Latest trend ectopic pregnancy management in a tertiary health center: a retrospective cohort study

Objective

The aim of this study is to investigate the incidence, risk factors, clinical presentation, management, morbidity and mortality of ectopic pregnancy (EP) by evaluating all cases treated in a tertiary care center in Ankara.

Methods

A total of 1243 cases were retrospectively studied who were diagnosed with ectopic pregnancy during the clinical course and were treated in the early pregnancy unit between January 2014 and December 2018. Demographic information from hospital records, e.g., risk factors, ultrasound findings, initial and followed up b-hCG levels, and treatment methods (followed up, medical, and surgical) were recorded.

Results

The incidence of EP was 7 per 1000 pregnancies. The mean age was 30.64±5.71 years. The most common risk factors for EP were previous abdominal surgery (37.8%) and previous miscarriage (28.6%). Eighty-three (22%) of patients diagnosed between 2013 and 2014, 129 (34.2%) of patients diagnosed between 2015 and 2016, and 165 (43.8%) of patients diagnosed between 2017 and 2018 had a history of Cesarean section. Seventy-seven (6.2%) cases were followed up, 487 (39.2%) were treated surgically, and 772 (62.1%) were treated with methotrexate.

Conclusion

Delivery by Cesarean section is a risk factor for the development of EP. Cesarean section has been shown to be an important factor in the increase of the incidence of EP over the years. As a result of this increase, new treatments have been developed and conservative surgical or drug treatments have been initiated. Close monitoring of the current literature evaluating ectopic pregnancies and treatment according to this literature will decrease mortality and morbidity rates.

Keywords

Cesarean section, conservative surgery, ectopic pregnancy, follow-up, medical treatment.

Introduction

An ectopic pregnancy (EP) is the implantation of the blastocyst outside the uterine cavity.[1] EP occurs in about 1% of all pregnancies, and women can be diagnosed earlier thanks to human chorionic gonadotropin (b-hCG) follow-up and high-resolution transvaginal ultrasonography.[2] It accounts for 4.9% of maternal deaths in developed countries and is a leading cause of maternal mortality.[3] Approximately 98% of tubal embryos are formed in the fallopian tube. In addition, there are EP located on the cornual side of the fallopian tubes (interstitial), in the cervix, in the Cesarean scar, in the ovary, or in the abdomen. In addition, the definition of “heterotopic” EP has evolved due to the increase in assisted reproductive technologies. There are two different gestational sacs, intrauterine and extrauterine.[4] All risk factors identified forz EP are from the mother, such as maternal history of pelvic inflammatory disease, Chlamydia trachomatis infection, smoking, tubal surgery, pregnancies through assisted reproductive technologies, and endometriosis.[5] The treatment method is based on the patient’s hemodynamic status, future fertility desire, b-hCG level, presence of tubal rupture, and sonographic findings.[6]
The aim of this study is to evaluate all EP cases treated in our hospital in terms of frequency, risk factors, clinical presentation, diagnostic methods, treatment methods, morbidity and mortality. Our secondary objective is to study the impact of the increasing Cesarean section rate on these cases.

