Association of Perforation of the Appendix with Female Tubal Infertility

David R. Urbach1,2,7, Loraine D. Marrett3,4, Rose Kung2,5 and Marsha M. Cohen2,5,6

1 Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
2 Clinical Epidemiology and Health Care Research Program, University of Toronto, Toronto, Ontario, Canada.
3 Division of Preventive Oncology, Cancer Care Ontario, Toronto, Ontario, Canada.
4 Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada.
5 The Centre for Research in Women's Health, University of Toronto, Toronto, Ontario, Canada.
6 Department of Health Administration, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
7 Present affiliation: Departments of Surgery and Health Administration, University of Toronto, Toronto, Ontario, Canada.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Although perforation of the appendix is considered a risk factor for female tubal infertility, the epidemiologic evidence supporting this relation is inconsistent. Risk factors for tubal infertility were compared for 121 women with documented primary tubal infertility attending in vitro fertilization clinics in Toronto, Canada, from July to December 1998 and 490 controls who were pregnant during the same time period. Self-administered questionnaires and review of medical records were used to assess exposures. The authors found that neither history of acute appendicitis nor perforation of the appendix was a statistically significant risk factor for tubal infertility. The crude odds ratio for perforated appendicitis was 3.4 (95% confidence interval (CI): 0.9, 12.9), and the adjusted odds ratio was 1.4 (95% CI: 0.3, 6.2). In addition to increased age and annual income, cigarette smoking (odds ratio (OR) = 2.0, 95% CI: 1.2, 3.2), history of endometriosis (OR = 6.0, 95% CI: 2.8,12.8), and history of pelvic inflammatory disease (OR = 6.0, 95% CI: 2.8, 12.8) were significantly associated with tubal infertility in multivariate analysis. These data do not provide substantial evidence that perforation of the appendix is an important risk factor for female tubal infertility.

appendicitis; bias (epidemiology); case-control studies; causality; fallopian tube diseases; infertility, female; risk factors

Abbreviations: CI confidence interval; OR odds ratio


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Many surgeons believe that girls and young women who suffer perforation of the appendix are at risk of developing subsequent tubal infertility. This conviction presumably arose from the clinical observation that acute appendicitis complicated by perforation sometimes caused severe intraabdominal infection. The resulting peritoneal adhesions were thought to obstruct the fallopian tubes, leading to tubal infertility. Several previous studies have found an association between complicated appendicitis and female infertility (1GoGoGo–4Go), whereas others have not detected a relation (5Go, 6Go).

The only well-designed case-control study examining the relation between perforation of the appendix and tubal infertility was reported in 1986 by Mueller et al. (7Go). This study found that appendiceal perforation increased the risk of primary tubal infertility (odds ratio (OR) = 4.8, 95 percent confidence interval (CI): 1.5, 14.9) and of secondary tubal infertility (OR = 3.2, 95 percent CI: 1.1, 9.6). However, self-reports of appendicitis were not confirmed with medical records, exposing the study's findings to the possibility that recall error might have biased the authors' estimate of the effect of appendiceal perforation (8Go, 9Go). In addition, perforation of the appendix appeared to be associated with secondary (as well as primary) tubal infertility, although nearly all of the women with secondary infertility who reported appendiceal perforation had at least one pregnancy after appendectomy. It is difficult to attribute tubal infertility to appendiceal perforation when one or more conventional pregnancies followed the presumptive causal exposure. Furthermore, the cases and controls in this study underwent appendectomies decades ago. Given the advances in surgical practice since then, it is not clear that the findings are generalizable to today's populations.

To further investigate the relation between appendicitis and tubal infertility, we conducted a case-control study comparing women with primary tubal infertility with pregnant women in Toronto, Canada. We sought to determine whether perforation of the appendix is an important risk factor for tubal infertility.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study participants
We recruited as study participants women aged 20–44 years attending in vitro fertilization clinics and low-risk obstetric clinics or obstetricians' offices at several centers in Toronto, Ontario, Canada, from July to December 1998. Four of the seven regional facilities providing infertility treatment participated in this study. Ethics approval for this research was obtained from the University of Toronto Human Subjects Review Committee and from the Research Ethics Boards of Women's College Hospital, The Toronto Hospital, and the Toronto East General Hospital.

