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Causes
Clinical
assessment
Investigation
Managing
miscarriage and
ectopic pregnancy
Recurrent
miscarriage
The author
DR KRISTY MILWARD,
sessional obstetric and
gynaecological sonologist,
ultrasound department, King
Edward Memorial Hospital,
Subiaco, WA.
Early pregnancy
BLEEDING
Background
EARLY pregnancy bleeding is
common, affecting up to 40% of
pregnant women. As such it is an
extremely common reason for presentation to general practice and
emergency services.
However, in many cases it does not
represent a true medical emergency
(albeit an emotional one) and, with a
logical approach to assessment, the
pregnant woman can often be reassured and the correct diagnosis
obtained with a minimum of reviews.
It has been shown that early pregnancy assessment units offer a clinical
and economic advantage in the care
of women with suspected early pregnancy loss. Such dedicated units are
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gradually becoming more available
to receive referrals from GPs.
However, many women still have
limited access to dedicated services
and, with understanding of the issues
at hand, the GP is still in an excellent
position to provide the necessary
basic care.
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16 October 2009 | Australian Doctor |
21
HOW TO TREAT Early pregnancy bleeding
Causes of early pregnancy bleeding
BLEEDING may represent a
range of conditions of early
pregnancy (table 1).
The term threatened miscarriage refers to bleeding
that occurs in a pregnancy
that is otherwise progressing
normally by clinical assessment and investigation. After
fetal cardiac motion has
become detectable on ultrasound, more than 90% of
threatened miscarriages will
continue with normal gestation. The cause of the bleeding usually relates to disruption of maternal vessels in
the decidua.
Miscarriage is the loss of
a pregnancy under 20 weeks
of gestation. Most occur in
the first trimester and a variety of terms is used to
describe different clinical presentations (table 2). However, the underlying process
and end result for the patient
are the same.
Molar pregnancy (hydatidiform mole) affects only an
estimated one in 1000 pregnancies. It includes partial
and complete mole.
Table 1: Causes of bleeding in early pregnancy
Threatened miscarriage
Figure 1: Ultrasound of complete molar pregnancy. The uterus is
filled with cystic placental villi, with no associated fetus.
Miscarriage (including incomplete/retained products of
conception)
Molar pregnancy
Ectopic pregnancy
Extrauterine sources — cervical bleeding (ectropion, polyps,
atypia)
Table 2: Clinical presentations of miscarriage
Complete miscarriage — spontaneous expulsion of products
of conception, with resolution of symptoms
Incomplete miscarriage — bleeding and cramping, with
products of conception visible in the uterine cavity
Missed miscarriage — non-viable, intact gestation sac within
the uterus, with delay to onset of symptoms of miscarriage
type but derived only from
paternal genetic material. It
is believed to be caused by
fertilisation of an empty
ovum by a single sperm, the
chromosomes of which are
then duplicated. The condition is associated with:
• Development of a large
hydropic placenta.
• High beta human chorionic gonadotrophin (betahCG) levels (and associated
symptoms,
particularly hyperemesis
Blighted ovum/anembryonic pregnancy — generally refers to
a missed miscarriage in which embryonic development
stopped before the embryonic pole was visible. The gestation
sac may continue to grow
Partial mole is associated
with a triploid karyotype. It
is believed to be caused by
fertilisation of a normal haploid ovum by two haploid
sperm. A fetus develops but
early demise is common
because of the karyotypic
anomaly. The placental
changes can be subtle and
may be unrecognised unless
histopathology of products
of conception is obtained
after curettage.
Complete mole is associated with a diploid karyo-
and sometimes hyperthyroidism).
• Uterine enlargement greater
than expected for gestation.
Ultrasound reveals a
uterus filled with cystic placental villi, with no associated fetus (figure 1). Because
of the risk of persistent gestational trophoblastic disease,
referral to a specialist is
appropriate for surgical evacuation, histopathology and
advice about subsequent
follow-up or management.
Ectopic pregnancy results
when implantation of the
conceptus occurs at a site
other than the uterine cavity.
It affects 1% of pregnancies,
and almost all (about 98%)
occur within the fallopian
tubes. Other potential sites
of implantation include the
peritoneal cavity, uterine
cornu (interstitium), caesarean scar, ovary and cervix.
Vaginal bleeding unrelated
to the pregnancy must
always be considered, to
avoid missing uncommon
but serious secondary
pathology.
Clinical assessment
History
A CLEAR history is vital not only in
establishing the likely diagnosis but
also in guiding appropriate investigation. The prior obstetric and gynaecological history, contraceptive use,
pattern of bleeding and associated
symptoms can help differentiate
between the possible causes of bleeding.
The menstrual cycle, contraceptive
use and date of first confirmation of
pregnancy can help to estimate the
likely gestational age. Accurate estimation of gestational age helps both
to guide appropriate investigation and
to interpret results.
Therefore the history should
include, at a minimum, the points
listed in table 3.
Examination
Clinical examination should be
directed by the history. Vital signs
must be assessed when bleeding is
heavy or pain is severe. Abdominal
palpation is necessary to assess the
location and severity of abdominal
pain, including presence of an ‘acute
abdomen’.
If concern exists about the possibil-
Table 3: Questions to ask the woman with early pregnancy bleeding
What is her age? Miscarriage risk increases with maternal age
What was the first day of last menstrual period (LMP) (with an indication as to the degree of certainty)?
