Iiit J Gynaecol Obstet 15: 125-127, 1977
The Risk of Post-Pill Amenorrhea: A Preliminary Report from the Menstruation and Reproduction History Research Program Gary S. Berger 1 , Robert N. Taylor, Jr. 1 , and Alan E. Treloar2 1
International Fertility Research Program, Research Triangle Park, North Carolina, USA
¿Menstruation and Reproduction History Research Program, Ruth E. Boynton Health Service, University of Minnesota, Minneapolis, Minnesota, USA
ABSTRACT Berger, G. S., Taylor, R. N., Jr. and Treloar, A. E. (International Fertility Research Program, Research Triangle Park, North Carolina, and Menstruation and Reproduction History Research Program, Ruth E. Boynton Health Service, University of Minnesota, Minneapolis, Minnesota, USA). The risk of post-pill amenorrhea: a preliminary report from the Menstruation and Reproduction History Research Program. Int J Gynaecol Obstet 15: 125-127, 1977 Menstrual cycle lengths prior to and after oral contraceptive use were prospectively recorded for 245 women. In this preliminary study, a difference in the distributions in the preand post-pill cycle lengths was observed. An increase of 5 days in the median cycle length occurred after oral contraceptive use had been discontinued. Although there was an approximately twofold relative risk of amenorrhea of 90 days' duration or more after discontinuing pill use, the differences in the rates of amenorrhea between the pre-pill and post-pill cycles were not statistically significant.
INTRODUCTION The clinical trials that eventually led to the widespread use of contraceptive pills began in 1956 when Rock et al. (4) reported that synthetic estrogen-progestogen compounds inhibited human ovulation. Ten years later, Sherman (5) reported nine cases of prolonged amenorrhea in patients who had discontinued use of commercially available oral contraceptives (OCs). Since then, literally hundreds of cases of "post-pill amenorrhea" have been reported in the English language medical literature; and, in the past decade, post-pill amenorrhea (PPA) has become a familiar and well-accepted concept. However, the reports which established This work ivas supported in part by the International Fertility Research Program, Research Triangle Park, North Carolina, USA (AID/csd-2979).
this concept employed various criteria for defining PPA and have been based primarily on uncontrolled, retrospective study of selected cases of amenorrheic women who reported previous use of birth control pills. Such an approach does not permit either the determination of the incidence of PPA among a known population of oral contraceptive users or the determination of the extent to which secondary amenorrhea occurring after OC use is attributable to the pill. The present study was undertaken in an effort to clarify these issues. METHODS The Menstruation and Reproduction History (MRH) Research Program at the University of Minnesota (7) maintains a data file of prospectively recorded menstrual histories, pregnancy events, contraceptive use, and other occurrences of possible reproductive significance. Records of 245 women from this program were selected for analysis as "cases". These included records of all women who: 1. Were from 20 to 39 years of age when they began using OCs 2. Used and subsequently discontinued using OCs between 1965 and 1969 3. Reported the precise dates on which they began and discontinued OCs, as well as the exact date they resumed menses after discontinuing the pill 4. Did not become amenorrheic while using OCs 5. Did not become pregnant before having at least one menstrual period after discontinuing OCs The duration of post-pill amenorrhea was analyzed for this group of women. Depending on whether the woman had or had not reported a withdrawal flow after discontinuing use of the pills,
Int J Gynaecol Obstet 15
126 G. S. Berger et al.
the duration of post-pill amenorrhea was defined as either the interval from the date the last pill was taken until the first day of withdrawal bleeding or the interval from the date the last pill was taken until the onset of the first reported menstrual period. Of the women selected for analysis, 91.0% were in their 20s, 57.2% were nulliparous, 26.4% were primiparous, and 16.4% were multiparous.
