Cigarette smoking as a risk factor for pelvic inflammatory disease Polly A. Marchbanks, PhD, Nancy C. Lee, MD, and Herbert B. Peterson, MD Atlanta, Georgia To examine the relationship between cigarette smoking and pelvic inflammatory disease we analyzed data from a hospital-based, case-control study of pelvic inflammatory disease. Case subjects were 197 women hospitalized with their first episode of pelvic inflammatory disease; control subjects were 667 women hospitalized with nongynecologic conditions. Logistic regression was used to control for potentially confounding factors, including number of recent sexual partners, frequency of intercourse, and previous episodes of gonorrhea. Compared with women who had never smoked, current cigarette smokers had a significantly elevated relative risk of pelvic inflammatory disease of 1.7 (95% confidence interval, 1.1 to 2.5) . Similarly, former cigarette smokers had a significantly elevated relative risk of pelvic inflammatory disease of 2.3 (95% confidence interval, 1.3 to 4.2). However, a dose-response relationship was not observed. These results suggest that cigarette smoking is associated with pelvic inflammatory disease. Whether or not this association is causal requires clarification. The high prevalence of cigarette smoking and the serious consequences of pelvic inflammatory disease make such clarification an important consideration for future research. (AM J OBSTET GVNECOL 1990;162:639-44.)
Key words: Pelvic inflammatory disease, cigarette smoking, women, epidemiology
In the United States, 28 % of adult women smoke cigarettes on a regular basis; approximately half of all U.S. women have smoked cigarettes at some time in their lives. I In 1985 two case-control studies reported that cigarette smoking was an independent risk factor for tubal infertility.2 3 Because tubal infertility is usually the result of pelvic inflammatory disease, we hypothesized that cigarette smoking could be related to an increased risk of pelvic inflammatory disease . To investigate this hypothesis, we analyzed data from the Women's Health Study.
Material and methods The Women's Health Study has been described in d etail! In brief, it was a multicenter, hospital-based, case-control study of pelvic inflammatory disease. Enrollment and data collection occurred from 1976 through 1978 in 16 U.S. hospitals . Potential case and control women were identified by a daily surveillance of hospital records. Each prospective participant was asked to consent to an interview during her hospital stay and to a review of her medical records after discharge. Stu~y population. Case subjects were women 18 to 44 yea rs of age with a discha rge diagnosis of pelvic From the DIViswn of Reproductive H ealth, Center for Chromc DISease P revention and Health PromotIOn, Centers f Ol' DISease Control. R eceivedfor pubbcation May 23,1 989; reVISed October 13,1989; accepted N ovember 1, 1989. R eprints not avaIlable.
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inflammatory disease. Control subjects were women 18 to 44 years of age with a discharge diagnosis of a nongynecologic condition. Because an original goal of the Women's Health Study was to examine tae relationship between contraceptive use and pelvic inflammatory disease, women with discharge diagnoses thought to influence contraceptive choice we re excluded from the pool of potential controls. Three additional groups of women were excluded from being potential case subjects or potential controls: (I) women who reported no sexua l intercourse in the previous year, (2) women who had been sterilized for 2':30 d ays, and (3) women whose partners had been sterilized for 2':60 days. Although data collection for the Women's Health Study began in October 1976, the collection of information with regard to smoking was not initiated until April 1977. Therefore we could not include case and control su bjects enrolled before April 1977 in this analysis. In addition, we excluded women with a history of pelvic inflammatory disease and women with a pregnancy within the previous 3 months . After all exclusions , 197 women remained eligible as case subjects and 667 women remained eligible as control subjects. Data collection. Standardized personal interviews were used to collect information with regard to each woman's reproductive, contraceptive, and medical histories . Recent sexual behavior was assessed through questions concerning each woma n's number of sexual partners in the previous 6 months and her usual frequency of sexual intercourse in the previous 6 months. Info rmation about cigarette smoking included current
639
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Marchbanks, Lee, and Peterson
March 1990 Am J Obstet Gynecol
Table I. Percentage distribution of cases and controls by eight selected characteristics* Cases
Characteristic
Age (yr) 18-19 20-24 25-29 ~30
Race White Black Other Unknown Education (yr) 12
Marital status Currently married Cohabiting Previously married Never married Unknown Number of recent sexual partners 0-1 2-3 ~4
Unknown Frequency of intercourse (per week) 0-1 2-5 ~6
Unknown Previous episodes of gonorrhea None ~1
Unknown Current method of contraception None Intrauterine contraceptive device Oral contraceptives Barrier, other Unknown
(n
= 197) (%)
Controls
(n
= 667) (%)
19.3 38.6 22.8 19.3
11.2 35.4 22.6 30.7
47.2 36.0 16.2 0.5
53.7 27.9 18.3 0.2
31.5 39.1 29.4
22.0 35.4 42.6
24.9
35.2
10.7 21.3
7.7 19.0
43.2
37.9
0.0
0.2
77.2 17.3 5.6 0.0
88.8 8.7 1.8 0.8
45.7 43.2 10.7 0.5
53.8 41.2 3.6 1.4
80.2 19.3 0.5
91.9 7.8 0.3
42.6 27.4
31.9 14.1
18.3
31.3
11.2
21.1
0.5
1.5
*Totals may not equal 100% because of rounding.
