Research

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OBSTETRICS

Hydatidiform mole and subsequent pregnancy

outcome: a population-based cohort study
Ulrika Joneborg, MD; Sandra Eloranta, PhD; Anna L. V. Johansson, MSc;
Lena Marions, MD, PhD; Caroline E. Weibull, MSc; Mats Lambe, MD, PhD
OBJECTIVE: The objective of the study was to investigate whether a

history of hydatidiform mole (HM) is associated with an increased risk

of adverse outcomes in subsequent pregnancies.
STUDY DESIGN: This was a nationwide cohort study with data from

population-based registers. The study population consisted of all

children registered in the Swedish Medical Birth Register 1973-2009
(n 3,730,825). Odds ratios (ORs) with 95% confidence intervals
(CIs) were estimated for adverse maternal and offspring pregnancy
outcomes by maternal history of HM prior to the delivery, with children
to women with no maternal history of HM as the reference. Risk
estimates were adjusted for maternal age at delivery and maternal
country of birth.
RESULTS: A history of HM was not associated with an increased
risk of adverse maternal outcomes in subsequent pregnancies

(n 5186). Women exposed to a molar pregnancy prior to the

index birth were at an almost 25% increased risk of preterm birth
(OR, 1.23; 95% CI, 1.06e1.43), whereas women with at least 1
birth between the HM and the index birth were at an increased risk
of a large-for-gestational-age birth and stillbirth (OR, 1.35; 95% CI,
1.10e1.67 and OR, 1.81; 95% CI, 1.11e2.96, respectively). The
risk of repeat mole was 0.4%.
CONCLUSION: Women with a history of HM are at no increased risk

of adverse maternal outcomes in subsequent pregnancies but have

an increased risk of large-for-gestational-age birth, stillbirth, and
preterm birth. However, in absolute terms, the risk of subsequent
adverse offspring outcomes is very low.
Key words: gestational trophoblastic neoplasia, hydatidiform mole,
pregnancy outcome, repeat mole, subsequent pregnancy

Cite this article as: Joneborg U, Eloranta S, Johansson ALV, et al. Hydatidiform mole and subsequent pregnancy outcome: a population-based cohort study. Am J Obstet
Gynecol 2014;211:681.e1-7.

ydatidiform mole (HM) is a

genetically abnormal conception
occurring in about 1 of 500-1000 pregnancies.1,2 The most important risk
factors for the development of HM
are maternal age, geographical factors
including ethnicity, and a previous molar
From the Division of Obstetrics and Gynecology,
Department of Womens and Childrens Health,
Karolinska University Hospital/Institutet
(Drs Joneborg and Marions), and Department
of Medical Epidemiology and Biostatistics,
Karolinska Institutet (Drs Eloranta, Lambe,
Ms Weibull, and Ms Johansson), Stockholm,
and Regional Cancer Centre, Uppsala University
Hospital, Uppsala (Dr Lambe), Sweden.
Received March 3, 2014; revised May 10, 2014;
accepted June 13, 2014.
This study was supported by Karolinska
Institutet Research Funds Reference number
2010/1950-31/4.
The authors report no conict of interest.
Corresponding author: Ulrika Joneborg, MD.
ulrika.joneborg@karolinska.se
0002-9378/$36.00
2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2014.06.030

pregnancy.1,3-5 Molar pregnancies are

classied as complete or partial hydatidiform mole based on different histopathological and cytogenetic features.6,7
An HM is considered to be a premalignant condition, with approximately
15% of complete and 1% of partial moles
progressing into a malignant gestational
trophoblastic neoplasia (GTN).2,8-10 To
ensure early recognition of a postmolar
GTN, levels of human chorionic gonadotropin are monitored following a diagnosis of HM. During the surveillance
period, women are recommended to
refrain from a new pregnancy.
Previous studies have documented
long-standing psychosocial consequences, including future fertility fears, in
women with a diagnosis of HM, and
women who do not conceive subsequent
to a diagnosis of gestational trophoblastic disease have been shown to have
poorer psychosocial outcome and are
at greater need of support.11-14
Results from earlier studies indicate
that women with a history of HM
can expect a normal future reproductive

outcome, except for a slightly increased

risk of a repeat mole.4,5,15,16 Similarly,
women treated for a GTN appear not to
be at increased risk of adverse subsequent pregnancy outcomes, although
there have been reports of an increased
risk of stillbirth, possibly reecting an
effect of chemotherapy rather than of
factors associated with the gestational
trophoblastic disease.5,17
However, because most earlier studies
have focused on the likelihood of a live
birth vs the risk of spontaneous abortion
and stillbirth, the aim of this nationwide
cohort study encompassing more than
3.7 million singleton births was to
examine the risk of subsequent adverse
maternal and offspring outcomes in
women with a history of HM.

