PERINATAL AND CHILDHOOD ORIGINS OF CARDIOVASCULAR DISEASE
Rae-Chi Huang, M.B., B.S., D.C.H., FRACP and Lawrie Beilin, M.B.B.S., M.D., FRCP,
FRACP, AO, School of Medicine and Pharmacology, Royal Perth Hospital, University of
Western Australia (M570), 50 Murray St., Perth, WA 6000, Australia, Tel: 61 8 9224
0258, Fax: 61 8 9224 0246, E-mail: firstname.lastname@example.org
Features of the metabolic syndrome comprise a major risk for cardiovascular disease and will
increase in prevalence with rising childhood obesity [1,2]. Birthweight and early life influences
affect development of obesity, hypertension, and dyslipidemia in children. Early life influences
include maternal smoking during pregnancy, duration of breastfeeding, and postnatal weight
Relationship between Birthweight and the Metabolic Syndrome
The literature in general has shown a linear negative relationship between birthweight and later
development of the metabolic syndrome or coronary heart disease [3,4]. We suggest that these
relationships should be reviewed in different contemporary populations. An inverse association
between birthweight and cardiovascular risk may be influenced by the inclusion of preterm
infants and further modified by the rising prevalence of obesity and gestational diabetes in
mothers, and overweight and obesity in children in both developed and developing countries.
These issues have been explored in a recent study of the “Raine” longitudinal childhood
cohort in Perth, Western Australia in which a subset of children monitored at age 8 showed a U-
shaped relationship between birthweight and the risk of exhibiting a cluster of features of the
metabolic syndrome (see Figure 1) . A similar U-shaped relationship between birthweight and
the risk of diabetes has been observed in two other distinct populations, including Pima Indians
 and Asians . The results of this Australian birth cohort study need to be taken in the
context of an ongoing longitudinal study. These children were analyzed at 8 years old and the
larger cohort of 1,800 is being followed through adolescence. As they pass through puberty,
changes in the relationships may emerge.
Why should the relation between birthweight and clusters of cardiovascular risk factors
differ between populations? Apart from the younger age of the Raine cohort we hypothesized
that the shape of the curve for birthweight plotted against subsequent cardiovascular risk can
differ according to population nutritional status and obesity rates. By extending the curve further
to the right of the birth weight axis there is a greater prominence of higher birthweights in those
at risk. In older cohorts the negative slope at the left hand of the curve has been more evident,
and reported as a continuous inverse relationship between birthweight and the metabolic
syndrome in adults [4,8,9].
We conjecture that a right shift in the birth weight plotted against risk of cardiovascular
disease curve may be developing due to increasing caloric excess and decreasing physical
activity in Western society over the last 80 years. Undernutrition during pregnancy causing poor
fetal growth is now less common; it is far more likely to exist in earlier cohorts [4,10,11]
affected by the Great Depression, World Wars, and the much-quoted Dutch famine  and in
contemporary developing countries . Consistent with this, the mean birth weight of the
Australian cohort was 3,501 g  compared with a mean of 3,166 g and 3,220 g during the
Dutch famine  and 2,600 g in girls and 2,800 g in boys in contemporary India . The mean
male birth weight in the Australian cohort is higher (3,533 g, SD = 458 g)  compared with the
males in the Helsinki Studies (3,456 g SD = 490) , but similar to those in the Hertfordshire
cohort (3,500 g SD 600 g) [4,10]. Low birth weight is now more likely to be due to preterm
birth, placental dysfunction, obstetric complications, maternal disease, poor social environment,
or genetic reasons. Important in developmental origins concepts is a gross mismatch between
pre- and post-natal environments. This is less likely to exist to a large extent in current Western
society, except with obstetric complications or in groups such as Native Americans, Australian
Aborigines, and recent immigrants.
Other Postnatal and Perinatal Influences on Childhood Risk of Cardiovascular Disease
Early environmental influences potentially affecting the risk of the cluster of features of the
metabolic syndrome include higher postnatal weight gain, maternal smoking, and shorter
duration of breast feeding.
