The impact of systemic methotrexate and surgical management on fertility preservation in tubal ectopic pregnancy among Saudi women

Abstract Background The impact of various management plans on subsequent fertility after tubal ectopic pregnancy (EP) is not well known. The objective of the present study was an evaluation of the subsequent fertility outcome among women with EP managed either surgical or medical with systemic methotrexate or medical management followed by surgical one. Patients and methods A retrospective cohort study was done by reviewing of medical records of all women diagnosed with EP at King Faisal Military Hospital, Southern Region, Saudi Arabia throughout the period from January 2015 to December 2016 provided that they were hemodynamic stable, with starting βhCG level less than 10000 IU/L, and adnexal mass less than 5 cm. These cases were followed for four years from January 2017 to December 2020. Results The study included 85 women with EP. Their mean age was 31.3 ± 6.7 years. Medical management (systemic Methotrexate) was followed in 48.2% of cases whereas surgical management was applied for 43.5% of them while medical management followed by surgical one was seen in 8.2% of cases. Complete follow-up throughout 2017–2020 was available for 52 women. A history of recurrent EP was observed among 3 women (5.8%). Most of them (75%) had a viable pregnancy. There was no statistically significant association between the method of management of EP and subsequent fertility, although the rate of normal pregnancy (intrauterine viable pregnancy ≥ 24 weeks which is the age of viability at our hospital) was higher among those managed surgically or by medical followed by surgical management than those managed medical only (84.6% and 100% vs. 62.5%). Conclusion Although the normal pregnancy rate was higher among those managed surgically or by medical followed by surgical management than those managed medically only, this was not statistically significant.


Introduction
The implantation of a fertilized ovum outside the endometrial cavity is known as an ectopic pregnancy (EP).The incidence rate of EP in all pregnancies is 1% [1].The most common localization is tubal, representing 95-99% of cases, whereas other localizations, including cervical, ovarian, and abdominal localization are rare [2,3].
The impact of various management plans on fertility after a tubal ectopic pregnancy is not well known.However, there is evidence to indicate that future fertility outcomes are improved following tubal conservation during surgery (salpingostomy) than during salpingectomy [4][5][6].
The management of EP has greatly improved over the last few years by the initiation and continuous advancement of transvaginal ultrasonography (TVUS), which is used in combination with the implementation of the beta-human chorionic gonadotropin (b-hCG) assay to allow early EP diagnosis, and consequently prevent adverse complications [7].Therefore, EP presentation has become a benign condition in almost all asymptomatic women, which can be managed without surgery, instead of being a life-threatening surgical emergency [8].
However, TVUS is the first-line diagnostic approach, and abdominal ultrasonography (AUS), computed tomography (CT), positron emission tomography-CT (PET-CT), and magnetic resonance imaging (MRI) have all been reported as supplementary investigations able to identify the implantation site, especially outside the tube (e.g. the hepatic implantation site in rare cases of abdominal pregnancy) [9].
Furthermore, with the development of laparoscopic techniques, it is now possible to manage EP cases effectively with a fast, minimally invasive intervention [10].
Non-surgical treatments of EP include expectant management and methotrexate (MTX) injection, either intramuscularly or intravenously.Treatment of uncomplicated EP with MTX is safe, effective, and less costly as compared to surgery [8,11].
When choosing the treatment modality for EP, many factors should be considered, such as the success rate, complication rate, side effects, costs, and fertility outcomes [12].However, the optimal treatment for subsequent fertility remains unclear [13].
Different treatment modalities are currently used to manage EPs; however, their influence on subsequent pregnancies remains controversial.This is a novel study comparing subsequent fertility rates among women with EP treated with different treatment modalities.

Study design
This retrospective cohort study reviewed the medical records of all women diagnosed with EP (85 patients) between January 2015 and December 2016.Patients were followed up for 4 years, from January 2017 to December 2020.

Study area and setting
This study was conducted at the Obstetrics and Gynecology Department of King Faisal Military Hospital (Armed Forces Hospital) in the Southern Region of Saudi Arabia.

