Table 3.

List of meta-analyses and main studies associating antibiotics exposure and obesity

Research/year	Population, type of study	Antibiotic treatment	Main findings	Remarks
List of meta-analyses
Gough et al. 2014 [99]	4,316 children aged 1 month -12 y.o., from 7 countries (International study) Meta-analyses from 10 RCTs	I) Antibiotics administration II) Control group (no antibiotics administered)	↑ Weight by 23.8 g /month among children receiving antibiotics (95% CI: 4.3, 43.3)	✓ Antibiotics administration was related to increased weight.
Shao et al. 2017 [100]	445,880 children from developed countries, International study Systematic review and meta-analyses of 15 studies	I) Antibiotics administered prenatal and up to 23 months of age II) Control group (no antibiotics administered)	✓ ↑ Risk of childhood overweight (RR 1.23; 95% CI: 1.13, 1.35) ✓ ↑ Risk of childhood obesity (RR 1.21; 95% CI: 1.13, 1.30) ✓ For every additional course of antibiotics administered: ↑ 7% Risk of overweight (RR 1.07; 95% CI: 1.01, 1.15) ↑ 6% Risk of obesity (RR 1.06; 95% CI: 1.02, 1.09)	✓ Administration of antibiotics prenatal to 23 months of age was related to increased risk of obesity during childhood.
Wan et al. 2020 [101]	1,253,035 children, China Meta-analysis from 23 observational studies		✓ Prenatal exposure to antibiotics was not related to childhood overweight/obesity, whereas a higher risk of overweight/obesity was noted in the subgroup analysis of the second trimester (risk ratio = 1.13; 95% CI: 1.06–1.22; P = 0.001). ✓ Antibiotics administration during infancy may increase the risk of childhood overweight/obesity (risk ratio = 1.14; 95% CI: 1.06–1.23; P = 0.001).	✓ Antibiotics administration during the second trimester of pregnancy and infancy may increase the risk of childhood overweight/obesity.
List of main studies
Thuny et al. 2010 [102]	96 adults aged 45–77 y.ο with suspected IE, France Case-control study	I) Gentamicin + vancomycin II) Gentamicin + amoxicillin III) Other antibiotics IV) Control group (no antibiotics administered)	↑ BMI in patients treated with antibiotics, when compared to controls	✓ Antibiotic treatment may have an effect on weight gain.
Saiman et al. 2010 [103]	260 children aged 6–18 y.o. with cystic fibrosis, USA Multicenter, double blind placebo-controlled randomized study	I) Azithromycin II) Placebo	↑Weight (+ 0.58 kg, 95% Cl 0.14, 1.02) in patients administered with antibiotics	✓ Slight weight gain with antibiotics administration.
Ajslev et al. 2011 [104]	28,354 children aged 7 y.o. from the Danish National Birth Control, Denmark Prospective longitudinal study	Antibiotic treatment up to 6 months of age	Conflicting results	✓ Antibiotics administered early in life have a different effect on children’s weight, which may vary according to maternal BMI.
Francois et al. 2011 [105]	69 adults aged 50–78 y.o. referred for upper gastrointestinal endoscopy, USA Prospective cohort study	I) Amoxicillin + Clarithromycin + PPI in Helicobacter pylori positive adults II) None in Helicobacter pylori negative adults	↑ BMI (+ 5%) in patients receiving antibiotics	✓ ↑ Ghrelin and leptin levels among patients receiving antibiotics.
Trasande et al. 2013 [106]	11,532 children from the Avon Longitudinal Study of Parents and Children Cohort, UK Prospective longitudinal study	I) Antibiotics administered during the first 2 years of life II) Control group (no antibiotics administered)	✓ ↑ Odds of overweight at 38 months of age (OR: 1.22) ✓ ↑ BMI at 38 months of age	✓ Antibiotics administered during the first 6 months of life were related to increased odds of overweight during early childhood.
Murphy et al. 2014 [107]	74,946 children aged 5–8 years old from the International study of asthma and allergies in childhood, (International study) Secondary analysis from a multicenter cross-sectional study	I) Antibiotics administered during the first 12 months of life II) Control group (no antibiotics administered)	✓ ↑ BMI (+ 0.11) among boys administered antibiotics	✓ Antibiotics administration was related to a small increase in BMI in boys, but not girls during childhood.
Bailey et al. 2014 [108]	65,480 children aged 24 months to 59 months, USA Retrospective cohort study	I) Antibiotics administered during 0-23 months of life II) Control group (no antibiotics administered)	✓ ↑ Risk of obesity with increased and additive exposure to antibiotics (≥ 4 courses) (RR 1.11; 95% CI: 1.02, 1.21) ✓ ↑ Risk of obesity with antibiotics exposure during 0–5 months of age (RR 1.11; 95% CI: 1.03, 1.19), but lesser with exposure at 6–11 mo of age (RR 1.09; 95% CI: 1.04, 1.14)	✓ Antibiotics administration during the first 2 years of life was related to obesity in early childhood.
Azad et al. 2014 [109]	723 children aged 9–12 y.o., Canada Case-control study	I) Antibiotics administered during the 1 year of life II) Control group (no antibiotics administered)	✓ ↑ Risk of overweight if they received antibiotics during the 1 year of life (32.4% vs 18.2% at age 12) ✓ ↑Odds of overweight more marked in boys than girls (aOR: 5.35; 95% CI: 1.94, 14.72).	✓ Boys were more likely to be overweight at 12 years old, if they had received antibiotics during the 1 year of life.
Angelakis et al. 2014 [110]	82 adults aged 40–70 y.o. with IE from Q fever, France Case-control study	I) Doxycycline + hydroxychloroquine administered for at least 18 months II) Control group (no antibiotics administered)	Conflicting results	✓ Doxycycline + hydroxychloroquine administration resulted in both weight gain and weight loss.