abstraction permitted a final determination of study eligibility. In addition, the review of medical records permitted an evaluation of the certainty of each pelvic inflammatory disease diagnosis. Among the 197 case subjects in this analysis. 71 women (36.0%) had a discharge diagnosis of pelvic inflammatory disease that was based on operative findings; 40 women (20.3%), although they did not undergo surgery, had a discharge diagnosis of pelvic inflammatory disease plus a temperature elevation of >38 0 C on 2 or more days plus a hospital stay 7 days or longer. Eighty-six women (43.7%) who did not meet the above criteria had a discharge diagnosis of pelvic inflammatory disease plus medical management (antibiotics) for pelvic inflammatory disease. Microbiologic information for the cases of pelvic inflammatory disease was not obtained. Definitions. For our analysis, we defined a woman's current method of contraception as that method used at any time during the 3 months before interview. If more than one method had been used during this time, we used the following priority to determine the current method: (1) intrauterine contraceptive device; (2) oral contraceptives; (3) barrier methods; and (4) other. We considered that a woman currently used no method of contraception if she had not used any contraceptive method during each of the 3 months before interview. We defined a woman as previously married if her reported marital status was separated, divorced, or widowed. We defined a woman as cohabiting if she was living with a man who was not her husband. Analysis. On the basis of previous work with the Women's Health Study: we identified eight covariates that might potentially confound an association between cigarette smoking and pelvic inflammatory disease: age, race, education, marital status, number of recent sexual partners, frequency of intercourse, history of gonorrhea, and current method of contraception. We used logistic regression models containing these eight covariates to compute a~justed odds ratios as estimators of the relative risk of pelvic inflammatory disease; 95% confidence intervals accompany all of our relative risk point estimates. 5 To determine if the effect of smoking on the relative risk of pelvic inflammatory disease differed among subgroups of women, we assessed our eight covariates as potential effect modifiers. Specifically, we applied a likelihood ratio test for heterogeneity to logistic regression models that included the relevant interaction terms. 5 Results
smoking status, the number of cigarettes smoked per day for both former and current smokers, and the time elapsed since last use of cigarettes. For both case and control subjects, medical record
Table I shows the percentage distribution of case and control subjects by the eight selected covariates. A higher percentage of case subjects were younger than 20 years old, were black, had not completed high school, were not currently married, had more than one
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Table II. Relative risk of pelvic inflammatory disease by current and former smoking status Smokzng status
Never Current:j: Former
Cases (n = 192)*
Controls (n = 6-12)*
Relative rzskt
95% confidence Interval
47 120
248 327
1.0 1.7 2.3
Referent
25
67
1.1-2.5
1.3-4.2
*Excludes one case and one control subject with unknown smoking status; excludes four cases and 24 controls with unknown values for covariates in the model. tAdjusted by logistic regression for age, race, education, marital status, number of recent sexual partners, frequency of intercourse, previous episodes of gonorrhea, and current method of contraception. :j:Current smokers include women who had stopped smoking within the 3 months before interview.
recent sexual partner, had intercourse ~6 times per week, and had a history of gonorrhea. A higher percentage of case women used an intrauterine contraceptive device or did not use a contraceptive method, whereas a higher percentage of control subjects used oral contraceptives or barrier methods. As mentioned in the Material and methods section, all relative risk estimates in our analysis were adjusted by logistic regression for these eight covariates. The relative risk of pelvic inflammatory disease by current and former smoking status is shown in Table II. Because women might have stopped smoking because of their hospitalization, current smokers included women who had stopped smoking within the 3 months before interview. Compared with women who had never smoked, current smokers had a singificantly elevated relative risk of 1.7. Similarly, former smokers had a significantly elevated relative risk of 2.3. (Although not shown here, when women who had stopped smoking within the 3 months before interview were categorized as former smokers, the relative risk for current smokers remained 1.7, and the relative risk for former smokers dropped unappreciably to 2.1.) For current and former smokers, compared with never smokers, we examined the relative risk of pelvic inflammatory disease according to time elapsed since last use of cigarettes (Table III). Although the relative risk point estimates were not greatly different, the relative risk of pelvic inflammatory disease was lowest for former smokers who had stopped smoking within the 3 months before interview. Somewhat higher relative risks of pelvic inflammatory disease were observed for current smokers and women who had stopped smoking in the more distant past. Compared with women who had never smoked, the relative risk of pelvic inflammatory disease among current smokers did not increase consistently as the number of cigarettes smoked per day increased (Table IV). We repeated this analysis among former smokers and, similarly, did not observe a dose-response relationship (not shown). To assess the eight co variates as potential effect modifiers, we started analysis with an initial logistic regres-
sion model that contained the exposure variable (smoking) and the covariates. We compared this model with a full model that contained the exposure variable, the covariates, and all two-factor (exposure-covariate) product terms. The full model was not a significant improvement over the initial model (p > 0.1). In addition to this omnibus test of statistical significance, we constructed logistic regression models to examine each potential effect modifier individually. No meaningful variations in relative risk of pelvic inflammatory disease were observed among women with differing levels of the eight covariates (not shown). Thus. the effect of smoking on relative risk of pelvic inflammatory disease did not appear to be remarkably different among these specific subgroups. of women. Otherwise stated, none of the eight covariates substantially modified the effect of smoking on relative risk of pelvic inflammatory disease. Comment
We found that both current and former cigarette smoking were associated with a statistically significant twofold increased relative risk of pelvic inflammatory disease. A dose-response relationship was not observed, nor was substantial effect modification detected. In this analysis we were limited to hospitalized cases of pelvic inflammatory disease. This meant we could not study a complete spectrum of disease because many women with pelvic inflammatory disease are never hospitalized. Furthermore, since pelvic inflammatory disease is difficult to diagnose correctly, some misclassification of disease undoubtedly occurred. However, almost 40% of the cases in this analysis met the most stringent criteria for pelvic inflammatory disease by having a diagnosis that was based on surgical findings. Among women who did not undergo surgery, the restriction to hospitalized patients with pelvic inflammatory disease and the use of a discharge diagnosis, rather than admission diagnosis, should have further reduced disease classification error. To explore the impact of certainty of diagnosis of pelvic inflammatory disease on our results, we repeated our assess,ment of the relative risk of pelvic inflammatory disease by cur-
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Marchbanks, Lee, and Peterson
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Table III. Relative risk of pelvic inflammatory disease among current and former smokers, according to time elapsed since last use of cigarettes Months since last use of czgarettes
Cases (n = 191)*
Controls (n = 639)*
Relative rzskt
95% Confidence interval
Never smoked Current smoker $3 4-12 >12
47 115 5 5 19
248 311 16 13 51
1.0 1.7 1.3 2.4 2.3
Referent 1.1-2.6 0.4-4.2 0.8-7.5 1.2-4.4
*Excludes two cases and four controls with unknown time since last use of cigarettes; excludes four cases and 24 controls with unknown values for covariates in the model. t Adjusted by logistic regression for age, race, education, marital status, number of recent sexual partners, frequency of intercourse, previous episodes of gonorrhea, and current method of contraception.
