Pregnancy after laparoscopic surgery for endometriosis: How long should we wait? A retrospective study involving a long‐term follow up at a university endometriosis center

To find the factors that influence the time until pregnancy after laparoscopic intervention and to evaluate the proper time to start assisted reproductive therapy (ART).

women have this disease. 4The monthly fecundity rate of women with endometriosis is significantly lower than the monthly fecundity rate of women without endometriosis (2%-10% vs. 15%-20%). 5e existence of endometriosis may negatively affect the spontaneous chance of conception as well as the chance of pregnancy after assisted reproductive therapy (ART), 6 which is a result of the plausible 7 inflammatory and immune modifications resulting from endometriosis.In many countries, such as Germany, laparoscopy combined with a biopsy and histology confirmation is the reference standard in the diagnosis of endometriosis. 8Additionally, laparoscopic surgery is considered to be the most effective way to treat endometriosis-associated infertility. 8,9The surgical factors influencing the outcome are still controversial.The surgical treatment methods are mostly based on the clinical treatment guidelines and an expert consensus. 8,10On the other hand, laparoscopic surgery performed to preserve fertility does not always improve the fertility situation. 11 Germany, over the last 15 years, with the establishment of endometriosis centers, efforts have been made to help patients with endometriosis.These centers are connected with reproductive medicine centers.Despite the collaboration, it is still a severe problem to predict potential fertility.Strict time management and a reproductive medical consultation are very important.In this study, through a long-term follow up, we intended to find those factors that influence the time until pregnancy after laparoscopic intervention and to evaluate the proper time to start ART.

| Ethical approval and informed consent
This study was approved on January 28, 2020, by the ethics committee of the University Hospital of Frankfurt in Germany (approval no.19-487).Informed verbal consent was obtained from all patients during their follow-up interviews.

| Participant selection and variables
This study is a retrospective study involving a long follow up at the University Hospital of Frankfurt, Germany.Consecutive patients younger than 50 years old (age range definition for endometriosis was provided by Stiftung Endometriose Forschung, Germany [www.endom etrio se-sef.de])who underwent laparoscopic intervention and histologic confirmation of endometriosis were reviewed.These laparoscopic surgeries were between 2007 and 2017.All the patients with an immediate desire for conception were considered.

All the patients who were supported by the Reproductive Medicine
Center of University Hospital of Frankfurt (the patients with regular menstruation, a follicle-stimulating hormone level less than 20 IU/ mL, and suitable ovarian follicle cyst on ultrasound) were selected.
From this group of patients, the women who were not able to get pregnant after at least 12 months of unprotected sex were enrolled in the study (Figure 1).
The data were collected from the patients' records and patients were followed up between January 2020 and January 2021 The data were analyzed with BiAS 11.10.To analyze differences in the cumulative pregnancy rates between the examined groups, the log-rank test and the Kaplan-Meier test were used.To compare the category variables, the χ 2 test and Fisher exact test were used.
The factors possibly influencing the time until pregnancy were examined using univariate and multivariate Cox regression (hazard ratio [HR]).A P value less than 0.05 was defined as statistically significant.

| RE SULTS
The ages of the patients were between 21 and 46 years (33.3 ± 4.6 years, mean ± standard deviation).At the end of the investigation period, 71 (69.9%) patients had become pregnant.The long-term follow up revealed a live birth rate of 58.8%.The remaining 42.2% (n = 42) did not have a successful pregnancy or delivery (Figure 1).Additionally, dividing the patients into two groups of younger than and older than 35 years of age showed no significant difference in the univariate analysis or in the cumulative rate of pregnancy (HR 1.15; 95% confidence interval [CI] 0.71-1.87;P = 0.56).In our group of patients, there were seven patients older than 40 years who were supported by our reproductive medicine center in Frankfurt and, because of that, we did not exclude this group of patients (Table 1).
There was no significant difference in the BMI between the patients who became pregnant (23.3 ± 4) and those who failed to achieve pregnancy (23.3 ± 5) during the study period (HR 0.98; 95% CI 0.92-1.04;P = 0.53) (Table 1).
In our group of patients, 76.5% were diagnosed with primary infertility, and 23.5% were diagnosed with at least a one-time pregnancy (secondary infertility).In regard to the time until pregnancy, the type of infertility was not a significant influencing factor (HR 0.84; 95% CI 0.48-1.49;P = 0.56).In addition, comparing the cumulative pregnancy rate showed no statistically significant difference between the patients with primary infertility and those with secondary infertility (P = 0.55; log-rank test).
In this study, the mean duration of infertility was 3.3 years.The duration of infertility (before the operation) in the group of patients who achieved pregnancy was shorter (2.7 ± 2.1 years) compared with that in the group who did not achieve pregnancy (4.7 ± 3.2 years) (HR 0.84; 95% CI 0.74-0.95).The longer the time of infertility, the longer the interval between the operation and pregnancy (P = 0.007) (Table 1).With each year of infertility, without any therapy, the chance of pregnancy diminished by 4.6%, reaching 26% (univariate analysis).
The highest pregnancy rate occurred 7 months after the operation.The time until pregnancy was evaluated.For seven (6.9%) patients, pregnancy occurred directly after laparoscopy; for three patients (2.9%), it occurred 1 month later; for two patients (2%), it occurred 2 months later; and for three patients (3%), it occurred 3 months later.
The highest pregnancy rate directly after the operation was in the patients with rASRM stage I (n = 4; 9.5%), and the highest pregnancy rate 7 months after the operation was also in these patients  pregnancy rate increased from the first to the second year by more than 10% (cumulative pregnancy rate of 61.8%, n = 63).From the 38th postoperative month onwards, the cumulative rate of pregnancy remained at 69.6%, meaning that there was no further occurrence of pregnancies (Figure 2).

