Neonatal sepsis is a major health problem in lower-middle income countries (LMIC). Antibiotic prophylaxis is one of the most common practices to neonatal sepsis. Little is known about how antibiotic prophylaxis affects neonatal sepsis epidemiology in LMICs. Mounting evidence suggests that antibiotics have a substantial effect on the microbiome and influences newborns' susceptibility to infection. This dissertation aims to 1) estimate the prevalence, incidence, and risk factors of neonatal sepsis and perinatal antibiotic prophylaxis use in Palembang, Indonesia; 2) assess the effects of perinatal antibiotic prophylaxis on neonatal sepsis incidence; and 3) explore the effects of perinatal antibiotic prophylaxis on newborns' gut microbiomes and evaluate whether microbiome features mediate the association of antibiotic prophylaxis with neonatal sepsis. To provide preliminary data, a retrospective study was conducted at Mohammad Hoesin Hospital, Indonesia, reviewing 306 neonatal sepsis cases and 3,657 deliveries between 2016 and 2018. Then, a prospective cohort recruited 1,002 mother-viable newborn pairs admitted for delivery at two Indonesian hospitals. Newborns were followed until the age of 28 days or until sepsis was observed. Adjusted relative risk and average treatment effect (ATE) of antibiotic prophylaxis for neonatal sepsis were estimated. Lastly, a nested case-control study matched 53 newborns with sepsis to 102 healthy infants by mode of delivery. Newborns' gut microbiomes from meconium and stool specimens were profiled using 16S ribosomal RNA sequencing. Mediation analysis assessed the relationships among perinatal antibiotic prophylaxis, newborns' microbiome features, and neonatal sepsis. The preliminary study showed that the neonatal sepsis hospital admission prevalence was 14.1%. The percentages of early-onset sepsis and late-onset sepsis were comparable. The proportion of culture-negative sepsis was 44%. Overall, 62.6% of all isolated organisms were multidrug-resistant bacteria. The prevalence of prophylactic antibiotic use during delivery was 47.1%. Premature rupture of membrane (PROM) and C-section were some factors that were strongly associated with prophylactic antibiotic use. In the cohort study, the cumulative incidence of neonatal sepsis was 10.4 per 100 live births. The proportion of culture-negative sepsis was three times higher than in the preliminary study. The neonatal sepsis risk was increased by PROM, foul-smelling amniotic fluid, high maternal leukocyte count, low birth weight, mixed feeding, and fasting. Of the newborns studied, 72% were exposed to antibiotic prophylaxis. The estimate of the ATE of perinatal antibiotic prophylaxis on neonatal sepsis was 0.10 (p< 0.0001). The causal effect was more robust for postnatal prophylaxis alone or with maternal exposure. The meconium and follow-up stool specimens of newborns with sepsis had a significantly lower alpha diversity than non-sepsis newborns. The microbiome analysis found that the meconium of newborns exposed to perinatal antibiotic prophylaxis exhibited a distinct gut microbiome community compared to the unexposed group. Although there were few suppression effects across perinatal antibiotic prophylaxis, microbiome features, and neonatal sepsis, no significant mediation effects were found. This study corroborates that neonatal sepsis incidence remains high despite the high use of perinatal antibiotic prophylaxis. Considering that the post-antibiotic era is nearing, there is an urgent need for non-antibiotic prevention strategies that are feasible in LMICs, which often have crippling resource constraints. Given this need, this dissertation elucidates the microbiome's potential role in the causal pathway of neonatal sepsis and is an advancement toward manipulation of the gut microbiome to prevent neonatal sepsis and injudicious antibiotic use.
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