Early Life Factors and the Long-Term Development of Asthma

Linköping University Medical Dissertations No. 1329

Early life factors and the long-term development of asthma

Hartmut Vogt

Linköping University Faculty of Health Sciences Department of Experimental and Clinical Medicine Division of Pediatrics 581 83 Linköping Sweden

Linköping 2012

Cover illustration by Barbara & Hartmut Vogt

ISBN: 978-91-7519-794-4 ISSN: 0345-0082

Paper I has been printed with permission from the American Academy of Pediatrics. Paper III has been printed with permission from John Wiley & Sons, Inc. Figure 1 has been printed with permission from Elsevier Limited.

Printed in Sweden by LiU-tryck, Linköping, Sweden, 2012.

“Das schönste Glück des denkenden Menschen ist, das Erforschliche erforscht zu haben und das Unerforschliche zu verehren.”

Johann Wolfgang von Goethe (1749-1832)

ORIGINAL PUBLICATIONS

This thesis is based on the following four papers, which will be referred to in the text by their Roman numerals.

I. Preterm Birth and Inhaled Corticosteroid Use in 6- to 19-Year-Olds: A Swedish National Cohort Study Hartmut Vogt, Karolina Lindström, Lennart Bråbäck, Anders Hjern Pediatrics 2011;127:1052–1059

II. Asthma heredity, cord blood IgE and asthma-related symptoms and medication in adulthood: a long-term follow-up in a Swedish birth cohort Hartmut Vogt, Lennart Bråbäck, Olle Zetterström, Katalin Zara, Karin Fälth- Magnusson, Lennart Nilsson Submitted

III. Migration and asthma medication in international adoptees and immigrant families in Sweden Lennart Bråbäck, Hartmut Vogt, Anders Hjern Clinical & Experimental Allergy, 2011 (41), 1108–1115

IV. Does pertussis vaccination in infancy increase the risk of asthma medication in adolescents? Hartmut Vogt, Lennart Bråbäck, Anna-Maria Kling, Maria Grünewald, Lennart Nilsson Submitted

ABSTRACT

Asthma, a huge burden on millions of individuals worldwide, is one of the most important public health issues in many countries. As genetic and environmental factors interact, asthma may be programmed very early in life, perhaps even in utero.

The aim of this thesis was to assess the impact of gestational age, cord blood immunoglobulin E (IgE), a family history of asthma, migration, and pertussis immunization in early life on the development of asthma in child and adult populations.

As a proxy for asthma disease, dispensed asthma medication was used as the main outcome variable based on data from the Swedish Prescribed Drug Register. Data from other national registers were used to control for confounders. Three of our studies were based on national cohorts, and one on a local birth cohort that was initiated in 1974–75.

Gestational age had an inverse dose-response relationship with dispensed asthma medication in 6– to 19-year-olds. Odds ratios for dispensed asthma medication increased with degree of prematurity compared with children born at term. Furthermore, asthma medication was more likely to be dispensed among children and adolescents born early term after 37–38 weeks’ gestation than among those at the same age who were born at term. Elevated cord blood IgE and a family history of asthma in infancy were associated with a two- to threefold increased likelihood of dispensed asthma medication and self-reported allergen-induced respiratory symptoms at the age of 32–34 years, but the predictive power was poor. Age at migration had an inverse dose-response relationship with dispensed asthma medication at the age of 6–25 years in adoptees and foreign-born children with foreign-born parents. International adoptees and children born in Sweden to foreign-born parents had three- to fourfold higher rates of dispensed asthma medication compared with foreign-born children who were raised by their foreign- born birth parents. No association was found between pertussis immunization in early infancy and dispensed asthma medication in 15-year-olds. The type of vaccine or vaccine schedule did not affect the outcome.

Fetal life is a vulnerable period. This thesis strengthens the evidence that every week of gestation is important for lung maturation. Cord blood IgE, however, did not predict the risk of asthma in adults. Furthermore, the study of migrating populations demonstrated that environmental changes at any age during childhood may affect the risk of asthma. Another, important public health message from this thesis is that vaccination against pertussis in early childhood can be considered safe with respect to the long-term development of asthma.

SVENSK SAMMANFATTNING

Astma har blivit allt vanligare och är idag ett stort folkhälsoproblem runt om i världen. En samverkan mellan arv och miljö bidrar till utvecklingen av astma och sjukdomen grundläggs ofta mycket tidigt i livet, inte sällan redan under fostertiden.

Syftet med denna avhandling var att undersöka hur graviditetslängd, immunglobulin E (IgE) i navelsträngsblod, ärftlighet för astma, migration och vaccination mot kikhosta tidigt i livet kan påverka utvecklingen av astma bland barn och vuxna. en födelsekohort som startades 1974-75 i Linköping. Data inhämtades till stor del frånTre av nationella våra studier register. baserades Uttag på av nationella astmamedicin kohorter, användes medan som den indikatorfjärde baserades för astma på baserat på uppgifter från det Svenska Läkemedelsregistret.

Uttag av astmaläkemedel bland 6-19-åringar visade ett omvänt samband med graviditetslängden. Risken var störst för de mest prematura barnen men en ökad risk sågs också bland fullgångna barn födda i graviditetsvecka 37-38 jämfört med barn födda efter 40-41 graviditetsveckor.

Förhöjt navelsträngs-IgE och ärftlighet för astma som barn visade ett samband med uttag av astmamedicin och självrapporterade allergeninducerade luftvägs- symptom vid 32-34 års ålder, men varken IgE eller ärftlighet kunde förutsäga risken för astmamedicinering som vuxen på ett tillräckligt bra sätt.

Uttag av astmamedicin jämfördes mellan utlandsfödda adoptivbarn med svenska adoptivföräldrar, svenskfödda barn till invandrade föräldrar, utlandsfödda barn till utlandsfödda föräldrar och svenskfödda barn till svenskfödda föräldrar. Uttaget av astmamedicin minskade med stigande ålder vid invandring till Sverige. Åldern vid invandring spelade större roll än varifrån i världen man kom till Sverige.

Vaccination mot kikhosta i tidig barndom påverkade inte risken för astma vid 15 års ålder. Typ av kikhostevaccin eller tidpunkt för vaccination påverkade inte heller sambandet.

Denna avhandling visar att varje graviditetsvecka är viktig för lungans mognad och astmautveckling senare i livet. Navelsträngs-IgE är däremot inte användbart som screening för utveckling av astma i vuxen ålder. Undersökningen av olika invandrar- grupper pekar på att miljön även efter födelsen påverkar risken för senare astma. Kikhostevaccination påverkade inte långtidsrisken för att senare utveckla astma, vilket ur ett folkhälsoperspektiv är ytterligare en viktig slutsats som kan dras från denna avhandling.

DEUTSCHE ZUSAMMENFASSUNG

Erwachsenenalter. Ein Zusammenspiel zwischen Erbfaktoren und Umwelt beein- Asthma gehört mit zu den häufigsten chronischen Erkrankungen im Kindes- und alter, oder sogar noch vor der Geburt. flusst die Entwicklung von asthmatischen Erkrankungen – oft bereits im frühen Kindes Diese Dissertation beschäftigt sich mit der Bedeutung verschiedener perinataler Fak- toren für die Entwicklung von Asthma bei Kindern und Erwachsenen (Schwanger- schaftsdauer, Nabelschnur-Immunglobulin E (IgE), positive Asthmafamilien- anamnese, Migration, Keuchhustenimpfung im Kleinkindesalter). Die Ergebnisse dieser Untersuchungen basieren hauptsächlich auf Daten aus nationalen Registern. Informationen aus dem Schwedischen Medikamentenregister über eingelöste Rezepte für Asthmamedikamente dienten als Indikator für Asthma.

Es zeigte sich ein umgekehrter Zusammenhang zwischen Schwangerschafts- dauer und dem Anteil eingelöster Rezepte bei Kindern und jungen Erwachsenen (6- 19 Jahre). Das Risiko war für extrem Frühgeborene am größten, jedoch hatten selbst Kinder, die zwei bis drei Wochen vor dem Termin geboren waren, immer noch ein erhöhtes Risiko im Vergleich zu am Termin geborenen Kindern. Wir fanden ein Zusammenhang zwischen einer erhöhten Menge Nabelschnur-IgE und einer positiven Asthmafamilienanamnese, sowie von den 32-34 Jahre alten Studienteilnehmern beschriebenen allergen-induzierten Luftwegssymtomen. Keiner dieser beiden Parameter zeigte jedoch einen ausreichend guten prädiktiven Wert für das Asthmarisiko im Erwachsenenalter. Die Studien beinhalteten auch einen Vergleich verschiedener Gruppen von Einwan- derern und Adoptivkindern mit in Schweden geborenen Kindern von in Schwe-

Mit steigendem Lebensalter bei Einwanderung nach Schweden nahm der Anteil den geborenen Eltern im Hinblick auf die Häufigkeit von Asthmamedikamenten. Alter der Kinder bei Einwanderung nach Schweden spielte eine größere Rolle als die Region,von eingelösten aus der sie Rezepten stammten. verschreibungspflichtiger Asthmamedikamente ab. Das

Alter von 15 Jahren. Dabei spielte weder der verabreichte Impfstofftyp noch der ZeitpunktEine Impfung der Impfung gegen Keuchhusten eine entscheidende hatte keinen Rolle. Einfluss auf das Asthmarisiko im

Insgesamt lässt sich feststellen, dass sowohl für die Lungenreifung, als auch die Ent- wicklung asthmatischer Erkrankungen im späteren Leben jede Schwangerschafts- woche von Bedeutung ist. Nabelschnur-IgE ist jedoch kein geeigneter Screenings- parameter für Asthma im Erwachsenenalter. Die Untersuchungen verschiedener Einwanderergruppen deuten auf die besondere Bedeutung von Umweltfaktoren hin, die auch noch nach der Geburt das Asthmarisiko bestimmen können. Die Keuchhusten- impfung zeigte keinerlei Auswirkungen auf das Langzeitrisiko für Asthma – eine weitere wichtige gesundheitswissenschaftliche Erkenntnis dieser Arbeit.

ABBREVIATIONS

ANY Any asthma medication aPANTI AcellularAnti-inflammatory pertussis treatment ATC Anatomical Therapeutic Chemical

BETA2 Beta2-agonist BMI Body Mass Index BPD Bronchopulmonary dysplasia CB-IgE Cord blood immunogloblin E CHC Child health center

DAG Directed Acyclic Graph DPTCI Diphtheria-pertussis-tetanusConfidence interval ENRIECO Environmental Health Risks in European Birth Cohorts GA2LEN Global Allergy and Asthma European Network

ICS Inhaled corticosteroids ILICD InterleukinInternational Classification of Disease INF Interferon ISAAC International Study of Asthma and Allergy in Childhood ITT Intention to treat LF+ Positive likelihood ratio LGA Large for gestational age LTRA Leukotriene antagonist OR Odds ratio

PP Per protocol PPVPIN PositivePersonal predictive identification value number QN Questionnaire RSV Respiratory syncytial virus SE Sensitivity SGA Small for gestational age SMBR Swedish Medical Birth Register

SPDR Swedish Prescribed Drug Register ThSP TSpecificity helper lymphocyte wP Whole cell pertussis WHO World Health Organization

TABLE OF CONTENTS

1 Introduction and background...... 17

1.1 Development in utero and fetal programming...... 17 1.1.1 Fetal programming...... 17 1.1.2 Lung development...... 17 1.2 Asthma...... 19 1.2.1 Historical background...... 19 1.2.2 Asthma today...... 19 1.3 Asthma prevalence...... 20

1.4 Birth cohorts...... 22

1.5 National registers...... 22 1.5.1 Swedish Prescribed Drug Register...... 23 1.5.2 Swedish Medical Birth Register...... 23 1.5.3 Other registers used...... 23

1.6 Preterm birth...... 24

1.7 Asthma heredity...... 25

1.8 Immunoglobulin E...... 26

1.9 Migration...... 26

1.10 Immunization...... 27 2 Aims of the thesis...... 29 3 Material and methods...... 31

3.1 Study population...... 31 3.1.1 Cohort I (Study I)...... 31 3.1.2 Cohort II (Study II)...... 31 3.1.3 Cohort III (Study III)...... 32 3.1.4 Cohort IV (Study IV)...... 32

3.2 Study variables (Studies I-IV)...... 37 3.2.1 Outcome variables...... 37 3.2.2 Questionnaire data...... 37 3.2.3 Confounding factors...... 37

3.3 Statistical analyses...... 39 3.3.1 Study I...... 39 3.3.2 Study II...... 40 3.3.3 Study III...... 40 3.3.4 Study IV...... 40 4 Ethical statements...... 42 5 Results...... 42

5.1 Prevalence...... 42

5.2 Gestational age (premature birth)...... 43 5.3 Cord blood immunoglobulin E...... 44 5.4 Family history of asthma...... 46 5.5 Prediction of asthma...... 47 5.6 Congruence between respiratory symptoms and asthma medication...... 49 5.7 Migration...... 50 5.8 Immunization...... 52 6 Discussion...... 55

6.1 General methodological considerations...... 55 6.2 Premature birth...... 57 6.3 Cord blood immunoglobulin E and family history of asthma...... 58 6.4 Migration...... 61 6.5 Immunization...... 63 7 Concluding remarks...... 67 8 Acknowledgments...... 70 9 Funding...... 73 10 References...... 74 11 Appendix...... 90 11.1 Questionnaire Study II...... 90 11.2 Map Study IV...... 92 17

1 INTRODUCTION AND BACKGROUND

1.1 Development in utero and fetal programming

1.1.1 Fetal programming There is increasing evidence that an insult during early life, especially fetal life, contributes to the development of diseases as an adult [1-3]. The hypothesis describing the result of disturbances during fetal life, often referred to as ‘fetal programming’, has attracted growing interest during the past decade. Reports about the association of low birth weight with metabolic and cardiovascular diseases in disease later in life [2, 4]. adulthood have given rise to a discussion about the influence of early life factors on Variations to maternal nutrition have been of special interest in the study of adverse intrauterine environments [5, 6]. There is convincing evidence that an impaired diet in adulthood [7]. Low birth weight and intrauterine weight gain are associated with impairedduring pregnancy postnatal can organ influence function fetal [8]. growth Low birth and weight,subsequent howver, disease is not development necessarily dependingan accurate on reflection their magnitude, of fetal growth, result andeither can in be normal caused or by reduced different birth factors. weight Insults [9]. Limitedat different access stages to food of the and gestational energy during process prenatal and lifesubsequent might lead prenatal to an inappropriate growth can, adaptive response by the fetus to a profuse nutritional postnatal environment, which in turn could lead to the development of disease in adulthood [10].

The placenta, as a natural interface between the maternal and fetal organisms, seems as a mediator of nutritional and hormonal factors [11]. to play a key role in fetal programming. It functions as an immunological barrier and Life in utero can already program for health and disease in adulthood [12, 13].

There is a strong association between pre- and perinatal exposure and hospitalization forDifferent respiratory factors symptoms, early in life including seem also asthma, to influence during the early development infancy [15]. of Anasthma increased [14]. risk of asthma can remain all the way into adulthood [16], but few studies have investigated these associations.

1.1.2 Lung development The development of the lung is a continuous process that starts early after conception and does not end until the age of 2–3 years, after which the lung continues to grow until body growth stops [17]. Disturbance of the developmental programming of the lung at any point during this development may have a crucial impact on its function and its susceptibility to harmful external factors [18, 19].

