Antibiotic Exposure in Infancy and Riskof Being Overweight in the First 24Months of LifeAntti Saari, MDa,b, Lauri J. Virta MD, PhDc, Ulla Sankilampi MD, PhDb, Leo Dunkel MD, PhDd, Harri Saxen MD, PhDe

abstractOBJECTIVE: Antibiotics have direct effects on the human intestinal microbiota, particularly ininfancy. Antibacterial agents promote growth in farm animals by unknown mechanisms, butlittle is known about their effects on human weight gain. Our aim was to evaluate the impact ofantibiotic exposure during infancy on weight and height in healthy Finnish children.

METHODS: The population-based cohort comprised 6114 healthy boys and 5948 healthy girlshaving primary care weight and height measurements and drug purchase data from birth to24 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 andunexposed 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 ingirls 0.07 SD [0.01 to 0.13, P , .05]). The effect was most pronounced after exposure tomacrolides 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, wasassociated with increased body mass in healthy children. Such effects may play a role in theworldwide childhood obesity epidemic and highlight the importance of judicious use ofantibiotics during infancy, favoring narrow-spectrum antibiotics.

WHAT’S KNOWN ON THIS SUBJECT:Subtherapeutic doses of antibiotics have beenused as growth promoters in animal farmingsince the 1950s. Antibiotic exposure duringinfancy is associated with increased body massin humans.

WHAT THIS STUDY ADDS: The weight-promotingeffect of antibiotics is most pronounced whenthe exposure occurs at ,6 months of age orrepeatedly during infancy. Increased body massis distinctly associated with exposure tocephalosporins and macrolides, especially inboys.

aDepartment of Pediatrics, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio,Finland; bDepartment of Pediatrics, Kuopio University Hospital, Kuopio, Finland; cDepartment of Research, SocialInsurance Institution, Turku, Finland; dWilliam Harvey Research Institute, Barts and the London School of Medicineand Dentistry, Queen Mary University of London, London, United Kingdom; and eChildren’s Hospital, University ofHelsinki and Helsinki University Hospital, Helsinki, Finland

Drs Saari, Virta, and Sankilampi carried out the acquisition of the data; Drs Saari and Virta carriedout the initial analyses and drafted the initial manuscript; Drs Sankilampi, Dunkel, and Saxencritically reviewed and revised the manuscript; Drs Dunkel and Saxen conceptualized and designedthe study; Dr. Dunkel designed the data collection instruments and coordinated and supervised datacollection; and all authors approved the final manuscript as submitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2014-3407

DOI: 10.1542/peds.2014-3407

Accepted for publication Jan 26, 2015

Address correspondence to Antti Saari, Kuopio University Hospital, PO Box 1777, FIN-70200 Kuopio,Finland. E-mail: antti.saari@kuh.fi

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2015 by the American Academy of Pediatrics

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The crucial role of antibiotics in theimprovement of human health isunquestionable, but their extendeduse today has revealed undesirableand unexpected consequences.1,2

Antibiotics have direct intestinaleffects, and the link between alteredgut microbiota and changes in humanmetabolism has become clearer.3,4

The intestinal microbiota in infants isparticularly vulnerable toperturbation.5 One of the unexpectedeffects of antibiotics has been theirpotential ability to promote growth.This was first observed in livestock,in which subtherapeutic doses ofantibiotics have been widely used foraccelerating weight gain since the1950s.6 In a few recent studies inchildren, it has been shown thatearly-life exposure to antibioticspromotes weight gain and increasesthe risk of obesity.7–11 Although thesestudies provide evidence thatantibiotics also promote weight gainin humans, whether this effect isdependent on specific antibiotic typeor amount of exposure has beeninsufficiently explored.

