Efficacy of early neonatal vitamin A supplementation in reducing mortality during infancy in Ghana, India and Tanzania: study protocol for a randomized controlled trial

NEOVITA Study Author Group, Rajiv Bahl, Nita Bhandari, Brinda Dube, Karen Edmond, Wafaie Fawzi, Olivier Fontaine, Jasmine Kaur, Betty R Kirkwood, Jose Martines, Honorati Masanja, Sarmila Mazumder, Salum Msham, Sam Newton, Maureen Oleary, Julia Ruben, Caitlin Shannon, Emily Smith, Sunita Taneja, Sachiyo Yoshida, Lisa Hurt, Thomas Gyan, Charlotte Tawiah, Seeba Amenga-Etego, Lu Gram, Seth Owusu Agyei, R C Agarwal, Amarnath Mehrotra, Anuraj Shankar, Nilupa Gunaratna, Said Aboud, Rodrick Kisenge, Alfa Muhihi, Christina Briegleb, Ramadhani Abdallah Noor, NEOVITA Study Author Group, Rajiv Bahl, Nita Bhandari, Brinda Dube, Karen Edmond, Wafaie Fawzi, Olivier Fontaine, Jasmine Kaur, Betty R Kirkwood, Jose Martines, Honorati Masanja, Sarmila Mazumder, Salum Msham, Sam Newton, Maureen Oleary, Julia Ruben, Caitlin Shannon, Emily Smith, Sunita Taneja, Sachiyo Yoshida, Lisa Hurt, Thomas Gyan, Charlotte Tawiah, Seeba Amenga-Etego, Lu Gram, Seth Owusu Agyei, R C Agarwal, Amarnath Mehrotra, Anuraj Shankar, Nilupa Gunaratna, Said Aboud, Rodrick Kisenge, Alfa Muhihi, Christina Briegleb, Ramadhani Abdallah Noor

Abstract

Background: Vitamin A supplementation of 6-59 month old children is currently recommended by the World Health Organization based on evidence that it reduces mortality. There has been considerable interest in determining the benefits of neonatal vitamin A supplementation, but the results of existing trials are conflicting. A technical consultation convened by WHO pointed to the need for larger scale studies in Asia and Africa to inform global policy on the use of neonatal vitamin A supplementation. Three trials were therefore initiated in Ghana, India and Tanzania to determine if vitamin A supplementation (50,000 IU) given to neonates once orally on the day of birth or within the next two days will reduce mortality in the period from supplementation to 6 months of age compared to placebo.

Methods/design: The trials are individually randomized, double masked, and placebo controlled. The required sample size is 40,200 in India and 32,000 each in Ghana and Tanzania. The study participants are neonates who fulfil age eligibility, whose families are likely to stay in the study area for the next 6 months, who are able to feed orally, and whose parent(s) provide informed written consent to participate in the study. Neonates randomized to the intervention group receive 50,000 IU vitamin A and the ones randomized to the control group receive placebo at the time of enrollment. Mortality and morbidity information are collected through periodic home visits by a study worker during infancy. The primary outcome of the study is mortality from supplementation to 6 months of age. The secondary outcome of the study is mortality from supplementation to 12 months of age. The three studies will be analysed independent of each other. Subgroup analysis will be carried out to determine the effect by birth weight, sex, and timing of DTP vaccine, socioeconomic groups and maternal large-dose vitamin A supplementation.

Discussion: The three ongoing studies are the largest studies evaluating the efficacy of vitamin A supplementation to neonates. Policy formulation will be based on the results of efficacy of the intervention from the ongoing randomized controlled trials combined with results of previous studies.

Trial registration: ClinicalTrials.gov NCT01138449.

Figures

Figure 1
Figure 1
Outline of implementation strategy common to the three studies.
Figure 2
Figure 2
Structure of the study flow chart.