M ATERIALS

AND

M ETHODS

Data sources
Data were obtained from 3 nationwide
Swedish population-based registers. Record linkage between registers is made
possible by use of an individually unique
national registration number assigned

DECEMBER 2014 American Journal of Obstetrics & Gynecology

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to all Swedish residents at birth or rst

permanent residency.18

registered. The SCR was used to identify

women diagnosed with HM.

The Swedish Medical Birth Register

The Swedish Medical Birth Register
(MBR) was established in 1973 and
contains more than 98% of all births
in Sweden and records information
on maternal characteristics, reproductive history, and complications during
pregnancy, delivery, and the neonatal
period.19 For the purpose of the present
study, all births in Sweden between
1973 and 2009 were identied in the
MBR.

The Multi-Generation Register

The Multi-Generation Register (MGR)
encompasses all individuals in Sweden
born in 1932 or later, who resided in
Sweden at some point after 1961. It
allows the identication of family structures, including information on reproductive history. Information from
the MGR allowed the identication of
births before 1973, not encompassed
in the MBR (Figure).

The Swedish Cancer Register

The Swedish Cancer Register (SCR) was
established in 1958 to monitor the cancer burden in the Swedish population.
Reporting of all newly diagnosed cancer
cases and some premalignant conditions, including HM, is mandatory.
Reports are made separately by both a
clinician and a pathologist or cytologist.20 No treatment data are available in
the SCR. Earlier studies have shown an
underreporting of approximately 20%
of all cases of HM to the SCR.21,22 The
SCR does not differentiate between
complete and partial hydatidiform mole,
and cases of postmolar GTN are not

Study population
A total of 3,730,789 births were identied in the MBR between 1973 and
2009. From these, we excluded multiple
births (n 90,128), children with
missing data on maternal country of
origin (n 169), and children born to a
woman with a childbirth and a diagnosis
of HM registered the same date (suggesting a twin molar pregnancy or a
third-trimester partial molar pregnancy)
(n 17, referring to 7 unique women).
To be able to perform a complete case
analysis, children with missing data on
small for gestational age (SGA) or large
for gestational age (LGA) were also

FIGURE

Identification of HM and subsequent births in 3 nationwide Swedish

population-based registers
Hydatidiform moles identified in the SCR
Child births identified in the MGR
Index child births identified in the MBR

1973

1958

2009

Example woman in study population

Molar pregnancy

HM exposure in
Statistical analysis:

Child1(MGR)

Not
included

Child 2 (MBR)
Index birth
1 birth between
HM and index

birth

Child 3 (MBR)
Index birth
1 birth between
HM and index

birth

HM, hydatidiform mole.

Joneborg. Hydatidiform mole and subsequent pregnancy outcome. Am J Obstet Gynecol 2014.

681.e2 American Journal of Obstetrics & Gynecology DECEMBER 2014

excluded (n 18,063). In this way, the

analyses encompassed 3,622,412 children and 1,878,917 mothers.

Exposure variable
Our exposure variable was maternal
history of HM prior to childbirth. Information on exposure was extracted
from the SCR, using the International
Classication of Diseases (ICD)-7: 173
and pathoanatomical diagnosis: 801
codes to identify all recorded cases of
HM. In this way, a total of 4940 cases
of HM were identied in the SCR
since 1958, 20 of which were identied
as a repeat mole.
By means of record linkage between
the MBR and the SCR, we found 3709
unique women with a rst diagnosis of
HM during the period that was included
in the analysis. Of these, 3071 women
had a diagnosis of HM prior to at least 1
of their childbirths, with a total of 5186
exposed births. The study population
was further stratied into a maternal
history of HM prior to the index pregnancy, dened as no birth between the
HM and the index pregnancy (n
2867), and a maternal history of HM
and at least 1 birth between the HM
and the index pregnancy (n 2319).
Information on births occurring prior
to 1973 was retrieved from the MGR.
Outcome variables
Outcomes of interest included adverse
maternal pregnancy outcomes (maternal
preeclampsia [PE]; ICD-8: 63703,
63704, 63709, 63799; ICD-9: 642E, 642F,
642H; ICD-10: O11, O14; maternal hypertension; ICD-8: 63701; ICD-9: 642D,
642X; ICD-10: O13, O16; placental
abruption; ICD-8: 6514; ICD-9: 641C;
ICD-10: O45 and premature rupture of
membranes [PROM]; ICD-8: 6610;
ICD-9: 658B, 658C; ICD-10: O42; and
adverse offspring outcomes [congenital
malformations; ICD-9: 740-759; ICD10: Q30-Q99, preterm birth (delivery
<37 gestational weeks), stillbirth,
neonatal mortality (child died <28 days
postpartum), SGA, and LGA]).23,24
Statistical analysis
An unconditional logistic regression
analysis was used to estimate the

