key: cord-0863451-dqtlpxsj authors: NAWSHERWAN,; KHAN, Suliman; ZEB, Falak; SHOAIB, Muhammad; NABI, Ghulam; UL HAQ, Ijaz; XU, Kang; LI, Hui title: Selected Micronutrients: An Option to Boost Immunity against COVID-19 and Prevent Adverse Pregnancy Outcomes in Pregnant Women: A Narrative Review date: 2020-11-03 journal: Iran J Public Health DOI: 10.18502/ijph.v49i11.4717 sha: ce20c367c5c34ea96f10623062a559f0fdf90ab3 doc_id: 863451 cord_uid: dqtlpxsj The coronavirus disease-19 (COVID-19) negatively affects immune system. It is linked with adverse pregnancy outcomes. These complications may be linked with the infections mediated deficiency of micronutrients in pregnant women. COVID-19 cause’s malabsorption of micronutrients thereby increases the risk of their deficiency. Both micronutrients deficiencies and poor micronutrients intake can compromise immune function and may increase the risk of pregnancy complications associated with COVID-19 infection. Vita-min A, C, D, E, and selected minerals iron (Fe), selenium (Se), and zinc (Zn) are the micronutrients essential for immuno-competency and play a significant role in the prevention of adverse pregnancy outcomes. Immune function and pregnancy outcomes can be improved by adequate intake of micronutrients in diet or in supplements form. Based on regulatory links between viral infection, micronutrients, immunity, and pregnancy outcomes, this review highlights the role of micronutrients in boosting immunity to reduce or prevent pregnancy complications in COVID-19 infected women. Nowadays, the coronavirus disease 2019 (COVID-19) is one of the most challenging public health threats across the globe. The emergence of COVID-19 infection was reported in Wuhan, Hubei Province, China, in Dec 2019 (1), declared as global pandemic by WHO on 11 th Mar 2020 (2) . COVID-19 infection is highly contagious and escalating rapidly around the world. Globally, it has infected more than 28 million people as of 11 th Sep, 2020, including the general population and pregnant women (3). Pregnancy is a state of physiological changes and partial immune suppression of the body predisposes pregnant women to viral infections. These changes can put pregnancy at higher risk and may increase the risk of pregnancy complications through respiratory viral infection (4) . Changes in immunological responses such as the development of immunologic adaptations that allow pregnant women to tolerate an antigenically distinctive fetus eventually may increase the risk of COVID-19 infection (5) . COVID-19 infection may have adverse effects on pregnancy outcomes, causing problems such as fetal distress, premature birth, newborn respiratory distress syndrome, and even neonatal death (6) . Moreover, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) are also known to be responsible for adverse pregnancy outcomes (7, 8) . Successful pregnancy outcomes and healthy maternal immune systems rely on adequate intake of micronutrients. Micronutrients including vitamins (A, C, D, E,) and minerals (Fe, Se, Zn) have a vital role in sustaining immune competency and preventing adverse pregnancy outcomes. The immune response is compromised with inadequate nutrition that predisposes individuals to infection. During pregnancy, deficiency of certain vitamins and minerals may increase the risk and severity of infection that result in pregnancy complications. Enrichment and fortification of diet with micronutrients can boost immunity against infection and prevent such consequences (9) (10) (11) . Pregnancy is a unique immunological state, in which maternal immune system protects maternal health and growing fetus from invading foreign pathogens. Immune cells such as natural killer (NK) cells and monocytes respond more strongly to viral infection, however, some immune cells function (T and B cells) are down-regulated during pregnancy (12) . In response to Hepatitis C virus in pregnant women, trophoblast cells and immune cells constantly produce Toll-like receptors (TLRs) and Nod-like receptors (NLRs) to combat such virus. Trophoblast cells can control viral replication by secreting interferon-beta (IFNβ) which further induces antiviral responses in the body (13) . However, it is not surprising that one of the molecular pathways called type-1 interferon (type 1 IFN) can actively inhibited by viruses (14) . Furthermore, Epstein-Barr virus (EBV) can also reduce IFNβ expression by inhibiting placental interferon regulatory factor 3 phosphorylation (IRF3), resulting in decrease antiviral responses (15) . In animal models, the influenza A virus protein non-structural 1 (NS1), associated with reduced production of interferonalpha (IFNα) and IFNβ (16) . The decreased production of IFNα and IFNβ would reduce the receptivity of the immune cells at the maternal-fetal interface and would decrease their capability to respond and control microorganisms. The presence of viral