Early-Life Antibiotic Exposure and the Risk of Overweight and Obesity in Children

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However, evidence associating the timing of antibiotic exposure to overweight and obesity is limited. Objectives The study explores whether the timing of early-life antibiotics or cumulative exposure is associated with childhood overweight and obesity. Methods This population-based cohort study included 33 095 children with 595 213 weight and height measurements linked to medical records and comprehensive national registers. Vaginally delivered children born in Northern Finland between the years 2007–2018 were followed until the end of 2019. Exposures included antibiotic exposure during the year before pregnancy, during pregnancy, in the perinatal period, and within the first 24 months of life. The primary outcomes were body mass index-for-age z-score (zBMI) at 24 months of age and the cumulative incidence of overweight and obesity up to 12 years of age. Analyses used linear mixed models and Cox hazard regression models adjusted for multiple covariates. Results Antibiotic exposure before pregnancy, during pregnancy, or in the perinatal period was not associated with subsequent overweight or obesity in children. In contrast, exposure during the first 24 months of life was linked to a higher zBMI at two years of age (mean difference in zBMI: 0.067 [95% CI, 0.041–0.094]) compared to unexposed children, after adjusting for covariates. Long-term analysis revealed an adjusted hazard ratio (HR) of 1.09 (95% CI 1.04–1.13) for overweight and 1.20 (95% CI, 1.10–1.31) for obesity. Conclusion Antibiotic exposure during the first two years of life was found to be associated with childhood overweight and obesity. No similar associations were observed for exposure before or at birth. Interventions aiming to reduce obesity-related effects should focus on minimizing early-life antibiotic use within the first two years of life. Health sciences/Medical research/Epidemiology Health sciences/Diseases/Endocrine system and metabolic diseases/Obesity Health sciences/Health care/Paediatrics Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction In 2022, over 159 million school-aged children and adolescents were affected by obesity—a nearly 25% increase from 1990. 1 While the etiology of obesity is multifactorial, individuals with obesity exhibit differences in gut microbiota composition and diversity compared to their lean counterparts. 2 , 3 Furthermore, changes in early-life gut microbiota have been linked to obesity in later childhood. 4 – 7 Children are widely exposed to antimicrobials in early life: approximately one-fourth are exposed to antibiotics during pregnancy, 8 one-third during vaginal birth, 9 and over half during the first two years of life. 10 Notably, perinatal antibiotic exposure has been linked to disruptions in children’s gut microbiota. 11 – 13 Interestingly, maternal microbiota may communicate with the developing fetus through microbiota-derived extracellular vesicles and metabolites even before birth. 14 , 15 Although antibiotic exposure in early childhood has been associated with an increased risk of weight gain in children, 16 – 20 the effects of antibiotic exposure during pregnancy and birth on weight gain remain more controversial (full literature review in the Supplement, Supplementary Table 1). 20 – 35 It is unclear whether children are more sensitive to obesity-related antibiotic exposure at specific time points in early life or whether cumulative exposure across time periods contributes to greater weight gain. In this population-based study of 33 095 vaginally delivered children, followed from before pregnancy up to 12 years of age, we examined the relationship between early-life antibiotic exposure and subsequent weight gain in children. We aimed to investigate whether the timing or cumulative exposure of early-life antibiotics is associated with an increased risk of overweight and obesity in childhood. Methods Study Cohort The study was a population-based, register-based prospective cohort study. Participants included vaginally delivered children born between January 1, 2007, and December 31, 2018, in Oulu University Hospital and Oulaskangas Hospital in Northern Finland. Mothers of the participants were followed one year before pregnancy until birth, and the children were followed from birth until December 31, 2019, or earlier if death or outmigration from Finland occurred. Data were obtained from national comprehensive registers as well as hospitals’ electronic medical records (Supplementary material). Growth data were retrieved from standardized growth measurements performed in child health clinics and schools. Permission for the study was granted by the National Institute for Health and Welfare, Helsinki, Finland (decision number THL/1522/5.05.00/2019). In Finland, register-based studies do not require separate medical ethics committee approval or individual consent. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. We have previously published data on intrapartum antibiotic exposure and immune-related and infectious diseases in childhood based on the same study cohort. 36 , 37 Inclusion and Exclusion Criteria Inclusion criteria were as follows: vaginally delivered child, gestation age ≥ 34 weeks, and the mother’s residence in North Ostrobothnia. Vaginal deliveries were selected because current guidelines recommend prophylactic antibiotics for all caesarean deliveries, 38 precluding the possibility of a control group without antibiotic exposure. Exclusion criteria were as follows: a major congenital anomaly defined by the European network of population-based registries for the epidemiologic surveillance of congenital anomalies (EUROCAT) and growth hormone therapy, identified by purchases of somatotropin or somatotropin agonists (anatomic-therapeutic-chemical [ATC] code H01AC) (Fig. 1 ). Antibiotic Exposures The timing of antibiotic exposure was classified as follows: 1) 12 months before pregnancy, 2) during pregnancy until 24 hours before birth, 3) perinatal exposure, including intrapartum antibiotic exposure (≤ 24 hours before birth and/or 0–6 days postnatal), and 4) early childhood exposure (7 days to 24 months). Exposure during pregnancy was further categorized by trimester, and childhood exposure was divided into the first six months and 6–24 months of life (Figs. 1 – 2 ). Additionally, we identified 16 groups based on children’s antibiotic exposure across these four periods. Data on antibiotic exposure one year before the beginning of pregnancy, during pregnancy, and in childhood were obtained from the National Health Insurance register, which includes all drug purchases from pharmacies according to their ATC codes. Data on perinatal antibiotic exposure, including intrapartum antibiotic exposure and postnatal antibiotic exposure, were collected from hospital’s structured electronic medical records. Growth Measurements and Growth Outcomes In Finland, trained nurses regularly measure children’s height and weight within the public healthcare system. Measurements are performed at least nine times in the first 12 months of life and then annually up to the age of 15 years. 39 According to Finnish Institute for Health and Welfare, 86% of children aged 1–2 years, 77% of those aged 3–6 years, and 76% of school-aged children participate in these examinations. 40 Standardized length or height and weight measurements were converted into body mass index (BMI) (weight [kg]/height [m] 2 ), BMI-for-age z-scores (zBMIs), and height-for-age z-scores (zHFAs) using Finnish national growth references. 