DISSERTATIONS | MAIJAKAISA HARJU | PRENATAL EXPOSURES AND CHILDHOOD ASTHMA | No 326
uef.fi
PUBLICATIONS OF
THE UNIVERSITY OF EASTERN FINLAND Dissertations in Health Sciences
ISBN 978-952-61-2011-9 ISSN 1798-5706
Dissertations in Health Sciences
THE UNIVERSITY OF EASTERN FINLAND
MAIJAKAISA HARJU
PRENATAL EXPOSURES AND CHILDHOOD ASTHMA
Intrauterine life and early infancy are critical time increasing risk of childhood asthma.
This retrospective study investigated prenatal factors affecting the risk and clarified the
contribution of maternal health matters and socioeconomic (SES) factors in relation
to childhood asthma. The results provided evidence of the increased asthma risk among children of mothers with decreased fecundity.
Both pre- and early-term delivery and parental smoking similarly increased the childhood asthma risk; maternal SES had no
such effect.
MAIJAKAISA HARJU
Prenatal Exposures and Childhood Asthma
MAIJAKAISA HARJU
Prenatal Exposures and Childhood Asthma
To be presented by permission of the Faculty of Health Sciences, University of Eastern Finland for public examination in Auditorium II, University Hospital of Kuopio,
Kuopio, on Friday, January 22nd 2016, at 12 noon
Publications of the University of Eastern Finland Dissertations in Health Sciences
Number 326
Department of Obstetrics and Gynecology, Institute of Clinical Medicine, Faculty of Health Sciences,
University of Eastern Finland Kuopio
2016
MAIJAKAISA HARJU
Prenatal Exposures and Childhood Asthma
To be presented by permission of the Faculty of Health Sciences, University of Eastern Finland for public examination in Auditorium II, University Hospital of Kuopio,
Kuopio, on Friday, January 22nd 2016, at 12 noon
Publications of the University of Eastern Finland Dissertations in Health Sciences
Number 326
Department of Obstetrics and Gynecology, Institute of Clinical Medicine, Faculty of Health Sciences,
University of Eastern Finland Kuopio
2016
Grano Oy Jyväskylä, 2016
Series Editors:
Professor Veli-‐‑Matti Kosma, M.D., Ph.D.
Institute of Clinical Medicine, Pathology Faculty of Health Sciences Professor Hannele Turunen, Ph.D.
Department of Nursing Science Faculty of Health Sciences Professor Olli Gröhn, Ph.D.
A.I. Virtanen Institute for Molecular Sciences Faculty of Health Sciences
Professor Kai Kaarniranta, M.D., Ph.D.
Institute of Clinical Medicine, Ophthalmology Faculty of Health Sciences
Lecturer Veli-‐‑Pekka Ranta, Ph.D. (pharmacy) School of Pharmacy
Faculty of Health Sciences Distributor:
University of Eastern Finland Kuopio Campus Library
P.O. Box 1627 FI-‐‑70211 Kuopio, Finland http://www.uef.fi/kirjasto ISBN (print): 978-‐‑952-‐‑61-‐‑2011-‐‑9
ISBN (pdf): 978-‐‑952-‐‑61-‐‑2012-‐‑6 ISSN (print): 1798-‐‑5706
ISSN (pdf): 1798-‐‑5714 ISSN-‐‑L: 1798-‐‑5706
Author’s address: Department of Obstetrics and Gynecology Kuopio University Hospital
University of Eastern Finland KUOPIO
FINLAND
Supervisors: Professor Leea Keski-‐‑Nisula, M.D., Ph.D.
Kuopio University Hospital University of Eastern Finland KUOPIO
FINLAND
Professor Seppo Heinonen, M.D., Ph.D.
Helsinki University Central Hospital University of Helsinki
HELSINKI FINLAND
Reviewers: Docent Petteri Hovi, M.D., Ph.D.
University of Helsinki and
Helsinki University Central Hospital; Pediatrics HELSINKI
FINLAND
Docent Marja Vääräsmäki, M.D., Ph.D.
Department of Obstetrics and Gynecology Oulu University Hospital
OULU FINLAND
Opponent: Docent Minna Tikkanen, M.D., Ph.D.
Helsinki University Central Hospital Department of Obstetrics and Gynecology University of Helsinki
HELSINKI FINLAND
Grano Oy Jyväskylä, 2016
Series Editors:
Professor Veli-‐‑Matti Kosma, M.D., Ph.D.
Institute of Clinical Medicine, Pathology Faculty of Health Sciences Professor Hannele Turunen, Ph.D.
Department of Nursing Science Faculty of Health Sciences Professor Olli Gröhn, Ph.D.
A.I. Virtanen Institute for Molecular Sciences Faculty of Health Sciences
Professor Kai Kaarniranta, M.D., Ph.D.
Institute of Clinical Medicine, Ophthalmology Faculty of Health Sciences
Lecturer Veli-‐‑Pekka Ranta, Ph.D. (pharmacy) School of Pharmacy
Faculty of Health Sciences Distributor:
University of Eastern Finland Kuopio Campus Library
P.O. Box 1627 FI-‐‑70211 Kuopio, Finland http://www.uef.fi/kirjasto ISBN (print): 978-‐‑952-‐‑61-‐‑2011-‐‑9
ISBN (pdf): 978-‐‑952-‐‑61-‐‑2012-‐‑6 ISSN (print): 1798-‐‑5706
ISSN (pdf): 1798-‐‑5714 ISSN-‐‑L: 1798-‐‑5706
Author’s address: Department of Obstetrics and Gynecology Kuopio University Hospital
University of Eastern Finland KUOPIO
FINLAND
Supervisors: Professor Leea Keski-‐‑Nisula, M.D., Ph.D.
Kuopio University Hospital University of Eastern Finland KUOPIO
FINLAND
Professor Seppo Heinonen, M.D., Ph.D.
Helsinki University Central Hospital University of Helsinki
HELSINKI FINLAND
Reviewers: Docent Petteri Hovi, M.D., Ph.D.
University of Helsinki and
Helsinki University Central Hospital; Pediatrics HELSINKI
FINLAND
Docent Marja Vääräsmäki, M.D., Ph.D.
Department of Obstetrics and Gynecology Oulu University Hospital
OULU FINLAND
Opponent: Docent Minna Tikkanen, M.D., Ph.D.
