{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:43:58Z","timestamp":1768513438920,"version":"3.49.0"},"reference-count":28,"publisher":"BMJ","issue":"12","license":[{"start":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T00:00:00Z","timestamp":1672358400000},"content-version":"unspecified","delay-in-days":29,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R01HD105492"],"award-info":[{"award-number":["R01HD105492"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Children who are HIV-exposed uninfected (HEU), that is, children who do not acquire HIV infection despite being born to mothers with HIV, have a higher risk of mortality, infectious morbidity and growth deficits than children who are HIV-unexposed uninfected (HUU). Prior research has focused on breast feeding and has pointed to changes in human milk oligosaccharides (HMOs) associated with maternal HIV that may influence the infant microbiome and thereby lead to these adverse outcomes. However, to our knowledge, no study has attempted to intervene along this pathway to reduce the occurrence of the adverse outcomes in children HEU. We will conduct a double-blind, randomised trial of a synbiotic intervention, which combines an HMO and probiotic, in breastfed infants HEU in South Africa to evaluate whether this intervention has promise to reduce excess infectious morbidity and growth faltering compared with controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and analysis<\/jats:title><jats:p>One hundred and forty-four breastfed infants HEU, aged 4 weeks, will be 1:1 randomised to receive either a daily synbiotic or an identical-looking placebo through age 24 weeks. Infants will be followed until age 48 weeks and outcomes of infectious morbidity, growth and biological measurements (eg, microbiota, inflammation and metabolome) will be assessed. Analyses will follow intention-to-treat principles comparing the cohorts as randomised. Infants HEU will be compared across arms with respect to the occurrence of infectious morbidity and growth outcomes through 4\u201324 weeks and 4\u201348 weeks using appropriate parametric and non-parametric statistical tests. Additionally, an observational cohort of 40 breastfed infants HUU will be recruited as a comparator group with no intervention.<\/jats:p><\/jats:sec><jats:sec><jats:title>Ethics and dissemination<\/jats:title><jats:p>Ethical approval for this study has been obtained from the ethics committees at Columbia University and Stellenbosch University. The findings will be disseminated in publications.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial registration number<\/jats:title><jats:p>ClinicalTrials.gov Identifier:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05282485\">NCT05282485<\/jats:ext-link>. SANCTR ID number: DOH-27-122021-6543.<\/jats:p><\/jats:sec>","DOI":"10.1136\/bmjopen-2022-069116","type":"journal-article","created":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T15:11:48Z","timestamp":1672413108000},"page":"e069116","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["Mitigating Infectious morbidity and Growth deficits in HIV-exposed uninfected infanTs with human Milk Oligosaccharide (MIGH-T MO): a randomised trial protocol"],"prefix":"10.1136","volume":"12","clinical-trial-number":[{"clinical-trial-number":"nct05282485","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2773-9310","authenticated-orcid":false,"given":"Rupak","family":"Shivakoti","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8046-9268","authenticated-orcid":false,"given":"Amy L","family":"Slogrove","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Laughton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mehr","family":"Shafiq","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisma","family":"Schoeman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard H","family":"Glashoff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng-Shiun","family":"Leu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lars","family":"Bode","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grace","family":"Aldrovandi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louise","family":"Kuhn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2022,12,30]]},"reference":[{"key":"2022123007101889000_12.12.e069116.1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00164"},{"key":"2022123007101889000_12.12.e069116.2","doi-asserted-by":"publisher","DOI":"10.1086\/498029"},{"key":"2022123007101889000_12.12.e069116.3","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jir019"},{"key":"2022123007101889000_12.12.e069116.4","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/S2352-4642(19)30023-9","article-title":"Fetal origins of postnatal growth faltering in HIV-exposed uninfected children","volume":"3","author":"Slogrove","year":"2019","journal-title":"Lancet Child Adolesc Health"},{"key":"2022123007101889000_12.12.e069116.5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3156.2009.02220.x"},{"key":"2022123007101889000_12.12.e069116.6","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(16)00055-4"},{"key":"2022123007101889000_12.12.e069116.7","unstructured":"Association of HIV infection with perinatal health outcomes