Australian and New Zealand Journal of Obstetrics and Gynaecology 2015; 55: 181–184
DOI: 10.1111/ajo.12316
Original Article
Serum b-hCG levels post-treatment of ectopic pregnancy with a single dose of intramuscular methotrexate Ignatius E. HADINATA,1 Lex W. DOYLE,1,2 Derrick THOMPSON1 and Leslie RETI1,3 1
The Royal Women’s Hospital, Parkville, 2The Department of Obstetrics and Gynaecology, The University of Melbourne, and 3School of Public Health and Human Biosciences, La Trobe University, Melbourne, Victoria, Australia
Background: The cytotoxic management of ectopic pregnancy using a single dose of intramuscular methotrexate injection has been well established as effective for a select number of women with unruptured tubal ectopic pregnancy where there are minimal symptoms. Aim: The purpose of this study was to create centile curves of serum b-hCG levels following successful treatment with a single dose of 50 mg/m2 of intramuscular methotrexate to treat ectopic pregnancy. Material and Methods: Data were retrieved from women treated at the Royal Women’s Hospital for ectopic pregnancy between 2006 and 2012. Only women with minimal symptoms, initial serum b-hCG ≤5000 IU/L and ectopic mass size of ≤35 mm on ultrasound were included. Two hundred and fifty-three cases of ectopic pregnancy were analysed. Results: Initial b-hCG of women in the study ranged from 18 to 3995 IU/L with a median of 497 (25th to 75th centiles; 222–1160) IU/L. The median levels of b-hCG levels at day 4, 7 and 14 postmethotrexate injection were 73.8, 47.2 and 10.4% of the initial b-hCG level, respectively. The 90th centiles of b-hCG levels at day 4, 7 and 14 were 124.7, 93.8 and 40.0% of initial b-hCG level, respectively. Conclusions: Whilst no comparison with those unsuccessfully treated was made, pending further validation studies, the use of these curves may reduce the reliance on specialist units and streamline care for many women with ectopic pregnancy, such as those whose b-hCG regress in line with centile values without crossing a certain threshold. Key words: ectopic pregnancy, gynaecology, hCG-beta, methotrexate, reproductive medicine.
Introduction Ectopic pregnancy is one of the leading causes of maternal mortality, accounting for 2.5% of all maternal deaths worldwide and 4.9% of all maternal deaths in developed countries according to a 2006 World Health Organization systematic review.1 Since the advent of modern diagnostic and management techniques, the mortality rate from ectopic pregnancy is in steady decline.2 In the 1980s and 1990s, medical management with cytotoxic agents such as methotrexate became accepted as a viable alternative to surgical treatment in a select group of women.3–6 The cytotoxic management of ectopic pregnancy using a single dose of intramuscular methotrexate injection has been well established as effective for a select number of women with unruptured tubal ectopic pregnancy where there are minimal symptoms.7 Stoval et al.8 created a
Correspondence: Dr Ignatius Eric Hadinata, The Royal Women’s Hospital, 20 Flemington Road, Parkville, Vic. 3052, Australia. Email: [email protected] Received 26 May 2014; accepted 3 January 2015.
protocol to treat women with unruptured tubal ectopic pregnancy of 5000 IU/L have a significantly lower rate of success with a single-dose methotrexate regimen.7 Our aim was to produce centiles to show the change in b-hCG levels in women who were successfully treated with a single dose of intramuscular methotrexate at 50 mg/m2. There are studies that attempt to look at other ways of identifying earlier those women who might need further intervention, such as by using the day-4 b-hCG level.10 By creating these centile graphs, we hope to provide a simple tool to assist clinicians in monitoring women with ectopic pregnancy, which has been treated with single dose of intramuscular methotrexate, and to predict whether further intervention is necessary.
