RETRACTED: Case–control study to develop and validate a questionnaire for the secondary prevention of endometriosis

Endometriosis is an estrogen-dependent, chronic gynecological disease characterized by the presence of endometrial glands and stroma outside the uterus, which can result in a broad spectrum of symptoms, including dysmenorrhea, pelvic pain and infertility [ 1 ]. The etiopathogenesis of endometriosis is uncertain but is probably a multifactorial process resulting in a heterogeneous disease [ 2 , 3 ]. Women affected by this pathology have suffered for years from chronic pelvic pain, as well as from pain during the menstrual cycle and sexual intercourse [ 4 , 5 ]. Recent studies revealed that the disease is present in around 1.5% of the general female population and 6–15% of hospitalized women [ 4 ]. The data provided by the Italian Agency for Medicinal Products report that in Italy the prevalence of endometriosis in asymptomatic women varies from 2% to 22%, depending on the diagnostic criteria used and the population studied: in women with severe dysmenorrhea and chronic pelvic pain the percentage ranges from 40 to 60% and in women with subfertility it sets around 20% and 30% [ 6 ]. Currently, hormonal and biological therapies for the treatment of endometriosis are under intense clinical investigation [ 7 ]. However, the majority of these compounds have only been evaluated in pre-clinical studies or early clinical trials. Thus, further extensive clinical research is necessary. Of note, late clinical trials on gonadotropin-releasing hormone antagonists (GnRH-ant) showed the most promising results for the treatment of endometriosis [ 7 ]. Although ultrasound evaluation has become the primary test in the diagnosis of pelvic endometriosis [ 8 ], the diagnosis of endometriosis can be confirmed only upon a direct visualization of the lesions; therefore the gold standard to identify and treat it therapeutically (removal of tissue, vacuolation, and lysis of any adhesion) is laparoscopy [ 5 ], which is a costly and invasive technique. Consequently, barring severe abdominopelvic symptomatology, a large part of the population relies on less invasive methods to investigate the disease, such as ultrasounds (US), Magnetic Resonance Imaging (MRI), and specific blood tests (looking for Ca-125 and Ca-19-9 markers). Besides, the disease's progression can be temporarily kept under control through hormonal pharmacological [ 9 ], postponing the surgical operation, especially in young women of reproductive age [ 10 ]. In any case, endometriosis is not easy to identify, and the process can take many years: from 8 to 11 years [ 5 ]. Reducing the delay in the diagnosis is paramount to prevent the most severe consequences of endometriosis, first of all, infertility and chronic pelvic pain [ 4 , 5 , 11 ]. The purpose of this study is to validate a simple and effective questionnaire to precociously identify women with endometriosis, leading them to the correct diagnostic approach and the most appropriate treatment.

This study has analyzed the results of a questionnaire which aimed to identify patients at high risk for endometriosis, through the association with risk factors and symptomatology. Its purpose was to shape up a prediction model that could identify women with suspected endometriosis to lead them to correct diagnostic procedures and rapid diagnosis. The results of our study reveal that women who suffer from food or drug allergies and who suffered from severe acne during adolescence are more at risk of being affected by endometriosis. We also found that women are also at risk when reporting non-menstrual abdominal pain for more than 2–3 days per month when regularly suffering from constipation, meteorism for more than one day per week, with defecatory urgency, incomplete defecation, urinatory urgency in one urination event out of five, dysuria during or at the end of urination more than one every five urination events. The risk of developing endometriosis is very high also for women who have taken the pill to cope with severe menstrual pain, nulliparae , women with a menstrual cycle shorter than 28 days, with heavy bleeding or suffer from chronic pelvic pain. Fall into the same type of category also women who suffer from severe dysmenorrhea which forced them to take drugs, stay home from school or work, who report painful defecation during the menstrual cycle, describe sexual intercourse as very painful more than half of the times–with a score higher than 3 in the VAS scale. In an effort to simplify the questionnaire, we conducted a step-down logistic regression analysis and could select only four of these variables, namely chronic pelvic pain, dyspareunia with VAS ≥ 3, painful defecation and acne, which are the optimal combination and guarantee the best sensitivity and specificity. With this method, the prediction model achieves 90.2% sensitivity and 75% specificity. In conclusion, we believe that our questionnaire could provide a powerful tool for the secondary prevention of endometriosis. Moreover, emerging evidence suggests that adolescents are subject to endometriosis much more often than previously thought [ 11 ], therefore a screening tool designed to allow young women to identify potential symptoms of endometriosis could facilitate the initial discussions between patients and physicians. The possibility to diagnose endometriosis precociously in young women could spare them years of pain and frustrations and, slow the course of the disease, and it would be possible to increase their reproductive potential.

