The Role of Breastfeeding in Primary

Prevention of Allergic Disease

Anang Endaryanto

Allergy Immunology Divison, Child Health Department, Faculty of Medicine

University of Airlangga, Dr. Soetomo General Hospital
 1 Introduction

O 2 A window of opportunity for preventing allergies

U
T Interplay of exposure that may impact
3 development of allergy
L
I
N
4 The role of breastfeeding in preventing allergy

E
5 Studies of breastfeeding in preventing allergy

6 Summary
1
Introduction
•  The role of breastfeeding in the prevention of allergies
has been studied since 1930, but it is still controversial.
•  Importance of breastfeeding in regulating newborn’s
immune system and gut mucosal barrier is widely
accepted.
•  Newborn’s gut is immature and needs the right amount
of breast milk in order to develop an optimal mucosal
barrier function.
•  Atopic diseases are spread worldwide and their
prevalence is rising.
•  Some factors in human milk are protective against atopy,
while others increase the risk of allergic susceptibility.
2
Immune function is
incomplete at birth until
The first six 6 months, resulting in
increased susceptibility
months of life to allergic sensitization
offer a window of
opportunity for
preventing Modulating immune
allergies function may have the
potential to prevent
allergies in early life
 2
The line of
development of
immune-
competence of
children with high
risk of allergy is
different from normal
children 6 months

Until a certain age the high risk line is below the normal line
 Interplay of exposure thatFig 1
may impact development of allergy
3

Renz H, et al. J Allergy Clin Immunol 2017;140:24-40.)

Journal of Allergy and Clinical Immunology 2017 140, 1-12DOI: (10.1016/j.jaci.2017.05.010)
Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions
 Primary
Prevention of
Allergic
Disease

Why Breastfeeding?
 van den Elsen et al. Breastmilk-Induced Microbiota for Allergy Prevention

Because
Breastfeeding
Shaping the Gut
Microbiota

van den Elsen LWJ, Garssen J, Burcelin

R and Verhasselt V (2019) Shaping the
Gut Microbiota by Breastfeeding: The
Gateway to Allergy Prevention?
Front. Pediatr 2019. 7:47. doi:
10.3389/fped.2019.00047

FIGURE 1 | The potential of breastmilk to prevent allergic disease by shaping of the neonatal gut microbiota. Breastmilk contains microbes as well as factors that
indirectly shape the gut microbiota of the neonate. Breastmilk can direct the early microbiota composition, i.e., favor the growth of Bifidobacteria and Lactobacillus,
and affect microbiota metabolic function, which subsequently can impact on immune development and maturation. The gut microbiota in early life impacts on immune
 4
Breastmilukla&tion
Immunoreg

Because
Breastfeeding
Induce
Thymic-Treg
Maturation

Melnik BC, John SM, Schmitz G, Milk: an exosomal microRNA transmitter promoting thymic regulatory T cell
maturation preventing the development of atopy? J Transl Med. 2014 Feb 12;12:43
 •  HEALTHY
Treg >> Allergy &ne •  ASYMTOMATIC
Autoimmuent
Developm

4 Treg >Th17

Treg<Th17

Treg<Th17

Treg >Th17
Orihara et. al. WAO Journal 2008, 9-14
 4 The role of breastfeeding Breastmilk
Component
in preventing allergy
β content
Oddy WH, Halonen M,
IgG-IgA 60 p = 0.017 p = 0.08 p = 0.6 p = 0.3
linear Martinez FD, Lohm- an IC, Stern
ell-medi- p = 0.006 p = 0.2 p = 0.9 p = 0.1 DA, Kurzius-Spencer M, et al:
50
TGF-β in human milk is
β1 was a associated withwheeze in
ffects on 40
infancy.
Ever wheeze, %

sruption J Allergy Clin Immunol

nation in 30
2003;112:723–728.
hat carry
20
the mu- Oddy WH. Breastfeeding,
ental ab- Childhood Asthma, and
10
hen suc- Allergic Disease.
al, mixed Ann Nutr Metab
0
eading to Lo Med Hi Lo Med Hi Lo Med Hi Lo Med Hi
2017;70(suppl 2):26–36
observed TGF-DŽ IL-10 TNF-į sCD14
stfeeding Breast milk cytokine dose

maternal
and milk
Fig. 4. Percent with ever wheeze at 1 year of age by tertiles of cyto-
atal sur-
6
dhood Asthma, and Allergic Disease
4 The role of breastfeeding Breastmilk
in preventing allergy Component

Breastfeeding
childhoodThe protective
asthma and al- Optimal nutrient
effectsisofcritical
sial. Breastfeeding composition
t of the infant through bio-
breastfeeding
t on healthy establishment
Bioactive
components
Healthy Asthma and other
may extend
or babies because of its im-
individual Immunoactive allergic diseases
against
ection against earlythe
infec- components
a major risk factor for asth-
development
through breastfeeding may
Maintaining gut
homeostasis Oddy WH. Breastfeeding,
of asthma and
llergic disease. Childhood Asthma, and
Modulation of
allergic immunity Allergic Disease.
Ann Nutr Metab
diseases. Development of 2017;70(suppl 2):26–36
6 months of life, and up to 2 gut microbiota
e “gold” standard for infant
health benefits for mother The protective effects of breastfeeding may extend against the devel-
uniquely suited to the hu- opment of asthma and allergic diseases.
5

Do the results of studies

support the role of
breastfeeding in
preventing allergic
disease?
5
A recent review finds that although
modulating human milk composition
may have the potential to prevent
allergies in early life, several studies have
so far shown conflicting evidence about
the protective role of breastfeeding
on allergies.
5

Breastfeeding is
associated with a reduced
risk of asthma & wheezing
illness
 5
American Journal of Epidemiology Advance Access published April 11, 2014

American Journal of Epidemiology

© The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of DOI: 10.1093/aje/kwu072
Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Systematic Reviews and Meta- and Pooled Analyses

Breastfeeding and Childhood Asthma: Systematic Review and Meta-Analysis

Cristian M. Dogaru*, Denise Nyffenegger, Aniña M. Pescatore, Ben D. Spycher,

and Claudia E. Kuehni
* Correspondence to Dr. Cristian M. Dogaru, University Campus Suffolk, School of Applied Social Sciences, Waterfront Building, Neptune Quay,
Ipswich IP4 1QJ, United Kingdom (e-mail: c.dogaru@ucs.ac.uk).

Initially submitted September 4, 2013; accepted for publication December 12, 2013.

Downloaded from http://aje.oxfordjournals.org/ at Seton

Included
Asthma and wheezing disorders117are of 1,464
common titles
chronic identified
health problems inby search.
childhood. Breastfeeding provides
The pooled odds ratios were:
health benefits, but it is not known whether or how breastfeeding decreases the risk of developing asthma. We per-
formed a systematic review and meta-analysis of studies published between 1983 and 2012 on breastfeeding and
0.78 (95% confidence interval: 0.74, 0.84) for 75 studies analyzing “asthma ever,”
asthma in children from the general population. We searched the PubMed and Embase databases for cohort, cross-
0.76 (95%
sectional, confidence
and case-control interval:
studies. 0.67,the0.86)
We grouped outcomesfor 46
into studies analyzing
asthma ever, “recent
recent asthma, asthma,”
or recent wheezing
0.81 (95%
illness confidence
(recent interval:
asthma or recent 0.76,
wheeze). Using0.87) for 94 studies
random-effects analyzing
meta-analyses, recent wheezing
we estimated pooled odds illness.
ratios of
the association of breastfeeding with the risk for each of these outcomes. We performed meta-regression and stratified
A positive association
meta-analyses. We included of117
breastfeeding withbyreduced
of 1,464 titles identified our search.asthma/wheezing
The pooled odds ratios were is supported
0.78 (95%
confidence interval: 0.74,by the
0.84)combined
for 75 studiesevidence of existing
analyzing “asthma studies.
ever,” 0.76 (95% confidence interval: 0.67,
0.86) for 46 studies analyzing “recent asthma,” and 0.81 (95% confidence interval: 0.76, 0.87) for 94 studies ana-
lyzing recent wheezing illness. After stratification by age, the strong protective association found at ages 0–2 years
diminished over time. We found no evidence for differences by study design or study quality or between studies in
Western and non-Western countries. A positive association of breastfeeding with reduced asthma/wheezing is sup-
5

Breastfeeding is
associated with a reduced
risk of eczema in the short
term but not at 6-7 years
of age
 7
Acta Pædiatrica ISSN 0803-5253

