THE EFFECT OF MATERNAL DIET DURING GESTATION ON THEDEVELOPMENT OF ALLERGIES IN OFFSPRING By Rachel Mistry A Senior Project submitted In partial fulfillment of the requirements for the degree of Bachelor of Science in Nutrition Food Science and Nutrition Department California Polytechnic State University San Luis Obispo, CA March 2015 R. Mistry ABSTRACT Consumption of allergenic foods, particularly cow’s milk, eggs, and peanuts, during gestation may play an essential role in the development of an allergic sensitization in the offspring. It remains unclear if an association between maternal diet throughout gestation has an effect on the development of an allergic condition. Thus, the purpose of this review is to compare the maternal diets of subjects from the general population and to describe factors that may contribute to the development of allergic conditions. Findings from studies with high-risk mothers show that maternal diet has little to no effect on the development of allergies in an infant if the child is genetically pre-disposed. Findings from long-term trials in allergy development show confounding results. As analysis of a randomized placebo-controlled clinical trial found significantly lower incidence rates of allergic conditions in mothers who consumed higher levels of n-3 polyunsaturated fatty acids. Additionally, various studies were examined that indicate an excessive supplementation of Vitamin D during gestation may account for higher incidence rates of childhood allergies. Another population-based study found that inadequate Vitamin D status is responsible for the increased prevalence of childhood allergies. This review analyzes various studies from 1986 onwards and concludes that although various nutrients may seem to hold promise in reducing the incidence of childhood allergies, more indepth studies accounting for confounding variables are required before a conclusion can be reached. R. Mistry INTRODUCTION The importance of proper nutrition during gestation and lactation, and its effect on fetal health has never been questioned. Increased prevalence and growing interest in various allergies, including lactose and gluten intolerance, has sparked research in maternal diet during gestation and its implications on the development of allergies in neonates (Falth-Magnusson,1992). Lactose intolerance and gluten intolerance can significantly affect and inhibit the ways in which a neonate obtains nutrients, which is why it is essential to determine if there is a correlation between maternal diet and the development of these conditions. Maternal nutrition and diet has serious implications for neonates in both atopic and dietary allergies. Growing evidence suggests a positive correlation between persistent food allergies and a maternal diet low in allergens (FalthMagnusson,1992). Further studies on the reported effects of maternal diet of neonate allergy-sensitivity have shown to decrease as exposure of dietary factor in maternal diet increases (Gerrand, 1986). In order to address these claims, the aim of this review is to evaluate whether maternal diet during gestation is associated with increased allergysensitivity in neonates. ALLERGIC SYMPTOMS AND DISEASE Over fifty years the rise in prevalence of allergic diseases has continued worldwide (Jackson, 2013). In the United States, allergenic conditions are the most common medical conditions affecting children (Friedman, 2006). In schoolchildren alone, sensitization rates to common allergens have risen between forty to fifty percent 1 R. Mistry worldwide (World Health Organization, 2012). In 2012, approximately twelve percent of children reported having skin allergies, and eight percent of children reported having dietary allergies (National Health Interview Survey, 2012). As summarized by Figure 1, the trend seen in a rise in prevalence of allergic diseases affecting the United States is a trend seen worldwide. Figure 1. Percentage of children aged 0-17 years with a reported allergic condition in the past 12 months: United States, 1997-2011. From CDC (2013). An allergy is considered as a hypersensitivity that occurs in response to a factor in the environment that would normally be considered harmless (Stone, 2002). The most common childhood allergies include skin, food, and respiratory allergies. Depending on the severity, a given allergy has the ability to interfere with the health of a child and affect their daily activities such as attending school (Baiardini, 2006). An extreme allergic reaction, inducing anaphylaxis, can be life threatening. The most 2 R. Mistry common source of anaphylaxis in children is food, which can also result in various other health implications including respiratory infections (De Silva, Mehr, Tey & Tang, 2008). Although dietary allergies produce the most significant responses, atopic allergies continue to pose a major health problem in industrialized countries. A child with an atopic allergy produces specific antibodies after being exposed to an antigen; this is referred to as being sensitized. When these antibodies do not cause physical symptoms in a child, the condition is referred to as atopy (Gold & Kemp, 2005). When clinical symptoms are present, the allergy is considered an atopic disease, and is identified by a specific combination of signs and symptoms (Gold & Kemp, 2005). A food allergy is considered a negative health response when exposed to a specific food resulting from a reproducible immune response (Sicherer & Sampson, 2014). Food allergies are a common chronic condition in children, affecting as many as eight percent of children throughout the United States, with growing evidence that numbers are still on the rise. (Sicherer & Sampson, 2014). Of the children in the United States who have dietary allergies, thirty percent of the children have more than one dietary allergy. The most common allergies include peanut, milk, and shellfish (Gupta, Springston & Warrier, 2011). On a worldwide scale, the prevalence of dietary allergies has risen significantly over the past fifty years (Pawankar, Canonica, Holgate & Lockey 2011). It is argued that the prevalence of allergies is only increasing due to increased awareness. However, the same methods that are currently being used for ascertainment of allergies were the same methods being used a decade ago (Burr, 1993). 