Abstract
OBJECTIVE: Antibiotics have direct effects on the human intestinal microbiota, particularly in infancy. Antibacterial agents promote growth in farm animals by unknown mechanisms, but little is known about their effects on human weight gain. Our aim was to evaluate the impact of antibiotic exposure during infancy on weight and height in healthy Finnish children.
METHODS: The population-based cohort comprised 6114 healthy boys and 5948 healthy girls having primary care weight and height measurements and drug purchase data from birth to 24 months. BMI and height, expressed as z-scores at the median age of 24 months (interquartile range 24 to 26 months), were compared between children exposed and unexposed to antibiotics using analysis of covariance with perinatal factors as covariates.
RESULTS: Exposed children were on average heavier than unexposed children (adjusted BMI-for-age z-score difference in boys 0.13 SD [95% confidence interval 0.07 to 0.19, P < .001] and in girls 0.07 SD [0.01 to 0.13, P < .05]). The effect was most pronounced after exposure to macrolides before 6 months of age (boys 0.28 [0.11 to 0.46]; girls 0.23 [0.04 to 0.42]) or >1 exposure (boys 0.20 [0.10 to 0.30]; girls 0.13 [0.03 to 0.22]).
CONCLUSIONS: Antibiotic exposure before 6 months of age, or repeatedly during infancy, was associated with increased body mass in healthy children. Such effects may play a role in the worldwide childhood obesity epidemic and highlight the importance of judicious use of antibiotics during infancy, favoring narrow-spectrum antibiotics.
What’s Known on This Subject:
Subtherapeutic doses of antibiotics have been used as growth promoters in animal farming since the 1950s. Antibiotic exposure during infancy is associated with increased body mass in humans.
What This Study Adds:
The weight-promoting effect of antibiotics is most pronounced when the exposure occurs at <6 months of age or repeatedly during infancy. Increased body mass is distinctly associated with exposure to cephalosporins and macrolides, especially in boys.
The crucial role of antibiotics in the improvement of human health is unquestionable, but their extended use today has revealed undesirable and unexpected consequences.1,2 Antibiotics have direct intestinal effects, and the link between altered gut microbiota and changes in human metabolism has become clearer.3,4 The intestinal microbiota in infants is particularly vulnerable to perturbation.5 One of the unexpected effects of antibiotics has been their potential ability to promote growth. This was first observed in livestock, in which subtherapeutic doses of antibiotics have been widely used for accelerating weight gain since the 1950s.6 In a few recent studies in children, it has been shown that early-life exposure to antibiotics promotes weight gain and increases the risk of obesity.7–11 Although these studies provide evidence that antibiotics also promote weight gain in humans, whether this effect is dependent on specific antibiotic type or amount of exposure has been insufficiently explored.
In addition to weight gain, linear growth in height may be affected by early antibiotic exposure. In children with severe malnutrition or chronic infections such as HIV, several studies have shown that both weight gain and linear growth in height improved with antibiotic therapy.12–15 However, the effect of early antibiotic exposure on height in healthy, well-nourished children has not been adequately elucidated.7–11
In the present population-based study, we aimed to evaluate the impact of antibiotic exposure during the first 24 months of age on weight and height gain in healthy Finnish children carefully screened for other risk factors and chronic conditions potentially affecting linear growth. Also, we evaluated the association between early-life antibiotic exposure and the risk of overweight and obesity in the study population. We assessed the potential differences between antibiotic types and evaluated the impact of early versus late and single versus repeated exposure.
Methods
Study Population
In Finland, child welfare clinics provide regular scheduled visits (12 during the first 24 months of age) covering almost 100% of the child population.16,17 At every visit, primary care nurses perform standardized weight and length/height measurements. For the current study, we initially included all children of the Finnish growth reference study population born between Jan. 1, 2003, and April 30, 2007, who attended child welfare clinics in the city of Espoo, Finland and who had ≥1 primary care visit after the age of 24 months (7584 boys and 7180 girls) (Fig 1).18 Espoo is Finland’s second largest city by population, with a significant net migration from all parts of Finland. Its population has grown >10-fold in the past 60 years. The majority of the population (94.4%) is of Finnish origin, which mirrors the whole of Finland (97.3%).19
Flow chart of the exclusion procedure of the study population.