REVIEW ARTICLE

Breastfeeding and asthma and allergies: a systematic review and

meta-analysis
CJ Lodge (clodge@unimelb.edu.au)1,2, DJ Tan1,3, MXZ Lau1, X Dai1, R Tham1, AJ Lowe1,2, G Bowatte1, KJ Allen2,4*, SC Dharmage1,2,*
1.Allergy and Lung Health Unit, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Carlton, Victoria,
Australia
2.Murdoch Childrens Research Institute and University of Melbourne Department of Paediatrics, Royal Children’s Hospital, Parkville, Victoria, Australia
3.NHMRC Centre of Research Excellence for Chronic Respiratory Disease, School of Medicine, University of Tasmania, Hobart, Tasmania, Australia
4.Institute of Inflammation and Repair, University of Manchester, UK

To systematically review the association between breastfeeding and childhood allergic disease.
Keywords ABSTRACT
Predetermined inclusion/exclusion criteria identified 89 articles from PubMed, CINAHL and EMBASE databases. Meta-
Allergic disease, asthma, meta-analysis, systematic Aim: To systematically review the association between breastfeeding and childhood
analyses
review performed for categories of breastfeeding and allergic outcomes. Meta-regression explored heterogeneity.
allergic disease.
Results:
Correspondence
Methods: Predetermined inclusion/exclusion criteria identified 89 articles from PubMed,
More vs. less breastfeeding (duration) CINAHL
Caroline Lodge, MBBS Grad Di Epi, PhD, Post-
• doctoral Research Fellow, Allergy and Lung Health
was associated with reduced
and EMBASE databases. risk of asthma for
Meta-analyses childrenfor
performed (5–18 years) of breastfeeding
categories
Exclusive
• Unit (ALHU), breastfeeding
Centre for Epidemiology forand 3–4 months andwasallergic
associated with Meta-regression
outcomes. reduced risk of explored
eczema ≤2 years (estimate principally from
heterogeneity.
Biostatistics, School of Population & Global Health,
Facultycross-sectional studies
of Medicine, Dentistry of Sciences,
& Health low methodological
Results: quality).
More vs. less breastfeeding (duration) was associated with reduced risk of asthma
No association
• The University found
of Melbourne, Level between breastfeeding
3, 207 Bouverie and(5–18
for children food allergy
years), (estimate
particularlyhad high heterogeneity and
in medium-/low-income low quality).
countries and with reduced
Street, University of Melbourne, Victoria 3010, risk of allergic rhinitis ≤5 years, but this estimate had high heterogeneity and low quality.
Conclusion:
Australia
Exclusive breastfeeding for 3–4 months was associated with reduced risk of eczema
There
• Tel: +61 is some evidence that breastfeeding
3 83440848| is protective for asthma (5–18 years).
≤2 years (estimate principally from cross-sectional studies of low methodological quality).
Fax: +61 3 93495815|
• Email:There is weaker evidence for a protective
clodge@unimelb.edu.au effectfound
No association for eczema
between≤2 years andand
breastfeeding allergic rhinitis
food allergy ≤5 years
(estimate of age,
had high
with greater protection for asthmaheterogeneity
Received and eczemaand inlowlow-income countries. found differences between study
quality). Meta-regression
13 May 2015; revised 29 June 2015; outcomes may be attributable to length of breastfeeding recall, study design, country
accepted 14 July 2015.
income and date of study inception. Some of the protective effect of breastfeeding for
DOI:10.1111/apa.13132
 st
0.92feed
odge et
al. 6 months – 2 years 11 ing an1.03)
(0.83; d asthm
a and al
16.2 0.0159 6 months – 2 years NOTE: Weights are from random11effects analysis 0.92 (0.83; 1.03)
lergies
3–20 years 14 1.04 (0.96; 1.14) 3–20 years 14 1.04
.1 .25 .5 (0.96; 1.14)
1
Study size Study size Odds Ratio
<1000 participants More vs 6 0.96 (0.89; 1.02) More 0 vs. Less 0.0261 <1000 participants 6 0.96 (0.89; 1.02)
. Less b Breastfe Study breastfe
1000–10000 participants reastfee 11 0.87 (0.72; 1.05) eding eding an
Study
d in g and th ID a nd asthm d the ri s
Figure 4 Meta-analysis.
1000–10000 Exclusive
participants breastfeeding >3–4 months
11 compared with less(0.72;
0.87 and risk of eczem
1.05)
e ris a and a k of whe Lo dg e et al.
≥10 000 ID participants country 5k of wheeze/as 1.07 (1.00; 1.16) llergies eze/asth
m ≥10 000 participants 5 1.07 (1.00; 1.16)
income thma 5-1 Cohort st a 5-18 ye
Year at birth 8 years ud y ars at ofbirth age
by Burr (199 Year
High inco
me Sears (2
3) Odds
1958–1994 Burr (199 12 1.01 (0.89; 1.13) 002) 0 0.0338

