Antibiotic Exposure in Infancy and Risk

of Being Overweight in the First 24

Months of Life
Antti Saari, MDa,b, Lauri J. Virta MD, PhDc, Ulla Sankilampi MD, PhDb, Leo Dunkel MD, PhDd, Harri Saxen MD, PhDe

OBJECTIVE: Antibiotics have direct effects on the human intestinal microbiota, particularly in abstract
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% condence 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.

a
Department of Pediatrics, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, WHATS KNOWN ON THIS SUBJECT:
Finland; bDepartment of Pediatrics, Kuopio University Hospital, Kuopio, Finland; cDepartment of Research, Social
Insurance Institution, Turku, Finland; dWilliam Harvey Research Institute, Barts and the London School of Medicine Subtherapeutic doses of antibiotics have been
and Dentistry, Queen Mary University of London, London, United Kingdom; and eChildrens Hospital, University of used as growth promoters in animal farming
Helsinki and Helsinki University Hospital, Helsinki, Finland
since the 1950s. Antibiotic exposure during
Drs Saari, Virta, and Sankilampi carried out the acquisition of the data; Drs Saari and Virta carried infancy is associated with increased body mass
out the initial analyses and drafted the initial manuscript; Drs Sankilampi, Dunkel, and Saxen
in humans.
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 WHAT THIS STUDY ADDS: The weight-promoting
collection; and all authors approved the nal manuscript as submitted.
effect of antibiotics is most pronounced when
www.pediatrics.org/cgi/doi/10.1542/peds.2014-3407 the exposure occurs at ,6 months of age or
DOI: 10.1542/peds.2014-3407 repeatedly during infancy. Increased body mass
Accepted for publication Jan 26, 2015 is distinctly associated with exposure to
Address correspondence to Antti Saari, Kuopio University Hospital, PO Box 1777, FIN-70200 Kuopio, cephalosporins and macrolides, especially in
Finland. E-mail: antti.saari@kuh. boys.
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright 2015 by the American Academy of Pediatrics

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PEDIATRICS Volume 135, number 4, April 2015 ARTICLE
The crucial role of antibiotics in the between antibiotic types and past 60 years. The majority of the
improvement of human health is evaluated the impact of early versus population (94.4%) is of Finnish
unquestionable, but their extended late and single versus repeated origin, which mirrors the whole of
use today has revealed undesirable exposure. Finland (97.3%).19
and unexpected consequences.1,2 To exclude children with possible
Antibiotics have direct intestinal METHODS prenatal conditions affecting growth
effects, and the link between altered and control for possible confounding
gut microbiota and changes in human Study Population factors statistically, we obtained Birth
metabolism has become clearer.3,4 In Finland, child welfare clinics Register data from the National
The intestinal microbiota in infants is provide regular scheduled visits Institutes of Health and Welfare.
particularly vulnerable to (12 during the rst 24 months of age) These data included maternal age,
perturbation.5 One of the unexpected covering almost 100% of the child smoking during pregnancy, parental
effects of antibiotics has been their population.16,17 At every visit, relationship, gestational age, mode of
potential ability to promote growth. primary care nurses perform delivery, parity, plurality, birth weight
This was rst observed in livestock, standardized weight and length/ and length, season at birth, and
in which subtherapeutic doses of height measurements. For the current possible congenital syndromes or
antibiotics have been widely used for study, we initially included all anomalies. First, 792 boys and 689
accelerating weight gain since the children of the Finnish growth girls with congenital syndromes or
1950s.6 In a few recent studies in reference study population born anomalies (165 boys and 134 girls),
children, it has been shown that between Jan. 1, 2003, and April 30, with preterm birth before 37 weeks
early-life exposure to antibiotics 2007, who attended child welfare of gestation (354 boys and 275 girls),
promotes weight gain and increases clinics in the city of Espoo, Finland or lacking birth data (324 boys and
the risk of obesity.711 Although these and who had $1 primary care visit 318 girls) were excluded. Second,
studies provide evidence that after the age of 24 months (7584 boys children with diagnosed postnatal
antibiotics also promote weight gain and 7180 girls) (Fig 1).18 Espoo is growth disorders or regular
in humans, whether this effect is Finlands second largest city by medication possibly affecting growth
dependent on specic antibiotic type population, with a signicant net (eg, glucocorticoids for asthma) were
or amount of exposure has been migration from all parts of Finland. Its removed (678 boys and 543 boys).18
insufciently explored. population has grown .10-fold in the The nal study population thus
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.1215 However,
the effect of early antibiotic exposure
on height in healthy, well-nourished
children has not been adequately
elucidated.711
In the present population-based
study, we aimed to evaluate the
impact of antibiotic exposure during
the rst 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 FIGURE 1
assessed the potential differences Flow chart of the exclusion procedure of the study population.