Is the cycle regular? Ovulation can be predicted to have occurred 14 days before the first missed cycle
What is the cycle length? Standard pregnancy dating wheels assume a 28-day cycle; short cycles have early ovulation
before day 14, long cycles have late ovulation beyond day 14
Were any contraceptive hormones in use at the time of conception? Ovulation timing cannot be predicted by LMP if this
were the case
Is an IUD in situ? Although pregnancy is uncommon, up to 50% may be ectopic
What was the first date of confirmation of pregnancy (by urine human chorionic gonadotrophin [UhCG] or other)? This
date provides a degree of certainty that the patient was at least four weeks pregnant at that time
What outcomes have occurred from previous pregnancies, including mode of delivery? Ectopic pregnancy has a 5-15%
recurrence rate; recurrent miscarriage increases the risk of repeat miscarriage
Was there any delay to conception? Subfertility is associated with an increased risk of ectopic pregnancy
Is there any history of gynaecological disease — endometriosis, pelvic infection (associated with increased risk of
ectopic pregnancy)?
What is the pattern of bleeding? Light prolonged spotting suggests ectopic pregnancy; fresh, heavy or clots is more
suggestive of miscarriage
Is there associated pain and, if so, what is the nature — crampy, sharp, central, unilateral?
Have any ultrasounds or blood tests already been performed during this pregnancy? What were the results?
What was the date and result of the last Pap smear?
What is the patient’s blood group? Rhesus D-negative women who are not iso-immunised will require prophylactic Rh
(D) immunoglobulin (anti-D)
ity of cervical bleeding, a speculum
examination should be performed. If
a recent Pap smear is normal, it may
be reasonable to delay speculum
examination until there have been
repeated episodes of bleeding.
In a woman with heavy vaginal
bleeding and associated cramping
pain, speculum examination should
be performed early, as products of
conception may be caught in the
cervix and visible at the external
os. Removal of such products (with
a pair of sponge forceps) will frequently result in rapid abatement
of symptoms.
Bimanual palpation of the pelvic
organs may aid in estimating gestation (from uterine size) or assessing pelvic pain, with the finding of
‘cervical excitation’ suggestive of
ectopic pregnancy. Cervical excitation refers to pain felt when the
cervix is rocked laterally — classically the pain should occur when
the cervix is rocked to the side of
the ectopic, thereby pushing the
fundus to the contralateral side and
stretching the adnexal tissues and
fallopian tube. However, it is neither a sensitive nor specific finding.
Investigation
AS with all areas of clinical
examination, investigation
should be directed by the
history and examination
findings. Each test requested
should aim to answer a specific clinical question and
direct further management
accordingly.
Quantitative beta-hCG
level
There are two primary uses
for a beta-hCG level. The
first is as a single level to
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| Australian Doctor | 16 October 2009
assist in the interpretation
of ultrasound findings.
The discriminatory level at
which an intrauterine pregnancy should be visible
varies slightly between laboratories and mode of ultrasound (transabdominal
versus transvaginal). With
the current quality of image
resolution, a healthy gestation sac is often visible with
transvaginal sonography at a
beta-hCG level of 1500 IU/L.
If a patient with a beta-
hCG above the discriminatory level has no intrauterine sac (or retained products
of conception) visible, the
differential diagnosis then
falls to ectopic pregnancy or
complete
miscarriage.
Therefore the initial betahCG level can be used to
help determine the information that an ultrasound
could provide.
The second use of betahCG is in serial testing for
assessing pregnancies too
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early to demonstrate by
ultrasonography (or where
such facilities are not available). After conception,
hCG is detectable in maternal plasma after 7-8 days.
Mainly produced in the
cells of the trophoblast,
levels rise rapidly and, in
healthy early pregnancy,
double every 48-72 hours.
Levels that rise appropriately are strongly suggestive
of a normal intrauterine
pregnancy. Falling results
(assuming gestation less
than 10 weeks) indicate a
failing pregnancy. Ectopic
pregnancies are often associated with levels that rise
slowly, plateau or even fluctuate.
Maximum beta-hCG
levels are obtained at about
10 weeks, after which there
is a gradual decline to 20
weeks, at which time they
stabilise. Serial testing is
therefore of most use
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HOW TO TREAT Early pregnancy bleeding
from page 22
between four and six weeks,
when ultrasonography is less
helpful.
After a gestation sac has
been identified in the uterus,
beta-hCG results can become
confusing, as levels can continue to rise in the absence
of a live fetus if trophoblastic
tissue is healthy. Beyond 10
weeks, serial testing should
not be performed, as levels
will fall naturally and this
may be confused with a failing pregnancy.
Because of the extremely
wide variation in normal
beta-hCG levels for each
stage of gestation, this test
cannot be reliably used as a
guide to gestational age of an
undated pregnancy. Instead,
if dating is unknown, it
should be used to indicate
the appropriate timing of
ultrasound examination (ie,
after levels have risen above
the discriminatory level).
Table 4: Typical gestation at which key findings can be made by ultrasound
Ultrasound
finding
Gestation for transvaginal scan
Gestation for
transabdominal scan
Intrauterine
gestation sac
Earliest four weeks and three days (sac
size 2mm*)
Latest five weeks and two days
Latest six weeks
Yolk sac visible
Five weeks and three days
Earliest five weeks and five days
Latest seven weeks
Embryonic pole Five weeks and six days
Earliest six weeks
Latest eight weeks
Cardiac activity
CRL ≥ 5mm
Earliest five weeks and six days (CRL= 2mm)
Latest six weeks and two days (CRL ≥ 5mm)
*Minimum size at which the sac can be detected, but not always distinguishable from a pseudosac at this size
CRL = crown–rump length
from miscarrying intrauterine pregnancies and it is not
possible to define a single
level at which viability (or
otherwise) can be confirmed.
Many authors have used
progesterone (and other biochemical markers) in models
aimed at predicting the success of conservative management of failing pregnancies.
Progesterone
Ultrasound
Serum progesterone levels are
higher in healthy intrauterine pregnancies than in
ectopic pregnancies or in
pregnancies that ultimately
miscarry. In the setting of a
pregnancy of unknown location, levels <25nmol/L are
unlikely to be associated with
a healthy, ongoing pregnancy.
