A randomized synbiotic trial to prevent sepsis among infants in rural India

A Corrigendum to this article was published on 29 November 2017

This article has been updated

Abstract

Sepsis in early infancy results in one million annual deaths worldwide, most of them in developing countries. No efficient means of prevention is currently available. Here we report on a randomized, double-blind, placebo-controlled trial of an oral synbiotic preparation (Lactobacillus plantarum plus fructooligosaccharide) in rural Indian newborns. We enrolled 4,556 infants that were at least 2,000 g at birth, at least 35 weeks of gestation, and with no signs of sepsis or other morbidity, and monitored them for 60 days. We show a significant reduction in the primary outcome (combination of sepsis and death) in the treatment arm (risk ratio 0.60, 95% confidence interval 0.48–0.74), with few deaths (4 placebo, 6 synbiotic). Significant reductions were also observed for culture-positive and culture-negative sepsis and lower respiratory tract infections. These findings suggest that a large proportion of neonatal sepsis in developing countries could be effectively prevented using a synbiotic containing L. plantarum ATCC-202195.

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Figure 1: Screening and enrolment of study infants in the sepsis trial.

Change history

  • 30 November 2017

    Please see accompanying Corrigendum (http://doi.org/10.1038/nature25006). In this Article, the statement ‘There were 88 culture-positive and 94 culture-negative cases’ has been corrected to ‘Apart from 88 cases of suspect sepsis that included both culture-negative and culture-positive infants, there were an additional 94 culture-negative cases’.

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Acknowledgements

We are thankful to the Indian Council of Medical Research and the Ministry of Health and Family Welfare Government of India for their review and timely clearance. The Government of Odisha, Department of Health and Family Welfare provided necessary approvals and directives at the block level for implementation of the project in the hospitals and the community setting. We are grateful to the Director of Capital Hospital, Bhubaneswar, and Ispat General Hospital for providing dedicated clinical research space and laboratory space to set up the Bactec blood culture, microbiology, and data management facilities. Our gratitude to Dayananda Das (now deceased) of Jana Sikshan Sansthan for his management skills and each of the >200 members in the three-tier community intervention team. K. Pradhan and K. Mishra deserve thanks for managing the study in the two districts. Our thanks to the DSMB members for reviewing all serious adverse events and convening yearly in person for further review of compiled data and providing valuable insights. This study could not have been possible without the unconditional support of the parents of the newborns born in the study districts and the physicians, nurse-midwives, and Anganwadi workers of the government system who provided assistance throughout the conduct of the study. This study was funded by grants U01 HD 40574 and R01 HD 53719 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, USA.

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Contributions

P.P. and I.G. conceived the study and P.P. wrote the first draft. P.P., S.N.P., I.G., N.P. and J.G.M. designed the study with help from the other authors. N.N., R.S., L.P. and A.M. were responsible for clinical operations. S.S.M. managed the field activities. J.J. and R.C. were in charge of developing microbiology protocols and standard operating procedures. R.C. was in charge of the reference laboratory and supervised the final strain designation of blood isolates. H.C. and L.B. conducted the data management and statistical analyses. D.C. managed the protocol from the principal investigator’s laboratory and handled data acquisition, microbiology quality assurance, and institutional review board matters. All authors contributed in writing different sections of the manuscripts.

Corresponding author

Correspondence to Pinaki Panigrahi.

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Competing interests

Following institutional procedures for federally funded grants, a new invention disclosure on the use of a combination of L. plantarum and fructooligosaccharides against infection and inflammation was made to the UNMC office of technology transfer (UNeMed). UNeMed, upon its decision not to pursue the invention, has released the rights to the inventor (P.P.). A PCT patent application has been filed (pending examination) and assigned to the Asian Institute of Public Health. None of the authors, including P.P., has any financial or management interest with any commercial entity.

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Reviewer Information Nature thanks R. Feng, T. Kollmann, D. J. Tancredi and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Figure 1 Site maps.

Location of study sites in Odisha, India. Source: India and Odisha state maps, redrawn to show the geographic location of study sites. Reproduced with permission from ref. 51.

Extended Data Figure 2 Site structure.

Three-tier structure for field operations and implementation of the clinical trial in the community. Reproduced with permission from ref. 51.

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Panigrahi, P., Parida, S., Nanda, N. et al. A randomized synbiotic trial to prevent sepsis among infants in rural India. Nature 548, 407–412 (2017). https://doi.org/10.1038/nature23480

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