3 R. Mistry ATOPIC ALLERGIES The development of atopic allergies is a combination of genetics and environmental factors, such as exposure to a specific allergen. Currently it is believed that genetics accounts for fifty percent of allergic sensitizations (Moffat & Cookson, 1998). The genetic influence on development of an atopic allergy is considered multifactorial; there is not one specific atopy gene that has been identified. Additionally, children who have inherited more than one atopy gene have a higher risk for becoming sensitized and develop an allergic reaction when exposed to a specific environmental allergen (Nickel, Lau, & Niggemann, 2002). It is unlikely that a change in genetic factors is what has caused the fifty year increase in prevalence of allergies. Environmental factors play a large role in the development of an allergenic disease and sensitization, such as an exposure to the allergen either through air, via oral intake, or through the placenta (Halken, 2004). Research has shown that approximately thirty percent of newborns have an older sibling or parent with either a previous or current atopic disease. Approximately forty to fifty percent of newborns that have double parent atopic heredity develop an atopic disease, whereas only twenty to thirty percent of newborns with single atopic heredity are likely to develop an atopic disease (Halken 2004). It is evident that atopic disease is hereditary, however, environmental and protective factors play a large role in the development of the disease. The atopic diseases, eczema, asthma and rhinoconjunctivitis, are the most common chronic diseases that occur during childhood (Gold & Kemp, 2005). Management of atopic allergies is most commonly achieved through avoidance of the identified trigger, though in some cases when the allergy is severe or the allergen is 4 R. Mistry commonly found in society, immunotherapy is provided as an alternative (Gold & Kemp, 2005). The current understanding of the factors that promote or prevent the development of atopic allergies is limited. Some studies have found that the “dose” of antigen that a child is exposed is a critical factor in the development of the condition. (Almqvist, Egmar, & Hedlin, 2003). In order for primary prevention interventions to be efficient, it is essential to increase research related to the onset of atopic allergies. There is hardly any difficulty when diagnosing atopic diseases; the features of the various diseases are very predominant. Presently, there are no known interventions that can cure atopic allergic responses. However, it is essential to determine the environmental trigger or the atopic onset and avoid it if possible. ECZEMA AND ASTHMA Eczema, the most prevalent atopic disease, presents with pruritis, the distribution of a rash, and constant relapses. Those who suffer from eczema are prone to dry and scaly skin, oozing or weeping skin, and thickened skin, which can lead to bacterial infections (National Institute of Arthiritis and Musculoskeletal and Skin Diseases [NIAMS], 2013). Although many children will begin remission upon entering into adulthood, their dry skin will persist for most of their lives. Those who suffer from eczema will also experience sensitivity to wool, soaps, perfumes, dusts, and in some cases, cigarette smoke (NIAMS, 2013). Of the atopic diseases, eczema traditionally manifests first, before the age of five. Forty percent of children with eczema progress to develop asthma and rhinoconjunctivitis, which is why it is so essential to determine if there is a maternal dietary factor that can be altered (Gold & Kemp, 2005). Numerous 5 R. Mistry research studies show the link between the presence of eczema early in life and the development of egg, milk, and/or peanut food allergies (Lack, 2008). Additionally, between 33% and 81% of children with eczema during infancy have food-allergies as well (Sampson, Eigenmann, Sicherer, Borkowski & Cohen, 1998). Within six months after birth, the presence of eczema is associated with an increased risk for a peanut food allergy. The allergy risk increases with the severity of the eczema (Lack, Fox, Northstone & Golding, 2003). Additionally, a recent study has shown that the risk of an egg, milk, or peanut allergy was twice as likely to occur in an infant if the eczema presented during the first six months of life rather than the second six months (Hill, Hosking, Benedictis, Oranje, Dieoge & Bauchau, 2008). Asthma is a chronic lung disease that results in inflamed and narrowed airways. Symptoms of asthma include wheezing, tightness of the chest, and coughing. Of the 25 million people who are diagnosed with asthma, 30% of them are children (National Heart, Lung, and Blood Institute [NHLBI], 2014). The airways that bring air to and from the lungs respond strongly when exposed to certain inhaled substances. Upon reaction, swelling occurs, airways narrow, and mucus is produced. Normally, asthma symptoms dissipate on their own. However, if the symptoms worsen and intensify, an asthma attack is likely to occur. On occasion, emergency assistance is required from extreme asthma attacks, which can also be fatal (NHLBI, 2014). Although asthma has no cure, life with this condition can be manageable. DIETARY ALLERGIES Although understanding of food allergies has increased over the past ten years, knowledge about the causes of food allergies is lacking. While there may be numerous 6 R. Mistry studies discussing the prevalence of dairy and peanut allergies in children in industrialized countries such as the United States, there are very few surveys measuring the prevalence of various food allergies at a global scale. Although The International Study on Allergies and Asthma in Childhood surveys individuals about atopic allergies, there is little or no mention of food allergies. Food allergies are considered acute medical occurrences resulting from an abnormal immunologic response to food protein. Food allergies are responsible for over half of the anaphylaxis cases that are presented to emergency rooms in developed countries (Smit, Cameron & Rainer, 2005). Awareness of food allergies has begun to increase. Within the past decade alone, the Centers for Disease Control and Prevention found an 18% increase of food allergy sensitivity in children (Branum & Lukacs, 2009). Because most food allergenic children manage their allergies through food avoidance, individuals with food allergies may need to supplement their diets to avoid an