infection can decline IFNβ signaling and inhibit IFNβ regulators, leading to abolish its immunomodulatory effects and may induce inflammation (17) . Based on the recent literature, COVID-19 infection is associated with cytokinestorm, lymphopenia, and inflammation. Pregnant women in their first and third trimester are produced pro-inflammatory state and the cytokinestorm because of COVID-19 infection that may induce more severe inflammation and leads to pregnancy complications (18) (19) (20) . Inflammation induced by COVID-19 infection may associate with adverse pregnancy outcomes such as miscarriage, preterm birth, still birth; affect several aspects of fetal brain development, and even preeclampsia in pregnancy. In such cases, the increased level of maternal inflammatory responses and the level of inflammatory cytokines including interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor (TNF)-α may affect fetal brain development and circulatory system, and can increase the risk of fetal mental disorders (21) . Moreover, coronavirus including SARS-CoV, MERS-CoV, and SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) are associated with miscarriages, intrauterine growth restriction (IUGR), preterm birth, low birth weight, and perinatal death. However, there is no vertical transmission of SARS-CoV, MERS-CoV and SARS-CoV-2 from mothers with SARS, MERS, and COVID-19 to their fetuses (22) . There has always been an intricate link between COVID-19 infection and micronutrients absorption. COVID-19 infection may affect absorption of micronutrients, cause certain complications such as diarrhea, and fever (22) . The malabsorption and nutrients losses during diarrhea, can lead to weak immune system, micronutrients deficiency and aggravate infection. In addition, fever substantially increases micronutrients requirements in viral infected individuals (22, 23) . The immune system plays a key role in protecting body against infections; consist of innate and adaptive immunity. Innate immunity considered as first line of defense against infections through physical protectors (skin and epithelial lining of the gastrointestinal and respiratory tracts), biochemical barriers (secretions, gastric acids and mucus), phagocytes, leukocytes, and natural killer cells. If innate immunity fails to combat with infection, a more complex adaptive immunity is triggered, mediated by T and B lymphocytes, which produces specific antibodies to kill and destroy the invading pathogens (24) . Pregnancy is a critical period for fetal growth and insufficient micronutrients intake can lead to impaired fetal development, predisposing neonates to chronic conditions later in life, poor maternal health, and adverse neonatal outcomes (25) . Pregnancy complications including preeclampsia, pregnancy-induced hypertension, intrauterine growth restriction (IUGR), low birth weight (LBW), and preterm delivery predict maternalneonatal lifelong morbidity and mortality (26) . Poor or insufficient micronutrients intake may associate with compromised immune system. However, micronutrients such as vitamins (A, C, D, E,) and minerals (Fe, Se, Zn) can improve the immune system and prevent adverse pregnancy outcomes (9, 25) . Vitamin A is one of the fat-soluble vitamins known as "anti-inflammatory vitamin". It con-tributes in the production, regulation, maturation, and functions of the immune cells including macrophages, neutrophils, natural killer T cells, dendritic cells (DCs), innate lymphoid cells (ILC), T cells (Thymus cell), and B cells (Bone marrow cells) (27) . Its deficiency is associated with impaired intestinal immune responses and increased the risk of mortality associated with respiratory infection (28) . Moreover, its supplementation has shown a significant reduction in morbidity and mortality in different infectious diseases such as diarrheal disease, measles-related pneumonia, and human immunodeficiency virus (HIV) infection (29, 30) . Level of vitamin A in serum is reduced with the advancing of gestational age, thus favoring its deficiency (31) . Human and animal models studies demonstrated that its deficiency is associated with congenital defects (32), IUGR (33), schizophrenia spectrum disorders (34), diabetes mellitus, gestational diabetes (35) , and anorectal malformations (36) . However, its sufficient intake can reduce the risk of anemia, LBW, vertical transmission of HIV (37), while excessive supplementation should also be avoided in pregnancy (38) . Therefore, an adequate vitamin A intake can be chosen as a basic option for enhancing the immune system prevents COVID-19 infection and adverse pregnancy outcomes. Vitamin C, a water-soluble vitamin known as ascorbic acid (39) is a potential antioxidant that reduces the risk of inflammation and susceptibility to infections (40) . It supports various functions of the innate and adaptive immunity including epithelial barrier