Methods

The study protocol was approved by the Ethics Committee of Etlik Zübeyde Hanım Women’s Health Training and Research Hospital (Date: 07/03/2019, Approval no: 04). This study was planned as a retrospective cohort study, and the principles of the Declaration of Helsinki were followed.
A total of 1243 cases retrospectively reviewed who had clinical features of EP, were diagnosed during the clinical course EP and were treated in the Early Pregnancy Department of Etlik Zübeyde Hanım Women’s Health Training and Research Hospital between January 2014 and December 2018 were included in this study. Demographic information from patient or hospital records, previous deliveries of multiparous women, complaints, clinical findings, risk factors, ultrasound findings, initial and subsequent b-hCG levels, treatment methods (follow-up, drug, surgical), and the total number of pregnant women in our hospital was recorded. The incidence of EP was calculated using this total number of pregnant women (EP * 1000 / Number of pregnant women who consulted the polyclinic).
The diagnosis of EP was established by serial b-hCG measurements and TVUSG evaluation. Patients were followed up or treated with medical or surgical treatment methods. Patients who underwent surgery underwent laparotomy or laparoscopic salpingectomy. In medical treatment, systemic methotrexate was administered with a dose of 50 mg/m2 as a single dose. The success of methotrexate therapy was evaluated by a decrease in serum b-hCG levels of 15% or more, measured between days 4 and 7 of treatment, and a decrease in serum b-hCG levels below 15 IU/L 35 days after treatment.[7] Patients who did not meet these criteria were considered treatment failures, and a second dose of systemic methotrexate was administered. Treatment success was assessed a second time according to the above criteria. Follow-up was performed in patients who had an initial b-hCG level <1000 IU/L, in whom the b-hCG level decreased during the follow-up period, who were clinically and hemodynamically stable, and who accepted the risks and duration of treatment. These patients were followed up with serial b-hCG measurements repeated every 48 hours. When b-hCG levels began to decline, weekly serial b-hCG measurements were performed until levels were normal or declined sufficiently. Surgical treatment was performed in patients who were hemodynamically unstable, who did not respond to methotrexate therapy, and who experienced rupture during medical therapy.

Statistical analysis

Data analysis was performed with SPSS software version 22.0 (Statistical Package for the Social Sciences, IBM Corp., Armonk, NY, USA). Descriptive statistics were presented as mean±standard deviation and median (minimum-maximum) for continuous variables and as numbers and percentages for categorical variables. The distribution of parameters was assessed by Shapiro-Wilk normality tests. The independent samples t-test was used for the normally distributed data and the Mann-Whitney U test for the non-normally distributed variables. A 5% general type I error level was used to derive statistical significance. P-values <0.05 were considered statistically significant.

Results

During the four-year period, 1243 cases of EP were treated. The incidence of EP was 7 per 1000 pregnancies. The minimum age at diagnosis was 18 years, the maximum age was 49 years, and the mean age was 30.64±5.71 years (Table 1). The most common risk factors for EP were previous abdominal surgery (37.8%) and previous miscarriage (28.6%). Other identified risk factors were smoking (26.4%), a history of pelvic inflammatory disease (0.2%), use of an intrauterine device (IUD) (8.3%), sterilization (0.8%), and a history of EP (12.2%). Most patients were multigravida (79%). There was a history of Cesarean delivery in 30.3% of cases. Two hundred and sixty-one (21.0%) patients had an extrauterine pregnancy in their first pregnancies. The symptom triad of secondary amenorrhea, vaginal bleeding, and abdominal pain was present in 116 (9.3%) cases. Bleeding was the most common complaint in 564 (45.4%) patients. Other symptoms at presentation included pain in 246 patients (19.8%) and menstrual irregularities in 120 patients (9.7%). One hundred and twenty-five (10.1%) patients had no symptoms. One hundred and eighteen (15.1%) patients had both symptoms, bleeding and pain (Table 1).
In 54 (4.3%) women, the diagnosis of EP was established based on clinical findings alone. In these cases, no intrauterine or extrauterine pregnancy was detected on ultrasonography. However, ultrasound detected an EP focus in 1189 (95.7%) cases (Table 2). EP was located in the fallopian tube in 1085 (87.1%) cases, with the ampulla being the most common site (63.7%, 691 patients). The location could not be determined in 54 (4.3%) patients; EP was located in the abdominal cavity in 5 (0.4%) patients and in the rudimentary horn in 2 (0.2%) patients; tubal twins were present in 2 (0.2%) patients; and cervical pregnancy was present in 1 (0.1%) patient (Table 2). Ruptured ectopic pregnancy was detected in 424 (34.1%) cases. EP was detected in 79 (6.4%) cases with a positive fetal heart rate on ultrasound. Our success rate was 98.7% in patients in whom we used the follow-up method. Four (0.3%) patients voluntarily refused treatment and were discharged, 1 (0.1%) patient was referred, 45 (3.6%) patients underwent therapeutic curettage (D/C), 4 (0.3%) patients underwent D/C + methotrexate; and T/C + Foley catheter was inserted into the uterine cavity for hemostasis in 7 (0.6%) cases. One case of cervical pregnancy was treated with methotrexate (Table 2). There were no patients who required intensive care after treatment. There was no EP-related death during the study period.
Seventy-seven (6.2%) cases were followed up, 484 (38.9%) were treated surgically, and 621 (50.0%) were treated with methotrexate. Rupture was noted in 424 (34.1%) of surgically treated patients. While 682 (54.9%) patients were treated with a single dose of methotrexate, 132 (10.6%) patients required a second methotrexate dose and 12 (1%) patients required a third methotrexate dose (Table 2). The success rate of drug treatment with methotrexate was 88.34%. Rupture developed in 90 patients (7.2%) who received methotrexate therapy during follow-up, and emergency surgery was performed. The median b-hCG level (n=83) (median: 2366 IU/L, min: 74 IU/L – max: 126676 IU/L) was higher in cases with rupture after methotrexate than in cases without rupture (n=625) (median: 519 IU/L, min: 21 IU/L – max: 170088 IU/L) (p<0.001). Rupture developed after a mean of 4.40±7.10 days during treatment with methotrexate. Our success rate for treatment with methotrexate in cases with fetal cardiac activity was 67.9% (19/28).

