Predictive value of serum βHCG level in ectopic pregnancy: A cross sectional study.

Mandana Mansour Ghanaie : Resources. Sanaz Hoshyarmanesh : Software. Seyedeh Maryam Asgari : Data curation. Seyed Mohammad Asgari Galebin : Funding acquisition. Fereshteh Fakor : Resources.

This study was approved by the Ethics Committee of Guilan University of Medical Sciences (Approval ID: IR.GUMS.REC.1400.534).

The mean age of patients in our study was 31.72 ± 5.11 years and there was no correlation between the success of the MTX treatment and maternal age. A total of 584 patients (84.6%) (584/690) were successfully treated with MTX. While 106 (15.4%) (106/690) had an unsuccessful treatment. The baseline characteristics are shown in Table  1 . There were significant differences in the history of fallopian surgery and the size of EP (>2 cm) between the two groups ( p  = 0.014, <0.001, respectively). On the other hand, there were no differences in the other baseline characteristics of the two groups (Tables  1 and  2 ). Baseline characteristics of patients. Success ( n  = 584) Fail ( n  = 105) Abbreviations: BMI, body mass index; EP, ectopic pregnancy. Unpaired t test. Clinical characteristics of patients. Success ( n  = 584) Fail ( n  = 105) Abbreviations: ART, assistant reproductive technology; FT, fallopian tube; OCP, oral contraceptive pill; PID, pelvic inflammatory disease; STD, sexual transmited disease. Fisher's exact test. There was no significant difference in the mean baseline ßHCG levels between the two groups ( p  = 0.098). The mean ßHCG concentration on the 4th day was significantly higher (>50%) in the failure group ( p  = 0.0001). Also, the mean ßHCG concentration on the 7th day was significantly higher (>60%) than the failure group ( p  = 0.0001) (Table  3 ). Mean ßHCG levels in the two groups. Independent t test. This study showed that a more than 59.9% decrease in ßHCG between the baseline and 4th days can increase the rate of successful treatment ( p  = 0.001). Also, a decrease of more than 81.6% in ßHCG between baseline and 7th day can increase the rate of successful treatment ( p  = 0.001). According to the ROC curve, the basal ßHCG cut off value for successful treatment was 504.5 with 58% sensitivity and 51% specificity (area = 0.557, Figure  1 ). βHCG. The 4th ßHCG cut off value for successful treatment was 429 with 73% sensitivity and 52% specificity (area = 0.67, Figure  2 ). ROC chart of ßHCG level on day 4. ROC, receiver operating characteristic. The 7th ßHCG cut off value for successful treatment was 279 with 81% sensitivity and 55% specificity (area = 0.768, Figure  3 ). ROC chart of ßHCG level on day 7. ROC, receiver operating characteristic. There was a significant difference between the 4th day ßHCG levels with patient's age ( p  = 0.004, r  = 0.118) and body mass index (BMI) ( p  = 0.040, r  = 0.084). Also, there was a significant difference between the 7th day ßHCG levels with patient's age ( p  = 0.006, r  = 0.113), BMI ( p  = 0.044, r  = 0.084), and gravidity ( p  = 0.011, r  = 0.105) (Table  4 ). The relation between baseline, the 4th and 7th day ßHCG concentrations and individual variables. Treatment Abbreviations: BMI, body mass index; EP, ectopic pregnancy. Pearson–Spearman test.

