Maternal vitamin D supplementation during pregnancy and lactation to prevent acute respiratory infections in infancy in Dhaka, Bangladesh (MDARI trial): protocol for a prospective cohort study nested within a randomized controlled trial

Shaun K Morris, Lisa G Pell, Mohammed Ziaur Rahman, Michelle C Dimitris, Abdullah Mahmud, M Munirul Islam, Tahmeed Ahmed, Eleanor Pullenayegum, Tahmid Kashem, Shaila S Shanta, Jonathan Gubbay, Eszter Papp, Michelle Science, Stanley Zlotkin, Daniel E Roth, Shaun K Morris, Lisa G Pell, Mohammed Ziaur Rahman, Michelle C Dimitris, Abdullah Mahmud, M Munirul Islam, Tahmeed Ahmed, Eleanor Pullenayegum, Tahmid Kashem, Shaila S Shanta, Jonathan Gubbay, Eszter Papp, Michelle Science, Stanley Zlotkin, Daniel E Roth

Abstract

Background: Early infancy is a high-risk period for severe acute respiratory infection (ARI), particularly in low-income countries with resource-limited health systems. Lower respiratory tract infection (LRTI) is commonly preceded by upper respiratory infection (URTI), and often caused by respiratory syncytial virus (RSV), influenza and other common community-acquired viral pathogens. Vitamin D status is a candidate modifiable early-life determinant of the host antiviral immune response and thus may influence the risk of ARI-associated morbidity in high-risk populations.

Methods/design: In the Maternal Vitamin D for Infant Growth (MDIG) study in Dhaka, Bangladesh (NCT01924013), 1300 pregnant women are randomized to one of five groups: placebo, 4200 IU/week, 16,800 IU/week, or 28,000 IU/week from 2nd trimester to delivery plus placebo from 0-6 months postpartum; or, 28,000 IU/week prenatal and until 6-months postpartum. In the Maternal Vitamin D for ARI in Infancy (MDARI) sub-study nested within the MDIG trial, trained personnel conduct weekly postnatal home visits to inquire about ARI symptoms and conduct a standardized clinical assessment. Supplementary home visits between surveillance visits are conducted when caregivers make phone notifications of new infant symptoms. Mid-turbinate nasal swab samples are obtained from infants who meet standardized clinical ARI criteria. Specimens are tested by polymerase chain reaction (PCR) for 8 viruses (influenza A/B, parainfluenza 1/2/3, RSV, adenovirus, and human metapneumovirus), and nasal carriage density of Streptococcus pneumoniae. The primary outcome is the incidence rate of microbiologically-positive viral ARI, using incidence rate ratios to estimate between-group differences. We hypothesize that among infants 0-6 months of age, the incidence of microbiologically-confirmed viral ARI will be significantly lower in infants whose mothers received high-dose prenatal/postpartum vitamin D supplements versus placebo. Secondary outcomes include incidence of ARI associated with specific pathogens (influenza A or B, RSV), clinical ARI, and density of pneumococcal carriage.

Discussion: If shown to reduce the risk of viral ARI in infancy, integration of maternal prenatal/postpartum vitamin D supplementation into antenatal care programs in South Asia may be a feasible primary preventive strategy to reduce the burden of ARI-associated morbidity and mortality in young infants.

Trial registration: NCT02388516 , registered March 9, 2015.

Keywords: Acute respiratory infection; Bangladesh; Infant; Influenza; Pneumonia; Pregnancy; Respiratory syncytial virus; Streptococcus pneumoniae; Vitamin D.

