European Journal of Obstetrics & Gynecology and Reproductive Biology 164 (2012) 138141

Contents lists available at SciVerse ScienceDirect

European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

First trimester bleeding and maternal cardiovascular morbidity

Jacob A. Lykke a,*, Jens Langhoff-Roos b,c
a

Department of Obstetrics and Gynecology, Roskilde Hospital, Roskilde, Denmark

Department of Obstetrics, Rigshospitalet, Copenhagen, Denmark
c
Faculty of Health Science, University of Copenhagen, Denmark
b

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 20 November 2011
Received in revised form 31 March 2012
Accepted 7 June 2012

Objectives: First trimester bleeding without miscarriage is a risk factor for complications later in the
pregnancy, such as preterm delivery. Also, rst trimester miscarriage has been linked to subsequent
maternal ischemic heart disease. We investigated the link between maternal cardiovascular disease
prior to and subsequent to rst trimester bleeding without miscarriage.
Study design: We performed a registry-based retrospective cohort study of 796,915 women who gave
birth to a singleton infant after 20 completed weeks in Denmark in 19782007. The exposures and
endpoints were registry diagnoses of cardiovascular diseases preceding pregnancy, rst trimester
vaginal bleeding without miscarriage, and subsequent maternal cardiovascular disease. In the adjusted
models, we considered preterm delivery, prelabor rupture of membranes, hypertensive pregnancy
disorders, fetal growth restriction, placental abruption and stillbirth as possible confounders. We used
logistic regression and Cox proportional hazard models to assess the associations.
Results: Women with pre-pregnancy cardiovascular disease had a 2.2-fold (95% CI 1.34.1) increased
risk of rst trimester bleeding without miscarriage, and rst trimester bleeding without miscarriage was
associated with a 1.6-fold (1.41.8) increase in risk of subsequent maternal ischemic hearth disease after
adjusting for other adverse pregnancy outcomes.
Conclusion: First trimester bleeding without miscarriage is associated with pre-pregnancy as well as
subsequent maternal cardiovascular morbidity.
2012 Elsevier Ireland Ltd. All rights reserved.

Keywords:
Adverse pregnancy outcome
Threatened miscarriage
Abortus imminens
Cardiovascular disease
Follow-up
Cohort
Registry

1. Introduction
First trimester bleeding is common in pregnancy, with an
incidence up to 2027%, and for about half of these women, the
pregnancy will end in miscarriage [1,2]. For the women with rst
trimester bleeding and an ongoing pregnancy, evidence is
mounting for an increased risk of later pregnancy complications
such as preterm delivery, placental abruption and pre-eclampsia
[3,4]. Recently, these latter pregnancy complications, as well as
fetal growth restriction, have been associated with increased
mortality and cardiovascular morbidity, including ischemic heart
disease, in the mother, suggesting that these women have a
predisposing vulnerable cardiovascular system [58].
Women who have experienced early miscarriage also seem to
be at increased risk of ischemic heart disease later in life [9,10].
Although some studies have investigated the consequences of rst
trimester bleeding on the risk of complications later in the

* Corresponding author at: Department of Obstetrics and Gynecology, Roskilde

Hospital, Kogevej 7, 4000 Roskilde, Denmark. Tel.: +45 4732 3200.
E-mail address: dr.lykke@dadlnet.dk (J.A. Lykke).
0301-2115/$ see front matter 2012 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ejogrb.2012.06.003

pregnancy, none has investigated the long-term outcome for the

mother.
We hypothesize that a vulnerable maternal cardiovascular
system will predispose to rst trimester threatened miscarriage,
other pregnancy complications and later cardiovascular morbidity.
Therefore, we designed a registry-based cohort study investigating
the association between (1) pre-pregnancy cardiovascular morbidity and rst trimester bleeding without miscarriage, and (2)
rst trimester bleeding and subsequent maternal cardiovascular
morbidity.
2. Materials and methods
The National Patient Registry (NPR) collects information on all
discharge diagnoses from hospitals and deliveries in Denmark.
Since 1977, the registry has had complete coverage and since 1994,
it has included diagnoses from outpatient clinics as well [11]. The
discharging physicians code each medical diagnosis by the
International Classication of Diseases (ICD). At delivery, birth
weight and gestational age are routinely recorded. In the earlier
years, gestational age was assessed by the last menstrual period;
gradually in later years, it has been veried and/or corrected by
early second trimester sonography.

