(DES) exposure, congenital anomalies or intrauterine disease (P = 0.03), and history of chlamydia infection (P = 0.02).

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2 formed during the follicular phase by one of the authors (G.D.A.) with patients' prior informed consent. Some patients also had other infertility factors that were treated whenever possible. From February 1985 through March 1986, 64 patients in the laser group (LAS) underwent C0 2 laser vaporization at the time of diagnostic laparoscopy of all endometrial implants and adhesions. LAS patients received no further endometriosis therapy for 1 year but were seen for regular examinations. From February 1984 through November 1985, a control group (CON) of 44 patients were managed with 6 months of danazol (Danocrine, Winthrop, New York, NY) (n = 8), nafarelin acetate (a gonadotropin-releasing hormone [GnRH] agonist available on a study protocol from Syntex Laboratories, Palo Alto, CA) (n = 1), Provera (Upjohn Co., Kalamazoo, MI) (n = 1), laparoscopic electrocoagulation (n = 16), observation without treatment (n = 14), or both medical and surgical treatment (n = 4). Patient selection to either laser or control cohorts was based solely on the random availability of a C0 2 laser at the time laparoscopy was scheduled. CON patients were managed based only on clinical indications. If the primary treatment was unsuccessful, defined as failure to conceive after approximately 1 year, repeat laparoscopy or danazol or both were recommended. Follow-up LAS and CON patients were followed concurrently from time of diagnostic laparoscopy to their last menstrual period if pregnant or last contact if not pregnant through April1987. Equipment A Cooper 250 Z laser (Cooper LaserSonics, Inc., Santa Clara, CA) and 10.7-mm Eder laser laparoscope (Eder/Weck, Chicago, IL) with 0.8-mm spot diameter were used. Power ranged from 2 to 35 watts (15 watts usually), with an approximate power density of 800 watts/cm 2 through 14,000 watts/cm 2 A continuous wave was used, pulsed by the surgeon with a foot pedal. Surgeries were performed with a three-puncture technique with the laser laparoscope connected to the laser arm and a video camera attached at the eyepiece. The laser energy was delivered through the 4-mm laser laparoscope channel. Alllaparoscopies were done with general endotracheal anesthesia. Data Analysis Statistical analysis was performed on the Stanford DEC-20 mainframe computer using BMDP Statistical Software. 10 Statistical analysis included t-tests, life-table analysis, and survival analysis with fixed covariates. Since length of follow-up varied between patients, direct comparison of pregnancy rates was not possible. Life-table analysis was used to give a more accurate estimate of clinical results by estimating what the observed cumulative pregnancy rate would have been if all patients had been followed for the same length of time after treatment Life tables can also assess the length of time to pregnancy and whether one treatment results in pregnancy earlier than another. The date of diagnostic laparoscopy was chosen as the starting point for life-table calculations, and last menstrual period, if pregnant, or last contact, if not pregnant, defined the end point. Threemonth intervals were used for analysis. Because of the variable length of follow-up and the variable length of time to pregnancy, survival analysis of fixed covariates was performed to determine the factors affecting pregnancy rates. The analysis used the Cox proportional hazard regression model, which evaluated the effects of covariates on pregnancy rate rather than time to pregnancy. Covariates selected by computer were assumed to remain constant over time and were associated with higher or lower pregnancy rates. 10 Cohort Characteristics RESULTS LAS and CON were comparable with respect to age, gravidity, years of infertility, male factor, and the 1985 revision of the American Fertility Society score (R-AFS). 14 For LAS and CON, respectively, age was 32.1 and 32.7 years, gravidity0.69 and 0.77, years infertile 3.4 and 4.0, and abnormal semen parameters 22% and 21%. As expected, the number of days of follow-up was significantly different between LAS and CON since CON patients were treated earlier in the study and LAS patients were treated more recently. Thirty-seven of 64 (58%) of LAS were nulliparous versus 23 of 44 (52%) for CON. LAS had significantly greater previous treatment for ovulation induction (P = 0.02), endometriosis (P = 0.02), and artificial insemination and cervical factor treatment (P = 0.03). CON had significantly greater incidence of myomata, diethylstilbestrol (DES) exposure, congenital anomalies or intrauterine disease (P = 0.03), and history of chlamydia infection (P = 0.02). There were no Vol. 50, No.5, November 1988 Adamson et al. Laser vs standard endometriosis therapy 705