Table IV. Relative risk of pelvic inflammatory disease among current smokers* by number of cigarettes smoked per day Ctgarettes smoked per day
Cases (n = 167)t
Controls (n = 573)t
Relattve risk;/:
95% Confidence tnterval
Never smoked 0-9 10-19 20-29 2:30
47 30 48 32 10
248 88 115 91 31
1.0 1.4 1.9 1.4 1.8
Referent 0.8-2.5 1.1-3.1 0.8-2.5 0.8-4.2
*Current smokers include women who had stopped smoking within the 3 months before interview. tExciudes 25 cases and 67 controls who were former smokers; excludes one case and three controls with unknown number of cigarettes smoked per day; excludes four cases and 24 controls with unknown values for covariates in the model. :j:Adjusted by logistic regression for age, race, education, marital status, number of recent sexual partners, frequency of intercourse, previous episodes of gonorrhea, and current method of contraception.
rent and former smoking status while restricting the analysis to the III women with more certain pelvic inflammatory disease diagnoses (71 women with a discharge diagnosis of pelvic inflammatory disease on the basis of operative findings, and 40 women with a discharge diagnosis of pelvic inflammatory disease plus a temperature elevation of >38 0 C on :2:2 days plus a hospital stay :2:7 days). The relative risk of pelvic inflammatory disease for current smokers dropped from 1.7 to 1.4 (95% confidence interval, 0.8 to 2.4), and the relative risk for former smokers increased from 2.3 to 2.5 (95% confidence interval, 1.3 to 5.1) (data not shown). When we further restricted our case group to the 71 women with the most certain discharge diagnoses of pelvic inflammatory disease based on operative findings, the relative risk of pelvic inflammatory disease for current smokers dropped from 1.7 to 1.3 (95% confidence interval, 0.7 to 2.4), and the relative risk for former smokers dropped from 2.3 to 2.2 (95% confidence interval, 0.9 to 5.1) (data not shown). Although these restrictions did not change markedly the relative risk point estimates, the smaller sample sizes resulted in wider confidence intervals and loss of statistical significance in three of the four situations. Because control subjects were hospitalized, our com-
paris on group probably did not represent accurately the smoking status of the general population of women from which the cases of pelvic inflammatory disease were derived. However, since hospitalized control subjects would be expected to have a higher prevalence of current smoking than the general population, any resulting bias should have tended to reduce, not elevate, the observed association between smoking and pelvic inflammatory disease. To investigate this potential bias further, we studied the nature of our control group in greater detail. Table V shows the composition of our control group by primary discharge diagnosis and smoking status. The majority of controls (83.6%) had trauma or surgical diagnoses. A somewhat higher percentage of medical control subjects were never smokers, and a somewhat higher percentage of trauma controls were current smokers. Former smokers were distributed more uniformly across discharge diagnosis categories. We compared the smoking status of our total control group with that of the U.S. female population (Table VI). Compared with the 1978 U.S. female population aged 20-44 years,6 the control group of the Women's Health Study contained fewer never smokers, more current smokers, and a similar percentage of former smokers. This comparison supported the expec-
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Table V. Percentage distribution of controls, by primary discharge diagnosis and smoking status* Smoking status
Never Current Former
Traumat (n = 172; 25.8%)
Surgicalt (n = 385; 57.8%)
Medical (n = 109; 16.4%)
33.1 55.2 11.6
39.5 46.8 13.8
47.7 39.5 12.8
(%)
(%)
*Totals may not equal 100% because of rounding. tl72 of the 666 controls with known smoking status had trauma diagnoses (172/666 :j:Exciudes one control with unknown smoking status.
tation that our hospital control group would have a higher prevalence of current smoking than the general population. Therefore any resulting bias should have reduced, not elevated, the observed association between smoking and pelvic inflammatory disease. Three additional sources of potential error should be recognized. First, we had incomplete exposure information . Most notably, we lacked data on duration of smoking and the age at which smoking began. This information would have enabled us to explore to a greater extent the possibility of a dose-response relationship between cigarette smoking and pelvic inflammatory disease. Second, although we were able to adjust simultaneously for eight covariates, uncontrolled confounding was a possibility, especially with regard to aspects of sexual behavior. Although we had substantial information about a woman's own sexual behavior, we had no information about the sexual behavior of her partner. Third, the small numbers of women in certain strata increased the likelihood that chance could have accounted for some of our findings. We are aware of no other study that reports the effect of cigarette smoking on relative risk of pelvic inflammatory disease. However, a number of studies have documented an association between cigarette smoking and infertility.2. 3. 7·9 Daling et al. 7 found that current cigarette smoking was a risk factor for tubal infertility (relative risk = 2.7) but not for infertility as a result of ovulatory factors, cervical factors, or endometriosis. The results of Phipps et al. 8 indicated that current cigarette smoking was a risk factor for cervical infertility (relative risk = 1.7) and tubal infertility (relative risk = 1.6). In contrast to our results related to pelvic inflammatory disease, former smokers have not been found to be at significantly increased relative risk of infertility,7.8 and a dose-response relationship between current cigarette smoking and infertility has been suggested.7.8 Cigarette smoking is known to increase the risk of cancer in organs having a direct interface with cigarette smoke (e.g., lung, larynx, and esophagus), but it also has been associated with cancer in certain distal sites (e.g., bladder, pancreas, and cervix). 1. 10 In addition, the
(%)
= 25.8%).