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association between maternal history of
HM and different adverse maternal and
offspring outcomes. Exposure to HM
was included in the regression models
using a dichotomous categorization
(ie, never exposed to HM vs exposed to
HM prior to index delivery) as well as a
3-level categorization (ie, never exposed
to HM, HM prior to index delivery, HM
followed by at least 1 childbirth prior to
index delivery). Births with no maternal
history of HM were used as the reference
group irrespective of categorization of
HM exposure.
Odds ratios (ORs) with 95% condence intervals (CIs) were calculated and
robust SEs were used in the logistic
regression analysis to account for the
dependency structure in the data (ie,
that the same woman could contribute
with >1 delivery).25 The strength of
the association between potential confounding variables (maternal age at index birth, country of origin, education,
smoking at rst visit to antenatal care,
and body mass index [BMI]) and HM
exposure prior to the index birth was
assessed using multinomial regression in
which the 3-level representation of HM
was included as the outcome variable
(Table 1). The unconditional logistic
regression models were adjusted for
maternal age at delivery (<20 years, 2029 years, 30-39 years, and 40 years old)
and region of birth (Europe, Africa, Asia,
and America) (Tables 2 and 3). P values
from Wald tests were calculated in all
regression models and a 5% signicance
level was used.
All data sets were merged and dened
using the Statistical Analysis Software
version 9.2 (SAS Institute, Cary, NC) and
were then exported to Stata version 12.1
(StataCorp 2011, release 12; StataCorp
LP, College Station, TX).
The study was approved by the Research Ethics Committee at Karolinska
Institutet (Stockholm, Sweden).

Research

TABLE 1

Distribution of HM exposure by maternal characteristics in deliveries

between 1973 and 2009 in Sweden
Characteristic

Deliveries

HM prior to
index deliverya

HM and at least 1
childbirth prior to
index deliverya

Age at birth, y
<20

118,838

39

20-29

2,043,266

1440

872

30-39

1,387,749

1288

1336

72,559

100

106

3,402,706

2685

2189

40

P < .001
Maternal country of origin
Europe (including Russia)
Africa

44,663

25

23

137,946

124

83

37,097

33

24

512,207

383

394

10-13

1,738,707

1357

1114

More than13

1,306,811

1099

797

64,687

28

14

2,088,502

1747

1425

295,828

232

197

Asia (including Oceania)

United States
P .1950
Maternal education, y
10

Missing
P < .001
Maternal smoking
No
1-9 cigarettes/day
10 cigarettes/day

164,775

117

106

1,073,307

771

591

134,012

104

56

19-24

1,321,924

1118

878

25-29

418,273

351

307

Missing
P .4592
Maternal BMI, kg/m2
<19

30
Missing

156,182

114

112

1,592,021

1180

966

3,622,412

2867

2319

P .0155
Total

BMI, body mass index; HM, hydatidiform mole.

R ESULTS
A total of 3,622,412 births between 1973
and 2009 were included in the analysis.
The distribution of HM exposure by
maternal characteristics is presented in
Table 1. A total of 0.14% of all births had
been exposed to a prior maternal molar

Note these numbers refer to deliveries, not unique women. Hence, women who have more than 1 exposed index delivery
contribute more than once to this table. The number of unique women with HM in this cohort was 3709. Of these, 3071 were
exposed to HM prior to at least 1 of their childbirths.

Joneborg. Hydatidiform mole and subsequent pregnancy outcome. Am J Obstet Gynecol 2014.

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TABLE 2

Association between HM and adverse maternal pregnancy outcomes

Model 1a

Outcome

Model 2a

No history
of HM

Previous history
of HM (ever)

HM and at least 1
childbirth prior to
index delivery

HM prior to
index delivery

Preeclampsia
OR (95% CI)

1.00 (reference)

0.75 (0.59e0.96)

P value
Number of events

0.79 (0.58e1.06)

.023
69,262

0.71 (0.50e1.02)
.074

77

44

33

Pregnancy hypertension
OR (95% CI)

1.00 (reference)

1.01 (0.74e1.38)

P value
Number of events

1.05 (0.70e1.57)

.947
27,577

0.96 (0.61e1.52)
.957

43

24

19

Placental abruption
OR (95% CI)

1.00 (reference)

