SELECTED PRENATAL
FACTORS EFFECTING
ALLERGY AND ASTHMA
OUTCOMES
Michael V. Keiley, M.D.
Adult and Childhood
Allergy and Asthma
Boise Valley Asthma and Allergy Clinic
BVAAC.com
Boise, Meridian, Eagle, Nampa, & Caldwell
1
SELECTED PRENATAL FACTORS
EFFECTING ALLERGY AND ASTHMA
OUTCOMES
2
SELECTED PRENATAL FACTORS
POTENTIALLY EFFECTING
POSTNATAL ALLERGY AND ASTHMA
OUTCOMES
•
•
•
•
•
•
•
Maternal Diet
Active smoking
Vitamin D
Prebiotics/probiotics
C-section
Maternal stress
Obesity
3
OTHER PRENATAL FACTORS
POTENTIALLY EFFECTING
POSTNATAL ALLERGY AND ASTHMA
OUTCOMES (continued)
• Acetaminophen (paracetamol)
exposure
• Traditional farm exposure
• Bisphenol A exposure
4
ALLERGIC CONDITIONS
•
•
•
•
Asthma/wheezing
Allergic rhinitis
Atopic dermatitis
IgE-mediated food allergy
5
It can be very difficult
to separate out the
impact of prenatal vs.
postnatal factors on
allergy and asthma
6
Specific postnatal
allergy and asthma
outcomes may be
driven by different
factors
7
Credibility of a Theory
•
•
•
•
•
•
Biological plausibility
Multiple studies over a range of ages
Meta-analyses
Randomized-controlled studies
Clinical vs. statistical significance
Guidelines from societies
8
Maternal Pregnancy
Diet
–Prevention of non-food
allergic illness
–Prevention of food
allergy
9
Maternal dietary
prevention of non-food
allergic illness
• “The available epidemiologic
evidence is weak but
nonetheless supportive with
respect to vitamins A, D and
E; zinc, fruit and vegetables;
and a Mediterranean diet for
the prevention of asthma”1
1. Nurmatov, U. J Allergy Clin Immun 20111;127:724-33.
10
Should a pregnant
woman who had a
previous child with
peanut allergy eat
peanut products during
her pregnancy ?
11
WE GREW UP WITH THE
NOTION OF THE PEANUT AS
A BENIGN, NUTRITIOUS,
CHARMING FELLOW . . .
BUT TO THE
PEANUT-ALLERGIC
PERSON AND
HIS/HER FAMILY, HE
IS A VICIOUS,
UNFORGIVING
MONSTER!
12
ALARMING CHARACTERISTICS
OF PEANUT ALLERGY
– 1-2% of infants/children in westernized English
speaking countries
– Associated with life-threatening anaphylaxis (50%
of reactions)
– Reaction may occur on first known exposure
(72%)
– Provocative dose for symptoms is lower than for
other allergens
– Occurs earlier in life than other food allergies
(median age 22 months)
– Accidental ingestion common (55% over three
years)
– Rarely outgrown
– Associated with a very impaired quality of life!
– 25-35% are also tree nut allergic
13
Recommendations for
peanut/tree nut consumption
during pregnancy and lactation
– AAP 2000: Mothers at risk of atopy should avoid peanuts during
pregnancy and lactation
– AAP 2008: The AAP rescinded their recommendations and replaced
it with a statement that the efficacy of this practice remains
unproven
– AAAAI/ACAAI Food Allergy Draft Practice Parameters 10/9/13: “Do
not recommend maternal allergen avoidance…because these
approaches have not been proven to be effective for primary
prevention of atopic disease”
– There are currently no clear recommendations regarding how to
proceed
– There are some additional data now available that might impact this
decision making process
14
Peanut and tree nut consumption
during pregnancy and allergic
disease in children
• Methods
– Data from Danish national Birth cohort
(n=61,908)
– Maternal peanut and tree nut intake was
assessed using a validated midpregnancy food
frequency questionnaire
– Allergic and asthma outcomes at 18 months
and 17 years of age
Msalova, S. et. al. J All Clin Immun 2012;130:724-32.
15
Peanut and tree nut consumption
during pregnancy and allergic
disease in children
• Results
– Maternal intake of peanuts and tree nuts was
inversely associated with asthma in children at
18 months of age
– Compared with mothers consuming no
peanuts, children whose mothers reported
eating peanuts 1 or more times per week were
0.66 times more likely to have a registry-based
and medication related asthma diagnosis,
respectively.