7
3) O dds R 1958–1994
atio vs. 12 1.01 (0.89; 1.13)
Sears (2
Oddy (200
2) More (95% Less CI)Breast feeding and the risk of eczema up to 2 years of age
1995–2008
Oddy (2
002) 10 1.00Rat(0.91;
io (95% 1.11) Burgess (200
CI) 6) 1995–2008 10 1.00 (0.91; 1.11)
Study design Miyake (2
002) Matheso
n (2007) Study0.52Study
(0.27, 0. design
Odds The only
003) Matheso ID 99) Ratio (95% CI)
n (2 00 2.
Cohort
Al-Mousa
w i (2004) 14 0. 52
0.96 (0.86; (0.27, 0. 1.07) Fr ed rikss on (2
7)
16.2
007) 0.0159
40 (1.36, 4.
0.74 (0.5Cohort
25 ) 14
allergic
0.96 (0.86; 1.07)
hist
Burgess 99) Elliott (200 4, 1.01
(2006) 2.40 (1.3 Cohort
1.03 (0.8study )
Matheso
Cross-sectional 11 1.04 (0.95; 6, 4.251.13)
) Sc
8)
9, and food all
1.10 (0.8 Cross-sectional 11 1.80 (1.01, 3.22) 1.04 (0.95; 1.13)
n (2007) 0.74 (0.5 ho ltens (200 1. 19
Matheso 4, 1.01) Kramer (2 9) Marini 3, 1.45)
)
Length n (200of 0.98 (0.6 009) Sariachvili 1.00 (0.63, 1.58) with a famil
Maiof recall
(2007)
7) breastfeeding 5, 1.48 ) Ku ll (2010)
1.46 (1Length
.0 2, 2.08) of recall of breastfeeding
0.54 (0.3 1.60 (1.0
≤1Fryears
edriksson 0, 0.97) Silvers (2 Dunlop 1, 2.53) 0.30 (0.11, 0.85)
Miyake (2
(2007) 14 0.94
1.03 (0(0.85;1.03)
.89, 1.19 Brew (201
012) 56.5 0.0040 0.83 (0.6 ≤1 years
Kerkhof 1, 1.12)
14 should be i
0.94 (0.85;1.03)
0.70 (0.32, 1.51)
007) 1.10 (0.8 ) 2) 0.57 (0.4
7–20
Elliott years
(2008)
10 1.11
1.46 (1.0
(1.01;
3, 1.45)1.22) Subtotal
(I-square Ludvigsson 1, 7–20
0. 80 ) years 10 1.11 (1.01;
0.93 (0.82, 1.05) wide confid
1.22)
d = 77.0% 0. 80 (0 .40, 1.60
Morass 2, 2.08) .
Control for(200confounding 0.73 (0.5 , p = 0.00 0.Miyake
63 (0.5Control
)
for confounding 0.79 (0.52, 1.21)
Nagel (2
009)
8)
1.60 (1.0
2, 1.03) Cr oss-sect
ional stud
0)
0.Schoetzau
92
0,
(0.84, 1.
0.79)
0.47 (0.30, 0.74)
(n = 163). F
Low
Scholtens 5 0.95 (0.74; 1, 2.53) 1.24) Selcuk (1
997) 0y 0.0286 01)
Low 5 1.04 (0.70, 1.55)0.95 (0.74; 1.24)demo
Kull (201
(2009) 1.03 (0.9
1, 1.17) Romieu
(2000)
1.08
0.
Moore(0.74, 1.
57) (110)
Medium 11 0.1.01
83 (0.6(0.90; 94 (0.80,
1, 1.12) 1.13)
0) Miyake (2 Silvers1.Medium 11 0.96 (0.90, 1.03) 1.01 (0.90; 1.13)
Lee (201 11)
2) 1.00 (0.7 Kurt (200
003)
Stelmach allergy (defi
High
Silvers (2
012) 9 0.1.02
92 (0.77,
1, 1.40) 1.13)
(0.92; Miyake (2
7) High 9 0.90 (0.83, 0.98)1.02 (0.92; 1.13)
Brew (2
012) 0.57 (0.4
1.09) 007) 0. 73Chuang
(0.39, 1. 1.49 (1.15, 1.93) data, associa
Setting
Subtota 1, 0.80) Morass (2
008) 0.91Hikino Setting
37)
1.43 (1.12, 1.82)
l (I-squa 0.63 (0.5 Nagel (2 (0.66, 1.
. High-income red = 70
country
.3%, p = 15 1.02
1.43
0, 0. 79)
(0.91; 1.14)
Nagel (2
00 9) 0 0.0358 0. 98Kramer
26)
(0.65, 1. High-income country 15 1.14 (0.65, 2.01) 1.02 (0.91;causation.
1.14) T
0.000) (0.48, 4. 009) 48)
Medium 27) 0.92 (0.8
/Low inco
Middle-/low-income country 8 0.920.94
(0 .8 (0.85; Selcuk (2
1.03) 01 Snidjers
6, 0.99) 0.77 (0.52, 1.15) controlled fo
Selcuk (1 me 4, 1.01) 0) 1.03 (0.9 Middle-/low-income country 8 0.94 (0.85; 1.03)
997) 1.08 (0.7
4, 1.57)
Demir (2
010) 1.00 (0Morales
1, 1.17) 0.42 (0.11, 1.59)
Romieu
Categorisation of breastfeeding Bjorksten .71, 1.Categorisation The main
(2000) 0.93 (0.8 40) (I-squared =of breastfeeding
Kurt (200 3, 1.04) (2011) 0.92 (0Subtotal
.7
70.5%, p = 0.000) 0.97 (0.86, 1.10)
7) Lee (201 7, 1.09)
NagEver
2) 0.74 (0..6 allergy was
el (200vs.9)
never 9 1.11 (0.98;1.25) Guibas (2
013)
0 0.0190 1, 0.90) Ever vs. never 9 1.11 (0.98;1.25)
Kramer 0.77 (0Cross-sectional
.59, 1.00 study
Exclusive
(2009) vs. other 9 0.73 (0 0.88
.39, 1.37(0.79; So ng (2014)
0.98) 0.50 (0.2 ) Exclusive vs. other 9 0.75 (0.56, 1.01)0.88 (0.79;the studies
0.98)
Selcuk (2
010) 0.91 (0.6 ) Su btotal (I-
squared
Suarez_Medina
2, 1. 12)
6, 1.26 0.99 (0.9
Demir More
(2010)vs. less (not in categories above) 7 0.92 (0.8
1.04 (0.93;
) . 1.16) = 25.9%
, p = 0.17 1.43 (0.4Subtotal
3, 1.06) More (I-squared = .%,
vs. less (notp =in.)categories above) 7 0.75 (0.56, 1.01)1.04 (0.93; 1.16) rep
parental
Guibas 6, 0.99) Case-Con 5) 8, 4.27)
Total 3)(2 25 0. 1.00 tro .
01 74 (0.6 1, 0.90(0.94;Al-M 1.06) l 1.
4.17Total 25 1.00 (0.94; 1.06)
42 (0.48,
Song (2014) 0.80 (0.4
0, 1.60)
) ou
Mai (200
sawi (200
4) 0.80 (0.5 Overall
0, 1.29)
) (I-squared = 70.0%, p = 0.000) 0.95 (0.85, 1.07) used oral fo
Subtota 7)
l (I-squa 0.77 (0.5 0.93 (0.8
. red = 9.1%
, p = 0.35 0.50 (0.2
9, 1.00) Subtotal
(I-square
d = 0.0%
7, 0.99)
NOTE: Weights are from random effects analysis standard for
Overall 9) 2, 1.12) . , p = 0.38
(I-square 1.42 (0.4 Overall 1)
tfeeding an d = 62.2
%, p = 0.
8, 4.17) (I-square 0.54 (0.3 .1 .25 .5 1 5
dNas
OTEthm : Waeian 000)
0.80 (0.5
0, 1.29)
d = 62.9%
, p = 0.000) 0, 0.97)
ghtsd aralelefrorgie 0.86 (0.7 NOTE: W 0.73 (0.5 Odds Ratio
m rasndom 9, 0.94) eights ar
e from ra 2, 1.03)
effects an ndom effe 0.68 (0.5
0, 0.91)
alysis
0.90
(0.82, 0.
cts analys
is DISCUSSION
More vs. Less .25 Breast
.5 feeding and the risk of Allergic 97) .25 0.90 (0.8 More vs. Less
Figure 5 Meta-analysis.
4, 0.97) MoreBreast
vs. lessfeeding and and
breastfeeding the risk
riskofof Allergic
eczema up to
nalysis. M Breast fe
eding Rhinitis by1 studytype Figure 2 .5 We found e
ore vs. le af te r O
3-4ddmson
Meta-analys 1 2 years of age Rhinitis by studytype
ssStudy
br Stud y
eastfeedin Ratio
ths and th Odds
5 is. More vs Lodge et alOdds Ra Study Odds asthma in c
g an d e ri sk . less brea . tio 5
ID ID risk of as of ecRatio
zema (95% CI) stfeeding an ID Ratio (95% CI)
thma aged up to 2 ye d risk of as the risk of e
5–18 year ars of ag thma aged
s stratified e 5–18 year
Cross-sectional
Cohort stu study by coeun
stim s Cross-sectional study 5 years of a
s dy try a
inte
coms ecompa Odds
Ehlaye 0.56 (0.43,ri0.72)
n
4 month Ragtioe(9 x5%cluCIsi) ve b Ehlaye 0.56 (0.43, 0.72)
between
breast Sun
Dunlop
62%, G0.76
s w it
(0.65,th0.89)
h o er feedin re a st feeding g outcome, Sun there was no association from pooling 0.7612 for food alle
esti-
(0.65, 0.89)
d by 5 c feeding ra d g ty p re a ter
ohort stPeroni Kerkhof a nd allerg (F ig . p 0.98 (0.69,
e +; Fig1.40) . 4 ). There
e s (re OR
0.74; 0.5
th an 3– mates Peroni
below the age of 5 years where heterogeneity 0.98was conclusions
(0.69, 1.40)
still
studies udies (3 ic rhinit S11). In ublicatio R e v e
(48,52–Siriaksorn
Lu
5 dvigsson
1,66,98–
100) an
is nonsign sh o
contr0.17 n (0.03,
ast, b th
ias on0.3 0.92)
th e
was som
e visual
7,0.97, I 2
(3
rse causa
ti o n too Siriaksorn
high for the estimate to be reliable (6 cohort, 0.176(0.03,
cross-0.92)
low to low.
5 ,5 ifi c w in e re 0 (0 fu
.11 n
was no0.8n5)el plot, wit evidence 7 ,7 w as explo
aried bBjorksten
ipants v 9,60,96,1 d 11 ant incre g1.00 a pro (0.93,
tectiv1.08)
, 5,77,79,8
0 1 – 1 0 5 years a ss a se in e e ff a ss o h m o o f 4 ) w it red bBjorksten
y 2 1.00 (0.93, 1.08)
1402 to e
Mitw
Kurtyakeeen 361 3 ). The fr om pooociati1.00
li
the ri0.7
on fo(0.94, und bsk 1.06)
0o e t (Fig. ciation
(0f.32,c1.5 S ) How
re
or a small studies
n onsignifi
cant ten
h only on sectional)
e findKurt
5 of(re 42 OR studies1.07; 0.92, 1.24, I 85%,
exposure, o
1.00Grade+;
(0.94, 1.06)
206 453
Lee
and 13
889 for
re OR 1
.05 (0.9 for thneg e90.90 studie etw a rg
eenlleth
1)
ic 6in itis afteevrer, there was with earl dency to ing evid
pt one
study (9Mo ore
for the
c ro b y 9, 1.12),xp2osu(0.57, re
s (5 c1.42)
0.9 ro
3 ss -s e e rirhsk o f n o y e c z e b re a Fig.
st fe
Lee
S13). There
e n c e owas
f no association when the 0.90 (0.57, 1.42)
studies (co
estimates
st %, o c ma symp
ss-sectio udy typ 1 cross 1.10 I (0.48, f 2.54) (0 .82
more , v1.0 tional, 4 eczema u ed longe a
Selcuk
8) were
p nal e, regard-secti4o3n Gra d s.5)le ss c o h o p to 2 to m s Selcukr for ch 1.10 (0.48, 2.54)
o p ulation ri sk for 9 e + b
(Fig. S12 reastfeedin rt ): y ears (3 7 ).from three cohorts ildren and one cross-sectional study were Grade rating
Song Grade +less of oaultcsto
-section+1.00 ;l Fig.(0.73,
Sc hoetzau based u1.36)
0.7 9dy) Subgrou Song 1.00 (0.73, 1.36)
cross me(0 .52(r , e 1)
age1.2 OR 0.9 ). Analy g (15 co p analysi
SuSubtotal
77%) an a0.88 5 ). 1.00) , fo und a 5re ; 0.85si, s1 horts, studies are a
btotal (I-sq (I-squared = 75.0%, p = 0.000) d no assA (0.77, pooled for food allergy after pthe age of 5 years (re OR 1.08;
findings ft er stud ie s .0 7 2 A g e s by met Subtotal (I-squared = 75.0%, = 0.000) 0.88 (0.77, 1.00)
uared = 61 (r e 2
ociationyears nei e O.67 (r
0.9 4 (0 R , 1.3 d uced , I = 70% o f eczema a -regressio
. O R 0.99; less ex for 3 estther the 0 2)
.8 8 0.77, , outcome n .1.58, I2 65%, Grade+; Fig. S14).
im7ates frever b; re
.6%, p = 0.
mates fo .
023)
st u
0.85, 1.1 p o su re s a 1.00, I 2 between
st u e x p la in 0.73, assessment o
r moCohort study dy foun cr 5, I 78w
2
%er
0.4 (0.30, 0.7 o4) m cohostrtfeeding, n dies, wit ed 16%Cohort study
ion of re vs. le d no o insste-sra ; Feiga.ss6o).cia studies or the mo 2 years h a lowe of the
studyOvty Codispoti
er
ss breast
feeding
eccti
tioo0.80
n (0.65,
nabl yst ies40.98)
uad0.7 Ote ned cwro ith ecze ma. Ever re vs. (Table 3
). Both
r risk fou Codispotivariability 0.80 (0.65, 0.98)
ant prote all
pe(I-o sqruared = 1 .1 6 , I 2 p re a
(0n .57
d , 0.9
o ss -s e c ti b re a st nd fo r childre
c ti Codispoti age 61o.6f %, p = 0.02 F o o d = 4 1.00
3 % , (0.93,
Grade +
n tal atope cohort
1.07) n 7) onal vs. never
:9 fe e d in g the stud Codispoti n up to 1.00 (0.93, 1.07)
ve effect outcom3) allergy sect
+
y (101). study, re e x recall w y design
1, I 74%
2
Strachan for allerg e io nal stu1.14 ; Fig. S7 OR 1.07; plaining ere relate and len
(Fig NO . TE
6 ic rhinit There w
e re dies (1.01,
a n d
1.29) ). More 0 .9 8 , 1 6 % a n d to 46 th Strachan g th o f ©2015 The Authors. Acta1.14 (1.01,published
Pædiatrica 1.29) by John Wiley & S
ever, a re : WA
). eig
fthts is: G
9 cora hodrt 6 co horts, re vs. less: Cohort st d 57% of e pSubtotal
ooled est(I-squared = 77.6%, p = 0.012)
ducedSubtotal
er arst(I-squared
era
from rand
tificati =fec77.6%, p c=ti0.012)
se e +(1(T 1 ab0.99
le (0.85,0.74 (0 1.15) O 14 cross u d th e 0.99 (0.85, 1.15)
om ef
on ts an o n a l st iesgges ,1 7 ,7 1 ;
0,79igF .57 , 0.9 7) R 1 .0 9; 0.99, 1 - ie s a nd breast b e tw een-stud im a tes,
risk of a
llergic rh by tion betw udsu
alysis ,8.5S,1 80).4Altho associate
was fo.u
tfeeding (10te1d,1w –107)uagh .20, I 2 86 d with lo feeding re . y variab
initis een it 08ea–1 k1ev )idin
0(0.84, envce ndth4e cm %, call of up ility.
stimateOverall
nd only(I-squared
below th.1= 74.2%, p5f =p0.000) brey oafstth 0.92 1.01) rooss re- vs. less feeding, wer poo Overall (I-squared
ar were = 74.2%, p = 0.000) 0.92 (0.84, 1.01)
ing 6 e .2o a fe e
e des ti e st fo
ig ra a
ti n in cr ca w le d to 1 y
rtic ingmaanted wa n tegory hilst incre risk for e
.6
an3al,ys0is..9Ex
s (4 cro
ss-sectioare from
e ag e
and Ofr
.5 ipants
Poth
1 in olee dcoehst foosdtoaollhigh g thea e seassdoricsk ia-, the heteroge cross-sec ased len eczema
fromWeights
8),cluIsiv
2 NOTE:
e 4br%ea, stf
8 Weights n a l, 2 random effects
dd
o s
m R atanalysis
io
127a8sso o im
rt s a te
5
rans gefrdom
ergy. fo T r
h th
e e es ti ers n e- ti o n a l study de g th o f b reastfeed NOTE: b re a st- are from random effects analysis
ss-sectio
nal stud
Gee radidng
e 0>3(F –4igm. on Pooling tocia1ti3o1n10bein from stu1d6ies numbm ate to be
reliable. pooled
risks. A sign were ing recall
OR 0.6 ies foun .1S1th0s).compam .25
redore of
withv less.5an12his est 1im
to ry 2 twetheen cbro ressa st fe
3 tow2 h1ich 766investigate eczema dditiona associate
d w
and .1 .25 .5 1 2
4, (0.64 d a re lessdbst
s. Ratio ris a o
te
k of eczem ll f sa (6ergcic -s e ce d in
tiongalan d the ri sk were ll y , lower p it h increased
, 0.82), 2 duced a ll Odds re
raatast fe(F a up to
ohd ois rte, a6secd stdudeieczs.ema b w h e se e n ooled e Odds Ratio
Breast fe I 6 9% e rg y, alth e digin 2
. gS9fo).undyears of age ssn ro id -soetcti fionn y familia n compare in middle-/ st imates fo
daal) dfo
0.88, 1.1 o2ugh heterogen
eding and no asso iffe l d to hig low-inco r
the risk of
eczema up ciation r rent risk in breastfee h-incom me coun
8, I 86 eity was w Figure 7 Meta-analysis. th e More vs. less ding cate and
breastfeeding risk of e co
food allergy tries
Figure 6 Meta-analysis. to 2 yearMore
s of agevs. less breastfeeding % and
; Fig. 7). risk of allergicv e rhinitis
ry high ith fo od eczema ri g o ry was u n tr ies. Figure
T h e 6 Meta-analysis. More vs. less breastfeeding and risk of allergic rhinitis Figure 7 M
published
by John Odds After st (RE OR sk comp also ass exclusive
Wiley & 44 ratificati 1.02; le ss . ared with ociated
Sons Ltd
on Ratio ( T on f both w ith a
7

