Can symptomatology help in the diagnosis of endometriosis? Findings from a national case control study Part 1

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1 DOI: /j x Epidemiology Can symptomatology help in the diagnosis of endometriosis? Findings from a national case control study Part 1 KD Ballard, a HE Seaman, b CS de Vries, c JT Wright a a Department of Women s Health and b Department of Pharmacoepidemiology, Postgraduate Medical School, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK c Department of Pharmacy and Pharmacology, University of Bath, Bath, UK Correspondence: Dr KD Ballard, Department of Women s Health, Postgraduate Medical School, Faculty of Health and Medical Sciences, University of Surrey, Daphne Jackson Road, Manor Park, Guildford, Surrey GU2 7WG, UK. k.ballard@surrey.ac.uk Accepted 5 July Published OnlineEarly 19 August Objective To determine the value of patient-reported symptoms in diagnosing endometriosis. Design A national case control study. Setting Data from the UK General Practice Research Database for years Sample A total of 5540 women aged years, diagnosed with endometriosis, each matched to four controls without endometriosis. Methods Data were analysed to determine whether specific symptoms were highly indicative of endometriosis. Odds ratios for these symptoms were derived by conditional logistic regression analysis. Main outcome measures Symptoms associated with endometriosis. Results The prevalence of diagnosed endometriosis was 1.5%. A greater proportion of women with endometriosis had abdominopelvic pain, dysmenorrhoea or menorrhagia (73%) compared with controls (20%). Compared with controls, women with endometriosis had increased risks of abdominopelvic pain (OR 5.2 [95% CI: ]), dysmenorrhoea (OR 8.1 [95% CI: ]), menorrhagia (OR 4.0 [95% CI: ]), subfertility (OR 8.2 [95% CI: ]), dyspareunia and/or postcoital bleeding (OR 6.8 [95% CI: ]), and ovarian cysts (OR 7.3 [95% CI: ]), and of being diagnosed with irritable bowel syndrome (IBS) (OR 1.6 [95% CI: ]) or pelvic inflammatory disease (OR 3.0 [95% CI: ]). Women with endometriosis were also found to consult the doctor more frequently than the controls and were twice as likely to have time off work. Conclusions Specific symptoms and frequent medical consultation are associated with endometriosis and appear useful in the diagnosis. Endometriosis may coexist with or be misdiagnosed as pelvic inflammatory disease or IBS. Keywords Diagnosis, endometriosis, General Practice Research Database, prevalence, symptoms. Please cite this paper as: Ballard K, Seaman H, de Vries C, Wright J. Can symptomatology help in the diagnosis of endometriosis? Findings from a national case control study Part 1. BJOG 2008;115: Introduction Endometriosis is the presence of endometrial gland and stroma-like tissue outside of the uterine cavity. Symptoms vary, but typically include dysmenorrhoea, pelvic pain unrelated to the menstrual cycle, deep dyspareunia and dyschezia. In addition to symptoms, a community-based study has shown that 20% of women with endometriosis experience subfertility. 1 Since the symptoms of endometriosis are nonspecific, often overlapping with those experienced in a range of gynaecological and gastrointestinal conditions, the process of reaching a diagnosis of endometriosis is often delayed. Indeed, studies report average delays of 11.7 years in the USA, 2 8 years in the UK, 1,3 and 6.7 years in Norway. 4 A definitive diagnosis of endometriosis can only be made at surgery, generally via laparoscopy, and there are well-recognised risks associated with this. 5,6 Moreover, studies report that between 21 7 and 46% 8 of women with chronic pelvic pain are found not to have any identified pathology at laparoscopy. Efforts to develop a nonsurgical method of diagnosing endometriosis have focused on imaging techniques, biomarkers, and patient-reported symptoms. While there is good evidence to support the use of transvaginal ultrasound for the diagnosis of endometrioma, 9 it has been shown to be less 1382 ª 2008 The Authors Journal compilation ª RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology

