of conservative and radical surgery for tubal pregnancy

Human Reproduction vol.13 no.7 pp.1804 1809, 1998 Fertility after conservative and radical surgery for tubal pregnancy Ben W.J.Mol 1,2,5, Henri C.Matthijsse 1, Dick J.Tinga 4, Ton Huynh 4, Petra J.Hajenius 1, Willem M.Ankum 1, Patrick M.M.Bossuyt 2 and Fulco van der Veen 3 1 Department of Obstetrics and Gynaecology, 2 Department of Clinical Epidemiology and Biostatistics and 3 Centre for Reproductive Medicine, Academic Medical Centre, University of Amsterdam, and 4 Department of Obstetrics and Gynaecology, Academic Hospital, University of Groningen, The Netherlands 5 To whom correspondence should be addressed at: Academic Medical Centre, Department of Clinical Epidemiology and Biostatistics, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands A retrospective cohort study was set up to evaluate the effectiveness of conservative and radical surgery for tubal pregnancy towards subsequent fertility. Consecutive patients undergoing conservative or radical surgery for tubal pregnancy between January 1990 and August 1993 in two university hospitals were included in the study. Outcome measures were spontaneous intrauterine pregnancy (IUP) and repeat ectopic pregnancy (EP). Of the 135 patients analysed, 56 underwent conservative surgery and 79 underwent radical surgery. Patients treated with conservative surgery achieved a higher 3-year cumulative pregnancy rate than those treated radically (P < 0.001, log-rank test). In patients treated conservatively, there was only one spontaneous IUP in the period between 18 months and 3 years after the tubal pregnancy. In contrast, patients treated radically continued to conceive in this period. Multivariate analysis showed a fecundity rate ratio (FRR) of 1.9 [95% confidence interval (CI): 0.91 to 3.8] for IUP after conservative surgery in the first 18 months of follow-up. In patients with a history of bilateral tubal disease the FRR was 3.1 (95% CI: 0.76 to 12), whereas in patients without a history of bilateral tubal disease the FRR was 1.4 (95% CI: 0.13 to 16). The FRR for repeat EP was 2.4 (95% CI: 0.57 to 11). Our data indicate a beneficial effect of conservative surgery towards subsequent fertility that was not, however, statistically significant in the multivariate analysis. In view of these inconclusive data and the importance of this major health problem, randomized studies are required to assess whether conservative surgery really improves the fertility prospects of patients with tubal pregnancy. Key words: conservative surgery/fertility outcome/radical surgery/tubal pregnancy Introduction In the surgical treatment of tubal pregnancy the clinician has a choice between a conservative and a radical approach. Conservative surgery is supposed to preserve tubal integrity, thereby improving the fertility prospects of the patient. Compared with radical surgery, it bears the risks of persistent trophoblast and, possibly, of repeat ectopic pregnancy (EP) in the operated tube (Hajenius et al., 1995; Clausen, 1996). To advise patients adequately on this choice, the probabilities of persistent trophoblast, future intrauterine pregnancy (IUP) and repeat EP, as well as the patients evaluation of these events, need to be known. Unfortunately, there are no randomized clinical trials comparing fertility after conservative and radical surgery. A recent cohort study reported an adjusted relative risk of IUP after conservative treatment of 1.2 [95% confidence intervals (CI): 0.68 to 2.2] compared with radical treatment (Job-Spira et al., 1996]. Conservative treatment was performed surgically in 96% of the patients and with methotrexate in 4%. The overall repeat EP rate was 6%, but no specification for the mode of treatment was given. A review of other cohort studies comparing fertility outcome after conservative and radical surgery showed no beneficial effect of conservative surgery on the IUP rate (Clausen, 1996), whereas the risk of repeat EP was not increased (Clausen, 1996; Mol et al., 1996). These data justify the question whether conservative surgery is superior to radical surgery, which is reflected in daily practice, where clinicians differ widely in their opinions about both treatment options and the role of pre-existing tubal disease regarding their decision (Rulin, 1995). The purpose of this study was to evaluate, by