Bleeding patterns after use of levonorgestrel emergency contraceptive pills

Contraception 73 (2006) 376 – 381

Original research article

Bleeding patterns after use of levonorgestrel emergency contraceptive pills Elizabeth G. Raymonda,*, Alisa Goldbergb, James Trussellc, Melissa Haysa, Elizabeth Roachb, Douglas Taylora a

Family Health International, PO Box 13950, Research Triangle Park, NC 27709, USA b Planned Parenthood League of Massachusetts, Boston, MA, USA c Office of Population Research, Princeton University, Princeton, NJ, USA Received 6 July 2005; revised 12 October 2005; accepted 17 October 2005

Abstract Objective: The objective of this study was to describe bleeding after use of an emergency contraceptive pill (ECP) regimen consisting of 1.5 mg of levonorgestrel in a single dose. Methods: We asked 120 women who had been treated with the regimen to keep daily bleeding diaries for 9 weeks. We compared bleeding patterns observed after treatment with usual patterns reported by the participants and with patterns observed in a prior study on women who had not taken ECPs. Results: Treatment in the first 3 weeks of the menstrual cycle significantly shortened that cycle as compared both with the usual cycle length and with the cycle duration in a comparison group. The magnitude of this effect was greater the earlier the pills were taken. In contrast, the duration of the first menstrual period after treatment increased significantly with cycle week of treatment and was longer in women who used the treatment than in those who did not. Intermenstrual bleeding occurred in only 5% of women in the first cycle after treatment. Conclusions: The effect of the single-dose levonorgestrel ECP regimen on the timing and duration of the next menstrual period depends on when during the cycle the pills are taken. Intermenstrual bleeding following treatment is uncommon. D 2006 Elsevier Inc. All rights reserved. Keywords: Emergency contraceptive pills; Vaginal bleeding; Menses; Levonorgestrel

1. Introduction Accurate information about the effect of emergency contraceptive pills (ECPs) on vaginal bleeding is important both for counseling of women considering the use of the method and for evaluation of events that occur after use. To date, findings from clinical studies have been inconsistent (Table 1) [1 – 8]. No prior study was designed specifically to study bleeding after treatment, and the methods for collecting and analyzing data are varied. Furthermore, no study had assessed bleeding patterns after the first posttreatment menstrual period. Anecdotal evidence from women submitting questions to the national emergency contraception website not-2-late.com [9] suggests that treatment may have prolonged effects. Finally, no study to date has included a comparison group of women who did 4 Corresponding author. Tel.: +1 919 405 1460; fax: +1 208 275 6440. E-mail address: [email protected] (E.G. Raymond). 0010-7824/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2005.10.006

not use ECPs. Because bleeding abnormalities, particularly unexpected changes in cycle length, are fairly common among untreated women [10], the lack of a comparison group compromises assessment of the degree to which any apparent irregularities are a result of ECPs. We designed a case-series study to characterize bleeding patterns prospectively for 9 weeks after use of an ECP regimen containing 1.5 mg of levonorgestrel as a single dose. This regimen differs from the regimen approved by the Food and Drug Administration in 1999 (i.e., 0.75 mg of levonorgestrel, followed by an identical second dose 12 h later). However, the single-dose regimen is supported by research that were published since the FDA approval [1,2] and is currently the regimen primarily recommended by the International Consortium for Emergency Contraception [11]. We compared the bleeding patterns observed among women in our study with patterns observed in a subset of participants in a recent large randomized trial of spermicide

E.G. Raymond et al. / Contraception 73 (2006) 376 –381

377

Table 1 Previous studies with data on bleeding patterns after use of levonorgestrel ECPs No. of given ECPsa

One dose (1.5 mg of levonorgestrel) von Hertzen et al. [1] 1379 Arowojolu et al. [2] and 600 Arowojolu and Okewole [3] Two doses (0.75 mg of levonorgestrel, repeated in 12 h) von Hertzen et al. [1] 1377 Arowojolu et al. [2] and 560 Arowojolu and Okewole [3] Ngai et al. [4] 1027 Hamoda et al. [5] 1035 Raymond et al. [6] 540 WHO Task Force on 1001 Postovulatory Methods of Fertility Regulation [7] Ho and Kwan [8] 440 a

Timing of next period as compared with expected z 8 days early

z 4 days early

z 4 days late

z 8days late

Intermenstrual bleeding

~10% 20%

~ 29% 34%

~15% 30%

5% 20%

N 17% 37%

~13% 30%

~ 31% 45%

~16%

5% 15%

N 16%

~ 20%

~ 40% V 22% 27% ~15%

~ 18% V 8% 32% ~ 28%

6%

41%

15%

18%

19% ~ 13%

6% b 14% 3%

In each study, subsets of these women were included in the bleeding analyses.