2 Symptomatology in the diagnosis of endometriosis accurate in nonovarian endometriosis. 10 There is also limited evidence supporting the use of magnetic resonance imaging in the diagnosis of pelvic endometriosis, 11 although slightly better results are being achieved with fat-suppressed images compared with conventional images. 12,13 Studies combining transvaginal ultrasound with other soft markers such as medical history, symptom reporting, and pelvic examination have also been unsuccessful in identifying nonovarian endometriosis. 14 Although serum biomarkers such as CA125 and CA19-9 have been studied extensively as potential diagnostic measures for endometriosis, they have been shown to be of limited value. 15 More recently, additional serum markers such as cytokine interleukin-6 and leptin have been investigated as potential diagnostic tools for endometriosis, 16,17 but so far, the evidence to support their predictive value is limited. Questionnaire-based studies have attempted to determine whether reported symptoms can be helpful in the diagnosis of endometriosis. Of particular note is a study of 1200 women undergoing laparoscopy for sterilisation, infertility, chronic pelvic pain or an abdominal hysterectomy for dysfunctional uterine bleeding. 18 Although the authors report that women with endometriosis experienced dysmenorrhoea more frequently than women with pelvic adhesions and a normal pelvis, other symptoms such as dyspareunia and pelvic pain were reported equally by women with endometriosis and those with adhesions. Using self-reported symptom questionnaires to look more specifically at deep infiltrating endometriosis has resulted in dyschezia and deep dyspareunia being identified as fairly strong predictors. 19,20 To date, however, studies have sampled from specific gynaecological populations, with women being recruited from hospital-based clinics. Yet, to improve the diagnostic delays in endometriosis, it is important to determine which symptoms are reported to physicians working within the community and whether these are useful in prompting further investigation to diagnose or exclude endometriosis. In this paper, we report the findings of a large, national, community-based, case control study investigating the symptom and consultation patterns experienced by women before a diagnosis of endometriosis. Methods Data source The source of data for this study was the UK General Practice Research Database (GPRD), which is the largest source of longitudinal data from general practice in the UK. Data are derived from GP consultations, including reported symptoms, any investigations, treatments, specialist referrals, and diagnoses (GP and hospital made), which are entered at the time of consultation onto the practice database. Anonymised data are available for about 40 million patient-years and the population covered is demographically similar to the UK general population. 21 The GPRD started harvesting data from contributing practices in 1987, and the volume and quality of the data have increased over the years. Since 1992, most data are considered to have reached research standard (up-to-standard). This study used data extracted from a version of the GPRD that provided data last collected from contributing practices in April 2002, with an average of 5.6 years follow up per patient. Diagnoses and symptoms were recorded using Oxford Medical Information System (OXMIS) 22 or Read codes 23 described in look-up dictionaries. Prescription data are almost complete as virtually all prescriptions issued by the GPs are generated via the computer system. 21 Referrals and admission to hospital are recorded, as is the receipt of hospital letters and discharge summaries. Smoking and drinking habits, height, weight, immunisation, laboratory results, and clinic attendances are recorded with some incompleteness that varies by practice. Study period The study period was from 2 January 1992 to 31 December Study population The study population comprised women aged years, registered with practices contributing up-to-standard data. Women registered with the GP as temporary or private patients were excluded from the study population. Identification of potential cases Following multicentre research ethics committee approval (06/MREC 04/72) and scientific approval from the Independent Scientific Advisory Committee (ISAC ), data were extracted from the main database. We have developed inhouse software to enable a woman s complete GPRD records to be viewed via an on-screen browser. The cohort of potential cases included all women with a code for endometriosis where the earliest date of diagnosis was after 1 January 1992 and who (a) were aged between 15 and 55 years on the earliest date of diagnosis (index date), (b) had at least 3 years of data between the patient registration date (or practice up-to-standard date) and the index date, and (c) had at least 3 months of registration time between the index date and the date of last data collection. Using the GPRD dictionaries of codes, a list of diagnosis/procedure codes that would supportadiagnosisofendometriosis (e.g. laparoscopy, endoscopy and laparotomy) and a list of drugs used to treat endometriosis (e.g. gonadotrophin-releasing hormone analogues and danazol) were compiled. The medical and prescribing records of all potential cases were searched to identify potential cases with records to support case status. The earliest diagnosis of ª 2008 The Authors Journal compilation ª RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology 1383

