Atherosclerosis xxx (2015) 1e8

Contents lists available at ScienceDirect

Atherosclerosis
journal homepage: www.elsevier.com/locate/atherosclerosis

Sex differences in cardiovascular risk factors and disease prevention

Yolande Appelman a, *, Bas B. van Rijn b, c, Monique E. ten Haaf a, Eric Boersma d,
Sanne A.E. Peters e, f
a
Department of Cardiology, VU University Medical Center, Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
b
Department of Obstetrics, Division Woman and Baby, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
c
Academic Unit of Human Development and Health, Princess Anne Hospital, University of Southampton, Coxford Rd, Southampton, Hampshire SO16 5YA,
United Kingdom
d
Thoraxcenter Cardiology, Erasmus MC, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
e
The George Institute for Global Health, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7LF,
United Kingdom
f
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands

a r t i c l e i n f o a b s t r a c t

Article history: Cardiovascular disease (CVD) has been seen as a men's disease for decades, however it is more common
Received 17 November 2014 in women than in men. It is generally assumed in medicine that the effects of the major risk factors (RF)
Received in revised form on CVD outcomes are the same in women as in men. Recent evidence has emerged that recognizes new,
22 January 2015
potentially independent, CVD RF exclusive to women. In particular, common disorders of pregnancy, such
Accepted 22 January 2015
Available online xxx
as gestational hypertension and diabetes, as well as frequently occurring endocrine disorders in women
of reproductive age (e.g. polycystic ovary syndrome (PCOS) and early menopause) are associated with
accelerated development of CVD and impaired CVD-free survival.
Keywords:
Cardiovascular disease
With the recent availability of prospective studies comprising men and women, the equivalency of
Risk factors major RF prevalence and effects on CVD between men and women can be examined. Furthermore,
Gender female-specific RFs might be identified enabling early detection of apparently healthy women with a
Atherosclerosis high lifetime risk of CVD.
Prevention Therefore, we examined the available literature regarding the prevalence and effects of the traditional
Sex-differences major RFs for CVD in men and women. This included large prospective cohort studies, cross-sectional
studies and registries, as randomised trials are lacking. Furthermore, a literature search was per-
formed to examine the impact of female-specific RFs on the traditional RFs and the occurrence of CVD.
We found that the effects of elevated blood pressure, overweight and obesity, and elevated cholesterol
on CVD outcomes are largely similar between women and men, however prolonged smoking is signif-
icantly more hazardous for women than for men. With respect to female-specific RF only associations
(and no absolute risk data) could be found between preeclampsia, gestational diabetes and menopause
onset with the occurrence of CVD.
This review shows that CVD is the main cause of death in men and women, however the prevalence is
higher in women. Determination of the CV risk profile should take into account that there are differences
in impact of major CV RF leading to a worse outcome in women. Lifestyle interventions and awareness in
women needs more consideration. Furthermore, there is accumulating evidence that female-specific RF
are of influence on the impact of major RF and on the onset of CVD. Attention for female specific RF may
enable early detection and intervention in apparently healthy women. Studies are needed on how to
implement the added RF's in current risk assessment and management strategies to maximize benefit
and cost-effectiveness specific in women.
© 2015 Elsevier Ireland Ltd. All rights reserved.

* Corresponding author. VU University Medical Center, Meibergdreef 1117, 1081 1. Introduction

HV Amsterdam, The Netherlands.
E-mail addresses: y.appelman@vumc.nl (Y. Appelman), B.Van-Rijn@soton.ac.uk Despite enormous declines in the burden of cardiovascular
(B.B. van Rijn), m.tenhaaf@vumc.nl (M.E. ten Haaf), h.boersma@erasmusmc.nl disease (CVD) in the past decades, mainly due to improvements in
(E. Boersma), S.A.E.Peters@umcutrecht.nl (S.A.E. Peters).

http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.027
0021-9150/© 2015 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Y. Appelman, et al., Sex differences in cardiovascular risk factors and disease prevention, Atherosclerosis
(2015), http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.027
2 Y. Appelman et al. / Atherosclerosis xxx (2015) 1e8
primary and secondary prevention, CVD disease remains a main
cause of premature death and disability among men and women
worldwide. Statistics from the World Health Organization (WHO)
show that an estimated 17.3 million people died of CVD in 2008 of
which 80% occurred in low- and middle income countries [1].
About 7.3 million deaths were due to coronary heart disease (CHD)
and 6.2 million were due to stroke [2]. It is expected that the
number of people who die from CVD, mainly from CHD and stroke,
will increase to reach 23.3 million by 2030 [1,3].
Although CVD has been seen as a men's disease for decades, it is
actually more common in women. In the European population, 38%
of deaths in women before the age of 75 years are due to CVD - in
men this figure is 37% - a figure that is partly explained by a higher
risk of competing events, i.e. the risk of dying from other causes
(Fig. 1) [4]. Most of the burden of CVD can be explained by a set of
traditional risk factors that affect both men and women, including
elevated blood pressure, smoking, overweight and obesity, dia-
betes, and elevated cholesterol. Already in 1999 the American Heart
Association (AHA) developed the first women-specific clinical
recommendations for CVD prevention, which led to increased
awareness of women's CVD risk, and to improved risk factor
management and treatment of CVD in women [5]. However,
despite these women-specific guidelines and accruing evidence for
clinically important sex differences in the prevalence of traditional
CVD risk factors, and in the effects of these risk factors on CVD
outcomes sex-specific risk remains poorly understood and the
prevention and management of stroke and cardiovascular risk
factors is essentially still the same for men and women.
Recent evidence has emerged that recognizes new, potentially
independent, CVD risk factors exclusive to women [6]. In particular,
common disorders of pregnancy, such as gestational hypertension
and diabetes, as well as frequently occurring endocrine disorders in
women of reproductive age (e.g. polycystic ovary syndrome (PCOS)
and early menopause) are associated with accelerated develop-
ment of CVD and impaired CVD-free survival [7,8]. Other risk fac-
tors, although not exclusive to women, have a much higher
prevalence in women than men. As an example, migraine occurs 3
times more often in women, and is associated with an increased
risk of stroke [9,10]. The most recent AHA guideline (2011) and
AHA/American Stroke Association (ASA) guideline (2014) for the
prevention of cardiovascular complications and stroke in women
recommends CVD risk assessment in women with certain repro-
ductive manifestations of CVD risk, such as adverse pregnancy
outcomes, and suggests that female-specific risk factors may
improve current CVD risk assessment strategies [11,12].
The purpose of this review is to examine the available literature
regarding the prevalence and effects of the traditional risk factors
Fig. 1. Death rates in Europe 2012. Death rates in Europe, men and women <75 years of age; latest available year (2012), reprinted with permission from the World Health Or-
ganization [13].
Please cite this article in press as: Y. Appelman, et al., Sex differences in cardiovascular risk factors and disease prevention, Atherosclerosis
(2015), http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.027
on the risk for CVD in men and women. Furthermore, the impact of
the female specific risk factors on the occurrence of CVD is
examined.
