FERTILITY AND STERILITY Copyright li) 1993 The Amerian Fertility Soiety Printed on aid-free paper in U.S.A. A quantitative overview of ontrolled trials in endometriosis-assoiated infertility* Edward G. Hughes, M..t Donna M. Fedorkow, M.D. John A. Collins, M.D. Department of Obstetris and Gyneology, MMaster University, Hamilton, Ontario, Canada Objetive: To undertake quantitative overviews of the following ommonly used treatments for endometriosis-assoiated infertility: ovulation suppression, laparosopi ablation, and onservative laparotomy. Design: A protool was prospetively defined detailing the researh question, mode of study identifiation, inlusion and exlusion, data extration, and pooling methods. Studies were assessed for relevane and validity by independent reviewers and their findings ompared. Data were extrated in a similar fashion. Patients: Women with visually diagnosed endometriosis, omplaining of infertility. Main Outome Measure: Pregnany as defined by positive pregnany test. Results: Twenty-five relevant randomized ontrolled trials and studies were identified with a total of 37 treatment omparisons. The ommon odds ratio (OR) from seven studies omparing ovulation suppression ( danazol, medroxyprogesterone aetate [MP A], or gestrinone) versus plaebo or no treatment was 0.85, suggesting no treatment benefit. The ommon OR for pregnany after ovulation suppression (MPA, gestrinone, or GnRH agonist) versus danazol was also nonsignifiant: 1.07. Although pooled data from trials of laparosopi surgery suggested a treatment benefit, signifiant heterogeneity between studies undermines this onlusion. Laparosopi data were similar to those from onservative laparotomy studies. Studies assessing onservative surgery plus danazol versus danazol alone showed no signifiant benefit from this adjunt. Conlusion: Ovulation suppression is an ineffetive treatment for endometriosis-assoiated infertility. Well-designed trials of laparosopi ablation deserve a high priority. Fertil Steril 1993;59:963-70 Key Words: Endometriosis, omparative study, meta-analysis How should we manage endometriosis-assoiated infertility? Although the literature addressing this question is growing rapidly, with at least 51 reviews published over the last 3 years, the answers remain highly ontentious. This is partiularly true for women with minimal and mild disease, in whom no Reeived Otober 15, 1992; revised and aepted January 27, 1993. *Supported by ontrat 91-R559 from the Royal Commission on New Reprodutive Tehnologies, P.O. ox 1566, Station, Ottawa, Ontario, Canada. t Reprint requests: Edward G. Hughes, M.., Department of Obstetris and Gyneology, MMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5. lear ausal assoiation an be defined between endometriosis and infertility (1). It remains possible that an underlying defet is responsible for both problems. Despite this onern, standard treatments aimed at the ablation of implants, suh as ovulation suppression and onservative surgery, have been adopted largely on the basis of unontrolled studies. Suh studies fail to take into aount the potential for spontaneous pregnany in untreated patients (2-4) and annot be used to assess the effetiveness of treatment. Although randomized ontrolled trials have been published omparing feundity after ovulation suppression with no treatment or plaebo (5-7), the Hughes et al. Endometriosis overview 963
small sample size of individual trials affords them limited statistial power. They are therefore unlikely to detet small but perhaps linially important differenes between treatment and ontrol groups. It is also likely that the onlusions of individual trials will differ in magnitude and diretion beause of the play of hane as well as differenes in population, intervention, and outome measured. The quality of evidene for surgial management is even more limited by the absene of truly randomized trials. Although a growing number of studies have been published (8-20) (Levinson CJ, abstrat), their validity is undermined by important baseline differenes between patient groups in terms of disease severity, time to treatment, and duration of follow-up. How then should we evaluate the evidene for these medial and surgial treatments? One option is to rely on published narrative review artiles and book