Cases were defined as women with primary infertility (those who had never achieved a conventional pregnancy) who had evidence of tubal disease on hysterosalpingography or laparoscopy with dye insufflation. Infertile women who had previously undergone tubal ligation were excluded. Women were eligible for inclusion as controls if they had clinical or sonographic evidence of an intrauterine pregnancy that was not conceived by using assisted reproductive technology and presented for obstetric care during the study period. Investigations documenting pregnancy and infertility were conducted by the individual health facilities according to their usual practice and were not reviewed by the study investigators.

Measurement of exposures
Self-administered questionnaires were either completed by study participants during the clinic visit or mailed to potential subjects with a stamped, addressed return envelope, in accordance with the preference of the participating institution. Questionnaires included items on demographics (date of birth, marital status, highest level of education, and annual household income in the previous year (<$30,000, $30,000–$60,000, >$60,000)) as well as on recognized risk factors for tubal infertility (cigarette smoking, history of pelvic inflammatory disease, abdominal or pelvic surgery, and history of endometriosis), contraceptive use, and obstetric history (for controls) (10GoGoGoGo–14Go). Study participants were asked whether they had ever had an appendectomy and, if so, whether it was an incidental appendectomy or whether the appendix was normal, inflamed, or perforated. In addition, participants who reported an appendectomy were asked to complete and sign a consent form authorizing release of copies of their operative and pathologic reports from the institution at which the appendectomy was performed.

We attempted to retrieve copies of all relevant medical records. Exposure to an appendectomy was considered to have occurred if a study subject reported a primary appendectomy (i.e., not incidental to another procedure). Perforation of the appendix was defined a priori as having occurred if any of the terms "perforation," "perforated," or "gross peritonitis" were present in either the operative or pathologic report describing either the surgeon's clinical impression of the appendix or the histopathologic status of the appendix according to the pathologist. If there was a discrepancy between self-report and medical records regarding the status of a removed appendix, status according to the medical records was used for subsequent analyses.

Statistical analysis
We estimated the prevalence of appendiceal perforation among controls to be 2 percent, and we determined that 121 cases and 484 controls would be required to detect, with 80 percent power and a two-tailed significance level of 0.05, an odds ratio of 4.0 or greater (the approximate risk reported by Mueller et al. (7Go)). Single variable comparisons of proportions between cases and controls were tested by using the chi-square test. Unconditional logistic regression was used to calculate crude and adjusted odds ratios (and 95 percent confidence intervals) as estimates of the relative risk of tubal infertility associated with appendicitis and other exposures. Multivariate logistic regression models were fit to assess adjusted risk. Exposures other than appendicitis that were associated with tubal infertility at the p < 0.10 level in univariate analyses were included in subsequent multivariable models. Associations between covariates were assessed, and correlated pairs of variables were not included in any models. Since no interactions were thought to be of any a priori interest, and because of limited power to detect higher-order effects, interaction terms were not included in regression models. Statistical significance was accepted if p < 0.05 or if the 95 percent confidence interval associated with the estimate of an odds ratio excluded 1.0.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The characteristics of the 122 cases and 490 controls are described in table 1. There were large between-group differences in the distributions of age and annual income, with cases more likely to be older and have a higher annual income compared with controls. Fewer cases than controls had university degrees. Cases were more likely than controls to be previous or current users of cigarettes and oral contraceptives and were also more likely to report a history of pelvic inflammatory disease or endometriosis. There were no statistically significant between-group differences with respect to marital status and previous use of an intrauterine contraceptive device.


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TABLE 1. Characteristics of women with primary tubal infertility (cases) and of pregnant women (controls), Toronto, Ontario, Canada, July 1998–December 1998*

 
Thirteen (10.7 percent) cases and 25 (5.1 percent) controls reported a previous primary (nonincidental) appendectomy. The operations occurred between 1963 and 1994 (median, 1979), and the median age at appendectomy was 15 years (range, 5–25). We were able to retrieve medical records for 10 (26.3 percent) subjects. A discrepancy between medical records and self-report was identified for only 1 person, a case who recalled an inflamed appendix but had a normal appendix according to the operative and pathologic records.