Materials and Methods This study was based on the Royal Women’s Hospital (Melbourne, Vic., Australia) which commenced electronic medical record-keeping of this aspect of gynaecological
© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists The Australian and New Zealand Journal of Obstetrics and Gynaecology
181
I. E. Hadinata et al.
admissions in 2006. The study was approved as an audit by the Royal Women’s Hospital Human Research Ethics Committee. The Royal Women’s Hospital pathology service uses the VITROSâ 5600 Integrated System (Ortho Clinical Diagnostics, 100 Indigo Creek Druve, Rochester, NY, USA) to analyse serum b-hCG levels. Interrogation of the inpatient electronic database was made for the years 2006–2012 with the criteria set as follows: Diagnosis: “Abdominal pregnancy” OR “Tubal pregnancy” OR “Ovarian pregnancy” OR “Other ectopic pregnancy” OR “Ectopic pregnancy, unspecified” AND Treatment: “Fetotoxic management for removal of ectopic pregnancy (Intramuscular injection of methotrexate)”. The database query produced 1007 inpatient admissions. These admissions were then manually inspected, and the inclusion and exclusion criteria were applied. Inclusion criteria were the following: admission for ectopic pregnancy, single dose of 50 mg/m2 IM methotrexate, documented ultrasound findings and documented b-hCG levels. Exclusion criteria were the following: multiple doses of methotrexate, non-IM route of administration, surgical intervention, initial b-hCG level of >5000 IU/L and ectopic pregnancy size of
>35 mm on ultrasound. We defined success as progression to an undetectable level of serum b-hCG and the absence of further intervention, such as repeat dosing or surgery. Of 1007 admissions, 156 were identified as multiple admissions for the same case, resulting in 851 unique cases. A further 11 cases were determined to not be ectopic pregnancies (1 intrauterine pregnancy and 10 gynaeoncology conditions). There were 13 cases of ectopic pregnancies that were not treated with intramuscular methotrexate (all were caesarean scar ectopic pregnancies that were treated with methotrexate injection directly into the ectopic pregnancy), 342 cases had no formal ultrasound findings recorded, and 28 cases had no documented b-hCG level. After applying the inclusion criteria, there were 457 cases identified. Applying the exclusion criteria, 118 cases received multiple doses of methotrexate and 61 cases received surgical intervention, leaving 278 cases of ectopic pregnancy treated successfully with a single dose of intramuscular methotrexate. Of these, 21 cases were found to have an ectopic pregnancy >35 mm on USS, and 6 cases had initial b-hCG >5000 IU/L (2 cases had both) leaving 253 cases for analysis.
Figure 1 Absolute b-hCG levels over the first three weeks post administration of methotrexate.
182
© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
b-HCG levels postmethotrexate for ectopic
We included 50 cases of pregnancy of unknown location where ultrasound was unable to locate an ectopic mass, but where the clinician decided to treat these cases of pregnancy of unknown location as likely ectopic pregnancy. The centiles for b-hCG levels for the first three weeks after treatment, starting with the value immediately preceding treatment, were calculated by using the skewness-median-coefficient of variation (LMS) method described by Cole and Green11 and were fitted by using LMS Chartmaker Light version 2.54.12 This method uses three curves, representing the median, coefficient of variation and skewness; the latter is expressed as a BoxCox power.
Results Of the 253 women included in the study, their mean (SD) age was 31.1 (5.7) years, ranging from 18.1 to 47.9 years. In the 203 cases with ectopic masses, the sizes ranged from 4 to 35 mm diameter, with a mean (SD) of 19.4 (6.6) mm. The initial b-hCG of women in the study ranged from 18 to 3995 IU/L with a median (25th to 75th centile) of 497 (222–1160) IU/L.
b-hCG values postadministration of methotrexate are shown as absolute values (Fig. 1) and as a percentage of the initial b-hCG (Fig. 2). Additional data concerning concentrations at various times are shown in the accompanying tables. If the 50 participants with no sac found on ultrasound were excluded, the percentage difference it made to the 90th centile for the % of b-hCG was 0.1% for day 4, 1.1% for day 7, 1.0% for day 14 and 2.2% for day 21.