Msalova, S. et. al. J All Clin Immun 2012;130:724-32.
16
Maternal consumption of peanut
during pregnancy is associated
with peanut sensitization in atopic
infants
• Methods
– 503 infants 3-15 months of age with likely milk
or egg allergy but no previous diagnosis of
peanut allergy
– IgE CAP-RAST to peanut obtained
– Frequency of maternal consumption of peanut
was assessed during pregnancy as well as
breast feeding
Sicherer, S. et. al. J All Clin Immun 2010;126:1191-97
17
Maternal consumption of peanut
during pregnancy is associated
with peanut sensitization in atopic
infants
• Results
– Frequency of peanut consumption during
pregnancy showed a dose-response
association with peanut IgE > 5 kU/L in breast
fed and non-breast infants
– Peanut consumption during breastfeeding was
not associated with a peanut IgE >5 kU/l
Sicherer, S. et. al. J All Clin Immun 2010;126:1191-97
18
Maternal consumption of peanut during pregnancy is
associated with peanut sensitization in atopic infants
Sicherer, S. et. al. J All Clin Immun 2010;126:1191-97
19
Epicutaneous peanut exposure
might play an important role
sensitization
– Peanut reactions usually occur on the 1st know
exposure
– In animal models cutaneous exposure induces
allergy (IgE and intestinal mast cell proliferation)
and oral exposure induces tolerance1
– Early-onset severe atopic dermatitis and the
application of Arachis (peanut) oil onto
eczematous skin are risk factors for the
development of peanut allergy2
– A dose-response relationship has been
demonstrated between household peanut
consumption and peanut allergy in young
children3
1. Bartnikas, J All Clin Immun 2013:131:417-43.
2. Lack, G. New England Journal of Medicine 2003;348:977-85.
3. Fox, A. J All Clin Immun 2009:123:417-423.
20
Peanut protein in household dust is
related to household peanut
consumption and is biologically active
• Methods
– 46 families with infants were recruited from a
pediatric allergy clinic
– Peanut protein was quantified in wipe and dust
samples form multiple sites throughout the
home
– Peanut consumption was assessed by using a
validated peanut food frequency questionnaire
– Whole dust samples were used to stimulate
basophils in peanut-monoallergic and 3
nonallergic children
21
Brough, A. et. al. J All Clin Immun 2013;1132:623-9
Peanut protein in household dust is
related to household peanut
consumption and is biologically active
• Results
– There was a significant positive correlation
between peanut protein in the infants bed, crib,
rail, and play area and reported household
peanut consumption over 1 and 6 months.
– Dust samples containing peanut protein
induced dose-dependent basophil activation in
children with peanut allergy
Brough, A. et. al. J All Clin Immun 2013;1132:623-9
22
Distribution of peanut protein in the home
environment
.
Brough, A. et. al. J All Clin Immun 2013;1132:623-9
23
THE PEANUT ALLERGEN
IN THE HOME
ENVIRONMENT MAY BE
MORE IMPORTANT
THAN THE PEANUT
PRODUCTS THAT THE
PREGNANT WOMEN
EATS!
24
SMOKING
25
SMOKING DURING
PREGNANCY
• Nicotine, carcinogens, and other
pathogens pass through the placental
barrier
• Intrauterine smoke exposure (IUS)
decreases blood flow as well as oxygen
and nutrient delivery
• Multiple studies including at least one
meta-analysis show impaired postnatal
lung function and more wheezing1
26
1. Burke, H. Pediatrics 2012;129:735-744.
SMOKING DURING
PREGNANCY
• IUS reduces age-related improvements in
bronchial hyperactivity1
• IUS decreases the effects of inhaled steroids on
airway hyperresponsiveness1
• IUS associated with hospitalization/mortality from
respiratory infections2
• It is very difficult to separate pre and postnatal
smoke exposure
1. Cohen, R. J All Clin Immun 2010:126:491-7.
2. Metzger, M. Pediatric Infectious Disease Journal 2013;32:e1-7.
27
Maternal smoking in
pregnancy and asthma in
preschool children
• Pooled analysis of 8 European birth
cohorts
• Effect of maternal smoking during
pregnancy but not during the 1st year on
wheezing and asthma at 4-6 years of age
• 21,600 children
• 735 exposed prenatally but not during the
1st year
Neuman, A. et. al. A. J Respir. Crit Care Med 2012;1861037-43
28
Maternal smoking in
pregnancy and asthma in
preschool children
• Results
– Maternal smoking exclusively during
pregnancy was associated with wheeze as well
as asthma at 4-6 years of age
– Maternal smoking only during the 1st trimester
was associated with asthma and wheezing at
4-6 years of age (oR 1.39)
Neuman, A. et. al. A. J Respir. Crit Care Med 2012;1861037-43
29
SMOKING
CESSATION SHOULD
BEGIN BEFORE
CONCEPTION!
