- Email: [email protected]
Lack of association between oral contraceptive use and ulcerative colitis
GASTROENTEROLOGY 1990;99:1032-1036
Lack of Association Between Oral Contraceptive Use and Ulcerative Colitis BRET A. LASHNER,
and STEPHEN
SUNANDA
V. KANE,
B. HANAUER
Section of Gastroenterology, University of Chicago Medical Center, Chicago, Illinois
Previous epidemiological studies suggesting an association between oral contraceptive use and ulcerative colitis incidence have been weak and conflicting. To measure a possible association, 46 incident cases of ulcerative colitis patients, women aged 18-50 years, were compared with peer-nominated agematched and sex-matched controls. There were no differences between case and control patients in demographic characteristics. There was no association between oral contraceptive use and ulcerative colitis (current use: odds ratio 0.70, 95% confidence interval 0.27-1.83; former use: odds ratio 1.14, confidence interval 0.41-3.15; current or former use: odds ratio 0.86, confidence interval 0.40-1.85). Stratifying by disease location (pancolitis or left-sided disease) also failed to identify an association. Controlling for possible confounding effects of cigarette smoking did not alter the lack of association between oral contraceptive use and ulcerative colitis. Similarly, testing for interaction failed to demonstrate any effect modification. Analyzing for duration of current oral contraceptive use or time interval since last use failed to demonstrate a “dose-response” effect. The study was of sufficient size to detect statistical significance for oral contraceptive use for odds ratios of 2.8 and higher. In this matched case-control study of incident cases and community controls, there was no association between oral contraceptive use and ulcerative colitis incidence. To date, there is no evidence suggesting that women predisposed to the development of ulcerative colitis should be advised to avoid oral contraceptive use.
vv
omen predisposed to develop ulcerative colitis (UC) are often advised to avoid using oral contraceptives because they are thought to be associated with disease and may be an etiologic agent. However, the available data implicating oral contraceptive use as an etiology for UC are weak and
conflicting. Three large cohort studies have demonstrated moderate elevations in relative risk with low statistical power because of the extremely small number of UC cases that develop (l-3). In distinction, women under age 50 have slightly lower age-specific incidence rates for UC than men (4). A case-control study using community controls showed a weak protective effect from oral contraceptive use (5), and a case series showed that women with UC used oral contraceptives rarely and less often than women with Crohn’s disease (CD) (6). As reported in our earlier study, there is no association between oral contraceptive use and CD (7). In reviewing the literature, it became clear that the purported risk of oral contraceptive use in UC was derived from weak and conflicting studies. This study was initiated to better define the association. The methods developed for studying CD patients were extended to a separate population of UC patients and matched control patients. As in our earlier study, the current one is a matched case-control study of incident cases and community controls. Materials and Methods Case and Control Patients The methods for this study were similar to a related case-control study of oral contraceptive use in CD (7). Cases were identified from the inflammatory bowel disease (IBD) registry of all outpatients evaluated since 1981. Eligible cases in the registry were all women with a confirmed diagnosis of UC whose date of symptom onset was after 1985 and whose age at that time was between 18 and 59. Disease was unequivocally diagnosed by radiological, endoscopic, or pathological evidence using standard criteria (8). To better define a population of incident cases, eligible case patients Abbreviations used in this paper: CI, con5dence interval; OR, odds ratio. o 1990 by the American Gastroenterological Association 0016-5065/90/$3.00
October 1999
had to have a date of symptom onset, rather than a date of disease diagnosis, within 3 years of the study questionnaire. Woman were excluded if they had had a hysterectomy or a contraindication for oral contraceptive use, such as hypertension or a history of thromboembolism. All cases were contacted and interviewed over the telephone by one of the investigators (S.V.K.). After obtaining verbal informed consent, but before collecting information for the study, the patient was asked to name two women friends from her neighborhood; these women were unrelated to each other and to the patient and were within 5 years of age of the patient. One of these friends was chosen at random, using a random number table, and was asked to participate in a telephone interview. If the control refused, had a hysterectomy, or had a contraindication for oral contraceptive use, the second peer-nominated control was contacted and entered into the study. Medical records were not examined for medication or oral contraceptive use because such information would not be available in all cases or in any controls.
Questionnaire The same standardized questionnaire was used for both cases and controls. The principal variable in the questionnaire concerned oral contraceptive use at the time of the case’s symptom onset; current use was defined as use within 12 months of symptom onset and former use was defined as at least 3 months of use until 12 months before symptom onset. Duration of current oral contraceptive use or duration of past use were recorded. Dose and the specific formulation were not recorded. Potential confounding variables such as cigarette smoking, age, race, and number of pregnancies were also collected. The study was approved by the Clinical Investigation Committee of the University of Chicago.
ORAL CONTRACEPTIVE
USE AND ULCERATIVE COLITIS
terms between current oral contraceptive use and current cigarette smoking were also tested with conditional logistic regression. Power calculations for matched data were performed for women who were either current or former users of oral contraceptives before symptom onset (10). Descriptive statistics are presented as mean + SD.
