STUDY QUESTION
Can the ability of the endometriosis fertility index (EFI) to predict non-assisted reproductive technology (ART) pregnancy after endometriosis surgery be confirmed by an external ...validation study?
SUMMARY ANSWER
The significant relationship between the EFI score and the time to non-ART pregnancy observed in our study represents an external validation of this scoring system.
WHAT IS KNOWN AND WHAT THIS PAPER ADDS
The EFI was previously developed and tested prospectively in a single center, but up to now no external validation has been published. Our data provide validation of the EFI in an external fertility unit on a robust scientific basis, to identify couples with a good prognosis for spontaneous conception who can therefore defer ART treatment, regardless of their revised American Fertility Society (rAFS) endometriosis staging.
DESIGN
Retrospective cohort study where the EFI was calculated based on history and detailed surgical findings, and related to pregnancy outcome in 233 women attempting non-ART conception immediately after surgery; all data used for EFI calculation and analysis of reproductive outcome had been collected prospectively as part of another study.
PARTICIPANTS AND SETTING
The EFI score was calculated (score 0–10) for 233 women with all rAFS endometriosis stages (minimal–mild, n = 75; moderate–severe, n = 158) after endometriosis surgery (1 September 2006–30 September 2010) in a university hospital-based reproductive medicine unit with combined expertise in reproductive surgery and medically assisted reproduction. All participants attempted non-ART conception immediately after surgery by natural intercourse, ovulation induction with timed intercourse or intrauterine insemination (with or without ovulation induction or controlled ovarian stimulation).
DATA ANALYSIS METHOD
All analyses were performed for three different definitions of pregnancy overall (any HCG >25 IU/l), clinical and ongoing >20 weeks. Six groups were distinguished (EFI scores 1–3, 4, 5, 6, 7+8, 9+10), and Kaplan–Meier (K–M) estimates for cumulative pregnancy rate were calculated. Subjects were censored when they were lost to follow-up, had subsequent surgery for endometriosis, started ovarian suppression or underwent ART. As K–M estimates might overestimate the actual event rate, cumulative incidence estimates treating ART as competing event were also calculated. Cox regression analysis was used to assess the performance of EFI and constituting variables. Performance of the score (prediction, discrimination) was quantified with the following methods: mean squared error of prediction (Brier score), areas under the receiver-operating curve and global concordance index Cτ.
MAIN RESULTS AND THE ROLE OF CHANCE
There was a highly significant relationship between the EFI and the time to non-ART pregnancy (cumulative overall pregnancy rate, P = 0.0004), with the K–M estimate of cumulative overall pregnancy rate at 12 months after surgery equal to 45.5% 95% confidence interval (CI) 39.47–49.87—ranging from 16.67% (95% CI 5.01–47.65) for EFI scores 0–3, to 62.55% (95% CI 55.18–69.94) for EFI scores 9–10. For each increase of 1 point in the EFI score, the relative risk of becoming pregnant increased by 31% (95% CI 16–47%; i.e. hazard ratio 1.31). The ‘least function score’—which assesses the tubal/ovarian function at conclusion of surgery—was found to be the most important contributor to the total EFI score among all the other variables (age, duration of infertility, prior pregnancy, AFS endometriosis lesion and total score).
BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION
The EFI score had a moderate performance in the prediction of the pregnancy rate. Indeed, the decrease in prediction error was rather small, as shown by the decrease in Brier score from 0.213 to 0.198, and low estimates for R² (13%) and Cτ (0.629).
GENERALIZABILITY TO OTHER POPULATIONS
As the EFI was validated externally in our own European population after initial testing by Adamson and Pasta (Endometriosis fertility index: the new, validated endometriosis staging system. Fertil Steril 2010;94:1609-1615) in an American population, it appears that the EFI can be used clinically to counsel infertile endometriosis patients receiving reproductive surgery in specialized centers about their post-operative conception options.
STUDY FUNDING/COMPETING INTEREST(S)
This research was supported by funds obtained via the Clinical Research Fund of the University Hospitals Leuven, Belgium, via the Ferring Chair in Reproductive Medicine and Surgery, and the Serono Chair in Reproductive Medicine granted to the Leuven University Fertility Center. The authors have no conflicts of interest to declare.
