Laparoscopic endometriosis treatment: is it better?*

FERTILITY AND STERILITY Copyright 1993 The American Fertility Society Selected paper from 1991 Pacific Coast Society Meeting Printed on acid-free paper in U.S.A. Laparoscopic endometriosis treatment: is it better?* G. David Adamson, M.D.t:j: Stacy J. Hurd, B.A.t David J. Pasta, M.S. t Bruce D. Rodriguez, B.A.:!: Fertility Physicians of Northern California, Palo Alto, and Stanford University School of Medicine, Stanford, California Objective: To assess the hypothesis that pregnancy rates (PRs) after operative laparoscopy (Laparoscopy Group) for endometriosis treatment would be equal to or greater than diagnostic laparoscopy only (No Treatment Group), diagnostic laparoscopy with medical treatment (Medical Treatment Group), and laparotomy (Laparotomy Group). Design: Prospectively recorded data were analyzed to identify significant variables affecting PRs. These variables were statistically controlled for using survival analysis with multiple fixed covariates to compare operative laparoscopy PRs versus other treatment PRs. Setting: Treatment was performed by the senior author in a referral reproductive endocrinology and surgery private practice. Patients: Five hundred seventy-nine infertile women were diagnosed with endometriosis. A subset (n = 258) considered to have endometriosis only was evaluated separately (Endometriosis-Only Subset). Interventions: Treatment groups included: No Treatment Group, Medical Treatment Group, Laparoscopy Group, and Laparotomy Group. Main Outcome Measure(s): Pregnancy was used as the indicator of treatment success. Results: Laparoscopy Group PRs were at least equal to all other treatment groups and were significantly higher than some other treatment groups in some comparisons. Conclusions: Operative laparoscopy is the treatment of choice for infertile women with endometriosis unless they have severe tubal and/or fimbrial disease. Fertil Steril1993;59:35-44 Key Words: Operative laparoscopy, endometriosis treatment, laparotomy, medical therapy, no treatment, diagnostic laparoscopy, survival analysis, statistics Laparoscopy has become an effective and precise diagnostic and treatment procedure in gynecology. However, because both laparoscopic and non-iaparoscopic endometriosis treatment options are available, choosing the optimal therapy for any individual Received August 22,1991; revised and accepted September 18, 1992. * Received award as Prize Paper by a Practicing Physician and was presented at the 39th Annual Meeting of the Pacific Coast Fertility Society, Indian Wells, California, April 10 to 14, 1991. t Fertility Physicians of Northern California. t Department of Gynecology and Obstetrics, Stanford University School of Medicine. Reprint requests: G. David Adamson, M.D., 540 University Avenue, Suite 200, Palo Alto, California 94301. patient can be difficult. Many researchers are attempting to determine which treatment of endometriosis is best (1-5). This study compares pregnancy rates (PRs) among patients in four endometriosis treatment groups: diagnostic laparoscopy followed by no treatment (No Treatment Group, n = 20), diagnostic laparoscopy followed by medical treatment (Medical Treatment Group, n = 50), operative laparoscopy performed at the time of diagnostic laparoscopy (Laparoscopy Group, n = 361), and laparotomy (Laparotomy Group, n = 148). Life table calculations were used to estimate PRs of the treatment groups. Survival analysis with multiple fixed covariates was used to identify factors that significantly affected Adamson et al. Laparoscopic endometriosis treatment 35

PRs and then to compare treatment groups while statistically controlling for those factors. MATERIALS AND METHODS Patient Selection, Categorization, and Treatment The study population was 579 infertility patients diagnosed with endometriosis at laparoscopy by a private practice reproductive endocrinologist and surgeon (G.D.A.) between 1980 and 1990. All patients were attempting pregnancy. The 50 patients in the Medical Treatment Group were treated with danazol (n = 41), medroxyprogesterone acetate (n = 3), gonadotropin-releasing hormone agonist (n = l),or a combination of drugs (n = 5). The 361 patients in the Laparoscopy Group were treated with CO 2 laser vaporization and/or resection (n = 334), electrosurgery (n = 21), sharp resection alone (n = 1), or some combination of the above (n = 5). The 148 patients in the Laparotomy Group were treated by CO 2 laser vaporization and resection (n = 63), electrosurgery (n = 5), sharp resection alone (n = 53), or a combination ofthe above (n = 27). A subset of the study population considered to have endometriosis as the only important infertility factor consisted of 258 patients (Endometriosis-Only Subset). The patients in Endometriosis-Only Subset were selected based on the presence of at least one normal tube with normal fimbria (diagnosed pretreatment) and normal male factor (sperm count > 20 X 106/mL, >30% motility, and >50% normal morphology). The Endometriosis-Only Subset treatment groups were No Treatment (n = 14), Medical Treatment (n = 34), Laparoscopy (n = 182), and Laparotomy (n = 28). Investigation and treatment of endometriosis were based on clinical indications. Associated ovulatory, pelvic, male, and cervical infertility factors were diagnosed and treated. Patients who could not be treated or managed successfully were excluded from the study. Surgical procedures were performed