Gynecology-endocrinology

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1 Gynecology-endocrinology FERTILITY AND STERILITY Copyright American Society for Reproductive Medicine Printed on acid-free paper in U. S. A. Primary infertility and oral contraceptive steroid use* Mary Ann Bagwell, Ph.D.H Shirley J. Thompson, Ph.D. 11 Cheryl L. Addy, Ph.D.11 Ann L. Coker, Ph.D.11 Elizabeth R. Baker, M.D.~ Richland Memorial Hospital and University of South Carolina, Columbia, South Carolina Objective: To determine the association between combined monophasic oral contraceptive (OC) use and primary infertility. Design: Case-control. Setting: Women serving as controls of the Cancer and Steroid Hormone Study. Participants: Women were 19 to 40 years of age at first conception or infertility diagnosis. Based on 24 consecutive months of unprotected intercourse without a recognized conception, 419 nulligravid women had primary infertility; controls were 2,120 fertile women. A calendar of each woman's reproductive history was used to determine fertility status and contraceptive use before infertility diagnosis or first conception. Main Outcome Measure: Primary infertility. Results: Combined monophasic OC use was associated with a lower frequency of primary infertility, particularly among younger (age 20 years) compared with older women (age 30 years) after adjusting for barrier method use and education. A similar association was found for duration of OC use. When adjusted for age at first conception or infertility and barrier method, both higher (>50 /-lg) and lower (:550 /-lg) estrogen dose use were associated with decreased risk of primary infertility. Conclusion: Combined monophasic OC use was associated with a lower frequency of primary infertility. Fertil Steril 1995;63: Key Words: Monophasic combined oral contraceptives, primary infertility, and unprotected intercourse Oral contraceptives (OCs) are used by more women than all other reversible methods of contra- Received May 19, 1994; revised and accepted January 18, * Data were provided by the Centers for Disease Control and Prevention, Atlanta, Georgia. Funding for the original data base was made possible by interagency agreement 3-Y01-HD between the Centers for Disease Control and the National Institute of Child Health and Human Development, with additional support from the National Cancer Institute, Bethesda, Maryland. t Richland Memorial Hospital. :j: Present address: South Carolina Department of Health and Environmental Control, Columbia, South Carolina. Reprint requests: Shirley J. Thompson, Ph.D., Department of Epidemiology and Biostatistics, University of South Carolina, Columbia, South Carolina (FAX: ). II School of Public Health, Department of Epidemiology and Biostatistics, University of South Carolina. ~ School of Medicine, Department of Obstetrics and Gynecology, University of South Carolina. ception combined (1). Several previous investigations have found a 3- to 6-month delay in conception for a majority of women after discontinuing OCs (2-5). Approximately 15% to 25% of women have a longer fertility delay after stopping OCs (4-6). The large prospective Oxford Family Planning Association study suggested that prolonged OC use may result in longer conception delays among older than younger women (6). These studies have been criticized for their inadequate comparison groups, highly selected samples, and failure to account for confounding factors and to differentiate between the various types of infertility. Our study addresses the relationship between OC use and primary infertility in a representative sample of women with documented reproductive histories from menarche to menopause for contraceptive methods before the onset of infertility. Bagwell et al. Infertility and oral contraceptive use 1161

