HHS Public Access Author manuscript Author Manuscript
Am J Obstet Gynecol. Author manuscript; available in PMC 2017 July 23. Published in final edited form as: Am J Obstet Gynecol. 2016 November ; 215(5): 590.e1–590.e5. doi:10.1016/j.ajog.2016.06.040.
Medical management of ectopic pregnancy with single-dose and 2-dose methotrexate protocols: human chorionic gonadotropin trends and patient outcomes
Author Manuscript
Michelle C. Mergenthal, MD, Suneeta Senapati, MD, Jarcy Zee, PhD, Lynne Allen-Taylor, PhD, Paul G. Whittaker, DPhil, Peter Takacs, MD, Mary D. Sammel, ScD, and Kurt T. Barnhart, MD Departments of Obstetrics and Gynecology (Drs Mergenthal, Senapati, Whittaker, Sammel, and Barnhart) and Biostatistics and Epidemiology (Dr Zee, Taylor, Whittaker, Sammel, and Barnhart), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; and Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA (Dr Takacs)
Abstract
Author Manuscript
BACKGROUND—Ectopic pregnancy, although rare, is an important cause of female morbidity and mortality and early, effective treatment is critical. Systemic methotrexate has become widely accepted as a safe and effective alternative to surgery in the stable patient. As the number and timing of methotrexate doses differ in the 3 main medical treatment regimens, one might expect trends in serum human chorionic gonadotropin and time to resolution to vary depending on protocol. Furthermore, human chorionic gonadotropin trends and time to resolution may predict ultimate treatment success. OBJECTIVE—This study hypothesized that the 2-dose methotrexate protocol would be associated with a faster initial decline in serum human chorionic gonadotropin levels and a shorter time to resolution compared to the single-dose protocol. STUDY DESIGN—A prospective multicenter cohort study included clinical data from women who received medical management for ectopic pregnancy. Rates of human chorionic gonadotropin change and successful pregnancy resolution were assessed. Propensity score modeling addressed confounding by indication, the potential for differential assignment of patients with better prognosis to the single-dose methotrexate protocol.
Author Manuscript
RESULTS—In all, 162 ectopic pregnancies were in the final analysis; 114 (70%) were treated with the single-dose methotrexate and 48 (30%) with the 2-dose protocol. Site, race, ethnicity, and reported pain level were associated with differential protocol allocation (P < .001, P = .011, P < . 001, and P = .035, respectively). Women had similar initial human chorionic gonadotropin levels in either protocol but the mean rate of decline of human chorionic gonadotropin from day 0 (day of administration of first dose of methotrexate) to day 7 was significantly more rapid in women who received the single-dose protocol compared to those treated with the 2-dose protocol (mean
Corresponding author: Kurt T. Barnhart, MD. [email protected]. The authors report no conflict of interest.
Mergenthal et al.
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Author Manuscript
change −31.3% vs −10.4%, P = .037, adjusted for propensity score and site). The 2 protocols had no significant differences in success rate or time to resolution. CONCLUSION—In a racially and geographically diverse group of women, the single- and double-dose methotrexate protocols had comparable outcomes. The more rapid human chorionic gonadotropin initial decline in the single-dose group suggested these patients were probably at lower risk for ectopic rupture than those getting the 2-dose protocol. A prospective randomized controlled design is needed to remove confounding by indication. Keywords ectopic pregnancy; human chorionic gonadotropin; methotrexate; protocol comparisons
Introduction Author Manuscript Author Manuscript
Ectopic pregnancy accounts for 1.5–2%1 of all pregnancies and is an important cause of morbidity and mortality in women of reproductive age. Early and effective treatment either with surgical or medical management is critical. Systemic methotrexate was first recognized as a medical treatment for unruptured ectopic pregnancy in 1982 by Tanaka et al,2 and it has since become widely accepted as a safe and effective alternative to surgery in the stable patient.3,4 Currently, there are 3 main treatment regimens for management of ectopic pregnancy with methotrexate: the multidose protocol, the single-dose protocol,5 and the 2dose protocol.6 As the number and timing of methotrexate doses differ in these protocols, one may expect trends in serum human chorionic gonadotropin (hCG) and time to resolution to vary depending on protocol. By extension, hCG trends and time to resolution may predict ultimate treatment success. As such, this study aimed to evaluate the association between methotrexate protocol (single dose vs 2 doses), hCG trends, and time to resolution of ectopic pregnancy with the hypothesis that the 2-dose protocol would be associated with faster initial decline in serum hCG levels and a shorter time to resolution.
