Prenatal antibiotic exposure and childhood asthma: a population-based study

Discussion

In this population-based study, prenatal antibiotic exposure was associated with a 23% increased risk of asthma, independent of postnatal antibiotic exposure and several established asthma risk factors. There was an apparent dose response with repeated prenatal exposures; however, similar associations were observed for maternal antibiotic use before and after pregnancy. These results neither firmly support nor refute a directly causal pregnancy-specific relationship between maternal antibiotic use and childhood asthma; however, they contribute to the growing body of evidence linking early-life antibiotic exposure and asthma risk, and raise important questions for further research.

Our results are consistent with a case–control study by Metsälä et al. [26] showing that both prenatal and postnatal exposure to antibiotics were associated with an increased risk of asthma in Finnish children. In another case–control study, Mulder et al. [27] found that prenatal antibiotic exposure in the third trimester of pregnancy was associated with an increased risk of asthma in Dutch children, with consistent results in a case–sibling sensitivity analysis. While these studies seem to support a causal relationship between prenatal antibiotic exposure and asthma development, other studies have used different approaches and challenged this hypothesis. For example, Örtqvist et al. [29] found that associations observed in Swedish children disappeared when using sibling controls, suggesting confounding by familial factors. In addition, Stokholm et al. [30] reported that maternal antibiotic use anytime from 80 weeks prior to 80 weeks following pregnancy was similarly associated with childhood asthma in Denmark. The authors speculated that maternal propensity for infection (rather than antibiotic use) is the causal factor linking prenatal antibiotic exposure with asthma development. Örtqvist et al. [36] recently confirmed this phenomenon in Sweden, finding similar associations for maternal exposure before, during and after pregnancy. Consistent with Stokholm et al. [30] and Örtqvist et al. [36], we have found that maternal antibiotic use before, during and after pregnancy is similarly associated with increased asthma risk in offspring. These results suggest the link between maternal antibiotic use and asthma in offspring is either not directly causal or not specific to pregnancy.

There are several potential explanations for a non-causal association between maternal antibiotic use and childhood asthma. First, the observed association may be confounded by healthcare utilisation patterns or other unmeasured factors that are shared within families, such as smoking and environmental exposures. Second, as Stokholm et al. [30] proposed, it is possible that maternal antibiotic use is a marker of genetic susceptibility to infections, which is inherited by offspring and imparts a predisposition for asthma. Third, as suggested by Weiss and Litonjua [38], a maternal deficiency in vitamin D or other immunomodulatory nutrient could explain both the increased risk of infection in mothers and increased risk of asthma in offspring. Finally, since maternal and child medication usage are strongly associated [39], it is possible that maternal antibiotic use is a surrogate for infant antibiotic use, which is known to influence asthma development [17, 18]. While we could not address environmental exposures, genetics or nutritional hypotheses in our administrative database study, our findings do not support the final explanation, since our results were unchanged following adjustment for infant antibiotic use.

Another approach to address confounding in prenatal exposure studies is to evaluate fathers’ exposures as a negative control. Mulder et al. [27] reported that maternal (but not paternal) antibiotic use during pregnancy was associated with child asthma at the age of 5 years, supporting a causal effect from in utero exposure. In contrast, Örtqvist et al. [36] showed that both maternal and paternal antibiotic use during pregnancy were associated with child asthma before 2.5 years, suggesting confounding by shared familial factors. Notably, however, the maternal association was stronger and persistent throughout childhood, whereas paternal exposure was not associated with child asthma after 2.5 years. Thus, while we could not address paternal exposure in our study, this approach warrants further investigation.

Notably, the dose response observed by Stokholm et al. [30] and others [26, 28, 31], and replicated in our study, suggests that antibiotics or some related underlying factor (whether genetic, nutritional or environmental) may be causally related to asthma development in offspring. While this pattern could indicate dose response in a confounder, research is warranted to pursue these hypotheses in other settings where causal mechanisms can be explored and tested, such as clinical cohorts and animal models. It must also be acknowledged that, while the overuse of antibiotics can promote antimicrobial resistance and microbiome dysbiosis, untreated infections can also be harmful, especially to a developing fetus. For example, urinary tract infections during pregnancy are associated with intrauterine growth restriction, preterm labour and miscarriage [40, 41]. Keeping this risk–benefit balance in mind, it is important to study and clarify the potentially unintended consequences of prenatal antibiotic exposure.

It is conceivable that maternal antibiotic use before, during and after pregnancy could impact infant microbiota and subsequent immune development. Pre-gestational antibiotic use may have long-term effects on the maternal microbiota that persist during pregnancy, and postpartum antibiotics could influence the transmission of maternal skin and breast milk microbiota to the infant [37]. Consistent with Mulder et al. [27], our finding that different types of antibiotics are differentially associated with child asthma lends support to this hypothesis, since different antibiotics will differentially impact maternal microbiota and their transmission to the infant. However, exposures occurring closer to the time of this microbial transfer would be expected to have a greater impact. The absence of any temporal gradient in our results, and those of Stokholm et al. [30], points to the involvement of additional mechanisms, as discussed later. Future research is needed to determine whether antibiotic-induced disruption of the maternal microbiota before pregnancy may persist during pregnancy or postpartum, whether postnatal maternal antibiotics impact maternal–infant sharing of microbes after pregnancy and whether these potential effects may influence asthma development.

Strengths of this study include the large unselected population, capturing virtually all children born in the province of Manitoba over an 18-year period, and the use of administrative healthcare data to objectively document asthma diagnoses, hospitalisations and antibiotic exposures. Using healthcare records eliminates recall bias, minimises loss to follow-up and provides key details that are not accurately captured by self-report, including the specific antibiotic type, dose and timing of exposure. Unlike most previous studies, we mutually adjusted our analyses for prenatal and postnatal antibiotic exposure during the first year of life; an important adjustment since maternal and infant healthcare utilisation tend to be correlated [39], but could be independently associated with child asthma development. In addition, we performed sensitivity analyses for maternal antibiotic use before and after pregnancy, although sibling controls and paternal exposures were not examined. Finally, our results confirm previous research [19] identifying maternal asthma, male sex, urban residence, premature birth, lower birth order, and antibiotic use during infancy as significant risk factors for asthma.

A limitation of our study is the lack of information about the indication for antibiotic treatment. In addition, exposure misclassification is possible since we cannot confirm patient compliance with filled prescriptions, and our database does not capture antibiotics administered in hospital. Thus, we could not account for intrapartum antibiotic prophylaxis for group B Streptococcus, which affects >20% of deliveries in Manitoba [42] and has been shown to influence infant gut microbiota development [43]. In addition, we could not account for indirect exposure to antibiotics in food or the environment [44]. Outcome misclassification is also possible, since asthma is commonly misdiagnosed in young children; however, we evaluated multiple disease definitions and required evidence of serious (hospitalisation) or persistent (multiple diagnoses or prescriptions) disease after 5 years of age to maximise specificity. Finally, confounding bias is possible since we could not account for potential confounders that are not captured in administrative databases, such as maternal and child nutrition, education, smoking and environmental exposures including pets, tobacco smoke, mould and daycare attendance.