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618 SAARI et al
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 dened 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 nal study
population from birth to 24 months
of age in primary care. Information on
antibiotics administered in hospitals
was not collected. The characteristics
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PEDIATRICS Volume 135, number 4, April 2015
of the study population by antibiotic
exposure are presented in
Supplemental Table 4. Age at rst
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 specic 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 unidentiable 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 rst 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
rst 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 x2 test. Those variables that
showed statistically signicant
differences between analyzed groups
were used as covariates (P , .05).
Thus, statistical adjustments were
performed with maternal smoking
after the rst trimester, parental
relationship, mode of delivery, birth
weight, and birth length for boys and
maternal smoking after the rst
trimester, mode of delivery, and birth
weight for girls.
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 quantied using
adjusted odds ratio (aOR) with 95%
condence interval (CI).
Data were analyzed by using SPSS
software (version 19, IBM Corp.,
Armonk, NY). P values ,.05 were
considered statistically signicant.
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.
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 rst time, the
619
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
Boys
n 4738 1376 1286 4828
Maternal 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 rst trimestera ,0.01 NS
No 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 ,0.05
Partner 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 NS
Vaginal 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 ,0.001
0 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 NS
Singleton 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 NS
Spring 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 NS
AGA 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 NS
AGA 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) 0
Yes 3707 (78.2) 1121 (81.5) 0 4828 (100)
Girls
n 5230 718 1540 4408
Maternal 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 rst trimesterc ,0.001 NS
No 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 NS
Partner 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 NS
Vaginal 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 ,0.001
0 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 NS
Singleton 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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620 SAARI et al
TABLE 1 Continued
Factor Underweight or Normal Weight Overweight or Obese P Unexposed Exposed P
Season at birth NS NS
Spring 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 ,0.05
AGA 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 NS
AGA 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) 0
Yes 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 nonsignicant; SGA, small for gestational age. , indicates P value is
not available.
a Not available: maternal smoking n = 172; maternal relationship n = 146.
b Finnish growth reference for birth size.20
c Not available: maternal smoking n = 153; maternal relationship n = 147.

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 (20.01 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 signicant
differences were in those who had
been exposed to antibiotics at 12 to
17 months (0.08 [0.00 to 0.15]).
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 rst
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 signicantly 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 20.00 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

TABLE 2 Characteristics of the Study Population in Relation to Exposure to Antibiotics at ,24 Months
Characteristics Boys (n = 6114) Girls (n = 5948)
a
Exposed Unexposed P Exposed Unexposed Pa
n (%) 4828 (79.0) 1286 (21.0%) 4408 (74.1%) 1540 (25.9%)
Number of measurements per child 14 (148) 11 (128) ,0.001 14 (136) 12 (132) ,0.001
Age at primary end point (y)b 2.06 (2.006.11) 2.05 (2.005.50) NS 2.06 (2.006.19) 2.05 (2.005.24) NS
zBMIb,c 0.05 (0.99) 20.09 (1.02) ,0.001 0.05 (1.01) 20.04 (1.00) ,0.01
zHFAb,c 0.00 (0.98) 20.08(1.00) ,0.01 20.02 (0.99) 20.05 (1.01) NS
Perinatal variables
Gestational age (wks) 40.1 (37.043.9) 40.1 (37.042.9) NS 40.3 (37.043.0) 40.3 (37.042.7) NS
Birth length (cm) 51.1 (1.95) 50.9 (1.96) ,0.01 50.3 (1.89) 50.2 (1.82) NS
Birth length z-scored 0.07 (1.00) 20.01 (1.01) ,0.01 0.10 (1.00) 0.08 (0.97) NS
Birth weight (kg) 3.65 (0.48) 3.61 (0.48) ,0.05 3.55 (0.46) 3.51 (0.45) ,0.01
Birth 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.18
d Finnish growth reference for birth size.20