Table VI. Percentage distribution of controls by smoking status compared with U.S. female population*
Smoking status
Never Current Former
Women 's Health Study controls (n = 666) t
(%)
39.2 47.8 13.1
U.S. female population, 20-44 yr, 1978:f: ( %)
50.9 35.3 13.8
*Totals may not equal 100% because of rounding. tExcludes one control with unknown smoking status. :j:Source: Health Interview Survey, Division of Health Interview Statistics, National Center for Health Statistics; data are based on household interviews with a sample of the civilian noninstitutionalized population.
constituents of cigarette smoke have been reported to affect other health conditions through complicated mechanisms. For example, cigarette smoking has been linked to decreased concentrations of estrogen and to estrogen-related effects such as early menopause, postmenopausal osteoporosis, and menstrual disorders. 9 • 11 Numerous studies have reported an association between cigarette smoking and adverse pregnancy outcomes such as low birth weight9 ; one study has reported an association between cigarette smoking and the occurrence of condyloma acuminatum. 12 The suggestion from case-control studies that cigarette smoking is a risk factor for ectopic pregnancy" lends support for a possible relationship between cigarette smoking and pelvic inflammatory disease. Because pelvic inflammatory disease is a well-established risk factor for ectopic pregnancy, perhaps cigarette smoking influences the occurrence of ectopic pregnancy through the intermediate condition of pelvic inflammatory disease . Similar to our results related to pelvic inflammatory disease, Chow et al. 13 found that the relative risk of ectopic pregnancy was increased in both former smokers (relative risk = 1.6) and current smokers (relative risk = 2.2). Evidence from both animal and human studies
644
Marchbanks, Lee, and Peterson
provides support for the theory that cigarette smoking could have an etiologic role in the development of pelvic inflammatory disease. Nicotine has been found to reduce tubal blood flow in rats l4 and to alter tubal motility in rhesus monkeys. 15 Tubal motility in women has been experimentally altered by cigarette smoking before uterotubal insufflation tests. 16 Endocrine function may be affected by cigarette smoking, and hypothalmic-pituitary-ovarian interrelationships may be disrupted. 17• 1B Cigarette smoking can affect cervical mucus constituents l9 . 2o and can depress immune function. 21 ,22 The precise mechanism through which cigarette smoking could mediate an increased relative risk of pelvic inflammatory disease is unclear. Our results suggest that both former smoking and current smoking are associated with pelvic inflammatory disease. If this association is causal, then the predominant mechanism of action is likely to be a permanent or longlasting change in anatomy, physiology, or both that is not yet fully understood. The data in this analysis were collected from women hospitalized for pelvic inflammatory disease during 1977 and 1978. Since these calendar years correspond roughly to the data collection periods in the two investigations that prompted our study hypothesis (1979198P and 1981-1983 2 ), data from the Women's Health Study were particularly appropriate for this hypothesis testing. It is possible, however, that the proportions of cases of hospitalized pelvic inflammatory disease attributable to various etiologic agents may have changed over time. We have no reason to believe that specific etiologic agents would affect possible mechanisms of action through which cigarette smoking could influence pelvic inflammatory disease occurrence. In summary, previous studies have suggested that cigarette smoking could be a risk factor for pelvic inflammatory disease. Because of the high prevalence of cigarette smoking and the serious consequences of pelvic inflammatory disease, we pursued this issue by analysis of existing data from the Women's Health Study. Although our analysis cannot provide conclusive answers, it suggests that cigarette smoking may somehow predispose women to pelvic inflammatory disease. The relationship between cigarette smoking and pelvic inflammatory disease needs to be clarified by epidemiologic investigations specifically designed to evaluate this possible association. REFERENCES 1. National Center for Health Statistics. Health, United States-1986. Hyattsville, Maryland: National Center for Health Statistics, 1986; DHHS publication no. (PHS) 871232.
March 1990 Am J Obstet Gynecol
2. Cramer DW, Schiff I, Schoenbaum SC, et al. Tubal infertility and the intrauterine device. N Engl J Med 1985; 312:941-7. 3. Daling JR, Weiss NS, Metch BJ, et al. Primary tubal infertility in relation to the use of an intrauterine device. N EnglJ Med 1985;312:937-41. 4. Burkman RT, The Women's Health Study. Association between intrauterine device and pelvic inflammatory disease. Obstet Gynecol 1981;57:269-76. 5. Kleinbaum DG, Kupper LL, Morgenstern H. Epidemiologic research. Belmont, California: Lifetime Learning Publications, 1982. 6. National Center for Health Statistics. Health, United States-1979. Hyattsville, Maryland: National Center for Health Statistics, 1979; DHEW publication no. (PHS) 801232. 7. Daling J, Weiss N, Spadoni L, et al. Cigarette smoking and primary tubal infertility. In Rosenberg MJ, ed. Smoking and reproductive health. Littleton, Mass: PSG Publishing Co, 1987:40-6. 8. Phipps WR, Cramer DW, Schiff I, et al. The association between smoking and female infertility as influenced by cause of the infertility. Ferti! Steril 1987;48:377-82. 9. Stillman RJ, Rosenberg MJ, Sachs BP. Smoking and reproduction. Ferril Steri! 1986;46:545-66. 10. Surgeon General. The health consequences of smoking: Cancer. Rockville, Maryland: Office on Smoking and Health, Department of Health and Human Services, 1982; DHHS publication no. (PHS) 82-50179. II. Baron JA. Smoking and estrogen-related disease. Am J Epidemiol 1984; 119:9-22. 12. Daling JR, Sherman KJ, Weiss NS. Risk factors for condyloma acuminatum in women. Sex Transm Dis 1986; 13: 16-8. 13. Chow W-H, DalingJR, Weiss NS, et al. Maternal cigarette smoking and tubal pregnancy. Obstet Gynecol 1988;71: 167-70. 14. Mitchell J A, Hammer RE. Effects of nicotine on oviducal blood flow and embryo development in the rat. J Reprod Ferti! 1985;74:71-6. 15. Neri A, Marcus SL. Effect of nicotine on the motility of the oviducts in the rhesus monkey: a preliminary report. J Reprod Ferti! 1972;31:91-7. 16. Neri A, Eckerling B. Influence of smoking and adrenaline (epinephrine) on the uterotubal insufflation test (Rubin test). Ferti! Steril 1969;20:818-28. 17. Mattison DR. The effects of smoking on fertility from gametogenesis to implantation. Environ Res 1982;28 :41 033. 18. Weathersbee PS. Nicotine and its influence on the female reproductive system. J Reprod Med 1980;25:243-50. 19. Holly EA, Petrakis NL, Friend NF, et al. Mutagenic mucus in the cervix of smokers. JNCI 1986;76:983-6. 20. Hellberg D, Nilsson S, Haley NJ, et al. Smoking and cervical intraepithelial neoplasia: nicotine and cotinine in serum and cervical mucus in smokers and nonsmokers. AM J OBSTET GVNECOL 1988;158:910-3. 21. Phillips B, Marshall E, Brown S, et al. Effect of smoking on human natural killer cell activity. Cancer 1985;56: 2789-92. 22. Hersey P, Prendergast D, Edwards A. Effects of cigarette smoking on the immune system: follow-up studies in normal subjects after cessation of smoking. Med J Aust 1983;2:425-9.