Results All 46 eligible cases were contacted and they agreed to participate. Four of the peer-nominated controls refused to participate, but the alternate control agreed. Table 1 provides characteristics of the case and the control groups. Both groups were similar in age, race, religion, marital status, and pregnancy fre-
quency. Oral contraceptive use was not different between groups. Current smoking in UC patients was rare (6.5%), and cases were less likely to be current smokers and more likely to be former smokers than controls. Table 2 demonstrates the results of the crude analysis of the association between oral contraceptive use and UC in the total group and in groups stratified by disease location. None of the ORs were significantly different from unity, and there was no apparent effect from stratifying by disease location. Table 3 demonstrates the results of the crude analysis of the association between cigarette smoking and UC. Generally, ORs were less than unity for current smoking and greater than unity for former smoking, but the results were not statistically significant in any stratum because of the low frequency of cigarette smoking among case and control patients. Table 1. Characteristics
Analysis Matched case-control methods for one control per case were used. Crude odds ratios (ORs) were calculated from the ratio of discordant pairs, and significance testing was performed using McNemar’s test (9,lO). A 95% confidence interval (CI) that excluded unity was statistically significant with P < 0.05. Stratified analyses were performed according to location of disease (pancolitis or left-sided disease) to examine for site-specific effects. Pancolitis was defined as continuous disease from the rectum to a point proximal to the splenic flexure; left-sided disease was defined as continuous disease from the rectum to a point distal to the splenic flexure. To adjust for possible confounding effects, conditional logistic regression was performed (9). Each model constructed contained the variables “current oral contraceptive use” and “former contraceptive use”: additional variables were included only if the fit was improved significantly according to the goodness-of-fit statistic. Differences between models in the goodness-of-fit statistic approximated a chi-squared distribution with the number of degrees of freedom taken as the difference in degrees of freedom between models. Models that included interaction
1033
Variable
Age Ml Range White Jewish Married Pregnancy Ever No. Range Family history of IBD Oral contraceptive use Current use Years Range Former use Years Range Cigarette smoking Current Former Pack-years (total) Range
of the Case and Control Groups Cases (n = 46)
Controls (n = 46)
32.1 * 8.4 19-48 44 17 22
31.6 f 6.5 18-48 38 9 19
15 1.9 zt 0.6 l-3 5
18 2.3 * 2.1 l-10 2
12 3.1 zt 1.8 l-6 10 3.2 zt 1.6 l-5
15 3.2 + 2.2 l-9 9 4.7 f 2.8 2-10
3 7 9.3 f 6.8 3-25
7 3 18.8 * 40.1 1-132
1034
LASHNER
GASTROENTEROLOGY
ET AL.
Table 2. The Association
Between
Oral Contraceptive
Use
Table 4. Conditional Logistic Regression Models forthe
and Ulcerative Colitis Stratified by Disease Location Oral contraceptive
use
Total group (46 pairs] Current use Former use Current or former use Pancolitis (15 pairs) Current use Former use Current or former use Left-sided colitis (31 pairs] Current use Former use Current or former use
Association Ulcerative
OR
95% CI
0.70 1.14 0.86
0.27-1.83 0.41-3.15 0.40-1.85
0.00 3.00 0.50
0.35-25.8 0.13-1.95
1.40 0.83 1.13
0.25-2.73 0.43-2.91
Table 4 demonstrates the results of the adjusted analysis (conditional logistic regression] to control for confounding effects and to test for “dose-response.” Model 1 controlled for the possible confounding effect of cigarette smoking. For oral contraceptive use, ORs did not differ greatly from unity and from the unadjusted values. Similarly, as in the unadjusted analysis, the effect of cigarette smoking on UC incidence was less than unity for current smoking and greater than unity for former smoking. The fit of model 1 did not differ significantly from the model that included only current and former contraceptive use (x2 = 4.4, 2 df, P = 0.111, thus implying that there was no confounding effect on oral contraceptive use from cigarette smoking. Models 2 and 3 in Table 4 tested for a possible “dose-response” for duration of current use or duraTable 3. The Association Between Cigarette Smoking and Ulcerative Colitisstratified by Disease Location Total group (46 pairs] Current smokers Former smokers Current or former smokers Pancolitis (15 pairs] Current smokers Former smokers Current or former smokers Left-sided disease (31 pairs) Current smokers Former smokers Current or former smokers
OR
95% CI
0.33 3.00 1.00
0.07-1.53 0.66-13.8 -
0.00
b
2
0.45-4.39
“rhe case, rather than the control. was a current user of oral contraceptives in all five discordant pairs for current oral contraceptive use among pairs with pancolitis (P < 0.05).
Cigarette smoking
Model No. 1
0
0
b
0.33
0.04-2.87
0.67 2.50 1.40
0.11-3.94 0.51-12.2 0.45-4.39
7’he case, rather than the control, was a current smoker in all three discordant pairs for current smokers among pairs with pancolitis (NW. bThe control patient, rather than the case patient, was a former smoker for the single discordant pair for smoking among pairs with pancolitis (NS].
Vol. 99, No. 4
Between Colitis
Oral Contraceptives
Variable
OR
95% CI
Current OC use Former OC use Current CS Former CS
0.68 0.71 0.33 3.58
0.24-1.93 0.22-2.30 0.06-1.66 0.64-20.0
Current OC use Less than 4 yr At least 4 yr Former OC use Current CS Former CS
1.13 0.53 0.68 0.33 3.72
0.23-5.65 0.16-1.79 0.21-2.20 0.65-1.69 0.66-20.9
0.68
0.24-1.94
0.74 0.70 0.33 3.59
0.09-5.81 0.18-2.77 0.06-1.67 0.64-20.0
Current OC use Former OC use Less than 4 yr At least 4 yr Current CS Former CS
3
and
OC. oral contraceptive; CS, cigarette smoking.
