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Pregnancy complications and maternal cardiovascular
risk: opportunities for intervention and screening?
Naveed Sattar, Ian A Greer
The link between defective nutrition of the fetus and vascular disease in later life is now well
established. Naveed Sattar and Ian Greer report on the intriguing probability that complications in
pregnancy also predispose mothers to later vascular and metabolic disease
Plentiful evidence now links low birth weight due to
intrauterine growth restriction and increased risk of
vascular disease in later adult life. This is considered to
be partly the result of programming through fetal
nutrition.
1
In contrast, much less attention has been
focused on the relation between adverse pregnancy
outcomes, such as pre-eclampsia, gestational diabetes,
preterm delivery, and intrauterine growth restriction,
and the mother’s subsequent health, and interesting
data are now increasingly linking the maternal
vascular, metabolic, and inflammatory complications
of pregnancy with an increased risk of vascular disease
in later life (table). This article summarises the emerg-
ing evidence to support this fascinating concept, notes
important areas for further research, and discusses
potential practical implications.
Metabolic syndrome
A key factor underlying cardiovascular disease and, in
particular, coronary heart disease, is the metabolic syn-
drome. The metabolic syndrome is a spectrum of
metabolic abnormalities associated with insulin resist-
ance, which is manifest as relative hyperglycaemia,
hyperlipidaemia, and disturbance of coagulation. The
normal physiological response to pregnancy repre-
sents a transient excursion into a metabolic syndrome
in which several components are acquired: a relative
degree of insulin resistance, definite hyperlipidaemia,
and an increase in coagulation factors.
12 13
Normal
pregnancy also involves upregulation of the inflamma-
tory cascade and an increase in white cell count.
14
Such
upregulation in non-pregnant women has recently
been recognised as an additional risk factor for cardio-
vascular disease, as markers of inflammation such as
C-reactive protein, interleukin-6, and raised white cell
count have been found to be independent predictors
of cardiovascular events and diabetes.
15
All these meta-
bolic changes of pregnancy are likely to be the result of
hormonal changes, either direct or indirect, through
regulation of early fat acquisition and its rapid mobili-
sation in the second half of pregnancy.
16
Such
metabolic responses could be considered as “stress”
tests of maternal carbohydrate and lipid pathways and
vascular function. In this way, adverse pregnancy
outcome may be an indicator of increased risk of
metabolic and vascular diseases in later life (figure).
Gestational diabetes
Perhaps the best studied example of gestational
diabetes is glucose metabolism in pregnancy. If the
mother fails to compensate adequately for the increase
in gestational insulin resistance by enhancing pancre-
atic insulin secretion, her regulation of glycaemia will
be affected and she will have a 30% risk of developing
type 2 diabetes in later life.
17
In fact, pregnancy itself
may accelerate the development of type 2 diabetes in
susceptible women.
18
Even if they remain glucose toler-
ant after their pregnancy, women with a history of
gestational diabetes show subtle yet significant
differences from controls in fasting lipid levels, blood
pressure, and microvascular and large vessel function,
consistent with an increased risk of diabetes.
23
From
Association of adverse pregnancy outcomes with risk of diabetes or risk factors for
coronary heart disease and vascular disease
Pregnancy outcome
Incidence in
pregnancy (%)
Risk factors shown to
be perturbed after
pregnancy Association or risk ratio (95% CI)
Gestational diabetes 1.9-5.0* Lipids
2
Increased risk of type 2 diabetes,
especially if recurrence of
gestational diabetes in a
subsequent pregnancy. No data on
coronary heart disease risk
Blood pressure
2
Large vessel function
3
Small vessel function
3
Pre-eclampsia 2-4 Lipids
4
Clotting
4
1.9 (1.0 to 3.5) v pregnancy
induced hypertension alone
7
Fasting insulin
5
1.7 (1.3 to 2.2) v no pre-eclampsia
8
Large vessel function
6
2.0 (1.5 to 2.5) v no pre-eclampsia
9
Low birth weight
(<2500 g)
5 Not studied 11.3 (3.5 to 36.1) v >3500 g
9
7.1 (2.6 to 18.7) v >3500 g
10
Preterm delivery
(<37 weeks)
5-6 Not studied 1.8 (1.3 to 2.5) v term delivery
9
2.1 (1.2 to 3.5) v term delivery
11
*Dependent on population studied, ethnic group, and diagnostic criteria.
Summary points
Women with a history of adverse pregnancy
outcome appear to be at increased risk of
metabolic and vascular diseases in later life
Pregnancy complications and coronary heart
disease may have common disease mechanisms
Women with a history of gestational diabetes
should be screened for type 2 diabetes and be
given counselling and appropriate lifestyle advice
Women who have had a very low birthweight
baby or combined complications seem to be at
severalfold increased risk of mortality from
cardiovascular causes and should be screened for
vascular risk factors in their late 30s.
