Breastfeeding, Asthma, and Atopic Disease: An Epidemiological Review of the Literature

Transcription

1 Oddy and Peat Breastfeeding, Asthma, and Atopic Disease / ARTICLE Breastfeeding, Asthma, and Atopic Disease: An Epidemiological Review of the Literature Wendy H. Oddy, PhD, Jennifer K. Peat, PhD Abstract Two main types of observational epidemiological studies have been used to question whether breastfeeding protects children from developing atopic disease and asthma. These are cohort studies of random samples of children and cohort studies of children with a family history of asthma or atopy. In each study type, exposure and outcome data are collected either prospectively or retrospectively. In this review, the primary objective was to assess the evidence of whether breastfeeding protects against asthma and atopic disease. As an outcome of this review, an analytical perspective with clinical implications is given. Keywords: breastfeeding, atopic disease, asthma, children The criteria for assessing the adequate measurement of exposure, outcome, and statistics of cohort studies on the development of asthma and allergy are listed in Table 1. 1 A lack of precision in defining and measuring breastfeeding could make a substantial contribution to the heterogeneity of measured breastfeeding practices; therefore, measurement error could be a factor in both the assessment of breastfeeding status and breastfeeding duration. There is evidence that mothers recall the duration of breastfeeding with accuracy within 1 month but only over a relatively short period of 1 to 3 years when compared with breastfeeding duration measured prospectively at regular intervals. 2 Further error occurs in retrospective reports because mothers tend to round Received for review, January 21, 2003; revised manuscript accepted for publication, May 8, Wendy H. Oddy is a research scientist supported by a National Health and Medical Research Council Public Health Australia Fellowship. Her research studies are based at the Telethon Institute for Child Health Research and the Department of Nutrition, Dietetics, and Food Science, Curtin University of Technology in Perth, Western Australia. Jennifer K. Peat is an associate professor based at the Department of Pediatrics and Child Health at the University of Sydney. Her studies of early risk factors for childhood asthma are managed from the Children s Hospital in Westmead, New South Wales, Australia. Acknowledgments are extended to Professor Paul Burton for his assistance with the review. Dr Oddy received travel awards from the National Health and Medical Research Council Australia, the Ian Potter Foundation, and the International Society for Research Into Human Milk and Lactation to travel to the United States, during which time this review was completed. J Hum Lact 19(X), 2003 DOI: / Copyright 2003 International Lactation Consultant Association their estimates to intervals such as 1, 3, or 6 months. Errors in reporting breastfeeding are unlikely to be random given that most mothers are aware that a longer duration of breastfeeding is desirable. Sampling criteria in studies could result in some selection bias, as is inevitable in most cohort studies. Such selection bias would be unlikely to influence findings but does lead to a loss of generalizability. Confounding factors are of major concern in observational studies. Education, smoking status, mother s diet, socioeconomic status, housing type and thus allergen exposure, home hygiene practices, birth complications, and many other factors differ between mothers who do and do not breastfeed. However, these effects have not influenced the results from previous studies in which a protective effect of breastfeeding has been found. Retrospective Studies In retrospective studies, breastfeeding data are collected backward in time. Asthma and atopy may be measured currently. (See the appendix for a glossary of terms.) Retrospective studies of breastfeeding and asthma have either shown no association. 3-7 a reduced risk, 5,8-10 or an increased risk. 11 In breastfeeding studies, and according to the criteria in Table 1, late maternal recall of breastfeeding is not acceptable, and therefore studies with retrospective breastfeeding data collection have not been included in this review. Only prospective studies, which collect exposure data forward in time, are thus included in this review. 1

2 2 Oddy and Peat J Hum Lact XX(X), 2003 Table 1. Criteria for Assessing the Adequacy of Cohort Studies of the Effect of Breastfeeding on the Development of Asthma and Allergy Measurement Exposure Outcome Statistics Prospective Population Studies Prospective cohort studies classify participants in the study on the basis of presence or absence of exposure (in the context of this review, the exposure is breastfeeding). The relevant events, both exposures and the outcomes of interest, have not yet occurred when the study is initiated. In some prospective studies, the exposure may have occurred but the outcomes have certainly not yet occurred. The studies that met the criteria in Table 1 are listed in Table and are reviewed after a brief discussion of the excluded population studies. Excluded Studies Criteria Nonreliance on late maternal recall of breastfeeding Blind ascertainment of infant feeding history Sufficient duration of breastfeeding Sufficient exclusivity of breastfeeding Strict diagnostic criteria Blind ascertainment of outcomes Consideration of severity of outcome Consideration of age of onset of outcome Control for confounding factors Assessment of dose-response effects Assessment of effects in children at high risk of outcome Adequate statistical power For some studies, it was unclear as to whether they met the criteria, and they were therefore not included in the review. 