Because of their high efficacy, there is a perception by some women that the use of oral contraceptives may be associated with an impairment in fertility after their discontinuation.1 Some studies have shown an initial (but temporary) delay in conception in the first few months after oral-contraceptive cessation.2–6 Within these studies, a number of characteristics were demonstrated to affect the fertility of the participants, including age and parity.3,4,6–8
Over the past 25 years, oral contraceptives have been modified to improve their safety and tolerability without compromising efficacy. Ongoing research has produced varying regimens, lower doses of each hormonal component, and new progestins. Drospirenone 3 mg/ethinylestradiol 30 micrograms (Yasmin, Bayer HealthCare Pharmaceuticals, Wayne, NJ) is a modern, low-estrogen-dose oral contraceptive that provides effective contraceptive protection, excellent cycle control, and good tolerability.9–12 Although it has been well-established that drospirenone 3 mg/ethinylestradiol 30 micrograms is both efficacious and well-tolerated, it is also important to confirm that this preparation does not have a detrimental effect on short-term and long-term fertility.
The European Active Surveillance Study on Oral Contraceptives (EURAS-OC) was designed to compare the short-term and long-term risks of both drospirenone-containing and other progestin-containing oral contraceptives marketed in Europe. In a planned secondary analysis, the effect of oral-contraceptive use on measures of fecundity in women enrolled in EURAS-OC who stopped using oral contraceptives with the intention of becoming pregnant was investigated. The purpose of the analysis was to determine whether prior oral-contraceptive use had a negative effect on the ability of women to conceive in both the short-term and long-term.
MATERIALS AND METHODS
EURAS-OC was a large-scale, prospective, active surveillance study designed to characterize and compare the short-term and long-term risks of both drospirenone-containing and other progestin-containing oral contraceptives marketed in Europe. The study was sponsored by the manufacturer of drospirenone 3 mg/ethinylestradiol 30 micrograms as a Phase IV commitment to European Health Authorities. The study was conducted by the independent academic research institute Berlin Center for Epidemiology and Health Research and was overseen by an independent data safety monitoring board. The protocol and primary endpoints of EURAS-OC, which was conducted between 2000 and 2005, have been published previously.13 In brief, the main clinical outcome of interest was the occurrence of cardiovascular events, including venous thromboembolism, myocardial infarction, stroke, arrhythmia, and sudden death. Secondary a priori defined outcomes included contraceptive failure (despite oral-contraceptive use) and return to fertility in women who stopped using oral contraceptives with the intention of becoming pregnant. A sample size of 50,000 women (with a total oral contraceptive exposure of 100,000 woman-years) was considered sufficient to test the noninferiority of drospirenone-containing oral contraceptives compared with levonorgestrel-containing oral contraceptives in terms of the risk of venous thromboembolism.
Enrolment in the EURAS-OC study began in January 2001 and ended on June 30, 2004. Recruitment occurred via a network of 1,113 existing medical practices in seven European countries (Austria, Belgium, Denmark, France, Germany, the Netherlands, and the United Kingdom). For the most part, participating physicians were gynecologists in private practice; in the United Kingdom and the Netherlands, physicians were general practitioners. The study was not conducted in fertility centers.
Within the study centers involved, all women who requested and received prescriptions for a new oral contraceptive were asked by their physicians whether they were willing to participate in the study (after a prescribing decision had been made). All physicians were required to explain the nature and purpose of the study to potential participants. Women were to be given ample opportunity to ask questions and were informed that they could withdraw from the study at any time without disadvantage and without the need to provide a reason. This information was provided on an informed-consent and data-privacy form, which all women were required to complete before entry into the study. The majority of women provided written informed consent at the physician's office; fewer than 2% of women completed the consent form at home. The study was approved by the Berlin Medical Board Ethics Commission.
The study population of EURAS-OC included both first-ever users of any oral contraceptive and switchers to a new oral contraceptive. The decision to include women who used any type of oral contraceptive was made to avoid physicians' prescribing behavior being affected by study participation. More specific inclusion and exclusion criteria were not applied owing to the noninterventional nature of the study.
To gather baseline data, enrolled women were asked to complete a questionnaire about their state of health and potential risk factors. More than 98% of participants completed the baseline questionnaire (after informed consent had been provided) in the physician's office. In addition, a full medical history, including details of medication and prior oral-contraceptive use, was taken for each participant. Each participant's contact details also were recorded, as were the contact details of relatives, friends, and their gynecologist/primary care physician (who could act as back-up contacts).
Follow-up questionnaires were completed by study participants every 6 months for a period of up to 5 years. Follow-up questionnaires documented the occurrence of adverse events and the reasons for oral-contraceptive cessation or a switch to another oral contraceptive, if applicable. The questionnaires did not collect information on the frequency of intercourse. All questionnaires were reviewed for completeness and plausibility/consistency; in the case of missing or inconsistent information, women were contacted directly by phone.