life-table analysis, the effectiveness of conservative and radical surgery towards fertility outcome, and the influence of pre-existing tubal disease on such effectiveness. Materials and methods Patients All patients who underwent primary surgery for tubal pregnancy in the Academic Medical Centre in Amsterdam and the Academic Hospital in Groningen between January 1990 and August 1993 were included in the study. Tubal pregnancy was diagnosed by combined transvaginal sonography and serum human chorionic gonadotrophin measurement (Ankum et al., 1993). Data on treatment were obtained retrospectively from the medical files. Two treatment groups were defined: patients undergoing conservative surgery (salpingo(s)tomy) and those undergoing radical surgery (salpingectomy). Surgery was performed either laparoscopically or by open surgery. Patients with complete tubal abortions, as well as those treated by milking or nettoyage only, were excluded from the study, as no choice had to be made between conservative and radical treatment. Patients with a solitary tube were also excluded, as radical treatment would effectively sterilize these patients, thereby leaving 1804 European Society for Human Reproduction and Embryology

Fertility after tubal pregnancy conservative surgery the only possibility for spontaneous conception. Patients in whom the index tubal pregnancy resulted from in-vitro fertilization (IVF) and embryo transfer were excluded from the analysis, as subsequent spontaneous conception was rather unlikely in these women. Patients with heterotopic pregnancies were also excluded, as they carried on their pregnancy and thus did not attempt to conceive for at least one year after initial surgery. Information on the following potential prognostic factors for future fertility was extracted from the medical files: age, parity, previous EP, previous tubal surgery, previous pelvic inflammatory disease (PID), known subfertility of a non-tubal cause at the date of treatment, surgical modality (i.e. laparoscopy or open surgery) and tubal pathology encountered at surgery. Subfertility of a non-tubal cause was considered to be present in the case of a sperm, ovulation or cervical factor. Tubal pathology observed at surgery was defined as the presence of hydrosalpinx, peritubal adhesions or phimosis. Follow-up Data on subsequent fertility were obtained by reviewing the medical files and, when this information was insufficient, by telephone interviews with the patients. In all patients the exact time-frame in which they were trying to conceive was registered. Those not trying to conceive were excluded from the analysis. Follow-up ended in the case of an IUP at the estimated date of conception. An IUP was defined as an ongoing pregnancy detected by ultrasound or the delivery of a child. Pregnancy outcome of each IUP was registered. If an IUP did not occur, follow-up ended on the day of last contact. In addition to IUP we also registered repeat EP. The date of occurrence of EP was also determined by the estimated date of conception. Data analysis Baseline characteristics of patients in both treatment groups were compared using Student s t-test or the χ 2 test. For both treatments, Kaplan Meier curves were constructed, estimating the cumulative probability of spontaneous IUP over time, which was the primary outcome measure. If an IUP was the result of IVF embryo transfer, time to pregnancy in this patient was considered to be censored, which meant that the patient was included in the analysis until the start of IVF embryo transfer only. The Kaplan Meier curves were tested for statistically significant differences using the log-rank test. The effect of conservative surgery compared with radical surgery was expressed as a fecundity rate ratio (FRR) with a 95% CI, calculated through Cox proportional hazard regression analysis (Cox, 1972). An FRR expresses the probability of spontaneous IUP per time unit for patients treated with conservative surgery, relative to the probability in those treated with radical surgery. The treatment effect was considered to be statistically significant if 1 was not included in the 95% CI. A Cox proportional hazard model only estimates an FRR correctly if this FRR is constant over time. Proportionality was tested visually from the Kaplan Meier curves. To adjust the FRR of conservative surgery