Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial.
Kenyon S,Pike K,Jones D R,Brocklehurst P,Marlow N,Salt A,Taylor D J
Lancet (London, England)
BACKGROUND:The ORACLE II trial compared the use of erythromycin and/or amoxicillin-clavulanate (co-amoxiclav) with that of placebo for women in spontaneous preterm labour and intact membranes, without overt signs of clinical infection, by use of a factorial randomised design. The aim of the present study--the ORACLE Children Study II--was to determine the long-term effects on children after exposure to antibiotics in this clinical situation. METHODS:We assessed children at age 7 years born to the 4221 women who had completed the ORACLE II study and who were eligible for follow-up with a structured parental questionnaire to assess the child's health status. Functional impairment was defined as the presence of any level of functional impairment (severe, moderate, or mild) derived from the mark III Multi-Attribute Health Status classification system. Educational outcomes were assessed with national curriculum test results for children resident in England. FINDINGS:Outcome was determined for 3196 (71%) eligible children. Overall, a greater proportion of children whose mothers had been prescribed erythromycin, with or without co-amoxiclav, had any functional impairment than did those whose mothers had received no erythromycin (658 [42.3%] of 1554 children vs 574 [38.3%] of 1498; odds ratio 1.18, 95% CI 1.02-1.37). Co-amoxiclav (with or without erythromycin) had no effect on the proportion of children with any functional impairment, compared with receipt of no co-amoxiclav (624 [40.7%] of 1523 vs 608 [40.0%] of 1520; 1.03, 0.89-1.19). No effects were seen with either antibiotic on the number of deaths, other medical conditions, behavioural patterns, or educational attainment. However, more children whose mothers had received erythromycin or co-amoxiclav developed cerebral palsy than did those born to mothers who received no erythromycin or no co-amoxiclav, respectively (erythromycin: 53 [3.3%] of 1611 vs 27 [1.7%] of 1562, 1.93, 1.21-3.09; co-amoxiclav: 50 [3.2%] of 1587 vs 30 [1.9%] of 1586, 1.69, 1.07-2.67). The number needed to harm with erythromycin was 64 (95% CI 37-209) and with co-amoxiclav 79 (42-591). INTERPRETATION:The prescription of erythromycin for women in spontaneous preterm labour with intact membranes was associated with an increase in functional impairment among their children at 7 years of age. The risk of cerebral palsy was increased by either antibiotic, although the overall risk of this condition was low. FUNDING:UK Medical Research Council.
10.1016/S0140-6736(08)61203-9
The balance between protective and pathogenic immune responses to pneumonia in the neonatal lung is enforced by gut microbiota.
Science translational medicine
Although modern clinical practices such as cesarean sections and perinatal antibiotics have improved infant survival, treatment with broad-spectrum antibiotics alters intestinal microbiota and causes dysbiosis. Infants exposed to perinatal antibiotics have an increased likelihood of life-threatening infections, including pneumonia. Here, we investigated how the gut microbiota sculpt pulmonary immune responses, promoting recovery and resolution of infection in newborn rhesus macaques. Early-life antibiotic exposure interrupted the maturation of intestinal commensal bacteria and disrupted the developmental trajectory of the pulmonary immune system, as assessed by single-cell proteomic and transcriptomic analyses. Early-life antibiotic exposure rendered newborn macaques more susceptible to bacterial pneumonia, concurrent with increases in neutrophil senescence and hyperinflammation, broad inflammatory cytokine signaling, and macrophage dysfunction. This pathogenic reprogramming of pulmonary immunity was further reflected by a hyperinflammatory signature in all pulmonary immune cell subsets coupled with a global loss of tissue-protective, homeostatic pathways in the lungs of dysbiotic newborns. Fecal microbiota transfer was associated with partial correction of the broad immune maladaptations and protection against severe pneumonia. These data demonstrate the importance of intestinal microbiota in programming pulmonary immunity and support the idea that gut microbiota promote the balance between pathways driving tissue repair and inflammatory responses associated with clinical recovery from infection in infants. Our results highlight a potential role for microbial transfer for immune support in these at-risk infants.
10.1126/scitranslmed.abl3981
Early-Life Antibiotic-Driven Dysbiosis Leads to Dysregulated Vaccine Immune Responses in Mice.