The embryonic phase of lung development is critical for cell differentiation and branching morphogenesis. The later stages occur during fetal and early postnatal 18 life when the lung is still growing and maturing structurally and functionally. During this stage of development, the lung is extra susceptible to adverse effects of by environmental pollutants such as those from tobacco smoke [20]. Yet, fetal or earlyenvironmental postnatal pollutantslife is not [17].the only Lung period growth during and function which lung are negativelydevelopment influenced can be phase of rapid growth and maturation [21]. Starting to smoke during adolescence hasdisturbed; been shown even adolescenceto result in impaired might be functional a vulnerable pulmonary period as development the lung is in [22]. its final The degree of impaired lung function depends on when the harmful impact during lung development occurs [23]. smoking,Maternal bothsmoking pre- hasand been postnatal, identified was shownas a risk to increasefactor for the asthma incidence and wheezingof wheezing in andinfants asthma and youngin small children. children In and a recent teenagers review, up toexposure 18 years to of maternal age by at and least passive 20% [24]. Some studies even describe an effect of prenatal tobacco exposure independent of postnatal exposure [25].

Lung development and its function seems not only to be susceptible to direct fetal and postnatal growth [26]. Restricted fetal growth has been shown to have adverse functional effects of effects environmental on lung development pollutants, but that is can also persist influenced into postnatal by impaired life. There are multiple causes of impaired growth (e.g. maternal malnutrition, placenta impairments depending on when during gestation growth retardation occurs [17]. Structuralinsufficiency), changes which include leads tosmaller different numbers types of of functional enlarged alveoliand structural with thicker pulmonary septal walls and basement membranes. The structural abnormalities and impaired lung lung aging [27]. function seen soon after birth persist or even progress with age and can influence Exposure to intrauterine infections, e.g. chorioamnionitis, can lead to premature amniotic environment are elevated, which could be the cause of premature labor [28]. labor that results in premature birth. Levels of proinflammatory cytokines in the environment on lung development [29, 30], and it is reasonable to believe that a similarAnimal effectmodels can have occur demonstrated in human beings. the influence of an intrauterine proinflammatory infectionsAs proinflammatory of the lower factors respiratory influence tract lung in developmentinfants show anin utero,association frequent with infections asthma, of the lower respiratory tract may influence postnatal lung development. Viral and various viral agents have been identified [31-33]. The infections occur most frequently during infancy, the postnatal phase of alveolarization [34]. 19

1.2 Asthma

1.2.1 Historical background and perhaps even earlier. A German Egyptologist, Georg Ebers, discovered a medical Asthma is believed to have been recognized as a specific disease in ancient Egypt, over 700 remedies described was a “mixture of herbs heated on a brick so that the suffererpapyrus could(ca. 1550 inhale BC) their in the fumes” 1870s [35]. that contained ancient prescriptions. One of the The term ‘asthma’ comes from the Greek verb ‘aazein’, meaning to pant or to exhale with open mouth, and is described for the first time in a Greek epic poem, the HippocratesIliad. The earliest meant text asthma containing as a clinical the word entity ‘asthma’ or as asmerely a medical a symptom. term is Thebelieved best to be the Corpus Hippocratum (~400 BC). It remains uncertain, however, whether clinical description of asthma in later antiquity is offered by the master clinician, theAretaeus Hippocratic of Cappadocia texts and (1st to somecentury extent AD). with The numerousthe statements mentions of Aretaeus of ’asthma‘ [36]. in the extensive writings of Galen (130–200 AD) appear to be in general agreement with

1.2.2 Asthma today on the typical symptoms seen and the known pathophysiological changes in the airways.Definitions for asthma are many in the literature, but are nowadays mostly based

Asthma attacks all age groups but often starts in childhood. It is a disease characterized by recurrent attacks of breathlessness and wheezing, which vary in severity and frequency from person to person. In an individual, they may occur from hour to hour and day to day.

This condition is due to inflammation of the air passages in the lungs and affects the sensitivity of the nerve endings in the airways so they become easily irritated. In an attack, the lining of the passages swell causing the airways to narrow and reducing the flow of air in and out of the lungs.

World Health Organization (WHO)

Similar to the WHO definition [33], the Global Initiative for Asthma (GINA), a disordercollaborating of the network airways, of healthin which care many professionals cells and and cellular public elements health officials are involved. around the world to reduce asthma prevalence, describes asthma as a chronic inflammatory recurrent episodes of wheezing, breathlessness, chest tightness and coughing with Chronic inflammation is associated with airway hyper-responsiveness that leads to variable, often reversible, airflow limitation [37]. 20

Asthma is a more heterogeneous than uniform disease, with different phenotypes and genetic and environmental factors [32]. Asthma phenotypes include allergen- inducedprobably asthma different as causes.well as Theynon-allergic can be definedasthma, by of theirwhich unique the latter interaction used to betweenbe more asthma is characterized by female predominance, increased symptom severity and latercommon debut in inadults life. An[31]. association Non-allergic, with also smoking called andintrinsic, chronic non-atopic rhinosinusitis or adult-onset, has been reported [19, 38]. The presence of allergy, or sensitization, is routinely evaluated by is rather common and has been demonstrated in about half of the population in the skin prick test and/or immunoglobulin E (IgE) immunoassays. Allergic sensitization proportion of patients with non-allergic asthma probably have coincidentally USA, with a positive skin prick test to one or more common allergens [39]. A significant positive skin prick tests and allergic rhinitis, which can lead to misclassification of asthmatheir asthma patients symptoms. with negative Increased skin prickIgE synthesis tests and may no hereditybe a risk of factor allergy for but asthma with independent of allergen-specific IgE-mediated allergic responses [32]. Non-allergic elevated levels of total IgE have been found to have more severe asthma and more 2-response (often referred to as impaired lung function than those with normal IgE [40]. It has been proposed that total IgE concentration reflects the intensity of a Th an “allergic immune response”) and asthma severity in these patients, but is not an expression of allergic asthma as specific IgE is missing [32].

[31].In children, asthma phenotypes include transient infant wheezing, non-atopic wheezing, wheezing mediated by IgE, and so-called late-onset childhood asthma

Transient infant wheezing occurs mainly during the first years of life and is not yearsassociated of life with and atopywhose or symptoms reduced lungoften function started atin conjunction school age [41].with Non-atopicearly viral infectionswheezing isof oftenthe lower seen respiratory among children tract. Viralwho continueinfections to usually wheeze continue beyond to the trigger first wheezing in these children [31]. Another group of children continue to wheeze even when older. This persistent wheezing type is often associated with atopy

Late-onset childhood asthma is another subtype of pediatric asthma that has been (IgE-mediated), bronchial hyper-responsiveness and reduced lung function [42]. low remission rate [43]. described as occurring during or after puberty. It affects mainly women and has a

1.3 Asthma prevalence

The prevalence of asthma and allergic diseases among children and young adults has steadily increased during the second half of the 19th century [44-46], above

European countries, however, the increase has not continued at the same rate as all in industrialized countries [47-50]. In countries like the USA or several Western before [47, 51-53]. Global initiatives like the International Study of Asthma and 21

Figure 1: Time trends of asthma symptoms in ISAAC Phase Three.

Allergies in Childhood (ISAAC) [54] have shown the different prevalence rates from a worldwide perspective [55-57] (Figure 1). asthma prevalence in the municipality of Linköping, Sweden, in 2002 compared with As members of the ISAAC Phase Three Study Group, we have investigated the change in the identical Phase One investigation in 1994. In contrast to our Nordic neighbors in Finland we found a significant decrease in 12-month wheezing, from 11.2% to 9.7%, prevalencebetween ISAAC rates Phase of 18.6% One and and 18.9%, ISAAC respectively, Phase Three but among the number teenagers of teenagers 13–14 years with aof diagnosis age. There of was asthma no change increased in “wheeze from 10.0% ever” to between 12.0% during Phases this One eight-year and Three, period with

[56]. Equally, a repeated cross-sectional survey in 1985, 1995 and 2005 among school children in Northern Sweden showed that the increase in asthmatic symptoms in theschool other children hand, physician-diagnosedhad peaked. Fewer children asthma hadhad increased questionnaire-reported compared with wheezing the same and other severe symptoms in 2005 compared with the previous investigations. On in Eastern Europe where prevalence previously was low showed a dramatic increase ininvestigations asthma prevalence conducted [57], 10 whereas and 20 years other before investigators [58]. In incontrast, Europe several have seen countries more stable prevalence rates in school children [59]. Similar to the effect we have seen in Swedish children in Linköping and in 22

have also shown that there is no ongoing increase in asthma prevalence. Lötvall andinvestigations colleagues infound Northern a prevalence Sweden of [58],physician-diagnosed studies of asthma asthma in adults of 8.3% in in Sweden adults 16–75 years of age in West Sweden, and the prevalence of respiratory symptoms youngwas found adults to frombe lower 1990 compared and 2008 with showed previous a decrease studies in [60]. the 12-monthIn Northern prevalence Sweden, ofa comparison wheezing from of two 20% questionnaire-based to 16% and an unchanged surveys ofrate respiratory of other obstructive symptoms airwayamong symptoms common in asthma during this period [61]. This stagnation might partly be caused by an increased awareness of asthma among Swedish physicians during recent years, which has led to increased prescription of asthma medication, symptoms, their prevalence decreases. especially of inhaled corticosteroids (ICS) [62]. With better treatment of asthma

1.4 Birth cohorts

Birth cohorts are commonly used in the investigation of causal factors and the development of asthma and allergies over time. Many birth cohorts have been established during recent decades, especially in Europe but also in other regions

Birthof the Cohortworld. Onein the of Unitedthe first Kingdom birth cohorts [64]. toThereafter study allergic many disease other studies in Europe started was duringinitiated the in 1990s Denmark [65-70] in 1985 and after[63], thefollowed turn of in the the millennium late 1980s [71].by the Isle of Wight A prospective birth cohort was initiated as early as 1973 in Linköping, Sweden, children were recruited with a follow-up rate of 97% at the age of 10–11 years [73]. with the emphasis on predictors of asthma and allergic disease [72]. Initially, 1,701 Cohort, which has been followed up at different points in time up to the age of 42 years,Only a butfew which birth cohortsoriginally started had an before entirely the different early 1970s, focus e.g. than the the British investigation 1958 Birth of the development of asthma [74]. Efforts made during recent years to build up networks between different birth cohorts have resulted in the GA2 example. Common databases with pooled data were established to allow meta- analysis and develop recommendationsLEN initiative for future [75] data and collecting. ENRIECO project [76], for

1.5 National Registers

Most data used in the analyses in this thesis have been retrieved from national

Swedish Medical Birth Register. registers. We mainly used data from the Swedish Prescribed Drug Register and the 23

1.5.1 Swedish Prescribed Drug Register This register contains data about all prescribed and dispensed drugs for the entire Swedish population from 1999 and onward. Since July 1, 2005 all data in this register atare birth. linked The on registeran individual also containsbasis by athe personal patient’s identifier, sex, age the and personal registered identification residence number (PIN), a 10-digit identification code all Swedish residents are assigned dispensation of different drugs and provides a useful tool for studying patterns of drugand is utilization updated [78].monthly [77]. This quite new register offers valuable data on the

1.5.2 Swedish Medical Birth Register almostThis register every newbornwas established child in inSweden. 1973 and The iscontent maintained and methods by the Swedishof data collection National haveBoard changed of Health since and Welfare.its establishment It contains in information 1973, but the on ante-register’s and perinatalbasic structure factors has for remained the same. Between 1973 and 1982 so-called “Medical Birth Reports” were the basis of information for the register, but since 1982 the three records of primary interest—the basic antenatal care record of the mother, the delivery record, and the record for the pediatric examination of the newborn infant—have been sent to the

National Board of Health for data registry. Most of the mothers were identified by their unique PIN. Their infants were linked to the Medical Birth Register using the al.PIN studied from The the Birth register Register on two at Statistics different Swedenoccasions, [79]. before and after the change in The register’s quality has been evaluated at different points in time. Cnattingius et conditions were pointed out. For so-called “hard” data such as perinatal survival or 1982. Problems with the validity of diagnosis and the risk of misclassification of rare ofbirth the weight register distribution, in 2003 and however, found that the onlyregister an acceptable contains data 1–2% of fairlyof the good records quality are missing[80]. The for National most of Boardthe years of Health[79]. and Welfare gave an overview on the quality

1.5.3 Other registers used The Swedish Hospital Discharge Register contains data about all hospital to the register, and since 1987 reporting covers the whole country. For 99% of all registereddischarges hospitalin Sweden stays, since the 1964. register It is contains mandatory one for or allmore public diagnoses caregivers based to reporton the asInternational good [81]. Classification of Disease (ICD). Except for the loss of some data, mainly concerning psychiatric diagnoses, the data quality of the register has been assessed The Swedish Register of Education was established in 1985 and contains information on the highest completed education for all Swedish citizens between 16 and 74 years of age. Data are reported continuously to Statistics Sweden, which updates the register annually [82]. 24

The Total Enumeration Survey, maintained by Statistics Sweden, contains infor mation for all Swedish citizens on income, pension, welfare and disability grants, as well as income from sickness assistance and taxes paid [83]. containing data which historically had been collected in parish registers and church The Total Population Register was established in 1968 as a computerized register status, place of birth, citizenship, and immigration and kinship status. Data are updatedbooks. It continuously. contains information This register about is maintained name, place by ofStatistics residence, Sweden sex, [84]. age, marital

The Swedish Multi-Generation Register, also maintained by Statistics Sweden, is part are based on information about people registered in Sweden since 1961 and those whoof the were Total born Population in 1932 Register. and later Data [85]. on family relationships for all Swedish citizens

1.6 Preterm birth

Pretermaccounts birth for numerousis defined asshort-term birth before complications 37 completed such weeks as of respiratory gestation (less distress, than 259 days). Premature birth, especially in infants with very low birth weight (VLBW), The risk of neonatal morbidity decreases with increasing gestational age, but still existsretinopathy even for of infants prematurity, born not sepsis, extremely and bronchopulmonary premature after 30–34 dysplasia weeks (BPD)of gestation [86]. and impaired lung function [88]. This contributes to an increased risk of asthma and bronchitis,[87]. Premature especially infants during are born early with infancy incompletely [89]. Bronchitis developed is particularly lungs, fewer common alveoli an inverse association between gestational age and the risk of asthma in children up toamong 10 years children of age. born The prematurely highest risk who was developed seen in children BPD. A bornstudy prior from to Alaska week showed 32 and remained even after controlling for birth weight [90]. The relation between prematurity and respiratory morbidity, including asthma, is rather complex. Many factors can lead to premature birth, which increases the risk of the risk of asthma, independent of prematurity itself. Finally, prenatal factors might increaseasthma. Apart the risk from of influencingasthma via theprematurity, risk of prematurity, and remaining prenatal exposure factors post-partum, can increase e.g. tobacco smoke, can further increase the risk of asthma [89]. Chorioamnionitis is a well-known cause of preterm delivery but has also been described as an independent risk factor for wheezing [91] and for physician- diagnosed asthma [92]. The risk of pulmonary diseases, including asthma, is probably higher if prematurity is caused by chorioamnionitis. Many studies that investigated the possible association between prematurity and asthma have not included chorioamnionitis in their analysis, which might explain the different results [93]. 25

PrematurelyExposure to borntobacco children smoke run contributesan increased torisk prematurity of severe respiratory and low syncytialbirth weight, virus but(RSV) also infections. increases Bronchiolitis susceptibility caused to RSV by infection RSV infection [94]. isThe a riskrelation factor between for asthma. RSV infection and an increased risk of asthma attenuates by time. More recently, several studies have also pointed out human rhinovirus as a strong predictor of asthma in schoolchildren [95].

Changesdecreased in prevalenceneonatal care of asthmamight influence among children the risk bornof respiratory very prematurely morbidity, [96]. including Signsasthma. of chronic It is plausible lung disease that the among introduction prematurely of surfactant born children treatment may persist has led until to a been shown that bronchial hyper-reactivity and impaired lung function can persist untiladulthood the teen and yearsis especially in infants common born amongbefore childrengestational developing week 28 BPD [98, [97].99]. ItMany has studies that have investigated the possible association between prematurity and respiratory problems have focused on early infancy. Few epidemiological studies have concentrated on the importance of prematurity as a risk factor for asthma and bronchitis among teenagers [99, 100] and young adults [16, 101, 102]—and results have been ambiguous. A lack of control for social status, exposure to tobacco smoke, and respiratory tract infections might have contributed to the different results in these studies.