tion since past use. Separating current oral contraceptive use into two strata according to duration of use [model 2) did not improve the fit of the regression (chi-squared 0.7, one degree of freedom, P = 0.40). Similarly, separating former oral contraceptive use into two strata according to duration since past use (model 3) did not improve the fit of the regression (chi-square 0.0, 1 degree of freedom, P = 1.00). Other logistic models that examined each of the other collected variables did not improve the fit or provide any additional insights into the association between oral contraceptive use and UC. Conditional logistic regression models that included interaction terms between current oral contraceptive use and current smoking did not improve the fit of the regression and did not demonstrate any significant effect modification. Adding an interaction term of current oral contraceptive use times current smoking to model 1 did not improve the fit of the regression (chi-squared 1.4, one degree of freedom, P = 0.24). The study was sufficiently large to detect statistical significance for oral contraceptive use ORs of 2.8 or higher [one-sided type I error of 5‘70, type II error of 20%, 26 discordant pairs for oral contraceptive use]. To demonstrate statistical significance with an OR of at least 2.0, more than 53 discordant pairs would be needed, which probably would have been achieved with a sample size of 94 pairs. Discussion In this matched case-control study of incident cases and community controls, there is no association between oral contraceptive use and UC. This conclu-
October 1990
sion is based on the facts that ORs were not significantly different from unity and there was no “doseresponse” effect, no confounding effects from cigarette smoking, or interaction between oral contraceptive use and cigarette smoking. The results appear to be externally valid, because the association between cigarette smoking and UC is consistent with previous studies. Our study contrasts with other studies on the subject. Three large cohort studies have suggested a weak but harmful effect from oral contraceptive use on the incidence of UC. The Royal College of General Practitioners studied 23,611 oral contraceptive users and compared them with 22,766 control patients matched for age and marital status (1). Sixteen current oral contraceptive users, one former user, and ten controls developed UC during the follow-up period. The incidence rate ratio was 2.06 for current users and 0.43 for former users. Neither relationship was statistically significant and neither was considered to be an important association by the investigators. No adjustment was made for possible confounding factors such as cigarette smoking. The Walnut Creek Contraceptive Study examined 17,939 women from 1968 for an average of 6.5 years (2). All six UC cases that developed were women under 40 years of age who were current oral contraceptive users. When UC patients were combined with the 10 subjects who developed CD, the relative risk of developing IBD for women 18-39 years old was 3.4 among current oral contraceptive users, and 2.5 among former users. Because of the small number of IBD cases, the results were of low statistical power making the relative risk estimates imprecise. Furthermore, the possibility of error caused by confounding and diagnostic bias was large. The Oxford Family Planning Association Contraceptive study followed 17,032 women from 1968 to 1974 in 17 family planning clinics in England and Scotland (3); 56% of the women were oral contraceptive users. Thirty-one cases of UC developed. Current users had an incidence rate ratio of 2.4, and former users had an incidence rate ratio of 2.6. The results were statistically significant but showed no dose-response effect. Users of more than 2 years had the same incidence rates as users of less than 2 years. In contrast, other studies have demonstrated a weak protective effect from oral contraceptive use on the incidence of UC. A case-control study from Baltimore, published as a letter to the editor, compared 35 incident cases of UC to 30 hospital controls and 38 community controls (5). The ORs were similar using each of the two control groups, were less than unity, and were not statistically significant. For community controls, the OR was 0.57 with a 95% CI of 0.11-2.88. A case series from England described only 3 of 35 incident cases of UC (8.6%) as current users of oral
ORAL CONTRACEPTIVE
USE AND ULCERATIVE
COLITIS
1035
contraceptives, a rate significantly lower statistically than was seen in incident cases of CD (63%) (6). Overall, implications in the literature of any effect from oral contraceptive use on the incidence of UC are weak and conflicting. Nonsmoking of cigarettes has been consistently identified as an etiologic factor in UC from numerous epidemiological studies and case reports (ll-161. Despite the choice of control group, ORs for current smokers have been significantly below unity. In contrast, former smokers have ORs greater than unity, although results are not always statistically significant. Case-control studies using a variety of control groups have ORs for current smokers ranging from 0.1-0.6 and ORs for former smokers ranging from 1.1-2.8 (11-19). Studies that examine sex-specific ORs demonstrate little difference between men and women (12,15,16,18,19). Even though the patients in two case reports of improved UC symptoms with cigarette smoking (or nicotine chewing gum) were women (20,21), there is no evidence that women and men demonstrate separate UC risks from smoking. Our study was not designed to specifically evaluate the relationship between cigarette smoking and UC. However, the consistency between the findings in our study and other studies designed to evaluate a smoking association provided external validity for our results and conclusions. Statistical significance for cigarette smoking in UC incidence in our study was not reached because of the extremely small number of cases who were current smokers and the small number of controls who were former smokers. Biased conclusions in our study may have been introduced from two sources: diagnostic bias from confusing mesenteric vascular ischemia with UC and selection bias from using peer-nominated controls. Mesenteric vascular ischemia induced by oral contraceptive use has been shown to induce gastrointestinal lesions similar to IBD, particularly CD lesions (22-25). Cellular infiltration of the lamina propria, granulomata, aphthoid ulceration, colonic skip lesions with rectal sparing, and stricture in the terminal ileum have been reported as rare complications in women using oral contraceptives. Confluent ulcerations in the colon can mimic UC lesions. These lesions completely reverse when oral contraceptives are discontinued. If cases of mesenteric vascular ischemia are used in epidemiological studies of IBD, the results would be biased toward a more positive association from oral contraceptive use. This diagnostic bias may partially explain some of the weak effects reported in the literature cohort studies; however, the rigorous diagnostic criteria of our registry and the demonstrated lack of effect from oral contraceptives minimize the possibility of this diagnostic bias in our study. The choice of controls in a case-control study can be
1036
LASHNER ET AL.
