Neonatal vitamin A supplementation associated with a cluster of deaths and poor early growth in a randomised trial among low-birth-weight boys of vitamin A versus oral polio vaccine at birth

Najaaraq Lund, Sofie Biering-Sørensen, Andreas Andersen, Ivan Monteiro, Luis Camala, Mathias Jul Jørgensen, Peter Aaby, Christine Stabell Benn, Najaaraq Lund, Sofie Biering-Sørensen, Andreas Andersen, Ivan Monteiro, Luis Camala, Mathias Jul Jørgensen, Peter Aaby, Christine Stabell Benn

Abstract

Background: The effect of oral polio vaccine administered already at birth (OPV0) on child survival was not examined before being recommended in 1985. Observational data suggested that OPV0 was harmful for boys, and trials have shown that neonatal vitamin A supplementation (NVAS) at birth may be beneficial for boys. We set out to test this research question in a randomised trial.

Methods: The trial was carried out at the Bandim Health Project, Guinea-Bissau. We planned to enrol 900 low-birth weight (LBW) boys in a randomised trial to investigate whether NVAS instead of OPV0 could lower infant mortality for LBW boys. At birth, the children were randomised to OPV (usual treatment) or VAS (intervention treatment) and followed for 6 months for growth and 12 months for survival. Hazard Ratios (HR) for mortality were calculated using Cox regression. We compared the individual anthropometry measurements to the 2006 WHO growth reference. We compared differences in z-scores by linear regression. Relative risks (RR) of being stunted or underweight were calculated in Poisson regression models with robust standard errors.

Results: In the rainy season we detected a cluster of deaths in the VAS group and the trial was halted immediately with 232 boys enrolled. The VAS group had significantly higher mortality than the OPV0 group in the rainy season (HR: 9.91 (1.23 - 80)). All deaths had had contact with the neonatal nursery; of seven VAS boys enrolled during one week in September, six died within two months of age, whereas only one died among the six boys receiving OPV (p = 0.05). Growth (weight and arm-circumference) in the VAS group was significantly worse until age 3 months.

Conclusion: VAS at birth instead of OPV was not beneficial for the LBW boys in this study. With the premature closure of the trial it was not possible to answer the research question. However, the results of this study call for extra caution when testing the effect of NVAS in the future.

Trial registration: http://www.clinicaltrials.gov NCT00625482. Registered 18 February 2008.

Figures

Figure 1
Figure 1
Trial profile.
Figure 2
Figure 2
Cumulative mortality curves as a function of receiving VAS or OPV. (a) Overall, (b) Dry season, (c) Rainy season.

