Pre-delivery administration of azithromycin to prevent neonatal sepsis and death: a phase iii double-blind randomized clinical trial (PregnAnZI-2 trial)
Background: Despite reduction in the risk of under-5 mortality in the last decade and a half, neonatal deaths have remained stable globally. Gram-positive bacterial infections are leading causes of neonatal sepsis and death. Because the mother is an important source for bacterial transmission to babies during the perinatal period, interventions that lower risk of transmission can potentially reduce invasive bacterial infections. The primary objective of the trial will assess the effect of intrapartum azithromycin on neonatal sepsis and mortality. Secondary objectives include the impact of the intervention on prevalence of carriage and resistance, puerperal infections, and infant growth.
Methods: This is a phase III, double-blinded, placebo-controlled randomized trial in which 12,000 women in labour are randomized to either a single dose of 2 g of oral azithromycin (AZI) or placebo in The Gambia and Burkina Faso. Mother/newborn pairs are followed-up at 28-days post-delivery to assess health and mortality. Passive visits are conducted to collect adverse events including hospitalizations. When clinically indicated, samples are collected for assessment of neonatal and puerperal sepsis. A cohort of 250 mother/newborn pair per country have been included in the carriage sub-study to assess bacterial colonization at day 0, 6, 28 and 4 months. Children of the first 1000 mothers recruited in each country are followed-up at 6 and 12 months for anthropometric assessments.
Conclusions: If successful, this simple implementable intervention has the potential to achieve wide coverage in Sub-Saharan Africa (SSA) where low-cost interventions to reduce neonatal sepsis and mortality and morbidity in mothers are urgently needed.
Trial registration: The trial was registered at ClinicalTrials.gov: NCT03199547.
Lawn JE, Blencowe H, Oza S, You D, Lee AC, Waiswa P, et al. Every Newborn: progress, priorities, and potential beyond survival. Lancet. 2014;384(9938):189-205.
Seale AC, Mwaniki M, Newton CR, Berkley JA. Maternal and early onset neonatal bacterial sepsis: burden and strategies for prevention in sub-Saharan Africa. Lancet Infect Dis. 2009;9(7):428-38.
Okomo U, Akpalu ENK, Le DK, Roca A, Cousens S, Jarde A, et al. Aetiology of invasive bacterial infection and antimicrobial resistance in neonates in sub-Saharan Africa: a systematic review and meta-analysis in line with the STROBE-NI reporting guidelines. Lancet Infect Dis. 2019;19(11):1219-34.
Drew RH, Gallis HA. Azithromycin--spectrum of activity, pharmacokinetics, and clinical applications. Pharmacotherapy. 1992;12(3):161-73.
Fry AM, Jha HC, Lietman TM, Chaudhary JS, Bhatta RC, Elliott J, et al. Adverse and beneficial secondary effects of mass treatment with azithromycin to eliminate blindness due to trachoma in Nepal. Clin Infect Dis. 2002;35(4):395-402.
Leach AJ, Shelby-James TM, Mayo M, Gratten M, Laming AC, Currie BJ, et al. A prospective study of the impact of community-based azithromycin treatment of trachoma on carriage and resistance of Streptococcus pneumoniae. Clin Infect Dis. 1997;24(3):356-62.
Harding-Esch EM, Edwards T, Mkocha H, Munoz B, Holland MJ, Burr SE, et al. Trachoma prevalence and associated risk factors in the gambia and Tanzania: baseline results of a cluster randomised controlled trial. PLoS Negl Trop Dis. 2010;4(11):e861.
Burr SE, Milne S, Jafali J, Bojang E, Rajasekhar M, Hart J, et al. Mass administration of azithromycin and Streptococcus pneumoniae carriage: cross-sectional surveys in the Gambia. Bull World Health Organ. 2014;92(7):490-8.
Keenan JD, Bailey RL, West SK, Arzika AM, Hart J, Weaver J et al. Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa. N Engl J Med. 2018;378(17):1583-92.
Roca A, Oluwalana C, Camara B, Bojang A, Burr S, Davis TM, et al. Prevention of bacterial infections in the newborn by pre-delivery administration of azithromycin: Study protocol of a randomized efficacy trial. BMC Pregnancy Childbirth. 2015;15:302.
Oluwalana C, Camara B, Bottomley C, Goodier S, Bojang A, Kampmann B et al. Azithromycin in Labor Lowers Clinical Infections in Mothers and Newborns: A Double-Blind Trial. Pediatrics. 2017;139(2).
Roca A, Oluwalana C, Bojang A, Camara B, Kampmann B, Bailey R, et al. Oral azithromycin given during labour decreases bacterial carriage in the mothers and their offspring: a double-blind randomized trial. Clin Microbiol Infect. 2016;22(6):565-69.
United Nations Population Division.World Population Prospects: 2019. Available at: https://www.worldbank.org/en/country/gambia. Accessed on 04 October 2020.
Jasseh M, Webb EL, Jaffar S, Howie S, Townend J, Smith PG, et al. Reaching millennium development goal 4 - the Gambia. Trop Med Int Health. 2011;16(10):1314-25.
United Nations Inter-Agency Group for Child Mortality Estimation.Levels & trends in child mortality: report 2019. New York. Available at: https://www.unicef.org/media/60561/file/UN-IGME-child-mortality-report-2019.pdf. Accessed on 04 October 2020.
Streatfield PK, Alam N, Compaore Y, Rossier C, Soura AB, Bonfoh B, et al. Pregnancy-related mortality in Africa and Asia: evidence from INDEPTH Health and Demographic Surveillance System sites. Glob Health Action. 2014;7:25368.
Conseil national de la statistique. Ministère de la santé/Burkina Faso. Available at: https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&cad=rja&uact=8&ved=2ahUKEwjAm8WO2b_1AhWfzjgGHUlfCMIQFnoECAMQAQ&url=http%3A%2F%2Fcns.bf%2FIMG%2Fpdf%2Fannuaire_ms_2018.pdf&usg=AOvVaw1mcpxT5n-SysCBvGc7BaBc. Accessed on 04 October 2020.
Cutland CL, Madhi SA, Zell ER, Kuwanda L, Laque M, Groome M, et al. Chlorhexidine maternal-vaginal and neonate body wipes in sepsis and vertical transmission of pathogenic bacteria in South Africa: a randomised, controlled trial. Lancet. 2009;374(9705):1909-16.
Getanda P, Bojang A, Camara B, Jagne-Cox I, Usuf E, Howden BP, et al. Short-term increase in the carriage of azithromycin-resistant Escherichia coli and Klebsiella pneumoniae in mothers and their newborns following intra-partum azithromycin: a post hoc analysis of a double-blind randomized trial. JAC Antimicrob Resist. 2021;3(1):dlaa128.
Norheim OF, Jha P, Admasu K, Godal T, Hum RJ, Kruk ME, et al. Avoiding 40% of the premature deaths in each country, 2010-30: review of national mortality trends to help quantify the UN sustainable development goal for health. Lancet. 2015;385(9964):239-52.
Salman S, Davis TM, Page-Sharp M, Camara B, Oluwalana C, Bojang A, et al. Pharmacokinetics of Transfer of Azithromycin into the Breast Milk of African Mothers. Antimicrob Agents Chemother. 2015; 60(3):1592-9.