1.10 (0.75e1.63)

P value
Number of events

1.05 (0.62e1.77)

.617
16,553

1.17 (0.68e2.02)
.841

27

14

13

PROM
OR (95% CI)

1.00 (reference)

0.88 (0.71e1.09)

P value
Number of events
Number of pregnancies

0.99 (0.76e1.30)

.247

0.74 (0.52e1.05)
.251

67,825

87

54

33

3,617,226

5186

2867

2319

CI, confidence interval; HM, hydatidiform mole; OR, odds ratio; PROM, premature rupture of membranes.
a

Both models were adjusted for maternal age at birth, maternal country of origin, and the correlation between siblings using a robust estimator of the SE.

Joneborg. Hydatidiform mole and subsequent pregnancy outcome. Am J Obstet Gynecol 2014.

pregnancy. There was an increase in the

exposure of HM prior to childbirth with
increasing maternal age (P < .001), an
increasing level of maternal education
(P < .001), and an increasing maternal
BMI (P .0155).
There was no evidence that women
with a history of HM were at increased
risk of subsequent adverse maternal
pregnancy outcomes such as PE, pregnancy hypertension, placental abruption, and PROM, compared with women
with no prior HM (Table 2). On the
contrary, women with a history of HM
had a 25% lower risk of PE compared
with the reference group (OR, 0.75; 95%
CI, 0.59e0.96).
LGA births were slightly more
common in women with a history of
HM, compared with women not previously exposed to HM (4.1% vs 3.3%;

P .025). The increased risk of LGA

birth was present only for women with at
least 1 child between the HM and the
index delivery (OR, 1.35; 95% CI,
1.10e1.67). There was also a greater
than 80% increased risk of stillbirth (OR,
1.81; 95% CI, 1.11e2.96) in the same
subgroup. The absolute risk of stillbirth
in this group was still very low, 0.69%,
compared with 0.37% in the reference
group. For women exposed to a HM just
prior to the index delivery, the risk of
preterm birth was increased by almost
25% (OR, 1.23; 95% CI, 1.06e1.43).
There were no detectable associations
between a history of HM and SGA birth,
malformations, or neonatal mortality
(Table 3).
Among all cases of HM registered in
the SCR, the occurrence of repeat mole
was 0.4%.

681.e4 American Journal of Obstetrics & Gynecology DECEMBER 2014

C OMMENT
The results of this large nationwide
cohort study could not demonstrate an
association between a history of HM
and adverse maternal outcomes in subsequent pregnancies. Instead, women
exposed to a previous molar pregnancy
had a 25% lower risk of PE. However, we
found evidence of an increased risk of
LGA birth, stillbirth, and preterm birth
among women with a history of HM.
The observed increases in risk were,
although statistically signicant, small
and inconsistent across exposed groups
when stratied by the relationship between the molar exposure and the rank
order of subsequent index births. This
may indicate that the elevated risks of
adverse outcomes reect confounding
factors rather than the molar exposure.
The occurrence of repeat mole was low

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Research

TABLE 3

Association between HM and adverse offspring pregnancy outcomes

Model 1a

Outcome

Model 2a

No history
of HM

Previous history
of HM (ever)

HM and at least 1
childbirth prior to
index delivery

HM prior to
index delivery

Small for gestational age

OR (95% CI)

1.00 (reference)

1.08 (0.92e1.27)

P value
Number of events

1.20 (0.98e1.46)

.332
110,283

0.94 (0.73e1.21)
.171

166

102

64

Large for gestational age

OR (95% CI)

1.00 (reference)

1.19 (1.02e1.39)

P value
Number of events

1.06 (0.87e1.29)

.025
118,328

1.35 (1.10e1.67)
.019

215

103

112

Preterm birth
OR (95% CI)

1.00 (reference)

1.13 (1.00e1.27)

P value
Number of events

1.23 (1.06e1.43)

.059
184,171

0.99 (0.83e1.20)
.025

296

178

118

Congenital malformations
OR (95% CI)

1.00 (reference)

1.05 (0.91e1.21)

P value
Number of events

1.08 (0.91e1.31)

.473
136,911

1.01 (0.81e1.25)
.660

204

117

87

Neonatal death
OR (95% CI)

1.00 (reference)

0.88 (0.51e1.51)

P value
Number of events

0.97 (0.49e1.95)

.644
10,508

0.76 (0.32e1.83)
.828

13

0.56 (0.25e1.25)

1.82 (1.12e2.97)

Stillbirth
OR (95% CI)

1.00 (reference)

1.13 (0.74e1.71)

P value
Number of events
Number of pregnancies

.569

.021

13,283

22

16

3,617,226

5186

2867

2319

CI, confidence interval; HM, hydatidiform mole; OR, odds ratio.

a

Both models were adjusted for maternal age at birth, maternal country of origin, and the correlation between siblings using a robust estimator of the SE.

