A new study suggests that the most commonly prescribed drugs during pregnancy are associated with a host of long-term health implications in children.
In a systematic review and meta-analysis of studies that covered 23 outcomes in nearly 22 million children, researchers from Australia and Switzerland found that exposure to antibiotics any time during pregnancy was associated with increased risk of various immunologic, metabolic, and neurobehavioral adverse health outcomes in children, including food allergies, obesity, inflammatory bowel disease, asthma, cerebral palsy, and cancer.
The findings were published late last week in the Journal of Infection.
The findings are concerning, because millions of women take antibiotics during their pregnancy. In a separate review and meta-analysis published earlier in the year in the same journal, researchers found that roughly one in four women worldwide have consumed antibiotics at some point during their pregnancy.
The authors of this paper say that while their findings don't imply antibiotics are the cause of these long-term health impacts, they nonetheless underscore the need for careful antibiotic use during pregnancy.
Risks higher with late-pregnancy use, repeated exposure
The review, led by researchers from the University of Melbourne and the University of Fribourg, identified 158 studies that investigated the association between antibiotic exposure during pregnancy and the development of adverse long-term health outcomes in newborns, babies, and children and adolescents aged 18 and younger.
The included studies, all conducted in industrialized countries, investigated 1,233,099 cases and 20,720,664 controls. All were observational studies, except for one randomized controlled trial.
Of the 23 outcomes investigated, the meta-analysis found that antibiotic exposure was associated with atopic dermatitis (13 studies; odds ratio [OR], 1.27; 95% confidence interval [CI], 1.06 to 1.52), food allergies (8 studies; OR, 1.25; 95% CI, 1.09 to1.44), allergic rhinoconjunctivitis (3 studies; OR, 1.16; 95% CI, 1.15 to 1.17), wheezing (7 studies; OR, 1.39; 95% CI, 1.14 to 1.69), asthma (17 studies; OR, 1.36; 95% CI, 1.24 to 1.50), inflammatory bowel disease (1 study; OR, 2.03; 95% CI, 1.11 to 3.71), obesity (6 studies; OR, 1.36; 95% CI, 1.12 to 1.64), cerebral palsy (4 studies; OR, 1.25; 95% CI, 1.10 to 1.43), epilepsy or febrile seizure (5 studies; OR, 1.16; 95% CI, 1.08 to 1.24), and cancer (33 studies; OR, 1.13; 95% CI, 1.01 to 1.26).
Although most of the studies didn't investigate antibiotic exposure during different trimesters separately, those that did found a stronger association with adverse long-term outcomes during the third trimester, the authors note. In addition, several studies reported a stronger association after repeated courses of antibiotics. The highest risk associations were found with exposure to penicillins (4 studies) and macrolides (2 studies) compared with tetracyclines, sulphonamides, fluoroquinolones, and nitrofurantoin.
No significant associations were found between prenatal antibiotic exposure and the risk of congenital malformations, preterm delivery, low birth weight, developing allergic sensitization or symptoms, celiac disease, increased weight gain or being overweight, juvenile idiopathic arthritis, type 1 diabetes mellitus, autism spectrum disease, attention-deficit/hyperactivity disorder, or neurodevelopmental disorders.
Potential mechanisms
The authors say the link between prenatal antibiotic exposure and long-term health impacts in children is multifaceted. They hypothesize, based on findings from animal and in vitro studies, that the link could be explained by mechanisms such as intestinal barrier dysfunction, immune system dysregulation, maternal and fetal microbiome disruption, metabolic perturbations, and epigenetic changes.
The impact of antibiotics on the microbial community in the gut has also been a focus of studies examining the impacts of antibiotic exposure in infancy, when the gut microbiome is developing.
"Early antibiotic exposure has been linked to a higher risk of obesity and metabolic disorders, possibly due to alterations in microbial communities that affect nutrient harvest and metabolic signalling," the authors wrote. "Moreover, the gut-brain axis, mediated by the microbiome, is crucial for neurodevelopment. Antibiotic-induced changes to this system during critical periods may affect cognitive and behavioural outcomes."
But they caution that there are many research gaps and that other external factors not accounted for in observational studies could contribute to the observed associations.
"Whilst there are feasible mechanisms by which antibiotic-induced dysbiosis might results in adverse clinical outcomes through changes in the microbiome altering immunological and other developmental pathways, reverse causation (protopathic bias) cannot be excluded in observational studies (i.e. maternal conditions that predispose to adverse outcomes might lead to antibiotic prescribing)," they wrote. "Other confounding factors, such as maternal conditions, genetic predispositions, and environmental influences also play a role."
They conclude that longitudinal studies with detailed data on antibiotic types, dosages, timing, and maternal health will be essential for clarifying the mechanisms.
