Calcium, Magnesium, and Zinc Supplementation during Pregnancy: The Additive Value of Micronutrients on Maternal Immune Response after SARS-CoV-2 Infection
Ioana Mihaela Citu, Cosmin Citu, Madalin-Marius Margan, Marius Craina, Radu Neamtu, Oana Maria Gorun, Bogdan Burlea, Felix Bratosin, Ovidiu Rosca, Mirela Loredana Grigoras, Andrei Motoc, Daniel Malita, Octavian Neagoe, Florin Gorun
Nutrients, doi:10.3390/nu14071445
Magnesium may contribute to the immune response during and after SARS-CoV-2 infection by acting as a cofactor for immunoglobulin production and other processes required for T and B cell activity. Considering magnesium as a recommended dietary supplement during pregnancy and the possible role of magnesium deficiency in COVID-19 and its complications, the current study sought to determine the effect of magnesium and magnesium-containing nutritional supplements on the immune response following SARS-CoV-2 infection in pregnant women, as well as to observe differences in pregnancy outcomes based on the supplements taken during pregnancy. The study followed a cross-sectional design, where patients with a history of SARS-CoV-2 infection during their pregnancy were surveyed for their preferences in nutritional supplementation and their profile compared with existing records from the institutional database. A cohort of 448 pregnant women with COVID-19 during 22 months of the pandemic was assembled, out of which 13.6% took a magnesiumonly supplement, and 16.5% supplemented their diet with a combination of calcium, magnesium, and zinc. Around 60% of patients in the no-supplementation group had the SARS-CoV-2 anti-RBD lower than 500 U/mL, compared with 50% in those who took magnesium-based supplements. A quantity of magnesium >450 mg in the taken supplements determined higher levels of antibody titers after COVID-19. Low magnesium dosage (<450 mg) was an independent risk factor for a weak immune response (OR-1.25, p-value = 0.003). The observed findings suggest supplementing the nutritional intake of pregnant women with magnesium-based supplements to determine higher levels of SARS-CoV-2 anti-RBD antibodies, although causality remains unclear.
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Conflicts of Interest: The authors declare no conflict of interest.
References
Acharya, Lee, Lee, Lee, Moon, Mortality Rate and Predictors of Mortality in Hospitalized COVID-19 Patients with Diabetes, Healthcare,
doi:10.3390/healthcare8030338Alejo, Mitchell, Chang, Chiang, Massie et al., Prevalence and Durability of SARS-CoV-2 Antibodies Among Unvaccinated US Adults by History of COVID-19, JAMA,
doi:10.1001/jama.2022.1393Alsaffar, Alwesaibi, Alhaddad, Alsenan, Alsheef et al., The Effectiveness of COVID-19 Vaccines in Improving the Outcomes of Hospitalized COVID-19 Patients, Cureus,
doi:10.7759/cureus.21485Bahat, Aldikactioglu Talmac, Bestel, Topbas Selcuki, Aydın et al., Micronutrients in COVID-19 Positive Pregnancies, Cureus,
doi:10.7759/cureus.10609Celewicz, Celewicz, Michalczyk, Woźniakowska-Gondek, Krejczy et al., Pregnancy as a Risk Factor of Severe COVID-19, J. Clin. Med,
doi:10.3390/jcm10225458Chang, Lee, Lin, Lu, Hsu et al., The Effect of Azithromycin Plus Zinc Sulfate on ACE2 Expression through IκBα of Human Respiratory Cells in SARS-CoV-2: In Vitro Study, COVID,
doi:10.3390/covid1010021Citu, Citu, Gorun, Sas, Tomescu et al., Immunogenicity Following Administration of BNT162b2 and Ad26.COV2.S COVID-19 Vaccines in the Pregnant Population during the Third Trimester, Viruses,
doi:10.3390/v14020307Cruz Melguizo, De La Cruz Conty, Carmona Payán, Abascal-Saiz, Pintando Recarte et al., Pregnancy Outcomes and SARS-CoV-2 Infection: The Spanish Obstetric Emergency Group Study, Viruses,
doi:10.3390/v13050853Dobrescu, Copaescu, Zmeu, Duta, Bedreag et al., Ghrelin levels and hunger sensation after laparoscopic sleeve gastrectomy compared with laparoscopic greater curvature plication in obese patients, Clin. Lab,
doi:10.7754/Clin.Lab.2019.191012Erol, Polat, Akdas, Ayral, Anuk et al., Maternal selenium status plays a crucial role on clinical outcomes of pregnant women with COVID-19 infection, J. Med. Virol,
doi:10.1002/jmv.27064Fanni, Gerosa, Nurchi, Manchia, Saba et al., The Role of Magnesium in Pregnancy and in Fetal Programming of Adult Diseases, Biol. Trace Elem. Res,
doi:10.1007/s12011-020-02513-0Gorun, Motoi, Malita, Navolan, Nemescu et al., Cytomegalovirus seroprevalence in pregnant women in the western region of Romania: A large-scale study, Exp. Ther. Med,