hapters, aepting that they may overemphasize data that support the reviewer's beliefs rather than all of the available evidene (a form of seletion bias). Meta-analysis provides an alternative. Through the establishment of a predetermined protool detailing the question of interest, mode of data identifiation, inlusion, exlusion, and ombination, quantitative overviews of this type attempt to identify and redue suh bias (21, 22). In the urrent report we have applied these priniples to ontrolled studies of the following ommonly used treatments for endometriosis-assoiated infertility: ovulation suppression, laparosopi ablation, and onservative laparotomy. MATERIALS AND METHODS The researh question posed was: in ouples with infertility assoiated with endometriosis diagnosed at laparosopy or laparotomy, do ommonly used treatments result in an inreased rate of linial pregnany? A ouple was onsidered infertile if unsuessful in oneiving after > 1 year. Pregnany was defined as the report of a positive pregnany test. The treatments of interest were danazol, medroxyprogesterone aetate (MPA), gestrinone, ombined oral ontraeptive (OC) pills, GnRH analogues (GnRH-a), laparosopi surgery with laser or eletroautery, onservative laparotomy, and ombinations of onservative surgery with ovulation suppression. Study Identifiation Relevant trials were identified using the following five strategies: [ 1] the National Library of Mediine Medline Database was searhed from 1966 to 1992 using medial subjet headings: endometriosis, infertility (female), pregnany, and therapy; [2] the Institute for Sientifi Information Siene Citation Index was hand searhed from January 1986 to Deember 1989; [3] additional studies were identified by hand searhing bibliographies of relevant trials; [4] abstrats from sientifi meetings were hand searhed from 1986 to 1992; and [5] individual authors of relevant studies were diretly ontated in an effort to identify other published and unpublished data. Study Inlusion Studies were inluded if they addressed the researh question as stated. Only randomized ontrolled trials and studies reporting pregnanies in two or more treatment arms were inluded. Studies were independently assessed for relevane by at least two authors. The level of interobserver agreement was good, based on an assessment of a sample of 50 trials (K = 0.68). Differenes in assessments of relevane were resolved by onsensus. Validity Assessment An assessment of quality of study design and exeution is essential when onsidering why the outomes of individual studies differ and when weighing the strength of any overall onlusions. A detailed assessment was undertaken by two authors, using a soring system devised to assess the elements of design and exeution that were felt to pose the greatest threats to validity. The major fators taken into onsideration were the use of random alloation to treatment, the method of randomization employed, the duration and ompleteness offollow-up, and the onsideration of potentially onfounding fators suh as female age and duration of infertility. ased on this system, studies soring 2':10 were plaed in ategory A, 5 to 9 ategory, and <5 ategory C (Tables 1 and 2) (5-20, 23-30) (Levinson CJ, abstrat). Sores given by independent reviewers showed a good level of agreement (K = 0.77). Data Extration and Analysis Demographi data, method of treatment, study design, and pregnany data were reorded independently by two reviewers. When more than one treatment arm was present in an individual study, treatment and ontrol data were inluded as separate omparisons (7-12, 16, 23) (Levinson CJ, abstrat). Tables (2 X 2) were generated for eah study, giving 964 Hughes et al. Endometriosis overview Fertility and Sterility