function, protecting leukocytes from oxidative stress, migration of neutrophils to the infection site, regulation of antimicrobial activities of phagocyte cells, natural killer (NK) cell functions, and reduction of lymphocyte proliferation and differentiation. Its administration to patients enhances the functions of various immune cells and ameliorates the severity of respiratory infection such as pulmonary tuberculosis, pneumonia, and coronavirus infections (41) (42) (43) . In human-controlled trials, vitamin C supplementation significantly reduced the incidence of pneumonia, suggesting that it might prevent the susceptibility of lower respiratory tract infections under certain conditions (44) . Vitamin C is crucial for embryogenesis, promoting fetal growth, progression of pregnancy, and delivery (45) . In an animal model, fetus was protected against lipopolysaccharide-induced intrauterine fetal death and IUGR (46) . Vitamin C in plasma decreases with advancing in gestational age (47) and its deficiency is associated with various pregnancy complications, especially in the third trimester (48) . Its supplementation found to reduce the risk of oxidative stress and may be important to prevent pregnancy complications, including preeclampsia, gestational hypertension, gestational diabetes, IUGR, and endothelial dysfunction (49, 50) . Therefore, sufficient vitamin C intakes could be a promising option to strengthen immune system that prevent COVID-19 infection and reduces negative pregnancy results. Vitamin D, a fat-soluble vitamin that is crucial to maintain calcium homeostasis and bone health (40) . In addition to these classical functions, its anti-inflammatory and immunomodulatory effects could not be ignored in the immune system. It plays a fundamental role both in innate and adaptive immunity (41) . To protect the body against pathogens, it promotes the differentiation of monocytes to macrophages; reduce immune cell proliferation and cytokine production. During influenza infection, through immune response the lungs epithelial cells start the conversion of inactive vitamin D to active vitamin D, which in turn promotes the production of cathelicidin. Increased production of cathelicidin is associated with reduce severity of infection and viral replication (47, 48) . However, reduced vitamin D level in calves is reported to increase risk of the bovine coronavirus infection (51) . However, therapeutic dose of vitamin D showed a statistically significant (42%) reduction in the incidence of influenza infection (52) . It has various kinds of actions in pregnancy, including its effect on angiogenesis, placental implantation, oxidative stress, and endothelial functions (53) . In the COVID-19 pandemic, many people are advised to stay at home. Therefore, they will not be able to spend time outdoors and expose skin to the sun, which may increase the risk of vitamin D deficiency. Deficiency of maternal vitamin D is common in pregnancy due to insufficient dietary intake and less exposure to sun that associated with preeclampsia (54, 55) , preterm birth (56), LBW (57, 58) , and also later in life associated with autoimmune diseases (59), asthma (60), and type 1 diabetes (61). Moreover, many observational and randomized clinical trials found that its supplementation is beneficial to both mother and developing fetus (62) . Therefore, vitamin D could be one of the effective choices to boost immunity, reduce severity of COVID-19 infection, and prevent adverse maternal-neonatal outcomes. Vitamin E, a fat-soluble vitamin is known as an antioxidant and its immunomodulatory effect has been observed in different animal and human studies (63) . It regulates macrophages which serve as antigen presenting cells (APC) and regulate NK cells and T cells by producing cytokines, while reduces reactive oxygen species (ROS), reactive nitrogen species (RNS), and prostaglandins (64) . It expedites activities of NK cells; regulates the maturation and functions of dendritic cells (DCs), increases interleukin-2 (IL-2) producing capacity of T cells, and enhances the humoral response of immune system (65) (66) (67) (68) . The decreased vitamin E status in calves associated with increased risk of bovine coronavirus (51) . Its supplementation enhances resistance against infectious disease and loweres viral titer of influenza (63, 69, 70) . It decreases oxidative stress during pregnancy that may cause preeclampsia, preterm delivery, and LBW (50, 71) . In a populationbased study, maternal vitamin E status was positively associated with fetal growth (72) . It has shown positive effect on pregnancy outcomes under some conditions (73, 74) . Therefore, vitamin E supplementation is likely to amplify immunity, promote resistance against COVID-19 infection and improve pregnancy outcomes. Iron (Fe) is one of the essential micronutrients and involved in many immunological functions such as production