References

    1. Black R, Allen LH, Bhutta ZA, Caulfield LE, de Onis M, Ezzati M, Mathers C, Rivera J. Maternal and Child Undernutrition Study Group. Maternal and Child undernutrition: global and regional exposures and health consequences. Lancet. 2008;371:5–22. doi: 10.1016/S0140-6736(08)60044-6.
    1. WHO. Global prevalence of vitamin A deficiency in populations at risk 1995-2005: WHO global database on vitamin A deficiency. Geneva: World Health Organization; 2009.
    1. Beaton GH, Martorell R, Aronson KJ. ACC/SCN State-of-the-Art Series Policy Discussion Paper No 13. Geneva: World Health Organization; 1993. Effectiveness of vitamin A supplementation in the control of young child morbidity and mortality in developing countries.
    1. Glasizou PP, Mackerras DE. Vitamin A supplementation in infectious diseases: A meta-analysis. BMJ. 1993;306:366–70. doi: 10.1136/bmj.306.6874.366.
    1. Fawzi WW, Chalmers TC, Herrera MG, Mosteller F. Vitamin A supplementation and child mortality. A meta-analysis. JAMA. 1993;269:898–903. doi: 10.1001/jama.1993.03500070078033.
    1. WHO/CHD Immunisation-Linked Vitamin, A Supplementation Study Group. Randomised trial to assess benefits and safety of vitamin A supplementation linked to immunisation in early infancy. Lancet. 1998;352:1257–63.
    1. West KP Jr, Katz J, Shrestha SR, LeClerq SC, Khatry SK, Pradhan EK, Adhikari R, Wu LS, Pokhrel RP, Sommer A. Mortality of infants < 6 mo of age supplemented with vitamin A: a randomised, double-masked trial in Nepal. Am J Clin Nutr. 1995;62:143–8.
    1. Idindili B, Masanja H, Urassa H, Bunini W, van Jaarsveld P, Aponte JJ, Kahigwa E, Mshinda H, Ross D, Schellenberg DM. Randomised controlled safety and efficacy trial of 2 vitamin A supplementation schedules in Tanzanian infants. Am J Clin Nutr. 2007;85:1312–9.
    1. Darboe MK, Thurnham DI, Morgan G, Adegbola RA, Secka O, Solon JA, Jackson SJ, Northrop-Clewes C, Fulford TJ, Doherty CP, Prentice AM. Effectiveness of an early supplementation scheme of high-dose vitamin A versus standard WHO protocol in Gambian mothers and infants: a randomised controlled trial. Lancet. 2007;369:2088–96. doi: 10.1016/S0140-6736(07)60981-7.
    1. Humphrey JH, Agoestina T, Wu L, Usman A, Nurachim M, Subardja D, Hidayat S, Tielsch J, West KP Jr, Sommer A. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr. 1996;128:489–96. doi: 10.1016/S0022-3476(96)70359-1.
    1. Klemm RD, Labrique AB, Christian P, Rashid M, Shamim AA, Katz J, Sommer A, West KP Jr. Newborn vitamin A supplementation reduced infant mortality in rural Bangladesh. Pediatrics. 2008;122:e242–50. doi: 10.1542/peds.2007-3448.
    1. Rahmathullah L, Tielsch JM, Thulasiraj RD, Katz J, Coles C, Devi S, John R, Prakash K, Sadanand AV, Edwin N, Kamaraj C. Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomised trial in southern India. BMJ. 2003;327:254. doi: 10.1136/bmj.327.7409.254.
    1. Benn CS, Diness BR, Roth A, Nante E, Fisker AB, Lisse IM, Yazdanbakhsh M, Whittle H, Rodrigues A, Aaby P. Effect of 50,000 IU vitamin A given with BCG vaccine on mortality in infants in Guinea-Bissau: randomised placebo controlled trial. BMJ. 2008;336:1416–20. doi: 10.1136/.
    1. Malaba LC, Iliff PJ, Nathoo KJ, Marinda E, Moulton LH, Zijenah LS, Zvandasara P, Ward BJ, Humphrey JH. ZVITAMBO Study Group. Effect of postpartum maternal or neonatal vitamin A supplementation on infant mortality among infants born to HIV-negative mothers in Zimbabwe. Am J Clin Nutr. 2005;81:454–60.
