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Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL 35233
2 To whom correspondence should be addressed. E-mail: rlg{at}uab.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • plausibility • micronutrient • deficiency • perinatal infection
Perinatal infection is a major cause of maternal, fetal and neonatal morbidity and mortality (1, 2). In developed countries these infections occur more commonly in the most deprived sections of the population; they also appear to occur more frequently in developing countries than in developed countries. Perinatal infections are more common among the poorest women and in the geographic areas with the least resources as well as with the most malnutrition; these facts have given rise to speculation that the relationship between infection and adverse pregnancy outcomes is at least in part mediated by some nutritional deficiency (3).
Nutritional deficits may increase the risk of perinatal infection by diminishing or abolishing protective mechanisms (4). Various epithelial surfaces such as the squamous epithelium of the skin and the mucosal surfaces of the lung, gastrointestinal tract and genitourinary tract provide the first line of defense against various microorganisms; various nutritional deficiencies have a well-documented negative effect on skin and mucus membrane integrity. The ability of various cells such as leukocytes and macrophages to phagocytize invading organisms is another type of defense. Cell-mediated responses of the T cells and natural killer (NK) 3 cells play a crucial role in controlling invading organisms as do the antibody-producing B cells. In addition to the specific cellular actions described above, other immune cell products such as cytokines and metalloproteases, as well as complement, are important components of the immune system that act together to protect pregnant women from infection (Table 1). Nutritional deficiencies have been linked to decreases of all cellular and serum immune functions.
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Several reviews have suggested that protein-energy-malnutrition (PEM) is one of the major causes of immunodeficiency worldwide (4– 7). Lymphoid atrophy, for example, is a prominent feature of PEM, with substantial reductions seen in the size of the thymus and the spleen. This relationship is not surprising because immune cells have a high requirement for energy and amino acids for both cell division and protein synthesis. Therefore, reduced availability of both energy and amino acids appears to substantially reduce the ability of the host to mount an appropriate immune response to various types of bacteria, viruses and other pathogens. Other immune deficiencies associated with PEM are decreased phagocytic activity by neutrophils and macrophages, decreased numbers of circulating T cells and impaired lymphokine production. PEM is also associated with impairment of many of the host barriers to infection, such as the integrity of the skin and mucus membranes. On the other hand, antibody response is usually maintained.
Micronutrients
Various micronutrients, including vitamins and minerals, are also believed to play an important role in mounting an immune response, and a deficiency of single micronutrients alone, or in combination with other micronutrients, is believed to substantially increase the risk of having a poor immune response to infection (4– 6, 8– 13) (Table 2). For this reason, this review will explore the plausible relationship between various micronutrient deficiencies and increased risk of perinatal infection. Individual vitamins and minerals will be discussed independently, although many authors believe that because of redundant immune system capabilities, decreased availability of a number of micronutrients appear to work in synergy in reducing or preventing a successful host response to an infection. These responses may be considered as maintaining the normal function of a wide variety of immune cells including macrophages, lymphocytes and neutrophils, including their ability to destroy or inactivate invading organisms through antibody and cytokine production and phagocytosis.
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Examples of the effects of trace elements on the immune system are shown in Table 3. Iron deficiency is extremely common in the developing world, with >50% of the world's population having some degree of deficient iron status based on a wide variety of tests (14, 15). Different types of immune cells appear to respond differently to various degrees of iron deficiency. For example, iron deficiency appears to have a stronger effect on cell-mediated immunity than on antibody production (4). Both neutrophil and NK cell activity are decreased with iron deficiency (14). Macrophages sequester iron as part of their normal function and this sequestration may limit various microorganisms' replication and toxicity because these functions are often iron dependent (15). Overall, substantial evidence exists that iron deficiency alters the immune response in a wide variety of animal models. However, because iron deficiency is rarely an isolated finding in humans, the extent of immune deficiency and the overall effect of iron deficiency on the burden of infectious disease-related adverse pregnancy outcomes is unknown.
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Zinc deficiency damages epithelial cells as well as the cells lining the gastrointestinal tract and pulmonary system. It is therefore likely that squamous and columnar epithelial cell damage associated with zinc deficiency allows various types of microorganisms to enter the body and become established in otherwise protected sites. Appropriate functioning of neutrophils and NK cells depends on normal zinc status whereas zinc deficiency reduces the ability to develop acquired immunity through repression of cytokine and antibody production. Zinc deficiency also inhibits normal macrophage functions including cytokine production, phagocytosis and intracellular killing.