However, ectopic pregnancies cannot be differentiated
With the continuously
improving
resolution
obtained from modern ultrasound machines (including
endo-cavitary probes) ultrasonography is increasingly
able to answer the important
questions raised when there
is bleeding in early pregnancy:
• What is the location of the
pregnancy?
• What is the gestation of the
pregnancy?
• Is a live embryo or fetus
present (and if so, how
many)?
• Is any placental pathology
apparent?
Additionally, ultrasound is
a highly acceptable investigation to the vast majority of
pregnant women. Although
invasive, with explanation of
the benefits most women will
also accept transvaginal
sonography, which is generally a painless examination
(and often better tolerated
than a transabdominal scan
with a very full bladder).
Table 4 shows the typical
gestation at which key findings can be made by ultrasound.
When referring any patient
for an ultrasound it is impor-
tant to keep in mind the
expected findings for the
known (or suspected) gestation and the questions that
ultrasound will be able to
answer.
Ultrasound has the advantage of providing immediate
information, which in many
situations (especially when
gestation is greater than six
weeks) will be conclusive
with a single examination.
However, ultrasound is more
costly than pathology testing
(MBS provides $60 for early
pregnancy scan and $28 for
beta-hCG).
Thus to minimise costs to
the state and patient budgets
and maximise useful information in a timely manner,
the clinical history and examination findings should direct
the physician to choose the
most appropriate initial
investigation.
At any time that an ultrasound is expected to be conclusive it makes sense that
this should be first line, and
biochemistry is likely to be
superfluous. In the setting of
a pregnancy of uncertain
location, biochemistry can be
added to aid in interpretation
of the ultrasound findings.
If an intrauterine gestation
is seen, but of uncertain viability, repeat ultrasound in 710 days is most likely to be
the most effective follow-up.
If the history suggests that
the gestation is too early to
expect that ultrasound will
contribute to the assessment,
serial beta-hCG should be
used until levels are high
enough to warrant ultrasound examination (or until
there is clinical suspicion of
ectopic pregnancy).
Pregnancies of unknown
location
These are defined by a positive beta-hCG test, with no
ultrasound evidence of
intrauterine or extrauterine
pregnancy, and no retained
products of conception
(RPOC). Serial beta-hCG
monitoring is indicated.
Ultrasonography should be
repeated if the level rises
above the discriminatory
zone, plateaus at <1500 IU/L
or there is onset of new
symptoms, suggestive of
ectopic pregnancy.
If the level is falling, conservative management is reasonable, but continued
monitoring is necessary until
the beta-hCG test is negative.
Low progesterone levels
are predictive of pregnancies
of unknown location likely
to resolve spontaneously.
Algorithms have been
described to aid in the management of these pregnancies. Histological examination of any tissue passed
vaginally is helpful in confirming the diagnosis of miscarriage and excluding an
ectopic pregnancy.
Management of miscarriage
THREE options exist for the management of miscarriage — conservative, medical and surgical.
Conservative management
Conservative management involves
awaiting events with the expectation that miscarriage will occur and
be completed without need for
medical intervention. The patient
should be counselled about expectations. This includes heavy vaginal
bleeding (heavier than a typical
menstrual bleed) with more cramping discomfort or pain.
Blood loss and pain typically
reach a peak as the sac is passed
— the patient may have passage of
clots, or may even note the presence of membranous tissue. After
the sac has been passed, symptoms
of pain typically ease rapidly and
vaginal loss gradually slows.
Patients should be advised to represent if bleeding is persisting or
there are symptoms of infection
(ongoing bleeding, malodorous discharge, lower abdominal pain, fever
and other systemic symptoms). They
should also be advised to present to
emergency care if bleeding is very
heavy or pain is unmanageable with
local heat packs, simple oral analgesics and NSAIDs.
The difficulty with this management option is selecting an appropriate population for whom success
is likely. Studies have shown that
completion of miscarriage is more
likely in women with:
• A smaller gestation sac.
• Incomplete (as compared with
missed) miscarriage.
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• Lower levels of beta-hCG and
progesterone.
In the setting of a missed miscarriage, onset of bleeding may not be
for several weeks and, for practical
as well as emotional reasons, this
may be unacceptable to many
women. When conservative management is selected, regular review
is reasonable to ensure the patient
is still happy with her choice and to
reconsider intervention (medical or
surgical) if time is passing without
miscarriage occurring.
If bleeding occurs and takes a
course suggestive of complete miscarriage, it is not necessary to
repeat the ultrasound scan as a
matter of routine. However, complete miscarriage can be difficult to
diagnose clinically and, if there is
ongoing bleeding, or symptoms of
infection, ultrasound is appropriate to evaluate for possible RPOC
or endometritis.
Be aware that RPOC can be a
difficult diagnosis on ultrasound,
and when heterogeneous echoes are
present with a total anteroposterior thickness <15mm, histological
confirmation of retained products
after curettage is less likely. Conservative management is usually
appropriate in this setting.
Pelvic infection rates appear to
be lower in the setting of expectant management, and prophylactic
antibiotics are not indicated.
Medical management
Medical management involves use
of medication to induce uterine
contractions and evacuate the uterine contents. Misoprostol is a commonly used agent in this setting.
When given as a single vaginal
dose of 800μg, 70% of women will
progress to complete miscarriage
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within three days. A repeat dose
can be given to women with
RPOC, resulting in successful treatment of up to 50% of these women
(15% overall failure rate). Some
bleeding may persist for as long as
three weeks.
Medical evacuation is probably
best suited to women with early
pregnancy demise and a small fetal
pole, as more advanced gestations
will typically be associated with
blood loss or pain levels that are
not acceptable to the patient,
resulting in their presentation to
emergency care during the course
of the miscarriage. Patients should
be aware of what to expect and
when to present for further attention.