41 Overweight and obesity were defined based on zBMI cutoffs corresponding to BMI values of 25 kg/m 2 and 30 kg/m 2 at age 18, respectively. 41 The first growth outcome was children’s zBMI and zHFA at 24 months (+/–3). The second outcome was the cumulative incidence of overweight and obesity up to 12 years of age. Covariates Study covariates included maternal age, parity, pre-pregnancy BMI, gestational diabetes, hypertensive disorders of pregnancy, smoking during pregnancy, prolonged rupture of membranes, mother’s highest education level, occupational status, maternal asthma, maternal autoimmune or neurodevelopmental disease diagnosis, gestational age, child’s birth year, sex, and birth weight. Maternal diagnoses were tracked for two years prior to pregnancy through the follow-up period. Data for the study covariates was obtained from national registers, including the Finnish Medical Birth Register, the Care Register for Health Care, and Statistics Finland, as well as electronic medical records. Study Sample Size Based on national estimates indicating that 22% of the Finnish children aged 2–16 years are overweight (ISO-BMI > 25 kg/m 2 ) and 6% (ISO-BMI > 30 kg/m 2 ) are with obesity, 42 the sample size was calculated with a significance level of 0.05, power of 80% and hazard ratio of 1.3. The required sample size (1:3) was determined to be 465 cases and 1,395 controls for overweight and 2097 cases and 6291 controls for obesity. The study cohort was deemed sufficient to meet these requirements. Data Cleaning and Validation Data cleaning involved the removal of clear typing errors, duplicate measurements, and outliers, resulting in the exclusion of 2231 measurements. Additionally, two authors (SA, MP) reviewed the growth curves for children whose height measurements deviated by more than 1.5 SDs, or whose relative weight percentage differed by more than 50%, between adjacent measurement points. Among the 1782 reviewed growth curves, 137 data points were excluded. Statistical Analysis The mean zBMI and zHFA values at 24 months of age were compared across antibiotic exposure groups. Differences between exposed and unexposed groups were analyzed using linear mixed models and pairwise comparisons, adjusting for birth year and sex in the first model and for all covariates in the second. Cumulative incidences of overweight and obesity from 24 months to the end of follow-up were compared across exposure groups using Cox proportional hazards regression. The first model adjusted for child’s birth year and sex, while the second adjusted for all covariates. Cumulative incidence curves were produced using survival function based on the fitted model hazard. Martingale residual plots confirmed no violations of linearity or proportional hazards assumptions (Supplementary Figs. 4–15). Deaths during the follow-up period were treated as competing risks. Analyses were conducted by statistician TP using IBM SPSS Statistics for Windows, version 29.0 (IBM Corp, Armonk, NY) and Stata Statistical Software, version 16 (StataCorp LLC, College Station, TX). Results Study Population The final study cohort comprised 33 095 children, with a total of 595 213 weight and height measurements (Fig. 1 , Supplementary Table 2). The mothers of 12 869 (38.9%) children were exposed to antibiotics one year before the beginning of pregnancy, and 9 073 (27.4%) mothers received antibiotics during pregnancy. In total, 6 983 (21.1%) children were exposed to perinatal antibiotics, and 22 453 (67.8%) children were exposed to antibiotics in the first 24 months of life. Seven (0.02%) deaths occurred during follow-up (Supplementary Table 2). Body Mass Index at Two Years of Age No significant association was found between zBMI at 24 months of age and antibiotic exposure one year before pregnancy, during pregnancy (any trimester), or perinatally (Fig. 2 , Supplementary Table 3). However, children exposed to antibiotics during the first six months of life or between six and 24 months of life exhibited higher zBMI at 24 months of age compared to unexposed children in an adjusted analysis (Fig. 2 , Supplementary Table 3). Next, we investigated the association of cumulative antibiotic exposure from one year before pregnancy until 24 months of age with zBMI at 24 months of age (Supplementary Fig. 16, Supplementary Tables 4–5). Higher zBMI at 24 months of age was observed in children who, in addition to childhood antibiotic exposure, were exposed to antibiotics one year before the beginning of pregnancy, during pregnancy, and perinatally in adjusted analyses (Supplementary Fig. 16, Supplementary Table 5). Childhood Overweight and Obesity The mean follow-up duration was 7.3 years, with a maximum of 12 years (Supplementary Table 2). In total, 10 710 (32.3%) children were with overweight (including obesity), while 2 726 (8.2%) were with obesity after 24 months of age. Antibiotic exposure one year before pregnancy was associated with an increased risk of childhood overweight (aHR 1.04 [95% CI, 1.001–1.08] (Fig. 3 , Supplementary Table 6) but not obesity (aHR 1.05 [95%, CI 0.97–1.14]) (Fig. 4 ). Antibiotic exposure during pregnancy or perinatally was not associated with childhood overweight or obesity (Figs. 4 –5). Perinatal antibiotic exposure was not associated with childhood overweight or obesity in adjusted analyses (Figs. 3 – 4 , Supplementary Table 6). Antibiotic exposure in the first 24 months of life was associated with subsequent overweight (aHR 1.09 [95% CI, 1.04–1.13]) (Fig. 4 , Supplementary Table 6) and obesity (aHR 1.20 [95% CI, 1.10–1.31]) (Figs. 3 – 4 , Supplementary Table 6). Growth in Height at Two Years of Age Higher zHFA at 24 months was associated with antibiotic exposure one year before pregnancy, during the first trimester, and within the first 6–24 months of life (Supplementary Tables 7–9, Supplementary Figs. 19–20). Discussion In this population-based cohort study of 33 095 children and their mothers, followed from one year before pregnancy up to 12 years of age, antibiotic exposure in the first two years of life was associated with childhood overweight and obesity. However, no similar associations were observed for antibiotic exposure before pregnancy, during pregnancy, or in the perinatal period. Most prior studies have examined associations between early-life antibiotics and overweight or obesity using one to two time points of antibiotic exposure (see summary of 75 studies in the Supplement). The timing of early antibiotic exposure has been specifically investigated in two cohorts. 20 , 33 , 34 In the a cohort of 156 381 vaginally delivered children in the US Kaiser-Permanente health system, exposure to intrapartum antibiotic prophylaxis was associated with a higher BMI in childhood, whereas other intrapartum antibiotics showed no association, and neonatal exposure was linked to a lower BMI. 33 , 34 In our study, these subgroups were combined into a perinatal exposure group, which was not associated with overweight or obesity in childhood. Consistent with the Kaiser-Permanente cohort, we found that childhood antibiotic exposure was associated with overweight or obesity in childhood. 36 A study involving a U.S. cohort of 8 793 children in Pennsylvania reported no association between prenatal antibiotic exposure and weight gain but did observe an association with repeated childhood antibiotic courses, as seen in the present study. 