Helsinki University Central Hospital Department of Obstetrics and Gynecology University of Helsinki
HELSINKI FINLAND
Harju, Maijakaisa
Prenatal Exposures and Childhood Asthma
University of Eastern Finland, Faculty of Health Sciences
Publications of the University of Eastern Finland. Dissertations in Health Sciences Number 326. 2016. 71 p.
ISBN (print): 978-‐‑952-‐‑61-‐‑2011-‐‑9 ISBN (pdf): 978-‐‑952-‐‑61-‐‑2012-‐‑6 ISSN (print): 1798-‐‑5706 ISSN (pdf): 1798-‐‑5714 ISSN-‐‑L: 1798-‐‑5706
ABSTRACT
Asthma affects 5–7% of children in Finland and is the most prevalent chronic disease in childhood. Both genetic and environmental factors have effects in its development.
Intrauterine life and early infancy are suggested to be critical time periods when specific events and exposures may affect prenatal programming, induce immunologic changes and alter immune development. Maternal lifestyle habits, such as smoking, as well as pregnancy and delivery factors such as preterm birth may affect the risk of the development of asthma up to adulthood.
The aim of this study was to identify more precisely prenatal factors affecting the risk of asthma in offspring and to clarify the contribution of maternal health matters and socioeconomic factors in relation to childhood asthma. The study population consisted of all 44 173 women who delivered at Kuopio University Hospital in 1989–2008, and their offspring, of whom 2661 (6.0%) had asthma before adulthood. We evaluated the association between several factors (maternal fecundity and infertility treatments, socioeconomic status, parental smoking and preterm delivery) and asthma among offspring.
The risk of asthma was significantly increased if the mother had reported any earlier infertility problems (aOR 1.4; CI 1.2–1.6) and it was also higher among the offspring of mothers having infertility treatments (aOR 1.5; CI 1.3–1.8) compared with children of mothers without such problems. Earlier recurrent miscarriages and prolonged time to index pregnancy increased the risk of asthma among offspring.
Delivery before 32 weeks of gestation increased the risk of asthma fourfold and the risk remained high among children born early term (37–38 weeks of gestation; aOR 1.2; CI 1.1–
1.4) compared to term. Prenatal parental smoking (both parents) elevated the risk of asthma almost fourfold (aOR 3.7; CI 3.2–4.4) and risk remained high with only paternal smoking (aOR 2.9; CI 2.0–2.6) compared to non-‐‑smoking. Parental cessation of smoking during pregnancy seemed to reduce the risk of asthma in offspring. Low maternal socioeconomic status did not increase the prevalence of asthma, but a protective effect against asthma was seen among families with entrepreneurs, consisting mostly of agricultural producers.
In conclusion, the results showed that maternal preconception health and lifestyle factors, and pregnancy-‐‑related factors have an impact on the long-‐‑term development of asthma in offspring. The results provide some evidence that fecundity factors might increase the incidence of asthma among offspring, and both pre-‐‑ and early-‐‑term delivery (even at 38 gestational weeks) considerably increases the risk of asthma, especially in families with the condition. Furthermore, both parents should be encouraged and supported in quitting smoking, since its influence on child health is substantial. Finnish public health services seem to offer equal-‐‑quality services independently of maternal SES, since the prevalence of asthma was not higher in relation to lower SES, as reported in other countries.
National Library of Medicine Classification: WA 30, WA 310, WF 553, WS 280, WQ 210
Medical Subject Headings: Asthma; Child; Prenatal Exposure Delayed Effects; Maternal Exposure; Pregnancy;
Maternal Health; Fertility; Infertility; Gestational Age; Premature Birth; Smoking; Socioeconomic Factors; Life Style; Risk Factors
Harju, Maijakaisa
Prenatal Exposures and Childhood Asthma
University of Eastern Finland, Faculty of Health Sciences
Publications of the University of Eastern Finland. Dissertations in Health Sciences Number 326. 2016. 71 p.
ISBN (print): 978-‐‑952-‐‑61-‐‑2011-‐‑9 ISBN (pdf): 978-‐‑952-‐‑61-‐‑2012-‐‑6 ISSN (print): 1798-‐‑5706 ISSN (pdf): 1798-‐‑5714 ISSN-‐‑L: 1798-‐‑5706
ABSTRACT
Asthma affects 5–7% of children in Finland and is the most prevalent chronic disease in childhood. Both genetic and environmental factors have effects in its development.
Intrauterine life and early infancy are suggested to be critical time periods when specific events and exposures may affect prenatal programming, induce immunologic changes and alter immune development. Maternal lifestyle habits, such as smoking, as well as pregnancy and delivery factors such as preterm birth may affect the risk of the development of asthma up to adulthood.
The aim of this study was to identify more precisely prenatal factors affecting the risk of asthma in offspring and to clarify the contribution of maternal health matters and socioeconomic factors in relation to childhood asthma. The study population consisted of all 44 173 women who delivered at Kuopio University Hospital in 1989–2008, and their offspring, of whom 2661 (6.0%) had asthma before adulthood. We evaluated the association between several factors (maternal fecundity and infertility treatments, socioeconomic status, parental smoking and preterm delivery) and asthma among offspring.
The risk of asthma was significantly increased if the mother had reported any earlier infertility problems (aOR 1.4; CI 1.2–1.6) and it was also higher among the offspring of mothers having infertility treatments (aOR 1.5; CI 1.3–1.8) compared with children of mothers without such problems. Earlier recurrent miscarriages and prolonged time to index pregnancy increased the risk of asthma among offspring.
Delivery before 32 weeks of gestation increased the risk of asthma fourfold and the risk remained high among children born early term (37–38 weeks of gestation; aOR 1.2; CI 1.1–
1.4) compared to term. Prenatal parental smoking (both parents) elevated the risk of asthma almost fourfold (aOR 3.7; CI 3.2–4.4) and risk remained high with only paternal smoking (aOR 2.9; CI 2.0–2.6) compared to non-‐‑smoking. Parental cessation of smoking during pregnancy seemed to reduce the risk of asthma in offspring. Low maternal socioeconomic status did not increase the prevalence of asthma, but a protective effect against asthma was seen among families with entrepreneurs, consisting mostly of agricultural producers.