3 Ballard et al. endometriosis was set as the provisional index date. Although all potential cases of endometriosis had an OXMIS/ Read code for endometriosis, it is possible that this code has been inaccurately assigned to the medical record. To improve the accuracy of case status, the potential cases were defined as definite, probable or possible according to the reliability of supporting evidence. An algorithm was developed to assist with the definition of case status. Definite cases had an OXMIS/ Read code of endometriosis and evidence of a hospital appointment associated with the diagnosis of endometriosis. This evidence consisted of at least one of the following: (a) a code for a recent surgical procedure (e.g. laparoscopy, sterilisation and hysterectomy); (b) recent referral to a gynaecologist for gynaecological symptoms (e.g. dyspareunia and pelvic pain); (c) at least two further records of endometriosis after the index date; and (d) a specific site of endometriosis recorded (e.g. chocolate cyst and endometriosis of the vagina). Probable cases also had an OXMIS/Read code for endometriosis and either had evidence of an associated hospital appointment or any of the other evidence listed (a) to (d). For a large proportion of potential cases (47%), however, particularly those prescribed treatment for endometriosis, case status could not be established easily and the entire GPRD records were viewed in the on-screen browser. Whenever the medical and/or prescribing histories remained uncertain, case status of the potential cases was reviewed by a gynaecologist (J.T.W.). Any potential cases who had an OXMIS/Read code for endometriosis but had insufficient evidence to classify them as definite or probable (no evidence of being seen in hospital, no further records of endometriosis) were defined as possible. Case status was determined using data obtained from the GPRD only and therefore we were unable to scrutinise the surgical records to confirm the presence of endometriosis. Women were excluded if (a) the index date fell during a pregnancy or within 42 days of delivery as it was not always possible to distinguish true cases of endometriosis from those with endometritis that had been coded in error as endometriosis, (b) the index date was 1 January in any year (indicating that a diagnosis had been recorded retrospectively), or (c) there was no evidence at all to support the diagnosis of endometriosis. The provisional index date was adjusted as necessary according to the supporting evidence. Selection of controls Four controls were selected for each case, matched on year of birth and practice and each control was registered with the contributing practice on the index date of the matched case. As with the cases, controls had at least 3 years data before and at least 3 months after the index date. Controls did not have any record of endometriosis at any time. Coding The medical records of cases and controls were reviewed for symptoms and diagnoses recorded in the 3-year period before the index date. These variables included abdominal, menstrual and pelvic symptoms or signs known to be associated with endometriosis (e.g. pelvic pain, dysmenorrhoea, ovarian cysts, and dyspareunia), other pelvic, menstrual or bowel symptoms, and lifestyle disturbances (e.g. time off work). Other diagnoses and symptoms identified among cases during case review were flagged among cases and controls. Body mass index (BMI) and smoking habit were recorded using measurements closest to the index date. Nonsmokers with a history of smoking were classified as ex-smokers. Women with a code for depression and/or a prescription for an antidepressant in the 3-year period before the index date were identified, diagnoses recorded and treatments issued during pregnancy or within 2 years after delivery were not included. The number of ill-health-related consultations during 1 year, 1 2 years and 2 3 years before the index date were established for cases and controls. The number of pregnancies before the index date, irrespective of outcome, was assessed for cases and controls. The number of signs and symptoms of any type recorded in the 3-year period before the diagnosis was calculated. Analyses The denominator used to calculate the incidence of endometriosis was derived by calculating the number of person-years contributed to the database by women aged years, stratified by age and year. The prevalence was calculated from the incidence rate and the average disease duration, 24 assuming that endometriosis is a menstrual-related disease and that the menopause occurs on average at age 50 years and 9 months. 