Breastfeeding (any or
exclusive) had no effect
on asthma and allergic
disease in the IoW cohort
 HHS Public Access
Author manuscript

5 Allergy. Author manuscript; available in PMC 2017 May 01.

Author Manuscript

Published in final edited form as:

Allergy. 2016 May ; 71(5): 661–670. doi:10.1111/all.12833.

Evaluating the efficacy of breastfeeding guidelines on long-term

outcomes for allergic disease
Victoria Biona,*, Gabrielle A. Locketta,*, Nelís Soto-Ramírezb, Hongmei Zhangb, Carina
Venterc,d, Wilfried Karmausb, John W. Hollowaya,e, and S. Hasan Arshadd,e,§
aHuman Development and Health, Faculty of Medicine, University of Southampton, Southampton,
UK
Author Manuscript

bDivision of Epidemiology, Biostatistics, and Environmental Health, School of Public Health,

University of Memphis, Memphis, TN, USA
cSchool of Health Sciences and Social Work, University of Portsmouth, UK
dThe David Hide Asthma and Allergy Research Centre, St. Mary’s Hospital, Isle of Wight, UK
eClinical
and Experimental Sciences, Faculty of Medicine, University of Southampton,
Southampton, UK

•  Breastfeeding
Abstract
(any or exclusive) had no effect on asthma and allergic disease in the
Background—WHO guidelines advocate breastfeeding for six months, and EAACI recommends
IoW cohort.
exclusive breastfeeding for 4–6 months. However, evidence for breastfeeding to prevent asthma
Author Manuscript

•  In the FAIR cohort,

alters any breastfeeding for >0–6 months
rhinitis, protected against asthma at
and allergic disease is conflicting. We examined whether following recommended breastfeeding
guidelines the long-term risks of asthma, eczema, or atopy.