an important source of selection bias. The association between oral contraceptive use and UC is best studied with community controls, rather than hospital controls, to avoid bias related to hospital admission rates (Berkson’s bias] (26). Peer-nominated community controls offer an efficient method of obtaining matched community controls (27). The use of friends as controls will bias the results only if the study exposure is a determinant of friendship (27). Whereas cigarette smoking, occupation, and alcohol use may be determinants of friendship, it is highly unlikely that oral contraceptive use, as the principal study exposure, is a determinant of friendship. This efficient method of collecting community controls for this population, we feel, is associated only with a small bias. The present study was of sufficient power to adequately examine a effect of oral contraceptive use on UC with an OR of at least 2.8. An association with an OR less than 2.8 can be clinically important and may be statistically significant with a larger sample size. However, review of our data with ORs for both current oral contraceptive use and current or former oral contraceptive use of less than unity does not suggest that increasing the sample size will lead to results that will be any more clinically useful even though there will be greater power. Most likely, oral contraceptive use is not an etiologic factor for UC and there is no interaction between oral contraceptive use and cigarette smoking in patients who develop UC. There is no evidence that women predisposed to the development of UC should be advised to avoid oral contraceptive use. References 1. Royal College of General Practitioners. Oral contraceptives and health: an interim report from the oral contraceptive study of the Royal College of General Practitioners. London: Pitman. 1974. 2. Ramcharan S, ed. The Walnut Creek contraceptive drug study: a prospective study of the side effects of oral contraceptives. Washington, DC: DHEW Publication 74-562.1981. 3. Vessey M. Jewel1 D. Smith A. Yeates D, McPherson K. Chronic inflammatory bowel disease, cigarette smoking, and use of oral contraceptives: findings in a large cohort study of women of childbearing age. Br Med J 1986;292:1101-1103. 4. Calkins BM, Lilienfeld AM, Garland CF. Mendeloff AI. Trends in the incidence rates of ulcerative colitis and Crohn’s disease. Dig Dis Sci 1984:29:913-920. 5. Calkins BM. Mendeloff AI, Garland C. Inflammatory bowel disease in oral contraceptive users (lett). Gastroenterology 1986: 91:523-524. 6. Rhodes JM, Cocker R. Allan RN, Hawker PC, Dawson J, Elias E. Colonic Crohn’s disease and use of oral contraception. Br Med J 1984:288:595-596. 7. Lashner BA, Kane SV, Hanauer SB. Lack of association be-
GASTROENTEROLOGY
8. 9.
10. 11. 12.
13.
14.
15. 16.
17. 18. 19. 20. 21. 22.
23
24.
25.
26. 27.
Vol. 99, No. 4
tween oral contraceptive use and Crohn’s disease: a communitybased matched case-control study. Gastroenterology 1989;97: 1442-1447. Kirsner JB, Shorter RG. eds. Inflammatory bowel disease. 3rd ed. Philadelphia: Lea & Febiger, 1988. Breslow NE, Day NE. Statistical methods in cancer research. The analysis of case-control studies. Volume 1. Lyon: International Agency for Research on Cancer, Publication No. 32.1980. Schlesselman JJ. Case-control studies. New York: Oxford, 1982. Benoni C, Nilsson A. Smoking habits in patients with inflammatory bowel disease. Stand J Gastroenterol1984:19:824-830. Franceschi S, Panza E, La Vecchia C, Parazzini F, Decarli A. Porro GB. Nonspecific inflammatory bowel disease and smoking. Am J Epidemiol1987;125:445-452. Tobin MV, Logan RFA, Langman MJS, McConnell RB, Gilmore IT. Cigarette smoking and inflammatory bowel disease. Gastroenterology 1987;93:316-321. Boyko EJ, Koepsell TD. Perera DR, Inui TS. Risk of ulcerative colitis among former and current cigarette smokers. N Engl J Med 1987;316:707-710. Jick H. Walker AM. Cigarette smoking and ulcerative colitis. N Engl J Med 1983;308:261-263. Lindberg E, Tysk C, Andersson K, Jarnerot G. Smoking and inflammatory bowel disease: a case-control study. Gut 198829: 352-357. Holdstock G, Savage D, Harman M, Wright R. Should patients with inflammatory bowel disease smoke? Br Med J 1984;288:362. Logan RFA, Edmond M, Somerville KW, Langman MJS. Smoking and ulcerative colitis. Br Med J 1984;288:751-753. Harries AD, Baird A, Rhodes J. Non-smoking: a feature of ulcerative colitis. Br Med J 1982;284:706. Roberts CJ, Diggle R. Non-smoking: a feature of ulcerative colitis (lett]. Br Med J 1984;288:440. Bures J, Fixa B, Komarkova 0, Fingerland A. Non-smoking: a feature of ulcerative colitis (lett]. Br Med J 1984;285:440. Hurwitz RL, Martin Al, Grossman BE. Waddell WR. Oral contraceptives and gastrointestinal disorders. Ann Surg 1970;172: 892-896. Morowitz DA, Epstein BH. Spectrum of bowel disease associated with use of oral contraceptives. Med Ann of DC 1973:42:610. Camelleri M, Schafler K, Chadwick VS, Hodgeson HJ, Weinbren K. Periportal sinusoidal dilatation, inflammatory bowel disease, and the contraceptive pill. Gastroenterology 1981;80:810815. Tedesco FJ, Volpicelli NA, Moore FS. Estrogen- and progesterone-associated colitis: a disorder with clinical and endoscopic features mimicking Crohn’s colitis. Gastrointest Endosc 1982;28: 247-249. Roberts RS. Spitzer WO, Delmore T, Sackett DL. A empiric demonstration of Be&son’s bias. J Chronic Dis 1978;31:119-128. Flanders WD, Austin H. Possibility of selection bias in matched case-control studies using friend controls. Am J Epidemiol 1986;124:150-153.
Received October 11.1989. Accepted April 19.1990. Address requests for reprints to: Bret A. Lashner, M.D., M.P.H., University of Chicago Medical Center, Box 490, 5841 South Maryland Avenue, Chicago, Illinois 60637. This research was supported by the David and Reva Logan Center for Clinical Gastrointestinal Research and the Gastrointestinal Research Foundation Junior Board.