Abstract
STUDY QUESTION
Does ultra-long downregulation with a GnRH agonist (triptorelin depot) in previously operated patients with endometriosis improve the rate of clinical pregnancy with positive ...fetal heart beat (CPHB) in the subsequent initiated fresh ART cycle?
SUMMARY ANSWER
Ultra-long downregulation with a GnRH agonist prior to ART did not improve the rate of CPHB in the subsequent fresh ART cycle in previously completely operated patients but the trial was underpowered due to early termination.
WHAT IS KNOWN ALREADY
Administration of GnRH agonists for a period of 3–6 months prior to ART in women with endometriosis may increase the odds of clinical pregnancy. However, the quality of the studies on which this statement is based is questionable, so these findings need confirmation.
STUDY DESIGN, SIZE, DURATION
A controlled, randomized, open label trial was performed between 1 June 2013 and 31 December 2016 (start and end of recruitment, respectively). Patients with prior complete laparoscopic treatment of any type or stage of endometriosis and an indication for ART were randomized (by a computer-generated allocation sequence) into two groups: the control group underwent ART stimulation in a classical long agonist protocol using preparation with oral contraceptives, the ultra-long group first underwent at least 3 months downregulation followed by a long agonist protocol for ART stimulation. The sample size was calculated to detect a superiority of the ultra-long downregulation protocol, based on the hypothesis that baseline CPHB rate in the control group of 20% would increase to 40% in the ultra-long group. For a power of 20% at a significance level of 5%, based on two-sided testing, including 5% of patients lost to follow-up, the necessary sample size was 172 patients (86 per group).
PARTICIPANTS/MATERIALS, SETTING, METHODS
This trial was conducted at the Leuven University Fertility Center, a tertiary care center for endometriosis and infertility, and a total of 42 patients were randomized (21 in the control group and 21 in the ultra-long group).
MAIN RESULTS AND THE ROLE OF CHANCE
Baseline characteristics were similar in both groups. The primary outcome studied—CPHB after the initiated ART treatment—did not differ and was 25% (5/20) in the control group, and 20% (4/20) in the ultra-long group (P > 0.999; relative risk (RR) 1.25, 95% CI 0.41–3.88). Cumulative (fresh + associated frozen) CPHB rates were also similar in the control versus ultra-long group (8/20, 40% vs 6/20, 30%, P = 0.7411; RR = 1.33, 95% CI 0.57–3.19). When other secondary outcomes were compared with the ultra-long group, patients from the control group had a shorter duration of stimulation (mean 11.8 days (SD ± 2.4) versus 13.2 days (SD ± 1.5), P = 0.0373), a lower total dose of gonadotrophins used (mean 1793 IU/d (SD ± 787) vs 2329 (SD ± 680), P = 0.0154), and a higher serum estradiol concentration (ng/ml) at the end of ovarian stimulation on the day of ovulation triggering or cycle cancellation (mean1971 (SD ± 1495) vs 929 (± 548); P = 0.0326), suggesting a better ovarian response in the control group.
LIMITATIONS, REASONS FOR CAUTION
Due to a strong patient preference, nearly exclusively against ultra-long downregulation (even though patients were thoroughly informed of the potential benefits), the targeted sample size could not be achieved and the trial was stopped prematurely.
WIDER IMPLICATIONS OF THE FINDINGS
Conditional power analysis revealed that the probability of confirming the study hypothesis if the study were completed would be low. We hypothesize that in patients with prior complete surgical treatment of endometriosis, the ultra-long protocol does not enhance ART-CPHB rates. Patient’s concerns and preferences regarding possible side-effects, and delay of ART treatment start with the ultra-long protocol should be taken into account when considering this type of treatment in women with endometriosis.
