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Association between appendicectomy in females and subsequent pregnancy rate: a cohort study
ORIGINAL ARTICLES: ENVIRONMENT AND EPIDEMIOLOGY
Association between appendicectomy in females and subsequent pregnancy rate: a cohort study Li Wei, Ph.D.,a Thomas MacDonald, M.D.,a and Sami Shimi, M.D.b a
Medicines Monitoring Unit, Division of Medical Sciences, School of Medicine; and b Division of Clinical and Population Sciences and Education, Department of Surgery and Molecular Oncology, Centre for Academic Clinical Practice, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland
Objective: To study whether subsequent pregnancy rate is reduced after appendicectomy. Design: A cohort study was carried out in the General Practice Research Database, a United Kingdom primary care database. Setting: University hospital. Patient(s): Female patients who underwent appendicectomy between 1986 and 2009 and appropriate comparators were followed until first pregnancy. Intervention(s): None. Main Outcome Measure(s): The association between appendicectomy and subsequent pregnancy was determined by Cox regression models. Result(s): The analyses included 76,426 appendicectomy patients, with 152,852 comparators from the database. There were 30,030 pregnancies (39.3%) in the appendicectomy cohort and 43,321 (28.3%) in the comparator cohort during a mean (SD) follow-up of 10.5 (6.6) years. Adjusted hazard ratios for subsequent birth rates were 1.54 (95% confidence interval, 1.52–1.56). Conclusion(s): Appendicectomy was associated with increased subsequent pregnancy rate in Use your smartphone this study. This suggests that a history of appendicectomy is not associated with impaired ferto scan this QR code tility. (Fertil SterilÒ 2012;98:401–5. Ó2012 by American Society for Reproductive Medicine.) and connect to the Key Words: Appendicectomy, pregnancy rates, cohort study Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/weil-appendicectomy-females-pregnancy-rate-cohort/
D
espite a recent decline in appendicectomy rates (1–3), appendicectomy remains one of the most common surgical operations performed worldwide. Both the acute inflammatory condition of appendicitis and/or the trauma of the surgical operation to remove the appendix might promote adhesion formation, particularly around the fallopian tubes, which could lead to tubal dysfunction and possible subfertility in women of childbearing age.
There has been controversy surrounding the association between appendicectomy and subsequent fertility. Some studies found no evidence for tubal infertility after appendicectomy (4–6). In contrast, other studies found that appendicectomy with or without proven appendicitis was associated with increased tubal infertility by virtue of an increase in ectopic pregnancies (7, 8). One epidemiologic study of first births after removal of a normal appendix in childhood found an
Received February 3, 2012; revised May 16, 2012; accepted May 18, 2012; published online June 7, 2012. L.W. has nothing to disclose. T.M. has nothing to disclose. S.S. has nothing to disclose. Reprint requests: Sami Shimi, M.D., Division of Clinical and Population Sciences and Education, Department of Surgery and Molecular Oncology, Centre for Academic Clinical Practice, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland DD1 9SY (E-mail: s.m. [email protected]). Fertility and Sterility® Vol. 98, No. 2, August 2012 0015-0282/$36.00 Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2012.05.016 VOL. 98 NO. 2 / AUGUST 2012
discussion forum for this article now.*
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increased rate of first births (9). However, many of these studies have had methodologic deficiencies that limit their reliability. A recent study we did in Tayside found increased subsequent pregnancy rate after appendicectomy (10). We were surprised by this result and sought to verify this finding using a larger national database. In this study we have used a large, validated database to verify whether female appendicectomy is associated with increased subsequent pregnancy rate.
MATERIALS AND METHODS Study Design This is a population-based cohort study using the General Practice Research Database (GPRD) (11). 401
ORIGINAL ARTICLE: ENVIRONMENT AND EPIDEMIOLOGY The GPRD is the world's largest computerized database of anonymized longitudinal medical records from primary care. It contains data from more than 500 primary care practices, with 4.4 million active patients throughout the United Kingdom (UK). The data have been collected since 1987, cover approximately 7% of the UK population, and are generalizable to the whole UK population. The GPRD also holds the Hospital Episode Statistics (HES) data for approximately 40% of the practices, which started from 1997 onward.
Study Cohorts Appendicectomy cohort. Data were extracted from the GPRD using the search terms for appendicectomy. Subjects were those who had an appendicectomy record and who were younger than 45 years between 1986 and 2009. They entered the study at the date of the appendicectomy and were followed up until September 2009. Comparator cohort. An exact age- and practice-matched cohort of two comparators for each study subject was generated from the rest of the GPRD female population who did not have an appendicectomy during the same period. Controls entered the study on the same date as the appendicectomy cohort.