Joneborg. Hydatidiform mole and subsequent pregnancy outcome. Am J Obstet Gynecol 2014.

compared with the estimates reported in

earlier studies.4,5
The risk increase of LGA birth in
women with a history of HM and at
least 1 birth between the molar pregnancy and the index pregnancy is difcult to correlate to the molar exposure
because no increased risk was observed
in the rst birth after the exposure.
This nding may reect an increase in
BMI with each pregnancy, resulting in

an increased risk of adverse offspring

outcomes.26,27 Because BMI has been
registered in the MBR only since 1992,
the data at hand did not provide sufcient power to control for BMI.
In the same way, an increased risk
of stillbirth following HM was observed
only in women with at least 1 childbirth
prior to the index pregnancy. This is
difcult to explain biologically and
may reect an inuence of unknown

confounding factors, including an increase in BMI with each pregnancy.26,27

It should be noted, however, that the
risk of stillbirth was comparable with
what was found in previous studies,
also in the subgroup with the highest
risk.4,5
Results from previous studies show
that women and their partners may
suffer long-time psychosocial consequences as well as future fertility fears

DECEMBER 2014 American Journal of Obstetrics & Gynecology

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following a HM diagnosis.11,13 It has also

been well documented that perceived
maternal stress is associated with preterm delivery.28,29 Our nding of an
increased risk of preterm birth restricted
to women with a rst pregnancy after a
molar diagnosis may therefore be related
to a higher level of anxiety and fear of
an adverse pregnancy outcome than in
women who already gave birth to at
least 1 child after the molar episode and
in women in general.
Studies designed to examine perceived
stress levels in subsequent pregnancies,
and pregnancy outcomes following a
molar pregnancy need to be performed
to verify this assumption. Preterm birth
has also been reported in association
with a history of pregnancy termination,
particularly following surgical management.30,31 Because uterine curettage is
the established method for evacuating an
HM, this may also contribute to the
increased risk of subsequent preterm
birth.
Our nding of a decreased risk of
maternal PE in women with a history of
HM was unexpected. Because the onset
of PE is more common in late pregnancy,32 this nding may partly be
explained by an increased risk of preterm
birth in women exposed to an HM, thus
reducing the time they are exposed to the
risk of developing PE. Also, it cannot be
excluded that maternal socioeconomic
status might have played a role because
HM was more common in women with a
high education. However, in a subset
analysis of all births with information on
the maternal level of education, the results regarding PE as outcome remained
unchanged.
Compared with previously published
data,4,5,17 the occurrence of repeat mole
in this study was low. This may reect
not only underreporting but also the
fact that there might have been confusion among the reporting clinicians and
pathologists/cytologists and the registrars of whether a new HM represents
a new event or a recurrence because
the SCR does not register disease
recurrences. 21,22
The strengths of the present study
included the nationwide populationbased design and the large size of the

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study population, allowing assessment
of rare adverse outcomes (PE, gestational
hypertension, PROM, placental abruption, stillbirth, neonatal mortality,
SGA, and LGA). The data at hand also
allowed the adjustment for known risk
factors for HM such as maternal age and
ethnicity.
Weaknesses included the previously
documented underreporting of HM to
the SCR,21,22 which may have diluted
possible differences in outcome between
the exposed group and the reference
group. Also, the absence of data on
postmolar GTN in the SCR might have
led to the inclusion of some women with
postmolar GTN treated with chemotherapy in the exposed cohort. For that
reason, it cannot be excluded that differences in adverse obstetric outcomes
reect chemotherapy related effects,
rather than the molar diagnosis. Because
complete and partial HM represent 2
different entities with possible different
effects on future pregnancies, an additional weakness was the lack of information on the subtypes of HM in the
SCR. In the case of selective underreporting of 1 of the 2 subtypes, the risk
of adverse outcomes might have been
over- or underestimated.
In conclusion, this large nationwide
cohort study found no association
between a history of HM and adverse
maternal outcomes in subsequent pregnancies. A slight but inconsistent
increased risk of LGA birth, stillbirth,
and preterm birth was observed, but for
the individual woman, the risk of adverse
offspring outcomes was low and barely
differed from that of the general population. The present ndings emphasize
that women treated for an HM can
expect normal future reproductive outcomes. Future studies should focus on
the possible association between levels
of perceived stress and premature birth
after a history of HM.
-

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