for other potential prognostic factors mentioned above, multivariate analysis was performed. The latter is especially important since potential prognostic factors for fertility also affect the choice between conservative and radical surgery. Differences in prognostic factors between patients undergoing radical surgery and those undergoing conservative surgery can be adjusted in a multivariate analysis. As both tubes are involved in fertility, one might postulate that conservative surgery is relatively more effective in preserving fertility where the contralateral tube is already damaged. To test this hypothesis, spontaneous IUP rates for conservative and radical treatment were determined after stratification for presence of tubal pathology. Two different definitions of tubal pathology were used: first, a medical history of tubal pathology, i.e. previous EP, previous PID or previous tubal surgery; and second, tubal pathology detected during surgery of the index EP, i.e. presence of hydrosalpinx, peritubal adhesions or phimosis. FRRs stratified for both a history of tubal pathology (absent, homolateral, contralateral or bilateral), and tubal pathology detected at surgery (absent, homolateral, contralateral or bilateral) were calculated. Interaction between tubal pathology and treatment was assessed by Cox regression using the follow-up data collected for each patient. Three-year cumulative rates were also calculated for repeat EP. The Kaplan Meier curves were compared using the log-rank test. In this analysis, time to EP was considered to be censored once IUP occurred. Univariate and multivariate Cox regression analysis were used to calculate FRR for repeat EP after conservative surgery compared with radical surgery. Results Between January 1990 and August 1993, 237 patients underwent surgery for tubal pregnancy. Six patients were treated by milking or were found to have complete tubal abortion, 24 had a solitary tube, seven had their index tubal pregnancy after IVF embryo transfer, and seven had both a solitary tube and their index tubal pregnancy after IVF embryo transfer. Of the remaining 193 patients, two had a heterotopic pregnancy, whereas follow-up data could not be obtained in 14 patients. The characteristics of the 14 patients lost to follow-up did not differ significantly from those available for analysis. Furthermore, 42 patients did not try to conceive after their initial tubal pregnancy. Baseline characteristics of the 135 patients available for analysis are presented in Table I. Fifty-six (41%) patients had conservative surgery, whereas 79 (59%) of the patients underwent radical surgery. Patients with conservative surgery were less likely to have a history of tubal surgery (P 0.07) or PID (P 0.04), and they showed tubal pathology less often at surgery (P 0.01). Almost 90% of the tubal pathologies detected at surgery were adhesions. Four of the patients undergoing conservative surgery had persistent trophoblast; all of these underwent a surgical reintervention. Fifty-four (40%) patients had a spontaneous IUP during follow-up, 30 after conservative surgery and 24 after radical surgery. Of the 30 patients with an IUP after conservative surgery, 22 (73%) delivered, two (7%) underwent a medical abortion and six (20%) had a spontaneous abortion. Of the 24 patients with an IUP after radical surgery, 18 (78%) delivered, two (9%) underwent a medical abortion, one (4%) had a spontaneous abortion, and in three (12%) patients pregnancy outcome was unknown. Furthermore, 18 patients had an IUP after IVF embryo transfer, 14 of which occurred in patients who had radical surgery. Figure 1 shows Kaplan Meier curves for IUP after both treatments for a 3-year period after initial surgery. Women treated with conservative surgery were more likely to conceive spontaneously (P 0.001, log-rank test). The 3-year cumulative spontaneous IUP rate was 62% after conservative surgery and 38% after radical surgery. There was only one spontaneous IUP after 18 months among patients who underwent conservative surgery, whereas patients 1805

