Each year, women were asked to report a list of symptoms by asking them if the following statements applied to their current situation: Have you recently gained weight? Do you often have nausea or want to vomit? Do you often have breast pain? Do you have no more or almost no more periods? Do you often have periods that last more than 1 week or breakthrough bleeding? Do you often have painful periods? Do you often have heavy periods? Do you often have swollen legs? (This last question was added only in the follow-up questionnaires from 2001 to 2004)
The response to each of these questions was used to construct eight binary variables for the analysis. Some of these symptoms (such as bleeding patterns) are clearly related to the intake of OCPs, whereas others are not (weight gain, swollen legs). However, these last symptoms may be perceived as potential OCP adverse effects in the general population and contribute to early pill discontinuation. In this study, we were interested not only in the physiological effects of the different types of OCPs but also in the women's personal experiences using these contraceptives.
We used logistic regression models to assess the odds of reporting a symptom according to the type of OCP used. Given that one woman could contribute to as many as five episodes, we introduced an intraclass correlation term at the individual level. Two series of eight models (one for each symptom) were estimated by using the first and second classification of OCPs. Each model was adjusted for the same set of potential confounders previously described in the literature and found to be associated (with P≤.20) either with the type of OCP or with the frequency of reported symptoms or both. The following confounders, measured at the time of each interview, were included in the models: age (18–24, 25–34, 35 or more years), prior pregnancy (yes/no), body mass index (less than 18.5, 18.5–25, 25 or more), marital status (married/cohabiting/single), professional activity (employed/unemployed/nonactive), level of education (less than high school graduation or high school graduation or more), income (high/medium/low), daily cigarette consumption (0, 1–9, or 10 or more cigarettes), type of regular gynecological follow-up (none/general practitioner/gynecologist), sexually transmitted infection in the last 12 months (yes/no), duration of use of the pill (less than 6 months, 7–12 months, more than 12 months), pill compliance (missed pills in the last month/no missed pills), prior change of pills because of adverse effects (yes/no), and year of interview.
Using the same methodology, we further examined the differences in the frequency of symptoms reported by third-generation compared with second-generation pill users, 20 mcg or less compared with more than 20 mcg third-generation pills, and finally triphasic compared with monophasic pill users among women using 30–40 mcg estrogen. The statistical power to detect such differences depends on the frequency of each symptom. In case of rare events, such as nausea, breakthrough bleeding, or lower frequency of menstrual periods, we were able to detect the following odds ratios (ORs) with a statistical power of 80%: OR less than 0.4 or OR greater than 2.2 in the comparison of third-generation versus second-generation pills, OR less than 0.3 or OR greater than 2.9 in the comparison of 20 mcg or less versus more than 20-mcg pills and monophasic versus triphasic pills. For more frequent events, such as heavy bleeding, painful periods, or swollen legs, these same estimations were OR less than 0.6 or OR more than 1.7 for third-generation versus second-generation pills, OR less than 0.4 or OR more than 2.2 for 20 mcg or less versus more than 20-mcg pills, and OR less than 0.5 or OR more than 2.0 for monophasic versus triphasic pills.
Statistical analyses were performed with Stata SE8 (StataCorp, College Station, TX). The study received the approval of the relevant French government oversight agency (the Commission Nationale de l'Informatique et des Libertés).
On average, each year more than half the women reported at least one symptom from the list of eight symptoms explored. The most common symptoms reported were recent weight gain (25.2%), painful periods (20.7%), swollen legs (20.9%), and heavy menstrual bleeding (15.6%) (Table 3). Painful menstrual periods and breakthrough bleeding or menorrhagia were more frequently reported at the start of pill use (1 year or less) than for longer durations of use (Table 3).
The reporting of several symptoms varied by pill composition. According to the first pill classification (by generation of progestin and estrogen dosage for third-generation pills (Table 4), women using progestin-only pills were more likely than others to report irregular menstrual bleeding (breakthrough bleeding, amenorrhea or reduced frequency of menstrual periods). Likewise, women using an extended regimen of a third-generation pill containing very low estrogen dosage (15 mcg) were more likely than women using pills with higher estrogen dosage to report a reduced frequency of menstrual bleeding. The odds of reporting breakthrough bleeding or heavy menstrual periods were lower among first-generation pill users compared with second-generation pill users. After excluding the 61 women using 50 mcg estrogen pills from the analysis, results remain unchanged with the exception of the effect of first-generation pill use on the frequency of breakthrough bleeding that was no longer significant (OR 0.3, 95% confidence interval [CI] 0.1–1.1], P=.06).
When comparing second and third-generation pill users, we found only one significant difference: a lower frequency of menstrual periods was more likely to be reported by third-generation pill users than second-generation pill users (OR 2.3, 95% CI 1.3–4.1, P=.003). Moreover, a subanalysis among women using the same dosage of estrogen (30 mcg) in which we distinguished the type of third-generation progestin (desogestrel or gestodene) found few differences between groups. Thirty-microgram gestodene pill users were less likely than 30-mcg levonorgestrel pill users to report pain during menstrual periods (OR 0.4, 95% CI 0.1–1.0, P=.04), 30-mcg desogestrel pill users were less likely than 30-mcg levonorgestrel pill users to report a reduction in the frequency of menstrual periods (OR 0.2, 95% CI 0.03–0.6, P=.01), and conversely, more likely to report breast pain (OR 2.5, 95% CI 1.1–5.7, P=.02).