effectiveness [12]. The women in both trials maintained daily bleeding diaries throughout the studies. 2. Materials and methods The ECP study was conducted at a Planned Parenthood clinic in Boston between June 2004 and March 2005. The study was approved by the institutional review board of Family Health International. To be eligible for the study, a woman had to meet the following criteria: she was aged between 18 and 35 years; she had taken ECPs (1.5 mg of levonorgestrel) on the day of enrollment or the previous day; she reported a usual menstrual cycle length of 23–32 days and a usual menstrual period duration of 3–7 days; the number of days since her last period did not exceed her usual cycle length; she had no history of intermenstrual bleeding within the past year not due to hormonal contraception; she had no bleeding on the day she took the ECPs before taking them; she had no history of medical conditions within the past year that might affect bleeding patterns (including recent pregnancy or breast-feeding); she had not recently used any drug or device (including contraceptives) that might affect bleeding; and she did not plan to use any such drug or device within the next 2 months. After each volunteer signed a written informed consent form, we interviewed her to assess eligibility and to obtain baseline demographic, medical, menstrual and other relevant information. We gave her paper diaries on which to record each day through the Saturday of the 10th week after she took the pills whether she had any vaginal bleeding and whether she considered such bleeding to be part of a menstrual period. We scheduled follow-up contacts at 4 and 9 weeks after admission to obtain further information about bleeding patterns, medical conditions, medication use, occurrence of pregnancy and other relevant history. When clinically appropriate, we

recommended pregnancy tests to women who had abnormal bleeding patterns. The comparison study had been described in detail elsewhere [12]. From the 1536 women enrolled in that trial, we selected a subpopulation who would have met the enrollment criteria for the ECP trial, except that we could assess medical conditions only for the 6 months prior to admission and use of noncontraceptive drugs only at the time of admission and we had no data on intermenstrual bleeding prior to admission or on usual duration of menses. We excluded women who had ever used ECPs before admission to the comparison study from our analysis population. All women in the comparison study kept daily bleeding diaries and provided detailed information about medical conditions, use of medications (including contraceptives) and pregnancies occurring after admission. The primary analysis population from each study consisted of all women who provided any menstrual diary data after admission. We included in the analysis each participant’s data from the day of ECP ingestion (for the ECP study population) or study admission (for the comparison study population) to the first of the following days: the last day she provided diary information, the day before she initiated use of any drug or device or developed any medical condition that could have affected bleeding patterns, the day before the estimated fertilization date of a pregnancy and Day 70 after ECP use (for the ECP study population) or admission (for the comparison study population). After applying these rules, if the diary showed bleeding on the last 1 or 2 days preceded by at least 2 days without bleeding, we excluded the terminal bleeding days from the analysis. We defined a follow-up menstrual period as any episode of at least 3 days of bleeding (either consecutive or separated only by 1 bleeding-free day) preceded by at least 2 days without bleeding. A complete menstrual period was one followed by at least 2 nonbleeding days. We defined a cycle as the interval from the onset of a

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menstrual period to the day before the onset of the next period (a complete cycle) or to the last day included in the analysis (an incomplete cycle). The first cycle began at the onset of the last menstrual period reported by the participant before admission. The second cycle began at the onset of the first follow-up menstrual period. We calculated the expected date of onset of each subsequent cycle by adding the usual cycle length reported at admission to the date of onset of the previous cycle. We defined intermenstrual bleeding as any bleeding not part of a menstrual period; by definition, each intermenstrual bleeding episode lasted only 1 or 2 consecutive days. We calculated the fertilization dates of pregnancies as 38 weeks before the estimated date of confinement as determined by first-trimester ultrasound. The analyses were entirely descriptive and exploratory. To compare the duration of cycle lengths and period lengths, we fit a series of generalized linear models to observed (log transformed) cycle length data. These models incorporated effects for usual cycle length (expressed as three groups: 23–25, 26–28 and 29–33 days), which was suspected to be related to future cycle length. These models allowed the variability of responses to differ between the two groups. In analyses of the first cycle, we also controlled for week of entry into the analysis to account for the inherent minimum limit on the duration of that cycle. Using the same modeling approach but without transforming the outcome, we compared the difference between usual and observed cycle lengths in the two studies, the incidence of intermenstrual bleeding and the incidence of bleeding in the first week of follow-up. In addition, for each group, we compared the first with the second cycle length, the first with the second period length and the difference from expected period length in the first and second cycles (for the ECP group only) using a similar generalized linear modeling approach but allowing for repeated measures for each subject. A p value of b .05 was considered to be significant in all analyses. For each outcome, the tabulated adjusted values are the least square means produced by the unequal variances model specified. All analyses were done using SAS Version 9. 3. Results We enrolled 120 women into the ECP study. Of these participants, 6 submitted no bleeding diaries and 1 was later discovered to be pregnant at enrollment. Thus, 113 participants (94%) contributed data to the primary analyses. All but 1 of the participants took the ECPs on the day of or the day before admission. One participant was discovered after admission to have taken the pills 3 days before admission. Her data were included in the analysis. The 113 participants who contributed data ranged in age from 18 to 34 years (median, 21 years). Most were white (Table 2), and all had finished high school. Of the 104 participants who provided a weight, the range was 41– 114 kg (median, 60 kg). None had any medical condition expected to affect bleeding, although in the past year, 1 had