30
VITAMIN D
31
Muehleisen, B. J All Clin Immun 2013;131:324-9. 2012;185:124-32.
Paul, G. Vitamin D and Asthma. Am J Respir Crit Care Med. 2012;185:124-32.
Vitamin D Guidelines
• Institute of Medicine: 20 ng/ml (50
nmol/l)1
• Endocrinology Society: 30 ng/ml (75
nmol/l)2 ( (20-30 ng/ml insufficient, <
20 ng/ml deficient)
• Conversion: ng/ml X 2.5 = nmol/l
1.
2.
Rosen, C. J Clin Endocrinol Metab 2012;97:1146-52.
Hollick, M. J Clin Endocrinol Metab 2011;96:1911-30.
34
Sharief, S. J Allergy Clin Immun 2011;127:1195-1202.
35
Vitamin D insufficiency is
associated with challenge-proven
food allergy in infants
• Methods
– 5276 one-year old infants assessed for food
allergy
– Food challenges were conducted on most of
the children with positive tests
– 274 food allergic children
– 207 non food allergic children were used as
controls
– Vitamin D status assessed (vitamin D
insufficiency 26-50 nmol/L)
Allen, K. et. al. A. J Al Clin immun 2013;131:1109-16
36
Vitamin D insuffeciency is
associated with challenge-proven
food allergy in infants
• Results
– Infants of Australian-born parents with vitamin D
insufficiency (<50 mmol/l) were more likely to be peanut
(aOR 11.51) and/or egg allergic (aOR 3.79)
– Infants of Australian-born parents with vitamin D
insufficiency were more likely to have multiple food
allergies than a single food allergy (aOR 10.48)
– Among infants that were food sensitized, vitamin D
insufficiency was associated with increased odds of
food allergy
Allen, K. et. al. A. J Al Clin immun 2013;131:1109-16
37
Allen, K. et. al. A. J All Clin Immun 2013;131:1109-16
Allen, K. J All Clin Immun 2013;131:1109-16
Vitamin D and food allergy in
patients with severe atopic
dermatitis
• Methods
– 39 patients referred for severe atopic
dermatitis and food allergy
– Patients with atopic dermatitis and food allergy
had their serum vitamin D levels compared to
those of patients with atopic dermatitis and no
food allergy
• Results
– For every 1-unit increase in 25-OH vitamin D,
the chances that someone had food allergy
decreased by 6% (p=0.01)
Mohiuddin, M. J Al Clin Immun 2013 (article in press)
40
Nurmatov, U. J Allergy Clin immun 2011;127:724-33.
Cord serum 25-OH vitamin D and
risk of early childhood wheezing
and atopic dermatitis.
• Methods
– Cord blood samples from the EDEN birth
cohort were analyzed for 25-OH vitamin D
– Follow-up for 5 years with ISSAC
questionnaire (asthma , wheeze, allergic
rhinitis, atopic dermatitis)
Baiz, K. et. al. A. J Al Clin Immun (article in press)
42
Cord serum 25-OH vitamin D and
risk of early childhood wheezing
and atopic dermatitis.
• Results
– Median cord serum 25-OH vitamin D level was
17.8 ng/ml
– There was an inverse association between 25OH vitamin D and transient wheezing as well
as atopic dermatitis
Baiz, K. et. al. A. J Al Clin Immun (article in press)
43
Cord serum 25-OH vitamin D and risk of early
childhood wheezing and atopic dermatitis.