RESULTS The cumulative percentage distribution of the length of post-pill amenorrhea shown in Fig. 1 is the cumulative rate of return of menstruation after discontinuing OC use. Twenty-five percent of the women had resumed menstruation by the 32nd day after they stopped taking pills. Fifty percent (the median) had resumed by the 38th day. By 90 days after discontinuing OCs, only seven (2.9%) of the women had not yet menstruated. Six of these seven women spontaneously resumed menstruation between 90 and 180 days after discontinuing OCs, and the last case resumed menstruation at 220 days. In Fig. 2 the cumulative frequency distribution for the first post-pill cycle is compared with the length of the cycle immediately before initiating OCs for the 245 study subjects. A significant shift in distribution (toward longer cycle lengths) is evident Percent of Women
, ,
in post-pill cycles, with a 5-day increase in the median value. However, after approximately 49 days, the differences between the two curves are not significant. At 90 days, the amenorrhea rate for post-pill cycles was 2.9%, based on seven cases, compared with 1.2% based on three cases for pre-pill cycles. Thus, the ratio of the rates or the relative risk of post-pill amenorrhea of 90 days' duration is 2.3, with a 90% confidence interval of 0.8 to 7.0. Moreover, the risk of amenorrhea of 90 days or longer attributable to OC use is 2.9-1.2 or 1.7%, with a 90% confidence interval of -0.4 to 3.9%. Similar results were obtained when the cumulative post-pill menstruation rate was compared with a random cycle selected from a group of women of similar age, race, and socioeconomic status who had never used OCs (Fig. 3). In this comparison, the rates of amenorrhea of 90 days or more were 1.8%, based on eight cases among the nonusers of OCs, and 2.9%, based on seven cases after use of OCs. These data yield a relative risk estimate of 1.6, with a 90% confidence interval of 0.7 to 3.8%, and an attributable risk estimate of 1.1%, with a 90% confidence inverval of -0.9 to 3.8%. Fig. 4 shows the cumulative menstruation rate by type of OC administered. The time required for return of menstruation tended to be shorter for women taking sequential pills than for those taking combination pills; however, the rates of amenorrhea of 90 days' duration or more were not significantly different (p>0.10).
Percent of Women Iftrr-
****'
80
60
40
OC Users - Pre-Pill Cycle OC Users - Post-Pill Cycle
20
0 0
7
14 21 28 35 42 49
56 63 70 77 84 90
Days Fig. 1 . Cumulative menstruation rate after discontinuing oral contraceptive use.
Int J Gynaecol Obstet 15
0
7
14 21 28 35
42 49
56 63 70
77 84 90
Days
Fig. 2. Cumulative percentage distribution of menstrual cycle lengths.
Risk of post-pili amenorrhea
Percent of Women 100
••*J 1
80
60
r /
40
— — OC Users - Post-Pill Cycle
j 1
\ 20
0
7
14
21 28 35
4 2 49
56
63 70
77 84 9 0
Days
Fig. 3. Cumulative percentage distribution of menstrual cycle lengths.
127
OC users based on records devoid of the potential errors of recall. Our data show a delay, averaging approximately 5 days, in return of menstruation in the cycle immediately after OCs are discontinued. By the seventh week after discontinuing OCs, there were no significant differences in menstruation rates between pre-pill and post-pill cycles. Thus, while the 90 days' amenorrhea rate was 2.3 times higher after pill use than before, these differences were not statistically significant at a 0.10 level, nor was there any significant difference in PPA rates of 90 days or more associated with various categories of OCs. Based on results of this preliminary study, our best estimate of the risk of post-pill amenorrhea of 90 days' duration attributable to OC use is approximately 1.1 to 1.7 per 100 women. Because of the low frequency of prolonged post-pill amenorrhea, a larger study population is needed to draw any further conclusions. We are now processing an additional 5 years of data from the Menstruation and Reproduction History Research Program in an effort to provide a more thorough analysis, the results of which will be reported in a subsequent communication.