with prior written informed consent of all patients. Endometriosis and adhesions were staged using the unrevised American Fertility Society (AFS) system from 1980 to 1985 (6). These scores were subsequently converted to the 1985 revised AFS system (7) by the senior author after review ofthe patients' surgical reports and accompanying comprehensive and detailed diagrams made at the time of surgery. The revised AFS system of classification was used from 1985 to 1990. All patients were followed until their last menstrual period (LMP) before pregnancy (defined as a positive serum beta human chorionic gonadotropin) or, if not pregnant, until the date of the patient's last contact. Follow-up letters were sent to nonpregnant patients who had not been in contact within the 6 months before data analysis. The laser used for most cases was a LaserSonics 250Z laser (Hereaus LaserSonics, Milpitas, CA). For laparoscopy, a 1O.7-mm Laser Laparoscope (Storz, Indianapolis, IN) with a 1- to 2-mm spot diameter was used. The laser was generally used in continuous superpulse waveform controlled by the surgeon with a foot pedal. A OA-ms pulse width and 600 pulses/s gave an integrated power output of 27 watts. Power density ranged approximately from 900 watts/cm 2 to 3,400 watts/cm 2 Laparoscopy since 1985 was performed with a videocamera connected to the eye piece. All surgeries were performed under general endotracheal anesthesia. Data Analysis The Stanford University IBM 3090-600 mainframe (International Business Machines, Armonk Village, NY) with BMDP Statistical Software (8) (BMDP Software, Inc., Los Angeles, CA) and SAS (9) (SAS Institute, Inc., Cary, NC) were used for analyses including frequency distributions, two-way tabulations, life table calculations, and survival analyses with multiple fixed covariates. Life table calculations estimate the cumulative PRs taking into account duration of follow-up on each patient (10, 11). Time zero for life table calculations was the initial diagnostic laparoscopy, operative laparoscopy, or laparotomy performed by the senior author. Duration of follow-up was determined from the LMP if pregnant, the last date of contact if not pregnant, or the date an additional treatment was started. Cumulative PRs were calculated at 3-month intervals. The Breslow test was used for statistical comparisons of groups except where the Mantel-Cox test is explicitly mentioned (12). Survival analysis with multiple fixed covariates using the Cox proportional hazards regression model identified time-invariant factors associated with increased or decreased PRs while accounting for variable length of follow-up. Comparisons of treatment groups were performed while controlling for these factors (covariates). All P values listed for survival analysis with multiple fixed covariates are from likelihood ratio tests. We have designated an alpha value of 0.05. Differences between groups are considered significant when P < 0.05 unless otherwise noted. In analyses 36 Adamson et al. Laparoscopic endometriosis treatment Fertility and Sterility

in which six comparisons are performed (i.e., pairwise comparison of 4 treatment groups), the Tukey method for multiple comparisons or the Bonferroni inequality is used to ensure overall significance at the 0.05 level (13). Application of the Bonferroni inequality is indicated by specifying the calculated P value and then multiplying it by six to obtain the Bonferroni-adjusted P value, denoted by pi; this procedure is known to be conservative. Cohort Characteristics RESULTS Characteristics of the four treatment groups (No Treatment Group, Medical Treatment Group, Laparoscopy Group, Laparotomy Group) for the entire population and the Endometriosis-Only Subset are given in Tables 1 and 2, respectively. There are significant differences among the groups for several variables. Perhaps most noteworthy is that the Laparotomy Group patients had markedly higher revised AFS total scores both for the entire population and the Endometriosis-Only Subset. For this reason, particular emphasis was placed on controlling for severity of disease in the analyses. Also while at least half of the No Treatment, Medical Treatment, and Laparoscopy Groups were included in the Endometriosis-Only Subset, less than one fifth of the Laparotomy Group qualified for the Endometriosis Only Subset. This implies that a relatively large fraction of the Laparotomy Group had other infertility factors, often relating to the tubes and fimbria. Life Table Calculations The estimated cumulative life table PRs (±SE) at 1, 2, and 3 years for the entire population and for the Endometriosis-Only Subset were calculated (Table 3). Included is the number of patients (n) and the number who became pregnant within the first 3 years of follow-up, regardless of the duration of follow-up (3-year PR). An additional 12 patients conceived after >3 years of follow-up. Life table PRs were significantly different across the four stages of endometriosis in the entire study population (Breslow, P < 0.001). Patients with minimal endometriosis had the highest estimated PRs, whereas those with severe endometriosis had the lowest. In contrast, for the Endometriosis-Only Subset, the PRs were comparable across all stages of endometriosis (P = 0.34). Even when patients with minimal and mild endometriosis are grouped together and compared with patients with moderate and severe disease, in the Endometriosis-Only Subset the difference