Table 2 Characteristics of the participants who provided diary data ECP study group (N = 113)

Comparison study group (N = 843)

n

%

n

%

26 50 20 4

63 318 268 194

7 38 32 23

11 60 16 6 7 42 16 24 56

96 406 19 303 19 234 579 160 0

11 48 2 36 2 28 69 19 –

4 28 48 20

140 282 215 206

17 33 26 24

Agea b 20 years 29 20 – 25 years 56 26 – 30 years 23 31 – 35 years 5 Race/ethnicitya Hispanic 12 White, not Hispanic 68 Asian, not Hispanic 18 Black, not Hispanic 7 Other, mixed, unknown 8 Finished collegea 48 Parousa 18 Smoke cigarettes 27 Previously used ECPs 63 Cycle day of entry into analysisa, Days 1–7 5 Days 8 – 14 32 Days 15 – 21 54 Day 22 or later 22

b

a

Denotes a significant difference between the two populations. For the ECP study, the day of ECP ingestion; for the comparison study, the day of study admission. b

had an oophorectomy for a dermoid cyst and another had had an ovarian cyst. Of the 63 women who reported having previously taken ECPs, 13 (21%) reported having had any unusual bleeding pattern after their last ECP use. Participants reported a median usual cycle length of 29 days and a median usual duration of menses of 5 days. Approximately three quarters of the participants took the ECPs between Days 8 and 21 after the onset of their last menstrual period. The comparison population consisted of 843 women who contributed diary data. This population was significantly older than the ECP study population, with a median age of 26 years (range, 18–35 years). Other demographic characteristics also differed substantially (Table 2): the comparison study included a lower proportion of Asian women and higher proportions of Black women, parous women and women who had not finished college. The median usual cycle length reported at admission was 28 days. In the comparison data set, none of the factors in Table 2 that differed between the study and comparison groups except cycle day of entry into the analysis was significantly related to length of the first cycle if usual cycle length was held constant. Of the 113 participants in the ECP data set, 95 (84%) contributed a full 9 weeks of usable diary data. Twelve (11%) used contraceptive hormones within 9 weeks after admission, and their subsequent data were censored. Six participants (5%) submitted b9 weeks of diary data and were subsequently lost to follow-up. These 18 women contributed between 7 and 54 days of data to the primary analyses. The only participant with missing bleeding data

E.G. Raymond et al. / Contraception 73 (2006) 376 –381

Fig. 1. Cycle length by cycle week of enrollment in the ECP and comparison studies. In this box and whisker plot, the line in the middle of each box is the median, the upper and lower edges of each box are the 25th and 75th percentiles, respectively, and the upper and lower ends of the whiskers are the 5th and 95th percentiles, respectively.

before her last day in the analysis was the one with the admission violation; her first 3 days after ECP ingestion were included as nonbleeding days. In the comparison population, 596 women (71%) contributed z 63 diary days to the analysis. Data from 77 Table 3 Number and duration of menstrual cycles Cycle 1

1

women were censored b63 days for the following reasons: 23 used hormonal contraception or another medication that might affect bleeding patterns, 3 developed a medical condition that might affect bleeding and 51 became pregnant. In addition, 170 other women contributed b 63 days of diary data. These 247 women contributed between 2 and 62 days to the analysis. Women in both the ECP study and the comparison study had a range of one to four menstrual cycles (0–3 complete cycles) during the 9 weeks of follow-up. In the ECP study, the duration of the first complete cycle increased consistently with cycle week of entry into the analysis (Fig. 1). After adjustment for usual cycle length, this trend was significant (Table 3). After adjustment for both usual cycle length and cycle week of entry into the analysis, the first complete cycle was significantly shorter than the second (pb .0001). None of these findings applied to the comparison study. When we controlled for usual cycle length, the first complete cycle was significantly shorter in the ECP study than in the comparison study among women entering the analysis in each of the first 3 weeks of the cycle; this difference was significantly greater the earlier the women entered the analysis (pb .0001). The duration of the second cycles did not differ significantly between the two studies. We found analogous results when we compared the observed with the expected length of the first cycle (Table 3). After adjustment for usual cycle length and cycle week of entry into the analysis, the first complete cycle in the ECP