27,28 One study, the Dunedin Cohort, did not meet the defined inclusion criteria. 29 This study was based on a cohort of 1661 infants recruited between 1972 and 1973 and assessed from ages 9 to 26 years using respiratory questionnaires, pulmonary function tests, and allergy skin tests. Following multifactor adjustment, breastfeeding was a risk for current asthma at 9 years, with an odds ratios (OR) of 1.94 (95% confidence interval [CI], ; P <.0001), and for current asthma at 9 to 26 years, with an OR of 1.83 (95% CI, ; P <.0001). However, the Dunedin Cohort study had a number of limitations. Children were enrolled at the age of 3 years, at which time data on breastfeeding recall were collected from mothers. 30 As with most historical studies, the results of this study cannot be easily generalized to present times when health and lifestyle practices have changed. The cohort was at a time (early 1970s) when breastfeeding rates were low. 30 In the hospital, suckling times and number of feeds were restricted and built up over several days. In addition, long periods of separation of mother and baby and nightly formula feeds could have limited establishment of breastfeeding. In the cohort, 47% of babies were never breastfed, and the modal time of cessation of breastfeeding was just 5 to 11 weeks. The Dunedin study does not meet criteria 1, 3, and 4 given in Table 1, that is, nonreliance on late maternal recall of breastfeeding, sufficient duration of breastfeeding, and sufficient exclusivity of breastfeeding. Neither does the study meet criteria 9, 10, and 11, that is controlling for major confounders such as rates of infections, evidence of a dose-response effect, and assessment of children at high risk of allergic outcome. Furthermore, the effects of other risk factors reported from this study seem inconsistent with biological plausibility. There was no dose-response effect, the prevalence of allergy and asthma was lowest and similar in the group breastfed for less than 4 weeks and for more than 16 weeks, the use of a sheepskin was a risk factor for asthma but not for house-dust-mite atopy, and father smoking but not mother smoking was a risk factor for asthma in the child. Thus, random error cannot be discounted. 31 In a second excluded study, a sample of 1753 infants in Dallas, Texas, was followed to 7 years of age. 27 According to their mother s choice, infants were fed breast, soy, or cow s milk from birth to 6 months, and allergic disease was defined at 7 years as atopic dermatitis, allergic rhinitis, asthma, and urticaria. No relationship was found between any outcome variable and early diet in this study. It is unclear in this study if there was any adjustment for any confounding factors. Furthermore, it was unclear whether each feeding group was large enough to demonstrate statistical power. In a third excluded study, the Christchurch Child Development Study included 1262 children born in New Zealand in Breastfeeding was assessed prospectively during the first 4 months of the child s life and was related to the occurrence of eczema at 2 years. Although eczema rates increased with solid food introduction (OR: 1.5, P <.05), there was no association between breastfeeding and the incidence of eczema. At 2 years, when 1156 (92%) of the cohort were studied, 32 symptoms of lower respiratory illness and symptoms that required medical attendance were less common in the breastfed group (P <.05). However, this result was

3 J Hum Lact XX(X), 2003 Breastfeeding, Asthma, and Atopic Disease 3 nonsignificant when the results were adjusted for social, demographic, and environmental factors. The cohort was followed to 4 years (n = 1110) at which time no association was found between asthma and either breastfeeding or early solid food introduction regardless of parental asthma history. 33 This study did not meet inclusion criteria because exclusivity of breastfeeding was not measured. Included Studies The First Population Study One of the first population studies, which prospectively followed a large sample of 20,061 infants to 9 months of age, found large differences in eczema prevalence with different feeding methods regardless of season. 12 Children who were never breastfed had 7 times the prevalence of eczema, and those partially breastfed had twice the prevalence of eczema when compared with only breastfed infants. The Finnish Study A cohort of 256 healthy babies in Finland was followed from before birth to 3 years. 