In addition to weight gain, lineargrowth in height may be affected byearly antibiotic exposure. In childrenwith severe malnutrition or chronicinfections such as HIV, several studieshave shown that both weight gain andlinear growth in height improvedwith antibiotic therapy.12–15 However,the effect of early antibiotic exposureon height in healthy, well-nourishedchildren has not been adequatelyelucidated.7–11

In the present population-basedstudy, we aimed to evaluate theimpact of antibiotic exposure duringthe first 24 months of age on weightand height gain in healthy Finnishchildren carefully screened for otherrisk factors and chronic conditionspotentially affecting linear growth.Also, we evaluated the associationbetween early-life antibiotic exposureand the risk of overweight andobesity in the study population. Weassessed the potential differences

between antibiotic types andevaluated the impact of early versuslate and single versus repeatedexposure.

METHODS

Study Population

In Finland, child welfare clinicsprovide regular scheduled visits(12 during the first 24 months of age)covering almost 100% of the childpopulation.16,17 At every visit,primary care nurses performstandardized weight and length/height measurements. For the currentstudy, we initially included allchildren of the Finnish growthreference study population bornbetween Jan. 1, 2003, and April 30,2007, who attended child welfareclinics in the city of Espoo, Finlandand who had $1 primary care visitafter the age of 24 months (7584 boysand 7180 girls) (Fig 1).18 Espoo isFinland’s second largest city bypopulation, with a significant netmigration from all parts of Finland. Itspopulation has grown .10-fold in the

past 60 years. The majority of thepopulation (94.4%) is of Finnishorigin, which mirrors the whole ofFinland (97.3%).19

To exclude children with possibleprenatal conditions affecting growthand control for possible confoundingfactors statistically, we obtained BirthRegister data from the NationalInstitutes of Health and Welfare.These data included maternal age,smoking during pregnancy, parentalrelationship, gestational age, mode ofdelivery, parity, plurality, birth weightand length, season at birth, andpossible congenital syndromes oranomalies. First, 792 boys and 689girls with congenital syndromes oranomalies (165 boys and 134 girls),with preterm birth before 37 weeksof gestation (354 boys and 275 girls),or lacking birth data (324 boys and318 girls) were excluded. Second,children with diagnosed postnatalgrowth disorders or regularmedication possibly affecting growth(eg, glucocorticoids for asthma) wereremoved (678 boys and 543 boys).18

The final study population thus

FIGURE 1Flow chart of the exclusion procedure of the study population.

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comprised 6114 boys and 5948 girls(80.6% and 82.8%, respectively, ofthe initial study population) (Fig 1).

Growth data, from birth to the latestprimary care visit after 24 months ofage, were collected from theelectronic health records. Potentiallyfalse measurements, typing errors,missing values, or duplicatedrecordings were evaluated by scatterplots and either corrected orexcluded. BMI (calculated as weight[kg]/height [m]2), length/heightmeasurements, and birth size datawere transformed into z-scores(BMI-for-age [zBMI] and height-for-age[zHFA]) according to Finnish growthreferences.18,20 Overweight andobesity were defined by nationalcutoffs for zBMI18 based on BMI-for-age percentile curves passing throughadult values of 25 kg/m2 and30 kg/m2.21

In Finland, antibacterial agents forsystemic use are available byprescription only and sold inregistered pharmacies. Purchasedmedications are reimbursed andregistered in the Drug PrescriptionRegister maintained by the SocialInsurance Institution of Finland (SII).Information on dispensation dates ofprescriptions and pharmaceuticalsare included in the database.22

According to the annual wholesalestatistical database compiled by theFinnish Medicines Agency, fromJan. 1, 2006, to Dec. 31, 2007, thePrescription Register of SII includeddata of 82% of all the outpatientconsumption of antibiotics. Weextracted information on all systemicantibiotics from the Drug PrescriptionRegister (anatomic-therapeutic-chemical code J01, antibacterials forsystemic use, World HealthOrganization Collaborating Centre forDrug Statistics Methodology, http://www.whocc.no/atcddd) purchasedfor the children in the final studypopulation from birth to 24 monthsof age in primary care. Information onantibiotics administered in hospitalswas not collected. The characteristics

of the study population by antibioticexposure are presented inSupplemental Table 4. Age at firstexposure was categorized into4 groups: birth to 5 months, 6 to11 months, 12 to 17 months, and18 to 23 months.