is not statistically significant (P = 0.18). Stratified life table calculations evaluated PRs according to the four treatment groups and two categories of grouped revised AFS endometriosis stages: minimal/mild endometriosis and moderate/severe endometriosis (Table 4). All possible pairs of treatment groups were also compared (Table 5). For women with minimal/mild endometriosis, all four treatment options were compared (Table 5). Because a total of six pairs of comparisons are possible, the Bonferroni inequality is used by multiplying the calculated P values by six. This calculation results in a conservative estimate of potential differences, reducing the chance a statistically significant difference will be claimed where none exists. In the entire population (n = 346), the Medical Treatment Group PRs are significantly lower than Laparoscopy Group PRs (PI = 0.006 X 6 = 0.036) Table 1 Characteristics of Entire Patient Population * No treatment Medical treatment Variable (n = 20) (n = 50) Age (y)t 32.2 ± 4.4 30.0 ± 4.1 Years infertile 4_5 ± 4.2 3.6 ± 2.4 Gravidity 1.2 ± 1.4 0.5 ± 0.8 Follow-up (d):j: 743 ± 986 658 ± 667 Revised AFS total 8.2 ± 10.8 7.6 ± 7.1 Sire totalll 1.9 ± 2.0 1.4 ± 2.7 Sire partner II 1.5 ± 2.0 1.3 ± 2.8 * The Tukey method for multiple comparisons was used to ensure overall significance at the 0.05 level (13). Groups were found to differ significantly as indicated. Values are means ± SD. t Medical Treatment Group was younger than Laparoscopy Group and Laparotomy Group. :j: Laparoscopy Group had shorter length of follow-up than Laparotomy Group. Laparoscopy Laparotomy All (n = 361) (n = 148) (n = 579) 33.1 ± 4.2 33.0 ± 4.3 32.8 ± 4.3 3.7 ± 2.9 3.5 ± 3.1 3.7 ± 3.0 0.8 ± 1.1 0.9 ± 1.4 0.8 ± 1.2 443 ± 449 691 ± 683 535 ± 562 16.1 ± 18.0 37.0 ± 32.9 20.4 ± 24.2 1.7 ± 2.6 1.1 ± 1.6 1.5 ± 2.4 1.4 ± 2.6 0.5 ± 1.4 1.2 ± 2.4 No Treatment Group, Medical Treatment Group, and Laparoscopy Group had lower revised AFS scores than the Laparotomy Group. II Laparotomy Group partners sired less with current partner and with all partners than the Laparoscopy Group. Adamson et al. Laparoscopic endometriosis treatment 37

Table 2 Characteristics of Endometriosis-Only Subset *t No Medical treatment treatment Variable (n = 14) (n = 34) Age {y):j: 31.8 ± 4.3 30.7 ± 4.1 Years infertile 3.4 ± 3.1 3.5 ± 2.0 Gravidity 1.4 ± 1.5 0.6 ± 0.8 Follow-up (d) II 719 ± 1065 736 ± 747 Revised AFS total1f 3.4 ± 4.4 7.1 ± 6.4 Sire total ** 1.6 ± 1.4 0.2 ± 0.5 Sire partnertt 1.3 ± 1.4 0.2 ± 0.5 * Male normal, and pretreatment at least one tube and fimbria normal. t The Tukey method for multiple comparisons was used to ensure overall significance at the 0.05 level (13). Groups were found to differ significantly as indicated. :j: Medical Treatment Group was younger than Laparoscopy Group. Values are means ± SD. No Treatment Group had greater number of previous pregnancies than the Laparotomy Group. II Laparoscopy Group had shorter length of follow-up than Medical Treatment Group and Laparotomy Group. Laparoscopy Laparotomy All (n = 182) (n = 28) (n = 258) 33.7 ± 3.9 32.7 ± 4.2 33.1 ± 4.1 3.6 ± 2.8 4.4 ± 2.8 3.7 ± 2.7 0.8 ± 1.3 0.2 ± 0.5 0.8 ± 1.2 420 ± 448 981 ± 916 539 ± 602 12.3 ± 12.0 26.0 ± 22.8 12.6 ± 13.8 0.9 ± 1.2 0.4 ± 0.6 0.8 ± 1.1 0.5 ± 0.9 0.1 ± 0.3 0.5 ± 0.9 1f No Treatment Group, Medical Treatment Group, and Laparoscopy Group had lower revised AFS scores than the Laparotomy Group. ** No Treatment Group partners sired more total pregnancies with all partners than Medical Treatment Group and Laparotomy Group, and the Medical Treatment Group partners sired less total pregnancies than the Laparoscopy Group. tt No Treatment Group partners sired more pregnancies with current partner than Medical Treatment Group, Laparoscopy Group, and Laparotomy Group. Laparoscopy Group partners sired more pregnancies with current partner than the Laparotomy Group. and significantly lower than Laparotomy Group PRs (PI = 0.001 X 6 = 0.006). In addition, the Medical Treatment Group PRs are lower than the No Treatment Group PRs, but the difference does not achieve statistical significance with the Bonferroni adjustment (PI = 0.012 X 6 = 0.072). In the Endometriosis Only Subset (n = 192), Laparoscopy Group PRs were significantly higher than Medical Treatment Group PRs (PI = 0.007 X 6 = 0.042) and No Treatment Group PRs were significantly higher than Medical Treatment Group PRs (PI = 0.003 X 6 = 0.018). Among the patients with moderate/severe endometriosis, all women but 11 were treated surgically. Therefore, only one comparison, between laparoscopy and laparotomy, is appropriate (Table 5). In the entire population (n = 222), Laparoscopy Group and Laparotomy Group PRs were not significantly different with proportionally more emphasis on earlier time intervals (Breslow, P = 0.054), but is with equal emphasis over the 3 years (Mantel-Cox, P = 0.043). After adjusting for severity of disease (moderate or severe), the differences are nonsignificant (Breslow, P = 0.10; Mantel-Cox, P = 0.08). It is noteworthy that the PRs for the Laparoscopy Group are lower than for the Laparotomy Group among patients with minimal or mild disease but higher among patients with moderate or severe disease. Neither difference is statistically significant, and our overall comparisons of the two groups adjusting for severity of disease is also nonsignificant Table 3 Estimated Cumulative Life Table PRs by Stage of Endometriosis Entire patient population