13 The babies were born at term during the first 3 months of Information on many factors including parental atopy and smoking, infant feeding, and socioeconomic indicators was collected. Information on breastfeeding was collected at ages 2 weeks and at 1, 2, 4, 6, 9, and 12 months. Atopy was defined as atopic dermatitis, food allergy, or respiratory allergy. Prolonged breastfeeding, defined as breastfeeding for 6 months or more, was found to protect against atopy in children with or without parental atopy. The cohort was reviewed again when the children were ages 10 and Substantial atopy was defined as atopic disease affecting more than one organ (e.g., both conjunctiva and nose), with more than one verified group of causative agents (pollen, animal dander, house dust mite), duration of symptoms exceeding that of the pollen season, and symptoms severe enough to require daily medications. Breastfeeding was defined as prolonged breastfeeding (6 months or longer), intermediate breastfeeding (1 to 6 months), and short or no breastfeeding (<1 month). At 17 years, the prevalence of atopy during follow-up was highest in the group with short or no breastfeeding, as follows: 42% (prolonged), 36% (intermediate), and 65% (short or no) for any atopy (P =.02); and 8%, 23%, and 54% (P <.001) for substantial atopy. The value of this study lies in the duration of the follow-up and in the comprehensive collection of exposure and outcome data. In this study, a clear prophylactic relationship between breastfeeding and atopic disease was found that was not modified by family history of atopic illness. Tucson Children s Respiratory Study The Tucson Children s Respiratory Study was designed to investigate risk factors for lower respiratory tract illness. Established between 1980 and 1984, 1246 healthy infants with detailed pediatric assessments were followed at defined intervals. Infant feeding patterns were recorded at well-child visits and from parent report. 34 In total, 29% of mothers stopped breastfeeding by 4 months, 15% stopped between 4 and 6 months, and 40% stopped thereafter. If an infant was breastfed for less than 1 month, the prevalence of wheeze was 12%; if breastfed for 1 to 3 months, the prevalence was 8%; and for 4 or more months, the prevalence was 5% (P <.005). After adjusting for maternal education, maternal smoking, ethnic origin, gender, parental history of respiratory illness, room sharing, and type of day care, bottle-feeding remained significantly associated with more wheezing illness at 4 months of age (OR: 1.7, P <.05). In this study, protection of breastfeeding against respiratory illness endured only minimally beyond the end of the breastfeeding period. A further analysis of the Tucson data was undertaken when the cohort was 6 years of age. At this time, recurrent wheeze was less common in nonatopic children who were breastfed as infants, compared to nonatopic children who were not breastfed, 15 signaling a difference in atopic status between breastfed or nonbreastfed infants. At 11 years of age, 16 an association between breastfeeding and asthma differed with maternal asthma status. Among children with a maternal history of asthma, the percentage of children who developed asthma was 9% for the never breastfed, 36% for those breastfed for 3 months or less, and 57% for those breastfed for 4 months or longer. However, breastfed children were significantly less likely to wheeze at age 6, 9, or 11 years if they had not been diagnosed with asthma at any age. Furthermore, in children whose mothers were in the lower two tertiles of immunoglobulin E (IgE), breastfeeding was associated with lower total serum IgE at age 6(P <.02) and at 11 years (P <.08). 17 However, for children whose mothers were in the highest tertile of IgE, breastfeeding for 4 months or longer was associated

4 4 Oddy and Peat J Hum Lact XX(X), 2003 with higher IgE levels in the child compared to those breastfed for less than 4 months (P <.01). These results suggest that there is an interaction between maternal asthma (or IgE) status and the effect of breastfeeding duration. A limitation of this study was that formula feeding was prevalent in the United States at the time of study recruitment 35 (more than 50%), and data on formula introduction were not collected. The Isle of Wight Studies The first Isle of Wight study was a prospective cohort study of 843 infants born between April 1977 and March The effect of breastfeeding on allergic disease (eczema, chronic rhinitis, asthma, or bronchitis) at 1 year of age was investigated. The incidence of allergic disease was greater in infants started on formula (12%) than in infants started on breastfeeding (10%) (P <.01). In this study, the direction of effect was protective in infants both with and without an atopic family history. The children in this study were followed until they reached their 2nd and 4th birthdays. 19 Breastfeeding did protect against eczema in this study. When children with recurrent wheezing at 4 years of age were examined, no association with breastfeeding was found, but in children with a parental history of allergy, 9% of children who were only breastfed had asthma, whereas 11% of children with mixed feeding had asthma. This study may have had a Type II error, which implies a lack of statistical power to detect a true effect of breastfeeding on recurrent wheeze. A second birth cohort began on the Isle of Wight in In this study, 1536 children were enrolled prenatally. After exclusions, 1456 babies (95%) were followed to 4 years of age. The diagnostic criteria were identical to the previous Isle of Wight study, although the end of exclusive breastfeeding was defined as the introduction to formula. In this study, children introduced to formula before 3 months of age had significantly more asthma at 4 years (OR: 1.8, 95% CI, ; P <.01). Eczema and rhinitis were slightly increased in children who were formula fed compared to children who were breastfed (13.2% formula fed, 10.7% breastfed). The Dundee Infant Feeding Study In the Dundee Infant Feeding Study, 674 children were followed from birth to assess the relationship between breastfeeding and infant illness in the first 2 years of life. 21 Mothers were recruited at 36 weeks. Breastfeeding was categorized as full breast-feeders (13 weeks or more), partial breast-feeders (breastfed but supplements introduced), early weaners (stopped breastfeeding before 13 weeks), and bottle-feeders (bottle-fed from birth). Full or partial breastfeeding was associated with a reduction in respiratory infections in babies up to 24 months of age (defined as coryza, accompanied by cough or wheeze, or both lasting 48 hours or more). After adjustment for father s social class, maternal age, and parental smoking, the rate of respiratory infections in babies who were bottle-fed (37%) was significantly greater than in the partial (24%) and full (26%) breast-feeders (P <.05), with the same trend seen for gastrointestinal illness (P <.01). This cohort was followed-up again at 7 years when 81% of children were available. 