imbalance or deficit of nutrients, depending on the food (Boyce, Assa’ad & Burks, 2011). Along with other health implications, numerous studies have demonstrated that children with persistent food allergies are significantly smaller in overall size than non-food allergenic children (Isolauri, Sutas, Salo, Isoisomppi & Kaila, 1998; Meyer, DeKoker & Dziubak, 2013; Flammarion, Santos & Guimber, 2011). Whether the allergies of children are perceived or diagnosed, the burden of having a dietary allergy has significant economic, emotional, and safety implications. Patients with dietary allergies need to become educated on how to avoid accidentally ingesting the allergen and how to identify allergic reaction symptoms (Sampson, 1999). Additionally, patients with food allergies and their families may experience anxiety, which may affect their quality of life due to the lack of 7 R. Mistry control over dietary risks (Bollinger, Dahlquist, Mudd, Sanntag, Dillinger & McKenna, 2006). The effects of food allergies are not limited to the patients and their families. Food allergies can significantly affect the economy and health care system. Anaphylaxis induced by food allergy can result in emergency care, visits to the emergency room, hospitalizations, and even death (Sampson & Burks, 1996). It is essential to determine if maternal diet gestation can affect food allergies, as approximately 150-200 people die every year from food-induced anaphylaxis each year (Bollinger et al., 2006). LACTOSE INTOLERANCE Lactose intolerance, one of the most prevalent dietary conditions, has serious implications if not correctly managed. Lactase, the enzyme responsible for the digestion of lactose found in milk, is located in the villi of the small intestine. Lactase activity is vital at birth in order to metabolize the lactose found in breast milk. Most children are born with high levels of lactase in their small intestines, allowing them to process milk late into life. As one grows older, a decrease in lactase activity is expected, but lactase persists, allowing adults to continue to digest dairy products (Swallow, 2003). Those who cannot digest lactose due to a shortage in the lactase enzyme allow lactose to travel through the gastrointestinal tract undigested. These undigested lactose particles elicit physical effects from the intolerance such as bloating, nausea, cramps, and diarrhea (Harvard Women’s Health, 2002). A Harvard study in 2002 explored the genetic basis behind lactose intolerance. The study found that all people suffering from lactose intolerance have the same two mutations in DNA, and that the prevalence in the genetic mutations was consistent around the world (Harvard Women’s Health, 2002). Varying intensities of lactose intolerance are present upon birth. One study (2009) 8 R. Mistry looking into congenital lactase deficiency in Finland found that the prevalence of the deficiency was much higher than expected - with a finding of 43% patients within one year (Torniainen, Savilahti & Jarvela, 2009). Children who suffer from congenital lactase deficiency experience symptoms so severe that they are unable to breastfeed, and in some cases the untreated disease can result in hospitalization (Torniainen et al., 2009). It is believed these deficiencies have developed from a mutation in the gene that codes for the lactase enzyme, but it is also believed that maternal diet during gestation plays a role in the development (Torniainen et al., 2009). Cow’s milk intolerance is an allergy that has more significance than other dietary allergies because it develops while the infant is rapidly growing (Boyce, 2011). Maternal avoidance of dairy products during breastfeeding has shown to alleviate symptoms of cow’s milk allergy (CMA), and maternal avoidance of dairy product during gestation has little effect on the infant developing this condition. Children who have dietary allergies, especially those with lactose intolerance or CMA, tend to follow elimination diets to prevent the onset of allergenic symptoms (Boyce et al., 2010). These limited diets combined with increased intestinal impermeability to the allergen(s), results in decreased nutrient absorption (Troncome, Caputo, Floria & Finelli, 1994). Additionally, children who suffer from CMA have been shown to suffer from inadequate nutrition and decreased growth in comparison to their non-allergic peers ( en, Konstantinou & Pilapil, 2013). Determining if there is a link between maternal diet during gestation and development of childhood allergies could aid in preventing children from suffering from various nutrient deficiencies resulting from diet modifications. 9 R. Mistry CELIAC DISEASE Another common dietary allergy found in children and adults is celiac disease. People who consume gluten that have celiac disease produce an immune response that destroys villi of the small intestine. Villi, the site of nutrient absorption, are essential for adequate nutrition. Although symptoms vary from person to person, the symptoms include abdominal bloating and pain, diarrhea, constipation, pale or fatty stools and weight loss (National Institute of Diabetes and Digestive and Kidney Diseases [NIKKD], 2012). Children suffering from celiac disease also can experience irritability. Malabsorption associated with celiac disease can have very serious implications in children during their developmental years. Malabsorption of nutrients could lead to failure to thrive, short stature, delayed puberty and dental defects (NIKKD, 2012). Eventually, villi flatten out and serious damage occurs, resulting in severe diarrhea and weight loss. People suffering from celiac disease are also prone to contract other autoimmune conditions such as arthritis, type 1 diabetes and liver disease (US National Library of Medicine, 2011). Celiac disease affects approximately one percent of the population, and the risk of developing celiac disease increases with variants of the HLADQA1 and HLA-DQB1 genes (US National Library of Medicine, 2011). These genes belong to an antigen complex, which will respond to gliadin, a protein component of gluten, when it enters the body it will elicit an inappropriate immune response. Due to the genetic nature of celiac disease, it is evident that this condition can be passed from mother to baby. Research shows that although celiac disease may be present in a family, the pattern of inheritance is unknown. Nearly