The investigation has been carried out in two stages: one focused on the development of an instrument for secondary endometriosis prevention and the other on its validation. During the first stage, we reviewed the literature and selected risk factors, symptoms and phenotypic traits of the women who have endometriosis to create a questionnaire. A combination of six literature databases was searched (PubMED, MEDLINE, Google Scholar; Web of Science, Scopus, Embase) to retrieve all relevant references. Subsequently, we asked 20 women, patients at the Reproductive Medicine Unit (RMU) of the Institute for Maternal and Child Health—IRCCS “Burlo Garofolo” in Trieste (Italy), to test its actual intelligibility, and we modified it according to the results. The second stage of the investigation was carried out through a case-control study. Patients with endometriosis had contacted the RMU because of their fertility problems, and they received, through the laparoscopy, a diagnosis, which, in most of the cases, has been confirmed by a histological report. The controls were enrolled from the list of healthy, asymptomatic women in the I trimester of pregnancy, who had contacted the IRCCS “Burlo Garofolo” to undergo the first-trimester obstetric ultrasound scan. Controls were women with spontaneous conception and did not include women who had been diagnosed with endometriosis or with any other symptomatic gynecological disease. The ultrasound, performed for unrelated reasons, confirmed they did not present lesions due to endometriosis. Furthermore, considering a negative case history, we were reasonably able to exclude endometriosis or other gynecological diseases. We also excluded from the study women affected by active chronic inflammatory bowel disease, since the disease could confuse the gastrointestinal symptoms, as well as foreign women who were not fluent in Italian. The women enlisted were of reproductive age, and an effort was made to create a group as homogeneous in age as possible to the enrolled cases. After signing a written informed consent form, women (both cases and controls) were interviewed in-person to answer the questionnaire. The study did not include minors, and was approved by the Institutional Review Board of the Institute for Maternal and Child Health–IRCCS Burlo Garofolo, Trieste (06.12.18). The questionnaire ( S1 File ) is divided into 8 modules, with 47 questions in total. The first module focuses on the responder’s knowledge of the disease. The issues of the other 7 modules concern physiological case history, family history, remote medical history, phenotypic traits, gastrointestinal symptoms, urinary symptoms, and, lastly, gynecological history. Physiological case history includes age, weight, height, Rhesus factor (Rh), and nutritional habits. Literature reveals that endometriosis is a disease affecting women of reproductive age [ 11 , 12 ], whose Body Mass Index (BMI) is lower than the one of controls [ 13 , 14 ]. In particular, it has been reported that for every unit increase in BMI (kg/m 2 ), there was an approximate 12–14% decrease in the likelihood of being diagnosed with endometriosis. Moreover, multivariate analysis showed that Rh-negative women are twice as likely to develop endometriosis [ 15 ]. Finally, it seems that eating fruit and vegetables may have a protective effect against the disease, unlike red meat and cured meat [ 12 ]. Regarding family history, the questionnaire investigates whether the women interviewed had mothers or sisters affected by endometriosis, considering the familiarity a major risk factor [ 5 , 16 ]. The remote medical history investigates, as reported in the literature, the relation between endometriosis and the following pathologies: allergies and asthma [ 17 – 20 ], systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, multiple sclerosis, coeliac disease, autoimmune thyroiditis [ 21 – 25 ], acne [ 26 – 28 ] and migraine [ 29 , 30 ]. In the module on phenotypic traits, the questions focused on natural hair’s color, eye’s color, complexion, skin sensitivity to sun exposure, number of nevi, and freckles. Some studies report a connection between endometriosis and red hair—although other studies contradict this association [ 31 – 33 ]–and between endometriosis and blue eyes [ 34 ]. It also appears that women affected by endometriosis have fairer skin, more nevi, and freckles and are more sensitive to sunlight [ 35 , 37 ]. The section concerning gastrointestinal symptoms investigated non-menstrual abdominal pain, constipation, meteorism, flatulence, defecatory urgency, and feeling of incomplete defecation. This assessment was based on the Visual Analogue Scale for Irritable Bowel Syndrome (VAS-IBS), a validated questionnaire that aims to investigate gastrointestinal symptoms in patients not affected by organic diseases [ 38 ]. Regarding urinary symptoms, the questions were focused on incomplete bladder emptying, pollakiuria, urinary urgency, nycturia, and dysuria without bacterial cystitis. We have paid particular attention to the differences between urination with and without the menstrual cycle. The questions have been taken from the American Urologic Association Symptom Index (AUASI), as modified by an Italian study group [ 39 ]. The obstetric-gynecological history investigated: any use of hormonal contraceptives, the reason why they are taken, any previous abortion, pregnancy, the age at which the menstrual cycle began, its regularity, frequency, the heaviness and length of menstrual bleeding, dysmenorrhea, any consequence on usual daily life, painful defecation during menstrual cycle, dyspareunia and chronic pelvic pain unrelated to the menstrual cycle [ 40 ]. Some studies showed that women who have endometriosis are more likely to have experienced premature menarche and more regular and shorter menstrual cycles, with more massive and longer bleeding than controls [ 41 ]. On the other hand, it appears that parity is inversely connected to the risk of endometriosis [ 5 , 12 ]. We investigated the degree of dysmenorrhea asking if the pain was so intense that it required the use of drugs and if it made usual daily activities impossible, when not treated [ 41 – 44 ]. For dyspareunia, the study used a Visual Analogue Scale (VAS) [ 45 ]. Painful defecation during the menstrual cycle and chronic pelvic pain seem to be very related symptoms to deep endometriosis [ 45 ]. Once the information had collected, the data entry was conducted with EpiData 3.1 (The EpiData Association, Odense M, Danmark), statistical analyses were carried out with the Stata/IC 14.1 software (StataCorp LP, College Station, U.S.A.) and R 3.1.3. (The R Foundation for Statistical Computing, Vienna, Austria). Bivariate analyses were conducted using the two-tailed Fisher's exact test for tables with categorical variables, the nonparametric Mann-Whitney test, which compares the values of continuous variables in two different groups, and logistic regressions with a single independent variable. Bivariate and multivariate logistic regressions were implemented through a specific method called Firth's penalized likelihood approach. This procedure makes it possible to manage small samples and, in particular, to manage cases that would present zero frequencies in the frequency tables, which would not allow the use of conventional approaches. We included variables that were significant in the bivariate analysis, while a step-down procedure discarded all the variables not significantly associated with the outcome, starting with those with a higher p-value. After obtaining a model with only significant variables, all the previously discarded variables were re-entered one-by-one to ascertain their significance. We thus obtained a final “predictive” logistic model. We also tried to generate a model adopting a decision tree method–a CART model using the R software–but the result was not as satisfactory as the one obtained with multivariate logistic regression.

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