Estimates of the risk of tubal infertility for various exposures are summarized in table 2. In multivariate analyses, cigarette smoking (OR = 2.0, 95 percent CI: 1.2, 3.2), pelvic inflammatory disease (OR = 6.0, 95 percent CI: 2.8, 12.8), and endometriosis (OR = 6.0, 95 percent CI: 2.8, 12.8) were strong determinants of tubal infertility. When adjusted for the effects of age, annual income, cigarette smoking, endometriosis, pelvic inflammatory disease, use of oral contraceptives, and use of an intrauterine contraceptive device, appendicitis (OR = 2.2, 95 percent CI: 0.9, 5.7) and perforation of the appendix (OR = 1.4, 95 percent CI: 0.3, 6.2) were nonsignificant risk factors.


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TABLE 2. Odds ratios and 95% confidence intervals for primary tubal infertility associated with various exposures, Toronto, Ontario, Canada, July 1998–December 1998*

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In a case-control study comparing women who had primary tubal infertility with pregnant controls, we did not find evidence of an important risk of infertility as a result of perforation of the appendix. Our results suggest that the association of perforation of the appendix with tubal infertility may not be as strong as previously thought (1GoGoGo–4Go, 7Go). However, the confidence intervals around the point estimates were wide and were nevertheless consistent with effect sizes as large as those reported previously (7Go).

A birth cohort effect may explain why the findings from the present study differ from previous research. Recent advances in the management of appendicitis, such as improved diagnostic tests, a trend toward earlier surgery, and the availability of better antibiotics, might have altered the natural history of perforated appendicitis. It is possible that women who had perforated appendicitis decades ago had a higher risk of developing infertility than women whose disease was of the same severity more recently. Alternatively, previous reports (7Go) may have overestimated the effect of appendiceal perforation on tubal infertility.

Andersson et al. (15Go) reached a conclusion similar to ours by using a different approach to evaluate the effect of appendicitis on subsequent fertility. With data from a large national database, they compared the rate of first birth of women who had an appendectomy when less than 15 years of age with age-matched controls and found that the cohort of women with a history of perforated appendicitis had a rate of birth and distribution of parity similar to controls (adjusted hazard ratio = 0.95, 95 percent CI: 0.88, 1.04). However, it is possible that the investigators' approach of analyzing only fertility rates might not have detected a modest effect on infertility rates.

An important finding of our study was that we did not detect significant evidence of recall bias. When self-reported appendectomy exposures were compared with medical records for cases and controls, agreement between self-report and medical records appeared to be good in both groups. Our ability to precisely quantify the accuracy of recall was limited by the relatively small number of events and by difficulty in obtaining some medical records. Most irretrievable medical records of previous appendectomies were unavailable because the appendectomies occurred many years ago and records were no longer available or because the appendectomies were performed in countries outside North America and the records could not be located.

In several ways, our study improves upon previous attempts to assess this association. We tried to minimize bias from recall error by using medical records to confirm reported exposures to appendicitis and appendiceal perforation. We also controlled for potential confounders of the relation between appendicitis and tubal infertility. Since women with tubal infertility attending in vitro fertilization clinics represent a population markedly distinct from pregnant or parous women with respect to age and socioeconomic status (16Go, 17Go), we controlled for these effects as well as the effects of other exposures known to be strongly related to tubal infertility.

Several limitations of our methodology must be considered. In case-control studies, care must be taken to ensure that controls are drawn from the same study base as cases to minimize bias in the estimates of risk (18Go, 19Go). We attempted to maintain a homogeneous study base by sampling controls from obstetric clinics in the same geographic areas as the in vitro fertilization clinics in which cases were enrolled. However, since there are many determinants (measurable and unmeasurable) of seeking infertility treatment, it is unlikely that an unselected sample of pregnant women would be drawn from the same base population as those seeking infertility care.

