Jinliang Zhu, Carsten Obel, Jørn Olsen Department of Public Health, University of Aarhus

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1 Parental smoking during pregnancy and short- and long-term adverse outcomes in offspring: Using data from ad hoc birth cohorts and registers in Denmark Jinliang Zhu, Carsten Obel, Jørn Olsen Department of Public Health, University of Aarhus Summary Smoking during pregnancy is among the leading preventable causes of adverse maternal and fetal outcomes. Evidence is emerging on the long-term consequences of maternal smoking during pregnancy. By using unique perspective collected data in the Medical Birth Register and ad hoc birth cohorts in Denmark and linkages to national registers, we will systematically estimate long-term adverse outcomes, including somatic and mental health, in particular overweight/growth and mental problems, in offspring of mothers who smoked during pregnancy. In the ad hoc birth cohorts, we have also data on maternal use of nicotine replacement and paternal smoking (passive smoking) during pregnancy. With these systematic and comprehensive data, we expect to be able to better understand the role of prenatal exposure to tobacco smoke and nicotine, as well as passive smoking, in the child growth and development. Our findings will add to the literature about smoking effect during pregnancy and provide more data on the role of nicotine. These results can be used when planning intervention, health service and social support among pregnant women who or whose partner smoke. Introduction Although maternal smoking during pregnancy has been decreasing, mange women still smoke during pregnancy, with estimated prevalence of 12 25% in US and of 13 36% in Europe, and in particular, women with a low social status and a partner who smokes have a higher smoking prevalence. 1 Tobacco smoke is made up of more than 7,000 chemicals, which include a variety of harmful chemicals such as nicotine, carbon monoxide, tar, benzene, and heavy metals. 2, 3 Nicotine is known to be the major psychoactive component, and thus nicotine has been the focus of the vast majority of studies with the associated effects in animal models or in human epidemiological investigations. Secondhand tobacco smoke also contains significant levels of nicotine. Median air nicotine concentration was 17 times higher in households with smokers (0.18 μg/m3) compared with households without smokers (0.01 μg/m3), and air nicotine and hair nicotine concentrations in women and children increased with the number of smokers in the household. 4 Mounting evidence suggests that many diseases may originate in utero. 5 Impaired fetal growth may alter cell structures or metabolisms of rapidly growing organs and could permanently change organ function. In utero exposure to tobacco smoke has been linked to pregnancy complications, fetal growth restriction, and abnormal neurodevelopment in many epidemiological studies. 6, 7 Animal models also indicate the deleterious developmental effect of prenatal nicotine exposure. 6 However, differences in biological responses between humans and experimental animals have also been noted. The detrimental effect of tobacco smoke on fetal growth is well documented, with suggested mechanisms of decreased oxygen availability and reduced blood flow to the fetus through compromised placental function including high umbilical artery resistance. 8 Maternal smoking is also a predictor for low cognitive function (low IQ scores or academic achievement) and for behavior problems (ADHD, conduct disorder, substance abuse). 6, 7 The causal link in this case is more difficult to claim, as maternal smoking during pregnancy is embedded with a host of social, environmental and genetic constellation, which all can influence the upbringing of a child and contribute to possible problems in the later life of the child. 6, 9 Timing of exposure, passive smoking, and nicotine replacement use have been less examined. Studies on long-term outcomes in children prenatally exposed to maternal smoking are sparse. In the Medical Birth Register, 10 there is information on maternal smoking during pregnancy since In the Danish National 1

2 Birth Cohort, 11 there is more detailed exposure information on maternal smoking, nicotine replacement use, and paternal smoking (passive smoking) during pregnancy collected in the 1 st, 2 nd and 3 rd interview. The 3 rd, 4nd interview and the 7-year follow-up have collected postnatal tobacco smoke exposure data. Aims The aims of this project: 1) To estimate the effect of prenatal maternal smoking, nicotine replacement use, and paternal smoking on fetal growth (birth weight and duration of gestation) and postnatal growth (obesity and overweight); 2) To estimate the effect of maternal smoking, nicotine replacement use, and paternal smoking, both prenatal and postnatal, on somatic and mental health, in particular overweight/growth and mental problems. Material and methods Study design The project will use data from the Danish National Birth Cohort (DNBC), Aarhus Birth Cohort (ABC) and Healthy Habits for Two (HHT), as well as data from Danish national registers. While national registers cover the whole country, the birth cohorts have detailed information on participating families (parents and children), in particular the follow-up of children from pregnancy, through childhood to early adulthood. Neuropsychological development has been evaluated through standardized questionnaires in the participating children. Birth cohorts and registers The Danish National Birth Cohort The Danish National Birth Cohort (DNBC) 11 recruited about 100,000 pregnant women from 1996 to 2002 and included continual health interviews, twice during pregnancy and again when the children were 6 months, 18 months, 7 years, and now 11 years old. Data from population-based registers are also linked to the cohort and updated frequently. The Aarhus Birth Cohort Aarhus Birth Cohort (ABC) 12 has collected longitudinal data on child growth and development. The cohort was established in the 1989 and is an ongoing birth cohort, where new members join continuously, and cohort members are followed continually through questionnaires and also national registers. Healthy Habits for Two (HHT) Women were recruited into the HHT cohort around the 36th week of pregnancy in Odense and Aalborg between April 1984 and April A follow-up contact about health and development of their children was carried out in 2002, and in 2005 an internet-based survey on sexuality and reproductive health was delivered in these children. These children can also be followed through nationwide health and societal registers. The Danish Medical Birth Register The Danish Medical Birth Register 10 contains information, including birth weight and gestational age at birth, on all live births and stillbirths by women with permanent residence in Denmark. It was established in 1969 and has been computerized since Maternal smoking has been reported since 1991 and with amount of cigarettes since The Danish National Hospital Register 2