every person who has celiac disease contains the specific variants of the HLA-DQA1 and HLA-DQB1 genes, 10 R. Mistry however, these genes are also found in thirty percent of the population (US National Library of Medicine, 2011). Due to this finding it appears there are other factors related to the development of celiac disease, including environmental factors, and possibly maternal diet during gestation. THE HYGIENE HYPOTHESIS The hygiene hypothesis is a theory that claims and an absence of exposure to microorganisms, infectious contaminants, and parasites increases the likelihood of a child developing an allergic disease through the suppression of the immune system and delaying its natural development (Okada, Kuhn, Feillet & Bach, 2010). Various epidemiological studies have researched the protective effect of infectious agents on the development or allergic disease. A direct link has been shown between the increase in development of immunological disorders and the decreasing level of infectious burden using epidemiological data (Okada et al., 2010). Having one or more older sibling has shown to be protective towards developing asthma or hay fever (Strachan, 1989). Additionally, daycare attendance during an infants first six months of life has shown to be protective towards the development of eczema and asthma (Ball et al., 2000). Although many studies have examined the hygiene hypothesis, little work has been related to the hygiene and the development of food allergies. Many studies, however, did look into the hygiene hypothesis and its relationship to the development of eczema, which is closely tied to the development of food allergies (Lack, 2008; Karmaus & Botezan, 2002). Some evidence suggests that use of antibiotics early in life may predispose a child to eczema. On the other hand, exposure to pets early in life has 11 R. Mistry protective effects towards eczema development (Lack, 2008). These studies may indirectly provide evidence for the role of microorganism exposure in preventing the development of dietary allergies. Although there is limited support for the role of the hygiene hypothesis in the development of dietary allergies, a Norweigan cohort study found that infants who were delivered via cesarean section were seven times more likely to have reactions to nuts, eggs, or fish (Eggesbø , Botten , Stugum H, Nafstad & Magnus , 2003). In this same study, infants of mothers who had allergies prior to birth were four times as likely to develop reactions to nuts, eggs, or fish when delivered via cesarean section (Eggesbø et al., 2003). Additionally, a meta-analysis looking into the association between cesarean delivery and the development of atopic conditions found multiple studies that confirm the effect of cesarean sections on increasing the risk of developing an allergic condition (Bager , Wohlfahrt , Westergaard , 2008). One explanation for this correlation is that the colonization of colonic microflora in the infant occurs early in life and aids in the protection of allergic diseases (Bager et al., 2008). These observations have led to the administration of probiotics or prebiotics to alter the gut flora in infants delivered via cesarean section. Although probiotic prevention studies have indicated that probiotics have a low protective effect towards the development of eczema, there is currently no evidence indicating that probiotics prevent dietary allergic conditions (Dioun, Harris & HIbberd, 2003). MATERNAL DIET DURING PREGNANCY Prenatal life is an essential time for the development of the immune system, and consequently the role of intrauterine exposure in the etiology of allergy has begun to 12 R. Mistry gain interest (Prescott, 2003). Maternal diet during gestation is proposed to affect the fetal immune system response that may result in a child becoming predisposed to childhood allergies (Devereux, Barker & Seaton, 2001). Throughout pregnancy, the placenta transfers essential nutrients from the maternal diet to the fetus. Consequently, it is possible that dietary factors that influence allergic disease conditions have the opportunity to exert their effects in utero (Harding, 2001). Intricate mechanisms of transport have been identified for both antioxidants and long-chain polyunsaturated fatty acids (Dutta-Ray, 2000). Additionally, it is suggested that both food and inhalant allergens, whether ingested or inhaled, cross the placental barrier when consumed by the mother (Szepfalusi, Loibichler, Pichler, Reisenberger, Ebner et al., 2000). It is still controversial whether maternal derived immunogenic nutrients or derived allergens result in an early sensitization in the fetus or a specific tolerance to an allergen is developed (Warner, Jones, Jones & Warner, 2000). A high postnatal intake of n-6 polyunsaturated fatty acids (PUFAs) has been associated with an elevated risk of developing an allergic due to the pro-inflammatory characteristics. On the other hand, n3 PUFAs and antioxidants are believed to have a positive, protective effect on the development of asthma and allergic responses (Devereux & Seaton, 2005). While there may be a biological basis for an effect of maternal dietary factors prenatally on the development of an allergic condition, the amount of studies looking into this subject is very minimal. Sausenthaler et al. prospectively analyzed a correlation between maternal diet during the last 4 weeks of gestation and allergic sensitization or development of eczema in the offspring at two years of age in 2641 children (2007). Maternal diet during the last 13 R. Mistry month of gestation was analyzed using a semi-quantitative food frequency questionnaire (FFQ) administered after birth. Data for this study were gathered using the LISA (Influences of Lifestyle-related Factors on the Immune System and the Development of Allergies in Childhood) Study. Subjects were recruited over two years throughout Germany, while questionnaire data on atopic family history, smoking during gestation, and maternal diet during pregnancy were obtained. Data on children’s health and lifestyle were collected every six months for two years. Once the children reached two years of age, blood was drawn and analyzed for total specific Immunoglobulin E. The result of this study indicated a strong correlation between maternal diet during the final four weeks of gestation and the development of childhood allergies in the