The growth of an undernourished fetus results in adaptive fetal programming or metabolic imprinting, with permanent changes in structure, metabolism and physiology of fetal organs and related pathophysiologic consequences in later life [1, 2]. Studies worldwide, regardless of socio-economic background, have linked low birth weight to cardiometabolic risk factors, related cardiovascular (CV) disease, and type 2 diabetes [3, 4]. Recently, we reported the adverse relationship of low birth weight to white blood cell count and pulsatile arterial function [5, 6].

Inflammation plays an important role in the pathogenesis of atherosclerosis [7–9]. Risk factors, e.g. cigarette smoking, hypertension, dyslipidemia and hyperglycemia promote inflammation, are well established. Biomarkers, including as oxidized low-density lipoproteins, interleukin-6, intercellular adhesion molecule-1 and high sensitivity C-reactive protein (hs-CRP, reflect the ongoing inflammatory process [8]. Of these, hs-CRP - an acute-phase reactant secreted by the liver - has emerged as an independent predictor of CV disease and type 2 diabetes [8–13]. In terms of birth weight, a few studies have demonstrated an inverse association between birth weight and hs-CRP in children and adults [14–16]. Consequently, the American Heart Association and Center for Disease Control recommended guidelines for the incorporation of hs-CRP into its CV disease risk stratification [8]. However, population-based data in this regard are scant. The present study examines this aspect in younger adults enrolled in the Bogalusa Heart Study, a biracial (35% black/65% white) community-based investigation of the natural history of CV disease

This community-based study demonstrates an inverse and independent association between birth weight and hs-CRP, a widely used biomarker of systemic inflammation. In addition, female sex, BMI and smoking were independent adverse correlates of hs-CRP. It is noteworthy that these findings support the emerging concept of intrauterine imprinting and its pathophysiologic consequences later in life by linking low birth weight to excess hs-CRP [1, 2].

Although previous study in children has failed to find significant association between birth weight and hs-CRP [16], our epidemiologic study is consistent with the MIDSPAN family study and Northern Finland 1966 birth cohort study in adults [14, 15]. However, this inverse relationship was not observed in black subjects in our analysis. Of note, black subjects had significantly lower birth weights and related higher hs-CRP levels than white subjects [17, 18].

Although observational studies like this cannot address the issue of causality, several putative mechanisms might link low birth weight to underlying perturbation in inflammatory pathways in utero. Undernutrition in utero causes permanent impairment in growth, structure, and function of muscle [19, 20], fat [21, 22], liver [23] and renal nephrons [9, 24] inter alia due to adaptive programming, resulting in cardiometabolic syndrome and related disorders in later life [3, 25]. Interestingly, in utero muscle growth is retarded in low-birth weight babies [25]; and since there is little muscle cell replication after birth [26], these individuals will develop a disproportionately high fat mass and related state of chronic low-grade inflammation induced by adipose tissue cells including monocytes in a nutritionally-rich environment of postnatal life [25, 27]. Acute-phase reactants secreted by the liver, including hs-CRP, are upregulated by interleukin-6, a proinflammatory cytokine synthesized by adipose tissue and cleared mainly by the kidneys. Hence, adaptive programming of any of these tissues may result in heightened inflammatory states later in life. Of note, Barker et al. [28] demonstrated an inverse relationship between birth weight and acute-phase reactant fibrinogen in adults. Furthermore, studies including our own have shown an inverse relationship between birth weight and the number of circulating leukocytes [5, 29], the cellular effectors of inflammation. However, a caveat relating to causality, is that the observed elevation in hs-CRP levels among low birth weight adults may be a reverse causation phenomenon secondary to underlying excess atherosclerosis [30, 31].

As in previous studies [18, 32], obesity measured as BMI has been identified as an independent correlate of hs-CRP in our cohort. As discussed above, this is consistent with the pathophysiological role of adipose tissue in regulating inflammation. Furthermore, sex, but not race, was retained as an independent correlate of hs-CRP in our subjects. The excess in hs-CRP in females, also noted in previous study [18], may be due to an estrogen effect [33]. Based on exogenous estrogen administration studies in women, this hormone has been implicated in the transcriptional control, clearance, or cytokine regulation of several acute-phase reactants produced by the liver, including hs-CRP [34], but the role of endogenous estrogen in this regard is unknown. The current observations on white and total subjects also support the known adverse influence of smoking behavior on hs-CRP levels [35]. The lack of adverse effect of smoking among black subjects may be due to differences in intensity and duration of smoking.

In conclusion, low birth weight for gestational age is characterized by increased hs-CRP levels. In conjunction with earlier studies, these findings support the view that low birth weight, albeit a crude surrogate indicator of adaptive fetal programming, is a potential early risk factor for the emergence of disorders related to the activation of inflammatory pathways. As stated by Barker [1], primary prevention lies in protecting fetal development.