Variable
A total of 46 patients (45.1%) had symptoms before the operation, including dysmenorrhea, dyspareunia, menstrual cycle anomalies, or abdominal pain.Thirty (65.2%) of these patients were pregnant during our follow up.In the univariate analysis, no significant correlation between the symptoms and the time from laparoscopy to pregnancy could be demonstrated (HR 0.84; 95% CI 0.52-1.35;P = 0.47).
Thirty-three (32.4%) patients had a partner with reduced fertility (which was defined and documented by the reproductive medicine center).Twenty-eight (84.8%) patients became pregnant after laparoscopic intervention.The cumulative pregnancy rate showed a significant difference between the group of patients with partners with infertility and the group without partners with infertility (P = 0.03).
Women with a partner with reduced fertility had higher postoperative pregnancy rates.In the group of patients with the reduced fertility of the partner, 69.7% of the patients had endometriosis in rASRM stage I or II, and 30.3% had endometriosis in rASRM stage III or IV.Thirty patients (91%) underwent ART after the operation with a success rate of 83%.Three patients (9%) achieved spontaneous pregnancies.The analysis was carried out using the multivariate approach with the influencing factors of the "reduced fertility of partner" and the "rARSM stage".The subfertility of the partner showed no significant prognostic effect on the time until pregnancy (P = 0.09).
Of the 102 patients, 49 (48%) had no abdominal operations, 36 (35.3%) had 1 (1%) previous abdominal operation, 7 (6.9%) had two previous abdominal operations, 5 (4.9%) had three previous abdominal operations and 4 (3.9%) had four previous abdominal operations.Our study showed that the number of previous operations had a negative influence on the time until pregnancy after surgery (P = 0.003).The analysis showed that any abdominal operation reduces the chance of postoperative pregnancy by up to 25% and prolongs the time until pregnancy (HR 0.84; 95% CI 0.58-0.97;P = 0.03).
Restoring the anatomy is an essential part of the surgical outcome of patients with endometriosis.In 90.2% of the patients (n = 92), at the end of the operation, the pelvic anatomy was defined as normal.
Although this factor was important concerning the pregnancy rate, it did not show any significance in the univariate analysis of the time until pregnancy (HR 2.7; 95% CI 1.0-7.4;P = 0.054).
A total of 23 patients (22.5%) had a recurrence of endometriosis in the follow-up period (14-20 months after the operation).In all of the patients of this group, ART had been used after the recurrence.
In the univariate analysis, the recurrence rate was shown as prognostically unfavorable regarding the time until pregnancy (HR 0.4; 95% CI 0.21-0.76;P = 0.005).
Comparing the times until pregnancy for the different rASRM stages showed that the highest cumulative pregnancy rate without undergoing ART was reached after 36 months for rASRM stage I, was reached after 24 months for rASRM stage II, and was reached after 12 months for rASRM stages III and IV.With ART, the highest cumulative pregnancy rate was reached after 36 months for rASRM stages I, II, and IV and was reached after 42 months for rASRM stage III.With ART, there was a chance for pregnancy until 42 months after the surgery, and, without ART, no pregnancy could be registered after 12 postoperative months (Tables 2 and 3).

