Prenatal programming: maybe not so hopeless after all?

T he concept that intrauterine environment significantly predisposes to cardiovascular disease has been investigated for many years. Barker and others, investigating the original hypothesis of Brenner, have identified a strong relationship between intrauterine growth retardation (IUGR) and low birth weight with the later development of hypertension in the adult.1 IUGR and low birth weight correlate with impaired renal development and reduced nephron number at birth.2 Autopsy studies found that subjects with essential hypertension had nearly 50% fewer nephrons than controls.3 Eventual hypertension may then result when the reduced nephron number leads to compensatory hyperfiltration and progressive nephron loss. The gradual reduction in nephrons would be predicted to decrease ultrafiltration surface area and limit sodium excretion.4 A weakness of this argument is that few kidney transplant donors, despite a 50% reduction in nephron mass, develop hypertension even after many years of follow-up. In this issue, Park et al. present evidence that some of the mechanisms of perinatal programming may be indirect.5 Park et al. evaluated cohorts of normal (>2,500 g) and low birth weight (<2,500 g) of infants. Children of twin and triplet gestation were excluded as were those from pregnancies complicated by pregnancy-induced hypertension. At 3 years of age, however, the formerly low birth weight infants have a statistically significantly higher serum uric acid. This effect was enhanced in those low birth weight children who have smaller placental size and especially in those who had the greatest weight gain in the intervening years. These observations parallel previous observations of prenatal risk of future hypertension and shed light on possible mechanistic pathways.6 Accumulating experimental and clinical evidence supports the possibility that uric acid may be a cause of hypertension, especially in children. Hyperuricemia is very common in adolescents with essential hypertension, seen in nearly 90% in one study.7 A recent randomized clinical trial, a double-blind placebo control cross-over trial, was performed in 30 hyperuricemic hypertensive adolescents. Allopurinol treatment was associated with a significant reduction in both casual and ambulatory blood pressure. In those subjects in whom uric acid levels decreased to <5 mg/dl during allopurinol therapy, blood pressure became normal in 86% (19 of 22 subjects) as compared to 3% (1 of 30 subjects) during the control period.7 Park and colleagues’ observation that children with a history of delivery at low birth weight have increased serum uric acid, and even at age 3 years have a slightly higher blood pressure, suggests a novel mechanism for higher blood pressure and increased cardiovascular risk. Altered intrauterine environment could lead to changes in metabolism that induce vascular changes and/or hypertension as childhood progresses. Although such a mechanism is not in conflict with the theory of reduced nephron mass as a contributing factor to hypertension, it does suggest a modifiable risk factor to render prenatal programming less hopeless. Further observational trials and interventional clinical trials are clearly needed to determine whether metabolic risk factors resulting from low birth weight might be modifiable targets for the reduction of hypertensive and cardiovascular risk.