20 In this study, antibiotic exposure during the first two years of life was associated with a higher zBMI at two years of age as well as with childhood overweight and obesity up to the age of 12 years. These findings align with several studies identifying early childhood as a sensitive period during which antibiotic exposure is associated with weight gain. 16 – 20 , 34 , 43 – 49 Even after adjusting for various confounding factors, however, the possibility of unmeasured confounding remains. For example, children from families in environments conducive to obesity may be more likely to receive antibiotics. Nonetheless, promoting antimicrobial stewardship in young children is crucial for broader public health reasons. 50 We found no association between maternal antibiotic exposure before pregnancy and childhood obesity, consistent with a previous study reporting no association. 23 Research on antibiotic exposure during pregnancy and subsequent childhood weight gain has yielded conflicting results, with some studies finding associations based on specific trimesters, 27 , 51 , 34 repeated antibiotic courses, 51 , 52 or variations based on sex 25 , 27 and birth weight. 26 However, consistent with our findings, cohort studies utilizing electronic health record data have generally reported no association between antibiotic exposure during pregnancy and childhood weight gain or obesity, with follow-up times ranging from five to 11 years. 21 , 47 Additionally, a sibling analysis of 151,359 children showed no link between antibiotic exposure during pregnancy and childhood obesity. 23 The growth-promoting effects of antibiotics have been well documented since the 1950s in farm animals, with proposed mechanisms including gut microbiome alterations. 53 In mouse models, antibiotic exposure after birth has been shown to influence gut microbiota, increase body fat, and induce obesity when microbiota from exposed mice are transferred to their germ-free counterparts. 54 Similarly, perinatal antibiotic exposure has been associated with gut microbiome alterations in human infants, 11 , 12 and antibiotic exposure during infancy has been linked to changes in the gut microbiome, weight gain, and childhood adiposity. 48 , 55 , 56 In our previous research, we reported that perinatal antibiotic exposure affected the infant gut microbiota even after the first year of life, with a greater impact than later antibiotic courses. 11 However, in this study, perinatal antibiotics were not associated with overweight or obesity in children. Emerging research suggests that maternal microbiota may interact with the fetus through maternal metabolites or microbiota-derived extracellular vesicles. 14 , 15 However, we found no association between maternal antibiotic exposure prior to birth and offspring overweight or obesity. While childhood obesity has risen globally in recent decades, the growth-promoting effects of antibiotics may have context-dependent benefits. For example, in low-income settings, Malawian children whose mothers received two doses of azithromycin during pregnancy, alongside improved malaria prevention, were taller and heavier up to five years of age. 57 However, biannual or annual mass azithromycin administration after birth did not seem to improve children’s growth in low-income settings. 58 , 59 A key strength of this study is the use of Finland’s national comprehensive registers and electronic health records, enabling the examination of antibiotic exposure at various time points in the same population and adjustment for several important covariates. We were able to explore antibiotic exposure starting one year before pregnancy and continuing into early childhood, whereas previous studies mostly focused on one or two antibiotic exposure time points. High-quality growth data were obtained from child health clinics and school health services for children up to 12 years of age, with minimal missing data. Additionally, deaths during the follow-up period were treated as competing risk. The main limitation of the study is the observational design, which allows us to report only associations, not causality. Even after adjusting for several covariates, it is possible that other unmeasured factors, such as infections themselves, treatment seeking, or physician’s prescription behavior, could be associated with subsequent obesity. Moreover, while antibiotic exposure before and during pregnancy and in childhood was determined based on purchase records, we did not have data on medication compliance. We used the current definitions for overweight and obesity based on BMI-values, however, the pragmatic definition criteria for obesity has been suggested to include other anthropometric measurements as well. 60 Data on ethnicity or breastfeeding were also unavailable, as they are not recorded in national registers in Finland. In conclusion, antibiotic exposure during the first two years of life was associated with childhood overweight and obesity. No similar associations were observed for antibiotic exposure before pregnancy, during pregnancy, or in the perinatal period. Public health interventions aiming to mitigate the obesity-related effects of early-life antibiotics should focus on the first two years of life. Authors’ contributions: SA was responsible for designing and concepting the study, cleaning and validating of the data, analyzing and interpretation of the data, performing the literature review, and drafting the manuscript. MP was responsible for designing and concepting the study, cleaning and validating of the data, interpretation of the data, performing the literature review and drafting the manuscript. ER was responsible for designing and concepting the study, acquiring of the data, interpretation of the data and drafting the manuscript. TP was responsible for designing the study, analyzing and interpretation of the data, and revising the manuscript for intellectual content. MH was responsible for designing and concepting the study, interpretation of the data, and drafting the manuscript. EK was responsible for designing and concepting the study, interpretation of the data and revising the manuscript for intellectual content. NP was responsible for designing and concepting the study, acquiring of the data, interpretation of the data and revising the manuscript for intellectual content. TR-L was responsible for designing and concepting the study, analyzing and interpretation of the data and revising the manuscript for intellectual content. TP and TR-L had full access to all the data in the study and were responsible for the integrity of the data and the accuracy of the data analysis. Declarations Competing interests: The authors declare no competing financial interests. Sources of funding and support The study was supported by the Pediatric Research Foundation, Finland, Alma och K.A. Snellman Foundation, Finnish Medical Foundation, University of Oulu and the Academy of Finland Profi6 AF 336449, Competitive Government Funding for Clinical Research (VTR), Academy of Finland, Sigrid Jusélius Foundation, and the Signe and Ane Gyllenberg Foundation. Role of the Funder/Sponsor The study supporters had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Data Availability Statement: The key elements of data will be shared upon reasonable request for clinical research purposes. Requests should be sent to Professor Terhi Ruuska-Loewald ( [email protected] ) with a full research plan. 