among Indian women with and without LTBI. The 50th Union conference on lung health, 2019. Hyderababad, India"},{"key":"2022123007101889000_12.12.e069116.8","doi-asserted-by":"crossref","first-page":"e38","DOI":"10.1097\/INF.0000000000001391","article-title":"A prospective cohort study of common childhood infections in South African HIV-exposed uninfected and HIV-unexposed infants","volume":"36","author":"Slogrove","year":"2017","journal-title":"Pediatr Infect Dis J"},{"key":"2022123007101889000_12.12.e069116.9","doi-asserted-by":"crossref","unstructured":"Evans C , Chasekwa B , Ntozini R , et al . Mortality, HIV transmission and growth in children exposed to HIV in rural Zimbabwe. Clin Infect Dis 2020.doi:10.1093\/cid\/ciaa076","DOI":"10.1093\/cid\/ciaa076"},{"key":"2022123007101889000_12.12.e069116.10","doi-asserted-by":"crossref","first-page":"157","DOI":"10.3389\/fped.2018.00157","article-title":"Surviving and thriving-shifting the public health response to HIV-exposed uninfected children: report of the 3rd HIV-exposed uninfected child workshop","volume":"6","author":"Slogrove","year":"2018","journal-title":"Front Pediatr"},{"key":"2022123007101889000_12.12.e069116.11","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s11904-019-00459-0","article-title":"Growth and neurodevelopment of HIV-exposed uninfected children: a conceptual framework","volume":"16","author":"Wedderburn","year":"2019","journal-title":"Curr HIV\/AIDS Rep"},{"key":"2022123007101889000_12.12.e069116.12","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2016.00383","article-title":"The immune system of HIV-exposed uninfected infants","volume":"7","author":"Abu-Raya","year":"2016","journal-title":"Front Immunol"},{"key":"2022123007101889000_12.12.e069116.13","doi-asserted-by":"publisher","DOI":"10.3945\/ajcn.112.039503"},{"key":"2022123007101889000_12.12.e069116.14","doi-asserted-by":"publisher","DOI":"10.3945\/jn.114.199794"},{"key":"2022123007101889000_12.12.e069116.15","doi-asserted-by":"crossref","unstructured":"Bender JM , Li F , Martelly S , et al . Maternal HIV infection influences the microbiome of HIV-uninfected infants. Sci Transl Med 2016;8:ra100.doi:10.1126\/scitranslmed.aaf5103","DOI":"10.1126\/scitranslmed.aaf5103"},{"key":"2022123007101889000_12.12.e069116.16","unstructured":"Health SANDo . Primary Healthcare (PHC) Standard Treatment Guidelines and Essential Medicines List for South Africa - 2020, 2020. Available: https:\/\/www.knowledgehub.org.za\/elibrary\/primary-healthcare-phc-standard-treatment-guidelines-and-essential-medicines-list-south [Accessed 30 Sept 2022]."},{"key":"2022123007101889000_12.12.e069116.17","doi-asserted-by":"publisher","DOI":"10.1097\/MPG.0000000000001520"},{"key":"2022123007101889000_12.12.e069116.18","first-page":"1143","article-title":"Data centre profile: the provincial health data centre of the Western cape province, South Africa","volume":"4","author":"Boulle","year":"2019","journal-title":"Int J Popul Data Sci"},{"key":"2022123007101889000_12.12.e069116.19","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.cct.2015.06.013","article-title":"The futility study--progress over the last decade","volume":"45","author":"Levin","year":"2015","journal-title":"Contemp Clin Trials"},{"key":"2022123007101889000_12.12.e069116.20","doi-asserted-by":"crossref","first-page":"jn243857","DOI":"10.3945\/jn.116.243857","article-title":"Complementary feeding interventions have a small but significant impact on linear and Ponderal growth of children in low- and middle-income countries: a systematic review and meta-analysis","volume":"147","author":"Panjwani","year":"2017","journal-title":"J Nutr"},{"key":"2022123007101889000_12.12.e069116.21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0086928"},{"key":"2022123007101889000_12.12.e069116.22","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jix367"},{"key":"2022123007101889000_12.12.e069116.23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0158772"},{"key":"2022123007101889000_12.12.e069116.24","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiu238"},{"key":"2022123007101889000_12.12.e069116.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.annepidem.2016.03.004"},{"key":"2022123007101889000_12.12.e069116.26","doi-asserted-by":"publisher","DOI":"10.1038\/nature13421"},{"key":"2022123007101889000_12.12.e069116.27","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J R Stat Soc Series B"},{"key":"2022123007101889000_12.12.e069116.28","doi-asserted-by":"crossref","unstructured":"Rubin D . Multiple imputation for nonresponse in surveys. New York: John Wiley & Sons, Inc, 1987.","DOI":"10.1002\/9780470316696"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2022-069116","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T07:04:43Z","timestamp":1728630283000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2022-069116"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12]]},"references-count":28,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12,30]]},"published-print":{"date-parts":[[2022,12]]}},"alternative-id":["10.1136\/bmjopen-2022-069116"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2022-069116","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12]]}}}