To ensure that all participants were followed continuously and that all data were collected, a four-level follow-up procedure was adopted. At the first level, when mailed questionnaires were not returned, two reminder letters were sent. Level 2 involved making multiple attempts to contact the participants and their relatives, friends, and their gynecologists/primary care physicians. If level 2 was unsuccessful, searches in national and international telephone and address directories were initiated (level 3). Finally, an official address search via governmental administrations was conducted (level 4). The rigorous follow-up procedure was undertaken in an attempt to minimize under-reporting of outcomes of interest.
During the course of the study, some participants switched to other oral contraceptives, switched to a nonhormonal form of contraception, or stopped using contraception altogether (either temporarily or permanently). However, all women participating in EURAS-OC, including those who stopped using oral contraceptives for any reason or who stopped using oral contraceptives because of pregnancy, were monitored until the end of the follow-up period (December 2005) unless they withdrew their informed consent.
The current analysis assessed measures of fecundity in those women who stopped using oral contraceptives with the intention of becoming pregnant while enrolled in EURAS-OC. Women included in the current analysis were monitored for at least 2 years after oral-contraceptive cessation. Primary outcomes included the rate of pregnancy and the time to pregnancy.
Pregnancy was confirmed using diagnostic procedures used in clinical practice, ie, in most cases, pregnancy was diagnosed by participating women at home using urine β-hCG tests. This was followed by a second diagnostic step of an ultrasound examination, allowing a precise calculation of the date of conception (±3–4 days in the majority of cases). If no ultrasound examination was available, the date of the birth of the child was used to calculate the date of conception. A diagnosis of pregnancy was made and the date of conception was calculated in the first trimester in more than 90% of women. The time to pregnancy calculation (the date of conception minus the last day of oral-contraceptive use) was undertaken by a member of the investigator team.
Owing to the nature of the current analysis, it was not possible to control the size of the sample. That is, women were included only if they stopped using oral contraceptives while enrolled in EURAS-OC because of planned pregnancy, and a woman's decision to do this was not in the control of the investigators. However, a post hoc analysis showed that pregnancy rates 1, 13, and 26 cycles after stopping oral-contraceptive use could be calculated with a high precision; 95% upper and lower confidence limits were approximately ±2 and ±4 percentage points of the point estimate for the complete cohort and subcohorts, respectively. Furthermore, the statistical power to detect a difference of approximately 10 percentage points between drospirenone-containing and levonorgestrel-containing oral contraceptives 13 and 26 cycles after stopping oral-contraceptive use was 95%. Therefore, it can be assumed that the sample size was sufficient to detect relevant differences between treatments.
The influences of age, parity, progestin type, ethinylestradiol dose, duration of oral-contraceptive use, and smoking status on the rate of pregnancy were investigated. Stratified analyses were performed for these individual factors as follows: age—younger than 25, 25–29, 30–34 and 35 years and older; ethinylestradiol dose—30 micrograms and 20 micrograms; parity—nulliparous and parous women; progestin type—drospirenone, levonorgestrel, and other; duration of use—24 months or less and more than 24 months; and smoking status—current smokers compared with current nonsmokers (ex-smokers or never smokers). Most statistical analyses are presented descriptively.
In addition, survival analyses using Cox regression models were applied to assess the effect of age, parity, progestin type, ethinylestradiol dose, duration of oral-contraceptive use, and smoking status. Each of the mentioned factors was included in the statistical model. Age and duration of oral-contraceptive use were considered continuous variables, and parity, progestin type, ethinylestradiol dose, and smoking status were considered discrete variables. Unadjusted and adjusted hazard ratios, 95% confidence intervals (CIs), and P-values were calculated.
Overall, 59,510 women were enrolled in EURAS-OC. A total of 836 women were excluded because of protocol violations, resulting in 58,674 women being followed-up for 142,475 women-years of observation. The maximum individual duration of follow-up was up to 5 years (mean 2.4 years). The number of women lost to follow-up was 1,401 (2.4%).
A total of 2,064 women (3.5%) participating in EURAS-OC explicitly stated that they had stopped oral-contraceptive use because of planned pregnancy and were included in the current analysis. The maximum individual duration of follow-up for these women was 5 years (mean 2.8±0.8 years). Before the discontinuation of oral-contraceptive use, 509 women had received drospirenone-containing oral contraceptives, 529 had received levonorgestrel-containing oral contraceptives, and 1,026 had received oral contraceptives containing other types of progestin. Other types of progestins included (in alphabetical order) chlormadinone acetate, cyproterone acetate, desogestrel, dienogest, gestodene, norethisterone, and norgestimate.