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Implementation and impact of pediatric antimicrobial stewardship programs: a systematic scoping review. Antimicrob Resist Infect Control 2020; 9: 3. Wang B, Liu J, Zhang Y, Yan C, Wang H, Jiang F et al. Prenatal Exposure to Antibiotics and Risk of Childhood Obesity in a Multicenter Cohort Study. Am J Epidemiol 2018; 187: 2159–2167. Chelimo C, Camargo Jr CA, Morton SMB, Grant CC. Association of Repeated Antibiotic Exposure Up to Age 4 Years With Body Mass at Age 4.5 Years. JAMA Netw Open 2020; 3: e1917577–e1917577. JUKES TH, WILLIAMS WL. Nutritional effects of antibiotics. Pharmacol Rev 1953; 5: 381–420. Cox LM, Yamanishi S, Sohn J, Alekseyenko A V, Leung JM, Cho I et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 2014; 158: 705–721. Korpela K, Zijlmans MAC, Kuitunen M, Kukkonen K, Savilahti E, Salonen A et al. Childhood BMI in relation to microbiota in infancy and lifetime antibiotic use. Microbiome 2017; 5: 26. Li P, Chang X, Chen X, Wang C, Shang Y, Zheng D et al. Early-life antibiotic exposure increases the risk of childhood overweight and obesity in relation to dysbiosis of gut microbiota: a birth cohort study. Ann Clin Microbiol Antimicrob 2022; 21: 46. Hallamaa L, Cheung YB, Maleta K, Luntamo M, Ashorn U, Gladstone M et al. Child Health Outcomes After Presumptive Infection Treatment in Pregnant Women: A Randomized Trial. Pediatrics 2018; 141. doi: 10.1542/peds.2017-2459 . Burr SE, Hart J, Edwards T, Harding-Esch EM, Holland MJ, Mabey DCW et al. Anthropometric indices of Gambian children after one or three annual rounds of mass drug administration with azithromycin for trachoma control. BMC Public Health 2014; 14: 1176. Arzika AM, Maliki R, Ali MM, Alio MK, Abdou A, Cotter SY et al. Effect of Mass Azithromycin Distributions on Childhood Growth in Niger. JAMA Netw Open 2021; 4: e2139351. Rubino F, Cummings DE, Eckel RH, Cohen R V, Wilding JPH, Brown WA et al. Definition and diagnostic criteria of clinical obesity. Lancet Diabetes Endocrinol 2025. doi: 10.1016/S2213-8587(24)00316-4 . Additional Declarations There is NO conflict of interest to disclose Supplementary Files SupplementaryTable1.docx Supplementary Table 1. Literature review of early antibiotic exposure and weight gain in children. 4.5Int.J.Obes.Ainonenetal.SupplementEarlyLifeAntibioticExposureandtheRiskofOverweightandObesityinChildren.docx Supplementary material for the manuscript: S. Ainonen, M. Paalanne, E. Ronkainen, T. Pokka, M. Honkila, E. Kajantie, N. Paalanne, T. Ruuska-Loewald. Early-Life Antibiotic Exposure and the Risk of Over Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Ainonen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIiWNgGAWjYFACxgcHgCQPhFPBwMAHpD4k4NXCbICk5QwDAxvQlBmEtCDZ2AbVgk+DfHsz44EfDHYy5uy9Bx8XzrNJbJNIYGx4gEeLwZnDDAd7GJJ5LHvOJRvP3JYG0YLPYQYS+QcO8DAw8xjcyDGT5t12GKSF/QE+LfIzkhkO/mGoB2kx/8075zBhWxhuJDMc5gEikC3MvA1EaAH55bCMwXEegzNnjKV5jqUZt/E8bMSrBRhizB/fVFTbGxzvMfzMU2Mj28+efLDxBz6HQexC4TE2ENQwCkbBKBgFowA/AACVBkqgkSN7PwAAAABJRU5ErkJggg==","orcid":"","institution":"1) University of Oulu 2) Oulu University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Sofia","middleName":"","lastName":"Ainonen","suffix":""},{"id":454392459,"identity":"8597b86a-97ab-47d1-a1ba-6df820834802","order_by":1,"name":"Marika Paalanne","email":"","orcid":"","institution":"1) University of Oulu 2-3) Oulu University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Marika","middleName":"","lastName":"Paalanne","suffix":""},{"id":454392460,"identity":"5ecd773b-9935-41d6-ba69-9caff3243c3f","order_by":2,"name":"Eveliina Ronkainen","email":"","orcid":"","institution":"1) University of Oulu 2-3) Oulu University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Eveliina","middleName":"","lastName":"Ronkainen","suffix":""},{"id":454392461,"identity":"3daf1f32-6ac1-48a3-8e99-831a41fdd452","order_by":3,"name":"Tytti Pokka","email":"","orcid":"","institution":"1) University of Oulu 2) Oulu University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tytti","middleName":"","lastName":"Pokka","suffix":""},{"id":454392462,"identity":"daa5342d-578e-4c78-9be2-9ce28c3373d7","order_by":4,"name":"Minna Honkila","email":"","orcid":"","institution":"1) University of Oulu 2-3) Oulu University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Minna","middleName":"","lastName":"Honkila","suffix":""},{"id":454392463,"identity":"d48cef96-2188-40d4-a69d-e5d52492bb4b","order_by":5,"name":"Eero Kajantie","email":"","orcid":"","institution":"1) Research Unit of Clinical Medicine 2) Population Health Unit 3) Department of Clinical and Molecular Medicine","correspondingAuthor":false,"prefix":"","firstName":"Eero","middleName":"","lastName":"Kajantie","suffix":""},{"id":454392464,"identity":"7810e633-c1d9-4a83-b89f-37fc80d8173a","order_by":6,"name":"Niko Paalanne","email":"","orcid":"","institution":"University of Oulu","correspondingAuthor":false,"prefix":"","firstName":"Niko","middleName":"","lastName":"Paalanne","suffix":""},{"id":454392465,"identity":"96a3b0a8-a9c9-4eaa-aac6-b0bf27d18773","order_by":7,"name":"Terhi Ruuska-Loewald","email":"","orcid":"","institution":"University of Oulu","correspondingAuthor":false,"prefix":"","firstName":"Terhi","middleName":"","lastName":"Ruuska-Loewald","suffix":""}],"badges":[],"createdAt":"2025-05-08 18:00:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6622850/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6622850/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82795018,"identity":"dcaaf481-d585-4f2a-998a-d0cab1ead25b","added_by":"auto","created_at":"2025-05-15 10:31:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":35136,"visible":true,"origin":"","legend":"\u003cp\u003eLegend: Study Design.\u003c/p\u003e","description":"","filename":"Ainonenetal.Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6622850/v1/5d60227b5a0f9c26d5887c36.png"},{"id":82795019,"identity":"bcdb272c-508e-4180-872a-fecd47a45387","added_by":"auto","created_at":"2025-05-15 10:31:52","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":33666,"visible":true,"origin":"","legend":"\u003cp\u003eLegend: Mean differences of body mass index-for-age Z-scores (zBMIs) at 24 months of age between children exposed to antibiotics and those not expose in analyses adjusted for all covariates.\u003c/p\u003e","description":"","filename":"Ainonenetal.Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6622850/v1/b6bd7a40ecf03eb9679386ae.png"},{"id":82795021,"identity":"f32c1927-c8d9-4be9-a2e9-a45931325780","added_by":"auto","created_at":"2025-05-15 10:31:52","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":933559,"visible":true,"origin":"","legend":"\u003cp\u003eLegend: Cumulative incidences of childhood overweight in children exposed to early antibiotics compared to unexposed ones in analyses adjusted for all covariates.\u003c/p\u003e","description":"","filename":"Ainonenetal.Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6622850/v1/53eb108e1634bb647224047f.png"},{"id":82796606,"identity":"d2ba3293-0b6c-4681-b0c6-811954d68d5e","added_by":"auto","created_at":"2025-05-15 10:39:52","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":919565,"visible":true,"origin":"","legend":"\u003cp\u003eLegend:\u003cstrong\u003e \u003c/strong\u003eCumulative incidences of childhood obesity in children exposed to early antibiotics compared to unexposed ones in analyses adjusted for all covariates.\u003c/p\u003e","description":"","filename":"Ainonenetal.Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-6622850/v1/95a45853509e454cc8dbbc73.png"},{"id":86018407,"identity":"a4eb1422-4000-4937-a530-1dffd86536cb","added_by":"auto","created_at":"2025-07-04 11:20:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2531362,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6622850/v1/c4a492a2-fd10-421c-8035-599cba55cc3d.pdf"},{"id":82795020,"identity":"87cf6986-4486-4b62-86b7-159951cad7e5","added_by":"auto","created_at":"2025-05-15 10:31:52","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":128772,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 1. Literature review of early antibiotic exposure and weight gain in children.