STUDY FUNDING/COMPETING INTEREST(S)
C.T. was during 2 years funded by a grant from the Clinical research Foundation of UZ Leuven (KOF) and during 2 years by the Research Foundation—Flanders (FWO grant number: 1700816N). C.T. reports grants from Clinical Research Foundation of the University Hospitals of Leuven (KOF), grants from Fund for Scientific Research Flanders (FWO), during the conduct of the study; grants, non-financial support and other from Merck SA, non-financial support and other from Gedeon Richter, non-financial support from Ferring Pharmaceuticals, outside the submitted work. T.D. is vice president and head of Global Medical Affairs Fertility, Research and Development, Merck KGaA, Darmstadt, Germany. He is also a professor in Reproductive Medicine and Biology at the Department of Development and Regeneration, Group Biomedical Sciences, KU Leuven (University of Leuven), Belgium and an adjunct professor at the Department of Obstetrics and Gynecology in the University of Yale, New Haven, USA. Neither his corporate role nor his academic roles represent a conflict of interest with respect to the work done by him for this study. A.C. reports personal fees from Merck S.p.A., outside the submitted work. The other co-authors have no conflict of interest.
TRIAL REGISTRATION NUMBER
UZ Leuven trial registry SS55300, EudraCT number 2013-000993-32, clinicaltrials.gov NCT02400801.
TRIAL REGISTRATION DATE
Registration for EudraCT on 1 March 2013.
DATE OF FIRST PATIENT’S ENROLMENT
4 September 2013.
Objective
To evaluate the reproducibility of the Endometriosis Fertility Index (EFI).
Design
Single‐cohort prospective observational study.
Setting
University hospital.
Population
Women undergoing ...laparoscopic resection of any rASRM‐stage endometriosis.
Methods
Details of pre‐ and peroperative findings were collected into a coded research file. EFI scoring was performed en‐bloc by three different raters (expert‐1 C.T., expert‐2 C.M., junior C.B.). Required sample size: 71. Definitions used for agreement: clinical (scores within same range: 0–4, 5–6, 7–10) and numerical (difference ≤1 EFI point).
Main outcome measures
Primary outcome: rate of clinical agreement between two experts.
Secondary outcomes: expert numerical agreement, clinical and numerical agreement between expert‐1 and junior, and within expert‐1 (intra‐observer), agreement of rASRM score and ‐stage.
Results
A near ‘inter‐expert’ clinical agreement rate (1.000, 95% CI 0.956‐1.000; P = 0.0149) was observed. The numerical agreement between two experts was also high (0.988, 95% CI 0.934–1.000); similarly, high agreement rates were observed for both ‘junior–expert’ comparisons (clinical 0 .963, 95% CI 0.897–0.992; numerical 0.988, 95% CI 0.934–1.000) and ‘intra‐expert’ comparisons (clinical 0.988, 95% CI 0.934–1.000; numerical 1.000, 95% CI 0.956–1.000). Reasons for disagreements were different scoring of the least‐function score and disagreements in rASRM scores. The reproducibility of the rASRM score was clearly inferior to that of the EFI for all comparisons.
Conclusion
The EFI can be reproduced reliably by different raters, further supporting its use in daily clinical practice as the principal clinical tool for postoperative fertility counselling/management of women with endometriosis.
Tweetable
A study confirming the high reproducibility of the EFI substantiates its use in daily clinical practice.
Tweetable
A study confirming the high reproducibility of the EFI substantiates its use in daily clinical practice.
Abstract
STUDY QUESTION
Can the Endometriosis Fertility Index (EFI) be estimated accurately before surgery?
SUMMARY ANSWER
The EFI can be estimated accurately based on mere clinical/ultrasound ...information, with some improvement after adding data from diagnostic laparoscopy.
WHAT IS KNOWN ALREADY
The EFI is a validated clinical instrument predicting the probability of pregnancy after endometriosis surgery without the use of ART. Being an end-of-surgery-score, it implies the decision for operative laparoscopy to be made in advance—hence, its role in the pre-surgical decision-making process remains to be established.
