5

Clinical presentation and management

of molar pregnancy
Shigeru Sasaki
*
MD, PhD
Associate Professor
Department of Obstetrics and Gynecology, Tama-Nagayama Hospital, Nippon Medical School, 1-7-1,
Nagayama, Tama City, Tokyo 206-8512, Japan
We can now detect molar pregnancy at a much earlier gestational age than before by using high
resolution vaginal ultrasonography. As a result, the current clinical presentation of complete
hydatidiform moles has clearly changed compared to that of the classic type of mole. The
diagnosis of molar pregnancy is nearly always made by ultrasonography. Ultrasonography does
not, however, always lead to diagnosis in the very early stages of gestation, before the chorionic
villi have attained the characteristic vesicular pattern. Therefore, a histopathological examination
of the products of conception should be required in all such cases. Hydatidiform moles should be
treated by evacuating the uterus surgically as soon as possible after diagnosis. The patients must
be followed up until their serial weekly serum human chorionic gonadotrophin (hCG) titre has
fallen to an undetectable level.
Key words: clinical presentation; hydatidiform mole; management of molar pregnancy.
CLINICAL PRESENTATION OF HYDATIDIFORM MOLE
The clinical presentation of complete hydatidiform moles (HMs) is well described in
most obstetrics and gynaecology textbooks.
1,2
The classic presenting symptoms and
ndings include vaginal bleeding, anaemia, excessive uterine enlargement, toxaemia of
pregnancy, hyperemesis gravidarum, hyperthyroidism, trophoblastic emboli and theca
lutein cysts associated with remarkably elevated human chorionic gonadotrophin
(hCG) titres.
3
Since high resolution vaginal ultrasonography became available, clinical
evaluation in early pregnancy has changed markedly. We can detect a blighted ovum at a
much earlier gestational age than before, and almost all patients with molar pregnancy
are diagnosed and treated before they develop the classic clinical presentation. As a
result, we now see far fewer patients with the classic clinical signs and symptoms of
molar pregnancy in daily clinical practice.
Soto-Wright et al
4
from the New England Trophoblastic Disease Centre reported
on 74 patients primarily managed at their centre from 1988 to 1993. According to
their report, the mean maternal age of patients with complete moles was 27.7 years
1521-6934/03/$ - see front matter Q 2003 Elsevier Ltd. All rights reserved.
Best Practice & Research Clinical Obstetrics and Gynaecology
Vol. 17, No. 6, pp. 885892, 2003
doi:10.1016/S1521-6934(03)00072-5, www.elsevier.com/locate/jnlabr/ybeog
*
Tel.: 81-42-371-2111; Fax: 81-3-3921-2840.
E-mail address: sasakimd@rr.iij4u.or.jp
(range 1651) and the mean estimated gestational age at evaluation was 11.8 weeks
(range 622). The mean uterine size at evaluation was 12.4 weeks (range 720) and
the mean level of pre-evacuation hCG was 345 415 mIU/ml (range 8281 680 300).
The most common presenting symptom was vaginal bleeding, occurring in 62 out of
74 (84%) patients. Uterine size greater than that for the expected date was
observed in 21 out of 74 (28%), anaemia in 4 out of 74 (4%), pre-eclampsia in 1
(1.3%), hyperemesis in 6 (8%) and theca lutein cysts in 6 out of 69 (9%). Seven cases
(9%) were asymptomatic. They noted that the presence of excessive uterine size,
anaemia, pre-eclampsia, hyperemesis and hyperthyroidism was signicantly less
common among current patients than in past cases at their centre. Gemer et al
5
from Israel have also reported the changing current clinical presentation of complete
molar pregnancy in 41 patients. In their paper, the mean maternal age was 30.1
years and the mean gestational age at evacuation was 10 weeks with a range of 7
14 weeks. The mean uterine size was compatible with 10 weeks gestation. The
mean pre-evacuation b-hCG was 275 901 IU/l (range 2011919 000). The most
common presenting symptom was vaginal bleeding, occurring in 24 out of 41 (58%)
patients. Excessive uterine size was observed in 18 (44%), anaemia in 1 (2%) and
hyperemesis in 1 (2%). No pre-eclampsia or hyperthyroidism were observed.
Although vaginal bleeding was the most common presenting symptom, 17 out of the
41 cases (41%) were asymptomatic. Furthermore, systemic manifestations such as
hyperemesis, pre-eclampsia, clinical thyrotoxicosis and respiratory distress were
exceedingly rare in this study. All ovarian cysts were small and were diagnosed only
by ultrasonography.