\u003c/p\u003e","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6622850/v1/a039cb7b57508369bc96509b.docx"},{"id":82795027,"identity":"675748ae-e27b-4e3c-9f06-7f3c3ddec997","added_by":"auto","created_at":"2025-05-15 10:31:52","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":2041097,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary material for the manuscript: S. Ainonen, M. Paalanne, E. Ronkainen, T. Pokka, M. Honkila, E. Kajantie, N. Paalanne, T. Ruuska-Loewald. Early-Life Antibiotic Exposure and the Risk of Over\u003c/p\u003e","description":"","filename":"4.5Int.J.Obes.Ainonenetal.SupplementEarlyLifeAntibioticExposureandtheRiskofOverweightandObesityinChildren.docx","url":"https://assets-eu.researchsquare.com/files/rs-6622850/v1/55aaa699e8a26197edc70618.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose","formattedTitle":"Early-Life Antibiotic Exposure and the Risk of Overweight and Obesity in Children","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn 2022, over 159\u0026nbsp;million school-aged children and adolescents were affected by obesity\u0026mdash;a nearly 25% increase from 1990.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e While the etiology of obesity is multifactorial, individuals with obesity exhibit differences in gut microbiota composition and diversity compared to their lean counterparts.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Furthermore, changes in early-life gut microbiota have been linked to obesity in later childhood.\u003csup\u003e\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eChildren are widely exposed to antimicrobials in early life: approximately one-fourth are exposed to antibiotics during pregnancy,\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e one-third during vaginal birth,\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e and over half during the first two years of life.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Notably, perinatal antibiotic exposure has been linked to disruptions in children\u0026rsquo;s gut microbiota.\u003csup\u003e\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Interestingly, maternal microbiota may communicate with the developing fetus through microbiota-derived extracellular vesicles and metabolites even before birth.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Although antibiotic exposure in early childhood has been associated with an increased risk of weight gain in children,\u003csup\u003e\u003cspan additionalcitationids=\"CR17 CR18 CR19\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e the effects of antibiotic exposure during pregnancy and birth on weight gain remain more controversial (full literature review in the Supplement, Supplementary Table\u0026nbsp;1).\u003csup\u003e\u003cspan additionalcitationids=\"CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e It is unclear whether children are more sensitive to obesity-related antibiotic exposure at specific time points in early life or whether cumulative exposure across time periods contributes to greater weight gain.\u003c/p\u003e \u003cp\u003eIn this population-based study of 33 095 vaginally delivered children, followed from before pregnancy up to 12 years of age, we examined the relationship between early-life antibiotic exposure and subsequent weight gain in children. We aimed to investigate whether the timing or cumulative exposure of early-life antibiotics is associated with an increased risk of overweight and obesity in childhood.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Cohort\u003c/h2\u003e \u003cp\u003eThe study was a population-based, register-based prospective cohort study. Participants included vaginally delivered children born between January 1, 2007, and December 31, 2018, in Oulu University Hospital and Oulaskangas Hospital in Northern Finland. Mothers of the participants were followed one year before pregnancy until birth, and the children were followed from birth until December 31, 2019, or earlier if death or outmigration from Finland occurred. Data were obtained from national comprehensive registers as well as hospitals\u0026rsquo; electronic medical records (Supplementary material). Growth data were retrieved from standardized growth measurements performed in child health clinics and schools. Permission for the study was granted by the National Institute for Health and Welfare, Helsinki, Finland (decision number THL/1522/5.05.00/2019). In Finland, register-based studies do not require separate medical ethics committee approval or individual consent. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. We have previously published data on intrapartum antibiotic exposure and immune-related and infectious diseases in childhood based on the same study cohort.\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eInclusion and Exclusion Criteria\u003c/h3\u003e\n\u003cp\u003eInclusion criteria were as follows: vaginally delivered child, gestation age\u0026thinsp;\u0026ge;\u0026thinsp;34 weeks, and the mother\u0026rsquo;s residence in North Ostrobothnia. Vaginal deliveries were selected because current guidelines recommend prophylactic antibiotics for all caesarean deliveries,\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e precluding the possibility of a control group without antibiotic exposure. Exclusion criteria were as follows: a major congenital anomaly defined by the European network of population-based registries for the epidemiologic surveillance of congenital anomalies (EUROCAT) and growth hormone therapy, identified by purchases of somatotropin or somatotropin agonists (anatomic-therapeutic-chemical [ATC] code H01AC) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eAntibiotic Exposures\u003c/h3\u003e\n\u003cp\u003eThe timing of antibiotic exposure was classified as follows: 1) 12 months before pregnancy, 2) during pregnancy until 24 hours before birth, 3) perinatal exposure, including intrapartum antibiotic exposure (\u0026le;\u0026thinsp;24 hours before birth and/or 0\u0026ndash;6 days postnatal), and 4) early childhood exposure (7 days to 24 months). Exposure during pregnancy was further categorized by trimester, and childhood exposure was divided into the first six months and 6\u0026ndash;24 months of life (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Additionally, we identified 16 groups based on children\u0026rsquo;s antibiotic exposure across these four periods.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eData on antibiotic exposure one year before the beginning of pregnancy, during pregnancy, and in childhood were obtained from the National Health Insurance register, which includes all drug purchases from pharmacies according to their ATC codes. Data on perinatal antibiotic exposure, including intrapartum antibiotic exposure and postnatal antibiotic exposure, were collected from hospital\u0026rsquo;s structured electronic medical records.\u003c/p\u003e\n\u003ch3\u003eGrowth Measurements and Growth Outcomes\u003c/h3\u003e\n\u003cp\u003eIn Finland, trained nurses regularly measure children\u0026rsquo;s height and weight within the public healthcare system. Measurements are performed at least nine times in the first 12 months of life and then annually up to the age of 15 years.\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e According to Finnish Institute for Health and Welfare, 86% of children aged 1\u0026ndash;2 years, 77% of those aged 3\u0026ndash;6 years, and 76% of school-aged children participate in these examinations.