Endometriosis-only subset No. Pregnant No. Pregnant pregnant pregnant No. in 3 y 1y 2y 3y No. in 3 y 1y 2y 3y % % % % % % All 579 274 36.9 ± 2.2' 53.6 ± 2.4 61.7 2.6 258 130 39.7 3.3 57.4 ± 3.6 65.8 ± 3.8 Minimal 161 91 49.8 ± 4.3 64.9 ± 4.5 73.7 4.6 91 49 44.8 5.7 61.2 ± 6.0 70.5 ± 6.1 Mild 185 89 38.0 ± 3.8 55.6 ± 4.3 62.3 4.6 101 49 40.9 5.2 54.9 ± 5.7 63.1 ± 6.4 Moderate 142 63 31.1 ± 4.2 50.5 ± 4.9 57.4 5.1 49 26 35.6 7.5 60.3 ± 8.3 71.1 ± 8.1 Severe 91 31 22.0 ± 4.6 35.8 ± 5.9 46.7 6.6 17 6 18.6 9.7 42.6 ± 13.6 42.6 ± 13.6 All minimal/mild 346 180 43.4 ± 2.3 59.8 ± 3.1 67.7 3.3 192 98 42.7 3.9 58.0 ± 4.2 66.8 ± 4.4 All moderate/severe 233 94 27.5 ± 3.1 44.7 ± 3.8 53.2 4.0 66 32 30.9 6.1 55.4 ± 7.2 63.2 ± 7.2 Values are estimates ± SE. 38 Adamson et al. Laparoscopic endometriosis treatment Fertility and Sterility

Table 4 Estimated Cumulative Life Table PRs by Treatment Group for Different Stages of Endometriosis Entire patient population No. Pregnant pregnant No. in 3 y 1y 2y % % Minimal/mild No treatment 15 10 53.3 ± 12.9' 66.7 ± 12.2 Medical treatment 44 20 26.5 ± 7.2 53.0 ± 8.9 Laparoscopy 241 122 43.6 ± 3.5 59.6 ± 3.8 Laparotomy 46 28 55.7 ± 7.9 65.6 ± 7.9 Moderate/severe t Laparoscopy 120 52 29.1 ± 4.5 50.8 ± 5.6 Laparotomy 102 37 23.8 ± 4.5 36.7 ± 5.3, Values are estimates ± SE. Endometriosis-only subset No. Pregnant pregnant 3y No. in 3 y 1y 2y 3y % % % % 66.7 ± 12.2 13 9 61.5 ± 13.5 69.2 ± 12.8 69.2 ± 12.8 62.3 ± 9.3 32 13 25.6 ± 8.4 47.7 ± 10.2 55.2 ± 11.2 67.8 ± 4.1 134 70 45.5 ± 4.7 60.4 ± 5.1 70.3 ± 5.4 74.3 ± 8.1 13 6 38.0 ± 15.1 50.4 ± 16.4 64.5 ± 16.8 62.2 ± 6.2 48 25 32.2 ± 7.5 70.0 ± 9.0 82.0 ± 8.5 44.4 ± 5.6 15 5 20.0 ± 10.3 26.7 ± 11.4 33.3 ± 12.2 t Eleven patients treated nonsurgically have been excluded from the entire patient population. Three patients treated nonsurgically have been excluded from the Endometriosis-Only Subset. (P = 0.86). In the Endometriosis-Only Subset population (n = 63), the Laparoscopy Group was significantly better than the Laparotomy Group when proportionally more emphasis was placed on earlier time intervals (Breslow, P = 0.031). When equal emphasis was placed on each time interval over 3 years, the superiority of Laparoscopy Group PRs compared with those for the Laparotomy Group is even clearer (Mantel-Cox, P = 0.005) (Table 5). Survival Analysis With Multiple Fixed Covariates Treatment groups were compared using survival analysis with multiple fixed covariates to account for variable follow-up time, variable time to pregnancy, and unequal distribution of factors identified as predictive of PRs. In the entire population, survival analysis was used to identify variables that were predictive of increased or decreased PRs; five variables were so identified. High pretreatment fimbrial score (range 0 to 8, with 0 = both sides completely occluded, nonfunctional, or absent, and 8 = both sides normal) was associated with increased PRs (P = 0.01). Longer duration of infertility (P < 0.001), higher revised AFS total score (P = 0.003), current ovulation therapy (P = 0.001), and high pretreatment tubal score (range 0 to 8, with o = both sides occluded, nonfunctional, or absent, and 8 = both sides normal) (P = 0.01) were associated with decreased PRs. Controlling for the five significant variables, the four treatment groups in the entire population were compared. There were no significant differences found overall (P = 0.20) or between individual pairs of treatment groups. Table 6 gives the details, including the sample sizes (n), the estimate of how much higher the PR is for the first group named compared with the second (Estimate) and the test that the two groups have equal PRs (X 2 and P value). In addition, because operative laparoscopy and diagnostic laparoscopy only (No Treatment) are both management options associated with completion of "therapy" at the time of diagnostic laparoscopy, they were grouped together and compared with a combined Medical Treatment and Laparotomy Group, both of which subsequently require more involved therapy and further time after diagnostic laparoscopy before completion of treatment. This comparison showed the No Treatment/Laparoscopy Group to have 33% higher PRs than the Medical Treatment/Laparotomy Group (P = 0.035) (Table 6). Predictive variables were also isolated in the Endometriosis-Only Subset. Three variables significantly affected PRs. Previous therapeutic abortion was associated with an increase in PR (P = 0.003). Longer duration of infertility (P = 0.005) and current ovulation therapy (P = 0.04) were associated with decreased PRs. In this population, in which every woman had at least one tube and fimbria completely normal, tubal status, fimbrial status, and revised AFS total score were no longer predictive of pregnancy. Controlling for these three significant variables, the four treatment groups were compared within the Endometriosis-Only Subset. The test for overall differences across the four groups was significant (P = 0.011). Pairwise comparison of the groups showed PRs significantly higher for the Laparoscopy Group than the Medical Treatment Group (Pi = 0.007 X 6 = 0.042) but not significantly higher than the Laparotomy Group (Pi = 0.031 X 6 Adamson et al. Laparoscopic endometriosis treatment 39