Lindholm and Flam
6
from Sweden have reported on 75 patients with complete
moles and 60 with partial moles. In the complete mole group, the mean gestational age
at the time of sonography was 12.4 weeks. Twelve patients had experienced no
symptoms. The three most commonly occurring symptoms were vaginal bleeding
(77%), abdominal pain (23%) and hyperemesis (19%). Some of the patients experienced
several symptoms. Only one patient suffered from pre-eclampsia. The uterus was
considered to be larger than expected for a date in 20%, equal in size expected for date
in 27% and smaller in 53%. In the partial mole group, the mean gestational age at the
time of sonography was 14.3 weeks. Vaginal bleeding was seen in 62% of the patients,
abdominal pain in 15% and hyperemesis in 8%. As we can see from these reports, the
current clinical presentation of complete HMs has clearly changed compared to that of
the classic type of mole. The clinical presentation of partial moles usually includes no
typical symptoms. Rather, the signs and symptoms are those of incomplete abortion or
missed abortion.
Practice points
The current clinical presentation of hydatidiform mole includes:
vaginal bleeding
excessive uterine size
hyperemesis
abdominal pain
sometimes, presentation is asymptomatic
886 S. Sasaki
DIAGNOSIS OF MOLAR PREGNANCY
The diagnosis of molar pregnancy is nearly always made by ultrasonography because
the chorionic villi of typical complete HMs proliferate diffusely with hydropic swelling
and produce a characteristic vesicular sonographical pattern around the 11th week of
gestation or later.
7
Abdominal ultrasonography brought about a kind of revolution in
pelvic examinations when it was rst introduced in this eld about three decades ago.
It clearly showed a snowstorm pattern when applied to patients with complete
moles. Since it was so impressive, many physicians may still today be under the
impression that moles show this classic sonographical pattern. Diagnostic imaging
equipment, including computed tomography (CT) scans, magnetic resonance imaging
(MRI) and ultrasonography, has made remarkable progress since then and is now
widely used. In particular, today, vaginal ultrasonography, which is non-invasive, simple
and reliable, is an essential routine examination associated with manual pelvic
examination in the rst trimester of pregnancy. It is no exaggeration to say that almost
every pelvic examination table has its own vaginal ultrasound machine, be it in any
hospital or private physicians ofce in Japan. We can now point out to our patients
the fetal heart beat at the end of the sixth week of gestation; if not, abnormal
pregnancies are strongly indicated.
Many molar pregnancies present with vaginal bleeding and are therefore often
diagnosed during evaluation for normal and/or threatened spontaneous abortion.
The latest high resolution ultrasonography can reveal a vesicular pattern of
complete moles instead of the snow storm pattern. Benson et al
8
reported that the
majority of rst trimester complete moles demonstrated a typical sonographical
appearance of a complex, echogenic, intrauterine mass containing many small cystic
spaces.
Ultrasonography does not, however, always lead to diagnosis in the very early
stages of gestation, before the chorionic villi have attained the characteristic vesicular
pattern. Lindholm and Flam
6
investigated what percentage of molar tissues are
missed in normal follow up after evacuation. Sonography was performed in 68
patients with complete moles and the correct diagnosis had been suspected in 84%
of these cases with the aid of sonography and/or macroscopy. In 53 patients with
partial moles, the correct diagnosis was suspected in only 30% of the cases. Their
conclusion was that if all the aborted materials in early pregnancy are not examined
by a pathologist, 16% of complete moles and 70% of partial moles will be missed in
follow up. They concluded, especially as far as partial moles are concerned, that
diagnosis was even more difcult to make with ultrasound and that this holds true
even if examination is performed in the second trimester. Often there will be no
symptoms and this, together with non-specic sonographical images, will make a
diagnosis of missed abortion likely. If small vesicles are observed in the aborted
material directly after evacuation with the naked eye, this supports a diagnosis of
HM. Lazarus et al
9
reviewed the ultrasonographical reports and clinical data of 21
cases of histologically diagnosed complete molar pregnancies with a mean gestational
age of 10.5 weeks at sonography. A diagnosis of molar pregnancy was made
prospectively on ultrasonography in 12 out of the 21 (57%), one on differential
diagnosis and 8 cases were not diagnosed as molar pregnancy. Five out of the ve
(100%) molar pregnancies of 13 weeks or more were prospectively diagnosed, while
only 8 cases out of 16 (50%) in earlier pregnancies were correctly diagnosed
prospectively. Other diagnoses were spontaneous abortion, thickened endometrium
and retained products of conception. No lutein cysts were identied prospectively.