Scientific Approval Approval for this study was obtained from the Independent Scientific Advisory Committee for Medicines and Healthcare products Regulatory Agency database research.
Exclusions Subjects were excluded from the study if they were aged <12 years or had <30 days of follow-up available. Subjects were censored after the first pregnancy, if they reached the age of 53 years, had a sterilization or hysterectomy or died, or at the end of follow up.
Study Outcome The study outcome was the first pregnancy, including live birth, recorded miscarriage, or termination during the follow-up period. These were ascertained from the general practitioner records with potential pregnancy codes and crossed-checked against a previous publication (12), or the HES database with the primary International Classification of Diseases (ICD)-9 codes (630–676) and ICD-10 codes (O00–O99 and Z34–Z39).
Definition of Covariates Age at entry to the study was a covariate, as was parity, use of oral contraceptives, number of previous hospitalizations, inflammatory bowel disease (ICD-9 codes 555, 556, 557, and 558 and ICD-10 codes K50, K51, and K52), pelvic inflammatory disease (ICD-9 codes 614 and 615 and ICD-10 codes N70, N71, N73, and N74), other abdominal surgery (defined by Office of Population Census and Surveys, 4th revision codes). 402
Statistical Analysis Data were presented as mean (SD) for continuous variables and as number (percentage) for categoric variables. Pregnancy events were plotted by Kaplan-Meier curves, and Cox proportional hazards regression models with a timedependent variable of oral contraceptives use were used to determine the association between the study and comparator groups. Univariate and multivariate analyses were carried out. In the multivariate models the hazards ratios (HRs) were adjusted for all covariates between the study and control groups. The results were expressed as HR (95% confidence interval [CI]). A ratio larger than 1 implied a greater probability of a pregnancy in the appendicectomy group earlier than in the comparator group.
Sensitivity Analysis Several sensitivity analyses were performed to test the robustness of the results. We repeated the analysis by using only the practices that had the HES dataset record-linked. In this case, appendicectomy, pregnancy, and the covariates (except oral contraceptives) were extracted from the HES dataset. All covariates were adjusted for 5 years before cohort study entry (baseline). A sensitivity analysis was carried out to exclude patients who may have been pregnant before and during the appendicectomy episode. Another sensitivity analysis was done that included covariates that occurred both before and after study entry in the matched cohort. Because of the time span of the study, with evolution in surgical practice, a further sensitivity analysis was carried out to assess the calendar year as a covariate. All statistical analyses were carried out using SAS (version 9.2) (SAS Institute).
RESULTS Characteristics The study contained 229,278 patients (76,426 patients in the appendicectomy cohort and 152,852 age- and practicematched patients in the comparator cohort) (Table 1). The appendicectomy cohort had more previous use of oral contraceptives and more previous hospitalization and comorbidity compared with the comparator cohort.
Pregnancy Rates During the follow-up, 39.3% patients (n ¼ 30,030) in the appendicectomy cohort and 28.3% (n ¼ 43,321) in the comparator cohort experienced pregnancy, with an average (SD) follow-up of 9.6 (6.7) and 10.9 (6.6) years for the two cohorts, respectively. The pregnancy events were more frequent in the appendicectomy cohort than in the comparator cohort: HR 1.54 (95% CI 1.52–1.56) (Table 2). Figure 1 shows the Kaplan-Meier plot of pregnancies between the two cohorts.
Sensitivity Analyses From the total cohort, there were 30,039 patients from practices that had data that can be linked to HES data (10,013 patients in the appendicectomy cohort and 20,026 patients in VOL. 98 NO. 2 / AUGUST 2012
Fertility and Sterility®
TABLE 1 Characteristics of subjects in the appendicectomy cohort and comparator cohort. Variable
Appendicectomy cohort (n [ 76,426)
Comparator cohort (n [ 152,852)
P value
21.1 (9.5) 9.6 (6.7) 25.0 (6.0) 18,268 (23.9) 16,882 (22.1)
21.1 (9.5) 10.9 (6.6) 25.9 (6.0) 26,702 (17.5) 28,310 (18.5)
– – < .01 < .01 < .01
Age (y) Follow-up time (y) Age at first birth after appendicectomy (y) Previous pregnancy Concurrent use of oral contraceptive Comorbidity at baseline Inflammatory bowel disease Pelvic inflammatory disease Other abdominal surgerya No. of hospitalizationsa 0 1 2 3 4 5þ
353 (0.5) 868 (1.1) 269 (0.4)
370 (0.2) 427 (0.3) 201 (0.1)
74,764 (97.8) 946 (1.2) 392 (0.5) 181 (0.2) 74 (0.1) 69 (0.1)
< .01 < .01 < .01 < .01
149,360 (97.7) 2436 (1.6) 699 (0.5) 241 (0.2) 70 (0.1) 56 (0.04)
Note: Data are numbers of subjects (percentage) or mean (SD). a Within HES practices. Wei. Appendicectomy and subsequent pregnancy. Fertil Steril 2012.
