Antibiotics in the first year of life and subsequent neurocognitive outcomes

Slykerman RF, Thompson J, Waldie KE, Murphy R, Wall C, Mitchell EA.

Antibiotics in the first year of life and subsequent neurocognitive outcomes.

Acta Paediatr. 2016 Oct 4.

Abstract

AIM:

There may be a link between disruption to the gut microbiota in early life and later neurocognitive outcomes. We hypothesised that antibiotic use in early life is associated with a detrimental effect on later neurocognitive outcomes.

METHODS:

871 European mothers and their children enrolled in the Auckland Birthweight Collaborative Study at birth. Information on antibiotic use during the first year of life and between 12 months and 3.5 years of age was gathered via maternal interview. Intelligence test scores and measures of behavioural difficulties were obtained when children were 3.5, 7 and 11 years of age.

RESULTS:

Antibiotic use in the first year of life was reported in 70% of the 526 children with antibiotic data assessed at age 3.5 years. Those who had received antibiotics had more behavioural difficulties and more symptoms of depression at follow up. Results were consistent across all standardised psychologist administered tests, as well as parent rated, teacher rated and self-report measures.

CONCLUSION:

This study demonstrates an association between antibiotic use in the first year of life and subsequent neurocognitive outcomes in childhood. If confirmed by further research these findings could have implications for the use of antibiotics for minor illnesses in infancy. 

Courtesy of:  http://www.mdlinx.com/neurology/medical-news-article/2016/10/05/antibiotic-neurocognitive-outcomes-childhood/6888439/?category=sub-specialty&page_id=1&subspec_id=317

From the article:

After adjustment for SGA status, sex, maternal school leaving age, maternal smoking in pregnancy,

method of delivery and breastfeeding duration, the following outcome variables remained statistically

significantly associated with antibiotic use: higher parent rated total behavioural difficulty score at age of 3.5 and 11 years (in particular conduct problems), higher self-rated peer difficulties, lower self-rated prosocial behaviour scores at age 11, higher parent rated ADHD symptoms at age 11, higher teacher reported symptoms of ADHD at age 11 and higher depression symptom scores at age 11.

Antibiotic use between the ages of 12 months and 3.5 years was not significantly associated with any

of the outcomes measures.   Furthermore, maternal antibiotic use during pregnancy  was not

significantly associated with any of the outcome measures. Information about the timing,

dosage and type of antibiotic given to mothers during pregnancy was not available. Admission to

hospital in the first 3.5 years of life was not significantly associated with any of the outcome measures ...

The finding that it is antibiotic use in the first year of life (as opposed to antibiotic use between 12

months and 3.5 years of life) that is associated with behavioural, mood and cognitive outcomes later

in childhood is consistent with the theoretical underpinnings of the development of the gut-brain axis.

This argues against the explanation that the confounding influence of chronic otitis media associated

with antibiotic use and deafness is the cause of poorer neurodevelopmental outcomes. The early

development and stabilisation of the gut microbiome in postnatal life and the concomitant continued

rapid development of the central nervous system implies that disruptions to the gut-brain axis during

this critical period are the most likely to have a long term impact on development.

Potential mechanisms by which the gut microbiota affects CNS function include altered microbial

composition, immune inactivation, vagal nerve activation, tryptophan metabolism, gut hormone

response, and through bacterial metabolites . Studies have linked early disruptions to the

development of the gut microbiota and development of the stress-response system particularly the

hypothalamic pituitary adrenal axis (HPA axis). The function of the HPA axis has been implicated in

emotional and behavioural outcomes later in life such as depression  and the link between

antenatal maternal stress and later anxiety and depression in offspring. Foster and McVey

Neufeld (2013) provide a review of the growing evidence that microbiota are involved in the early

development of the HPA axis and thus the later functional outcomes associated with the function of

the stress response system.  In short, animal models indicate that the function of the HPA axis

differs according to the composition of the gut microbiota in mice. In 2004 it was reported that the

stress reactivity of the HPA axis was linked to the microbiota of rodents. Germ free mice (who have no commensal bacteria) had exaggerated stress responses when restrained compared with house-

specific pathogen free mice. Germ free mice have also been found to have more anxiety like

behaviour on measures such as the elevated plus maze and the forced swim test.  As an

alternative to using germ free mice the effect of antibiotic exposure on the gut microbiota and

observable behavioural outcomes have also been modelled in mice.  A recent study investigated the

effects of antibiotic induced gut dysbiosis in adult mice.  In addition to demonstrating disruption to

the gut microbiota, antibiotic treated mice had impaired novel object recognition memory which is

consistent with previous reports.  Changes in circulating metabolites, cerebral signalling

molecules and expression of neuropeptides such as brain derived neurotrophic factor (BDNF) were

also demonstrated posing a plausible pathway connecting antibiotic induced dysbiosis to cognitive

outcomes.