J.A. Lykke, J. Langhoff-Roos / European Journal of Obstetrics & Gynecology and Reproductive Biology 164 (2012) 138141

139

Table 1
Prepregnancy morbidity and rst trimester bleeding without miscarriage.
Prepregnancy morbidity

(a) Cardiovascular disease

No
Yes
(b) Diabetes mellitus type 1
No
Yes
(c) Diabetes mellitus type 2
No
Yes

Adjusteda

Women in group

Cases

Crude

OR

CI

OR

CI

785,310
11,605

98.5%
1.5%

18,696
433

2.4%
3.7%

1
2.28

(Reference)
(1.274.11)

0.006

1
2.28

(Reference)
(1.274.11)

0.006

795,399
1516

99.8%
0.2%

19,090
39

2.4%
2.6%

1
0.89

(Reference)
(0.651.22)

0.46

1
0.73

(Reference)
(0.501.08)

0.11

794,924
1991

99.8%
0.2%

19,071
58

2.4%
2.9%

1
1.13

(Reference)
(0.871.47)

0.36

1
1.31

(Reference)
(0.951.80)

0.10

Year and maternal age at delivery were considered in both models.

a
In the adjusted model, we adjusted for the all 3 morbidities. Total number of women n = 796,915.

We extracted information on all singleton deliveries beyond 20

weeks of gestation in Denmark from 1st January 1978 to 1st
October 2007, which accrued 1,795,806 deliveries of 965,475
women. From this population, we dened the rst study
population as women aged 1550 years with a rst delivery,
n = 796,915; in the second population, being a subpopulation of the
rst, we excluded those women with a preceding cardiovascular
diagnosis (n = 11,605; 1.5%) or type 1 and 2 diabetes (excluding
women with concomitant cardiovascular diseases: n = 2387; 0.3%)
and women who died or emigrated within 3 months of delivery
(n = 65 and n = 567). Thus, the second study population consisted of
782,287 women.
In the rst cohort, the exposures were pre-pregnancy cardiovascular disease and diabetes mellitus types 1 and 2, and the
endpoint was rst trimester bleeding without miscarriage. In the
second cohort, the exposure was rst trimester bleeding without
miscarriage, and the endpoint was subsequent cardiovascular
disease in the mother, i.e. hypertension, ischemic heart disease,
stroke, thromboembolic event and diabetes.
First trimester vaginal bleeding was veried by a physician, that
is women referred to a clinic, examined by a physician and having a
discharge diagnosis of vaginal bleeding before 12 completed weeks
of gestation. Of note, women who later experienced actual
miscarriage or induced abortion before 20 completed weeks were
not included in the study population.
The adverse pregnancy outcomes were preterm delivery before
37 weeks of gestation, which was stratied into delivery before 28
completed weeks, 2831 weeks, and 3236 weeks; hypertensive
pregnancy disorders stratied into gestational hypertension, mild
pre-eclampsia, and severe pre-eclampsia (including eclampsia and
the HELLP syndrome); small- and large-for-gestational-age offspring dened as a birth weight 2 standard deviations below or
above the mean, respectively, in a standardized distribution for
gender and gestational age [12]; placental abruption; and
stillbirth. Implausible values of birth weight and gestational age
were classied as missing. Collectively, missing values occurred
more frequently in the earlier years; all missing values were
analyzed as separate groups.
The follow-up endpoints were death from all causes, and the
rst diagnosis of hypertension, ischemic heart disease, stroke,
thromboembolism and diabetes. We used specic ICD-8 and -10
codes for these diagnoses (see online supplement for details).
Women emigrated or deceased were censored at the time of
emigration or death.
We used multivariable logistic regression to calculate the
associations between pre-pregnancy cardiovascular morbidity and
rst trimester bleeding without miscarriage, and Cox proportional
hazard models including years from delivery to event or censoring
as the time-dependent variable to calculate the hazard ratio (HR)