Materials and Methods
Author Manuscript
This prospective cohort study included clinical data collected at 3 academic medical centers from Aug. 1, 2007, through June 30, 2009: the University of Pennsylvania, the University of Miami, and the University of Southern California. The study was approved by the institutional review board at each of these institutions. Informed consent was obtained from all individual participants included in the study. Subjects were initially encountered both as emergency room and as emergency walk-in consultations, but all methotrexate was given on an obstetric outpatient basis. None of the subjects conceived using assisted reproductive technologies. Women who: (1) presented with first-trimester vaginal bleeding, pelvic pain, or both; (2) were diagnosed with ectopic pregnancy; and (3) underwent medical management with either the single-dose or 2-dose methotrexate protocols were included and followed up to assess treatment outcome. Diagnosis of ectopic pregnancy was made by ultrasound, abnormal serum hCG trend, and/or by the absence of products of conception after uterine evacuation according to American Congress of Obstetricians and Gynecologists guidelines.4 Women with nontubal ectopic pregnancies (ie, interstitial/cornual, cesarean delivery scar, cervical, intra-abdominal, or ovarian) and heterotopic pregnancies were Am J Obstet Gynecol. Author manuscript; available in PMC 2017 July 23.
Mergenthal et al.
Page 3
Author Manuscript
excluded from the analysis. Women initially treated via salpingostomy or who had initial serum hCG levels >10,000 mIU/mL were also excluded. Single-dose methotrexate was administered in accordance with the protocol originally described by Stovall et al5 in 1991. In brief, methotrexate is administered intramuscularly (IM) at a dose based on body surface area (50 mg/m2) on day 0. Serum hCG is then measured on posttreatment days 4 and 7. If at least a 15% decrease in hCG is observed between days 4–7, these women are then followed up with weekly hCG measurements until the result is negative. If the decline between days 4–7 is
Am J Obstet Gynecol. Author manuscript; available in PMC 2017 July 23. Published in final edited form as: Am J Obstet Gynecol. 2016 November ; 215(5): 590.e1–590.e5. doi:10.1016/j.ajog.2016.06.040.
Medical management of ectopic pregnancy with single-dose and 2-dose methotrexate protocols: human chorionic gonadotropin trends and patient outcomes
Author Manuscript
Michelle C. Mergenthal, MD, Suneeta Senapati, MD, Jarcy Zee, PhD, Lynne Allen-Taylor, PhD, Paul G. Whittaker, DPhil, Peter Takacs, MD, Mary D. Sammel, ScD, and Kurt T. Barnhart, MD Departments of Obstetrics and Gynecology (Drs Mergenthal, Senapati, Whittaker, Sammel, and Barnhart) and Biostatistics and Epidemiology (Dr Zee, Taylor, Whittaker, Sammel, and Barnhart), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; and Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA (Dr Takacs)
Abstract
Author Manuscript
BACKGROUND—Ectopic pregnancy, although rare, is an important cause of female morbidity and mortality and early, effective treatment is critical. Systemic methotrexate has become widely accepted as a safe and effective alternative to surgery in the stable patient. As the number and timing of methotrexate doses differ in the 3 main medical treatment regimens, one might expect trends in serum human chorionic gonadotropin and time to resolution to vary depending on protocol. Furthermore, human chorionic gonadotropin trends and time to resolution may predict ultimate treatment success. OBJECTIVE—This study hypothesized that the 2-dose methotrexate protocol would be associated with a faster initial decline in serum human chorionic gonadotropin levels and a shorter time to resolution compared to the single-dose protocol. STUDY DESIGN—A prospective multicenter cohort study included clinical data from women who received medical management for ectopic pregnancy. Rates of human chorionic gonadotropin change and successful pregnancy resolution were assessed. Propensity score modeling addressed confounding by indication, the potential for differential assignment of patients with better prognosis to the single-dose methotrexate protocol.