Mikkelsen et al. 2015 [74]	12 adults aged 18–40 y.o., healthy men, Denmark Interventional study	I) Administration of gentamicin, meropenem and oral vancomycin	↑ Weight (+ 1.3 kg)	✓ A 4 days administration of antibiotics resulted in weight gain as well as increased YY peptide secretion
Saari et al. 2015 [111]	12,062 children aged > 24 months from a Finish birth control, Finland Population-based study	I) Antibiotics administration during the first 24 months of life II) Control group (no antibiotics administered)	↑ BMI with antibiotics administration (boys + 0.13 SDS, girls + 0.07 SDS)	✓ Antibiotics administration during the first 2 years of life was related to increased BMI SDS. The effect was more prominent with macrolides administration during the first 6 months (boys + 0.28 SDS, girls + 0.23 SDS)
Edmonson and Ei ckhoff, 2016 [112]	607 Children aged 2 months to 5.9 y.o. from the Randomized intervention for children with vesicoureteral reflux, USA Secondary analysis of data from a RCT	I) Trimethoprim-sulfamethoxazole treatment for 2 years II) Control group (no antibiotics administered)	No effect noted on the prevalence of overweight/obesity at 24 months (Antibiotic 24.8% vs Placebo 25.7%)	✓ Administration of trimethoprim-sulfamethoxazole for 2 years had no effect on weight among children with recurrent urinary tract infections.
Sc Scott et al. 2016 [113]	21,714 children aged 4 y.o. from the Health improvement network in the UK, UK Retrospective cohort study	I) Antibiotics administered before 2 years of age II) Control group (no antibiotics administered)	✓ ↑ Odds of obesity at 4 y (OR: 1.21; 95% CI: 1.07, 1.38) ✓ ↑ Odds of obesity with repeated administration of antibiotics: ✓ 3–5 prescriptions (OR: 1.41; 95% CI: 1.20, 1.65) ✓ ≥ 6 prescriptions (OR: 1.47; 95% CI: 1.19, 1.82)	✓ Antibiotics administration during the first 2 years of life was related to an increased odds of childhood obesity, especially if repeated exposure to antibiotics occurred.
Li et al. 2017 [114••]	26,0556 children aged 2–18 y.o. from the Kaiser permanente North California population, USA Longitudinal birth control study	I) Children with infection administered with antibiotics II) Children with infection not administered with antibiotics III) Control group (no infection and not antibiotics administered)	✓ No relationship between antibiotic use during infancy with odds of childhood obesity (OR: 1.01; 95% CI: 0.98, 1.04) ✓ ↑ Odds of childhood obesity in children with infection compared with controls (OR: 1.25; 95% CI: 1.20, 1.29)	✓ Infection rather than antibiotics administration during infancy was related to an increased odds of childhood obesity.
Stark et al. 2019 [115]	333,353 children from the US Department of defense TRICARE, USA Cohort study	I) Antibiotics administered during the first 24 months of age II) Histamine H2 receptors antagonists administration III) PPIs administration	✓ Antibiotics administration was related to childhood obesity (HR 1.26; 95% CI 1.23 to 1.28). ✓ This association persisted regardless of the antibiotic class, while it strengthened with each additional class of antibiotic administered.	✓ Antibiotics administered in the first 2 years of life are related to an increased risk of childhood obesity.
Kelly et al. 2019 [116]	8,286 children from the Irish national longitudinal study of children, Ireland Secondary longitudinal study	I) Antibiotics administration during the second and third years of life II) Control group (no antibiotics administered)	✓ Any antibiotic administration between 2 and 3 y.o. did not predict risk of overweight or obesity at age 5. ✓ ≥ 4 courses of antibiotics between 2 and 3 years of age were independently related to obesity at age 5 (odds ratio 1.6, 95% confidence interval 1.11–2.31)	✓ Number of antibiotic courses, rather than antibiotic use per se, is suggested to be an important factor in the link between early antibiotic exposure and childhood obesity.
Park et al. 2020 [117]	31,733 children aged 30–36 months and 4–6 y.o. from Korea, South Korea Retrospective cohort study	I) Antibiotics administration during the first 24 months of life II) Control group (no antibiotics administered)	✓ Children who used ≥ 5 antibiotic classes had higher odds of obesity than those who used only 1 class (OR 1.42, 95% CI 1.12–1.8). ✓ Children with > 180 days of antibiotics administration had increased risk of obesity than those with 1-–30 days of antibiotics administration (OR 1.40, 95% CI 1.19–1.64). ✓ Children with earlier antibiotics administration had increased risk of obesity (OR 1.15 per 6 months, 95% CI 1.08–1.22).	✓ Increased number of antibiotic classes, longer duration of antibiotic administration and earlier antibiotics administration (before 24 months of age) was related to childhood obesity at 30–36 months of age.
Chelimo et al. 2020[118]	6,853 children aged 54 months, New Zealand	I) Antibiotics administration during 48 months of age	✓ Administration of antibiotics for ≥ 9 times was related to an increased likelihood of obesity, when compared with no exposure (adjusted odds ratio, 2.41; 95% CI, 1.07–5.41). Children whose exposure began in the 1 year of life had a higher adjusted mean (SD) BMI-for-age z score than those not exposed (1.06 [0.05] vs 0.89 [0.09]; P = .03),	✓ Repeated antibiotics administration in early childhood was related to a higher mean BMI-for-age z score and an increased likelihood of obesity.

BMI body mass index, CI confidence intervals, HR hazard ratio, IE infective endocarditis, OR odds ratio, PPIs proton pump inhibitors, RCT randomized controlled trials, SDS standard deviation score, y.o. years old