25 Odds ratios (with 95% CI) for endometriosis were calculated for the variables measured using conditional logistic regression analysis. Univariate and stepwise conditional logistic regression analyses (criteria for inclusion: P < 0.05) were performed to identify risk factors for endometriosis. Sensitivity analyses were carried out by stratifying by case certainty (i.e. definite, probable, or possible cases). Results We identified 5540 cases of endometriosis diagnosed between 2 January 1992 and 31 December Of those cases, 2972 (53.6%) were considered definite, 1535 (27.7%) were probable and 1033 (18.7%) were possible cases. The incidence of diagnosed endometriosis was 0.97/1000 observed womenyears when all 5540 cases were included and 0.77/1000 observed women-years when just the definite and probable cases were included. The average age of diagnosis was 35.1 years 1384 ª 2008 The Authors Journal compilation ª RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology

4 Symptomatology in the diagnosis of endometriosis and the prevalence of diagnosed endometriosis was calculated to be 1.5% when all cases were included and 1.2% when the possible cases were removed. The cases with endometriosis were matched to controls, with the majority of cases (85%) having four controls. The characteristics of cases and controls are described in Table 1. Using unadjusted odds ratios, we found an inverse relationship between endometriosis and increasing BMI. Using women with a BMI of as the reference group, those with a BMI of or 35+ were at a 30% reduced risk of endometriosis. There was no evidence of an association between endometriosis and smoking habit (Table 1) or alcohol consumption (data not shown). Cases were less likely to have an unknown smoking status, possibly because of increased medical consultation among women with endometriosis. Cases were 20% less likely than controls to have ever been pregnant. The symptoms and diagnoses recorded for cases and controls in the 3 years before the index date (date of endometriosis diagnosis for cases and matched for controls) are given in Table 2. When compared with women without endometriosis, women with endometriosis were more likely to have a record of recognised symptoms including dysmenorrhoea (OR 9.8 [95% CI: ]), dyspareunia (OR 9.4 [95% CI: ]), and pelvic pain (OR 13.5 [95% CI: ]). We also found that women with endometriosis were more likely to have a history of menorrhagia (OR 5.0 [95% CI: ]) and to experience subfertility/infertility (OR 6.2 [95% CI: ]). Bowel symptoms were also more likely to be recorded in women with endometriosis than those without the disease, with 10.6% of women with endometriosis being diagnosed with irritable bowel syndrome (IBS) compared with 3.3% of women without endometriosis (OR 3.5 [95% CI: ]). Urinary symptoms, such as cystitis, urinary tract infection, and dysuria, were also reported more frequently in cases than controls, as was the diagnosis of pelvic inflammatory disease (PID) (OR 6.4 [95% CI: ]). Women with endometriosis were found to be more likely to report sleep disturbance to the GP (OR 1.4 [95% CI: ]) and were twice as likely to have had medically certificated time off from work (OR 2.0 [95% CI: ]). The rate of GP consultation in the years preceding the index date was significantly higher among cases than controls, especially in the year before the index date (Table 3). Overlapping symptoms recorded among cases and controls were grouped into abdominopelvic symptoms, symptoms associated with sexual intercourse, rectal symptoms, and urinary tract symptoms. The risk estimates for each of the grouped variables are given in Table 4. Stepwise conditional logistic regression analysis indicated that, after adjustment, rectal symptoms (dyschezia or rectal bleeding), backache, dysuria, and constipation were not significantly associated with endometriosis. The remaining variables were included in the full conditional logistic regression model (Table 5). Table 1. Characteristics of cases and controls, with unadjusted odds ratios for endometriosis (95% CI in parentheses) Controls (n ) % Cases (n ) % OR (95% CI) Age group (years) BMI closest to index (diagnosis) date, ( ) Reference ( ) ( ) ( ) Unknown ( ) Smoking status closest to index (diagnosis) date Nonsmoker Reference Smoker ( ) Ex-smoker ( ) Unknown ( ) Parity No history of pregnancy Reference History of 1 2 pregnancies ( ) History of 31 pregnancies ( ) ª 2008 The Authors Journal compilation ª RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology 1385

