Vitamin research — Preparing for the Future
That adequate intakes of various vitamins, minerals, and other micronutrients are needed for optimal function of the organism is a truism.
Humans require an adequate intake of micronutrients in order to maintain normal bodily function. Though it is possible to obtain sufficient doses from a healthy diet, proper micronutrient nutrition is not always possible, especially in low- and middle-income countries. In developed countries, national intake surveys have shown inadequate micronutrient status for vulnerable population groups, such as children, women during pregnancy and lactation, the elderly, and people who are ill, as well as for young to middle-aged adults who make unhealthy food and other lifestyle-related choices that become risk factors. Micro-nutrient deficiencies and long-term insufficient intakes are associated with adverse health effects ranging from severe birth defects to chronic diseases. The costs of treating these health implications, as well as the productivity lost due to micronutrient deficiency-related morbidity and mortality, have been found in various studies to be economically significant. Interventions aimed at correcting insufficient micronutrient intakes have been generally proven cost effective.
While personal nutritional choices affect an individual’s health condition, thereby influencing productivity and economic contribution to society, nutrition interventions carried out by the state also have the potential to affect economic output in signifi-cant ways. To date, little research has been undertaken with respect to identifying the economic aspects associated with nutrition interventions or nutrition programs and their health benefits (1). Among the studies of nutrition interventions in which health-related economic implications of the intervention have been addressed, some have investigated the economic burden of micronutrient deficiencies and malnutrition, as well as potential healthcare cost savings as a result of fortification and/or supple-mentation. The lack of implementation of many cost-effective interventions implies that both policymakers and the public need better information on the economic potential of nutrition-related health effects.
Folate (also known as vitamin B9 or folic acid) deficiency is notable in that it has afflicted the populations of developed as well as undeveloped countries. Folate deficiencies often result in neural tube defects (NTDs), which occur at a very early stage of development. Although adequate intakes of folic acid have been shown to effectively reduce the risk of NTDs and measures have been taken to increase awareness of it, its full preventive potential has not been realized in most countries. To understand the economic burden of NTDs and the economic impact of preventing NTDs with folic acid, a systematic review was performed on relevant studies (2). A total of 14 cost-of-illness studies and 10 economic evaluations on prevention of NTDs with folic acid were identified. Consistent findings were reported across all of the cost-of-illness studies. The lifetime direct medical cost for patients with NTDs is significant, with the majority of cost being for inpatient care, for treatment at initial diagnosis in childhood, and for comorbidities in adult life. The lifetime indirect cost for patients with an open spinal column (spina bifida) – the most common permanently disabling birth defect in the United States – is even greater due to increased morbidity and premature mortality. Caregiver time costs are also significant.
The direct medical costs of NTDs are borne by healthcare payers, such as health insurance programs, and include factors, such as drugs and hospitalizations for managing NTDs directly and for managing comorbidi-ties. The annual direct medical cost per patient in the US was estimated to be €42,943 ($51,574) in 2003 for NTD (3) and between €11,728 ($11,061) in 1993 and €54,270 ($65,177) in 2003 for spina bifida (4, 5). In Spain, the social security system spent direct medical costs of €3,825,037 ($2,953,138) in 1988 per year for the care of patients with spina bifida (6), representing approximately €3,541 ($2,734) per person per year. A significant proportion of the cost burden occurs during childhood. For example, in the US in 2003 , total hospital charges for newborns with NTDs amounted to €62 million ($74 million) for spina bifida, €1 million ($1 million) for anencephaly (a baby born without parts of the brain and skull) and €9 million ($11 million) for encephalocele (when a baby’s skull does not close completely before birth) (3). While children and adolescents with spina bifida incur medical expenditures several times higher than children and adolescents without the disease (4, 7), young adults with the condition also continue to be high users of medical care. Almost half of the hospital admissions for adults with spina bifida are due to secondary conditions (such as serious urologic infections, renal calculi, pressure ulcers, and osteomyelitis), and the financial costs of these admissions are substantial (8). The annual direct medical cost per patient for the treatment of spina bifida comorbidities in the US ranged between €2,466 and €4,873.
Broader costs, such as lost work time, caregiver costs, and costs due to premature loss of life, are typically referred to as indirect costs. In a US study (9), caregivers of children with spina bifida worked an annual average of 7.5 to 11.3 h less per week, depending on disability severity. Differences in work hours by caregivers of children with spina bifida translated into lifetime costs of €95,186 ($111,755) in 2002. Another study estimated an average reduction of paid work time of 14 h per week for mothers and 5 h per week for fathers of children with spina bifida (10). The estimated caregiver time costs to care for a child with spina bifida until age 25 ranged from €142,477 to €171,303 ($164,675 to $197,991) in 2001, depending on the discount rates used in estimating the present value of future costs (11). Total lifetime costs for patients with spina bifida amounted to €528,425 ($620,484) in 2002 (12). Just 37.1% of the total was attributable to direct medical costs, with the costs associated with special education and development services accounting for 6.5% and 0.3% respectively. The remaining 56.1% of the total were indirect costs: €303,690 ($356,553), of which €117,613 ($138,086) were due to increased morbidity and €186,085 ($218,477) due to premature mortality.