Figures

Fig. 1
Fig. 1
Maternal Vitamin D Acute Respiratory Infection (MDARI) trial flow diagram

References

    1. Liu L, et al. Global, regional, and national causes of child mortality in 2000–13, with projections to inform post-2015 priorities: an updated systematic analysis. Lancet. 2015;385(9966):430–440. doi: 10.1016/S0140-6736(14)61698-6.
    1. Muhe L, et al. Case–control study of the role of nutritional rickets in the risk of developing pneumonia in Ethiopian children. Lancet. 1997;349(9068):1801–1804. doi: 10.1016/S0140-6736(96)12098-5.
    1. Najada AS, Habashneh MS, Khader M. The frequency of nutritional rickets among hospitalized infants and its relation to respiratory diseases. J Trop Pediatr. 2004;50(6):364–368. doi: 10.1093/tropej/50.6.364.
    1. Siddiqui TS, Rai MI. Presentation and predisposing factors of nutritional rickets in children of Hazara Division. J Ayub Med Coll Abbottabad. 2005;17(3):29–32.
    1. White AN, et al. Let the sun shine in: effects of ultraviolet radiation on invasive pneumococcal disease risk in Philadelphia, Pennsylvania. BMC Infect Dis. 2009;9:196. doi: 10.1186/1471-2334-9-196.
    1. Hansdottir S, et al. Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. J Immunol. 2008;181(10):7090–7099. doi: 10.4049/jimmunol.181.10.7090.
    1. Hansdottir S, et al. Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state. J Immunol. 2010;184(2):965–974. doi: 10.4049/jimmunol.0902840.
    1. Gordon YJ, et al. Human cathelicidin (LL-37), a multifunctional peptide, is expressed by ocular surface epithelia and has potent antibacterial and antiviral activity. Curr Eye Res. 2005;30(5):385–394. doi: 10.1080/02713680590934111.
    1. Gordon YJ, et al. CAP37-derived antimicrobial peptides have in vitro antiviral activity against adenovirus and herpes simplex virus type 1. Curr Eye Res. 2009;34(3):241–249. doi: 10.1080/02713680802714066.
    1. Bergman P, et al. The antimicrobial peptide LL-37 inhibits HIV-1 replication. Curr HIV Res. 2007;5(4):410–415. doi: 10.2174/157016207781023947.
    1. Howell MD, et al. Selective killing of vaccinia virus by LL-37: implications for eczema vaccinatum. J Immunol. 2004;172(3):1763–1767. doi: 10.4049/jimmunol.172.3.1763.
    1. Sabetta JR, et al. Serum 25-hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults. PLoS One. 2010;5(6):e11088. doi: 10.1371/journal.pone.0011088.
    1. Ginde AA, Mansbach JM, Camargo CA., Jr Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the third national health and nutrition examination survey. Arch Intern Med. 2009;169(4):384–390. doi: 10.1001/archinternmed.2008.560.
    1. Berry DJ, et al. Vitamin D status has a linear association with seasonal infections and lung function in British adults. Br J Nutr. 2011;106(9):1433–1440. doi: 10.1017/S0007114511001991.
    1. Laaksi I, et al. An association of serum vitamin D concentrations < 40 nmol/L with acute respiratory tract infection in young Finnish men. Am J Clin Nutr. 2007;86(3):714–717.
    1. Wayse V, et al. Association of subclinical vitamin D deficiency with severe acute lower respiratory infection in Indian children under 5 y. Eur J Clin Nutr. 2004;58(4):563–567. doi: 10.1038/sj.ejcn.1601845.
    1. Karatekin G, et al. Association of subclinical vitamin D deficiency in newborns with acute lower respiratory infection and their mothers. Eur J Clin Nutr. 2009;63(4):473–477. doi: 10.1038/sj.ejcn.1602960.
    1. McNally JD, et al. Vitamin D deficiency in young children with severe acute lower respiratory infection. Pediatr Pulmonol. 2009;44(10):981–988. doi: 10.1002/ppul.21089.
    1. Roth DE, et al. Vitamin D status and acute lower respiratory infection in early childhood in Sylhet, Bangladesh. Acta Paediatr. 2010;99(3):389–393. doi: 10.1111/j.1651-2227.2009.01594.x.
    1. Roth DE, et al. Vitamin D status is not associated with the risk of hospitalization for acute bronchiolitis in early childhood. Eur J Clin Nutr. 2009;63(2):297–299. doi: 10.1038/sj.ejcn.1602946.