In conclusion, the results showed that maternal preconception health and lifestyle factors, and pregnancy-‐‑related factors have an impact on the long-‐‑term development of asthma in offspring. The results provide some evidence that fecundity factors might increase the incidence of asthma among offspring, and both pre-‐‑ and early-‐‑term delivery (even at 38 gestational weeks) considerably increases the risk of asthma, especially in families with the condition. Furthermore, both parents should be encouraged and supported in quitting smoking, since its influence on child health is substantial. Finnish public health services seem to offer equal-‐‑quality services independently of maternal SES, since the prevalence of asthma was not higher in relation to lower SES, as reported in other countries.
National Library of Medicine Classification: WA 30, WA 310, WF 553, WS 280, WQ 210
Medical Subject Headings: Asthma; Child; Prenatal Exposure Delayed Effects; Maternal Exposure; Pregnancy;
Maternal Health; Fertility; Infertility; Gestational Age; Premature Birth; Smoking; Socioeconomic Factors; Life Style; Risk Factors
Harju, Maijakaisa
Prenatal Exposure and Childhood Asthma Itä-‐‑Suomen yliopisto, Terveystieteiden tiedekunta
Publications of the University of Eastern Finland. Dissertations in Health Sciences Numero 326. 2016. 71 s.
ISBN (print): 978-‐‑952-‐‑61-‐‑2011-‐‑9 ISBN (pdf): 978-‐‑952-‐‑61-‐‑2012-‐‑6 ISSN (print): 1798-‐‑5706 ISSN (pdf): 1798-‐‑5714 ISSN-‐‑L: 1798-‐‑5706 TIIVISTELMÄ
Suomessa 5-‐‑7 % lapsista sairastaa astmaa ja se on yleisin lasten pitkäaikaissairaus. Astmaan sairastumiseen vaikuttavat sekä perintö-‐‑ että ympäristötekijät. Sekä raskaudenaikaiset altisteet että varhaislapsuuden tapahtumat voivat aiheuttaa immunologisia muutoksia ja vaikuttaa yksilön immunologiseen kehitykseen. Äidin raskaudenaikaisten elintapojen, kuten tupakoinnin, sekä synnytyksenaikaisten tekijöiden, kuten ennenaikaisen synnytyksen on todettu olevan merkittäviä riskitekijöitä lasten astman synnyssä aina aikuisikään asti.
Tämän työn tarkoituksena oli selvittää raskaudenaikaisten tekijöiden (mm. äidin elintavat ja sosioekonominen asema) vaikutusta lapsen riskiin sairastua astmaan.
Tutkimusaineisto koostui 1989-‐‑ 2008 Kuopion Yliopistollisessa sairaalassa synnyttäneistä 44 173 äidistä ja heidän lapsistaan, joista 2661 (6 %) sairastui astmaan ennen aikuisikää.
Tutkimuksessa selvitimme äidin hedelmällisyyden ja hedelmöityshoitojen, sosioekonomisen luokan, vanhempien tupakoinnin ja ennenaikaisen synnytyksen yhteyttä lapsen riskiin sairastua astmaan.
Äidin aiemmat lapsettomuusongelmat ja–hoidot lisäsivät merkitsevästi lapsen riskiä sairastua astmaan (aOR 1.4; CI 1.2-‐‑1.6 ja aOR 1.5; CI 1.3-‐‑1.8) verrattuna lapsiin, joiden äideillä ei ollut vastaavia ongelmia. Äidin aiemmat toistuvat keskenmenot ja pitkittynyt raskauden viive ennen kyseistä raskautta lisäsivät myös lapsen riskiä sairastua astmaan spontaanisti alkaneissa raskauksissa.
Alle 32. raskausviikolla syntyneillä lapsilla oli nelinkertainen riski sairastua astmaan ja lisääntynyt riski todettiin myös täysiaikaisissa, ennen 39. raskausviikkoa syntyneillä lapsilla (aOR 1.2; CI 1.1-‐‑1.4) verrattuna täysiaikaisina syntyneisiin. Vanhempien raskaudenaikainen tupakointi lähes nelinkertaisti lapsen sairastumisriskin (aOR 3.7; CI 3.2-‐‑4.4). Isän raskaudenaikaisen tupakoinnin merkitys lapsen sairastumisriskiin korostui, sillä perheissä, joissa vain isä tupakoi raskausaikana, lapsen sairastumisriski oli lähes kolminkertainen (aOR 2.9; CI 2.0-‐‑2.6) verrattuna tupakoimattomiin vanhempiin. Vanhempien raskaudenaikainen tupakoinnin lopettaminen vähensi lapsen riskiä sairastua astmaan.
Äidin matala sosioekonominen luokka ei lisännyt lapsen astmaan sairastumisriskiä, mutta syntyminen yrittäjäperheeseen, jotka olivat suurelta osin maanviljelijöitä, oli yhteydessä pienempään sairastuvuuteen.
Tutkimustuloksemme osoittivat, että äidin terveydellisillä tekijöillä, elintavoilla ja raskaudenaikaisilla tekijöillä oli merkitystä lapsen riskiin sairastua astmaan. Molempia vanhempia tulisi kannustaa ja tukea tupakoimattomuuteen, koska sillä oli vahva yhteys lapsen vähentyneeseen riskiin sairastua astmaan. Tutkimustuloksemme viittaavat epäsuorasti, kuinka suomalainen sosiaali-‐‑ ja terveydenhuoltojärjestelmä mahdollistaa kaikille perheille tasapuolisen terveydenhoidon; lapsen sairastuvuus astmaan ei ollut suurentunut alemmissa sosiaaliluokissa, toisin kuin useissa kansainvälisissä tutkimuksissa on osoitettu.
Luokitus: WA 30, WA 310, WF 553, WS 280, WQ 210
Yleinen suomalainen asiasanasto: astma; lapset; lapsuus; altistuminen; sikiö; raskaus; hedelmällisyys;
hedelmättömyys; hedelmättömyyshoito; ennenaikainen synnytys; tupakointi; sosioekonomiset tekijät;
sosioekonominen asema; elintavat; riskitekijät
Harju, Maijakaisa
Prenatal Exposure and Childhood Asthma Itä-‐‑Suomen yliopisto, Terveystieteiden tiedekunta
Publications of the University of Eastern Finland. Dissertations in Health Sciences Numero 326. 2016. 71 s.