-¿JS^SM-JT**
REFERENCES
—
High Dose Combined (N = 74)
— — Medium Dose Combined {N = 44) Low Dose Combined (N = 73) Sequential IN = 32)
7
14 21 28 35 42 49 56 63 70 77 84 90 Days
Fig. 4. Cumulative menstruation rate after OC discontinuation, by type of contraceptive.
DISCUSSION The concept of post-pill amenorrhea has received considerable attention in the past decade. With few exceptions (1-3, 6), however, previous reports have been based on retrospective analyses of data from selected women with varying lengths of post-pill amenorrhea following OC use. No similar consideration has been given to the cycles following OC use among the total population of women at risk (i.e., all OC users). In the present study, the duration of post-pill amenorrhea was analyzed for a cohort of
1. Evrard, J R, Buxton, B H & Erickson, D: Amenorrhea following oral contraception. Am J Obstet Gynecol 124:88, 1976. 2. Larsson-Cohn, U: The length of the first three menstrual cycles after combined oral contraceptive treatment. Acta Obstet Gynecol Scand 4S.-416, 1969. 3. Rice-Wray, E, Correu, M D, Gorodovsky, J, Esquivei, J & Goldzieher, J W: Return of ovulation after discontinuance of oral contraceptives. Fértil Steril 18:212, 1967. 4. Rock, J, Pincus, G & Garcia, C R: The effects of certain 19-noresteroids on the human menstrual cycle. Science 124:891. 1956. 5. Sherman, R P: Amenorrhea after treatment with oral contraceptives. Lancet 2:1110, 1966. 6. Steele, S J, Mason, B & Breth, A: Amenorrhea after discontinuing combined estrogen-progesterone oral contraceptive. Br Med J 4.343, 1973. 7. Treloar, A E: Menstruation and reproduction: historical review of a research program. Boynton Health Service, University of Minnesota, Minneapolis, 1976 (mimeo).
Address for reprints: Gary S. Berger International Fertility Research Program Research Triangle Park North Carolina 27709 USA Int J Gynaecol Obstet 15
The Risk of Post-Pill Amenorrhea: A Preliminary Report from the Menstruation and Reproduction History Research Program Gary S. Berger 1 , Robert N. Taylor, Jr. 1 , and Alan E. Treloar2 1
International Fertility Research Program, Research Triangle Park, North Carolina, USA
¿Menstruation and Reproduction History Research Program, Ruth E. Boynton Health Service, University of Minnesota, Minneapolis, Minnesota, USA
ABSTRACT Berger, G. S., Taylor, R. N., Jr. and Treloar, A. E. (International Fertility Research Program, Research Triangle Park, North Carolina, and Menstruation and Reproduction History Research Program, Ruth E. Boynton Health Service, University of Minnesota, Minneapolis, Minnesota, USA). The risk of post-pill amenorrhea: a preliminary report from the Menstruation and Reproduction History Research Program. Int J Gynaecol Obstet 15: 125-127, 1977 Menstrual cycle lengths prior to and after oral contraceptive use were prospectively recorded for 245 women. In this preliminary study, a difference in the distributions in the preand post-pill cycle lengths was observed. An increase of 5 days in the median cycle length occurred after oral contraceptive use had been discontinued. Although there was an approximately twofold relative risk of amenorrhea of 90 days' duration or more after discontinuing pill use, the differences in the rates of amenorrhea between the pre-pill and post-pill cycles were not statistically significant.
