Low Birth Weight as a Risk Factor for Hypertension

Daniel T. Lackland, DrPH, Brent M. Egan, MD, Pamela L. Ferguson, MS, PhD

Disclosures
In This Article

Low Birth Weight

Low birth weight (<2500 grams) affects 7.6% of all births in the United States.[2] As shown in Figure 2, the low birth weight rate among African Americans is twice that of Caucasians, and is slightly higher for residents of the South compared to other parts of the United States. The maternal-fetal environment can be influenced by several factors resulting in a baby born at low birth weight.[8,9] Maternal undernutrition and/or imbalanced nutrient intake have been proposed as major contributing factors to low birth weight.[10] While maternal diabetes is most often associated with larger babies, the risk of low birth weight is also increased from diabetes and impaired glucose tolerance.[11,12] Likewise, maternal hypertension increases the risk of intrauterine growth restriction and low birth weight.[13]

As previously indicated, there have been numerous ecologic and observational studies[4,14,15] that identified significant inverse associations of birth weight with blood pressure levels at various ages in later life. While the relationship has been detected at different ages, the strength of the inverse association increases with age such that among 64-71 year olds, systolic blood pressure was decreased by 5.2 mm Hg for each kilogram increase of birth weight.[16]

As the prevalence of hypertension is associated with socioeconomic status it could be argued that the association between low birth weight and disease merely reflects low socioeconomic status. However, studies[14,17] have examined socioeconomic status directly and the associations between low birth weight and disease are independent of social influences. Thus, other mechanisms are probably involved. While the mechanisms for the birth weight/hypertension relationship remain unclear, there are observational and experimental results that provide some direction for future study. Some of the proposed mechanisms are presented in Figure 3. In addition to the increased risk of low birth weight, animal models show that an imbalance of macronutrients in the maternal diet can have short- and long-term effects on the blood pressure of offspring.[18] Animal studies of diets with a low protein-to-carbohydrate ratio in pregnant rats resulted in long-term elevation of blood pressure in the offspring. Similar conclusions are suggested from a dietary study of 40-year-old men and women in the United Kingdom.[19] The path of growth associated with the development of hypertension is characterized by slow growth in utero, followed by accelerated "compensatory" growth in weight and height.[7,14] This is consistent with findings in children, among whom those who were small at birth but are currently heavy, have the highest blood pressures and most evidence for insulin resistance.[20,21,22]

Proposed mechanisms for fetal origins of hypertension.

Another proposed mechanism for the hypertension-birth weight relationship involves arterial compliance and elastogenesis. The elasticity of the aorta was directly related to size at birth among 50-year-old men and women.[23] A decreased arterial compliance is associated with elevated blood pressure and hypertension.[24,25] While direct evidence remains to be detected, it has been proposed that the decreased arterial compliance seen in those of low birth weight is due to a decreased amount of elastin present in the vessel wall resulting from in utero effects on vascular elastogenesis.[20]

Maternal and fetal exposure to glucocorticoids has been proposed as a possible mechanism for the association of low birth weight and hypertension. An overexposure of the fetus to glucocorticoids has been associated with retarded fetal growth in humans.[26] Exposure of the undernourished fetus to maternal glucocorticoids has been associated with hypertension in adult life.[27] The mechanism linking increased glucocorticoid exposure in utero to hypertension later in life is unknown. However, increased sensitivity to glucocorticoids may enhance angiotensin-converting enzyme activity and raise angiotensin II, which could influence blood pressure levels.[28]

Some authors suggest that the mechanism through which low birth weight leads to hypertension is that small babies have reduced numbers of nephrons increasing the risks for the development of adverse health outcomes later in life.[29,30] While the number of nephrons in the normal population varies from 300,000 to 1.1 million and greater,[31] 60% of the complement of nephrons is complete during the last trimester.[32] The reduced number of nephrons in low birth weight individuals purportedly leads to hyperfiltration of each nephron and resulting glomerular sclerosis, further nephron death, and a cycle of increasing blood pressure and nephron death.[33,34,35] Since not all low birth weight individuals develop hypertension, other factors are involved. As one example, obesity magnifies the relationship between low birth weight and clinical manifestations of the insulin resistance syndrome as the strength of the association increases with body mass.[36,37,38] In turn, adult obesity is associated with an increased renal filtration load.[39] This imbalance between the functional demands and the structurally limited filtration in those of low birth weight tends to raise blood pressure in order to maintain sodium-volume homeostasis, i.e., pressure natriuresis.[40] This proposed mechanism of reduced nephrons/increased body mass/pressure natriuresis is consistent with Guyton's findings proposed years before the fetal origin hypothesis, and clearly identifies the critical role of the kidney in any theory linking low birth weight to hypertension.[41] The importance of fetal development and the kidney is further supported by the observation that low birth weight was strongly associated with early onset chronic renal failure attributed to hypertension, diabetes, and other diagnoses of chronic renal failure.[34,35]

The association of birth weight with hypertension may not be homogeneous, but modulated by demographic factors, as suggested by a study[42] in which birth weight was associated with the prescription of different antihypertensive medications for various race/sex groups. Specifically, birth weight was associated with the use of calcium channel antagonists in black women and ACE inhibitors in white men, suggesting the birth weight/blood pressure relationship may involve a relatively complex mechanism. While the proposed explanations are plausible, it is essential to continue research to identify the mechanisms linking low birth weight to subsequent health.

In summary, the association of low birth weight and the development of hypertension among adults is a worldwide phenomenon. While the mechanisms remain unclear and warrant continued research, the implications of the association are significant. Further study in this area will contribute to a better understanding of the pathogenesis of hypertension. Understanding the association may assist the clinician treating hypertension by identifying fetal and early-life factors affecting therapeutic responses. Evidence suggests that various factors from "womb to tomb," including low birth weight, are important in the pathogenesis and treatment of hypertension.

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