Australian and New Zealand Journal of Obstetrics and Gynaecology 2014; 54: 469–474
DOI: 10.1111/ajo.12247
Original Article
Single-dose methotrexate treatment for ectopic pregnancy and pregnancy of unknown location and progesterone as a predictor of success Joyce WU,1 Joanne P. LUDLOW,1,2 Bradley De VRIES,1,2 Kirsten BLACK1,2 and Philip BEALE3 1
RPA Women and Babies, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia, 2Discipline of Obstetrics, Gynaecology and Neonatology, University of Sydney, Camperdown, New South Wales, Australia and 3Cancer Services, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
Background: The use of single-dose intramuscular administration of methotrexate in the treatment of ectopic pregnancies (EP) is a well-established practice. This study evaluates its use at a novel dose of 40 mg/m2 body surface area (BSA). Objective: To evaluate the efficacy and safety of single-dose methotrexate treatment 40 mg/m2 for tubal EP and persistent pregnancies of unknown location (PUL) and determine whether serum progesterone is a predictor of treatment success. Materials and Methods: Retrospective cohort study of patients receiving intramuscular methotrexate 40 mg/m2 for the treatment of EP or PUL at Royal Prince Alfred Hospital over five years. Results: One hundred and eighteen women received single-dose methotrexate with an overall success of 84%. Surgical intervention was needed in 16.6%. Pretreatment beta-hCG level and ectopic diagnosis were independent variables predictive of the need for surgery (P = 0.003 and 0.02, respectively). Serum progesterone level was not predictive of the need for a second dose or surgery. The sensitivity and specificity at pretreatment beta-hCG of 1202 IU/L were 84% and 74%, respectively. Commonly reported side effects included nausea, abdominal pain and heavy vaginal bleeding. Significant treatment-related adverse effects were rare. Conclusion: Single-dose IM methotrexate at a novel dose of 40 mg/m2 is a safe and effective treatment for selected EP and persistent PUL. The risk of surgery was positively correlated to serum beta-hCG level and the diagnosis of EP. Progesterone was not a risk factor for surgery. Further studies are required to confirm the efficacy of this dose regimen and explore the safety of expectant management as an alternative to methotrexate treatment. Key words: ectopic pregnancy, medical management of ectopic pregnancy, methotrexate, pregnancy of unknown location, progesterone.
Introduction Ectopic pregnancies (EP) are a life-threatening condition, responsible for 5% of maternal deaths in high-resource settings.1 Ectopic pregnancies comprise 3% of all early pregnancy presentations to the Early Pregnancy Assessment Service (EPAS) at Royal Prince Alfred Hospital (RPAH) in Sydney, Australia. Early diagnosis of EP allows prevention of significant mortality and morbidity.1 Although surgical intervention remains the
Correspondence: Dr Joyce Wu, RPA Women and Babies Executive Unit, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia. Email: [email protected] Received 23 September 2013; accepted 17 July 2014
mainstay of management, medical treatment with methotrexate (MTX) has been established as an effective alternative to surgery for treating ectopic pregnancies since the 1980s.2,3 At our institution, the use of MTX has been extended to treat persistent pregnancies of unknown location (PUL) where the ultrasound shows no evidence of intra- or extrauterine pregnancy, the serum beta-hCG is not rising or falling appropriately, and the possibility of a viable intra-uterine pregnancy has been excluded. The most widely accepted protocol for both of these indications is a single-dose intramuscular injection of MTX 50 mg/m2 body surface area (BSA) responsible for.3 This causes minimal side effects and avoids the complications associated with surgery.4 Up to two doses were administered in the original study. As frequent follow-up visits are required to monitor patients’ clinical status, trends in beta-hCG levels and haematological or
© 2014 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists The Australian and New Zealand Journal of Obstetrics and Gynaecology
469
J. Wu et al.
biochemical derangements, it is only suitable for compliant women reliable in returning for medical reviews. Reported success rates in studies employing this single-dose regimen vary between 68 and 95%,3–7 with most studies demonstrating higher treatment success with second or third doses of MTX. Recent studies have consistently shown that a higher pretreatment serum beta-hCG level is associated with lower treatment success.8–10 The role of the serum progesterone level remains unclear. The highest level of beta-hCG at which MTX can be safely administered without increasing the risk of ectopic rupture has not been established. The protocol adopted by the RPAH differs from that originally proposed by Stovall and Ling in that the MTX is administered at 40 mg/m2 BSA. The rationale was to minimise side effects while achieving equivalent efficacy to 50 mg/m2 BSA. Other than a small study comparing the efficacy between 50 mg/m2 and 25 mg/m2,11 the use of the single-dose MTX at a lower dose than 50 mg/m2 has not been reported. Our study objectives were to evaluate the efficacy and safety of the single-dose MTX 40 mg/m2 BSA in the treatment of tubal EP and PUL and to determine whether the serum progesterone level is a predictor of treatment success as measured by the requirement for surgery.