Surgical management
Referral is required for women for
whom surgical management is
desired. Patient preference (avoiding
delay or bleeding associated with
other methods) or other factors
may determine need for surgical
management. Surgical management
is required for:
• Late miscarriage, with a larger
fetal pole.
• Heavy bleeding in the setting of
spontaneous or medically managed miscarriage.
• Suspected secondary infection
with sepsis.
Evacuation of the uterus by suction D&C is typically performed
under general anaesthesia. The
cervix is dilated by mechanical
means (although medical ripening
with vaginal misoprostol, typically
at a dose of 400μg, may be performed before surgery) and suction
is used to remove products of conception. Metal curette instruments
may be used to check the cavity is
empty, although this is not essential.
Risks of this method include:
• Cervical trauma.
• Uterine perforation (with the
potential further complication of
bowel injury).
• Retained products.
• Infection.
• Development of Asherman’s syndrome (which, if severe, may
obliterate the cavity, preventing
further pregnancy).
It has the advantage of providing
a reasonably safe method of emptying the uterus quickly, with minimal discomfort for the patient, and
lower blood loss. Return to normal
physical health is rapid and many
women seem to consider this
method the least emotionally traumatic, as they do not have to experience the physical aspects of the
miscarriage.
The appropriate management
choice for any one patient will
depend on a variety of factors,
including the gestational age, ultrasound findings, surgical risk factors and patient’s preference and
previous experiences. If uncertain,
patients can be referred to early
pregnancy assessment units, where
they can receive further counselling
about their options, and be provided medical treatment or a booking for day surgery admission for
curettage if desired.
Management of ectopic pregnancy
OF all ectopic pregnancies,
98% occur in the fallopian
tube, and the following primarily addresses the management of these.
Before the common use of
ultrasound to permit early
diagnosis of ectopic pregnancy, many cases represented surgical emergencies
and were treated by salpingectomy. However, with
very early diagnosis, the risk
of significant maternal
haemorrhage is lower,
thereby permitting more
conservative management.
Referral of any patient
with a suspected ectopic
pregnancy is appropriate, at
the earliest possible convenience. Unstable patients
should be transferred as an
emergency, after institution
of basic resuscitative needs
(IV line, fluids).
The decision about choice
of management is made on
an individual basis, taking
into account the patient’s:
• Clinical condition.
• Reproductive history.
• Desire for future fertility.
• Risk factors for surgery
and medical management.
• Investigation findings.
Surgical treatment may be
performed via laparotomy or
laparoscopy. The two surgical options are salpingec-
Before the
common use of
ultrasound to
permit early
diagnosis of
ectopic
pregnancy, many
cases represented
surgical
emergencies and
were treated by
salpingectomy.
tomy, excising the affected
fallopian tube with the pregnancy intact, and salpingotomy, incising the tube over
the pregnancy and removing
trophoblastic tissue with forceps, leaving the tube to
heal.
The advantages of salpingectomy include lower
recurrence rate of subsequent ectopic pregnancies,
(with still reasonably high
intrauterine pregnancy
rates), and no need for postoperative serial beta-hCG
monitoring. However, the
cost is infertility if the contralateral tube is lost to sub-
sequent ectopic pregnancy or
is already obstructed by the
underlying process, which
may have caused the ectopic.
Tubal conservation by
salpingotomy may not be
possible if significant tubal
damage is noted at the time
of surgery, or if haemostasis
cannot be achieved. If conservation is successful, betahCG levels must be monitored until negative, because
of the possibility of retained
trophoblastic tissue.
Future fertility rates with
salpingotomy are slightly
higher than for salpingectomy (85% versus 80%),
but this is at the cost of a
significantly higher rate of
recurrent ectopic pregnancy
(15% versus 5%).
Medical management by
systemic methotrexate is
suitable for patients who
meet certain clinical criteria.
They must be clinically
stable and willing to attend
for serial review and quantitative beta-hCG tests. The
initial beta-hCG level should
be below a threshold level
(which may differ between
hospital laboratories and
protocols).
Any adnexal mass visible
on ultrasound should be
small and without a live
embryo. Free fluid should be
of small volume or absent.
Additionally patients should
not have medical conditions
that prevent use of
methotrexate.
Medical management may
also be indicated after failed
surgical treatment, such as persisting beta-hCG after salpingotomy.
Methotrexate is administered intramuscularly at a dose
of 1mg/kg (or 50mg/m 2 of
body surface area) after baseline haematology and biochemistry. Admission to hospital is typically recommended,
in case of tubal rupture as the
ectopic tissue initially swells.
Recurrent miscarriage — when and how to investigate
MISCARRIAGE is a frequent
event. Up to 15% of all conceptions are lost before implantation. An estimated 15% of
recognised pregnancies are lost
in the early stages of pregnancy.
As gestation advances, the
miscarriage risk declines, with
fewer than 5% of live pregnancies over eight weeks’ gestation
ending in miscarriage. For most
women (>80%) a successful
pregnancy will follow a miscarriage, or even two consecutive
miscarriages.
The most commonly used
definition of recurrent miscarriage is three consecutive pregnancy losses (a situation that
affects about 1% of women,
but by chance alone would be
expected to affect 0.34%).
After three miscarriages the
chance of success in the subsequent pregnancy is still up to
75%. However, an underlying
cause may be present in 50%
of couples, so investigation is
warranted after three consecutive losses.