Finally, our analysis shows only one significant difference in the frequency of symptoms with a decrease in the dosage of estrogen for third-generation pill users: 20-mcg or less pills were associated with a lower frequency of menstrual periods compared with higher dosage pills (OR 5.2, 95% CI 2.3–11.4, P<.001).
Despite a smaller sample size (1,173 episodes [32.8% of all episodes] had a duration of use of 1 year or less), we found greater differences in the reporting of symptoms by pill composition for the first year of use than for longer durations of use. Thus, in addition to the differences described above (with the exception of the association between first-generation pill use and breakthrough bleeding, which was no longer significant), recent first-generation pill users were more likely than second-generation pill users to report a decrease in the frequency of menstrual periods (OR 5.1, 95% CI 1.5–16.7) or having swollen legs (OR 7.4, 95% CI 1.7–32.7), and conversely, less likely to report experiencing pain during menstrual periods (OR 0.1, 95% CI 0.01–0.6). In addition, the use of third-generation pills containing 20 mcg estrogen was associated with a higher frequency of nausea (OR 3.6, 95% CI 1.2–10.8) and the use of macro-progestin pills (Luthenyl or Lutheran, Tables 1 and 2) with a lower frequency of breast pain (OR 0.3, 95% CI 0.1–1.0) compared with second-generation pill use.
Using the second classification, by dosage of estrogen and sequence of administration (monophasic, biphasic, or triphasic pills) (Table 5), results from the multivariate analysis show the same effect of low-dose estrogen pills (15 mcg) or progestin-only pills on the reporting of irregular menstrual periods described above. In contrast, women using the highest dosage of estrogen pills (50 mcg) were less likely to report breakthrough bleeding. They were also less likely to report breast pain. In addition, results indicate a higher tendency to report heavy menstrual bleeding among progestin-only minipill users (P=.06) and a lower likelihood of reporting pain during menstrual periods among women using triphasic 30–40 mcg estrogen pills, compared with users of 30–35 mcg estrogen monophasic pills.
Similar differences were found among recent progestin-only pill users and women using low-dose 15 mcg estrogen pills, with the exception that heavy menstrual bleeding was no longer associated with recent use of progestin-only minipills. Likewise, the associations described above for recent 50 mcg estrogen pill users (which only accounted for 18 episodes) and the lower frequency of pain during menstrual periods among triphasic pills users were no longer significant. Conversely, additional differences were found among recent 20 mcg estrogen pill users who were more likely than 30–35 mcg estrogen monophasic pills users to report nausea (OR 4.3, 95% CI 1.4–12.9) and recent weight gain (OR 1.8, 95% CI 1.0–3.0). This association was also found among recent progestin-only minipill users (OR 2.4, 95% CI 1.0–5.7). Thus, with the exception of the lower frequency of pain during menstrual periods, we found no difference in the reporting of symptoms according to the sequence of administration (monophasic, biphasic, or triphasic) among women using 30–40 mcg estrogen pills, who account for 71% of the sample. When we restricted this analysis to women using the same generation of progestin (monophasic versus triphasic third-generation 30–40 mcg estrogen pills), no differences remain (results not shown).
The change of OCP because of adverse effects was only available in the follow-up interviews (2001–2004). In these 4 last years, we found that 10.7% of OCP episodes were preceded by a change in OCP because of adverse effects in the last 12 months. When we restrict the multivariate analysis to the OCP episodes collected at follow-up interviews, we found no effect of the change of OCP because of adverse effects on the frequency of reported symptoms. Likewise, this variable had no effect on the reporting of symptoms among recent OCP episodes, with the exception of nausea, more frequently reported in case of a change of pill because of adverse effects in the preceding year.
This study shows that some symptoms are frequently reported by OCP users: one fourth reported recent weight gain (25.2%), one fifth reported painful periods (20.7%) or swollen legs (20.9%), and one sixth (15.6%) experienced heavy menstrual bleeding. As is commonly described, recent OCP users were significantly more likely to report breakthrough bleeding than long-term OCP users. They were also more likely to report pain during their menstrual cycle. This decrease in the reporting of menstrual symptoms by duration of use may reflect a physiological adaptation to the hormonal regimen and/or the selection of women who experience the least symptoms over time. The frequency of other symptoms did not vary by duration of OCP use.
The questions on perceived symptoms were not specifically related to the use of OCPs. Thus, these results should not be interpreted as a measure of the prevalence of OCP adverse effects. However, they do capture the differences in the frequency of perceived symptoms according to the type of OCP used, after controlling for a large number of potential confounders. One limitation of this comparison is the statistical power of the analysis, which is generally low in the case of rare events (nausea, breakthrough bleeding, or lower frequency of menstrual periods). This is particularly acute in the analysis of different estrogen dosages in third-generation pills.