    1. Gogia S, Sachdev HPS. Neonatal vitamin A supplementation for prevention of mortality and morbidity in infancy: systematic review of randomized controlled trials. BMJ. 2009;338:b919. doi: 10.1136/bmj.b919.
    1. Bhutta ZA, Haider BA, Cousens S, Kirkwood BR, Black RE. Neonatal vitamin A supplementation and infant survival in Asia. Lancet. 2008;371:1746–1748.
    1. Benn CS, Fisker AB, Napirna BM, Roth A, Diness BR, Lausch KR, Ravn H, Yazdanbakhsh M, Rodrigues A, Whittle H, Aaby P. Vitamin A supplementation and BCG vaccination at birth in low birthweight neonates: two by two factorial randomized controlled trial. BMJ. 2010;340:c1101. doi: 10.1136/bmj.c1101.
    1. Kirkwood B, Humphrey J, Moulton L, Martines J. Neonatal vitamin A supplementation and infant survival. Lancet. 2010;376:1643–4.
    1. Kirkwood BR, Hurt L, Etego SA, Tawiah C, Zandoh C, Danso S, Hurt C, Edmond K, Hill Z, ten Asbroek G, Fenty J, Owusu-Agyei S, Campbell O. for the ObaapaVitA Trial Team. Meeting the millennium development goals for maternal and child survival: Does vitamin A supplementation of women of reproductive age have a role to play? Findings of the "Obaapavita" cluster randomised trial in Ghana. Lancet. 2010;375:1640–9. doi: 10.1016/S0140-6736(10)60311-X.
    1. Newton S, Filteau S, Owusu-Agyei S, Ampofo W, Kirkwood BR. Seroprotection associated with infant vitamin A supplementation given with vaccines is not related to antibody affinity to Hepatitis B and Haemophilus influenzae type b vaccines. Vaccine. 2010;28:4738–41. doi: 10.1016/j.vaccine.2010.05.001.
    1. Cox SE, Staalsoe T, Arthur P, Bulmer JN, Tagbor H, Hviid L, Frost C, Riley EM, Kirkwood BR. Maternal vitamin A supplementation and immunity to malaria in pregnancy in Ghanaian primigravids. Trop Med Int Health. 2005;10:1286–97. doi: 10.1111/j.1365-3156.2005.01515.x.
    1. National Aids Control Organisation, Ministry of Health and Family Welfare Government of India. HIV Sentinel Surveillance and HIV Estimation in India 2007. A Technical Brief. New Delhi: Government of India; 2008. Available at .
    1. Anand K, Lakshmy R, Janakarajan VN, Ritvik A, Misra P, Pandey RM, Kapoor SK, Sankar R, Bulusu S. Effect of consumption of micronutrient fortified candies on the iron and vitamin A status of children aged 3-6 years in rural Haryana. Indian Pediatr. 2007;44:823–9.
    1. DWCD. Vitamin A deficiency.
    1. International Institute of Population Sciences (IIPS) and Macro International. National Family Health Survey (NFHS-3), 2005-2006: India. Mumbai: IIPS; 2007.
    1. Bhandari N, Mazumder S, Bahl R, Martines J, Black RE, Bhan MK. An Educational Intervention to Promote Appropriate Complementary Feeding Improves Child Feeding Practices and Linear Growth in Rural Haryana, India. J Nutr. 2004;134:2342–2348.
    1. National Bureau of Statistics (NBS) [Tanzania] and ORC Macro. Tanzania Demographic and Health Survey 2004-05. Dar es Salaam, Tanzania: National Bureau of Statistics and ORC Macro; 2005.
    1. Assmann SF, Pocock SJ, Enos LE, Kasten LE. Subgroup analysis and other (mis) uses of baseline data in clinical trials. Lancet. 2000;355:1064–69. doi: 10.1016/S0140-6736(00)02039-0.
    1. Ioannidis JP, Evans SJ, Gøtzsche PC, O'Neill RT, Altman DG, Schulz K, Moher D. CONSORT Group. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med. 2004;141:781–8.
    1. O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35:549–56. doi: 10.2307/2530245.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