offspring. Specifically, maternal diets that were high in vegetable oils, vegetable fat, celery, margarine, citrus fruit, and raw sweet peppers were found to have a positive correlation with the development of an allergic sensitization or eczema in the offspring at two years of age. On the other hand, maternal diets that were high in fish consumption during the final four weeks of gestation were shown to decrease the risk of childhood allergic sensitization or eczema. These conclusions are in agreement with the hypothesis that childhood allergic sensitization and diseases may be affected by exposure to maternally allergens or pro-inflammatory factors while in-utero. Potential allergens in celery, bell peppers, and citrus fruit have already been characterized; the observed development of allergic diseases in offspring may be a result from the allergenicity of these foods. This study failed to assess the lifestyle factors of the expectant mothers, so we are unable to rule out these findings (Sausenthaler, Kompauer & Borte, 2007). Vegetable oils and margarine contain a higher concentration of n-6 PUFAs, 14 R. Mistry which could explain the observed association between higher maternal consumption of these fats during gestation and the development of allergic diseases and eczema in their offspring (Lebensmittelchemie, 2000). This theory is supported by the findings of numerous studies supporting that higher margarine consumption has an adverse effect on allergic conditions in both adults and children (Bolte, Frye, Hoelscher, Meyer, Wjst, et al., 2001; Bolte, Winkler, Holscher, Thefeld, Weiland, et al., 2005; Nagel & Linseisen, 2005; Sausenthaler et al., 2006). On the other hand, there is indication that fish intake has a positive effect on asthma and other allergies, possibly due to the n-3 PUFAs found in oily fish and their associated anti-inflammatory properties (Dunder, Kuikka, Turtinen, Rasanen & Uhari, 2001). Currently, no recommendations related to n-3 PUFAs are being made to mothers instructing them to modify their diets in order to prevent their offspring from developing allergies due to insufficient evidence. Additional intervention trials will need to be performed to confirm or deny the new findings of this study. Very few studies have looked into the effects of maternal diet during pregnancy and the development of allergic diseases in the offspring. A randomized placebocontrolled clinical trial including 83 pregnant women with atopic allergies studied the relationship between early dietary from twenty weeks of gestation onwards. The women were recruited to the study because they were considered to be at high risk for allergic disease. Women were excluded from the study if they smoked, had complicated pregnancies, or consumed fish more than twice a week. All of the subjects had a history of asthma and/or rhinitis, and experienced sensitivity when exposed to common allergens. The subjects completed an FFQ at twenty and thirty weeks of gestation, 15 R. Mistry which was used to account for any dietary change. The women were block-randomized according to body mass index, parity, and maternal allergic condition. The subjects of this trial took fish-oil capsules containing n-3 PUFAs and the control group consumed capsules of olive oil. Subject compliance was assessed through analysis of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) incorporation into cell membranes of red blood cells. Randomization of the capsules occurred away from the location of subject recruitment, and the overseeing physician remained blinded to the groups throughout the study. The findings are as follows: infants whose mothers took the fish-oil capsules were shown to have considerably lower levels of Interleukin-13 in their umbilical cord blood than the control group. Interleukin-13 is a protein coded by humans that is associated with the development of asthma. The follow-up on this study showed that children whose mothers consumed fish-oil capsules during their pregnancy were less likely to demonstrate a sensitization to eggs, in addition to having milder atopic dermatitis by one year of age (Dunstan, 2003). In a nested case-control study including 691 school-aged children, telephone interviews were used to assess maternal fish intake during gestation. Subjects in this study were part of the Children’s Health Study (CHS), a population-based study that took place in southern California. Upon entering the study, parents of the subjects had to answer questionnaires describing demographics, household characteristics, respiratory health, and environmental factors that may affect the development of an atopic disease. All grade-school children from the CHS with asthma were selected to take part in this study, and controls (children who were asthma free) were randomly selected. The biological mother was interviewed for most of the subjects, and maternal 16 R. Mistry intake of fish during gestation was measured in four categories: oily fish, non-oily fish, fish sticks, and canned fish. The findings are as follows: a reduced risk of childhood asthma was associated with consumption of oily fish at least once a month during pregnancy, but only occurred in children born to asthmatic mothers (Salam Li, Langholz & Gilliland, 2005). While the recall of maternal diet over an extended period of time may be lacking detail, these findings are in accordance with the observation that high maternal fish intake during gestation reduces the risk of developing atopic diseases in children. However, most of the children in this study were non-Hispanic White, so this study lacks external validity. It is possible that maternal consumption of oily fish may reduce the number of cell membrane pro-inflammatory lipid mediators in their offspring, consequently reducing their child’s risk of asthma. It is also possible that consumption of oily fish in asthmatic mothers reduced their own severity of the condition, consequently reducing the low birth weight and premature birth, both of which are associated with an increased asthma risk (Salam et al., 2005). An additional prospective investigation was performed by Martindale et al. to determine if maternal antioxidant consumption during gestation was correlated with atopic diseases and respiratory issues in childhood (2005). A sample of 1924 women were recruited to take part in this study while attending their first prenatal appointment at Aberdeen