2 MATERIALS AND METHODS The control group from the Cancer and Steroid Hormone Study (CASH) served as the sample for this infertility study. The CASH study was a multicenter population-based case-control study of women 20 to 54 years of age conducted between December 1980 and April 1983 to investigate the relationship between OC use and the risk of breast, ovarian, and endometrial cancers. The sampling and methods of the CASH study have been described in detail elsewhere (7-9). In brief, each participant was interviewed in person using a pretested standardized questionnaire about reproductive events, monthly contraceptive practices, medical histories, medical service use, personal characteristics, and health habits. Photographs of all OCs marketed in the United States after 1960 were used to facilitate recall. The interviews used a month-by-month calendar to record major life events such as marriage, divorce, births, and deaths from menarche to menopause. With these major life events as a framework for recall, a record of monthly sexual activity, monthly contraceptive use, and all pregnancies was entered on the calendar (7, 8). Women who were sexually active during the month and neither pregnant nor using a contraceptive of any kind were considered at risk for pregnancy. Primary infertility was defined, using life events calendar data, as 24 consecutive months of unprotected intercourse without a recognized conception occurring in nulligravida women. The ending date of the 24 months of unprotected intercourse was used as the date of infertility diagnosis. Fertility was defined as having a recognized conception without a prior period of24 consecutive months of unprotected intercourse without a recognized conception as determined from the calendar of life events. Of the 4,754 women in the control group ofthe CASH study, 3,975 were eligible for study after excluding women whose partners had an infertility diagnosis (n = 85) and women whose 24 months of unprotected intercourse occurred after a recognized conception (n = 694). Further excluded were never-married women (n = 229), women with missing information on length of pregnancy or year of conception (n = 30) or age at first conception or infertility (n = 139), women with breast surgery of unknown outcome before first conception or primary infertility (n = 1), women who used OCs other than the combined type only (sequential n = 25; unknown type n = 55; more than one type in same month n = 1), and women who were considered unreliable respondents (n = 6). Women younger than age 19 years (n = 842) or older than age 40 years (n = 3) at the time of first conception 1162 Bagwell et al. Infertility and oral contraceptive use or infertility diagnosis also were excluded because of the likelihood of more anovulatory cycles or irregular menstrual periods associated with these ages. Hormone users (n = 35) were excluded because it could not be determined if the hormone had been prescribed to treat infertility. Because few women reported intrauterine device (IUD) use (n = 24), these women were excluded from the analysis rather than conducting subanalyses for IUD use. Again, because of the small numbers of women with conditions linked with infertility (20 women with a history of pelvic inflammatory disease, 20 with endometriosis, and 6 with polycystic ovarian disease), these women were excluded from the analysis rather than adjusting for these factors in subsequent modeling. The group of excluded women were similar to the remaining study sample on reproductive, behavioral, and demographic characteristics, except that proportionally more of the women removed from the sample reported having 2e: 16 years of education. The final study sample consisted of 419 infertile and 2,120 fertile women. Dates of contraceptive use and dates of first conception or infertility diagnosis were obtained from CASH calendar data. Contraceptive use before the date of first conception or infertility was used in this study to characterize contraceptive use by method (e.g., OCs or barrier methods). The OCs were coded to a particular dose of estrogen and/or progestin by the Cancer Steroid and Hormone Study team. Combined monophasic OCs used by the study women were norethindrone acetate and ethinyl E 2, norgestrel and ethinyl E 2, norethindrone and ethinyl E 2, ethynodiol diacetate and ethinyl E2, medroxyprogesterone acetate and ethinyl E 2, norethynodrel and mestranol, norethindrone and mestranol, and ethynodiol diacetate and mestranol. Triphasic and biphasic pills were not available at the time of the study. A woman was considered a user if she used only a combined OC or a combined plus unknown type of OC for 2e:3 consecutive months before first conception or infertility diagnosis and was considered a nonuser if she used OCs <3 consecutive months or never used OCs before first conception or infertility diagnosis. The OC dose was based on the amount of estrogen in the combined pill. Generally, :535 f-lg of estrogen would be considered low-dose use. Using this definition, only a small number of women were low-dose users. Therefore, categories of >50 f-lg (higher dose) and :550 f-lg (lower dose) were examined. Duration of OC use was categorized into >24 months, :524 months, or nonuse before first conception or infertility diagnosis. Because of the sparsity of the data, dose and duration were combined to evaluate the cumulative effect of dose. Higher dose users were Fertility and Sterility