3 The Danish National Hospital Register 14 has collected nationwide data on all non-psychiatric hospital admissions since 1977 and outpatients as well since The Danish Psychiatric Central Register The Danish Psychiatric Central Register 15 contains information on all psychiatric admissions, including admissions to both psychiatric hospitals and psychiatric wards in general hospitals since 1969 and information about all psychiatric outpatient contacts since The Register of Medicinal Product Statistics All Danish residents are provided tax-supported health care by the National Health Service, which refunds the costs of most physician-prescribed drugs. The prescribed medicine is registered in the Register of Medicinal Product Statistics. 16 Information on growth (fetal growth: birth weight and gestational age, and postnatal growth: height and weight) Information on fetal growth including birth weight and gestational age can be obtained from the Danish Medical Birth Register. Information on postnatal growth including height and weight can be obtained from the ad hoc birth cohorts. Information on somatic health We will identify children hospitalized as inpatient admission or outpatient contact from the hospital discharge registers, including the Danish National Hospital Register and the Danish Psychiatric Central Register. For all participants in the birth cohorts, we also have disease information from questionnaires. Information on mental health including ADHD We will identify children diagnosed with ADHD (F90, HKD; Hyperkinetic Disorder) and other mental problems in the national hospital discharge registers. To capture children with ADHD treated outside the hospital system we further include children treated with ADHD medication. The SDQ (and DAWBA) is regarded as the standardized measures of emotional, behavioral, and social functioning in children and adolescents from ages 3 to 16. For all participants in the birth cohorts, we have this questionnaire information. Information on covariates We will use interview data collected during pregnancy and after birth from the birth cohorts. Additional family factors including parental health and disease profile and family socioeconomic status will be obtained from the national hospital discharge registration system and the Integrated Database for Longitudinal Labor Market Research 17 at Statistics Denmark, respectively. Data analysis We will use logistic regression analysis to estimate the effect of prenatal maternal smoking, use of nicotine replacement, paternal smoking on fetal growth (eg, low birthweight and preterm birth) and postnatal growth (eg, obesity and overweight). We will use logistic and Cox regression analysis to estimate the effect of prenatal maternal smoking, use of nicotine replacement, paternal smoking on neurodevelopment (milestones, mental disorders) and disease occurrence (somatic diseases, eg, diabetes, asthma) in the children. A number of covariates will be taken into account in these analyses. Anticipated results and impact We expect to be able to better understand the role of tobacco smoke and nicotine, as well as passive smoking, in the child growth and development by using perspective collected data in the Medical Birth 3

4 Register and ad hoc birth cohorts. Smoking during pregnancy is among the leading preventable causes of adverse maternal and fetal outcomes. Our findings will add to the literature about smoking effect and may provide more data on the role of nicotine. These results will provide more information on smoking effect which can be used when planning intervention, health service and social support. Research plan Jul 2014-Dec 2014 Jan 2015-Jun 2019 Data preparation and cleaning Data analysis, 3-4 publications Articles planned for publication: Article 1: The effect of prenatal maternal smoking, use of nicotine replacement, and paternal smoking on fetal growth and postnatal growth Article 2: The effect of prenatal maternal smoking, use of nicotine replacement, and paternal smoking on mental problems in children Article 3: The effect of prenatal maternal smoking, use of nicotine replacement, and paternal smoking on disease profile in children Article 4: The mediation of low birthweight on the associations between prenatal maternal smoking and long-term outcomes later in life Feasibility This project will be conducted at Department of Public Health, University of Aarhus. The participating researchers have many years of experience with research in the fields of fetal programming of chronic diseases including mental health, as well as with analysis of epidemiological data from questionnaires and national registers. 4

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