Earlier investigation (after
two miscarriages) may be reasonable in the setting of
advanced maternal age, relative
infertility or if there are points
in the medical history that suggest the possibility of an underlying condition. However, if the
couple are young and otherwise
healthy, investigation is unlikely
to be beneficial after just two
losses, although empathy and
support are vital because of the
high level of anxiety found in
Table 5: Causes of recurrent miscarriage
Maternal age — associated with increased aneuploidy rates
Parental genetic factors — balanced translocations, mosaicism
Thrombophilic disorders — antiphospholipid antibodies, inherited
thrombophilias
Endocrine disorders — diabetes mellitus, thyroid autoantibodies
Uterine anatomical disorders — congenital malformations, cervical
incompetence
Table 6: Routine investigations for recurrent miscarriage
Pelvic ultrasound — 3D gynaecological imaging ± sonohysterography
to further evaluate the cavity
Antiphospholipid antibody screen (lupus anticoagulant, anticardiolipin
antibodies — IgG and IgM, antinuclear factor)
Thrombophilia screen (antithrombin III, proteins C and S, activated
protein C resistance (APCR) ± factor V Leiden mutation if APCR
positive)
Thyroid peroxidase antibodies and TSH/free T4
Parental karyotyping
Table 7: Other investigations for recurrent miscarriage
Glucose tolerance test or glycated haemoglobin (if strong family history
or other clinical reason to suspect undiagnosed diabetes)
Day 3 FSH (marker of ovarian reserve)
Luteinising hormone:FSH ratio, sex-hormone-binding globulin,
testosterone and free androgen index in women with long cycles
Prolactin levels
couples with multiple miscarriages.
Numerous factors may be
involved in the aetiology of
recurrent miscarriage. Causes of
recurrent miscarriage are listed
in table 5.
Depending on the underlying
diagnosis (if one is present)
treatment may be available,
although there is still a relative
lack of evidence regarding the
most appropriate strategies to
manage varying conditions.
A thorough history is the
starting point in assessing recurrent miscarriages. Details of the
miscarriages should be obtained
(methods of confirmation of
pregnancy, gestation at miscarriage, findings of any investigations performed at the time) as
this may point to different possible underlying causes (eg, chromosomal or endocrine in early
loss; anatomical in later loss).
The menstrual, medical and
relevant surgical history should
be obtained, as should a family
history of recurrent miscarriage
or thrombosis.
General physical examination
may yield findings suggestive of
endocrine disease, but most conditions associated with recurrent
miscarriage and amenable to
treatment are diagnosed with
laboratory investigations.
A list of investigations for
women with recurrent miscarriage is provided in table 6.
Other investigations are less
likely to be beneficial, but may
be warranted in some patients,
depending on the clinical history
and results of other tests (see
table 7). Because of the lack of
consensus over investigation and
management of recurrent pregnancy loss, referral to a specialist for advice is appropriate after
preliminary investigation.
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Serial beta-hCG testing is
performed according to protocols of the institution —
typically twice a week initially, until readings fall
below a certain level, after
which weekly testing is
acceptable. Monitoring continues until the beta-hCG
test is negative, which may
take four weeks or more.
Patients must use contraception for three months.
The anti-folate action of
methotrexate increases the
risk of neural tube defects
in subsequent pregnancies if
sufficient delay does not
occur. Therefore high-dose
(5mg daily) folate supplementation is necessary when
there is unintended early
pregnancy.
Comparison of medical
and surgical management
(single IM methotrexate
versus salpingotomy) shows
similar success rates, future
reproductive success and
ectopic recurrence rates.
Adverse effects are more
common with medical treatment, and length of followup
more
prolonged,
although immediate recovery is faster. Overall costs of
successful medical treatment
are lower and patient satisfaction is reported to be
improved.
Summary of recommendations
Referral of patients to a dedicated early
pregnancy assessment unit (if available) is
associated with clinical and economic
advantages — Level IV evidence.
Expectant management of incomplete
miscarriage is highly effective — Level Ib
evidence.
Medical treatment of incomplete and early
miscarriage is an alternative to surgical
evacuation, with similar efficacy — Level Ib
evidence.
Vaginal, sublingual and oral dosing of
misoprostol have similar efficacy for medical
uterine evacuation — Level Ib evidence.
Medical treatment of missed miscarriage
requires a higher dose (or longer duration of
treatment) with misoprostol — Level Ib evidence.
Histological examination of tissue passed at
spontaneous or medically managed miscarriage
is desirable, particularly to confirm the diagnosis
of miscarriage and exclude ectopic pregnancy
and gestational trophoblastic disease — Level IV
evidence.
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16 October 2009 | Australian Doctor |
25
HOW TO TREAT Early pregnancy bleeding
Author’s case studies
Early light spotting with a
history of previous
miscarriage
A 26-YEAR-old woman presents with one day of light spotting in early pregnancy. She has
had a previous nine-week miscarriage. Her menstrual cycle
is regular, 24 days in length
and her last menstrual period
began five weeks ago. She had
a positive urine hCG one week
ago. She has had no pain. Her
Pap smears are up to date and
the last result was normal. Her
blood group is A-negative
(antibody screen negative).
Her pulse is 80 beats per
minute and blood pressure
105/60mmHg. Her abdomen
is soft and non-tender. Speculum examination is not performed.
At five weeks’ gestation,
with positive urine test a week
earlier, a transvaginal ultrasound might show a small
intrauterine gestation sac
(assuming all is well), but no
yolk sac or fetal pole. However, pregnancy may be more
advanced because of the
shorter cycle.
If no sac is visible, the differential diagnosis would include
early miscarriage, ectopic or
normal intrauterine pregnancy
with ovulation later than
expected (and positive urine at
the limits of sensitivity).
There is nothing in the history that suggests urgency of
investigation, although with the
history of miscarriage, the
woman is likely to be anxious.
An ultrasound performed as
the initial investigation may be
able to confirm intrauterine
gestation or may reveal a small
adnexal mass if the location is
ectopic. It is likely that a fetal
pole will not be seen, which
may then prompt a further
ultrasound a week later.
If biochemistry is chosen as
the initial investigation, a single
test will need to be followed
either by ultrasound (if the
result is above the discriminatory level) or further testing in
2-3 days if the result is lower
than expected. Either option
may be taken.