To exclude children with possible prenatal conditions affecting growth and control for possible confounding factors statistically, we obtained Birth Register data from the National Institutes of Health and Welfare. These data included maternal age, smoking during pregnancy, parental relationship, gestational age, mode of delivery, parity, plurality, birth weight and length, season at birth, and possible congenital syndromes or anomalies. First, 792 boys and 689 girls with congenital syndromes or anomalies (165 boys and 134 girls), with preterm birth before 37 weeks of gestation (354 boys and 275 girls), or lacking birth data (324 boys and 318 girls) were excluded. Second, children with diagnosed postnatal growth disorders or regular medication possibly affecting growth (eg, glucocorticoids for asthma) were removed (678 boys and 543 boys).18 The final study population thus comprised 6114 boys and 5948 girls (80.6% and 82.8%, respectively, of the initial study population) (Fig 1).
Growth data, from birth to the latest primary care visit after 24 months of age, were collected from the electronic health records. Potentially false measurements, typing errors, missing values, or duplicated recordings were evaluated by scatter plots and either corrected or excluded. BMI (calculated as weight [kg]/height [m]2), length/height measurements, and birth size data were transformed into z-scores (BMI-for-age [zBMI] and height-for-age [zHFA]) according to Finnish growth references.18,20 Overweight and obesity were defined by national cutoffs for zBMI18 based on BMI-for-age percentile curves passing through adult values of 25 kg/m2 and 30 kg/m2.21
In Finland, antibacterial agents for systemic use are available by prescription only and sold in registered pharmacies. Purchased medications are reimbursed and registered in the Drug Prescription Register maintained by the Social Insurance Institution of Finland (SII). Information on dispensation dates of prescriptions and pharmaceuticals are included in the database.22 According to the annual wholesale statistical database compiled by the Finnish Medicines Agency, from Jan. 1, 2006, to Dec. 31, 2007, the Prescription Register of SII included data of 82% of all the outpatient consumption of antibiotics. We extracted information on all systemic antibiotics from the Drug Prescription Register (anatomic-therapeutic-chemical code J01, antibacterials for systemic use, World Health Organization Collaborating Centre for Drug Statistics Methodology, http://www.whocc.no/atcddd) purchased for the children in the final study population from birth to 24 months of age in primary care. Information on antibiotics administered in hospitals was not collected. The characteristics of the study population by antibiotic exposure are presented in Supplemental Table 4. Age at first exposure was categorized into 4 groups: birth to 5 months, 6 to 11 months, 12 to 17 months, and 18 to 23 months.
In addition to exposure to any type of antibiotic, 3 specific groups of the most frequently used antibiotics, penicillins (phenoxymethylpenicillin and combination of amoxicillin and clavulanate, anatomic-therapeutic-chemical code J01C), cephalosporins (J01D), and macrolides (J01FA), were analyzed separately. The number of separate purchases in the same child was calculated and categorized as none, 1, 2 or 3, and ≥4 episodes (any antibiotic, penicillins) and as none, 1, and ≥2 (cephalosporins, macrolides).
Permission for the current study was obtained from Espoo Municipality Institutional Review Board, SII, and the National Institutes of Health and Welfare. Ethical approval was not necessary, because we used only encrypted register data and did not contact the unidentifiable study subjects.
Statistical Analysis
Weight and height gain was compared in the exposed and unexposed child population using the covariance analysis method, with random effects for subjects. Boys and girls were analyzed separately to observe gender-related differences. The first height and weight measurements at 24 months of age (or after) were used as the primary end points (expressed as ≥24 months, median [interquartile range] age was 24 [24 to 26] months). zBMI and zHFA were examined in relation to general exposure (yes/no), age at first exposure (birth to 5 months, 6 to 11 months, 12 to 17 months, and 18 to 23 months), and number of separate exposure episodes. The prevalence of perinatal factors possibly interfering with postnatal growth or affecting the exposure to antibiotics (Table 1) were compared by using χ2 test. Those variables that showed statistically significant differences between analyzed groups were used as covariates (P < .05). Thus, statistical adjustments were performed with maternal smoking after the first trimester, parental relationship, mode of delivery, birth weight, and birth length for boys and maternal smoking after the first trimester, mode of delivery, and birth weight for girls.