3 divided into categories of >50 j-lg of estrogen and >24 months duration or >50 j-lg of estrogen and :=; 24 months duration. Lower dose use (:=;50 j-lg of estrogen) for any duration had to be used in the analysis because of the small numbers of infertile women when this category was divided into :=;24 months or >24 months duration. Potential confounding variables taken from the interview questionnaire were age at first conception or infertility (continuous), quetelet index at age 18 defined as weight in grams divided by square of height in centimeters (continuous), age when smoking was initiated «18 years, ~ 18 years, or nonsmoker before first conception or infertility diagnosis), income (:=;$19,999, $20,000 to $39,999, and ~$40,000), education defined as years of school completed ( < 12, 12 to 15, and ~ 16), and race (white or other). Barrier methods of contraception (diaphragm, condom, and spermicide use) were classified as use or nonuse before first conception or infertility diagnosis based on calendar data. Logistic regression was used to estimate univariate odds ratios (OR) and to evaluate the association of OC use and infertility while controlling for several confounders simultaneously (10). Two factor interactions of each of the potential confounders with OC Table 1 Characteristics of the Study Population According to Fertility Status*t Characteristic Age at first conception or infertility (y) 19 to to to 39 Quetelet index at age 18 :;;; to 2.09 ;",2.10 Missing Race White Other Missing Education (y) ;",16 12 to 15 <12 Unknown Income (U.S. dollars) ;",40,000 20,000 to 39,999 :;;;19,999 Unknown/no answer Age smoking initiated Nonsmoker ;",18 <18 y Unknown Infertile 120 (28.64) 133 (31.74) 166 (39.62) 135 (32.37) 141 (33.81) 141 (33.81) (82.82) 72 (17.18) 0 92 (22.01) 261 (62.44) 65 (15.55) (29.44) 168 (42.64) 110 (27.92) (53.70) 106 (25.30) 88 (21.00) 0 * Infertile, n = 419; fertile, n = 2,120. t Values in parentheses are percentages. Fertile 659 (31.08) 814 (38.40) 647 (30.52) 659 (31.20) 800 (37.88) 653 (30.92) 8 1,908 (90.04) 211 (9.96) (26.82) 1,393 (65.77) 157 (7.41) (28.26) 974 (48.39) 470 (23.35) 107 1,223 (57.80) 509 (24.05) 384 (18.15) 4 Table 2 Contracepting Practices and Univariate Associations for Primary Infertility 95% Contraceptive use Infertile* (n = 419) Fertile* (n = 2,120) Odds ratio Confidence interval OC Nonuser 381 (90.93) 1,819 (85.80) (9.07) 301 (14.20) ,0.86 OC estrogen dose Nonuser 381 (91.36) 1,819 (86.54) 1.00,.,; 5O l'g 14 (3.36) 104 (4.95) , 1.14 > 5O l'g 22 (5.28) 179 (8.52) ,0.93 Unknown 2 18 OC duration (mo) Nonuser 381 (90.93) 1,819 (85.80) 1.00,.,;24 19 (4.53) 151 (7.12) ,0.98 >24 19 (4.53) 150 (7.08) ,0.99 Any barrier method use Nonuser 347 (82.82) 1,233 (58.16) (17.18) 887 (41.84) ,0.38 * Values in parentheses are percentages. use were considered in a stepwise backwards elimination model selection procedure. Final models consisted of the OC exposures (ever use, dose, duration), statistically significant interactions, and variables judged to be confounders and/or strong risk factors for primary infertility in these data. In the presence of interaction with a continuous variable, ORs were reported for two representative levels of the variable. RESULTS The primary infertility cases were similar to controls with respect to age when smoking was initiated and quetelet index. A higher proportion of the infertile women compared with the fertile women were 24 to 39 years of age at first conception or infertility. This difference in age distribution also was evidenced by a slightly higher mean age at infertility diagnosis (23.4 ± 3.9 years, mean ± SD) than mean age at first conception (22.6 ± 3.2 years) among fertile women. A higher percentage of infertile than fertile women were of other than white race and had less than a high school education (Table 1). Fourteen percent of the fertile women compared with 9% of those who were infertile were OC users. Average duration of OC use was slightly longer for the fertile group (33.6 ± 27.7 months, range 3 to 138 months) than for the infertile group (30.1 ± 27.5 months, range 3 to 133 months). Infertile women were no more likely to have high OC estrogen dosage (>50 versus :=;50 j-lg) or longer durations of OC use (>24 versus :=;24 months) than were fertile controls. A higher proportion of fertile women (41.8%) compared with infertile women (17.2%) reported any use Bagwell et al. Infertility and oral contraceptive use 1163