1.7 Asthma heredity

The accumulation of asthma disease in certain families has led to intensive research about the heredity of this disease and its predictive power in identifying individuals almost a third of 1,472 school beginners in the municipality of Linköping, Sweden, at risk. In the late 1970s, Kjellman demonstrated a family history of atopic disease in association between family history of asthma or atopy and childhood asthma. Despite methodologicalevaluated by questionnaires differences between[103]. Since studies, then, familymany studieshistory haveof asthma investigated has been the the potential association of asthma heredity and asthma in adults. identified as a strong predictor of asthma risk [104]. Few studies have investigated seems to be important in the process [105, 106]. However, the fetus shares an environmentAlthough it is withunclear the how mother. asthma This is might inherited, explain both why maternal maternal and asthma paternal tends influence to be where gene expression is determined by an imbalance between the maternal and the paternalmore important allele, has than been paternal discussed asthma as the [106]. reason Imprinting, for a maternal an epigenetic dominant mechanism, inheritance of asthma [107, 108]. Twin studies have shown a possible asthma heritability of up to 60–70%, and heredity seems to be extra important for disease severity [109]. The large variability in the asthma phenotype might be an expression of the variability in genetic factors that determine the development of asthma. Gene-environmental 26 interaction has been a key concept in the elucidation of genetic susceptibility and

Althoughenvironmental a family influences history ofthat asthma finally has lead been to clinical shown disease to be strongly [17, 109, associated 110]. with asthma in childhood, it fails to identify the majority of children at risk [104].

1.8 Immunoglobulin E

Immunoglobulin E (IgE) is one of five isotypes of human immunoglobulins and is produced by plasma cells. Plasma cells normally produce IgM, and it requires different mediators (e.g. interleukin-4 and -13) and cell surface interactions between representB and T cells the toinfant’s induce baseline synthesis production of another at immunoglobulin birth. Contamination isotype with [111]. maternal IgE is not transferred via the placenta, and cord blood IgE (CB-IgE) levels are believed to the infant’s atopic predisposition [112]. This has to be taken into account in studies blood, however, might influence the validity of CB-IgE levels as a measurement of investigating the role of CB-IgE for the development of atopic diseases. Total IgE levels increase from birth and peak in teenage years [113]. The levels of total IgE in human milk are insignificantly low [114], but an association between levels of IgE in mothers and their infants has been reported [115].

CB-IgE has previously been studied as a predictor of asthma and other allergic diseases, with conflicting results [116-121]. A Danish study showed no correlation between high levels of CB-IgE and allergic disease at 18 months of age [118]. In the same birth cohort, a significantly greater number of children with elevated cord blood IgE levels developed allergic disease before 5 years of age [122]. In an alAmerican investigated birth a cohort,birth cohort elevated of 200 CB-IgE consecutively was identified born children as a risk and factor concluded for allergic that sensitization at ages 4 and 10 years, and asthma at 10 years of age [120]. Pesonen et diseasesan elevated until CB-IgE adulthood. level predicts Moreover, subsequent the number atopy of up individuals to the age in of the20 yearsstudies [119]. that Few studies have investigated the potential correlation between CB-IgE and atopic [121]. Many studies have concentrated on high-risk infants only [116]. have been conducted was often quite low [119], and follow-up rates were poor

1.9 Migration causes of the differences observed [56, 57, 123, 124]. Rapid changes in asthma prevalenceThe global over variation a short in period asthma of prevalencetime [125] and has geographical raised many differences questions aboutin asthma the prevalence within the same ethnic group [126, 127] can hardly be explained by genetics alone. To disentangle the genetic and environmental causes, studies on migrating populations can act as a natural experiment, as these populations 27 experience faster changes in lifestyle and environment than a more homogenous population does [128]. Studies often deal with population groups emigrating from high disease prevalence [129-131]. An increased prevalence of asthma has been low-prevalence, poorly developed regions and countries to an affluent region with Farm studies have delivered evidence that protective exposures might already act in uterolinked [133]. to urbanization, affluence and changes in diet and microbial contacts [132]. Migrants adapt to a different extent to lifestyles in their new environment, and protective factors related to exposures in their birth environment weaken with duration of residence in their new environment. Migrant studies provide an macro-environments, as recently pointed out by Kuehni in an editorial [134]. opportunity to investigate the influence of early life conditions such as micro- and Since 1970 most immigrants in Sweden are refugees or relatives of refugees. Foreign- born adoptees differ in several aspects from other immigrants. Many children are adopted from orphanages into mainly higher social class families, and the children adapt rapidly to the Swedish lifestyle of their host family.

1.10 Immunization that a lack of infections during early infancy might increase the risk of asthma and allergicThe ‘hygiene diseases hypothesis’, because whichof lower was exposure first proposed to microorganisms by Strachan in [135]. 1989, Differentsuggests causal explanations have been discussed, all leading to a shift in immune regulation and response that results in an increased susceptibility to asthma and allergic diseases [136]. diseases, common childhood vaccinations have been suspected as a possible cause As a consequence of the ‘hygiene hypothesis’ and the absence of certain infectious investigations have focused on the role of pertussis or combined diphtheria- of the increase in asthma and allergic diseases in affluent countries [137]. Several have found an increased risk of asthma and atopic disease in certain age groups after pertussis-tetanus (DPT) immunization, with contradictory results. Earlier studies effect against atopic disease among immunized children [141-144]. More recent pertussis or DTP vaccination [137-140]. Other studies even proposed a protective asthma [145-147], including the only randomized controlled trial published so far studies did not find any association between pertussis vaccination and the risk of

[148]. In most of these previous studies a whole cell pertussis (wP) vaccine was used. Acellular pertussis (aP) toxin has been shown to induce a strong specific IgE response, above all after a booster when originally vaccinated with an aP vaccine why[149, a 150]. connection An association between between pertussis total vaccine IgE and and specific the development IgE to pertussis of asthma toxin andhas allergiesbeen described might be for suspected. wP vaccine especially in children with atopy [151], which is 28

Although there is no convincing evidence for the association between early infancy immunization against pertussis and asthma or atopic disease later in childhood, vaccines in the development of allergic diseases [153, 154]. Due to methodological incongruence[152] it seems betweentoo early tothe finally different discard studies, the possible further causal investigations or contributory on a rolelarger of seems particularly important as parental fear concerning vaccine safety and the riskscale of that developing are well-controlled other diseases for has possible been biasrecognized have been as a requestedmajor obstacle [155]. to This the immunization of infants [156, 157]. 29

2 AIMS OF THE THESIS

The general aim of this study was to investigate different pre- and postnatal factors medication was used as a proxy for asthma. that might influence the long-term development of asthma. Dispensation of asthma

The specific aims of each individual paper were: 1 To examine the potential effect of gestational age in general and the degree of prematurity on dispensation of inhaled corticosteroids as a proxy for

asthma in children aged 6–19 years (Paper I). childhood were associated with, and could predict, allergy-related 2 respiratoryTo assess whether symptoms CB-IgE and levels dispensation and a family of asthma history medication of asthma at in 32–34 early

3 Toyears sort of outage (Paperthe independent II). effects of population of origin and age at immigration/being born in Sweden on dispensation of asthma medication at the age of 6–25 years in international adoptees, raised by Swedish-born parents, and children raised by their foreign-born birth parents

4 To(Paper determine III). whether pertussis immunization in infancy contributes to a

higher rate of dispensed asthma medication at the age of 15 (Paper IV). 30 31

3 MATERIAL AND METHODS

3.1 Study population

3.1.1 Cohort I (Study I) The study population was created from the 1,142,806 children born in Sweden during 1987–2000 according to the Swedish Medical Birth Register. All infants

Swedish Multi-Generation Register, and being residents in Sweden on December 31, fulfilled the criteria of being offspring of two Swedish parents, according to the in2005 Sweden according [128]. to the Register of the Total Population. Offspring of foreign-born Fromparents this were population excluded we because excluded of 33,183 the influence children of who ethnicity had at leaston asthma one malformation prevalence malformations (undescended testicles, pre-auricular appendage and congenital (ICD-10 Q00–Q99) reported at birth by the attending pediatrician. However, minor exclusion from the study. Moreover,nevus) and 8,797 hip children dislocation with were a registered considered birth insignificantweight for gestational and did notage above lead to3 SD or less than -6 SD, according to the growth chart developed by Maršál et al [158], were excluded as probable coding errors [159], leaving 1,100,826 individuals to be included in the study population.

3.1.2 Cohort II (Study II) The study is based on a follow-up of a Swedish asthma and allergy birth cohort containing all infants consecutively born from December 1, 1974 to December

1,701 were able to be enrolled in the original study. Development of asthma and 31, 1975 at Linköping County Hospital. Of 1,884 infants born during that period, separately and in combination, was investigated on different occasions [73, 160- allergic disease in relation to both CB-IgE and family history of asthma or atopy, diagnosis at the age of 6–7 years and at 10–11 years was taken from the original 162]. Information about the asthma heredity status of the study population, asthma paper charts. Information about CB-IgE values was extracted from the original Figure 2: The original magnetic magnetic tape the data were stored on (Figuretape 2). from which parts of the data were extracted. 32

population to investigate the current asthmatic and allergic status of these now In 2007 we conducted a questionnaire-based follow-up of the original study adult individuals. Almost all former study participants could be identified by their PIN. Forty-five individuals had to be excluded as either no valid address could be located or their PIN turned out to be incorrect. A total of 1,238 (72.8%) answered the postal questionnaire. An additional 11 individuals had to be excluded for various reasons, leaving 1,227 individuals (72.1%). Drug Register and the Swedish Medical Birth Register. The registers linked to 1,661 In a second phase the same study population was linked to the Swedish Prescribed

3.1.3(97.6%) Cohort individuals III (Study at III) the age of 32–34 years (Figure 3). All individuals born during 1980–2000, who were alive and registered as residents in

Multi-GenerationSweden on December Register. 31, 2005 were identified in the Register of the Total Population. The biological and/or adoptive parents of these individuals were identified in the

Information about region of birth, date of immigration, sex and year of birth in the Total Population Register was linked to the study subjects and their parents. Based on this information we identified three categories of residents with a non-Swedish twobackground: foreign-born (1) international parents. We adoptees; selected (2)four residents regions bornof origin outside where of Sweden there were who considerableimmigrated to numbers Sweden of with children their inparents; all three and categories; (3) residents Eastern born Europe, in Sweden East Asia,with South Asia and Latin America. Eastern Europe included the former Eastern Bloc countries, excluding Yugoslavia; Latin America included all countries in the Americas

Thissouth population of the USA; included South Asia 24,252 included international India, Pakistan, adoptees Sri withLanka two and Swedish-born Bangladesh. adoptiveEast Asia parents,included 47,986 all Asian foreign-born, countries east and of 40,971 the Indian Swedish-born peninsula. with two foreign- born parents. To this population we added 1,770,092 Swedish-born residents with two Swedish-born parents as a comparison group. The age of the study subjects ranged from 6 to 20 years.

3.1.4 Cohort IV (Study IV) controlOur study group population we included is based 98,475 on more children than 80,000 born duringformer participantsa 6-month period in an efficacy before andtrial afterof aP the vaccines vaccination that has trial previously and who beenwere describednot offered in pertussis detail [163, immunization 164]. As a as there had not been general pertussis vaccination in Sweden for 14 years at that time. Another 21,485 children who were born during the vaccination trial but who were not vaccinated for several reasons were included as a control group in certain analyses (Figure 4). 33

1,884 children born Dec 1, 1974 –Dec 31, 1975

1,701 available for CB-lgE Questionnaire data Register data

45 excluded: 19 excluded: could not be tracked could not be register-li nked

1,666 eligible for follow-up (97.9%) 1,682 eligible for follow-up (98.9%)

22 excluded: did not want to participate 1,644 (96.6%) 10 excluded: deceased 406 excluded: did not answer

1,238 (72.8%) 4 excluded: CB-IgE 10 kU/l or 6 excluded: not documented CB-IgE 10 kU/l ≥ 3 excluded: ≥ inconsistent answers 5 excluded: CB-IgE not

4 excluded: documented could not be register-linked

1,227 1,661 with QN + register data register-linked (72.1%) (97.6%)

Figure 3: Flow chart of the study population in Study II. CB-IgE = Cord blood immunoglobulin E; PIN = Personal identification number; QN = Questionnaire 34

Time of birth 1993 1994

Non-vaccinated 21,485 children

Non-vaccinated Non-vaccinated 1 46,217 children Vaccinated 79,705 children 52,258 children

Jun 30

Jan 1 Jun 1 Dec 31 May 31 Dec 31 Jan 1 Dec 31

Measurement of dispensed asthma medication

2008 2009 2010

Figure 4: Timeline of the study population in Study IV with respect to time of birth, vaccination status and dispensed asthma medication at 15 years of age. 134 individuals were registered as vaccinated outside the vaccination period.

counties, except the city of Gothenburg and 10 surrounding municipalities were eligibleIn brief, forinfants enrolment born between in the initial June 1,trial, 1993 as and were May infants 31, 1994 born in between 22 out of June 24 Swedish 1, 1993 and June 30, 1994, in Malmöhus county, Sweden (Appendix 11.2). byInfants a CHC were physician/study enrolled in the physicianstudy at 1–3 at weeks6–8 weeks of age of if theyage, wereand if residing parental within consent the defined study areas, were registered at the child health center (CHC), were examined other circumstances that could interfere with communication and follow-up; if they plannedwas obtained. to move Children out of thewere study excluded area within because one of year; parental if they language had certain difficulties known or suspected chronic diseases according to the following contraindications—serious neurological disease, uncontrolled epilepsy/infantile spasms, treatment with chronic illness (with signs of cardiac or renal failure or failure to thrive), progressive post-partum.gammaglobulin, immunosuppression due to treatment or disease, HIV, previous culture-confirmed pertussis; or if the first vaccine dose was given later than 92 days vaccines at ages 3, 5 and 12 months according to the Swedish vaccination schedule Infants were vaccinated with a series of three intramuscular injections with DTP 35

2, 4 and 6 months. As different vaccines were compared in the initial study, infants for DT at that time. In two counties the trial DTP vaccines were given at the age of roughlyenrolled the in thesame study size. were vaccinated with a two-, three-, five-component acellular DTaP vaccine or a whole-cell DTwP vaccine. The four different vaccine groups were The cohort was linked to the Swedish Medical Birth Registers and the Swedish of birth, parity, maternal age at childbirth, maternal body mass index and smoking habitsPrescribed in early Drug pregnancy,Register using mode the of PIN. delivery, Information maternal concerning diseases mother’s and pregnancy country complications, malformations, gestational age and birth weight were obtained from the Swedish Medical Birth Register.

We excluded 1,331 individuals from the analyses who were deceased at the time the register data were retrieved. We also excluded 4,998 children with at least one

(undescended testicles, pre-auricular appendage, congenital nevus and hip malformation reported at birth (ICD-9 740–759). However, as minor malformations included. Another 1,042 individuals were excluded for different reasons, leaving a dislocation) were considered insignificant, children with these conditions were total of 199,665 individuals at the age of 15 years for the analyses (Figure 5).

207,036 infants eligible

Non-vaccinated Vaccinated

124,244 20,719 20,674 20,704 20,695

1,152 deceased 42 41 58 38

12 missing municipality code 20 23 29 19

3,120 major malformations at birth 480 485 457 456

missing in SMBR 253 224 232 230

98,475 21,485 19,924 19,901 19,928 19,952

Figure 5: Flow chart of the study population in Study IV, children born January 1, 1993 to December 31, 1994 in the study area divided in non-vaccinated and vaccinated. SMBR = Swedish Medical Birth Register 36

Table 1: List of ATC codes used in Studies I-IV for definition of the outcome variable dispensed asthma medication. ANY = any asthma medication; ICS = inhaled corticosteroids; ANTI = anti-inflammatory treatment.