Study population
All EP patients at King Faisal Military Hospital (Armed Forces Hospital), Southern Region, Saudi Arabia underwent a review of their medical records, which were uploaded to an electronic file system.The patients were identified through their medical record numbers from pharmacy and inpatient ward records as MTX therapy was only administered to admitted patients according to the hospital protocol.Patients who underwent surgical management were identified from operating room records.Using the patients' medical records, all medical data, including previous inpatient admissions, clinic visits, operative procedures, and laboratory investigations, could be traced through the electronic system.
All 85 patients diagnosed with EP were eligible for inclusion, provided that they met the following inclusion criteria: hemodynamically stable, starting b-hCG level <10,000 IU/L, adnexal mass <5 cm, and complete medical records.
The exclusion criteria included women with hepatorenal dysfunction, abnormal complete blood count (CBC) results (such as white blood cells [WBCs] < 4000 and platelets <10,000), positive extrauterine cardiac activity, incomplete follow-up, and non-adherence to the treatment protocol.Our protocol was to administer a single intramuscular dose of MTX (50 mg/m2).Treatment success was described as a > 15% decrease in b-hCG levels between days 4 and 7, followed by weekly reductions in b-hCG level measurements until negative.

Data collection
Electronic and hard copies of EP files were reviewed from January 2015 to December 2016 to collect study data.Criteria for diagnosis of EP utilized in this study were b-hCG levels above the discrimination zone (1500-2000 IU/L), accompanied by the absence of an intrauterine pregnancy by TVUS, or abnormally raised b-hCG levels below the discrimination zone, accompanied by TVUS indicating EP (adnexal mass and/or free fluid in the peritoneal cavity).These patients were followed up for 4 years, from January 2017 to December 2020 (all patients were contacted through their phone numbers).A checklist was prepared to collect the following information: Personal characteristics (age and body mass index); Obstetric and gynecological history; TVUS findings; Treatment taken (surgical [in the form of salpingectomy] or non-surgical).
Outcome data included interval to pregnancy, recurrent EP, miscarriage, subsequent fertility rate, infertility, and use of ovulation induction methods.

Data entry and statistical analysis
Data entry and analysis were performed using the Statistical Package for Social Sciences (SPSS, version 26.0).The double-entry method was applied to decrease the data entry errors.Data were presented using descriptive statistics in the form of frequencies and percentages for categorical variables and means, ranges, and standard deviations (SD) for continuous quantitative variables.Chi-square tests were used for data analysis.One-way analysis of variance (ANOVA) was used to compare the mean of a continuous variable between more than two different groups.Statistical significance was considered at p < .05.

Results
The study included 85 women with an EP, aged from 16 to 51 years, with an arithmetic mean of 31.3 years and a SD of 6.7 years.Their body mass indices ranged between 18 and 54 kg/m 2 (28.7 ± 5.2 kg/m 2 ) (Table 1).
Table 2 summarizes their parities and gynecological histories.Nulliparous women represented 16.5% of the sample, whereas those whose parity exceeded three represented 21.2%.Most patients (83.5%) had no gynecological problems.
Regarding the TVUS findings, the ectopic size ranged between 8 and 50 mm, with a mean of 20.1 mm and a SD of 8.9 mm.Cardiac activity was reported in 6.1% of the cases.More than half (51.2%) of patients underwent pelvic collection.Among them, the amount of collection ranged between 4 and 2500 ml (181.2 ± 427.5 ml) (Table 3).
The b-hCG level was available in 68 cases and ranged between 218 and 9366 IU/L (2663.8 ± 1771.5 IU/L), as illustrated in Figure 1.
Medical management (systemic MTX) was followed in 48.2% of cases, surgical management was applied in 43.5% of cases, and medical management followed by surgical management occurred in 8.2% of cases, as shown in Figure 2.
Complete follow-ups throughout 2017-2020 were available for 52 women (61.2%), whereas 33 patients (38.8%) were lost to follow-up.The outcomes of tubal EP management are summarized in Table 4.The interval to pregnancy ranged from 9 to 47 months (mean, 26.2 and SD, 25 months).Three women (5.8%) had a history of recurrent EP.Most (75%) had normal pregnancies, and 19.2% had miscarriages.Only one woman (1.9%) reported the use of ovulation induction methods (Table 4).
There was no statistically significant association between the method of management of EP and subsequent fertility, although the rate of normal pregnancy (intrauterine viable pregnancy 24 weeks, which is the age of viability at our hospital) was higher among those managed surgically or by medical management followed by surgical management than in those managed only medically (84.6% and 100% vs. 62.5%) (Table 5).