In addition to exposure to any type ofantibiotic, 3 specific groups of themost frequently used antibiotics,penicillins (phenoxymethylpenicillinand combination of amoxicillin andclavulanate, anatomic-therapeutic-chemical code J01C), cephalosporins(J01D), and macrolides (J01FA), wereanalyzed separately. The number ofseparate purchases in the same childwas calculated and categorized asnone, 1, 2 or 3, and $4 episodes (anyantibiotic, penicillins) and as none, 1,and $2 (cephalosporins, macrolides).

Permission for the current study wasobtained from Espoo MunicipalityInstitutional Review Board, SII, andthe National Institutes of Health andWelfare. Ethical approval was notnecessary, because we used onlyencrypted register data and did notcontact the unidentifiable studysubjects.

Statistical Analysis

Weight and height gain wascompared in the exposed andunexposed child population using thecovariance analysis method, withrandom effects for subjects. Boys andgirls were analyzed separately toobserve gender-related differences.The first height and weightmeasurements at 24 months of age(or after) were used as the primaryend points (expressed as $24months, median [interquartile range]age was 24 [24 to 26] months). zBMIand zHFA were examined in relationto general exposure (yes/no), age atfirst exposure (birth to 5 months, 6 to11 months, 12 to 17 months, and18 to 23 months), and number ofseparate exposure episodes. Theprevalence of perinatal factorspossibly interfering with postnatalgrowth or affecting the exposure to

antibiotics (Table 1) were comparedby using x2 test. Those variables thatshowed statistically significantdifferences between analyzed groupswere used as covariates (P , .05).Thus, statistical adjustments wereperformed with maternal smokingafter the first trimester, parentalrelationship, mode of delivery, birthweight, and birth length for boys andmaternal smoking after the firsttrimester, mode of delivery, and birthweight for girls.

The relationship between antibioticexposure before the age of 24 monthsand the risk of overweight $24months was analyzed using logisticregression. The magnitude of theassociations was quantified usingadjusted odds ratio (aOR) with 95%confidence interval (CI).

Data were analyzed by using SPSSsoftware (version 19, IBM Corp.,Armonk, NY). P values ,.05 wereconsidered statistically significant.

RESULTS

Children who received systemicantibiotics during infancy were onaverage heavier than unexposedchildren at the age of $24 months(Table 2). Unadjusted and adjusteddifferences of mean zBMI were 0.13(95% CI 0.07 to 0.20, P , .001) and0.13 (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 $24months were also slightly taller thanunexposed boys (zHFA 0.08, 95% CI0.02 to 0.14, P , .01) withoutadjustment, whereas no differencewas observed in girls or in adjustedheights in boys.

Effect of Age at First AntibioticExposure on Growth

In boys, exposure to antibiotics atvirtually any age before 24 monthswas associated with higher zBMI thanin unexposed children (Fig 2). Theyounger the boy was when exposedto antibiotics for the first time, the

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TABLE 1 Perinatal Factors Potentially Associated With Weight Status at $24 Months of Age or With Antibiotic Exposure in Infancy

Factor Underweight or Normal Weight Overweight or Obese P Unexposed Exposed P

Boysn 4738 1376 1286 4828Maternal age, y NS NS,30 1922 (40.6) 555 (40.3) 539 (41.9) 1939 (40.1)$30 2816 (59.4) 821 (59.7) 747 (58.1) 2889 (59.9)

Maternal smoking after first trimestera ,0.01 NSNo 4319 (91.2) 1221 (88.7) 1163 (90.4) 4378 (90.7)Yes 289 (6.1) 113 (8.2) 77 (6.0) 324 (6.7)

Maternal relationshipa 0.001 ,0.05Partner 4358 (92.0) 1238 (90.0) 1154 (89.7) 4451 (92.2)Single 263 (5.6) 109 (7.9) 93 (7.2) 270 (6.0)

Gestational age, wks NS NS,40 2290 (48.3) 642 (46.7) 623 (48.4) 2310 (47.9)$40 2448 (51.7) 734 (53.3) 663 (51.6) 2518 (52.1)