Maternity Hospital. Nurses administered questionnaires to collect data on gestational age, parity, education, smoking habit, occupation, and family history of allergies. FFQs were used to assess maternal diet during gestation at 34 weeks. Maternal and cord blood samples were drawn at delivery for analysis of serum 17 R. Mistry antioxidant levels. Questionnaires were mailed to the parent within the cohort at 6, 12, and 24 months of age. Reminders were also mailed out to subjects who failed to reply promptly. The questionnaire enquired about asthma, eczema and rhinitis symptoms, along with number of children in the house, antibiotic use, and presence of pets in the household. Multivariate analyses were performed for each follow-up, because associations between maternal antioxidant intake and development of asthma or eczema were believed to become apparent. The results of this study determined a negative association between maternal consumption of Vitamin E during gestation and the development of asthma in children at two years of age. Children whose mothers were atopic and consumed Vitamin E also had decreased risks of eczema development. On the other hand, high vitamin C intake during gestation was shown to increase development of asthma and eczema during childhood. Overall, this study showed that there are no protective effects of antioxidant consumption during gestation on the development of atopic or allergic diseases (Martindale, McNeill, Devereux, Campbell, Russell et al., 2005). It is possible that some response bias could alter the results of this study, however, serum levels of antioxidants were also examined upon childbirth. It is unlikely that mothers changed their diet while pregnant, because they were unaware of the study focus until receiving the FFQ. One of the weaknesses of this study is that it relies on mailed questionnaires to receive a follow-up on the infants. Ideally, a physician would assess each infant. However, it is likely that this study has strong external validity due to the large population size and consideration for confounding variables, such as antibiotic use. 18 R. Mistry ELIMINATION DIET Immunoglobulin E (IgE) responses to allergens have been determined to be an important precursor to the development of allergenic diseases in childhood (Wahn, Bergmann, Kulig, Forster & Bauer, 1997). Sensitization to IgE is believed to start very early in life, even in utero, as maternal antigens may cross the placenta (Black, 1997). Maternal diet during gestation has been associated with development of allergies in infants and children due to early IgE sensitization (Van Gool, Thijs & Dagnelie, 2004). During pregnancy, essential nutrients from the mother are provided to the fetus through the placenta. The placenta plays an essential role of regulating immune responses in the fetus and may also aid in the transfer of dietary allergens from the mother to the fetus (Kerkhof, WIlga & Smit, 2005). The implications of placental transfer of antigens indicate that allergy-related factors may have begun to exert their influence on the fetus prior to birth (Kerkhof et al., 2005). Because diet is a modifiable factor, it is important to determine if maternal diet during pregnancy affects the development of allergic conditions in childhood so that early prevention measures may be taken. To test this theory, in 1987, 212 expectant Swedish mothers from allergy-prone families enrolled in a randomized, prospective, allergy-prevention study. These subjects abstained from consuming milk and eggs from the seventh month of pregnancy until birth. This study looked into the onset of allergic diseases in the children of mothers who abstained from consuming cow’s milk with the development of allergic conditions in children whose mothers consumed a normal diet throughout gestation. Randomization of this study was based on assignment of numbers prior to study, numbers were distributed in sealed envelopes after obtaining consent. Incidence of allergic disease 19 R. Mistry was evaluated with skin prick testing, serum-IgE determinations, physical examinations, and questionnaires. The findings of this study were as follows: five years after birth, 95% of children in the study were found to have developed some form of allergic disease. Analysis of the children was completed by a physician blind to treatment allocation. The incidence of eczema, asthma, and rhinoconjunctivitis was equally common throughout the test groups. Children whose mothers consumed the elimination diet were found to have higher levels of food intolerance to egg. This long-term followup suggests that maternal elimination diet is not successful in preventing the onset or development of an allergic condition in a child who is genetically predisposed (FälthMagnusson, 1987). Although this study may be internally valid to the genetically predisposed mothers, the small sample size limits the external validity of these findings. Additionally, this study is at a low risk for bias due to the concealment of the assigned diets. Some infants suffering from eczema experience a relief in symptoms when cow’s milk, egg, or other antigens are eliminated from their mother’s diet (Kramer & Kukuma, 2012). However, it is indicated that there is not a protective effect of maternal dietary antigen avoidance and the incidence of atopic allergies during the first 18 months of infancy (Kramer et al., 2012). In 2004, 497 high-risk mothers entered into a randomized multifaceted primary prevention study. High-risk families were considered as having at least one first degree relative with asthma or two family members with a history of allergic diseases. Mothers following the intervention diet abstained completely from consuming nuts and fish throughout gestation, decreased their consumption of dairy and eggs during the third 20 R. Mistry trimester, and while breastfeeding their infant for up to one year. If needed, a partially hydrolyzed supplement was provided to mothers for the first year of adherence to this elimination diet. Mothers following the control diet followed the recommended care by their regular physician. Follow-up data collection was performed using epicutaneous testing at 1, 2, and 7 years of age. This study concluded that children at a higher risk for developing allergic diseases often become sensitized to common foods throughout infancy, but oftentimes the severity of sensitization