Lack of Association Between Oral Contraceptive Use and Ulcerative Colitis BRET A. LASHNER,
and STEPHEN
SUNANDA
V. KANE,
B. HANAUER
Section of Gastroenterology, University of Chicago Medical Center, Chicago, Illinois
Previous epidemiological studies suggesting an association between oral contraceptive use and ulcerative colitis incidence have been weak and conflicting. To measure a possible association, 46 incident cases of ulcerative colitis patients, women aged 18-50 years, were compared with peer-nominated agematched and sex-matched controls. There were no differences between case and control patients in demographic characteristics. There was no association between oral contraceptive use and ulcerative colitis (current use: odds ratio 0.70, 95% confidence interval 0.27-1.83; former use: odds ratio 1.14, confidence interval 0.41-3.15; current or former use: odds ratio 0.86, confidence interval 0.40-1.85). Stratifying by disease location (pancolitis or left-sided disease) also failed to identify an association. Controlling for possible confounding effects of cigarette smoking did not alter the lack of association between oral contraceptive use and ulcerative colitis. Similarly, testing for interaction failed to demonstrate any effect modification. Analyzing for duration of current oral contraceptive use or time interval since last use failed to demonstrate a “dose-response” effect. The study was of sufficient size to detect statistical significance for oral contraceptive use for odds ratios of 2.8 and higher. In this matched case-control study of incident cases and community controls, there was no association between oral contraceptive use and ulcerative colitis incidence. To date, there is no evidence suggesting that women predisposed to the development of ulcerative colitis should be advised to avoid oral contraceptive use.
vv
omen predisposed to develop ulcerative colitis (UC) are often advised to avoid using oral contraceptives because they are thought to be associated with disease and may be an etiologic agent. However, the available data implicating oral contraceptive use as an etiology for UC are weak and
conflicting. Three large cohort studies have demonstrated moderate elevations in relative risk with low statistical power because of the extremely small number of UC cases that develop (l-3). In distinction, women under age 50 have slightly lower age-specific incidence rates for UC than men (4). A case-control study using community controls showed a weak protective effect from oral contraceptive use (5), and a case series showed that women with UC used oral contraceptives rarely and less often than women with Crohn’s disease (CD) (6). As reported in our earlier study, there is no association between oral contraceptive use and CD (7). In reviewing the literature, it became clear that the purported risk of oral contraceptive use in UC was derived from weak and conflicting studies. This study was initiated to better define the association. The methods developed for studying CD patients were extended to a separate population of UC patients and matched control patients. As in our earlier study, the current one is a matched case-control study of incident cases and community controls. Materials and Methods Case and Control Patients The methods for this study were similar to a related case-control study of oral contraceptive use in CD (7). Cases were identified from the inflammatory bowel disease (IBD) registry of all outpatients evaluated since 1981. Eligible cases in the registry were all women with a confirmed diagnosis of UC whose date of symptom onset was after 1985 and whose age at that time was between 18 and 59. Disease was unequivocally diagnosed by radiological, endoscopic, or pathological evidence using standard criteria (8). To better define a population of incident cases, eligible case patients Abbreviations used in this paper: CI, con5dence interval; OR, odds ratio. o 1990 by the American Gastroenterological Association 0016-5065/90/$3.00
October 1999
had to have a date of symptom onset, rather than a date of disease diagnosis, within 3 years of the study questionnaire. Woman were excluded if they had had a hysterectomy or a contraindication for oral contraceptive use, such as hypertension or a history of thromboembolism. All cases were contacted and interviewed over the telephone by one of the investigators (S.V.K.). After obtaining verbal informed consent, but before collecting information for the study, the patient was asked to name two women friends from her neighborhood; these women were unrelated to each other and to the patient and were within 5 years of age of the patient. One of these friends was chosen at random, using a random number table, and was asked to participate in a telephone interview. If the control refused, had a hysterectomy, or had a contraindication for oral contraceptive use, the second peer-nominated control was contacted and entered into the study. Medical records were not examined for medication or oral contraceptive use because such information would not be available in all cases or in any controls.
Questionnaire The same standardized questionnaire was used for both cases and controls. The principal variable in the questionnaire concerned oral contraceptive use at the time of the case’s symptom onset; current use was defined as use within 12 months of symptom onset and former use was defined as at least 3 months of use until 12 months before symptom onset. Duration of current oral contraceptive use or duration of past use were recorded. Dose and the specific formulation were not recorded. Potential confounding variables such as cigarette smoking, age, race, and number of pregnancies were also collected. The study was approved by the Clinical Investigation Committee of the University of Chicago.
ORAL CONTRACEPTIVE
USE AND ULCERATIVE COLITIS
terms between current oral contraceptive use and current cigarette smoking were also tested with conditional logistic regression. Power calculations for matched data were performed for women who were either current or former users of oral contraceptives before symptom onset (10). Descriptive statistics are presented as mean + SD.