ISBN (print): 978-‐‑952-‐‑61-‐‑2011-‐‑9 ISBN (pdf): 978-‐‑952-‐‑61-‐‑2012-‐‑6 ISSN (print): 1798-‐‑5706 ISSN (pdf): 1798-‐‑5714 ISSN-‐‑L: 1798-‐‑5706 TIIVISTELMÄ
Suomessa 5-‐‑7 % lapsista sairastaa astmaa ja se on yleisin lasten pitkäaikaissairaus. Astmaan sairastumiseen vaikuttavat sekä perintö-‐‑ että ympäristötekijät. Sekä raskaudenaikaiset altisteet että varhaislapsuuden tapahtumat voivat aiheuttaa immunologisia muutoksia ja vaikuttaa yksilön immunologiseen kehitykseen. Äidin raskaudenaikaisten elintapojen, kuten tupakoinnin, sekä synnytyksenaikaisten tekijöiden, kuten ennenaikaisen synnytyksen on todettu olevan merkittäviä riskitekijöitä lasten astman synnyssä aina aikuisikään asti.
Tämän työn tarkoituksena oli selvittää raskaudenaikaisten tekijöiden (mm. äidin elintavat ja sosioekonominen asema) vaikutusta lapsen riskiin sairastua astmaan.
Tutkimusaineisto koostui 1989-‐‑ 2008 Kuopion Yliopistollisessa sairaalassa synnyttäneistä 44 173 äidistä ja heidän lapsistaan, joista 2661 (6 %) sairastui astmaan ennen aikuisikää.
Tutkimuksessa selvitimme äidin hedelmällisyyden ja hedelmöityshoitojen, sosioekonomisen luokan, vanhempien tupakoinnin ja ennenaikaisen synnytyksen yhteyttä lapsen riskiin sairastua astmaan.
Äidin aiemmat lapsettomuusongelmat ja–hoidot lisäsivät merkitsevästi lapsen riskiä sairastua astmaan (aOR 1.4; CI 1.2-‐‑1.6 ja aOR 1.5; CI 1.3-‐‑1.8) verrattuna lapsiin, joiden äideillä ei ollut vastaavia ongelmia. Äidin aiemmat toistuvat keskenmenot ja pitkittynyt raskauden viive ennen kyseistä raskautta lisäsivät myös lapsen riskiä sairastua astmaan spontaanisti alkaneissa raskauksissa.
Alle 32. raskausviikolla syntyneillä lapsilla oli nelinkertainen riski sairastua astmaan ja lisääntynyt riski todettiin myös täysiaikaisissa, ennen 39. raskausviikkoa syntyneillä lapsilla (aOR 1.2; CI 1.1-‐‑1.4) verrattuna täysiaikaisina syntyneisiin. Vanhempien raskaudenaikainen tupakointi lähes nelinkertaisti lapsen sairastumisriskin (aOR 3.7; CI 3.2-‐‑4.4). Isän raskaudenaikaisen tupakoinnin merkitys lapsen sairastumisriskiin korostui, sillä perheissä, joissa vain isä tupakoi raskausaikana, lapsen sairastumisriski oli lähes kolminkertainen (aOR 2.9; CI 2.0-‐‑2.6) verrattuna tupakoimattomiin vanhempiin. Vanhempien raskaudenaikainen tupakoinnin lopettaminen vähensi lapsen riskiä sairastua astmaan.
Äidin matala sosioekonominen luokka ei lisännyt lapsen astmaan sairastumisriskiä, mutta syntyminen yrittäjäperheeseen, jotka olivat suurelta osin maanviljelijöitä, oli yhteydessä pienempään sairastuvuuteen.
Tutkimustuloksemme osoittivat, että äidin terveydellisillä tekijöillä, elintavoilla ja raskaudenaikaisilla tekijöillä oli merkitystä lapsen riskiin sairastua astmaan. Molempia vanhempia tulisi kannustaa ja tukea tupakoimattomuuteen, koska sillä oli vahva yhteys lapsen vähentyneeseen riskiin sairastua astmaan. Tutkimustuloksemme viittaavat epäsuorasti, kuinka suomalainen sosiaali-‐‑ ja terveydenhuoltojärjestelmä mahdollistaa kaikille perheille tasapuolisen terveydenhoidon; lapsen sairastuvuus astmaan ei ollut suurentunut alemmissa sosiaaliluokissa, toisin kuin useissa kansainvälisissä tutkimuksissa on osoitettu.
Luokitus: WA 30, WA 310, WF 553, WS 280, WQ 210
Yleinen suomalainen asiasanasto: astma; lapset; lapsuus; altistuminen; sikiö; raskaus; hedelmällisyys;
hedelmättömyys; hedelmättömyyshoito; ennenaikainen synnytys; tupakointi; sosioekonomiset tekijät;
sosioekonominen asema; elintavat; riskitekijät
Acknowledgements
This study was carried out at the Department of Obstetrics and Gynecology, Kuopio University Hospital in 2008–2014. I owe my deepest gratitude to everyone who has contributed to this study, and I would especially like to thank the following persons:
I am grateful to my supervisor Professor Seppo Heinonen, M.D., Ph.D., for giving me the opportunity to carry out my scientific work, for his inspiring attitude towards my research and for his encouraging and motivating support during all these years.
I wish to express my deepest gratitude to my supervisor Professor Leea Keski-‐‑Nisula, M.D., Ph.D., for her enormous support, guidance and effort in the creation of this work. The amount of understanding and support that I received was outstanding and this helped me to take the first steps into the world of science and made me believe in myself and scientific research even during the tough times.
I would also like to give my thanks to Professor Juha Räsänen, M.D., Ph.D., for his kind support and encouraging words.
I wish to thank my co-‐‑author and friend Leena Georgiadis, M.D., for her never-‐‑ending optimism and encouraging support. May our friendship last forever!
I am also deeply grateful to my friend and co-‐‑author Kaisa Raatikainen, M.D., Ph.D., who has been the recipient of my numerous questions and supported me in statistical and data management methods.
I wish to thank another co-‐‑author, Sari Räisänen, Ph.D., R.N., R.M., for her guidance and encouraging support.
I also owe my thanks to my co-‐‑authors Mika Gissler, Ph.D., and Juha Pekkanen, M.D., Ph.D., for their participation and expert knowledge.