INTRODUCTION The clinical trials that eventually led to the widespread use of contraceptive pills began in 1956 when Rock et al. (4) reported that synthetic estrogen-progestogen compounds inhibited human ovulation. Ten years later, Sherman (5) reported nine cases of prolonged amenorrhea in patients who had discontinued use of commercially available oral contraceptives (OCs). Since then, literally hundreds of cases of "post-pill amenorrhea" have been reported in the English language medical literature; and, in the past decade, post-pill amenorrhea (PPA) has become a familiar and well-accepted concept. However, the reports which established This work ivas supported in part by the International Fertility Research Program, Research Triangle Park, North Carolina, USA (AID/csd-2979).
this concept employed various criteria for defining PPA and have been based primarily on uncontrolled, retrospective study of selected cases of amenorrheic women who reported previous use of birth control pills. Such an approach does not permit either the determination of the incidence of PPA among a known population of oral contraceptive users or the determination of the extent to which secondary amenorrhea occurring after OC use is attributable to the pill. The present study was undertaken in an effort to clarify these issues. METHODS The Menstruation and Reproduction History (MRH) Research Program at the University of Minnesota (7) maintains a data file of prospectively recorded menstrual histories, pregnancy events, contraceptive use, and other occurrences of possible reproductive significance. Records of 245 women from this program were selected for analysis as "cases". These included records of all women who: 1. Were from 20 to 39 years of age when they began using OCs 2. Used and subsequently discontinued using OCs between 1965 and 1969 3. Reported the precise dates on which they began and discontinued OCs, as well as the exact date they resumed menses after discontinuing the pill 4. Did not become amenorrheic while using OCs 5. Did not become pregnant before having at least one menstrual period after discontinuing OCs The duration of post-pill amenorrhea was analyzed for this group of women. Depending on whether the woman had or had not reported a withdrawal flow after discontinuing use of the pills,
Int J Gynaecol Obstet 15
126 G. S. Berger et al.
the duration of post-pill amenorrhea was defined as either the interval from the date the last pill was taken until the first day of withdrawal bleeding or the interval from the date the last pill was taken until the onset of the first reported menstrual period. Of the women selected for analysis, 91.0% were in their 20s, 57.2% were nulliparous, 26.4% were primiparous, and 16.4% were multiparous.
RESULTS The cumulative percentage distribution of the length of post-pill amenorrhea shown in Fig. 1 is the cumulative rate of return of menstruation after discontinuing OC use. Twenty-five percent of the women had resumed menstruation by the 32nd day after they stopped taking pills. Fifty percent (the median) had resumed by the 38th day. By 90 days after discontinuing OCs, only seven (2.9%) of the women had not yet menstruated. Six of these seven women spontaneously resumed menstruation between 90 and 180 days after discontinuing OCs, and the last case resumed menstruation at 220 days. In Fig. 2 the cumulative frequency distribution for the first post-pill cycle is compared with the length of the cycle immediately before initiating OCs for the 245 study subjects. A significant shift in distribution (toward longer cycle lengths) is evident Percent of Women
, ,
in post-pill cycles, with a 5-day increase in the median value. However, after approximately 49 days, the differences between the two curves are not significant. At 90 days, the amenorrhea rate for post-pill cycles was 2.9%, based on seven cases, compared with 1.2% based on three cases for pre-pill cycles. Thus, the ratio of the rates or the relative risk of post-pill amenorrhea of 90 days' duration is 2.3, with a 90% confidence interval of 0.8 to 7.0. Moreover, the risk of amenorrhea of 90 days or longer attributable to OC use is 2.9-1.2 or 1.7%, with a 90% confidence interval of -0.4 to 3.9%. Similar results were obtained when the cumulative post-pill menstruation rate was compared with a random cycle selected from a group of women of similar age, race, and socioeconomic status who had never used OCs (Fig. 3). In this comparison, the rates of amenorrhea of 90 days or more were 1.8%, based on eight cases among the nonusers of OCs, and 2.9%, based on seven cases after use of OCs. These data yield a relative risk estimate of 1.6, with a 90% confidence interval of 0.7 to 3.8%, and an attributable risk estimate of 1.1%, with a 90% confidence inverval of -0.9 to 3.8%. Fig. 4 shows the cumulative menstruation rate by type of OC administered. The time required for return of menstruation tended to be shorter for women taking sequential pills than for those taking combination pills; however, the rates of amenorrhea of 90 days' duration or more were not significantly different (p>0.10).
