Review articleTrimester-specific association between antibiotics exposure during pregnancy and childhood asthma or wheeze: the role of confounding
Introduction
Asthma, a syndrome of reversible respiratory obstruction that predominantly occurs among the children [1], poses a great disease burden in many countries in recent years [2]. In 2016, it was reported that asthma accounted for 2.87% in the global total Disability-Adjusted Life Year among children aged 5–14 years. A body of evidence from animal and epidemiologic studies suggest that embryonic and fetal development is a critical stage for subsequent development of the immune and neuroendocrine systems, and prenatal exposures to antibiotics potentially increase the risk of developing asthma and wheezing in children [3], which motivates many researchers to investigate the role of maternal antibiotics exposure during pregnancy in later occurrence of childhood asthma and wheeze [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15].
Increasing epidemiologic studies suggest a significant association between prenatal exposure to antibiotics and increased risk of asthma or wheeze in offspring. A previous meta-analysis also pointed out that antibiotic exposure during pregnancy could increase the risk of wheeze or asthma in childhood, which mainly focused on the maternal antibiotics use throughout the pregnancy [16]. But the subgroup analysis on specific trimester was only based on two original studies, which may result in an unstable effect size largely influenced by only one study. So, in the following years, growing number of studies have been focused on trimester-specific risk; nevertheless, findings from different studies were inconsistent [6], [7], [8], [9], [10], [11], [12], [15]. For instance, a study observed no statistical association between infant wheezing and prenatal antibiotics exposure during the second and third trimesters [8]. Another study showed that antibiotics exposure during the two trimesters were both significantly associated with the risk of asthma in children [11]. Therefore, there needed a meta-analysis and systematic review to evaluate the pooled trimester-specific effect of maternal antibiotics use. Induction of asthma by prenatal antibiotics is biologically plausible, which is considerably through the modification of the bacterial ecology of the mother and fetus.
An alternative explanation for the association is that it is because of confounding by indication. That is, this association is confounded by a third factor that is an indication for antibiotic prescription during pregnancy while at the same time being a risk factor for childhood asthma or wheeze. Family confounding may play an important role in the association, such as maternal age, maternal asthma history, and so on. Remarkably, infection during pregnancy leads to increased chance of antibiotics use, and it is reported that antenatal infections are associated with childhood asthma [11], [17]. Besides, presence of siblings has been linked with asthma or wheeze [18], [19]. But there is a dispute over the statements. Randomized controlled trials for this uncertain relationship may never be conducted, given the ethical concern. Therefore, the purposes of this meta-analysis were to (1) to specially evaluate the association between prenatal antibiotics exposure during specific trimester and the risk of asthma or wheeze in offspring and (2) clarify whether the association is independent of potential confounding.
Section snippets
Search strategy and study selection
PubMed, Web of Science, and Cochrane Central Register of Controlled Trials were searched for records up to March 7, 2018. Search strategy was shown in Table S1. No publication language restriction was applied. Eligible studies included case–control studies or cohort studies that assessed the relationship between prenatal antibiotics use during pregnancy and the risk of childhood asthma or wheeze.
Studies were included if they met the following criteria: (1) studies were published before March 7,
Literature search
We identified 3272 articles initially. Four hundred eighty-two records were excluded for duplicates, and 2757 records were excluded after screening the titles and abstracts. Full texts of 22 studies were assessed for their eligibility. Fourteen studies did not provide effect size for any specific trimester. Eight original studies met the inclusion criteria for the final meta-analysis (Fig. 1).
Characteristics of included studies
The characteristics of each included study were summarized in Table 1. The age of study population
Summary of main results
If pregnant mother's exposure to antibiotics can elevate the risk of childhood asthma or wheeze, identifying the critical time-window will be important for both early detection and intervention of such disease in practice. To our knowledge, it was the first meta-analysis to specially evaluate pooled effects of prenatal antibiotics use in each trimester and to explore potential confounding factors in the observed association. Our results revealed positive crude association between maternal use
Acknowledgments
This work was not funded by any funding.
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The authors report no conflict of interest regarding the content herein.