Discussion

In our study, the incidence of EP was 7 per 1000 pregnancies (EP * 1000 / number of pregnant women). Although it is difficult to determine the incidence of EP, the incidence seems to have steadily increased over the years. The reason may be the actual increase in the prevalence of the disease, the increase in pelvic inflammatory disease (PID), the advanced age of mothers, and, in parallel, the increasing use of assisted reproductive techniques and the development of diagnostic methods.[8] In a large population study conducted in the United Kingdom, the incidence of EP was reported to be 12.5 per 1000 births, while it was reported to be 0.58% for Saudi Arabia.[9,10]
Studies have shown that EP cases mostly occur between the ages of 26–35 years.[11] In the study by Divyesh et al., 71.66% of cases were in the age group of 21–30 years.[12] In our study, the mean age of patients was 30.64±5.71 years, and 79.4% of patients were between 25–39 years old, and our results are consistent with the literature. The reason could be that in this age range, fertility is quite high and women use fewer contraceptive methods in this period. While some studies in the literature have shown that ectopic pregnancies are more common in multiparous women,[12,13] others have found that they are more common in primiparous women.[14,15] According to our results, the incidence of EP was higher in multigravid women. In our study, we found that 399 women had no living children. Choosing appropriate treatment for these women is important to optimize their future reproductive outcomes.
The most common risk factors in our study were previous abdominal surgery (37.8%) and previous miscarriage (28.6%). Similar to our study, there are also studies in the literature showing that previous miscarriages are among the most common risk factors for EP.[16,17] The rate of previous abdominal surgery has been reported to range from 12% to 42.6% on EP.[18,19] In other studies, the most common cause among risk factors was previous Cesarean delivery (31.5%).[6,20] In our study, in accordance with the literature, 30.3% of cases had a history of Cesarean delivery. Given these results, it is clear that the increased rate of Cesarean section in patients over the years contributes to the increase in ectopic pregnancies (especially pregnancies due to Cesarean scars).
Previous tubal surgery or previous ectopic pregnancy is the most important risk factor for EP.[21,22] In our study, 151 (12.2%) patients had a previous ectopic pregnancy. Our results show that traditional risk factors still play a crucial role in the occurrence of EP. While the symptom triad of vaginal bleeding, pelvic pain, and secondary amenorrhea in the first trimester may indicate an ectopic pregnancy, these symptoms may also occur in an intact intrauterine pregnancy or as a result of an early miscarriage.[23] In our study, the triad of secondary amenorrhea, vaginal bleeding, and abdominal pain was present in 116 (9.3%) cases. This is in agreement with the results of another study in which only 9% of patients were asymptomatic.[24]
A study conducted in Pakistan found that clinical features alone are useful for the diagnosis of ectopic pregnancy.[25] In our hospital, the diagnosis was established based on clinical findings in only 54 (4.3%) women with EP. However, ultrasonography was helpful for diagnosis in 1189 (95.7%) cases. The widespread use of ultrasound imaging in the last two decades has significantly changed the practice of obstetrics and gynecology.[26] Early diagnosis reduces the risk of tubal rupture and allows more conservative medical management.[27]
One study reported that 65.3% of women presented with ruptured ectopic pregnancy and hemoperitoneum.[28] It was reported that 70–100% of ectopic pregnancies were ruptured at the time of diagnosis.[29] In earlier years, the diagnosis of EP was based on vaginal bleeding and abdominal pain, and there were significant limitations in early detection.[5] More recently, EP has been diagnosed by determining serum levels of b-hCG and by vaginal ultrasound techniques. Therefore, hemoperitoneum is now less common. Although our institution is a tertiary center, the rate of patients presenting with rupture is quite low (34.1%) compared to the literature.