will decrease with age. Partial food avoidance diets during pregnancy and breastfeeding were shown to be ineffective in preventing sensitization, and may increase risk of sensitization in high-risk children (Appelt, Chan-Yeung, Watson, Dimisch-Ward, Ferguson, et al., 2004). Risk of bias is difficult to judge in this study due to the lack of detail on the method of randomization or the effect of losses of subjects in-between follow-ups. In 1995, 288 mothers took part in a prospective, randomized, controlled study of food allergen avoidance. Prior to the third trimester, families from the Kaiser Foundation Health Plan of San Diego with documentation of an allergic sensitivity were randomized into a maternal food allergen avoidance group or a standard maternal dietary group. Mothers in the food allergen avoidance group, with nutritionist supervision, were assigned to avoid all egg, peanut, and cow’s milk products. They were also instructed to supplement their diet with prenatal vitamins and calcium throughout the final trimester of gestation and throughout lactation. Infants received a casein hydrolysate formula or were breastfed until they reached twelve months of age. Additionally, solid foods were introduced to the infants in a delayed fashion: cow’s milk, soy, corn and citrus fruits were introduced between 12 and 18 moths, while peanuts and fish were not introduced 21 R. Mistry until 36 months of age. Mothers following the control diet followed the diet recommended by the Academics of Obstetric and Gynecology and Pediatrics. Infants who did not breastfeed were supplemented with a cow’s milk-based whey infant formula. Both groups received recommendations to breast feed for a minimum of 4 months. Immunologic outcomes were determined by skin prick tests (SPTs), total serum IgE levels, and urine cotinine levels. The results of this study found no difference between the groups in prevalence of: food allergy, dermatitis, rhinitis, atopic disease, asthma, or serum IgE levels (Zeiger & Heller, 1995). In 1988, the effects of maternal consumption of cow’s milk and eggs on the immune response of the fetus were evaluated in Stockholm. The women were allocated into four different diet groups: free consumption (no cow’s milk or eggs), reduced consumption (no apparent intake), normal consumption (0.5L of milk/day and 3 eggs/week), and high consumption (1L of milk/day and 1 egg/day). These diets were followed during the last three months of pregnancy. The four groups were comparable, however randomization method was not specified, they were characterized in regards to demographic data, serum IgE concentrations, and serum IgG levels in response to specific food allergens. Women met with a dietitian regularly, those abstaining from cow’s milk were provided with a 1g supplement of calcium everyday. At delivery, samples of umbilical cord blood were collected for analysis of IgE concentrations. Analysis of IgE levels in response to major allergens was performed when the cord blood had high concentrations of IgE. This study found that the differences of maternal IgE concentrations between the four groups at week 28 of gestation and at delivery were insignificant. Although, in both the reduced consumption group and the high 22 R. Mistry consumption group, IgE levels were 20% higher at delivery than they were at 28 weeks of gestation. This study claims that it is not justifiable to recommend diet modifications during the final trimester to protect from the development of an allergic condition (Lilja, Dannaeus, Falth-Magnusson, Graff-Lonnevig, Johansson et al., 1998). Another prospective cohort study determined that increasing maternal consumption of various foods during pregnancy might increase the risk of allergic sensitization in the fetus, whereas increasing exposure to vitamin D may have a beneficial effect. The subjects in this study were mother-infant pairs who participated in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Nutrition Study. A nutrition study was initiated within the framework of the DIPP study, which aimed to examine the affect of maternal diet during gestation and lactation on the development of tyle 1 diabetes mellitus, asthma, and allergic conditions in infants. Only children whose mothers had completed a food frequency questionnaire (FFQ) and with completed serum IgE analyses completed could take part in the trial. A FFQ containing 181 items was utilized to assess the adequacy and quantity of maternal dietary intake during the eighth month of gestation. Food frequency data were converted into average intakes using specialized software. At five years of age, children were analyzed for specific IgE concentrations, including responses to: cow’s milk, egg, fish, wheat, and timothy grass. This study concluded that higher consumption of citrus fruits and dairy throughout gestation increased the risk of developing allergic diseases in the infants. However, the study also found that infants whose mothers consumed high levels of Vitamin D during gestation had lower rates of sensitivity to food allergens. It is possible that misreporting occurs with FFQs, however, the FFQs were validated against two 5-day dietary recalls, 23 R. Mistry which was shown to adequately assess dietary recalls of the mothers. This study is strong due to the large sample size and the fact it is population based (Nwaru, Ahonen, Kaila, Erkkola, Haapala, et al., 2009). Studies on the effects of maternal elimination diets and allergen avoidances during gestation on atopic conditions and allergic sensitizations in infants and children provide conflicting results. Although various studies focused mostly on the exclusion of dairy, eggs, or peanuts, no study has focused on the elimination of citrus fruits, celery, or raw sweet pepper intake during gestation. The prescription of an allergen-elimination diet during pregnancy is highly unlikely to significantly decrease the likelihood of the infant developing an atopic allergy, and may adversely impact fetal nutrition or health (Kramer et al., 2012). VITAMIN D EFFECT One explanation for the growing rate of asthma and allergies is the Vitamin D hypothesis. There are two forms of this hypothesis, the Vitamin D excess hypothesis and the Vitamin D deficiency hypothesis. The Vitamin D excess hypothesis argues that excess Vitamin D intake leads to an increased level of allergies. This phenomena was first noticed in German