Discussion In this study, we have created centile curves for both absolute and relative changes in b-hCG levels over the first three weeks after treatment in women who have been successfully treated with the single-dose IM methotrexate regimen. We believe that this is the first attempt at creating such curves in the literature. Strengths of the study include the large number of pregnancies managed in the same tertiary unit that have contributed to the centile curves. In addition, we have included a range of centiles from the 3rd through to the 97th, inclusive, so clinicians might choose which one to follow, depending on an individual women’s characteristics.
Figure 2 Relative b-hCG levels over the first three weeks post administration of methotrexate. © 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
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I. E. Hadinata et al.
We included 50 women with no sac found on ultrasound (i.e. pregnancy of unknown location) to reflect usual clinical practice in managing such cases. Whether their data were included or not had little effect on the centile curves. Weaknesses include the fact that participants who failed single-dose methotrexate treatment were excluded. Hence, a prospective study is needed to validate the predictive value of these curves in clinical practice, where some participants require no further treatment, but where some do require further intervention, including surgery in some cases. Kirk et al.13 reported the b-hCG levels of 45 women successfully treated with single-dose methotrexate over the first seven days after treatment. In their study, the median value was 490 IU/L at day 0 in 30 women, similar to the median value of 522 IU/L the 203 women with value at day 0 in our study. In their study, the bhCG was 349 IU/L on day 4, and 171 (IU/L) on day 7, representing changes from baseline to 71% on day 4 and 35% on day 7. In our study, the corresponding median values were similar at 363 IU/L on day 4, and 176 (IU/ L) on day 7 from the same 203 women with values at day 0, representing changes from baseline of 70% on day 4 and 34% on day 7. The main difference between our study and that of Kirk et al. was that they also reported b-hCG values from 22 women who failed treatment with single-dose methotrexate, a group not included in our study. Figures 1 or 2 could be used by clinicians for women who have been treated with the single-dose methotrexate (50 mg/m2) regimen who meet the criteria outlined above (minimal symptoms, ectopic mass
DOI: 10.1111/ajo.12316
Original Article
Serum b-hCG levels post-treatment of ectopic pregnancy with a single dose of intramuscular methotrexate Ignatius E. HADINATA,1 Lex W. DOYLE,1,2 Derrick THOMPSON1 and Leslie RETI1,3 1
The Royal Women’s Hospital, Parkville, 2The Department of Obstetrics and Gynaecology, The University of Melbourne, and 3School of Public Health and Human Biosciences, La Trobe University, Melbourne, Victoria, Australia
Background: The cytotoxic management of ectopic pregnancy using a single dose of intramuscular methotrexate injection has been well established as effective for a select number of women with unruptured tubal ectopic pregnancy where there are minimal symptoms. Aim: The purpose of this study was to create centile curves of serum b-hCG levels following successful treatment with a single dose of 50 mg/m2 of intramuscular methotrexate to treat ectopic pregnancy. Material and Methods: Data were retrieved from women treated at the Royal Women’s Hospital for ectopic pregnancy between 2006 and 2012. Only women with minimal symptoms, initial serum b-hCG ≤5000 IU/L and ectopic mass size of ≤35 mm on ultrasound were included. Two hundred and fifty-three cases of ectopic pregnancy were analysed. Results: Initial b-hCG of women in the study ranged from 18 to 3995 IU/L with a median of 497 (25th to 75th centiles; 222–1160) IU/L. The median levels of b-hCG levels at day 4, 7 and 14 postmethotrexate injection were 73.8, 47.2 and 10.4% of the initial b-hCG level, respectively. The 90th centiles of b-hCG levels at day 4, 7 and 14 were 124.7, 93.8 and 40.0% of initial b-hCG level, respectively. Conclusions: Whilst no comparison with those unsuccessfully treated was made, pending further validation studies, the use of these curves may reduce the reliance on specialist units and streamline care for many women with ectopic pregnancy, such as those whose b-hCG regress in line with centile values without crossing a certain threshold. Key words: ectopic pregnancy, gynaecology, hCG-beta, methotrexate, reproductive medicine.