STUDY DESIGN, SIZE, DURATION
Single-cohort prospective observational study in 82 patients undergoing complete endometriosis excision (between June and December 2016). Two methods were used to estimate the final EFI: type A based on non-surgical clinical/ultrasound findings only, and type B based on the combination of non-surgical clinical/ultrasound findings and diagnostic laparoscopy data. To calculate EFI type A, an algorithm was created to translate non-surgical clinical/imaging information into rASRM (revised American Society of Reproductive Medicine)—and EFI points. EFI type A and type B estimates were assessed for their clinical and numerical agreement with the final EFI score. Agreement was defined as clinical if EFI scores were within the same range (0–4, 5–6, 7–10), and numerical if their difference was ≤1.
PARTICIPANTS/MATERIALS, SETTING, METHODS
All 82 patients underwent complete laparoscopic CO2-laser excision of any rASRM stage of endometriosis in the Leuven University Fertility Centre (LUFC) of University Hospitals Leuven, a tertiary referral centre for both endometriosis and infertility. An anonymized clinical research file was created. For each patient, three different data sets were created, in order to allow the estimation of the (surgical part) EFI and of the rASRM scores, defined as follows: ‘Estimated type A’ contained only non-surgical clinical/imaging data, ‘Estimated type B’ included type A information plus the information of the diagnostic laparoscopy and ‘Final EFI’ included information of type A, type B and all intra-operative information required to calculate the final EFI. To calculate EFI type A without surgical information, a set of rules was used to translate pre-surgical clinical/imaging information into (rASRM and EFI points). Scoring was done by one person (C.T.), with a time interval of 4 weeks between sessions for each EFI type. Next to the EFI, also rASRM score and stage were calculated.
MAIN RESULTS AND THE ROLE OF CHANCE
Agreement rate between estimated EFI type A and final EFI was high for both the clinical (0.915; 95% CI 0.832–0.965) and numerical definition (0.878; 95% CI 0.787–0.940). Agreement rates between estimated EFI type B and final EFI were even higher (clinical (0.988; 95% CI 0.934–1.000), numerical (0.963; 95% CI 0.897–0.992)).
LIMITATIONS, REASONS FOR CAUTION
Type A estimation is dependent on high-level gynaecological ultrasound expertise, which may not be available in all clinics. A small number of patients had no prior clinical, ultrasound (hard markers) or surgical confirmation of the diagnosis of endometriosis. When applying the estimated EFI type A in clinical practice, a priori assumptions of the presence or absence of endometriosis will need to be made in adjunct to the estimation of the estimated type A EFI when counselling patients on the potential benefit of an (at least diagnostic) laparoscopy. The level of agreement for type A or B should also be taken into account when counselling patients on the type of efforts undertaken to attempt to diagnose or rule out endometriosis.
WIDER IMPLICATIONS OF THE FINDINGS
As this study reports, the EFI can be estimated accurately based on clinical/ultrasound data only without the need for any surgical data. This means that the EFI could be used as an instrument to guide joint physician–patient decision-making between surgery, ART or other fertility management options for the individualized treatment of women with endometriosis-related infertility.
STUDY FUNDING/COMPETING INTEREST(S)
During this study period, C.T. was supported by FWO (Research Fund Flanders, Grant number 1700816N) and UZ Leuven KOF (University Hospitals Leuven, Klinisch Onderzoeksfonds).
The LUFC received unrestricted research grants from Ferring Pharmaceuticals and Merck SA. Gedeon Richter and MSD sponsored travel to and attendance at scientific meetings. C.M. received consultancy fees from Lumenis (paid to KU Leuven, no private revenue). T.D. has been vice-president and head of global medical affairs infertility for the multinational pharmaceutical company Merck (Darmstadt, Germany) since 1 October 2015. He continues his academic appointment on a part-time basis as Professor of Reproductive Medicine at the University of Leuven (KU Leuven). T.D. has been vice-president and head of global medical affairs infertility for the multinational pharmaceutical company Merck (Darmstadt, Germany) since October 2015. He is also a Guest Professor in Reproductive Medicine and Biology at the Department of Development and Regeneration, Group Biomedical Sciences, KU Leuven (University of Leuven), Belgium, and an Adjunct Professor at the Department of Obstetrics and Gynecology in the University of Yale, New Haven, USA. This work was initiated before he joined Merck KGaA in October 2015, and completed during the subsequent years.