    1. Science M, et al. Low serum 25-hydroxyvitamin D level and risk of upper respiratory tract infection in children and adolescents. Clin Infect Dis. 2013;57(3):392–397. doi: 10.1093/cid/cit289.
    1. Urashima M, et al. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr. 2010;91(5):1255–1260. doi: 10.3945/ajcn.2009.29094.
    1. Camargo CA, Jr, et al. Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia. Pediatrics. 2012;130(3):e561–e567. doi: 10.1542/peds.2011-3029.
    1. Manaseki-Holland S, et al. Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: a randomised controlled superiority trial. Lancet. 2012;379(9824):1419–1427. doi: 10.1016/S0140-6736(11)61650-4.
    1. Goldring ST, et al. Prenatal vitamin d supplementation and child respiratory health: a randomised controlled trial. PLoS One. 2013;8(6):e66627. doi: 10.1371/journal.pone.0066627.
    1. Palacios, C. and L. Gonzalez, Is vitamin D deficiency a major global public health problem? J Steroid Biochem Mol Biol. 2014;144 Pt A: p. 138–45.
    1. Homaira N, et al. Incidence of respiratory virus-associated pneumonia in urban poor young children of Dhaka, Bangladesh, 2009–2011. PLoS One. 2012;7(2):e32056. doi: 10.1371/journal.pone.0032056.
    1. Nasreen S, et al. Population-based incidence of severe acute respiratory virus infections among children aged <5 years in rural Bangladesh, June-October 2010. PLoS One. 2014;9(2):e89978. doi: 10.1371/journal.pone.0089978.
    1. Roth DE, et al. Randomized placebo-controlled trial of high-dose prenatal third-trimester vitamin D3 supplementation in Bangladesh: the AViDD trial. Nutr J. 2013;12:47. doi: 10.1186/1475-2891-12-47.
    1. Roth DE, et al. Maternal vitamin D supplementation during pregnancy and lactation to promote infant growth in Dhaka, Bangladesh (MDIG trial): study protocol for a randomized controlled trial. Trials. 2015;16:300. doi: 10.1186/s13063-015-0825-8.
    1. Ross AC, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96(1):53–58. doi: 10.1210/jc.2010-2704.
    1. Loeffelholz MJ, et al. Duration of rhinovirus shedding in the upper respiratory tract in the first year of life. Pediatrics. 2014;134(6):1144–1150. doi: 10.1542/peds.2014-2132.
    1. Munywoki PK, et al. Influence of age, severity of infection, and co-infection on the duration of respiratory syncytial virus (RSV) shedding. Epidemiol Infect. 2015;143(4):804–812. doi: 10.1017/S0950268814001393.
    1. Loeb M, et al. Longitudinal study of influenza molecular viral shedding in Hutterite communities. J Infect Dis. 2012;206(7):1078–1084. doi: 10.1093/infdis/jis450.
    1. World Health Organization . Integrated management of childhood illness: chart booklet. 2014.
    1. Edwards KM, et al. Burden of human metapneumovirus infection in young children. N Engl J Med. 2013;368(7):633–643. doi: 10.1056/NEJMoa1204630.
    1. Poehling KA, et al. The underrecognized burden of influenza in young children. N Engl J Med. 2006;355(1):31–40. doi: 10.1056/NEJMoa054869.
    1. Hall CB, et al. The burden of respiratory syncytial virus infection in young children. N Engl J Med. 2009;360(6):588–598. doi: 10.1056/NEJMoa0804877.
    1. Weinberg GA, et al. Field evaluation of TaqMan array card (TAC) for the simultaneous detection of multiple respiratory viruses in children with acute respiratory infection. J Clin Virol. 2013;57(3):254–260. doi: 10.1016/j.jcv.2013.03.016.
    1. Bauer P, et al. Testing strategies in multi-dose experiments including active control. Stat Med. 1998;17(18):2133–2146. doi: 10.1002/(SICI)1097-0258(19980930)17:18<2133::AID-SIM901>;2-2.
    1. Lipsitz SR, Parzen M. A jackknife estimator of variance for Cox regression for correlated survival data. Biometrics. 1996;52(1):291–298. doi: 10.2307/2533164.

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