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Risk of recurrent molar pregnancies followingcomplete and
partial hydatidiform moles
ARTICLE in HUMAN REPRODUCTION JULY 2015
Impact Factor: 4.57 DOI: 10.1093/humrep/dev169 Source:
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Great Ormond Street Hospital for Children N
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Brighton and Sussex University Hospitals NH
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Imperial College London
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ORIGINAL ARTICLEEarly pregnancy
Risk of recurrent molar pregnancies
following complete and partial
hydatidiform moles
N. Eagles1, N.J. Sebire1,2, D. Short1, P.M. Savage1, M.J.
Seckl1,3,
and R.A. Fisher1,3,*1Trophoblastic Tumour Screening &
Treatment Centre, Imperial College Healthcare NHS Trust, Charing
Cross Campus, Fulham Palace Road,
London W6 8RF, UK2Department of Paediatric Laboratory Medicine,
UCL Institute of Child Health, London WC1N 3JH, UK 3Department
of
Surgery and Cancer, Imperial College London, London W12 0NN,
UK
*Correspondence address. E-mail: [email protected]
Submitted on April 17, 2015; resubmitted on June 9, 2015;
accepted on June 19, 2015
studyquestion: What isthe risk of further molar pregnanciesfor
women with oneor more hydatidiformmoles (HM) in relationto
molarsubtype.
summaryanswer: Women with a complete hydatidiformmole(CM) havea
1 in 100 and 1 in 4 riskof further CM after one or two con-secutive
CM, respectively, while women with a partial hydatidiform mole (PM)
have only a small increase in risk for further molar
pregnancies.
what is known already: Women with a molar pregnancy have an
increased risk of further HM. A small subgroup of womenwith
recurrent HM has an autosomal recessive condition, familial
recurrent hydatidiform moles (FRHM), that predisposes them to
molar
pregnancies.
study design, size,duration: A retrospectivestudyof subsequent
pregnancies in 16 000women registered at a centralized
referralcentre, with a CM or PM, between 1990 and 2009.
participants/materials, setting, methods: Onehundredand
sixty-six women with two or more molar pregnancies were
identified from electronic records and patient notes.
Histopathological features of all molar tissue were reviewed in
these cases and genotypingperformed where diagnosis was not
possible on the basis of histopathological features alone. In
addition, genotyping of molar tissue was
performed in all cases of women with three or more CM to
establish whether the tissue was diploid and biparental or
androgenetic.
main results and the role of chance: This study confirms an
increased recurrence risk of1% fora secondmolarpregnancyand in
addition that this risk is associated with CM rather than PM. The
data further indicate that the risk of a third HM is associated
almost ex-
clusivelywithCM andenabledan estimatethat1 in640
womenregisteredwitha CMhas therare conditionFRHM. The
studyalsofound that there
was no significant difference between the risk of developing
gestational trophoblastic neoplasia (GTN) for typical sporadic CM
and the diploid
biparental CM associated with FRHM (GTN; proportion difference
0.05, Z 0.87,P 0.29).
limitations, reasons for caution: While pathology was reviewed
for all women with two or more molar pregnancies, not allcases
registered underwent central review particularly those women
registered in the early 1990s. It is therefore possible that the
total number
of CM and PM may differ slightly from that stated. While women
were followed for a minimum of 5 years, it is possible that some
women may
subsequently have further molar pregnancies that will not have
been included in the present study.
wider implications of the findings: This is thelargest study to
date on recurrence formolar pregnancies, andas such providesthe
most detailed information so far regarding therisk of further molar
pregnancies for women with a PM or CM. Furthermore, the data
provide
new insights into the incidence of the rare autosomal recessive
condition, FRHM, important information for counselling women with
molar
pregnancies.
study funding/competing interest(s): No competing interests
declared. No funding was obtained for this study.
Key words: complete hydatidiform mole / partial hydatidiform
mole / recurrent hydatidiform moles / gestational trophoblastic
neoplasia /
NLRP7
& The Author 2015. Published by Oxford University Press on
behalf of the European Society of Human Reproduction and
Embryology. All rights reserved.
For Permissions, please email: [email protected]
Human Reproduction, Vol.0, No.0 pp. 1 9, 2015
doi:10.1093/humrep/dev169
Hum. Reprod. Advance Access published July 22, 2015
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Introduction
Hydatidiform moles (HM) characterized by hydropic swelling of
the
placental villi, hyperplasia of villous trophoblast and absent,
or abnor-
mal, fetal development occur in 1 in 600 pregnancies in the UK
popu-
lation (Savage et al., 2013). However, this increases 10-fold
for
women who have already experienced a molar pregnancy. A
10-year
survey of over 5000 subsequent pregnancy outcomes following
a
molar pregnancy found that outcomes were similar to the
normal
population except for the risk of a subsequent HM which
occurred
in 1 in 68 pregnancies (Savageet al., 2013). This observation
supports
previous reports that the risk of an HM in a subsequent
pregnancy
increases to 12% following a molar pregnancy (Bagshawe et
al.,
1986; Berkowitz et al., 1998;Lorigan et al., 2000; Matsui et
al., 2001;
Sebireet al., 2003) and may be as high as 23% for women with
two
consecutive molar pregnancies (Bagshawe et al., 1986;
Berkowitz
etal., 1998;Loriganet al., 2000;Sebireet al., 2003). Subsequent
preg-
nancy outcomes for women with three or more molar
pregnancies
have not been systematically reported.