between rst trimester bleeding without miscarriage and later

death and cardiovascular morbidity.
After initial stratication in all the models, we found no
evidence of signicant interactions. All odds ratios (OR) and hazard
ratios (HR) are presented with 95% condence intervals (CI). In the
tables, we additionally present the number of women (n) and
percentages (%) in each category and outcome. SPSS (v18.0 for
Macintosh, SPSS Inc.; Chicago, Illinois, USA) was used for all
calculations. The study was approved by the Danish Data
Protection Agency.
3. Results
In the rst cohort, the mean age of the women was 26.8 years
(range 15.048.8 years; interquartile range 23.529.6 years); in
the second cohort, the mean age of the women was 26.5 years
(range 15.048.8 years; interquartile range 23.529.6 years). In the
rst cohort, 19,129 women had rst-trimester bleeding without
miscarriage (2.4%); in the second cohort, 18,311 women had rsttrimester bleeding without miscarriage (2.3%). In the second
cohort, 770 women had bleeding without miscarriage after 12
weeks of gestation: These women were included in the control
group. The median follow-up time from delivery to time of
censoring was 14.6 years (range 0.2530.2 years; interquartile
range 7.6121.8 years) corresponding to 11,600,945 person-years
of observation. During this follow-up period, 15,902 (2.0%)
emigrated and 8876 (1.1%) died.
The risk of rst-trimester bleeding without miscarriage was
increased 2.28-fold (1.274.11) in women with cardiovascular
disease preceding the rst pregnancy (Table 1a). In contrast,
women with pre-pregnancy diabetes, either type 1 or 2, had the
same risk of rst-trimester threatened miscarriage as women
without these disorders (Table 1b and c).
In the follow-up study of the second cohort (Table 2), the
cardiovascular morbidity was signicantly increased. In general,
the associations were slightly attenuated when adjusting for
preterm delivery, primary rupture of membranes, hypertensive
pregnancy disorders, fetal growth, placental abruption and
stillbirth. The strongest association was observed in subsequent
thromboembolic event and ischemic heart disease, in which
women with rst-trimester bleeding without miscarriage had a
risk increased 1.61-fold (1.341.93) and 1.58-fold (1.391.79),
respectively.
4. Comment
The present study shows that women with pre-pregnancy
cardiovascular disease have increased risk of rst-trimester
bleeding without miscarriage, and, vice versa, that women

140

J.A. Lykke, J. Langhoff-Roos / European Journal of Obstetrics & Gynecology and Reproductive Biology 164 (2012) 138141

Table 2
First trimester bleeding without miscarriage and subsequent maternal cardiovascular morbidity.
Outcome

Hypertension
Ischemic heart disease
Stroke
Thrombolic event
Diabetes mellitus

Control

Case

Adjusteda

Crude

HR

CI

HR

CI

18,101
8264
8738
3760
6520

2.4%
1.1%
1.1%
0.5%
0.9%

450
252
249
121
200

2.5%
1.4%
1.4%
0.7%
1.1%

1.25
1.60
1.44
1.66
1.60

(1.141.37)
(1.411.82)
(1.271.63)
(1.381.98)
(1.391.84)

<0.001
<0.001
<0.001
<0.001
<0.001

1.20
1.58
1.41
1.61
1.51

(1.091.32)
(1.391.79)
(1.251.60)
(1.341.93)
(1.311.74)

<0.001
<0.001
<0.001
<0.001
<0.001

Year and maternal age at delivery were considered in both models.