Only a few studies have evaluated the cost effectiveness of prevention strategies for NTDs. Most of these studies evaluated the cost-effectiveness of folic acid fortification in foods while very few evaluated the cost-effectiveness of periconceptional supplementation of folic acid (2).The results from the economic evaluations demonstrate that folic acid fortification in food and periconceptional folic acid supplement use are cost-effec-tive ways to reduce the incidence and prevalence of NTDs. In food fortification studies, the benefit-cost ratio, a measure of cost-benefit analysis, ranged from 4.3 to 1 in the US (13), 11.8 to 1 in Chile (14) and 30 to 1 in South Africa (15), suggesting that the economic benefit from the prevention of NTDs greatly exceeded the cost of folic acid fortification in these countries. The cost savings per life year gained was estimated to be €1,168 in the Netherlands (16). The cost per disability-adjusted quality of life (DALY) averted was estimated to be close to €80 in Chile (14) and €7,518 for voluntary fortification in Australia and New Zealand. The cost per quality-adjusted life year (QALY), a measure of cost-utility, was estimated to be €854 in the Netherlands (16). Similarly, economic evaluations suggest that periconceptional supplementation of folic acid is a good use of healthcare resources and justifies further promotion of the use of folic acid supplementation prior to pregnancy. In the Netherlands in 2000, the cost per life year gained from pericon-ceptional supplementation of folic acid was estimated to be €2,108 (NLG 3,900) (17). In the US, the cost per QALY gained from the NTD recurrence prevention programs promoting folic acid supplementation ranged from €12,240 to €45,963 ($14,700 to $55,200) in 2003, which led the authors to conclude that the NTD recurrence prevention program provided value for the money spent relative to other public health inter-ventions (18).
In all the countries where the cost-benefit of folic acid for the prevention of NTDs was evaluated, several millions to hundreds of millions of euros (or dollars) of net benefit or cost savings were estimated. These results strongly support the continuation of folic acid for the prevention of NTDs, especially in countries with NTD prevalence far above the observed floor for folic acid-preventable NTD (19).
Vitamin A and beta-carotene
Vitamin A deficiency is an endemic nutrition problem throughout much of the developing world, affecting especially the health and survival of infants, young children, and pregnant and lactating women. These age and life-stage groups represent periods when both nutrition stress is high and the diet is likely to be chronically deficient in vitamin A. Health consequences of vitamin A deficiency include diminished immune system function, night-blindness, mild to severe (blinding) stages of xerophthalmia (abnormal dryness of the eyeball and thickening of the cornea), and increased risk of mortality. Vitamin A supplementation is low cost, fairly easy to implement on a broad scale, and has been shown to prevent deficiency-related diseases and mortality. The most recent meta-analysis of 16 published vitamin A supplementation trials confirmed a 24% reduction in risk of all-cause mortality in children aged six months to five years in response to vitamin A (20). In addition, the analysis showed a 28% reduction in cause-specific mortality associated with diarrhea. Incidences of diarrhea (15 %) and measles (50 %) in vitamin A-treated children were significantly reduced. Evidence suggested that vitamin A produced a large reduction in the incidence and prevalence of night blindness and a large reduction in the prevalence of xerophthalmia. Among women, one large trial has so far reported a 44% reduction in mortality related to pregnancy with weekly, low-dose supplementation with vitamin A or its precursor beta-carotene (21). In developed countries, beta-carotene provides a significant portion of daily vitamin A intake. For example, the level is about 30% in the US (22), where animal products that contain preformed vitamin A, such as liver and egg yolk, are not consumed in very large quantities. In low-income populations of developing countries, dietary carotenoids can provide up to 80% of daily vitamin A intake (23). Fortification of margarine and products consumed by infants and young children has been the approach used to prevent vitamin A deficiency in most industrialized countries for the last 70 years. On average, for example, some 20 to 50% of the vitamin A supply in Europe comes from vitamin A added as a fortificant to food.
Cost effectiveness can be measured by cost per death averted or cost per disability-adjusted life-year (DALY). The costs of vitamin A fortification and supplementation per DALY saved are very modest. Because supplementation is more costly than fortification (by a factor of at least 2 and up to 10), their recommended use depends on the circumstances. If the deficiency is not widespread across the population, but there is a narrowly defined target group that can be reached readily without compliance issues, supplementation may be preferable (24). This is the case, for example, with high-dose vitamin A supplements for young children, where the doses can be administered in combination with immunization. According to WHO estimates, the cost per DALY saved for vitamin A fortification is about €30 ($40) and €196 ($255) for supplementation in Africa (25).