Cycle 2

Cycle week of entry into analysis All

379

2

ECP study Total no. of cycles 113 5 32 No. of complete cycles 111 4 32 Complete cycles Cycle length (days) Median 11 19 Median adjusted for 12.2b 19.2b a usual cycle length Difference from usual cycle length (days) Median 17 10.5 Median adjusted for 13.8b 8.6b a usual cycle length Comparison study Total no. of cycles 843 140 282 No. of complete cycles 798 127 265 Complete cycles Cycle length (days) Median 28 28 Median adjusted for 25.8 27.9 usual cycle length Difference from usual cycle length (days) Median 0 1 Median adjusted for 0.5 0.1 usual cycle length

3

Table 4 Number and duration of menstrual periods

z4

Period 1 54 53

26 24.8b

3 3.2b

215 204

22 22

31 29.6

2 1.5b

206 202

111 94

27.5 26.6

2 0.6

798 599

28 29.4

31 33.1

28 28.2

0 0.6

3 5.1

1 1.9

a Within Cycle 1, values increase significantly with cycle week of entry into the analysis (p b .05). b Significantly different from the corresponding measure in the comparison study (p b .05).

Period 2

Cycle week of entry into analysis All

1

2

3

ECP study Total no. of periods 111 4 32 No. of complete periods 108 4 31 Complete periods Period length (days) Median 3 5 Median adjusted for 3.2b 5.3 usual cycle lengtha Difference from usual period length (days) Median 1 1 Median adjusted for 1.3 0.4 usual cycle length Comparison study Total no. of periods 798 127 No. of complete periods 785 122 Complete periods Period length (days) Median 5 Median adjusted for 4.9 usual cycle length

265 261

5 5.0

z4

53 51

22 22

94 91

6 5.8b

7 6.4b

6 5.6b

1 0.7

1 1.5

1 0.7

204 202

5 5.0

202 200

5 4.9

599 580

5 5.0

a For Period 1, values increase significantly with cycle week of entry into the analysis (p b .05). b Significantly different from the corresponding measure in the comparison study (p b .05).

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Table 5 Other bleeding patterns after admission

Intermenstrual bleeding Cycle 1 Cycle 2a Either Cycle 1 or Cycle 2 Any bleeding within the first 7 days (including menses) a

ECP study (N = 113)

Comparison study (N = 843)

n

%

n

%

6 9 15 59

5 8 13 52

31 28 58 184

4 4 7 22

Proportions are of total number of second cycles; see Table 3.

study was significantly shorter than expected based on the reported usual cycle length (pV .0001). In the comparison study, the first complete cycle was longer than expected (p b.0001). The lengths of the second cycles were not significantly different from expected in either population. After adjustment for usual cycle length, the duration of the first menstrual period in the ECP study increased significantly with cycle week of ECP ingestion (Table 4). In contrast, in the comparison study, menstrual period length was unrelated to cycle week of enrollment. The first period was significantly longer in the ECP study than in the comparison study among women who entered the analysis in the third cycle week or later, as was the duration of the second menstrual period among all women. Intermenstrual bleeding occurred in no more than 8% of women in any cycle in either study (Table 5). The incidence of intermenstrual bleeding in either the first or the second cycle was higher in the ECP group (p = .05). After adjustment for baseline cycle length and cycle week of entry into the analysis, a significantly higher proportion of women in the ECP study than in the comparison study had bleeding in the first week of the analysis (p b.0001). Of the 109 women in the ECP study who provided data on nonbleeding side effects of the ECPs, 32 (29%) reported at least one such complaint, including nausea (n =20, 18%), fatigue (n =9, 8%), abdominal pain (n = 5, 5%), breast tenderness, headache and dizziness (n = 4 women each, 4%). No participant reported vomiting or diarrhea. 4. Discussion Our study found that when taken in the first 3 weeks of the menstrual cycle, ECPs consisting of 1.5 mg of levonorgestrel in a single dose significantly shortened that cycle as compared both with the usual cycle length and with the cycle duration in a comparison group of similar women who had not taken ECPs. The magnitude of this effect was greater the earlier the pills were taken. This regimen taken later in the cycle had no effect on cycle length but did cause prolongation of the next menstrual period. The ECPs had no effect on the duration of the second menstrual cycle after use, but the second period was prolonged. Intermenstrual bleeding was uncommon