The demographic characteristics of all women included in the current analysis (at the time that oral-contraceptive use was stopped) and of all women enrolled in EURAS-OC are presented in Table 1. The mean age of women in the current analysis was 28.1 years (compared with a mean age of 25.2 years in the overall study).13 The mean number of years of education for women in the current analysis was 12.8 years. The loss-to-follow-up rate in the current analysis was low—the number of women who were lost to follow-up was 14 (0.7%).
Overall, 21.1% (95% CI 19.4–23.0%) of the past oral-contraceptive users analyzed were pregnant one cycle after stopping oral-contraceptive use. After three cycles, the rate of pregnancy had increased to 45.7% (95% CI 43.6–47.9%) (Fig. 1). One year (13 cycles) after stopping oral-contraceptive use, the overall rate of pregnancy was 79.4% (95% CI 77.6–81.1%) (Fig. 1). Approximately 45% of women who did not become pregnant in the first year after oral contraceptive discontinuation did so in the second year; 2 years (26 cycles) after stopping oral-contraceptive use, the overall rate of pregnancy was 88.3% (95% CI 86.8–89.6%) (Fig. 1). The median time to pregnancy in those women who did become pregnant was three cycles (mean 5.5 cycles).
The effect of age on the rate of pregnancy after stopping oral-contraceptive use is shown in Figure 2. Up to the age of 35 years, age had only a minor (although statistically significant) influence on the rate of pregnancy (P<.01). The adjusted hazard ratio for women up to the age of 25 years compared with women aged 25–34 years was 1.2 (95% CI 1.1–1.4). However, as expected, women older than 35 years had a notably lower rate of pregnancy than did younger women (adjusted hazard ratio 0.5, 95% CI 0.3–0.7, P<.001).
The rate of pregnancy was lower in nulliparous women than in parous women in the initial months after oral-contraceptive cessation but was almost identical after 1 year (Fig. 3). However, parous women were older than nulliparous women. After adjustment for age, the pregnancy rate was found to be statistically significantly higher in parous women (hazard ratio 1.4, 95% CI 1.2–1.6, P<.001).
The type of progestin received had no major effect on the rate of pregnancy after oral-contraceptive cessation, and women who received drospirenone-containing oral contraceptives had a rate of pregnancy that was similar to that in women who received oral contraceptives containing levonorgestrel and oral contraceptives containing other progestins (Fig. 4). The adjusted hazard ratio for drospirenone-containing compared with levonorgestrel-containing oral contraceptives was 0.9 (95% CI 0.8–1.1).
A comparison of the rate of pregnancy in women who received oral contraceptives containing ethinylestradiol 20 micrograms and 30 micrograms did not show a statistically significant difference (adjusted hazard ratio 1.1, 95% CI 0.9–1.2).
The duration of oral-contraceptive use had no major effect on the rate of pregnancy after oral-contraceptive cessation. The rate of pregnancy after one cycle was 25.0% (95% CI 16.9–34.7%) in women who had used oral contraceptives for 24 months or less, compared with 20.7% (95% CI 18.4–23.2%) in women who had used oral contraceptives for more than 24 months. The corresponding rates after 1 year were 81.0% (95% CI 71.9–88.2%) and 79.3% (95% CI 76.8–81.6%). Women who had used oral contraceptives for 24 months or less were, on average, 3 years younger than women who had used oral contraceptives for more than 24 months (26.7 compared with 29.6 years). Of those women who had used oral contraceptives for 24 months or less and for more than 24 months, 8.1% and 3.3%, respectively, were 35 years or older. Cox regression analyses yielded an adjusted hazard ratio of 1.0 (95% CI 0.9–1.1).
Current smokers had a statistically significantly lower rate of pregnancy compared with nonsmokers (age-adjusted hazard ratio 0.8, 95% CI 0.7–0.9, P=.015).
The results of the current analysis show that prior oral-contraceptive use does not have a negative effect on the ability of women to conceive in both the short-term and long-term. Parity, the type of progestin used, and the duration of oral-contraceptive use have no major influence on fecundity after stopping oral-contraceptive use. Up to age 35 years, age had only a minor influence on the rate of pregnancy; however, rates of pregnancy were reduced in women older than 35 years.