A relatively new strategy for addressing micronutrient deficiencies is biofortification, a method of breeding plants that are naturally high in micronutrients. The benefit-cost ratio of investments in plant breeding for crops designed to fight malnutrition is generally high (26). A few studies have considered the economic underpinnings of biofortification (27). The economic value of DALYs saved was analyzed, for example, in the context of rice biofortified with the provitamin A beta-carotene (‘Golden Rice’) in the Philippines (28). The researchers estimated that the annual losses due to vitamin A deficiency without biofortified rice is
€110 million ($144 million) for children, €38 million ($50 million) for pregnant women, and €64 million ($84 million) for lactating women for a total loss of €213 million ($278 million). They projected that the total loss would be reduced by €68 million ($88 million) with Golden Rice. They also estimated the costs of developing and disseminating the biofortified rice and then calculated a rate of return on the investment of 66 to 133%, depending on assumptions. One study found high levels of cost effectiveness of Golden Rice in India (29). One study estimated the benefits of vitamin A-fortified cassava in Nigeria (30). It was calculated that vitamin A deficiency in that country caused annual losses of €844 million ($1,100 million) for children, €119 million ($155 million) to pregnant women, and €114 million ($148 million) to lactating women for a total of €1,077 million ($1,403 million). The researchers projected that biofortified cassava would reduce those losses by €38 to €134 million ($49 to $175 million) in children, €20 to €48 million ($26 to $62 million) in pregnant women, and €18 to €45 million ($23 to $59 million) in lactating women, for a total benefit of €76 to €227 million ($99 to $296 million).
Further investigation of the costs of such approaches is needed, but this will be challenging because of the confounding factors and long timelines associated with analyzing a number of nutrition-related diseases. This makes a complete analysis complex. Though small in number, studies available to date suggest that supple-mentation and fortification are cost effective and can be powerful tools to reduce illness, and the associated costs.
Vitamin D is well known for its effects on calcium and bone metabolism. Vitamin D deficiency results in rickets in infants and small children and osteoporosis in adults. However, it is becoming increasingly clear that vitamin D has a much broader range of actions in the human body than once believed. Studies indicate that this vitamin influences physiological processes in muscles, the cardiovascular and nervous systems and immune response (31). Europeans generally have low blood vitamin D (25-hydroxyvitamin D) concentra-tions owing to the higher latitudes, largely indoor living, low natural dietary sources of vitamin D, such as cold-water ocean fish, and a lack of effective vitamin D fortification of food in most of the countries. Based on estimates from observational studies and randomized controlled trials, an optimal serum 25(OH)D level of at least 40 ng/mL, effective in reducing the risk of fractures and several diseases, has been suggested (32). This could be achieved by a daily intake of 2000 to 3000 IU of vitamin D. In most European countries, the 25(OH)D levels are typically 15 to 20 ng/mL below this target.
One study indicated that increasing Europeans’ serum 25(OH)D levels to at least 40 ng/mL all year round could significantly reduce rates and economic burdens of several types of diseases, including cancer, cardio-vascular disease, diabetes mellitus, respiratory infections and dental/periodontal diseases. Based on a re-view of the scientific evidence to date – not on randomized controlled trials of vitamin D supplementation –, beneficial effects of adequate vitamin D and calcium levels were assumed to be a reduction by 15 to 30% in risk of vitamin D-sensitive diseases. For 2007, the reduction in direct plus indirect economic burden of disease in a total of 17 European countries was estimated at €187,000 million ($244,000 million) per year. The estimated cost of providing 2000 to 3000 IU of vitamin D3 per day by a combination of food fortification, supplements and natural and artificial UVB irradiation, along with ancillary costs, such as education and testing, was estimated to be about €10,000 million ($13,000 million) per year (33). Not included in this study was an estimated reduction of mortality rates by 10 to 20% that would increase life expectancy by about 2 to 3 years. Considering that these effects are similar for Germany, another study estimated a cost saving effect of improving vitamin D status in the country up to €37.5 billion ($49 billion) annually (34). The calculation considered the fact that premature death due to vitamin D-sensitive diseases can also save money, e.g. money that has otherwise to be paid for retirement.
The researchers concluded that it would be beneficial for the health ministries of these countries to familia-rize themselves with the health benefits of vitamin D and the need for achieving adequate vitamin D reple-tion, including the need for ensuring that health care staff and the public are adequately educated (33). Though additional studies are warranted to evaluate the benefits and potential risks of vitamin D supplemen-tation and fortification, steps to increase vitamin D levels can be implemented now based on what is already known.
That adequate intakes of various vitamins, minerals, and other micronutrients are needed for optimal function of the organism is a truism.