Is Being First-Born a Risk Factor for Cardiovascular Diseases?
Is Being First-Born a Risk Factor for Cardiovascular Diseases?
Irrespective of the timing and nature of possible stressors in utero, it is clear that first-borns are phenotypically different to later-borns in both childhood and adulthood. Studies have shown that first-born children were taller (with a progressive reduction in height with subsequent births) and had greater circulating IGF-I concentrations than later-born children. There was a reduction of 1.3 cm in height in second-born children compared with first-borns, with a further 2 cm decrease from second- to third-born children. Other studies revealed similar difference in height between first- and later-borns. Taller stature in childhood is positively associated with overweight status and obesity later in life, and a large study in Brazil of over 2000 men found that first-borns were taller and had greater fat mass than later-borns.
There is also mounting evidence that first-borns have an increased risk of adverse health outcomes later in life. Earlier studies have shown that first-borns were more likely to develop Type 1 diabetes mellitus, allergic disorders and psychological issues. In a prospective cohort study, primogeniture was a significant risk factor for increased adiposity in young adulthood. Nearly four decades ago, a study in young adults suggested that first-borns were at a greater risk of developing hypertension. An unpublished study presented at an American Heart Association forum 12 years ago by Ferratini and colleagues indicated that primogeniture was associated with an increased rate of heart disease in a population of 358 patients. The previously mentioned Brazilian study also found that, in association with their increased fat mass, first-borns had higher metabolic risk z-scores compared with later-borns. The metabolic risk z-score was calculated as the average of the z-scores of fat mass, lipid profile and blood pressure, with a higher score indicative of a higher risk of the metabolic syndrome. The same research group observed a similar increase in metabolic risk among first-born women.
Importantly, we have recently shown that insulin sensitivity (as determined by Bergman's minimal model) was 21% lower in first-born children compared with later-borns. It is worth noting that neither a reduction in birth weight nor current adiposity explain the observed difference in insulin sensitivity, as both were accounted for in all statistical models. To put the observed reduction in insulin sensitivity in context, the magnitude of the change (20%) is similar to the increase seen with medications used to treat diabetes in adults, such as metformin.
A reduction in insulin sensitivity (insulin resistance) with compensatory hyperinsulinism is associated with metabolic and cardiovascular diseases. Insulin resistance leads to reduced endothelial cell production of nitric oxide, greater myosin light chain activation with vasoconstriction and reduced skeletal muscle glucose transport. In a cohort of 208 apparently healthy middle-aged nonobese men, insulin resistance was an independent predictor of many disorders 4–11-years later, including Type 2 diabetes mellitus, hypertension, coronary heart disease, stroke and cancer. Facchini et al. showed that 36% of individuals in the least insulin-sensitive tertile suffered one or more of these adverse events; by contrast, no events were recorded among individuals in the most insulin-sensitive tertile.
Furthermore, 24-h ambulatory blood pressure monitoring showed that first-born children also had higher daytime systolic (+5 mmHg) and diastolic (+4 mmHg) blood pressure. This is equivalent to the observed difference in systolic and diastolic pressure between an obese child and a child of normal BMI. Higher blood pressure tracks from childhood into adulthood and the prevalence of hypertension is 3.6-times more common in those with a childhood blood pressure in the highest quintile. In the prospective 1993 Pelotas birth cohort, the difference in systolic blood pressure in first-borns was attributed to early catch-up growth and the difference in diastolic blood pressure to reduced physical activity. Nonetheless, the increased blood pressure seen in first-borns may have long-term consequences for cardiovascular health.
Phenotypic Differences & Cardiovascular Risk
Irrespective of the timing and nature of possible stressors in utero, it is clear that first-borns are phenotypically different to later-borns in both childhood and adulthood. Studies have shown that first-born children were taller (with a progressive reduction in height with subsequent births) and had greater circulating IGF-I concentrations than later-born children. There was a reduction of 1.3 cm in height in second-born children compared with first-borns, with a further 2 cm decrease from second- to third-born children. Other studies revealed similar difference in height between first- and later-borns. Taller stature in childhood is positively associated with overweight status and obesity later in life, and a large study in Brazil of over 2000 men found that first-borns were taller and had greater fat mass than later-borns.
There is also mounting evidence that first-borns have an increased risk of adverse health outcomes later in life. Earlier studies have shown that first-borns were more likely to develop Type 1 diabetes mellitus, allergic disorders and psychological issues. In a prospective cohort study, primogeniture was a significant risk factor for increased adiposity in young adulthood. Nearly four decades ago, a study in young adults suggested that first-borns were at a greater risk of developing hypertension. An unpublished study presented at an American Heart Association forum 12 years ago by Ferratini and colleagues indicated that primogeniture was associated with an increased rate of heart disease in a population of 358 patients. The previously mentioned Brazilian study also found that, in association with their increased fat mass, first-borns had higher metabolic risk z-scores compared with later-borns. The metabolic risk z-score was calculated as the average of the z-scores of fat mass, lipid profile and blood pressure, with a higher score indicative of a higher risk of the metabolic syndrome. The same research group observed a similar increase in metabolic risk among first-born women.
Importantly, we have recently shown that insulin sensitivity (as determined by Bergman's minimal model) was 21% lower in first-born children compared with later-borns. It is worth noting that neither a reduction in birth weight nor current adiposity explain the observed difference in insulin sensitivity, as both were accounted for in all statistical models. To put the observed reduction in insulin sensitivity in context, the magnitude of the change (20%) is similar to the increase seen with medications used to treat diabetes in adults, such as metformin.
A reduction in insulin sensitivity (insulin resistance) with compensatory hyperinsulinism is associated with metabolic and cardiovascular diseases. Insulin resistance leads to reduced endothelial cell production of nitric oxide, greater myosin light chain activation with vasoconstriction and reduced skeletal muscle glucose transport. In a cohort of 208 apparently healthy middle-aged nonobese men, insulin resistance was an independent predictor of many disorders 4–11-years later, including Type 2 diabetes mellitus, hypertension, coronary heart disease, stroke and cancer. Facchini et al. showed that 36% of individuals in the least insulin-sensitive tertile suffered one or more of these adverse events; by contrast, no events were recorded among individuals in the most insulin-sensitive tertile.
Furthermore, 24-h ambulatory blood pressure monitoring showed that first-born children also had higher daytime systolic (+5 mmHg) and diastolic (+4 mmHg) blood pressure. This is equivalent to the observed difference in systolic and diastolic pressure between an obese child and a child of normal BMI. Higher blood pressure tracks from childhood into adulthood and the prevalence of hypertension is 3.6-times more common in those with a childhood blood pressure in the highest quintile. In the prospective 1993 Pelotas birth cohort, the difference in systolic blood pressure in first-borns was attributed to early catch-up growth and the difference in diastolic blood pressure to reduced physical activity. Nonetheless, the increased blood pressure seen in first-borns may have long-term consequences for cardiovascular health.