Baiz, K. et. al. A. J All Clin Immun (article in press)
44
PROBIOTICS
45
Prebiotics and probiotics
• Probiotics: Live microorganisms administered in
adequate amounts to that confer a beneficial
health effect on the host1
• Prebiotics: nondigestible food components that
beneficially effect the health of the host by
selectively stimulating the growth and/or activity
of one or a limited number of bacteria in the colon
and thereby improve host health2
• Synbiotic: contains both prebiotics and
probiotics3
1. Sanders, M. Gut 20013:62:787-796
2. Gibson, G. J Nutr 1995;125:1401-1412
3. Screzenmeir, J. Am J Clin Nut 2001:73:S361-S364
46
Probiotics
• Several meta-analyses show efficacy of probiotics in the
prevention of atopic dermatitis
• Other issues:
– Strain(s)
– Quality control (not FDA approved)
– Dose?
– Administer to mom, baby, or both?
– Probiotics plus or minus prebiotics
– Administer to entire population or those at risk?
– Safety (rare risk of bacteremia in high risk subjects)
– May occasionally contain milk protein
47
48
Pfefferle, P. et. al. J All Clin Immun 2013;131:1453-63.
Probiotic milk consumption in
pregnancy and infancy and
subsequent allergic illness
• Methods
– Norway mother and child cohort study (MoBa)
– 40,164 infants at low risk of allergy
– Probiotic milk/yogurt consumption assessed
– Biola milk/yogurt, Cultura milk
(lactobacillus/bifidobacterium)
– Questionaire data regarding atopic dermatitis,
allergic rhinitis, and asthma
Bertelson, R. et. al. J All Clin Immun 2013 (in press)
49
Probiotic milk consumption in pregnancy and infancy and
subsequent allergic illness
50
Bertelson, R. et. al. J All Clin Immun 2013 (in press)
Maternal probiotic supplementation during pregnancy and
breast-feeding reduces the risk of eczema in the infant.
51
Ratuva, S. J All Clin Immun 2012;130:1355-60.
Recommendations from
Scientific Societies
•
American Academy of Pediatrics 2010: Further confirmatory evidence is
necessary before a routine recommendation for routine use can be made.
There may be some long term benefit of prebiotics in reducing atopy in
otherwise healthy children1
•
World Allergy Organization 2012: Probiotics do not have an established
role in the prevention of allergy2
•
AAAAI/ACAAAI Draft Practice Parameters for Food Allergy (10/19/13): “Do
not routinely recommend supplementation of the maternal or infant diet
with probiotics or prebiotics as a means to prevent food allergy because
there is insufficient evidence to support a beneficial effect”
1. Thomas, D. et. al. Pediatrics 2010:126:1217-31
2. Fiocchi, A. World Allergy Organ J5,148-167 (2012)
52
DELIVERY BY
C-SECTION
53
Delivery by c-section
• Fetal intestine is sterile
• After delivery, the intestine is colonized
• C-section: more colonization with C. difficile,
Clostridium cluster I, less colonization with
bifiobacteria, bacteroides, E. coli
• C-section (skin surface microbiota), vaginal
delivery (mother’s vaginal microbiota)
• This altered intestinal microbiota may interfere
with the development of immunologic tolerance
Penders, J. et. al. J All Clin Immun 2013;132:60107.
54
Delivery by c-section
• Multiple studies show prevention of
asthma, food allergy, and allergic
rhinitis
• 2 meta-analyses show at least
moderate preventative impact1,2
1. Bager, P. Clinical and Experimental Allergy 2008;38:634-642.
2. Thavagnanam, S.Clinical and Experimental Allergy 2008;38:629-633.
55
Delivery by c-section increases
the risk for food sensitization at 2
years
• Methods
– 572 children from Detroit were studied and the
mode of delivery was noted
– Blood was drawn for IgE CAP-RAST tests to
milk, egg, and peanut near the child’s 2nd
birthday
– Mom’s atopic status was noted
– Atopy was defined as having one specific IgE
greater than or equal to 0.35kU/L
Yonnus, M. et. al. A. J All Clin Immun 2013 (Abstract #82, #465 presented at the American Academy of Allergy, Asthma,
56
and Immunology Meeting in San Antonio, Tx.)
Delivery by c-section increases
the risk for food sensitization at 2
years
• Results
– C-section rate was 35.3%
– 40.9% of the children were sensitized to at
least 1 food
– Children of atopic mothers were more like to
be sensitized to at least one food (odds ratio
1.8)
– infants delivered by C-section tended to be
sensitized to the allergen they were exposed to
at home (mite, cat, dog)
Yonnus, M. et. al. A. J All Clin Immun 2013 (Abstract #82 presented at the American Academy of Allergy, Asthma, and
57
Immunology Meeting in San Antonio, Tx.)