If the patient can be reassured, selecting ultrasound as
the initial option, but delaying
the examination by a couple of
days, may help to improve the
chance of a conclusive result.
Alternatively, two beta-hCG
levels 72 hours apart, with an
Take-home messages
Figure 2: The tiny fetal pole is immediately adjacent to the yolk
sac.
Figure 3: M-mode confirms fetal cardiac activity.
Figure 4: The endometrium is regular, with no evidence of a
gestation sac.
Figure 5: Calipers outline the ectopic mass, adjacent to the left
ovary.
ultrasound scheduled to follow,
could be selected.
In the given case, the patient
was seen in the early pregnancy assessment unit and
had both beta-hCG and transvaginal ultrasound performed.
The beta-hCG level was
17,500 IU/L, and transvaginal
scan showed a single intrauterine pregnancy. The
crown–rump length (CRL)
was 2mm (figure 2), with car-
diac activity demonstrated
(figure 3). These findings are
average for five weeks and six
days’ gestation, and consistent
with early ovulation in a short
menstrual cycle.
Although the patient is Rh
negative, current guidelines
suggest that there is insufficient
evidence to use prophylactic
anti-D in the setting of threatened miscarriage with an ongoing pregnancy.
Early spotting with groin
pain
A 30-year-old woman presents
with spotting and intermittent
left iliac fossa pain in early
pregnancy. She is at six weeks
and four days’ gestation by certain LMP (with a regular 28day cycle).
Blood group is B-positive.
Her pulse and blood pressure
are normal. The abdomen is
soft and non-tender to palpation. Speculum examination
reveals a closed cervix, with a
small amount of fresh blood at
the os. Bimanual palpation is
unremarkable.
Transvaginal ultrasound as
first-line investigation is unable
to demonstrate an intrauterine
pregnancy. There is no ultrasound evidence of ectopic pregnancy.
Beta-hCG performed on the
same day (to aid interpretation
of the ultrasound) is 960 IU/L.
This is below the discriminatory level, so it is not possible
to exclude an early intrauterine pregnancy with ovulation
later than expected. Ectopic
pregnancy and failing intrauterine pregnancy also cannot be
ruled out. As the patient is
stable, review with repeat betahCG is scheduled for 48 hours
later.
At the review appointment,
the beta-hCG has risen to
1430 IU/L (a rise of <66%).
The patient has had an
increase in left iliac fossa pain,
prompting repeat ultrasound.
The uterus is empty (although
the hCG is still below the discriminatory zone) (figure 4).
However, a left adnexal mass
(typical donut-shape) is now
visible superior to the left
ovary (figure 5). There is no
free fluid in the pelvis.
The patient was referred to a
tertiary centre. Her FBC, EUC
and LFTs were normal. After
counselling she elected to be
treated with IM methotrexate
and was admitted for observation. Serial beta-hCG monitoring subsequent to the
methotrexate showed a gradually falling level, which
became negative after five
weeks.
Light early bleeding with
mild cramping and
suprapubic tenderness
A 34-year-old woman presents with two days of light
vaginal bleeding at seven
weeks and four days’ gestation by LMP. She had mild
cramping on the first day of
bleeding. Her menstrual cycle
is regular and 28 days in
length. She is G3P2 and the
pregnancy is planned.
Urine hCG was positive on
day 30 of the cycle. Her last
Pap smear, taken 14 months
ago, was normal. Blood
group is O-positive. Her
pulse and blood pressure are
normal. Her abdomen is soft,
with mild suprapubic tenderness.
Ultrasound is the appropriate first-line investigation, as
a normal intrauterine pregnancy will be clearly visible,
with expected CRL of
14mm. If an ectopic is present, it is likely that a mass
would be visible at this gestation. It would be reasonable
to await ultrasound results
before deciding whether
beta-hCG testing is necessary.
In this case ultrasound
reveals an intrauterine gestation sac with a single fetal
pole. The CRL is 4mm and
no fetal cardiac activity is
present. The findings are
consistent with a gestation of
six weeks and one day.
Missed miscarriage cannot be
diagnosed on ultrasound
findings alone (requiring a
CRL of 5mm with no fetal
cardiac motion to confirm a
non-viable pregnancy).
In this situation repeat
ultrasound may be recommended in 7-10 days to
assess progress. However,
using the clinical history to
aid interpretation of the
ultrasound it is possible to
confirm missed miscarriage.
The patient gives a reliable
history, with home pregnancy testing at the time of
the missed period, so dates
could not be more than 3-4
days out. Conservative management could be selected,
but medical management
would also be appropriate.
When diagnosing miscarriage and planning medical
or surgical intervention, it is
vital that the patient accepts
there is sufficient evidence
that the pregnancy is not
ongoing. If there is any
doubt, there is no harm in
waiting for a repeat scan,
assuming the patient is
advised of what to do should
heavy bleeding commence.
Take a detailed history,
attempting to date the
pregnancy as best able.
Utilise past history to
ascertain risks of
miscarriage or ectopic
pregnancy (keeping in mind
that many women have no
risk factors for either
outcome).
Select the most appropriate
first-line investigation to
best answer the clinical
question at hand — don’t
just order tests as routine.
Consider results of
investigations in the light of
the known clinical history.
Aim to minimise follow-up
investigations when
possible — if ultrasound
has shown an early
intrauterine sac, wait for
repeat ultrasound rather
than performing serial betahCG.
Transvaginal ultrasound is
relatively inexpensive, easy
to obtain and acceptable to
most women.
Don’t forget the blood
group and anti-D
prophylaxis for Rh (D)negative women with
miscarriage or ectopic
pregnancy.
When to refer
Missed or incomplete
miscarriage when
conservative management
is not desired or has failed.
Advise such women about
the option of medical
management.
Suspected ectopic
pregnancy.
Molar pregnancy.