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PEDIATRICS Volume 135, number 4, April 2015 621
FIGURE 2
Adjusted differences of means (95% CI) for zBMI and zHFA at the median age of 24 months between exposed and unexposed children (zero line) classied
by age at rst antibiotic exposure. A and B, boys; C and D, girls. Statistical adjustments: Maternal smoking after rst trimester, parental relationships,
mode of delivery, birth weight and birth length for boys; Maternal smoking after rst trimester, mode of delivery and birth weight for girls.

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.
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
signicantly 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 rst 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).
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
rst exposure before the age of
6 months or repeatedly during the rst
23 months of age had the largest effect
on BMI. Overall, infant boys were
exposed to antibiotics signicantly
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,1215
and similar ndings have been only
recently reported in well-nourished
children in afuent Western
countries.711 Antibiotics increase
body fat mass in mice, which is
assumed to result from changes in
composition of the intestinal
microbial ora.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 efcient 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

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622 SAARI et al
FIGURE 3
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. AD, boys; EH, girls. Statistical adjustments: Maternal smoking after rst
trimester, parental relationships, mode of delivery, birth weight and birth length for boys; Maternal smoking after rst trimester, mode of delivery and
birth weight for girls.

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

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PEDIATRICS Volume 135, number 4, April 2015 623
TABLE 3 Odds of Becoming Overweight at the Age of 24 Months According to Age at First Exposure pronounced effects of antibiotics on
to Antibiotics and Number of Exposures ,24 Months growth in boys.
Antibiotic Exposure Boys Girls
To our knowledge, ours is the rst
aOR 95% CI aOR 95% CI study to report the effects of
Unexposed 1.00 Reference 1.00 Reference antibiotic exposure in growth in
Age at rst exposure, mo height in Western countries.711
Any antibiotics Linear growth seems to be affected
,6 1.34a 1.06 to 1.66 1.16 0.87 to 1.56
especially after repeated exposure to
611 1.26a 1.02 to 1.45 1.14 0.92 to 1.42
1217 1.18 0.88 to 1.32 1.08 0.85 to 1.38 antibiotics, when the increase in
1823 1.25 0.99 to 1.61 1.15 0.87 to 1.52 weight is also the most pronounced.
Penicillins Increase in weight in early childhood
,6 1.28 0.99 to 1.62 1.20 0.87 to 1.66 often also leads to acceleration in
611 1.29a 1.04 to 1.49 1.20 0.97 to 1.50
growth in height, which therefore
1217 1.28 0.95 to 1.42 1.04 0.81 to 1.33
1823 0.95 0.78 to 1.28 1.15 0.87 to 1.52 may be an event secondary to weight
Cephalosporins gain after multiple antibiotic
,6 1.44 0.97 to 2.35 1.25 0.67 to 2.35 exposures in infancy. However, the
611 1.44a 1.04 to 1.84 1.18 0.79 to 1.76 prevalent use of antibiotics in early
1217 1.46a 1.06 to 1.82 1.27 0.88 to 1.82
1823 1.10 0.78 to 1.43 1.11 0.75 to 1.64
infancy might also contribute to the
Macrolides secular change in height observed in
,6 1.65a 1.09 to 2.31 1.53 0.90 to 2.60 Western countries in the past
611 1.41a 1.09 to 1.70 1.11 0.82 to 1.50 decades,27 since even minor bacterial
1217 1.10 0.84 to 1.34 1.28 0.95 to 1.71 infections would have at least
1823 1.42a 1.18 to 1.93 1.21 0.88 to 1.65
No. of exposures ,24 mo
a transient suppressive effect on
Any antibiotics growth if left untreated;28 thus the
1 1.16 0.92 to 1.48 1.03 0.81 to 1.32 growth-promotion effect of
23 1.28a 1.04 to 1.59 1.14 0.91 to 1.42 antibiotics during infancy might be
$4 1.27a 1.04 to 1.55 1.19 0.96 to 1.48 supported in this nding.
Penicillins
1 1.13 0.90 to 1.41 1.11 0.89 to 1.40 We found that growth-promotion
23 1.29a 1.05 to 1.58 1.19 0.96 to 1.48 effects varied between different types
$4 1.35a 1.07 to 1.69 1.11 0.85 to 1.44
of antibiotics, and that macrolides
Cephalosporins