farming communities where there was minimal supplementation of Vitamin D in foods, which could account for the lower prevalence of childhood allergies (Wjst, 2005). Additionally, this argument was supported in Bavaria when allergy-incidence spiked while coinciding with vitamin D intervention programs to prevent rickets in children (Lack, 2008). Furthermore, this research is supported by the cohort observational study performed 24 R. Mistry by Milner et al., (2004) which showed that infants who received Vitamin D supplementation were at an increased risk of developing a food allergy. Data were taken from the National Center for Health Statistics 1988 Maternal-Infant Health Survey, which followed the health of mothers and their infants from birth until 3 years of life. In 1991, a longitudinal follow-up of the >8000 patients was performed to measure outcomes of disease. The findings of this study showed a positive correlation between the development of asthma and food allergies with a high use of vitamins throughout the first six months of life (Milner, Stein, McCarter & Moon, 2004). Likewise, in a cohort study including 12,058 infants, the odds ratio for developing an allergy was 1:7 if infants were treated with regular Vitamin D supplementation. Mothers were contacted during their pregnancy and follow-ups were performed at 1, 14, and 31 years of life. Structured questionnaires were administered to the women throughout pregnancy, and data on the children were obtained during visits to health centers from nurses and general practitioners. At age 31, all subjects were sent a questionnaire including questions about asthma, rhinitis and eczema. Of the subjects with frequent Vitamin D supplementation, 31% tested positive for at least one skin prick test, 28% had allergic rhinitis and 7% had asthma. This study found that the incidence of allergic conditions was significantly greater in subjects receiving regular supplementation of Vitamin D compared to those who supplemented their diets irregularly or not at all (Hyppönen, Sovio, Wjst, Pekkanen, & Hartikainen, 2004). The large sample size of this study combined with the extended follow-up time provides this study with external validity. Weaknesses of this study include the use of questionnaires, which may sometimes result in misreporting in pregnant mothers. 25 R. Mistry On the other hand, the Vitamin D deficiency hypothesis states that inadequate Vitamin D is responsible for the increased prevalence of allergies. The strongest study supporting this evidence shows that locations furthest from the equator have the highest incidence rates of childhood asthma. This study collected EpiPen prescriptions in 2004 throughout the United States, while state populations were used to calculate average number of prescriptions per person. The argument is that a western lifestyle, including more time spent indoors, including less exposure to sunlight, and consequently less Vitamin D absorption, is what is responsible for the increase in allergy prevalence. Figure 2 demonstrates this pattern throughout the United States. Figure 2. Number of EpiPen prescription per 1000 persons by state, ranging from 2.7 to 11.8. From Camargo (2007) The northernmost states prescribe approximately two to three times more 26 R. Mistry EpiPens, which are used for treatment for acute allergic reactions, than Southern states. There was also an inverse correlation between the prescription of EpiPen prescription and the incidence of melanoma in the population, indicating that the differences between the northern and southern EpiPen prescriptions is directly related to sunlight exposure (Camargo, Clark, Kaplan, Lieberman & Wood, 2007). An increased maternal Vitamin D intake during gestation has also been shown to decrease allergen sensitivity in offspring (Nwaru et al., 2009). Just as the Vitamin D hypothesis can be explained in multiple ways, multiple immunologic explanations support the hypotheses. It is shown that Vitamin D has the ability to inhibit T-cell proliferation and production in-vitro, indicating that it is likely this occurs in-utero as well (Cantorna, Zhu, Froicu & Wittke, 2004). However, literature also shows that Vitamin D has the ability to promote the growth of T-cells in-vitro and in-utero, which would promote down regulation of an allergic inflammation (Cantorna et al., 2004). The controversy over Vitamin D is still unsolved, more research into Vitamin D supplementation during pregnancy and infancy will be helpful. SUMMARY Currently, there are still plenty of questions in regard to exposure to a food allergen both in maternal and infant diet. Until recently, the American Academy of Pediatrics (AAP) recommended that common food allergens such as peanuts, milk, and eggs, should be avoided until the third year of life in families with a history of atopy (AAP, 2000). Additionally, pediatricians would often recommend that mothers avoid peanuts during gestation and lactation if there was a family history of atopy (Committee 27 R. Mistry on Toxicity of Chemicals in Food, 1998). The AAP changed its position and stated that they are unsure if certain dietary avoidance tactics actually prevent allergies. There is very little evidence-based research that state when an infant should be exposed to an allergen, what quantities should be introduced, and if infants should be exposed regularly or irregularly. In general, the conventional wisdom has been that exposure to food allergens early in life during pregnancy or lactation could lead to food allergies and that preventative strategies should eliminate allergenic foods from pregnancy, breastfeeding, and early infancy. It has been found that mothers who are considered high-risk for allergies cannot alter the outcome of their offspring developing an allergic condition due to the strong genetic tie allergies have. Overall, not enough externally valid research has been completed on maternal exclusion diets. Their effect on the development of allergies in the offspring still remains controversial. Although incorporation of various nutrients into the maternal diet may seem to aid in the reduction of incidence of developing an allergic condition, additional in-depth studies accounting for confounding variables are required before a conclusion can be reached. 28 R. Mistry REFERENCES Almqvist C., Egmar A., & Hedlin G. (2003). 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