I wish to thank Docent Petteri Hovi and Docent Marja Vääräsmäki, the official reviewers of this dissertation, for their constructive criticism and guidance. Their suggestions for corrections have significantly improved my thesis. You did not make this easy!
I want to thank statistical expert Olavi Kauhanen, MSc., for his kind and patient assistance in statistics and for always finding time to reconsider when problems arose. For further statistical guidance and help, I want to thank Tuomas Selander, Kuopio University Hospital – you saved me from madness!
I owe my thanks to Nick Bolton, Ph.D., for revision of the English language of this thesis.
I wish to express my thanks to all the midwives at Kuopio University Hospital, who did an enormous job in collecting the Birth Register data. I especially wish to thank them for sharing and for supporting me for all these years. I am deeply thankful to all my co-‐‑
workers and friends at Varkaus Hospital.
I wish to thank all of my wonderful colleagues, present and former, at Kuopio University Hospital for all the support I have received. I am especially deeply grateful to my friends Niina Kudjoi, Pirkko Juvonen and Kirsi Rinne for sharing the rocky road of life with me.
Acknowledgements
This study was carried out at the Department of Obstetrics and Gynecology, Kuopio University Hospital in 2008–2014. I owe my deepest gratitude to everyone who has contributed to this study, and I would especially like to thank the following persons:
I am grateful to my supervisor Professor Seppo Heinonen, M.D., Ph.D., for giving me the opportunity to carry out my scientific work, for his inspiring attitude towards my research and for his encouraging and motivating support during all these years.
I wish to express my deepest gratitude to my supervisor Professor Leea Keski-‐‑Nisula, M.D., Ph.D., for her enormous support, guidance and effort in the creation of this work. The amount of understanding and support that I received was outstanding and this helped me to take the first steps into the world of science and made me believe in myself and scientific research even during the tough times.
I would also like to give my thanks to Professor Juha Räsänen, M.D., Ph.D., for his kind support and encouraging words.
I wish to thank my co-‐‑author and friend Leena Georgiadis, M.D., for her never-‐‑ending optimism and encouraging support. May our friendship last forever!
I am also deeply grateful to my friend and co-‐‑author Kaisa Raatikainen, M.D., Ph.D., who has been the recipient of my numerous questions and supported me in statistical and data management methods.
I wish to thank another co-‐‑author, Sari Räisänen, Ph.D., R.N., R.M., for her guidance and encouraging support.
I also owe my thanks to my co-‐‑authors Mika Gissler, Ph.D., and Juha Pekkanen, M.D., Ph.D., for their participation and expert knowledge.
I wish to thank Docent Petteri Hovi and Docent Marja Vääräsmäki, the official reviewers of this dissertation, for their constructive criticism and guidance. Their suggestions for corrections have significantly improved my thesis. You did not make this easy!
I want to thank statistical expert Olavi Kauhanen, MSc., for his kind and patient assistance in statistics and for always finding time to reconsider when problems arose. For further statistical guidance and help, I want to thank Tuomas Selander, Kuopio University Hospital – you saved me from madness!
I owe my thanks to Nick Bolton, Ph.D., for revision of the English language of this thesis.
I wish to express my thanks to all the midwives at Kuopio University Hospital, who did an enormous job in collecting the Birth Register data. I especially wish to thank them for sharing and for supporting me for all these years. I am deeply thankful to all my co-‐‑
workers and friends at Varkaus Hospital.
I wish to thank all of my wonderful colleagues, present and former, at Kuopio University Hospital for all the support I have received. I am especially deeply grateful to my friends Niina Kudjoi, Pirkko Juvonen and Kirsi Rinne for sharing the rocky road of life with me.
I want to thank my dear sister and her husband, Minna and Anssi, and their children, Lotta and Topi – thank you for being such dear friends and thank you for sharing everything with me.
I owe my warmest thanks to my dear parents, Kaija and Simo, for their support, love and encouragement throughout my life.
Luru, the joy of my life, grateful for the time together!
Finally, my darling sons, Antti and Aleksi, I am so proud of you! Thank you for your patience, understanding and support. I want you to remember that we should always have challenges in order to move forward in life. There is nothing more important to me or more loved than you are. After all, now it’s finally done! ; o ))
Kuopio, November 2015
Maijakaisa Harju
This study was supported financially by Kuopio University Hospital EVO and VTR grants, the Finnish Cultural Foundation of Northern Savo, the Finnish Medical Foundation, the Ida Montini Foundation, the Kerttu and Kalle Viik Foundation, the Jalmari and Rauha Ahokas Foundation, The Organization for Respiratory Health in Finland, Kuopio University Foundation and the Kuopio Respiratory Health Foundation.
List of original publications
This dissertation is based on the following original publications:
I Harju M, Keski-‐‑Nisula L, Raatikainen K, Pekkanen J, Heinonen S. Maternal fecundity and asthma among offspring – is the risk programmed
preconceptionally? Retrospective observational study. Fertility and Sterility. 2013 Mar 1;99(3):761-‐‑767.
II Harju M, Keski-‐‑Nisula L, Georgiadis L, Räisänen S, Gissler M, Heinonen S. The Burden of Childhood Asthma and Late Preterm and Early Term Births. Journal of Pediatrics. 2014 Feb;164(2):295-‐‑299.
III Harju M, Keski-‐‑Nisula L, Georgiadis L, Heinonen S. Parental smoking and cessation during pregnancy and the risk of childhood asthma. Submitted.
IV Harju M, Keski-‐‑Nisula L, Georgiadis L, Raatikainen K, Räisänen S, Heinonen S.
Contribution of socioeconomic status to the risk of asthma among offspring. BMC Public Health. 01/2015; 15(1):27. DOI: 10.1186/s12889-‐‑015-‐‑1357-‐‑6.
The publications were reprinted with the permission of the copyright owners.
I want to thank my dear sister and her husband, Minna and Anssi, and their children, Lotta and Topi – thank you for being such dear friends and thank you for sharing everything with me.
I owe my warmest thanks to my dear parents, Kaija and Simo, for their support, love and encouragement throughout my life.
Luru, the joy of my life, grateful for the time together!