Most molar pregnancies fall into one of two major types,
complete
hydatidiform mole (CM) or partial hydatidiform mole (PM), based
ontheir morphological features and underlying genotype. CM have
a
moredistinct phenotypewith dysmorphic villi and marked
trophoblastic
hyperplasia (Sebire, 2010) reflectingthe factthat all 46
chromosomesare
derived from the father(Kajiiand Ohama, 1977). PMs are triploid
con-
ceptions with an additional set of chromosomes from the
father
(Jacobset al., 1982;Lawleret al., 1982). Morphologically they
have a
range of villi, from normal to overtly cystic, and focal
trophoblastic
hyperplasia (Sebire, 2010).
Whererecurrent molar pregnancies have been defined as CM or
PM,
thesecond molar pregnancy maybe of eithertype but is more
usually of
the same type as the index mole (Berkowitzet al., 1998;Sebireet
al.,
2003). However, for women with two or more molar pregnancies
sub-
sequent molar pregnancies are more likely to be CM (Berkowitz et
al.,1998). It is now recognized that women with recurrent HM
include a
number of women with familial recurrent hydatidiform mole
(FRHM),
a rare autosomal recessive condition in which affected women
have a
predisposition to pregnancy losses, most of which are CM
(Fisher
et al., 2004). To date, mutations in two genes, NLRP7 (NLR
family,
pyrin domain containing 7) (Murdochet al., 2006) and KHDC3L
(KH
domain containing 3-like, subcortical maternal complex
member)
(Parryet al., 2011) have been shown to be responsible for75
and
5% of cases of FRHM, respectively. Affected women can be
identified
by genotyping of the CM. Sporadic CM are androgenetic while
those
associated with FRHM are diploid but biparental in origin
(Helwani
et al., 1999;Fisheret al., 2000). However, at present the
incidence of
this rare condition is not known.
Both CM and PM are clinically important, being associated with a
sig-
nificant increased risk of developing gestational trophoblastic
neoplasia
(GTN), rates being around 15 and 1% for CM and PM,
respectively
(Savageet al., 2013). Whether this risk increases in subsequent
molar
pregnancies remains controversial (Berkowitz et al., 1998;
Lorigan
etal., 2000;Matsuiet al., 2001).
Ourobjectives in undertaking this study were to examine
subsequent
pregnancy outcomesfor all women registeredwith theirfirst
molarpreg-
nancy during a 20-year period at a large national referral
centre in order
to obtain a more accurate risk of subsequent molar pregnancies
for
women with one or more molar pregnancies, to determine
whether
the nature of the index pregnancy affected this risk, to
estimate the inci-
dence of FRHM and assess the risk of persistent disease for
recurrent
molar pregnancies.
Materials and Methods
Study population
In the UK, the management of women with molar pregnancies is
centra-
lized, and all women with a HM are registered for hCG monitoring
at
one of three screening centres, the largest of which is Charing
Cross Hos-
pital, London. All women registered at Charing Cross Hospital
for their first
molar pregnancy during the 20-year period from 1990 to 2009
(inclusive)
were identified from the electronic databases. It is current
policy for all
women registered with the centre to undergo further monitoring
after
any subsequent pregnancy, enabling data on further pregnancies
to be col-
lected. Subsequent pregnancies were recorded during the study
and for a
further 5-year follow-up period. All women who had further HM in
the
next, or any subsequent pregnancy during the follow-up period,
were iden-
tified. Women who were referred for a second opinion from
overseas werenot included in the present study.
Data were collected on patient age, previous obstetric history,
obstetric
history subsequent to the index molar pregnancy, subtype of HM
and the
frequency of persistent trophoblastic disease.
Histopathological review
In order to exclude women with non-molar pregnancies from
unnecessary
screening, since 1990, it has been the policy of the
Trophoblastic Screening
Service to request material for histopathological review from
pregnancies
registered with the service with a local diagnosis of PM. From
1995, this
was extended to include histopathological review for all cases
registered re-
gardless of local pathology subtype. In addition, for the
present study, a
central pathological review was performed retrospectively
according tostandard protocols for all cases with recurrent HM
where both had not pre-
viously been reviewed.