Perinatal Factors Potentially Associated With Weight Status at ≥24 Months of Age or With Antibiotic Exposure in Infancy
The relationship between antibiotic exposure before the age of 24 months and the risk of overweight ≥24 months was analyzed using logistic regression. The magnitude of the associations was quantified using adjusted odds ratio (aOR) with 95% confidence interval (CI).
Data were analyzed by using SPSS software (version 19, IBM Corp., Armonk, NY). P values <.05 were considered statistically significant.
Results
Children who received systemic antibiotics during infancy were on average heavier than unexposed children at the age of ≥24 months (Table 2). Unadjusted and adjusted differences of mean zBMI were 0.13 (95% CI 0.07 to 0.20, P < .001) and 0.13 (95% CI 0.07 to 0.19, P < .001), respectively, for boys and 0.08 (95% CI 0.03 to 0.14, P < .01) and 0.07 (0.01 to 0.13, P < .05) for girls. Exposed boys at the age of ≥24 months were also slightly taller than unexposed boys (zHFA 0.08, 95% CI 0.02 to 0.14, P < .01) without adjustment, whereas no difference was observed in girls or in adjusted heights in boys.
Characteristics of the Study Population in Relation to Exposure to Antibiotics at <24 Months
Effect of Age at First Antibiotic Exposure on Growth
In boys, exposure to antibiotics at virtually any age before 24 months was associated with higher zBMI than in unexposed children (Fig 2). The younger the boy was when exposed to antibiotics for the first time, the greater the adjusted difference between zBMI scores at the age of ≥24 months: <6 months 0.23 (95% CI 0.12 to 0.33), 6 to 11 months 0.14 (0.06 to 0.16), 12 to 17 months 0.08 (−0.01 to 0.12), and 18 to 23 months 0.13 (0.02 to 0.24). In girls, a similar tendency was observed, but the only significant differences were in those who had been exposed to antibiotics at 12 to 17 months (0.08 [0.00 to 0.15]).
Adjusted differences of means (95% CI) for zBMI and zHFA at the median age of 24 months between exposed and unexposed children (zero line) classified by age at first antibiotic exposure. A and B, boys; C and D, girls. Statistical adjustments: Maternal smoking after first trimester, parental relationships, mode of delivery, birth weight and birth length for boys; Maternal smoking after first trimester, mode of delivery and birth weight for girls.
The most pronounced associations were observed between macrolide exposure at any age <24 months and higher zBMI (from 0.28 [0.11 to 0.46] at <6 months to 0.23 [0.12 to 0.35] at 18 to 23 months) (Fig 2). In girls, macrolide exposure at <6 months was associated with mean zBMI difference 0.23 (0.04 to 0.42). Age at first exposure to any antibiotics (12 to 17 months), penicillins (12 to 17 months), cephalosporins (18 to 23 months), and macrolides (6 to 11) months was significantly associated with changes in height for boys (Fig 2). Exposure to any antibiotics and penicillins at 6 to 11 months of age resulted in similar tendencies for girls.
Number of Antibiotic Exposures in Infancy and Growth
In boys, multiple courses of antibiotics before the age of 24 months increased zBMI score (Fig 3). Adjusted difference of mean zBMI to unexposed children was 0.09 (95% CI −0.00 to 0.18) in those exposed once, 0.10 (0.02 to 0.18) in those exposed 2 or 3 times, and 0.18 (0.10 to 0.26) in those exposed ≥4 times to any antibiotics. There was a linear trend in the number of antibiotic exposures (P < .001). Multiexposed girls (≥4 times) were also on average heavier (0.13 [0.06 to 0.20]) than unexposed girls, and their zBMI increased with the number of exposures as well (P < .001). The most pronounced difference in mean zBMI between exposed and unexposed children at the age of ≥24 months was found for boys (0.20 [0.10 to 0.30]) having ≥2 exposures to macrolides or girls (0.17 [0.05 to 0.29]) having ≥2 exposures to cephalosporins.
Adjusted differences of means (95% CI) for zBMI and zHFA at the median age of 24 months according to the separate courses of antibiotic exposures from birth to 23 months of age compared with unexposed (zero line) children. A–D, boys; E–H, girls. Statistical adjustments: Maternal smoking after first trimester, parental relationships, mode of delivery, birth weight and birth length for boys; Maternal smoking after first trimester, mode of delivery and birth weight for girls.