Results All 46 eligible cases were contacted and they agreed to participate. Four of the peer-nominated controls refused to participate, but the alternate control agreed. Table 1 provides characteristics of the case and the control groups. Both groups were similar in age, race, religion, marital status, and pregnancy fre-
quency. Oral contraceptive use was not different between groups. Current smoking in UC patients was rare (6.5%), and cases were less likely to be current smokers and more likely to be former smokers than controls. Table 2 demonstrates the results of the crude analysis of the association between oral contraceptive use and UC in the total group and in groups stratified by disease location. None of the ORs were significantly different from unity, and there was no apparent effect from stratifying by disease location. Table 3 demonstrates the results of the crude analysis of the association between cigarette smoking and UC. Generally, ORs were less than unity for current smoking and greater than unity for former smoking, but the results were not statistically significant in any stratum because of the low frequency of cigarette smoking among case and control patients. Table 1. Characteristics
Analysis Matched case-control methods for one control per case were used. Crude odds ratios (ORs) were calculated from the ratio of discordant pairs, and significance testing was performed using McNemar’s test (9,lO). A 95% confidence interval (CI) that excluded unity was statistically significant with P < 0.05. Stratified analyses were performed according to location of disease (pancolitis or left-sided disease) to examine for site-specific effects. Pancolitis was defined as continuous disease from the rectum to a point proximal to the splenic flexure; left-sided disease was defined as continuous disease from the rectum to a point distal to the splenic flexure. To adjust for possible confounding effects, conditional logistic regression was performed (9). Each model constructed contained the variables “current oral contraceptive use” and “former contraceptive use”: additional variables were included only if the fit was improved significantly according to the goodness-of-fit statistic. Differences between models in the goodness-of-fit statistic approximated a chi-squared distribution with the number of degrees of freedom taken as the difference in degrees of freedom between models. Models that included interaction
1033
Variable
Age Ml Range White Jewish Married Pregnancy Ever No. Range Family history of IBD Oral contraceptive use Current use Years Range Former use Years Range Cigarette smoking Current Former Pack-years (total) Range
of the Case and Control Groups Cases (n = 46)
Controls (n = 46)
32.1 * 8.4 19-48 44 17 22
31.6 f 6.5 18-48 38 9 19
15 1.9 zt 0.6 l-3 5
18 2.3 * 2.1 l-10 2
12 3.1 zt 1.8 l-6 10 3.2 zt 1.6 l-5
15 3.2 + 2.2 l-9 9 4.7 f 2.8 2-10
3 7 9.3 f 6.8 3-25
7 3 18.8 * 40.1 1-132
1034
LASHNER
GASTROENTEROLOGY
ET AL.
Table 2. The Association
Between
Oral Contraceptive
Use
Table 4. Conditional Logistic Regression Models forthe
and Ulcerative Colitis Stratified by Disease Location Oral contraceptive
use
Total group (46 pairs] Current use Former use Current or former use Pancolitis (15 pairs) Current use Former use Current or former use Left-sided colitis (31 pairs] Current use Former use Current or former use
Association Ulcerative
OR
95% CI
0.70 1.14 0.86
0.27-1.83 0.41-3.15 0.40-1.85
0.00 3.00 0.50
0.35-25.8 0.13-1.95
1.40 0.83 1.13
0.25-2.73 0.43-2.91
Table 4 demonstrates the results of the adjusted analysis (conditional logistic regression] to control for confounding effects and to test for “dose-response.” Model 1 controlled for the possible confounding effect of cigarette smoking. For oral contraceptive use, ORs did not differ greatly from unity and from the unadjusted values. Similarly, as in the unadjusted analysis, the effect of cigarette smoking on UC incidence was less than unity for current smoking and greater than unity for former smoking. The fit of model 1 did not differ significantly from the model that included only current and former contraceptive use (x2 = 4.4, 2 df, P = 0.111, thus implying that there was no confounding effect on oral contraceptive use from cigarette smoking. Models 2 and 3 in Table 4 tested for a possible “dose-response” for duration of current use or duraTable 3. The Association Between Cigarette Smoking and Ulcerative Colitisstratified by Disease Location Total group (46 pairs] Current smokers Former smokers Current or former smokers Pancolitis (15 pairs] Current smokers Former smokers Current or former smokers Left-sided disease (31 pairs) Current smokers Former smokers Current or former smokers
OR
95% CI
0.33 3.00 1.00
0.07-1.53 0.66-13.8 -
0.00
b
2
0.45-4.39
“rhe case, rather than the control. was a current user of oral contraceptives in all five discordant pairs for current oral contraceptive use among pairs with pancolitis (P < 0.05).
Cigarette smoking
Model No. 1
0
0
b
0.33
0.04-2.87
0.67 2.50 1.40
0.11-3.94 0.51-12.2 0.45-4.39
7’he case, rather than the control, was a current smoker in all three discordant pairs for current smokers among pairs with pancolitis (NW. bThe control patient, rather than the case patient, was a former smoker for the single discordant pair for smoking among pairs with pancolitis (NS].
Vol. 99, No. 4
Between Colitis
Oral Contraceptives
Variable
OR
95% CI
Current OC use Former OC use Current CS Former CS
0.68 0.71 0.33 3.58
0.24-1.93 0.22-2.30 0.06-1.66 0.64-20.0
Current OC use Less than 4 yr At least 4 yr Former OC use Current CS Former CS
1.13 0.53 0.68 0.33 3.72
0.23-5.65 0.16-1.79 0.21-2.20 0.65-1.69 0.66-20.9
0.68
0.24-1.94
0.74 0.70 0.33 3.59
0.09-5.81 0.18-2.77 0.06-1.67 0.64-20.0
Current OC use Former OC use Less than 4 yr At least 4 yr Current CS Former CS
3
and
OC. oral contraceptive; CS, cigarette smoking.