Table 5 Pairwise Comparison of Treatment Groups for Different Stages of Endometriosis Using Estimated Cumulative Life Table PRs Entire patient population Endometriosis-only subset Comparison Minimal/mild (n = 346) Moderate/severe (n = 222)* Minimal/mild (n = 192) Moderate/severe (n = 63)t Laparoscopy versus no treatment Laparoscopy versus medical treatment Laparoscopy versus laparotomy No treatment versus medical treatment No treatment versus laparotomy Medical treatment versus laparotomy 0.30 0.006* 0.092 0.012 0.99 0.001* 0.054 0.14 0.007* 0.72 0.003* 0.16 0.15 0.031 * Eleven patients treated nonsurgically have been excluded. t Three patients treated nonsurgically have been excluded. * Statistically significant after Bonferroni adjustment. Mantel-Cox statistic P = 0.005. = 0.186). The No Treatment Group was associated with somewhat higher PRs than the Medical Treatment Group, but the difference was nonsignificant (PI = 0.040 X 6 = 0.240). Additional survival analyses for the Endometriosis-Only Subset showed Laparoscopy Group PRs were superior to Laparotomy Group PRs, with no statistically significant variation according to severity of disease. As was done for the entire population, the No Treatment Group and the Laparoscopy Group were combined and compared against the combined Medical Treatment and Laparotomy Group. The No Treatment/ Laparoscopy Group had estimated PRs nearly twice as high as the Medical Treatment/Laparotomy Group (P = 0.001) (Table 6). This last survival analysis within the Endometriosis-Only Subset was repeated using gravidity along with years of infertility and ovulation therapy as a predictive set rather than the set including therapeutic abortion because it was felt that gravidity may be a more appropriate predictor in other patient populations. Comparison of treatment groups yielded results comparable with those given previously except that No Treatment Group PRs were comparable with Medical Treatment Group PRs (PI = 0.10 X 6 = 0.60). The possibility of a time trend in PRs was evaluated. The year of entry into the study was tested as a possible additional predictor, both in a model assuming proportional hazards for the four treatment groups and in a model not requiring proportional hazards across the four groups. The entry year was found to be nonsignificant in both the entire population and the Endometriosis-Only Subset (P> 0.20 in all cases). This implies no time trend in PRs after controlling for treatment group and the key predictors described above. However, the year of entry into the study is associated with which treatment patients received. The implications of this association are discussed below. To evaluate the effect of controlling for the variabies identified as predictive of pregnancy, the survival analyses were repeated without those variables being controlled. In the entire population, there were Table 6 Pairwise Comparison of Treatment Groups Controlling for Significant Variables Using Survival Analysis With Fixed Covariates Entire patient population * Endometriosis-only subset t No. Estimate X2 Pvalue No. Estimate X2 Pvalue % % Laparoscopy versus no treatment 361/20 7 0.05 0.83 182/14-14 0.22 0.64 Laparoscopy versus medical treatment 361/50 42 2.92 0.087 182/34 101 7.22 0.007 Laparoscopy versus laparotomy 361/148 29 2.27 0.13 182/28 87 4.65 0.031 No treatment versus medical treatment 20/50 33 0.64 0.43 14/34 135 4.20 0.040 No treatment versus laparotomy 20/148 20 0.30 0.58 14/28 118 3.26 0.071 Laparotomy versus medical treatment 148/50 11 0.15 0.70 28/34 8 0.04 0.85 No treatment and laparoscopy versus medical treatment and laparotomy 381/198 33 4.43 0.035 196/62 98 10.97 0.001 * Controlled for years infertile, revised AFS total score, ovu- t Controlled for years infertile, ovulation treatment, prior lation treatment, fimbria score, tubes score. therapeutic abortion. 40 Adamson et al. Laparoscopic endometriosis treatment Fertility and Sterility

no differences between treatment options, whether controlling or not controlling for predictive variables except that Laparoscopy Group PRs were higher than Laparotomy Group PRs when no controls were made, and were equal to Laparotomy Group PRs when controls were made for the predictive variables. Similarly, for the Endometriosis-Only Subset, the No Treatment Group PRs were higher than Laparotomy Group PRs when no controls were made and were equal in the presence of the three predictive variables. DISCUSSION Our data support the proposition that infertile women with endometriosis can be treated at laparoscopy if the equipment and skill of the surgeon permit (1, 2, 4, 5, 14, 15). In every analysis, Laparoscopy Group PRs were equal to or higher than other treatment options whether it was in the entire population (n = 579), the Endometriosis-Only Subset with at least one normal tube and fimbria and normal male (n = 258), patients with minimal or mild endometriosis, or in patients with moderate or severe endometriosis (Tables 3 to 5). Furthermore, even when significant variables were controlled for, Laparoscopy Group PRs were equal to or higher than other treatments (Table 6). These differences are up to 101 % better than other treatment modalities and could consequently be of clinical importance to the patient. The statistical power to detect group differences in this study varies according to the groups being compared. For example, the comparison of the Laparoscopy Group (n = 361) to the Laparotomy Group (n = 148) in the entire population has approximately 80% power to detect the difference between a 50% PR and a 64% PR at the Bonferroni-adjusted alpha level of 0.05/6 = 0.0083. For a comparison for patients with minimal