Materials and Methods We undertook a retrospective cohort study to evaluate the efficacy and safety of 40 mg/m2 BSA single-dose MTX in the treatment of tubal EP and PUL at RPAH. The serum progesterone level as a predictor of treatment success was a secondary outcome. Women treated from 1 March 2004 to 30 June 2009 were included in the study. Cases were identified by reviewing computer-generated pharmacy prescriptions of systemic MTX and EPAS encounter records. Women were excluded if they received intramuscular MTX for indications other than tubal EP or persistent PUL. Persistent PUL is defined in our protocol where ultrasound shows no evidence of intra- or extrauterine pregnancy and the serum beta-hCG is not rising (more than 66%) or falling (>50%) appropriately in 48 hours. Following this protocol, viable intra-uterine pregnancies should be safely excluded, and the probability of failed intra-uterine pregnancy is very small. The suitable candidates for single-dose MTX were haemodynamically stable with normal baseline haematological, renal and hepatic function, an adnexal mass ≤3 cm, no free fluid in the pelvis, no embryonic cardiac activity on transvaginal ultrasound, and a serum beta-hCG of ≤10 000 IU/L. Women also had agreed to attend frequent follow-up visits. All women who fulfilled the criteria and consented for medical management were administered 40 mg/m2 BSA intramuscular MTX. Pretreatment serum progesterone level and serum beta-hCG levels on days 0, 4 and 7 were obtained. If a fall of >15% in serum beta-hCG levels between days 4 and 7 was not achieved, a second dose of MTX was administered on day 7. If the decrease in serum 470
beta-hCG between days 4 and 7 was appropriate (>15%), subsequent serum beta-hCG was monitored weekly. Cases were defined as a treatment success if the serum betahCG level decreased to
DOI: 10.1111/ajo.12247
Original Article
Single-dose methotrexate treatment for ectopic pregnancy and pregnancy of unknown location and progesterone as a predictor of success Joyce WU,1 Joanne P. LUDLOW,1,2 Bradley De VRIES,1,2 Kirsten BLACK1,2 and Philip BEALE3 1
RPA Women and Babies, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia, 2Discipline of Obstetrics, Gynaecology and Neonatology, University of Sydney, Camperdown, New South Wales, Australia and 3Cancer Services, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
Background: The use of single-dose intramuscular administration of methotrexate in the treatment of ectopic pregnancies (EP) is a well-established practice. This study evaluates its use at a novel dose of 40 mg/m2 body surface area (BSA). Objective: To evaluate the efficacy and safety of single-dose methotrexate treatment 40 mg/m2 for tubal EP and persistent pregnancies of unknown location (PUL) and determine whether serum progesterone is a predictor of treatment success. Materials and Methods: Retrospective cohort study of patients receiving intramuscular methotrexate 40 mg/m2 for the treatment of EP or PUL at Royal Prince Alfred Hospital over five years. Results: One hundred and eighteen women received single-dose methotrexate with an overall success of 84%. Surgical intervention was needed in 16.6%. Pretreatment beta-hCG level and ectopic diagnosis were independent variables predictive of the need for surgery (P = 0.003 and 0.02, respectively). Serum progesterone level was not predictive of the need for a second dose or surgery. The sensitivity and specificity at pretreatment beta-hCG of 1202 IU/L were 84% and 74%, respectively. Commonly reported side effects included nausea, abdominal pain and heavy vaginal bleeding. Significant treatment-related adverse effects were rare. Conclusion: Single-dose IM methotrexate at a novel dose of 40 mg/m2 is a safe and effective treatment for selected EP and persistent PUL. The risk of surgery was positively correlated to serum beta-hCG level and the diagnosis of EP. Progesterone was not a risk factor for surgery. Further studies are required to confirm the efficacy of this dose regimen and explore the safety of expectant management as an alternative to methotrexate treatment. Key words: ectopic pregnancy, medical management of ectopic pregnancy, methotrexate, pregnancy of unknown location, progesterone.