Nevertheless, our study shows some variation in the symptoms reported among a wide variety of types of OCPs. Our results confirm those of previous clinical trials showing an increase the likelihood of abnormal bleeding patterns among progestin-only pill users,8 which persists over time. Although these bleeding irregularities do not threaten health, they are the most common reported reason for discontinuation, thus relegating these pills to a second-line contraceptive option.3
Our analysis shows a reduction in the frequency of menstrual periods among women using extended or continuous regimens (which also happen to be those who use progestin-only or very low-dose estrogen pills), compared with classic cyclic regimens. These findings add to the growing body of literature on continuous OCP regimens that are gaining wider popularity in developed countries as a means to avoid menstruation for medical or personal reasons.9,10,11 Further contraceptive benefits of continuous administration on menstruation-related symptoms (nausea and breast tenderness), discussed in a recent review of the literature,11 could not be examined in our study because the only extended pill regimens available in our survey have lower estrogen dosage than do the cyclic pills. Other variations in the sequence of administration of OCPs (monophasic or triphasic) had little impact on the frequency of symptoms reported. Thus, consistent with the conclusion of a recent Cochrane review,12 our results offer no evidence of an improvement in the bleeding patterns of women using triphasic pills compared with those of monophasic pill users.
We further found no evidence to suggest a decrease in the reporting of symptoms with decreasing estrogen dosages in women using combined OCPs. Comparing 20 mcg or less pills with higher estrogen dosage third-generation pills, we found only an increase in the reporting of lower frequency of periods among women using the lowest estrogen pill regimens. Although insufficient statistical power may affect these conclusions, they are nevertheless consistent with the conclusions of another recent review of the literature comparing 20 mcg or less pills with higher estrogen dosage pills.4 In France, as in many other industrialized countries, third-generation pills are increasingly favored over second-generation pills13 on the basis of the two following arguments: the reduction in the risk of estrogen adverse events (although 40% of third-generation pills prescribed in France carry the same dose of estrogens as in second-generation pills) and the improvement of progestogenic and androgenic proprieties theoretically resulting in better tolerance. Our findings cast doubt on this second hypothesis because we found no decrease in the frequency of reported symptoms between third- and second-generation pills in general and very few differences if we select only women using the same estrogen dosage and distinguish the type of progestin component in third-generation pills.
In our survey, menstrual nuisances such as painful or heavy periods were not uncommon, even among long-term third-generation pill users (14.6% reported heavy bleeding, 17.6% painful periods, and 7.8% lower frequency of periods after 1 year of method use). However, unlike in randomized trials, we cannot rule out the possibility of selective prescribing in our study. Indeed, because third-generation pills are promoted as being better-tolerated than second-generation pills, women who experience the most hormone-related symptoms may be more likely to be prescribed a third-generation OCP in the first place or to switch from second- to third-generation because of effects.14 This later selection is partially mitigated in our analysis by controlling for a change of pill because of adverse effects in the year preceding the interview. That change had no effect on the frequency of reported symptoms in the multivariate models, which suggests that the overall selection bias due to OCP switching is limited in our survey. Nonetheless, the Cocon survey, based on women's reports, cannot capture the reasoning that governs the type of OCP prescribed, and future research should also focus on physicians' prescribing attitudes. The absence of an overall improvement in the reporting of symptoms between second- and third-generation pill users is consistent with the conclusions of the recent Cochrane review, which indicated similar acceptability, reasons for discontinuation, and overall adverse effects between second- and third-generation pills, which were both preferred to first-generation pills. In one of the trials included in this review, however, fewer women reported intermenstrual bleeding when using gestodene compared with levonorgestrel.15 We found no such association in our survey, but found that women using 30 mcg gestodene pills reported less pain during their menstrual period than women using 30 mcg levonorgestrel pills. As highlighted in the conclusion of the Cochrane review, future research should focus on well-designed randomized trials to further our understanding of the independent effect of the type of progestin on OCP tolerance. Such an understanding of an effect, if any, of the combination of estrogen dosage, progestin component, and sequence of administration is essential to guide physicians' choice of the type of OCPs that best suits a woman's needs. However, beyond the choice of the right OCP formulation that theoretically decreases the likelihood of very rare and severe medical outcomes associated with low-dose estrogen pills, providers should also recognize the importance of counseling about OCP-related symptoms. A recent study among women using implants showed that those who anticipated possible adverse effects reported lesser bleeding irregularities than those who had not been counseled.16 Likewise, in a prospective study among 943 new OCP users in the United States, Rosenberg and colleagues17 found an association between the degree of satisfaction with the pill and higher ratings of patient-provider interaction.
In the absence of sufficient evidence-based data to support the existence of differences in the tolerance profile of low-dose combined pills currently available, future well-designed randomized trials are needed to guide providers in their choice of OCPs. Research is also needed to assess the effectiveness of counseling on the tolerance of OCPs, an intervention that may prove to be more rewarding than basing the choice of OCPs on their theoretical properties.
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