1 1.39a 1.10 to 1.76 1.05 0.80 to 1.38 had the most pronounced weight-
$2 1.15 0.84 to 1.58 1.46a 1.03 to 2.05 increasing effect in children. The
Macrolides impact of macrolides may be due to
1 1.20 0.96 to 1.49 0.94 0.94 to 1.50 their pharmacokinetics. Unlike
$2 1.47a 1.16 to 1.86 0.88 0.88 to 1.55
amoxicillin and cephalosporins,
Statistical adjustments included maternal smoking after rst trimester, parental relationship, mode of delivery, birth
weight, and birth length for boys; maternal smoking after rst trimester, mode of delivery, and birth weight for girls.
which are eliminated by the kidneys
a P value ,.05 and most likely have very little direct
contact with the colonic microbiota,
macrolides are excreted in bile and
both genders in 1 group.9 It is into account.26 The results of our
participate in the enterohepatic cycle,
noteworthy that the data of Bailey study suggest that the growth-
which may explain this specic
et al were not adjusted for perinatal promotion effect of antibiotic
difference from other antibiotics. Our
factors.10 In addition, 3 of 5 previous exposure might be different in males
nding was at least partially in line
studies in well-nourished children and females. This is consistent with
with the results by Bailey et al,10 even
were based on medication data the recent studies of Azad et al8 and
though they were only grouped into
obtained from questionnaires,7,9,11 Murphy et al.11 However, Azad et al
narrow-spectrum (penicillins) and
and 1 on data from medical records.10 had a relatively small sample size and
broad-spectrum (cephalosporins and
In our study, as well as in that of Azad large number of dropouts,8 and the
macrolides) antibiotics.
et al,8 the use of antibiotics was growth data of Murphy et al were not
collected from the medication converted into z-scores,11 and We conrmed earlier observations
registries. Our data based on therefore it still remains unknown that the use of antibiotics in infancy is
medicine purchases probably reects how exact the observed gender associated with the risk of being
real use better than data for difference was. There might also be overweight in boys. In our study, girls
prescribed medications, in which some other, as yet unexplored, did not have a statistically signicant
primary noncompliance is not taken mechanisms explaining the more risk for being overweight, which

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624 SAARI et al
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
inuenced 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
FINANCIAL DISCLOSURE: The authors have indicated they have no nancial relationships relevant to this article to disclose.
FUNDING: Supported by the National Graduate School of Clinical Investigation (Dr Saari), the Pivikki 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 conicts of interest to disclose.
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SAARI et al
Antibiotic Exposure in Infancy and Risk of Being Overweight in the First 24
Months of Life
Antti Saari, Lauri J. Virta, Ulla Sankilampi, Leo Dunkel and Harri Saxen
Pediatrics 2015;135;617; originally published online March 30, 2015;
DOI: 10.1542/peds.2014-3407
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Services http://pediatrics.aappublications.org/content/135/4/617.full.ht
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Supplementary Material Supplementary material can be found at:
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5/peds.2014-3407.DCSupplemental.html
References This article cites 27 articles, 4 of which can be accessed free
at:
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright 2015 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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Antibiotic Exposure in Infancy and Risk of Being Overweight in the First 24
Months of Life
Antti Saari, Lauri J. Virta, Ulla Sankilampi, Leo Dunkel and Harri Saxen
Pediatrics 2015;135;617; originally published online March 30, 2015;
DOI: 10.1542/peds.2014-3407

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/135/4/617.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2015 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org at Pontificia Universidad Catolica de Chile on May 5, 2015