4 Table 3 Summary of Multiple Logistic Regression Models for Oral Contraceptive Use and Primary Infertility Variable Oral contraceptive use model* OC Nonuser Age at first conception or infertility (y) OC dose modelt OC estrogen dose Nonuser s50 J1g >50 J1g Odds ratio % Confidence interval 0.14, , , ,0.65 * Adjusted for education and barrier method use. t Adjusted for age at first conception or infertility and use of any barrier method. of barrier methods. The use of other contraceptive methods such as periodic abstinence or withdrawal were not explored in these data. Table 2 shows contraceptive practices and unadjusted associations for primary infertility. Oral contraceptive use was associated with less primary infertility in that the unadjusted odds of OC use among the infertile women were only 0.60 (95% confidence interval = 0.42,0.86) times the same odds among the fertile women. This association remained consistent for duration of OC use, but findings were nonsignificant for lower dose use. No statistically significant differences were found when comparing the infertile and fertile groups for side effects. Sixty-one percent of the infertile women and 60% of the fertile women never stopped OC use due to side effects. Side effects reported included nausea, vomiting, breast tenderness, breast swelling, lack of energy, depression, irritability, and other medical reasons (data not shown). Multiple logistic regression was used to evaluate the relationship between OC use and primary infertility while simultaneously adjusting for several variables. Race, education, age when smoking was initiated, quetelet index at age 18, age at first conception or infertility diagnosis, and barrier method use were found to be associated with both primary infertility and OC use and therefore were included as potential confounders. The final model, summarized in Table 3, revealed that OC use was associated with decreased risk of primary infertility, with a stronger effect for younger women. Thus, among 20- year-old women, the odds of OC use for women with primary infertility were 0.27 times the same odds for fertile women, whereas among 30-year-old 1164 Bagwell et al. Infertility and oral contraceptive use women, the odds of OC use for women with primary infertility were 0.68 times the same odds for fertile women after adjusting for education and barrier method use. However, the finding for 30-year-old women was not statistically significant. When duration of OC use was considered without regard to dose, a statistically significant interaction with age at first conception or infertility was found (results not shown). As in the OC use model, a stronger association of duration of OC use and primary infertility was seen among younger women. When OC dose was examined, both high- and lowdose use were associated with decreased risk of primary infertility after adjusting for age at first conception or infertility and any barrier method use. Next, the cumulative effect of estrogen dose on primary infertility was examined. After adjusting for barrier method use and age at first conception or infertility, each combination of dose and duration was associated with decreased risk of primary infertility (results not shown). However, this finding was based on a very small number of infertile users within each of the dose and duration categories. DISCUSSION The findings of this study are consistent with those of other studies that demonstrated short fertility delays for the majority of women who used OCs (2-6). Pardthaisong and Gray (3) reported that, within 3 months of stopping OC use, 50% of women surveyed had conceived; only 5.7% had not conceived at the end of 2 years. In a larger and more controlled study, Bracken and colleagues (2) found OC users to be less likely to conceive during the first six full cycles after discontinuing contraception than users of other contraceptive methods. The large prospective Oxford Family Planning Association contraceptive study found some impairment in fertility