\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eStandardized length or height and weight measurements were converted into body mass index (BMI) (weight [kg]/height [m]\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e), BMI-for-age z-scores (zBMIs), and height-for-age z-scores (zHFAs) using Finnish national growth references.\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e Overweight and obesity were defined based on zBMI cutoffs corresponding to BMI values of 25 kg/m\u003csup\u003e2\u003c/sup\u003e and 30 kg/m\u003csup\u003e2\u003c/sup\u003e at age 18, respectively.\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e The first growth outcome was children\u0026rsquo;s zBMI and zHFA at 24 months (+/\u0026ndash;3). The second outcome was the cumulative incidence of overweight and obesity up to 12 years of age.\u003c/p\u003e\n\u003ch3\u003eCovariates\u003c/h3\u003e\n\u003cp\u003eStudy covariates included maternal age, parity, pre-pregnancy BMI, gestational diabetes, hypertensive disorders of pregnancy, smoking during pregnancy, prolonged rupture of membranes, mother\u0026rsquo;s highest education level, occupational status, maternal asthma, maternal autoimmune or neurodevelopmental disease diagnosis, gestational age, child\u0026rsquo;s birth year, sex, and birth weight. Maternal diagnoses were tracked for two years prior to pregnancy through the follow-up period. Data for the study covariates was obtained from national registers, including the Finnish Medical Birth Register, the Care Register for Health Care, and Statistics Finland, as well as electronic medical records.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStudy Sample Size\u003c/h2\u003e \u003cp\u003eBased on national estimates indicating that 22% of the Finnish children aged 2\u0026ndash;16 years are overweight (ISO-BMI\u0026thinsp;\u0026gt;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e) and 6% (ISO-BMI\u0026thinsp;\u0026gt;\u0026thinsp;30 kg/m\u003csup\u003e2\u003c/sup\u003e) are with obesity,\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e the sample size was calculated with a significance level of 0.05, power of 80% and hazard ratio of 1.3. The required sample size (1:3) was determined to be 465 cases and 1,395 controls for overweight and 2097 cases and 6291 controls for obesity. The study cohort was deemed sufficient to meet these requirements.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData Cleaning and Validation\u003c/h3\u003e\n\u003cp\u003eData cleaning involved the removal of clear typing errors, duplicate measurements, and outliers, resulting in the exclusion of 2231 measurements. Additionally, two authors (SA, MP) reviewed the growth curves for children whose height measurements deviated by more than 1.5 SDs, or whose relative weight percentage differed by more than 50%, between adjacent measurement points. Among the 1782 reviewed growth curves, 137 data points were excluded.\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eThe mean zBMI and zHFA values at 24 months of age were compared across antibiotic exposure groups. Differences between exposed and unexposed groups were analyzed using linear mixed models and pairwise comparisons, adjusting for birth year and sex in the first model and for all covariates in the second.\u003c/p\u003e \u003cp\u003eCumulative incidences of overweight and obesity from 24 months to the end of follow-up were compared across exposure groups using Cox proportional hazards regression. The first model adjusted for child\u0026rsquo;s birth year and sex, while the second adjusted for all covariates. Cumulative incidence curves were produced using survival function based on the fitted model hazard. Martingale residual plots confirmed no violations of linearity or proportional hazards assumptions (Supplementary Figs.\u0026nbsp;4\u0026ndash;15). Deaths during the follow-up period were treated as competing risks.\u003c/p\u003e \u003cp\u003eAnalyses were conducted by statistician TP using IBM SPSS Statistics for Windows, version 29.0 (IBM Corp, Armonk, NY) and Stata Statistical Software, version 16 (StataCorp LLC, College Station, TX).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eStudy Population\u003c/h2\u003e \u003cp\u003eThe final study cohort comprised 33 095 children, with a total of 595 213 weight and height measurements (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Supplementary Table\u0026nbsp;2). The mothers of 12 869 (38.9%) children were exposed to antibiotics one year before the beginning of pregnancy, and 9 073 (27.4%) mothers received antibiotics during pregnancy. In total, 6 983 (21.1%) children were exposed to perinatal antibiotics, and 22 453 (67.8%) children were exposed to antibiotics in the first 24 months of life. Seven (0.02%) deaths occurred during follow-up (Supplementary Table\u0026nbsp;2).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eBody Mass Index at Two Years of Age\u003c/h2\u003e \u003cp\u003eNo significant association was found between zBMI at 24 months of age and antibiotic exposure one year before pregnancy, during pregnancy (any trimester), or perinatally (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Supplementary Table\u0026nbsp;3). However, children exposed to antibiotics during the first six months of life or between six and 24 months of life exhibited higher zBMI at 24 months of age compared to unexposed children in an adjusted analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Supplementary Table\u0026nbsp;3).\u003c/p\u003e \u003cp\u003eNext, we investigated the association of cumulative antibiotic exposure from one year before pregnancy until 24 months of age with zBMI at 24 months of age (Supplementary Fig.\u0026nbsp;16, Supplementary Tables\u0026nbsp;4\u0026ndash;5). Higher zBMI at 24 months of age was observed in children who, in addition to childhood antibiotic exposure, were exposed to antibiotics one year before the beginning of pregnancy, during pregnancy, and perinatally in adjusted analyses (Supplementary Fig.\u0026nbsp;16, Supplementary Table\u0026nbsp;5).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eChildhood Overweight and Obesity\u003c/h2\u003e \u003cp\u003eThe mean follow-up duration was 7.3 years, with a maximum of 12 years (Supplementary Table\u0026nbsp;2). In total, 10 710 (32.3%) children were with overweight (including obesity), while 2 726 (8.2%) were with obesity after 24 months of age. Antibiotic exposure one year before pregnancy was associated with an increased risk of childhood overweight (aHR 1.04 [95% CI, 1.001\u0026ndash;1.08] (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Supplementary Table\u0026nbsp;6) but not obesity (aHR 1.05 [95%, CI 0.97\u0026ndash;1.14]) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Antibiotic exposure during pregnancy or perinatally was not associated with childhood overweight or obesity (Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u0026ndash;5). Perinatal antibiotic exposure was not associated with childhood overweight or obesity in adjusted analyses (Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Supplementary Table\u0026nbsp;6). Antibiotic exposure in the first 24 months of life was associated with subsequent overweight (aHR 1.09 [95% CI, 1.04\u0026ndash;1.13]) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Supplementary Table\u0026nbsp;6) and obesity (aHR 1.20 [95% CI, 1.10\u0026ndash;1.31]) (Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Supplementary Table\u0026nbsp;6).