after ECP use although more common than among women who had not taken ECPs. Our definitions of cycle and menstrual period were adapted from those introduced by the World Health Organization (WHO) for analyses of bleeding patterns among users of various contraceptive methods [13]. The only substantial difference between the WHO definitions and ours was that whereas the WHO considered even 1 single isolated day of bleeding to be a bleeding episode, we required a period to be at least 3 consecutive days of bleeding (or 2 bleeding days separated by 1 bleeding-free day). We made this modification to increase the clinical relevance of our results; we suspected that few women would regard a sequence of only 1 or 2 consecutive bleeding days as a period. A very large study conducted over several decades indicated that b 5% of untreated women ever have bleeding episodes b 3 days long [14]. We considered bleeding of such short duration to be intermenstrual bleeding, a category that does not exist in the strict WHO classification system. Our definition of a cycle corresponds to the WHO segment. Most prior studies that reported data on bleeding patterns after ECP use did not use standardized definitions of cycles or periods. Without definitions, a pattern such as the one we observed of an early menstrual period followed by a cycle of normal duration could have been interpreted as early intermenstrual bleeding followed by delayed menses. Indeed, several large studies on levonorgestrel ECPs did report high incidences of such patterns [1–3,7]. However, the early periods identified by our analysis were generally of normal or expected length, and the women with these early periods for the most part had no other bleeding abnormality. Moreover, the length of the second cycle after ECP use was normal. Our data suggest that ECPs hasten the end of the current menstrual cycle, but thereafter the hormonal cyclicity is bresetQ and proceeds normally. Our finding that treatment early in the cycle disrupts cycle length is consistent with results of recent studies indicating that ECPs have demonstrable biologic effects when taken before ovulation [15]. However, the observation that ingestion late in the cycle influences the length of subsequent period suggests an endometrial effect even when pills are taken after ovulation. The specific nature of this effect and whether it might contribute to the contraceptive efficacy of the regimen are unknown. A key strength of our analysis was the comparison of our data with prospectively collected bleeding data from a group of women who had not taken ECPs. Because menstrual irregularities are quite common [10], without such a comparison, we would not have been able to determine whether the abnormal bleeding patterns we saw after ECP use were a result of the ECPs or were merely coincidental. We were fortunate to have available to us another study that included relevant data to allow us to select a subgroup of women who would have met our admission criteria and collected bleeding information in a similar fashion to our

E.G. Raymond et al. / Contraception 73 (2006) 376 –381

study. However, clearly, the comparison population was different in many ways from our population. All of our comparative analyses were adjusted for usual cycle length, but it is certainly possible that some differences in bleeding patterns between the two populations were due to factors other than ECP ingestion. Participant weight, for example, which is known to influence ovarian hormone secretion and uterine bleeding [16], was not available in the comparison data set. Several biases were inherent in our study design. For example, our exclusion of women whose periods were late likely resulted in an artifactual shortening of the first cycle length. On the other hand, women enrolling in any study are more likely to do so during a long cycle than a short one, which selects for enrollment cycles that are longer than the average. Restriction of the analysis to the first 70 days after admission truncated the length of the last complete cycle; this bias would have applied to the second cycle more often than to the first. These competing biases may have affected the results of the comparisons between the first and second cycle lengths within each study. However, since the biases presumably applied similarly to both studies, we have no reason to believe that they had any impact on the comparisons of the two populations. In our study, we did not perform routine pregnancy testing on all participants. Some of the apparent bleeding abnormalities, thus, may be due to unrecognized pregnancies that aborted very early in gestation. Nevertheless, our results should represent women’s self-perceived experience with the method and should be useful in clinical counseling. An early menstrual period (or bleeding of at least 3 days’ duration) will likely be welcome to many women using ECPs, who are eager for evidence that they are not pregnant. Our findings support the recommendation [11] that a pregnancy test should be considered if menses are delayed. In addition, women should be informed that after using this ECP regimen, their next ovulation may come earlier than expected and, therefore, prompt initiation of regular contraception is advisable. Acknowledgment Support for this study was provided by Family Health International (FHI) with funds from the William and Flora Hewlett Foundation and the Barr Laboratories. The views expressed in this article do not necessarily reflect those of

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