Ancillary genetic testing
ForcaseswithadifferentialdiagnosisofCMorPM,p57KIP2
(cyclin-dependent
kinase inhibitor 1C) immunostaining (Castrillonet al., 2001) was
performed
to confirm or exclude CM, while genotyping was performed for
cases with a
differential diagnosis of PM or non-molar miscarriage(Fisheret
al., 2014).
Genotyping of the molar tissue for patients with three or more
HM was
carried out as part of routine clinical practice and if shown to
be diploid
and biparental, patients were investigated for mutations in
NLRP7 (Wang
etal., 2009) andKHDC3L(Parryet al., 2011).
Statistical analyses
Descriptivestatisticswere calculatedand frequenciesof outcomes
according
to HM subtype were examined using comparison of proportion test
(Stats-
Direct, UK). AP-value ,0.05 was considered significant.
Ethical approval
ThisprojectwasapprovedbytheJointResearchComplianceOfficeofImper-
ial College London and Imperial College Healthcare NHS Trust
(reference
number 15HH2513).
2 Eagleset al.
https://www.researchgate.net/publication/12336203_Characteristics_of_Women_with_Recurrent_Molar_Pregnancies?el=1_x_8&enrichId=rgreq-2e33b86e-0801-4842-8f86-efa96edc6b30&enrichSource=Y292ZXJQYWdlOzI4MDM5MDk2NztBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==https://www.researchgate.net/publication/12336203_Characteristics_of_Women_with_Recurrent_Molar_Pregnancies?el=1_x_8&enrichId=rgreq-2e33b86e-0801-4842-8f86-efa96edc6b30&enrichSource=Y292ZXJQYWdlOzI4MDM5MDk2NztBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==https://www.researchgate.net/publication/12336203_Characteristics_of_Women_with_Recurrent_Molar_Pregnancies?el=1_x_8&enrichId=rgreq-2e33b86e-0801-4842-8f86-efa96edc6b30&enrichSource=Y292ZXJQYWdlOzI4MDM5MDk2NztBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==https://www.researchgate.net/publication/12336203_Characteristics_of_Women_with_Recurrent_Molar_Pregnancies?el=1_x_8&enrichId=rgreq-2e33b86e-0801-4842-8f86-efa96edc6b30&enrichSource=Y292ZXJQYWdlOzI4MDM5MDk2NztBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==https://www.researchgate.net/publication/12336203_Characteristics_of_Women_with_Recurrent_Molar_Pregnancies?el=1_x_8&enrichId=rgreq-2e33b86e-0801-4842-8f86-efa96edc6b30&enrichSource=Y292ZXJQYWdlOzI4MDM5MDk2NztBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==https://www.researchgate.net/publication/12336203_Characteristics_of_Women_with_Recurrent_Molar_Pregnancies?el=1_x_8&enrichId=rgreq-2e33b86e-0801-4842-8f86-efa96edc6b30&enrichSource=Y292ZXJQYWdlOzI4MDM5MDk2NztBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==https://www.researchgate.net/publication/12336203_Characteristics_of_Women_with_Recurrent_Molar_Pregnancies?el=1_x_8&enrichId=rgreq-2e33b86e-0801-4842-8f86-efa96edc6b30&enrichSource=Y292ZXJQYWdlOzI4MDM5MDk2NztBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==https://www.researchgate.net/publication/12336203_Characteristics_of_Women_with_Recurrent_Molar_Pregnancies?el=1_x_8&enrichId=rgreq-2e33b86e-0801-4842-8f86-efa96edc6b30&enrichSource=Y292ZXJQYWdlOzI4MDM5MDk2NztBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==https://www.researchgate.net/publication/22581618_Andronetic_origin_of_hydatidiform_mole?el=1_x_8&enrichId=rgreq-2e33b86e-0801-4842-8f86-efa96edc6b30&enrichSource=Y292ZXJQYWdlOzI4MDM5MDk2NztBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==https://www.researchgate.net/publication/22581618_Andronetic_origin_of_hydatidiform_mole?el=1_x_8&enrichId=rgreq-2e33b86e-0801-4842-8f86-efa96edc6b30&enrichSource=Y292ZXJQYWdlOzI4MDM5MDk2NztBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==https://www.researchgate.net/publication/16912629_Genetic_studies_on_hydatidiform_moles_I_The_origin_of_parial_moles?el=1_x_8&enrichId=rgreq-2e33b86e-0801-4842-8f86-efa96edc6b30&enrichSource=Y292ZXJQYWdlOzI4MDM5MDk2NztBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==https://www.researchgate.net/publication/16912629_Genetic_studies_on_hydatidiform_moles_I_The_origin_of_parial_moles?el=1_x_8&enrichId=rgreq-2e33b86e-0801-4842-8f86-efa96edc6b30&enrichSource=Y292ZXJQYWdlOzI4MDM5MDk2NztBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==https://www.researchgate