Author Manuscript
RESULTS—In all, 162 ectopic pregnancies were in the final analysis; 114 (70%) were treated with the single-dose methotrexate and 48 (30%) with the 2-dose protocol. Site, race, ethnicity, and reported pain level were associated with differential protocol allocation (P < .001, P = .011, P < . 001, and P = .035, respectively). Women had similar initial human chorionic gonadotropin levels in either protocol but the mean rate of decline of human chorionic gonadotropin from day 0 (day of administration of first dose of methotrexate) to day 7 was significantly more rapid in women who received the single-dose protocol compared to those treated with the 2-dose protocol (mean
Corresponding author: Kurt T. Barnhart, MD. [email protected]. The authors report no conflict of interest.
Mergenthal et al.
Page 2
Author Manuscript
change −31.3% vs −10.4%, P = .037, adjusted for propensity score and site). The 2 protocols had no significant differences in success rate or time to resolution. CONCLUSION—In a racially and geographically diverse group of women, the single- and double-dose methotrexate protocols had comparable outcomes. The more rapid human chorionic gonadotropin initial decline in the single-dose group suggested these patients were probably at lower risk for ectopic rupture than those getting the 2-dose protocol. A prospective randomized controlled design is needed to remove confounding by indication. Keywords ectopic pregnancy; human chorionic gonadotropin; methotrexate; protocol comparisons
Introduction Author Manuscript Author Manuscript
Ectopic pregnancy accounts for 1.5–2%1 of all pregnancies and is an important cause of morbidity and mortality in women of reproductive age. Early and effective treatment either with surgical or medical management is critical. Systemic methotrexate was first recognized as a medical treatment for unruptured ectopic pregnancy in 1982 by Tanaka et al,2 and it has since become widely accepted as a safe and effective alternative to surgery in the stable patient.3,4 Currently, there are 3 main treatment regimens for management of ectopic pregnancy with methotrexate: the multidose protocol, the single-dose protocol,5 and the 2dose protocol.6 As the number and timing of methotrexate doses differ in these protocols, one may expect trends in serum human chorionic gonadotropin (hCG) and time to resolution to vary depending on protocol. By extension, hCG trends and time to resolution may predict ultimate treatment success. As such, this study aimed to evaluate the association between methotrexate protocol (single dose vs 2 doses), hCG trends, and time to resolution of ectopic pregnancy with the hypothesis that the 2-dose protocol would be associated with faster initial decline in serum hCG levels and a shorter time to resolution.
Materials and Methods
Author Manuscript
This prospective cohort study included clinical data collected at 3 academic medical centers from Aug. 1, 2007, through June 30, 2009: the University of Pennsylvania, the University of Miami, and the University of Southern California. The study was approved by the institutional review board at each of these institutions. Informed consent was obtained from all individual participants included in the study. Subjects were initially encountered both as emergency room and as emergency walk-in consultations, but all methotrexate was given on an obstetric outpatient basis. None of the subjects conceived using assisted reproductive technologies. Women who: (1) presented with first-trimester vaginal bleeding, pelvic pain, or both; (2) were diagnosed with ectopic pregnancy; and (3) underwent medical management with either the single-dose or 2-dose methotrexate protocols were included and followed up to assess treatment outcome. Diagnosis of ectopic pregnancy was made by ultrasound, abnormal serum hCG trend, and/or by the absence of products of conception after uterine evacuation according to American Congress of Obstetricians and Gynecologists guidelines.4 Women with nontubal ectopic pregnancies (ie, interstitial/cornual, cesarean delivery scar, cervical, intra-abdominal, or ovarian) and heterotopic pregnancies were Am J Obstet Gynecol. Author manuscript; available in PMC 2017 July 23.
Mergenthal et al.
Page 3
Author Manuscript
excluded from the analysis. Women initially treated via salpingostomy or who had initial serum hCG levels >10,000 mIU/mL were also excluded. Single-dose methotrexate was administered in accordance with the protocol originally described by Stovall et al5 in 1991. In brief, methotrexate is administered intramuscularly (IM) at a dose based on body surface area (50 mg/m2) on day 0. Serum hCG is then measured on posttreatment days 4 and 7. If at least a 15% decrease in hCG is observed between days 4–7, these women are then followed up with weekly hCG measurements until the result is negative. If the decline between days 4–7 is