22 The prevalence of wheeze, breathlessness, or cough at age 7 was significantly reduced if a child had been exclusively breastfed for at least 15 weeks (P <.05). The prevalence for respiratory symptoms was 17% (95% CI, 15.9%-18.1%) for exclusive breastfeeding, 31% (95% CI, 26.8%-35.2%) for partial breastfeeding, and 32.2% (95% CI, 30.7%- 33.7%) for bottle-feeding; P <.01. The Western Australian Pregnancy Cohort Study The Western Australian Pregnancy Cohort Study 23 was designed to investigate the relation between the duration of exclusive breastfeeding and the development of asthma in children at 6 years of age. The study included 2187 children ascertained through antenatal clinics in Perth and followed to 6 years. After adjustment for confounders, the introduction of formula milk before 4 months was a significant risk factor for doctordiagnosed asthma (OR, 1.25; 95% CI, ), wheeze 3 or more times since 1 year (OR, 1.41; 95% CI, ), wheeze in the past year (OR, 1.31; 95% CI, ), sleep disturbance due to wheeze in the past year (OR, 1.42; 95% CI, ), age asthma diagnosed (hazard ratio, 1.22; 95% CI, ), age at first wheeze (OR, 1.36; 95% CI, ), and positive skin reaction to at least one common aeroallergen (OR, 1.30; 95% CI, ). In this study, there was a significant reduction in the risk of childhood asthma at age 6 years if exclusive breastfeeding was continued for at least 4 months after birth in either atopic or nonatopic children. 23,24 The strengths of the Western Australian Pregnancy Cohort Study include its representativeness of the gen-

5 J Hum Lact XX(X), 2003 Breastfeeding, Asthma, and Atopic Disease 5 eral population. Mothers were enrolled in the study in mid-pregnancy, leaving little scope for selection bias. Dropout at birth due to early death or loss to follow-up was rare (0.4%), and the study population was large with a high response rate. 36 Collection of outcome data was prospective, at frequent intervals, and based on validated questionnaires. Breastfeeding and respiratory history data were collected by diary card and verified by nurse interview. 23,37 After allowing for covariates, the findings showed that exclusive breastfeeding has a substantial protective effect against respiratory illness in the first 6 years of life. National Longitudinal Survey of Children and Youth The National Longitudinal Survey of Children and Youth provided a sample of 2184 children between the ages of 12 and 24 months, whose mothers reported data on breastfeeding and asthma. 25 Outcomes included parental report of physician-diagnosed asthma and wheeze in the previous year. After adjustment for smoking, low birth weight, low maternal education, and gender, duration of breastfeeding for 9 months or less was found to be a risk factor for asthma (OR, 2.39; 99% CI, ) and wheeze (OR, 1.54; 99% CI, ). Swedish Study Results of a prospective birth cohort study 26 suggest that exclusive breastfeeding has a preventive effect on the early development of multiple allergic diseases. The parents of 4089 infants completed questionnaires about exposures, allergic symptoms, and feeding at 2 months and 1 and 2 years of age. Children exclusively breastfed for 4 months or more had less asthma with an adjusted OR of 0.7, less atopic dermatitis with an adjusted OR of 0.8, and less suspected allergic rhinitis by age 2 than children exclusively breastfed for a shorter period of time. There was a significant risk reduction for asthma related to partial breastfeeding during 6 months or more (OR adj, 0.7; 95% CI, ). Children with a parental history of atopic disease derived the greatest benefit from breastfeeding. Summary of Population and Cohort Studies Studies that met the criteria for inclusion in this review demonstrated a pattern of protection with breastfeeding and a risk of formula (Table 2). Studies of the relation between breastfeeding and illnesses are subject to possible limitation by misclassification of exposure and outcome and by confounding. To correct for limitations, 4 standards for breastfeeding studies have been established. 