Table 1 Randomized Controlled Trials and Cohort Studies of Medial Treatments for Endometriosis-Assoiated Infertility Validity Treatment Endometriosis Authors Year lass alloation stage Thomas and 1987 A Random (double- All stages Cooke (5) blind) exluding tubal disease ayer eta!. (6) A RCT Kistner (35) stage I Telimaa et a!. (7) A RCT AFS stage I to IV (36) Levinson abstrat 1989 Prospetive AFS stage I (36) Hull et a!. (23) 1987 AFS stage I, II (36) adawy eta!. (16) Aosta mild severe (37) Pouly eta!. (12) 1987 Mild moderate Fedele et a!. (24) 1989 A RCT Revised AFS I to IV (38) Fedele eta!. (25) 1989 RCT Revised AFS I to IV (38) Henzl et a!. (26) Random (double- Revised AFS I blind) to IV (38) Dmowski et al. 1989 RCT Revised AFS I (27) to IV (38) Shaw eta!. (28) 1992 RCT Revised AFS I to IV (38) Nobel and 1979 RCT All stages Lethworth (29) Other Duration of diagnoses Follow- Life-table infertility exluded Treatment Control up analysis y >1 Gestrinone Plaebo 12 2 to 2.2 12 4.1 to 4.2 12 MPA 12 3.17 to 3.75 18 to 30 MPA 3 to 4 1 to 58 >2 14 to 57 mo Gestrinone 18 3.25 to 3.75 userelin 12 aetate Nafarelin 12 3.29 userelin 12 aetate Gosereline 12 Mestranol norethynodrel the number of pregnant and nonpregnant ouples among treatment and ontrol groups. The Mantel Haenszel method was hosen for ombination of data (31). This approah employs odds ratios (ORs), whih losely approximate to relative risks but may be ombined in a statistially robust manner. Odds ratios for pregnany from individual studies and pooled estimates of treatment effet sizes are provided in Figures 1 to 3 (5-8, 10-13, 16, 23-30) (Levinson CJ, abstrat). In ombining studies, it is essential that differenes between them be arefully onsidered. Clearly, if major differenes exist in terms of population, intervention, or outome, it would be inappropriate to onlude that a pooled estimate of effet size aurately reflets the effetiveness ofthe treatment under investigation. Differenes between studies were therefore assessed qualitatively (linial heterogeneity) and quantitatively (statistial heterogeneity) using the reslow-day method (32). RESULTS A total of 37 treatment omparisons were identified among 25 studies. Twenty-four trials were published in full and one in abstrat only (Levinson CJ, abstrat). One study omparing laparosopi eletrooagulation with diagnosti laparosopy was exluded beause the data neessary to generate a 2 X 2 table ould not be extrated (33). No unpublished studies were identified. Ovulation Suppression Seven studies that ompared an ovulation suppression agent ( danazol, MP A, or gestrinone) with either plaebo or no treatment were identified (Table 1) (5-7, 12, 16, 23) (Levinson CJ, abstrat). Two studies ompared danazol and MP A with a ontrol (7, 23). For the purpose of this overview, eah treatment arm has been inluded as a separate trial. Design features of eah study are listed in Table L Three were randomized linial trials (RCT) (5-7), and four were studies (12, 16, 23) (Levinson CJ, abstrat). All RCTs had lass A validity sores, whereas studies were lassed as or C. Two of the RCTs reported the method of randomization (5, 6). None of the RCTs used a rossover design, and ointervention with other treatments did not appear to be present. One RCT and one study exluded other infertility diagnoses from their samples (5, 16). None of the retrospetive studies addressed possible ointervention or ontamination with other diagnosti groups. In these studies, treatment was generally alloated on the basis of disease severity. Hughes et al. Endometriosis overview 965
Table 2 Quasi-Randomized and Cohort Studies of Surgial Treatment for Endometriosis-Assoiated Infertility Other Validity Treatment Endometriosis Duration of diagnoses Followup Authors Year lass alloation stage infertility exluded Treatment Control Life-table analysis Levinson abstrat Paulson et al. (8) Ronnberg and Jarvinen (9) Nowroozi et al. (30) Fayez et al. (10) Chong et al. (11) Pouly et al. (12) Seiler et al. (13) Shenken and Malinak (14) Guzik and Rok (15) adawy et al. (16) Garia and David (17) Olive and Lee (18) Federii et al. (19) uttram et al. (20) 1989 1991 1984 1987 1990 1987 1982 1983 1977 1985 Prospetive Quasirandom Prospetive AFS stage I (36) AFS stage I and II (36) All stages AFS stage I and II (36) RevisedAFS stage I and II (38) AFS stage I Mild and moderate Aosta moderate (37) Mild AFS I and II (36) Aosta mildsevere (37) Aosta mildsevere (37) Aosta mildsevere (37) AFS stage I to IV (36) Revised AFS stage I to IV (38) y 2.6 3.5 to 4.7 2.8 to 3.8 4.2 >2 2.75 to 2.8 1 to >4.9 3to4 3.4 4 to 5.5 Laparosopi eletroautery ± danazol Laparosopi laser or eletroautery or onservative laparotomy Laparosopi eletroautery or laparotomy ± danazol Laparosopi eletroautery Laparosopi exision ± danazol C02 laser ± danazol Laparosopi eletroautery ±danazol Laparosopi