tion since past use. Separating current oral contraceptive use into two strata according to duration of use [model 2) did not improve the fit of the regression (chi-squared 0.7, one degree of freedom, P = 0.40). Similarly, separating former oral contraceptive use into two strata according to duration since past use (model 3) did not improve the fit of the regression (chi-square 0.0, 1 degree of freedom, P = 1.00). Other logistic models that examined each of the other collected variables did not improve the fit or provide any additional insights into the association between oral contraceptive use and UC. Conditional logistic regression models that included interaction terms between current oral contraceptive use and current smoking did not improve the fit of the regression and did not demonstrate any significant effect modification. Adding an interaction term of current oral contraceptive use times current smoking to model 1 did not improve the fit of the regression (chi-squared 1.4, one degree of freedom, P = 0.24). The study was sufficiently large to detect statistical significance for oral contraceptive use ORs of 2.8 or higher [one-sided type I error of 5‘70, type II error of 20%, 26 discordant pairs for oral contraceptive use]. To demonstrate statistical significance with an OR of at least 2.0, more than 53 discordant pairs would be needed, which probably would have been achieved with a sample size of 94 pairs. Discussion In this matched case-control study of incident cases and community controls, there is no association between oral contraceptive use and UC. This conclu-
October 1990
sion is based on the facts that ORs were not significantly different from unity and there was no “doseresponse” effect, no confounding effects from cigarette smoking, or interaction between oral contraceptive use and cigarette smoking. The results appear to be externally valid, because the association between cigarette smoking and UC is consistent with previous studies. Our study contrasts with other studies on the subject. Three large cohort studies have suggested a weak but harmful effect from oral contraceptive use on the incidence of UC. The Royal College of General Practitioners studied 23,611 oral contraceptive users and compared them with 22,766 control patients matched for age and marital status (1). Sixteen current oral contraceptive users, one former user, and ten controls developed UC during the follow-up period. The incidence rate ratio was 2.06 for current users and 0.43 for former users. Neither relationship was statistically significant and neither was considered to be an important association by the investigators. No adjustment was made for possible confounding factors such as cigarette smoking. The Walnut Creek Contraceptive Study examined 17,939 women from 1968 for an average of 6.5 years (2). All six UC cases that developed were women under 40 years of age who were current oral contraceptive users. When UC patients were combined with the 10 subjects who developed CD, the relative risk of developing IBD for women 18-39 years old was 3.4 among current oral contraceptive users, and 2.5 among former users. Because of the small number of IBD cases, the results were of low statistical power making the relative risk estimates imprecise. Furthermore, the possibility of error caused by confounding and diagnostic bias was large. The Oxford Family Planning Association Contraceptive study followed 17,032 women from 1968 to 1974 in 17 family planning clinics in England and Scotland (3); 56% of the women were oral contraceptive users. Thirty-one cases of UC developed. Current users had an incidence rate ratio of 2.4, and former users had an incidence rate ratio of 2.6. The results were statistically significant but showed no dose-response effect. Users of more than 2 years had the same incidence rates as users of less than 2 years. In contrast, other studies have demonstrated a weak protective effect from oral contraceptive use on the incidence of UC. A case-control study from Baltimore, published as a letter to the editor, compared 35 incident cases of UC to 30 hospital controls and 38 community controls (5). The ORs were similar using each of the two control groups, were less than unity, and were not statistically significant. For community controls, the OR was 0.57 with a 95% CI of 0.11-2.88. A case series from England described only 3 of 35 incident cases of UC (8.6%) as current users of oral
ORAL CONTRACEPTIVE
USE AND ULCERATIVE
COLITIS
1035
contraceptives, a rate significantly lower statistically than was seen in incident cases of CD (63%) (6). Overall, implications in the literature of any effect from oral contraceptive use on the incidence of UC are weak and conflicting. Nonsmoking of cigarettes has been consistently identified as an etiologic factor in UC from numerous epidemiological studies and case reports (ll-161. Despite the choice of control group, ORs for current smokers have been significantly below unity. In contrast, former smokers have ORs greater than unity, although results are not always statistically significant. Case-control studies using a variety of control groups have ORs for current smokers ranging from 0.1-0.6 and ORs for former smokers ranging from 1.1-2.8 (11-19). Studies that examine sex-specific ORs demonstrate little difference between men and women (12,15,16,18,19). Even though the patients in two case reports of improved UC symptoms with cigarette smoking (or nicotine chewing gum) were women (20,21), there is no evidence that women and men demonstrate separate UC risks from smoking. Our study was not designed to specifically evaluate the relationship between cigarette smoking and UC. However, the consistency between the findings in our study and other studies designed to evaluate a smoking association provided external validity for our results and conclusions. Statistical significance for cigarette smoking in UC incidence in our study was not reached because of the extremely small number of cases who were current smokers and the small number of controls who were former smokers. Biased conclusions in our study may have been introduced from two sources: diagnostic bias from confusing mesenteric vascular ischemia with UC and selection bias from using peer-nominated controls. Mesenteric vascular ischemia induced by oral contraceptive use has been shown to induce gastrointestinal lesions similar to IBD, particularly CD lesions (22-25). Cellular infiltration of the lamina propria, granulomata, aphthoid ulceration, colonic skip lesions with rectal sparing, and stricture in the terminal ileum have been reported as rare complications in women using oral contraceptives. Confluent ulcerations in the colon can mimic UC lesions. These lesions completely reverse when oral contraceptives are discontinued. If cases of mesenteric vascular ischemia are used in epidemiological studies of IBD, the results would be biased toward a more positive association from oral contraceptive use. This diagnostic bias may partially explain some of the weak effects reported in the literature cohort studies; however, the rigorous diagnostic criteria of our registry and the demonstrated lack of effect from oral contraceptives minimize the possibility of this diagnostic bias in our study. The choice of controls in a case-control study can be
1036
LASHNER ET AL.