2. Major risk factors that affect both men and women
2.1. Elevated blood pressure
Elevated blood pressure is a major public-health challenge
worldwide; it is estimated to be responsible for an annual 7.5
million deaths, about 12.8% of the total of all deaths and to account
for 57 million disability adjusted life years (DALYS), about 3.7% of all
DALYS [14]. The prevalence of hypertension is broadly similar in
men and women, and is projected to increase with population
growth and aging in both sexes. In 2000, nearly a billion adults, 27%
of all men and 26% of all women, had hypertension; these estimates
are projected to increase to 1.5 billion adults, 29% of men, and 30%
of women, in 2025 [14,15,16].
The Global Burden of Metabolic Risk Factors of Chronic Diseases
Collaborating Group recently conducted large-scale analyses to
estimate the global trends in systolic blood pressure (SBP) levels
between 1980 and 2008 [17]. In 2008, the age-standardized systolic
blood pressure worldwide was 4 mmHg higher in men than in
women; men on average had an SBP of 128.1 mmHg compared to
124.4 mmHg in women. Between 1980 and 2008, global levels of
mean SBP had decreased by 0.8 mmHg in men and by 1.0 mmHg
per decade in women and the prevalence of uncontrolled hyper-
tension had fallen from 33% in 1980 to 29% in 2008 in men and from
29% to 25% in women. These trends, however, varied markedly
among men and women living in different regions of the world.
Where SBP levels had fallen considerably by about 3e4 mmHg per
decade in men and women living in higher-income countries, most
likely due to successful implementation of lifestyle and therapeutic
interventions [18], opposite trends were seen in many lower and
middle-income countries including countries in Oceania, east Af-
rica, and south and southeast Asia were SBP levels rose with
0.8e1.6 mmHg per decade in men and 1.0e2.7 mmHg per decade
for women, with no evidence that trends were curbing [17].
Studies have reported conflicting results on whether the
strength of the association between increments in SBP and future
risk for CVD is the same for men as for women [19,20,21,22]. A
recent pooled analysis that included data from prospective cohort
studies on more than 1.2 million individuals and over 50,000 car-
diovascular events systematically examined whether the magni-
tude of the association between SBP and risk of CHD and stroke was
similar in women and men [23]. After consideration of differences
in other major cardiovascular risk factors, every 10 mmHg
 Y. Appelman et al. / Atherosclerosis xxx (2015) 1e8
increment in SBP was associated with a 15% increased risk of CHD
and a 25% increased risk of stroke in both men and women (Fig. 2A).
There were also no discernible sex differences in analyses stratified
by age group, nor was there any evidence to suggest a sex difference
in non-Asian versus Asian populations [23]. The authors concluded
that, although effective preventive actions are expected to be
beneficial in all individuals, on a population level those living in
low-and middle-income countries might especially benefit as ma-
jor increments in blood pressure-attributable burden of CVD are to
be expected in these regions due to the effects of population growth
and ageing, as well as the relatively low levels of awareness,
treatment and control of hypertension [24].
2.2. Cigarette smoking
Cigarette smoking causes nearly 6 million deaths per year; 5
million of these deaths are amongst direct users, whereas another
notable 600,000 individuals die as a result of being exposed to
second-hand smoke. In the 20th century, 100 million deaths, 16% of
all deaths in men and 7% in women, were estimated to be due to
smoking [14,25]. At present, nearly 80% of the more than 1 billion
smokers worldwide live in low- and middle-income countries, and
the global prevalence of smoking is nearly 5 times as high in men as
it is in women (48% versus 10%) [26]. Smoking characteristics also
Fig. 2. Relative risk for coronary heart disease and stroke. Relative risk for coronary heart disease (CHD) and stroke in women and in men per 10-mm Hg increase in systolic blood
pressure (A); for current smokers versus non-smokers (B); for people with diabetes versus without diabetes (C) and per 5 kg/m2 in body mass index (D). Lines show 95% confidence
intervals.
Please cite this article in press as: Y. Appelman, et al., Sex differences in cardiovascular risk factors and disease prevention, Atherosclerosis
(2015), http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.027
3
vary considerably between sexes [27]; women who smoke tended
to start smoking later in life, and to smoke fewer cigarettes than
men. Women who now start smoking, however, are increasingly
beginning to commence smoking at the same age and with similar
amounts as men. The anticipated burden of smoking-related dis-
eases may therefore become disproportionately larger in women
than in men, not only because of changes in the important sex
differences in the popularity of smoking and smoking patterns over
the last century [27,28], but also because of a potentially stronger
association between prolonged smoking and cardiovascular disease
risk in women than in men.
The first indication that women who smoke might have a
greater relative risk of CVD came from a Danish study, which
showed that women who smoke had a 50% greater CHD risk than
their male counterparts [29]. Additional studies have also sug-
gested that the association between smoking and CHD risk is
greater in women than in men, but only among the heaviest
smokers (>20 cigarettes per day) [30]. Two recent meta-analyses
provided reliable estimates of the association between smoking
and CHD and stroke in men and women [31,32]. The first meta-
analysis with data from 74 prospective cohort studies, nearly 2.4
million men and women and 44,000 coronary events, showed that,
while the beneficial effects of smoking cessation on coronary risk
were similar in women and men, women who smoke had a 25%
4 Y. Appelman et al. / Atherosclerosis xxx (2015) 1e8
greater relative risk of CHD than men, independent of differences in
baseline characteristics (Fig. 2B) [31]. In the second meta-analysis,
involving data from nearly 4 million individuals and more than
42,000 strokes, there was no clear evidence for a greater excess risk
of smoking in women compared with men; the pooled relative risk
for stroke associated with current smoking was 1.83 (95% CI: 1.58;
2.12) in women and 1.67 (95% CI: 1.49; 1.88) in men (Fig. 2B) [32]. In
a sensitivity analysis that explored the association in Occidental
cohorts (where the smoking epidemic is known to be relatively
mature) versus Oriental cohorts, smoking conferred a 10% greater
risk of stroke in women than in men in the Occidental populations.
This finding suggests that there is a small but real sex difference in
the effect of smoking on stroke risk, which is currently not visible
due to the relative immaturity of the smoking epidemic in women
in most parts of the world [25,27,28]. Alternatively, it might be that
the mechanisms driving the excess risk of smoking in women, such
as a potentially greater absorption of toxic chemicals from the same
amount of cigarettes in women [33], may be more pronounced for
CHD than for stroke. Future studies are required to examine the
effects of prolonged smoking in women and men, independent of
the attenuating but persisting sex differences in smoking behavior,
and if confirmed, to clarify the mechanisms underpinning these
differences.
2.3. Diabetes mellitus
Prevalence rates of diabetes rates are rising globally; where 8.3%
of all men and 7.5% of all women had diabetes in 1980, estimates
from 2008 were 9.8% in men and 9.2% in women [14,34]. The total
number of individuals dying from the consequences of high fasting
blood sugar or diabetes was 3.4 million in 2004, with more than
80% of these deaths occurring in low- and middle income countries
[3,35].
There is substantial evidence that diabetes is a more potent risk
factor for CHD and stroke in women than in men, i.e. the presence
of diabetes negates the biological female advantage that is often
used to explain why women have lower absolute rates of CHD and
stroke compared to men [36,37]. In a pooled analysis of over
850,000 individuals and 28,000 coronary events, it was demon-
strated that the presence of diabetes nearly tripled the risk of CHD
in women (RR: 2.82 [95% CI: 2.35; 3.38]) whereas it more than
doubled the risk in men (RR: 2.16 [95% CI: 1.82; 2.56]); the relative
risk for CHD thus being 44% greater in women with diabetes than in
similarly affected men (Fig. 2C) [36]. In addition, a similarly large
meta-analysis including data from over 750,000 individuals and
more than 12,500 strokes showed that the relative effect of dia-
betes on stroke risk was 27% greater in women compared with
men: the RR of stroke associated with diabetes was 2.28 (95% CI
1.93; 2.69) in women and 1.83 (95% CI 1.60; 2.08) in men, inde-
pendent of sex differences in other major cardiovascular risk factors
(Fig. 2C) [37]. This sex differential was seen consistently across
major predefined stroke, study, and participant subtypes, which
included a comparison of individuals from Asian and non-Asian
populations.