.net/publication/8257383_Familial_recurrent_hydatidiform_mole_A_review?el=1_x_8&enrichId=rgreq-2e33b86e-0801-4842-8f86-efa96edc6b30&enrichSource=Y292ZXJQYWdlOzI4MDM5MDk2NztBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==https://www.researchgate.net/publication/8257383_Familial_recurrent_hydatidiform_mole_A_review?el=1_x_8&enrichId=rgreq-2e33b86e-0801-4842-8f86-efa96edc6b30&enrichSource=Y292ZXJQYWdlOzI4MDM5MDk2NztBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==https://www.researchgate.net/publication/8257383_Familial_recurrent_hydatidiform_mole_A_review?el=1_x_8&enrichId=rgreq-2e33b86e-0801-4842-8f86-efa96edc6b30&enrichSource=Y292ZXJQYWdlOzI4MDM5MDk2NztBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==https://www.researchgate.net/publication/51610573_Mutations_Causing_Familial_Biparental_Hydatidiform_Mole_Implicate_C6orf221_as_a_Possible_Regulator_of_Genomic_Imprinting_in_the_Human_Oocyte?el=1_x_8&enrichId=rgreq-2e33b86e-0801-4842-8f86-efa96edc6b30&enrichSource=Y292ZXJQYWdlOzI4MDM5MDk2NztBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==https://www.researchgate.net/publication/51610573_Mutations_Causing_Familial_Biparental_Hydatidiform_Mole_Implicate_C6orf221_as_a_Possible_Regulator_of_Genomic_Imprinting_in_the_Human_Oocyte?el=1_x_8&enrichId=rgreq-2e33b86e-0801-4842-8f86-efa96edc6b30&enrichSource=Y292ZXJQYWdlOzI4MDM5MDk2NztBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==https://www.researchgate.net/publication/12336203_Characteristics_of_Women_with_Recurrent_Molar_Pregnancies?el=1_x_8&enrichId=rgreq-2e33b86e-0801-4842-8f86-efa96edc6b30&enrichSource=Y292ZXJQYWdlOzI4MDM5MDk2NztBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==https://www.researchgate.net/publication/12336203_Characteristics_of_Women_with_Recurrent_Molar_Pregnancies?el=1_x_8&enrichId=rgreq-2e33b86e-0801-4842-8f86-efa96edc6b30&enrichSource=Y292ZXJQYWdlOzI4MDM5MDk2NztBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==https://www.researchgate.net/publication/12336203_Characteristics_o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tBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==https://www.researchgate.net/publication/16125038_Complete_and_partial_hydatidiform_mole_in_Hawaii_cytogenetics_morphology_and_epidemiology?el=1_x_8&enrichId=rgreq-2e33b86e-0801-4842-8f86-efa96edc6b30&enrichSource=Y292ZXJQYWdlOzI4MDM5MDk2NztBUzoyNjc0NDIyNjE4NTIxNjFAMTQ0MDc3NDYxMjEzOQ==
-
7/25/2019 Dyornal2
4/10
Results
Frequency of second molar pregnancies
During the period 19902009, 16 523 women were registered
with
their first molar pregnancy of which 7037 were CM, 8553 were
PM
and 933 (registeredin the early 1990s prior to routine central
pathology
review) were HM unclassified. Of the 16 523 women registered,
166
(1%) went on to have a molar pregnancy in the next (88 women) or
ina subsequent (78 women) pregnancy. For women with two or more
molar pregnancies, the firstwas a CM in 110 cases and a PM in
56cases.
For those women in whom the initial molar pregnancy was a CM,
the
second molar pregnancy was most likely to be in the consecutive
preg-
nancy, while women in whom the initial pregnancy was a PM
were
more likely to experience intervening miscarriages or live
births before
a second molar pregnancy (Fig. 1). For women diagnosed with a
CM,
the risk of a further HM in the next pregnancy was 0.91% (64
cases
from 7037 registered; TableI). However, for women with PM, the
risk
was lower being 0.28% (24 cases from 8553 registered). The risk
of a
further molar pregnancy after one or more non-molar intervening
preg-
nancies was also higher following an initial diagnosis of CM,
0.65% (46
cases from 7037 registered), compared with PM, 0.37% (32
cases
from 8553 registered) (Table II). Approximately 80% of the
second
HM, regardless of whether they occurred in the next or a
subsequent
pregnancy, were of the same histopathological type as the index
mole.
Age distribution of women with two or more
molar pregnancies
Themedian ageat which women experienced theirfirst
molarpregnancy
was 24 years (range 13 49) in women in whom the first HM was a
CM,
and30(range1843)inwomeninwhomthefirstmolarpregnancywasa
PM (Fig.2).