| DISCUSS ION
Endometriosis is a benign condition that causes long-lasting inflammation, leading to infertility.It has been clearly revealed that there is a close link between this disease and infertility, affecting almost Cumulative pregnancy rate of 102 patients demonstrated with 95% confidence intervals.
11.4% of women of childbearing ages. 1,12,13In the last few years, minimally invasive laparoscopic surgery has been accepted as the best and most preferred technique for managing endometriosis. 14In this study, through a long-term follow up, we investigated the factors influencing the time until pregnancy after laparoscopy for endometriosis.
In our study, 69.9% and 58.8% of the patients achieved pregnancy and live births, respectively, which is similar to the numbers reported by Shi et al., 15 is higher than some studies 16,17 and is lower than the figures reported by Hui et al. 11 Age, years of infertility, and previous pregnancy were all evaluated as factors to be considered in the endometriosis fertility index. 18en comparing the patients under and above the age of 35 years, no significant difference could be shown (P = 0.56).Here, we also showed that there was no difference between the studied groups regarding the symptoms or type of infertility (primary vs. secondary).
In the present study, we demonstrated that a longer period of infertility without treatment negatively influences the time until pregnancy, which is also confirmed in other studies. 14,19e difference in the BMI between the groups of patients was also not significant.It is important to mention that, in some studies, a lower BMI has been reported as a factor related to a better pregnancy rate. 20,21evious abdominal operations also negatively affected the time leading up to pregnancy.On the other hand, the complete treatment of endometriosis lesions reduced the time until pregnancy and restored the anatomy of the pelvis; but despite playing an important role, it had no significant effect on the time until pregnancy.
Pliszkiewicz et al. 22 encouraged the use of radical conservative laparoscopic surgery, and the effect of previous abdominal operations in this group of patients was emphasized. 16,23As has been reported in other studies, 24 in our study, the recurrence of endometriosis was also a prognostically unfavorable factor regarding the time until pregnancy.
The median time until pregnancy was 8 months, and, on average, it took 10 months until pregnancy occurred.It seems that the first 12 months after the operation are an optimal time for pregnancy, which is similar to the findings reported elsewhere. 4As shown in the patients with rASRM stage I, until 36 months had passed, a pregnancy could be expected, and, in those with rASRM stage II, until 24 months passed, a pregnancy could be expected.In the group of patients with rASRM stages III and IV, no spontaneous pregnancy was reported after the 12th month.Interestingly, with the help of ART, in all the groups of patients, pregnancy could be expected at least until the 36th month after the operation.Additionally, undergoing ART can help patients regardless of their rASRM stage.
The group of patients with reduced fertility in their partners had a higher fertility rate and a shorter time from operation to pregnancy.

(
mean follow-up time of 70 months) through the standardized questionnaires filled out during follow-up consultation interviews.The parameters included age, duration of infertility (the time spent trying to get pregnant before the operation), body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters), symptoms of endometriosis (abdominal pain, dysmenorrhea, and dyspareunia), primary versus secondary infertility, partner with reduced fertility, revised American Society for Reproductive Medicine classification of endometriosis (rASRM), time until pregnancy (from surgical intervention to the first day of the last period), deliveries and live births, operation-related factors (previous operations, complete treatment of endometriosis, restoration of the anatomy, and recurrence), and treatment with ART.
(n = 4; 9.5%).For rASRM stage III, the highest postoperative pregnancy rate was 5-6 months after the operation (n = 4, 25%), whereas, for rASRM stage IV, it was 5-8 months after the operation (n = 4, 13.8%).Eight patients (7.8%) achieved pregnancy more than 2 years after laparoscopy.The longest time until pregnancy was 38 months after the operation.The median time until pregnancy (10.8 ± 9.4) was 8 months.In summary, 27 patients (26.5%) became pregnant during the first 6 months after laparoscopy, and 49 patients (48%) became pregnant during the first 12 months after laparoscopy.The cumulative F I G U R E 1 Flowchart of study population.TA B L E 1 Patients' characteristics and their effect on pregnancy rate after the operation.a

n Cumulative pregnancy rate 6 months 12 months 18 months 24 months 36 months 42 months
Pregnancy with and without ART depending on rASRM in follow-up of at least 42 months.a Cumulative pregnancy rate with and without ART depending on rASRM.a TA B L E 2 a Data are presented as number (percentage) unless otherwise stated.TA B L E 3Note: The highest-reached cumulative pregnancy values are shown in bold.Abbreviations: ART, assisted reproductive therapy; rASRM, revised American Society for Reproductive Medicine classification of endometriosis.a Data are presented as number (percentage) unless otherwise stated.