The mechanisms by which diabetes confers a greater excess risk
for CHD and stroke in affected women than in affected men remain
unclear. A sex disparity in the management and treatment of car-
diovascular risk factors in individuals with diabetes, to the detri-
ment of women, is possibly involved [38,39,40,41,42,43,44]. Most
recently, data on nearly 2 million individuals with diabetes from
the in the United Kingdom suggested that women with diabetes
were less likely than men with diabetes to receive care processes
recommended by the national guidelines and to meet treatment
targets [45]. Standard care processes, including annual checks for
the effectiveness of diabetes treatment, management of
Please cite this article in press as: Y. Appelman, et al., Sex differences in cardiovascular risk factors and disease prevention, Atherosclerosis
(2015), http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.027
cardiovascular risk factors and the emergence of early complica-
tions, were received by 58% of women and 62% of men, and 34% of
women and 37% of men met all treatment targets for HbA1c, blood
pressure, and cholesterol. While evidently of importance, these sex
disparities in the treatment and management of individuals with
diabetes alone, however, may be too small to explain all of the
excess relative risk for CVD in women with diabetes.
Alternatively, as the detrimental effects of glucose already occur
at glycemic levels below the threshold for the diagnosis of diabetes,
it might be that the transition from normoglycemia, to impaired
glucose tolerance and overt diabetes is more detrimental in women
than in men. As diabetes may remain undetected for many years
(about 183 million people with diabetes, 50% of all people with
diabetes, are undiagnosed) [46], its diagnosis is often made at an
advanced stage when major metabolic alterations and vascular
complications have already occurred in most patients [47,48].
Accumulating evidence suggests that these adverse changes in
metabolic and vascular risk factor profile in pre-diabetic individuals
are greater in women than they are in men [49,50,51,52,53,54,55].
Consequently, the diabetes-related excess risk of cardiovascular
disease in women may not be due to any significant sex difference
in the effects and complications of diabetes itself, but rather the
result of the combination of both a greater deterioration in car-
diovascular risk factor levels and a chronically elevated, but undi-
agnosed and untreated, cardiovascular risk profile in the pre-
diabetic state [56,57].
Future studies will be needed to determine the role of sex-
specific cardiovascular risk factor trajectories and their contribu-
tion to cardiovascular risk.
2.4. Overweight and obesity
Excess body weight is estimated to cause nearly 3 million deaths
worldwide each year [14,58]. In 2008, nearly 1.5 billion individuals
were overweight (i.e. body mass index (BMI) 25e30), a third of all
adults; of these more than 300 million women and nearly 200
million men were obese (i.e. BMI
30) [59]. Estimates from the
Global Burden of Disease group indicated that the world's average
had increased with 0.5 kg/m2 per decade in women and 0.4 kg/m2
in men to an average level of BMI of 24.1 kg/m2 for women and of
23.8 kg/m2 for men in 2008. The prevalence of overweight in men
and women differs according to the level of development of a
country; levels of BMI are typically higher in men than women in
most high-income countries whereas the reverse is more common
in lower and middle-income countries. Regions with almost flat
trends or even potential decreases in mean population BMI level are
Central and Eastern Europe for women, and Central Africa and
South Asia for men. Out of all of the high-income countries, men
and women from the USA had, with a mean BMI of over 28 kg/m2 in
both sexes, the highest mean population level of BMI [59].
Large-scale analyses of the Prospective Studies Collaboration
(PSC) and the Emerging Risk Factors Collaboration (ERFC) have
shown that the association between BMI and CHD is broadly
identical between men and women whereas the risk for stroke
associated with increments in BMI may be higher in men than in
women [60,61]. In the PSC, each 5 kg/m2 higher BMI was associated
with an increased risk for CHD of 1.35 (95% CI: 1.28; 1.43) in women
and 1.42 (95% CI: 1.35; 1.48) in men and with an increased risk for
fatal stroke of 1.30 (95% CI: 1.19; 1.42) in women and 1.50 (95% CI:
1.38; 1.65) in men (Fig. 2D). Analyses from the Asian-Pacific Cohort
Studies Collaboration (APCSC) also demonstrated the approxi-
mately equal strength of the association between the presence of
overweight or obesity and the risk of CHD between men and
women in both Asian and Australasian populations [62,63]. More-
over, despite the widely recognised sex dimorphism in the body fat
 Y. Appelman et al. / Atherosclerosis xxx (2015) 1e8 5

distribution there is no evidence that measures of abdominal cholesterol and risk of CHD [63,68]. Analyses of 302,430 individuals
adiposity, such as waist circumference or waist-to-hip-ratio have a from 68 prospective studies contributing to the ERFC indicated that,
different relationship with risk for CHD or stroke than BMI as after adjustment for other cardiovascular risk factors, the associa-
measure of general adiposity, nor that the associations between tion between HDL cholesterol levels and fatal CHD did not vary
excess CHD or stroke risk induced by measures of abdominal materially by sex: each 1-SD increase in HDL cholesterol lowered
adiposity are differential between men and women [61]. the risk of CHD mortality with 26% (95% CI: 17; 33%) in women and
with 21% (95% CI: 16; 26) in men [66]. It was also shown that, after
other cardiovascular risk factors had been accounted for, there was
2.5. Raised cholesterol
no association between triglycerides and risk for fatal CHD in both
sexes [66].
Raised cholesterol is responsible for over 2.6 million deaths
(4.5% of the total deaths), and for 29.7 Disability Adjusted Life Years
3. Female-specific risk factors
(DALY's) each year [14]. Women of younger age tend to have more
favorable lipid profiles than men, but cholesterol rises after the
3.1. Pregnancy as a risk factor for CV disease
menopausal transition to levels higher than in men [64]. Globally,
mean total cholesterol changed little between 1980 and 2008,
Pregnancy poses a substantial challenge to cardiovascular sys-
falling by less than 0.1 mmol/L per decade in men and women; the
tem of the mother, and pregnancy-associated complications are
global mean age-standardized total cholesterol is 4.76 mmol/L in
often the result of the mother's inability to adapt to this vascular
women and 4.64 mmol/L in men [65]. The prevalence of raised total
and metabolic “stress test” [6]. Consequently, several pregnancy
cholesterol is generally similar between sexes, but is strongly
outcomes (e.g. gestational hypertension and diabetes) have the
related to the income level of the country. Around a quarter of
ability to reveal valuable information about the underlying car-
adults in low income countries, a third of adults in lower middle
diovascular health of the mother. Since about 80e90% of women
income countries, and over half of all adult population from high-
worldwide have one or more children [69], evaluation of pregnancy
income countries had raised total cholesterol [14].