Key words: Pelvic inflammatory disease, cigarette smoking, women, epidemiology
In the United States, 28 % of adult women smoke cigarettes on a regular basis; approximately half of all U.S. women have smoked cigarettes at some time in their lives. I In 1985 two case-control studies reported that cigarette smoking was an independent risk factor for tubal infertility.2 3 Because tubal infertility is usually the result of pelvic inflammatory disease, we hypothesized that cigarette smoking could be related to an increased risk of pelvic inflammatory disease . To investigate this hypothesis, we analyzed data from the Women's Health Study.
Material and methods The Women's Health Study has been described in d etail! In brief, it was a multicenter, hospital-based, case-control study of pelvic inflammatory disease. Enrollment and data collection occurred from 1976 through 1978 in 16 U.S. hospitals . Potential case and control women were identified by a daily surveillance of hospital records. Each prospective participant was asked to consent to an interview during her hospital stay and to a review of her medical records after discharge. Stu~y population. Case subjects were women 18 to 44 yea rs of age with a discha rge diagnosis of pelvic From the DIViswn of Reproductive H ealth, Center for Chromc DISease P revention and Health PromotIOn, Centers f Ol' DISease Control. R eceivedfor pubbcation May 23,1 989; reVISed October 13,1989; accepted N ovember 1, 1989. R eprints not avaIlable.
6/1/17882
inflammatory disease. Control subjects were women 18 to 44 years of age with a discharge diagnosis of a nongynecologic condition. Because an original goal of the Women's Health Study was to examine tae relationship between contraceptive use and pelvic inflammatory disease, women with discharge diagnoses thought to influence contraceptive choice we re excluded from the pool of potential controls. Three additional groups of women were excluded from being potential case subjects or potential controls: (I) women who reported no sexua l intercourse in the previous year, (2) women who had been sterilized for 2':30 d ays, and (3) women whose partners had been sterilized for 2':60 days. Although data collection for the Women's Health Study began in October 1976, the collection of information with regard to smoking was not initiated until April 1977. Therefore we could not include case and control su bjects enrolled before April 1977 in this analysis. In addition, we excluded women with a history of pelvic inflammatory disease and women with a pregnancy within the previous 3 months . After all exclusions , 197 women remained eligible as case subjects and 667 women remained eligible as control subjects. Data collection. Standardized personal interviews were used to collect information with regard to each woman's reproductive, contraceptive, and medical histories . Recent sexual behavior was assessed through questions concerning each woma n's number of sexual partners in the previous 6 months and her usual frequency of sexual intercourse in the previous 6 months. Info rmation about cigarette smoking included current
639
640
Marchbanks, Lee, and Peterson
March 1990 Am J Obstet Gynecol
Table I. Percentage distribution of cases and controls by eight selected characteristics* Cases
Characteristic
Age (yr) 18-19 20-24 25-29 ~30
Race White Black Other Unknown Education (yr) 12
Marital status Currently married Cohabiting Previously married Never married Unknown Number of recent sexual partners 0-1 2-3 ~4
Unknown Frequency of intercourse (per week) 0-1 2-5 ~6
Unknown Previous episodes of gonorrhea None ~1
Unknown Current method of contraception None Intrauterine contraceptive device Oral contraceptives Barrier, other Unknown
(n
= 197) (%)
Controls
(n
= 667) (%)
19.3 38.6 22.8 19.3
11.2 35.4 22.6 30.7
47.2 36.0 16.2 0.5
53.7 27.9 18.3 0.2
31.5 39.1 29.4
22.0 35.4 42.6
24.9
35.2
10.7 21.3
7.7 19.0
43.2
37.9
0.0
0.2
77.2 17.3 5.6 0.0
88.8 8.7 1.8 0.8
45.7 43.2 10.7 0.5
53.8 41.2 3.6 1.4
80.2 19.3 0.5
91.9 7.8 0.3
42.6 27.4
31.9 14.1
18.3
31.3
11.2
21.1
0.5
1.5
*Totals may not equal 100% because of rounding.