38 These include avoidance of detection bias, definition of the outcome event (i.e., asthma, atopic disease, eczema, respiratory illness), definition of breastfeeding, and adjustment for potential confounding variables. In studies that met all 4 recommended standards, the ORs consistently exhibited an expected direction of effect that suggests biological plausibility and specific protective effects of breast milk. Although the range of magnitude of effect is not large ( ), in population terms this is large enough to be of public health significance. The apparent inconsistency in the literature is partly because researchers have measured different aspects of atopy and asthma in children of different ages, using different ways of measuring those outcomes. Another problem is that, despite the best intentions of the researchers and the use of multivariate statistical models, it is not possible to entirely control for confounding variables. There are many factors that may influence both the mother s likelihood of breastfeeding and the risk of children developing atopy, such as the appearance of a rash in the first months of life. Many nutritionists working in this area have focused on food avoidance such as cow s milk in high-risk infants, rather than on breastfeeding or breast milk quality. Sampling criteria could lead to selection bias, as is inevitable in some cohort studies. For example, the Tucson participants were recruited from middle-class families who obtained care from pediatricians via an HMO, whereas the Dunedin sample was a hospital-based cohort but, similarly, the infants came from a socioeconomically advantaged population, and non-europeans were underrepresented. Meta-analyses A meta-analysis of 9 studies, some included in this review, 22,39-46 was undertaken to examine the association between breastfeeding and the development of asthma. 47 The meta-analysis, which was based on a random-effects model, showed that children breastfed for at least 3 months of age were significantly protected from the development of asthma by an estimated OR of 0.80 (95% CI, ). This is equivalent to an increased odds (OR, 1.25; 95% CI, ) in children breastfed for less than 3 months. Other meta-analyses concluded a protective effect of between 26% and 30% from exclusive breastfeeding during the first 3 months of life against developing

6 6 Oddy and Peat J Hum Lact XX(X), 2003 Table 2. Summary of Studies of the Effect of Formula Feeding on Atopic Risk: Population Prospective Observational Studies First Author, Age at Statistical Effect, Odds Ratio (OR) Year, Reference Population, Outcome Reference and 95% Confidence Interval Confounding Factors Number N (mo or y) Outcome Group (95% CI) in Model Grulee, ,061 9 mo Eczema Formula vs bf* OR, 7.0 Seasonal influence Saarinen, , 10, 17 y Manifest Formula vs 42% prolonged bf, 36% partial bf, Parental atopy, smoking, atopy prolonged bf 65% short/no bf, P =.02 socioeconomic indicators Wright, y Wheeze in Bf vs formula OR, 0.45; 95% CI, Maternal education, atopic children if no history, ethnicity, smoking, maternal asthma socioeconomic indicators. 6, 11 y Wheeze in Bf vs formula OR, 5.7; 95% CI, atopic children with asthmatic mothers Hide, , 2, 4 y Asthma Formula vs bf 12% vs 10% Parental history Tariq, y Asthma Formula vs bf OR, 1.8; 95% CI, Environmental factors, seasons, socioeconomics Wilson, , 7 y Respiratory Formula vs bf 17% exclusive bf, 31% partial bf, Maternal age, social class symptoms 32% bottle-fed; P <.01 Oddy, y Asthma MD Formula vs bf OR, 1.25; 95% CI, Environmental factors, socioeconomic indicators, parental history Atopic symptoms Formula vs bf OR, 1.30; 95% CI, Dell, y Asthma Formula vs bf OR, 2.39; 99% CI, Parental smoking, birth weight, maternal education, gender Wheeze Formula vs bf OR, 1.54; 99% CI, Kull, y Asthma Bf vs formula OR, 0.70; 95% CI, Parental history, gender, maternal age, smoking, year of home construction Gdalevich, Meta-analyses Children Atopic dermatitis Bf vs Formula OR, 0.68; 95% CI, Numerous Asthma Bf vs formula OR, 0.70; 95% CI, *bf = breastfeeding. asthma, allergic rhinitis, and atopic eczema during childhood. Studies of Children With a Family History The family prospective cohort study classifies participants in the study on the basis of presence or absence of exposure but according to presence or absence of the disease in the mother or father. As in the population cohort study, the relevant exposure and outcome events have not yet occurred when the study is initiated. The studies that met the strict criteria defined in Table 1 for the study of breastfeeding and atopic disease for family cohort studies are listed in Table Although 2 studies examined the effect of a maternal avoidance diet during lactation on allergic manifestation, they are included in this review due to their relevance. 54,55 The relation of breastfeeding to atopy in children with a family history appears controversial. Of the studies that did not meet the criteria due to small sample size and lack of control for confounding, no effect 60 of a risk relationship with breastfeeding was apparent. 61 In a 1987 British study, 97 children with a family history of atopy 60 showed no significant evidence of protection provided by breastfeeding as measured by skin-prick test at age 5 years. Another British study of 92 infants 61 in 1985 showed that the prevalence of allergic disease at 5 years appeared to be greater in those who were breastfed for more than 3 months (definite disease, 65%) than in those bottle-fed (definite disease, 46%). Randomized Controlled Trials A large randomized controlled trial of 519 infants born in 2 maternity hospitals in South Wales was conducted. 51,52 The trial was based on the withholding of cow s milk, with soy milk given to infants who were not breastfed. Most infants in the control group received cow s milk formula. Only 2% of infants were exclusively breastfed for 8 weeks or more; therefore, the effects of exclusive breastfeeding could not be exam-