outcome may provide a unique and early opportunity to prevent
To date, there has been no systematic evaluation of the sex-
CVD in women. Table 1 summarizes current evidence of associa-
specific effects of major lipids on cardiovascular risk. Results from
tions between pregnancy outcomes and long-term CV risk.
large-scale individual participant data meta-analyses, however,
generally suggest that the associations between several major
3.2. Hypertensive disorders of pregnancy
lipids and the risk of CHD or stroke are similar between men and
women [66,67,68]. Analyses from the PSC on almost 900,000 in-
Hypertensive disorders of pregnancy, in particular pregnancy-
dividuals and over 33,000 coronary deaths demonstrated that, in
induced hypertension (PIH) and preeclampsia, occur in 2e10% of
both men and women, each 1 mmol/L lower total cholesterol
women [70] and are strongly associated with future maternal CVD
reduced the risk of mortality from CHD with about a half lower in
risk. In a recent meta-analysis by Bellamy et al. among 3.5 million
early middle age (40e49 years), about a third lower in later middle
women, preeclampsia was associated with an RR of 2.1 for CHD at
age (50e69 years), and about a sixth lower in old age (70e89 years)
14 years follow-up compared with women following normotensive
[67]. The APCSC also showed no evidence of a sex difference in total
pregnancy [71]. Similarly, women who experience preeclampsia or
PIH had a 2-fold RR for future stroke. Generally, 10-year event risks
Table 1 following a pregnancy complicated by preeclampsia are estimated
Female-Specific Risk Factors associated with Cardiovascular Disease. to be low (<20%), even though several major CVD risk factors may
Female-specific risk factor CVDf CHDg HTh Stroke T2DMi
be present, but expected lifetime CVD risk is likely to be high
a
[72,73,74]. Following current AHA guidelines, preventive in-
PCOS [89,90,95,96] C C CCC
e e
terventions after one or more hypertensive pregnancy are therefore
POIb [93] CC CC e e e
PIHc [71] CC C CCC C CC probably not indicated until later in life, or until evidence exists
Preeclampsia [71] CC CC CCC CC CC that earlier risk reduction is effective.
GDMd [76,77,81] CC CC CCC e CCC
Parity
1 [85] CC e e e e 3.3. Gestational diabetes mellitus
Parity
5 [85] CCC e e e e
Miscarriage
1 [97] e C e e e
Miscarriage 2þ/3þ [98] e CC e e e Gestational diabetes mellitus (GDM) has a prevalence of 3e5 %
Preterm birth < 37 w CC C C CC CC of all pregnancies and is similarly associated with an increased
[84,99,100,101,102] likelihood of CVD later in life [75]. Most of this risk appears
SGA < 10th centilee [82] CC CC e CC e
mediated by the development of type 2 diabetes (T2DM), for which
Stillbirth [98] e CC e e e
a recent meta-analysis [76] estimated a lifetime RR of 7.4 for
C weak association, Relative Risk (RR) between 1 and 1.5 in cohort studies CC women who experience gestational diabetes, compared with
moderate association, RR between 1.5 and 2.5 in cohort studies CCC strong as-
sociation, RR
2.5 in cohort studies.
women with normoglycemic pregnancies. This effect appeared
a
PCOS, Polycystic Ovary Syndrome, diagnosis according to the 2003 Rotterdam similar among different ethnic groups [77,78]. Even milder forms of
consensus criteria. glucose intolerance during pregnancy appear predictive of long-
b
POI, Primary Ovarian Insufficiency, defined as spontaneous (non-surgical) term T2DM risk, although the extent to which this is explained
menopause before the age of 40 years.
c by other CVD risk factors such as maternal obesity is inconclusive
PIH, Pregnancy-Induced Hypertension, defined by ISSHP criteria (BP
140/
90 mm Hg without significant proteinuria). [78,79]. Notably, a history of hypertensive disease in pregnancy is
d
GDM, Gestational Diabetes Mellitus, different criteria combined. also associated with an increased T2DM risk. In the largest study on
e
SGA, Small-for-Gestational Age, i.e. birth weight <5th centile. hypertensive disease in pregnancy to date of 782,287 women from
f
CVD, Cardio Vascular Disease. Denmark, Lykke and colleagues estimated the HR for T2DM at 3.1
g
CHD, Coronary Heart Disease.
h
HT, Hypertension.
after PIH, 3.5 after mild preeclampsia, and 3.7 after severe pre-
i
T2DM, Type 2 Diabetes Mellitus. eclampsia [80]. Hence, long-term T2DM risk appears to be depen-
dent on the severity of the pregnancy-associated hypertensive

Please cite this article in press as: Y. Appelman, et al., Sex differences in cardiovascular risk factors and disease prevention, Atherosclerosis
(2015), http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.027
6 Y. Appelman et al. / Atherosclerosis xxx (2015) 1e8
disease. Similar, in a small study of 203 Chinese women, a history of
GDM was associated with an adjusted RR of 3.3 for the presence of
hypertension 15 years after delivery [77]. Data on CVD event rates
after GDM are sparse and no long-term cohort studies are available.
In a cross-sectional study among 332 women with a first-degree
relative with T2DM, women who reported a previous history of
GDM had a 1.85 increased risk of CVD when compared with 663
women without such a history [81].
3.4. Placental disorders and fetal growth
Not only maternal complications in pregnancy, but also with
pregnancies complicated by fetal and placental complications (i.e.
without the presence of maternal disease) such as fetal growth
restriction and stillbirth appear to be associated with long-term
CVD risk for the mother. In an analysis by Ray et al. [8] in over 1
million women, the proportion of women free of CVD was already
steadily declining in those who experienced one or a combination
of
1 adverse maternal or fetal outcomes within the first decade
after delivery, as opposed to a fairly stable CVD risk in women
without such complications. Overall, women affected by placental
syndromes had a 2-fold RR of CVD, which increased up to 4.4 for
women with placental disorders and stillbirth [8]. Similarly, a
number of cohort studies have shown that women affected by
placental conditions translating to impaired fetal growth, are at risk
of long-term CV complications. In a study by Lykke et al. among
782,287 women, mothers who gave birth to infants with a birth
weight <2 Standard Deviation (SD) below the average had RRs of
CVD, ischemic heart disease and stroke of 2.5, 1.5 and 1.6, respec-
tively [82]. Mechanisms underlying the associations between
placental disorders and long-term CV health are still unclear, and
the predictive value of these different pregnancy outcomes as in-
dependent risk factors for CVD remains to be investigated.
3.5. Other pregnancy complications
Weak to moderate associations were found for other, less clearly
defined, pregnancy-associated complications and subsequent
maternal CV risk (Table 1). One study of 728,297 Danish women
with a previous delivery after 20 weeks gestational age found an
association between first-trimester vaginal bleeding without
miscarriage, and a subsequent 1.5-fold increased maternal risk of
T2DM [83]. In the same cohort, associations were found between
preterm birth (<37 weeks) at different gestational age intervals,
and long-term T2DM risk with HRs of 1.9 for delivery at 32e36
weeks to 2.1 for delivery before 27 weeks gestational age [84]. Even
parity itself has been evaluated as a risk factor for CV events, with
one study suggesting a 2-fold higher prevalence of CVD in pri-
miparous versus nulliparous women, which a further increase to
2.8 in women with
5 deliveries after adjustment for several CVD
risk factors [85]. However, the significance of this finding is un-
certain, as interactions with pregnancy complications are likely to
have occurred.