the comparator cohort). The adjusted HR was changed slightly from 1.54 (95% CI 1.52–1.56) to 1.57 (95% CI 1.49–1.65). A sensitivity analysis excluded women who were pregnant before and during the appendicectomy episode. The adjusted HR was 1.65 (95% CI 1.63–1.68). We have also done an analysis by including confounding variables both before study entry and during the follow-up, and we found similar results (adjusted HR was 1.56 [95% CI 1.54–1.58]). In addition, we found no calendar year effect over the study period (1986–2009), with the adjusted HR for the appendicectomy cohort 1.54 (1.51–1.56) for the main analysis and 1.59 (1.51–1.67) for the sensitivity analysis.
DISCUSSION The results from this cohort study using a national database found significantly increased pregnancy rates after appendicectomy in comparison with comparators. This was in agreement with our previous finding using the Medicines Monitoring Unit (MEMO) database from the National Health Service Tayside population (10). In that study, the pregnancy events were more frequent in the appendicectomy cohort than
TABLE 2 Impact of appendicectomy on pregnancy outcome. Parameter Main analysis Comparator Appendicectomy Sensitivity analysis Comparator Appendicectomy
Unadjusted HR (95% CI)
Adjusteda HR (95% CI)
P value
1.00 1.61 (1.58–1.63)
1.00 1.54 (1.52–1.56)
< .01
1.00 1.67 (1.59–1.76)
1.00 1.57 (1.49–1.65)
< .01
a
Adjusted for previous pregnancy, use of oral contraceptives, inflammatory bowel disease, pelvic inflammatory disease, other abdominal surgery, and number of hospitalizations before study entry. Wei. Appendicectomy and subsequent pregnancy. Fertil Steril 2012.
VOL. 98 NO. 2 / AUGUST 2012
in the comparator cohort: HR 1.20 (95% CI 1.10–1.31). These data led us to suggest that at the very least appendicectomy does not seem to be associated with reduced fertility. In the present study, the previous pregnancy rate and use of oral contraceptives were higher in the appendicectomy cohort than in the comparator group. The higher previous pregnancy rate in the appendicectomy cohort suggests that the cohort of females considered as a group is at the higher end of the fertility scale, at least before their appendicectomy. In addition, the higher previous pregnancy rate suggests that more of this cohort have already engaged in sexual activity. The higher use of oral contraceptives in this cohort may also influence modulation of endogenous sex hormones in oral contraceptives users. This is reported to confer a higher socio-sexual interest among these females across the cycle, without the significant fluctuations related to naïve cycle phases (13). Alternatively, this may simply be a matter of self-selection, in that females who take the oral contraceptive are more likely to be involved in a sexual relationship. Although the higher previous pregnancy rate and use of oral contraceptives in the appendicectomy cohort provides a possible explanation for the apparent increase in subsequent pregnancy rates in this cohort, it provides no explanation for the relationship with appendicectomy. In this study we have also found that women who had an appendicectomy tended to have a subsequent pregnancy at an earlier age than in the comparator cohort. Conception is dependent on a certain number of biological factors, including fertility. It is also dependent on a number of socioeconomic conditions. An early and increased conception rate has been found in women with short education and low socioeconomic status (14). There is some evidence that appendicitis is also associated with a low socioeconomic status (15, 16). This, however, does not explain all the observed apparent increase in subsequent pregnancies after appendicectomy in this study, because some females who had an appendicectomy did not have appendicitis. In addition, in a sensitivity analysis we 403
ORIGINAL ARTICLE: ENVIRONMENT AND EPIDEMIOLOGY
FIGURE 1
Kaplan-Meier plot of pregnancy outcome between the two cohorts in the GPRD analysis. Wei. Appendicectomy and subsequent pregnancy. Fertil Steril 2012.