5 Ballard et al. Table 2. Symptoms and diagnoses recorded in the 3 years before the index (diagnosis) date among cases and controls, with unadjusted odds ratios for endometriosis Controls (n ) % Cases (n ) % OR (95% CI) Dysmenorrhoea ( ) Pelvic pain ( ) Dyspareunia ( ) Abdominal pain (cause not specified) ( ) Menorrhagia ( ) Menstrual problems (other) ( ) Intermenstrual pain ( ) Infertility/subfertility ( ) Irritable bowel syndrome ( ) Constipation ( ) Rectal bleeding ( ) Dyschezia ( ) Cystitis ( ) Urinary tract infection ( ) Dysuria ( ) Pelvic inflammatory disease ( ) Vaginal discharge ( ) Ovarian cysts ( ) Ovary pain ( ) Premenstrual tension ( ) Fibrocystic breast disease ( ) Postcoital bleeding ( ) Backache ( ) Depression* ( ) *Not including postnatal depression, diagnoses/treatments prescribed during pregnancy or within 2 years of delivery. Adjusted risk estimates for endometriosis demonstrated significant associations between endometriosis and a history, over the previous 3 years, of abdominopelvic symptoms, dysmenorrhoea, menorrhagia, infertility/subfertility, symptoms associated with sexual intercourse (dyspareunia or postcoital bleeding), ovarian cysts, vaginal discharge, other menstrual problems, fibrocystic breast disease, urinary tract symptoms, PID, and IBS. We also found that after adjusting for other factors, smoking and increasing BMI were associated with a statistically significant decreased risk of endometriosis. Cases were significantly more likely than controls to have a record of any one of the symptoms/diagnoses measured (OR 5.0 [95% CI: ]), and the risk of endometriosis increased as the number of symptoms/diagnoses recorded before the index date increased (Table 6). About 87.9% (n = 4870) of women with endometriosis had one or more of the symptoms included in the regression model (dysmenorrhoea, menorrhagia, other menstrual problems, vaginal discharge, abdominopelvic pain, symptoms associated with sexual intercourse, and urinary tract symptoms). Adding subfertility/infertility to this list of symptoms accounted for 90.8% (n = 5030) of women with endometriosis. This compares with 45.1% (9582) of women without endometriosis reporting one or more of the key symptoms and 45.7% (9702) with the inclusion of subfertility/infertility. Table 7 illustrates that abdominopelvic pain was reported by 51.8% of the cases and 13.8% of the controls, accounting for much of the variance between the cases and the controls. Having analysed the data using all the cases and matched controls, we then stratified the cases by diagnosis certainty and repeated the analysis. When using the definite endometriosis diagnosis group as the cases, we found that the relationship between symptoms, notably abdominopelvic pain, dysmenorrhoea, symptoms associated with sexual intercourse, infertility, menorrhagia, and ovarian cysts, and endometriosis was strengthened. There was little change, however, in the relationship between endometriosis and nonspecific diagnoses such as IBS and PID. The relationship between endometriosis and urinary symptoms (urinary tract infection and cystitis), however, became much weaker when using the definite endometriosis diagnosis group only, and these symptoms were no longer associated with endometriosis risk. Discussion To our knowledge, this is the first study to quantify the association between endometriosis and a wide range of symptoms and diagnoses. The use of a national database has enabled us 1386 ª 2008 The Authors Journal compilation ª RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology

6 Symptomatology in the diagnosis of endometriosis Table 3. Rates of consultation with a GP before the index (diagnosis) date, with unadjusted odds ratios for endometriosis (95% CI in parentheses) Controls (n ) % Cases (n ) % OR (95% CI) Number of consultations in the year before the index date None ( ) Reference ( ) ( ) ( ) Number of consultations 1 2 years before the index date None ( ) Reference ( ) ( ) ( ) Number of consultations 2 3 years before the index date None ( ) Reference ( ) ( ) ( ) to identify a large sample of endometriosis cases with four matched controls, which allows us to carry out detailed analysis of the symptoms and diagnoses associated with this disease. Our endometriosis prevalence of 1.5% confirms a previously reported prevalence of 1.44%, 1 where patient records in four UK general practices were hand-searched to obtain data relating to endometriosis. Although the prevalence of endometriosis is widely reported to range from 8 to 15%, 26 this elevated figure is likely to be due to the methodological differences, with most studies drawing their samples from women attending gynaecological clinics, whereas our sample reflected the rates of diagnosed endometriosis within the population at large. We show that women with a diagnosis of endometriosis have a significantly higher chance of experiencing abdominopelvic pain, menstrual-related symptoms (dysmenorrhoea, menorrhagia, and other menstrual problems), symptoms related to sexual intercourse (dyspareunia and postcoital bleeding), vaginal discharge, fibrocystic breast disease, ovarian cysts, urinary symptoms (urinary tract infections and cystitis), and subfertility, than women