A new method of monitoring methotrexate for ectopic pregnancy by blood beta-hCG values

  Ectopic pregnancy is a common obstetrical and gynecological emergency, accounting for 2% of all pregnancies and 9% to 10% of maternal deaths, and the incidence of ectopic pregnancy in the infertile population has been increasing in recent years. MTX is an antimetabolic drug and is used for the conservative treatment of early ectopic pregnancy.  MTX is an antimetabolic drug and a folic acid antagonist. It blocks the reduction of dihydrofolate to the biologically active tetrahydrofolate by binding to intracellular dihydrofolate reductase. Tetrahydrofolate is an essential coenzyme in the synthesis of purines and pyrimidines, so when intracellular tetrahydrofolate is depleted, the synthesis of DNA, RNA and proteins is also reduced, leading to cell death. Cellular trophoblast cells are highly sensitive to MTX, and MTX can inhibit their proliferation process, affect the formation of intermediate and syncytial trophoblast cells, and restrict the growth of trophoblast cells, leading to embryonic arrest, death and resorption. The single-dose regimen of systemic MTX has become the standard chemotherapy regimen for patients with ectopic pregnancy because of its high success rate and ease of use, and because MTX acts mainly on S-stage cells, it may also inhibit normal cells that proliferate rapidly, such as gastrointestinal mucosa epithelium, hepatocytes and blood cells, resulting in certain adverse effects. Some scholars have also found that MTX can cause side effects such as nausea, vomiting and abdominal pain, which may be caused by the destruction of ectopic gestational sacs due to MTX. Therefore, it is necessary to find a highly sensitive and specific monitoring protocol to rapidly and accurately determine the efficacy of MTX in the treatment of ectopic pregnancy.  A D1 blood β-hCG of 2000 mIU/mL is usually used as the cut-off value for intrauterine pregnancy diagnosis by transvaginal ultrasound, and for this reason we divided 151 patients into groups with D1 blood β-hCG values ≥2000 mIU/mL and <1999 mIU/mL. The traditional method of monitoring the efficacy of MTX for ectopic pregnancy is to compare D7 with D4 blood β-hCG values, and treatment was successful if D7 decreased by ≥15% compared to D4 blood β-hCG values and clinical signs were stable.Natale A et al. studied 1067 patients with ectopic pregnancy treated with MTX using traditional monitoring criteria and concluded that 14.5% of patients required repeat MTX treatment and found that Blood β-hCG values tended to be higher on the fourth day in patients with ectopic pregnancy treated with a single dose of MTX, probably because of the 36-hour half-life of blood β-hCG and the continued release of blood β-hCG from dead trophoblast cells. Clinical signs and symptoms such as vaginal bleeding and abdominal pain may occur in some patients on the fourth day of treatment, while D4 blood β-hCG values may rise compared to D1, often leading to errors in clinical judgment and unnecessary tests or treatments (such as surgery or reuse of MTX). In this study, among 151 patients, 47 (31.1%) had elevated D4 compared to D1 blood β-hCG values, and the percentages of people with elevated D4 blood β-hCG values in the two groups were 27.8% and 39.5%, respectively, which were not statistically significant (P>0.05).  Potter MB et al. demonstrated a positive correlation between D1 blood β-hCG values and re-treatment with MTX in patients with ectopic pregnancy. In the present study, 151 patients, 25 (16.6%) required repeat MTX treatment, the percentages of numbers in the two groups were 12.0% and 27.9%, respectively, which was statistically significant when comparing the two groups. the study by Gabbur et al. found that the level of decrease in D7 compared to D1 blood β-hCG values was a more important predictor of repeat MTX treatment. This study found that the level of decrease in D7 compared to D1 blood β-hCG values ≤ 50% was 100% (DOT β-hCG values < 2000 mIU/mL group) and 91.7% (DOT β-hCG values ≥ 2000 mIU/mL group) sensitive in predicting repeat MTX treatment. alshimmiri et al. In the treatment of 77 ectopic pregnancies treated with single dose MTX process, once D7 blood β-hCG values decreased less than 30% compared to D1, re-MTX treatment was given, resulting in 3.9% (3/77) of patients requiring re-MTX treatment and 5.2% (4/77) of patients requiring surgical treatment. In this study, we found that the sensitivity of D7 compared with D1 blood β-hCG value decreased ≤50%, the sensitivity of the two groups was 100% and 91.7%, respectively, which can be a new option for monitoring of ectopic pregnancy treated with MTX, which not only can avoid the trouble of treatment caused by the increase of D4 blood β-hCG value, but also can reduce the trauma caused by D4 blood sampling.  Although the choice of surgical treatment mainly depends on clinical symptoms, and blood β-hCG value cannot be used as a judgment criterion for surgical treatment, it was found in the study that the surgery rate increased with the increase of D1 blood β-hCG value in the group with blood β-hCG ≥ 2000 mIU/mL compared with the group with < 2000 mIU/mL, and the percentages of numbers in the two groups were 13.0% and 44.2%, respectively (P<0.05) The percentage of patients who underwent surgery after repeated MTX treatment was 2.8% and 11.6%, respectively (P<0.05), which may be related to the rapid development of laparoscopic surgery in recent years, and patients tend to choose surgery when the efficacy of drug treatment is not significant.  In conclusion, traditional monitoring methods have limitations in clinical application, and this study found that a ≥50% decrease in blood β-hCG in D7 compared with D1 predicted that patients did not need follow-up treatment such as MTX again, which could better guide clinical practice.