7 J Hum Lact XX(X), 2003 Breastfeeding, Asthma, and Atopic Disease 7 Table 3. Summary of Studies of the Effect of Formula Feeding on Atopic Risk: Family Prospective Observational Studies First Author, Age at Statistical Effect, Odds Ratio (OR) Year, Reference Population, Outcome Reference and 95% Confidence Interval Confounding Factors Number N (mo or y) Outcome Group (95% CI) in Model Burr, Wheeze Bf vs formula OR, 0.53; 95% CI, Social class, parental smoking, gender, birth weight Lucas, Any allergy or Formula vs bf OR, 3.6; 95% CI, Birth weight eczema Sigurs, Allergy or Elimination diet 11% vs 28% Parental smoking, pets in house eczema during lactation vs control Chandra, Any allergy Bf vs formula 14% vs 78% Pets in house, parental smoking (eczema or wheeze) Chandra, Any allergy Bf vs formula OR, 0.42; 95% CI, Pets in house, parental smoking, (eczema, daycare attendance asthma, or rhinitis) *bf = breastfeeding. ined in this study. After adjustment for common confounders, there was a decrease in wheezing in breastfed children (OR, 0.53; 95% CI, ; P <.001), although no difference was evident for eczema. Subsequent follow-up 62 until 7 years showed that the protection afforded by breastfeeding persisted for wheezing (any breastfeeding, 22% wheeze; never breastfed, 43% wheeze) (P <.001). In a 5-center randomized study stratified by the mother s intention to breastfeed, 777 low-birth-weight infants (<1850 g) born during 1982 to 1984 were followed to 18 months. 53 Among infants with atopic heredity, cow s milk formula gave an increased risk of allergy and eczema (OR, 3.6; 95% CI, ) in comparison to infants with no family history who were breastfed. Prenatally Randomized, Physician-Blinded, Parallel-Controlled Trial Although not directly the same as the other studies in this review, a prenatally randomized, physicianblinded, parallel-controlled trial was included here due to the direct relevance to the breastfeeding of atopic infants. In this trial, the effect of a maternal and infant food allergen avoidance diet combined with currently recommended practices for infants born to atopic parents was compared to controls. 54 The prophylactic group (n = 103) followed a maternal avoidance diet (milk, egg, peanut) in the third trimester of pregnancy and during lactation. This group fed their infant with breast milk or Nutramigen (protein hydrolysate formula), and the mother avoided feeding the infant any solid food for 6 months. After 6 months, cow s milk, corn, soy, citrus, and wheat were avoided for 1 year; egg until 2 years of age; and peanut and fish for 3 years. Most dropouts occurred prenatally due to the strictness of the regime (64/167; 38%; leaving 103 in the prophylactic group). The control group (n = 185) followed guidelines recommended by the American Academy of Pediatrics. Cumulative prevalence of atopic disorders occurred less frequently in the prophylactic treated than in control infants, primarily at 12 months of age (16.2% prophylactic; 27.1% control group; P =.039). However, results from the trial when the children were 7 years of age suggest that perinatal maternal and infant food allergen avoidance compared to standard feeding practices did not modify infant atopic disease and are of limited duration (13.9% positive food skin test in prophylactic group; 15.4% in control group). 55 Canadian Studies In Canada, 37 children with an atopic older sibling and who were breastfed for at least the first 6 weeks of life were compared to 37 children with a similar sibling but who were formula fed. 56 The 2 groups did not differ in any other respect and were compared at 2 years of age. Lower rates of eczema (P <.001), recurrent wheeze (P <.01), and serum IgE (P <.001) in the breastfed group indicated a reduced atopic risk as compared to the formula-fed children. The risk of respiratory infection was half as common in the breastfed infants (P <.001). A study from the same group found that elevated cord blood IgE (>0.7 µ/ml) was associated with a high risk of atopic disease in the first 2 years of life. 57 Of 53 high-risk infants with cord blood IgE > 0.7 µ/ml, 29% of breastfed

8 8 Oddy and Peat J Hum Lact XX(X), 2003 infants (9/31) developed atopy, whereas 86% showed symptoms of atopy in the formula-fed group (19/22) (P <.01). Of 67 infants with cord blood IgE < 0.7 µg/ml, breastfed infants developed atopic disease less than formula-fed infants did (7% vs. 33%; P <.05). For the entire study group (regardless of cord blood IgE levels), the occurrence of atopy among the breastfed infants (12%) was significantly lower (P <.001) than in the formula-fed infants (32%). The same researchers assessed the effect of different formulas on atopic disease in a double-blind study of high-risk infants. 58 Initially, infants were allocated to 1 of 2 groups depending on maternal feeding preference. If the mother chose to formula feed, the infant was randomized into 1 of 3 formula groups: whey hydrolysate, conventional cow s milk based, or soy based. A 4th group of infants who were exclusively breastfed for 4 months or longer was included. There were 72 infants in each group totaling 288 in the study. A protective effect of exclusive breastfeeding for 4 months or longer against atopic disease until at least 5 years (OR, 0.42; 95% CI, ) compared to infants fed cow s milk based or soy formula was apparent. Interestingly, feeding whey hydolysate reduced the incidence of atopic symptoms in high-risk infants (OR, 0.32; 95% CI, ), and this approach appeared beneficial compared to breastfeeding without maternal dietary restriction or soy-based formula feeding. 