Study I Study II Study III Study IV Time period 2006 2006-2008 2006 2008-2010

dispensed prescriptionsNumber of ≥1/year ≥2/3 years ≥1/year ≥1/year

variable Outcome ANY ICS ANY ANTI ICS ANY ANTI ATC code Substance

R03AC02 Salbutamol X X X

R03AC03 Terbutaline X X X

R03AC12 Salmeterol X X X

R03AC13 Formoterol X X X Salbutamol + R03AK04 X X X X X X others Salmeterol + R03AK06 X X X X X X others Formoterol + R03AK07 X X X X X X others

R03BA01 Beclometasone X X X X X X X

R03BA02 Budesonide X X X X X X X

R03BA05 Fluticasone X X X X X X X Mometasone R03BA07 X X X X X X X furoate R03BA08 Ciclesonide X X Sodium R03BC01 X cromoglicate R03CC02 Salbutamol X

R03CC03 Terbutaline X

R03DC03 Montelukast X X X X X 37

3.2 Study variables (Studies I–IV)

3.2.1 Outcome variables Dispensation of asthma medication was used as a proxy for asthma diagnosis in all four studies. The information on asthma medication was based on data from the

DataSwedish about Prescribed the dispensation Drug Register. of anti-asthmatic All study individuals drugs werewere linkedrecorded to the according register using their PIN.

2 to their corresponding Anatomical Therapeutical Chemical (ATC) code. Codes 2-agonists and other drugs that were used in the different studies included selective β -agonists (R03AC), inhaled corticosteroids (ICS; R03BA), combinations of β Differentfor obstructive drug airwayvariables disease were (R03AK04 created through(any asthma R03AK07) medication, and leukotriene inhaled antagonists (LTRA; R03DC03). codes from the register. The combination of variables differed slightly between the fourcorticosteroids, studies and anti-inflammatory is displayed in Table treatment) 1. using different combinations of ATC

3.2.2 Questionnaire data respiratoryIn the follow-up symptoms study as(Paper well as II) nose-eye former participants symptoms and in askin birth symptoms cohort were (Appendix asked to answer a postal questionnaire with a total of 20 questions regarding different smoking habits, current and former occupation, dietary and physical habits and 1). Additionally, the questionnaire contained questions about current and former coughresidential due statusto contact (“Having with livedpollen on from a farm”) trees during or grass?” the first or five“… due years to ofcontact life. with furredA positive pets?” answer was used to the as questiona marker “Doof respiratory you become symptoms breathless, resulting start to from wheeze contact or with pollen or furred pets.

3.2.3 Confounding factors of different confounding variables on our outcome variables, asthma medication Data from different national registers were used to control for the potential influence

(Studies I–IV) and reported respiratory symptoms (Study II). In Study II additional indata the from analysis. the postal Table questionnaires 2 displays the were different available variables for the used cohort in the (current corresponding smoking, studiesresidential and status their source. during the first five years of life and fish diet), which were used 38

Table 2: List of study variables used in Studies I-IV.

VARIABLES SOURCE OF DATA DEFINITIONS/DESCRIPTIONS STUDY

Gestational Age Swedish Medical Birth Register measurements in early pregnancy (weeks Mainly (70.1%) according to ultrasound I, II, IV

10-18); remaining: reported last menstrual SGA Swedish Medical Birth period (II = reported last menstrual period) Register by Maršál et al (based on intrauterine Study I: <-2 SD according to scale created I, II, IV

sex,ultrasound birth weight, measurements) gestational [158] age (weeks, Study II, IV: dichotomized; calculated using LGA Swedish Medical Birth Dichotomized; calculated using sex, birth days) similar to Study I Register II, IV weight, gestational age (weeks, days) Cesarean delivery Swedish Medical Birth similar to Study I Register Dichotomized (yes/no) I, II, IV Asphyxia Swedish Medical Birth Register Apgar score ≤7 at 5 minutes I, II, IV Multiple birth Swedish Medical Birth Register Dichotomized (singleton = yes, no singleton I Chorioamnionitis Swedish Medical Birth = no) Register Maternal diagnosis at birth = O41.1 (ICD- I Maternal smoking Swedish Medical Birth 10) Register clinicInformation after 8 routinelyto 12 weeks’ collected gestation. by midwife I, IV at the first visit to the maternity health cigarettes/d, and missing Categorized into no, 1–9 cigarettes/d, ≥10 Respiratory Syncytial Swedish Hospital Virus Discharge Register 1987–2005 ≥1 discharge with diagnosis J12.1 or J20.5 I, IV (ICD-10) before 12 months of age Maternal education Highest formal education attained by each Education Register Swedish National no longer a Swedish resident, we reported I, III paternalindividual education up to 2005. if possible. If the mother Categorized was

by years of education into ≤9, 10–12, 13– Maternal age Swedish Medical Birth Categorized in years 12–19, 20–24, 25–29, 14, ≥15 and missing Register I, II, IV Social assistance Total Enumeration Cash income allowance from local social 30–34, 35–39, ≥40 authorities after a thorough means investigation to guarantee the applicant a I, III Income survey of 2005 minimum standard of living Maternal/paternal asthma medication Drug Register starting with R03 during 2006 Swedish Prescribed Study I: ≥1 dispensed drug with ATC code I, IV

codeStudy according IV (maternal to Table asthma 1 only): ≥1 dispensed drug (ANY, ICS, ANTI) with ATC Family history of At least one of the parents or a sibling was asthma cohort reported to have asthma (data collected on Original data birth enrolment to the birth cohort at 18 months II

of age) 39

Table 2: continued

VARIABLES SOURCE OF DATA DEFINITIONS/DESCRIPTIONS STUDY

Geographical Register of the Total residency Study I: Dichotomized (urban/rural) I, III Current smoking Population Study III: large city, other city and rural Residential status Dichotomized “Having lived on a farm Postal questionnaire Dichotomized (yes/no) II Postal questionnaire II Fish diet Categorized as never, 1–2x/week and >2x/ during the first 5 years of life” (yes/no) week Postal questionnaire II Season of birth cohort Original data birth Categorized as winter (Dec–Feb), spring II (Mar–May), summer (Jun–Aug) and fall Mother’s country of Swedish Medical Birth (Sep–Nov) birth Register Dichotomized: II, IV Study II = Scandinavian/Other, Swedish Medical Birth Study IV=Swedish/Other Register Parity Categorized as 1, 2, 3, ≥4 or missing I, II, IV cohort Cord blood IgE Original data birth Dichotomized (<0.9 kU/l, ≥0.9 kU/l) II Mother’s body mass Swedish Medical Birth Continuous variable index Register IV Swedish Medical Birth distress Register Neonatal respiratory Dichotomized (yes/no) according to IV neonatal diagnosis 768–770 (ICD-9) 3.3 Statistical analyses

The statistical analyses were performed using PASW statistics 18 for Windows Release 18.0.1 (SPSS Inc, Chicago, IL) or IBM SPSS Statistics for Windows Release 19.0.0, respectively, in Studies I-III, and partly in Study IV. All remaining analyses in Study IV were performed using R statistical software version 2.14.2 (Vienna, Austria) [165].

Logistic regression was used to calculate odds ratios (OR) with 95% confidence controllingintervals (95% for numerous CI) as estimates potential of confounders. effect with asthma medication (Studies I–IV) and self-reported respiratory symptoms (Study II) as the outcome variable while 3.3.1 Study I

In Study I we used four models to investigate the effects of preterm birth on girls,dispensed decreasing ICS. Age with was older entered age inas boys a continuous and increasing variable with in olderall models age in according girls, we includedto the age an profile interaction of ICS termdispensation. of age*sex As in the all agemodels. profile Model differed 1 was between adjusted boys for andage assistance, parental asthma medication and maternal smoking during pregnancy and sex only. In Model 2 we added county of residence, maternal education, social as confounders. In Models 3 and 4 we investigated potential mediating variables 40 by adding the potential perinatal mediators SGA, chorioamnionitis, multiple birth, asphyxia and cesarean delivery in Model 3, and hospital admission due to RSV infection in Model 4.

3.3.2 Study II dispensed self-reported respiratory symptoms and anti-asthma medication, respectively,Chi-square test and was to compare used for basic bivariate characteristics comparisons of the between study CB-IgEpopulation level with and respect to the two different outcomes measured. Fisher’s exact test was used instead, positive predictive value and positive likelihood ratio were calculated following standardin case there statistical were cells measures with expected [166]. counts of less than five. Sensitivity, specificity, history of asthma on self-reported respiratory symptoms and the dispensation of anti-asthmaticWe used two models medication to investigate at the age the of role 32–34 of elevated years. BothCB-IgE models and a positivewere adjusted family for sex, season of birth, maternal age, SGA, LGA, gestational age, mother’s country of birth, cesarean section and parity. When analyzing the role of self-reported respiratory symptoms we added current smoking, having lived on a farm during the first five years of life and fish consumption per week as covariates in the model. at 10–11 years of age and asthma medication at 32–34 years of age was evaluated usingThe flow common of the studycontingency population tables. with respect to asthma diagnosis at 6–7 years of age,

3.3.3 Study III

All models were adjusted for residency (large city, other city and rural) and for sex. includedAge was entered maternal as education a continuous and variable the socio-economic with an interaction indicator, term social age*sex assistance. reflecting the linear age pattern when each sex was analyzed separately. The final model also 3.3.4 Study IV vaccinationWe performed as registeredtwo main typesin the of initial analyses: trial anwith intent non-vaccinated to treat analysis children (ITT) with and no a per protocol analysis (PP). In the PP analysis we compared children who received regard to vaccination period. In the ITT analysis all children born in the vaccination 6period, months regardless before and of whetherafter the theyvaccination were immunized period. (n=79,705) or non-immunized (n=21,451) children, were compared with non-vaccinated children born during the analyses. To disentangle potential confounding factors in this study, a Directed The influence of confounders was deemed to be different for these two types of described before and will only be outlined here [167]. A crucial assumption in the DAGAcyclic is thatGraph there (DAG) are was no causalused (Figure relationships 6). The in technique the data otherof using than DAGs those has drawn been 41

Confounders 1 Confounders 2

Pollen count Attitudes

Infections during Access to health care infancy Demographics Demographics etc. etc.

Time of Vaccination Vaccination Asthma Prescription birth schedule

Figure 6: Directed Acylic Graph illustrating confounding in Study IV. as directed arrows into the graph. An arrow, however, does not imply that a causal relationship is present.

scheduleInstead of andonly prescription.investigating theThis association setting allowed between us vaccination to avoid certainand prescription types of confounders,(PP analysis), described we initially as studiedConfounders the relationship 2 in Figure between 6. This intendedmethod of vaccination avoiding confounders is referred to as “intent to treat” in the clinical trials setting. Treatment was allocated deterministically based on time of birth. Controlling for time of birth per se was not possible here, as at every point in time only one of the alternatives to control for the variables described in Confounders 1 in Figure 6. We also tested whether(offer vaccination/do time period was not associatedoffer vaccination) with the was potential available. confounders. Instead, we Spring had to1993 try

Confounders(non-vaccination 1 includes period) variableswas compared that withmight spring have 1994changed (vaccination during the period), two-year and periodfall 1993 from (vaccination which the cohortperiod) was with collected. fall 1994 The (non-vaccination vaccination schedule period). was performed so that seasons were similar for vaccination and non-vaccination periods; thus seasons could be omitted from the analysis. Other factors, such as pollen counts and 42 circulation of infections, may have changed during the two years, but have not been measured in this study. confoundersFor the PP analysis, measured additional were associated variables suchwith asnon-compliance attitudes toward in healththe vaccination care may period.act as confounders (Confounders 2 in Figure 7). We checked which of the potential

For the ITT analysis, all confounders that were statistically associated with time Confoundersperiod were included were added in the one multivariate at a time and analysis. all simultaneously For the PP analysis, for each all confoundersscenario. statistically significant2 test was usedfor one to analyze or both categorical of time period data onand the compliance univariate associationwere used. between vaccination status and potential confounders and asthma medication. For continuousPearson’s chi variables, a Wilcoxon test was used. A logistic regression model was size for vaccination on asthma medication while controlling for numerous potential confounders.used to calculate odds ratios (OR), with 95% confidence intervals (95%CI) as effect

4 ETHICAL STATEMENTS

Regional Ethical Review Board in Linköping, Linköping University, approved all Study I was approved by the Regional Ethical Review Board in Stockholm. The procedures and study protocols for Studies II–IV. Participants in Study II provided written informed consent by answering the postal questionnaires. The linkage of analyzeddata to the anonymously. National registers was approved and performed by the National Board of Health and Welfare and did not require any verbal or written consent as data were 5 RESULTS

5.1 Prevalence

The prevalence rates for anti-asthmatic medication varied between the different studies (Table 3). The prevalence of dispensed inhaled corticosteroids in Studies I, II and IV ranged from 3.16% to 4.89% depending on sex and age. In Studies I and III we mainly used ICS (ICS alone or as a combination with other drugs) as the outcome measurement (dispensation period 2006). In Studies II and IV we included all combination medicines (R03AK) as well as leukotriene receptor antagonists (R03DC03) in the variable “anti-inflammatory medication”, above all as montelukast dependingbecame more on frequentlysex and age. used in recent years (dispensation period 2006–2008 and Self-reported2008–2010 respectively). respiratory symptoms The prevalence associated rates with varied contact between with 3.58% pollen andand 4.53%furred pets were found to be 15.0% and 9.7%, respectively. Certain sex-associated variation has been noticed and is displayed in Table 3. 43

Table 3: Prevalence rates (%) for dispensed asthma medication (Stud- ies I-IV) and self-reported allergen-induced respiratory symptoms (Study II). ANY = any asthma medication; ICS = inhaled corticosteroids; ANTI = anti-inflammatory treatment (ICS + leukotriene antagonists); BETA2 = beta2-agonist; M = male; F = female 1≥ 1 dispensed prescription/year; 2≥2 dispensed prescriptions/3 years;

Study Age BETA2 Respiratory Respiratory symptoms symptoms ANY ICS ANTI (years) M F M F M F M F (pollen)M F (furredM pets)F

1 6–19 7.39 6.45 4.89 3.78

I 2 32–34 6.69 6.55 3.58 3.16 3.70 3.52 5.50 4.61 14.52 15.36 10.02 9.44

II 1 15 6.60 7.35 4.53 4.35 4.68 4.48 5.99 6.83

IV1 6–25 adoption/immigration and country of birth Prevalence rates of ICS differed between 1.4% and 10.4% dependent on mean age at III

5.2 Gestational age (premature birth)

Degree of immaturity showed an inverse dose-response relationship with dispensed prescribed ICS in the model adjusted for sex and age (Model 1). Compared with children born between 39 and 41 weeks of gestation, the OR for dispensed prescribed ICS increased with degree of prematurity, from 1.11 (95% CI 1.08-1.14) potentialfor children confounding born moderately factors prematuresuch as county (weeks of residence, 37–38) to maternal 2.23 (95% education, CI 1.93–2.58) social assistance,for children parental born extremely asthma medication premature and (weeks maternal 23–28). smoking Adjusting during the pregnancy model for had only marginal effects on the association (Figure 7). mediators such as SGA, chorioamnionitis, multiple birth, asphyxia and cesarean The ORs were slightly attenuated when adjusting the analysis for perinatal delivery (Figure 7, Model 3). The introduction of cesarean delivery contributed to the attenuation of the ORs in this model with an OR for cesarean delivery of 1.13 (95% CI 1.09–1.16) and 1.20 (95% CI 1.17–1.23) after removal of gestational age from the model. The addition of SGA and chorioamnionitis did not affect the ORs for gestational age. The ORs for SGA in models with and without gestational age were 1.06 (95% CI 1.00–1.12) and 1.16 (95% CI 1.10–1.22), respectively. Corresponding ORs for chorioamnionitis were 1.03 (95% CI 0.83–1.26) and 1.32 (95% CI 1.09– 1.61). 44

Figure 7: Odds ratios for dis- 2,5 pensed asthma medication (inhaled corticosteroids) by gestational age. Blue squares: ORs with 95% CIs after 2 adjustment for age and sex (Model 1). Red circles: ORs with 95% CIs after adjustment for age, sex, county of 1,5 residence, maternal education, social assistance, parental asthma medication, maternal smoking during pregnancy, 1 SGA, chorioamnionitis, multiple birth, asphyxia, and cesarean delivery (Model 3).