without a diagnosis of endometriosis. Although these symptoms are, on the whole, commonly recognised as being associated with endometriosis, previous studies have not been able to quantify the size of the associated risk when compared with women without endometriosis. While we recognise that women without endometriosis may also report symptoms typical of endometriosis, we have shown that this is the exception rather than the rule. In particular, 73% of women with endometriosis reported experiencing abdominopelvic pain, dysmenorrhoea, or menorrhagia compared with just 20% of the controls. Indeed, our data suggest that some symptoms are much more specifically related to endometriosis than has been previously suggested in the literature. For example, while hospital-based studies of gynaecological patients report that between and 50% 18 of women experience dysmenorrhoea, we found that just 3.4% of our controls reported this symptom compared with 24.6% of women with endometriosis. Similarly, only 1.5% of our controls reported experiencing pelvic pain compared with 15.6% of the cases. We also found that an increasing number of symptoms led to a vastly higher chance of having endometriosis. While we recognise that the symptoms we identified as being associated with endometriosis are not entirely specific to the condition, there is good evidence to suggest that women reporting multiple symptoms should prompt further appropriate investigation to exclude or confirm a diagnosis of endometriosis. The use of GP recorded symptoms as a prompt for further investigation into endometriosis, however, is not without problems. For example, our risk estimates for individual symptoms demonstrate that only 15.6% of women with endometriosis had a record of pelvic pain but 45.1% had a record Table 4. Unadjusted odds ratios for endometriosis associated with grouped variables Group Controls (n ) % Cases (n ) % OR (95% CI) Abdominopelvic pain* ( ) Symptoms associated with sexual intercourse** ( ) Rectal symptoms*** ( ) Urinary tract symptoms**** ( ) *Abdominopelvic symptoms: abdominal pain not otherwise specified, pelvic pain, intermenstrual pain, ovary pain. **Postcoital bleeding, dyspareunia. ***Rectal bleeding and dyschezia. ****Cystitis, urinary tract infections. ª 2008 The Authors Journal compilation ª RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology 1387

7 Ballard et al. Table 5. Adjusted risk estimates for endometriosis associated with risk factors recorded during the 3 years before the index date Diagnoses/symptoms OR (95% CI) Dysmenorrhoea 8.1 ( ) Menorrhagia 4.0 ( ) Other menstrual problems 1.6 ( ) Infertility/subfertility 8.2 ( ) Pelvic inflammatory disease 3.0 ( ) Irritable bowel syndrome 1.6 ( ) Vaginal discharge 1.3 ( ) Ovarian cysts 7.3 ( ) Fibrocystic breast disease 1.4 ( ) Abdominopelvic pain* 5.2 ( ) Symptoms associated with sexual intercourse** 6.8 ( ) Urinary tract symptoms*** 1.2 ( ) Lifestyle factors BMI, ( ) BMI Reference BMI ( ) BMI ( ) BMI ( ) Unknown BMI 0.9 ( ) Nonsmoker Reference Smoker 0.8 ( ) Ex-smoker 0.9 ( ) Unknown smoking status 0.7 ( ) *Abdominal pain not otherwise specified, pelvic pain, intermenstrual pain, ovary pain. **Postcoital bleeding, dyspareunia. ***Cystitis, urinary tract infections. of abdominal pain. This suggests that a great proportion of the symptoms being reported by women with endometriosis are perceived by GPs to be of abdominal nature rather than of pelvic nature. It is possible that some of the abdominal pain entries are coding errors, but this is unlikely to account for the majority of the entries. Moreover, one symptom that rarely appeared in the GP records was dyschezia, with only two cases and three controls being identified as suffering from this symptom. Since studies have shown that 29% of women with endometriosis experience bowel pain, 28 it would seem that dyschezia is either not being reported to GPs or is not being recorded in the GP medical records as dyschezia. This, together with the finding that abdominal pain was recorded frequently in women with endometriosis, may in part explain the reason for an increased diagnosis of IBS among women with endometriosis, with GPs possibly perceiving women s symptoms as bowel related. Since hospital-based studies of selective populations report that between and 45% 28 of women with endometriosis experience dyspareunia, our finding that 9.2% of women with endometriosis had a record of dyspareunia may reflect an under-reporting of this symptom within general practice. However, this under-reporting appears to occur in both the cases and the controls, with dyspareunia being reported in one study by 46% of women attending a general or gynaecological outpatient appointment 29 and by 23% of gynaecology patients found to have a normal pelvis. 