Mode of delivery ,0.05 NSVaginal 3971 (83.8) 1118 (81.3) 1078 (83.8) 4013 (83.1)Cesarean 767 (16.2) 258 (18.8) 208 (16.2) 815 (16.9)

Parity NS ,0.0010 sibling 2282 (48.2) 640 (46.5) 709 (55.1) 2213 (45.8)$1 siblings 2256 (51.8) 736 (53.5) 577 (44.9) 2615 (54.2)

Plurality NS NSSingleton 4638 (97.9) 1351 (98.2) 1259 (98.0) 4730 (98.0)Twin 100 (2.1) 25 (1.8) 27 (2.0) 98 (2.0)

Season at birth NS NSSpring or summer 2035 (43.0) 556 (40.4) 553 (43.0) 2037 (42.2)Autumn or winter 2703 (57.0) 820 (59.6) 733 (57.0) 2791 (57.8)

Birth size, weightb ,0.001 NSAGA 4541 (95.8) 1310 (95.2) 1224 (95.2) 4628 (95.9)SGA 129 (2.7) 15 (1.1) 36 (2.8) 105 (2.2)LGA 68 (1.4) 51 (3.7) 26 (2.0) 95 (1.9)

Birth size, lengthb ,0.001 NSAGA 4532 (95.7) 1288 (93.6) 1230 (95.6) 4589 (95.1)SGA 101 (2.1) 21 (1.5) 28 (2.2) 95 (1.9)LGA 105 (2.2) 67 (4.9) 28 (2.2) 144 (3.0)

Exposure to antibiotics at ,24 mo ,0.05 —

No 1031 (21.8) 255 (18.2) 1286 (100) 0Yes 3707 (78.2) 1121 (81.5) 0 4828 (100)

Girlsn 5230 718 1540 4408Maternal age, years NS ,0.05,30 y 2182 (41.7) 291 (40.5) 664 (43.2) 1810 (41.1)$30 y 3048 (58.3) 427 (59.5) 876 (56.8) 2598 (58.9)

Maternal smoking after first trimesterc ,0.001 NSNo 4770 (91.2) 630 (87.7) 1399 (90.8) 4001 (90.8)Yes 324 (6.2) 71 (9.9) 88 (5.7) 307 (7.0)

Maternal relationshipc NS NSPartner 4767 (91.1) 646 (90.0) 1382 (89.7) 4039 (91.6)Single 336 (6.4) 52 (7.2) 107 (6.9) 273 (6.2)

Gestational age, weeks NS NS,40 2344 (44.8) 321 (44.7) 696 (45.2) 1969 (44.7)$40 2886 (55.2) 397 (55.3) 844 (54.8) 2439 (55.3)

Mode of delivery ,0.05 NSVaginal 4414 (84.4) 584 (81.3) 1299 (84.4) 3702 (84.0)Cesarean section 816 (15.6) 134 (18.7) 241 (15.6) 706 (16.0)

Parity NS ,0.0010 sibling 2487 (47.6) 340 (47.4) 825 (53.6) 2001 (45.4)$1 siblings 2743 (52.4) 378 (52.6) 715 (46.4) 2407 (54.6)

Plurality NS NSSingleton 5127 (98.0) 709 (98.7) 1514 98.4) 4323 (98.1)Twin 103 (2.0) 9 (1.3) 26 (1.6) 85 (1.9)

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greater the adjusted differencebetween zBMI scores at the age of$24months: ,6 months 0.23 (95% CI 0.12to 0.33), 6 to 11 months 0.14 (0.06 to0.16), 12 to 17 months 0.08 (20.01 to0.12), and 18 to 23 months 0.13 (0.02to 0.24). In girls, a similar tendencywas observed, but the only significantdifferences were in those who hadbeen exposed to antibiotics at 12 to17 months (0.08 [0.00 to 0.15]).