0 23-28 29-32 33-34 35-36 37-38 39-41

≥42 had been hospitalized for RSV infection. The addition of hospitalization due to RSV An increased prevalence of dispensed prescribed ICS was seen among children who

infection in the multivariate analysis, however, did not affect the ORs for gestational age (Model 4). 5.3 Cord blood immunoglobulin E

Elevated CB-IgE (≥0.9 kU/l) was found in 153/1,227 (12.5%) of the study participants levelswho answered ranged from the postaldetection questionnaires level 0.9 to 9.7 and kU/l 205/1,661 and were (12.3%) slightly of more those common who could in malesbe linked than to in the females. prescription register at the age of 32–34 years. Elevated CB-IgE

Respiratory symptoms were twice as common in those with elevated CB-IgE levels with a crude OR 2.01 (95% CI 1.33–3.05) for those reporting respiratory symptoms 45

respiratory symptoms due to contact with furred pets, respectively. Adjusting for potentialdue to contact confounding with pollenfactors and(sex, 2.03current (95% smoking, CI 1.25–3.31) having lived for in those a farm reporting during

SGA, LGA, gestational age, mother’s country of birth, cesarean section, parity and the first five years of life, fish consumption per week, season of birth, maternal age, positive family history of asthma) did not alter the associations significantly.

Elevated CB-IgE was associated with a 2–2.5-fold increased likelihood of dispensed asthma medication at 32–34 years of age. The crude OR for any asthma medication analysiswas 1.98 for (95% several CI 1.22–3.21)potential confounding and for anti-inflammatory factors (sex, season treatment of birth, 2.70maternal (95% age, CI SGA,1.50–4.89) LGA, gestational for individuals age, mother’s born with country elevated of CB-IgE.birth, cesarean Adjusting section, the multivariate parity and positive family history of asthma) changed the association only marginally (Table 4).

Table 4: Odds ratios (ORs) with 95% confidence intervals (95% CI) for the risk of respiratory symptoms and the risk of asthma medication (≥2 prescriptions/2006–2008) at the age of 32–34 years. 1Final model adjusted for sex, current smoking, having lived on a farm during the first five years of life, fish consumption per week, season of birth, maternal age, small for gestational age, large for gestational age, gestational age, mother’s country of birth, cesarean section, parity and positive family history of asthma. 2Final model adjusted for sex, season of birth, maternal age, small for gestational age, large for gestational age, gestational age, mother’s country of birth, cesarean section, parity and positive family history of asthma.

CB-IgE < 0.9 kU/l CB IgE ≥ 0.9 kU/l

Respiratory symptoms OR Crude OR (95% CI) Adjusted OR (95% CI) due to contact with 1 1 pollen 2.01 (1.33–3.05) 2.08 (1.34–3.22) Respiratory symptoms 1 due to contact with 1 furred pets 1.98 (1.18–3.32) 2.03 (1.25–3.31) Any asthma 2 1 medication 1.95 (1.19–3.20) 1.98 (1.22–3.21)

1 2 treatment Anti-inflammatory 2.70 (1.50–4.89) 2.64 (1.45–4.83) 46

5.4 Family history of asthma

Self-reported respiratory symptoms and the need of dispensed asthma medication for self-reported respiratory symptoms due to contact with pollen and due to contact were increased among those with a positive family history of asthma. The crude OR with furred pets were 2.38 (95 CI% 1.38–4.10) and 3.04 (1.68–5.51), respectively. For any asthma medication and anti-inflammatory treatment the corresponding rates were 2.75 (95% CI 1.55–4.87) and 2.72 (95% CI 1.30–5.70), respectively. Adjusting Tablefor different 5: Odds confounding ratios (ORs) variables with 95% changed confidence the estimatesintervals (95% only marginallyCI) for the risk(Table of re5).- spiratory symptoms and the risk of asthma medication (≥2 prescriptions/2006–2008) at the age of 32–34 years in relation to family history of asthma (FHA). CB-IgE = Cord blood immunoglobulin E 1Final model adjusted for sex, current smoking, having lived on a farm during the first five years of life, fish consumption per week, season of birth, maternal age, small for gestational age, large for gestational age, gestational age, mother’s country of birth, cesarean section, parity and elevated CB-IgE (≥ 0.9 kU/l). 2Final model adjusted for sex, season of birth, maternal age, small for gestational age, large for gestational age, gestational age, mother’s country of birth, cesarean section, parity and elevated CB-IgE (≥ 0.9 kU/l ).

Negative FHA Positive FHA

Respiratory symptoms due to OR Crude OR (95% CI) Adjusted OR (95% CI) 1 1 contact with pollen 2.38 (1.38–4.10) 2.28 (1.03–5.07) Respiratory symptoms due to 1 1 contact with furred pets 3.04 (1.68–5.51) 2.95 (1.59–5.49)

Any asthma medication 1 2

2.75 (1.55–4.87) 2.67 (1.49–4.78)

1 2

Anti-inflammatory treatment 2.72 (1.30–5.70) 2.59 (1.20–5.42) 47

5.5 Prediction of asthma were low for allergen-induced self-reported respiratory symptoms and asthma The predictive values of elevated CB-IgE or a family history of asthma at 18 months medication in this adult population (Table 6). The combination (“and/or”) of these two presumptive factors did not increase the predictive values sufficiently. If both factors were combined (“and”) the sensitivity (SE) for anti-inflammatory medication was 2, specificity (SP) 99 and positive predictive value (PPV+) 7. If either of the factors was positive (“or”), the corresponding numbers were SE 40, SP 83 and PPV+ 8. Table 6: Sensitivity, specificity and predictive values of elevated CB-IgE (≥ 0.9 kU/l) or positive family history of asthma (FHA+) for respiratory symptoms due to pollen or furred pets and asthma medication (≥ 2 prescriptions/3 years) at the ages of 32–34 years. CB-IgE = Cord blood immunoglobulin E; CB-IgE+ = Cb-IgE ≥ 0.9 kU/l; SE = sensitivity; SP = specificity; PPV = positive predictive value; LR+ = positive likelihood ratio. SE, SP and PPV given as percentages. FHA+

SECB-IgE+ LR+ SE LR+ Respiratory symptoms 20 89SP 24PPV 1.8 11 95SP 28PPV 2.2 due to pollen Respiratory symptoms 21 89 16 1.8 14 95 23 2.8 due to pets

Any asthma medication 21 88 11 1.8 15 94 15 2.5

27 88 8 2.3 15 94 8 2.5 medication Anti-inflammatory

treatmentFigure 8 shows at 32–34 the yearsflow of of different age. individuals with asthma diagnosis at 6–7 and 10–11 years of age as well as those with dispensed anti-inflammatory asthma

9Most cases of thehad cases been withdiagnosed dispensed with anti-inflammatory asthma on both follow-up treatment occasions at 32–34 in years childhood of age andhad hadnot beenbeen reporteddispensed having asthma asthma medication at the ageat 32–34 of 6–7 years or 10–11 of age. years The (49/60).proportion Only of individuals with elevated CB-IgE was higher in those who had asthma in childhood but had not been dispensed any anti-inflammatory asthma medication (no longer asthma) at the age of 32–34 years (36.7%) compared with those who had been dispensed asthma medication as adults (26.7%). 48

Birth 6–7 yrs 10–11 yrs 32–34 yrs

Never 1,661 1,6131 1,5901 1,541 Asthma

48 23 49

25 1

Asthma at 48 48 9 60 different ages

23 16 22 1

No longer 23 60 Asthma 22

Figure 8: Flow of individuals with asthma diagnosis at 6–7 and 10–11 years and anti-inflammatory treatment at 32–34 years of age. Corresponding individuals are marked with blue or red numbers describing individual flows over time. 1figures based on the total numbers of individuals linked to the Swedish Medical Birth Register (n=1,661). 49

5.6 Congruence between respiratory symptoms and asthma medication

Reported respiratory symptoms and dispensation of asthma medication prescriptions of any asthma medication and 71.4% of those who purchased at least corresponded only partly. In all, 65.3% of those with at least two dispensed due to pollen. The corresponding rates for respiratory symptoms due to contact withtwo prescriptions furred pets were of anti-inflammatory 52.1% and 56.1%, drugsrespectively. had reported Among respiratorythose with respiratory symptoms symptoms due to pollen, only 27.4% had purchased at least two prescriptions of drug. For those with reported respiratory symptoms due to contact with pets, the correspondingany asthma medication rates were and 33.0% 16.8% and at 20.0%, least two respectively. purchases of an anti-inflammatory

The rates were similar for agreement between self-reported allergen-induced respiratory symptoms and dispensation of beta2-agonists. The agreement between respiratory symptoms and asthma medication of beta2-agonists and anti- inflammatory medication (≥2 dispensations/3-year period) is displayed in Figure 9.

82 135

14 10 2 21 27 6 3

7 10 12 8 4

Figure 9: Proportional Venn diagrams illustrating the agreement between allergen-induced self-reported respiratory symptoms (pollen- and pet-induced respiratory symptoms) and asthma medication (beta2-agonists and anti-inflammatory medication). Venn diagrams generated with the help of Venn diagram online tool at http://venndiagram.tk/ provided by Dr Tim Hulsen (Radboud University Nijmegen, The Netherlands). 50

5.7 Migration with foreign-born parents compared with adoptees and children born in Sweden. Dispensation of prescribed ICS was less prevalent in foreign-born individuals

The ORs for dispensed prescribed ICS by region of origin after logistic regression with adjustment for sex and age were significantly lower in foreign-born children with foreign-born parents in all regions: Eastern Europe 0.34 (95% CI 0.25–0.57), East Asia 0.19 (95% CI 0.16–0.22), South Asia 0.31 (95% CI 0.27–0.36) and Latin medicationAmerica 0.48 varied (95% in CI Swedish-born 0.43–0.54) in individuals comparison with with foreign-born Swedish-born parents children compared with withSwedish-born the Swedish parents. majority In contrast, population. the Swedish-bornprevalence of individualsdispensed prescribed with parents asthma born in Eastern Europe had a decreased risk (OR 0.54) of dispensed ICS whereas those born in Sweden with parents born in South Asia had a slightly higher risk (OR 1.26).

Dispensation of prescribed ICS was less likely in adoptees from Eastern Europe than in Swedish-born individuals with Swedish-born parents (OR 0.27), but was higher in adoptees from all other continents (Figure 10).

EASTERNEastern EUROPEEurope

EASTEast ASIAAsia

SOUTHSouth ASIAAsia

LATINLatin AMERICA America

00 00.5.5 11.0.0 11.5.5 22.0.0 OR OR

Figure 10: Own and parental region of birth as risk factors for dispensed asthma medication. Odds ratios after adjustment also for age, sex and rural/urban residency (reference group = Swedish-born children with Swedish-born parents). Foreign-born with Swedish-born adoptive parents, Swedish-born with foreign-born parents Foreign-born with foreign-born parents 51

Among adopted individuals we investigated the relation between age at adoption association in the unadjusted model as well as in the models adjusted for region of and the dispensation of prescribed ICS and found an inverse dose-response birth, maternal education and received social assistance (Figure 11).

11.0.0

00.8.8

00.6.6 R O OR 00.4.4

00.2.2

0 0 00 11-2-2 33-4-4 55++ AGEAg eAT a tADOPTION adoption (y (YEARS)ears)

Figure 11: Risk of dispensed asthma medication by age at adoption. Blue 1squares.0 : unadjusted ORs with 95% CIs. Red circles: ORs after adjustment for sex, geographical residency (urban/rural) and region of birth. 0.8

0.6 R O LatinRegion America. of birth Thehad anassociation effect on thebecame likelihood somewhat of ICS weaker being dispensed, after adjustment with adoptees for age from 0 South.4 Asia having a higher risk (OR 1.26) compared with adoptees from assistance had only marginal effects on the association. at adoption (aOR 1.21). Adjustment for maternal education and receiving social Among0. 2non-adopted foreign-born children, age at immigration showed an inverse between adopted children and the age of adoption. Adjustment for region of birth dose-response0 relationship with dispensed prescribed ICS similar to the association 0-4 5-9 10-14 15+ had only a marginal effect onAg thise at associationimmigrati (Figureon (yea 12).rs) 1.0

0.8

0.6 R O 0.4

0.2

0 52 0 1-2 3-4 5+ Age at adoption (years)

11.0.0

00.8.8

00.6.6 R O OR 00.4.4

00.2.2

0 0 00-4-4 55-9-9 110-140-14 115+5+ AGEAg ATe a tIMMIGRATION immigration ( (YEARS)years) Figure 12: Risk of dispensed asthma medication by age at immigration. Blue squares: unadjusted ORs with 95% CIs. Red circles: ORs after adjustment for sex, geographical residency (urban/rural) and region of birth

Region of birth influenced the likelihood of ICS being dispensed differently for the different regions. In comparison with immigrants from Latin America, the likelihood Theof ICS association being dispensed between was lowerthe different in immigrants immigrant from all categories other regions. and dispensed foreign-bornprescribed ICS individuals after logistic with regression foreign-born showed parents a higher in riskthe modelfor adoptees adjusted (aOR for 3.94) sex, ageand andSwedish-born parental region. individuals with foreign-born parents (aOR 3.36) compared with

5.8 Immunization medication in all children born during the vaccination period compared with childrenThe ITT analysisborn during demonstrated the 6 months a slightly before reduced and duringlikelihood the of6 dispensedmonths after asthma the vaccination period in the univariate analysis. The association disappeared, however, after adjustment for confounding factors (Table 7). The type of vaccination schedule (2, 4 and 6 months or 3, 5 and 12 months) did not affect the association. 53

Table 7: Odds ratios (ORs) and 95% confidence intervals (95% CI) for the risk of dispensed asthma medication at 15 years of age (ITT analysis). 1Multivariate regression adjusted for maternal age, mother’s country of birth, cesarean section, maternal smoking, asphyxia, mother’s BMI, parity and mother’s asthma medication.

VaccinationITT analysis period

Non-vaccinated 1

Any asthma medication OR1 OR (95% CI) aOR (95% CI)

0.97 (0.93 – 1.00) 0.99 (0.95 – 1.03) 1

Anti-inflammatory treatment 0.94 (0.90 – 0.98) 0.97 (0.92 – 1.01) 2-agonists 1

β 0.97 (0.94 – 1.01) 0.99 (0.95 – 1.03) 1 WhenInhaled we corticosteroids compared all vaccinated children born0.97 in (0.91the vaccination– 0.99) 0.97 period (0.92 –with 1.01) all non-vaccinated children born both outside and in the vaccination period in the PP analysis, there was no significant association between pertussis vaccination and Asthmadispensed medication asthma medication was less likely (Table to 8).be dispensed in non-vaccinated children who Table 8: Odds ratio (OR) and 95% confidence intervals (95% CI) for the risk of dispensed asthma medication at 15 years of age (PP analysis). 1Multivariate regression adjusted for maternal age, mother’s country of birth, gestational age, cesarean section, maternal smoking, asphyxia, mother’s BMI, parity, mother’s asthma medication and child’s respiratory distress.