The possibility that maternal vascular risk factors,
potentially ‘modifiable’ before pregnancy,
correlate with increased risk of preterm delivery
and low birth weight, and thus fetal
programming, requires further investigation
Education and debate
Glasgow Royal
Infirmary University
NHS Trust,
Glasgow G31 2ER
Naveed Sattar
reader in
endocr inology and
metabolism
Ian A Greer
professor of obstetrics
and gynaecology
Correspondence to:
N Sattar
nsattar@clinmed.gla.
ac.uk
BMJ 2002;325:157–60
157BMJ VOLUME 325 20 JULY 2002 bmj.com
our current knowledge of risk factors, all these
observations predict an increased risk of coronary
heart disease in women with previous gestational
diabetes.
Hypertensive complications
Pre-eclampsia, which complicates 2-4% of pregnancies,
remains one of the commonest causes of maternal and
fetal morbidity and mortality. However, early findings
conflict with more recent data on the long term conse-
quences for mothers. The early work by Leon Chesley
and others suggested that women with pregnancy
induced hypertension and eclampsia did not develop
later chronic hypertension,
19–21
but others have found
an increase in risk of later hypertension, especially
when the hypertension in pregnancy began before 30
weeks’ gestation.
22
There does seem to be agreement,
however, that mothers who have uncomplicated preg-
nancies have a lower incidence of subsequent
hypertension than does the general female population
of similar age and race.
19
Recent studies have found
that women with a history of pre-eclampsia have
higher circulating concentrations of fasting insulin,
lipid, and coagulation factors post partum than do
controls matched for body mass index.
45
They also
seem to show a specific defect of endothelial-
dependent vascular function as compared with women
with a history of a healthy pregnancy, independently of
maternal obesity, blood pressure, and metabolic distur-
bances associated with insulin resistance or dyslipidae-
mia.
6
This pattern of metabolic and vascular changes in
women with a history of pre-eclampsia is nearly identi-
cal to the abnormalities seen in this condition at
diagnosis
—
namely, exaggerated lipid and insulin levels,
disturbed haemostatic factors, and endothelial dys-
function.
16
It is not surprising, therefore, that the
specific vascular lesion of pre-eclampsia, termed acute
“atherosis,” in the placental bed, is similar to that
observed in atherosclerosis, including foam cells
loaded with lipid. Thus the genotypes and phenotypes
underlying vascular disease may also underlie pre-
eclampsia.
These changes in risk markers in women with a
history of pre-eclampsia predict that they may be at an
increased risk of coronary heart disease. Jonsdottir and
colleagues
7
examined causes of death in 374 women
with a history of hypertensive complications in
pregnancy and noted that their death rate from
complications of coronary heart disease (standardised
mortality ratio 1.47; 95% confidence interval 1.05 to
2.02) was significantly higher than expected from
analysis of population data from public health and
census reports during corresponding periods. More-
over, they noted that the relative risk of dying from
coronary heart disease (risk ratio 2.61; 1.11 to 6.12) was
significantly higher among women who had had
eclampsia or pre-eclampsia (risk ratio 1.90; 1.02 to
3.52) compared with those with hypertension alone.
7
A
prospective cohort study using data from the Royal
College of General Practitioners’ oral contraceptive
study also reported that a history of pre-eclampsia
increased the risk of cardiovascular conditions in later
life. For total ischaemic heart disease the relative risk
was 1.7 (1.3 to 2.2). Furthermore, the increased risk
could not be explained by underlying chronic
hypertension.
8
A retrospective cohort study from Scot-
land using hospital discharge data has also recently
reported an association between pre-eclampsia and
later ischaemic heart disease in the mother (risk ratio
2.0; 1.5 to 2.5).
9
Prospective evaluation of women in
pregnancy, with long term follow up, is now required to
discover the mechanisms underlying this association. It
is also important to determine whether this finding can
identify risk that otherwise might not have been
evident or whether the use of established risk factors
such as hypertension and obesity would have identified
these women as being “at risk” and offered an
opportunity for primary prevention.
Low birth weight
Intriguingly, recent retrospective studies have noted
that women who have delivered a baby weighing less
than 2500 g have 7-11 times the risk of death from
cardiovascular causes of women with babies weighing
3500 g or more.
910
These findings seemed not to be
confounded by socioeconomic status, and the associ-
ation was too strong to be explained by maternal
smoking. The observations suggest a link between
maternal risk factors for coronary heart disease and
fetal programming. The maternal genotypes and phe-
notypes associated with increased risk of coronary
heart disease may also underlie intrauterine growth
restriction and fetal programming. In turn this will lead
to a perpetuation of risk factors through generations.