The most pronounced associationswere observed between macrolideexposure at any age ,24 months andhigher zBMI (from 0.28 [0.11 to 0.46]at,6 months to 0.23 [0.12 to 0.35] at18 to 23 months) (Fig 2). In girls,

macrolide exposure at ,6 months wasassociated with mean zBMI difference0.23 (0.04 to 0.42). Age at firstexposure to any antibiotics (12 to17 months), penicillins (12 to17 months), cephalosporins (18 to23 months), and macrolides (6 to 11)months was significantly associatedwith changes in height for boys (Fig 2).Exposure to any antibiotics andpenicillins at 6 to 11 months of ageresulted in similar tendencies for girls.

Number of Antibiotic Exposures inInfancy and Growth

In boys, multiple courses ofantibiotics before the age of

24 months increased zBMI score(Fig 3). Adjusted difference of meanzBMI to unexposed children was 0.09(95% CI 20.00 to 0.18) in thoseexposed once, 0.10 (0.02 to 0.18) inthose exposed 2 or 3 times, and 0.18(0.10 to 0.26) in those exposed $4times to any antibiotics. There wasa linear trend in the number ofantibiotic exposures (P , .001).Multiexposed girls ($4 times) werealso on average heavier (0.13 [0.06 to0.20]) than unexposed girls, and theirzBMI increased with the number ofexposures as well (P , .001). Themost pronounced difference in meanzBMI between exposed and

TABLE 1 Continued

Factor Underweight or Normal Weight Overweight or Obese P Unexposed Exposed P

Season at birth NS NSSpring or summer 2212 (42.3) 312 (43.5) 660 (42.8) 1864 (42.3)Autumn or winter 3018 (57.7) 406 (56.5) 880 (57.2) 2544 (57.7)

Birth size / wtb ,0.001 ,0.05AGA 4999 (95.6) 678 (94.4) 1480 (96.2) 4196 (95.2)SGA 103 (2.0) 6 (0.8) 29 (1.9) 79 (1.8)LGA 128 (2.4) 34 (4.7) 31 (2.0) 133 (3.0)

Birth size / lengthb NS NSAGA 4976 (95.1) 685 (95.4) 1465 (95.2) 4195 (95.2)SGA 100 (1.9) 7 (1.0) 29 (1.8) 80 (1.8)LGA 154 (3.0) 26 (3.6) 46 (3.0) 133 (3.0)

Exposure to antibiotics , 24 mo NS —

No 1374 (26.3) 166 (23.1) 1540 (100) 0Yes 3856 (73.3) 552 (76.9) 0 4408 (100)

Values are expressed as n (%). AGA, appropriate for gestational age; LGA, large for gestational age; NS, statistically nonsignificant; SGA, small for gestational age. —, indicates P value isnot available.a Not available: maternal smoking n = 172; maternal relationship n = 146.b Finnish growth reference for birth size.20c Not available: maternal smoking n = 153; maternal relationship n = 147.

TABLE 2 Characteristics of the Study Population in Relation to Exposure to Antibiotics at ,24 Months

Characteristics Boys (n = 6114) Girls (n = 5948)

Exposed Unexposed P a Exposed Unexposed P a

n (%) 4828 (79.0) 1286 (21.0%) 4408 (74.1%) 1540 (25.9%)Number of measurements per child 14 (1–48) 11 (1–28) ,0.001 14 (1–36) 12 (1–32) ,0.001Age at primary end point (y)b 2.06 (2.00–6.11) 2.05 (2.00–5.50) NS 2.06 (2.00–6.19) 2.05 (2.00–5.24) NSzBMIb,c 0.05 (0.99) 20.09 (1.02) ,0.001 0.05 (1.01) 20.04 (1.00) ,0.01zHFAb,c 0.00 (0.98) 20.08(1.00) ,0.01 20.02 (0.99) 20.05 (1.01) NSPerinatal variablesGestational age (wks) 40.1 (37.0–43.9) 40.1 (37.0–42.9) NS 40.3 (37.0–43.0) 40.3 (37.0–42.7) NSBirth length (cm) 51.1 (1.95) 50.9 (1.96) ,0.01 50.3 (1.89) 50.2 (1.82) NSBirth length z-scored 0.07 (1.00) 20.01 (1.01) ,0.01 0.10 (1.00) 0.08 (0.97) NSBirth weight (kg) 3.65 (0.48) 3.61 (0.48) ,0.05 3.55 (0.46) 3.51 (0.45) ,0.01Birth weight z-scored 20.07 (0.97) 20.12 (1.00) NS 20.02 (1.01) 20.08 (0.96) ,0.05

