1 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

2 SELECTED PRENATAL FACTORS EFFECTING ALLERGY AND ASTHMA OUTCOMES

3 SELECTED PRENATAL FACTORS POTENTIALLY EFFECTING POSTNATAL ALLERGY AND ASTHMA OUTCOMES Maternal Diet Active smoking Vitamin D Prebiotics/probiotics C-section Maternal stress Obesity

4 OTHER PRENATAL FACTORS POTENTIALLY EFFECTING POSTNATAL ALLERGY AND ASTHMA OUTCOMES (continued) Acetaminophen (paracetamol) exposure Traditional farm exposure Bisphenol A exposure

5 ALLERGIC CONDITIONS Asthma/wheezing Allergic rhinitis Atopic dermatitis IgE-mediated food allergy

6 It can be very difficult to separate out the impact of prenatal vs. postnatal factors on allergy and asthma

7 Specific postnatal allergy and asthma outcomes may be driven by different factors

8 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

9 Maternal Pregnancy Diet –Prevention of non-food allergic illness –Prevention of food allergy

10 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:

11 Should a pregnant woman who had a previous child with peanut allergy eat peanut products during her pregnancy ?

12 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!

13 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

14 –AAP 2000: Mothers at risk of atopy should avoid peanuts during pregnancy and lactation –AAP 2008: The AAP rescinded their recommendations and replaced it with a statement that the efficacy of this practice remains unproven –AAAAI/ACAAI Food Allergy Draft Practice Parameters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 Recommendations for peanut/tree nut consumption during pregnancy and lactation

15 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:

16 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:

17 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:

18 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:

19 Maternal consumption of peanut during pregnancy is associated with peanut sensitization in atopic infants Sicherer, S. et. al. J All Clin Immun 2010;126:

20 Epicutaneous peanut exposure might play an important role sensitization –Peanut reactions usually occur on the 1 st know exposure –In animal models cutaneous exposure induces allergy (IgE and intestinal mast cell proliferation) and oral exposure induces tolerance 1 –Early-onset severe atopic dermatitis and the application of Arachis (peanut) oil onto eczematous skin are risk factors for the development of peanut allergy 2 –A dose-response relationship has been demonstrated between household peanut consumption and peanut allergy in young children 3 1. Bartnikas, J All Clin Immun 2013:131: Lack, G. New England Journal of Medicine 2003;348: Fox, A. J All Clin Immun 2009:123:

21 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 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

22 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 Peanut protein in household dust is related to household peanut consumption and is biologically active

23 Distribution of peanut protein in the home environment Brough, A. et. al. J All Clin Immun 2013;1132:623-9.

24 THE PEANUT ALLERGEN IN THE HOME ENVIRONMENT MAY BE MORE IMPORTANT THAN THE PEANUT PRODUCTS THAT THE PREGNANT WOMEN EATS!

25 SMOKING

26 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 wheezing 1 1. Burke, H. Pediatrics 2012;129:

27 SMOKING DURING PREGNANCY IUS reduces age-related improvements in bronchial hyperactivity 1 IUS decreases the effects of inhaled steroids on airway hyperresponsiveness 1 IUS associated with hospitalization/mortality from respiratory infections 2 It is very difficult to separate pre and postnatal smoke exposure 1.Cohen, R. J All Clin Immun 2010:126: Metzger, M. Pediatric Infectious Disease Journal 2013;32:e1-7.

28 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 1 st year Neuman, A. et. al. A. J Respir. Crit Care Med 2012;

29 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 1 st 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;

30 SMOKING CESSATION SHOULD BEGIN BEFORE CONCEPTION!

31 VITAMIN D

Muehleisen, B. J All Clin Immun 2013;131: ;185:

Paul, G. Vitamin D and Asthma. Am J Respir Crit Care Med. 2012;185:

34 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.Rosen, C. J Clin Endocrinol Metab 2012;97: Hollick, M. J Clin Endocrinol Metab 2011;96:

35 Sharief, S. J Allergy Clin Immun 2011;127:

36 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 nmol/L) Allen, K. et. al. A. J Al Clin immun 2013;131:

37 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:

Allen, K. et. al. A. J All Clin Immun 2013;131:

Allen, K. J All Clin Immun 2013;131:

40 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)

Nurmatov, U. J Allergy Clin immun 2011;127:

42 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)

43 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 25- OH vitamin D and transient wheezing as well as atopic dermatitis Baiz, K. et. al. A. J Al Clin Immun (article in press)

44 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)

45 PROBIOTICS

46 Prebiotics and probiotics Probiotics: Live microorganisms administered in adequate amounts to that confer a beneficial health effect on the host 1 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 health 2 Synbiotic: contains both prebiotics and probiotics 3 1.Sanders, M. Gut 20013:62: Gibson, G. J Nutr 1995;125: Screzenmeir, J. Am J Clin Nut 2001:73:S361-S364

47 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

48 Pfefferle, P. et. al. J All Clin Immun 2013;131:

49 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)

50 Bertelson, R. et. al. J All Clin Immun 2013 (in press) Probiotic milk consumption in pregnancy and infancy and subsequent allergic illness

51 Ratuva, S. J All Clin Immun 2012;130: Maternal probiotic supplementation during pregnancy and breast-feeding reduces the risk of eczema in the infant.

52 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 children 1 World Allergy Organization 2012: Probiotics do not have an established role in the prevention of allergy 2 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: Fiocchi, A. World Allergy Organ J5, (2012)

53 DELIVERY BY C-SECTION

54 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.

55 Delivery by c-section Multiple studies show prevention of asthma, food allergy, and allergic rhinitis 2 meta-analyses show at least moderate preventative impact 1,2 1.Bager, P. Clinical and Experimental Allergy 2008;38: Thavagnanam, S.Clinical and Experimental Allergy 2008;38:

56 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 2 nd 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, and Immunology Meeting in San Antonio, Tx.)

57 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 Immunology Meeting in San Antonio, Tx.)

58 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.

59 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.

60 MATERNAL PRENATAL STRESS

61 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)

62 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 2 nd 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)

63 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)

64 Guxens, M. et. al. A. J All Clin Immun 2013 (article in press) Parental psychological distress during pregnacy and wheezing in preschool children: The generation R study

65 Wright, R. et. al. A. Am J Resp Crit Care Med 2013: 187: Disrupted and prenatal maternal cortisol, maternal obesity, and childhood wheeze

66 Wright, R. et. al. A. Am J Resp Crit Care Med 2013: 187: Disrupted and prenatal maternal cortisol, maternal obesity, and childhood wheeze

67 MATERNAL OBESITY

68 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 doctor- diagnosed asthma –The effect was unrelated to child BMI and stronger in nonatopic children Harpsoe, M. J All Clin Immun 2013;131:

69 Harpsoe, M. J All Clin Immun 2013;131: Maternal obesity, gestational weight gain, and risk of asthma and atopic disease in offspring: A study within the Danish National Birth Cohort

70 What should a pregnant women do if she wants to prevent potential allergies and asthma in her offspring?

71 I am not aware of any specific recommendations from any organizations

72 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/m 2 )

73 More studies are desperately needed!

74

75 QUESTIONS