3 Table 1 Distribution of Patients by Stage of Endometriosis LAS CON R-AFS staging Number % (n = 64) Number % (n = 44) I Minimal II Mild III Moderate IV Severe differences for previous fimbrial surgery, operative laparoscopy, laparatomy, or adhesiolysis. Patients were staged at laparoscopy with the R AFS scoring system. Approximately 20% of patients in LAS had moderate or severe disease versus 30% in CON (Table 1). The difference in the distribution of minimal, mild, moderate, and severe disease was not statistically significant between LASandCON. At the time of diagnostic laparoscopy, LAS and CON had no statistical differences for adhesions, fimbrial damage, or other diseases, including myomata, DES exposure, congenital anomalies, or intrauterine disease. There was a significant difference between the LAS and CON in operative laparoscopy since all LAS underwent operative laparoscopy while only 20 of 44 in CON had laparoscopic electrocoagulation (P = ). Only 1 patient, in CON, had a laparotomy to treat unilateral proximal tubal occlusion and was censored from the study at the time oflaparotomy, 9 months postlaparoscopy. Nonspecific treatments, including cervical factor treatment and donor insemination, were not significantly different; neither was ovulation induction. Medical therapy was significantly different since only 4 patients in LAS required postoperative danazol, whereas 14 in CON received medical treatment (P = ). There were no complications of therapy (death, laparotomy, hemorrhage, infection, anesthesia, hospitalization, thermal injuries), and patients were generally discharged from the hospital within 2 hours after surgery. Pregnancy Rate All ofthe 108 patients were at risk for pregnancy. A direct comparison between the two cohorts was not possible because of the shorter duration of follow-up in LAS. The total pregnancy rate for LAS (37.5%) was lower than for CON (43.2%). This reflects the shorter follow-up for the LAS group (mean 167 days versus 284 days for CON) rather than a lower rate of pregnancy. Our data were comparable to other reported crude pregnancy rates. 1-3 Pregnancy rates were similar for nulliparous and parous women in the two cohorts. Pregnancy rates in CON were higher for those who had surgical treatment (electrocoagulation at laparoscopy), but the numbers are small and not statistically significant. The spontaneous abortion rate in LAS was 2 of 64 total patients or 2 of 22 pregnancies (9.1% ). The abortion rate in CON was 5 of 19 pregnancies (26.3%). The numbers were too small to conclude that the lower abortion rate in LAS was clinically significant. There were no ectopic pregnancies in either cohort. Life-Table Analysis Life-table analysis estimated the cumulative pregnancy rate (±standard error of the mean) at 1 year for LAS as 0.55 ± 0.09 and 0.68 ± 0.12 at 15 months. For CON, the estimated pregnancy rate was 0.43 ± 0.09 at 1 year, 0.52 ± 0.10 at 15 months and 0.74 ± 0.12 at 21 months. For ALL, the estimated pregnancy rate was 0.50 ± 0.06 at 1 year, ± 0.07 at 15 months and 0.78 ± 0.10 at 24 months. Figure 1 shows the cumulative pregnancy rates estimated by life-table analysis. We were unable to fit maximum-likelihood estimations to our data. 13 In 4 of 5 90-day intervals, LAS showed a higher estimated pregnancy rate than CON. The LASestimated pregnancy rate was 14% of those exposed in the first quarter postlaparoscopy, 21% in the second, 27% in the third, 11% in the fourth, and 100, , - - Laser (n = 64) ~ Control (n = 44) I= 6.7"4 p(breslow) = 0.10 (1) (6) /I ')5"" r r-1/ (2) (12) T/ I 1 <~,... 1 (9) /.-1 (13) (r~, (21)... -r... (31) (5) 3 38 )~-~--'::12: _... 18:--~2~1-..J TIME (months) Figure 1 Life-table estimates of cumulative pregnancy rates for LAS and CON in 3-month intervals after diagnostic laparoscopy. Bars indicate standard error of the mean and numbers indicate number of patients (n). f =monthly fecundity rates. 706 Adamson et al. Laser us standard endometriosis therapy Fertility and Sterility