3.6. Ethnicity
Current studies on the associations between disorders of preg-
nancy and long-term CV risk have limited power to estimate ethnic
and racial differences as most studies have included predominantly
North American and European populations despite the fact that
there are known differences in the prevalence of these diseases
between populations. As an example, preeclampsia is more com-
mon among women of African-Caribbean origin [86], but these
women were underrepresented in the current CVD follow-up
cohorts.
Please cite this article in press as: Y. Appelman, et al., Sex differences in cardiovascular risk factors and disease prevention, Atherosclerosis
(2015), http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.027
4. Reproductive endocrine disorders and future CVD risk
4.1. Polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) is the most common endo-
crine disorder in women, affecting around 5e10% of women of
reproductive age. PCOS is characterized by excessive production of
androgens that leads to ovarian dysfunction, and is often accom-
panied by insulin resistance [87]. As a result, women experience a
menstrual disorder and fertility problems. Women with PCOS are
predisposed toT2DM, chronic hypertension and dyslipidaemia and
several other metabolic disturbances consistent with increased
CVD risk [88]. A meta-analysis by Moran et al. [89] found a 2-fold
increased RR for metabolic syndrome associated with PCOS.
Recently, Daan et al. [88] reported a 17% prevalence of metabolic
syndrome in a cohort of 2288 women with PCOS, primarily asso-
ciated with hyperandrogenism. However the prevalence in the
control population was not reported. Also, evidence for an
increased risk of CV events in women with PCOS is limited and
remains to be established [90].
4.2. Menopause
Menopause signals the transition from reproductive to non-
reproductive life, and is associated with several biological
changes to the endocrine system relevant to CV health. Age at
menopause logically translates to the interval of estrogen and
androgen exposure and is associated with a modest risk difference
in CVD. In a meta-analysis by Atsma et al. [91], age at menopause of
less than 50 years was independently associated with an RR of 1.38
(95% CI 1.15e1.35) of CVD, and early menopause due to surgical
removal of the ovaries with a pooled RR of 4.55 (95% CI 2.56e8.01).
Very early age at menopause < the age of 40 years, now often
named primary ovarian insufficiency (POI), occurs in 1e2% of
women [92]. This condition is characterized by early deprivation of
the pool of ovarian follicles, leading to amenorrhea, loss of fertility
and extended estrogen and androgen deprivation. In most cases,
the cause of POI is unknown. In a recent meta-analysis [93] POI has
been associated with an increased hazard ratio (HR) of CHD of 1.69
(95% CI 1.29e2.21), and HR of 1.61 (95% CI 1.22e2.12) for total CVD.
No consistent association exists between POI and long-term risk of
stroke. Prevalence of POI is higher in African American and Hispanic
populations, and lower in Asian women [94]. However, there are no
data to suggest that ethnic differences play a role in modifying CVD
risk after POI.
5. Conclusion
Cardiovascular diseases remain the world's leading cause of
death and disability in both men and women but affect more
women than men. Most of the burden of CVD is by means of the
traditional risk factors. While the effects of raised blood pressure,
overweight and obesity, and raised cholesterol on cardiovascular
outcomes are largely similar between women and men, prolonged
smoking and diabetes are significantly more hazardous for women
than for men. Further research into the mechanisms responsible for
the observed sex differences in traditional risk factor effects would
not only improve our understanding of the etiology of CVD, but
could also inform health policy makers and guideline committees
in tailoring specific interventions for the treatment and manage-
ment of these risk factors in both men and women. Furthermore,
awareness of these differences among women and medical pro-
fessionals is of great importance in order to lower the risk of CVD.
In addition, several female-specific risk factors can be identified
during reproductive life that may enable early detection of
 Y. Appelman et al. / Atherosclerosis xxx (2015) 1e8
apparently healthy, relatively women with an expected low 10-year
major event risk but with a high lifetime risk of CVD. However,
considerable challenges remain to determine whether or not these
female specific risk factors improve current risk assessment stra-
tegies, how to and when to screen women affected by one or more
reproductive manifestations of CVD risk, and how to best imple-
ment current risk management strategies in these women to
maximize benefit and cost-effectiveness.
References
[1] Global Status Report on Noncommunicable Diseases 2010, World Health
Organization, Geneva, 2011.
[2] Global Atlas on Cardiovascular Disease Prevention and Control, World Health
Organization, Geneva, 2011.
[3] C.D. Mathers, D. Loncar, Projections of global mortality and burden of disease
from 2002 to 2030, PLoS Med. 3 (11) (2006 Nov) e442.
[4] 2012 edition, European Cardiovascular Disease Statistics, European Heart
Network and European Society of Cardiology, 2012.
[5] L. Mosca, S.M. Grundy, D. Judelson, et al., Guide to preventive cardiology for
women. AHA/ACC scientific statement consensus panel statement, Circula-
tion 99 (18) (1999 May 11) 2480e2484.
[6] N. Sattar, I.A. Greer, Pregnancy complications and maternal cardiovascular
risk: opportunities for intervention and screening? BMJ 325 (7356) (2002 Jul
20) 157e160.
[7] S.M. Veltman-Verhulst, B.B. van Rijn, H.E. Westerveld, et al., Polycystic ovary
syndrome and early-onset preeclampsia: reproductive manifestations of
increased cardiovascular risk, Menopause 17 (5) (2010 Sep) 990e996.
[8] J.G. Ray, M.J. Vermeulen, M.J. Schull, et al., Cardiovascular health after
maternal placental syndromes (CHAMPS): population-based retrospective
cohort study, Lancet 366 (9499) (2005 Nov 19) 1797e1803.
[9] M.C. Kruit, M.A. van Buchem, P.A. Hofman, et al., Migraine as a risk factor for
subclinical brain lesions, JAMA 291 (4) (2004 Jan 28) 427e434.
[10] G. Mancia, E.A. Rosei, E. Ambrosioni, et al., Hypertension and migraine co-
morbidity: prevalence and risk of cerebrovascular events: evidence from a
large, multicenter, cross-sectional survey in Italy (MIRACLES study),
J. Hypertens. 29 (2) (2011 Feb) 309e318.
[11] L. Mosca, L.J. Appel, E.J. Benjamin, et al., Evidence-based guidelines for car-
diovascular disease prevention in women. American heart association sci-
entific statement, Arterioscler. Thromb. Vasc. Biol. 24 (3) (2004 Mar)
e29ee50.
[12] C. Bushnell, L.D. McCullough, I.A. Awad, et al., Guidelines for the prevention
of stroke in women: a statement for healthcare professionals from the
american heart association/American stroke association, Stroke 45 (5) (2014
May) 1545e1588.
[13] M. Nichols, N. Townsend, R. Luengo-Fernandez, et al., European Cardiovas-
cular Disease Statistics, European Heart Network, Brussels, 2012 (European
Society of Cardiology, Sophia Antipolis).
[14] Global Health Risks: Mortality and Burden of Disease Attributable to Selected
Major Risks, World Health Organization, Geneva, 2009.
[15] P.M. Kearney, M. Whelton, K. Reynolds, et al., Worldwide prevalence of
hypertension: a systematic review, J. Hypertens. 22 (1) (2004 Jan) 11e19.
[16] P.M. Kearney, M. Whelton, K. Reynolds, et al., Global burden of hypertension:
analysis of worldwide data, Lancet 365 (9455) (2005 Jan 15) 217e223.