Finally, my darling sons, Antti and Aleksi, I am so proud of you! Thank you for your patience, understanding and support. I want you to remember that we should always have challenges in order to move forward in life. There is nothing more important to me or more loved than you are. After all, now it’s finally done! ; o ))
Kuopio, November 2015
Maijakaisa Harju
This study was supported financially by Kuopio University Hospital EVO and VTR grants, the Finnish Cultural Foundation of Northern Savo, the Finnish Medical Foundation, the Ida Montini Foundation, the Kerttu and Kalle Viik Foundation, the Jalmari and Rauha Ahokas Foundation, The Organization for Respiratory Health in Finland, Kuopio University Foundation and the Kuopio Respiratory Health Foundation.
List of original publications
This dissertation is based on the following original publications:
I Harju M, Keski-‐‑Nisula L, Raatikainen K, Pekkanen J, Heinonen S. Maternal fecundity and asthma among offspring – is the risk programmed
preconceptionally? Retrospective observational study. Fertility and Sterility. 2013 Mar 1;99(3):761-‐‑767.
II Harju M, Keski-‐‑Nisula L, Georgiadis L, Räisänen S, Gissler M, Heinonen S. The Burden of Childhood Asthma and Late Preterm and Early Term Births. Journal of Pediatrics. 2014 Feb;164(2):295-‐‑299.
III Harju M, Keski-‐‑Nisula L, Georgiadis L, Heinonen S. Parental smoking and cessation during pregnancy and the risk of childhood asthma. Submitted.
IV Harju M, Keski-‐‑Nisula L, Georgiadis L, Raatikainen K, Räisänen S, Heinonen S.
Contribution of socioeconomic status to the risk of asthma among offspring. BMC Public Health. 01/2015; 15(1):27. DOI: 10.1186/s12889-‐‑015-‐‑1357-‐‑6.
The publications were reprinted with the permission of the copyright owners.
Contents
1 INTRODUCTION ... 1
2 REVIEW OF THE LITERATURE ... 3
2.1 Childhood asthma ... 3
2.1.1 Definition and classification of pediatric asthma ... 3
2.1.2 Epidemiology of childhood asthma ... 3
2.1.3 Genetics and epigenetics of asthma ... 5
2.1.4 Asthma pathophysiology ... 6
2.1.4.1 Short-‐‑term changes in asthma ... 6
2.1.4.2 Long-‐‑term changes in asthma ... 6
2.1.4.3 Virus infections ... 7
2.1.4.4 Differential diagnosis ... 7
2.1.5 Symptoms and presentations ... 7
2.1.6 Diagnosis and monitoring of pediatric asthma ... 8
2.1.7 Medicine reimbursement and principles of management in pediatric asthma 9
2.2 Early risk factors of childhood asthma 10 2.2.1 Maternal characteristics ... 10
2.2.1.1 Maternal asthma and atopy ... 10
2.2.1.2 Maternal stress ... 11
2.2.1.3 Maternal diseases ... 11
2.2.1.4 Maternal age and parity ... 12
2.2.1.5 Maternal obesity and subfertility ... 12
2.2.2 Pregnancy and delivery characteristics ... 14
2.2.2.1 Gestational age ... 14
2.2.2.2 Mode of delivery ... 14
2.2.2.3 Fetal growth ... 15
2.2.2.4 Maternal infections during pregnancy ... 15
2.2.2.5 Maternal nutrition and medication ... 16
2.2.3 Postnatal factors ... 18
2.2.3.1 Early life risks ... 18
2.2.3.2 Breastfeeding and nutrition ... 18
2.2.3.3 Early life infections ... 19
2.2.4 Pollution and chemicals ... 20
2.2.4.1 Maternal smoking and environmental tobacco smoke 20
2.2.4.2 Pollutants ... 20
2.2.5 Socioeconomic risk factors ... 21
3 AIMS OF THE STUDY ... 23
4 MATERIALS AND METHODS ... 25
Contents
1 INTRODUCTION ... 1
2 REVIEW OF THE LITERATURE ... 3
2.1 Childhood asthma ... 3
2.1.1 Definition and classification of pediatric asthma ... 3
2.1.2 Epidemiology of childhood asthma ... 3
2.1.3 Genetics and epigenetics of asthma ... 5
2.1.4 Asthma pathophysiology ... 6
2.1.4.1 Short-‐‑term changes in asthma ... 6
2.1.4.2 Long-‐‑term changes in asthma ... 6
2.1.4.3 Virus infections ... 7
2.1.4.4 Differential diagnosis ... 7
2.1.5 Symptoms and presentations ... 7
2.1.6 Diagnosis and monitoring of pediatric asthma ... 8
2.1.7 Medicine reimbursement and principles of management in pediatric asthma 9
2.2 Early risk factors of childhood asthma 10 2.2.1 Maternal characteristics ... 10
2.2.1.1 Maternal asthma and atopy ... 10
2.2.1.2 Maternal stress ... 11
2.2.1.3 Maternal diseases ... 11
2.2.1.4 Maternal age and parity ... 12
2.2.1.5 Maternal obesity and subfertility ... 12
2.2.2 Pregnancy and delivery characteristics ... 14
2.2.2.1 Gestational age ... 14
2.2.2.2 Mode of delivery ... 14
2.2.2.3 Fetal growth ... 15
2.2.2.4 Maternal infections during pregnancy ... 15
2.2.2.5 Maternal nutrition and medication ... 16
2.2.3 Postnatal factors ... 18
2.2.3.1 Early life risks ... 18
2.2.3.2 Breastfeeding and nutrition ... 18
2.2.3.3 Early life infections ... 19
2.2.4 Pollution and chemicals ... 20
2.2.4.1 Maternal smoking and environmental tobacco smoke 20
2.2.4.2 Pollutants ... 20
2.2.5 Socioeconomic risk factors ... 21
3 AIMS OF THE STUDY ... 23
4 MATERIALS AND METHODS ... 25
4.1 Study population ... 25
4.1.1 Kuopio University Hospital Birth Register ... 25
4.1.2 Data collection ... 25
4.1.3 Final study population ... 26
4.2 Asthma among offspring ... 27
4.3 Definitions ... 27
4.3.1 Maternal pre-‐‑pregnancy characteristics ... 27
4.3.2 Pregnancy and delivery characteristics ... 28
4.4 Statistical analysis ... 28
4.5 Ethical considerations ... 30
5 RESULTS ... 31
5.1 Characteristics of the study population ... 31
5.2 Risk of asthma among offspring ... 33
5.2.1 Infertility ... 33
5.2.2 Gestational age at birth ... 35
5.2.3 Parental smoking during pregnancy ... 36
5.2.4 Maternal socioeconomic status during pregnancy and perinatal risks ... 36
