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 protocol to treat women with unruptured tubal ectopic

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
pregnancy of <35 mm in size on ultrasound, where a
single dose of methotrexate (50 mg/m2) was given as an
intramuscular injection. Furthermore, it has been found
that pretreatment serum b-hCG level is a significant
predictor of treatment success9 and that women with
levels 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.

Correspondence: Dr Ignatius Eric Hadinata, The Royal Materials and Methods

Women’s Hospital, 20 Flemington Road, Parkville, Vic. 3052,
Australia. Email: eric@hadinata.com.au This study was based on the Royal Women’s Hospital
(Melbourne, Vic., Australia) which commenced electronic
Received 26 May 2014; accepted 3 January 2015. medical record-keeping of this aspect of gynaecological

© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists 181
The Australian and
New Zealand Journal
of Obstetrics and
Gynaecology
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
Figure 1 Absolute b-hCG levels over the first three weeks post administration of methotrexate.
182
>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 pregnan-
cies 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.
© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists

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 Box-
Cox 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.
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
b-HCG levels postmethotrexate for ectopic
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.
183
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 b-
hCG 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 <35 mm on ultrasound
and initial b-hCG level <5000 IU/L), to predict whether
or not the treatment is likely to succeed. The percentage
change curve (Fig. 2) might be preferable in clinical
practice to the centile curve for absolute b-hCG level
(Fig. 1) due to the wide variability of initial b-hCG levels.
However, whichever method is used and whichever centile
proves most useful would need to be prospectively
evaluated to ensure that no troublesome ectopic pregnancy
goes undetected.
A major limitation of this study is that by design,
women who had unsuccessful treatment were excluded.
Therefore, our next step is to do a prospective study to
determine if women whose b-hCG level regress in line
with centile values, without crossing a certain threshold
(such as the 90th centile), can be followed up safely and
exclusively in the nonspecialist setting. Pending further
validation studies, the use of such curves may be able to
reduce the reliance on specialist units and streamline care
for many women with ectopic pregnancy.
184 © 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
Caution should be used when extrapolating this graph
to monitor women who do not meet the criteria used in
this study. It also should not be used to monitor women
who underwent a different treatment regiment, such as
different methotrexate dose, multiple dosing regimen or
nonintramuscular administration route.
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