DISCUSSION
This systematic review demonstrates an inverse relationship between
offspring birthweight and maternal CVD mortality. Our meta-analysis
shows an approximately 1.5 times increased risk of death from CVD among
women who gave birth to SGA infants compared to women who gave birth to
AGA infants. The meta-analyses also demonstrated that BMI and total
cholesterol levels were higher among women who gave birth to infants
diagnosed as having IUGR compared to women who experienced uncomplicated
pregnancies.
The evidence for the association between offspring birthweight and
maternal CVD mortality was provided by eight large data linkage studies
conducted in six countries1, 2, 4, 15-20. All studies
provided consistent findings and showed a reduction in offspring
birthweight associated with increased maternal CVD mortality or an
increase in offspring birthweight associated with a reduction in
maternal CVD mortality. All of these results were shown to be
significant after adjusting for relevant confounding factors. All
studies that compared CVD mortality among women who gave birth to SGA vs
AGA infants demonstrated a HR between 1.31-3.5 for women who gave birth
to SGA infants after adjusting for relevant confounding
factors2, 4, 16 while the pooled analysis showed a RR
of 1.45 with no significant heterogeneity among the three studies
(Chi2 P 0.48, I2 = 0%).
A few mechanistic pathways could be implicated in the association
between offspring size at birth and maternal CVD risk. One plausible
mechanism is the genetic contribution. CVD has a substantial genetic
component, and polymorphisms in several genes encoding
glucokinase21, angiogenic pathway22,
angiotensinogen23, clotting
factors24 are associated with both restricted fetal
growth and risk of CVD. The evidence for a genetic link between
offspring birthweight and maternal risk for CVD is supported by studies
that have shown an association between offspring birthweight and
parental CVD risk. Li and colleagues (2010) in a data linkage study of
1,400,383 primigravida and their spouses demonstrated an adjusted HR of
1.13 (95% CI: 1.03 to 1.24) among fathers of low birth weight
infants2. Consistent with the above findings, Davey
Smith and colleagues reported an adjusted HR of 0.94 (95% CI: 0.89 to
0.99) for CVD mortality among fathers for each one SD increase in
offspring birthweight1. The theory for a genetic
association is further strengthened by a number of multigenerational
studies, reporting a strong association between birthweight of
grandchild and CVD mortality in grandparents (HR of 0.86, 95% CI: 0.83
to 0.89 for 1kg increase in birthweight 25 and HR
between 0.95-0.99 for one quintile increase in
birthweight)26. The genetic theory is further
supported by a recent study of 1,353,956 births that showed an
association between offspring birthweight and CVD mortality among aunts
and uncles (HRs between 0.90 (95% CI 0.86 to 0.95) and 0.93 (95% CI
0.91 to 0.95) for one SD increase in offspring
birthweight)4.
Another plausible mechanism linking offspring size at birth with
maternal CVD risk is shared environmental and behavioural factors. For
example, smoking is a risk factor for both low birthweight and CVD.
Women who smoke during pregnancy are at a higher risk of giving birth to
growth restricted infants. These women are likely to continue smoking,
increasing their subsequent risk of CVD. Partners of women who smoke are
likely to be smokers themselves and hence would also be at higher risk
of developing CVD. Hence, the association between offspring size at
birth and paternal CVD risk could also be explained by environmental and
behavioural factors shared by both parents.
The third plausible theory on the association between offspring size at
birth and maternal CVD risk suggests maternal/fetal nutritional factors
and intrauterine programming as a potential contributor. Women who
themselves had poor intrauterine growth and LBW tend to give birth to
SGA infants27. This association may be mediated via
poor placentation or effects of intrauterine programming. Pregnancy may
also act as a “second hit” for women who were born
small28. Pregnancy is increasingly being considered as
a physiological stress test for the female cardiovascular system and
those who were born “small”, when exposed to a second hit of
pregnancy, may develop pregnancy complications including intrauterine
growth restriction28.
This systematic review and meta-analysis demonstrates evidence of an
association between offspring size at birth and maternal CVD mortality.
However, there was insufficient data to compare conventional CVD risk
factors among women who gave birth to small babies compared to women who
have birth to AGA infants due to the limited number of studies reporting
on the outcomes. Pooled evidence from two small studies demonstrate
higher BMI and higher serum total cholesterol levels among women who
gave birth to growth restricted infants compared to women who had
uncomplicated pregnancies. However, the sample sizes in these analyses
were very small. Hence, larger studies are required for meaningful
comparisons. In addition, only few studies reported on cohorts of
normotensive women who gave birth to small infants, hence, confounding
due to maternal gestational hypertension and preeclampsia is a real
possibility. Another limitation in the current literature is the paucity
of information on women’s age in studies reporting on the associations
between offspring size at birth and maternal CVD mortality. The reported
follow up periods of the included studied varied from 4 years to
~47 years postpartum. Hence, some of the studies
reported CVD mortality among old aged women.
Overall, this systematic review and meta-analysis shows that women who
give birth to SGA infants are at higher risk of CVD mortality compared
to women who give birth to AGA infants. Genetic, environmental and
behavioural factors could all contribute to this association. Larger
well characterised cohorts with the ability to distinguish CVD risk
factor profiles at a young age between normotensive and hypertensive
women who give birth to SGA infants are required to identify the true
association between offspring size at birth and maternal risk for CVD.