18 This compares with 1% of our controls reporting dyspareunia. Despite this possible under-reporting or under-recording in both our cases and controls, we still found a nine times greater risk of dyspareunia in women with endometriosis when compared with the controls. In addition to experiencing specific symptoms, we found that women with endometriosis have a significantly higher risk of being diagnosed with IBS and PID than women without a diagnosis of endometriosis. Moreover, the adjusted risk estimates showed that women had both an increased risk of receiving a diagnosis of PID and an additional risk of vaginal discharge. The relationship between these diagnoses and endometriosis is examined further in a separate paper. 30 Given that our data show that women with endometriosis are at an increased risk of experiencing a range of symptoms and of being diagnosed with other nonspecific conditions such as IBS, it is perhaps unsurprising to also find that women with endometriosis were at greater risk of experiencing sleep disturbances and of being medically signed off of work. Based on estimates of the number of hours missed from work, it has been suggested that endometriosis costs $1023 per patient per year due to loss of employment time. 31 While we did not look specifically at the costs associated with endometriosis, our finding that women with endometriosis consult with the family doctor at a much greater rate than women without endometriosis raises important questions about the impact of a delayed diagnosis on the use of healthcare resources. Our study shows that over each of the 3 years leading to a diagnosis, women with endometriosis consulted the GP more than twice as many times as women without endometriosis. The particularly high rate of consultation occurring in the year before diagnosis may arise as a result of medical treatment being instigated or investigations being carried out, although it may also result from an increased severity and frequency of symptom reporting, which could in turn prompt the GP to refer to a hospital-based specialist. Whatever the cause of this increased consultation rate, around one-quarter of the sample were attending the GP services at least every month and the personal and monetary costs associated with this are likely to be considerable. In addition to symptoms, we found that 9.6% of women with endometriosis had a record of subfertility/infertility, which is lower than the 26% infertility rate found among a younger and partially self-selected cohort of women with endometriosis. 28 These differences in fertility rates may arise from the broader age range in our population (15 55 years), with young women not yet experiencing fertility problems ª 2008 The Authors Journal compilation ª RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology

8 Symptomatology in the diagnosis of endometriosis Table 6. Number of endometriosis-related symptoms being reported before the index (diagnosis) date (95% CI in parentheses) Number of endometriosis-related symptoms before the index (diagnosis) date Unadjusted OR (95% CI) ( ) ( ) ( ) ( ) ( ) ( ) 7 or more symptoms 84.7 ( ) It is also possible that there is an under-reporting of fertility problems in the GP records, although this is unlikely as GPs are required to record all major medical history and women in the UK generally access fertility services via the GP. We recognise that it is difficult to calculate the infertility rate among women with endometriosis reliably, simply because the diagnosis of endometriosis often occurs during investigations of the cause of infertility. 32 The majority of studies, therefore, report the rate of endometriosis among infertility patients, with between and 30% 34 of women with infertility being found to have endometriosis. As might be expected, we found that women with endometriosis had a significantly lower parity than women without endometriosis. Although we were primarily investigating the relationship between symptoms and endometriosis, we considered the role of BMI, smoking, and alcohol consumption in endometriosis. While alcohol consumption was found to be unrelated to endometriosis, current smokers were found to be at a lower risk of endometriosis after adjusting for other factors. This is in line with the findings of other studies. 27,35 One possible explanation for this finding lies in the relationship between smoking and increased anti-inflammatory cytokines. 