Is Vitamin D Inadequacy in Early Life an Instance of the "Barker Hypothesis"?

In 1986, David Barker, a British epidemiologist, noted a connection between small infant birth size and risk of heart disease later in adult life.1 The theory that certain adult-onset diseases might have their roots in nutritional insults sustained in the perinatal period (either in utero or in the early months of infancy—or perhaps both) has since been known as “the Barker hypothesis” or sometimes “The Fetal Origins Hypothesis.” The original association between undernutrition in utero and late-life heart disease has been difficult to confirm, but the idea that early-life influences can have important downstream consequences is intuitively attractive and is supported by such concrete instances as perinatal thyroid function (and, its cognate, adequate dietary iodine), which is absolutely essential for early-life brain development and maturation. Perinatal iodine deficiency and hypothyroidism from any cause are recognized as important contributors worldwide to mental retardation and learning disabilities during childhood and adult life. In this example, iodine deficiency and its consequences certainly qualify as an outspoken instance of the Barker hypothesis in operation. A critical feature of diseases occurring by way of the Barker hypothesis is the nutritional irreversibility of the long-latency disorders that result. Beyond certain critical points in development, full nutrient repletion is not able to offset or reverse the early inadequacy. This irreversibility is the major stimulus for the better elucidation of these disorders, leading to emphasis on the imperative of early-life preventive nutrition. The Barker hypothesis has been elaborated and evaluated in several reviews,2–4 but to the best of my knowledge, there has been no attempt to evaluate the hypothesis specifically for vitamin D. Thus, what I propose to explore in this very brief review is the evidence relating unrecognized, perinatal vitamin D inadequacy to increased risk of certain chronic diseases later in life, that is, to ascertain whether any such effects might be an instance of the “Barker hypothesis.” I deliberately avoid use of labels such as “deficient” or “insufficient” in characterizing vitamin D status, as these terms are often linked to specific values for serum 25-hydroxyvitamin D [25(OH)D], about which there is considerable controversy. Instead, I use terms such as “low” or “inadequate,” referencing in each such use prevailing values for vitamin D status or input relative to values found in those individuals who do not manifest the disorders concerned. I defer until the end of this review consideration of the actual, numerical range of vitamin D status values that appears to permit avoidance of the Barker effect if it is present. Also, it is important to be clear that I am not including in this exploration the well-known downstream skeletal effects of classic rickets, for example, the pelvic deformation that is considered to have been a major factor in the evolution of pale skin for populations living in, or migrating to, high latitudes. Rickets in childhood is a serious disorder and fortunately is evident and both preventable and treatable. Instead, where I focus here is on the nonskeletal consequences both of untreated rickets and of lesser degrees of vitamin D inadequacy, often not clinically apparent and occurring at critical periods during maturation, in some instances well before the life stages when rickets is typically manifest. For most of the disorders concerned, etiology is almost always multi-factorial. The relation to vitamin D inadequacy should be understood simply as just one of the conditions that, when met, together lead to expression of the diseases concerned. Removing that single factor will not usually be expected completely to eradicate the disease of interest, but will reduce its expression at a population level. For the handful of diseases discussed in what follows, the extent of that risk reduction appears to be large enough to demand serious attention, including more research.