and regulation of cytokines, generation of ROS that kill pathogens, differentiation and proliferation of T lymphocytes and essential component of certain enzymes which are important for the functioning of immune cells (75, 76) . Its deficiency affects the functions of macrophages, neutrophils, NK cells, B cells, and T cells. Moreover, Fe deficiency harms both pro-and antiinflammatory cytokines including IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, TNF-α, and IFN-γ (77) . Medicinal Fe and food fortification may reduce the risk and severity of respiratory infections (78) . It promotes normal growth and development of fetus (79) . Its deficiency affects more than 50% of all pregnant women in both developed and developing countries and may lead to anemia, IUGR, SGA, perinatal morbidity and mortality, induces maternalneonatal stress, and can damage fetal erythrocytes. Furthermore, Fe deficiency can cause long-term cognitive and behavioral problems in childhood. Iron supplementation in pregnancy showed significantly higher mean birth weight and lower incidence of LBW (80, 81) . Fe supplementation could be effective for strengthening immunity, reduce the risk and severity of COVID-19 infection and prevent maternal-neonatal morbidity and mortality. Selenium (Se) is also an essential micronutrient that plays a significant role in optimal immune responses. Selenium-dependent enzymes (selenoproteins) are crucial for the antioxidant host defense system affecting leukocytes function. Selenium has found an immuno-stimulator of innate immune cell functions, T cells proliferation, and NK cells activities (76, 82) . Macrophages activity, functions of NK cells, activation and functions of T and B cells are impacted by dietary Se intake (83) . Its insufficient intake is associated with susceptible immune system and increased incidence, severity, and progression of viral infections such as influenza, HIV and Coxsackie virus. However, its sufficient intake above the recommended levels has been shown to enhance immune compe-tence and resistance against influenza infections in both human studies and animal models (84, 85) . In general, pregnancy associated with increased oxidative stress. It reduces oxidative stress and prevents perinatal morbidity and mortality (86, 87) . During pregnancy, Se level in maternal blood reduces significantly and cause miscarriage, pre-eclampsia, and IUGR (88, 89) . Its supplementation has a positive effect on hypertension (90) therefore; Se may have the potential to boost immunity, reduce pregnancy complications and severity of COVID-19 infection. Zinc (Zn) promotes the development and functions of macrophages, neutrophils, and NK cells (91) . It modulates cytokine release, induces proliferation of CD8+ T cells, activates and develops T lymphocyte (75, 76) and prevents free radicalinduced injury during inflammatory process (91) . Its deficiency is associated with decreased phagocytosis, reduced production of macrophages, cytokines, decreased DCs maturation, and adversely affects the growth and function of T and B cells (92) . Its supplementation increases immune functions and decreases the risk and severity of acute lower respiratory infections (91, 93) . Increased intracellular concentration of Zn with pyrithione can efficiently reduce the RNA viruses' replication and at low concentrations inhibits the replication of SARS-CoV (94) . Zn is essential for embryogenesis and normal fetal growth and its requirement in third trimester of pregnancy is two times higher than non-pregnant women. Due to its increased transfer from mother to developing fetus, concentration of Zn in maternal serum declines (95, 96) . Its deficiency limits fetal growth and can be teratogenic in severe cases. Its supplementation reduces preterm birth, increases neonatal birth weight, reduces incidence of gestational hypertension and increases neonatal head circumference (96) (97) (98) . Hence, Zn supplementation alone or in combination with pyrithione can enhance immunity, inhibit SARS-CoV-2 replications, and improve maternalneonatal outcomes. The Recommended Dietary Allowances (RDA) of micronutrients is shown in Table 1 . The novel coronavirus disease (COVID-19) is highly contagious. It has infected more than three million people around the globe. Pregnant women are more susceptible to respiratory viral infections compared to non-pregnant women due to physiological and immunological changes. The COVID-19 infection may suppress the immune system in pregnancy and put pregnant women at higher risk of complications. The COVID-19 infection associated with inflammation and cytokine-storm that can cause adverse perinatal outcomes. Moreover, COVID-19 infection associated with diarrhea may affect absorption of micronutrients and increase the risk of micronutrients deficiency in pregnant women. Micronutrients deficiency in pregnancy associated with decline immune