Percent of Women Iftrr-
****'
80
60
40
OC Users - Pre-Pill Cycle OC Users - Post-Pill Cycle
20
0 0
7
14 21 28 35 42 49
56 63 70 77 84 90
Days Fig. 1 . Cumulative menstruation rate after discontinuing oral contraceptive use.
Int J Gynaecol Obstet 15
0
7
14 21 28 35
42 49
56 63 70
77 84 90
Days
Fig. 2. Cumulative percentage distribution of menstrual cycle lengths.
Risk of post-pili amenorrhea
Percent of Women 100
••*J 1
80
60
r /
40
— — OC Users - Post-Pill Cycle
j 1
\ 20
0
7
14
21 28 35
4 2 49
56
63 70
77 84 9 0
Days
Fig. 3. Cumulative percentage distribution of menstrual cycle lengths.
127
OC users based on records devoid of the potential errors of recall. Our data show a delay, averaging approximately 5 days, in return of menstruation in the cycle immediately after OCs are discontinued. By the seventh week after discontinuing OCs, there were no significant differences in menstruation rates between pre-pill and post-pill cycles. Thus, while the 90 days' amenorrhea rate was 2.3 times higher after pill use than before, these differences were not statistically significant at a 0.10 level, nor was there any significant difference in PPA rates of 90 days or more associated with various categories of OCs. Based on results of this preliminary study, our best estimate of the risk of post-pill amenorrhea of 90 days' duration attributable to OC use is approximately 1.1 to 1.7 per 100 women. Because of the low frequency of prolonged post-pill amenorrhea, a larger study population is needed to draw any further conclusions. We are now processing an additional 5 years of data from the Menstruation and Reproduction History Research Program in an effort to provide a more thorough analysis, the results of which will be reported in a subsequent communication.
-¿JS^SM-JT**
REFERENCES
—
High Dose Combined (N = 74)
— — Medium Dose Combined {N = 44) Low Dose Combined (N = 73) Sequential IN = 32)
7
14 21 28 35 42 49 56 63 70 77 84 90 Days
Fig. 4. Cumulative menstruation rate after OC discontinuation, by type of contraceptive.
DISCUSSION The concept of post-pill amenorrhea has received considerable attention in the past decade. With few exceptions (1-3, 6), however, previous reports have been based on retrospective analyses of data from selected women with varying lengths of post-pill amenorrhea following OC use. No similar consideration has been given to the cycles following OC use among the total population of women at risk (i.e., all OC users). In the present study, the duration of post-pill amenorrhea was analyzed for a cohort of
1. Evrard, J R, Buxton, B H & Erickson, D: Amenorrhea following oral contraception. Am J Obstet Gynecol 124:88, 1976. 2. Larsson-Cohn, U: The length of the first three menstrual cycles after combined oral contraceptive treatment. Acta Obstet Gynecol Scand 4S.-416, 1969. 3. Rice-Wray, E, Correu, M D, Gorodovsky, J, Esquivei, J & Goldzieher, J W: Return of ovulation after discontinuance of oral contraceptives. Fértil Steril 18:212, 1967. 4. Rock, J, Pincus, G & Garcia, C R: The effects of certain 19-noresteroids on the human menstrual cycle. Science 124:891. 1956. 5. Sherman, R P: Amenorrhea after treatment with oral contraceptives. Lancet 2:1110, 1966. 6. Steele, S J, Mason, B & Breth, A: Amenorrhea after discontinuing combined estrogen-progesterone oral contraceptive. Br Med J 4.343, 1973. 7. Treloar, A E: Menstruation and reproduction: historical review of a research program. Boynton Health Service, University of Minnesota, Minneapolis, 1976 (mimeo).
Address for reprints: Gary S. Berger International Fertility Research Program Research Triangle Park North Carolina 27709 USA Int J Gynaecol Obstet 15