The median b-hCG level (2366 vs. 519) was higher in cases with rupture after methotrexate administration than in those without rupture (p<0.001). This result is similar to the study by Mirbolouk et al. on the predictive value of maternal serum b-hCG concentration in ruptured ectopic pregnancies.[30]
In our study, according to the treatment protocol of our hospital, in cases without acute abdominal findings and with intact hemodynamics, drug treatment or follow-up was the first treatment option. Although the number of cases in which we used the follow-up method is small, (77, 6.2%), our treatment success rate is 98.7%, which is consistent with the literature.[31,32] In appropriately selected cases, treatment-free follow-up and drug treatment with methotrexate have comparable success rates.[33] Our cumulative success rate for treatment with methotrexate is 88.3%, which is lower than the rates reported in the literature.[32,34] The reason for this may be that treatment with methotrexate is also used in patients with positive fetal cardiac activity, high b-hCG levels, and hemodynamically stable patients. Drug treatment with methotrexate can be used in ectopic pregnancy with rupture or fetal cardiac activity, provided that hemodynamic findings are normal and surgical treatment is readily available. In one study, the success rate of methotrexate treatment in cases with positive fetal cardiac activity was 33.3% (2/6).[35] The b-hCG level, the presence of fetal cardiac activity on USG or free abdominal fluid monitoring, and hemoglobin and hematocrit levels are among the parameters that influence the choice of treatment.[36] However, the most important consideration in the choice of treatment in our study is the hemodynamic tolerability of the case. Compared with many studies that reported a high rate of surgical treatment,[29,37] recent studies have reported a rapid decrease (from 98% to 62% and from 50% to 27%, respectively) in cases undergoing surgical treatment.[32,34] This is attributed to the establishment of early pregnancy units (EPAU), where EP is likely to be diagnosed at an early stage when medical treatment is still appropriate. Our hospital also has an early pregnancy unit, and surgical treatment was required only in 38.9% of cases.
Maternal mortality due to EP has been reported between 0% and 1.3% in various studies.[29,37] Mortality is mostly due to hemorrhage after rupture of EP caused by delayed referral and diagnosis. In our study, there was no death due to EP.
The main limitation of this study is that the data from a single center were presented retrospectively. In addition, because of the recent COVID-19 pandemic, we were unable to increase the number of patients we enrolled.

Conclusion

All physicians should be aware that the diagnosis of ectopic pregnancy should be considered when a woman of childbearing age presents with abdominal pain with or without amenorrhea. It should be remembered that delivery by Cesarean section is a risk factor for the development of EP and that the increase in Cesarean deliveries over the years has contributed to the increase in ectopic pregnancies (especially in pregnancies with Cesarean scar). Therefore, reassessing groups with risk factors for ectopic pregnancy, updating early diagnosis, and treating high-risk patients according to the current literature will decrease mortality and morbidity rates. The latest trend in the treatment of ectopic pregnancy is conservative surgery or drug treatment.

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	File/Dsecription
	Table 1. Baseline and clinical characteristics of the study population.
	Table 2. Disease features of the study population.