have matched patients for general practice location as a surrogate for socioeconomic status. This has made little change to the point estimate. Another possible explanation for the association between appendicectomy and increased subsequent pregnancy rate is based on the relationship between the fluctuations in female sex hormones across the menstrual cycle in creating a suitable environment for the growth and maturation of the fertilized oocyte and the inflammatory or anti-inflammatory effects of these hormones (17). It has been reported that the frequency of acute appendicitis in the luteal phase of the menstrual cycle was more than twice the frequency of the disease in the remaining half of the menstrual cycle. This suggests that the female sex hormone fluctuations might play an etiologic role in the development of acute appendicitis or influence the inflammatory process in the appendix (18, 19). Pathologically, the female sex hormone fluctuations may influence the initial inflammatory process in the lymphoid tissue of the appendix, which subsequently becomes engorged and obstructs the lumen, leading to acute appendicitis (20). In addition, those hormones produce far-reaching effects on the peripheral and central nervous systems to modulate pain (17, 21, 22). These hormonal factors in combination influence both fertility and pain perception, necessitating admission for surgical exploration, whether or not the pain is caused by appendicitis. Thus the ‘‘symptoms’’ of appendicitis might be falsely expressed in some females with ‘‘normal’’ hormonal responses. The association between appendicectomy and subsequent pregnancy rate was consistent in two large UK populationrepresentative samples (MEMO database and the GPRD). It is also consistent with the only large well-designed epidemiologic study of first births after appendicectomy in young females (9). However, it is not consistent with other, much smaller studies that have been published. This is mainly because many of the studies were descriptive case series with limited numbers and without an appropriate comparison group (5, 6). Other studies had a more appropriate epidemiologic design but looked specifically at the relationship between appendicectomy and tubal infertility (23) or examined 404
appendicectomy as a risk factor for ectopic pregnancy (6, 8, 24). There were other methodologic flaws in these studies (25), including the study population (7, 8), comparability of the groups (26), unreliability of data (8), recall bias (24, 26), and determination of exposure (7). An unknown proportion of the appendicectomy cohort had a normal appendix. This is a reflection of historical surgical practice before the laparoscopic era. The advent of laparoscopy in the early 1990s and its routine use has undoubtedly reduced the rates of ‘‘negative’’ appendicectomy from 20%–30% (27) to approximately 5% (28). Although there is evidence of reduced adhesion formation after laparoscopic surgery, this did not affect tubal patency (29). The benefits of laparoscopic surgery have been repeatedly demonstrated for a variety of procedures. Although surgical practice is moving toward increasing the adoption of laparoscopic appendicectomy with emphasis on fertile women (30), there is little evidence that this will have a profound effect on fertility in young women. Although there is a recent trend toward more conservative management of appendicitis with intravenous antibiotics in recent years (31), it is unknown what the impact of this will be on future fertility.
Strengths and Limitations The strengths of the present study are large number of patients studied and the use of a well-validated database. The use of first pregnancy as an outcome and the control for several potential confounders of the relationship between appedicectomy and pregnancy are also strengths. The main challenges of this study are the coding for the outcome and covariates, and there were some data missing from the database. The higher point estimates obtained in the sensitivity analysis that used the subset of GPRD that had hospitalization data record-linked does suggest that some of these limitations are important. In addition, the database had no reliable records on elective appendicectomies, previous infertility treatment, other contraception methods, or on the desire for pregnancy in either cohort. Finally, the present study was observational, and confounding factors could not be fully controlled, a limitation of all observational studies.
Clinical Implications On the basis of the results of the present study, we believe that clinicians can take comfort that the removal of a normal appendix does not seem to have adverse consequences on fertility. Several studies have shown a 19%–40% rate of pathologically abnormal appendix in the setting of no visual abnormality (32). Because naked eye or laparoscopic inspection is not always reliable, it seems prudent that all young women presenting with symptoms, clinical signs, and laboratory results suggestive of appendicitis should proceed to laparoscopy. In accordance with Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) guideline for laparoscopic appendicectomy, if no other pathology is identified, the decision to remove the appendix should be considered, but on the basis of the individual clinical scenario (33). Further, in the assessment of subfertility, a history of appendicectomy VOL. 98 NO. 2 / AUGUST 2012
Fertility and Sterility® should not be associated with impaired fertility. This study did not examine patients with appendicitis, ruptured appendix, or peritonitis secondary to appendicitis. The degree to which these pathologies are risk factors for pelvic adhesions, ectopic pregnancies, and infertility was not addressed by this study. In conclusion, appendicectomy did not incur risk of reduced fertility; rather, it was associated with increased pregnancy rates. A history of appendicectomy is not associated with impaired fertility.
