Assessing the risk factors and management outcomes of ectopic pregnancy: A retrospective case-control study

Abstract Background Ectopic pregnancy (EP) is the implantation of a fertilized egg outside the uterine cavity or in an unusual location. According to the clinical case reports, hormonal contraceptive failures may be related to emergency contraceptives and EP. EP may be treated medically, surgically, or expectantly. Currently, there is no consensus regarding whether a multiple- or double-dose regimen with methotrexate (MTX) or an additional dose could be more effective than a single-dose regimen. Objective This study aimed to assess risk factors and treatment outcomes for EP. Materials and Methods This case-control study was conducted in Tehran, Iran from March 2020 to March 2021. The case group was comprised of all EP-diagnosed cases (n = 191). Based on the levels of β-human chorionic gonadotropin, MTX was administered to stable individuals with no surgical indications. Risk factors were assessed through 2 control groups: intrauterine pregnancy (n = 190) and nonpregnant groups (n = 180). Results The medical treatment significantly improved with an extra dose of MTX, especially in individuals with higher β-human chorionic gonadotropin concentrations and gestational age > 7.5 wk (p = 0.002). Considering risk factors, it is assumed that hormonal contraceptive failures, including both oral and emergency contraceptives, may increase the EP likelihood (p < 0.001). Conclusion Based on our findings, we recommended an additional dose of MTX for subjects who are further along in their pregnancy. It is also concluded that failure of contraceptive pills increases the chances of EP.


Introduction
Ectopic pregnancy (EP) is the implantation of a fertilized egg outside the uterine cavity or in the scar resulting from a prior cesarean section. This complicated pregnancy has the potential to increase maternal morbidity and mortality. Even though the incidence of EP increased 6-fold between the 1970s and 1990s, recent research indicates that the statistics have remained relatively stable. EP still accounts for approximately 2% of all pregnancies and 10% of all pregnancy-related deaths (1)(2)(3)(4)(5). EP is diagnosed by a combination of symptoms, clinical examination, serial beta-human chorionic gonadotropin (β-hCG) measurements, and ultrasonographic imaging. Symptoms include abdominal pain and vaginal bleeding between the 6 th and 10 th wk of pregnancy (6).
Several factors have been linked to EP, with previous EP, pelvic surgery, pelvic inflammatory disease, Chlamydia trachomatis infection, and smoking is the most studied and well-known (7,8).
In recent years, however, it has been suggested that certain medications, specifically emergency contraceptive pills, are a major cause (9,10). In addition, it has been hypothesized that ovulation induction and assisted reproductive technologies (ART) may also contribute to the development of EP (11)(12)(13).
The most common sites for the implantation of an ectopic gestational sac are the fallopian tubes, the cervix, the ovary, and the caesarian scar (14,15). These pathologies necessitate a specific treatment; consequently, depending on the examinations, laboratory tests, and imaging, EP can be managed by observation, surgery, or medication (16)(17)(18). In cases of rupture, surgical removal of conception products is considered the definitive treatment for EP and is the method of choice. Surgical treatment includes salpingectomy, salpingostomy for tubal EP, and cesarean scar pregnancy curettage, among others (19)(20)(21).
Conservative therapies are recommended if the case meets the criteria for medical management, and the fallopian tubes are saved (1,18,22,23  Data were collected using the medical records at the hospital. In addition to being interviewed, subjects were asked to complete a structured questionnaire assessing their past medical and surgical history, infertility and ART, and use of contraceptive pills and devices. The nonpregnant control subjects were women with regular sexual activity and no nonmedical causes of infertility.

Materials and Methods
The choice of treatment according to the protocol was based on β-hCG concentration and if the patients were either hemodynamically unstable or showed signs of rupture or had any indications such as failure to medical treatment they were candidate for surgery of the patients (Table I).
Moreover, pregnant control subjects were selected from those without abnormalities or anatomical malformations that could confound the analysis.
This study was designed with 2 control groups, intrauterine and nonpregnant women, to assess the relationship between EP and risk factors, particularly contraceptives used during the most recent ovulation cycle. Both control groups consisted of sexually active women of reproductive age. The cases and controls were matched regarding age (± 5 yr), gravidity, and parity in a ratio of 1:1. A simgle dose of MTX on day 1 measurement of β-hCG on days 1, 4, and 7 then β-hCG is measured weekly until undetectable and if the difference is below 15%, an extra dose is given then β-hCG is measured weekly until undetectable MTX is given on days 1, 3, 5, and 7 folinic acid (1 mg/kg IM) is also administered on days 2, 4, 6, 8 MTX is given until the β-hCG level decreases more than 15% in 48 hr, or 4 doses of MTX are shown, then β-hCG is measured weekly until undetectable MTX: Methotrexate; β-hCG: Beta-human chorionic gonadotropin

Ethical considerations
This study was ethically approved by the Ethical Committee of Tehran University of Medical Sciences, Tehran, Iran (Code: IR.TUMS.IKHC.REC.1398.295). All participants signed informed consent forms to share data for scientific purposes.