Values are expressed as the median (range) or mean (SD).a Unadjusted difference.b First measurement at the age of $24 mo.c Finnish growth reference.18d Finnish growth reference for birth size.20

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unexposed children at the age of $24months was found for boys (0.20[0.10 to 0.30]) having $2 exposuresto macrolides or girls (0.17 [0.05 to0.29]) having $2 exposures tocephalosporins.

Multiexposed boys were on averagetaller than the unexposed boys whenthey had used any antibiotics orpenicillins ($4 times) (adjusted zHFA0.09 [95% CI 0.03 to 0.15] and 0.11[0.04 to 0.18], respectively) orcephalosporins or macrolides ($2times) (zHFA 0.13 [0.03 to 0.23] and0.11 [0.04 to 0.19]) (Fig 3). Girls whohad 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 every5 boys and 1 of every 10 girls wasoverweight or obese (Table 1). Therisk of being overweight wassignificantly associated with earlierantibiotic exposure and increasingnumber of separate antibiotic coursesin 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 girlswhen the first antibiotic exposuretook place at ,6 months of age. Fouror more courses of antibioticsresulted in aOR 1.27 (1.04 to 1.55) inboys and 1.19 (0.96 to 1.48) in girls.aOR was 1.65 (1.09 to 2.31) for boyswho were exposed to macrolides at,6 months (Table 3).

DISCUSSION

In this population-based study with12 062 healthy children, we showedthat antibiotic exposure in infancy isindependently associated withenhanced growth, in both weight andheight, at the age of 24 months. Thefirst exposure before the age of6 months or repeatedly during the first23 months of age had the largest effecton BMI. Overall, infant boys wereexposed to antibiotics significantlyearlier and more frequently than girls,and the growth-promoting effect ofantibiotics was also more pronouncedin boys. In addition, exposure to broad-spectrum antibiotics such as

macrolides showed the mostpronounced effects on growth.

Severely malnourished infants havebeen shown to gain weight fasterwhen they are given antibiotics,12–15

and similar findings have been onlyrecently reported in well-nourishedchildren in affluent Westerncountries.7–11 Antibiotics increasebody fat mass in mice, which isassumed to result from changes incomposition of the intestinalmicrobial flora.23,24 In theseexperimental murine studies, theeffect of antibiotics was shown notonly to be dependent on the increasein the energy intake or hormonalchanges that regulate satiety but alsowas associated with alterations in theexpression of microbial genes, whichcontribute to the conversion ofcarbohydrates to short-chain fattyacids.23,24 Thus, more efficient energyharvesting in the colon is assumed todecrease energy loss in the stools. Asimilar mechanism might be true inhumans as well, and the growthpromotion associated with antibiotic

FIGURE 2Adjusted differences of means (95% CI) for zBMI and zHFA at the median age of 24 months between exposed and unexposed children (zero line) classifiedby 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.

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exposure shown in this study and inprevious studies could be linked tothese intestinal changes. Of note, ina recent study, a more pronouncedgrowth-promoting effect of antibioticexposure was reported in male thanfemale mice.25

The strength of our study, incomparison with previous studies, isthat the child population wascarefully screened for other potentialfactors that might alter growth. Theseindividuals were excluded, andstatistical adjustment was made for

birth size and perinatal factors. Also,the growth data are based onstandardized measurementsperformed by educated nurses.Growth data were based on self-measurements in 2 previousstudies,7,11 and Trasande et al pooled

FIGURE 3Adjusted differences of means (95% CI) for zBMI and zHFA at the median age of 24 months according to the separate courses of antibiotic exposures frombirth to 23 months of age compared with unexposed (zero line) children. A–D, boys; E–H, girls. Statistical adjustments: Maternal smoking after firsttrimester, parental relationships, mode of delivery, birth weight and birth length for boys; Maternal smoking after first trimester, mode of delivery andbirth weight for girls.