POSTNATAL WEIGHT GAIN
The components of the adult metabolic syndrome are largely driven by obesity. Our Australian
childhood cohort showed large BMI and weight differences between children at high and low
risk of the cluster of abnormalities including high blood pressure, BMI, and relative dyslipidemia
. Postnatal weight gain after 12 months of age was the dominant factor associated with the
presence of the metabolic syndrome cluster at age 8, a finding similar to that recently reported
for BP and obesity in the same cohort . These results are in keeping with a study of 300
contemporary British 5 year olds , and with analysis of a healthy high school population
which showed that postnatal weight gain and current weight were the dominant factors
associated with insulin resistance rather than low birth weight .
Weight, BMI, and waist girth are surrogate measures of body fat mass. Studies focusing
on body composition and body fat/muscle ratio may provide a better indication of the impact of
postnatal growth on risk of cardiovascular disease. We have observed that high risk children are
also taller with greater arm circumferences from 3 years of age onwards .
Timing or trajectories of postnatal weight gain are likely to be important. The patterns of
postnatal weight gain that evolve into greatest cardiovascular risk have differed in studies. The
Australian longitudinal study of 8-year-old children demonstrated that excess postnatal weight
gain in the first year or weight at 1 year does not have an independent influence on development
of the high risk cluster . This differs from findings from a Helsinki Cohort of 8,760 people
which demonstrated that small size at birth, low BMI at 2 years of age, and high BMI at 11 years
of age were each associated with later coronary events . Perhaps the suggestion from the two
studies above is that there is a window in early infancy of 1 to 2 years where excess postnatal
weight gain does not determine cardiovascular risk. In contradiction to this however, an earlier
study showed that infants with early rapid weight gain in the first 4 months of life are at greater
risk . These findings need to be explored in more detail with maturation of cohorts.
SMOKING IN PREGNANCY
Smoking appears to be an important modifier of the relationship between birthweight and
cardiovascular risk. Despite maternal smoking being associated with lower birth weight and
increased SBP in offspring, a positive relationship was seen between birth weight and SBP in
early childhood when mothers were smokers in pregnancy . We observed that newborns at
greatest risk of developing the metabolic syndrome cluster were those large for gestational age
born to mothers who smoked throughout pregnancy . We hypothesize that within the maternal
smoking group, well known to cause lower birth weight , those newborns who, not only
escape growth retardation, but are in fact large for gestational age, are unusual due to genetic
make-up or exposure to maternal hyperglycemia. They are subsequently selected for particular
risk of cardiovascular disease. Conversely, for babies born to non-smokers, the greatest risk is in
lowest percentage expected birthweight quintile. However, smoking is associated with
socioeconomic status and adverse lifestyle  which could also confound these relationships.
Retrospective studies have shown variable breast feeding effects ranging from modest protective
 to possible adverse  effects upon the risk of ischemic cardiovascular disease in
adulthood. Further, an association between longer breast feeding and lower risk of overweight
between 9-14 years of age has been reported . The Australian Raine cohort showed a lower
likelihood of the high risk metabolic syndrome cluster in children breastfed for ≥ 4 months
compared to < 4 months and that breast feeding ≥ 4 months is associated with lower weight at
age 1 year . However, these observations may be confounded by the fact that shorter duration
of breastfeeding is also associated with maternal characteristics such as obesity, smoking, and
lower education  .
The relationship between birthweight and cardiovascular disease may not be a straight forward
negative linear relationship. To be applicable to current Western disease trends, it needs to be
studied in contemporary, well-nourished populations of full-term newborns. We found a
prominence of higher as well as lowest birthweights in those at risk while investigating such a
population. Future health programs should focus on both pre- and post-natal factors (reducing
excess childhood weight gain and smoking during pregnancy). Possibly the greatest benefits may
arise from targeting the heaviest, as well as lightest newborns, especially with a history of
maternal smoking during pregnancy.
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Figure 1. Proportion in the high risk cluster in different percent expected birth weight (PEBW) Download full-text
*represents p < 0.05 compared to 2nd PEBW quintile group. (Reproduced from )
PEBW quintilesPEBW quintiles
Proportion in High Risk Cluster Group
PEBW rangePEBW range
Proportion in High Risk Cluster Group