Multiexposed boys were on average taller than the unexposed boys when they had used any antibiotics or penicillins (≥4 times) (adjusted zHFA 0.09 [95% CI 0.03 to 0.15] and 0.11 [0.04 to 0.18], respectively) or cephalosporins or macrolides (≥2 times) (zHFA 0.13 [0.03 to 0.23] and 0.11 [0.04 to 0.19]) (Fig 3). Girls who had been exposed to cephalosporin ≥2 times were taller on average (0.14 [0.03 to 0.25]).
Risk of Overweight
At the age of ≥24 months, 1 of every 5 boys and 1 of every 10 girls was overweight or obese (Table 1). The risk of being overweight was significantly associated with earlier antibiotic exposure and increasing number of separate antibiotic courses in boys, but not in girls (Table 3). The aOR was 1.34 (95% CI 1.06 to 1.66) in boys and 1.16 (0.87 to 1.56) in girls when the first antibiotic exposure took place at <6 months of age. Four or more courses of antibiotics resulted in aOR 1.27 (1.04 to 1.55) in boys and 1.19 (0.96 to 1.48) in girls. aOR was 1.65 (1.09 to 2.31) for boys who were exposed to macrolides at <6 months (Table 3).
Odds of Becoming Overweight at the Age of 24 Months According to Age at First Exposure to Antibiotics and Number of Exposures <24 Months
Discussion
In this population-based study with 12 062 healthy children, we showed that antibiotic exposure in infancy is independently associated with enhanced growth, in both weight and height, at the age of 24 months. The first exposure before the age of 6 months or repeatedly during the first 23 months of age had the largest effect on BMI. Overall, infant boys were exposed to antibiotics significantly earlier and more frequently than girls, and the growth-promoting effect of antibiotics was also more pronounced in boys. In addition, exposure to broad-spectrum antibiotics such as macrolides showed the most pronounced effects on growth.
Severely malnourished infants have been shown to gain weight faster when they are given antibiotics,12–15 and similar findings have been only recently reported in well-nourished children in affluent Western countries.7–11 Antibiotics increase body fat mass in mice, which is assumed to result from changes in composition of the intestinal microbial flora.23,24 In these experimental murine studies, the effect of antibiotics was shown not only to be dependent on the increase in the energy intake or hormonal changes that regulate satiety but also was associated with alterations in the expression of microbial genes, which contribute to the conversion of carbohydrates to short-chain fatty acids.23,24 Thus, more efficient energy harvesting in the colon is assumed to decrease energy loss in the stools. A similar mechanism might be true in humans as well, and the growth promotion associated with antibiotic exposure shown in this study and in previous studies could be linked to these intestinal changes. Of note, in a recent study, a more pronounced growth-promoting effect of antibiotic exposure was reported in male than female mice.25
The strength of our study, in comparison with previous studies, is that the child population was carefully screened for other potential factors that might alter growth. These individuals were excluded, and statistical adjustment was made for birth size and perinatal factors. Also, the growth data are based on standardized measurements performed by educated nurses. Growth data were based on self-measurements in 2 previous studies,7,11 and Trasande et al pooled both genders in 1 group.9 It is noteworthy that the data of Bailey et al were not adjusted for perinatal factors.10 In addition, 3 of 5 previous studies in well-nourished children were based on medication data obtained from questionnaires,7,9,11 and 1 on data from medical records.10 In our study, as well as in that of Azad et al,8 the use of antibiotics was collected from the medication registries. Our data based on medicine purchases probably reflects real use better than data for prescribed medications, in which primary noncompliance is not taken into account.26 The results of our study suggest that the growth-promotion effect of antibiotic exposure might be different in males and females. This is consistent with the recent studies of Azad et al8 and Murphy et al.11 However, Azad et al had a relatively small sample size and large number of dropouts,8 and the growth data of Murphy et al were not converted into z-scores,11 and therefore it still remains unknown how exact the observed gender difference was. There might also be some other, as yet unexplored, mechanisms explaining the more pronounced effects of antibiotics on growth in boys.