58,59 Distilling the Evidence, Epidemiological Issues Biological Plausibility A large body of literature on the biochemistry of human milk provides biological plausibility for the hypothesis that breastfeeding protects against the development of asthma and allergic symptoms. Breast milk contains a vast array of beneficial and multifunctional compounds including antimicrobial, immunomodulating, and bioactive molecules These molecules, which are well adapted to infants mucosal sites, are not well represented in infant formula. Breast milk is also a rich source of omega-3 fatty acids, which have anti-inflammatory effects. It is not currently known which of the many components in milk may account for the protective effect, but several pathways are likely Recent evidence shows that human milk contains cytokines, which are small soluble glycoproteins with established actions on the immune system. 74 Cytokines are pluripotent polypeptides that act in autocrine/ paracrine fashions binding to specific cellular receptors, operating in networks and orchestrating immune system development and functions. 75 Early milk has an abundance of these components at a time when neonatal organ system immaturity exists, suggesting that the bioactive compounds of milk may be important in neonatal development. 76 At face value, the evidence appears confusing and contradictory. However, this is in large part a consequence of a number of key issues that seriously complicate the interpretation of the available evidence and are often not taken into full and proper consideration. These issues include low statistical power, misclassification of information, causal pathway modeling, and effect modification (statistical interaction). Low Statistical Power Asthma and atopy are complex, multifactorial diseases, and therefore it is inevitable that most single causes (i.e., breastfeeding) will have relatively small effects on overall disease prevalence. In mainstream epidemiology and clinical science, most studies have an adequate power to detect ORs of a moderate size, that is, 2 or greater. However, on the basis of published metaanalyses, the true relative risk linking breastfeeding to childhood asthma may be 1.2 to In terms of breastfeeding, in which a large proportion of infants are exposed to early formula feeding, small ORs such as this have public health importance. Consequently, studies that appear large by conventional standards may be underpowered, and the interpretation of individual nonsignificant results may be misleading. 78,79 Misclassification of Information Both the primary exposure (breastfeeding) and the primary outcomes (asthma, atopic disease, and eczema) are subject to serious potential misclassification, particularly when assessed retrospectively. Study results may be confounded by the early introduction of infant formula as small amounts of early formula milk may be damaging to the development of an infant s immune system. It is therefore important to consider formula introduction in analysis, even if a mother does go on to predominantly breastfeed. Causal Pathway Modeling A complex disease such as asthma is likely to arise from the action of a series of etiological determinants strung out along a number of complex causal pathways. A given secondary exposure may either be a con-

9 J Hum Lact XX(X), 2003 Breastfeeding, Asthma, and Atopic Disease 9 founder, and therefore we need to adjust for it, or may be part of the causal pathway linking the exposure to the outcome of interest, and therefore we must not adjust for it. Some social class variables (e.g., educational attainment) fall into this latter category, and naïve adjustment may be seriously misleading. For example, if educational attainment is associated with asthma/ atopy solely because better education is associated with a greater understanding of the benefits of breastfeeding and breastfeeding protects against asthma, then educational attainment will be associated with both the exposure and the outcome of interest and might appear to be a confounder. But here in this case, the education is, in a sense, causing the breastfeeding, and to adjust for it will in effect remove some of the real variation in the outcome of breastfeeding that is the very foundation of the analysis itself. Thus, the formal definition of a confounder explicitly excludes determinants on a common causal pathway. 80 In other words, inappropriate adjustment for determinants lying on a causal pathway of interest may lead to shrunken estimates and inflated standard errors and will reduce an already limited statistical power still further. Effect Modification (Statistical Interaction) It is possible that the association between breastfeeding and asthma and atopy will vary at different levels of a key third variable, such as the underlying genetic risk of atopy. Indeed, evidence from Tucson 16 and elsewhere 60 would suggest that this may be the case. Such interactions not only complicate interpretation but also reduce statistical power. Resolving the Conflict Given these considerations, we should realistically expect to find relatively small relative risks for the effect of breastfeeding with large standard errors. This means that, even if a real association between breastfeeding and asthma/atopy exists, many studies will generate nonsignificant estimates, and a nontrivial proportion will produce estimates that apparently go in the wrong direction. Two complementary solutions to this problem are (1) to carry out meta-analyses 47 and (2) to undertake large population-based studies with careful assessment of exposures, outcomes, and relevant confounders. If an exposure is rare and the outcome does not have serious, life-threatening consequences, then a relative