B.W.J.Mol et al. Table I. Baseline characteristics Conservative surgery Radical surgery P-value n 56 (41%) n 79 (59%) Mean age (SD) (years) 30.1 (5.6) 31.4 (4.8) 0.24 a Nulliparity (%) 22 (39) 19 (24) 0.07 Homolateral EP in history (%) 0 4 (5) 0.08 Contralateral EP in history (%) 2 (4) 3 (4) 0.91 Previous tubal surgery (%) 5 (9) 16 (21) 0.07 Previous PID (%) 5 (9) 15 (18) 0.04 Subfertility at time of EP (%) 5 (9) 8 (10) 0.82 Homolateral tubal pathology (%) 9 (16) 40 (51) 0.01 Peritubal adhesions 8 (14) 36 (45) Hydrosalpinx 0 4 (5) Phimosis 1 (2) 0 (0) Contralateral tubal pathology (%) 15 (27) 38 (48) 0.01 Peritubal adhesions 10 (18) 35 (44) Hydrosalpinx 4 (7) 1 Phimosis 1 (2) 2 (2) Laparoscopy (%) 22 (39) 7 (9) 0.01 a P-value calculated with Student s t-test; all other P-values calculated with χ 2 test. EP ectopic pregnancy; PID pelvic inflammatory disease. Figure 1. Kaplan Meier curves for the occurrence of intrauterine pregnancy (IUP) after surgery for ectopic pregnancy. Continuous lines represent fertility after radical surgery; dotted lines represent fertility after conservative surgery. Curves starting in the lower left corner represent spontaneous intrauterine pregnancies; curves starting at the upper left corner represent intrauterine pregnancies following IVF embryo transfer. who had radical surgery continued to conceive after this period. The proportionality assumption, needed to express the effect of treatment in an FRR, was therefore only valid in the first 18 months of follow-up. The FRR for spontaneous IUP in the first 18 months after the index EP are presented in Table II. Univariate analysis shows that the FRR on IUP after conservative surgery was 2.5 (95% CI: 1.4 to 4.4). After multivariate adjustment, the FRR of conservative surgery decreased to 1.9 (95% CI: 0.91 to 3.8). Of the other characteristics, previous tubal surgery and homolateral as well as contralateral tubal pathology detected at surgery had the strongest impact on future fertility, with adjusted FRRs of 0.63, 0.72 and 0.48 respectively. 1806 Spontaneous 3-year IUP rates and FRRs after conservative and radical surgery stratified for tubal pathology are presented in Table III. The point estimates of treatment effects differed considerably between patients with and without a history of bilateral tubal disease. The FRR were 3.1 in the presence of a history of bilateral tubal disease and 1.4 in its absence. Tubal pathology observed during surgery only influenced the FRR slightly. Twelve patients had an EP during follow-up, five after conservative and seven after radical surgery. The 3-year cumulative repeat EP rate was 28% after conservative surgery and 23% after radical surgery (P 0.07; log-rank test). Of the five repeat EPs after conservative surgery, four were

Fertility after tubal pregnancy Table II. Fecundity rate ratios (FRR) for the occurrence of spontaneous intrauterine pregnancy Univariate analysis Multivariate analysis FRR 95% CI FRR 95% CI Conservative surgery 2.5 1.4 to 4.4 1.9 0.91 to 3.8 Age (per year) 0.93 0.87 to 0.98 0.95 0.89 to 1.0 Nulliparity 1.1 0.57 to 2.0 1.2 0.60 to 2.4 Homolateral EP in history 1.5 0.21 to 11 1.1 0.13 to 8.8 Contralateral EP in history 0.67 0.09 to 4.9 1.4 0.17 to 11 Previous tubal surgery 0.58 0.23 to 1.5 0.63 0.09 to 2.1 Previous PID 0.94 0.84 to 1.0 0.94 0.88 to 1.1 Subfertility at time of EP 1.5 0.64 to 3.5 1.3 0.49 to 3.4 Homolateral tubal pathology at surgery 0.32 0.15 to 0.69 0.72 0.26 to 2.0 Contralateral tubal pathology at surgery 0.33 0.15 to 0.70 0.48 0.18 to 1.2 Laparoscopy 1.5 0.77 to 2.9 1.2 0.58 to 2.6 EP ectopic pregnancy; PID pelvic inflammatory disease. Table III. The effectiveness of conservative surgery compared with radical surgery in preselected strata a Conservative surgery Radical surgery FRR conservative 95% CI (n 56) (n 79) versus radical surgery No history of tubal disease (%) 25/46 (54) 18/50 (36) 1.4 0.68 to 2.7 History of homolateral tubal disease (%) 0/0 1/2 (50) History of contralateral tubal disease (%) 1/2 (50) 0/2 (0) History of bilateral tubal disease (%) 4/8 (50) 5/25 (25) 3.1 0.76 to 12 No tubal pathology at surgery (%) 26/41 (63) 15/31 (48) 2.0 0.87 to 4.8 Homolateral tubal pathology at surgery (%) 1/1 (100) 3/15 (20) Contralateral tubal pathology at surgery (%) 2/6 (33) 3/8 (38) 0.80 0.13 to 4.9 Bilateral tubal pathology at surgery (%) 1/8 (13) 3/25 (12) 1.4 0.13 to 16 a Data indicate 3-year absolute pregnancy rates and fecundity rate ratios (FRR) for the occurrence of intrauterine pregnancy in the first 18 months. CI confidence interval. homolateral. Of the seven repeat EPs after radical surgery, one was located in the tubal remnant. The