10 years (RR=0.50,
Methods—The 95%CI=0.32–0.79,
effect of non-exclusive (0, p=0.003) but not
>0–6, >6 months), andother outcomes,
exclusive while
breastfeeding
4, >4 months) on repeated measures of asthma (10, 18 years), eczema, rhinitis, and atopy (1-or-2,
(0,exclusive
>0–

breastfeeding
4, 10, 18 for >4risks
years) months protected
were estimated against
in the IoW cohort (repeated
n=1456) using rhinitis
log-linear(RR=0.36,
models with

95%CI=0.18–0.71, p=0.003).
generalised estimating equations. The Food Allergy and Intolerance Research (FAIR) cohort
(n=988), also from the IoW, was examined to replicate results.

•  LongerResults—Breastfeeding
breastfeeding was protective
(any or exclusive)against late-onset
had no effect on asthma and wheeze
allergicin the IoW
disease
IoW cohort. In the FAIR cohort, any breastfeeding for >0–6 months protected against asthma at 10
cohort.
in the

years (RR=0.50, 95%CI=0.32–0.79, p=0.003) but not other outcomes, while exclusive
breastfeeding for >4 months protected against repeated rhinitis (RR=0.36, 95%CI=0.18–0.71,
Author

p=0.003). Longer breastfeeding was protective against late-onset wheeze in the IoW cohort.
 TABLE 2 TABLE 3
Effect of duration of non-exclusive breastfeeding on risk of allergic disease in exclusive
Effect of the IoW and FAIR cohorts
breastfeeding duration on risk of allergic disease in the IoW an

5
Author Manuscript

Author Manuscript
Duration of non-exclusive breastfeeding (months) Duration of exclusive breastfeeding (months)
(RR; 95 CI; p value) (RR; 95 CI; p value)

0 >0–6 >6 0 >0–4 >4

IoW Unadjusted IoW Unadjusted

The Isle of Wight (IoW) cohort
Asthma Ref. 1.06; (0.80–1.40); 0.709 0.91; (0.65–1.27); 0.563 Asthma Ref. 1.02; (0.78–1.34); 0.873 0.91; (0.62–1.35); 0.648

Eczema Ref. 1.30; (0.98–1.71); 0.065 1.20; (0.88–1.63); 0.253 Eczema Ref. 1.01; (0.79–1.31); 0.923 1.44; (1.06–1.95); 0.018

Rhinitis Ref. 0.99; (0.85–1.15); 0.848 0.92; (0.77–1.09); 0.327 Rhinitis Ref. 0.99; (0.85–1.15); 0.892 0.98; (0.81–1.20); 0.867

Atopy Ref. 1.03; (0.84–1.26); 1.029 1.05; (0.84–1.31); 0.695 Atopy Ref. 1.02; (0.84–1.24); 0.863 1.19; (0.94–1.50); 0.157

IoW Adjusted IoW Adjusted

Asthma Ref. 1.02; (0.75–1.39); 0.908 0.95; (0.66–1.36); 0.769 Asthma Ref. 1.04; (0.76–1.41); 0.812 1.00; (0.66–1.50); 0.982

Eczema Ref. 1.32; (0.97–1.80); 0.076 1.10; (0.77–1.57); 0.585 Eczema Ref. 1.11; (0.83–1.48); 0.495 1.37; (0.97–1.93); 0.075

Author Manuscript
Author Manuscript

Rhinitis Ref. 1.01; (0.85–1.20); 0.945 0.90; (0.74–1.10); 0.311 Rhinitis Ref. 1.04; (0.88–1.23); 0.670 1.00; (0.81–1.24); 0.978

Atopy Ref. 0.98; (0.80–1.21); 0.869 1.04; (0.83–1.30); 0.733 Atopy Ref. 0.94; (0.77–1.15); 0.533 1.09; (0.86–1.37); 0.487

FAIR Unadjusted FAIR Unadjusted

Asthma Ref. 0.57; (0.37 – 0.87); 0.010
The Food Allergy and Intolerance Research (FAIR) cohort
0.82; (0.52 – 1.29); 0.381 Asthma Ref. 0.74; (0.51 – 1.08); 0.117 0.21; (0.03 – 1.41); 0.107
Eczema Ref. 1.05; (0.85–1.30); 0.650 1.09; (0.85–1.40); 0.478 Eczema Ref. 1.05; (0.87–1.28); 0.592 1.10; (0.72–1.66): 0.665
Rhinitis Ref. 0.93; (0.78–1.11); 0.408 0.86; (0.69–1.07); 0.172 Rhinitis Ref. 0.96; (0.82–1.14); 0.660 0.31; (0.15–0.62); <0.001
Atopy Ref. 1.09; (0.78–1.54); 0.605 1.40; (0.97–2.03); 0.069 Atopy Ref. 1.19; (0.87–1.62); 0.285 1.11; (0.61–2.04); 0.732
FAIR Adjusted FAIR Adjusted
Asthma Ref. 0.50; (0.32 – 0.79); 0.003 0.89; (0.56 – 1.41); 0.614 Asthma Ref. 0.68; (0.46 – 0.99); 0.045 0.20; (0.03 – 1.37); 0.101
Eczema Ref. 1.01; (0.81–1.26); 0.940 1.05; (0.81–1.36); 0.697 Eczema Ref. 1.03; (0.84–1.27); 0.746 1.07; (0.70–1.63); 0.762
Rhinitis Ref. 1.01; (0.84–1.22); 0.925 0.95; (0.75–1.20); 0.675 Rhinitis Ref. 1.05; (0.88–1.24); 0.614 0.36; (0.18–0.71); 0.003
Atopy Ref. 0.97; (0.69–1.35); 0.848 1.14; (0.78–1.67); 0.490 Atopy Ref. 1.09; (0.80–1.49); 0.574 0.96; (0.52–1.77); 0.884
Author Ma
Author M

Effect of breastfeeding duration was assessed on asthma (n=1087) at ages 10 and 18, and onEffect
eczema n=1106), breastfeeding
of (exclusive rhinitis (n=1109), and was
duration atopyanalysed on asthma(n=1011) at 10 and 18, and on eczema(n=1
(n=1052) at ages 1-or-2, 4, 10 and 18 in the IoW cohort; and on asthma (n=460) at 10 years,(andn=978)
on eczema (n=834),
at 1-or-2, 4, 10 and 18 in nthe
rhinitis( IoW and
=819), cohort; and on asthma at 10, and eczema, rhinitis, and atopy at 1,
atopy
CI: confidence
(n=791) at 1, 2, 3 and 10 years in the FAIR cohort. CI: confidence interval. IoW adjusted models controlledinterval. IoW cohort
for maternal adjusted models
socioeconomic status, controlled maternal socioeconomic status, maternal smo
birth, sibling
maternal smoking during pregnancy, season of birth, sibling order, sex, parental history of relevant allergicorder, sex, and
disease, parental historyalso
for asthma of relevant
RLRTI.allergic disease, and for asthma also RLRTI. FAIR cohor
5

Breastfeeding is
associated with a reduced
risk of allergic rhinitis
 Clinical and Experimental Otorhinolaryngology Vol. 12, No. 3: 301-307, August 2019 https://doi.org/10.21053/ceo.2018.01781
pISSN 1976-8710 eISSN 2005-0720
Original Article

