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9/29/2024

Medical Management of Ectopic Pregnancy

Ectopic pregnancy complicates approximately 2% of recognized pregnancies and is the leading cause of pregnancy-associated death in the first trimester. Surgical intervention has been the criterion standard treatment. However, technological advances and improved patient screening have enabled earlier diagnosis, allowing for less-invasive medical management via intramuscular methotrexate. Methotrexate, a folate antagonist acting on the dihydrofolate reductase enzyme, blocks production of certain nucleotides and amino acids, thus inhibiting DNA synthesis. Inhibition of DNA synthesis affects actively dividing cells, including gestational trophoblasts. While medical management potentially avoids the inherent risks of surgery, patient selection and counseling are imperative to ensure safe management because tubal rupture or hemorrhage can occur despite appropriate treatment and/or decreasing concentrations of human chorionic gonadotropin (hCG).

When there is high clinical suspicion or diagnosis of an ectopic pregnancy, the patient should be counseled regarding surgical or medical treatment. When assessing whether a patient is a candidate for methotrexate, evaluating for contraindications is important. Clinically significant diseases of the kidneys, liver, gastrointestinal tract, or lungs, which may worsen with methotrexate, are absolute contraindications to its use. Additional absolute contraindications include allergy to methotrexate, diseases of the immune or hematopoietic systems, potential intrauterine pregnancy, or current breastfeeding. Finally, patients who are unable or unwilling to follow-up for serial monitoring, who are hemodynamically unstable, or who have a ruptured ectopic pregnancy are not candidates. Several additional relative contraindications to methotrexate have been suggested, likely because they foreshadow a decreased rate of successful treatment. These include the presence of fetal cardiac activity, significantly elevated pretreatment hCG concentration (>5000 IU/L), an ectopic mass larger than 4 cm, and refusal to accept a blood transfusion. Recommended baseline screening includes a thorough history and physical examination, complete blood cell count, liver function tests, serum creatinine measurement, determination of blood type and Rh, and hCG measurement.

Three dosing regimens have been studied: single-dose, 2-dose, and multidose. The single- and 2-dose regimens are given at a dose of 50 mg/m2, with methotrexate being administered on day 1 in the single-dose regimen and on days 1 and 4 in the 2-dose regimen. The hCG concentration is measured on days 1, 4, and 7. A 15% decrease between days 4 and 7 indicates treatment success in both regimens, and hCG is then measured weekly until negative. The multidose regimen is administered at 1 mg/kg, alternating with folinic acid, 0.1 mg/kg intramuscularly. Methotrexate is given on days 1, 3, 5, and 7 until a 15% decrease in hCG is observed. Folinic acid is given on days 4, 6, and 8. Once the requisite drop in hCG is achieved, no further doses of methotrexate are given, and the hCG concentration should be monitored until it enters the nonpregnancy range. Patients should be counseled to avoid prenatal vitamins, foods containing folate, and nonsteroidal anti-inflammatory drugs, as they can all adversely impact treatment effectiveness. A recent meta-analysis documented that the 2-dose regimen had a significantly higher rate of treatment success and lower rate of treatment failure when compared with the single-dose regimen. While not statistically significant, the multidose regimen also trended toward improved outcomes as compared with outcomes of the single-dose regimen. Despite greater treatment success in these groups, adverse effects were also more prevalent as the dose of methotrexate accumulated. Given these data, a reasonable approach is to reserve the multidose regimen for ectopic pregnancies at higher risk for treatment failure and to use the 2-dose or single-dose regimens as first-line therapy. 

 

Further Reading:

 

American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Gynecology. ACOG Practice Bulletin No. 193: Tubal Ectopic Pregnancy. Obstet Gynecol. 2018 Mar;131(3):e91-e103. doi: 10.1097/AOG.0000000000002560.

 

Practice Committee of American Society for Reproductive Medicine. Medical treatment of ectopic pregnancy: a committee opinion. Fertil Steril. 2013 Sep;100(3):638-44. doi: 10.1016/j.fertnstert.2013.06.013. Epub 2013 Jul 10. PMID: 23849842.

 

Alur-Gupta S, Cooney LG, Senapati S, et al. Two-dose versus single-dose methotrexate for treatment of ectopic pregnancy: a meta-analysis. Am J Obstet Gynecol. 2019 Aug;221(2):95-108.e2. doi: 10.1016/j.ajog.2019.01.002. Epub 2019 Jan 7. PMID: 30629908; PMCID: PMC6612469.

 

Published: September 2024

 

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This document is designed to aid practitioners in providing appropriate obstetric and gynecologic care. Recommendations are derived from major society guidelines and high-quality evidence when available, supplemented by the opinion of the author and editorial board when necessary. It should not be construed as dictating an exclusive course of treatment or procedure to be followed.

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