Introduction Ectopic pregnancy is one of the leading causes of maternal mortality, accounting for 2.5% of all maternal deaths worldwide and 4.9% of all maternal deaths in developed countries according to a 2006 World Health Organization systematic review.1 Since the advent of modern diagnostic and management techniques, the mortality rate from ectopic pregnancy is in steady decline.2 In the 1980s and 1990s, medical management with cytotoxic agents such as methotrexate became accepted as a viable alternative to surgical treatment in a select group of women.3–6 The cytotoxic management of ectopic pregnancy using a single dose of intramuscular methotrexate injection has been well established as effective for a select number of women with unruptured tubal ectopic pregnancy where there are minimal symptoms.7 Stoval et al.8 created a
Correspondence: Dr Ignatius Eric Hadinata, The Royal Women’s Hospital, 20 Flemington Road, Parkville, Vic. 3052, Australia. Email: [email protected] Received 26 May 2014; accepted 3 January 2015.
protocol to treat women with unruptured tubal ectopic pregnancy of 5000 IU/L have a significantly lower rate of success with a single-dose methotrexate regimen.7 Our aim was to produce centiles to show the change in b-hCG levels in women who were successfully treated with a single dose of intramuscular methotrexate at 50 mg/m2. There are studies that attempt to look at other ways of identifying earlier those women who might need further intervention, such as by using the day-4 b-hCG level.10 By creating these centile graphs, we hope to provide a simple tool to assist clinicians in monitoring women with ectopic pregnancy, which has been treated with single dose of intramuscular methotrexate, and to predict whether further intervention is necessary.
Materials and Methods This study was based on the Royal Women’s Hospital (Melbourne, Vic., Australia) which commenced electronic medical record-keeping of this aspect of gynaecological
© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists The Australian and New Zealand Journal of Obstetrics and Gynaecology
181
I. E. Hadinata et al.
admissions in 2006. The study was approved as an audit by the Royal Women’s Hospital Human Research Ethics Committee. The Royal Women’s Hospital pathology service uses the VITROSâ 5600 Integrated System (Ortho Clinical Diagnostics, 100 Indigo Creek Druve, Rochester, NY, USA) to analyse serum b-hCG levels. Interrogation of the inpatient electronic database was made for the years 2006–2012 with the criteria set as follows: Diagnosis: “Abdominal pregnancy” OR “Tubal pregnancy” OR “Ovarian pregnancy” OR “Other ectopic pregnancy” OR “Ectopic pregnancy, unspecified” AND Treatment: “Fetotoxic management for removal of ectopic pregnancy (Intramuscular injection of methotrexate)”. The database query produced 1007 inpatient admissions. These admissions were then manually inspected, and the inclusion and exclusion criteria were applied. Inclusion criteria were the following: admission for ectopic pregnancy, single dose of 50 mg/m2 IM methotrexate, documented ultrasound findings and documented b-hCG levels. Exclusion criteria were the following: multiple doses of methotrexate, non-IM route of administration, surgical intervention, initial b-hCG level of >5000 IU/L and ectopic pregnancy size of
>35 mm on ultrasound. We defined success as progression to an undetectable level of serum b-hCG and the absence of further intervention, such as repeat dosing or surgery. Of 1007 admissions, 156 were identified as multiple admissions for the same case, resulting in 851 unique cases. A further 11 cases were determined to not be ectopic pregnancies (1 intrauterine pregnancy and 10 gynaeoncology conditions). There were 13 cases of ectopic pregnancies that were not treated with intramuscular methotrexate (all were caesarean scar ectopic pregnancies that were treated with methotrexate injection directly into the ectopic pregnancy), 342 cases had no formal ultrasound findings recorded, and 28 cases had no documented b-hCG level. After applying the inclusion criteria, there were 457 cases identified. Applying the exclusion criteria, 118 cases received multiple doses of methotrexate and 61 cases received surgical intervention, leaving 278 cases of ectopic pregnancy treated successfully with a single dose of intramuscular methotrexate. Of these, 21 cases were found to have an ectopic pregnancy >35 mm on USS, and 6 cases had initial b-hCG >5000 IU/L (2 cases had both) leaving 253 cases for analysis.