an important source of selection bias. The association between oral contraceptive use and UC is best studied with community controls, rather than hospital controls, to avoid bias related to hospital admission rates (Berkson’s bias] (26). Peer-nominated community controls offer an efficient method of obtaining matched community controls (27). The use of friends as controls will bias the results only if the study exposure is a determinant of friendship (27). Whereas cigarette smoking, occupation, and alcohol use may be determinants of friendship, it is highly unlikely that oral contraceptive use, as the principal study exposure, is a determinant of friendship. This efficient method of collecting community controls for this population, we feel, is associated only with a small bias. The present study was of sufficient power to adequately examine a effect of oral contraceptive use on UC with an OR of at least 2.8. An association with an OR less than 2.8 can be clinically important and may be statistically significant with a larger sample size. However, review of our data with ORs for both current oral contraceptive use and current or former oral contraceptive use of less than unity does not suggest that increasing the sample size will lead to results that will be any more clinically useful even though there will be greater power. Most likely, oral contraceptive use is not an etiologic factor for UC and there is no interaction between oral contraceptive use and cigarette smoking in patients who develop UC. There is no evidence that women predisposed to the development of UC should be advised to avoid oral contraceptive use. References 1. Royal College of General Practitioners. Oral contraceptives and health: an interim report from the oral contraceptive study of the Royal College of General Practitioners. London: Pitman. 1974. 2. Ramcharan S, ed. The Walnut Creek contraceptive drug study: a prospective study of the side effects of oral contraceptives. Washington, DC: DHEW Publication 74-562.1981. 3. Vessey M. Jewel1 D. Smith A. Yeates D, McPherson K. Chronic inflammatory bowel disease, cigarette smoking, and use of oral contraceptives: findings in a large cohort study of women of childbearing age. Br Med J 1986;292:1101-1103. 4. Calkins BM, Lilienfeld AM, Garland CF. Mendeloff AI. Trends in the incidence rates of ulcerative colitis and Crohn’s disease. Dig Dis Sci 1984:29:913-920. 5. Calkins BM. Mendeloff AI, Garland C. Inflammatory bowel disease in oral contraceptive users (lett). Gastroenterology 1986: 91:523-524. 6. Rhodes JM, Cocker R. Allan RN, Hawker PC, Dawson J, Elias E. Colonic Crohn’s disease and use of oral contraception. Br Med J 1984:288:595-596. 7. Lashner BA, Kane SV, Hanauer SB. Lack of association be-
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26. 27.
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tween oral contraceptive use and Crohn’s disease: a communitybased matched case-control study. Gastroenterology 1989;97: 1442-1447. Kirsner JB, Shorter RG. eds. Inflammatory bowel disease. 3rd ed. Philadelphia: Lea & Febiger, 1988. Breslow NE, Day NE. Statistical methods in cancer research. The analysis of case-control studies. Volume 1. Lyon: International Agency for Research on Cancer, Publication No. 32.1980. Schlesselman JJ. Case-control studies. New York: Oxford, 1982. Benoni C, Nilsson A. Smoking habits in patients with inflammatory bowel disease. Stand J Gastroenterol1984:19:824-830. Franceschi S, Panza E, La Vecchia C, Parazzini F, Decarli A. Porro GB. Nonspecific inflammatory bowel disease and smoking. Am J Epidemiol1987;125:445-452. Tobin MV, Logan RFA, Langman MJS, McConnell RB, Gilmore IT. Cigarette smoking and inflammatory bowel disease. Gastroenterology 1987;93:316-321. Boyko EJ, Koepsell TD. Perera DR, Inui TS. Risk of ulcerative colitis among former and current cigarette smokers. N Engl J Med 1987;316:707-710. Jick H. Walker AM. Cigarette smoking and ulcerative colitis. N Engl J Med 1983;308:261-263. Lindberg E, Tysk C, Andersson K, Jarnerot G. Smoking and inflammatory bowel disease: a case-control study. Gut 198829: 352-357. Holdstock G, Savage D, Harman M, Wright R. Should patients with inflammatory bowel disease smoke? Br Med J 1984;288:362. Logan RFA, Edmond M, Somerville KW, Langman MJS. Smoking and ulcerative colitis. Br Med J 1984;288:751-753. Harries AD, Baird A, Rhodes J. Non-smoking: a feature of ulcerative colitis. Br Med J 1982;284:706. Roberts CJ, Diggle R. Non-smoking: a feature of ulcerative colitis (lett]. Br Med J 1984;288:440. Bures J, Fixa B, Komarkova 0, Fingerland A. Non-smoking: a feature of ulcerative colitis (lett]. Br Med J 1984;285:440. Hurwitz RL, Martin Al, Grossman BE. Waddell WR. Oral contraceptives and gastrointestinal disorders. Ann Surg 1970;172: 892-896. Morowitz DA, Epstein BH. Spectrum of bowel disease associated with use of oral contraceptives. Med Ann of DC 1973:42:610. Camelleri M, Schafler K, Chadwick VS, Hodgeson HJ, Weinbren K. Periportal sinusoidal dilatation, inflammatory bowel disease, and the contraceptive pill. Gastroenterology 1981;80:810815. Tedesco FJ, Volpicelli NA, Moore FS. Estrogen- and progesterone-associated colitis: a disorder with clinical and endoscopic features mimicking Crohn’s colitis. Gastrointest Endosc 1982;28: 247-249. Roberts RS. Spitzer WO, Delmore T, Sackett DL. A empiric demonstration of Be&son’s bias. J Chronic Dis 1978;31:119-128. Flanders WD, Austin H. Possibility of selection bias in matched case-control studies using friend controls. Am J Epidemiol 1986;124:150-153.
Received October 11.1989. Accepted April 19.1990. Address requests for reprints to: Bret A. Lashner, M.D., M.P.H., University of Chicago Medical Center, Box 490, 5841 South Maryland Avenue, Chicago, Illinois 60637. This research was supported by the David and Reva Logan Center for Clinical Gastrointestinal Research and the Gastrointestinal Research Foundation Junior Board.