Clinical presentation and management of molar pregnancy 887
They encountered a spectrum of unusual sonographical appearances of complete
moles including an intrauterine anechoic uid collection similar to a gestational sac, a
uid collection with a complex echogenic mass similar to an oedematous placenta, a
heterogeneously thickened endometrium and echogenic uiduid levels with the
endometrium. hCG levels were not always elevated in the rst trimester. They also
concluded that it is not always possible to make a diagnosis of early molar pregnancy
by ultrasonography and that, therefore, histological examination of specimens
remains important.
Sebire et al
10
reported that of the 155 cases of histologically conrmed complete or
partial HMs that they examined, only 53 (34%) were suspected as moles
sonographically. They concluded that although molar pregnancy may be suspected on
routine rst-trimester ultrasound examination, the majority of cases are sonographi-
cally diagnosed as missed miscarriage and/or anembryonic pregnancy in routine
practice, and that a histopathological examination of the products of conception is
required in all such cases.
From these reports, it can be seen that the application of high resolution
ultrasonography in early abnormal pregnancies does not always give us an exact
diagnosis. If the aborted material is not sent for microscopical examination, adequate
follow ups of these patients will not be performed. Histopathological examinations
should always be done as far as possible and samples should be kept for DNA analysis
for a nal diagnosis when histology can not differentiate molar pregnancy from
abortion. Genetic marker analysis is now quite useful and has become essential in
diagnosis. Polymerase chain reaction may not only be rapid but also accurate in
identifying and classifying complete and partial HMs.
Another important characteristic of molar pregnancy is its ability to produce hCG
due to trophoblastic proliferation. Without doubt, serum quantitative hCG provides
very important information for deciding on the likelihood of a molar pregnancy.
Romero et al
11
reported that serum hCG levels of greater than 92 000 mIU/ml
associated with absent fetal heart beat indicate a diagnosis of complete hydatidiform
moles. However, Lazaras et al
9
reported that there was no association between
elevated b-hCG and the correct diagnosis of moles in either the prospective or
retrospective review of their cases in early gestation. Serum hCG, on the other hand,
should be examined consecutively when abnormal pregnancies are suspected through
ultrasonography.
hCG level decreases quickly if the patient has an abortion, but it does not in molar
pregnancy. The measurement of serum hCG is denitely an important tool in reaching
a diagnosis of molar pregnancy.
Practice points
The diagnosis of hydatidiform moles is established by:
history
clinical examination
ultrasound examination
serum hCG levels
histopathological examination
cytogenetic and molecular biological examination
888 S. Sasaki
MANAGEMENT OF HYDATIDIFORM MOLES
Evacuation
HMs should be treated by evacuating the uterus surgically as soon as possible after
diagnosis. Evacuation should be done by suction curettage with oxytocin or
prostaglandin infusion. In our protocol (Figure 1)
12
, a second evacuation is done
routinely 1 week after the rst evacuation to ensure no residual molar tissue in the
uterine cavity. When evacuation is not carried out by an expert, as is sometimes the
case, a persistently raised hCG level can occasionally be seen in the residual. From this
point of view, the second evacuation is effective not only to protect against this risk, but
also to educate non-experts. Although hysterectomy does not prevent trophoblastic
sequelae, it may be performed with the mole in situ if the patient desires surgical
sterilization. Chest X-rays are also used routinely to rule out pulmonary lesions. Partial
moles should be treated and followed up in the same manner, because it is now well
known that partial moles also develop trophoblastic sequelae.
13,14
Management post-evacuation
Patients must be followed up until their serial weekly serum hCG titre has fallen to
undetectable levels. Soto-Wright et al
4
found in their study that pre-evacuation serum
hCG levels of greater than 200 000 mIU/ml were signicantly associated with the
development of persistent gestational trophoblastic diseases. In Japan we have our own
hCG regression curve post-evacuation calculated from collected data (Figure 2).
15
The
collected data show that the hCG titre generally falls to below 1000 mIU/ml within 5
weeks of the rst evacuation in spontaneous resolution. Most of the patients whose
hCG titres are more than 1000 mIU/ml at the 5th week after the rst evacuation suffer
subsequently from persistent trophoblastic disease. In more than 90% of
If patient desires
Hysterectomy First time evacuation
Second time evacuation
Weekly serum hCG
Spontaneous
resolution
Persistent
trophoblastic disease
hCG regression curve post-evacuation
Second follow-up Treatment
MOLE
Figure 1. Algorithm for the management of hydatidiform moles. hCG, human chorionic gonadotrophin.
Clinical presentation and management of molar pregnancy 889
the spontaneous resolution cases, their hCG titres decreased to under 100 mIU/ml at
the 8th week. In some patients with persistent trophoblastic disease, their hCG titres
decreased at one point to undetectable levels and then rose again by the 20th week.