eletroautery ± danazol laparotomy laparotomy or danazol or danazol or danazol alone alone mo 12 15 12 to 66 8 12 12 14 to 57 7 >12 Up to 72 1 to 58 Up to 60 Up to 40 >15 The ORs for individual studies ranged from 0.4 to 1.33, all with 95% onfidene intervals (CI) inluding unity. The ommon OR for pregnany trials was 0.85 (95% CI, 0.95 to 1.22) (Fig. 1). Clearly, there was linial heterogeneity between studies be- ause different interventions were used. However, effet sizes were similar in studies examining danazol and progestins, refleted by a lak of statistial heterogeneity (reslow-day = 3.20, P = 0.92). Six RCTs were identified, omparing gestrinone, GnRH-a or an OC with danazol (24-29). Their Author Design Pregnanies/Patients Supresslon Control Thomas et al(5) RCT 5/20 4/17 ayer RCT 13/37 17/36 etal(6) o-----4-- ~ Author Design Pregnanies/Patients Supresslon Control Fedele RCT &/20 7/19 et al(24) Tellrnaa et a1(7) RCT 6/18 6/14 Tellmaa et al{7) RCT 7/17 6/14 Levinson etal* Cohort 17/41 9/21 Hull Cohort 16/52 21/56 et al(23) >---1 - Hull Cohort 18/38 21/58 ~ ------< et al(23) adawy Cohort 16/38 9/14 et al{16) Pauly eta1(12) Cohort Common Odds Ratio 4/10 3/7 * Levinson CJ, Abatrat 0.1 0.5 1 2.0 10 reslow-day = 3.20 {p = 0.92) o-t Fedele RCT 13/30 12/32 et ai(2s) Hanzl atal{26) Drnowekl et al(27) Shaw et al(28) RCT 42/104 18/45 RCT 8/18 5/8 RCT 33/113 13/54 Noble RCT 4/10 7/12 et al(29) Common Odds Ratio reslow-day = 2.18 (p = 0.70} 0.1 0.5 1 2.0 10 Figure 1 Controlled studies omparing ovulation suppression versus no treatment in women with endometriosis-assoiated infertility: ORs for pregnany. Figure 2 Randomized ontrolled trials omparing ovulation suppression versus danazol in women with endometriosis-assoiated infertility: ORs for pregnany. 966 Hughes et al. Endometriosis overview Fertility and Sterility
Author Design Pregnanies/Patients Levinson etal* Paulson., 1(8) Nowroozl etal(30) Fayez etal(10) Chona etal(11) Seller etal(13) Laparoaopy Cohort 44/83 Cohort 235/311 Quasi-random 42/88 Cohort 10/82 Cohort 37/IS Cohort 20/415 Common Odds Ratio * Levinson CJ, Abstrat restow-d<iy = 30.3 (p < 0.001) 0.01 Control 8/21 71/157 10/54 20/78 23/47 15/41 >---< >------------< >----< 0.1 0.5 1 2.0 10 100 Figure 3 Controlled studies omparing laparosopi laser/ autery versus no treatment or danazol in the treatment of endometriosis-assoiated infertility: ORs for pregnany. validity sores range from A to C. Only one trial desribed the method of randomization (26). None used a rossover design. However ointervention with lomiphene and other infertility treatments was a onern in three studies (24, 25, 27). Contamination through the inlusion of other diagnosti groups was also a onern (26, 27, 29), and in two trials, >40% of patients dropped out of one or more treatment arms (28, 29). The ommon OR for pregnany after these ovulation suppression agents ompared with danazol was 1.07 (95% CI, 0.71 to 1.61) (Fig. 2). Again, although these studies assess different interventions, there was no statistial evidene of heterogeneity between them (reslow-day = 2.18, p = 0.70). Thus, in the treatment of endometriosis-assoiated infertility, the ombined data from trials omparing danazol, gestrinone, or MPA with plaebo or no treatment failed to show any treatment benefit. Trials omparing gestrinone, GnRH -a, or an OC pill with an ative ontrol, danazol, demonstrated no differene in subsequent feundity between groups. Larger trials of this treatment approah do not appear to be warranted on the basis of these findings. Laparosopi Surgery One quasi-randomized (30) and five studies (8, 10, 11, 13) (Levinson CJ, abstrat) were identified, omparing laparosopi surgery with no treatment or danazol (Table 2). Validity sores plaed them in ategories and C. Only two studies expliitly exluded patients with other infertility diagnoses (8, 30). One employed a variety of unspeified infertility treatments in the follow-up period (30). In addition to onerns of ointervention among the studies, signifiant seletion bias is likely to have ourred on the basis of disease severity. Three of the five studies identified demonstrated signifiant benefit from laparosopi destrution of endometrioti implants when ompared with no treatment or danazol (8, 10, 30). Odds ratios for individual studies ranged from 