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Association between appendicectomy in females and subsequent pregnancy rate: a cohort study Li Wei, Ph.D.,a Thomas MacDonald, M.D.,a and Sami Shimi, M.D.b a
Medicines Monitoring Unit, Division of Medical Sciences, School of Medicine; and b Division of Clinical and Population Sciences and Education, Department of Surgery and Molecular Oncology, Centre for Academic Clinical Practice, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland
Objective: To study whether subsequent pregnancy rate is reduced after appendicectomy. Design: A cohort study was carried out in the General Practice Research Database, a United Kingdom primary care database. Setting: University hospital. Patient(s): Female patients who underwent appendicectomy between 1986 and 2009 and appropriate comparators were followed until first pregnancy. Intervention(s): None. Main Outcome Measure(s): The association between appendicectomy and subsequent pregnancy was determined by Cox regression models. Result(s): The analyses included 76,426 appendicectomy patients, with 152,852 comparators from the database. There were 30,030 pregnancies (39.3%) in the appendicectomy cohort and 43,321 (28.3%) in the comparator cohort during a mean (SD) follow-up of 10.5 (6.6) years. Adjusted hazard ratios for subsequent birth rates were 1.54 (95% confidence interval, 1.52–1.56). Conclusion(s): Appendicectomy was associated with increased subsequent pregnancy rate in Use your smartphone this study. This suggests that a history of appendicectomy is not associated with impaired ferto scan this QR code tility. (Fertil SterilÒ 2012;98:401–5. Ó2012 by American Society for Reproductive Medicine.) and connect to the Key Words: Appendicectomy, pregnancy rates, cohort study Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/weil-appendicectomy-females-pregnancy-rate-cohort/
D
espite a recent decline in appendicectomy rates (1–3), appendicectomy remains one of the most common surgical operations performed worldwide. Both the acute inflammatory condition of appendicitis and/or the trauma of the surgical operation to remove the appendix might promote adhesion formation, particularly around the fallopian tubes, which could lead to tubal dysfunction and possible subfertility in women of childbearing age.
There has been controversy surrounding the association between appendicectomy and subsequent fertility. Some studies found no evidence for tubal infertility after appendicectomy (4–6). In contrast, other studies found that appendicectomy with or without proven appendicitis was associated with increased tubal infertility by virtue of an increase in ectopic pregnancies (7, 8). One epidemiologic study of first births after removal of a normal appendix in childhood found an
Received February 3, 2012; revised May 16, 2012; accepted May 18, 2012; published online June 7, 2012. L.W. has nothing to disclose. T.M. has nothing to disclose. S.S. has nothing to disclose. Reprint requests: Sami Shimi, M.D., Division of Clinical and Population Sciences and Education, Department of Surgery and Molecular Oncology, Centre for Academic Clinical Practice, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland DD1 9SY (E-mail: s.m. [email protected]). Fertility and Sterility® Vol. 98, No. 2, August 2012 0015-0282/$36.00 Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2012.05.016 VOL. 98 NO. 2 / AUGUST 2012
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
increased rate of first births (9). However, many of these studies have had methodologic deficiencies that limit their reliability. A recent study we did in Tayside found increased subsequent pregnancy rate after appendicectomy (10). We were surprised by this result and sought to verify this finding using a larger national database. In this study we have used a large, validated database to verify whether female appendicectomy is associated with increased subsequent pregnancy rate.
MATERIALS AND METHODS Study Design This is a population-based cohort study using the General Practice Research Database (GPRD) (11). 401
ORIGINAL ARTICLE: ENVIRONMENT AND EPIDEMIOLOGY The GPRD is the world's largest computerized database of anonymized longitudinal medical records from primary care. It contains data from more than 500 primary care practices, with 4.4 million active patients throughout the United Kingdom (UK). The data have been collected since 1987, cover approximately 7% of the UK population, and are generalizable to the whole UK population. The GPRD also holds the Hospital Episode Statistics (HES) data for approximately 40% of the practices, which started from 1997 onward.
Study Cohorts Appendicectomy cohort. Data were extracted from the GPRD using the search terms for appendicectomy. Subjects were those who had an appendicectomy record and who were younger than 45 years between 1986 and 2009. They entered the study at the date of the appendicectomy and were followed up until September 2009. Comparator cohort. An exact age- and practice-matched cohort of two comparators for each study subject was generated from the rest of the GPRD female population who did not have an appendicectomy during the same period. Controls entered the study on the same date as the appendicectomy cohort.