PPVaccinated analysis

Non-vaccinated 1

Any asthma medication OR1 OR (95% CI) aOR (95% CI)

1.01 (0.97 – 1.04) 0.99 (0.95 – 1.03) 1

Anti-inflammatory treatment 0.98 (0.94 – 1.02) 0.97 (0.92 – 1.01) 2-agonists 1

β 1.02 (0.98 – 1.06) 1.00 (0.96 – 1.04) 1

Inhaled corticosteroids 0.99 (0.95 – 1.03) 0.97 (0.92 – 1.01) were born during the vaccination period than in non-vaccinated children born outside any asthma medication was anti-inflammatory treatment the vaccination period. The crude OR for dispensation of confounding0.89 (95% CI factors. 0.84–0.94); the corresponding OR for was 0.87 (95% CI 0.81–0.94). These differences disappeared after adjustment for 54

2 Additional analyses using selective β -agonists and ICS alone showed similar results with a crude OR for dispensation of β -agonists of 0.88 (95% CI 0.83–0.94) and ICS of 0.87 (95% CI 0.81–0.94) respectively. After adjustment for confounding factors, Thethese type associations of pertussis also vaccine became and insignificant. the vaccination schedule did not affect the risk that asthma medication would be dispensed. 55

6 DISCUSSION

6.1 General methodological considerations

practicallyStudies I, III the and entire IV are Swedishbased entirely population on population-based in the particular register age datagroups, except which the presumablydata about immunization makes these insamples Study IV.representative In these data of sets these we managedage groups to ininvestigate Sweden. countries. Indeed, our findings might even be generalized to other similar populations in other Data from national registers enable us to investigate large sample sizes with high often struggle with these very parameters, resulting in small sample sizes and lowresponse response rates. rates. Other Although type of these studies, kinds e.g. of birthstudies cohort often orprovide case-control an opportunity studies, confounding factors, they tend to be vulnerable to selection bias. to collect extensive data with good quality about exposure and outcome as well as related to non-response as data can be analyzed anonymously. As registers in the In contrast, register-based studies are a useful tool for investigating selection bias and tax returns, it can be an advantage to use these data as they contain other informationNordic countries than alsoself-reported contain socioeconomic data. The use dataof data on areasfrom alike smaller occupations, study together income with data from national registers can sometimes solve the problem of missing data or decrease the loss of study participants, especially in long-term follow-ups like

Asthat register of our birthdata arecohort collected in Study prospectively II [168]. and independently from both the study exposureindividuals to andbe minimized. the research The question, enormous it isdata possible sets we to retrieved avoid several from typesthe registers of bias madesuch as it recallpossible and to selection adjust our bias. analyses It also forallows various the misclassificationconfounding factors of outcome that directly and

“instrumental” use of register data, however, often creates other problems. As we haveor indirectly to accept might “proxy” have data influenced as a measure our outcome of exposure variable, or outcome, asthma we medication. will often Theend of bias in the data. Moreover, when using proxy data for real confounders in a study, theup withrisk ofattenuated residual confoundingeffect measures increases [168]. [168,It is seldom 169]. Additionally, easy to measure certain the lifestyle extent factors, such as breastfeeding and current smoking, normally cannot be controlled for using register data.

Asthma medication as the primary outcome variable has its limitations [170]. register contains only information about dispensed asthma medication, and it is impossiblePrescription to data know lack exactly information whether about the diagnosispatient really or disease consumed severity. the Besides,drug [171]. the However, when a drug has been prescribed by a physician and purchased by the 56 patient, this could be interpreted as a reasonable marker of asthma diagnosis. We have concentrated our investigations on the groups between 6 and 34 years of age due to diagnostic problems and the risk of overtreatment in very young individuals [172]. asthma medication [173] and contribute to an under-diagnosis of asthma related Poor economic resources on the part of parents could influence the purchase of ratherto socioeconomic low maximum status. amount In Sweden per year there for is hisa reimbursement or her medicines. system We foralso medicines adjusted forthat various require socioeconomica prescription, variableshowever, whichin our meansanalyses, that but every this patient did not pays affect only the a association between measured exposure and asthma medication.

As dispensation of any asthma medication is not entirely equal to asthma diagnosis or symptoms, we mainly investigated the dispensation of ICS and LTRA as these gooddrugs, agreement especially betweenICS, are used register-based by a considerable prescription number data of onindividuals asthma medication, with active actualdisease drug [174] use and and are physician-diagnosedmore likely to present asthma clinically has significant been demonstrated disease [62]. inFairly the Scandinavian countries [175, 176]. A comparison of prescription databases in the the study of drug use and that the proportion of coding and data errors is very low [171].Nordic countries has shown that register data provide valid and reliable data for The rates of dispensed asthma medication in our investigations correlate fairly well with other studies about asthma prevalence in Sweden using other outcome variables [60-62, 177]. on different occasions [73, 161, 162]. Response rates differed slightly between The birth cohort in Study II has been followed during childhood and investigated inthe adulthood, previous follow-uphowever, couldand our be follow-upanonymoulsy at 32–34 linked years to the of Swedish age (≤ 10 Medical individuals Birth Register,between evenfollow if they up at might 6–7, not 10–11 have and been 32–34 included years). in all All follow-ups subjects during in the childhood. follow-up There might be individual subjects with an asthma diagnosis that we have missed of individuals with respect to both asthma diagnosis and medication, and elevated when investigating asthma prevalence over time in the birth cohort and the flow would be very small in relation to the whole study population, and the likelihood ofCB-IgE participation (Figure 8).is probably However, higher the number in subjects of thesewith asthma presumably than missingin those subjectswithout asthma. Therefore, we consider this a minor problem that should not interfere significantly with our results. 57

6.2 Premature birth of immaturity at birth in 6- to 19-year-olds. The multivariate analysis indicates that immaturityThis study showed per se seemsan increased to be the risk most of of importantICS dispensation factor dependingfor the effect on ofthe preterm degree

Lungbirth developmenton ICS dispensation is a continuous in children process and teenagers. that does not end with birth, but continues into childhood. Every week of maturation is important for the development of the lung, and curtailed pulmonary development as a result of preterm delivery leads to during the last trimester of pregnancy in particular, [179] making it plausible that a deficit in the structure and function of the lung [178]. Lung maturation is greatest of external harmful factors during this vulnerable period, plays an important role in thedamage increased due to risk unfinished of asthma lung medication development, in childhood possibly and combined adolescence. with the influence

The association found between the degree of prematurity and the dispensation of by Jaakola et al that showed stronger effects of prematurity in younger populations [89].asthma Another medication Swedish was study attenuated similar byto increasingours failed age.to show This an is effectin line of with prematurity findings on asthma medication in infants born after 28 weeks’ gestation [180], perhaps due to the older age group (25.5–35 years) that was investigated. increaseThe population for this in group our investigation was only 10% was but sufficiently accounted large for almost to detect 2% an of increased all cases onrisk a populationeven in individuals level as born 20% early of all term children after were 37–38 born weeks’ early gestation term. The (Figure group 7). of The infants risk born extremely preterm, however, accounted only for 0.2% of all cases.

Only a few studies have investigated the long-term outcome of asthma and late relatedpreterm to birth. late preterm A retrospective birth in a study cohort from of almost the USA 8,000 found children a significant 18 months increase of age [181].in persistent Another asthma retrospective diagnosis, cohort use study of ICS of and about number 71,000 of children acute respiratory in the USA foundvisits an association between late premature birth and recurrent wheezing at three years of age [182]. Investigations of long-term outcome, however, are rare [180]. study it was associated with a 20% increased risk of asthma medication. Some of Cesarean delivery has been desscribed as a risk factor for asthma [183]. In our after adjustment for gestational age. Unnecessary early deliveries should therefore bethe avoided effect, however, to prevent was the related increased to immaturity risk of asthma at birth later because in life. theStudies OR was have reduced shown use of labor induction and performing cesarean sections at 34–36 weeks’ gestation [184,that the 185]. increase in rate of late preterm births has been influenced by the growing 58

Chorioamnionitis is a common complication in pregnancy and contributes to preterm labor [28], but has also been described as an independent risk factor for wheezing [14] and physician-diagnosed asthma in early childhood [92]. We did not after adjustment for gestational age. The focus on school-aged children in our study, however,find that chorioamnionitisdoes not exclude contributedpotential effects to an on increased the need risk for ofasthma asthma medication medication in younger children. Furthermore, the setting of our study design probably detects into account. only severe cases of clinically significant chorioamnionitis, which has to be taken An association between socioeconomic disadvantage and both asthma and preterm birth was demonstrated in our study. Adjustment in our model for our resulted only in marginal effects, indicating that socioeconomic confounding was no majortwo socioeconomic problem in this indicators study. A (maternal more serious education methodological and social concernassistance), in this however, study is probably the regional variation in our outcome variable. There are differences in access to the health care system, with better access in urban areas than in rural areas. There might be a bias through regional patterns of access to care that overlap with regional rates of preterm birth and asthma prevalence. Adjusting for county variation failed to demonstrate any major effects. Therefore we believe that such bias was minor.

6.3 Cord blood immunoglobulin E and family history of asthma

We were able to follow up 72% of the former infants of the birth cohort by response rates in cohorts with a similar long-term follow-up [38, 186, 187]. Some otherquestionnaire birth cohorts at the haveage of shown 32–33 loweryears, whichresponse is comparable rates also into, follow-ups or even better at lower than, ages [75]. Moreover, almost 98% of the original cohort could be linked to the Swedish Medical Birth Register with information on different confounding factors and information

2008. about asthma medication from the Swedish Prescribed Drug Register from 2006– The two- to threefold higher risk of asthma medication being dispensed and a family history of asthma which we found in our analyses are consistent with the allergen-induced respiratory symptoms among individuals with elevated CB-IgE or results of similar investigations in pediatric populations [116, 117, 120]. Only two previous studies have investigated the association between CB-IgE and asthma and kU/Lallergic was disease associated in adults, with awith two- conflicting to threefold results increased [119, risk 187]. of allergicIn the Finnish symptoms study at by Pesonen et al. of 200 unselected full-term newborns, elevated CB-IgE above 0.5 the age of 20 years [119]. In contrast, Shah et al., who followed up 670 subjects in the Detroit Childhood Allergy Study, was unable to find any consistent association 59

Methodological variances may explain some of the differences. Continuous cut-off between elevated CB-IgE and asthma or other atopic diseases at 18–21 years [187]. in the two Scandinavian studies, including ours. Besides, the Finnish population is levels for CB-IgE were used in the Detroit study in contrast to the fixed cut-off levels between Scandinavian populations depending on the geographical distribution [188].probably Thus genetically the results more of thesimilar Finnish to ours, study although might be there more are comparable significant differencesto ours. As we no longer have access to the blood samples from our study population, we were unable to assess how analyses based on IgE measured as a continuous variable or lower cut-off levels for CB-IgE than 0.9kU/l would have affected the outcome.

High CB-IgE values could be the result of maternofetal contamination. A Danish cohort study of 200 children with maternal asthma suggested that maternal IgE antibodies contributed to high CB-IgE values in about 50% of all individuals with CB- otherIgE values studies over have 0.5 kU/l. suggested The suspected that maternofetal contamination contamination was based on of the cord detection blood ofis IgA and allergen-induced specific IgE in the sampled cord blood [112]. In contrary, uncommon. IgA antibodies were detected in less than 5%, even in mother-child pairs with high IgE levels against the same allergen. Low concordance between specific IgE in cord blood and maternal blood for inhalant allergens was demonstrated as an indicator of no significant maternofetal contamination. The agreement between specific IgE for food allergens in cord blood and maternal blood was much better. The authors interpreted their findings as an indication of sensitization already in utero, especially against food allergens. The high CB-IgE values were considered haveto be shownchiefly such the resultopposing of synthesization results. However, by thethey fetus differ and in severalnot due parameters, to maternofetal such ascontamination laboratory methods [189, 190]. for detecting It is not easythe different to elucidate immunoglobulins, why these different the method studies of the cohorts, just to mention some of the differences between the studies that might securing adequate cord blood samples from the neonates, and the characteristics of As we no longer have access to the original blood samples, we were unable to have influenced the different results. ofcontrol maternofetal for the proportioncontamination of IgAin our in cordstudy, blood, we excluded which issubjects more orwith less rather standard high procedure nowadays when investigating the role of CB-IgE. To account for the risk

18–24CB-IgE monthslevels (≥ was 10.0 reported kU/l) as in suggestedour birth cohortin a previous [160], indicating study [116]. that Furthermore, the majority good agreement between high CB-IgE levels and high total IgE levels at the age of of high IgE levels in cord blood are of fetal origin. This is similar to the findings in the Danish study. Bønnelykke et al found that children with elevated CB-IgE levels and indications of maternofetal contamination had significantly lower IgE levels at 6 months of age compared with children with elevated CB-IgE levels without indications of maternofetal contamination. Furthermore, elevated CB-IgE levels were not significantly associated with IgE levels at 6 months of age in samples with indications of maternofetal transfer of IgE after adjustment for maternal IgE levels. 60

which transfer was not indicated [112]. This was in contrast to a highly significant independent association for samples in We used information from the Swedish Medical Birth Register and the postal including season of birth, cesarean section, and gestational age. Controlling for thesequestionnaires different factors, to adjust however, our analysis changed for the different associations potential we found confounding only marginally. factors medicationElevated CB-IgE and respiratory and a family symptoms history of in asthma adulthood based in the on analysis.information collected in early life remained as highly significant and independent risk factors for asthma inexpensive,The use of questionnaires simple tool which to investigate can easily the be prevalence used in large of asthma surveys is [192],rather butcommon their in epidemiological studies, but might not be optimal [191]. Questionnaires are an subjective errors [193]. use is not unquestioned, mainly due to the risk of recall bias and other possible To increase the accuracy of our study, we also investigated the dispensation of asthma medication was less common than self-reported allergen-induced respiratory medication beyond the survey using postal questionnaires. Dispensed asthma 20–30% of those who reported symptoms had purchased any asthma medication. symptoms, and the two outcomes only partly overlapped (figure 9). Only about breathlessness or coughing. Some subjects might have reported non-asthmatic symptomsOur definition from the of airways, allergy-related and others respiratory probably had symptoms mild symptoms included without wheezing, need of medication. those who had purchased any asthma medication, which is in line with reviews indicatingIn contrast, that allergy-related only approximately respiratory 50% symptoms of all asthma were is reportedassociated by with 50–70% allergy of [194]. As mentioned above, the prevalence of our variable any asthma medication was fairly similar to prevalence rates of physician-diagnosed asthma in recent studies among young Swedish adults [60, 61]. The odds ratios for both outcomes is important to bear in mind that asthma is a disease with different phenotypes but alsowere different fairly comparable etiologies. even We saw though that they most were individuals markers who of partly had been different dispensed entities. anti- It inflammatory medication as adults had not had an asthma diagnosis in childhood measure(Figure 8),asthma which reveals underlines different the prevalence assumption rates that [195]. we are measuring different phenotypes of asthma. It is not surprising that the use of different methods to epidemiological studies, different measurements can, and should, be used as long asAs the there investigator is currently is aware no ‘golden of each standard’ measurement’s for the particular definition advantages of asthma and in disadvantages. 61

The predictive capability of our two investigated variables, CB-IgE and family history forof asthma, identifying was poor.individuals In line withat risk, other and previous the predictive studies ability in younger did not adults improve [119, 187],even neither CB-IgE nor family history of asthma was a sufficient screening parameter in utero, which is underlined by the higher proportions of individuals with elevated when both parameters were combined. CB-IgE might be a sensor for sensitization allergicIgE at birth asthma among are asthmaticsmore dominant in childhood in childhood compared years with [31], adult these asthmatics could have in been this expectedbirth cohort but (Figurehave not 8). been Bearing demonstrated in mind that so far different in adults phenotypes below 30 yearsof asthma of age. with

6.4 Migration

Migration studies may allow us to disentangle the effects of early environmental exposures from later environmental and socioeconomic influences after migration [134]. In this study we have compared the risk of asthma medication in three well- defined categories of migrants with Swedish-born children of Swedish-born parents. and age at immigration [129, 196-198] or duration of residence in the new country Previous studies have already shown an association between the risk of asthma between age at immigration and the risk of asthma medication in international adoptees[196, 199-201]. raised byIn Swedishour investigation parents, aswe well also as demonstrated foreign-born childrena negative raised relationship by their birth parents. from less developed regions with low asthma prevalence to a more developed region An increased risk of asthma is usually a consequence for children of all ages moving Asian women was the same regardless of whether they were born in the United with higher asthma prevalence. In a British study, the risk of asthma among South-

Kingdom or had immigrated before the age of five years, whereas South-Asian wewomen also migratingsaw a gradually after five declining years of likelihood age had aof considerably dispensed asthmalower risk medication of asthma, in which did not change with increasing age [130]. In our much larger study population asthmaindividuals among migrating immigrants after thefrom age the of former five years. Soviet This Union was in and line Ethiopia, with an butIsraeli not study from Westernthat showed Europe an inverse [198]. relation between age at immigration to Israel and the risk of

Adoptees had an almost fourfold increased likelihood of dispensed asthma medication compared with immigrants from the same regions of birth; the exceptions were two years of age whereas the mean age at migration among immigrants was around tenadoptees years fromin this Eastern study. Europe The highest (Figure likelihood 10). Most of thedispensed adoptees asthma were adopted medication before in young adults was seen in subjects who had immigrated in early infancy. Equally, 62 the protective effect on asthma medication of being born in low- or median-income regions was closely related to the duration of residency in the native country. A low level of cultural adaptation among immigrants may further counteract the effects of asthma-promoting exposures in the new society [202, 203], in contrast to adoptees who are rather instantly integrated into the Swedish lifestyle.