0.84 to 7.63. The ommon OR for all studies was 2.67 (95% CI, 2.08 to 3.45, Fig. 3), suggesting a treatment benefit. However, signifiant linial and statistial heterogeneity was present between studies (reslow-day = 30.3, P < 0.0001), rendering their ombination highly questionable. ased on these data, larger randomized ontrolled trials are warranted to address this treatment modality. Laparosopi Surgery Plus Five studies that ompared laparosopi surgery plus danazol versus danazol alone were identified (9-12) (Levinson CJ, abstrat). Seletion bias and ontamination of results through inlusion of other infertility diagnoses would again be expeted in these studies. Their validity was lassed as or C. Three of the five reports failed to demonstrate signifiant differenes between treatment and ontrol groups (11, 12) (Levinson CJ, abstrat). Ronnberg and Jarvinen (9) found a lower pregnany rate (PR) in patients reeiving laparosopi surgery plus danazol, whereas Fayez et al. (10) reported a higher rate in this group ompared with danazol alone (10). The ommon OR for these trials was 1.42 (95% CI, 0.94 to 2.14). One again, signifiant statistial heterogeneity was present (reslow-day = 19.35, P < 0.001), rendering the ombination of data inappropriate. In summary, these studies offer little support for the use of laparosopi surgery with adjuvant danazol versus no treatment or danazol alone. Conservative Laparotomy Six studies omparing onservative surgery with no treatment (8, 14, 17, 18) or danazol (8, 9, 15) were identified. Validity sores plaed them in ategories and C. Other infertility diagnoses were expliitly exluded in only one study (8). A major onern in these and other surgial reports was the potential for differene in time to treatment and length of follow-up between intervention and ontrol groups. Three of the six studies failed to demonstrate any differene in PR between treatment and ontrol Hughes et al. Endometriosis overview 967
groups (9, 14, 17). Two studies demonstrated statistially signifiant positive effets of surgery on rude PRs (8, 15). When umulative PRs in treatment groups were ompared, two studies found them to be similar (15, 16). One found umulative PR to be higher postlaparotomy in women with severe disease (18). Although a fourth study reports some umulative pregnany data, these authors do not report monthly feundity in treatment and ontrol groups (8). Odds ratios for individual studies range from 0.29 to 4.35, with a ommon OR of 1.62 (95% CI, 1.27 to 2.10). One again, signifiant heterogeneity exists between studies (reslow-day = 48.9, P < 0.0001). When the largest retrospetive study of Paulson et al. (8) that demonstrated the greatest treatment effet was exluded, the ommon OR fell to 1.06 (95% CI, 0.77 to 1.45, reslow-day= 25.42, P < 0.0001). The mode of treatment alloation, based largely on disease severity, and the potential for differenes in the time to treatment and duration of follow-up in these studies highlight the need for further investigation with randomized ontrolled trials. Conservative Laparotomy Plus One trial ompared laparotomy plus danazol with no treatment (16) and four with danazol alone (9, 16, 19, 20). All studies used a design. Their ombination demonstrated no signifiant treatment benefit from surgery plus danazol (ommon OR 1.01; 95% CI, 0.67 to 1.52). Signifiant heterogeneity existed between studies (reslow-day = 8.88, P = 0.03). These trials failed to demonstrate signifiant benefit from a ombination of surgery and danazol. DISCUSSION These overviews highlight the level of evidene on whih urrent treatment of endometriosis-assoiated infertility is based. The highest quality data available demonstrate no benefit from ovulation suppression with danazol, MP A, gestrinone, or GnRH -a. Although less rigorous studies suggest that laparosopi ablation and onservative laparotomy may be benefiial, the high degree of heterogeneity between studies suggests that important fators other than treatment may be responsible for the apparent improvement in PRs after these surgial interventions. Of partiular importane are the researh methods used. All but three (20, 30) (Levinson CJ, abstrat) surgial studies employed a retrospetive design, raising onerns over the potential for bias. Treatment alloation was based largely on