36 Since much of the pain associated with endometriosis is probably mediated through an inflammatory response to the ectopic endometrial-like tissue, it is possible that smoking suppresses endometriosis-related pain symptoms, which in turn reduces the likelihood of endometriosis diagnosis. The point estimates of an association between increased BMI and endometriosis, suggestive of a decreased risk of endometriosis among obese women, were similar to those found by Missmer et al. 35 in the US Nurses Health Study. The US Nurses Health Study, however, contained fewer endometriosis cases and in that study, the association between obesity and endometriosis failed to reach statistical significance. As with any study, there are strengths and limitations relating to the study method that influence what we are able to conclude. One particular concern of any retrospective database study surrounds the quality of the data. Key to this has been our use of data collected after 1992 and from practices that have been rigidly assessed for their ability to produce high-quality up-to-standard data. The validity of data stored on the GPRD, unlike many other databases, is maintained and Table 7. Frequency of key symptoms reported by cases and controls Controls, % (n) Cases, % (n) Abdominopelvic pain* 13.8 (2926) 51.8 (2867) Abdominopelvic pain and/or dysmenorrhoea 16.2 (3448) 64.2 (3555) Abdominopelvic pain and/or dysmenorrhoea and/or menorrhagia 20.4 (4329) 73.1 (4052) Abdominopelvic pain and/or dysmenorrhoea and/or menorrhagia and/or other 28.6 (6070) 79.8 (4422) menstrual problems Abdominopelvic pain and/or dysmenorrhoea and/or menorrhagia and/or other 39.2 (8319) 84.7 (4694) menstrual problems and/or vaginal discharge Abdominopelvic pain and/or dysmenorrhoea and/or menorrhagia and/or other 39.7 (8435) 86.3 (4783) menstrual problems and/or vaginal discharge and/or symptoms associated with sexual intercourse** Abdominopelvic pain and/or dysmenorrhoea and/or menorrhagia and/or other 40.4 (8577) 89.5 (4960) menstrual problems and/or vaginal discharge and/or symptoms associated with sexual intercourse** and/or subfertility/infertility Abdominopelvic pain and/or dysmenorrhoea and/or menorrhagia and/or other menstrual problems and/or vaginal discharge and/or symptoms associated with sexual intercourse** and/or subfertility/infertility and/or urinary symptoms*** 45.7 (9702) 90.8 (5030) *Abdominal pain not otherwise specified, pelvic pain, intermenstrual pain, ovary pain. **Postcoital bleeding, dyspareunia. ***Cystitis, urinary tract infections. ª 2008 The Authors Journal compilation ª RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology 1389

9 Ballard et al. monitored centrally, with constant quality checking of data being submitted. However, as described in the Methods section, some data smoking, BMI and alcohol were incomplete and this needs to be considered when interpreting the results. Although previous concerns have been expressed about the quality of symptom data reported on a different, and much smaller, GP database, 37 we have used a database where quality measures are in place. A further concern to us was the ability to determine a diagnosis of endometriosis accurately. To overcome this problem, we stratified the data by certainty of endometriosis diagnosis, and having found that the stratified analysis made little difference to the reported findings, we feel reasonably confident in our diagnostic inclusion criteria. Conclusion Our reported endometriosis prevalence of 1.5%, while lower than the 8 15% prevalence widely reported from hospitalbased studies, reflects the prevalence of diagnosed endometriosis in the UK general population. In this large nationwide case control study, we have demonstrated that the symptoms associated with endometriosis are relatively uncommon in women without endometriosis, and are therefore more specific than previously reported in smaller selective samples. In particular, women experiencing abdominopelvic pain, menstrual-related symptoms (dysmenorrhoea and menorrhagia), symptoms related to sexual intercourse (dyspareunia and postcoital bleeding), ovarian cysts, and subfertility have a high risk of having endometriosis, especially if they experience more than one of these symptoms. We have also shown that women with endometriosis are at greater risk of being diagnosed with IBS or PID and suggest that this needs to be investigated further to determine whether it is a misdiagnosis effect or a genuine co-morbidity. We present this study in a further paper (H. E. Seaman et al., unpubl obs.). Probably as a consequence of the symptoms experienced, we found a high medical consultation rate among women with endometriosis in the 3 years leading to diagnosis. We suggest that the delays in being diagnosed with endometriosis may be reduced by more detailed history taking and better recognition of key symptoms by GPs. Disclosure of interest None of the authors have any conflicting financial interests. Contribution to authorship K.B. and J.W. are responsible for the idea for the study and securing funding. All authors contributed towards the data analysis and preparation of the manuscript. 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