To our knowledge, ours is the first study to report the effects of antibiotic exposure in growth in height in Western countries.7–11 Linear growth seems to be affected especially after repeated exposure to antibiotics, when the increase in weight is also the most pronounced. Increase in weight in early childhood often also leads to acceleration in growth in height, which therefore may be an event secondary to weight gain after multiple antibiotic exposures in infancy. However, the prevalent use of antibiotics in early infancy might also contribute to the secular change in height observed in Western countries in the past decades,27 since even minor bacterial infections would have at least a transient suppressive effect on growth if left untreated;28 thus the growth-promotion effect of antibiotics during infancy might be supported in this finding.
We found that growth-promotion effects varied between different types of antibiotics, and that macrolides had the most pronounced weight-increasing effect in children. The impact of macrolides may be due to their pharmacokinetics. Unlike amoxicillin and cephalosporins, which are eliminated by the kidneys and most likely have very little direct contact with the colonic microbiota, macrolides are excreted in bile and participate in the enterohepatic cycle, which may explain this specific difference from other antibiotics. Our finding was at least partially in line with the results by Bailey et al,10 even though they were only grouped into narrow-spectrum (penicillins) and broad-spectrum (cephalosporins and macrolides) antibiotics.
We confirmed earlier observations that the use of antibiotics in infancy is associated with the risk of being overweight in boys. In our study, girls did not have a statistically significant risk for being overweight, which can be explained by the generally lower risk of overweight in girls. However, the worldwide obesity epidemic is real,29,30 and among Finnish adolescents, for instance, the prevalence of being overweight has almost doubled in the past 2 decades31 and is more pronounced for boys.18,31 An increase in the use of antibiotics could be an additional contributing factor to the development of excess weight problems.10,24
A limitation of our study is the lack of data regarding some potential confounders that may have influenced the growth of the children, such as maternal weight and paternal data. However, in the subgroup of children with known maternal BMI before pregnancy (3551 boys and 3470 girls), the difference of adjusted mean zBMI (95% CI) between children that were exposed and not exposed to antibiotics at <6 months was 0.12 (0.01 to 0.24) in boys and 0.07 (−0.04 to 0.19) in girls (Supplemental Fig 4). Thus, the results of our study are not likely to be biased even though analyses were performed without maternal BMI as a covariate. Paternal factors probably had a more minor influence on offspring growth compared with maternal factors.7 Limitations of this study also include the lack of data on intrapartum antibiotics (eg, prophylactic dosing before cesarean section) and breastfeeding.
Children in our study received antibiotics for various indications, which were not included in the database. In Finland, antibiotics are mostly prescribed to this age group to treat respiratory infections,32 which are not expected to influence the intestinal microbiota directly. In addition, gastrointestinal infections, which are mostly viral and treated with fluid therapy, are only exceptionally a reason for antibiotic use in Finland.32
Conclusions
Antibiotic exposure at the age of <6 months or repeatedly during infancy has an increasing effect on body mass and height at 24 months of age in healthy children. Exposure to macrolides seems to have the most pronounced effect on body composition. Such effects on growth may have played a role in the childhood obesity epidemic worldwide. These results highlight the importance of critical use of antibiotics in early infancy, favoring narrow-spectrum antibiotics and avoiding repeated exposure when possible.
Footnotes
- Accepted January 26, 2015.
- Address correspondence to Antti Saari, Kuopio University Hospital, PO Box 1777, FIN-70200 Kuopio, Finland. E-mail: antti.saari{at}kuh.fi
Drs Saari, Virta, and Sankilampi carried out the acquisition of the data; Drs Saari and Virta carried out the initial analyses and drafted the initial manuscript; Drs Sankilampi, Dunkel, and Saxen critically reviewed and revised the manuscript; Drs Dunkel and Saxen conceptualized and designed the study; Dr. Dunkel designed the data collection instruments and coordinated and supervised data collection; and all authors approved the final manuscript as submitted.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Supported by the National Graduate School of Clinical Investigation (Dr Saari), the Päivikki and Sakari Sohlberg Foundation (Dr Saari), and Kuopio University Hospital State Research Funding (Dr Saari, Dr Sankilampi).
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
References
- Copyright © 2015 by the American Academy of Pediatrics
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