a 24/4 versus 21/7 regimen of a 15 EE/60 gestodene (GSD) COC, ovarian activity was monitored with ultrasound scans and blood samples every other day over five cycles.16 The 24/4 regimen inhibited ovarian activity more effectively than the 21/7 regimen (figure 1), with a greater increase in serum estradiol with the 21/7 regimen (figure 2).

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Figure 1

Mean diameter of the largest follicle-like structure with 21- and 24-dayregimens. ◼, 7-day pill-free interval; ◻, 4-day placebo-pill interval; –◼–, 21-day; --○--, 24-day. Adapted from Ref,16 with permission from Elsevier.

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Figure 2

Mean serum estradiol (17β-E₂) concentration with 21- and 24-day regimens. ◼, 7-day pill-free interval; ◻, 4-day placebo-pill interval; –◼–, 21-day; --○--, 24-day. Adapted from Ref,16 with permission from Elsevier.

Similarly, in a double-blind RCT of 20 EE/3000 DRSP,17 there were two parallel treatment cycles of either a 24/4 (n=49) or a 21/7 (n=50) regimen. Ovarian activity was monitored by vaginal ultrasound scans and hormone measurements every 3 days for the duration of the study. In the second cycle, one woman in the 21/7 group ovulated following the 7-day CFI and another woman had a luteinized unruptured follicle (LUF). This was followed by a third treatment cycle for both groups, with the initial three active pills replaced by placebos. The ovarian activity scores were significantly greater in both groups. In the 21/7+3 group there were four apparently normal ovulations. Of potentially greater interest, one woman ovulated in the other group taking 24 active tablets followed by a CFI of 4+3 days. The deliberate dosing error, which only lengthened her CFI to the ‘normal’ 7 days, permitted one ovulation, just as among the 21/7 group in the earlier control cycle. Comparing 24/4 and 21/7 cycles, the researchers reported a significant 6-fold greater ovarian suppression by Hoogland scoring, with neither ovulation nor LUF, when the CFI was restricted to 4 days.

A systematic review of the effect of extending the CFI to between 8 and 14 days found wide variability in the amount of follicular development and incidence of ovulation.12 In one study of a 9-day pill-free interval, presumptive ovulation as indicated by serum progesterone levels ≥3 ng/mL occurred in 3/34 women taking 20 EE/100 LNG and in 2/35 women using triphasic 35 EE/180–250 norgestimate (NGT).18 Yet in a study of a 10-day CFI, 12/30 women taking 20 EE/150 DSG and 8/34 women in each of the 30 EE/75 GSD or phasic 30–40 EE/50–100 GSD groups developed follicles greater than 18 mm, but no normal ovulations were reported in either group after resumption of COC-taking.19

Zapata et al 12 also note that when escape ovulation has occurred, the cycles are usually abnormal. However, given individual variation in responses, as described below, risk of pregnancy cannot be excluded. While a shortened 3–4-day CFI provides greater ovarian suppression,16 20 eliminating the CFI completely is even more effective.21 22

Cervical mucus

The suggestion that the cervical mucus effect may provide adjunctive contraceptive protection following 7-day or even longer CFIs12 should be considered with caution. Although a study examining cervical mucus in 28 women throughout 7-, 9- and 11-day CFIs in four cycles reported that cervical mucus remained unfavourable to sperm penetration, the authors remark on the individual variation in response.23 A recent review found the existing evidence base to be very limited for the contribution of progestogen-affected mucus to contraceptive efficacy.24 Furthermore, any such effect of the progestogen component of COCs must be at its lowest if a fertile ovulation is pending, whether due to a true ‘pill-failure’ after a 7-day CFI or after a lengthened CFI, as it will be at least 168 hours since the progestogen was last ingested. Indeed, users of all marketed progestogen-only pills (POPs) are advised to assume loss of the contraceptive effect on their cervical mucus much earlier when a tablet is taken late.

Acceptability of continuous/extended regimens

Even in the absence of typical menstrual disorders, menstrual periods can still have an adverse effect on women’s lives. In a questionnaire study of 270 women of reproductive age, after excluding women with menstrual symptoms such as headache, dysmenorrhea, menorrhagia or premenstrual syndrome, 75.6% reported that their normal menstrual periods interfered with their sex lives, 28.8% preferred not having their period when at work and 48.4% reported that periods interfered with sport.44 Overall, 56.3% of the women stated that they would prefer amenorrhoea or reduced menstrual frequency, among whom almost three-quarters would be prepared to use medication to achieve this.

Of 220 women who selected their own regimen following trials of extended cycles, 60% continued the extended cycle for more than 2 years and 88% of 121 such women chose to use a continuous flexible regimen, Option 1 as described below.45

In a questionnaire survey of 1001 women attending family planning clinics and 290 contraceptive providers in China, South Africa, Nigeria and Scotland, only among black women in Africa did the majority ‘like’ having periods. In all other groups, most women disliked periods, which were ‘inconvenient’ and associated with menstrual problems. In all except the Chinese centres, the majority of women would be willing to try a contraceptive that induced amenorrhea.46

Option 1. Continuous flexible (or tailored) regimen

The continuous flexible regimen comprises uninterrupted daily pill-taking, with the user option of a 3–4-day pill break to manage excessive unscheduled bleeding, but always preceded by at least 7 days of pills.11 This is associated with significantly fewer annual days of bleeding than other regimens.35–37 A 20 µg EE formulation should be the first-line choice, given the lower annual hormone dose compared with formulations with 30 or 35 µg EE and a favourable bleeding profile.

Option 2. ’Tricycling' with shortened CFIs

These extended-use options of a fixed duration of pill-taking before a shortened CFI have similar potential to minimise user failures. A common version is 84/4 for women who favour quarterly withdrawal bleeds, but since in the UK COCs usually come in packs of three cycles, a satisfactory variant is 63/4. A 20 µg EE product should be first-line, taken as three or four consecutive packets, followed by a 4-day CFI.

Option 3. For women preferring monthly bleeds

Women who prefer a monthly bleed may still benefit from improved contraceptive efficacy and margin for error with the COC of their choice if their CFI is no longer than 4 days. Correct intervals between packets can now easily be achieved by using apps that permit the user to alter the number of days on which she is reminded either to take or not to take tablets. Not all apps incorporate appropriate safeguards to minimise the risks of missing a reminder.50 We recommend ’myPill Birth Control Reminder', an app that is available free on both Android and iOS platforms.