Previous reproductive outcomes
Thirty-three(30%)of thewomenin whomthe initial pregnancy wasa
CM
had experienced a previous live birth. However, for 59 (54%),
this was
their first pregnancy (Fig. 3). For women with an initial PM,
for 18
(32%) this was their first pregnancy while 38 had experienced
previous
live births (n 17), miscarriages (n 9) or both (n 12).
Time interval between consecutive molar
pregnancies
For women with two consecutive HM, the subsequent HM
occurred
most frequently in the first or second year following the
initial HM
diagnosis, regardless of whether the initial HM was CM or PM
(Fig. 4).
The maximum time interval between consecutive molar pregnancies
in
the present series was 6 years for two consecutive PM and 15
years
for two consecutive CM. For women with intervening pregnancies,
the
time interval to the second HM was more variable, with a
maximum
time interval between the first and second HM of 14 years for PM
and
22 years for CM. Of the 79 women who experienced intervening
preg-
nancies beforea secondHM, 36had multiple pregnancies, 23a
singlelive
birth, 17a single miscarriage, onepatienta stillbirthand
anothera termin-
ation of a fetus with Edward syndrome.
Frequency of three or more molar
pregnanciesOf the 166 women who had a second molar pregnancy, 22
(13%) went
on tohavea third HM.However,mostwomenwhohad a third HMwere
women who hadpreviously hadtwo consecutive CM.Of the52 women
with two consecutive CM, 12 (23%) had a CM in a subsequent
preg-
nancy. Only a single patient of the 20 cases with two PM went on
to
have a third PM while one went on to have a CM. A single patient
with
a CM followed by a PM in the next pregnancy went on to have
a
further PM in a subsequent pregnancy (TableIII).
A further 7 of 37 (19%) women with two non-consecutive CM
also
went on to have a third molar pregnancy (Table IV). None of
the
women in this series with two non-consecutive PM experienced
any
further molar pregnancies.
Other reproductive outcomes in women
with three molar pregnancies
In most women with three or more molar pregnancies, all three
molar
pregnancies were CM (TableV). Seven of the 19 cases with three
or
Figure1 Pregnancy.outcomes following theindexmolar pregnancyin
women with twoor more molar pregnancies.CM, complete hydatidiform
mole;
PM, partial hydatidiform mole. Figures represent number of cases
in each category.
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moreCMhadonlyCM,withtwowomenhavingasmanyaseightCMwith
no other pregnancy types. The remaining 12 women had a history
of
miscarriage (n 6), live birth (n 2) or both (n 4). In two cases
in
which two of the three molar pregnancies were
histopathologically
PM, and the single case with three PM, genotyping confirmed a
typical
dispermic triploid conception of the PM in all cases.
Genotypingof CMin the 19women withthree CM identified 8
women
with genetically typical, androgenetic CM (Fig. 5). Eleven women
were
diagnosed with FRHM in which the CMs were diploid and
biparental
having an equal contribution to the genome from both parents. In
one
case, the patient declined further investigations, nine were
shown to be
homozygous or compound heterozygotes for mutations or known
patho-
logical variants in NLRP7. A single patient was found to have a
mutation, in
KHDC3L(TableV). The chance of having FRHM for women
registered
with the National Trophoblastic Screening Service at Charing
Cross Hos-
pital,in orderto monitor their hCGlevels, followingan HM is 1 in
1500 and
for those with histopathologically confirmed CM, the chance is 1
in 640.
No mutations or pathological variants were identified in NLRP7
or
KHDC3Lin any of the women with three androgenetic CHM.
Risk of development of GTN
The 166 women in the current study experienced a total of 248
CM. In
most cases, the CM resolved spontaneously following evacuation
of the
molar pregnancy. However, following 22 (8.9%) of the CM, hCG
levels
failed to fall to normal indicating the presence of GTN
requiring che-
motherapeutic intervention. Although women with diploid
biparental
CHM were generally younger (mean age 24 years; range 1630)
when
treated than women with androgenetic CHM (mean age 31 years;
range
18 52), there wasno significant differencein therequirement
forchemo-
therapybetween the two groups. Six of the 50 CM (12%) in women
with
FRHM required chemotherapy compared with 16 of 198 CM (8%)
in
women with sporadic CM (GTN; proportion difference 0.05, Z
0.87,
P 0.29). The need for treatment was similar for successive CM,
with
11 of 121 (9%) first CM, 7 of 89 (8%) second CM and 2 of 19
(11%)
third CMrequiringchemotherapy.Of thefurther 19CM in
womenexperi-
encing 4 or more CM, 2 (11%) went on to require treatment for
GTN.