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both genders in 1 group.9 It isnoteworthy that the data of Baileyet al were not adjusted for perinatalfactors.10 In addition, 3 of 5 previousstudies in well-nourished childrenwere based on medication dataobtained from questionnaires,7,9,11

and 1 on data from medical records.10

In our study, as well as in that of Azadet al,8 the use of antibiotics wascollected from the medicationregistries. Our data based onmedicine purchases probably reflectsreal use better than data forprescribed medications, in whichprimary noncompliance is not taken

into account.26 The results of ourstudy suggest that the growth-promotion effect of antibioticexposure might be different in malesand females. This is consistent withthe recent studies of Azad et al8 andMurphy et al.11 However, Azad et alhad a relatively small sample size andlarge number of dropouts,8 and thegrowth data of Murphy et al were notconverted into z-scores,11 andtherefore it still remains unknownhow exact the observed genderdifference was. There might also besome other, as yet unexplored,mechanisms explaining the more

pronounced effects of antibiotics ongrowth in boys.

To our knowledge, ours is the firststudy to report the effects ofantibiotic exposure in growth inheight in Western countries.7–11

Linear growth seems to be affectedespecially after repeated exposure toantibiotics, when the increase inweight is also the most pronounced.Increase in weight in early childhoodoften also leads to acceleration ingrowth in height, which thereforemay be an event secondary to weightgain after multiple antibioticexposures in infancy. However, theprevalent use of antibiotics in earlyinfancy might also contribute to thesecular change in height observed inWestern countries in the pastdecades,27 since even minor bacterialinfections would have at leasta transient suppressive effect ongrowth if left untreated;28 thus thegrowth-promotion effect ofantibiotics during infancy might besupported in this finding.

We found that growth-promotioneffects varied between different typesof antibiotics, and that macrolideshad the most pronounced weight-increasing effect in children. Theimpact of macrolides may be due totheir pharmacokinetics. Unlikeamoxicillin and cephalosporins,which are eliminated by the kidneysand most likely have very little directcontact with the colonic microbiota,macrolides are excreted in bile andparticipate in the enterohepatic cycle,which may explain this specificdifference from other antibiotics. Ourfinding was at least partially in linewith the results by Bailey et al,10 eventhough they were only grouped intonarrow-spectrum (penicillins) andbroad-spectrum (cephalosporins andmacrolides) antibiotics.

We confirmed earlier observationsthat the use of antibiotics in infancy isassociated with the risk of beingoverweight in boys. In our study, girlsdid not have a statistically significantrisk for being overweight, which

TABLE 3 Odds of Becoming Overweight at the Age of 24 Months According to Age at First Exposureto Antibiotics and Number of Exposures ,24 Months

Antibiotic Exposure Boys Girls

aOR 95% CI aOR 95% CI

Unexposed 1.00 Reference 1.00 ReferenceAge at first exposure, moAny antibiotics,6 1.34a 1.06 to 1.66 1.16 0.87 to 1.566–11 1.26a 1.02 to 1.45 1.14 0.92 to 1.4212–17 1.18 0.88 to 1.32 1.08 0.85 to 1.3818–23 1.25 0.99 to 1.61 1.15 0.87 to 1.52

Penicillins,6 1.28 0.99 to 1.62 1.20 0.87 to 1.666–11 1.29a 1.04 to 1.49 1.20 0.97 to 1.5012–17 1.28 0.95 to 1.42 1.04 0.81 to 1.3318–23 0.95 0.78 to 1.28 1.15 0.87 to 1.52

Cephalosporins,6 1.44 0.97 to 2.35 1.25 0.67 to 2.356–11 1.44a 1.04 to 1.84 1.18 0.79 to 1.7612–17 1.46a 1.06 to 1.82 1.27 0.88 to 1.8218–23 1.10 0.78 to 1.43 1.11 0.75 to 1.64