at 24 months, which had almost vanished by 48 months for the 25 to 29 year olds, but continued to 72 months for the 30 to 34 year olds (6). This apparent disparity in risk for older women between the Oxford study and our findings may be explained in part by use of birth of child rather than conception date to indicate return of fertility by the Oxford group, by possible differences in underlying rates of permanent infertility, and by differences in OC types and duration of use. Survey data show infertile women are more likely to be older, black, and less educated (11). The observed association between OC use and primary infertility may be explained in part by the fact that women in this study may have been at low risk of infertility. The majority were white, well educated, and in their early 20s at the time of first conception or infertility diagnosis. Fertility and Sterility

5 The relatively short-term use of OCs by the study women also may account for the lower frequency of infertility after discontinuing OC use. The average duration of OC use in this study was 30.1 months (range 3 to 133 months) for infertile women and 33.5 months (range 3 to 138 months) for fertile women. OCs had been available only for a short time when these women were young. A few women used OCs and another contraceptive method simultaneously while changing from one method to another. The CASH team classified them as OC users. Although these women could not be analyzed separately because ofthe manner in which these data were coded, including them as OC users would tend to increase slightly the duration of OC use. The reason women began using OCs was not obtained in the CASH data. Women with irregular menstrual cycles or those with amenorrhea who were treated with OCs may continue to have these problems after discontinuing OCs. In these data such women would be classified as infertile. Our inability to differentiate reasons for OC use may result in OC use in part being a marker for infertility. This misclassification, if operational, likely would result in a biasing ofthe odds ratio away from the null. We found that OC use was associated significantly with a reduction of infertility; the true measure of associ a tion actually may have been weaker. Whether any woman received treatment for infertility was unknown. Successful treatment during the 24-month period of unprotected intercourse likely would result in the woman being classified as fertile and, therefore, the effect of OCs on primary infertility could be overestimated. "Hormone users" were excluded because hormones are used to treat infertility. Coital frequency and whether women were attempting to conceive also were unknown. Our study had several strengths deserving mention. Our definition of contraceptive use before first conception or infertility diagnosis provides the prospective temporal sequence that improves the inferences that may be drawn from these data. Exposure to smoking and reproductive diseases also were measured in the interval of unprotected intercourse or before the dates of first conception or infertility diagnosis. The quality of the CASH data, specifically the detail of the calendar data and the care with which these data were collected, minimized misclassification. Standardized interviews used memory aids and photographs of OCs to assist recall. Subjects first were asked to identify major life events around which recall of OC use was recorded. Data were available for examining the individual effects of estrogen dose, the duration of use, and the cumulative effects when combining dose and duration. Many c~se-control studies of infertility have been clinic based and are limited because of selecting women choosing to seek care for infertility. Our use of the CASH control group, which was selected randomly from the general population, make this analysis one of the few population-based case-control studies of infertility. Data were available to allow us to exclude women with secondary infertility; these results relate to more permanent primary infertility. Important potential confounders were assessed including demographic characteristics, other methods of contraception, and lifestyle habits such as smoking and quetelet index at age 18 affected by diet and exercise. Multiphasic low-dose preparations introduced in 1985 could have a different effect on infertility than monophasic preparations. There is evidence demonstrated by