[17] G. Danaei, M.M. Finucane, J.K. Lin, et al., National, regional, and global trends
in systolic blood pressure since 1980: systematic analysis of health exami-
nation surveys and epidemiological studies with 786 country-years and 5.4
million participants, Lancet 377 (9765) (2011 Feb 12) 568e577.
[18] B.M. Egan, Y. Zhao, R.N. Axon, US trends in prevalence, awareness, treatment,
and control of hypertension, 1988-2008, JAMA 303 (20) (2010 May 26)
2043e2050.
[19] M.J. O'Donnell, D. Xavier, L. Liu, et al., Risk factors for ischaemic and intra-
cerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a
case-control study, Lancet 376 (9735) (2010 Jul 10) 112e123.
[20] S. Yusuf, S. Hawken, S. Ounpuu, et al., Effect of potentially modifiable risk
factors associated with myocardial infarction in 52 countries (the INTER-
HEART study): case-control study, Lancet 364 (9438) (2004 Sep 11)
937e952.
[21] S. Lewington, R. Clarke, N. Qizilbash, et al., Age-specific relevance of usual
blood pressure to vascular mortality: a meta-analysis of individual data for
one million adults in 61 prospective studies, Lancet 360 (9349) (2002 Dec
14) 1903e1913.
[22] C.M. Lawes, A. Rodgers, D.A. Bennett, et al., Blood pressure and cardiovas-
cular disease in the Asia Pacific region, J. Hypertens. 21 (4) (2003 Apr)
707e716.
[23] S.A. Peters, R.R. Huxley, M. Woodward, Comparison of the sex-specific as-
sociations between systolic blood pressure and the risk of cardiovascular
disease: a systematic review and meta-analysis of 124 cohort studies,
including 1.2 million individuals, Stroke 44 (9) (2013 Sep) 2394e2401.
[24] M. Pereira, N. Lunet, A. Azevedo, et al., Differences in prevalence, awareness,
treatment and control of hypertension between developing and developed
Please cite this article in press as: Y. Appelman, et al., Sex differences in cardiovascular risk factors and disease prevention, Atherosclerosis
(2015), http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.027
7
countries, J. Hypertens. 27 (5) (2009 May) 963e975.
[25] M. Eriksen, MJRH, The Tobacco Atlas, fourth ed., American Cancer Society,
Atlanta, GA, 2012. New York, NY: World Lung Foundation.
[26] S.C. Hitchman, G.T. Fong, Gender empowerment and female-to-male smok-
ing prevalence ratios, Bull. World Health Organ 89 (3) (2011 Mar 1)
195e202.
[27] G.A. Giovino, S.A. Mirza, J.M. Samet, et al., Tobacco use in 3 billion individuals
from 16 countries: an analysis of nationally representative cross-sectional
household surveys, Lancet 380 (9842) (2012 Aug 18) 668e679.
[28] A.D. Lopez, CNPT, A Descriptive Model of the Cigarette Epidemic in Devel-
oped Countries, third ed, Tob Control, 1994, pp. 242e247.
[29] E. Prescott, M. Hippe, P. Schnohr, et al., Smoking and risk of myocardial
infarction in women and men: longitudinal population study, BMJ 316
(7137) (1998 Apr 4) 1043e1047.
[30] M. Woodward, T.H. Lam, F. Barzi, et al., Smoking, quitting, and the risk of
cardiovascular disease among women and men in the Asia-Pacific region, Int.
J. Epidemiol. 34 (5) (2005 Oct) 1036e1045.
[31] R.R. Huxley, M. Woodward, Cigarette smoking as a risk factor for coronary
heart disease in women compared with men: a systematic review and meta-
analysis of prospective cohort studies, Lancet 378 (9799) (2011 Oct 8)
1297e1305.
[32] S.A. Peters, R.R. Huxley, M. Woodward, Smoking as a risk factor for stroke in
women compared with men: a systematic review and meta-analysis of 81
cohorts, including 3,980,359 individuals and 42,401 strokes, Stroke 44 (10)
(2013 Oct) 2821e2828.
[33] M. Woodward, H. Tunstall-Pedoe, W.C. Smith, et al., Smoking characteristics
and inhalation biochemistry in the Scottish population, J. Clin. Epidemiol. 44
(12) (1991) 1405e1410.
[34] G. Danaei, M.M. Finucane, Y. Lu, et al., National, regional, and global trends in
fasting plasma glucose and diabetes prevalence since 1980: systematic
analysis of health examination surveys and epidemiological studies with 370
country-years and 2.7 million participants, Lancet 378 (9785) (2011 Jul 2)
31e40.
[35] L. Mosca, E.J. Benjamin, K. Berra, et al., Effectiveness-based guidelines for the
prevention of cardiovascular disease in womene2011 update: a guideline
from the American heart association, J. Am. Coll. Cardiol. 57 (12) (2011 Mar
22) 1404e1423.
[36] R. Huxley, F. Barzi, M. Woodward, Excess risk of fatal coronary heart disease
associated with diabetes in men and women: meta-analysis of 37 prospec-
tive cohort studies, BMJ 332 (7533) (2006 Jan 14) 73e78.
[37] S.A. Peters, R.R. Huxley, M. Woodward, Diabetes as a risk factor for stroke in
women compared with men: a systematic review and meta-analysis of 64
cohorts, including 775,385 individuals and 12,539 strokes, Lancet 383 (9933)
(2014 Jun 7) 1973e1980.
[38] A. Ferrara, C.M. Mangione, C. Kim, et al., Sex disparities in control and
treatment of modifiable cardiovascular disease risk factors among patients
with diabetes: translating research into action for diabetes (TRIAD) study,
Diabetes Care 31 (1) (2008 Jan) 69e74.
[39] H.U. Kramer, E. Raum, G. Ruter, et al., Gender disparities in diabetes and
coronary heart disease medication among patients with type 2 diabetes:
results from the DIANA study, Cardiovasc Diabetol. 11 (2012) 88.
[40] D.J. Wexler, R.W. Grant, J.B. Meigs, et al., Sex disparities in treatment of
cardiac risk factors in patients with type 2 diabetes, Diabetes Care 28 (3)
(2005 Mar) 514e520.
[41] I. Gouni-Berthold, H.K. Berthold, C.S. Mantzoros, et al., Sex disparities in the
treatment and control of cardiovascular risk factors in type 2 diabetes,
Diabetes Care 31 (7) (2008 Jul) 1389e1391.
[42] G.J. Winston, R.G. Barr, O. Carrasquillo, et al., Sex and racial/ethnic differences
in cardiovascular disease risk factor treatment and control among in-
dividuals with diabetes in the multi-ethnic study of atherosclerosis (MESA),
Diabetes Care 32 (8) (2009 Aug) 1467e1469.
[43] L. Franzini, D. Ardigo, F. Cavalot, et al., Women show worse control of type 2
diabetes and cardiovascular disease risk factors than men: results from the
MIND IT study group of the Italian society of diabetology, Nutr. Metab.
Cardiovasc Dis. 23 (3) (2013 Mar) 235e241.
[44] G. Penno, A. Solini, E. Bonora, et al., Gender differences in cardiovascular
disease risk factors, treatments and complications in patients with type 2
diabetes: the RIACE Italian multicentre study, J. Intern Med. 274 (2) (2013
Aug) 176e191.