Womenin thestudy experienced a total of123PM,of which4
(3.3%)pro-
gressed to GTN. All cases requiring treatment occurred in the 45
women
with recurrent PM. Of the four patients who required treatment
for GTN
after a PM, a single patient required treatment for her first PM
while three
others required treatment for their second PM. In all cases,
genotyping con-
firmed that the PM that progressed to GTN were typical diandric
PM.
...................
........................................................................................
Table II Frequency of a second HM in pregnancies
subsequent to the next pregnancy for women having an
initial diagnosis of CM or PM.
First HM Second HM Total Total registered
CM PM
CM 37 9 46 7037
PM 7 25 32 8553
...................
........................................................................................
TableI Frequencyof a secondHM inthe nextpregnancy
for women having an initial diagnosis of CM or PM.
First HM Second HM Total Total registered
CM PM
CM 52 12 64 7037
PM 4 20 24 8553
HM, hydatidiform mole; CM, complete hydatidiform mole; PM,
partial hydatidiform
mole.
Figure 2 Age at diagnosis for the first molar pregnancy in women
with two or more molar pregnancies. CM, complete hydatidiform mole;
PM, partial
hydatidiform mole.
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Discussion
This study, of over 16 000 women registered for follow-up after
a
diagnosis of HM, confirms an increased recurrence risk of 1%
for
women who have experienced an initial molar pregnancy above that
of
the normal population. The study has also demonstrated that this
risk
is associated with CMratherthan PM.Theriskof a thirdHM is
associated
almost exclusively with CM while 1 in 640 women registered with
a CM
has therare condition FRHM whichaccounts formost, but not all,
cases
of women with three or more CM. There is no significant
difference in
need for chemotherapy between typical sporadic CM anddiploid
bipar-
ental CM associated with FRHM or with successive CM in women
with
multiple molar pregnancies.
Figure3 Reproductive outcomes prior to thefirst molar
pregnancyin women withtwo or more molar pregnancies.CM, complete
hydatidiform mole;
PM, partial hydatidiform mole. Figures represent number of cases
in each category.
Figure 4 Timeinterval between first andsecond molar pregnancies
forwomen with (A) consecutive and (B) subsequent CM (red) andPM
(blue). HM,
hydatidiform mole.
............................
........................................................................................
Table III Frequency of a thirdHM for women who have
had two consecutive HM.
Previous HM Third HM Total
CM PM
Two CM (52) 12 12Two PM (20) 1 1 2
CM + PM (16) 1 1
............................
........................................................................................
Table IV Frequency of a third HM for women with two
non-consecutive HM.
Previous HM Third HM Total
CM PM
Two CM (37) 7 7
Two PM (22)
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.................................................................................................................................................................................................
Table V Reproductive history for women with three molar
pregnancies.
Case Age at diagnosis (years) Total HM Prior pregnancies First
HM Subsequent reproductive outcomes N
FRHM (diploid and biparental CM)
8 16 3 CM CM Misc CM p
18 24 4 CM CM CM Misc CM SA p
30 25 3 CM CM CM p
69 30 3 CM CM CM p
82 16 7 CM CM CM CM CM CM CM
87 29 4 CM CM CM CM p
115 20 8 CM CM CM CM CM CM CM CM
117 18 8 CM CM CM CM CM CM CM CM p
122 26 3 CM CM CM p
133 23 3 CM CM Misc Misc CM p
138 24 4 CM Misc CM CM CM p
Recurrent Androgenetic CM37 24 3 Misc CM Miscc Misc CM CM
39 27 3 CM CM CM Misc LB
52 29 3 CM Misc Misc Misc CM Misc Misc CM
58 24 3 LB, Misc CM Misc CM CM
63 20 3 CM LB CM LB LB CM
66 24 4 CM Misc CM LB CM CM
93 23 5 CM Misc CM LB Misc Misc CM CM CM
149 26 3 Misc CM CM CM
Recurrent PM
27 32 3 LB, Misc PM PM CM Misc LB
77 24 3 PM PM PM LB
84 29 3 CM PM Misc LB PM LB
Misc, miscarriage; SB, stillbirth; LB, live birth.aReported
inWanget al.(2009).bReported inParryet al.(2011).cReported
inDixonet al.(2012).
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One of the major concerns for couples experiencing a molar
preg-
nancy is future fertility and the risk of further molar
pregnancies. This isof particular concern forthe 50% of women with
a CM andthe one-third
of women with a PM for whom an HM is their first pregnancy.
While
other reproductive outcomes following a molar pregnancy are
similar
to the general population, the risk of an HM has been reported
to
increase with successive molar pregnancies (Bagshawe et al.,
1986;
Berkowitzet al., 1998;Loriganet al., 2000;Matsuiet al.,
2001;Sebire
et al., 2003;Savageet al., 2013,Vargaset al., 2014).