Discussion
Whichever management method is used for EP (medical in the form of systemic MTX or surgery in the form of salpingectomy), the main objective, besides the effectiveness of management, is the preservation of female fertility and reduction of the recurrence of EP [14].It has been documented that surgical intervention is the gold standard for EP management,   despite observations that systematic MTX is a safe and effective alternative [15].The present study prospectively evaluated fertility outcomes among women with EPs managed either surgically or non-surgically with systemic MTX.In this study, most patients with tubal EPs (75%) had normal pregnancies.Although the rate of normal pregnancy was higher among those managed surgically, or medically followed by surgical management, than among those managed medically alone (84.6% and 100% vs. 62.5%, respectively), this was not statistically significant.Baggio et al. reported a statistically significant cumulative incidence of intrauterine clinical pregnancy of 65.3% for expectant management, 55.3% for MTX, and 39.5% for surgery [16].The Royal College   of Obstetricians and Gynecologists Green-top Guideline stated that there is no difference in the rate of fertility, risk of future tubal EP, or tubal patency rates between the different management methods [17].Baggio et al. [16] showed that expectant management resulted in higher intrauterine clinical pregnancy and live birth rates and a shorter time between treatment and first intrauterine conception than surgery.Furthermore, Helmy et al. [18] reported that spontaneous intrauterine pregnancy occurred in 83.7% of women managed expectantly and 63.9% of women managed surgically, with no significant difference between the two groups regarding the risk of recurrent EP.In the current study, recurrent EP was observed in three women (5.8%), with no difference observed between the different lines of management.Similarly, Yousefnezhad et al. [6] reported no significant differences in the adverse consequences of pregnancy, such as recurrent EP, miscarriage, and premature delivery, between women treated medically and those treated surgically, and reported fertility rates in the medical and surgical group of 56.6% and 47.6%, respectively, with no statistically significant difference between groups.
The present study has some limitations.First, this was a single-center study, which could impact our ability to generalize the results to other centers and is subject to selection bias.Second, this was a retrospective cohort study dependent on record review; therefore, blinded randomized controlled trials are needed to validate the results.Another limitation was that we could not exclude spontaneous abortions versus EPs among those managed with medical treatment.However, the strengths of this study include a relatively long follow-up period for intrauterine pregnancies and EP recurrence.
In conclusion, surgical intervention is the gold standard line of EP management.However, although the rate of normal pregnancy was higher among those managed surgically or medically followed by surgical management than those managed medically only, this was not significant.Further multicenter, populationbased studies with larger sample sizes are warranted.

Funding
The author(s) reported there is no funding associated with the work featured in this article.

Figure 1 .
Figure 1.Level of beta human chorionic gonadotropin among women with ectopic pregnancy.

Figure 2 .
Figure 2. Type of management applied to women with tubal ectopic pregnancy.

Table 1 .
Age and body mass index of the women with ectopic pregnancy, King Faisal Military Hospital, Southern Region, Saudi Arabia (January 2015-December 2016).

Table 2 .
Parity and gynecological history of the women with ectopic pregnancy, King Faisal Military Hospital, Southern Region, Saudi Arabia (January 2015-December 2016).
ERPC: evacuation of retained products of conception.

Table 3 .
Transvadinal ultrasound findings of the women with ectopic pregnancy, King Faisal Military Hospital, Southern Region, Saudi Arabia (January 2015-December 2016).

Table 4 .
Outcome of management of women with ectopic pregnancy, King Faisal Military Hospital, Southern Region, Saudi Arabia (January, 2015-December 2016).

Table 5 .
Impact of Type of management of ectopic pregnancy on subsequent fertility.One-way analysis of variance (ANOVA) test. b