Lynn Miriam Anne,Tumes Damon John,Choo Jocelyn Mei,Sribnaia Anastasia,Blake Stephen James,Leong Lex Ee Xiang,Young Graeme Paul,Marshall Helen Siobhan,Wesselingh Steve Lodewijk,Rogers Geraint Berian,Lynn David John
Cell host & microbe
Antibody-mediated responses play a critical role in vaccine-mediated immunity. However, for reasons that are poorly understood, these responses are highly variable between individuals. Using a mouse model, we report that antibiotic-driven intestinal dysbiosis, specifically in early life, leads to significantly impaired antibody responses to five different adjuvanted and live vaccines. Restoration of the commensal microbiota following antibiotic exposure rescues these impaired responses. In contrast, antibiotic-treated adult mice do not exhibit impaired antibody responses to vaccination. Interestingly, in contrast to impaired antibody responses, immunized mice exposed to early-life antibiotics display significantly enhanced T cell cytokine recall responses upon ex vivo restimulation with the vaccine antigen. Our results demonstrate that, in mice, antibiotic-driven dysregulation of the gut microbiota in early life can modulate immune responses to vaccines that are routinely administered to infants worldwide.
10.1016/j.chom.2018.04.009
Fetal and early life antibiotics exposure and very early onset inflammatory bowel disease: a population-based study.
Örtqvist Anne K,Lundholm Cecilia,Halfvarson Jonas,Ludvigsson Jonas F,Almqvist Catarina
Gut
OBJECTIVE:Earlier studies on antibiotics exposure and development of IBD (Crohn's disease (CD) and ulcerative colitis (UC)) may have been biased by familial factors and gastroenteritis. We aimed to estimate the association between antibiotics during pregnancy or infantile age and very early onset (VEO) IBD. DESIGN:In this cohort study of 827 239 children born in Sweden between 2006 and 2013, we examined the link between exposure to systemic antibiotics and VEO-IBD (diagnosis <6 years of age), using Cox proportional hazard regression models. Information on antibiotics and IBD was retrieved from the nationwide population-based Swedish Prescribed Drug Register and the National Patient Register. We specifically examined potential confounding from parental IBD and gastroenteritis. RESULTS:Children exposed to antibiotics during pregnancy were at increased risk of IBD compared with general population controls (adjusted HR (aHR) 1.93; 95% CI 1.06 to 3.50). Corresponding aHRs were 2.48 (95% CI 1.01 to 6.08) for CD and 1.25 (95% CI 0.47 to 3.26) for UC, respectively. For antibiotics in infantile age, the aHR for IBD was 1.11 (95% CI 0.57 to 2.15); for CD 0.72 (95% CI 0.27 to 1.92) and 1.23 (95% CI 0.45 to 3.39) for UC. Excluding children with gastroenteritis 12 months prior to the first IBD diagnosis retained similar aHR for antibiotics during pregnancy and CD, while the association no longer remained significant for IBD. CONCLUSION:We found that exposure to antibiotics during pregnancy, but not in infantile age, is associated with an increased risk of VEO-IBD regardless of gastroenteritis. The risk increase for exposure in pregnancy may be due to changes in the microbiota.
10.1136/gutjnl-2017-314352
Paternal microbiome perturbations impact offspring fitness.
Nature
The gut microbiota operates at the interface of host-environment interactions to influence human homoeostasis and metabolic networks. Environmental factors that unbalance gut microbial ecosystems can therefore shape physiological and disease-associated responses across somatic tissues. However, the systemic impact of the gut microbiome on the germline-and consequently on the F offspring it gives rise to-is unexplored. Here we show that the gut microbiota act as a key interface between paternal preconception environment and intergenerational health in mice. Perturbations to the gut microbiota of prospective fathers increase the probability of their offspring presenting with low birth weight, severe growth restriction and premature mortality. Transmission of disease risk occurs via the germline and is provoked by pervasive gut microbiome perturbations, including non-absorbable antibiotics or osmotic laxatives, but is rescued by restoring the paternal microbiota before conception. This effect is linked with a dynamic response to induced dysbiosis in the male reproductive system, including impaired leptin signalling, altered testicular metabolite profiles and remapped small RNA payloads in sperm. As a result, dysbiotic fathers trigger an elevated risk of in utero placental insufficiency, revealing a placental origin of mammalian intergenerational effects. Our study defines a regulatory 'gut-germline axis' in males, which is sensitive to environmental exposures and programmes offspring fitness through impacting placenta function.
10.1038/s41586-024-07336-w