abstraction permitted a final determination of study eligibility. In addition, the review of medical records permitted an evaluation of the certainty of each pelvic inflammatory disease diagnosis. Among the 197 case subjects in this analysis. 71 women (36.0%) had a discharge diagnosis of pelvic inflammatory disease that was based on operative findings; 40 women (20.3%), although they did not undergo surgery, had a discharge diagnosis of pelvic inflammatory disease plus a temperature elevation of >38 0 C on 2 or more days plus a hospital stay 7 days or longer. Eighty-six women (43.7%) who did not meet the above criteria had a discharge diagnosis of pelvic inflammatory disease plus medical management (antibiotics) for pelvic inflammatory disease. Microbiologic information for the cases of pelvic inflammatory disease was not obtained. Definitions. For our analysis, we defined a woman's current method of contraception as that method used at any time during the 3 months before interview. If more than one method had been used during this time, we used the following priority to determine the current method: (1) intrauterine contraceptive device; (2) oral contraceptives; (3) barrier methods; and (4) other. We considered that a woman currently used no method of contraception if she had not used any contraceptive method during each of the 3 months before interview. We defined a woman as previously married if her reported marital status was separated, divorced, or widowed. We defined a woman as cohabiting if she was living with a man who was not her husband. Analysis. On the basis of previous work with the Women's Health Study: we identified eight covariates that might potentially confound an association between cigarette smoking and pelvic inflammatory disease: age, race, education, marital status, number of recent sexual partners, frequency of intercourse, history of gonorrhea, and current method of contraception. We used logistic regression models containing these eight covariates to compute a~justed odds ratios as estimators of the relative risk of pelvic inflammatory disease; 95% confidence intervals accompany all of our relative risk point estimates. 5 To determine if the effect of smoking on the relative risk of pelvic inflammatory disease differed among subgroups of women, we assessed our eight covariates as potential effect modifiers. Specifically, we applied a likelihood ratio test for heterogeneity to logistic regression models that included the relevant interaction terms. 5 Results
smoking status, the number of cigarettes smoked per day for both former and current smokers, and the time elapsed since last use of cigarettes. For both case and control subjects, medical record
Table I shows the percentage distribution of case and control subjects by the eight selected covariates. A higher percentage of case subjects were younger than 20 years old, were black, had not completed high school, were not currently married, had more than one
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Table II. Relative risk of pelvic inflammatory disease by current and former smoking status Smokzng status
Never Current:j: Former
Cases (n = 192)*
Controls (n = 6-12)*
Relative rzskt
95% confidence Interval
47 120
248 327
1.0 1.7 2.3
Referent
25
67
1.1-2.5
1.3-4.2
*Excludes one case and one control subject with unknown smoking status; excludes four cases and 24 controls with unknown values for covariates in the model. tAdjusted by logistic regression for age, race, education, marital status, number of recent sexual partners, frequency of intercourse, previous episodes of gonorrhea, and current method of contraception. :j:Current smokers include women who had stopped smoking within the 3 months before interview.
recent sexual partner, had intercourse ~6 times per week, and had a history of gonorrhea. A higher percentage of case women used an intrauterine contraceptive device or did not use a contraceptive method, whereas a higher percentage of control subjects used oral contraceptives or barrier methods. As mentioned in the Material and methods section, all relative risk estimates in our analysis were adjusted by logistic regression for these eight covariates. The relative risk of pelvic inflammatory disease by current and former smoking status is shown in Table II. Because women might have stopped smoking because of their hospitalization, current smokers included women who had stopped smoking within the 3 months before interview. Compared with women who had never smoked, current smokers had a singificantly elevated relative risk of 1.7. Similarly, former smokers had a significantly elevated relative risk of 2.3. (Although not shown here, when women who had stopped smoking within the 3 months before interview were categorized as former smokers, the relative risk for current smokers remained 1.7, and the relative risk for former smokers dropped unappreciably to 2.1.) For current and former smokers, compared with never smokers, we examined the relative risk of pelvic inflammatory disease according to time elapsed since last use of cigarettes (Table III). Although the relative risk point estimates were not greatly different, the relative risk of pelvic inflammatory disease was lowest for former smokers who had stopped smoking within the 3 months before interview. Somewhat higher relative risks of pelvic inflammatory disease were observed for current smokers and women who had stopped smoking in the more distant past. Compared with women who had never smoked, the relative risk of pelvic inflammatory disease among current smokers did not increase consistently as the number of cigarettes smoked per day increased (Table IV). We repeated this analysis among former smokers and, similarly, did not observe a dose-response relationship (not shown). To assess the eight co variates as potential effect modifiers, we started analysis with an initial logistic regres-
sion model that contained the exposure variable (smoking) and the covariates. We compared this model with a full model that contained the exposure variable, the covariates, and all two-factor (exposure-covariate) product terms. The full model was not a significant improvement over the initial model (p > 0.1). In addition to this omnibus test of statistical significance, we constructed logistic regression models to examine each potential effect modifier individually. No meaningful variations in relative risk of pelvic inflammatory disease were observed among women with differing levels of the eight covariates (not shown). Thus. the effect of smoking on relative risk of pelvic inflammatory disease did not appear to be remarkably different among these specific subgroups. of women. Otherwise stated, none of the eight covariates substantially modified the effect of smoking on relative risk of pelvic inflammatory disease. Comment
We found that both current and former cigarette smoking were associated with a statistically significant twofold increased relative risk of pelvic inflammatory disease. A dose-response relationship was not observed, nor was substantial effect modification detected. In this analysis we were limited to hospitalized cases of pelvic inflammatory disease. This meant we could not study a complete spectrum of disease because many women with pelvic inflammatory disease are never hospitalized. Furthermore, since pelvic inflammatory disease is difficult to diagnose correctly, some misclassification of disease undoubtedly occurred. However, almost 40% of the cases in this analysis met the most stringent criteria for pelvic inflammatory disease by having a diagnosis that was based on surgical findings. Among women who did not undergo surgery, the restriction to hospitalized patients with pelvic inflammatory disease and the use of a discharge diagnosis, rather than admission diagnosis, should have further reduced disease classification error. To explore the impact of certainty of diagnosis of pelvic inflammatory disease on our results, we repeated our assess,ment of the relative risk of pelvic inflammatory disease by cur-
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Table III. Relative risk of pelvic inflammatory disease among current and former smokers, according to time elapsed since last use of cigarettes Months since last use of czgarettes
Cases (n = 191)*
Controls (n = 639)*
Relative rzskt
95% Confidence interval
Never smoked Current smoker $3 4-12 >12
47 115 5 5 19
248 311 16 13 51
1.0 1.7 1.3 2.4 2.3
Referent 1.1-2.6 0.4-4.2 0.8-7.5 1.2-4.4
*Excludes two cases and four controls with unknown time since last use of cigarettes; excludes four cases and 24 controls with unknown values for covariates in the model. t Adjusted by logistic regression for age, race, education, marital status, number of recent sexual partners, frequency of intercourse, previous episodes of gonorrhea, and current method of contraception.