Scientific Approval Approval for this study was obtained from the Independent Scientific Advisory Committee for Medicines and Healthcare products Regulatory Agency database research.
Exclusions Subjects were excluded from the study if they were aged <12 years or had <30 days of follow-up available. Subjects were censored after the first pregnancy, if they reached the age of 53 years, had a sterilization or hysterectomy or died, or at the end of follow up.
Study Outcome The study outcome was the first pregnancy, including live birth, recorded miscarriage, or termination during the follow-up period. These were ascertained from the general practitioner records with potential pregnancy codes and crossed-checked against a previous publication (12), or the HES database with the primary International Classification of Diseases (ICD)-9 codes (630–676) and ICD-10 codes (O00–O99 and Z34–Z39).
Definition of Covariates Age at entry to the study was a covariate, as was parity, use of oral contraceptives, number of previous hospitalizations, inflammatory bowel disease (ICD-9 codes 555, 556, 557, and 558 and ICD-10 codes K50, K51, and K52), pelvic inflammatory disease (ICD-9 codes 614 and 615 and ICD-10 codes N70, N71, N73, and N74), other abdominal surgery (defined by Office of Population Census and Surveys, 4th revision codes). 402
Statistical Analysis Data were presented as mean (SD) for continuous variables and as number (percentage) for categoric variables. Pregnancy events were plotted by Kaplan-Meier curves, and Cox proportional hazards regression models with a timedependent variable of oral contraceptives use were used to determine the association between the study and comparator groups. Univariate and multivariate analyses were carried out. In the multivariate models the hazards ratios (HRs) were adjusted for all covariates between the study and control groups. The results were expressed as HR (95% confidence interval [CI]). A ratio larger than 1 implied a greater probability of a pregnancy in the appendicectomy group earlier than in the comparator group.
Sensitivity Analysis Several sensitivity analyses were performed to test the robustness of the results. We repeated the analysis by using only the practices that had the HES dataset record-linked. In this case, appendicectomy, pregnancy, and the covariates (except oral contraceptives) were extracted from the HES dataset. All covariates were adjusted for 5 years before cohort study entry (baseline). A sensitivity analysis was carried out to exclude patients who may have been pregnant before and during the appendicectomy episode. Another sensitivity analysis was done that included covariates that occurred both before and after study entry in the matched cohort. Because of the time span of the study, with evolution in surgical practice, a further sensitivity analysis was carried out to assess the calendar year as a covariate. All statistical analyses were carried out using SAS (version 9.2) (SAS Institute).
RESULTS Characteristics The study contained 229,278 patients (76,426 patients in the appendicectomy cohort and 152,852 age- and practicematched patients in the comparator cohort) (Table 1). The appendicectomy cohort had more previous use of oral contraceptives and more previous hospitalization and comorbidity compared with the comparator cohort.
Pregnancy Rates During the follow-up, 39.3% patients (n ¼ 30,030) in the appendicectomy cohort and 28.3% (n ¼ 43,321) in the comparator cohort experienced pregnancy, with an average (SD) follow-up of 9.6 (6.7) and 10.9 (6.6) years for the two cohorts, respectively. The pregnancy events were more frequent in the appendicectomy cohort than in the comparator cohort: HR 1.54 (95% CI 1.52–1.56) (Table 2). Figure 1 shows the Kaplan-Meier plot of pregnancies between the two cohorts.
Sensitivity Analyses From the total cohort, there were 30,039 patients from practices that had data that can be linked to HES data (10,013 patients in the appendicectomy cohort and 20,026 patients in VOL. 98 NO. 2 / AUGUST 2012
Fertility and Sterility®
TABLE 1 Characteristics of subjects in the appendicectomy cohort and comparator cohort. Variable
Appendicectomy cohort (n [ 76,426)
Comparator cohort (n [ 152,852)
P value
21.1 (9.5) 9.6 (6.7) 25.0 (6.0) 18,268 (23.9) 16,882 (22.1)
21.1 (9.5) 10.9 (6.6) 25.9 (6.0) 26,702 (17.5) 28,310 (18.5)
– – < .01 < .01 < .01
Age (y) Follow-up time (y) Age at first birth after appendicectomy (y) Previous pregnancy Concurrent use of oral contraceptive Comorbidity at baseline Inflammatory bowel disease Pelvic inflammatory disease Other abdominal surgerya No. of hospitalizationsa 0 1 2 3 4 5þ
353 (0.5) 868 (1.1) 269 (0.4)
370 (0.2) 427 (0.3) 201 (0.1)
74,764 (97.8) 946 (1.2) 392 (0.5) 181 (0.2) 74 (0.1) 69 (0.1)
< .01 < .01 < .01 < .01
149,360 (97.7) 2436 (1.6) 699 (0.5) 241 (0.2) 70 (0.1) 56 (0.04)
Note: Data are numbers of subjects (percentage) or mean (SD). a Within HES practices. Wei. Appendicectomy and subsequent pregnancy. Fertil Steril 2012.