Long-term Breastfeeding in the Prevention of Allergic

Rhinitis: Allergic Rhinitis Cohort Study for Kids
5 (ARCO-Kids Study)
Doo Hee Han1,* ·Jae-Min Shin2,*·Seokyung An3,4,5·Jong Seung Kim6·Dong-Young Kim1·Sungji Moon3,4,5
Jung-Soo Kim7·Joong Saeng Cho8·Si Whan Kim9·Young Hyo Kim10·Hwan-Jung Roh11·Woo Sub Shim12
Ki-Sang Rha13·Sang-Wook Kim14,15·Seung-Sin Lee16·Dae Woo Kim17·Kyu-Sup Cho11·Hyo Jin Yim1
Sue K. Park3,4,5 ·Chae-Seo Rhee1,18,19,20
1
Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul; 2Department of Otorhinolaryngology, Soonchunhyang
Data from 1,374
University College ofchildren
Medicine, participating
Seoul; 3Departmentin of the Allergic
Preventive Rhinitis
Medicine, CohortUniversity
Seoul National Study College
for kids (ARCO-kids
of Medicine, Seoul; study)
4
wasof
Department
5 6
Biomedical
analyzed Science, Seoul
with results: National University Graduate School, Seoul; Cancer Research Institute, Seoul National University, Seoul; Department of
Otolaryngology-Head and Neck Surgery, Chonbuk National University Medical School, Jeonju; 7Department of Otorhinolaryngology-Head and Neck
Compared
• Surgery, Schoolwith short-term
of Medicine, breastfeeding
Kyungpook (<6 months),
National University, Daegu; 8long-term
Department of breastfeeding (≥12 and
Otolaryngology-Head months) was significantly
Neck Surgery, Kyung Hee University
9
School of Medicine, Seoul; Department of Otolaryngology-Head and Neck Surgery, Hallym University Sacred
associated with a lower prevalence of AR (adjusted odds ratio [aOR], 0.54; 95% confidence interval [CI], 0.34 Heart Hospital, Hallym University College
to 0.88).
of Medicine, Anyang; 10Department of Otorhinolaryngology-Head and Neck Surgery, Inha University College of Medicine, Incheon; 11Department of
Children in the AR group
• Otorhinolaryngology-Head alsoSurgery,
and Neck had a higher cesarean
Pusan National delivery
University rateofthan
School those
Medicine, in the
Busan; 12
NAR group
Department (39.1% vs. 32.8%,
of Otorhinolaryngology-Head and
13
Neck Surgery, Chungbuk National University College of Medicine, Cheongju; Department of Otolaryngology-Head and Neck Surgery, Chungnam
P=0.05).
National University School of Medicine, Daejeon; 14Department of Otorhinolaryngology, Gyeongsang National University Hospital, Jinju; 15Institute of
Regarding
• Health Sciences,the combined
Gyeongsang effects
National of mode
University, of delivery
Jinju; 16
andofduration
Department of breastfeeding,
Otolaryngology-Head and Necklong-term
Surgery, Ewhabreastfeeding
Womans UniversitywithSchool
a of
Medicine, Seoul; Department of Otorhinolaryngology-Head and Neck Surgery, SMG-SNU Boramae Medical Center, Seoul; 18Graduate School of
17
vaginal delivery
Immunology, strongly
Seoul National suppressed
University College ofthe development
Medicine, of AR,ofcompared
Seoul; 19Institute Allergy andto short-term
Clinical breast-
Immunology, feeding
Seoul Nationalwith a cesarean
University Biomedical
delivery (aOR, 0.47; 95% CI, 0.30 to 0.73).
Research Center, Seoul; 20
Sensory Organ Research Institute, Seoul National University Biomedical Research Center, Seoul, Korea
Conclusion.
•  Long-term breastfeeding (≥12 months) and a vaginal delivery are associated with a lower risk of
Objectives.
developingThere is a great AR.
childhood deal of interest in the possibility that environmental factors may influence the risk of develop-
ing allergic rhinitis (AR) in early life. We investigated the simultaneous effects of mode of delivery and duration of
breastfeeding on the development of AR in children.
Methods. Data from 1,374 children participating in the Allergic Rhinitis Cohort Study for kids (ARCO-kids study) was an-
alyzed. All subjects were divided into AR or non-allergic rhinitis (NAR) groups. Data on environmental factors, mode
 Variable Non-allergic rhinitis Allergic rhinitis OR (95% CI)a) OR (95% CI)b) OR (95% CI)c)
Table 1. Selected characteristics of allergic rhinitis and non-allergic lings. Compared with short-term breastfeeding (<6 months),
rhinitis in 1,374 children from the Allergic Rhinitis Cohort Study for Mode of delivery
long-term breastfeeding (≥12 months) was significantly associ- Han DH et al. Long-term Breastfeeding Prevents Childhood AR 305
kids (ARCO-kids), 2009–2011 Vaginal delivery 195 (67.2) 613 (60.9) 1.00 1.00 1.00
ated with a lower prevalence of AR (OR, 0.53; 95% CI, 0.37 to
Non-allergic rhinitis Allergic rhinitis Cesarean
0.74); thisdelivery
association remained statistically95 (32.8) significant393 (39.1)ac-
after 1.30 (0.98–1.72) 1.25 (0.94–1.66) 1.26 (0.93–1.66)