Table IV. Relative risk of pelvic inflammatory disease among current smokers* by number of cigarettes smoked per day Ctgarettes smoked per day
Cases (n = 167)t
Controls (n = 573)t
Relattve risk;/:
95% Confidence tnterval
Never smoked 0-9 10-19 20-29 2:30
47 30 48 32 10
248 88 115 91 31
1.0 1.4 1.9 1.4 1.8
Referent 0.8-2.5 1.1-3.1 0.8-2.5 0.8-4.2
*Current smokers include women who had stopped smoking within the 3 months before interview. tExciudes 25 cases and 67 controls who were former smokers; excludes one case and three controls with unknown number of cigarettes smoked per day; excludes four cases and 24 controls with unknown values for covariates in the model. :j:Adjusted by logistic regression for age, race, education, marital status, number of recent sexual partners, frequency of intercourse, previous episodes of gonorrhea, and current method of contraception.
rent and former smoking status while restricting the analysis to the III women with more certain pelvic inflammatory disease diagnoses (71 women with a discharge diagnosis of pelvic inflammatory disease on the basis of operative findings, and 40 women with a discharge diagnosis of pelvic inflammatory disease plus a temperature elevation of >38 0 C on :2:2 days plus a hospital stay :2:7 days). The relative risk of pelvic inflammatory disease for current smokers dropped from 1.7 to 1.4 (95% confidence interval, 0.8 to 2.4), and the relative risk for former smokers increased from 2.3 to 2.5 (95% confidence interval, 1.3 to 5.1) (data not shown). When we further restricted our case group to the 71 women with the most certain discharge diagnoses of pelvic inflammatory disease based on operative findings, the relative risk of pelvic inflammatory disease for current smokers dropped from 1.7 to 1.3 (95% confidence interval, 0.7 to 2.4), and the relative risk for former smokers dropped from 2.3 to 2.2 (95% confidence interval, 0.9 to 5.1) (data not shown). Although these restrictions did not change markedly the relative risk point estimates, the smaller sample sizes resulted in wider confidence intervals and loss of statistical significance in three of the four situations. Because control subjects were hospitalized, our com-
paris on group probably did not represent accurately the smoking status of the general population of women from which the cases of pelvic inflammatory disease were derived. However, since hospitalized control subjects would be expected to have a higher prevalence of current smoking than the general population, any resulting bias should have tended to reduce, not elevate, the observed association between smoking and pelvic inflammatory disease. To investigate this potential bias further, we studied the nature of our control group in greater detail. Table V shows the composition of our control group by primary discharge diagnosis and smoking status. The majority of controls (83.6%) had trauma or surgical diagnoses. A somewhat higher percentage of medical control subjects were never smokers, and a somewhat higher percentage of trauma controls were current smokers. Former smokers were distributed more uniformly across discharge diagnosis categories. We compared the smoking status of our total control group with that of the U.S. female population (Table VI). Compared with the 1978 U.S. female population aged 20-44 years,6 the control group of the Women's Health Study contained fewer never smokers, more current smokers, and a similar percentage of former smokers. This comparison supported the expec-
Cigarette smoking and pelvic inflammatory disease
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Table V. Percentage distribution of controls, by primary discharge diagnosis and smoking status* Smoking status
Never Current Former
Traumat (n = 172; 25.8%)
Surgicalt (n = 385; 57.8%)
Medical (n = 109; 16.4%)
33.1 55.2 11.6
39.5 46.8 13.8
47.7 39.5 12.8
(%)
(%)
*Totals may not equal 100% because of rounding. tl72 of the 666 controls with known smoking status had trauma diagnoses (172/666 :j:Exciudes one control with unknown smoking status.
tation that our hospital control group would have a higher prevalence of current smoking than the general population. Therefore any resulting bias should have reduced, not elevated, the observed association between smoking and pelvic inflammatory disease. Three additional sources of potential error should be recognized. First, we had incomplete exposure information . Most notably, we lacked data on duration of smoking and the age at which smoking began. This information would have enabled us to explore to a greater extent the possibility of a dose-response relationship between cigarette smoking and pelvic inflammatory disease. Second, although we were able to adjust simultaneously for eight covariates, uncontrolled confounding was a possibility, especially with regard to aspects of sexual behavior. Although we had substantial information about a woman's own sexual behavior, we had no information about the sexual behavior of her partner. Third, the small numbers of women in certain strata increased the likelihood that chance could have accounted for some of our findings. We are aware of no other study that reports the effect of cigarette smoking on relative risk of pelvic inflammatory disease. However, a number of studies have documented an association between cigarette smoking and infertility.2. 3. 7·9 Daling et al. 7 found that current cigarette smoking was a risk factor for tubal infertility (relative risk = 2.7) but not for infertility as a result of ovulatory factors, cervical factors, or endometriosis. The results of Phipps et al. 8 indicated that current cigarette smoking was a risk factor for cervical infertility (relative risk = 1.7) and tubal infertility (relative risk = 1.6). In contrast to our results related to pelvic inflammatory disease, former smokers have not been found to be at significantly increased relative risk of infertility,7.8 and a dose-response relationship between current cigarette smoking and infertility has been suggested.7.8 Cigarette smoking is known to increase the risk of cancer in organs having a direct interface with cigarette smoke (e.g., lung, larynx, and esophagus), but it also has been associated with cancer in certain distal sites (e.g., bladder, pancreas, and cervix). 1. 10 In addition, the
(%)
= 25.8%).
Table VI. Percentage distribution of controls by smoking status compared with U.S. female population*
Smoking status
Never Current Former
Women 's Health Study controls (n = 666) t
(%)
39.2 47.8 13.1
U.S. female population, 20-44 yr, 1978:f: ( %)
50.9 35.3 13.8
*Totals may not equal 100% because of rounding. tExcludes one control with unknown smoking status. :j:Source: Health Interview Survey, Division of Health Interview Statistics, National Center for Health Statistics; data are based on household interviews with a sample of the civilian noninstitutionalized population.