the comparator cohort). The adjusted HR was changed slightly from 1.54 (95% CI 1.52–1.56) to 1.57 (95% CI 1.49–1.65). A sensitivity analysis excluded women who were pregnant before and during the appendicectomy episode. The adjusted HR was 1.65 (95% CI 1.63–1.68). We have also done an analysis by including confounding variables both before study entry and during the follow-up, and we found similar results (adjusted HR was 1.56 [95% CI 1.54–1.58]). In addition, we found no calendar year effect over the study period (1986–2009), with the adjusted HR for the appendicectomy cohort 1.54 (1.51–1.56) for the main analysis and 1.59 (1.51–1.67) for the sensitivity analysis.
DISCUSSION The results from this cohort study using a national database found significantly increased pregnancy rates after appendicectomy in comparison with comparators. This was in agreement with our previous finding using the Medicines Monitoring Unit (MEMO) database from the National Health Service Tayside population (10). In that study, the pregnancy events were more frequent in the appendicectomy cohort than
TABLE 2 Impact of appendicectomy on pregnancy outcome. Parameter Main analysis Comparator Appendicectomy Sensitivity analysis Comparator Appendicectomy
Unadjusted HR (95% CI)
Adjusteda HR (95% CI)
P value
1.00 1.61 (1.58–1.63)
1.00 1.54 (1.52–1.56)
< .01
1.00 1.67 (1.59–1.76)
1.00 1.57 (1.49–1.65)
< .01
a
Adjusted for previous pregnancy, use of oral contraceptives, inflammatory bowel disease, pelvic inflammatory disease, other abdominal surgery, and number of hospitalizations before study entry. Wei. Appendicectomy and subsequent pregnancy. Fertil Steril 2012.
VOL. 98 NO. 2 / AUGUST 2012
in the comparator cohort: HR 1.20 (95% CI 1.10–1.31). These data led us to suggest that at the very least appendicectomy does not seem to be associated with reduced fertility. In the present study, the previous pregnancy rate and use of oral contraceptives were higher in the appendicectomy cohort than in the comparator group. The higher previous pregnancy rate in the appendicectomy cohort suggests that the cohort of females considered as a group is at the higher end of the fertility scale, at least before their appendicectomy. In addition, the higher previous pregnancy rate suggests that more of this cohort have already engaged in sexual activity. The higher use of oral contraceptives in this cohort may also influence modulation of endogenous sex hormones in oral contraceptives users. This is reported to confer a higher socio-sexual interest among these females across the cycle, without the significant fluctuations related to naïve cycle phases (13). Alternatively, this may simply be a matter of self-selection, in that females who take the oral contraceptive are more likely to be involved in a sexual relationship. Although the higher previous pregnancy rate and use of oral contraceptives in the appendicectomy cohort provides a possible explanation for the apparent increase in subsequent pregnancy rates in this cohort, it provides no explanation for the relationship with appendicectomy. In this study we have also found that women who had an appendicectomy tended to have a subsequent pregnancy at an earlier age than in the comparator cohort. Conception is dependent on a certain number of biological factors, including fertility. It is also dependent on a number of socioeconomic conditions. An early and increased conception rate has been found in women with short education and low socioeconomic status (14). There is some evidence that appendicitis is also associated with a low socioeconomic status (15, 16). This, however, does not explain all the observed apparent increase in subsequent pregnancies after appendicectomy in this study, because some females who had an appendicectomy did not have appendicitis. In addition, in a sensitivity analysis we 403
ORIGINAL ARTICLE: ENVIRONMENT AND EPIDEMIOLOGY
FIGURE 1
Kaplan-Meier plot of pregnancy outcome between the two cohorts in the GPRD analysis. Wei. Appendicectomy and subsequent pregnancy. Fertil Steril 2012.