6 DISCUSSION ... 39
6.1 Importance of the study ... 39
6.2 Main findings ... 39
6.3 Findings in relation to other studies ... 40
6.4 Validity and limitations ... 43
6.5 Clinical significance of the results ... 45
6.6 Generalizability of the results ... 46
6.7 Suggestions for preventive measures and future research ... 47
7 CONCLUSIONS ... 49
8 REFERENCES ... 51
ORGINAL PUBLICATIONS (I–IV) ... 71 APPENDIX: QUESTIONNAIRE FORMS
Abbreviations
AADs Anti-‐‑asthma drugs aHR Adjusted hazard ratio aOR Adjusted odds ratio ART Assisted reproductive
technology
ATC Anatomical Therapeutic Chemical Classification System
BMI Body mass index (kg/m²) CI Confidence interval CS Cesarean section
ETS Environmental tobacco smoke FENO Fractional exhaled nitric
oxide
FEV1 Forced expiratory volume in 1 second
FIMEA Finnish Medicines Agency FVC Forced vital capacity
GDM Gestational diabetes mellitus GINA The Global Initiative for
Asthma
GWs Gestational weeks
iCAALL International Collaboration in Asthma, Allergy and
Immunology
ICD International Statistical Classification of Diseases and Related Health Problems ICON International Consensus on
Pediatric Asthma ICSI Intracytoplasmic sperm
injection
ISAAC The International Study of Asthma and Allergies in Childhood
IUGR Intrauterine growth retardation
IVF In vitro fertilization
KELA Social Insurance Institution of Finland (Kansaneläkelaitos) KUH Kuopio University Hospital NICU Neonatal intensive care unit OR Odds ratio
PEF Peak expiratory flow
PRC Population Register Center (Väestörekisterikeskus) PROM Premature rupture of
membranes
SES Socioeconomic status SGA Small for gestational age THL National Institute for Health
and Welfare (Terveyden ja hyvinvoinnin laitos)
4.1 Study population ... 25
4.1.1 Kuopio University Hospital Birth Register... 25
4.1.2 Data collection ... 25
4.1.3 Final study population... 26
4.2 Asthma among offspring... 27
4.3 Definitions... 27
4.3.1 Maternal pre-‐‑pregnancy characteristics ... 27
4.3.2 Pregnancy and delivery characteristics... 28
4.4 Statistical analysis... 28
4.5 Ethical considerations ... 30
5 RESULTS... 31
5.1 Characteristics of the study population ... 31
5.2 Risk of asthma among offspring... 33
5.2.1 Infertility... 33
5.2.2 Gestational age at birth ... 35
5.2.3 Parental smoking during pregnancy... 36
5.2.4 Maternal socioeconomic status during pregnancy and perinatal risks... 36
6 DISCUSSION... 39
6.1 Importance of the study... 39
6.2 Main findings ... 39
6.3 Findings in relation to other studies ... 40
6.4 Validity and limitations ... 43
6.5 Clinical significance of the results... 45
6.6 Generalizability of the results... 46
6.7 Suggestions for preventive measures and future research... 47
7 CONCLUSIONS... 49
8 REFERENCES... 51
ORGINAL PUBLICATIONS (I–IV)... 71 APPENDIX: QUESTIONNAIRE FORMS
Abbreviations
AADs Anti-‐‑asthma drugs aHR Adjusted hazard ratio aOR Adjusted odds ratio ART Assisted reproductive
technology
ATC Anatomical Therapeutic Chemical Classification System
BMI Body mass index (kg/m²) CI Confidence interval CS Cesarean section
ETS Environmental tobacco smoke FENO Fractional exhaled nitric
oxide
FEV1 Forced expiratory volume in 1 second
FIMEA Finnish Medicines Agency FVC Forced vital capacity
GDM Gestational diabetes mellitus GINA The Global Initiative for
Asthma
GWs Gestational weeks
iCAALL International Collaboration in Asthma, Allergy and
Immunology
ICD International Statistical Classification of Diseases and Related Health Problems ICON International Consensus on
Pediatric Asthma ICSI Intracytoplasmic sperm
injection
ISAAC The International Study of Asthma and Allergies in Childhood
IUGR Intrauterine growth retardation
IVF In vitro fertilization
KELA Social Insurance Institution of Finland (Kansaneläkelaitos) KUH Kuopio University Hospital NICU Neonatal intensive care unit OR Odds ratio
PEF Peak expiratory flow
PRC Population Register Center (Väestörekisterikeskus) PROM Premature rupture of
membranes
SES Socioeconomic status SGA Small for gestational age THL National Institute for Health
and Welfare (Terveyden ja hyvinvoinnin laitos)
1 Introduction
Asthma and allergic diseases are the most common chronic diseases in childhood, affecting nearly 10% of children worldwide. Their prevalence has been increasing in recent decades in several Western countries (Subbarao et al. 2009, Asher 2010), including Finland (Latvala et al. 2005). Part of the increase might be a result of awareness of symptoms and increased rates of reporting (Algert et al. 2011), but it cannot be explained only on the basis of better knowledge of diagnosis. Both genetic and environmental factors play an important role in the development of asthma (Subbarao et al. 2009, Rehan et al. 2012).
Pre-‐‑ and postnatal factors may play an important role in the development of asthma (Asher 2010, Kozyrskyj et al. 2011, Peters et al. 2013). According to Barker’s hypothesis (de Boo, Harding 2006, Barker et al. 2013), the period of pregnancy and the intrauterine environment might alter fetal development, with persistent effects on lifetime health. Early epigenetic programming may already occur in utero, where various forms of prenatal exposure such as maternal smoking, stress and anxiety, infections, and infertility treatments, and fetal growth may have an influence on the development of the fetal immune system (Kozyrskyj et al. 2011, Algert et al. 2011, Tedner et al. 2012, Peters et al.