or mild endometriosis in the Endometriosis-Only Subset between the No Treatment Group (n = 13) and the Laparotomy Group (n = 13), the difference would need to be a 50% PR compared with a rate> 90% to achieve 80% power. The power of any given comparison is closely related to the number of pregnancies in the group. The number of pregnancies in the first 3 years of followup and other information given in Tables 3 and 4 permit the calculation of power using an approximate method (16). It should be emphasized that the conclusions of this study do not rest on the non significance of comparisons, rendering power calculations somewhat academic. With two minor exceptions, the estimated PR for the Laparoscopy Group is always higher than any other group. One exception is the comparison with the Laparotomy Group for minimal and mild disease. The life table calculations show a slightly better PR for the Laparotomy Group (Table 4), but the difference is nonsignificant even before applying the Bonferroni adjustment (P = 0.092) (Table 5). Furthermore, after adjusting for severity of disease (minimal or mild), the difference nearly vanishes (P = 0.22). The other exception is the comparison of the Laparoscopy Group with the No Treatment group in the Endometriosis-Only Subset. In that comparison, the estimated cumulative 3-year PR is virtually identical in the life table calculation (Table 4), and the PR for the Laparoscopy Group is only 14% lower in the survival analysis with fixed covariates (Table 6). With only 14 patients in the No Treatment Group, it is difficult to attach much importance to this exception either. A strength of this study is the statistical model used to identify and control for factors that affect PRs and may be unequal in nonrandomized treatment groups (10, 11). Once identified, variables significantly affecting pregnancy were included in the proportional hazards model, to permit comparisons among the treatment groups as though these variables had the same values in each group. We identified five significant variables as predictors of pregnancy in the entire patient population and three in the Endometriosis-Only Subset. After controlling for these significant variables, none of the other potential predictors of pregnancy (except for treatment group in the Endometriosis-Only Subset) was found to be statistically significant as an additional predictor. It is possible that other sets of predictors would do as well in predicting pregnancy as the sets of five and three predictors presented here. Furthermore, other variables may be important predictors of pregnancy for other patient populations. However, we used the most statistically significant predictors, and our population is large enough that these variables are likely to be predictive in other endometriosis populations. Better pretreatment fimbrial status was associated with higher PRs in the entire population. This contrasted with poorer pretreatment tubal status, which was associated with higher PRs. This essentially means that the worse the tubes (excluding fimbria) were to begin with, the better the subsequent PRs. We conjectured that this finding might be because of our inclusion of tubal ligation reversal patients. The 20 tubal ligation reversal patients had an overall Adamson et al. Laparoscopic endometriosis treatment 41

estimated life table PR at 3 years of 81 % ± 11 %, a rate higher than the 61.7% estimated for the entire population. We therefore repeated the survival analysis with multiple fixed covariates after excluding these 20 patients. All predictive variables remained the same, and we found that pretreatment tubal status was still negatively related to subsequent PRs. Because tubal adhesions were treated surgically, the results indicate that improvement in PR can be obtained through salpingolysis. Postoperative tubal score may be a more accurate predictor of pregnancy and is currently being evaluated in a subsequent study. Year of entry into the study was not predictive of subsequent PRs but was associated with the treatment patients received. In the early part ofthe study, patients with minimal or mild disease tended to be in the Medical Treatment Group or the No Treatment Group, whereas those with moderate or severe disease tended to be treated more by laparotomy. Regardless of revised AFS endometriosis stage, patients entering in the later years were more likely to have been treated by laser laparoscopy (Laparoscopy Group). For this reason, a time trend in PRs is a possible alternative explanation for the relatively poor results for the Medical Treatment Group and the relatively good results for the Laparoscopy Group. It is not, however, a possible explanation for the relatively good results for the No Treatment Group. In the absence of any time trend after controlling for the treatment group and key predictors and in the absence of any plausible explanation for an improvement in PR over time, we find treatment group differences a more reasonable explanation for the observed differences in PRs among treatment groups. Treatment groups were comp~ed with each other while adjusting for the set of significant variables as predictors (Table 6). In the entire population, there were no significant differences in PRs among treatment groups. Because the Laparoscopy Group and the No Treatment Group clinically allow the patient to attempt pregnancy immediately, whereas the Laparotomy Group and the Medical Treatment Group