Funding
This work was supported by grants from the Medical Research Council,
British Heart Foundation, Food Standards Agency, Arthritis Research UK,
National Osteoporosis Society, International Osteoporosis Foundation,
Cohen Trust, European Union’s Seventh Framework (FP7/2007-2013),
projects EarlyNutrition and ODIN under grant agreement numbers 289346
and 613977, NIHR Southampton Biomedical Research Centre, University of
Southampton and University Hospital Southampton NHS Foundation Trust,
NIHR Musculoskeletal Biomedical Research Unit, University of Oxford and
British Lung Foundation.
Key words : Atopic eczema, antibiotics, laxatives, microbiome
Abbreviations: UK Working Party Criteria for the Definition of
Atopic Dermatitis (UK WPDC), Directed Acyclic Graph (DAG), Odds Ratio
(OR)
Word count: 1026
Figures: Figure 1. Directed Acyclic Graph (DAG) demonstrating the
relationship between laxative and antibiotic exposure (exposure), infant
atopic eczema (outcome) and variables. Confounders identified are:
maternal BMI, parity, breastfeeding duration and infant sex.
Tables: Table 1. Atopic eczema at age 12 months in relation to
exposure to maternal antibiotic use, maternal laxative use and infant
antibiotic use.
The risk of developing atopic eczema is influenced by various events
pre-conception, during pregnancy and throughout the neonatal
period.1, 2 Recent reports have suggested that early
life exposure to microbiome altering medications, such as antibiotics
and laxatives, could impact the risk of atopic eczema in infancy and
childhood. For example, in this Journal, Lin et al., 2022 reported an
increased risk of allergic disease in offspring whose mother used
laxatives in pregnancy independent of laxative exposure in the offspring
but no associations were found for maternal antibiotic
use.3
As the evidence on this topic is sparse, in this study we aimed to
further examine whether maternal gestational exposure to antibiotics or
laxatives were associated with the risk of atopic eczema in infancy. We
also examined the link between offspring antibiotic exposure in the
first 12 months of life and risk of infantile atopic eczema.
Within the UK Southampton Women’s Survey, a prospective mother-offspring
cohort, maternal antibiotic and laxative exposure during pregnancy were
contemporaneously recorded by research nurses during in-person
interviews in early (median 11.8 weeks’ gestation ) and late (median
34.5 weeks’ gestation) pregnancy; n=248 and n=304 reported antibiotic
exposure, and n=67 and n=72 laxative exposure in early and late
pregnancy, respectively. At age 12 months, offspring antibiotic exposure
was recorded (n=1433 exposed); of these, 10.1% were exposed to maternal
antibiotic use in early pregnancy 12.3% to maternal antibiotic use in
late pregnancy, 2.5% to maternal laxative use in early pregnancy and
3.4% to maternal laxative use in late pregnancy. Atopic eczema was
ascertained using the UK Working Party Criteria (UK WPDC) for the
Definition of Atopic Dermatitis4 at ages 6 and 12
months (cohort n= 2907 and 2870, respectively (n= 262 and 270, with
eczema)).
We used a Directed Acyclic Graph (DAG) to identify potential confounders
and competing exposures that should be included in our statistical
models5; these were maternal BMI, parity,
breastfeeding duration and infant sex (Figure 1). Standard univariable
and multivariable logistic regression analyses were carried out
adjusting for potential confounders as identified by the DAG to relate
maternal use of antibiotics and laxatives in pregnancy, and infant
antibiotic exposure to infantile atopic eczema at ages 6 and 12 months
(Stata version 14.1, Statacorp LP, TX). Antibiotic exposure captured at
age 12 months was not used to predict infant eczema at 6 months.
We found no associations between maternal antibiotic use in pregnancy
and infantile atopic eczema (Table 1). Similarly, maternal laxative use
had no associations with infantile atopic eczema at ages 6 or 12 months.
Findings were unaltered taking into account potential confounders. The
use of antibiotics in infancy, however, was associated with an increased
risk of atopic eczema at 12 months and remained significant in
multivariable analyses (OR (95% CI) 1.57 (1.21-2.05), p=0.001) (Table
1). The risks of atopic eczema at age 12 months were similar in those
who had antibiotics in the first 6 months and those who had antibiotics
during age 6-12 months compared to those who did not have antibiotics.
Exposure to antibiotics once only (n=794), 2-3 times (n=458) and more
than three times (n=164) in the first year of life were associated with
similarly increased risks of atopic eczema (1.50 (1.10-2.03), p=0.01,
1.60 (1.12-2.28), p=0.009 and 1.59 (0.94-2.68), p=0.085, for once only,
2-3 times and more than three times, respectively).
The findings support evidence that postnatal antibiotic exposure is
associated with the infant’s risk of developing atopic eczema. Further
work is needed to disentangle whether the postnatal antibiotic exposure
plays a causal role in infantile eczema, or whether the antibiotic
exposure occurs as a consequence of the eczema. Our data provides
limited information on the condition for which antibiotics were
prescribed and the sample size for documented individual infections is
too small to draw conclusions (e.g. pneumonia 4%, bronchitis 15%), but
the similar relationships for early and late infancy antibiotic exposure
provide weak evidence against the antibiotics simply being prescribed as
a consequence of the eczema
Wohl et al reported an increased risk of atopic eczema at the age of 2
years in infants whose mothers took antibiotics during
pregnancy.6 In our study maternal gestational
antibiotic or laxative exposure, however, were not related to infant
atopic eczema. A systematic review of prenatal and infant antibiotic
exposure and childhood allergic disease reported that prenatal
antibiotics had an overall effect on eczema but the findings for infant
antibiotic exposure were less consistent.7 Variation
in definition of eczema or in study methodology may have contributed to
this. In our study, atopic eczema was defined by UK WPDC which are
recognized diagnostic criteria used in clinical and research settings
and involved a standardized questionnaire and an examination undertaken
by trained research nurses. Data on infant exposure to laxatives was not
available in this cohort. We also used a DAG which is a robust method
for identifying cofounders in large observational epidemiological
studies.5
Gut microbiome regulates the gut environment but it also influences the
regulation of the microbiome of barrier sites such as the skin and the
lungs. The timing of dysbiosis that is likely to impact the offspring’s
developing immune system is not known but it has been suggested that the
first 6 months after birth should be considered a time of susceptibility
as the microbiome develops rapidly and may induce long-term
immunological changes.7, 8 Supportive evidence from
animal studies has shown that antibiotic exposure in neonatal mice was
associated with shifts in the gut microbiome and subsequent signs of
allergic asthma. These changes were not seen in exposed adult
mice.9 Nonetheless, alterations in the microbiome may
be related to atopic eczema and not a direct effect of antibiotics.
Maternal enteric dysbiosis may result from medications, which in turn
may cause enteric dysbiosis of the fetus via the translocation of
microbes through the bloodstream, and increase their predisposition to
developing allergic disease. While we did not demonstrate evidence for
this, we did identify that antibiotic use in infancy was associated with
development of atopic eczema during the first 12 months of life. Based
on our data and the results of recent studies, we recommend further
research to examine the impact of early life antibiotic and laxative
exposure on the microbiome-immune-atopy axis.