2013). Furthermore, factors related to delivery and the neonatal period, such as prematurity, birth mode and early-‐‑life infections, may influence the development of asthma in offspring (Subbarao et al. 2009, Algert et al. 2011, Kozyrskyj et al. 2011, Neu, Rushing 2011). In addition, parental history of asthma, male sex and exposure to environmental tobacco smoke are all well-‐‑known risk factors of asthma in offspring (Asher 2010, Algert et al. 2011, Kozyrskyj et al. 2011). Most of these perinatal factors are linked to parental socioeconomic status (SES) and thus socioeconomic disparities may influence the burden of asthma via indirect pathways.
The present study was aimed at identifying possible perinatal risk factors affecting the burden of asthma during childhood. We conducted an observational register study using Kuopio University Hospital birth register data on 45 030 women and their live-‐‑born children born during 1989–2008 to examine the associations between maternal fecundity and SES, gestational age at birth and parental smoking, and the risk of asthma in childhood.
1 Introduction
Asthma and allergic diseases are the most common chronic diseases in childhood, affecting nearly 10% of children worldwide. Their prevalence has been increasing in recent decades in several Western countries (Subbarao et al. 2009, Asher 2010), including Finland (Latvala et al. 2005). Part of the increase might be a result of awareness of symptoms and increased rates of reporting (Algert et al. 2011), but it cannot be explained only on the basis of better knowledge of diagnosis. Both genetic and environmental factors play an important role in the development of asthma (Subbarao et al. 2009, Rehan et al. 2012).
Pre-‐‑ and postnatal factors may play an important role in the development of asthma (Asher 2010, Kozyrskyj et al. 2011, Peters et al. 2013). According to Barker’s hypothesis (de Boo, Harding 2006, Barker et al. 2013), the period of pregnancy and the intrauterine environment might alter fetal development, with persistent effects on lifetime health. Early epigenetic programming may already occur in utero, where various forms of prenatal exposure such as maternal smoking, stress and anxiety, infections, and infertility treatments, and fetal growth may have an influence on the development of the fetal immune system (Kozyrskyj et al. 2011, Algert et al. 2011, Tedner et al. 2012, Peters et al.
2013). Furthermore, factors related to delivery and the neonatal period, such as prematurity, birth mode and early-‐‑life infections, may influence the development of asthma in offspring (Subbarao et al. 2009, Algert et al. 2011, Kozyrskyj et al. 2011, Neu, Rushing 2011). In addition, parental history of asthma, male sex and exposure to environmental tobacco smoke are all well-‐‑known risk factors of asthma in offspring (Asher 2010, Algert et al. 2011, Kozyrskyj et al. 2011). Most of these perinatal factors are linked to parental socioeconomic status (SES) and thus socioeconomic disparities may influence the burden of asthma via indirect pathways.
The present study was aimed at identifying possible perinatal risk factors affecting the burden of asthma during childhood. We conducted an observational register study using Kuopio University Hospital birth register data on 45 030 women and their live-‐‑born children born during 1989–2008 to examine the associations between maternal fecundity and SES, gestational age at birth and parental smoking, and the risk of asthma in childhood.
2 Review of the literature
2.1 CHILDHOOD ASTHMA
2.1.1 Definition and classification of pediatric asthma
The definition and diagnosis of childhood asthma is challenging, since it has several manifestations and disease courses and symptoms may vary depending on age and apparent triggers. According to international guidelines, asthma is defined as a chronic inflammatory disorder associated with variable airflow obstruction, which reverses either spontaneously or after use of medication. It is usually associated with bronchial hyper-‐‑responsiveness and evidence of chronic airway inflammation. Recurrent wheeze, cough, shortness of breath and chest tightness are the most common symptoms and signs of asthma (Papadopoulos et al. 2012, Martinez, Vercelli 2013). However, not all children who wheeze early in life will have asthma later on (Szefler et al.
2014).
Since the definition, diagnosis and management of pediatric asthma is challenging as a result of the lack of uniform diagnostic criteria, the International Study of Asthma and Allergies in Childhood (ISAAC) was set up in 1991. The purpose of the study was to maximize the value of epidemiological research worldwide in pediatric asthma and allergic diseases and to establish standardized methodology for research (Asher, Weiland 1998, Patel et al. 2008). Since then, several guidelines have been set up to promote uniform diagnosis and management of childhood asthma.
The Global Initiative for Asthma (GINA) was launched in 1995 (Bousquet et al. 2007) and similar guidelines were established in Finland in 1994, when the National Asthma Program was established (GINA report 2014). In 2002, the Childhood Asthma mini-‐‑program was launched to cover more sufficiently specific problems related to pediatric asthma. In addition, in 2012, the International Collaboration of Asthma, Allergy and Immunology (iCAALL), consisting of several societies, complied an International Consensus (ICON) on Pediatric Asthma and the purpose was to highlight the key messages that are common to many of the existing guidelines, to critically review and comment on any differences and thus provide concise reference material on pediatric asthma (Papadopoulos et al. 2012). These guidelines are now in use in Finland (Haahtela et al.
2013, Papadopoulos et al. 2012).
According to international consensus guidelines (GINA and ICON reports), pediatric asthma can be classified into different phenotypes, where classification may be dependent on the age of the children or on the apparent trigger, such as viruses, exercise or allergens. Besides this, some authors classify asthma according to the nature of the specific type of airway inflammation, but the traditionally and most frequently used classification is to define asthma as non-‐‑allergic and allergic types (Maslan, Mims 2014). Furthermore, classifying asthma according to severity or control of the disease gives guidance to its treatment (Papadopoulos et al. 2012). However, according to recent guidelines, asthma is no longer considered as a single disease depending on single factor, but rather as a series of complex, overlapping individual phenotypes (Papadopoulos et al. 2012, Cottini, Asero 2013, GINA report 2014). Such differences in classification are thought to improve recognition and understanding of the underlying genetic basis and pathophysiologic mechanisms, and, further, the response to treatment (Cottini, Asero 2013).
2.1.2 Epidemiology of childhood asthma
In Finland, asthma is one of the most common chronic diseases in children and a significant cause of hospitalization (Säynäjäkangas et al. 2007). During the past few decades, the overall incidence of asthma has increased from 6% to 9.4% (Haahtela et al. 2013), but the burden of asthma has considerably decreased, since the number of hospital days has fallen and the increase in the cost of asthma has ended (Haahtela et al. 2006). The number of children with asthma and asthma-‐‑like symptoms has increased, especially in younger age groups, but the need for hospitalization because of asthma attacks has declined in recent years in all age and both sex groups. Young
