Maternal antibiotic exposure during pregnancy and risk of IBD in offspring: a population-based cohort study

We read with interest the randomised controlled trial by Dierikx et al that demonstrated the lack of longterm impact of antenatal antibiotics on offspring gut microbiome. Antibiotics in early life are implicated in IBD risk, potentially mediated by gut microbiome perturbations and altered host–microbe interactions. 3 However, data on offspring IBD risk with maternal antibiotics exposure during pregnancy are limited and conflicting. 5 We conducted a populationbased cohort study to better understand this relationship, including the impact of cumulative antibiotic exposure, the trimester of antibiotic exposure and narrowspectrum versus broadspectrum antibiotics on offspring IBD risk. Using historical, prospectively collected data in crosslinked nationwide Danish registers of individuals born between 1997 and 2003 and followed up to 2018, we estimated the impact of systemic antibiotic exposure during pregnancy on offspring risk of IBD, Crohn’s disease (CD) and UC after adjusting for relevant covariates. Further details are available in online supplemental materials. A total of 416 833 (8 103 366 personyears) pregnant womenoffspring dyads were included of whom 296 974 (71.2%), 80 036 (19.2%), 25 335 (6.1%) and 14 488 (3.5%) received 0, 1, 2 and ≥3 courses of antibiotics, respectively. Mothers with immunemediated diseases and smoking during pregnancy received antibiotics more frequently than those without (online supplemental table 1). Other baseline characteristics were comparable across exposure groups. Overall, maternal antibiotic exposure during pregnancy, compared with none, was not associated with offspring IBD, UC or CD risk (adjusted HR (aHR) 1.01, 95% CI 0.91 to 1.12; aHR 1.03, 95% CI 0.89 to 1.2; and aHR 0.99, 95% CI 0.86 to 1.14, respectively). Exposure to <3 courses of antibiotics was not associated with offspring IBD risk, while exposure to ≥3 courses of antibiotics was associated with increased risk of IBD (aHR 1.29, 95% CI 1.03 to 1.62; figure 1). This was driven by UC (aHR 1.45, 95% CI 1.06 to 2.00) but not CD (aHR 1.15, 95% CI 0.83 to 1.60) risk. There was no impact of the trimester of antibiotic exposure or narrowspectrum versus broadspectrum antibiotics (online supplemental table 2). In this populationbased cohort study, we report on the potential safety of fewer than three courses of maternal antibiotics during pregnancy. Additional courses were associated with a 45% increase in UC, but not CD, risk. Antibiotic exposure during infancy and childhood is linked with IBD, although the absolute risk is low. 7 In a case–control study, maternal infections, a surrogate for antibiotic exposure, were not associated with offspring IBD risk. In another study, third trimester antibiotics was associated with very earlyonset IBD in the offspring. In this analysis, we uncover further nuances. Safety of one to two courses of antibiotics towards offspring IBD risk is consistent with data on lack of microbiome disruption. For further courses, benefits should be weighed against risks. Differences in UC and CD risk may suggest differences in disease pathogenesis and warrant further study. Strengths of this study include the use of a prospective, unselected, nationwide cohort and long followup permitting study of adultonset IBD in addition to pediatriconset IBD. There was no loss to followup and we included potential confounding variables. Limitations include lack of data on antibiotics indication, making it challenging to uncouple the two. There is risk of unmeasured and residual confounding and misclassification bias. However, all medications and diagnosis codes are recorded consistently with continuous updates. Misclassification, if any, is likely to be nondifferential. In summary, we report on the impact of cumulative antibiotic exposure during pregnancy on offspring IBD risk. These data not only support the aforementioned study but also offer further distinctions in clinical decisionmaking during pregnancy. Translational studies to characterise host–microbe interactions with cumulative antibiotics will be informative.