These ndings indicate that the hCG titres at the 5th, 8th and 20th weeks after the rst
evacuation are crucial for predicting persistent trophoblastic disease. From these
observations, we conclude that when the serial hCG titre is always below this
discrimination line and reaches an undetectable level by the 20th week, resolution is
spontaneous. If the hCG titre shows a plateau for 3 weeks or rises for 2 weeks and then
crosses this discrimination line at any point during the follow up as far as the 20th week,
trophoblastic sequelae, i.e. persistent trophoblastic disease, arise in the patient.
Recently, an international consensus has been reached that it is acceptable to wait to
observe hCG regression to undetectable levels for up to 6 months (24 weeks) after
molar evacuation (data from the IXth World Congress on Gestational Trophoblastic
Diseases, Jerusalem, 1998 and the Xth World Congress on Gestational Trophoblastic
Diseases, Tbilishi, 2000).
Management of spontaneous resolution
After spontaneous resolution, the patient is subsequently seen monthly for 6 months,
then at 3-monthly intervals for a further 2 years and then at least once a year for as long
as possible for the early detection of any recurrence of gestational trophoblastic disease
and to ensure that hCG levels remain undetectable. If patients want to conceive, they
are generally advised not to become pregnant again until after the rst 6 months of
follow up and are given reliable contraception, preferably in the form of the pill.
Oral contraceptives do not appear to increase the risk of post-molar trophoblastic
tumours andmay, therefore, be safely prescribedafter molar evacuation during the entire
interval of hCG monitoring.
16
A Gynecologic Oncology Group (GOG) study
17
also
20 weeks
1st evacuation
10
6
10
5
10
4
10
3
10
2
0.5
2nd evacuation
h
C
G

(
m
I
U
/
m
l
)
5 8
Figure 2. Serum human chorionic gonadotrophin (hCG) level regression curve post-evacuation
(discrimination line). Reprinted, with permission, from The Japan Society of Obstetrics and Gynecology and
the Japanese Pathological Society
15
, p. 12.
890 S. Sasaki
supported the idea that oral contraceptives are the preferred method of contraception
after evacuation of HMs, while the Charing Cross group recommended the use of oral
contraceptives after biochemical remission.
18
Palmer
19
reported that the relative risk of
persistent gestational trophoblastic tumours was increased by long-term oral contra-
ceptive use before conception, although his nding was not statistically signicant.
Further study is needed on this point.
SUMMARY
Blighted ova can be detected at a much earlier gestational age than before and almost
all patients with molar pregnancy are diagnosed and treated before they develop the
classic clinical presentation. As a result, the current clinical presentation of complete
hydatidiform moles (HMs) has clearly changed compared to that of the classic type of
mole. The clinical presentation of partial moles usually includes no typical symptoms.
Rather, the signs and symptoms are those of incomplete abortion or missed
abortion.
The latest high resolution ultrasonography can reveal a vesicular pattern of complete
moles instead of the snow storm pattern. Ultrasonography does not, however, always
lead to diagnosis in the very early stages of gestation, before the chorionic villi have
attained the characteristic vesicular pattern. If all the aborted materials in early
pregnancy are not examined by a pathologist, 16% of complete moles and 70% of partial
moles will be missed in follow up. Histopathological examinations should always be
done as far as possible. Samples should be kept for DNA analysis for a nal diagnosis
when histology cannot differentiate molar pregnancy from abortion. The measurement
of serum human chorionic gonadotrophin (hCG) is denitely an important tool for
reaching a diagnosis of molar pregnancy.
HMs should be treated by evacuating the uterus surgically as soon as possible after
diagnosis. The patients must be followed up until their serial weekly serum hCG titre
has fallen to undetectable levels. In cases where the serial hCG reaches an undetectable
level by the 24th week after molar evacuation, resolution is spontaneous. Patients are
generally advised not to become pregnant again until after the rst 6 months of follow
up and are given reliable contraception, preferably in the form of the pill.
Practice points
Required investigations for patients with hydatidiform moles include:
clinical examination
chest X-ray
blood cell count with platelet, blood urea nitrogen (BUN), creatinine and liver
function tests on admission
blood group
thyroid function tests if necessary
Prothrombin time (PT), partial thromboplastin time(PTT), prothrombin and
brinogen, if clinically indicated
serum human chorionic gonadotrophin (hCG) immunoassay: a specimen of
serum for hCG should be obtained prior to and one day after the evacuation
digital oximetry, blood gases and lung scan if necessary
Clinical presentation and management of molar pregnancy 891
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Research agenda
further study on the effect of long-term oral contraceptive use on the relative
risk of persistent gestational trophoblastic disease is needed
892 S. Sasaki