The rates of pregnancy described here are within the ranges of those described in studies exploring rates of conception in couples who used natural family planning methods in an attempt to become pregnant14,15 and who, for the most part, had not stopped oral-contraceptive use immediately before trying to conceive.15,16 In a study by Dunson et al,14 the cumulative probability of conception after one and three cycles was comparable with that in the current analysis. Similarly, the number of women who were unable to conceive was comparable, as was the proportion of women not conceiving in the first year who did in the second year. In a study by Gnoth et al,15 the proportion of women who did not conceive was not greatly influenced by age up to age 35 years; however, women aged 35 years had a notably lower rate of pregnancy than did younger women. This observation also was seen in the current analysis, which suggests that, up to age 35 years, age has only a minor influence on fertility and, more importantly, any negative effect of aging on a woman's ability to conceive is not exacerbated by previous oral-contraceptive use. The findings of Dunson et al also show that any differences in the rates of conception in our analysis and in studies that employed natural family planning techniques may arise from the fact that fertility was not optimized in the current analysis. In addition, it was not known how often women were having intercourse in the current analysis, which is known to have a significant effect on the rate of conception.14
The findings of the current analysis have important implications for clinical practice. Firstly, a substantial proportion of women not conceiving in the first year did so in the second year, which highlights the need for counseling to reassure women that they may not necessarily have fertility problems if they have not conceived within the first year after cessation of oral contraceptives. Secondly, the duration of use of oral contraceptives had no major effect on fertility, which is in agreement with other studies that have shown no reduction (or indeed an increase) in the rate of conception with an increasing duration of past oral-contraceptive use.17,18 Although women in the current analysis using oral contraceptives for a longer duration had a slightly lower rate of pregnancy than did women using oral contraceptives for a shorter period of time, this was a result of the effect of age, as shown by the Cox regression analysis. Thus, it is important to counsel women that aging, but not long-term oral-contraceptive use, can impinge on their ability to become pregnant. This is particularly important because many women delay motherhood until their late 30s, and prolonged use of oral contraceptives until this age may be an unnecessary worry to some women. Related to this, many women incorrectly believe that a periodic temporary discontinuation of hormonal contraceptives is required to preserve fertility.19 As a result of this misperception, some women may temporarily discontinue using oral contraceptives on the assumption that they will not need an alternative form of contraception and are subsequently at risk for an unintended pregnancy. In being made aware that 1) prolonged oral-contraceptive use will not have a long-term detrimental effect on their fertility and that 2) rapid conception after oral-contraceptive cessation is possible, women also should be advised on the immediate need for adequate prenatal care, (ie, the need for optimal periconceptional levels of folate to reduce the risk of neural tube defects).
The current analysis showed that nulliparous women had a lower rate of pregnancy than did parous women, which is consistent with previous study data.4,6,7 This observation is consistent with the finding that parous women have already “proven” their fertility whereas nulliparous women have not, meaning that, within any group of nulliparous women, there inevitably will be some women who are infertile (or women with partners who are infertile) whose inclusion in the group will reduce the relative rate of fertility.
Our data showed that the progestin type had no major effect on the rate of pregnancy over the short-term and long-term. The results of this analysis specifically confirm that drospirenone 3 mg/ethinylestradiol 30 micrograms does not have a beneficial or a detrimental effect on long-term fertility. Previous data suggest that the dose of estrogen used may affect conception rates after oral-contraceptive cessation, with women discontinuing oral contraceptives with higher doses of estrogen (50 micrograms or more) having a greater delay in conception than women discontinuing oral contraceptives with lower doses of estrogen (less than 50 micrograms).6 Nowadays, the use of preparations containing ethinylestradiol 50 micrograms is uncommon; therefore, a similar comparison could not be done. However, a comparison of preparations containing ethinylestradiol 20 micrograms and 30 micrograms demonstrated that the rate of pregnancy was not affected by the dose of ethinylestradiol (20 micrograms compared with 30 micrograms). Finally, the well-known negative effects of smoking on fertility20 were confirmed in this analysis.
The results of the current analysis appear to contradict several studies that have reported an initial (but temporary) delay in fertility after discontinuation of oral contraceptives.1–6,18,21 It is possible that such delays may be unrelated to oral-contraceptive use. Many young women who experience cycle irregularities often are prescribed oral contraceptives, and these irregularities may recur after their discontinuation. In addition, in any study exploring rates of fertility in women, there always will be some women who will not conceive regardless of their history of contraceptive use.
Limitations of the current analysis include an absence of information on the frequency of intercourse and on the male partner. Also, because of the design of EURAS-OC, although the reasons for failure to become pregnant were available for many women who did not become pregnant despite their intention to do so, these were not systemically captured for all such women.
The results of this analysis provide precise information on the overall rates of pregnancy and time to pregnancy in women who previously have used oral contraceptives and discontinue them because of planned pregnancy. The findings suggest that previous oral-contraceptive use does not negatively affect the rate of pregnancy or the time to pregnancy. Moreover, a comparison of data in the current analysis with historical data shows that the negative effect of aging on the ability to become pregnant is not augmented by previous oral-contraceptive use. Finally, the type of progestin received, parity, and duration of past oral-contraceptive use do not have a major influence on the ability of previous oral-contraceptive users to become pregnant.
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