4 tst 2nd 3rd 4th QUARTER Figure 2 Pregnancy rates for LAS and CON for each 3- month interval after diagnostic laparoscopy. Bars indicate standard error of the mean and numbers indicate number of patients(*). Percent = Number ofpatient:e becoming pregnant during quarter pregnant Patients at start of quarter- (Number becoming pregnant during quarter/2) of medical or surgical therapies versus LAS, we compared LAS versus only those control group patients who received treatment (not including CON patients who had no treatment). This treated control group (CONRX) contained 30 patients. The estimated cumulative pregnancy rates for CONRX were 0.43 ± 0.10 at 1 year and 0.56 ± 0.11 at 15 months, resulting in a significant difference from LAS (P = 0.04). If life-table analysis began at the end of medical therapy, CON had an estimated cumulative pregnancy rate of 0.28 ± 0.07 at 6 months, ± 0.09 at 12 months, and 0.75 ± 0.14 at 21 months, and monthly fecundity rates increased to 5.5%. After adjusting for medical therapy, we still observed higher estimated pregnancy rates in LAS, but these were not significant (P = 0.59). 25% in the fifth quarters (Fig. 2). While patient!'! in LAS appeared to get pregnant sooner than those in CON, the difference in the two curves, with the Breslow calculation, 10 was not quite statistically significant (P = 0.10). In nulliparous patients, life table estimates for cumulative pregnancy rates for LAS were 0.57 ± 0.11 at 1 year and 0.71 ± 0.11 at 15 months. For CON, the estimated rates were 0.45 ± 0.12, 0.53 ± 0.13 and 0.66 ± 0.15 at 12, 15, and 21 months, respectively (P = 0.08). Because patients in CON may have received medical therapy during which time they were not at risk for pregnancy, LAS would be expected to have higher cumulative pregnancy rates than CON shortly after treatment. In our patients, LAS had higher rates for the first three quarters after treatment. The monthly fecundity rates, defined as the number of conceptions divided by total person months of exposure over all time periods, were 5.5% for ALL, 6. 7% for LAS, and 4.5% for CON (P = 0.08 for LAS versus CON, Z-statistic = 1.37). 15 Estimated times at which the estimated cumulative pregnancy rate (ECPR) was equal to 50% were 270 days for LAS and 428 days for CON. To compare the efficacy of laser and electrocoagulation therapies, we combined LAS and electrocoagulation patients and compared them to those receiving all other treatments. The estimated cumulative pregnancy rate for LAS plus electrocoagulation was 0.66 ± 0.09 at 15 months versus 0.55 ± 0.12 for all other treatments. The difference between the two estimates (P = 0.17) was slightly less than for LAS versus CON. To evaluate the effect Survival Analysis of Fixed Covariates Survival analysis identified factors that affected pregnancy rates. Previous pregnancy in the patient, a pregnancy sired by the current partner, previous laparotomy, or use of the C0 2 laser at laparoscopy was associated with increased pregnancy rates but was not statistically significant. Adhesions, previous fimbrial disease, and other diseases (e.g., myomata, DES exposure, congenital anomalies or intrauterine disease) were associated with significantly higher pregnancy rates (Table 2). Covariates that were associated with decreased pregnancy rates were increased age, previous diagnosis of adhesions, current ovulation induction postlaparoscopy, and current medical treatment. These were associated with substantial and statistically significant decreases in pregnancies (Table 3). A higher R-AFS endometriosis score, previous other pelvic or cervical disease, and positive chlamydia antibody titer had small effects on pregnancy that were not statistically significant. The coefficient indicates the relationship between the covariate and pregnancy rate. Positive coefficients are associated with increased pregnancy rates and, therefore, a positive relationship with pregnancy. The coefficient is a measure of the impact of the parameter, while coefficient/standard error is a measure of the reliability of the covariate's effects on pregnancy. If the coefficient/ standard error was <1, there would be no significant relationship between the covariate and pregnancy rate (i.e., the covariate could either increase or decrease the pregnancy rate). Negative coeffi- Vol. 50, No.5, November 1988 Adamson et al. Laser vs standard endometriosis therapy 707

5 Table2 Survival Analysis with Fixed Covariates Which Increase Pregnancy Rates Covariate Number Coefficient Standard error Coeff/Std err Pvalue Sired by partner (with any woman) Sired by partner (with patient) O.o7 Laser laparoscopy Previous laparotomy Previous fimbrial disease Current adhesions Current other disease a a Artificial insemination donor, artificial insemination husband, intrauterine insemination, steroids, and cervical factor treatment. cients are associated with decreased pregnancy rates in a similar manner. DISCUSSION These results indicate that C0 2 laser vaporization at laparoscopy was safe and effective in treating endometriosis. Since patients were followed for varying lengths of time and LAS had a shorter average length of follow-up, pregnancy rates determined by life-table analysis provided a more accurate estimate of the clinical results While LAS estimated pregnancy rates were not significantly greater than for CON (P = 0.10), LAS achieved pregnancy at a higher overall rate as well as at shorter posttreatment intervals than CON. Olive and Martin recently reported similar results of rapid increase in cumulative pregnancy rate after laser therapy for endometriosis. 