responses and adverse pregnancy outcomes including preeclampsia, preterm birth, LBW, IUGR, congenital anomalies, and perinatal mortality (Fig. 1) . In pregnancy, increased physiological changes require increased nutrients intake to support the fetus development, placental tissue, and hence successful pregnancy outcomes. Sufficient intake of micronutrients can prevent negative pregnancy outcomes and may boost immunity against COVID-19 infection in pregnant women. Due to malabsorption of micronutrients in COVID-19 infection and increased requirement of micronutrients in pregnancy, it is highly recommended for pregnant women to take the tolerable upper intake level (UL) of micronutrients. Pregnant women are encouraged to take variety of foods including, fresh vegetables and legumes, fruits, grains (high cereals fiber varieties), dairy products (milk, yogurt, cheese), meat (lean meat, fish, poultry, egg), and micronutrient supplements. However, excessive intake of micronutrient supplements should be avoided in pregnancy, which may increase the risk of adverse pregnancy outcomes (38, 99) . We would suggest that randomized clinical studies to be conducted to explore the individual vitamins impact on immune function and pregnancy complications associated with micronutrients absorptions. In addition to develop specific mechanisms through which specific micronutrient modulates physiological, biochemical and immunological responses during pregnancy in context of precision nutrition. Ethical issues (Including plagiarism, informed consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors. A novel coronavirus from patients with pneumonia in China 2019 World Health Organization. WHO Director-General's opening remarks at the media briefing on COVID-19 -11 Effects of influenza on pregnant women and infants Coronavirus (COVID-19 Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome Middle East respiratory syndrome coronavirus (MERS-CoV) infection during pregnancy: report of two cases & review of the literature The role of vitamins and minerals on the immune system Conference on 'Transforming the nutrition landscape in Africa'. Plenary Session 1: Feeding the immune system Vitamin and mineral supplementation in pregnancy: evidence to practice An immune clock of human pregnancy Hepatitis C virus sensing by human trophoblasts induces innate immune responses and recruitment of maternal NK cells: potential implications for limiting vertical transmission The PD-1/PD-L1 inhibitory pathway is altered in pre-eclampsia and regulates T cell responses in pre-eclamptic rats Murine gammaherpesvirus 68: a model for the study of Epstein-Barr virus infections and related diseases Type 1 interferons and the virus-host relationship: a lesson in detente Type I interferons regulate susceptibility to inflammation-induced preterm birth Clinical features of patients infected with 2019 novel coronavirus in Wuhan The unique immunological and microbial aspects of pregnancy Is COVID-19 receiving ADE from other coronaviruses? Microbes and Infection Maternal influenza infection is likely to alter fetal brain development indirectly: the virus is not detected in the fetus An analysis of 38 pregnant women with COVID-19, their newborn infants, and maternal-fetal transmission of SARS-CoV-2: maternal coronavirus infections and pregnancy outcomes The Interaction between Nutrition and Infection The immune system and aging: a review Micronutrient deficiencies in pregnancy worldwide: health effects and prevention Micronutrients in pregnancy The effect of vitamin A on epithelial integrity Role of vitamin A in the immune system Vitamin effects on the immune system: vitamins A and D take centre stage Vitamin A and immunity to viral, bacterial and protozoan infections Serum retinol levels in pregnant adolescents and their relationship with habitual food intake, infection and obstetric, nutritional and socioeconomic variables Serum levels of some micronutrients and congenital malformations: A prospective cohort study in healthy Saudi-Arabian firsttrimester pregnant women Metabolic syndrome: Role of maternal undernutrition and fetal programming Low maternal retinol as a risk factor for schizophrenia in adult offspring Vitamin A and gestational diabetes The effect of vitamin A deficiency during pregnancy on anorectal malformations Vitamin A and pregnancy: A narrative review Vitamin A: too much of a good thing Ascorbic acid and the brain: rationale for the use against cognitive decline Vitamin C and the common cold Vitamin C and the Immune System The clinical effects of vitamin C supplementation in elderly hospitalised patients with acute respiratory infections Vitamin C and SARS coronavirus Vitamin C intake and susceptibility to pneumonia Expression and characterization of vitamin C transporter in the human trophoblast cell line HTR-8/SVneo: Effect of steroids, flavonoids and NSAIDs Ascorbic acid