Macrolides,6 1.65a 1.09 to 2.31 1.53 0.90 to 2.606–11 1.41a 1.09 to 1.70 1.11 0.82 to 1.5012–17 1.10 0.84 to 1.34 1.28 0.95 to 1.7118–23 1.42a 1.18 to 1.93 1.21 0.88 to 1.65

No. of exposures ,24 moAny antibiotics1 1.16 0.92 to 1.48 1.03 0.81 to 1.322–3 1.28a 1.04 to 1.59 1.14 0.91 to 1.42$4 1.27a 1.04 to 1.55 1.19 0.96 to 1.48

Penicillins1 1.13 0.90 to 1.41 1.11 0.89 to 1.402–3 1.29a 1.05 to 1.58 1.19 0.96 to 1.48$4 1.35a 1.07 to 1.69 1.11 0.85 to 1.44

Cephalosporins1 1.39a 1.10 to 1.76 1.05 0.80 to 1.38$2 1.15 0.84 to 1.58 1.46a 1.03 to 2.05

Macrolides1 1.20 0.96 to 1.49 0.94 0.94 to 1.50$2 1.47a 1.16 to 1.86 0.88 0.88 to 1.55

Statistical adjustments included maternal smoking after first trimester, parental relationship, mode of delivery, birthweight, and birth length for boys; maternal smoking after first trimester, mode of delivery, and birth weight for girls.a P value ,.05

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can be explained by the generallylower risk of overweight in girls.However, the worldwide obesityepidemic is real,29,30 and amongFinnish adolescents, for instance, theprevalence of being overweight hasalmost doubled in the past 2decades31 and is more pronouncedfor boys.18,31 An increase in the use ofantibiotics could be an additionalcontributing factor to thedevelopment of excess weightproblems.10,24

A limitation of our study is the lackof data regarding some potentialconfounders that may haveinfluenced the growth of thechildren, such as maternal weightand paternal data. However, in thesubgroup of children with knownmaternal BMI before pregnancy(3551 boys and 3470 girls), thedifference of adjusted mean zBMI(95% CI) between children that were

exposed and not exposed toantibiotics at ,6 months was 0.12(0.01 to 0.24) in boys and 0.07 (20.04to 0.19) in girls (Supplemental Fig 4).Thus, the results of our study are notlikely to be biased even thoughanalyses were performed withoutmaternal BMI as a covariate. Paternalfactors probably had a more minorinfluence on offspring growthcompared with maternal factors.7

Limitations of this study also includethe lack of data on intrapartumantibiotics (eg, prophylactic dosingbefore cesarean section) andbreastfeeding.

Children in our study receivedantibiotics for various indications,which were not included in thedatabase. In Finland, antibiotics aremostly prescribed to this age group totreat respiratory infections,32 whichare not expected to influence theintestinal microbiota directly. In

addition, gastrointestinal infections,which are mostly viral and treatedwith fluid therapy, are onlyexceptionally a reason for antibioticuse in Finland.32

CONCLUSIONS

Antibiotic exposure at the age of ,6months or repeatedly during infancyhas an increasing effect on body massand height at 24 months of age inhealthy children. Exposure tomacrolides seems to have the mostpronounced effect on bodycomposition. Such effects on growthmay have played a role in thechildhood obesity epidemicworldwide. These results highlightthe importance of critical use ofantibiotics in early infancy, favoringnarrow-spectrum antibiotics andavoiding repeated exposure whenpossible.

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.

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DOI: 10.1542/peds.2014-3407 originally published online March 30, 2015; 2015;135;617Pediatrics 

Antti Saari, Lauri J. Virta, Ulla Sankilampi, Leo Dunkel and Harri SaxenMonths of Life

Antibiotic Exposure in Infancy and Risk of Being Overweight in the First 24

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DOI: 10.1542/peds.2014-3407 originally published online March 30, 2015; 2015;135;617Pediatrics 

Antti Saari, Lauri J. Virta, Ulla Sankilampi, Leo Dunkel and Harri SaxenMonths of Life

Antibiotic Exposure in Infancy and Risk of Being Overweight in the First 24

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