FRR for repeat EP in the first 3 years after the index EP are presented in Table IV. The univariate FRR for EP after conservative surgery was 1.5 (95% CI: 0.47 to 4.7). Multivariate adjustment changed the FRR for conservative surgery to 2.4 (95% CI: 0.57 to 11). The risk for repeat EP was strongly increased by nulliparity, by a previous EP before the index EP, and by previous tubal surgery. Discussion This study compares fertility outcome after conservative and radical surgery for tubal pregnancy. Patients treated with conservative surgery achieved a higher 3-year cumulative pregnancy rate than those treated radically. In patients treated conservatively, there was only one spontaneous IUP in the period between 18 months and 3 years after the index tubal pregnancy. In contrast, patients treated radically continued to conceive in this period. In the first 18 months of follow-up, women who were treated with conservative surgery were almost twice as likely to conceive as those treated with radical surgery, as indicated by the FRR of 1.9 (95% CI 0.91 to 3.8). These conservatively treated women also had an increased risk of EP [FRR 2.4 (95% CI: 0.57 to 11)]. Time to pregnancy was censored in 18 women who had a successful IVF embryo transfer, in 14 after radical surgery, and in four after conservative surgery. Since the fertility prognosis in these patients was likely to be worse than in those who did not undergo IVF embryo transfer, we may have underestimated the effect of conservative surgery due to bias known as differential informative censoring (Stolwijk et al., 1996). In the present study 40% of the patients spontaneously had an ongoing treatment-independent IUP, with 3-year cumulative pregnancy rates of 62% after conservative surgery and 38% after radical surgery. Other studies have reported ongoing IUP rates between 32% (Clasen et al., 1997) and 57% (Langebrekke et al., 1993). However, comparison of pregnancy rates between studies is hampered due to the fact that most studies report on absolute IUP rates in patients with a variable duration of follow-up, whereas such IUP rates can only be correctly interpreted if differences in follow-up are controlled for by survival analysis, as was done in the present study. Furthermore, the baseline prognosis between different centres varies considerably. In this study for instance, many patients are evaluated for subfertility while EP occurs, thereby decreasing the fertility prospects of the entire cohort. There are no randomized clinical trials comparing conservative and radical surgery. Most cohort studies reporting on this subject have methodological limitations (Langebrekke et al., 1993; Ory et al., 1993; Zockler et al., 1995; Clausen, 1996). Differences in duration of follow-up are not taken into account, and some studies fail to report on the desire for pregnancy 1807

B.W.J.Mol et al. Table IV. Fecundity rate ratios (FRR) for the occurrence of repeat ectopic pregnancy (EP) Univariate Multivariate analysis analysis FRR 95% CI FRR 95% CI Conservative surgery 1.5 0.47 to 4.7 2.4 0.57 to 11 Age (per year) 1.0 0.89 to 1.1 0.99 0.86 to 1.1 Nulliparity 2.9 0.65 to 14 3.6 0.70 to 18 Homolateral EP in history 4.3 0.54 to 33 4.4 0.36 to 54 Contralateral EP in history 3.1 0.40 to 24 3.2 0.23 to 43 Previous tubal surgery 1.3 0.35 to 4.8 3.9 0.60 to 26 Previous PID 0.92 0.73 to 1.2 0.90 0.69 to 1.1 Homolateral tubal pathology 0.69 0.22 to 2.2 0.75 0.14 to 4.1 Contralateral tubal pathology 0.99 0.32 to 3.1 0.79 0.18 to 3.4 PID pelvic inflammatory disease. among patients. How subsequent pregnancies were achieved remains unclear, which is worrisome, since pregnancies occurring through IVF embryo transfer reflect a failure of the primary goal to preserve the possibility of spontaneous conception. A recent cohort study, addressing these issues, reported conservative surgery to be slightly more effective than radical surgery, although the difference was not statistically significant (Job-Spira et al., 1996). The present study estimates the beneficial effect of conservative surgery to be stronger, although the difference still was not statistically significant. An explanation for the better fertility rates after conservative surgery might be that after conservative surgery two potentially functional tubes facilitate pregnancy, whereas after radical surgery only one tube does