a
In the adjusted model, we adjusted for the preterm delivery, primary rupture of membranes, hypertensive disorders, SGA/LGA, placental abruption, and stillbirth. Total
number of women n = 782,287; control n = 763,976; cases n = 18,311.

experiencing rst-trimester bleeding without miscarriage have

increased risk of subsequent cardiovascular disease. The associations between rst-trimester bleeding and later maternal cardiovascular diseases persist after adjustment for later pregnancy
complications, which are associated with rst-trimester bleeding
[3] as well as subsequent maternal cardiovascular morbidity [58],
and thus could act as potential confounders.
Previously, Smith et al. found that early miscarriage was an
indicator of subsequent maternal ischemic heart disease [9], and
Kharazmi et al. found a doseresponse effect by the number of
miscarriages experienced [10]. Early miscarriage is often associated with chromosomal aberrations in the conceptus [13] and thus
the exposure studied may be different from the present one;
however, part of the antiphospholipid syndrome (anti-b2-glycoprotein I antibodies, IgM isotype) has been associated with both
rst trimester bleeding and miscarriage [14], a nding that links
these events with cardiovascular events.
Our ndings suggest that rst-trimester bleeding without
miscarriage is not an arbitrary event with consequences limited to
the ongoing pregnancy; rather, it is an event associated with a prepregnancy cardiovascular susceptibility that emerges during
pregnancy as rst-trimester bleeding and later as overt cardiovascular disease.
Two general models have been proposed explaining early
vaginal bleeding an intrinsic and an extrinsic model. The intrinsic
model centers on an impaired invasion of cytotrophoblasts and
remodeling of the spiral arteries, which, appealingly, also explains
the observed link to later adverse pregnancy outcome [4,15].
Furthermore, this impaired cytotrophoblast invasion has also been
demonstrated in actual miscarriage [16]; the bleeding in threatened miscarriage may in this aspect represent a near miss of the
same pathophysiological process as miscarriage. The extrinsic
model focuses on random events such as intercourse. Previously,
the idea of implantation bleeding or bleeding after intercourse was
widespread, but there seems to be no evidence supporting these
beliefs [17]. The obsoleteness of these extrinsic and random
explanations renders the intrinsic model more plausible. Added to
this, we previously showed that early rst-trimester bleeding in a
rst pregnancy carries risk of pregnancy complications over into a
second pregnancy, and vice versa. This indicates the existence of a
common etiology or proclivity to rst-trimester bleeding, adverse
pregnancy outcomes, and cardiovascular disease. Thrombophilia,
inherited and acquired, may be one of several candidates.
Women with pre-pregnancy morbidity may be more anxious
and prone to seek medical attention for rst-trimester bleeding
and thus more likely to have a diagnosis registered in the Registry,
resulting in bias away from the null hypothesis. We found,
however, that in women with pre-pregnancy type 1 or type 2
diabetes the risk of bleeding did not differ from that of the control
group, which is in contrast to the risk in women with prepregnancy cardiovascular disease. This indicates that pre-pregnancy morbidity per se does not inuence the chance of
registration of rst-trimester bleeding in the Registry.

In conclusion, rst-trimester bleeding without miscarriage is a

marker of a susceptible maternal cardiovascular system. Together
with previous studies on long-term maternal consequences of
pregnancy complications [5,6,18], our ndings support the
hypothesis of pregnancy as the stress test for life [19].
Conict of interest
Both authors have nothing to declare.
Funding
None.
Author contribution
JAL designed the study and performed the data analyses; both
authors contributed equally to the manuscript.
Ethics
The study was approved by the Danish Data Protection Agency
(2005-41-5262 & 2007-41-1544).
Level of evidence
II observational study.