doi:10.3892/etm.2020.8945Guan, Liang, Zhao, Liang, Chen et al., Comorbidity and its impact on 1590 patients with COVID-19 in China: A nationwide analysis, Eur. Respir. J,
doi:10.1183/13993003.00547-2020Gupta, Khenduja, Pandey, Sati, Sofi et al., Dietary Intake of Minerals, Vitamins, and Trace Elements Among Geriatric Population in India, Biol. Trace Element Res,
doi:10.1007/s12011-017-0972-8Iddir, Brito, Dingeo, Fernandez Del Campo, Samouda et al., Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19 Crisis, Nutrients,
doi:10.3390/nu12061562Junaid, Ejaz, Abdalla, Abosalif, Ullah et al., Effective Immune Functions of Micronutrients against SARS-CoV-2, Nutrients,
doi:10.3390/nu12102992Karmouty-Quintana, Thandavarayan, Keller, Sahay, Pandit et al., Emerging Mechanisms of Pulmonary Vasoconstriction in SARS-CoV-2-Induced Acute Respiratory Distress Syndrome (ARDS) and Potential Therapeutic Targets, Int. J. Mol. Sci,
doi:10.3390/ijms21218081Kawano, Matsuoka, Takishita, Omae, Effects of Magnesium Supplementation in Hypertensive Patients, Hypertension,
doi:10.1161/01.HYP.32.2.260Killilea, Maier, A connection between magnesium deficiency and aging: New insights from cellular studies, Magnes. Res
Marcos, Editorial: A Review of Micronutrients and the Immune System-Working in Harmony to Reduce the Risk of Infection, Nutrients,
doi:10.3390/nu13114180Mostafa, Kandeil, Shehata, El Shesheny, Samy et al., Middle East Respiratory Syndrome Coronavirus (MERS-CoV): State of the Science, Microorganisms,
doi:10.3390/microorganisms8070991Nasser, Naffaa, Mashiach, Azzam, Braun, The association between serum magnesium levels and communityacquired pneumonia 30-day mortality, BMC Infect. Dis,
doi:10.1186/s12879-018-3627-2Nawsherwan, Khan, Zeb, Shoaib, Nabi et al., Selected Micronutrients: An Option to Boost Immunity against COVID-19 and Prevent Adverse Pregnancy Outcomes in Pregnant Women: A Narrative Review, Iran. J. Public Health,
doi:10.18502/ijph.v49i11.4717O'driscoll, Ribeiro Dos Santos, Wang, Cummings, Azman et al., Age-specific mortality and immunity patterns of SARS-CoV-2, Nature,
doi:10.1038/s41586-020-2918-0Ota, Mori, Middleton, Tobe-Gai, Mahomed et al., Zinc supplementation for improving pregnancy and infant outcome, Cochrane Database Syst. Rev,
doi:10.1002/14651858.CD000230.pub5Palaiodimos, Ali, Teo, Parthasarathy, Karamanis et al., Obesity, Inflammation, and Mortality in COVID-19: An Observational Study from the Public Health Care System of New York City, J. Clin. Med,
doi:10.3390/jcm11030622Propper, Smell/Taste alteration in COVID-19 may reflect zinc deficiency, J. Clin. Biochem. Nutr,
doi:10.3164/jcbn.20-177Rabaan, Al-Ahmed, Muhammad, Khan, Sule et al., Role of Inflammatory Cytokines in COVID-19 Patients: A Review on Molecular Mechanisms, Immune Functions, Immunopathology and Immunomodulatory Drugs to Counter Cytokine Storm, Vaccines,
doi:10.3390/vaccines9050436Rude, Magnesium, Modern Nutrition in Health and Disease
Shittu, Afolami, Improving the efficacy of Chloroquine and Hydroxychloroquine against SARS-CoV-2 may require Zinc additives-A better synergy for future COVID-19 clinical trials, Infez. Med
Sinopoli, Isonne, Santoro, Baccolini, The effects of orally administered lactoferrin in the prevention and management of viral infections: A systematic review, Rev. Med. Virol,
doi:10.1002/rmv.2261Skalny, Rink, Ajsuvakova, Aschner, Gritsenko et al., Zinc and respiratory tract infections: Perspectives for COVID-19 (Review), Int. J. Mol. Med,
doi:10.3892/ijmm.2020.4575Skirrow, Barnett, Bell, Riaposova, Mounier-Jack et al., Women's views on accepting COVID-19 vaccination during and after pregnancy, and for their babies: A multi-methods study in the UK, BMC Pregnancy Childbirth,
doi:10.1186/s12884-021-04321-3Stewart, Lambourne, Thorp-Jones, Thomas, Implementation of early management of iron deficiency in pregnancy during the SARS-CoV-2 pandemic, Eur. J. Obstet. Gynecol. Reprod. Biol,
doi:10.1016/j.ejogrb.2020.12.055Toprak, Kurt, Sarı, Şarkış, Us et al., Magnesium Replacement Improves the Metabolic Profile in Obese and Pre-Diabetic Patients with Mild-to-Moderate Chronic Kidney Disease: A 3-Month, Randomised, Double-Blind, Placebo-Controlled Study, Kidney Blood Press. Res,
doi:10.1159/000468530Trapani, Rosanoff, Baniasadi, Barbagallo, Castiglioni et al., The relevance of magnesium homeostasis in COVID-19, Eur. J. Nutr,
doi:10.1007/s00394-021-02704-yUta, Neamtu, Bernad, Mocanu, Gluhovschi et al., The Influence of Nutritional Supplementation for Iron Deficiency Anemia on Pregnancies Associated with SARS-CoV-2 Infection, Nutrients,