both require time until the completion of treatment without chance of pregnancy after diagnostic laparoscopy, No Treatment/Laparoscopy PRs were compared with Medical Treatment/Laparotomy PRs. The No Treatment/Laparoscopy Group had significantly higher PRs than the Medical Treatment/Laparotomy Group, indicating that it is more beneficial to an infertile patient to treat the endometriosis at the initial laparoscopy or to do nothing rather than to treat medically or with laparotomy. Pairwise comparison of treatment groups in the Endometriosis-Only Subset revealed differences between treatment groups with PRs for the Laparoscopy Group being higher than for the Medical Treatment Group and Laparotomy Group, although not significantly higher than Laparotomy Group according to the conservative Bonferroni-adjusted P value (Table 6). No Treatment Group PRs were also higher than the Medical Treatment Group PRs, but again not significantly. As in the entire population, the PRs for the combined No Treatment/Laparoscopy Group were significantly higher than for the combined Medical Treatment/Laparotomy Group. The results of the survival analysis not controlling for predictive variables were similar to the results of the survival analysis controlling for predictive variables, with one group difference statistically significant without controls but nonsignificant with controls in each population. The fact that a group difference disappears when controlling for predictive variables demonstrates the importance of controlling for predictive variables in the survival analysis. By statistically adjusting for the distribution of the predictive variables between the groups, a more accurate assessment of treatment effect is obtained. Whether controls were made or not, No Treatment/ Laparoscopy Group PRs were always higher than Medical Treatment/Laparotomy Group PRs. This can occur because the treatment groups are fairly similar or because the differences between the groups occur only with variables not associated with PRs. Both life table calculations and survival analysis with multiple fixed covariates indicate that women with minimal or mild endometriosis had higher PRs than women with moderate or severe disease in the entire population, whereas extent of disease was not predictive in the Endometriosis-Only Subset (Table 3). The explanation for this result could be that the women in the Endometriosis-Only Subset all had at least one tube and fimbria completely normal. Therefore, this subset may be less likely to suffer from a great degree of anatomic distortion (i.e., because of adhesions). Our data suggest that the severity of endometriosis will not be indicative of subsequent PRs provided that the patient has at least one normal tube and fimbria. This finding supports arguments that the current staging system for endometriosis may be an inadequate predictor of fertility (17). Women with moderate and severe endometriosis were evaluated separately because some physicians 42 Adamson et al. Laparoscopic endometriosis treatment Fertility and Sterility

have questioned the efficacy of laparoscopy in treating moderate and severe disease (4, 5, 15). In the entire patient population, life table analyses for patients with moderate and severe disease only and survival analyses controlling for severity of disease both showed Laparoscopy Group PRs were at least comparable with those for the Laparotomy Group (Table 5). In the Endometriosis-Only Subset, life table PRs were significantly higher for Laparoscopy Group than Laparotomy Group (Table 5). These findings suggest that laparoscopy is at least as effective as laparotomy in treating moderate or severe endometriosis without extensive tubal disease. With PRs being at least equivalent, other factors such as lower cost, shorter hospital stay and recovery time (15, 18), and less physical and psychological stress to the patient make operative laparoscopy the preferred treatment for some infertile women with endometriosis. We believe that moderate and severe endometriosis can be effectively treated laparoscopically, even when endometriomas are present (19). Laparotomy should be reserved for patients who require major surgery to correct tubal or fimbrial disease or other pelvic conditions not treatable at laparoscopy. We found that Medical Treatment Group PRs are consistently lower than No Treatment Group and Laparoscopy Group PRs. This finding is in part because of our calculation of follow-up time starting the Medical Treatment Group at the diagnostic laparoscopy when the endometriosis was diagnosed. We chose this starting point to account for the "real" time that the patients lost during their medical treatment. Other studies have started calculations for the Medical Treatment Group at the completion of their medical regimens (20, 21). To compare our results, we ran an additional survival analysis with multiple fixed covariates controlling for the significant predictive variables and using follow-up time starting after the patients' medical treatment had ceased. Analyzed in this fashion, there were no longer significant differences between the Medical Treatment Group and each of the other treatment options. Therefore, if one does not take into account the time lost during medical therapy (typically 3 to 6 months), Medical Treatment Group PRs are no longer lower than others. However, Medical Treatment Group PRs are in no instances significantly higher than other treatment