Appendix A. Supplementary data

Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.ejogrb.
2012.06.003.
References
[1] Everett C. Incidence and outcome of bleeding before the 20th week of pregnancy: prospective study from general practice. British Medical Journal
1997;315:324.
[2] Hasan R, Baird DD, Herring AH, Olshan AF, Jonsson Funk ML, Hartmann KE.
Association between rst-trimester vaginal bleeding and miscarriage. Obstetrics and Gynecology 2009;114:8607.
[3] van Oppenraaij RHF, Jauniaux E, Christiansen OB, et al. Predicting adverse
obstetric outcome after early pregnancy events and complications: a review.
Human Reproduction Update 2009;15:40921.
[4] Lykke JA, Dideriksen KL, Lidegaard , Langhoff-Roos J. First-trimester vaginal
bleeding and complications later in pregnancy. Obstetrics and Gynecology
2010;115:93544.
[5] Smith GCS, Pell JP, Walsh D. Pregnancy complications and maternal risk of
ischaemic heart disease: a retrospective cohort study of 129,290 births. Lancet
2001;357:20026.
[6] Lykke JA, Langhoff-Roos J, Sibai BM, Funai EF, Triche EW, Paidas MJ. Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and
type 2 diabetes mellitus in the mother. Hypertension 2009;53:94451.

J.A. Lykke, J. Langhoff-Roos / European Journal of Obstetrics & Gynecology and Reproductive Biology 164 (2012) 138141
[7] Lykke JA, Paidas MJ, Triche EW, Langhoff-Roos J. Fetal growth and later
maternal death, cardiovascular disease and diabetes. Acta Obstetricia et
Gynecologica Scandinavica 2012;91:50310.
[8] Lykke JA, Paidas MJ, Damm P, Triche EW, Kuczynski E, Langhoff-Roos J. Preterm
delivery and risk of subsequent cardiovascular morbidity and type-II diabetes in
the mother. British Journal of Obstetrics and Gynaecology 2010;117:27481.
[9] Smith GCS, Pell JP, Walsh D. Spontaneous loss of early pregnancy and risk of
ischaemic heart disease in later life: retrospective cohort study. British Medical Journal 2003;326:4234.
[10] Kharazmi E, Dossus L, Rohrmann S, Kaaks R. Pregnancy loss and risk of
cardiovascular disease: a prospective population-based cohort study (EPICHeidelberg). Heart 2011;97:4954.
[11] Andersen TF, Madsen M, Jrgensen J, Mellemkjoer L, Olsen JH. The Danish
National Hospital Register. A valuable source of data for modern health
sciences. Danish Medical Bulletin 1999;46:2638.
[12] Marsal K, Persson PH, Larsen T, Lilja H, Selbing A, Sultan B. Intrauterine growth
curves based on ultrasonically estimated foetal weights. Acta Paediatrica
1996;85:8438.

141

[13] The Eshre Capri Workshop Group. Genetic aspects of female reproduction.
Human Reproduction Update 2008;14:293307.
[14] Mezzesimi A, Florio P, Reis FM, et al. The detection of anti-beta2-glycoprotein I
antibodies is associated with increased risk of pregnancy loss in women with
threatened abortion in the rst trimester. European Journal of Obstetrics
Gynecology and Reproductive Biology 2007;133:1648.
[15] Johns J, Hyett J, Jauniaux E. Obstetric outcome after threatened miscarriage
with and without a hematoma on ultrasound. Obstetrics and Gynecology
2003;102:4837.
[16] Hustin J, Jauniaux E, Schaaps JP. Histological study of the materno-embryonic
interface in spontaneous abortion. Placenta 1990;11:47786.
[17] Harville EW, Wilcox AJ, Baird DD, Weinberg CR. Vaginal bleeding in very early
pregnancy. Human Reproduction 2003;18:19447.
[18] Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of
cardiovascular disease and cancer in later life: systematic review and metaanalysis. British Medical Journal 2007;335:974.
[19] Williams D. Pregnancy: a stress test for life. Current Opinion in Obstetrics and
Gynecology 2003;15:46571.