5
Variable P-valuea)
(n=313) (n=1,061) Table 2. ORsforfor
Breastfeeding
counting eachsex,
duration
age, factor
(mo)MOD, in allergic
numberrhinitis
of and non-allergic
siblings, parental rhinitis
atopyin 1,374 children from the Allergic Rhinitis Cohort Study for kids (ARCO-
Demographics kids),
<6 2009–2011
history, and living area (aOR, 0.54; 95%
91 (39.4) CI, 0.34 to 0.88).
417 (54.7) 1.00 1.00 1.00
Age (yr) 6.9±2.6 8.1±2.6 <0.001 Compared with breastfeeding for <6 months, breastfeeding
Sex 0.003 6–11 50 (21.6) 162 (21.2)for 0.77 (0.52–1.15) 0.78 (0.52–1.16) 0.80 (0.57–1.14)
Variable
6–11 months was not statistically Non-allergic rhinitisrelatedAllergic
significantly to therhinitis
risk OR (95% CI) a)
OR (95% CI) b)
OR (95% CI)c)
Male 193 (61.7) 748 (70.5) ≥12 90 (39.0) 184 (24.1) 0.53 (0.37–0.74) 0.50 (0.35–0.72) 0.54 (0.34–0.88)
Female 120 (38.3) 313 (29.5) of AR
Mode (OR, 0.77; 95% CI, 0.52 to 1.15; aOR, 0.80; 95% CI,
of ofdelivery
Number siblings
Living area 0.035 0.57 to 1.14). Children born by cesarean delivery had an in-
Rural 33 (11.5) 78 (7.6)
0Vaginal
creased
delivery
prevalence of AR compared
195 (67.2)those born by
58with
(20.1) 613vaginal
211 (60.9)
(20.9) 1.00
1.00 1.00
1.00 1.00
1.00
Urban 264 (88.5) 947 (92.4) 1Cesarean but
delivery, delivery
when this was added201 95 (32.8)
to(69.6)
the multivariable 393models,
637 (39.1)
(63.2) 1.30(0.54–1.07)
0.76 (0.98–1.72) 1.25(0.56–1.12)
0.79 (0.94–1.66) 1.26(0.51–1.41)
0.89 (0.93–1.66)
Maternal factor 30 and
(10.4)was no longer 160statisti-
(15.9) 1.15 (0.70–1.90) 1.31 (0.78–2.17) 1.13 (0.70–1.84)
Breastfeeding
the
≥2 association duration (mo) less evident
became
Maternal age at marriage (yr) 26.8±3.3 27.0±3.2 0.368
cally significant (OR, 1.30; 95% CI, 0.98 to 1.72; aOR, 1.26;
Maternal age at birth (yr) 29.5±3.6 29.9±3.7 0.132 <6 are presented as number (%). The total
Values 91 (39.4)
number of children does417 (54.7)
not equal to 1,374 because1.00 of missing data. 1.00 1.00
95% CI, 0.93 to 1.66). There was no appreciable association be-
Weight gain during 13.8±5.9 13.5±5.8 0.557 OR, odds ratio; CI, confidence
6–11 the number of siblings and theinterval. 50 (21.6)
pregnancy (kg) tween risk of AR in the162 (21.2)
stratified 0.77 (0.52–1.15) 0.78 (0.52–1.16) 0.80 (0.57–1.14)
a)
Adjusted
≥12 for the child’s age and sex (1). Adjusted
b)
90 (39.0) for (1) plus duration of breastfeeding,
184 (24.1) 0.53and(0.37–0.74)
number of siblings0.50in (0.35–0.72)
the analysis using “mode of delivery;”
0.54 (0.34–0.88)
Prenatal factor analysis.
(1) plus mode of delivery, and number of siblings in the analysis using “breastfeeding duration;” (1) plus mode of delivery, and duration of breastfeeding in
Birth weight (kg) 3.2±0.5 3.3±0.4 0.131 NumberTableof3siblings
shows ORs for the combination of breastfeeding dura-
Gestational age (wk) 39.2±1.8 39.3±1.7 0.309 the analysis using “number of siblings” (2). c)Adjusted for (2) plus parental atopy history, and living area.
tion and MOD in AR and NAR. Compared with children born
Mode of delivery 0.051 0 58 (20.1) 211 (20.9) 1.00 1.00 1.00
by cesarean delivery who were breastfed for <6 months, those
Vaginal delivery 195 (67.2) 613 (60.9) 1 3.by
born
Table ORs for thedelivery
vaginal combination 201 (69.6)
andofbreastfed
breastfeeding duration
for ≥12 and
months 637the(63.2)
mode of delivery
showed 0.76in(0.54–1.07) 0.79non-allergic
allergic rhinitis and (0.56–1.12) rhinitis0.89 (0.51–1.41)
in 1,374 children
Cesarean delivery 95 (32.8) 393 (39.1)
Postnatal factor from ≥2 the Allergic
resistance to theRhinitis Cohort Study
development 30 (10.4)
for kids
of AR (OR,(ARCO-kids), 160
0.46; 95% 2009–2011 (15.9)
CI, 0.30 to 1.15 (0.70–1.90) 1.31 (0.78–2.17) 1.13 (0.70–1.84)
Breastfeeding initiation 0.313 0.73; aOR, 0.47; 95% CI, 0.30 to 0.73). Moreover, longer breast-
Yes 231 (73.8) 763 (71.9)
Values
Variable
feedingare andpresented as number
vaginal delivery (%). The totalthe
showed number
lowest of children
fordoes
AR. notrhinitis
riskNon-allergic equal toAllergic
1,374 rhinitis
because ofORmissing
(95% CI)data.
a)
OR (95% CI)b) OR (95% CI)c)
No 82 (26.1) 293 (28.1) OR, odds ratio; CI, confidence interval. d) and mode of delivery
Combination of breastfeeding duration (mo)
Breastfeeding duration (mo) <0.001 a)
Adjusted for thedelivery
child’s age and sex (1). b)Adjusted for (1) plus duration of breastfeeding,
32 (13.9)
and number of1.00
159 (20.9)
siblings in the analysis
1.00
using “mode1.00
of delivery;”
<6 91 (39.4) 417 (54.7) <6/Cesarean
(1) plus modedelivery
of delivery, andDISCUSSION
number of siblings in the analysis using “breastfeeding
59 (25.5)
duration;” (1) plus mode of delivery, and duration of breastfeeding
257 (33.7) 0.89 (0.55–1.43) 0.92 (0.57–1.49) 0.90 (0.52–1.56)
in
6–11 50 (21.6) 162 (21.2) <6/Vaginal
≥12 90 (39.0) 184 (24.1) the6–11/Cesarean
analysis usingdelivery
“number of siblings” (2). c)Adjusted for (2) plus parental
17 (7.4)
atopy history, and living
47 (6.2)
area.
0.64 (0.32–1.27) 0.64 (0.31–1.27) 0.75 (0.42–1.32)
Number of siblings 0.048 The results from this large-population study indicate that long-
0 58 (20.1) 211 (20.9)
6–11/Vaginal
term delivery (≥12 months) is strongly associated
breastfeeding 33 with
(14.3) a 115 (15.1) 0.76 (0.44–1.31) 0.68 (0.42–1.41) 0.62 (0.38–1.03)
1 201 (69.6) 637 (63.2) Table 3. ORs risk
≥12/Cesarean
decreased for delivery
the
ofcombination
AR in Korean of breastfeeding
children. This duration and19the
is consistent mode of delivery
(8.2)
with 71 (9.3)in allergic
0.57rhinitis and non-allergic
(0.26–1.37) rhinitis0.64
0.65 (0.45–1.64) in 1,374 children
(0.37–1.08)
≥2 30 (10.4) 160 (15.9) from the Allergic
previous
≥12/Vaginal Rhinitis
delivery
reports thatCohort Study for kids
breastfeeding is (ARCO-kids),
associated with 2009–2011
71 (30.7)
a de- 113 (14.8) 0.46 (0.30–0.73) 0.46 (0.30–0.72) 0.47 (0.30–0.73)
Allergy-related history
creased
Higher riskrisk
(shortofbreastfeeding
allergic diseases [6,17,18].
and cesarean In a birth cohort
delivery) study
32 (13.9) 159 (20.9) 1.00 1.00 1.00
Parental atopy history 0.011
Variable
in Sweden,
Intermediate riskearly
(vaginalexclusive
delivery but breastfeeding
short breastfeedingfor ≥4or Non-allergic
months rhinitis Allergic
was
76 (32.9) rhinitis 0.76
304 (39.9) OR(0.51–1.13)
(95% CI)a) 0.76 OR(0.51–1.13)
(95% CI)b) 0.80 OR(0.51–1.24)
(95% CI)c)
No 284 (90.7) 919 (86.6)
shown to reduce
intermediateofbreastfeeding the risk of eczema and the onset of the allergic
Yes 29 (9.3) 142 (13.4) Combination breastfeedingbut cesarean
duration (mo)delivery)
d)
and mode of delivery
Food allergy historyb) 0.022 march at the age of four [13]. Another study in the United States
Lower risk
<6/Cesarean (vaginal delivery
delivery but intermediate breastfeeding 52
32(22.5)
(13.9) 186
159(24.4)
(20.9) 0.65 (0.43–0.99)
1.00 0.65 (0.42–0.99)
1.00 0.63 (0.41–0.97)
1.00
No 259 (87.4) 850 (81.6) showed that prolonged breastfeeding (≥4 months) in African-
or longer breastfeeding but cesarean delivery)
Yes 37 (12.6) 192 (18.4) <6/Vaginal delivery
American subjects reduced the risk of AR at age 3 [12]. The 59 (25.5)
pro- 257 (33.7) 0.89 (0.55–1.43) 0.92 (0.57–1.49) 0.90 (0.52–1.56)
Pets at homeb) 0.300 Lowest risk (longer breastfeeding and vaginal delivery) 71 (30.7) 113 (14.8) 0.46 (0.30–0.73) 0.46 (0.30–0.72) 0.47 (0.30–0.73)
tective mechanisms
6–11/Cesarean deliveryof breastfeeding against allergic disease 17 (7.4)are 47 (6.2) 0.64 (0.32–1.27) 0.64 (0.31–1.27) 0.75 (0.42–1.32)
No 270 (90.3) 911 (88.0)
not well
Values understood.
are presented as number However,
(%). The several
total number possible mechanisms
of children does not equal to 1,374 because of missing data.
Yes
Parental smoking
At the time of pregnancy
19 (9.7) 125 (12.0)

0.257
Long-term breastfeeding (≥12 months) and a
OR,
6–11/Vaginal delivery
haveoddsbeenratio;proposed
≥12/Cesarean
a) ing, beneficial
Adjusted
CI, confidence
for child’delivery
seffects
age andon
to explain
interval. these protective effects includ-
sex.lung
b) development
Adjusted suchsexasand
for child’s age,
33 (14.3)
19number
increased
115 (15.1) 0.76 (0.44–1.31) 0.68 (0.42–1.41) 0.62 (0.38–1.03)
(8.2) of siblings.71c)(9.3)
Adjusted for0.57child’
(0.26–1.37)
s age, sex,0.65 (0.45–1.64)
number of siblings,0.64 (0.37–1.08)
parental atopy
No
Yes
52 (24.3)
162 (75.7)
222 (28.4)
561 (71.6) vaginal delivery are associated with a lower risk
≥12/Vaginal
elasticity
posure
Higher
and
riskto(short
delivery
efficiency
exogenous
d)

breastfeeding
of lung
antigens,
parenchyma
and strengthened
and cesarean delivery)
[19],
host 32
71
decreased (30.7)
defence
ex-
history and living area. <6 Months: shorter duration; 6–11 months: intermediate; ≥12 months: longer duration.
(13.9)
113 (14.8)
159 (20.9)
0.46 (0.30–0.73)
1.00
0.46 (0.30–0.72)
1.00
0.47 (0.30–0.73)
1.00

of developing childhood AR.