References

    1. Benn CS, Diness BR, Roth A, Nante E, Fisker AB, Lisse IM, Yazdanbakhsh M, Whittle H, Rodrigues A, Aaby A. Effect of 50,000 IU vitamin A given with BCG vaccine on mortality in infants in Guinea-Bissau: randomised placebo controlled trial. BMJ. 2008;336:1416–1420.
    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 randomised controlled trial. BMJ. 2010;340:c1101.
    1. West KP, 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 randomized, double-masked trial in Nepal. Am J Clin Nutr. 1995;62:143–148.
    1. Malaba LC, Iliff PJ, Nathoo KJ, Marinda E, Moulton LH, Zijenah LS, Zvandasara P, Ward BJ, Humphrey JH. the 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;81:454–460.
    1. Humphrey JH, Iliff PJ, Marinda ET, Mutasa K, Moulton LH, Chidawanyika H, Ward BJ, Nathoo KJ, Malaba LC, Zijenah LS, Zvandasara P, Ntozini R, Mzengeza F, Mahomva AI, Ruff AJ, Mbizvo MT, Zunguza CD. Effects of a single large dose of vitamin A, given during the postpartum period to HIV-positive women and their infants, on child HIV infection, HIV-free survival, and mortality. J Infect Dis. 2006;193:860.
    1. Humphrey JHA. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr. 1996;128:489–496.
    1. Klemm RDW, Labrique AB, Christian P, Rashid M, Shamim AA, Katz J, Sommer A, West KP. Newborn vitamin A supplementation reduced infant mortality in rural Bangladesh. Pediatrics. 2008;122:e242.
    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.
    1. Bhaskaram P, Nair KM, Hemalatha P, Murthy N, Nair P. Systemic and mucosal immune response to polio vaccination with additional dose in newborn period. J Trop Pediatr. 1997;43:232–234.
    1. Dong DX, Hu XM, Liu WJ, Li JS, Jin YC, Tan SG, Chen TQ, Fu JZ, Niu BY, Yu HM. Immunization of neonates with trivalent oral poliomyelitis vaccine (Sabin) Bull World Health Organ. 1986;64:853–860.
    1. John TJ. Immune response of neonates to oral poliomyelitis vaccine. BMJ (Clinical Res ed) 1984;289:881.
    1. Khare S, Kumari S, Nagpal IS, Sharma D, Verghese T. Oral polio vaccination in infants: beneficial effect of additional dose at birth. Indian J Pediatr. 1993;2:275–281.
    1. Weckx LY, Schmidt BJ, Herrmann AA, Miyasaki CH, Novo NF. Early immunization of neonates with trivalent oral poliovirus vaccine. Bull World Health Organ. 1992;70:85–91.
    1. Benn CS, Fisker AB, Rodrigues A, Ravn H, Sartono E, Whittle H, Yazdanbakhsh M, Aaby P. Sex-differential effect on infant mortality of oral polio vaccine administered with BCG at birth in Guinea-Bissau. A natural experiment. PLoS ONE. 2008;3:e4056.
    1. Sartono E, Lisse IM, Terveer EM, van de Sande PJM, Whittle H, Fisker AB, Roth A, Aaby P, Yazdanbakhsh M, Benn CS. Oral polio vaccine influences the immune response to BCG vaccination. A natural experiment. PLoS ONE. 2010;5:e10328.
    1. Ballard JL, Khoury JC, Wedig K, Wang L, Eilers-Walsman BL, Lipp R. New Ballard Score, expanded to include extremely premature infants. J Pediatr. 1991;119:417–423.
    1. WHO Multicentre Growth Reference Study Group. “WHO child growth standards: length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age,” Methods and Development. Geneva: World Health Organization; 2006. p. 312.
    1. Barros AJ, Hirakata VN. Alternatives for logistic regression in cross-sectional studies: an empirical comparison of models that directly estimate the prevalence ratio. BMC Med Res Methodol. 2003;3:21.
    1. Fisker AB, Benn CS, Diness BR, Martins C, Rodrigues A, Aaby P, Bibby BM. The effect of 50 000 IU vitamin A with BCG vaccine at birth on growth in the first year of life. J Trop Med. 2011;2011:570170.
    1. Humphrey JH, Agoestina T, Juliana A, Septiana S, Widjaja H, Cerreto MC, Wu LS, Ichord RN, Katz J, West KP. Neonatal vitamin A supplementation: effect on development and growth at 3 y of age. Am J Clin Nutr. 1998;68:109–117.
    1. Hadi H, Dibley MJ, West KP. Complex interactions with infection and diet may explain seasonal growth responses to vitamin A in preschool aged Indonesian children. Eur J Clin Nutr. 2004;58:990–999.