Statistical analysis
We utilized SPSS software (v. 26, IBM Corp.) for statistical analysis. Pearson's Chi-square test was used to determine the treatment outcomes' differences. After using logistic regression models, we also calculated the odds ratio (OR) with a 95% confidence interval (CI) to analyze the possible association between risk factors and EP. Furthermore, we utilized t tests and Analysis of variance (ANOVA) to determine the significance of mean and variance differences. P < 0.05 were deemed statistically significant. To evaluate the risk factors, we utilized cross-tabulation, Chi-square tests, and logistic regression models that were adjusted and unadjusted for age, parity, gravidity, smoking, previous EP, pelvic

Results
Among 234 patients who had a differential diagnosis of EP; 191 cases met the eligibility criteria and were included in the study. Furthermore, 190 pregnant women and 180 nonpregnant women were included in control groups. The patients in all groups were matched for age and demographic variables (Table II).  (Table III).
Results show that the average β-hCG levels prior to treatment, gestational age and parity were higher among corneal and cesarian scar in case group (Table IV) Table II demonstrates that certain characteristics make subjects more susceptible to certain ectopic pregnancies. In addition, the levels of β-hCG, gestational age, and parity in corneal and scar pregnancies are significantly higher (Figure 1).
One of the primary objectives of this study was to determine the relationship between the proposed risk factors and EP. To this end, we compared the cases to 2 randomly selected control groups (intrauterine and nonpregnant).
Only tubal EPs and scar pregnancies were analyzed because only these 2 categories had sufficient sample sizes for statistical analysis (Table V).
Regarding medical treatment failure, out of the 89 medically treated cases, we observed 12 failures. The results show that the cesarean section scar site yielded the highest failure rate, with 46.7%, followed by the cornea (16.7%) and tubal EP (6.3%) (27).
In terms of the type of surgery, 41 cases of tubal pregnancy were treated with salpingectomy, while only 7 cases were treated with salpingostomy. We also evaluated the cases of CSPs who received potassium chloride injections; only one of 5 CSPs who received KCl injections failed and required a second injection. The failure of medical treatment may necessitate invasive surgery by the gynecologist. In our study, 12 cases did not respond to medical treatment, 4 underwent suction and curettage (cesarean scar pregnancy), 7 underwent salpingectomy, and 1 underwent fetal reduction (corneal pregnancy) (Table V).
To evaluate the efficacy of our clinical protocol and the role of additional doses, we assessed the protocol using failure rates for various EP types.
The overall analysis revealed that the additional dose could increase the success rate of both scar and tubal EPs. Since this data was a paired The results revealed that the primary difference between the 2 groups was in gestational age, which was almost 1.5 wk older in the group that required the additional dose (Tables VI and   VII).
Regarding our findings regarding risk factors, specifically pharmaceutical contraceptives, we hypothesize that using contraceptives reduces the likelihood of both IUP and EP. However, it significantly increases the chances of EP if it fails. This is crucial for emergency contraceptives because the correlation has not been extensively studied (12,28,36).
Other risk factors, including smoking, intrauterine device use, and previous surgery, were investigated, and a correlation was established (5). Furthermore, our research indicates that ovulation induction increases the likelihood of EP. In 2014, a study concluded that OCPs and LNG-EC increased the risk of EP by up to 4 times that of women who did not use contraception and by up to 7 times that of women whose contraception failed (10,22).

Several additional cases of ectopic pregnancies
with LNG-EC and other emergency contraceptives have been reported (3,5,16). This phenomenon indicates that individuals with a positive history of contraceptive use and other risk factors and symptoms should strongly suspect EP. As an alternative medical approach, this method not only reduces the rate of surgical procedures but also decreases the possibility of infertility.

Conclusion
In summary, we conclude that the recommended clinical approach can perform better if a higher dose is administered. Our data also indicates a strong correlation between the use of contraceptives, particularly emergency contraceptives, and EP.