constituents of cigarette smoke have been reported to affect other health conditions through complicated mechanisms. For example, cigarette smoking has been linked to decreased concentrations of estrogen and to estrogen-related effects such as early menopause, postmenopausal osteoporosis, and menstrual disorders. 9 • 11 Numerous studies have reported an association between cigarette smoking and adverse pregnancy outcomes such as low birth weight9 ; one study has reported an association between cigarette smoking and the occurrence of condyloma acuminatum. 12 The suggestion from case-control studies that cigarette smoking is a risk factor for ectopic pregnancy" lends support for a possible relationship between cigarette smoking and pelvic inflammatory disease. Because pelvic inflammatory disease is a well-established risk factor for ectopic pregnancy, perhaps cigarette smoking influences the occurrence of ectopic pregnancy through the intermediate condition of pelvic inflammatory disease . Similar to our results related to pelvic inflammatory disease, Chow et al. 13 found that the relative risk of ectopic pregnancy was increased in both former smokers (relative risk = 1.6) and current smokers (relative risk = 2.2). Evidence from both animal and human studies
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provides support for the theory that cigarette smoking could have an etiologic role in the development of pelvic inflammatory disease. Nicotine has been found to reduce tubal blood flow in rats l4 and to alter tubal motility in rhesus monkeys. 15 Tubal motility in women has been experimentally altered by cigarette smoking before uterotubal insufflation tests. 16 Endocrine function may be affected by cigarette smoking, and hypothalmic-pituitary-ovarian interrelationships may be disrupted. 17• 1B Cigarette smoking can affect cervical mucus constituents l9 . 2o and can depress immune function. 21 ,22 The precise mechanism through which cigarette smoking could mediate an increased relative risk of pelvic inflammatory disease is unclear. Our results suggest that both former smoking and current smoking are associated with pelvic inflammatory disease. If this association is causal, then the predominant mechanism of action is likely to be a permanent or longlasting change in anatomy, physiology, or both that is not yet fully understood. The data in this analysis were collected from women hospitalized for pelvic inflammatory disease during 1977 and 1978. Since these calendar years correspond roughly to the data collection periods in the two investigations that prompted our study hypothesis (1979198P and 1981-1983 2 ), data from the Women's Health Study were particularly appropriate for this hypothesis testing. It is possible, however, that the proportions of cases of hospitalized pelvic inflammatory disease attributable to various etiologic agents may have changed over time. We have no reason to believe that specific etiologic agents would affect possible mechanisms of action through which cigarette smoking could influence pelvic inflammatory disease occurrence. In summary, previous studies have suggested that cigarette smoking could be a risk factor for pelvic inflammatory disease. Because of the high prevalence of cigarette smoking and the serious consequences of pelvic inflammatory disease, we pursued this issue by analysis of existing data from the Women's Health Study. Although our analysis cannot provide conclusive answers, it suggests that cigarette smoking may somehow predispose women to pelvic inflammatory disease. The relationship between cigarette smoking and pelvic inflammatory disease needs to be clarified by epidemiologic investigations specifically designed to evaluate this possible association. REFERENCES 1. National Center for Health Statistics. Health, United States-1986. Hyattsville, Maryland: National Center for Health Statistics, 1986; DHHS publication no. (PHS) 871232.
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2. Cramer DW, Schiff I, Schoenbaum SC, et al. Tubal infertility and the intrauterine device. N Engl J Med 1985; 312:941-7. 3. Daling JR, Weiss NS, Metch BJ, et al. Primary tubal infertility in relation to the use of an intrauterine device. N EnglJ Med 1985;312:937-41. 4. Burkman RT, The Women's Health Study. Association between intrauterine device and pelvic inflammatory disease. Obstet Gynecol 1981;57:269-76. 5. Kleinbaum DG, Kupper LL, Morgenstern H. Epidemiologic research. Belmont, California: Lifetime Learning Publications, 1982. 6. National Center for Health Statistics. Health, United States-1979. Hyattsville, Maryland: National Center for Health Statistics, 1979; DHEW publication no. (PHS) 801232. 7. Daling J, Weiss N, Spadoni L, et al. Cigarette smoking and primary tubal infertility. In Rosenberg MJ, ed. Smoking and reproductive health. Littleton, Mass: PSG Publishing Co, 1987:40-6. 8. Phipps WR, Cramer DW, Schiff I, et al. The association between smoking and female infertility as influenced by cause of the infertility. Ferti! Steril 1987;48:377-82. 9. Stillman RJ, Rosenberg MJ, Sachs BP. Smoking and reproduction. Ferril Steri! 1986;46:545-66. 10. Surgeon General. The health consequences of smoking: Cancer. Rockville, Maryland: Office on Smoking and Health, Department of Health and Human Services, 1982; DHHS publication no. (PHS) 82-50179. II. Baron JA. Smoking and estrogen-related disease. Am J Epidemiol 1984; 119:9-22. 12. Daling JR, Sherman KJ, Weiss NS. Risk factors for condyloma acuminatum in women. Sex Transm Dis 1986; 13: 16-8. 13. Chow W-H, DalingJR, Weiss NS, et al. Maternal cigarette smoking and tubal pregnancy. Obstet Gynecol 1988;71: 167-70. 14. Mitchell J A, Hammer RE. Effects of nicotine on oviducal blood flow and embryo development in the rat. J Reprod Ferti! 1985;74:71-6. 15. Neri A, Marcus SL. Effect of nicotine on the motility of the oviducts in the rhesus monkey: a preliminary report. J Reprod Ferti! 1972;31:91-7. 16. Neri A, Eckerling B. Influence of smoking and adrenaline (epinephrine) on the uterotubal insufflation test (Rubin test). Ferti! Steril 1969;20:818-28. 17. Mattison DR. The effects of smoking on fertility from gametogenesis to implantation. Environ Res 1982;28 :41 033. 18. Weathersbee PS. Nicotine and its influence on the female reproductive system. J Reprod Med 1980;25:243-50. 19. Holly EA, Petrakis NL, Friend NF, et al. Mutagenic mucus in the cervix of smokers. JNCI 1986;76:983-6. 20. Hellberg D, Nilsson S, Haley NJ, et al. Smoking and cervical intraepithelial neoplasia: nicotine and cotinine in serum and cervical mucus in smokers and nonsmokers. AM J OBSTET GVNECOL 1988;158:910-3. 21. Phillips B, Marshall E, Brown S, et al. Effect of smoking on human natural killer cell activity. Cancer 1985;56: 2789-92. 22. Hersey P, Prendergast D, Edwards A. Effects of cigarette smoking on the immune system: follow-up studies in normal subjects after cessation of smoking. Med J Aust 1983;2:425-9.
