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.