    1. Aaby P, Whittle HC, Benn CS. Vaccine programmes must consider their effect on general resistance. BMJ. 2012;344:e3769.
    1. Kirkwood B, Humphrey J, Moulton L, Martines J. Neonatal vitamin A supplementation and infant survival. Lancet. 2012;376:1643.
    1. Yakymenko D, Benn CS, Martins C, Diness BR, Fisker AB, Rodrigues A, Aaby P. The impact of different doses of vitamin A supplementation on male and female mortality. A randomised trial from Guinea-Bissau. BMC Pediatr. 2011;1:77.
    1. Aaby P, Rodrigues A, Biai S, Martins C, Veirum JE, Benn CS, Jensen H. Oral polio vaccination and low case fatality at the paediatric ward in Bissau, Guinea-Bissau. Vaccine. 2004;22:3014–3017.
    1. Aaby P, Hedegaard K, Sodemann M, Nhante E, Veirum JE, Jakobsen M, Lisse I, Jensen H, Sandstrom A. Childhood mortality after oral polio immunisation campaign in Guinea-Bissau. Vaccine. 2005;23:1746–1751.
    1. Contreras G. Effect of the administration of oral poliovirus vaccine on infantile diarrhoea mortality. Vaccine. 1989;7:211–212.
    1. Contreras G. Sabin’s vaccine used for nonspecific prevention of infant diarrhea of viral etiology. Bull Pan Am Health Organ. 1974;8:123–132.
    1. Seppälä E, Viskari H, Hoppu S, Honkanen H, Huhtala H, Simell O, Ilonen J, Knip M, Hyöty H. Viral interference induced by live attenuated virus vaccine (OPV) can prevent otitis media. Vaccine. 2011;29:8615–8618.
    1. Hafler DA, Fox DA, Benjamin D, Blue ML, Weiner HL. Secondary immune amplification following live poliovirus immunization in humans. Clin Immunol Immunopathol. 1987;44:321–328.
    1. Rook GAW, Stanford JL. Give us this day our daily germs. Immunol Today. 1998;19:113–116.
    1. Ryan M, Murphy G, Ryan E, Nilsson L, Shackley F, Gothefors L, Oymar K, Miller E, Storsaeter J, Mills KH. Distinct T-cell subtypes induced with whole cell and acellular pertussis vaccines in children. Immunology. 1998;93:1–10.
    1. Abrams SA, Hilmers DC. Postnatal vitamin A supplementation in developing countries: an intervention whose time has come? Pediatrics. 2008;122:180–181.
    1. Benn CS, Whittle H, Fisker A, Aaby P. Neonatal vitamin A supplementation in South Asia: rapid implementation or understanding the variation? BMJ Rapid Responses. 2008;336:7658.
    1. Benn CS, Fisker AB, Jørgensen MJ, Aaby P. Conflicting evidence for neonatal vitamin A supplementation. Vaccine. 2008;26:4111.
    1. Benn CS, Rodrigues A, Yazdanbakhsh M, Fisker AB, Ravn H, Whittle H, Aaby P. The effect of high-dose vitamin A supplementation administered with BCG vaccine at birth may be modified by subsequent DTP vaccination. Vaccine. 2009;27:2891–2898.
    1. Bhutta Z, Ahmed T, Black R, Cousens S, Dewey K, Giugliani E, Haider B, Kirkwood B, Morris S, Sachdev H, Shekar M. What works? Interventions for maternal and child undernutrition and survival. Lancet. 2008;371:417–440.
    1. Tielsch JM. Vitamin A supplements in newborns and child survival. BMJ. 2008;336:1385–1386.
    1. West K, Jr, Sommer A. Newborn vitamin A dosing: Policy implications for Southern Asia and Africa. Istanbul, Turkey: Abstract presented at 1st Micronutrient Forum Meeting; 2007.
    1. Mutua M, Kimani-Murage E, Ettarh R. Childhood vaccination in informal urban settlements in Nairobi, Kenya: Who gets vaccinated? BMC Public Health. 2011;11:6.
    1. Global Polio Eradication Initiative Strategic Plan 2010–2012. [ ]
    1. Mullooly JP, Schuler R, Mesa J, Drew L, DeStefano F. Wheezing lower respiratory disease and vaccination of premature infants. Vaccine. 2011;29:7611–7617.
    1. Aaby P, Garly ML, Nielsen J, Ravn H, Martins C, Balé C, Rodrigues A, Benn CS, Lisse IM. Increased female–male mortality ratio associated with inactivated polio and diphtheria-tetanus-pertussis vaccines: Observations from vaccination trials in Guinea-Bissau. Pediatr Infect Dis J. 2007;26:247.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