16 This is at least partially due to the LAS treatment being completed at the initial laparoscopy and not requiring several months of postoperative medical treatment. It may also be due to more rapid healing with laser vaporization and, therefore, decreased time from surgery to conception. 17 In addition, the increased cure rate in LAS could have been due to decreased adhesion formation or recurrence after C0 2 laser treatment. Two recent studies suggested a decrease in adhesion formation or recurrence. 1 s. 19 Diamond et al., however, found significant adhesion formation after C0 2 laser therapy. 6 The date of laparoscopy was chosen as the starting point for life-table calculations. Since treatment of patients in both cohorts commenced immediately after diagnosis of endometriosis and all patients desired pregnancy, the life tables estimated the probabilities of pregnancy at discrete intervals from the time when treatment began, not when it ended. In CON, therefore, periods of medical therapy, generally lasting for 6 months, were included in the life-table time interval, but patients were not at risk for pregnancy during the treatment. This had the effect of decreasing CON pregnancy rates during the first several months posttreatment. When this effect was eliminated by beginning life-table analysis at the end of medical therapy, we still observed a higher estimated cumulative pregnancy rate for LAS, but the difference between LAS and CON with adjustments for medical therapy was less significant than the original analysis (P = 0.59). We attempted to describe the cumulative pregnancy with a two-parameter model. 13 Because of the sample size and follow-up, we were unable to fit maximum-likelihood estimates to our estimated cumulative pregnancy curves. Our monthly fecundity rates, 4.5% for CON and 6. 7% for LAS, are within the range of those reported by others (2% to 11%). 16 Olive and Martin observed monthly fecundity rates of 3.5%, 2.5%, and 5.8% in patients with AFS I, II, and III, respectively, in patients treated only with C0 2 laser. 16 Table 3 Survival Analysis with Fixed Covariates Which Decrease Pregnancy Rates Covariate Number Coefficient Standard error Coeff/Std err Pvalue Age R-AFSscore Previous adhesions Previous other disease Chlamydia titer positive Current ovulation induction Current medical treatment Adamson et al. Laser vs standard endometriosis therapy Fertility and Sterility

6 The differences between estimated life table cumulative pregnancy rates were less for LAS combined with electrocoagulation versus all other therapies than for LAS versus CON, indicating that C0 2 laser therapy was at least as effective as and possibly more effective than electrocoagulation. The difference between LAS and CON was greater when CON included only patients receiving medical or surgical therapy (CONRX). This may reflect mild disease in patients receiving no treatment who tended to conceive shortly after initial laparoscopy. When this group was removed, LAS was significantly different from CONRX (P = 0.04). Limitations of our study must be considered. Patients were not randomized to treatment cohorts so there was the possibility of selection bias. This selection bias was minimized because patients were assigned to a treatment group as a sole function of the availability of a C0 2 laser, and this availability was not used in any way as a criterion for scheduling surgery. In addition, only infertile patients diagnosed at laparoscopy with endometriosis (by G.D.A.) were included in the study. A second limitation was the use of multiple treatment modalities (surgical, medical and expectant) in the control group rather than a single treatment for comparison. We assumed that this would have minimal effect on our results since published studies that compared treatment modalities have not shown significant differences between the treatments that were included in CON Nevertheless, numerous studies have shown a trend toward higher pregnancy rates after surgical compared to medical treatment. An additional limitation was our failure to document disease status with secondlook laparoscopy. Our study and control cohorts were well matched, but our control group contained patients treated with surgical and medical (n = 30) as well as expectant therapy (n = 14) rather than focussing on one conventional treatment modality. We did, however, evaluate laser versus medical and/or surgical therapy. The results of the survival analysis of