Eastern Europe than to adoptees from other continents and the Swedish majority population.It was less This likely could that be asthma explained medication to a large would extent be by dispensed the higher to age adoptees at migration from in adoptees from Eastern Europe.

Dispensed asthma medication was more common among adoptees from Asia and Latin America than in Swedish-born children with Swedish-born parents (Figure medical attendance [204]. Adoptive parents might be more eager to seek medical care10). Thisfor their might children, partly after be an a effectusually of long differences and time-consuming in behavior relatedadoption to process. seeking We found the highest rate of dispensed asthma medication in adoptees from South Asia. Similarly, children born in Sweden with parents born in South Asia had slightly increased odds for dispensed asthma medication compared with children born in Sweden to Swedish-born parents. This might suggest a genetic predisposition for asthma in the South-Asian population.

Studies on gene-environment interaction have demonstrated that the expression of multi-centerspecific genes studies is determined have suggested by their very setting. low asthmaA genetic prevalence variant might in children either inlead some to, or protect from, asthma depending on the environmental influence [205]. Recent centers in India [55, 206], leading to the assumption that particular environments responsein certain thatregions might in Indiabe important protect from in an asthma. environment It has been rich proposedin worms that and certain other parasites.populations This in tropicalimmune areas response have mightdeveloped deviate a strong into anpro-inflammatory allergic response immune when drawn with the development of metabolic diseases such as diabetes mellitus. An adaptationmigrating into in utero an environment to an environment with less determined microbial exposure by an impaired [207]. Parallels energy supplycan be with an excess of food [208]. Amight register-based lead to an ‘inadequatestudy in Sweden metabolic showed response’ an increased when born risk into of typean environment 1 diabetes mellitus in children born in Sweden with family origins in low incidence countries. birth, regardless of whether the children grew up with their biological or Swedish- bornIn this parents. study the This risk led of developingto the conclusion diabetes that was the not effect influenced observed by migration might be after the ourconsequence study showed of changes a clear in association environmental between exposures age at migration(changes into Swedennutrition and or the developmentexposure to infections) of asthma, either indicating during the pregnancy importance or earlyof both infancy the pre- [209]. and In postnatal contrast, environment, even several years after birth. 63

Another, possibly more ‘prosaic’, explanation for the higher prevalence of asthma among South Asians might be diagnostic bias, as suggested by Kuehni, who proposed that South Asians might be diagnosed with, and treated for, asthma more often due to false-positive low lung function as spirometers lack “ethnic-specific norm values” [134],[134]. althoughSimilarly, onlyphysicians a proportion might beof asthmainfluenced is attributable by the higher to allergyprevalence [210]. of allergic diseases in South Asians and therefore tend to prescribe ICS to patients with asthma Low prevalence of asthma medication could be an expression of under-diagnosed asthma or underuse of prophylactic medication due to economic reasons, which has been reported from different developed countries [211-213]. A similar pattern less than 17 years were living in relative poverty in Sweden compared with 8% of Swedish-bornmight also exist children in Sweden. with InSwedish-born 2001, almost parents. 50% of Thethe proportionimmigrant childrenof immigrant aged children living in economic vulnerability decreases with duration of residency in Sweden [214]. Factors such as language barriers, health-seeking behavior, low health asthmaliteracy andmedication inadequate as a access proxy tofor health asthma care underestimates contribute to athe reduced true prevalence utilization of asthma medicationin immigrants, in immigrants especially [215].among There those is who a significant have recently risk that arrived. dispensed This might contribute to the lower rates of dispensation of asthma medication in foreign- born children with foreign-born parents than among adoptees and Swedish-born children with Swedish-born parents seen in our study. This, however, can hardly explain the similar and inverse association between age at migration and dispensed asthma medication both in adoptees and foreign-born children with foreign-born parents despite the socioeconomic disparities and potential differences in health- seeking behavior between the two groups. Adopted children are overrepresented in upper social classes whereas non-adopted immigrants are more common in the lower social classes. Furthermore, the inverse relationship of age at migration with dispensed asthma medication persisted even after adjustment for socioeconomic indicators.

6.5 Immunization as an infant and asthma medication in some analyses. When adjusting for several sociodemographicOur study revealed and a weakperinatal negative factors, association there was betweenno difference pertussis in the vaccinationprevalence of dispensed asthma medication between unvaccinated and vaccinated children in this cohort. reportPrevious a possiblestudies investigatingincreased risk the of impactasthma of after immunization infant immunization on asthma for have pertussis. shown Thecontradictory authors stated results that [137-141, there was 146-148]. no other In explanatory 1994, Odent factor et al wereexcept the pertussis first to 64 vaccination for the tremendous increase in asthma prevalence in this group. However, immunizationas this rather short have report struggled lacked with detailed certain information, methodological the results problems remained such as difficult recall biasto assess on both [137]. exposure Other studies and outcome, that showed as well an as increased the problem risk ofof asthmavery small after control infant groups [139, 140]. McKeever et al also found an association between vaccination and the development of allergic disease in an American birth cohort. He stated, however, that the association that was found could be explained by sampling bias rather than a biological effect, as children with a higher prevalence of allergic disease had fewer physician visits than the group of children with fewer asthma cases [216]. any association between pertussis immunization and asthma [145-148]. Yet, these Our findings are in line with a number of more recent studies that do not report above all very small control groups and/or low response rates [145-147], which is studies have also been confronted with some significant methodological problems, There have also been discussions about a potential protective effect of infant immunizationwhy further large-scale, on the development well controlled of investigationsasthma and otherhave been allergic requested diseases. [155]. But number of non-vaccinated children in their analyses [141-144]. Furthermore, in again, studies suggesting such a protective effect have failed to include a sufficient regardingmost of these adverse studies events wP vaccines [217]. wereWe have used, been which able might to induceinvestigate a more the prominent effect of acellularimmunological vaccine reaction on asthma than medication aP vaccines, on which a large typically scale. showThis is lower important reactogenicity as most

induce a more Th2 increasedof the current risk ofpertussis developing vaccines allergy contain was shown aP vaccine, [218]. which has been reported to The role of infections-interleukin-dominated and immunizations on profile the immune than wP system vaccines, is complex although and no

especially tuberculosis are known to induce a Th1-deviated immune response [219, not fully understood. Diseases such as pertussis but also measles, influenza and shown to take part in the suppression of a Th2 immune response [219]. Szabo et 220], which leads to an increased synthesis of interferon γ (INF-γ). INF-γ has been develop into either Th1 or Th2 al have presented a model in which naive Th cells, via interleukin-12 (IL-12), can 1 cells depending on the presence of interleukin-4 (IL- 2 cells and the development of atopic 4). The Th -dominated inflammatory environment after certain infections might disorders. Moreover, a Th1-induced cytokine environment could lead naive Th cells prevent the development of allergen-specific Th toward a Th1 development by expressing certain transcriptions factors needed for the differentiation of Th2 cells or inducing transcription factors for the synthesis of

Th1 cells [221].

However, there are signs that Th1 and Th2 responses might be able to coexist simultaneously at different places in the same organism as Mycobacterium bovis, the causative agent of tuberculosis in cattle, strongly inhibits a local Th2 response in the lung, but not the systemic allergic response [222, 223]. Even the timing of the infection in relation to the infected subject’s age has been discussed as crucial to the suppression of the atopic phenotype. As the neonatal immune system has a 65

Th2 overweight which shifts to Th1 children who develop atopy do not lose their Th2 response [219]. The inability to during the infant’s first year of life, it seems that why atopic children do not shift toward a Th1-dominated immune response [224]. produce sufficient amounts of INF-γ as neonates has been suggested as the reason have the greatest impact on the inhibition of atopic disorders during the immediate postnatalFollowing period that concept, or early infectious childhood, diseases with infections that induce later the in lifesynthesis having of no INF-γ suppressive should

to suppress the Th2 immune response, the timing of the vaccination might also be crucialeffect, as with suggested regard byto Erbits effect [219]. on If the timingdevelopment of the infection of asthma influences and atopic the diseases. capability A Canadian study of about 12,000 children suggested that a vaccination delay of more than two months reduced the risk of asthma. We were able to compare children vaccinated at 2, 4 and 6 months with children vaccinated at 3, 5 and 12 months, and found that the timing of the vaccination did not affect the outcome. The Canadian study, however, used retrospective data, which could have led to selection bias [225].

The design of our study, with data about exposure and outcome, vaccination status and asthma medication, collected independently of each other and based on registers, minimized recall bias. Access to numerous potential confounding factors from the registers made it possible to adjust for other potential causes of asthma in this age group. To further overcome certain types of confounders, such as parental

Most previous studies were unable to account for this type of bias as control groups mainlyattitudes contained to vaccination children and whose health parents care inhad general, decided we not performed to vaccinate an their ITT children;analysis. of the studies, as there is reason to believe that this group of individuals differs in moreand these than control just attitude groups to were vaccination. very small. This This became might obvious have influenced when we the focused outcome on was less likely among those born during the vaccination period than among those bornthe non-vaccinated outside the vaccination children in ourperiod study: in wethe saw univariate that dispensed analysis. asthma This medication difference disappeared after adjusting for multiple confounding factors.

medicationSince misclassification could otherwise of exposure have been may somewhat reduce the diluted. estimated However, effects there in an might ITT stillanalysis, be other we also factors performed that may a havePP analysis. changed A duringtrue effect our studyof vaccination period and on thatasthma we certainwere unable outdoor to measure, allergens e.g. that pollen are prevalent count. However, during the vaccination immunization with anseason aP vaccine [226]. Asduring the thenon-vaccinated pollen season childrenhas been borndemonstrated during the not vaccinationto influence periodspecific formIgE for a heterogeneous group, the complete impact on our analysis cannot be easily not to participate and who lived in larger urban areas where the participation rates hadclarified. been It lower is known than that elsewhere the group [164]. mainly The includes fact that children the dispensation of parents whoof asthma chose medication was less likely among children in this group than among non-vaccinated 66 children born outside the vaccination period, as seen in our unadjusted analysis, emphasizes the importance of the ITT analysis in this population. It underlines the trialassumption due to the that lack parental of detailed attitudes information to vaccination is a weakness and medication in our analysis might forinfluence which the result. Our inability to control for the different types of non-participation in the large population of vaccinated and non-vaccinated individuals enables us to assess awe possible cannot associationfully compensate. between None immunization the less, the and unique asthma setting medication of our studyin teenagers with a in such an extensive manner. 67

7 CONCLUDING REMARKS

We showed an association between degree of immaturity, expressed by gestational age, and dispensed asthma medication as a proxy for asthma in 6–19-year-olds in Sweden. This association was independent of socioeconomic confounders and perinatal mediators. Furthermore, we showed that it was more likely that asthma medication would be dispensed even to children born early term after 37–38 weeks’ gestation compared with children born at term.

The clear inverse dose-response relationship of gestational age with dispensed asthma medication shows that every week in the womb is important for the development of the child and its risk of developing diseases such as asthma. Most studies so far have highlighted the part insults play during early fetal development and their causal role in future disease development. As lung development is a continuous process until several years after birth, it is plausible that even infants born almost at term have an increased susceptibility to harmful effects on their lungs, although this had not been shown in such a large population sample earlier.

The follow-up of our birth cohort that was started in 1974 showed a two- to threefold increased likelihood for dispensed asthma medication at the age of 32–34 years for seemsindividuals to lose born its importancewith an elevated with increasingCB-IgE or aage. positive Most offamily the individuals history of asthma. in our birth cohortCB-IgE whohas beenhad been proposed dispensed as a markerasthma medicationfor sensitization during in 2006–2008 utero. As a hadrisk not factor been it diagnosed as having asthma as a child. Moreover, the proportion of individuals with of age than among adults with asthma medication. The predictive value of elevated elevated CB-IgE was higher among children with asthma at 6–7 and 10–11 years not a useful screening marker for adult asthma. cord blood IgE was poor, even when combined with a family history of asthma. It is genetic susceptibility to disease development probably varies during life in utero and postnatally,The influence as does of pre- the and impact postnatal of different environmental external stimuli. factors The is understudy of debate. migrating The populations can help to differentiate between genetic and various environmental

Weinfluences demonstrated on disease the development. importance of age at migration to Sweden for the need of asthma medication at 6–25 years of age. We were able to assess three different migrating groups originating from regions in which asthma prevalence is usually low. We were further able to show that age at migration to Sweden was a more important factor for the dispensation of asthma medication than population of origin, which further underlines the assumption that environmental factors play an important role in the development of asthma not only during fetal life but also later in childhood. 68

The importance of infections during early infancy for the development of the immune system has been discussed for a long time. The ‘hygiene hypothesis’ postulated that the lack of infections could lead to an unfavorable development of the immune system, which in turn leads to a higher risk of asthma and allergies.