Selenium appears to have several roles in protection from infection (20). First, often in conjunction with vitamin E, selenium appears to act as an oxidant scavenger and protects against oxidative damage (21). Selenium also appears to stimulate T-cell proliferation and macrophage cytotoxicity.
Vitamins
Examples of the effects of vitamins on the immune system are shown in Table 4. Vitamin A deficiency has been demonstrated in many areas of the world. Vitamin A likely plays a role in reducing infection through its role in enhancing epithelial cell differentiation and the barrier function of the host as well as through its effect on more traditional immune functions (22). Vitamin A regulates keratin synthesis by squamous cells and appears to maintain the integrity of mucosal epithelial surfaces—especially of the gut and lung (23). In animals, vitamin A deficiency decreases T-cell proliferation and various types of antibody production (24). The ability of neutrophils to phagocytize various organisms and to generate oxidant molecules appears to be reduced in the absence of appropriate levels of vitamin A (4, 25). These effects are generally reversible with vitamin A treatment. In humans, a wide variety of observational studies have discerned an association between vitamin A deficiency and infection whereas in supplementation trials the prevalence of a variety of infections have been reduced (4). Vitamin A supplementation improves antibody response to vaccines, maintains gut integrity and reduces the incidence and severity of infections associated with diarrhea and measles (26).
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. Vitamin C also reduces T-cell death and increases NK activity. It is highly concentrated in neutrophils and appears to be used during infection to prevent oxidative damage. Although the results are mixed, vitamin C supplementation may reduce the incidence of the common cold and other viral infections. Vitamin C supplementation may also increase lymphoproliferation and phagocytosis by neutrophils and macrophages. Vitamin C can reduce damage to lymphocytes by reactive oxygen intermediates. Vitamin E is a potent antioxidant and its deficiency results in increased free radical membrane damage (21, 30, 31). Supplementation with vitamin E increases lymphocyte proliferation and interleukin-2 responses and improves antibody response to vaccines.
Fatty acids
Fish oil contains large quantities of the n–3 polyunsaturated fatty acids, eicosapentaenoic acid and docosahexaenoic acid. In both in vivo and in vitro studies, these fatty acids have been shown to modulate T-cell function (4, 32– 33). In general, increasing intake of dietary fish oil suppresses interleukin-2 secretion and T-cell proliferation, thus accounting for the anti-inflammatory effects.
An interesting observation
An interesting example of the interaction between the nutritional status of the host and response to infection was described by Beck (34). Mice with selenium deficiency developed myocarditis when exposed to coxsackie virus whereas mice without selenium deficiency did not. The difference in response was explained by the fact that a normally avirulent virus became virulent by replicating in a nutritionally deficient host. Beck hypothesizes that an epidemic of neuropathy in Cuba was likely associated with a coxsackie virus that mutated as a result of replication in an oxidatively stressed host. The illness, which was associated with dietary limitations that occurred in the early 1990s during food shortages, was more common in adults with low levels of various antioxidants. The epidemic subsided with a program of oral vitamin and mineral supplementation. These findings suggest that outbreaks of a disease originally attributed to a nutritional deficiency may actually be the result of infection by a virus whose pathogenicity has changed as a result of replicating in a nutritionally deficient host. Coxsackie viruses are increasingly implicated in adverse pregnancy outcomes (35), and the interaction between micronutrient deficiencies and these viruses on various pregnancy outcomes has not been studied.
Conclusion
This very limited review demonstrates that at least three minerals and three vitamins, as well as some fatty acids, have well-documented effects on the immune system. Decreases in several of these micronutrients have been shown to be related to increases in clinical infection, and several randomized trials suggest that supplementation with one or more of these micronutrients may reduce susceptibility or ameliorate the effect of various types of infection. However, virtually no literature relates micronutrient deficiencies to infections that are clearly related to pregnancy outcomes. Therefore, although this review suggests biological plausibility in that micronutrient deficiencies are related to infection and that micronutrient supplementation has reduced infection-related morbidity and mortality, as of now, evidence is generally lacking that micronutrient supplementation can reduce infection-related adverse pregnancy outcomes.
Research needed
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FOOTNOTES |
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3 Abbreviations used: NK, natural killer; PEM, protein-energy-malnutrition.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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