[45] National Diabetes Audit 2012-2013dReport 1: Care Processes and Treat-
ment Targets, Health and Social Care Information Centre, 2014.
[46] Diabetes Atlas, fifth ed., International Diabetes Federation, Brussels, Belgium,
2011.
[47] J.A. Beckman, F. Paneni, F. Cosentino, et al., Diabetes and vascular disease:
pathophysiology, clinical consequences, and medical therapy: part II, Eur.
Heart J. 34 (31) (2013 Aug) 2444e2452.
[48] F. Paneni, J.A. Beckman, M.A. Creager, et al., Diabetes and vascular disease:
pathophysiology, clinical consequences, and medical therapy: part I, Eur.
Heart J. 34 (31) (2013 Aug) 2436e2443.
[49] R.W. Evans, T.J. Orchard, Oxidized lipids in insulin-dependent diabetes
mellitus: a sex-diabetes interaction? Metabolism 43 (9) (1994 Sep)
1196e1200.
[50] B.V. Howard, L.D. Cowan, O. Go, et al., Adverse effects of diabetes on multiple
cardiovascular disease risk factors in women. The strong heart study, Dia-
betes Care 21 (8) (1998 Aug) 1258e1265.
8 Y. Appelman et al. / Atherosclerosis xxx (2015) 1e8
[51] M.W. Mansfield, D.M. Heywood, P.J. Grant, Sex differences in coagulation and
fibrinolysis in white subjects with non-insulin-dependent diabetes mellitus,
Arterioscler. Thromb. Vasc. Biol. 16 (1) (1996 Jan) 160e164.
[52] N. Ossei-Gerning, I.J. Wilson, P.J. Grant, Sex differences in coagulation and
fibrinolysis in subjects with coronary artery disease, Thromb. Haemost. 79
(4) (1998 Apr) 736e740.
[53] H.O. Steinberg, G. Paradisi, J. Cronin, et al., Type II diabetes abrogates sex
differences in endothelial function in premenopausal women, Circulation
101 (17) (2000 May 2) 2040e2046.
[54] S.G. Wannamethee, O. Papacosta, D.A. Lawlor, et al., Do women exhibit
greater differences in established and novel risk factors between diabetes
and non-diabetes than men? The British regional heart study and British
women's heart health study, Diabetologia 55 (1) (2012 Jan) 80e87.
[55] M. Garaulet, F. Perex-Llamas, T. Fuente, et al., Anthropometric, computed
tomography and fat cell data in an obese population: relationship with in-
sulin, leptin, tumor necrosis factor-alpha, sex hormone-binding globulin and
sex hormones, Eur. J. Endocrinol. 143 (5) (2000 Nov) 657e666.
[56] R.P. Donahue, K. Rejman, L.B. Rafalson, et al., Sex differences in endothelial
function markers before conversion to pre-diabetes: does the clock start
ticking earlier among women? The Western New York study, Diabetes Care
30 (2) (2007 Feb) 354e359.
[57] S.M. Haffner, H. Miettinen, M.P. Stern, Relatively more atherogenic coronary
heart disease risk factors in prediabetic women than in prediabetic men,
Diabetologia 40 (6) (1997 Jun) 711e717.
[58] M. Ezzati, A.D. Lopez, A. Rodgers, et al., Selected major risk factors and global
and regional burden of disease, Lancet 360 (9343) (2002 Nov 2) 1347e1360.
[59] M.M. Finucane, G.A. Stevens, M.J. Cowan, et al., National, regional, and global
trends in body-mass index since 1980: systematic analysis of health exam-
ination surveys and epidemiological studies with 960 country-years and 9.1
million participants, Lancet 377 (9765) (2011 Feb 12) 557e567.
[60] D. Wormser, S. Kaptoge, A.E. Di, et al., Separate and combined associations of
body-mass index and abdominal adiposity with cardiovascular disease:
collaborative analysis of 58 prospective studies, Lancet 377 (9771) (2011 Mar
26) 1085e1095.
[61] G. Whitlock, S. Lewington, P. Sherliker, et al., Body-mass index and cause-
specific mortality in 900,000 adults: collaborative analyses of 57 prospec-
tive studies, Lancet 373 (9669) (2009 Mar 28) 1083e1096.
[62] M.C. Ni, A. Rodgers, W.H. Pan, et al., Body mass index and cardiovascular
disease in the Asia-Pacific Region: an overview of 33 cohorts involving
310,000 participants, Int. J. Epidemiol. 33 (4) (2004 Aug) 751e758.
[63] S.A. Peters, M. Woodward, T.H. Lam, et al., Sex disparities in risk and risk
factors for ischemic heart disease in the Asia-Pacific region, Eur. J. Prev.
Cardiol. 21 (5) (2014 May) 639e646.
[64] K.A. Matthews, E. Meilahn, L.H. Kuller, et al., Menopause and risk factors for
coronary heart disease, N. Engl. J. Med. 321 (10) (1989 Sep 7) 641e646.
[65] F. Farzadfar, M.M. Finucane, G. Danaei, et al., National, regional, and global
trends in serum total cholesterol since 1980: systematic analysis of health
examination surveys and epidemiological studies with 321 country-years
and 3.0 million participants, Lancet 377 (9765) (2011 Feb 12) 578e586.
[66] A.E. Di, N. Sarwar, P. Perry, et al., Major lipids, apolipoproteins, and risk of
vascular disease, JAMA 302 (18) (2009 Nov 11) 1993e2000.
[67] S. Lewington, G. Whitlock, R. Clarke, et al., Blood cholesterol and vascular
mortality by age, sex, and blood pressure: a meta-analysis of individual data
from 61 prospective studies with 55,000 vascular deaths, Lancet 370 (9602)
(2007 Dec 1) 1829e1839.
[68] X. Zhang, A. Patel, H. Horibe, et al., Cholesterol, coronary heart disease, and
stroke in the Asia Pacific region, Int. J. Epidemiol. 32 (4) (2003 Aug) 563e572.
[69] J.W. Rich-Edwards, A. Fraser, D.A. Lawlor, et al., Pregnancy characteristics
and women's future cardiovascular health: an underused opportunity to
improve women's health? Epidemiol. Rev. 36 (1) (2014) 57e70.
[70] J.A. Hutcheon, S. Lisonkova, K.S. Joseph, Epidemiology of pre-eclampsia and
the other hypertensive disorders of pregnancy, Best. Pract. Res. Clin. Obstet.
Gynaecol. 25 (4) (2011 Aug) 391e403.
[71] L. Bellamy, J.P. Casas, A.D. Hingorani, et al., Pre-eclampsia and risk of car-
diovascular disease and cancer in later life: systematic review and meta-
analysis, BMJ 335 (7627) (2007 Nov 10) 974.
[72] G.N. Smith, J. Pudwell, M. Walker, et al., Ten-year, thirty-year, and lifetime
cardiovascular disease risk estimates following a pregnancy complicated by
preeclampsia, J. Obstet. Gynaecol. Can. 34 (9) (2012 Sep) 830e835.
[73] B.B. van Rijn, M.E. Nijdam, H.W. Bruinse, et al., Cardiovascular disease risk
factors in women with a history of early-onset preeclampsia, Obstet.
Gynecol. 121 (5) (2013 May) 1040e1048.
[74] W. Hermes, A. Franx, M.G. van Pampus, et al., 10-Year cardiovascular event
risks for women who experienced hypertensive disorders in late pregnancy:
the HyRAS study, BMC Pregnancy Childbirth 10 (2010) 28.