Figure 1 Absolute b-hCG levels over the first three weeks post administration of methotrexate.
182
© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
b-HCG levels postmethotrexate for ectopic
We included 50 cases of pregnancy of unknown location where ultrasound was unable to locate an ectopic mass, but where the clinician decided to treat these cases of pregnancy of unknown location as likely ectopic pregnancy. The centiles for b-hCG levels for the first three weeks after treatment, starting with the value immediately preceding treatment, were calculated by using the skewness-median-coefficient of variation (LMS) method described by Cole and Green11 and were fitted by using LMS Chartmaker Light version 2.54.12 This method uses three curves, representing the median, coefficient of variation and skewness; the latter is expressed as a BoxCox power.
Results Of the 253 women included in the study, their mean (SD) age was 31.1 (5.7) years, ranging from 18.1 to 47.9 years. In the 203 cases with ectopic masses, the sizes ranged from 4 to 35 mm diameter, with a mean (SD) of 19.4 (6.6) mm. The initial b-hCG of women in the study ranged from 18 to 3995 IU/L with a median (25th to 75th centile) of 497 (222–1160) IU/L.
b-hCG values postadministration of methotrexate are shown as absolute values (Fig. 1) and as a percentage of the initial b-hCG (Fig. 2). Additional data concerning concentrations at various times are shown in the accompanying tables. If the 50 participants with no sac found on ultrasound were excluded, the percentage difference it made to the 90th centile for the % of b-hCG was 0.1% for day 4, 1.1% for day 7, 1.0% for day 14 and 2.2% for day 21.
Discussion In this study, we have created centile curves for both absolute and relative changes in b-hCG levels over the first three weeks after treatment in women who have been successfully treated with the single-dose IM methotrexate regimen. We believe that this is the first attempt at creating such curves in the literature. Strengths of the study include the large number of pregnancies managed in the same tertiary unit that have contributed to the centile curves. In addition, we have included a range of centiles from the 3rd through to the 97th, inclusive, so clinicians might choose which one to follow, depending on an individual women’s characteristics.
Figure 2 Relative b-hCG levels over the first three weeks post administration of methotrexate. © 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
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I. E. Hadinata et al.
We included 50 women with no sac found on ultrasound (i.e. pregnancy of unknown location) to reflect usual clinical practice in managing such cases. Whether their data were included or not had little effect on the centile curves. Weaknesses include the fact that participants who failed single-dose methotrexate treatment were excluded. Hence, a prospective study is needed to validate the predictive value of these curves in clinical practice, where some participants require no further treatment, but where some do require further intervention, including surgery in some cases. Kirk et al.13 reported the b-hCG levels of 45 women successfully treated with single-dose methotrexate over the first seven days after treatment. In their study, the median value was 490 IU/L at day 0 in 30 women, similar to the median value of 522 IU/L the 203 women with value at day 0 in our study. In their study, the bhCG was 349 IU/L on day 4, and 171 (IU/L) on day 7, representing changes from baseline to 71% on day 4 and 35% on day 7. In our study, the corresponding median values were similar at 363 IU/L on day 4, and 176 (IU/ L) on day 7 from the same 203 women with values at day 0, representing changes from baseline of 70% on day 4 and 34% on day 7. The main difference between our study and that of Kirk et al. was that they also reported b-hCG values from 22 women who failed treatment with single-dose methotrexate, a group not included in our study. Figures 1 or 2 could be used by clinicians for women who have been treated with the single-dose methotrexate (50 mg/m2) regimen who meet the criteria outlined above (minimal symptoms, ectopic mass