We studied the potential impact of pertussis vaccination in infancy on dispensed were able to investigate a large population from a former vaccine trial with about asthma medication at the age of 15 years. In contrast to most previous studies we unvaccinated children. 80,000 vaccinated children and a sufficiently large control group of about 100,000 infants with non-vaccinated infants born outside the vaccination trial during a periodThe unique when setting general of ourpertussis investigation vaccination was that was we not were available able to in compare Sweden. vaccinated We found in teenagers, regardless of vaccination schedule or vaccine type. no statistically significant effect of immunization on dispensed asthma medication

Our study presents evidence that pertussis immunization in early childhood has no significant impact on the development of asthma. asthma disease in the long term. The susceptibility to different insults seems to In conclusion, genetic and environmental factors influence the development of underline above all the importance of different environmental factors and show that thevary risk depending of developing on which asthma stage seemsduring topre- be or determined postnatal lifeby theymany occur. different Our studiesfactors from life in utero to childhood. 69

WHAT THIS THESIS SHOWS:

the need of asthma medication at 6–19 years. • Every week of gestation is important for lung development and showed a higher rate of dispensed asthma medication compared • withEven children infants born born at early term. term after 37–38 weeks’ gestation

asthma in infancy were associated with a two- to threefold in- • creasedElevated likelihood cord blood that immunoglobulin asthma medication E and would a family be dispensedhistory of and of allergen-induced self-reported respiratory symptoms at 32–34 years. Their predictive power, however, was poor.

origin for the need of dispensed asthma medication at 6–25 • years.Age at Themigration likelihood is a morethat asthma important medication factor than will populationbe dispensed of decreases with increasing age at migration.

pensed asthma medication at 15 years of age, regardless of • vaccinationPertussis immunization schedule or vaccine in early type. infancy has no effect on dis- 70

8 ACKNOWLEDGMENTS

There are many people out there who deserve my gratitude and thanks for all the fromhelp I1974–75 received duringin Linköping my years as wellas a PhDas all student. the anonymous I would like subjects to thank in theall the datasets study usedmembers for this of ISAACthesis. PhaseWithout Three them in my Linköping research and would the notmembers have been of the possible. birth cohort

LennartI especially Nilsson want, tomy thank: main supervisor for sharing his remarkable enthusiasm, curiosity and engagement in research, and for his endless support throughout these years. You introduced me to research by making me part of the ISAAC follow-up in Linköping, which was the start of my PhD project. You never gave up on me even when researchI was tempted and to to his do patients. so myself. Thank I admire you for your all the impressive fruitful discussions knowledge, about which research seems unending… and I have hardly met a person with such a tremendous commitment to

Lennartbut also Bråbäcklife in general. I owe you a lot!

, co-supervisor in Sundsvall. Thanks to modern technique and above understandingall to your fantastic of epidemiological involvement, theproblems distance and between contexts. Linköping You have and always Northern been availableSweden felt at ratheralmost shortnon-existent. notice, which You have has always been much encouraged appreciated me, and and I admire“life-saving” your at times. Thank you for guiding me through these years—I would not have made it Karinwithout Fälth-Magnusson your help! , co-supervisor during the last years of my research project, toformer become Head a ofpediatrician the Department and then of Pediatric supported and myAdolescent doctoral Medicine. thesis in I manywill always ways remember the first time we met at the hospital. You gave me a job and the chance only research problems— and you always have an answer and a kind word. Thank throughout the years. It has always been easy to talk to you about everything, not

Andersyou! Hjern and Karolina Lindström, appreciated co-authors and excellent researchers, who I will always look up to. Together with Lennart Bråbäck, you two Mariaintroduced Grünewald me to the and work Anna-Maria with national “Mia” registers, Kling ,which appreciated I thank youco-authors for. who introduced me to the world of Directed Acyclic Graphs. Thank you for all your valuable input and for your almost 24-hour support in statistical matters. I hope we can continue to cooperate in the future! 71

All the staff at the Allergy Center in Linköping, especially Kicki Helander, for all your

Additionally,help during the Olle years Zetterström and especially and Katalin with Zara ISAAC,, appreciated which was co-authors part of my for initiation their work as witha PhD the student, follow-up although of the these birth studies cohort, never and Agnethareally made Karlsson it into, who my thesis! was engaged in collecting data from the original paper charts. Without you all, there would probably never have been a follow-up of our birth cohort.

Linköping for their support and interest in my work, especially Britt-Marie Holmqvist, AllIrene my Devenney colleagues, Mikael at theBehrendtz Department and Ulf of Samuelsson, Pediatric and my closest Adolescent colleagues Medicine at the in pediatric oncology ward. You had to work extra hard during certain periods to allow me to concentrate on my research projects.

Sven Mattsson, my clinical supervisor during the years as pediatric intern. You not only shared your clinical wisdom with me, but also showed me how interesting research can be.

Christina Johansson and Nina Nelson, respective present and former Heads of the work in the clinic to work with this thesis. Department of Pediatric and Adolescent Medicine for providing time off from my Peter Bang and Johnny Ludvigsson, respective present and former Heads of the

Division of Pediatrics, for making us never forget the importance of research and Bengtreminding Björkstén us that we do not have to “save lives” 24 hours a day!

, former Head of the Division of Pediatrics, for including me in the HenrikISAAC project Passmark in Linköping. link the different registers. , Swedish National Board of Health and Welfare, who helped us to Ann-Christine Gilmore-Ellis and Madeleine Örlin for fantastic administrative support.

Jens Hermansson my dear friend and, system computer software specialist, specialist Dirk Holste at IBM, who Sweden enthusiastically in Stockholm, decoded who helpedparts of to the extract data from the originalthe magnetic data settape. from the rather antique magnetic tape, and

Olle Eriksson and Karl Wahlin Science, Linköping University for statistical guidance. , at the Department of Computer and Information Max Kjellman investigation. , the initiator of the birth cohort (Paper II), for his advice on this 72

Stefan Croner, who together with Max Kjellman once started the birth cohort and gave us the opportunity to investigate the development of asthma over such a long and allergies while he was still among us, he will always be remembered. period of time. For that and for everything I have learned from him about asthma Pia Laurin and Carola Holste for critical reading of the dissertation.

Maurice Devenney still wonder if you will soon call me again to discuss the differences between ‘risk’, for his valuable work with revision of the English language. I

All‘likelihood’ our friends and who ‘need’!! helped us during the last weeks and months by taking care of our

Mykids dear and parents,supporting Hanna us in and different Eberhard ways. Kie Nowß, who it will gave soon me be the my opportunity turn! to grow up in a safe, supportive environment together with my sister Elisabeth.

Ihr habt meine Ziele nie in Frage gestellt, und mich von klein an in dem unterstützt, gekommen.was ich mir vorgenommen habe. Ihr habt mich nie zurückgehalten und mir vieles ermöglicht - dafür bin ich euch auf ewig dankbar! Ohne euch, wäre ich nie soweit My grandmother, Maria Schaudt, whose long life has taught her many things that she shared with her grandson during many long conversations.

Liebe Oma, du musstest 101 Jahre alt werden, um zu erleben, dass aus deinem Enkel Mydoch parents-in-law, noch ein RICHTIGER Ulla and Doktor Henning geworden Vogt, who ist! have supported us especially during the past months by taking care of the kids, the household and everything while I was not available for the rest of my family. Vielen Dank, für eure ganze Hilfe - ohne euch Lowehätten and wir Thyra das nicht geschafft! Liebe zu euch kann ich nicht in Worte fassen... , my beloved children. I cannot imagine a life without you! Meine And Barbara, my beloved wife and companion for life. Thank you for all your support and patience through all these years, and especially for the help with the layout of this book. Thank you for being the one you are—thank you for sharing our dreams…

Ich liebe dich! 73

9 FUNDING

This work was supported by the Swedish Asthma and Allergy Association

(Astma & Allergiförbundet), ALF Grants, County Council of Östergötland, Linköping University Hospital’s Research Fund, Office for Postgraduate Medical Education, County Council of Östergötland and the non-profit organization, OSTMA, Linköping. 74

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. 2006;24(12):2035-2042. BMJ. 146. Maitra A., Sherriff A., Griffiths M., Henderson J. Pertussis vaccination in infancy and asthma or allergy in later childhood: birth cohort study. 2004;328(7445):925-926. 147. Spycherbased cohort B. D., study. Silverman Pediatrics M., Egger M., Zwahlen M., Kuehni C. E. Routine vaccination against pertussis and the risk of childhood asthma: a population- . 2009;123(3):944-950. 148. Nilssonof a randomized L., Kjellman controlled N.-I. M., trial Björksten of 3 vaccines. B. Allergic Arch disease Pediatr at Adolesc the age Med of 7. years after pertussis vaccination in infancy: results from the follow-up 149. Duchén K., Granstrom M., Hedenskog S., Blennow M., Björkstén B. 2003;157(12):1184-1189. with adsorbed and non-adsorbed whole cell pertussis vaccines. Vaccine. Immunoglobulin E and G responses to pertussis toxin in children immunised

1997;15(14):1558-1561.Allergy 150. Nilsson L., Gruber C., Granström M., Björkstén B., Kjellman N.-I. M. Pertussis IgE and atopic disease. . 1998;53(12):1195-1201. 151. Odelramimmunization H., in Granström relation to M., atopy, Hedenskog local reactions S., Duchén and aluminium K., Björkstén content of B. theImmunoglobulin vaccines. Pediatr E Allergy and G Immunol responses to pertussis toxin after booster

. 1994;5(2):118-123. 152. KoppenVaccine S., de Groot R., Neijens H. J., Nagelkerke N., van Eden W., Rumke H. C. No epidemiological evidence for infant vaccinations to cause allergic disease. vaccinations. 2004;22(25-26):3375-3385. to cause allergic disease. Vaccine 153. Bernsen R. M., van der Wouden J. C. Re: no epidemiological evidence for infant cause allergic disease. Vaccine . 2005;23(12):1427. 154. da Cunha SS. Reply to: No epidemiological evidence for infant vaccinations to associated with asthma? A meta-analysis. 2005;23(30):3875. of observational studies. Pediatrics. 155. Balicer R. D., Grotto I., Mimouni M., Mimouni D. Is childhood vaccination

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157. Heininger U. An internet-based survey on parental attitudes towards immunization.2005;23(24):3103-3107. Vaccine

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172. Zuidgeest M. G., van Dijk L., Smit H. A., van der WoudenBMC J. Health C., Brunekreef Serv Res. B., Leufkens H. G., et al. Prescription of respiratory medication without an asthma diagnosis in children: a population based study. 2008;8:16. Pediatr Pulmonol 173. Kozyrskyj A. L., Mustard C. A., Simons F. E. Inhaled corticosteroids in childhood medicationsasthma: Income as a differences proxy for prevalence in use. of asthma in children. 2003;36(3):241-247. and adolescents 174. Furu K., Skurtveit S., Langhammer A., Nafstad P. UseEur of J Clin anti-asthmatic Pharmacol.

in Norway: a nationwide prescription database analysis. 2007;63(7):693-698. 175. Furucomparison K., Karlstad with aO., population-based Skurtveit S., Haberg prescription S. E., Nafstad database. P., London J Clin EpidemiolS. J., et al.. High validity of mother-reported use of antiasthmatics among children: a

prescription2011;64(8):878-884. data and diagnosis. Eur J Clin Pharmacol 176. Moth G., Vedsted P., Schiotz P. Identification of asthmatic children using time and by age. Clin Respir J . 2007;63(6):605-611. 178.177. ColinBjerg A.A., A., Rönmark McEvoy C.,E. CastileAsthma R. in G. school Respiratory age: prevalence morbidity andand lung risk functionfactors by in preterm infants of 32 to 36 weeks’. 2008;2 gestational Suppl 1:123-126. age. Pediatrics 128. . 2010;126(1):115- full term infants? Early Hum Dev 179. Resch B., Paes B. Are late preterm infants as susceptible to RSV infection as . 2011;87 Suppl 1:S47-49. Pediatrics. 180. Crump C., Winkleby M. A., Sundquist J., Sundquist K. Risk of asthma in young adults who were born preterm: a Swedish national cohort study. 2011;127(4):e913-920. Pediatrics 181. Goyal N. K., Fiks A. G., Lorch S. A. Association of late-preterm birth with asthma wheezingin young children: in the third practice-based year of life among study. children born. 2011;128(4):e830-838. at 32 weeks’ gestation 182. Escobar G. J., Ragins A., Li S. X., Prager L., Masaquel A. S., Kipnis P. Recurrent Arch Pediatr Adolescor later: Med relationship to laboratory-confirmed, medically attended infection 183. Thavagnanamwith respiratory S., Fleming syncytial J., virusBromley during A., Shields the first M. yearD., Cardwell of life. C. R. A meta- analysis of the. 2010;164(10):915-922. association between Caesarean section and childhood asthma. Clin Exp Allergy

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11 APPENDIX

11.1 Questionnaire Study II

Allergi i Östergötland Kodnr: ….. Datum 2007-04-30 Prövare Olle Zetterström Universitetssjukhuset i Linköping Bilaga 2

Frågeformulär Besvara frågorna genom att kryssa i lämpligt alternativ och genom att skriva på den prickade linjen. Ja Nej

1 Brukar Du bli andfådd, få pip i bröstet eller hostattacker: a) vid ansträngning ( ) ( ) b) i kyla ( ) ( ) c) vid ansträngning utomhus i kallt väder ( ) ( ) d) i dammiga miljöer ( ) ( ) e) av cigarett- eller tobaksrök ( ) ( ) f) av bilavgaser ( ) ( ) g) av starka dofter (parfym, kryddoft, trycksvärta, rengöringsmedel, etc) ( ) ( ) h) av pollen från växter som gräs och eller träd ( ) ( ) i) vid kontakt med pälsdjur ( ) ( )

2 Har Du någon gång reagerat med andningssvårigheter inom 3 timmar efter att Du tagiten värktablett? ( ) ( )

a) Om Ja på fråga 2: Kommer Du ihåg namnet på medicinen? ………………………

3 Har Du nästäppa nästan alltid? ( ) ( )

4 Får du nästäppa vid tillfällig exponering för pollen eller pälsdjur? ( ) ( )

5 Har du snuva nästa alltid? ( ) ( )

6 Får du snuva vid tillfällig exponering för pollen eller pälsdjur? ( ) ( )

7 Har du daglig kontakt med något pälsdjur? ( ) ( )

Om Ja på fråga 7:Vilket/vlika djur?......

8 Är Du rökare (inklusive feströkning)? ( ) ( )

a) Om Ja på fråga 8: Ungefär hur många cigaretter röker Du per dag? Mindre än 5 ( ) 5 – 14 ( ) 15 – 24 ( ) 25 eller mer ( ) b) Om Ja på fråga 8: Vid vilken ålder började Du att röka?......

8 Är Du före detta rökare? ( ) ( )

a) Om Ja på fråga 9: Hur många år rökte du?......

b) Om Ja på fråga 9: Hur många cigaretter per dag rökte du?......

c) Om Ja på fråga 9: Vid vilken ålder började Du att röka?......

10 Är Du yrkesverksam? ( ) ( )

Om Ja på fråga 10: a) Vilket är ditt nuvarande arbetet?...... b) Hur många år har Du arbetat inom detta yrke?......

Allergi i Östergötland Kodnr: ….. Datum 2007-04-30 Prövare Olle Zetterström Universitetssjukhuset i Linköping Bilaga 2 Ja Nej

11 Har du varit verksam inom något/några andra yrken? ( ) ( ) a) Om Ja på fråga 11 a) Specifiera vilket arbete och antal år i yrket: Yrke 1………………. Antal år………… Yrke 2………………. Antal år…………

12 Har Du varit mycket utsatt för damm, gaser eller rök i arbetet? ( ) ( )

13 Bodde Du på landsbygden under Dina fem första levnadsår? ( ) ( ) Om Ja på fråga 13: Ingick djurhållning i din familj? ( ) ( )

14 Hur många gånger/vecka äter Du fisk? Aldrig ( ) 1-2 ggr ( ) Mer än 2ggr ( )

15 Hur många gånger/ vecka motionerar Du mer än 30 minuter? (motionera = springa, cykla, gå snabbt, simma t ex) Aldrig ( ) 1-2 ggr ( ) Mer än 2ggr ( )

16 Har Du eksem som barn? ( ) ( )

17 Har Du någon gång haft ett kliande utslag som kommit och gått i minst 6 ( ) ( ) månader?

18 Har Du under de senaste 12 månaderna haft handeksem? ( ) ( )

19 Är Du allergisk eller överkänslig för Nickel? ( ) ( )

20 Har Du haft någon period med nässelutslag (upphöjda, hudfärgade eller blekröda ( ) ( ) utslag, ofta med röda kanter)?

Jag är Man ( ) Kvinna ( )

Tack för Din medverkan!

11.2 Map Study IV