We evaluated the rate of βHCG level changes from the baseline to the 4th and 7th days after SD MTX in predicting success of medical treatment in EP. The results showed that the changes in βHCG levels at baseline and 4th days, significantly predictive the success of pharmacotherapy. In the successful group, there was a 172.41 (19.5%) drop. In βHCG titration on the 4th day, compared to baseline. In the successful group, there was a 172.41 (19.5%) drop, in βHCG titration on the 4th day, compared to baseline, while in the failed group, there was a 161.14 (14.9%) increase in βHCG titration on the 7th day compared to baseline. A drop more than 59.9% between baseline and 4th day and a drop more than 81.6% between baseline and 7th day, predict more successful MTX Therapy. In this study, the success rate of the medical management of EP with MTX was found to be 84.7% which appears to be slightly lower than the international rate with an average of 90%, however, our study had a higher success rate than the study conducted by Keshta et al., 11 which presented a success rate of 68.9%. In keshta,s 11 study, The mean baseline ßHCG levels were significantly lower in the successful group (1403) compared with the unsuccessful group (2845). The baseline ßHCG cut off value for successful treatment in Keshta's 11 study was 2141 with 72% sensitivity and 75% specificity. Similarly, in our study the mean baseline ßHCG levels were lower in the successful group (882.35) than the unsuccessful group (1083.99), but there were no significant differences between the two groups ( p  = 0.098). The sample size in our study was greater than Keshta's 11 study (690 vs. 58, respectively). In our study, baseline ßHCG cut off value for successful treatment was 504.5 with 58% sensitivity and 51% specificity. The 4th‐day cut off value for successful treatment in our study was 429 and the 7th‐day cut off level was 279. In the Levin's 13 study, the treatment success rate with single dose MTX was 62.7% and the optimal cut‐off points for prediction of treatment success were an increment of less than 17% in the 24 h before treatment and a decrease of more than 22% between the days 1 and 4 ßHCG concentration. In a study conducted by Yildiz et al., 14 the success rate of SD MTX treatment was 77.2% and the mean ßHCG level in the successful and unsuccessful groups was 783 and 1802, respectively ( p  59.9% decrease between days baseline and 4 and 81.6% decrease between the baseline and 7th day, increase the probably of successful treatment ( p  = 0.001, p  = 0.001, respectively). In contrast to the study by Yildiz et al., 14 there was a significant difference between the size of EP mass and a successful treatment ( p  = 0.001). 14 In a study by Bozorgan et al., 15 a ßHCG drop between the baseline and 4th day happened in 84% of patients and was a predictor of successful treatment ( p  = 0.0001). The corresponding figure was 59.9% for our study. 15 In a study by Pulaleglu et al., 16 the overall success rate with SD MTX was 77.2% and the baseline ßHCG level in the failed group was significantly higher than the successful group (3887 vs. 2589, respectively, p  < 0.017). They calculated that according to ROC analysis, baseline ßHCG <1362 mIU/mL is suitable for SD MTX treatment with 71.8% sensitivity and 68.2% specificity. In this study, the EP mass size was not related with a successful SD MTX treatment. 16 Tasgoz et al. 17 showed a successful rate of 72.2% in SD MTX treatment. The deep off of 35% between days baseline and 4 increased the success rate ( p  < 0.07). 17 In a study conducted by Watanabe et al., 18 ROC analysis showed that prediction of a successful treatment was possible with daily ßHCG changes of <+12.6 with 87% sensivity and 71% specificity and the time interval between the start and the end of treatment was related with first day ßHCG. 18 In Cohen et al.'s 19 study, the success rate with SD MTX treatment was 75% and the mean changes of ßHCG within 48 h before the start of treatment was significant, moreover a less than 12% increase in ßHCG levels within 48 h before the treatment was a good predictor factor for successful treatment. Goh et al. 20 suggested that a ≥5% rise in serum ßHCG levels of days baseline to four could predict treatment failure of SD/MTX for tubal EP and conversely, a <5% rise or any drop of βHCG levels in days baseline to four can reliably predict treatment success. Skubisz et al. verified that a decline in serum ßHCG between days baseline and 4 after MTX treatment for EPs with pretreatment serum βHCG levels of ≤3000 IU/L, provides an early indication of the likelihood of treatment success, and performs just as well as the existing measure, which only provides prognostic information on day 7. 21

A decrease in the ßHCG value and/or a cut‐off decrease of 59.9% on the baseline, 4th day can predict the successful treatment of tubal EP with SD MTX. Although the most important predictive factor for successful treatment is the ßHCG level on days 4 and 7.

Ectopic pregnancy (EP) is a condition in which the developing blastocyst is implanted in a tissue other than the endometrial lining of uterine cavity, most commonly in the fallopian tube (95%). 1 The incidence rate of EP is 1%–2% of all pregnancies. 2 Approximately 2.7% of pregnancy‐related deaths in the first trimester are caused by EP. 3 The treatment options for EP include: medical, surgical, or expectant. Methotrexate (MTX) is a folic acid antagonist recommended for an unruptured tubal pregnancy with hemodynamic stability. 4 In contrast to the surgical intervention, medical treatment results in fallopian tube sparing and cost reduction. 5 Generally, the three most common protocols are single‐dose (SD), double‐dose (DD), and multiple‐dose (MD) of MTX. 4 To date, the advantages of the different protocols were unclear due to a lack of comparative studies, but according to a recently published meta‐analysis, the DD protocol is more successful than the SD protocol. 6 Many studies have shown increased treatment failure of SD rather than MD. 7 , 8 , 9 Also, the success rate of treatment with MD is higher than with DD but MD causes a considerable increase in creatinine. 10 The available literature on the medical management of EP is scant and limited to a few parameters related to the management protocols.  11 We investigate the predictive value of serum βHCG level and it's changes from the baseline to the 4th and 7th days after SD MTX treatment in successful treatment of tubal EP. In this study, we evaluated the medical management of EP with SD MTX treatment. We studied different ßHCG measurements to enable cut‐off values for prediction of MTX treatment success.