Recurrent miscarriage after
preliminary investigations.
Further reading
Available on request from
julian.mcallan@
reedbusiness.com.au
Online resource
UpToDate For Patients provides clear information for
patients and comprehensive
details for members:
www.uptodate.com/patients
GP’s contribution
Case study
DR LINDA MANN
Leichhardt, NSW
26
CS, 39, has one live child and has had
five ‘miscarriages’. In three of these
miscarriages the beta-hCG test became
negative before eight weeks’ gestation,
with conservative management. Two
of her miscarriages were managed surgically. CS has been assessed by a private specialist group and no remediable cause for her recurrent miscarriage
pattern has been determined. She has a
regular 28-day cycle.
She is now pregnant (positive urine
| Australian Doctor | 16 October 2009
beta-hCG on day 35 of her cycle), and
presents at five weeks’ gestation with
faint bleeding, which is a pattern she
has had before. She has not had any
pain and there is no tenderness on
examination. We had discussed early
transvaginal ultrasound at six weeks
when her last miscarriage occurred.
Questions for the author
How do I manage this very anxious
woman?
This situation obviously requires a
www.australiandoctor.com.au
great deal of compassion and understanding for her inevitable anxiety.
With her given presentation, the question is going to be whether or not the
pregnancy is progressing as expected.
There is no significant reason to suspect ectopic pregnancy at present.
Ultrasound at this time could only be
expected to demonstrate the location
of the pregnancy (assuming normal
progress). No fetal pole will be visible
and therefore no reassurance can be
given regarding viability.
The options are to wait for an ultrasound at or beyond six weeks or to
arrange serial biochemistry. The decision will depend on CS’s preferences.
Two beta-hCG levels 48 hours apart
will provide the fastest information
and, if the rise is reassuring, CS may be
more comfortable with waiting a few
more days to have an ultrasound without further beta-hCG monitoring. If
results are not as reassuring or symptoms are continuing, ongoing betacont’d page 28
HOW TO TREAT Early pregnancy bleeding
from page 26
hCG levels can be performed
until a diagnosis is made or
ultrasound is indicated.
If she has an ongoing pregnancy, what discussion
should we have about the
risks of prenatal diagnosis?
At 39 her background risk
of having a fetus affected by
trisomy 21 is about one in
70. If she is concerned about
this risk and desires more
information, my advice
would be to recommend first
trimester screening (FTS)
rather than a diagnostic procedure. FTS will provide her
with a pregnancy-specific risk
assessment with no risk to
the pregnancy from screening.
Patients of this age can still
achieve a low-risk result
from screening (best result is
20-fold reduction in risk, to
one in 1400). Even if she
receives a high-risk result
(greater than one in 300)
knowing the pregnancy-specific risk may help her decide
whether or not to accept the
risk of miscarriage from a
diagnostic procedure such as
amniocentesis. A result of
one in 250, for example,
while still ‘high risk’ may be
quite acceptable to her given
her background risk and previous losses. FTS detects up
to 93% of fetuses affected by
trisomy 21 in women of CS’s
age.
General questions for the
author
Can bleeding in early pregnancy be related to a bleeding diathesis? Should I test
for this in women who have
bleeding with no apparent
uterine cause?
While a bleeding diathesis
may exist in women with
pregnancy bleeding, testing
for this when no other cause
is apparent is not generally
required. Bleeding at the placental-decidual interface is
frequently not visible on
ultrasound.
In addition to this, women
with underlying medical conditions will often already
have been diagnosed because
of other bleeding issues,
including menorrhagia.
However, if a patient with
persisting unexplained bleeding also has a prior history
of abnormal bleeding unrelated to pregnancy, further
testing may be warranted.
For women who have conservative therapy of miscarriage, how long until normal
cycles usually resume? When
do they need to resume contraception if that is their
choice?
Ovulation and return of
menstrual cycles should not
occur until the miscarriage
has occurred and beta-hCG
levels are negative. As the
How to Treat Quiz
timing of actual miscarriage
(spontaneous expulsion of
pregnancy
tissue)
is
extremely variable with conservative management, so
will be the time to next ovulation.
It may be difficult to predict ovulation timing, and if
contraception is desired, I
would advise that caution is
best from the beginning, and
recommend use of barrier
contraception (to avoid confusion as to the cause of any
irregular bleeding) until the
miscarriage is complete and
hormonal methods can be
started, if preferred. Ovulation and conception in the
first month after a miscarriage is not uncommon.
Can GPs supervise medical
management of miscarriage?
There is no particular
reason why a GP overseeing
care of women having conservative management of miscarriage might not also offer
medical management. In both
situations arrangements need
to be in place for review of
progress (either in person or
by telephone contact).
A plan also needs to be
made for where the patient
should seek assistance in the
event of very heavy vaginal
bleeding or unmanageable
cramping pain. If this is not
the managing GP, it would
be reasonable to provide the
patient with documentation
regarding ultrasound and
biochemistry results, as well
as confirmation of date and
dose of misoprostol used.
Thus, if an emergency arises
out of hours the patient can
self-refer to the local hospital
or other service and provide
all the necessary details to the
new managing medical officer.
Misoprostol
is
not
approved for use in management of miscarriage, thus
requiring private prescription
(or supply directly from the
GP).
Apart from ectopic pregnancy, when do we need to
monitor post-event betahCG?
In addition to ectopic pregnancy follow-up (medical or
tube-conserving surgery)
beta-hCG monitoring is
required for pregnancies of
unknown location, due to
the possibility of an ectopic
location. Molar pregnancies
(both partial and complete
mole) also require serial
monitoring after surgical
intervention.
Weekly levels should be
performed until three consecutive negative levels are
obtained. In women at high
risk of recurrent disease
(based on presence of a
number of specific features)
extended monitoring for up
to six months is appropriate.