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eGrowth in Height at Two Years of Age\u003c/h2\u003e \u003cp\u003eHigher zHFA at 24 months was associated with antibiotic exposure one year before pregnancy, during the first trimester, and within the first 6\u0026ndash;24 months of life (Supplementary Tables\u0026nbsp;7\u0026ndash;9, Supplementary Figs.\u0026nbsp;19\u0026ndash;20).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this population-based cohort study of 33 095 children and their mothers, followed from one year before pregnancy up to 12 years of age, antibiotic exposure in the first two years of life was associated with childhood overweight and obesity. However, no similar associations were observed for antibiotic exposure before pregnancy, during pregnancy, or in the perinatal period.\u003c/p\u003e \u003cp\u003eMost prior studies have examined associations between early-life antibiotics and overweight or obesity using one to two time points of antibiotic exposure (see summary of 75 studies in the Supplement). The timing of early antibiotic exposure has been specifically investigated in two cohorts.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e In the a cohort of 156 381 vaginally delivered children in the US Kaiser-Permanente health system, exposure to intrapartum antibiotic prophylaxis was associated with a higher BMI in childhood, whereas other intrapartum antibiotics showed no association, and neonatal exposure was linked to a lower BMI.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e In our study, these subgroups were combined into a perinatal exposure group, which was not associated with overweight or obesity in childhood. Consistent with the Kaiser-Permanente cohort, we found that childhood antibiotic exposure was associated with overweight or obesity in childhood.\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e A study involving a U.S. cohort of 8 793 children in Pennsylvania reported no association between prenatal antibiotic exposure and weight gain but did observe an association with repeated childhood antibiotic courses, as seen in the present study. \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn this study, antibiotic exposure during the first two years of life was associated with a higher zBMI at two years of age as well as with childhood overweight and obesity up to the age of 12 years. These findings align with several studies identifying early childhood as a sensitive period during which antibiotic exposure is associated with weight gain.\u003csup\u003e\u003cspan additionalcitationids=\"CR17 CR18 CR19\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan additionalcitationids=\"CR44 CR45 CR46 CR47 CR48\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e Even after adjusting for various confounding factors, however, the possibility of unmeasured confounding remains. For example, children from families in environments conducive to obesity may be more likely to receive antibiotics. Nonetheless, promoting antimicrobial stewardship in young children is crucial for broader public health reasons.\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWe found no association between maternal antibiotic exposure before pregnancy and childhood obesity, consistent with a previous study reporting no association.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e Research on antibiotic exposure during pregnancy and subsequent childhood weight gain has yielded conflicting results, with some studies finding associations based on specific trimesters,\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e repeated antibiotic courses,\u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e,\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e or variations based on sex\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e and birth weight.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e However, consistent with our findings, cohort studies utilizing electronic health record data have generally reported no association between antibiotic exposure during pregnancy and childhood weight gain or obesity, with follow-up times ranging from five to 11 years.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e Additionally, a sibling analysis of 151,359 children showed no link between antibiotic exposure during pregnancy and childhood obesity.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe growth-promoting effects of antibiotics have been well documented since the 1950s in farm animals, with proposed mechanisms including gut microbiome alterations.\u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e In mouse models, antibiotic exposure after birth has been shown to influence gut microbiota, increase body fat, and induce obesity when microbiota from exposed mice are transferred to their germ-free counterparts.\u003csup\u003e\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e Similarly, perinatal antibiotic exposure has been associated with gut microbiome alterations in human infants,\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e and antibiotic exposure during infancy has been linked to changes in the gut microbiome, weight gain, and childhood adiposity.\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e,\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e,\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e In our previous research, we reported that perinatal antibiotic exposure affected the infant gut microbiota even after the first year of life, with a greater impact than later antibiotic courses.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e However, in this study, perinatal antibiotics were not associated with overweight or obesity in children. Emerging research suggests that maternal microbiota may interact with the fetus through maternal metabolites or microbiota-derived extracellular vesicles.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e However, we found no association between maternal antibiotic exposure prior to birth and offspring overweight or obesity.\u003c/p\u003e \u003cp\u003eWhile childhood obesity has risen globally in recent decades, the growth-promoting effects of antibiotics may have context-dependent benefits. For example, in low-income settings, Malawian children whose mothers received two doses of azithromycin during pregnancy, alongside improved malaria prevention, were taller and heavier up to five years of age.\u003csup\u003e\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e However, biannual or annual mass azithromycin administration after birth did not seem to improve children\u0026rsquo;s growth in low-income settings.\u003csup\u003e\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e,\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eA key strength of this study is the use of Finland\u0026rsquo;s national comprehensive registers and electronic health records, enabling the examination of antibiotic exposure at various time points in the same population and adjustment for several important covariates. We were able to explore antibiotic exposure starting one year before pregnancy and continuing into early childhood, whereas previous studies mostly focused on one or two antibiotic exposure time points. High-quality growth data were obtained from child health clinics and school health services for children up to 12 years of age, with minimal missing data. Additionally, deaths during the follow-up period were treated as competing risk.