TRIAL REGISTRATION NUMBER
study registration number at UZ Leuven Clinical Trial Centre: S59221.
The International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) and International Deep Endometriosis Analysis (IDEA) group, the European Endometriosis League (EEL), the European Society ...for Gynaecological Endoscopy (ESGE), the European Society of Human Reproduction and Embryology (ESHRE), the International Society for Gynecologic Endoscopy (ISGE), the American Association of Gynecologic Laparoscopists (AAGL) and the European Society of Urogenital Radiology (ESUR) elected an international, multidisciplinary panel of gynecological surgeons, sonographers and radiologists, including a steering committee, which searched the literature for relevant articles in order to review the literature and provide evidence-based and clinically relevant statements on the use of imaging techniques for non-invasive diagnosis and classification of pelvic deep endometriosis. Preliminary statements were drafted based on review of the relevant literature. Following two rounds of revisions and voting orchestrated by chairs of the participating societies, consensus statements were finalized. A final version of the document was then resubmitted to the society chairs for approval.
Twenty statements were drafted, of which 14 reached strong and three moderate agreement after the first voting round. The remaining three statements were discussed by all members of the steering committee and society chairs and rephrased, followed by an additional round of voting. At the conclusion of the process, 14 statements had strong and five statements moderate agreement, with one statement left in equipoise. This consensus work aims to guide clinicians involved in treating women with suspected endometriosis during patient assessment, counseling and planning of surgical treatment strategies.
This Consensus Statement should be cited as: ‘G. Condous, B. Gerges, I. Thomassin-Naggara, C. Becker, C. Tomassetti, H. Krentel, B.J. van Herendael, M. Malzoni, M. S. Abrao, E. Saridogan, J. Keckstein, G. Hudelist and Collaborators. Non-invasive imaging techniques for diagnosis of pelvic deep endometriosis and endometriosis classification systems: An International Consensus Statement. Eur. J. Radiol. 2024. https://doi.org/10.1016/j.ejrad.2024.111450.’
Background
At present, the only way to conclusively diagnose endometriosis is laparoscopic inspection, preferably with histological confirmation. This contributes to the delay in the diagnosis of ...endometriosis which is 6–11 years. So far non-invasive diagnostic approaches such as ultrasound (US), MRI or blood tests do not have sufficient diagnostic power. Our aim was to develop and validate a non-invasive diagnostic test with a high sensitivity (80% or more) for symptomatic endometriosis patients, without US evidence of endometriosis, since this is the group most in need of a non-invasive test.
Methods
A total of 28 inflammatory and non-inflammatory plasma biomarkers were measured in 353 EDTA plasma samples collected at surgery from 121 controls without endometriosis at laparoscopy and from 232 women with endometriosis (minimal–mild n = 148; moderate–severe n = 84), including 175 women without preoperative US evidence of endometriosis. Surgery was done during menstrual (n = 83), follicular (n = 135) and luteal (n = 135) phases of the menstrual cycle. For analysis, the data were randomly divided into an independent training (n = 235) and a test (n = 118) data set. Statistical analysis was done using univariate and multivariate (logistic regression and least squares support vector machines (LS-SVM) approaches in training- and test data set separately to validate our findings.
Results
In the training set, two models of four biomarkers (Model 1: annexin V, VEGF, CA-125 and glycodelin; Model 2: annexin V, VEGF, CA-125 and sICAM-1) analysed in plasma, obtained during the menstrual phase, could predict US-negative endometriosis with a high sensitivity (81–90%) and an acceptable specificity (68–81%). The same two models predicted US-negative endometriosis in the independent validation test set with a high sensitivity (82%) and an acceptable specificity (63–75%).
Conclusions
In plasma samples obtained during menstruation, multivariate analysis of four biomarkers (annexin V, VEGF, CA-125 and sICAM-1/or glycodelin) enabled the diagnosis of endometriosis undetectable by US with a sensitivity of 81–90% and a specificity of 63–81% in independent training- and test data set. The next step is to apply these models for preoperative prediction of endometriosis in an independent set of patients with infertility and/or pain without US evidence of endometriosis, scheduled for laparoscopy.
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