groups. Because we are unable to document advantages for using medical treatment over other therapies in the treatment of minimal or mild endometriosis and because medical treatment requires a significant amount of time, cost, and potential for side effects, we recommend treatment at the initiallaparoscopy or no treatment for minimal and mild endometriosis when the only symptom is infertility. In each of our analyses, No Treatment Group PRs were equivalent to Laparoscopy Group PRs. Therefore, in select patients with infertility as the only symptom no treatment may be appropriate. However, with so few patients in the No Treatment Group (n = 20 for entire study population, n = 14 for Endometriosis-Only Subset), the statistical power to detect differences is small. Furthermore, some physicians feel that endometriosis may be a progressive disease (22). As a preventive as well as a therapeutic measure, treating endometriosis at the initial laparoscopy would seem to be the preferred treatment option. However, extensive dissection of superficial endometriosis staged as minimal or mild may lead to adhesion formation. Careful consideration of this potential complication is imperative before performing this operation, especially in younger patients or those with short duration of infertility. No treatment may be the best approach in these patients. The advantages of laparoscopic surgery documented here combined with the data from other studies permit us to recommend that operative laparoscopy be considered the best treatment for infertile women with endometriosis unless laparotomy is required for tubal repair or other disease that cannot be managed laparoscopically. We believe these results provide answers to some of the questions and a response to some ofthe criticism of the expanding role of operative laparoscopic surgery in gynecology (23-25). However, gynecological surgeons must recognize their own laparoscopic skills and limitations and use their surgical judgment in selecting patients for operative laparoscopy. REFERENCES 1. Daniell JF. The role of lasers in infertility surgery. Fertil Steril 1984;42:815-23. 2. Martin DC. CO 2 laser laparoscopy for the treatment of endometriosis with infertility. J Reprod Med 1985;30:409-12. 3. Diamond MP, Daniell JF, Martin DC, Feste J, Vaughn WK, McLaughlin DS. Tubal patency and pelvic adhesions at early second-look laparoscopy following intraabdominal use of the carbon dioxide laser: initial report of the intraabdominallaser study group. Fertil Steril 1984;42:717-23. 4. Nezhat C, Crowgey SR, Garrison CPo Surgical treatment of endometriosis via laser laparoscopy. Fertil Steril1986;45:778-83. 5. Adamson GD, Lu J, Subak LL. Laparoscopic CO 2 laser vaporization of endometriosis compared with traditional treatments. Fertil Steril1988;50:704-1O. Adamson et al. Laparoscopic endometriosis treatment 43

6. The American Fertility Society. Classification of endometriosis. Fertil Steril 1979;32:633-4. 7. The American Fertility Society. Revised American Fertility Society classification of endometriosis: 1985. Fertil Steril 1985;43:351-2. 8. Dixon WJ, Brown MB, Engelman L, Hill MA, Jennrich RI. BMDP Statistical Software Manual. Berkeley: University of California Press, 1988. 9. SAS. Version 6. Cary (NC): SAS Institute Inc., 1990. 10. Cramer DW, Walker AM, Schiff I. Statistical methods in evaluating the outcome of infertility therapy. Fertil Steril 1979;32:80-6. 11. Olive DL. Analysis of clinical fertility trials: a methodologic review. Fertil SteriI1986;45:157-71. 12. Miller RG Jr. Survival analysis. New York: John Wiley and Sons, 1981. 13. Miller RG Jr. Simultaneous statistical inference. 2nd ed. New York: Springer-Verlag, 1981. 14. Feste JR. Laser laparoscopy: a new modality. J Reprod Med 1985;30:413-7. 15. Murphy AA, Schlaff WD, Hassiakos D, Durmusoglu F, Damewood MD, Rock JA. Laparoscopic cautery in the treatment of endometriosis-related infertility. Fertil Sterill991;55: 246-51. 16. Freedman LS. Tables of the number of patients required in clinical trials using the logrank test. Stat Med 1982;1:121-9. 17. Adamson GD, Frison L, Lamb EJ. Endometriosis: studies of a method for the design of a surgical staging system. Fertil Steril 1982;38:659-66. 18. Levine RJ. Economic impact of pelvis co pic surgery. J Reprod Med 1985;30:655-9. 19. Adamson GD, Subak LL, Pasta DJ, Hurd SJ, von Franque 0, Rodriguez BJ. Comparison of CO 2 laser laparoscopy with laparotomy for treatment of endometriomata. Fertil Steril 1992;57:965-73. 20. Guzick DS, Rock JA. A comparison of danazol and conservative surgery for the treatment of infertility due to mild or moderate endometriosis. Fertil Steril 1983;40:580-4. 21. Henzl MR, Corson SL, Moghissi K, Buttram VC, Berquist C, Jacobsen C. Administration of nasal nafarelin as compared with oral danazol for endometriosis. N Engl J Med 1988;318: 485-9. 22. Houston DE. Evidence for the risk of pelvic endometriosis by age, race, and socioeconomic status. Epidemiol Rev 1984;6: 167-91. 23. Grimes DA. Frontiers of operative laparoscopy: a review and critique ofthe evidence. Am J Obstet GynecoI1992;166:1062-71. 24. Gant NF. Infertility and endometriosis: comparison ofpregnancy outcomes with laparotomy versus laparoscopic techniques. Am J Obstet Gynecol 1992;166:1072-81. 25. McDonough PG. The need for technology assessment in the reproductive sciences. Am J Obstet GynecoI1992;166:1082-90. 44 Adamson et al. Laparoscopic endometriosis treatment Fertility and Sterility