protects against lipopolysaccharide-induced intra-uterine fetal death and intra-uterine growth retardation in mice Total serum vitamin C concentration in pregnant women: Implications for a healthy pregnancy Estimation of ascorbic acid status in normal pregnancy Vitamin C and E supplementation in women at risk of preeclampsia is associated with changes in indices of oxidative stress and placental function Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: A randomised trial Acute phase response elicited by experimental bovine diarrhea virus (BVDV) infection is associated with decreased vitamin D and E status of vitamin-replete preruminant calves Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren Vitamin and pregnany outcomes Maternal vitamin D deficiency increases the risk of preeclampsia A nested case-control study of midgestation vitamin D deficiency and risk of severe preeclampsia Association of low serum 25-hydroxyvitamin D levels in pregnancy with glucose homeostasis and obstetric and newborn outcomes Vitamin D may be a link to Black-White disparities in adverse birth outcomes Maternal early pregnancy vitamin D status in relation to fetal and neonatal growth: results of the multi-ethnic Amsterdam Born Children and their Development cohort Maternal intake of vitamin D during pregnancy and risk of advanced beta cell autoimmunity and type 1 diabetes in offspring Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica Use of cod liver oil during pregnancy associated with lower risk of Type I diabetes in the offspring The Implications of Vitamin D Status During Pregnancy on Mother and her Developing Child The Role of Vitamin E in Immunity Exploring the full spectrum of macrophage activation Effect of micronutrient status on natural killer cell immune function in healthy free-living subjects aged ≥90 Inhibition of NF-kappa B and oxidative pathways in human dendritic cells by antioxidative vitamins generates regulatory T cells Vitamin E-enhanced IL-2 production in old mice: Naive but not memory T cells show increased cell division cycling and IL-2-producing capacity Long-term dietary antioxidant supplementation reduces production of selected inflammatory mediators by murine macrophages Vitamin E supplementation increases T helper 1 cytokine production in old mice infected with influenza virus Vitamin E supplementation decreases lung virus titers in mice infected with influenza Oxidative stress, diet and the etiology of preeclampsia A Comparison of Vitamin E Status and Associated Pregnancy Outcomes in Maternal-Infant Dyads between a Nigerian and a United States Population Low maternal vitamin E intake during pregnancy is associated with asthma in 5-year-old children Immune Function and Micronutrient Requirements Change over the Life Course Multivitamin supplementation supports immune function and ameliorates conditions triggered by reduced air quality The role of iron in immunity and inflammation: implications for the response to infection. Diet, Immunity and Inflammation Iron, its relation to immunity and infectious disease Case study on iron in mental development -in memory of John Beard Global, regional, and national trends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and non-pregnant women for 1995-2011: a systematic analysis of populationrepresentative data Influence of mineral and vitamin supplements on pregnancy outcomes The role of selenium in inflammation and immunity: From molecular mechanisms to therapeutic opportunities Selenium, Selenoproteins, and Immunity Selenium deficiency increases the pathology of an influenza virus infection Selenium, immune function and resistance to viral infections The antioxidant role of selenium and seleno-compounds Oxidative stress and inflammation in pregnancy Selenium in reproductive health Low selenium status is associated with the occurrence of the pregnancy disease preeclampsia in women from the United Kingdom Blood pressure and blood selenium: a cross-sectional and longitudinal population study Zinc and immune function: the biological basis of altered resistance to infection Zinc and its role in immunity and inflammation Zinc supplementation reduces the incidence of acute lower respiratory infections in infants and preschool children: a double-blind controlled trial Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture Physiology of pregnancy and nutrient metabolism Zinc: an essential but elusive nutrient Potential contribution of maternal zinc supplementation during pregnancy to maternal and child survival The importance of antioxidant micronutrients in pregnancy Daily oral iron supplementation during pregnancy Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic d_id=10026 101. Dietary Reference Intakes for Calcium, Phosphorous, Magnesium, Vitamin D, and Fluoride Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids The authors have no conflict of interest regarding this review.