fixed covariates were largely predictable. Current adhesions and other diseases (myomata, DES exposure, congenital anomalies, or intrauterine disease) were associated with higher pregnancy rates. Increased pregnancy rates associated with these diseases may have reflected our ability to improve outcome when disease was diagnosed and treated. Previous lap a rotomy and previous fimbrial disease covariates appeared to increase pregnancy rates but were probably anomalous due to small numbers. In- creased but not quite statistically significant pregnancy rates were associated with use of the C0 2 laser at laparoscopy (P = 0.09). Age, previous adhesions, and current medical treatment were associated with decreased pregnancy rates. The reduced pregnancy rate associated with previous adhesions may reflect more severe or longstanding disease or both, some of which was treated at laparotomy, with further risk of adhesion formation. Fecundity decreased with ovulation induction, which is expected since even with effective ovulation induction fecundity is lower than in normally ovulating women. This study confirms that the C0 2 laser is a safe and effective new technology to treat endometriosis. Our results showed a trend to increased early pregnancy rates after C0 2 laser laparoscopy treatment of endometriosis compared with traditional treatments. Ongoing evaluation should enable us to determine whether C0 2 laser laparoscopy treatment is directly and significantly associated with the increased cure rate and monthly probability of conception among those cured. The precision of the C0 2 laser allows extensive disease to be treated at laparoscopy and treatment can be completed at the same time as the initial diagnostic laparoscopy. These advantages combined with the favorable results of this and other studies allow us to recommend the use of C0 2 laser laparoscopic vaporization for the treatment of endometriosis and associated adhesions. Acknowledgments. The authors appreciate the assistance of David S. Guzick, M.D., Ph.D., and Jerry Halpern, Ph.D., in reviewing the manuscript and statistics. REFERENCES 1. Buttram VC Jr: Conservative surgery for endometriosis in the infertile female: a study of 206 patients with implications for both medical and surgical therapy. Fertil Steril31: 117, Guzick DS, Rock JA: A comparison of danazol and conservative surgery for the treatment of infertility due to mild or moderate endometriosis. 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7 at early second-look laparoscopy following intraabdominal use of the carbon dioxide laser: initial report of the intraabdominallaser study group. Fertil Steril42:717, Nezhat C, Crowgey SR, Garrison CP: Surgical treatment of endometriosis via laser laparoscopy. Fertil Steril45:778, Council on Scientific Affairs: Lasers in medicine and surgery. JAMA 256:900, Kelly RW, Roberts DK: C0 2 laser laparoscopy: a potential alternative to danazol in the treatment of stage I and II endometriosis. J Reprod Med 28:638, BMDP Statistical Software. Berkeley, University of California Press, 1985, p Olive DL: Analysis of clinical fertility trials: a methodologic review. Fertil Steril45:157, Guzick DS, Rock JA: Estimation of a model of cumulative pregnancy following infertility therapy. Am J Obstet Gynecol140:573, Guzick DS, Bross DS, Rock JA: A parametric method for comparing cumulative pregnancy curves following infertility therapy. Fertil Steril 37:503, The American Fertility Society: Revised American Fertility Society classification of endometriosis: Fertil Steril 43:351, Cramer DW, Walker AM, Schiff I: Statistical methods in evaluating the outcome of infertility therapy. Fertil Steril 32:80, Olive DL, Martin DC: Treatment of endometriosis-associated infertility with C02 laser laparoscopy: the use of oneand two-parameter exponential models. Fertil Steril 48:18, Tulandi T: Hydrosalpinx: comparison of electrosurgery and laser surgery. (Abstr. 171.) Fertil Steril41:73S, Bellina JH, Hemmings R, Voros JI, Ross LF: Carbon dioxide laser and electrosurgical wound wound study with an animal model: a comparison of tissue damage and healing patterns in peritoneal tissue. Am J Obstet Gynecol148:327, Sadoul G, Beuret T, Algava G, Serpeau D: La microchirurgie tubaire distale au laser C02. Etude experimentale et analyze d'une serie de 95 cas. J Gynecol Obstet Biol Reprod 13:94 7' Hull ME, Moghissi KS, Magyar DF, Hayes MF: Comparison of different treatment modalities of endometriosis in infertile women. Fertil Steril47:40, Schenkin RS, Malinak LR: Conservative surgery versus ex-_ pectant management for the infertile patient with mild endometriosis. Fertil Steril37:183, Adamson et al. Laser vs standard endometriosis therapy Fertility and Sterility