have matched patients for general practice location as a surrogate for socioeconomic status. This has made little change to the point estimate. Another possible explanation for the association between appendicectomy and increased subsequent pregnancy rate is based on the relationship between the fluctuations in female sex hormones across the menstrual cycle in creating a suitable environment for the growth and maturation of the fertilized oocyte and the inflammatory or anti-inflammatory effects of these hormones (17). It has been reported that the frequency of acute appendicitis in the luteal phase of the menstrual cycle was more than twice the frequency of the disease in the remaining half of the menstrual cycle. This suggests that the female sex hormone fluctuations might play an etiologic role in the development of acute appendicitis or influence the inflammatory process in the appendix (18, 19). Pathologically, the female sex hormone fluctuations may influence the initial inflammatory process in the lymphoid tissue of the appendix, which subsequently becomes engorged and obstructs the lumen, leading to acute appendicitis (20). In addition, those hormones produce far-reaching effects on the peripheral and central nervous systems to modulate pain (17, 21, 22). These hormonal factors in combination influence both fertility and pain perception, necessitating admission for surgical exploration, whether or not the pain is caused by appendicitis. Thus the ‘‘symptoms’’ of appendicitis might be falsely expressed in some females with ‘‘normal’’ hormonal responses. The association between appendicectomy and subsequent pregnancy rate was consistent in two large UK populationrepresentative samples (MEMO database and the GPRD). It is also consistent with the only large well-designed epidemiologic study of first births after appendicectomy in young females (9). However, it is not consistent with other, much smaller studies that have been published. This is mainly because many of the studies were descriptive case series with limited numbers and without an appropriate comparison group (5, 6). Other studies had a more appropriate epidemiologic design but looked specifically at the relationship between appendicectomy and tubal infertility (23) or examined 404
appendicectomy as a risk factor for ectopic pregnancy (6, 8, 24). There were other methodologic flaws in these studies (25), including the study population (7, 8), comparability of the groups (26), unreliability of data (8), recall bias (24, 26), and determination of exposure (7). An unknown proportion of the appendicectomy cohort had a normal appendix. This is a reflection of historical surgical practice before the laparoscopic era. The advent of laparoscopy in the early 1990s and its routine use has undoubtedly reduced the rates of ‘‘negative’’ appendicectomy from 20%–30% (27) to approximately 5% (28). Although there is evidence of reduced adhesion formation after laparoscopic surgery, this did not affect tubal patency (29). The benefits of laparoscopic surgery have been repeatedly demonstrated for a variety of procedures. Although surgical practice is moving toward increasing the adoption of laparoscopic appendicectomy with emphasis on fertile women (30), there is little evidence that this will have a profound effect on fertility in young women. Although there is a recent trend toward more conservative management of appendicitis with intravenous antibiotics in recent years (31), it is unknown what the impact of this will be on future fertility.
Strengths and Limitations The strengths of the present study are large number of patients studied and the use of a well-validated database. The use of first pregnancy as an outcome and the control for several potential confounders of the relationship between appedicectomy and pregnancy are also strengths. The main challenges of this study are the coding for the outcome and covariates, and there were some data missing from the database. The higher point estimates obtained in the sensitivity analysis that used the subset of GPRD that had hospitalization data record-linked does suggest that some of these limitations are important. In addition, the database had no reliable records on elective appendicectomies, previous infertility treatment, other contraception methods, or on the desire for pregnancy in either cohort. Finally, the present study was observational, and confounding factors could not be fully controlled, a limitation of all observational studies.
Clinical Implications On the basis of the results of the present study, we believe that clinicians can take comfort that the removal of a normal appendix does not seem to have adverse consequences on fertility. Several studies have shown a 19%–40% rate of pathologically abnormal appendix in the setting of no visual abnormality (32). Because naked eye or laparoscopic inspection is not always reliable, it seems prudent that all young women presenting with symptoms, clinical signs, and laboratory results suggestive of appendicitis should proceed to laparoscopy. In accordance with Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) guideline for laparoscopic appendicectomy, if no other pathology is identified, the decision to remove the appendix should be considered, but on the basis of the individual clinical scenario (33). Further, in the assessment of subfertility, a history of appendicectomy VOL. 98 NO. 2 / AUGUST 2012
Fertility and Sterility® should not be associated with impaired fertility. This study did not examine patients with appendicitis, ruptured appendix, or peritonitis secondary to appendicitis. The degree to which these pathologies are risk factors for pelvic adhesions, ectopic pregnancies, and infertility was not addressed by this study. In conclusion, appendicectomy did not incur risk of reduced fertility; rather, it was associated with increased pregnancy rates. A history of appendicectomy is not associated with impaired fertility.
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