A special case of selection bias important in research on infertility risk factors in which cases ascertained from in vitro fertilization clinics are used is that of incomplete case ascertainment (20Go). Increased age and higher socioeconomic status are important determinants of seeking infertility treatment for women with infertility (16Go, 17Go). Therefore, infertile women who are younger and poorer are less likely to be ascertained as cases if study subjects are taken from clinic patient lists. Because age (21Go, 22Go) and socioeconomic factors (23Go) are also related to the incidence of appendicitis and appendiceal perforation, it is possible that the estimate of risk derived from a case-control study will be biased.

We found that several exposures confounded the relation between perforation of the appendix and tubal infertility, as reflected by the marked difference between the crude and adjusted odds ratios (OR = 3.4 vs. OR = 1.4) for appendiceal perforation. The reason that age functions as a confounding variable is clear. Increased age is a determinant of tubal infertility and is also associated with a higher risk of exposure to appendectomy because of the greater number of years at risk for developing appendicitis. Why exposures such as pelvic inflammatory disease and endometriosis are also confounders is less obvious, since there is no biologic explanation of why these conditions should be associated with perforation of the appendix. We found that both pelvic inflammatory disease and endometriosis were more common in cases and controls who also reported appendiceal perforation (data not shown). It is possible that women with these conditions are at high risk of undergoing an appendectomy and receiving a diagnosis of appendiceal perforation. Pelvic inflammatory disease and endometriosis may mimic the clinical features of appendicitis. A surgeon, believing that appendicitis is the cause of the acute illness, may encounter a "difficult" appendix and leave a patient with the impression that she had a complication of appendicitis.

Although an improvement over self-reports, operative and pathologic reports may not represent the severity of appendicitis with perfect accuracy. Since misclassification with respect to this measurement would be nondifferential for cases and controls, the effect of such error would be to bias the odds ratio toward 1.0 ("no effect"). Since we did not attempt to validate exposures to risk factors other than appendicitis, it is possible that differential exposure misclassification error for other exposures (such as smoking and pelvic inflammatory disease) contributed to biased estimates of risk of those exposures as well as of the adjusted risk of perforated appendicitis corrected for those exposures. If recall bias led to underreporting of these risk factors by cases compared with controls, then our crude estimates of risk for these determinants of tubal infertility would be spuriously low.

Because the prevalence of perforation of the appendix is low and the risk of infertility associated with appendiceal perforation does not appear to be large, it is unlikely that perforation of the appendix has a substantial impact on the total burden of infertility that occurs in a population. With our point estimate of the risk of tubal infertility from appendiceal perforation, the proportion of tubal infertility attributable to appendiceal perforation is 0.9 percent (24Go). Even if the upper limit of the 95 percent confidence interval for the risk of appendiceal perforation (6.2) is used, the population attributable risk is 2.8 percent.

In conclusion, perforation of the appendix does not appear to be an important risk factor for subsequent tubal infertility, especially when viewed in the context of other risk factors. On the basis of our findings, we do not believe that surgeons treating young women with abdominal pain and a low likelihood of having appendicitis should be aggressive in recommending appendectomy, if the sole reason for doing so is concern over future fertility.


    ACKNOWLEDGMENTS
 
This research project was supported by the physicians of Ontario through The Physicians' Services Incorporated Foundation. Dr. Urbach was supported by the Surgical Scientist Training Program, Department of Surgery, University of Toronto. Dr. Cohen is the recipient of a Senior Scientist Award from the Medical Research Council of Canada.

The assistance of the following persons in recruiting study participants is appreciated: Nancy Bryceland, Carole Craig, Dr. Elaine Herer, Dr. Murray Kroach, Dr. Susan Tarshis, Julie Tolentino, Dr. Gerald Urbach, Dr. Michael Virro, Dr. Fay Weisberg, and Dr. Arthur Zaltz.


    NOTES
 
Reprint requests to Dr. David R. Urbach, Toronto Western Hospital, 399 Bathurst Street, Room MP8-332, Toronto, Ontario, Canada M5T 2S8 (e-mail: david.urbach{at}uhn.on.ca).


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication February 22, 2000. Accepted for publication July 18, 2000.