risk that is small (e.g., 1.25) may not be worth studying. However, when the exposure is both common and modifiable and the outcome is costly in terms of mortality, morbidity, and economics, 81 a small relative risk is of great public health relevance. The putative association between childhood asthma/atopy and breastfeeding unquestionably meets these criteria. Causality Previous studies that have shown a protective effect of breastfeeding on asthma and atopy have fulfilled strict criteria for assessing causality from observational studies, 82 that is, biological plausibility, consistency of findings, strength of association, temporality (exposure to breastfeeding before atopy develops), and a doseresponse relationship. However, there is the possibility that the protection of breastfeeding on the immune system will be down regulated over time, with current diet taking over as the important immune system regulator. More work is needed in this exciting area of research. In this review, 29 studies were evaluated as to whether they met strict criteria for assessing the adequacy of cohort studies to detect an effect of breastfeeding on asthma and atopic disease. Of the 29 studies, 15 met the strict criteria, 2 were unclear, and 12 did not meet the criteria. Of the 15 that showed a protective effect of breastfeeding (or conversely a risk of formula feeding), all met the strict criteria. Of the 12 that did not meet the criteria, 3 showed a negative effect of breastfeeding, 4 showed a positive effect of breastfeeding, and 5 showed no effect of breastfeeding at all. As evidenced by the studies that met the strict criteria for the study of breastfeeding and atopic disease, all demonstrated a protective effect of breastfeeding or, conversely, a risk of formula feeding. However, the continuing protective effect of breastfeeding on asthma and atopy later in adolescence and adulthood has yet to be confirmed in larger longitudinal studies. We conclude that the evidence of consistency and strength of the association is clear in that breastfeeding protects against asthma and atopic disease in childhood. Future Directions It is clear that mothers should be encouraged to breastfeed because of the multiple health benefits conferred by their milk. Since many mothers stop breastfeeding their infants before the recommended 6 months postpartum, health care workers must continue to explore all effective interventions to promote and support breastfeeding.

10 10 Oddy and Peat J Hum Lact XX(X), 2003 Because achievements in promoting breastfeeding have been based on consistent scientific evidence, they should not be eroded on the basis of a few studies that show a negative relation to asthma as discussed in this article. It is essential that scientists strive to collect better evidence to support or refute causal associations between breastfeeding and childhood illnesses. In the meantime, positive health messages about breastfeeding as the preferred method of infant feeding must continue to be disseminated. Appendix Glossary Atopic disease Atopic disease or atopy is a spectrum of allergic diseases that give rise to a range of clinical disorders. These disorders include asthma, infantile eczema, atopic dermatitis, rhinitis, conjunctivitis, gastro-enteritis, food allergy, dyspnoea, bronchospasm, diarrhea, sinusitis, laryngospasm, urticaria, and anaphylaxis. Atopy should be viewed as reflecting a pivotal component of the immune system and the inflammatory response. 83 This condition is distinguished by high blood levels of immunoglobulin E (IgE), which can lead to a generalized and prolonged hypersensitivity to common environmental antigens, including house dust mite, animal dander, and pollen. Asthma Asthma, a common chronic illness in childhood, is the result of a complex interaction between several cells, mediators, and neural pathways, leading to an inflammatory response associated with airway hypersensitivity that clinically manifests as recurrent irrative cough, paroxysmal dyspnoea, wheezing, prolonged expiration, or breathlessness. 84 This definition highlights the pathogenetic mechanisms associated with inflammation, rather than emphasizing the bronchospasm that may be associated with asthma. 85 Asthma is characterized by the presence of cells such as eosinophils, mast cells, basophils, and CD25+ T lymphocytes in the airway walls. 86 The importance of airway inflammation in the pathogenesis of asthma is clearly established with airway inflammation found even in mild asthma. 87 Breastfeeding The duration of breastfeeding can be measured in numerous ways. First, as the duration of exclusive breastfeeding defined by the age that other milk is introduced; second, as the duration of any breastfeeding (also referred to as breastfeeding per se ), defined as the age at which breastfeeding stopped and as binary, categorical or continuous variables. Exclusive and any breastfeeding are usually highly correlated (P <.001); therefore, both exposures are often analyzed as continuous and binary, and just one is usually reported in final analyses. A variety of dichotomization cut points is possible but often based on a cut point at 3 or 4 months for the duration of exclusive breastfeeding and 6 months for the duration of any breastfeeding. References 1. Kramer MS. Does breastfeeding help protect against atopic disease? Biology, methodology, and a golden jubilee of controversy. J Pediatr. 1988;112: Webb K, Marks GC, Lund-Adams M, Rutishauser I. 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