Introduction Ectopic pregnancies (EP) are a life-threatening condition, responsible for 5% of maternal deaths in high-resource settings.1 Ectopic pregnancies comprise 3% of all early pregnancy presentations to the Early Pregnancy Assessment Service (EPAS) at Royal Prince Alfred Hospital (RPAH) in Sydney, Australia. Early diagnosis of EP allows prevention of significant mortality and morbidity.1 Although surgical intervention remains the
Correspondence: Dr Joyce Wu, RPA Women and Babies Executive Unit, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia. Email: [email protected] Received 23 September 2013; accepted 17 July 2014
mainstay of management, medical treatment with methotrexate (MTX) has been established as an effective alternative to surgery for treating ectopic pregnancies since the 1980s.2,3 At our institution, the use of MTX has been extended to treat persistent pregnancies of unknown location (PUL) where the ultrasound shows no evidence of intra- or extrauterine pregnancy, the serum beta-hCG is not rising or falling appropriately, and the possibility of a viable intra-uterine pregnancy has been excluded. The most widely accepted protocol for both of these indications is a single-dose intramuscular injection of MTX 50 mg/m2 body surface area (BSA) responsible for.3 This causes minimal side effects and avoids the complications associated with surgery.4 Up to two doses were administered in the original study. As frequent follow-up visits are required to monitor patients’ clinical status, trends in beta-hCG levels and haematological or
© 2014 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists The Australian and New Zealand Journal of Obstetrics and Gynaecology
469
J. Wu et al.
biochemical derangements, it is only suitable for compliant women reliable in returning for medical reviews. Reported success rates in studies employing this single-dose regimen vary between 68 and 95%,3–7 with most studies demonstrating higher treatment success with second or third doses of MTX. Recent studies have consistently shown that a higher pretreatment serum beta-hCG level is associated with lower treatment success.8–10 The role of the serum progesterone level remains unclear. The highest level of beta-hCG at which MTX can be safely administered without increasing the risk of ectopic rupture has not been established. The protocol adopted by the RPAH differs from that originally proposed by Stovall and Ling in that the MTX is administered at 40 mg/m2 BSA. The rationale was to minimise side effects while achieving equivalent efficacy to 50 mg/m2 BSA. Other than a small study comparing the efficacy between 50 mg/m2 and 25 mg/m2,11 the use of the single-dose MTX at a lower dose than 50 mg/m2 has not been reported. Our study objectives were to evaluate the efficacy and safety of the single-dose MTX 40 mg/m2 BSA in the treatment of tubal EP and PUL and to determine whether the serum progesterone level is a predictor of treatment success as measured by the requirement for surgery.
Materials and Methods We undertook a retrospective cohort study to evaluate the efficacy and safety of 40 mg/m2 BSA single-dose MTX in the treatment of tubal EP and PUL at RPAH. The serum progesterone level as a predictor of treatment success was a secondary outcome. Women treated from 1 March 2004 to 30 June 2009 were included in the study. Cases were identified by reviewing computer-generated pharmacy prescriptions of systemic MTX and EPAS encounter records. Women were excluded if they received intramuscular MTX for indications other than tubal EP or persistent PUL. Persistent PUL is defined in our protocol where ultrasound shows no evidence of intra- or extrauterine pregnancy and the serum beta-hCG is not rising (more than 66%) or falling (>50%) appropriately in 48 hours. Following this protocol, viable intra-uterine pregnancies should be safely excluded, and the probability of failed intra-uterine pregnancy is very small. The suitable candidates for single-dose MTX were haemodynamically stable with normal baseline haematological, renal and hepatic function, an adnexal mass ≤3 cm, no free fluid in the pelvis, no embryonic cardiac activity on transvaginal ultrasound, and a serum beta-hCG of ≤10 000 IU/L. Women also had agreed to attend frequent follow-up visits. All women who fulfilled the criteria and consented for medical management were administered 40 mg/m2 BSA intramuscular MTX. Pretreatment serum progesterone level and serum beta-hCG levels on days 0, 4 and 7 were obtained. If a fall of >15% in serum beta-hCG levels between days 4 and 7 was not achieved, a second dose of MTX was administered on day 7. If the decrease in serum 470
beta-hCG between days 4 and 7 was appropriate (>15%), subsequent serum beta-hCG was monitored weekly. Cases were defined as a treatment success if the serum betahCG level decreased to