Birth by cesearean section,
allergic rhinitis, and allergic
sensitization among children with
a parental history of atopy
• Methods
– 432 children with a parental history
of atopy were followed from birth
to the age of 9 years
– Major outcome: asthma, allergic
rhinitis, or atopy at 9 years of age
– Prospective birth cohort study
Pistiner, M. et. al. A. J All Clin Immun 2008;122:274-9.
58
•
Birth by cesearean section,
allergic rhinitis, and allergic
sensitization among children with
a parental history of atopy
• Results
– Children born by C-section had a
2-fold higher odds ratio of atopy
– Birth by C-section was
significantly associated with the
odds of allergic rhinitis (odds ratio
2.1), but not asthma
Pistiner, M. et. al. A. J All Clin Immun 2008;122:274-9.
59
MATERNAL
PRENATAL
STRESS
60
Maternal prenatal psychological
distress and postnatal allergy and
asthma outomes
• A handful of studies have linked some measure of prenatal
maternal stress to postnatal infant/childhood wheezing
• Any association between maternal stress during pregnancy
might be explained by other mechanisms such as social,
behavior, or environmental factors
• From a causative and preventative perspective, it is
important to isolate out intrauterine mechanisms
• One way to do this is to compare maternal with paternal
psychological stress both before and after delivery
• Multiple theories: altered infant HPA axis, altered innate and
adaptive immune responses, epigenetic programming.
Guxens, M. et. al. A. J All Clin Immun 2013 (article in press)
61
Parental psychological distress
during pregnacy and wheezing in
preschool children: The
generation R study
•
• Methods
– Population bases cohort study of 4848
children from Rotterrdam, Netherlands
– Maternal and paternal stress was assessed in
the 2nd trimester and several months after
delivery with validated questionnaire
– Wheezing in the children was annually
examined by questionnaires from 1-4 years
– Physician diagnosed asthma was reported at 6
years
Guxens, M. et. al. A. J All Clin Immun 2013 (article in press)
62
Parental psychological distress
during pregnacy and wheezing in
preschool children: The
generation R study
•
• Results
– Mothers with psychological distress during
pregnancy had an increased odds of wheezing
in their children from 1-4 years of life
– Similar positive association were noted with
the number of wheezing episodes, wheezing
patterns, and physician diagnosed asthma at 6
years
Guxens, M. et. al. A. J All Clin Immun 2013 (article in press)
63
Parental psychological distress during pregnacy and
wheezing in preschool children: The generation R study
64
Guxens, M. et. al. A. J All Clin Immun 2013 (article in press)
Disrupted and prenatal maternal cortisol, maternal
obesity, and childhood wheeze
65
Wright, R. et. al. A. Am J Resp Crit Care Med 2013: 187:1186-93
Disrupted and prenatal maternal cortisol, maternal
obesity, and childhood wheeze
66
Wright, R. et. al. A. Am J Resp Crit Care Med 2013: 187:1186-93
MATERNAL
OBESITY
67
Maternal obesity, gestational weight
gain, and risk of asthma and atopic
disease in offspring: A study within the
Danish National Birth Cohort
• Methods
– Cohort study of 38, 874 mother-child pairs from the Danish National
Birth Cohort
– Maternal pre pre-pregnancy body mas index (BMI ) and gestational
weight gain (GWG) assessed
– Survey assessment of asthma, wheezing, atopic eczema , and hay
fever at 18 months and 6 years of age
• Results
– Maternal BMI and to a lesser extent GWG were associated doctordiagnosed asthma
– The effect was unrelated to child BMI and stronger in nonatopic
children
Harpsoe, M. J All Clin Immun 2013;131:1033-40.
68
Maternal obesity, gestational weight gain, and risk of asthma
and atopic disease in offspring: A study within the Danish
National Birth Cohort
69
Harpsoe, M. J All Clin Immun 2013;131:1033-40.
What should a
pregnant women do if
she wants to prevent
potential allergies and
asthma in her
offspring?
70
I am not aware of any
specific
recommendations
from any
organizations
71
Some steps that a pregnant women (or
someone contemplating pregnancy)
might consider
• Smoking cessation
• Increase 25-OH vitamin D to >30 ng/ml
• Keep peanut products out of the home?
• Take a probiotic?
• Avoid unnecessary C-sections
• Minimize stress
• Lower their BMI if obese (> 30 kg/m2)
72
More studies
are desperately
needed!
73
74
QUESTIONS
75