severity, with moderate or severe disease being over-represented in the surgial group. This type of seletion bias might lead to an underestimation of the effiay of surgial intervention. In examining the effet of disease severity on the outome of all interventions, limited data were available. Most studies assessing ovulation suppression inluded patients with mild and moderate disease. Among those that inluded all degrees of severity, pregnany data were not reported in treatment groups aording to stage (5, 7, 16, 24-29). Studies assessing laparosopi surgery inluded only patients with mild and moderate disease. One study reported outome by treatment and severity and showed very similar results in patients with mild and moderate endometriosis (8). Of the studies assessing onservative laparotomy, only two gave data speifi to intervention and stage (15, 20). Similar rude PRs were reported in women with mild and moderate disease undergoing surgery (15), whereas women undergoing ombined danazol and surgery demonstrated a trend toward lower PRs with inreased severity (20). Major differenes in the time to treatment were also likely between s. Relatively feund women might oneive before they ould be onsidered and sheduled for surgery, plaing them in the expetant or medial treatment group for the purpose of analysis, again leading to an underestimation of the effiay of surgery. Differene in duration of follow-up is a third major onfounder of studies. Although many investigators reported the range or mean duration of follow-up, none speifially addressed the differenes between groups. If these were present, rude PRs would probably be inflated in the surgial group beause of longer follow-up in those patients. The inlusion of patients with other diagnoses, whether they were "orreted" or not, and ointervention with other infertility treatments are perhaps less powerful soures of bias. The diretion of influene here would depend on the level of ontamination and ointervention in eah group. What strategies are available to ombat these biases? Life-table analysis, taking into aount the number of dropouts through loss to follow-up and pregnany, may orret some problems of inomplete follow-up. This approah was used in 12 of 25 studies (Tables 1 and 2). However, life-table analysis is founded on the assumption that duration of follow-up is similar between groups and that the outome of interest ours with similar frequeny in 968 Hughes et al. Endometriosis overview Fertility and Sterility
those who are lost and those who remain under observation. Multivariate analysis is also a useful tool in assessing the importane of o fators that infiuene feundity, suh as disease stage, female age, and duration of infertility. Proportional hazards analysis is partiularly useful in dealing with timedependent variables (34). Unfortunately, multivariate analysis was not a feature of reported studies. Seurely randomized treatment alloation with similar duration of follow-up between groups remains the most powerful approah in preempting these biases. Although the data from studies of onservative laparotomy and laparosopi surgery both highlight the need for suh trials, a laparosopy study should be given higher priority for three reasons. First, surgial trials involving major interventions suh as laparotomy are umbersome to undertake and partiularly prone to seletion bias. Randomization at the time of diagnosti laparosopy, to ablation of visible endometriosis or no ablation, with the same duration of follow-up in eah group is a far more workable design. Seond, with inreasing experiene and aeptane, operative laparosopy is superseding laparotomy under many irumstanes. Finally, beause the majority of patients with endometriosis have minimal or mild disease, most an be safely treated via the laparosope. These are ompelling reasons for undertaking an operative laparosopy trial, but what results should we expet? If the redution or elimination of visible endometriosis by medial means does not improve feundity, how might surgial ablation be expeted to do so? This again begs the question that annot at present be answered: does endometriosis ause infertility or does an underlying defet ause infertility and this most enigmati ondition? 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