doi:10.3390/nu14040836Vimercati, De Nola, Trerotoli, Metta, Cazzato et al., COVID-19 Infection in Pregnancy: Obstetrical Risk Factors and Neonatal Outcomes-A Monocentric, Single-Cohort Study, Vaccines,
doi:10.3390/vaccines10020166Wen, Chen, Tang, Wang, Zhou et al., Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19: A meta-analysis, Ann. Med,
doi:10.1080/07853890.2022.2034936Zanza, Romenskaya, Manetti, Franceschi, La Russa et al., Cytokine Storm in COVID-19: Immunopathogenesis and Therapy, Medicina,
doi:10.3390/medicina58020144Álvarez Bartolomé, Abdallah Kassab, Cruz Melguizo, De La Cruz Conty, Forcen Acebal et al., Critical Care in SARS-CoV-2 Infected Pregnant Women: A Prospective Multicenter Study, Biomedicines,
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'abstract': '<jats:p>Magnesium may contribute to the immune response during and after SARS-CoV-2 infection '
'by acting as a cofactor for immunoglobulin production and other processes required for T and '
'B cell activity. Considering magnesium as a recommended dietary supplement during pregnancy '
'and the possible role of magnesium deficiency in COVID-19 and its complications, the current '
'study sought to determine the effect of magnesium and magnesium-containing nutritional '
'supplements on the immune response following SARS-CoV-2 infection in pregnant women, as well '
'as to observe differences in pregnancy outcomes based on the supplements taken during '
'pregnancy. The study followed a cross-sectional design, where patients with a history of '
'SARS-CoV-2 infection during their pregnancy were surveyed for their preferences in '
'nutritional supplementation and their profile compared with existing records from the '
'institutional database. A cohort of 448 pregnant women with COVID-19 during 22 months of the '
'pandemic was assembled, out of which 13.6% took a magnesium-only supplement, and 16.5% '
'supplemented their diet with a combination of calcium, magnesium, and zinc. Around 60% of '
'patients in the no-supplementation group had the SARS-CoV-2 anti-RBD lower than 500 U/mL, '
'compared with 50% in those who took magnesium-based supplements. A quantity of magnesium '
'>450 mg in the taken supplements determined higher levels of antibody titers after '
'COVID-19. Low magnesium dosage (<450 mg) was an independent risk factor for a weak immune '
'response (OR-1.25, p-value = 0.003). The observed findings suggest supplementing the '
'nutritional intake of pregnant women with magnesium-based supplements to determine higher '
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{'key': 'ref30', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/14651858.CD000230.pub5'},
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'series-title': 'Modern Nutrition in Health and Disease',
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'article-title': 'Magnesium',
'author': 'Rude',
'year': '2012'},
{'key': 'ref32', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s12011-017-0972-8'},
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'first-page': '77',
'article-title': 'A connection between magnesium deficiency and aging: New insights from '
'cellular studies',
'volume': '21',
'author': 'Killilea',
'year': '2008',
'journal-title': 'Magnes. Res.'},
{'key': 'ref34', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s12011-020-02513-0'},
{'key': 'ref35', 'doi-asserted-by': 'publisher', 'DOI': '10.1186/s12879-018-3627-2'},
{'key': 'ref36', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/ijms221910559'},
{'key': 'ref37', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41586-020-2918-0'},
{'key': 'ref38', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/healthcare8030338'},
{'key': 'ref39', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/jcm11030622'},
{'key': 'ref40', 'doi-asserted-by': 'publisher', 'DOI': '10.3164/jcbn.20-177'},
{ 'key': 'ref41',
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'article-title': 'Improving the efficacy of Chloroquine and Hydroxychloroquine against '
'SARS-CoV-2 may require Zinc additives—A better synergy for future '
'COVID-19 clinical trials',
'volume': '28',
'author': 'Shittu',
'year': '2020',
'journal-title': 'Infez. Med.'},
{'key': 'ref42', 'doi-asserted-by': 'publisher', 'DOI': '10.3892/ijmm.2020.4575'},
{'key': 'ref43', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/covid1010021'},
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{'key': 'ref45', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/jmv.27064'},
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