We cannot influence genotype, but phenotype might
be altered. Therefore, improving the mother’s risk fac-
tor status and metabolic profiles before or early in
pregnancy
—
for example, by stopping smoking,
increasing physical activity in sedentary women,
improving diet, and loss of weight by obese
women
—
could benefit fetal development and reduce
the vascular risk of future generations.
Preterm delivery
Women with a history of delivery before 37 weeks had
around twice the normal risk of coronary heart disease
in observational studies.
911
Although reliable data on
maternal smoking, a major potential confounder, were
not available, maternal smoking seemed not to be a
confounder in this relation as such women were not at
increased risk of smoking related cancers. Preterm
labour is recognised to be an inflammatory phenom-
Age
Vascular risk factors
Neonatal
life
Population with complicated pregnancy eg pre-eclampsia
Healthy population
Threshold for vascular or metabolic disease
Middle
age
Pregnancies
Risk factors for vascular disease are identifiable during excursions
into the metabolic syndrome of pregnancy
Education and debate
158 BMJ VOLUME 325 20 JULY 2002 bmj.com
enon with a leucocyte infiltrate in the cervical and uter-
ine tissues, even in the absence of infection.
23
The
association between preterm labour and coronary
heart disease might therefore be related to up-
regulation of chronic inflammatory pathways. Women
with a “proinflammatory” phenotype may develop
greater upregulation of the chronic inflammatory
pathways than is seen in normal pregnancy, leading to
preterm labour. This would help explain why these
same women will be at increased risk of coronary heart
disease in later life, as inflammation is an independent
predictor of coronary heart disease in men and
women.
24
Again, confirmation of this important obser-
vation is needed, ideally in prospective studies, along
with an exploration of the inflammatory mechanisms
common to both clinical problems.
Future research
Most of the above findings come from observational
studies with relatively small numbers of cases or end
points, and so require confirmation in larger cohorts
with longer periods of follow up, adequate control
groups, and proper attention to confounding by smok-
ing. These should examine whether established risk
factors account for excess risk associated with
pregnancy complications or if novel factors might be
implicated. Simultaneously, large prospective longitu-
dinal studies (of several thousand women) examining
changes in conventional risk factor pathways (lipids,
blood pressure, haemostatic factors) and novel
pathways (inflammation, insulin resistance) during and
after pregnancy should be undertaken. Such studies
lend themselves well to long term follow up with the
eventual aim of linking pregnancy outcome to
maternal vascular risk factor status at the first antenatal
visit in the short term, to post-pregnancy risk factor
status in the medium term, and to vascular and
metabolic disease end points in later life. This design
could also examine whether the pattern of risk factor
perturbances is unique to individual complications or
similar in all. Clearly, a variety of study designs are
needed to confirm associations and to work out the
mechanisms and causality.
Implications
A major problem in the prevention of vascular disease
has been the difficulty in identifying individuals at risk
at an early enough stage for them to benefit from
intervention such as modification of their lifestyle. For
example, by the time type 2 diabetes is diagnosed,
more than 30-50% of patients will already have
evidence of vascular disease. Clearly, women with a his-
tory of gestational diabetes are candidates for
screening for diabetes. This should take the form of
measurement of fasting plasma glucose any time
between 6 weeks and 6 months post partum, and
thereafter regularly at intervals guided by initial results.
A diagnosis of diabetes is now made if the plasma glu-
cose concentration is 7 mmol/l or above on two occa-
sions. If a result between 6.1 and 6.9 mmol/l is
recorded on two occasions, then an oral glucose toler-
ance test is advised. All women with such a history
should be counselled about their increased risk of
developing type 2 diabetes and the benefits of modify-
ing their lifestyle. This is important, as improved diet
and physical activity have recently been shown to pre-
vent the onset of type 2 diabetes in people at high
risk.
25 26
Even if initial plasma glucose concentrations
are normal, regular checks are warranted, particularly
if gestational diabetes recurs in a second pregnancy, to
allow early identification and treatment of asympto-
matic diabetes.
Similarly, if other adverse pregnancy outcomes
—
pre-eclampsia, intrauterine growth restriction, and
preterm labour
—
are confirmed as indicators of
increased vascular risk in mothers, these women may
benefit from screening and primary prevention
strategies. Such intervention could be focused on the
perimenopausal years (a time when risk of vascular
disease increases rapidly) or even earlier. This may be
particularly relevant in mothers with low birthweight
babies (under 2500 g), in whom relative risks for
coronary heart disease seem to be increased several-
fold (table). In addition, as risk ratios for complications
seem to be additive, a woman with multiple pregnancy
complications, such as pre-eclampsia combined with
preterm delivery and a baby in the lowest fifth of birth
weights, is at severalfold increased risk of coronary
heart disease.