The present study has confirmed the frequency of a second
molar
pregnancyas 1%and that,whilethe secondHM maybe of
eitherhisto-
logical type, in most cases thephenotype is similar to theindex
mole. Of
the8553women with histologicalPM, only 11(0.13%) went on
tohavea
CMwhileof the7029 with CM,only21 (0.3%) experienceda
subsequent
PM at some time in their reproductive history. While the
frequency of
second HM may be a slight overestimate since a small number
of
women registered with a single molar pregnancy are unclassified
as
CM or PM,and thereforenot included in thetotalnumberof molar
preg-
nancies, this overall figureis similar to that from previous
smaller studies.
What this large detailed study has enabled is the clear
demonstration
that the frequency of a second HM in the next pregnancy is
significantly
greater for CM than PM (Z 24.54, P, 0.0001). For a woman
with
a PM there was no increased frequency of a CM in the next
pregnancy
while the risk of a second PM was about twice that of the
general popu-
lation in the UK (Savageet al., 2013). The risk of a second PM
might be
underestimated as women registered with a PM may have
occasionally
had prior miscarriages that might have been unrecognized
PM.However, this figure is still considerably less than the risk of
a second
HM of the same type for women with a CM. In the present
study,
women with a CM had a 1 in 138 chanceof a CM in the next
pregnancy,
10timeshigher than that of thegeneralpopulation. Thelow
frequency of
recurrent moles among women with PM, not noted in earlier
smaller
studies, may reflect the fact that all cases reported to have
two or
more PM were reviewed by an expert in the field and
genotyped
where a differential diagnosis was not possible thus excluding
cases
with a diagnosisof possible or probable PM that mayhavebeen
included
in earlier studies.
This study has demonstrated not only that the risk of
consecutive or
subsequent molar pregnancies is different for women with a CM
com-
pared with PM butalso has highlighted differences in age and
reproduct-
ive outcomes for these two groups. Women who experience
further
molar pregnancies after a PM aremore likely to have had previous
preg-
nancies, including live births, than women with CM who go on to
have
further molar pregnancies, for more than half of whom the index
case
is their first pregnancy. Women in whom the first pregnancy was
a CM
have a median age 5 years less than women in whom the first HM
is a
PM but demonstrate a greater age range. Finally, further CM in
women
with a CM are most likely to occur in the next pregnancy, while
further
PM in women with an initial diagnosis of PM are more likely to
occur
after one or more intervening pregnancies.
Figure 5 Partialelectropherograms showing thealleles identified
following amplificationof shorttandem repeats (STRs)in DNA
fromparents and molar
tissue in representative cases with three or more CM. (A) Case
147 in which the molar tissue has only a single, paternally derived
allele for both loci,
D13S1358 and Tyrosine Hydroxylase (TH01) and is therefore
androgenetic. (B) Case 121 in which the CM has a single maternally
derived and a single
paternally derived allele consistent with a diploid biparental
origin for both loci, D8S1179 and D21S11.
Frequency of recurrent hydatidiform moles 7
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The frequency of further HM in subsequent pregnancies will
depend
on the number of pregnancies experienced by the cohort.
Since
women in whom the index pregnancy was a PM went on to have
an
average of 3.5 further pregnancies and the frequency of further
HM
was not much greater in subsequent pregnancies than in the next
preg-
nancy, having a PM does not appear to significantly increase the
risk of
further HM in later pregnancies.
The different characteristics observed between women with CM
and
PM may reflect the fact that among women with recurrent CM is a
sub-
group of women with FRHM, an inherited predisposition to molar
preg-
nancies, who arehighly unlikelyto have hada previous
normalpregnancy
andwill therefore experience their first CM at a younger age.
Followinga
second molar pregnancy these women are likely to proceed to
further
molar pregnancies unless the condition is recognized. However,
not all
womenwiththreeCMhaveFRHM(vanderSmagt etal.,2006; Buyukkurt
et al., 2010; Dixon etal., 2012) andone of theobjectivesof this
study was
to determine the risk of a third molar pregnancy for women who
had
experienced two HM, and to estimate the frequency of FRHM in
our
population.
FRHMresults fromsingle gene mutationswith an
autosomalrecessive
pattern of inheritance rather than the presence of two paternal
copiesof the genome that characterizes typical sporadic PM and CM (
Hoffner
and Surti, 2012). To date, two genes NLRP7 (Murdochet al.,
2006)
and KHDC3L (Parryet al., 2011) have been reported to account
for
75 and 5% of affected cases, respectively. The mechanisms by
which
mutationsinthesegenesgivesrisetomolarpregnancies,withpathologic-
al characteristics that are usually indistinguishable from
sporadic CM
(Sebireet al., 2013), is unknown. Reports in the literature that
CM in
this condition show aberrant imprinting similar to that seen in
sporadic
CM (Fisheret al., 2002;Judsonet al., 2002;El-Maarriet al.,
2003;Kou
et al., 2008;Hayward et al., 2009) suggest that these genes are
normally
involved in setting or maintaining the maternal imprint in the
oocyte.