so. Therefore, the monthly fecundity after radical surgery might be lower as compared with conservative surgery. This mechanism would also explain why patients who had radical surgery continued to conceive after 18 months, whereas those who had conservative surgery almost stopped conceiving after 18 months. If this hypothesis were true, time to pregnancy would be shorter after conservative surgery, but cumulative IUP rates after both treatments would be equal if sufficient follow-up time were allowed. Only a small minority of the patients undergoing conservative surgery underwent tubal patency testing after their index EP, to confirm whether conservative surgery really preserved tubal patency. Therefore, it was not possible to evaluate if infertility after conservative surgery resulted from an occluded tube. Other studies have reported a tubal patency rate of more than 80% after conservative surgery (Vermesh et al., 1989). Conservative surgery might be more effective in patients with contralateral tubal damage than in patients with a healthy contralateral tube. To evaluate this hypothesis, we performed separate analyses for patients with and without a history of tubal disease and for patients with and without tubal pathology detected at surgery. These subgroup analyses showed that the conservative surgery was three times as effective as radical surgery in preserving fertility in patients with a history of bilateral tubal disease, defined as previous EP, previous PID or previous tubal surgery (FRR 3.1). In contrast, conservative surgery was only slightly more effective in patients without a history of tubal disease (FRR 1.4). The second subgroup analysis showed that the tubal status as observed at surgery only influenced the effectiveness of conservative surgery 1808 slightly (FRR 2.0 in the absence of tubal pathology at surgery and 1.4 in its presence). For clinical practice, this finding suggests that the probability of spontaneous fertility is always slightly higher after conservative surgery, but that conservative surgery seems especially effective in patients with a history of bilateral tubal disease. This hypothesis is also confirmed by a recent study reporting on fertility after radical surgery showing that IUP rates were significantly lower in patients with contralateral tubal disease or previous tubal surgery (Dubuisson et al., 1996). The same phenomenon was observed in the study performed by Silva et al. (1993), in which conservative surgery was slightly better than radical surgery in patients without tubal damage, but much better in patients with tubal damage. However, in that particular study the radical surgery group consisted of only 24 patients, and multivariate analysis was not performed. Pouly et al. (1991) advocated that patients with severe tubal disease be treated radically, as their probability of developing a repeat EP outweighs the probability of an IUP, whereas patients with mild or absent tubal disease should be treated conservatively. However, this guideline was based on a study following patients who were all treated conservatively, whereas the fertility course after radical surgery was not reported. In a recent threshold analysis comparing conservative surgery and radical surgery followed by three cycles of IVF embryo transfer, we found that fertility rates after conservative surgery should be at least 2.2% better than after radical surgery, to make it a cost-effective treatment (Mol et al., 1997). This difference corresponds with an FRR of 1.05. The results of the present study, and those reported by Job-Spira et al. (1996) show an FRR of conservative surgery above this threshold. We feel these data to be the best possible estimates of the effectiveness of conservative and radical surgery so far, but clearly a randomized clinical trial of these two treatments is necessary to provide the definitive answer. Consequently, such a trial should focus on an improvement of fertility rate after conservative surgery with an FRR of 1.05, rather than on the detection of any statistically significant difference between conservative and radical surgery. References Ankum, W.M., Van der Veen, F., Hamerlynck, J.V.Th.H. and Lammes, FB. (1993) Laparoscopy: a dispensable tool in the diagnosis of ectopic pregnancy? Hum. Reprod., 8, 1301 1306.

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