9
It is notable that the absolute risk of cor-
onary heart disease in women in their 40s is very low,
thus only factors which increase risk severalfold should
be targeted. Screening in these women would take the
form of routine coronary heart disease assessment
including measurements of blood pressure, fasting lip-
ids (total cholesterol, triglyceride, and high density
lipoprotein cholesterol), and glucose concentrations;
the risk of coronary heart disease can then be
ascertained from the widely available risk factor charts.
To help ensure that appropriate women are screened
and given relevant health education, adverse preg-
nancy outcomes could be used in general practitioners’
computer databases for targeted health screening pro-
grammes. Indeed, such interventions could start at the
routine postpartum review at six weeks, when these
women could be made aware of their potentially
increased risk of coronary heart disease.
The second implication of an association between
maternal coronary heart disease risk and adverse
pregnancy outcome, particularly low birth weight and
preterm delivery, is the potential for modification of
risk factors before a subsequent pregnancy or in early
pregnancy. For example, increased physical activity in
women who are sedentary may result in a better preg-
nancy outcome for both mother and child. Indeed,
there are preliminary data to support this hypothesis:
increasing exercise during pregnancy may increase
birth weight
27
and reduce the risk of gestational
diabetes.
28
Such data would suggest that complications
are not simply genetically determined, but that lifestyle
factors play a major role. At present this remains
speculative, and further research is needed to examine
this important question.
Funding: None.
Competing interests: None declared.
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(Accepted 8 November 2001)
When I use a word
Ough ough
Cough, pronounced coff, is onomatopoeic in origin, from the
sound of the closure of the glottis plus the sound of air whizzing
or wheezing through the trachea. Other languages have different
ways of mimicking the sound of a cough. The Greek word was
âçî (bex), with its guttural stem âç÷- (bekh-). The Latin word was
tussis, with its own form of onomatopoeia, giving modern words
like toux (French), tosse (Italian and Portuguese), and toz
(Spanish). However, more northerly languages have Husten
(German), hoost (Dutch), hoste (Danish), and hosta (Swedish),
which sound like a cough without the initial closure of the glottis,
more like what we call huffing, as in huffing and puffing (which
nowadays means objecting loudly). According to Lewis Carroll,
uffish, a nonsense word that he used in Jabberwocky, reflected a
state of mind in which “the voice is gruffish, the manner roughish,
and the temper huffish.” And among drug users, to huff means to
inhale, usually in reference to marihuana.
Coughing and huffing come together in the German word for
whooping cough, Keuchhusten. And the half-cough of clearing
the throat to attract attention is called a hem, giving the
interjection ahem (compare the French hein). In As You Like It
(act 1, scene 3) Rosalind says that there are burs in her heart.
“Hem them away,” says Celia.
Prompted by the unusual pronunciation of cough, George
Bernard Shaw suggested that ghoti spelt fish
—
“gh” as in cough,
“o” as in women, and “ti” as in nation. But, of course, ough is not
always pronounced off, as the table shows.
An American friend has told me that there is a US town called
Gough, pronounced “gaff,” but I suspect that this is just “goff”
spoken with a strong American accent.
Notice that slough and shough can each be pronounced in
three different ways. And the correct way to pronounce the title of
this piece is “Oh oh.”
Enough.
Jeff Aronson clinical pharmacologist, Oxford
Thirteen different ways of pronouncing –ough
Pronunciation Example
English pronunciations
Aw Bought, brought, fought, nought, ought, rought, sought, thought, wrought
Off Cough, trough
Oh Dough, furlough, though
Oo Brougham, through (also, in USA, slough)
Ow Bough, clough, doughty, drought, nought, plough, slough, sough
Uff chough, clough, enough, grough, rough, shough, slough, tough
Uh Borough, thorough (in USA these are pronounced “oh-roh,” but in England they are pronounced “uh-ruh,” giving an extra category)
Scottish and Irish pronunciations
Okh (as in loch) Brough (an alternative spelling of broch), dought, hough, lough, turlough
Ookh Sough, through-stane
Alternative pronunciations with -ough
Og, ok Shough (=shock), hough (=hock) (these arise because the English cannot pronounce “okh”; for example, for loch, they say “lock” instead
of “lokh”)
Ug Oughly (=ugly, 17th century, used by Milton in Comus (1634) line 695)
Up Hiccough (misspelling; should be hiccup (see BMJ 1996;313:1326))
Education and debate
160 BMJ VOLUME 325 20 JULY 2002 bmj.com