The lead author Fereshteh Fakor affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

The authors declare no conflicts of interest.

This cross‐sectional study was conducted at Alzahra Hospital, Rasht, Iran, from 14th February 2020 to 17th October 2022. STROBE checklist was use to evaluated quality of study process. 12 This study was approved by the ethics committee of Guilan university of medical sciences by ethical code IR.GUMS.REC.1400.534. The ethical principles for medical research of the World Medical Association (WMA)'s declaration of Helsinki were followed in this study. Medical records of 713 women with EP who were candidates for medical treatment with MTX at the Department of Obstetrics and Gynecology (Alzahra University—affiliated Tertiary Referral Center for Academic Training & Research) were collected. All patients consented to receive SD MTX for EP. However, 23 were excluded either due to withdrawal of medical treatment ( n  = 2), history of renal disease ( n  = 1), shifting to surgical intervention ( n  = 15), missing data from the hospital electronic medical records ( n  = 2), and the loss of follow‐up after the completion of the treatment course ( n  = 3). The patients were then divided into two groups based on the final treatment outcome. Six hundred ninety women were identified as being eligible for inclusion in the study. The diagnosis of EP was made by transvaginal ultrasound finding of the ectopic gestational sac and abnormal changes of ßHCG titrations. The inclusion criteria for medical treatment of EP in Alzahra hospital were: unruptured EP, no hemoperitoneum, hemodynamic stability, absence of any fetal cardiac activity detection by ultrasound, ßHCG levels <5000 mIU/mL, adnexal mass of less than 4 cm, no history of allergy to MTX, no breast feeding, lack of renal, hepatic, blood or active lung disease, absence of anemia or thrombocytopenia or immune deficiency and no peptic ulcers. Baseline investigations such as full blood count, ßHCG, renal, and liver function tests were performed for all patients on baseline and a SD of 50 mg/m 2 MTX was administered intramuscularly. Follow up assessments were performed on days baseline, 4 and 7, and then weekly until the ßHCG value was negative (<5 IU/mL) and/or follow up assessments included serum ßHCG measurements, ultrasound imaging, assessment of general health and symptoms such as abdominal pain and evaluation for side effects of MTX like liver and renal deranged function tests. Also, Serum ßHCG levels were measured on days 4 and 7. Patients were given another dose of intra muscular MTX (1 mg/kg body weight) if the decrease in serum βHCG level was less 15% between days 4 and 7, on alternating doses. Leucovorin (0.1 mg/kg) has given on each day after MTX injection. A second course of MTX and leucovorin was given if previously falling βHCG level, rose or plateaued on two consecutive serum βHCG titrations. Those who received the second dose of MTX due to inadeaduate fall in serum βHCG level were exclude from study. The patients were hospitalized and watch expectantly following the drug administration while being cheked for signs of ruptured EP or acute abdomen. Indications of surgery was 1. Acute abdomens 2. Rupture of EP 3. Persistent mass in spite of sufficient fall of serum βHCG level 4. Rise or sufficient fall in spite of multi dose MTX regimen. MTX success was described by Levin et al. 13 as a completely negative ßHCG level after MTX injection. Also any failure was shown by the need to perform surgery or to receive additional doses of MTX. 12 Data were analyzed using SPSS version 22 software. Quantitative data were defined by mean and standard deviation and qualitative data were described by number and percentage. A two‐sample unpaired t test was used to compare normally distributed continuous variables between the two groups. A two‐sided Mann–Whitney test was used to compare non‐normally parametric variables between the groups. Normality of data was examined with the Shapiro–Wilk test in which Chi‐square and crosstabs were used to compare percentages in each group. Fisher‐Freeman‐Halton exact test in crosstabs was used to compare percentage between the groups when one out of four cells had an expectation of less than five. Furthermore, a two‐sided simple linear regression analysis was used to assess the correlation between initial ßHCG levels and the drop in ßHCG level between days baseline and seven after medical treatment. The area under the receiver operator curve (ROC) was used to evaluate the predictive value of the ßHCG decrease and successful treatment. ROC was presented as an optimum cut‐off point and 95% confidence interval with sensitivity and specificity. All p values of less than 0.05 were considered statistically significant.

Supporting information. Click here for additional data file.