In the present study, 14% of women with two HM had a third
molar
pregnancy. This risk was clearly associated with CM. In the
presentstudy, only two women with consecutive PM had a third HM,
one
having a third PM and the other a CM. Genotyping showed the PM
in
both cases to be typical dispermic PM. Both patients have also
achieved
normallive births. Forwomen with two CM,23% of thosewith
twocon-
secutiveCM and19%of thosewith two non-consecutive CM,had a
third
CM.While thefrequency of a third HM after twoPM is small,for
women
withtwo CMit is.1 in 5. Genotyping of the CM in these cases
showed
that of the 15 women with no live births, 11 had FRHM while four
had
typical androgenetic CM. All four womenwho had live births in
addition
to CM, in thepresent study, had CM of androgenetic origin.
However, a
history of live births does not necessarily exclude a diagnosis
of FRHM
since occasional live births have been seen in women with CM of
bipar-
ental origin (Murdoch et al., 2006) andin cases with confirmed
homozy-
gous mutations in NLRP7 (Mahadevanet al., 2013; Nguyen and
Slim,
2014). An absence of live births in women with FRHM in this
series
may reflect the small number of cases in the series.
Genotyping of molar tissue in women with three or more CM is
recommended for the correct diagnosis of FRHM. This distinction
is im-
portant because women with androgenetic CM may have
subsequent
normal pregnancies and can reduce the risk of further CM with
IVF
andPGD(Ogilvie etal.,2009)whilewomenwithFRHMneedtoconsider
IVF with ovum donation to achieve a normal pregnancy ( Fisheret
al.,
2011). Diagnosis can be confirmed by demonstrating that the
patient is
homozygous or is a compound heterozygote for mutations or
patho-
logical variants inNLRP7orKHDC3L, although an absence of such
var-
iants does not exclude a diagnosis of FRHM as 20% of women
with
recurrent diploid biparental CM do not have mutations in these
genes
suggesting the possibility of other genes associated with this
condition
(Wanget al., 2009;Dixonet al., 2012).
If women with FRHM areexcluded from theanalysis, theriskof a
third
CM after twoCM is 11%, with most women
havinginterveningpregnan-
cies. However, a number of these women experience miscarriages
for
which no pathology is available that may represent unrecognized
early
loss of molar pregnancies.
Following a CM the risk of developing GTN varies with age but
is
around 14%, considerably higher than the 1% for women with a
PM
(Savageet al., 2013). This risk is likely to reflect the greater
aberrant
imprinting associated with the absence of a maternal copy of
the
genome, and the consequent loss of maternally expressed genes,
in
typical CM. While a number of maternally imprinted genes have
been
shown to have a paternal epigenotype in diploid biparental CM
(Fisher
et al., 2002;Judsonet al., 2002;El-Maarriet al., 2003;Kouet al.,
2008;
Haywardet al., 2009) other maternal imprints may be correctly
set in
diploid biparental CM (Hayward et al., 2009). So although
pathologicallysimilar to androgenetic CM, theoretically gene
expression in diploid
biparental CM might be sufficiently different to reduce the risk
of post-
molar GTN. However, this study showed that the risk of diploid
bipar-
ental CM progressing to GTN is not significantly different to
that of
androgenetic CM. Further investigation of imprinting defects in
these
unusual CM mayprovideinsight into thedevelopmentof
GTNfollowing
molar pregnancies.
In conclusion, analysis of subsequent pregnancy outcomes
following a
molar pregnancy at a large national referral centre during a
20-year
period hasconfirmedthat womenwith a molar pregnancy are at
increased
risk of further HM but that the risk of another PM in the next
pregnancy is
small, compared with the 1 in 100 risk of a further CM following
an index
pregnancy with CM. Only a single patient in the present series
had threeconsecutive PM while nearly one in four women with two
consecutive
CM had another CM in the next pregnancy, over half of whom
have
FRHM. However, overall, FRHM is rare, affecting only 1 in 650
women
registered with a CM, and the most likely pregnancy outcome,
even after
two molar pregnancies, is a full term normal delivery
Authors roles
N.E., N.J.S. and D.S. were involved in acquisition of data. N.E.
and N.J.S.
were involved in analysis and interpretation of data. P.M.S. and
M.J.S.
were responsible for managing the patients in the study. All
authors
contributed to drafting and editing the manuscript. R.A.F. was
respon-sible for project design, oversight of all data acquisition
and analysis,
interpretation and final manuscript preparation.
Funding
N.J.S. is part supported by an NIHR Senior Investigator
award.
Conflict of interest
None to declare.
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