\u003c/p\u003e \u003cp\u003eThe main limitation of the study is the observational design, which allows us to report only associations, not causality. Even after adjusting for several covariates, it is possible that other unmeasured factors, such as infections themselves, treatment seeking, or physician\u0026rsquo;s prescription behavior, could be associated with subsequent obesity. Moreover, while antibiotic exposure before and during pregnancy and in childhood was determined based on purchase records, we did not have data on medication compliance. We used the current definitions for overweight and obesity based on BMI-values, however, the pragmatic definition criteria for obesity has been suggested to include other anthropometric measurements as well.\u003csup\u003e\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e\u003c/sup\u003e Data on ethnicity or breastfeeding were also unavailable, as they are not recorded in national registers in Finland.\u003c/p\u003e \u003cp\u003eIn conclusion, antibiotic exposure during the first two years of life was associated with childhood overweight and obesity. No similar associations were observed for antibiotic exposure before pregnancy, during pregnancy, or in the perinatal period. Public health interventions aiming to mitigate the obesity-related effects of early-life antibiotics should focus on the first two years of life.\u003c/p\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eAuthors\u0026rsquo; contributions:\u003c/h2\u003e \u003cp\u003e SA was responsible for designing and concepting the study, cleaning and validating of the data, analyzing and interpretation of the data, performing the literature review, and drafting the manuscript. MP was responsible for designing and concepting the study, cleaning and validating of the data, interpretation of the data, performing the literature review and drafting the manuscript. ER was responsible for designing and concepting the study, acquiring of the data, interpretation of the data and drafting the manuscript. TP was responsible for designing the study, analyzing and interpretation of the data, and revising the manuscript for intellectual content. MH was responsible for designing and concepting the study, interpretation of the data, and drafting the manuscript. EK was responsible for designing and concepting the study, interpretation of the data and revising the manuscript for intellectual content. NP was responsible for designing and concepting the study, acquiring of the data, interpretation of the data and revising the manuscript for intellectual content. TR-L was responsible for designing and concepting the study, analyzing and interpretation of the data and revising the manuscript for intellectual content. TP and TR-L had full access to all the data in the study and were responsible for the integrity of the data and the accuracy of the data analysis.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting interests:\u003c/h2\u003e \u003cp\u003eThe authors declare no competing financial interests.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eSources of funding and support\u003c/strong\u003e \u003cp\u003eThe study was supported by the Pediatric Research Foundation, Finland, Alma och K.A. Snellman Foundation, Finnish Medical Foundation, University of Oulu and the Academy of Finland Profi6 AF 336449, Competitive Government Funding for Clinical Research (VTR), Academy of Finland, Sigrid Jus\u0026eacute;lius Foundation, and the Signe and Ane Gyllenberg Foundation.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eRole of the Funder/Sponsor\u003c/strong\u003e \u003cp\u003eThe study supporters had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eData Availability Statement:\u003c/h2\u003e \u003cp\u003eThe key elements of data will be shared upon reasonable request for clinical research purposes. Requests should be sent to Professor Terhi Ruuska-Loewald ([email protected]) with a full research plan. Data sharing will be restricted to key elements following general data protection regulations in the European Union.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePhelps NH, Singleton RK, Zhou B, Heap RA, Mishra A, Bennett JE \u003cem\u003eet al.\u003c/em\u003e Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults. The Lancet 2024; 403: 1027\u0026ndash;1050.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLe Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F, Falony G \u003cem\u003eet al.\u003c/em\u003e Richness of human gut microbiome correlates with metabolic markers. 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Lancet Diabetes Endocrinol 2025. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S2213-8587(24)00316-4\u003c/span\u003e\u003cspan address=\"10.1016/S2213-8587(24)00316-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6622850/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6622850/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEarly antibiotic exposure has been associated with increased weight gain and obesity in children. However, evidence associating the timing of antibiotic exposure to overweight and obesity is limited.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study explores whether the timing of early-life antibiotics or cumulative exposure is associated with childhood overweight and obesity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis population-based cohort study included 33 095 children with 595 213 weight and height measurements linked to medical records and comprehensive national registers. Vaginally delivered children born in Northern Finland between the years 2007–2018 were followed until the end of 2019. \u0026nbsp;Exposures included antibiotic exposure during the year before pregnancy, during pregnancy, in the perinatal period, and within the first 24 months of life. The primary outcomes were body mass index-for-age z-score (zBMI) at 24 months of age and the cumulative incidence of overweight and obesity up to 12 years of age. Analyses used linear mixed models and Cox hazard regression models adjusted for multiple covariates.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAntibiotic exposure before pregnancy, during pregnancy, or in the perinatal period was not associated with subsequent overweight or obesity in children. In contrast, exposure during the first 24 months of life was linked to a higher zBMI at two years of age (mean difference in zBMI: 0.067 [95% CI, 0.041–0.094]) compared to unexposed children, after adjusting for covariates. Long-term analysis revealed an adjusted hazard ratio (HR) of 1.09 (95% CI 1.04–1.13) for overweight and 1.20 (95% CI, 1.10–1.31) for obesity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAntibiotic exposure during the first two years of life was found to be associated with childhood overweight and obesity. No similar associations were observed for exposure before or at birth. Interventions aiming to reduce obesity-related effects should focus on minimizing early-life antibiotic use within the first two years of life.\u003c/p\u003e","manuscriptTitle":"Early-Life Antibiotic Exposure and the Risk of Overweight and Obesity in Children","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-15 10:31:47","doi":"10.21203/rs.3.rs-6622850/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a4bb967e-169d-4e27-8863-c5c909f68dd3","owner":[],"postedDate":"May 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":48319189,"name":"Health sciences/Medical research/Epidemiology"},{"id":48319190,"name":"Health sciences/Diseases/Endocrine system and metabolic diseases/Obesity"},{"id":48319191,"name":"Health sciences/Health care/Paediatrics"}],"tags":[],"updatedAt":"2025-07-04T11:12:39+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-15 10:31:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6622850","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6622850","identity":"rs-6622850","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}