Researchers find link between prenatal/postnatal exposure and AD, but familial factors confound it

Maternal antibiotic use in prenatal and early postnatal life may be linked to the incidence of atopic dermatitis (AD) in early childhood, researchers found, but familial factors may muddy the association.

While genetic history of atopy is the main risk factor for children to develop AD, disturbances to the gut biome caused by exposure to antibiotics during or after pregnancy may be a factor, explained Mwenya Mubanga, MD, PhD, of the Department of Medical Epidemiology and Biostatistics as the Karolinska Institutet in Stockholm, Sweden, and colleagues. However, evidence for the association has been mixed.

In order to address discrepancies in previous analyses, Mubanga and colleagues conducted a large, population-wide, register based study of Swedish mother-and-child pairs to examine the link between antibiotic exposure in early life and the risk of AD in childhood. They used sibling control participants in an attempt to adjust for familial factors.

“In this cohort study, antibiotic use in prenatal and early postnatal life was associated with risk of atopic dermatitis in early childhood,” they reported in JAMA Network Open. “Although the association between maternal antibiotic use at any time during pregnancy and atopic dermatitis during childhood was confounded by familial (genetic and environmental) factors, the use of antibiotics during the first year of life was associated with risk of atopic dermatitis, although it was partly confounded by familial factors. Further research should be conducted to determine the underlying mechanisms and the atopic dermatitis phenotypes that are more likely to be associated with other conditions, such as asthma and allergic rhinitis.”

In an invited commentary accompanying the study, Ayman Grada, MD, of Boston University School of Medicine in Boston, and Christopher G. Bunick, MD, PhD, of Yale School of Medicine in New Haven, Connecticut, noted that when looking into the association between antibiotic exposure and negative outcomes linked to dysbiosis—or the imbalance of the body’s microbiota—it is important to consider the difference between broad- and narrow-spectrum antibiotics.

“Broad-spectrum antibiotics, such as doxycycline, azithromycin, amoxicillin and clavulanic acid, mupirocin, and fluoroquinolones, target a wide range of gram-positive and gram-negative bacteria, whereas narrow-spectrum antibiotics, such as vancomycin, fidaxomicin, and sarecycline, only target limited types of clinically relevant bacteria,” they explained.

Use of the latter has been encouraged by the CDC and is “among the main ways physicians will practice antibiotic stewardship in the future.” Comparatively, “treating skin conditions with broad-spectrum antibiotics is like using a bazooka to kill a mosquito and can severely harm the microbiome,” they argued.

Grada and Bunick concluded that the findings by Mubanga et al, as well as those from previous studies with mixed results on the associations between antibiotic use and AD, “strongly warrant additional investigation to explore the impact of antibiotics in AD and other inflammatory diseases, considering important aspects of antibiotics, including their spectrum of activity, mode of action, effect on resistance potentiation, dosing, duration of use, and route of administration,” while avoiding “painting narrow-spectrum and broad-spectrum with the same brush.”

For their analysis, Mubanga and colleagues used data on mother-child pairs from the Swedish Medical Birth Register for all singleton children born from March 1, 2006-Dec. 31, 2012 (n=730,774). The Medical Birth Register was linked to other national registers for information on health, socioeconomic, and demographic data. Patients were followed-up until an AD outcome, emigration from Sweden, death, or the end of the study on Dec. 31, 2015.

The study authors also conducted a sibling-control analysis “to account for a shared familial environment for both prenatal life and the first year of life as exposures,” they explained.

The study exposures were maternal exposure to systemic antibiotics during pregnancy and the child’s exposure to systemic antibiotics during the first year of life, as defined by a dispensed prescription in the Swedish Prescribed Drug Register. AD was defined as a compound outcome from the National Patient Register and the Swedish Prescribed Drug Register.

Of the 722,767 singleton children included in the final analysis, the mean age was 5.8 years and 48.6% were female. Over the course of follow-up, 21.2% were exposed to antibiotics in utero, while 23.8% were exposed during the first year of life.

“The risk of atopic dermatitis among children exposed to prenatal antibiotics was greater than that among children who were not exposed (adjusted hazard ratio [aHR], 1.10; 95% CI, 1.09-1.12),” the study authors found. “In the sibling-control analysis, no association was observed (aHR, 0.96; 95% CI; 0.92-1.00). Exposure to antibiotics during the first year of life was associated with a greater risk of atopic dermatitis (aHR, 1.52; 95% CI, 1.50-1.55), with attenuated associations in the sibling-control analysis (aHR, 1.24; 95% CI, 1.20-1.29).”

Mubanga and colleagues noted that the sibling-control design of their analysis was both a strength and a limitation. On the one hand, the sibling-control group allowed them to adjust for “unmeasured genetic and environmental confounders shared by siblings. We were able to adjust for some important covariates, including maternal history of asthma, mode of delivery, maternal history of tobacco use, and area of residence.”

On the other hand, they “could not rule out the possibility of residual confounding owing to factors not shared by siblings. We are aware that use of the sibling-control design may have resulted in some potential crossover effects and that the analysis design is more sensitive to measurement error.”

Additional limitations included that important variables were only available at antenatal booking, with no additional information during the first year of life; the difficulty in finding validated measures of eczema at the population level for children; and a possible misclassification of the outcome, as it’s possible only pediatric patients with the most severe forms of AD or those seen for other medical conditions are reported in the Prescribed Drug Register and National Patient Register.

  1. Maternal antibiotic use in prenatal and early postnatal life may be linked to incidence of atopic dermatitis (AD) in early childhood, though familial factors may confound the association.

  2. Further research should be conducted to explore the impact of antibiotics in AD and other inflammatory diseases.

John McKenna, Associate Editor, BreakingMED™

Study coauthor D’Onofrio reported receiving grants from the Swedish Initiative for Research on Microdata in the Social and Medical Sciences during the conduct of the study. Almqvist reported receiving grants from the Swedish Research Council, the Swedish Heart-Lung Foundation, Stiftelsen Frimurare Barnhuset in Stockholm, and the Strategic Research Program in Epidemiology at Karolinska Institutet during the conduct of the study.

Grada reported being the head of research and development at Almirall US, being a physician editor for both VisualDx and Merck Manuals, and receiving a small stipend for his role on the editorial board of the Journal of Investigative Dermatology. Bunick reported receiving honoraria for consulting and speaking for Allergan and Almirall, SA.

Cat ID: 449

Topic ID: 75,449,730,449,138,192,923,925

Author