GnRH challenge tests that triphasic preparations suppress gonadotropin less than preparations containing 50 p,g of ethinyl E2 (the estrogen preparation most frequently used by women in this study). However, no differences in gonadotropin suppression have been found for various low-dose preparations (12). Because multiphasic OCs more closely mimic the menstrual cycle than monophasics, their effects on primary infertility also should be explored. In summary, the results indicated that combined monophasic OC use was associated with a lower frequency of primary infertility. An OC-age interaction revealed that, although OC use was associated with a decreased risk of infertility, the effect was stronger for younger women (age 20 years, OR = 0.27; age 30 years, OR = 0.68) after adjusting for barrier method use and education. This association was consistent within various estrogen dose and duration categories. These findings are somewhat reassuring for women who have used combined monophasic OCs in the past and women contemplating long periods of OC use. Acknowledgments. The authors acknowledge the following contributors to the Cancer and Steroid Hormone Study: Study Design and Coordination: The Division of Reproductive Health, Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Principal Investigator: George L. Rubin, M.B., F.R.A.C.P.; Project Director: Phyllis A. Wingo, Ph.D., M.S.; Project Associates: Nancy C. Lee, M.D., Michele G. Mandel, B.A., Herbert B. Peterson, M.D. Data Collection Centers Principal Investigators: Atlanta: Raymond Greenberg, M.D.; Connecticut: J. Wister Meigs, M.D., and W. Douglas Thompson, Ph.D.; Detroit, Michigan: G. Marie Swanson, Ph.D.; Iowa: Elaine Smith, Ph.D.; New Mexico: Charles Key, M.D., and Dorothy Pathak, Ph.D.; San Francisco, California: Donald Austin, M.D.; Seattle, Washington: David Thomas, M.D.; Utah: Joseph Lyon, M.D., and Dee West, Ph.D. Pathology Review Principal Investigators: Fred Gorstein, M.D., Robert McDivitt, M.D., and Stanley J. Robboy, M.D. Project Consultants: Lonnie Burnett, M.D., Robert Hoover, M.D., Peter M. Layde, M.D., M.Sc., Howard W. Ory, M.D., M.Sc., James J. Schlesselman, Ph.D., David Schot- Bagwell et ai. Infertility and oral contraceptive use 1165

6 tenfeld, M.D., Bruce Stadel, M.D., Linda A. Webster, M.S.P.H., and Colin White, M.B.B.S. Pathology Consultants: Walter Bauer, M.D., William Christopherson, M.D., Deborah Gersell, M.D., Robert Kurman, M.D., Allen Paris, M.D., and Frank Vellios, M.D. REFERENCES 1. Forest JD, Fordyce RR. U.S. women's contraceptive attitudes and practice: how have they changed in the 1980s? Fam Plann Perspect 1988;20: Bracken MB, Hellenbrand KG, Holford TR. Conception delay after oral contraceptive use: the effect of estrogen dose. Fertil Steril 1990;53: Pardthaisong T, Gray RH. The return of fertility following discontinuation of oral contraceptives in Thailand. Fertil SteriI1981;35: WesthoffCF, Bumpass L, Ryder NB. Oral contraception, coital frequency, and the time required to conceive. Soc BioI 1969; 16: Wolfers D. The probability of contraception after discontinuance of oral contraceptives: a note on "oral contraception, coital frequency, and the time required to conceive," by Westhoff, Bumpass, & Ryder. Social BioI 1970;17: Vessey MP, Smith MA, Yeates D. Return of fertility after discontinuation of oral contraceptives: influence of age and parity. Br J Fam Plann 1986;11: Sattin RW, Rubin GL, Wingo PA, Webster LA, Ory HW. Oralcontraceptive use and the risk of breast cancer. N Engl J Med 1986;315: Marchbanks PA, Peterson HB, Rubin GL, Wingo PA, CASH Group. Research on infertility: definition makes a difference. Am J Epidemiol 1989; 130: Wingo PA, Ory HW, Layde PM, Lee NC, CASH Group. The evaluation of the data collection process for a multicenter, population-based, case-control design. Am J Epidemiol 1988; 128: Breslow NE, Day NE. Unconditional logistic regression for large strata. In: Breslow NE, Day NE, editors. Statistical methods in cancer research. Lyon, France: International Agency for Research on Cancer, 1980: Congress of the United States. Infertility: medical and social choices. Washington, DC: Office of Technology Assessment, U.S. Government Printing Office, 1988: Foster DC. Low-dose monophasic and multiphasic oral contraceptives: a review of potency, efficacy, and side effects. Semin Reprod EndocrinoI1989;7: Bagwell et ai. Infertility and oral contraceptive use Fertility and Sterility