At the time of current enrollment 0.201 mechanisms against infection through enhancement of the im-
No 75 (35.0) 471 (39.9) Intermediate risk (vaginal delivery but short breastfeeding or 76 (32.9) 304 (39.9) 0.76 (0.51–1.13) 0.76 (0.51–1.13) 0.80 (0.51–1.24)
ma mature immune system
and wheezing [20,21].
in breastfed Furthermore,
children compareditwith is thought
that ofthat of the most natural and best forms of preventive medicine [29].
Yes 139 (65.0) 278 (60.1) intermediate breastfeeding
immunosuppressive but cesarean
factors in breast delivery)
milk downregulate inflam-
children
Lower
who
riskand
were
(vaginal
neverbutbreastfed
delivery
by their asthmatic mothers
intermediate breastfeeding
For this reason, most studies [6,12-15,18] on the duration of
Values are presented as mean±standard deviation or number (%). The mation prevent the development of allergies [22]. 52 (22.5) 186 (24.4) 0.65 (0.43–0.99) 0.65 (0.42–0.99) 0.63 (0.41–0.97)
total number of children does not equal to 1,374 because of missing data. [24]. The
orDespite Osaka
longer breastfeeding Maternal
these data,but and Child
thecesarean Health
effects delivery) Study did not find
of breastfeeding on allergic dis- a breastfeeding for prevention of allergic disease have focused on
a)
To test the differences between the two groups (allergic rhinitis vs. non-
allergic rhinitis), we used the Student t-test for continuous variables and statistically
ease remain
Lowest significant
risk (longer relationship
controversial.
breastfeeding andbetween
Several
vaginal the duration
studies of breast-
have suggested
delivery) that early,113
71 (30.7) exclusive
(14.8) breastfeeding,
0.46 (0.30–0.73)and 0.46were designed0.47
(0.30–0.72) with a rela-
(0.30–0.73)
the Pearson chi-square or Fisher exact test for categorical variables. b)There
prolonged breastfeeding increases the risk of developing allergic
The conflicting data may be due to
variations in study methodologies
and outcome measures,
as well as heterogeneity in human
milk composition & presence of a
potential endogenous relationship
between breastfeeding & outcome
 Advertisem
5 Presence of a potential endogenous relationship
between breastfeeding & outcome

ORIGINAL ARTICLE

Breastfeeding and the risk of childhood

asthma: A two‐stage instrumental
variable analysis to address endogeneity
Nivita D. Sharma

First published: 29 June 2017 |

https://doi.org/10.1111/pai.12750 | Cited by: 1
Sharma ND. Breastfeeding and the risk of childhood asthma: A two-stage instrumental variable analysis
to address endogeneity. Pediatr Allergy Immunol. 2017 Sep;28(6):564-572.
Get access to the full version of this article. View Me

access options below. Cita

Several explanations for the inconsistent results
on the effects of breastfeeding on childhood 5
asthma have been suggested.
Investigate one unexplored explanation, which is
the presence of a potential endogenous
relationship between breastfeeding and
childhood asthma.
Endogeneity exists when an explanatory variable is
correlated with the error term for reasons such as
selection bias, reverse causality, and unmeasured
confounders.

Unadjusted endogeneity will bias the effect

of breastfeeding on childhood asthma.

To investigate potential endogeneity, a cross-sectional study of

breastfeeding practices in 87 pediatric patients in Georgia,
USA was conducted using generalized linear modeling (GLM) and a
two-stage instrumental variable analysis.
When endogeneity was not taken into
account, duration of breastfeeding was found to
5
significantly increase the risk of childhood
asthma (relative risk ratio (RR) = 2.020, 95% CI
(1.143- 3.570)).

After adjusting for endogeneity, duration of

breastfeeding significantly reduced the risk of
childhood asthma (RR = 0.003, 95% CI
(0.000-0.240)).

The findings suggest that researchers should

consider evaluating how the presence of
endogeneity could affect the relationship
between duration of breastfeeding and the risk of
childhood asthma.
 Table 2: Model for Risk of Asthma Prior to Accounting for Endogeneity in Pediatric Patientsa

Independent variables Risk Ratio 95% CI

ccepted Accepted
DEBF

Mother’s education (bachelor’s degree or higher = 1, 1.361

2.020*

0.742
1.143

2.492
3.570
5
otherwise 0)
Table 3: Multivariate Two-Stage IV Model for Risk of Asthma in Pediatric Patientsa Model for Risk of Asthma Prior to
Biomother asthma (yes = 1, no = 0) 2.686** 1.522 4.743
Accounting for Endogeneity in Pediatric
Patientsa
Biomother allergy (yes = 1, no = 0) 1.071 0.620 1.850 Table 3: Multivariate Two-Stage IV Model for Risk of Asthma in Pediatric Patients a
Article
First-Stage (OLS Regression) Dependent Variable: Duration of Exclusive Breastfeeding
Older biosibling asthma (yes = 1, no = 0) 2.221* 1.087 4.538
Independent variables Coefficient 95% CI
Older biosibling allergy (yes = 1, no = 0) 0.333* 0.136 0.814

pted Article
Mother’s education (bachelor’s degree or higher = 1, 0.340** 0.122 0.558
First-Stage (OLS Regression) Dependent Variable: Duration of Exclusive Breastfeeding
Premature
otherwise (yes
0) = 1, no = 0) 1.768* 0.997 3.134

Physical
Biomotheractivity
asthma(hours
(yes =per
1, day)
no = 0) 1.044
-0.273 0.677
-0.670 1.610
0.123 Independent variables Coefficient 95% CI
Pets 12 months
Biomother (yes(yes
allergy = 1,=no
1, =no0)= 0) 0.666
-0.012 0.357
-0.232 1.242
0.209 Mother’s education (bachelor’s degree or higher = 1, 0.340** 0.122 0.558
Constant
Older biosibling asthma (yes = 1, no = 0) 0.098
-0.247 0.020
-0.583 0.478
0.090 otherwise 0)
a
Tablebiosibling
Older reports GLM
allergyPoisson log-link
(yes = 1, no = 0)function to estimate0.592**
the relative 0.264
risk of asthma with
0.920 Biomother asthma (yes = 1, no = 0) -0.273 -0.670 0.123
First-Stage (OLS Regression) Dependent
(1/df) Deviance = 0.686, AIC = 1.538, and BIC = -292.080. Confidence intervals are based on
Premature (yes = 1,
patient-clustered no = standard
robust 0) errors. DEBF = duration of-0.094 -0.384
exclusive breastfeeding. 0.196
Biomother allergy (yes = 1, no = 0) -0.012 -0.232 0.209
Variable:
Income
*p < 0.05 Duration
(natural logarithm ofcode
of median zip Exclusive
income) 0.371 -0.240 0.983
Older biosibling asthma (yes = 1, no = 0) -0.247 -0.583 0.090
Breastfeeding
Constant
**p < 0.01 -2.910 -9.498 3.678

Older biosibling allergy (yes = 1, no = 0) 0.592** 0.264 0.920

Second-Stage (GLM Poisson Log-Link) Dependent Variable: Asthma

This article is protected

Independent variablesby copyright. All rights reserved.Risk Ratio 95% CI Premature (yes = 1, no = 0) -0.094 -0.384 0.196
Predicted DEBF 0.003** 0.000 0.240
Income (natural logarithm of median zip code income) 0.371 -0.240 0.983
Mother’s education (bachelor’s degree or higher = 1, 11.214** 2.384 52.741
otherwise 0) Constant -2.910 -9.498 3.678
Biomother asthma (yes = 1, no = 0) 0.538 0.166 1.737
Second-Stage (GLM Poisson Log-Link) Dependent Variable: Asthma
Biomother allergy (yes = 1, no = 0) 1.242 0.713 2.166
Independent variables Risk Ratio 95% CI
Older biosibling asthma (yes = 1, no = 0) 0.457 0.162 1.292

Older biosibling allergy (yes = 1, no = 0) 14.370* 1.051 196.428

Second-Stage (GLM Poisson0.003**
Predicted DEBF Log-Link)
0.000 0.240

Premature (yes = 1, no = 0) 0.940 0.448 1.971 Mother’sDependent

education (bachelor’s Variable: Asthma
degree or higher = 1, 11.214** 2.384 52.741
Physical activity (hours per day) 1.017 0.659 1.569 otherwise 0)

Pets 12 months (yes = 1, no = 0) 0.622 0.334 1.156 Biomother asthma (yes = 1, no = 0) 0.538 0.166 1.737
Constant 128.038 1.183 13863.49
Biomother allergy (yes = 1, no = 0) 1.242 0.713 2.166
a
The first stage regression corresponds to the OLS model in which the dependent variable is
the natural logarithm of the duration of exclusive breastfeeding, where duration of Older biosibling asthma (yes = 1, no = 0) 0.457 0.162 1.292
2 2
 Summary
•  The first six months of life offer a window of opportunity for
preventing allergies, and as a result there’s been a lot of interest in the
effects of human milk on allergies.
•  A recent review finds that although modulating human milk
composition may have the potential to prevent allergies in early
life, several studies have so far shown conflicting evidence about
the protective role of breastfeeding on allergies.
•  Breastfeeding is associated with a reduced risk of eczema in the
short term but not at 6-7 years of age.
•  The conflicting data may be due to variations in study
methodologies and outcome measures, as well as heterogeneity in
human milk composition & presence of a potential endogenous
relationship between breastfeeding & outcome