[75] A. Ben-Haroush, Y. Yogev, M. Hod, Epidemiology of gestational diabetes
mellitus and its association with type 2 diabetes, Diabet. Med. 21 (2) (2004
Feb) 103e113.
[76] L. Bellamy, J.P. Casas, A.D. Hingorani, et al., Type 2 diabetes mellitus after
gestational diabetes: a systematic review and meta-analysis, Lancet 373
(9677) (2009 May 23) 1773e1779.
[77] W.H. Tam, R.C. Ma, X. Yang, et al., Cardiometabolic risk in chinese women
Please cite this article in press as: Y. Appelman, et al., Sex differences in cardiovascular risk factors and disease prevention, Atherosclerosis
(2015), http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.027
with prior gestational diabetes: a 15-year follow-up study, Gynecol. Obstet.
Invest 73 (2) (2012) 168e176.
[78] J. Pirkola, A. Pouta, A. Bloigu, et al., Prepregnancy overweight and gestational
diabetes as determinants of subsequent diabetes and hypertension after 20-
year follow-up, J. Clin. Endocrinol. Metab. 95 (2) (2010 Feb) 772e778.
[79] R. Retnakaran, B.R. Shah, Mild glucose intolerance in pregnancy and risk of
cardiovascular disease: a population-based cohort study, CMAJ 181 (6e7)
(2009 Sep 15) 371e376.
[80] J.A. Lykke, J. Langhoff-Roos, B.M. Sibai, et al., Hypertensive pregnancy dis-
orders and subsequent cardiovascular morbidity and type 2 diabetes melli-
tus in the mother, Hypertension 53 (6) (2009 Jun) 944e951.
[81] D.B. Carr, K.M. Utzschneider, R.L. Hull, et al., Gestational diabetes mellitus
increases the risk of cardiovascular disease in women with a family history
of type 2 diabetes, Diabetes Care 29 (9) (2006 Sep) 2078e2083.
[82] J.A. Lykke, M.J. Paidas, E.W. Triche, et al., Fetal growth and later maternal
death, cardiovascular disease and diabetes, Acta Obstet. Gynecol. Scand. 91
(4) (2012 Apr) 503e510.
[83] J.A. Lykke, J. Langhoff-Roos, First trimester bleeding and maternal cardio-
vascular morbidity, Eur. J. Obstet. Gynecol. Reprod. Biol. 164 (2) (2012 Oct)
138e141.
[84] J.A. Lykke, M.J. Paidas, P. Damm, et al., Preterm delivery and risk of subse-
quent cardiovascular morbidity and type-II diabetes in the mother, BJOG 117
(3) (2010 Feb) 274e281.
[85] J.M. Catov, A.B. Newman, K. Sutton-Tyrrell, et al., Parity and cardiovascular
disease risk among older women: how do pregnancy complications mediate
the association? Ann. Epidemiol. 18 (12) (2008 Dec) 873e879.
[86] A.B. Caughey, N.E. Stotland, A.E. Washington, et al., Maternal ethnicity,
paternal ethnicity, and parental ethnic discordance: predictors of pre-
eclampsia, Obstet. Gynecol. 106 (1) (2005 Jul) 156e161.
[87] P. Bouchard, B.C. Fauser, PCOS: an heterogeneous condition with multiple
faces for multiple doctors, Eur. J. Endocrinol. 171 (4) (2014 Oct) E1eE2.
[88] N.M. Daan, Y.V. Louwers, M.P. Koster, et al., Cardiovascular and metabolic
profiles amongst different polycystic ovary syndrome phenotypes: who is
really at risk? Fertil. Steril. (2014 Sep 16).
[89] L.J. Moran, M.L. Misso, R.A. Wild, et al., Impaired glucose tolerance, type 2
diabetes and metabolic syndrome in polycystic ovary syndrome: a system-
atic review and meta-analysis, Hum. Reprod. Update 16 (4) (2010 Jul)
347e363.
[90] L.J. Shaw, C.N. Bairey Merz, R. Azziz, et al., Postmenopausal women with a
history of irregular menses and elevated androgen measurements at high
risk for worsening cardiovascular event-free survival: results from the na-
tional institutes of healthenational heart, lung, and blood institute spon-
sored women's ischemia syndrome evaluation, J. Clin. Endocrinol. Metab. 93
(4) (2008 Apr) 1276e1284.
[91] F. Atsma, M.L. Bartelink, D.E. Grobbee, et al., Postmenopausal status and early
menopause as independent risk factors for cardiovascular disease: a meta-
analysis, Menopause 13 (2) (2006 Mar) 265e279.
[92] M. De Vos, P. Devroey, B.C. Fauser, Primary ovarian insufficiency, Lancet 376
(9744) (2010 Sep 11) 911e921.
[93] J.E. Roeters van Lennep, K.Y. Heida, M.L. Bots, et al., Cardiovascular disease
risk in women with premature ovarian insufficiency: a systematic review
and meta-analysis, Eur. J. Prev. Cardiol. (2014 Oct 20). Epub ahead of print.
[94] J.L. Luborsky, P. Meyer, M.F. Sowers, et al., Premature menopause in a multi-
ethnic population study of the menopause transition, Hum. Reprod. 18 (1)
(2003 Jan) 199e206.
[95] J. Schmidt, K. Landin-Wilhelmsen, M. Brannstrom, et al., Cardiovascular
disease and risk factors in PCOS women of postmenopausal age: a 21-year
controlled follow-up study, J. Clin. Endocrinol. Metab. 96 (12) (2011 Dec)
3794e3803.
[96] S. Wild, T. Pierpoint, P. McKeigue, et al., Cardiovascular disease in women
with polycystic ovary syndrome at long-term follow-up: a retrospective
cohort study, Clin. Endocrinol. (Oxf) 52 (5) (2000 May) 595e600.
[97] C.T. Oliver-Williams, E.E. Heydon, G.C. Smith, et al., Miscarriage and future
maternal cardiovascular disease: a systematic review and meta-analysis,
Heart 99 (22) (2013 Nov) 1636e1644.
[98] E. Kharazmi, L. Dossus, S. Rohrmann, et al., Pregnancy loss and risk of car-
diovascular disease: a prospective population-based cohort study (EPIC-
Heidelberg), Heart 97 (1) (2011 Jan) 49e54.
[99] J.M. Catov, C.S. Wu, J. Olsen, et al., Early or recurrent preterm birth and
maternal cardiovascular disease risk, Ann. Epidemiol. 20 (8) (2010 Aug)
604e609.
[100] J.A. Lykke, J. Langhoff-Roos, C.J. Lockwood, et al., Mortality of mothers from
cardiovascular and non-cardiovascular causes following pregnancy compli-
cations in first delivery, Paediatr. Perinat. Epidemiol. 24 (4) (2010 Jul 1)
323e330.
[101] G.D. Smith, E. Whitley, M. Gissler, et al., Birth dimensions of offspring, pre-
mature birth, and the mortality of mothers, Lancet 356 (9247) (2000 Dec 16)
2066e2067.
[102] H.U. Irgens, L. Reisaeter, L.M. Irgens, et al., Long term mortality of mothers
and fathers after pre-eclampsia: population based cohort study, BMJ 323
(7323) (2001 Nov 24) 1213e1217.