Comparison with other studies
Our results are consistent with a cross-sectional study by McKeever et
al., who used a birth cohort of 24690 children derived from the General
Practice Research Database in the United Kingdom, and found a positive
association between prenatal antibiotic use and doctor-diagnosed eczema
in a dose-related manner.20 In line with our results,
their study also revealed that infections during pregnancy increased the
risk of allergic diseases and adjusting for them did not notably affect
the estimates. Dom et al. conducted a prospective birth cohort study of
773 children in Belgium. A questionnaire was used to investigate
parent-reported eczema, and the results revealed that prenatal
antibiotic exposure was strongly positively associated with eczema in
children up to 4 years old after adjusting for post-natal
antibiotics.21 Conversely, two Danish cohort studies
that used a prospective design were conducted by Stensballe et al. and
the results showed that prenatal antibiotic use did not influence the
risk of eczema in 411 and 30675 children,
respectively.22 However, their follow-up period was
shorter and did not take exposure in all trimesters into account. In
addition, a study by Sasaki et al. who used a Japanese nationwide
dataset to conduct a prospective birth cohort study showed no
association between prenatal antibiotic exposure and diagnosed or
observed AD at 1 year old in 70408 children (aOR 1.01, 95% CI
0.97-1.06).23 Similar to the study by Stensballe et
al., their follow-up period was also shorter and excluded children born
through cesarean delivery, which may influence the risk of prenatal
antibiotic exposure in AD.
A recent prospective cohort study performed by Mubanga et al.
investigated 722767 singleton children and 74663 discordant siblings in
Sweden. In line with our results, they found the risk of AD was greater
in children exposed to prenatal antibiotics than in those who were not
exposed (aHR 1.10, 95% CI 1.09-1.12), whereas no such increased risk
was found in the sibling-control analysis, suggesting some familial
confounders.24 Based on the covariates they adjusted
for, we further adjusted the maternal comorbidities, maternal AD,
maternal allergic rhinitis, gestational infections, and maternal
acetaminophen use during pregnancy, which may be potential risk factors
according to previous studies.12,25,26 In addition,
their study revealed an apparent dose-response relationship, and the
category of infection did not modify the association of maternal
antibiotic use and child AD, which was consistent with our results. In
terms of the trimester-specific association between antibiotic exposure
during pregnancy and childhood AD, their results were comparable with
our results in that the risk increased in all trimesters; however, our
data showed a slightly higher risk in the first and second trimesters
compared with the third trimester, which might be explained by
antibiotics-related dysbiosis or immunomodulatory effects, phenomena
that are known to have a greater impact during early pregnancy.
Several studies and meta-analyses revealed that post-natal antibiotics
and acetaminophen exposure were associated with an increased risk of AD,
especially within the first year of
life.27-29Antibiotics and acetaminophen are frequently
used to treat infection. However, reverse causation must be taken into
consideration, so we performed a subgroup analysis by independently
examining the effects of these two medications on AD. After excluding AD
diagnosed before 1 year of age, the positive association was still
present in the prenatal antibiotic exposure group regardless of
postnatal antibiotic use, but the adjusted hazards reduced to null in
children who were not exposed to postnatal acetaminophen, suggesting
that some confounders common to both prenatal antibiotics and postnatal
acetaminophen use existed (e.g., infection, fever, or AD itself).
However, the majority (87%) of AD patients in our cohort were diagnosed
before 1 year of age, so this negative association could only represent
the minority (13%) of AD patients diagnosed after 1 year of age. Our
results are consistent with a study by Dom et al. that found adjusting
for post-natal antibiotics did not significantly change the result
showing prenatal antibiotic use increased the risk of childhood
AD.21
Even though our results showed a positive association between maternal
use of antibiotics during pregnancy and childhood AD, this does not
necessarily imply a causal link between the two. A registry-based cohort
study conducted by Stokholm et al. investigated the temporal association
between maternal antibiotic use and childhood asthma and showed that the
risk of asthma was similar among 80 weeks before pregnancy, during
pregnancy, and 80 weeks after pregnancy.30 The authors
suspected that maternal antibiotic use is a surrogate marker of maternal
propensity for infection, which is the true cause of childhood asthma.
Loewen et al. replicated their results in a retrospective cohort study
and proposed that some unmeasured factors, such as healthcare
utilization patterns, shared familial factors, and maternal deficiency
of vitamin D or other immunomodulatory nutrients may explain both the
increased risk of maternal antibiotic use/infection and the increased
risk of asthma in offspring.31 While we could not
address the temporal association between maternal antibiotic use before
and after pregnancy, our results were unchanged after adjusting for
three common infections during pregnancy. Furthermore, maternal
antibiotic use may also be a surrogate marker of infant antibiotic use,
which is associated with asthma and AD.31 Our data
showed that infants born to mothers who received antibiotics during
pregnancy were indeed more likely to be exposed to postnatal
antibiotics; however, the positive association between maternal
antibiotic use during pregnancy and childhood AD remained significant in
the subgroup analysis independent of infant antibiotic use.