Correction
How to Treat Depression
in Adolescents (25
September 2009) should
have stated that 60% of
youth with major depressive
disorder (rather than youth
in general) report suicidal
ideation and 30% will
actually make an attempt.
Australian Doctor
apologises for the error.
INSTRUCTIONS
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Early pregnancy bleeding
— 16 October 2009
1. Which TWO statements are correct?
a) Miscarriage is the loss of a pregnancy up to
24 weeks’ gestation
b) After fetal cardiac motion has become
detectable on ultrasound, up to 65% of
threatened miscarriages will continue with
normal gestation
c) ‘Missed miscarriage’ refers to a non-viable,
intact gestational sac within the uterus, with
delay to onset of symptoms of miscarriage
d) ‘Blighted ovum’ generally refers to a missed
miscarriage in which embryonic
development stopped before the embryonic
pole was visible
2. Which TWO statements are correct?
a) About 1% of pregnancies are ectopic
b) About 65% of ectopic pregnancies occur in
the fallopian tube
c) Partial hydatidiform mole is associated with
a diploid karyotype
d) Ultrasound in complete hydatidiform mole
reveals a uterus filled with cystic placental
villi, with no associated fetus
3. Which TWO statements are correct?
a) A beta-hCG level is a reliable guide to
gestational age of an undated pregnancy
b) In healthy early pregnancy, beta-hCG levels
double every 48-72 hours
c) After a gestation sac has been identified in
the uterus, beta-hCG levels can
continue to rise in the absence of a live
fetus
d) Falling beta-hCG levels after 10 weeks’
gestation are indicative of a failing
pregnancy
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4. Which THREE statements are correct?
a) While the discriminatory level at which an
intrauterine pregnancy should be visible
varies, a healthy gestation sac is often
visible with transvaginal sonography at a
beta-hCG level of 1000 IU/L
b) If the beta-hCG is above the discriminatory
level but no intrauterine sac (or retained
products of conception) is visible, the
differential diagnosis is ectopic pregnancy
or complete miscarriage
c) In pregnancies of unknown location,
ultrasonography should be repeated if the
beta-hCG level plateaus at <1500 IU/L or
there is onset of new symptoms suggestive
of ectopic pregnancy
d) If an intrauterine gestation is seen on
ultrasound but is of uncertain viability,
repeat ultrasound in 7-10 days is most likely
to be the most effective follow-up
5. Which TWO statements are correct?
a) The earliest gestation at which an
intrauterine gestation sac could be
expected to be seen on transvaginal
ultrasound would be four weeks and three
days
b) The earliest gestation at which fetal cardiac
activity could be expected to be seen on
transvaginal ultrasound is five weeks and
six days
c) A single serum progesterone level of
<25nmol/L is confirmation that the
pregnancy is not viable
d) Serum progesterone levels can differentiate
ectopic pregnancies from miscarrying
intrauterine pregnancies
6. Which TWO statements about
management of miscarriage are correct?
a) All patients who have conservative
management of miscarriage must have a
follow-up ultrasound to ensure complete
evacuation of the uterus
b) Prophylactic antibiotics should be routinely
prescribed for conservative management of
miscarriage
c) Indications for surgical management include
late miscarriages and heavy bleeding
d) Many women consider surgery the least
emotionally traumatic method of managing
miscarriage
7. Which THREE statements about the
medical management of miscarriage using
misoprostol are correct?
a) Medical evacuation is probably best suited
to women with early miscarriage and a small
fetal pole
b) About two-thirds of women treated with a
single dose of misoprostol will progress to
complete miscarriage within three days
c) The overall failure rate of management of
miscarriage with misoprostol is about 30%
d) Bleeding may persist for up to three weeks
after management with misoprostol
8. Which THREE statements about the
management of ectopic pregnancy are
correct?
a) Referral of any patient with a suspected
ectopic pregnancy is appropriate, at the
earliest possible convenience
b) Comparison of medical and surgical
management for ectopic pregnancy shows
similar success rates, future reproductive
success and ectopic recurrence rates
c) Adverse effects are more common with
surgical treatment compared with medical
treatment of ectopic pregnancy
d) Medical management of ectopic pregnancy
with methotrexate may be indicated after
failed surgical treatment
9. Which TWO statements about management
of ectopic pregnancy are correct?
a) Rates of recurrent ectopic pregnancy after
salpingotomy are very similar to those after
salpingectomy
b) Future fertility rates with salpingotomy are
slightly higher than for salpingectomy
c) It may take four weeks or more for beta-hCG
levels to become negative after management
of ectopic pregnancy with methotrexate
d) Patients who have been treated with
methotrexate for ectopic pregnancy can try for
another pregnancy the following month
10. Which TWO statements about recurrent
miscarriage are correct?
a) Even after two consecutive miscarriages, most
women will be able to achieve a successful
pregnancy
b) About 1% of women suffer recurrent
miscarriage (three consecutive pregnancy
losses)
c) After three miscarriages the chance of
success in the subsequent pregnancy is
about 30%
d) An underlying cause may be found in up to
20% of couples after three consecutive
pregnancy losses
CPD QUIZ UPDATE
The RACGP now requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the 2008-10 triennium. You
can complete this online along with the quiz at www.australiandoctor.com.au. Because this is a requirement, we are no longer able to accept the quiz by post
or fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online.
HOW TO TREAT Editor: Dr Wendy Morgan
Co-ordinator: Julian McAllan
Quiz: Dr Wendy Morgan
NEXT WEEK The incidence of several important STIs is steadily increasing in Australia, amid an ongoing chlamydia epidemic. The next How to Treat comprises the first part of a two-part series on STIs. Part 1
focuses on screening, while in the following week part 2 looks at investigation and management. The author is Dr Catriona Ooi, director, sexual health, Hunter New England Area Health Service, NSW.
28
| Australian Doctor | 16 October 2009
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